News Releases

Peripheral Blood From Patients with Metastatic Solid Tumors Is A Source of p53-reactive T cells

Burns, Matthew — Fri, 24 Jan 2020 02:49:45

PHILADELPHIA — T cells targeting p53 hotspot mutations can be harvested from peripheral blood of patients with metastatic solid epithelial cancers, according to results published in Clinical Cancer Research, a journal of the American Association for Cancer Research.

This finding could facilitate the development of adoptive cell therapy for solid epithelial tumors with p53 mutations.

"Solid epithelial cancers accounted for approximately 90 percent of the 600,000 cancer-related deaths in the United States last year," said Steven Rosenberg, MD, PhD, chief of the Surgery Branch at the National Cancer Institute's Center for Cancer Research and a pioneer in adoptive cell therapy. "Our goal is to apply adoptive cell therapy to treat these cancers." While adoptive cell therapy has shown success for the treatment of melanoma and some blood and bone marrow cancers, the treatment of solid epithelial cancers with this therapy has been challenging, explained Rosenberg.

Successful adoptive cell therapy for solid epithelial cancers relies on the selective recognition of cancer-specific mutations by T cells. "Approximately half of all human cancers contain mutations in the p53 protein. These mutations do not exist in normal cells, which means that they could be selectively targeted without affecting normal cells," said Rosenberg. "Accordingly, we have put significant effort into identifying T cells that can recognize common p53 mutations in solid cancers."

Another advantage to targeting p53 mutations is that they appear to be essential for a cancer to maintain malignancy, explained Rosenberg. Therefore, it is less likely that the cancer cells will lose the mutation and become resistant to the therapy.

A study published earlier this year – led by Rosenberg and colleagues Parisa Malekzadeh, MD, and Drew Deniger, PhD – identified p53-targeting T cells by examining the immune cells found inside of tumors. "This was a very important finding in the development of immunotherapy for solid epithelial cancers," said Rosenberg. "However, the problem with finding T cells in the tumor is that it requires major surgery to resect the tumor. We were interested in determining if we could identify p53-targeted T cells from peripheral blood instead."

In this study, Rosenberg and colleagues isolated peripheral blood cells from nine patients with tumors that had p53 mutations. Since the frequency of T cells in peripheral blood is about 0.1 percent of the frequency within the tumor, the authors developed an in vitro stimulation method to expand the number of T cells to a level that was detectable in their assays.

The expanded T cells were then tested in cell cultures for reactivity to mutant p53. Peripheral blood T cells from five of the nine patients were reactive for mutant p53 in cell cultures. All five of these patients also had p53-reactive T cells within their tumors, while the four patients without p53-reactive T cells in peripheral blood lacked p53-reactive T cells within their tumors.

The p53-reactive T cells were selective for mutated p53 and were not reactive against normal p53 in these experiments.

"Our results indicate that an obstacle to performing adoptive cell therapy, which is the need to resect tumors with surgical procedures to obtain T cells, may not be necessary," said Rosenberg. "In theory, we could do a blood draw and then identify and expand reactive T cells using techniques similar to those used in this study. These findings bring us closer to the practical application of targeting common cancer mutations, such as those in p53."

Since these experiments were performed using cell cultures, clinical studies are needed to determine if any T cells isolated from peripheral blood or from the tumor would be effective against p53-mutated solid tumors in patients.

In addition, future studies from Rosenberg and colleagues will examine ways to improve the identification and expansion of T cells from peripheral blood and to overcome obstacles within the tumor. Furthermore, Rosenberg and colleagues are interested in developing "off-the-shelf" reagents to target p53 mutations. "In theory, we could have T cell receptors that recognize p53 mutations readily available to put into patients' cells, which would help expedite the process for adoptive cell therapy," explained Rosenberg.

This study was sponsored by the Intramural Research Program of the National Institutes of Health at the Center for Cancer Research, National Cancer Institute. Rosenberg declares no conflicts of interest.

Press Release Published Date: 1/28/2020 10:05 PM

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Stand Up To Cancer Announces International Team on Early Detection of Gastric Cancer, World’s Third Leading Cause of Cancer Death

Burns, Matthew — Mon, 27 Jan 2020 01:08:58

SANTA MONICA, CA. – January 27, 2020 – Stand Up To Cancer (SU2C) announced today that an international team of experts will take a new approach to fighting the world's third-leading cause of cancer death–stomach (or gastric) cancer.

"Too often, gastric cancer is detected at an advanced stage, when it is very hard to treat," said Phillip A. Sharp, PhD, Institute professor, David H. Koch Institute for Integrative Cancer Research at MIT, the Nobel Laureate who serves as chair of SU2C's Scientific Advisory Committee. "This new team will apply its technological prowess to the challenge of detecting gastric cancer at an early stage, potentially saving many thousands of lives."

The SU2C Gastric Cancer Interception Research Team: Early Detection and Interception of Diffuse and Intestinal Gastric Cancer was introduced at the SU2C Scientific Summit 2020, a meeting organized by the American Association for Cancer Research, SU2C's Scientific Partner, at which scientists, advocates, funders, and others hear reports on the progress of numerous SU2C-supported teams and individual researchers.

The $3 million research team will be funded over three years and is supported by generous grants from the Cless Family Foundation and Sara and Jeff Schottenstein Family Charitable Fund.

Andrew T. Chan, MD, MPH, professor of medicine at Harvard Medical School and director of cancer epidemiology at the Massachusetts General Hospital Cancer Center, will serve as leader of the SU2C Gastric Cancer Interception Research Team. The co-leader is Sandra Ryeom, PhD, associate professor of cancer biology at the University of Pennsylvania's Perelman School of Medicine. The team features researchers from the University of Chicago, City of Hope Comprehensive Cancer Center, Memorial Sloan Kettering Cancer Center and Samsung Medical Center.

The research team will conduct intensive studies to identify biomarkers, such as particular bits of DNA and cells that are shed from the tumor that circulate in the blood system and indicate the presence of gastric cancer.

"Gastric cancer can be a devastating diagnosis because it carries such a poor prognosis," stated Marty Cless. "After witnessing my father lose his battle with this disease, the urgency is early detection. Developing new diagnostic tools to find these cancers earlier will improve patient outcomes and change the prognosis from dire to hopeful."

"Bringing early interception to gastric cancer patients in collaboration with SU2C and the Cless family is key to help gastric patients triumph over this devastating disease," said Jeff Schottenstein. "This project honors the memory of my inspirational, kind and beautiful wife, Sara Schottenstein, who lost her battle with gastric cancer in 2016. Sara was such a warm and loving person. I am deeply touched to know that her legacy includes helping others in such a meaningful way."

In addition to U.S.-based scientists, the team includes researchers at the Samsung Medical Center in Seoul, South Korea, the country with the highest rate of stomach cancer in the world, according to the World Cancer Research Fund (WCRF).

Stomach cancer – also known as gastric cancer – is the fifth most common cancer worldwide, and third-leading cause of cancer death, according to the WCRF. Around 952,000 new cases of stomach cancer occurred around the world in 2012, accounting for seven percent of all new cases of cancer. About 70 percent of cases of stomach cancer occur in less developed countries with about half of all cases in Eastern Asia, particularly China.

In the United States, the rate of survival five years after diagnosis is only 32 percent, according to the National Cancer Institute. Survival rates are lower in less-developed countries, according to the WCRF. The poor prognosis is attributed largely to the fact that symptoms often appear only at a late stage in the development of the cancer.

"We have been actively involved in developing new endoscopic imaging techniques that can define areas of the stomach that are at high risk of developing cancer," Chan said. "We can also use this information to derive new blood-based biomarkers that can be used for early detection of stomach cancer."

Techniques to be explored include a tiny, pill-sized camera that can be swallowed by a patient without sedation, Chan said. This camera can provide detailed images of the lining of the stomach to identify abnormal areas that might be precancerous.

When validated in clinical trials, the refined techniques will help doctors detect precancers in populations at high risk.

The team will be the sixth SU2C team focusing on cancer Interception, which is the concept of detecting and diagnosing cancer at a very early stage and/or developing techniques to prevent precancerous lesions from developing into full-blown cancer. Teams established earlier focus on cancers of the lung and pancreas and on multiple myeloma, a malignancy of the bone marrow.

Key team members include:

Andrew T. Chan, MD, MPH
Massachusetts General Hospital
Team Leader

Sandra Ryeom, PhD
University of Pennsylvania
Co-leader

Daniel Catenacci, MD
University of Chicago
Principal

Jeeyun Lee, MD
Samsung Medical Center
Principal

Yanghee Woo, MD
City of Hope Comprehensive Cancer Center
Principal

Sam Yoon, MD
Memorial Sloan Kettering Cancer Center
Principal

Marina Magicheva-Gupta, MPH
Massachusetts General Hospital
Project Manager

Patient Advocates

Aki Agata Smith
Stomach Cancer Awareness Network
Patient Advocate

Marisa Ajdelman
Stomach Cancer Awareness Network
Patient Advocate

About Stand Up To Cancer
Stand Up To Cancer® (SU2C) raises funds to accelerate the pace of research to get new therapies to patients quickly and save lives now. SU2C, a division of the Entertainment Industry Foundation, a 501(c)(3) charitable organization, was established in 2008 by media and entertainment leaders who utilize these communities' resources to engage the public in supporting a new, collaborative model of cancer research, to increase awareness about cancer prevention, and to highlight progress being made in the fight against the disease. As of December 2019, more than 1,600 scientists representing more than 180 institutions are involved in SU2C-funded research projects.

Under the direction of our Scientific Advisory Committee, led by Nobel laureate Phillip A. Sharp, PhD, SU2C operates rigorous competitive review processes to identify the best research proposals to recommend for funding, oversee grants administration, and ensure collaboration across research programs.

Current members of the SU2C Council of Founders and Advisors (CFA) include Katie Couric, Sherry Lansing, Kathleen Lobb, Lisa Paulsen, Rusty Robertson, Sue Schwartz, Pamela Oas Williams, and Ellen Ziffren. The late Laura Ziskin and the late Noreen Fraser are also co-founders. Sung Poblete, PhD, RN, serves as SU2C's CEO. For more information, visit StandUpToCancer.org.

About The Cless Family Foundation
The Cless Family Foundation was formed in 1991 by Ruth and Gerhard Cless. Since its inception, the foundation's focus has been dedicated to improving and supporting education in the sciences, technology, and engineering. The foundation's support has evolved to include promising advancements in the medical field as our family, like many others, has faced life threatening illnesses and want to do whatever we can to improve future outcomes. Today, Gerhard's legacy is carried on by the Cless children and grandchildren who were taught to live by the golden rule, support causes you believe in and help those under served.

About the Sara and Jeff Schottenstein Foundation
The Sara and Jeff Schottenstein Fund honors Sara Schottenstein who lost her brave battle against gastric cancer in 2016 by supporting cancer patients and cancer research, particularly championing gastric cancer research. Sara was kind, warm, and beautiful, and deeply loved and respected by her family, friends and community. Her legacy lives on through her three adoring children as well as the critical work of this Fund.

Media Contact:
Jane E. Rubinstein
Sr. VP Communications
646-386-7969 ofc / 516-993-0708 cell
jrubinstein@su2c.org

Press Release Published Date: 1/27/2020 8:00 AM

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Targeted Therapy Combination Shows Promising Antitumor Activity in Aggressive Meningiomas

Burns, Matthew — Fri, 17 Jan 2020 11:45:52

PHILADELPHIA — The targeted therapy combination of the mTOR inhibitor everolimus (Afinitor) and the somatostatin agonist octreotide (Sandostatin) yielded promising antitumor activity and survival outcomes in patients with aggressive meningiomas, according to the results of a phase II trial published in Clinical Cancer Research, a journal of the American Association for Cancer Research.

Meningiomas are the most common primary brain tumors in adults, representing 37 percent of the total. Standard treatment is surgery, followed by radiotherapy and radiosurgery for more aggressive tumors. "Aggressive meningiomas represent about 20 percent of tumors treated with surgery, and prognosis is poor for patients with tumors that progress following radiotherapy and radiosurgery," said Thomas Graillon, MD, PhD, assistant professor of neurosurgery at La Timone Hospital in Marseille, France. Systemic therapies have failed to show clear signals of efficacy or substantial clinical benefit, he added.

"The combination of everolimus and octreotide yielded a meaningful, prolonged tumor stabilization in many patients," noted Graillon. "Our results indicate that this combination treatment could be considered as a viable treatment option for aggressive meningiomas and studied further in a randomized trial."

Meningiomas frequently demonstrate an activated mechanistic target of rapamycin (mTOR) pathway and express somatostatin receptor 2 (SSTRA2). Somatostatin is a hormone found in the central nervous system that inhibits the release of growth hormone. In previous preclinical research, Graillon and colleagues demonstrated that the combination of everolimus and octreotide had an additive antitumor effect in primary cell cultures derived from fresh operative tissue samples.

The CEVOREM (Combination of EVerolimus and Octreotide in REsistant Meningiomas) trial tested the effectiveness of everolimus and octreotide in 20 adults with mainly grades 2 or 3 meningiomas as defined by the World Health Organization (WHO). Two patients had grade 1 tumors, 10 had grade 2 tumors, and eight had grade 3 tumors. All patients received 10 mg of oral everolimus daily, and 30 mg of octreotide administered monthly by intramuscular injection.

Progression-free survival (PFS) at six months was 55 percent, meeting the study's primary endpoint. "This significantly exceeds the typical rate of about 10-20 percent for patients with aggressive meningiomas who are ineligible for further surgery or radiosurgery," Graillon said.

Six- and 12-month overall survival rates were 90 percent and 75 percent, respectively. The investigators also reported a decrease of more than 50 percent in the tumor growth rate in 78 percent of tumors at three months.

The drug combination was well tolerated in most patients, in line with current use among patients with pancreatic neuroendocrine tumors, Graillon noted. Eleven of 20 patients developed stomatitis, including three with grade 3 adverse events, requiring the discontinuation of everolimus in one patient and both drugs in another patient.

The investigators assessed tumor growth rate at enrollment (with a documented minimal growth rate for inclusion in the trial) and at three and six months after treatment using radiological methods, including 3D T1-weighted gadolinium-enhanced millimetric magnetic resonance imaging. "Our results suggest that analyzing the 3D tumor growth rate is a more appropriate method for assessing treatment activity in this select group of patients," Graillon said. "3D tumor growth rate under versus before treatment is a sensitive and complementary endpoint to six-month PFS that should be included in future randomized trials."

The main limitations of the study were the small number of patients and the non-randomization.

The study was led with Olivier Chinot, MD, and the neurooncology team, and was supported by Institut National du Cancer in France. Novartis Pharma of France provided the drugs used in the study. The authors declare no conflict of interest.

Press Release Published Date: 1/21/2020 7:05 PM

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Adolescent and Young Adult Cancer Survivors May Have an Elevated Risk of Hospitalizations

Burns, Matthew — Wed, 15 Jan 2020 04:49:29

PHILADELPHIA — Adolescent and young adults who survived at least two years after a cancer diagnosis had nearly double the risk of being hospitalized compared with their siblings and unrelated, age-matched people without cancer, according to results published in Cancer Epidemiology, Biomarkers, & Prevention, a journal of the American Association for Cancer Research.

“Few studies have investigated health risk in adolescents and young adults after cancer treatment,” said Chelsea Anderson, PhD, MPH, a postdoctoral fellow at the American Cancer Society. “Our results underscore the importance of long-term, risk-based follow-up care to prevent and treat severe late effects and other health conditions in this patient population.”

Approximately 70,000 American adolescents and young adults, defined as those between the age of 15 and 39 years, are diagnosed with cancer each year. As five-year survival rates have steadily climbed higher over the past few decades to more than 80 percent for all cancer types combined, more cancer survivors have an increased risk of adverse health outcomes later in life as a result of their cancer treatment.

Previous studies on the impact of cancer treatment on late morbidities and hospitalizations among survivors of childhood cancer, such as the Childhood Cancer Survivor Study, have included survivors from birth to 20 years and focused on selected cancers common among children, such as leukemia and central nervous system tumors. As a result, hospitalization patterns have not been well-characterized for adolescents and young adults, especially those with breast, colorectal, and other cancer types that are more common at the older end of the age group.

Anderson and colleagues at the University of Utah and the University of North Carolina examined the risk of first hospitalization and rate of total hospitalizations among adolescents and young adult cancer survivors using data from the Utah Population Database. The resource links statewide population records to cancer diagnosis information in the Utah Cancer Registry, which is part of the National Cancer Institute’s Surveillance Epidemiology and End Results (SEER) program, as well as hospital discharge information from the Utah Department of Health.

The researchers analyzed data for 6,330 cancer survivors, 12,924 siblings, and 18,171 age-matched people without cancer.

The risk of a first hospitalization among adolescent and young adult cancer survivors was 1.78 times higher compared with their siblings and 1.93 times higher than unrelated, age-matched people without cancer.

Compared with controls, the risk of a first hospitalization increased 4.76-fold for survivors of leukemia, 3.45-fold for survivors of central nervous system tumors, 2.83-fold for survivors of colorectal cancers, 2.76-fold for survivors of non-Hodgkin lymphoma, and 2.37-fold for survivors of breast cancer. The lowest risks of a first hospitalization were for cervical/uterine cancers and melanoma.

The rate of total hospitalizations increased by 56 percent for adolescent and young adult cancer survivors compared with controls.

Cancer survivors also had more than double the risk for several other conditions, including infectious and parasitic diseases, nervous system diseases, circulatory diseases, skin diseases, respiratory conditions, injury, and poisoning. They also had a somewhat elevated risk for digestive, mental, musculoskeletal, and genitourinary diseases.

“A better understanding of the burden of hospitalizations among AYA cancer survivors may help to anticipate future health care utilization in more recently diagnosed patients,” Anderson said. “These findings may also inform the development of guidelines for follow-up care for adolescent and young adult cancer survivors.”

The main limitation of the study was that the number of hospitalizations was too small to perform analyses on specific cancer types or diagnostic codes within groups. The research was limited to hospitalizations that occurred in Utah. The study authors were not able to identify patients who were undergoing active cancer treatment during the follow-up period; therefore, some hospitalizations could reflect toxicities associated with some cancer therapies.

The study was funded by St. Baldrick’s Foundation. Anderson declares no conflicts of interest.

Press Release Published Date: 1/19/2020 7:05 PM

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New AACR Journal, Blood Cancer Discovery, Publishes Its First Paper

Venango, Kathleen — Thu, 16 Jan 2020 01:01:55

PHILADELPHIA — The American Association for Cancer Research (AACR) today announced that its latest journal, Blood Cancer Discovery, has published its first accepted article online. Blood Cancer Discovery is the ninth journal in the AACR’s prestigious portfolio of scientific publications.

According to Riccardo Dalla-Favera, MD, co-editor-in-chief, “The field of hematologic malignancies has historically been at the forefront of seminal discoveries, including those that have played a major role in innovative research in other tissue and tumor types. Given the multidisciplinary scientific programs of the AACR, the launch of this latest journal provides an excellent opportunity to bring together researchers from numerous fields in order to accelerate the rate at which science can impact patient care. To this end, Blood Cancer Discovery will identify and showcase the most compelling work in the field.”

The first paper published in Blood Cancer Discovery is titled “Mutational landscape and patterns of clonal evolution in relapsed pediatric acute lymphoblastic leukemia.”

“This study is the most comprehensive analysis of the genome of childhood ALL at several steps during treatment and at relapse. For this reason, we are confident it will become a classic in the field,” said Kenneth C. Anderson, MD, co-editor-in-chief of Blood Cancer Discovery.

“ALL is one of the most common causes of death from cancer for children in the United States,” said study author Charles G. Mullighan, MD, member of the Department of Pathology and deputy director of the St. Jude Children’s Research Hospital Comprehensive Cancer Center in Memphis. “Our study provides a tapestry of the genetic changes in pediatric ALL and how these genetic changes alter over time as the patient is treated and as the leukemia relapses. This information has the potential to be translated into new strategies for early detection of relapse and the development of treatments to prevent clinical occurrence.”

Mullighan and colleagues comprehensively analyzed a series of leukemia cell samples from 92 children with relapsed ALL, 67 with B-cell ALL and 25 with T-cell ALL. Samples were obtained at diagnosis, at several times during treatment, and at the point of relapse. Samples were analyzed using a number of different techniques, including exome, genome, and transcriptome sequencing, digital-droplet PCR, and xenografting.

The researchers identified 50 significantly mutated genes at relapse and multiple patterns of clonal evolution, including genes that are mutated at diagnosis and enriched at relapse, and other genes that are only mutated after initial diagnosis. Among the changes detected over time was an increase in RAS pathway mutations at B-cell ALL relapse. RAS pathway mutations accounted for 17.9 percent of the mutations in patients at diagnosis, and 31.3 percent of the mutations at relapse. In T-cell ALL, PI3K-AKT pathway mutations were common in patients at diagnosis and were infrequently detected at relapse.

Mullighan highlighted three parts of the study as having the potential for clinical translation:

distinguishing between relapse and second primary leukemias;
identification of a subset of hypermutated leukemias; and
early detection of relapse-driving mutations using digital-droplet PCR.

“This inaugural paper reflects the high caliber of articles to be included in Blood Cancer Discovery,” said Margaret Foti, PhD, MD (hc), chief executive officer of the AACR. “Editors-in-chief Dalla-Favera and Anderson, both distinguished international researchers and leaders in the field of hematologic oncology, are overseeing an editorial board comprised of world-renowned experts who will guide the acceptance of leading blood cancer research studies from laboratories and clinics all over the world.”

This study by Mullighan and colleagues was supported in part by the American Lebanese Syrian Associated Charities of St. Jude Children’s Research Hospital, the St. Baldrick’s Foundation, the Henry Schueler Foundation, the National Cancer Institute, the Dutch Cancer Society, the American Society of Hematology, the Leukemia & Lymphoma Society, the KiKa Foundation, the China Scholarship Council, the Royal Netherlands Academy of Arts and Sciences, the Princess Margaret Cancer Centre Foundation, the Ontario Institute for Cancer Research, the Canadian Institutes of Health Research, the Canadian Cancer Society Research Institute, the Terry Fox Research Institute, Genome Canada through the Ontario Genomics Institute, and the Canada Research Chair program.

Mullighan has received research grants from the following corporations: AbbVie, Loxo Oncology, and Pfizer. He has received speakers bureau honoraria from Amgen and Pfizer; and he is a member of the scientific advisory board for Illumina.

A preview issue of Blood Cancer Discovery will be available at the AACR’s Annual Meeting in April 2020. For more information or to submit a manuscript, please visit www.AACRjournals.org/bcd. To learn about the AACR’s publications program, which spans the spectrum of cancer research, please visit www.AACRjournals.org.

Press Release Published Date: 1/16/2020 9:00 AM

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American Cancer Survivors Face Substantial Financial Hardship and Financial Sacrifices

Burns, Matthew — Wed, 15 Jan 2020 11:26:59

PHILADELPHIA —American cancer survivors, particularly those 64 years or younger, faced substantial medical financial hardship and sacrifices in spending, savings, or living situation, according to data from a survey published in Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research.

“As the number of cancer survivors grows, the costs of cancer treatments rise, and patient cost-sharing increases, there is a growing need for financial intervention at multiple levels to help cancer survivors minimize their risk of financial hardship,” said epidemiologist Xuesong Han, PhD, senior principal scientist in Health Services Research at the American Cancer Society. “We hope our findings will inform the development of future health policies and interventions in care delivery.”

In the United States, the number of cancer survivors increased by 1.4 million people in the past three years, reaching more than 16.9 million as of January 1, 2019. The economic burden of cancer is significant for American cancer survivors: Previous studies have reported that as high as two-thirds of cancer survivors face medical financial hardship. However, few studies have examined the intensity of financial hardship across multiple domains, or sacrifices made as a result of cancer treatment and its longer-term effects.

Han and colleagues identified cancer survivors from the 2016 Medical Expenditure Panel Survey (MEPS), a nationally representative survey that collected information on health insurance coverage, health care utilization and expenditures, and health conditions.

Participants detailed the effects of their cancer, cancer treatment, and how their cancer experience has affected their finances, health insurance coverage, and employment status. Financial hardships included problems paying medical bills, financial distress, or delaying or forgoing medical care due to cost concerns. Financial sacrifices due to cancer included changes in spending and use of savings as a result of cancer treatment and its lasting effects.

Because people over the age of 65 years are generally eligible for Medicare insurance coverage, Han and colleagues examined results for adult survivors under and over the age of 65.

Of the 401 cancer survivors aged 18 to 64 years, 54 percent reported they had faced medical financial hardship as a result of cancer diagnosis and treatment, and 54 percent said they had made financial sacrifices in spending, savings, or their living situation. Nearly a quarter reported trouble paying medical bills, needing to borrow money, or filing for bankruptcy due to cancer diagnosis and treatment. More than 40 percent were worried about finances and almost 30 percent were worried about forgoing or delaying care because of cost concerns.

Of the 562 cancer survivors aged 65 years or older, medical financial hardship and sacrifices were less prevalent; 42 percent reported ever facing medical financial hardship, and 38 percent said they had made financial sacrifices.

Factors that were significantly associated with more intense financial hardship included low income and educational attainment, minority racial/ethnic status, comorbidity, lack of private insurance coverage, extended employment change, and recent cancer treatment.

Financial hardship has been linked to higher symptom burden and worse quality of life, and in extreme cases, such as bankruptcy, it is associated with an increased risk of death, Han explained.

“Overall, health insurance coverage is critically important for cancer patients and survivors,” said Han. “Even those who had private insurance coverage reported financial hardship, suggesting that the types of coverage and extent of patient cost-sharing are important too.”

“Provisions of the Affordable Care Act that have expanded insurance coverage options, such as the Medicaid expansion, have been associated with reductions in financial hardship among cancer survivors in other studies,” Han explained. “Employers can play a large role in mitigating hardship through flexible workplace accommodations such as availability of paid and unpaid sick leave, and supportive programs for both survivors and family members.”

The main limitations of the study were the potential for recall bias in the self-reported surveys and lack of data on clinical features of cancer stage and treatment. The researchers defined measures of insurance coverage, family income, and number of comorbidities as current estimates at survey time, however they defined measures of financial hardship and sacrifices as ever occurring.

The authors declare no conflict of interest.

Press Release Published Date: 1/14/2020 7:05 PM

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Circulating Tumor DNA May Be Predictive of Disease Progression in Patients with Rectal Cancer

Burns, Matthew — Tue, 3 Dec 2019 10:35:19

PHILADELPHIA — Detection of circulating tumor DNA (ctDNA) after neoadjuvant chemoradiotherapy was associated with poor response and increased risk of metastases in patients with locally advanced rectal cancer, according to results published in Clinical Cancer Research, a journal of the American Association for Cancer Research.

“Responses to neoadjuvant chemoradiotherapy are variable in patients with rectal cancer,” said senior author David Cunningham, MD, director of clinical research and consultant medical oncologist at The Royal Marsden in London. “If we can accurately differentiate the good responders from the poor responders, we may be able to adapt treatment and move away from a one-size-fits-all approach.”

Current methods to assess responses to neoadjuvant chemoradiotherapy include imaging and direct examination of surgically removed tissue. However, traditional methods for assessing response on imaging can be challenging due to the scarring of tumor tissue arising from treatment. In addition, “15 to 20 percent of patients have no evidence of cancer remaining in the tissue after neoadjuvant treatment. Establishing whether these patients could have been spared from surgery if their responses had been detected beforehand is an area of active research,” explained Cunningham.

In this study, Cunningham and colleagues assessed the potential of ctDNA to predict tumor response and disease progression in patients with rectal cancer. The study enrolled patients with locally advanced rectal cancer, as well as patients with non-metastatic rectal cancer who were recommended to receive chemoradiotherapy. Blood samples were used to look for ctDNA and if present, to measure levels of ctDNA. Samples were collected before, during, and after chemoradiotherapy, as well as after surgery. For patients who did not receive surgery, blood samples were collected every three to six months after chemoradiotherapy until within three months of tumor regrowth.

Forty-seven patients were evaluable for ctDNA and primary tumor response. Thirty-three percent of patients with poor tumor responses, as measured by tumor regression grade on magnetic resonance imaging, had detectable levels of ctDNA after chemoradiotherapy, compared to 5 percent of patients with good tumor responses. All three patients with pathologic complete responses had detectable ctDNA prior to chemoradiotherapy and undetectable ctDNA from mid-treatment onwards. Detection of ctDNA was not associated with tumor response measured by RECIST.

Detection of ctDNA after chemoradiotherapy and persistence of ctDNA during treatment was also associated with the development of metastasis. Seven of the 10 patients (70 percent) with detectable ctDNA upon completion of chemoradiotherapy went on to develop metastases, compared to four of the 37 patients (11 percent) who did not have detectable ctDNA after chemoradiotherapy. Furthermore, metastasis-free survival was significantly shorter in patients with detectable ctDNA upon completion of chemoradiotherapy and in those with ctDNA that persisted throughout treatment.

The authors also found that detection of ctDNA after surgery was associated with relapse. All three patients with detectable ctDNA post-surgery experienced relapse, compared to zero relapses among the 20 patients without detectable ctDNA post-surgery.

“Our results indicate that ctDNA can be used to identify patients who have a greater risk of developing metastases or experiencing relapse,” said first author Shelize Khakoo, MD, medical oncologist at The Royal Marsden.

The authors are currently recruiting colon and rectal cancer patients into a multicenter study that will use the presence or absence of ctDNA to guide treatment decisions after surgery. “If the associations we’ve observed during the neoadjuvant period are confirmed, detection of ctDNA could also be used to tailor treatment for patients with rectal cancer in an attempt to prevent cancer spread,” said Cunningham.

A limitation of the study is the small sample size.

This study was supported by the National Institute for Health Research Biomedical Research Centre at The Royal Marsden/The Institute of Cancer Research. Cunningham has received grants from 4SC, Amgen, AstraZeneca, Bayer, Celgene, Clovis, Eli Lilly, Janssen, Medimmune, Merck, Merrimack, and Sanofi. Khakoo declares no conflicts of interest.

Press Release Published Date: 12/17/2019 10:05 PM

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The AACR-MPM Oncology Charitable Foundation Announces First Grants to Support Transformative Cancer Research

Burns, Matthew — Mon, 16 Dec 2019 04:01:05

PHILADELPHIA, PA and CAMBRIDGE, MA - Two grants for research that could transform cancer therapies have been funded through an innovative partnership between the American Association for Cancer Research (AACR) and MPM Capital through its management of the UBS Oncology Impact Fund (OIF). This unique grant program allows investigators who can make a significant impact to pursue transformative research.

The AACR-MPM Oncology Charitable Foundation Transformative Cancer Research Grants program is announcing its first two grants totaling $800,000 in support of research that has the potential to explore new approaches to cancer treatment. These grants mark only the beginning of a long-term commitment by MPM Capital to finance groundbreaking research, and the program expects to announce another grant opportunity in mid-2020.

“Cancer is the second leading cause of death in the United States, and there is a vital need for high-impact, transformative research that will markedly reduce the incidence, morbidity, and mortality of this devastating disease,” said Margaret Foti, PhD, MD (hc), chief executive officer of the AACR. “The AACR is delighted to partner with UBS and MPM Capital in support of early-career and mid-career scientists whose exciting research holds promise for catalyzing paradigm-shifting advances in cancer research that will result in breakthroughs in cancer treatment.”

MPM Capital’s investment strategy is focused on developing breakthrough therapies based on cutting-edge science, to treat diseases with severe unmet medical needs. The UBS OIF, a first-of-its-kind impact fund investing exclusively in oncology therapeutics, is managed by MPM Capital in collaboration with UBS. Through the innovative impact structure of UBS OIF, MPM Capital is committed to funding academic research to develop novel cancer cures in addition to providing access to cancer care in the developing world.

"It is gratifying to see the efforts from our collaboration with UBS and the AACR supporting such important science," said Christiana Bardon, MD, MBA, Managing Director of the UBS Oncology Impact Fund (OIF) and Trustee of the AACR Foundation. “These competitive grants are funding groundbreaking research programs that have incredible potential to transform how we treat cancer.” These grants were selected through a highly competitive review process including an expert review panel chaired by MIT Nobel Laureate H. Robert Horvitz, PhD, an advisor to MPM Capital.

Tom Naratil, President of UBS Americas and Co-President of UBS Global Wealth Management, said: ”We are thankful and excited that through our innovative collaboration with MPM Capital and the AACR, we can now fund groundbreaking research projects that could lead to new therapies against cancer. We hope the UBS Oncology Impact Fund will become a case study of how private investments in healthcare can be a valuable part of our clients' portfolio while having a profound societal benefit at the same time.”

The first two grants from the AACR-MPM Oncology Charitable Foundation grants program are:

“Reconstructing the differentiation dynamics and genealogy of cancer cells”

Sahand Hormoz, PhD, of the Dana-Farber Cancer Institute, will study how genetic alterations in stem cells that generate new blood cells can disrupt normal blood development and cause cancers known as myeloproliferative neoplasms (MPNs). MPNs may behave as an indolent disease or progress to more aggressive diseases that can be life-threatening. Hormoz will reconstruct the lineage history of the mutated stem cells and characterize them by leveraging a single-cell profiling technology platform developed in his lab. The findings from the study are likely to provide in-depth understanding of when MPN-like blood cancers originated in individual patients and how they evolved over time. A better understanding of how MPNs form can potentially transform treatments for these diseases, allowing the development of patient-specific targeted therapies.

“This award recognizes the importance of innovative research and gives my lab the freedom to tackle fundamental questions in blood cancers using creative approaches that otherwise would not be possible,” Hormoz said.

“Deciphering the mechanisms of ferroptosis signaling and death in cancer”

Liron Bar-Peled, PhD, of the Massachusetts General Hospital Cancer Center, will focus on understanding how metabolic reprogramming in cancer cells can be targeted to develop therapeutic strategies. Using novel proteomic and metabolomic technologies, he aims to understand how altered metabolic pathways in cancer cells induce a form of cell death known as ferroptosis. A better understanding of this type of cell death will improve our knowledge of how cells succumb to ferroptosis and lay the foundation for a potentially powerful way of fighting cancer.

“We are now emboldened to undertake creative and cutting-edge research to address fundamental biochemical mechanisms by which cancer cells adapt to metabolic stress,” Bar-Peled said. “The ultimate goal is to translate these basic discoveries into therapeutic insights for cancer patients.”

Each project will receive $400,000 over a two-year period. Under the program, proposed research must represent a highly innovative approach to a major problem or challenge in cancer research that may not be funded through conventional channels. The funded projects are expected to catalyze important advances in cancer research and should have a potentially transformative impact on future clinical practice. The projects can be in any area of basic, translational, or clinical research.

Press Release Published Date: 12/17/2019 4:00 AM

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The AACR and St. Baldrick’s Foundation Partner on a New Scientific Achievement Award and Grant to Support Pediatric Cancer Research

Burns, Matthew — Mon, 16 Dec 2019 11:08:23

The American Association for Cancer Research and the St. Baldrick’s Foundation are pleased to announce the creation of the AACR-St. Baldrick’s Foundation Award for Outstanding Achievement in Pediatric Cancer Research. This award will not only recognize an individual for outstanding achievement in pediatric cancer research but will also provide generous support for a junior faculty investigator at the level of Assistant Professor or equivalent conducting impactful research that has the potential to accelerate breakthroughs against pediatric cancer.

The AACR-St. Baldrick’s Foundation Award for Outstanding Achievement in Pediatric Cancer Research will be presented to an individual who has significantly contributed to any area of pediatric cancer research. The recipient will be selected by the AACR and the St. Baldrick’s Foundation based on the recommendation of a committee of internationally recognized pediatric cancer experts. The inaugural recipient will be recognized during the Opening Ceremony of the AACR Annual Meeting, to be held April 24-29, 2020, in San Diego, and will also present an award lecture during the meeting.

Once selected, the awardee will be afforded the opportunity to nominate junior faculty level researchers to be considered to receive a one-year, $75,000 AACR-St. Baldrick’s Foundation Career Development Award in Pediatric Cancer Research. Candidates must be involved in cancer research, cancer medicine, or cancer-related science at any academic institution in the world and must have demonstrated promise for continued substantive contributions to pediatric cancer research. From the list of candidates provided by the awardee, a grant recipient will be chosen by the award selection committee. This individual will be formally announced at the AACR Annual Meeting 2020 and invited to present a research lecture in conjunction with the annual AACR Pediatric Cancer Research Special Conference, to be held in the fall of 2020.

This program represents the first time that an AACR scientific achievement award has been linked to a research grant opportunity. The goal of this initiative will be to spotlight significant scientific accomplishments, while simultaneously fostering the career advancement of pediatric cancer researchers. Furthermore, it is intended to stimulate an ongoing mentor-mentee relationship between the award and grant recipients and will serve to further bolster both the AACR’s and the St. Baldrick’s Foundation’s existing commitment to pediatric cancer research.

“Cancer is the leading cause of death from disease among children in the United States,” said Margaret Foti, PhD, MD (hc), chief executive officer of the AACR. “The AACR is thrilled to be partnering with the St. Baldrick’s Foundation, which has contributed so much to the pediatric cancer community, to establish a scientific achievement award and grant that will recognize extraordinary contributions to the field of pediatric cancer research and help further catalyze scientific innovation that will drive progress for children with cancer around the world.”

“The realities of childhood cancer are grim. Worldwide, every two minutes, a child is diagnosed with cancer. In the U.S., one in five kids diagnosed with cancer will not survive. This partnership between St. Baldrick’s and the AACR is one of many steps to help turn these statistics around,” said Kathleen Ruddy, CEO of the St. Baldrick’s Foundation. “Recognizing the extraordinary efforts that scientists have already made through a scientific achievement award and this unique grant will inspire and support future progress toward cures for all childhood cancers.”

Nominations for the inaugural AACR-St. Baldrick’s Foundation Award for Outstanding Achievement in Pediatric Cancer Research will be accepted until January 20, 2020. For more information and to submit nominations, please visit www.aacr.org/research/awards.

Press Release Published Date: 12/16/2019 5:30 AM

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Circulating Tumor DNA May Help Predict Recurrence in Patients with Early Triple-Negative Breast Cancer

Burns, Matthew — Fri, 6 Dec 2019 02:14:13

SAN ANTONIO — The presence of circulating tumor DNA (ctDNA) in early-stage triple-negative breast cancer helped predict the risk of recurrence in women who had undergone surgery after neoadjuvant chemotherapy, according to data presented at the 2019 San Antonio Breast Cancer Symposium (SABCS), held Dec. 10–14.

“For patients who have triple-negative breast cancer with residual disease, the risk of recurrence is exceptionally high,” said the study’s senior author, Bryan P. Schneider, MD, professor of Medicine and Medical and Molecular Genetics at Indiana University School of Medicine. “Novel therapies and technologies are critical, including those that can potentially predict the risk of relapse.”

ctDNA, or tumor DNA derived from plasma, is being explored as a way detect cancer, guide treatment, and monitor patients during remission. The presence of ctDNA can signal the presence of cancer.

“If you are a woman with triple-negative breast cancer, after surgery you are in a constant ‘watch and wait’ scenario, in fear of the cancer coming back,” said the study’s first author, Milan Radovich, PhD, associate professor of Surgery and Medical and Molecular Genetics at Indiana University School of Medicine. “We know that a significant proportion of these women will have disease relapse after surgery. ctDNA is a powerful tool to be able to predict recurrence and could help us identify the best ways to manage care for women diagnosed with this disease.”

Conversely, the authors – researchers in the Indiana University Melvin and Bren Simon Cancer Center and the Vera Bradley Foundation Center for Breast Cancer Research – said that superior outcomes for those who did not have ctDNA could potentially set the stage for clinical studies evaluating the ability to reduce post-surgical treatment for these patients.

In this study, the authors and colleagues analyzed plasma samples that had been collected from patients enrolled in the BRE12-158 clinical trial, which studied genomically directed therapy versus physician’s choice of treatment after preoperative chemotherapy in patients with triple-negative breast cancer. The trial enrolled 196 women, and ctDNA was sequenced in 142 patients using the FoundationOne Liquid Test.

Mutated ctDNA was detected in 90 of the patients, representing 63 percent. TP53 was the most commonly mutated gene, followed by others that are commonly associated with breast cancer.

At 17.2 months of follow-up, detection of ctDNA was significantly associated with inferior distant disease-free survival (DDFS). Patients with ctDNA had a median DDFS of 32.5 months, while the patients without ctDNA had not reached the median.

At 24 months, the DDFS probability was 56 percent in ctDNA-positive patients, compared with 81 percent in ctDNA-negative patients. In multivariate analysis, when the researchers controlled for factors including residual cancer burden; tumor size, grade, and stage; age; and race, detection of ctDNA remained independently associated with inferior DDFS. Overall, ctDNA-positive patients were three times as likely to have distant disease recurrence than ctDNA-negative patients.

Detection of ctDNA was also associated with inferior overall survival; ctDNA-positive patients had 4.1 times increased risk of death compared with ctDNA-negative patients.

“This study establishes that triple-negative breast cancer patients who have ctDNA after neoadjuvant therapy have a higher risk of recurrence,” Schneider said. “This may set the stage for further clinical trials for these high-risk patients, evaluating novel ways to prevent recurrence.”

The authors said a clinical trial expected to begin in 2020 will further examine ctDNA’s potential in guiding therapy for those patients who are at high risk of recurrence. They also noted that sequencing technology is developing rapidly, and will likely become more sensitive and more specific over time.

Schneider and Radovich said one limitation of this study is that the follow-up period is still ongoing, so results may change in future analysis.

This study was funded by the Vera Bradley Foundation for Breast Cancer and the Indiana University Grand Challenge Precision Health Initiative. The trial was managed by the Hoosier Cancer Research Network and enrolled at 26 sites across the U.S. The authors declare no conflict of interest.

Press Release Published Date: 12/13/2019 3:30 AM

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Residual Cancer Burden Can Predict Outcomes for Patients With Any Breast Cancer Type

Venango, Kathleen — Wed, 11 Dec 2019 10:49:00

SAN ANTONIO — A large meta-analysis of breast cancer patients showed that residual cancer burden after neoadjuvant chemotherapy is an accurate long-term predictor of recurrence and survival across all breast cancer subtypes, according to data presented at the 2019 San Antonio Breast Cancer Symposium (SABCS), held Dec. 10–14.

“In recent years, many single-institution studies have shown that residual cancer burden after neoadjuvant chemotherapy can tell us a great deal about a patient’s prognosis after surgery,” said the study’s lead author, W. Fraser Symmans, MD, professor and director of research operations, Department of Pathology, at The University of Texas MD Anderson Cancer Center in Houston. “We undertook this meta-analysis to help determine whether this is true for all subtypes, and how generalizable previous findings might be.”

Symmans explained that residual cancer burden is assessed through several factors, including the size of the primary tumor, the percentage of the tumor that is invasive versus in situ, and the involvement of lymph nodes. A calculator hosted by MD Anderson calculates residual cancer burden index and assigns a classification of pathologic complete response, RCB-I (minimal burden), RCB-II (moderate burden), or RCB-III (extensive burden).

In this study, Symmans and colleagues from the I-SPY Clinical Trials Consortium compiled and analyzed data from 12 cancer centers or clinical trials, representing approximately 5,100 patients. Using mixed effect models, they examined associations between the RCB index and event-free survival (EFS) and distant recurrence-free survival (DRFS).

The residual cancer burden index was tightly associated with both EFS and DRFS, and was consistent across 12 clinical sites and all four types of breast cancer. In terms of EFS, the analysis of RCB categories showed:

For hormone receptor (HR)-positive/HER2-negative, 11 percent of patients were classified as having a pCR, 11 percent as RCB-I, 53 percent as RCB-II, and 25 percent as RCB-III. At the 10-year follow-up, 19 percent of the pCR group had had a recurrence or had died, compared with 14 percent of the RCB-I group, 31 percent of the RCB-II group, and 48 percent of the RCB-III group.
For HR-positive/HER2-positive, 38 percent of patients were classified as having a pCR, 20 percent as RCB-I, 33 percent as RCB-II, and 8 percent as RCB-III. At the 10-year follow-up, 9 percent of the pCR group had had a recurrence or had died, compared with 17 percent of the RCB-I group, 36 percent of the RCB-II group, and 55 percent of the RCB-III group.
For HR-negative/HER2-positive, 69 percent of patients were classified as having a pCR, 11 percent as RCB-I, 16 percent as RCB-II, and 4 percent as RCB-III. At the 10-year follow-up, 7 percent of the pCR group had had a recurrence or had died, compared with 15 percent of the RCB-I group, 37 percent of the RCB-II group, and 40 percent of the RCB-III group.
For HR-negative/HER2-, 43 percent of patients were classified as having a pCR, 12 percent as RCB-I, 33 percent as RCB-II, and 11 percent as RCB-III. At the 10-year follow-up, 14 percent of the pCR group had had a recurrence or had died, compared with 25 percent of the RCB-I group, 39 percent of the RCB-II group, and 75 percent of the RCB-III group.

“The measurement of RCB index is strongly prognostic, allowing us to measure risk of recurrence with confidence,” Symmans said. “This meta-analysis of residual cancer burden provides real-world evidence of how patients are responding to neoadjuvant treatments, and calibration of RCB index to prognostic risk enables us to determine the most appropriate next steps for breast cancer patients.”

Symmans said that while not all cancer centers routinely collect data on residual cancer burden, this analysis shows that pathologists can implement it with accurate results, adding to its potential as a predictor of recurrence within breast cancer subtypes.

Symmans said one limitation of the study is that it is based on data from multiple institutions, leading to some variation in clinical methods, the handling of specimens, and possible other factors. Some data on residual cancer burden were collected prospectively and some were collected retrospectively.

“Looking ahead, if we can standardize the reporting of residual cancer burden, that will only improve its usefulness in determining long-term prognosis,” Symmans said.

This research was funded by the Department of Defense, a National Institutes of Health program grant, the Cancer Prevention Research Institute of Texas, and the Breast Cancer Research Foundation. Symmans co-holds a patent for a mathematical formula used in MD Anderson’s RCB index.

Press Release Published Date: 12/13/2019 3:30 AM

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Oral Paclitaxel Yielded Better Outcomes Than Intravenous Paclitaxel for Metastatic Breast Cancer Patients in Phase III Trial

Venango, Kathleen — Wed, 11 Dec 2019 11:06:38

SAN ANTONIO — Metastatic breast cancer patients who received an oral formulation of the chemotherapy drug paclitaxel had better response and survival and less neuropathy than patients who received intravenous paclitaxel, according to results of a phase III trial presented at the San Antonio Breast Cancer Symposium, held Dec. 10-14.

Paclitaxel is widely used to treat patients with metastatic breast cancer. It is generally administered intravenously. In this trial, researchers evaluated an oral form of the drug, given in combination with encequidar, a p-glycoprotein pump inhibitor that allows the oral paclitaxel to be absorbed into the bloodstream.

“Oral administration of cancer chemotherapy is very important for cancer patients, especially in areas where patients have difficulty accessing infusion clinics regularly,” said the study’s lead investigator, Gerardo Antonio Umanzor Funez, MD, medical oncologist with Centro Oncologico Integral, who conducted the study with DEMEDICA of San Pedro Sula, Honduras.

In this trial, researchers enrolled 402 metastatic breast cancer patients. The patients were randomly assigned in a 2:1 ratio to receive either 205mg/m² of oral paclitaxel plus encequidar (Pac+E) for three days a week, or 175mg/ m² paclitaxel intravenously (IV Pac) every three weeks. Their tumors were evaluated for response and confirmed at two consecutive evaluations by a blinded, independent radiology company.

The primary endpoint was radiologically confirmed tumor response rate at two consecutive timepoints; secondary endpoints were progression-free survival (PFS) and overall survival (OS).

Results showed that 35.8 percent of the Pac+E group had a confirmed tumor response, compared with 23.4 percent in the IV Pac group. In evaluating the pre-specified modified intention to treat population, which excludes patients who did not have target tumors that could be evaluated by the central radiologist per RECIST or who did not receive sufficient treatments, the response rate was 40.4 percent for the Pac+E group and 25.6 percent for the IV Pac group.

In measuring the durability of response, the researchers found that in 51 percent of the Pac+E group who had a confirmed response, the response lasted more than 150 days, compared with 38 percent of the IV Pac group who had a response. Furthermore, a higher percentage of Pac+E patients are continuing to receive treatment.

Ongoing analysis of PFS showed a median of 9.3 months for the Pac+E group, compared with 8.3 months for the IV Pac group. OS was 27.9 months for the Pac+E group, compared with 16.9 months for the IV Pac group.

The researchers said the Pac+E group reported higher rates of neutropenia, infection, and gastrointestinal side effects. They reported lower incidence and severity of neuropathy — 17 percent, compared with 57 percent in the IV Pac group. Grade 3 neuropathic symptoms were experienced by 1 percent of the patients in the Pac+E group, versus 8 percent in the IV Pac group.

Updated figures may be provided at SABCS.

“This oral form of paclitaxel provides a new therapeutic option for patients, in particular, for those who cannot easily travel,” Umanzor said. “While blood counts still need to be monitored, oral administration allows patients to remain home during therapy, and avoid spending significant time in the chemotherapy unit.

“We were pleasantly surprised that responses were durable, conferring an early survival advantage with minimal neuropathy,” he continued.

Umanzor said the next step will be testing the tolerability of oral paclitaxel in patients at high risk of developing peripheral neuropathy. The oral formulation may also be studied in other cancers, either as a monotherapy or in combination with other agents.

Umanzor pointed out that while the study’s primary endpoint of confirmed tumor response was evaluated blindly, the study could not be blinded at the clinical site. This may have created bias in the reporting of adverse events, he explained. Also, the study was statistically powered only for confirmed response rate and not for the secondary endpoints.

The study was funded by Athenex, the maker of the oral form of paclitaxel. Umanzor declares no conflicts of interest.

Press Release Published Date: 12/13/2019 3:30 AM

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Long-term Follow-up Shows Estrogen Alone and Estrogen Plus Progestin Have Opposite Effects on Breast Cancer Incidence in Postmenopausal Women

Venango, Kathleen — Wed, 11 Dec 2019 11:44:38

SAN ANTONIO — Long-term follow-up results from two large, randomized, placebo-controlled Women's Health Initiative (WHI) trials in postmenopausal women showed that the use of estrogen alone as menopausal hormone therapy decreased breast cancer incidence and death with persistent results after discontinuation of use, while estrogen plus progestin increased breast cancer incidence with persistent results after discontinuation of use, according to results presented at the San Antonio Breast Cancer Symposium, held Dec. 10-14.

“Menopausal hormone therapy with estrogen plus progestin (for postmenopausal women with an intact uterus) and estrogen alone (for postmenopausal women with prior hysterectomy) continues to be used by millions of women worldwide,” said Rowan T. Chlebowski, MD, PhD, chief of the Division of Medical Oncology and Hematology at Harbor-UCLA Medical Center, and an investigator at The Lundquist Institute. “Nonetheless, after nearly half a century, menopausal hormone therapy influence on breast cancer incidence and mortality remains unsettled, with discordant findings from prospective observational studies compared to findings from randomized clinical trials.”

Earlier this year, findings published by the Collaborative Group on Hormonal Factors in Breast Cancer from a meta-analysis of 58 observational studies showed estrogen plus progestin as well as estrogen alone were both associated with significantly increased risk of breast cancer incidence, while in the Million Women Study, both estrogen plus progestin as well as estrogen alone were associated with significantly increased breast cancer mortality.

The current report updates earlier findings from two randomized WHI clinical trials on breast cancer incidence and breast cancer mortality in women randomly assigned to conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA), CEE alone, or placebo, with more than 19 years of cumulative follow-up.

“In the two randomized, placebo-controlled WHI clinical trials involving 27,347 postmenopausal women, CEE plus MPA significantly increased breast cancer incidence, with these adverse effects persisting over a decade after discontinuing use,” noted Chlebowski. “And in contrast to decades of observational study findings, in the WHI trial, CEE alone significantly reduced breast cancer incidence and significantly reduced deaths from breast cancer, with these favorable effects persisting over a decade after discontinuing use.”

Chlebowski added, “While there are differences in characteristics of participants in the observational studies compared with those in the WHI randomized trials, the discordance between the randomized clinical trial findings with respect to estrogen alone use and observational findings are difficult to reconcile.”

Chlebowski and colleagues enrolled postmenopausal women aged 50 to 79 years with no prior breast cancer in one of two randomized clinical trials at 40 U.S. centers from 1993 to 1998, and followed the patients through September 2016. Postmenopausal women with an intact uterus received CEE and MPA (8,506) or placebo (8,102) for a median of 5.6 years. Postmenopausal women who had undergone hysterectomy received CEE alone (5,310) or placebo (5,429) for a median of 7.2 years.

After 16.1 years of cumulative follow-up, among those who received CEE alone, there were 520 incident breast cancers during the post-intervention period. Compared with women who had received placebo, those who had received CEE were 23 percent less likely to have been diagnosed with breast cancer and 44 percent less like to die from the disease, and these positive outcomes are in agreement with the earlier findings from this trial during the intervention period.

After 18.3 years of cumulative follow-up, among those who received CEE plus MPA, there were 1,003 incident breast cancers during the post-intervention period. Compared with women who had received placebo, those who had received CEE plus MPA were 29 percent more likely to have been diagnosed with breast cancer, and this negative outcome is in agreement with the earlier finding from this trial during the intervention period. CEE plus MPA was associated with an increased risk for death from breast cancer in the extended analysis, but it did not reach statistical significance.

Key limitations of the study include that the breast cancer mortality analyses were not protocol-specified. However, death from breast cancer is the most clinically relevant breast cancer outcome, Chlebowski noted. In addition, the trials evaluated one dose and schedule of CEE plus MPA or CEE alone, respectively, and findings may not apply to other preparations, doses, or schedules.

The WHI program is supported by the National Heart, Lung, and Blood Institute; National Institutes of Health; Department of Health and Human Services; and the National Cancer Institute. Chlebowski has received honoraria from Novartis, AstraZeneca, and Genentech; and consulting fees from Novartis, AstraZeneca, Pfizer, Puma, Immunomedics, and Genentech.

Press Release Published Date: 12/13/2019 3:30 AM

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AACR Applauds Confirmation of Stephen M. Hahn, MD, as FDA Commissioner

Burns, Matthew — Fri, 13 Dec 2019 03:53:59

PHILADELPHIA — The American Association for Cancer Research (AACR), the world’s first and largest cancer research organization, commends the U.S. Senate for confirming Stephen M. Hahn to be the next commissioner of the U.S. Food and Drug Administration (FDA). Hahn was approved in the U.S. Senate on Thursday by a vote of 72-18.

“On behalf of the Board of Directors of the American Association for Cancer Research (AACR), and the 44,000 laboratory researchers, physician-scientists, other health care professionals, and patient advocates who constitute our national and international membership, I wish to extend our heartfelt congratulations to Dr. Hahn,” said Margaret Foti, PhD, MD (hc), chief executive officer of the AACR. “The AACR is looking forward to working closely with him and his extraordinary team at the FDA to help facilitate and expedite the development and approval of safe and effective treatments for cancer patients.”

Hahn has been a member of the AACR since 1999. He was an inaugural member of the AACR Radiation Science and Medicine Working Group Steering Committee and the AACR Radiation Oncology Task Force. Hahn is a member of the AACR Gertrude B. Elion Cancer Research Award Scientific Review Committee. He served in 2018 as cochair of the Workshop on Clinical Development of Drug-Radiotherapy Combinations held in partnership with the FDA, the AACR, and the American Society for Radiation Oncology (ASTRO).

“Dr. Hahn brings impressive qualifications to this extremely important position, including his background as a highly regarded physician and extremely effective scientific administrator," said AACR President Elaine R. Mardis, PhD, co-executive director of the Institute for Genomic Medicine at Nationwide Children's Hospital. "Dr. Hahn understands the challenges that patients face every day, and also knows firsthand the importance of utilizing science-based evidence to evaluate the safety and efficacy of new therapies and devices.”

Through its synergistic partnership with the FDA, the AACR has provided thought leadership, scientific guidance, and feedback to the FDA on a number of important scientific topics and initiatives, and the AACR looks forward to continuing this strong partnership under Commissioner Hahn.

Press Release Published Date: 12/12/2019 7:00 PM

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MINDACT Trial Data Reveal Certain Women With Luminal Breast Cancer May Be Undertreated With Tamoxifen Alone

Venango, Kathleen — Wed, 11 Dec 2019 11:30:44

SAN ANTONIO — Among women with hormone receptor (HR)-positive, HER2-negative breast cancer with a high clinical risk (determined by tumor size and histologic grade) and low genomic risk (determined by MammaPrint), those 40 to 50 years old had a greater benefit from chemotherapy than those older than 50, according to data from an unplanned subgroup analysis of the MINDACT trial presented at the 2019 San Antonio Breast Cancer Symposium, held Dec. 10–14.

“Younger women with breast cancer are underrepresented in clinical trials, and treatment decisions are often based on data obtained in older, postmenopausal women,” said Fatima Cardoso, MD, director of the Breast Unit at the Champalimaud Clinical Center/Champalimaud Foundation in Lisbon, Portugal. “It is important to examine how age impacts treatment efficacy and disease recurrence in patients with breast cancer to determine the best treatment option for each patient.”

While most patients with HR-positive breast cancer are treated with endocrine therapy, the selection of patients that will derive clinical benefit from the addition of chemotherapy is an area of current research, explained Cardoso.

The goal of the MINDACT trial is to compare the utility of the 70-gene signature commercial diagnostic test MammaPrint with common clinical-pathological criteria (determined by modified

Adjuvant!Online) to select breast cancer patients with zero to three positive nodes for adjuvant chemotherapy. A recent analysis of the TAILORx trial revealed that patients who were 50 years old or younger had an estimated chemotherapy benefit in reducing distant recurrence at nine years if they had an Oncotype DX recurrence score (RS) of 16-20 with high clinical risk, or if they had RS of 21-25, irrespective of clinical risk.

“We conducted this unplanned analysis of the MINDACT trial to determine if the addition of chemotherapy had an age-dependent impact on distant metastasis-free survival (DMFS) among certain breast cancer patients, as was seen recently in an analysis of the TAILORx trial,” said Cardoso.

Cardoso and colleagues evaluated five-year DMFS among HR-positive, HER2-negative breast cancer patients enrolled in the MINDACT trial who had a low genomic risk and a high clinical risk and were randomized to receive chemotherapy based on either clinical or genomic risk.

Because there were only two DMFS events in patients under 40 years old, the researchers restricted their analysis to patients older than 40, resulting in a total population of 1,264 patients.

Among this group, 399 patients were aged 40 to 50, and 865 patients were older than 50. Among patients older than 50, the estimated five-year DMFS was similar between patients who received and who did not receive chemotherapy (95.2 percent versus 95.4 percent, respectively).

However, among patients 40 to 50 years old, the estimated five-year DMFS for patients who received chemotherapy was 96.2 percent versus 92.6 percent for those who did not receive chemotherapy.

“Similar to the TAILORx trial, we found that women classified as high risk of recurrence by traditional clinical-pathological factors but low risk by MammaPrint had a worse outcome if treated with tamoxifen alone, and that the benefit of chemotherapy may eventually be higher in this group,” said Cardoso.

“In both of these trials, the vast majority of women received tamoxifen alone (without ovarian suppression) as adjuvant chemotherapy,” noted Cardoso. “Therefore, we are unable to determine if the results seen in younger women are due to the direct effect of chemotherapy or through chemotherapy-induced ovarian suppression.

“These findings, while hypothesis-generating, are not yet practice-changing as they require confirmation,” continued Cardoso. “However, our results and the TAILORx trial results seem to indicate that younger women with high clinical risk and low genomic risk (per MammaPrint) or with an intermediate RS (per Oncotype DX) may benefit from additional treatment.”

This specific study represents a subset analysis of the MINDACT trial and is therefore only exploratory, representing a limitation of the study, noted Cardoso.

The MINDACT trial was supported by grants from the European Commission Sixth Framework Program, the Breast Cancer Research Foundation, Novartis, F. Hoffmann–La Roche, Sanofi-Aventis, Eli Lilly, Veridex, the National Cancer Institute (U.S.), the European Breast Cancer Council–Breast Cancer Working Group, the Jacqueline Seroussi Memorial Foundation for Cancer Research, Prix Mois du Cancer du Sein, Susan G. Komen for the Cure, Fondation Belge contre le Cancer, Dutch Cancer Society (KWF), the Netherlands Genomics Initiative–Cancer Genomics Center, Association le Cancer du Sein, Parlons-en!, the Brussels Breast Cancer Walk-Run and the American Women’s Club of Brussels, NIF Trust, German Cancer Aid, the Grant Simpson Trust and Cancer Research UK, Ligue Nationale contre le Cancer, and the EORTC Cancer Research Fund. Whole-genome analysis was provided by Agendia without cost.

Cardoso has advisory roles with Amgen, Astellas Pharma/Medivation, AstraZeneca, Celgene, Daiichi-Sankyo, Eisai Inc., GE Oncology, Genentech, GlaxoSmithKline, MacroGenics, Medscape, Merck-Sharp, Merus, Mylan, Mundipharma, Novartis, Pfizer, Pierre Fabre, prIME Oncology, Roche, Sanofi, Seattle Genetics, and Teva Pharmaceutical Industries Ltd.

Press Release Published Date: 12/12/2019 11:15 AM

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Combining Atezolizumab with Neoadjuvant Chemotherapy Does Not Improve Pathologic Complete Response Rates for Patients with Triple-Negative Breast Cancer

Venango, Kathleen — Tue, 10 Dec 2019 07:48:31

SAN ANTONIO — The addition of the anti-PD-L1 immunotherapeutic atezolizumab (Tecentriq) to neoadjuvant chemotherapy for patients with triple-negative breast cancer (TNBC) did not improve the rate of pathologic complete response when compared to chemotherapy alone, according to preliminary results from the NeoTRIPaPDL1 trial, which were presented at the San Antonio Breast Cancer Symposium, held Dec. 10-14.

“TNBC is an aggressive subtype of breast cancer with a high probability of relapsing,” said Luca Gianni, MD, president of the Fondazione Michelangelo in Milan. “Currently, the only treatment for early-stage TNBC is chemotherapy. While chemotherapy can be successful in some patients, relapse and resistance to chemotherapy are common, even after good initial responses.”

In this study, Gianni and colleagues examined the effect of adding the immune checkpoint inhibitor atezolizumab to neoadjuvant chemotherapy. “TNBC tumors often harbor immune cells called lymphocytes,” explained Gianni. “We reasoned that treating patients with an immune checkpoint inhibitor, in combination with chemotherapy, could boost the antitumor immune response.” Atezolizumab in combination with the chemotherapy drug nab-paclitaxel is currently approved by the U.S. Food and Drug Administration and the European Medicines Agency for the treatment of some patients with locally advanced or metastatic TNBC.

The study enrolled 280 female patients, aged 18 or older, with early high-risk and locally advanced or inflammatory TNBC. Patients were randomly assigned to receive neoadjuvant carboplatin and nab-paclitaxel (Abraxane), which are both chemotherapy drugs, with or without atezolizumab. The primary aim of the study, which is ongoing, is to determine five-year event-free survival rates. The secondary aim is to determine the rate of pathologic complete response, which can be a good predictor of long-term outcomes, explained Gianni.

Gianni and colleagues reported the data on pathologic complete response. They found that the addition of atezolizumab to neoadjuvant chemotherapy for approximately six months resulted in slightly higher rates of pathologic complete response when compared to neoadjuvant chemotherapy alone in the intent-to-treat population (43.5 percent vs. 40.8 percent); however, the increase was not statistically significant. Among patients whose tumors tested positive for PD-L1, 51.9 percent of patients in the atezolizumab plus chemotherapy arm had pathologic complete responses compared to 48.0 percent of those in the chemotherapy only arm, but this difference was also not significant.

“Our observations may indicate that there is no therapeutic benefit to adding atezolizumab to neoadjuvant chemotherapy compared to chemotherapy alone, or it may simply mean that any beneficial effects of the combination will be seen in the long term,” said Gianni. “Pathologic complete response does not provide information about the quality of response, which is why we did not use it as the primary endpoint for this study. Further analyses may reveal differences in the quality of response between the treatment groups.”

Biological samples collected from patients before, during, and after neoadjuvant treatment will be examined for lymphocyte infiltration, DNA mutations, and/or levels of circulating tumor DNA, which may reveal differences between the treatment groups, added Gianni.

Gianni and colleagues also reported that atezolizumab was well tolerated in the majority of enrolled patients. Immune-mediated adverse events of any grade were observed in approximately 8 percent of patients. Infusion reactions were the most commonly observed immune-mediated adverse event, and approximately 1.4 percent of infusion reactions were grade 3 or higher.

A limitation of the study is that the reported results are limited to the initial effects of the combination treatment and do not account for the effects of therapies administered after surgery.

This study was sponsored by Roche and Celgene. Gianni has served advisory roles for ADC Therapeutics, AstraZeneca, Celgene, Eli Lilly, G1 Therapeutics, Genentech, Genomic Health, MSD, Oncolytics Biotech, Odonate Therapeutics, Onkaido Therapeutics, Roche, Pfizer, Taiho Pharmaceutical, Sandoz, Seattle Genetics, Synthon, and Zymeworks. Gianni has consulted for Forty Seven Inc., Genenta Science, METIS Precision Medicine, Novartis, Odonate Therapeutics, Revolution Medicines, Synaffix, and Zymeworks. Gianni has received support for research from Zymeworks, Daiichi Sankyo, Zymeworks, and Revolution Medicines. Gianni is a co-inventor on a patent for PD-L1 expression in anti-HER2 therapy.

Press Release Published Date: 12/12/2019 3:30 AM

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Breast Cancer Preventive Effects of Anastrozole Persist Long After Stopping Treatment

Venango, Kathleen — Wed, 11 Dec 2019 09:49:33

SAN ANTONIO — Breast cancer incidence among postmenopausal women at high risk for developing the disease continued to be significantly reduced 5.9 years after stopping five years of the aromatase inhibitor anastrozole, according to data from the International Breast Cancer Intervention Study II (IBIS-II) Prevention trial presented at the 2019 San Antonio Breast Cancer Symposium, held Dec. 10–14. The study is being simultaneously published in the The Lancet.

“IBIS-II Prevention was designed to investigate whether five years of anastrozole can safely and effectively prevent breast cancer in postmenopausal women who are at high risk for the disease,” said Jack Cuzick, PhD, cochairman of the International Breast Cancer Intervention Studies. “In 2013, we reported that in the first seven years of follow-up, anastrozole significantly reduced breast cancer incidence compared with placebo and that it did so with very few side effects.

“Our new data show that after a median of 10.9 years of follow-up there continues to be a significant reduction in breast cancer incidence,” continued Cuzick, who is also director of the Wolfson Institute of Preventive Medicine, head of the Centre for Cancer Prevention, and the John Snow Professor of Epidemiology at Queen Mary University of London. “It is exciting to see that anastrozole has a continued impact on breast cancer incidence even after stopping treatment, as this strengthens the case for its use as a breast cancer prevention therapy.”

Cuzick and colleagues enrolled 3,864 postmenopausal women at increased risk for developing breast cancer in the IBIS-II Prevention study from 2003 to 2012. Women were considered to be at high risk for breast cancer if they fulfilled any one of a number of criteria, including having two or more blood relatives with breast cancer, having a mother or sister who developed breast cancer before the age of 50, and having a mother or sister who had breast cancer in both breasts. Among the participants, 1,920 were randomly assigned to anastrozole for five years and 1,944 to placebo. Five-year adherence to treatment was 74.6 percent for anastrozole and 77.0 percent for placebo, which is not significantly different.

After a median follow-up of 10.9 years, the researchers found that women assigned to anastrozole were 50 percent less likely to have developed breast cancer compared with women assigned to the placebo.

Cuzick explained that there were no new adverse side effects to add to those reported in 2013, which were mostly small increases in muscle aches and pains, and hot flashes. “No excess of fractures or other serious side effects were seen with anastrozole,” he said.

“The 50 percent reduction in likelihood of breast cancer incidence after 10.9 years of follow-up is slightly less than the 53 percent reduction we reported after the first seven years of follow-up, but it is still a significant effect and larger than that seen for tamoxifen,” said Cuzick. “Another way to consider the data is that it translates into an estimated 29 women needing to be treated with anastrozole for five years to prevent one breast cancer during treatment and in the next five years.

“This is far fewer women than the estimated 49 women that need to be treated with tamoxifen for five years to prevent one breast cancer in the same time period,” added Cuzick. “Therefore, our new results strongly suggest that anastrozole should be the preferred therapy for breast cancer prevention in postmenopausal women at increased risk for the disease, with tamoxifen used for women who experience severe side effects from anastrozole.”

Cuzick cautioned that the preventive benefits of anastrozole are seen for estrogen receptor–positive breast cancer and for ductal carcinoma in situ but not for estrogen receptor–negative

breast cancer. This is to be expected, he says, because anastrozole targets the estrogen pathway.

At the time of analysis, 129 deaths had been reported, with no significant difference in all-cause mortality between the anastrozole and placebo groups. There had been only five deaths from breast cancer, two among those assigned anastrozole and three among those assigned placebo.

“This is too few breast cancer deaths to determine if anastrozole reduces breast cancer mortality, so we are planning to follow the IBIS-II Prevention participants for longer to investigate this,” Cuzick concluded.

This study was supported by AstraZeneca, Cancer Research UK, and the National Health and Medical Research Council Australia. Cuzick is a consultant for Myriad Genetics.

Press Release Published Date: 12/12/2019 3:30 AM

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Partial Breast Irradiation May be as Effective as Whole Breast Irradiation in Preventing Recurrence in Patients with Early Breast Cancer

Venango, Kathleen — Wed, 11 Dec 2019 10:20:05

SAN ANTONIO — A 10-year follow-up study of breast cancer patients who had been treated with accelerated partial breast irradiation (APBI) after surgery showed that their rates of recurrence were similar to those of patients who had received whole breast irradiation (WBI), according to data presented at the 2019 San Antonio Breast Cancer Symposium (SABCS), held Dec. 10–14. The study suggests that the less invasive partial breast procedure may be an acceptable choice for patients with early breast cancer.

Many patients diagnosed with early breast cancer undergo surgery known as a lumpectomy, followed by a course of radiation. “Postoperative radiation still represents a mainstay of adjuvant treatment for breast cancer, able to significantly reduce the local relapse occurrence rate,” explained the study’s lead author, Icro Meattini, MD, of the University of Florence in Italy.

In recent years, researchers have sought to determine whether APBI might be as effective as WBI in preventing recurrence. Meattini’s study examined 10-year follow-up data for women enrolled in the APBI IMRT trial, a randomized phase III trial. The five-year follow-up from the trial showed no significant difference in tumor recurrence or survival rates.

The APBI IMRT trial enrolled 520 women over age 40 who had either stage 1 or stage 2 breast cancer. Between 2005 and 2013, the patients were randomly assigned in a 1:1 ratio to receive either APBI or WBI. The patients in the APBI arm received a total of 30 Gray (Gy) of radiation to the tumor bed in five daily fractions, while those in the WBI arm received a total of 50 Gy in 25 daily fractions to the whole breast, plus a boost of 10 Gy to the tumor bed in five daily fractions.

Both treatment arms were comparable in terms of age, tumor size, tumor type, and adjuvant endocrine treatment, and both achieved a median 10-year follow-up. The majority of the patients had hormone receptor-positive, HER2-negative breast cancer, and most were over age 50.

The study showed that after 10 years, 3.3 percent of patients in the APBI group had experienced a recurrence of breast cancer, compared to 2.6 percent in the group that received WBI. These

results were comparable to the five-year results, in which the group that received APBI had a 2.4 percent recurrence rate, and the group that received WBI had a 1.2 percent recurrence rate. Both differences were not statistically significant.

Overall survival at the 10-year mark was also very similar between the two groups: 92.7 percent for the women who had received APBI and 93.3 percent for the women who received WBI.

Breast-cancer specific survival was 97.6 percent for those who received APBI and 97.5 percent for those who received WBI.

The distant metastasis-free survival rate was 96.9 percent both for the women who received APBI and for those who received WBI.

“These results reinforce the initial promising results from the previous study,” Meattini said. “Accelerated partial breast irradiation can produce excellent disease control.”

Partial breast vs. whole breast radiation has been a topic of multiple clinical trials. A study presented at SABCS in 2018 showed that while the results were close, WBI proved slightly more effective in reducing recurrence rates.

Meattini said this growing body of research may help clinicians recommend that patients at lower risk of recurrence choose to receive APBI, while those at a higher risk of recurrence may be recommended for WBI.

“In well-selected cases, there is no difference in patients’ outcomes whether they are treated with APBI or WBI,” he said. “A once-daily regimen of external APBI might also produce an improved quality of life, with less toxicity, and can potentially reduce the overall treatment time.” He added that APBI may also be less likely to cause cosmetic changes and is less expensive to administer than WBI.

“Partial breast irradiation is one of the primary examples of effective de-escalation of treatment in breast oncology,” Meattini said. “For many patients, partial breast irradiation may be an optimal choice that is cost-effective, safe, and efficacious.”

Meattini said the study’s chief limitation is its relatively small size.

This study was supported by the Radiation Oncology Unit of the Florence University Hospital. Meattini declares no conflicts of interest.

Press Release Published Date: 12/12/2019 3:30 AM

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Neoadjuvant Treatment with Pembrolizumab Improves Pathologic Complete Response Rates for Patients with Triple-Negative Breast Cancer with Lymph Node Involvement

Venango, Kathleen — Wed, 11 Dec 2019 12:03:50

SAN ANTONIO — The addition of the anti-PD-1 immunotherapeutic pembrolizumab (Keytruda) to neoadjuvant chemotherapy increased the rates of pathologic complete response (pCR) in patients with triple-negative breast cancer (TNBC) who had lymph node involvement, according to results from the KEYNOTE-522 trial, which were presented at the San Antonio Breast Cancer Symposium, held Dec. 10-14.

Results on pCR rates from this trial were previously presented at the European Society of Medical Oncology annual meeting, held earlier this year. The latest data presented here included subgroup analyses of patients with lymph node involvement.

“TNBC is an aggressive subtype of breast cancer with a higher recurrence rate within the first five years after diagnosis compared to other subtypes,” said Peter Schmid, MD, PhD, professor of cancer medicine at Barts Cancer Institute in London. “It has been known for some time that involvement of lymph nodes is associated with an even higher risk of recurrence in patients with TNBC.”

The current standard of care for early-stage TNBC is chemotherapy. Large analyses have demonstrated that patients who have a pCR to neoadjuvant chemotherapy have a positive outlook with very low rates of recurrence, particularly in patients with more aggressive cancers like TNBC, explained Schmid.

“Currently, the pCR rate for standard chemotherapy treatment using an anthracycline and taxane combination is about 40 percent, or about 50 percent if a platinum-based drug is added to the combination,” added Schmid. “There continues to be a significant need for new regimens that can increase the pCR rate and increase long-term, event-free survival for patients with TNBC.”

In this study, Schmid and colleagues examined the effect of adding the immune checkpoint inhibitor pembrolizumab to neoadjuvant chemotherapy and adjuvant therapy in patients with early-stage TNBC. Treatments targeting the PD-1/PD-L1 pathway were previously shown to be effective for patients with metastatic TNBC.

The study enrolled 1,174 patients, aged 18 years or older, with previously untreated, non-metastatic, centrally confirmed TNBC. Patients were randomly assigned 2:1 to receive either pembrolizumab plus chemotherapy or placebo plus chemotherapy as neoadjuvant treatment. After neoadjuvant treatment, patients underwent definitive surgery and received radiation therapy as indicated. Patients received either adjuvant pembrolizumab or placebo until recurrence or unacceptable toxicity. The primary endpoints of the study, which is ongoing, are pCR and event-free survival.

Schmid and colleagues have previously reported that patients in the pembrolizumab plus chemotherapy arm had a significantly higher rate of pCR compared to patients in the chemotherapy alone arm (64.8 percent vs. 51.2 percent), regardless of PD-L1 expression.

The latest data presented here showed that among patients whose cancers had spread to the lymph nodes, 64.8 percent of those in the pembrolizumab plus chemotherapy arm had a pCR, compared to 44.1 percent in the chemotherapy only arm. High rates of pCR were also observed in patients with stage III disease.

“Our results suggest that adding pembrolizumab to neoadjuvant chemotherapy is beneficial for patients with the most aggressive disease and the highest unmet need,” said Schmid. “I think the results have the potential to be practice-changing.”

A limitation of the study is that event-free analyses are still preliminary, as the study is ongoing.

“After 15 months of follow-up, we see a strong favorable trend for event-free survival, but it has not yet met the predefined boundaries of statistical significance,” said Schmid. “Additional analyses will follow in the near future.”

This study was sponsored by MSD. Schmid has received research support from AstraZeneca, Genentech, Roche, OncoGenex Pharmaceuticals, Novartis, Astellas, and Medivation and has received honoraria or consultation funds from Pfizer, AstraZeneca, Novartis, Roche, Merck, Boehringer Ingelheim, Bayer, Eisai, Celgene, and Puma.

Press Release Published Date: 12/12/2019 3:30 AM

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Combining Endocrine Therapy with a CDK4/6 Inhibitor Results In Similar Response Rates to Chemotherapy for High-Risk Luminal B Breast Cancer

Venango, Kathleen — Wed, 11 Dec 2019 11:18:26

SAN ANTONIO — Neoadjuvant treatment with the CDK4/6 inhibitor ribociclib (Kisqali) and the aromatase inhibitor letrozole (Femara) produced response rates similar to multi-agent chemotherapy in patients with high-risk luminal B breast cancer, according to results from the SOLTI-1402/CORALLEEN trial presented at the San Antonio Breast Cancer Symposium, held Dec. 10-14.

Data from this study are being published simultaneously in The Lancet Oncology.

“The current standard treatment for high-risk luminal B breast cancer is neoadjuvant chemotherapy, but this is associated with high levels of toxicity,” said Joaquin Gavilá, MD, medical oncologist at the Instituto Valenciano de Oncologia in Valencia, Spain. Neoadjuvant endocrine therapy is an alternative to chemotherapy, but it has not shown high levels of efficacy for high-risk breast cancer, explained Gavilá. “Finding an effective alternative to multi-agent chemotherapy for patients with high-risk breast cancer is a priority,” he added.

Previous studies showed that combining endocrine therapy with CDK4/6 inhibitors, drugs designed to prevent cancer cells from dividing, resulted in similar response rates to chemotherapy for metastatic breast cancers. “We already knew that the combination of endocrine therapy with CDK4/6 inhibitors was efficacious in advanced breast cancers, so we were interested in investigating the efficacy of this combination for high-risk, early-stage breast cancer,” explained Gavilá.

In this study, the authors examined the efficacy of the CDK4/6 inhibitor ribociclib in combination with the aromatase inhibitor letrozole in patients with high-risk, luminal B, stage I to III operable breast cancer. The study enrolled 106 patients, who were randomly assigned 1:1 to receive either the ribociclib and letrozole combination or multi-agent chemotherapy as neoadjuvant treatment. The intention-to-treat analysis included 101 patients who had tissue samples available at the time of surgery.

At the time of surgery, 48 percent of the 49 patients in the ribociclib plus letrozole treatment arm had low risk of recurrence scores, as measured by PAM50, compared to 47.1 percent of the 52 patients treated with chemotherapy. Intrinsic subtype conversion to luminal A, which is a less aggressive subtype, occurred in 88 percent of patients in the ribociclib plus letrozole arm and in 84.3 percent of the chemotherapy arm. Rates of low residual cancer burden were 8 percent in the ribociclib plus letrozole arm and 11.8 percent in the chemotherapy arm. Rates of PEPI 0, another indicator of favorable prognosis, were 24 percent in the ribocliclib-letrozole arm and 17.6 percent in the chemotherapy arm.

Grade 3 and 4 toxicities were observed in 54.9 percent of patients in the ribociclib plus letrozole arm compared to 69.2 percent of patients in the chemotherapy arm.

“Our results indicate that neoadjuvant treatment with a combination of ribociclib and letrozole has similar clinical benefits as standard multi-agent chemotherapy, and with less toxicity,” said Gavilá. “We believe that this combination is worth exploring as an alternative to chemotherapy for patients with high-risk luminal B breast cancer.”

Gavilá cautioned that the results are preliminary and need to be confirmed in future clinical trials.

The SOLTI-1402/CORALLEEN study was sponsored by Novartis, the Breast Cancer Research Foundation, the American Association for Cancer Research, and Breast Cancer Now Career Catalyst. Gavilá has served an advisory role for Novartis, Pfizer, and Eli Lilly and Company and has served a consultancy role for Roche, Novartis, and MSD. Gavilá is a member of the governing board at the SOLTI Breast Cancer Research Group.

Press Release Published Date: 12/11/2019 11:15 AM

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New HER2 Antibody-drug Conjugate Yielded Promising Clinical Responses in Breast Cancer Patients Pretreated with T-DM1

Venango, Kathleen — Tue, 10 Dec 2019 05:54:19

SAN ANTONIO — The investigational HER2-targeted antibody-drug conjugate [Fam-] trastuzumab deruxtecan (T-DXd) demonstrated durable objective responses in patients with HER2-positive breast cancer who were heavily pretreated, including with T-DM1 (Kadcyla) and other HER2-targeted treatments, according to results from the phase II clinical trial DESTINY-Breast01 presented at the San Antonio Breast Cancer Symposium, held Dec. 10-14.

Data from this study are being published simultaneously in the New England Journal of Medicine.

“Although HER-2 directed therapies such as trastuzumab (Herceptin), pertuzumab (Perjeta), and T-DM1 have led to improved outcomes for patients with HER2-positive advanced breast cancer, resistance to these drugs develops almost inevitably and we do not have a clear standard of care for these patients once resistance occurs,” said Ian Krop MD, PhD, associate chief of the Division of Breast Oncology at Dana-Farber Cancer Institute. “Thus, there clearly is an unmet medical need for new and improved therapies for such patients.”

Similar to T-DM1, T-DXd has a monoclonal antibody targeted toward HER2, but unlike T-DM1, which has a microtubule inhibitor as the cytotoxic payload, T-DXd has a topoisomerase 1 inhibitor as the payload. T-DXd has eight molecules of the payload, which is twice as many as T-DM1, Krop explained.

Data published from a prior phase I study showed T-DXd yielded an objective response rate of 59 percent in patients with advanced HER-2 positive breast cancer previously treated with T-DM1. The U.S. Food and Drug Administration granted priority review to T-DXd in October.

In the phase II study, Krop and colleagues enrolled 253 patients with metastatic HER2-positive breast cancer previously treated with T-DM1. The trial had three parts, I, IIa, and IIb, and overall, 184 patients received the recommended phase II dose (RP2D) of 5.4 mg/kg T-DXd. The patients had received a median of six prior treatments for advanced disease, including HER2-targeted therapeutics.

The overall response rate in the 184 patients who received the RP2D was 60.9 percent, with 6 percent complete responses (CR) and 54.9 percent partial responses (PR). The median progression free survival was 16.4 months.

“Both of these measures of efficacy are substantially higher than that seen in any other study of patients with pretreated HER2-positive metastatic breast cancer,” Krop said.

The disease control rate in the 184 patients was 97 percent. “This suggests that the vast majority of cancers in this population seem to have at least some sensitivity to this agent,” Krop noted. “Consistent with this, the objective response rate to T-DXd appeared largely independent of tumor hormone receptor status, prior exposure to pertuzumab, and prior history of brain metastases.”

Ninety-nine percent of the patients had treatment-emergent adverse events (TEAEs), with 57 percent experiencing TEAEs of grade 3 or higher, including decreased neutrophil count, nausea, anemia, decreased lymphocyte count, and fatigue; 15 percent of patients discontinued treatment because of TEAEs.

Interstitial lung disease (ILD) was observed in 25 patients. “ILD is a serious concern in patients treated with T-DXd,” said Krop. “While these events were primarily grade 1 or 2, there were unfortunately four grade 5 ILD-related deaths (2.2 percent) on the study. Because of this potential toxicity, close monitoring for signs and symptoms of ILD is recommended for early detection. If ILD is suspected, evaluations should include high-resolution CT, pulmonologist consultation, pulmonary function tests, and other tests. Although data on treatment for T-DXd-induced ILD are limited, if diagnosed, interruption of treatment and prompt intervention with glucocorticoids is recommended.”

Krop added, “The high rate of durable responses observed with trastuzumab deruxtecan in patients whose cancers had progressed on T-DM1 and other therapies suggests this agent could provide a new treatment option for this patient population.”

A limitation of the study is that this was a single-arm trial and therefore it is not possible to determine whether T-DXd is more effective than other therapies from these data.

The study was sponsored by Daiichi Sankyo Inc. and AstraZeneca. Krop received grant support and research support from Genentech/Roche and Pfizer; personal fees from Daiichi Sankyo, Macrogenics, AstraZeneca, and Genentech/Roche.

Press Release Published Date: 12/11/2019 3:00 AM

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Updated APHINITY Trial Data Show Addition of Pertuzumab to Trastuzumab Plus Chemotherapy Continues to Yield Clinical Benefit in Patients With Operable HER2-positive Early Breast Cancer

Venango, Kathleen — Tue, 10 Dec 2019 07:13:32

SAN ANTONIO — Data from six-year analysis of the APHINITY trial showed that adding pertuzumab to the previous standard of trastuzumab plus chemotherapy after surgery continued to reduce the risk of recurrence and death in patients with HER2-positive early breast cancer, according to data presented at the 2019 San Antonio Breast Cancer Symposium, held Dec. 10–14.

Fewer deaths were seen in patients treated with pertuzumab, although the survival benefit was not statistically significant at this time.

“The addition of trastuzumab to chemotherapy after surgery has revolutionized treatment outcomes for patients with HER2-positive early breast cancer, yet roughly 30 percent of patients will still experience recurrence of their disease, a condition for which effective treatments are now available but cure is no longer possible,” said Martine Piccart, MD, PhD, cofounder of Breast International Group and Scientific Director at the Institut Jules Bordet in Brussels. “By adding a different yet complementary HER2 inhibitor, pertuzumab, to this treatment regimen, we hope to further reduce the risk of recurrence and advanced disease in this patient population.”

Earlier results from the phase III APHINITY trial comparing pertuzumab or placebo added to the standard adjuvant chemotherapy plus trastuzumab in patients with operable HER2-positive early breast cancer have been previously reported. They showed that patients treated with pertuzumab had improved rates of estimated three-year invasive disease-free survival (IDFS; time from randomization up to recurrence or death) compared with those in the placebo arm (94.1 percent versus 93.2 percent, respectively). The addition of pertuzumab reduced the relative risk of recurrence by 19 percent, which was statistically significant. The overall survival (OS) did not significantly differ between the two arms in the earlier analysis. The current study reports on the six-year interim analysis of OS and an updated descriptive analysis of IDFS and cardiac safety.

Between November 2011 and August 2013, the APHINITY trial randomly assigned 2,400 patients to the pertuzumab arm and 2,405 patients to the placebo arm. The data cutoff for this updated OS analysis was June 19, 2019, corresponding to a median follow-up time of 74.1 months.

After six years of follow-up, Piccart and colleagues found in this descriptive analysis of IDFS that among the overall population, those in the pertuzumab arm had a reduced relative risk of breast cancer recurrence or death by 24 percent compared with the placebo arm.

Similar to their previous findings, Piccart and colleagues found that patients whose cancer had spread to their lymph nodes continued to derive greatest clinical benefit with the addition of pertuzumab to standard treatments. In the six-year updated analysis, the researchers found that, among patients with node-positive disease, the IDFS in the pertuzumab arm was 87.9 percent, while the IDFS in the placebo arm was 83.4 percent, representing a 4.5 percent improvement. The addition of pertuzumab to trastuzumab and chemotherapy after surgery translated to a reduced relative risk of recurrence by 28 percent in this cohort.

In this updated analysis, one additional primary cardiac event was reported in the pertuzumab arm, and one additional secondary cardiac event was reported in each arm; no new cardiac safety concerns emerged, noted Piccart. “Incidence of primary cardiac events remains less than 1 percent in both arms (0.8 percent in the pertuzumab arm versus 0.3 percent in the placebo arm), providing further evidence that adding pertuzumab to trastuzumab and chemotherapy is safe in the long term,” she said.

“Following this interim analysis, the evidence is now even stronger than adding pertuzumab to the previous standard of care reduces the risk of disease recurrence for patients with HER2-positive breast cancer,” said Piccart. “Altogether, the clinical benefit of pertuzumab, which is exemplified by its treatment effect against breast cancer and its lack of additional significant side effects, is enhanced for women at high risk of breast cancer recurrence in this curative setting.

“A main limitation of APHINITY is that although we have seen fewer deaths among the patients who received treatment with pertuzumab, our data is still immature and have not shown definitive improvement in overall survival. A longer follow-up is needed to see any significant survival benefit,” Piccart said. The next interim analysis is scheduled to take place in 2022.

“Ongoing research using the biological specimens and clinical data collected from this very large study would help in refining the characteristics of the patients who will most benefit from

pertuzumab, particularly among those considered to be at lower risk of recurrence only on the basis of absence of lymph node disease,” she added.

This study was supported by Roche.

Piccart has served as a consultant on the scientific advisory board at Roche, for which she has received honoraria. Additionally, Piccart is a consult for the advisory boards of AstraZeneca, Camel-IDS, Crescendo Biologics, Debiopharm, G1 Therapeutics, Huya Bioscience International, Immunomedics, Eli Lilly, The Menarini Group, Merck, Novartis, Odonate Therapeutics, PeriphaGen, Pfizer, and Seattle Genetics. She is a scientific board member for Oncolytics and Radius.

Piccart’s institution receives funding from Eli Lilly, Merck, Pfizer, Radius Health, Roche/Genentech, AstraZeneca, Novartis, Servier Pharmaceuticals, and Synthon Pharmaceuticals.

Press Release Published Date: 12/11/2019 3:00 AM

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Addition of S-1 to Post-operative Endocrine Therapy Improves Outcomes for Patients with Hormone Receptor-positive, HER2-negative Breast Cancer

Venango, Kathleen — Tue, 10 Dec 2019 07:35:08

SAN ANTONIO — A post-operative combination of S-1, an oral fluoropyrimidine-based drug, with endocrine therapy significantly increased invasive disease-free survival (iDFS) and improved five-year iDFS estimates in patients with hormone receptor (HR)-positive, HER2-negative breast cancer, according to results from a phase III study presented at the San Antonio Breast Cancer Symposium, held Dec. 10-14.

“Although we have made remarkable progress with systemic therapy for breast cancer, many patients still experience disease recurrence,” said Masakazu Toi, MD, PhD, professor of breast surgery at Kyoto University Hospital.

HR-positive, HER2-negative breast cancer, also referred to as luminal breast cancer, is the most common breast cancer subtype, accounting for approximately 67 percent of cases. Patients with this subtype are often treated with endocrine therapies, which work in various ways to prevent hormones from activating cancer growth. Although this subtype is associated with a favorable five-year relative survival rate, there is a risk of disease recurrence several years after treatment, explained Toi. “Because of the risk of recurrence, there is interest in identifying novel post-operative adjuvant therapies to be used in conjunction with endocrine therapy,” said Toi.

S-1 is a combination drug composed of tegafur, which is a 5-fluorouracil prodrug that inhibits DNA synthesis and cell division, and gimeracil and oteracil, which promote tegafur activity and prevent gastrointestinal toxicity, respectively. Previous studies suggested that combining tegafur with endocrine therapy could improve anti-tumor efficacy.

In this study, Toi and colleagues examined the efficacy of S-1 in combination with adjuvant endocrine therapy in patients. The study enrolled 1,939 patients with stage I-III HR-positive, HER2-negative breast cancer with intermediate or higher risk of recurrence in the full analysis set. The study included patients from 139 centers in Japan. Patients were randomized to receive either S-1 and endocrine therapy or endocrine therapy alone as adjuvant treatment.

The median follow-up after treatment was 51.4 months. Among the 957 patients in the S-1 arm, 101 experienced disease recurrence (iDFS events), compared to 155 of the 973 patients in the control arm (10.6 percent versus 15.9 percent). The estimated five-year iDFS was 86.9 percent for patients in the S-1 arm compared to 81.6 percent in the control arm.

“We found that the postoperative adjuvant use of S-1 in combination with standard endocrine therapy significantly reduced iDFS events and improved five-year iDFS estimates in patients with HR-positive and HER2-negative breast cancer,” said Toi. Furthermore, the S-1 treatment was well tolerated and manageable, according to Toi. Major toxicities associated with S-1 treatment included signs of bone marrow suppression, such as decreased neutrophil counts; gastrointestinal toxicities, such as nausea and diarrhea; hyperpigmentation; and fatigue.

“Our findings support the addition of S-1 to standard endocrine therapy in the post-operative adjuvant setting for patients with HR-positive, HER2-negative disease and an intermediate or higher risk of recurrence,” said Toi.

A limitation of the study is that it only included patients from Japan, and the toxicity profile may be slightly different between Asian and non-Asian patients, explained Toi.

The study was sponsored by the Comprehensive Support Project of the Public Health Research Foundation and Taiho Pharmaceutical. Toi has served advisory roles for Kyowa Kirin, Bristol- Myers Squibb, Daiichi Sankyo, Genomic Health, and Konica Minolta. Toi has received honoraria from Taiho, Chugai, Takeda, Pfizer, Kyowa-Kirin, Eisai, Daiichi-Sankyo, AstraZeneca, Eli Lilly, Genomic Health, Novartis, Konica Minolta, and Shimadzu. Toi has received research grants from Taiho, Kyowa Kirin, AstraZeneca, Shimadzu, AFI Technology, and Astellas. Toi has received additional funds from Chugai, Pfizer, Nippon Kayaku, Terumo, JBCRG Association, and the Kyoto Breast Cancer Research Network.

Press Release Published Date: 12/11/2019 3:00 AM

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BRAF Inhibitor Shows Promising Results in Pediatric Patients with Low-Grade Glioma

Burns, Matthew — Tue, 3 Dec 2019 10:38:06

PHILADELPHIA — Dabrafenib (Tafinlar), a BRAF inhibitor approved to treat certain types of adult melanoma, showed activity in pediatric patients with low-grade glioma, according to results published in Clinical Cancer Research, a journal of the American Association for Cancer Research.

“Low-grade glioma is the most common brain tumor seen in children. While the prognosis is quite favorable, neurological disability is a major problem,” said Darren Hargrave, MD, clinical professor of pediatric neuro-oncology at the Great Ormond Street Hospital in London.

“A major consideration for treatment, particularly in children, is that the brain is a very vulnerable organ,” explained Hargrave. “The goal of treatment is to stop the tumor from growing, but we also want to cause the least amount of damage possible to the normal brain.”

Patients are often treated with surgery to remove all or part of the tumor, which may be followed by chemotherapy or radiotherapy. While chemotherapy and radiotherapy are both effective treatments, there are trade-offs to each of these options, explained Hargrave. Chemotherapy generally does not cause significant side effects to the normal brain, but patients can experience other severe side effects and admissions to the hospital during the treatment course, which can range from 12 to 18 months. On the other hand, radiotherapy is usually administered for only six weeks, but there is a greater risk of damage to the normal brain. Due to the greater risks of radiotherapy, most patients are initially treated with chemotherapy.

In this phase I/IIa study, Hargrave and colleagues examined the efficacy of an oral targeted therapy called dabrafenib in patients with pediatric low-grade glioma. Dabrafenib selectively inhibits a mutated form of the BRAF protein that causes cell growth. This BRAF mutation is often found in pediatric low-grade gliomas.

“The theoretical advantage of a targeted therapy is that the tumor can be controlled, even shrunk, while causing less damage to normal tissue,” said Hargrave. “Limiting the adverse effects on normal tissue has the potential to improve long-term outcomes and treatment burden.”

The study enrolled a total of 32 patients, aged 1 to 18 years, whose tumors had the BRAF mutation. All patients had received at least one prior therapy. Fifteen of these patients were enrolled in the phase I portion of the study, which was also published in Clinical Cancer Research earlier this year, and 17 were enrolled in the phase II portion. All 17 patients in the phase II portion were treated with the recommended phase II dose determined in the phase I study. An additional seven patients in the phase I portion had been treated at this dose. All patients were treated with a pediatric formulation of dabrafenib.

Five patients were not evaluable for objective response but were evaluable and met the criteria for stable disease. Based on independent radiological review, responses were observed in 14 of the 27 evaluable patients. One patient had a complete response, and 13 had partial responses. The median duration of response was 26 months, with a median progression-free survival of 35 months. Eleven patients experienced disease progression.

Treatment-related adverse events were observed in 29 patients, and nine patients experienced grade 3 or 4 treatment-related adverse events. There were no treatment-related deaths; however, one patient died two weeks after discontinuing the therapy due to disease progression.

“The number, rapidity, and degree of responses we saw with dabrafenib were higher than what we might expect when treating progressive relapsed pediatric low-grade glioma with chemotherapy,” said Hargrave, but he cautioned that results from a randomized phase III study comparing first-line dabrafenib in combination with the MEK inhibitor trametinib and chemotherapy are needed before any direct comparisons can be made. The phase III study is currently open for enrollment.

“If the phase III study shows clinical benefit, dabrafenib could become a new front-line treatment option for pediatric low-grade glioma,” Hargrave added. Hargrave and colleagues are also testing trametinib, alone and in combination with dabrafenib, for the treatment of pediatric patients with previously treated low-grade glioma.

A limitation of the study is the lack of data on long-term side effects. Additionally, the study design did not allow researchers to determine the optimal duration of treatment. Another study currently in development will aim to collect these data.

This study was sponsored by GlaxoSmithKline and Novartis. Hargrave has consulted and served on advisory boards for Novartis, AstraZeneca, Bayer, Boehringer Ingelheim, Celgene, and Roche. Hargrave has received funding from AstraZeneca.

Press Release Published Date: 12/5/2019 10:05 PM

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Anti-CTLA-4 Antibody Tremelimumab Shows Efficacy in Patients With Metastatic Bladder Cancer

Burns, Matthew — Wed, 27 Nov 2019 08:51:03

PHILADELPHIA — Treatment with the investigational anti-CTLA-4 agent tremelimumab showed clinical responses in patients with pretreated metastatic bladder cancer, according to results from a phase II clinical trial published in Clinical Cancer Research, a journal of the American Association for Cancer Research.

The standard-of-care first-line treatment for patients with metastatic bladder cancer is systemic platinum-based chemotherapy. The U.S. Food and Drug Administration (FDA) has approved the PD-1 inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) and the PD-L1 inhibitors atezolizumab (Tecentriq), durvalumab (Imfinzi), and avelumab (Bavencio) for the treatment of locally advanced or metastatic bladder cancer that has progressed during or after platinum-based chemotherapy.

“There is a significant unmet medical need to improve long-term treatment outcomes for patients with advanced bladder cancer who have progressed following primary treatment,” said Padmanee Sharma, MD, PhD, professor in the Department of Genitourinary Medical Oncology and Immunology at The University of Texas MD Anderson Cancer Center. “Our results indicate that blocking CTLA-4 with tremelimumab may produce comparable clinical efficacy as seen with PD-1/PD-L1 inhibitors in this patient population.”

Antibodies that inhibit the immune checkpoint proteins CTLA-4 and PD-1/PD-L1 have distinct mechanisms of action and generate unique T-cell responses, Sharma explained. Further, resistance to the inhibition of one of these pathways does not confer resistance to the inhibition of the other checkpoint pathway, she added. “It is important to develop therapies targeting both of these pathways so that we can manipulate different phases of the immune response and allow for improved antitumor efficacy through combination therapy,” she added.

The aim of this open-label, multicenter trial was to evaluate the safety and efficacy of tremelimumab in patients with advanced solid tumors. This study reports on the subgroup of patients with advanced bladder cancer.

At the time of data cut-off, 32 patients had been enrolled in the trial. All had metastatic disease, and 29 patients had received prior cytotoxic chemotherapy. Patients received 750mg of tremelimumab via IV administration every four weeks for seven cycles, followed by administration every 12 weeks for two additional cycles for up to 12 months. The mean treatment duration was 3.5 months.

After a median follow-up of 9.3 months, the overall response rate was 18.8 percent, including two complete responses and four partial responses. The median overall survival was 10.3 months, and the median progression-free survival was 2.6 months.

More than half of the patients experienced adverse events (AEs) of grade 3 or higher, most commonly colitis (three patients) and anemia (three patients). Roughly one-third of patients had an AE that led to discontinuation of treatment.

“While patients tend to experience more side effects with inhibition of CTLA-4 compared with inhibition of PD-1/PD-L1, the nature of these side effects is very similar to those observed with anti-PD-1/PD-L1 therapies and can be managed using similar approaches,” Sharma explained.

“Our results demonstrate that CTLA-4 blockade via tremelimumab can provide clinical benefit for patients with metastatic bladder cancer, highlighting the need for further studies with larger numbers of patients,” Sharma said. Future work will focus on the administration of tremelimumab in patients whose disease has progressed following treatment with anti-PD-1/PD-L1, she added.

Limitations of the study include the small sample size and lack of a randomized control, which limits its broader applicability, noted Sharma.

This study was sponsored by AstraZeneca.

Sharma reports consulting for, and stock or other ownership in Apricity, BioAtla, Codiak Biosciences, Constellation Pharmaceuticals, Dragonfly Therapeutics, Forty-Seven Inc., Hummingbird Bioscience, ImaginAb, Jounce Therapeutics, Lytix Biopharma, Marker Therapeutics, Merck & Co., Neon Therapeutics, Oncolytics Biotech, Pieris Pharmaceuticals, and Polaris Group

Press Release Published Date: 12/4/2019 5:00 AM

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Commercial Prognostic Tests for Prostate Cancer May Not Be Accurate in African American Men

Burns, Matthew — Thu, 21 Nov 2019 01:06:50

PHILADELPHIA — Commercial gene expression tests that guide treatment decisions for prostate cancer may not accurately predict risk of disease progression in African American patients, according to results published in Cancer Epidemiology, Biomarkers, and Prevention, a journal of the American Association for Cancer Research.

“When a man is diagnosed with low- or intermediate-risk prostate cancer, commercially available tests may be used to measure gene expression in the prostate tumor. This information is used to estimate the likelihood of disease progression and can influence how the patient’s cancer is treated,” said Travis A. Gerke, ScD, assistant member at Moffitt Cancer Center.

African American men have a 70 percent greater risk of prostate cancer and are more than twice as likely to die from the disease compared to European American men. However, OncotypeDX Prostate, Prolaris, and Decipher—three of the commercial gene expression tests for prostate cancer—were developed and validated in predominantly European American cohorts, explained Gerke.

“Unfortunately, African Americans are underrepresented across many areas of public health research, and prognostic biomarker discovery in prostate cancer is no exception,” said Gerke. “Because African American men have a high risk of aggressive prostate cancer, they represent a patient population in critical need of prognostic tools to help with the early stages of treatment decision-making.”

In this study, Gerke and colleagues examined whether gene expression patterns differed by race for the genes included in the OncotypeDX Prostate, Prolaris, and Decipher tests. All three of these tests are recommended by the National Comprehensive Cancer Network guidelines to predict outcomes in men with low- or intermediate-risk prostate cancer.

The study used NanoString, a gene expression panel, to compare the expression of 60 genes included in the commercial tests from tumor samples of 327 patients, which included 95 African American patients and 232 European American patients. The analysis showed that 48 percent of the genes included in the panels were expressed at different levels in African American men than in European American men. This finding was not entirely surprising given known racial differences in disease aggressiveness, explained Gerke.

However, the authors found that the risk predictions provided by Prolaris and Decipher based on the risk scores were not significantly different between African American and European American men. Furthermore, the OncotypeDX scores provided more favorable risk prediction for African American men compared to European American men. These risk predictions were unexpected because, on average, African American men have worse outcomes than European American men, Gerke noted.

“The risk predictions for African American men from these commercial gene tests conflict with the likely clinical outcomes for these patients,” said Gerke. “Until the risk prediction accuracy of the tests has been thoroughly studied in African American patients, we urge caution in their use for clinical decision-making. We hope that our report escalates interest in validating the utility of genomic risk predictors in African American men.”

One limitation of the study is the lack of follow-up data to compare the outcomes of the patients with the predicted outcomes from this study. Future studies examining long-term disease progression and survival will be necessary for direct evaluation of the accuracy of the tests in predicting prognosis.

Another limitation was that the analysis used a common gene panel called NanoString instead of the commercial panel of each test. While this allowed for uniform assessment across all three gene expression tests, the deviation from each test’s protocol may have impacted the findings.

This study was sponsored by Moffitt Team Science, the V Foundation, Cancer Center Support to the Moffitt Cancer Center, the Cortner-Couch Chair for Cancer Research from the University of South Florida School of Medicine, Lesa France Kennedy, and the State of Florida.

Gerke declares no conflicts of interest.

Press Release Published Date: 11/21/2019 10:05 PM

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Oncotype DX Breast Recurrence Score Reveals Sex-related Differences in Mortality Prediction in Patients With Early-stage ER-positive Breast Cancer

Burns, Matthew — Mon, 18 Nov 2019 01:27:43

PHILADELPHIA — The associations of breast cancer recurrence scores (RS) with mortality measured using Oncotype DX, a commercial diagnostic test, were markedly different between male and female patients with early-stage estrogen receptor (ER)-positive breast cancer, with the threshold for RS score in predicting mortality in men being lower than the threshold for women, according to results published in Clinical Cancer Research, a journal of the American Association for Cancer Research.

“Male breast cancer is relatively rare, and most treatment decisions are based on evidence derived from female breast cancer trials,” said first author Fei Wang, MD, PhD, visiting postdoctoral scholar at the Vanderbilt Epidemiology Center in Nashville, Tennessee. “Our results highlight the fact that male and female breast cancers may not be identical, and that additional research is needed to elucidate the best treatment options for men with breast cancer.”

The 21-gene Oncotype DX test is recommended for patients with early-stage ER-positive, HER2-negative breast cancer to quantify the likelihood of distant recurrence (on a scale of 0-100), which may guide chemotherapy treatment decisions, explained senior author Xiao-Ou Shu, MD, PhD, professor of cancer research at the Vanderbilt Ingram Cancer Center. Additionally, this test may be predictive of breast cancer mortality in this patient population, she said.

Because this test was developed and validated in female breast cancer patients, little is known about its performance in male breast cancer patients, Shu noted. “We set out to study if the Oncotype DX recurrence score had the same utility to predict mortality in men compared with women,” Shu said.

Using information from the National Cancer Database (NCDB), the Vanderbilt team analyzed data from patients with ER-positive, HER2-negative, stage 1 or stage 2 invasive breast cancer diagnosed between 2010 and 2014. The final analysis included 848 male and 110,898 female patients. All patients had received an Oncotype DX test.

The authors evaluated the relationship between RS and mortality in both male and female patients. They also evaluated the five-year overall survival across low-, intermediate-, and high-risk groups based on the RS categories as indicated by traditional categorization (17 or lower, 18-30, and 31 or greater), and by the TAILORx RS categorization, which was utilized in the TAILORx trial (10 or lower, 11-25, and 26 or greater).

The distribution of RS was markedly different between male and female patients; men had a significantly higher proportion of patients with an RS of 10 or less, as well as a significantly higher proportion of patients with an RS of 31 or greater, compared with women.

Among male patients, RS was associated with increased mortality risk up to a score of 21, beyond which the risk plateaued. However, among female patients, RS was associated with increased mortality risk only above a score of 23, beyond which the risk continued to increase.

“We found in our study that both the distribution and prognosis predictive utility of the Oncotype DX recurrence score differed between male and female breast cancer patients, suggesting a possible biological difference between male and female breast cancers, which requires further investigation,” Shu said.

The researchers found that the traditional RS categories of Oncotype DX, which were associated with mortality in female patients, were not significantly associated with mortality among male patients. However, the researchers observed that men with intermediate- and high-risk RS according to TAILORx cutoffs had significantly higher risks of mortality compared with men with a low-risk TAILORx RS.

“Even though the Oncotype DX test was not specifically designed for men, it still has some prognosis predictive utility in male patients with early-stage ER-positive/HER2-negative breast cancer,” said Shu.

The primary outcome of the study was total mortality, not breast cancer-specific mortality, representing a major limitation of the study. Additionally, the researchers did not have access to detailed treatment information (including treatment compliance) or information about pre-existing health conditions or lifestyle habits, added Shu.

This study was supported by an Ingram Cancer Professorship fund to Shu, and Wang was supported by the China Scholarship Council. Wang and Shu declare no conflicts of interest.

Press Release Published Date: 11/19/2019 10:05 PM

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Long-term Survival Rate for Subset of Patients With Advanced Melanoma Following BRAF- and MEK-targeted Treatment Combination Higher Than Historical Rate

Burns, Matthew — Wed, 13 Nov 2019 11:38:07

PHILADELPHIA — Almost 40 percent of patients with metastatic melanoma harboring BRAF V600E mutations who were treated with a combination of a BRAF-targeted and a MEK-targeted therapeutic and who had not previously been treated with a BRAF-targeted therapeutic were alive after five years of follow-up, according to results published in Clinical Cancer Research, a journal of the American Association for Cancer Research.

According to the National Cancer Institute’s SEER data, the five-year survival rate for metastatic melanoma among patients diagnosed between 2009 and 2015 was 24.8 percent.

Early results from the BRIM7 phase I clinical trial evaluating the BRAF V600E inhibitor vemurafenib (Zelboraf) in combination with the MEK1 inhibitor cobimetinib (Cotellic) in patients with BRAF V600E metastatic melanoma have been previously reported. They showed that 87 percent of patients who received the combination and had not previously been treated with a BRAF-targeted therapeutic had a partial or complete response. This study provides extended follow-up results from the trial, including overall survival (OS) data.

“When this study was initiated, the treatments available yielded long-term benefit at four or five years for only about 10 percent of patients diagnosed with metastatic melanoma,” said Antoni Ribas, MD, professor in the Department of Medicine at University of California in Los Angeles and the Jonsson Comprehensive Cancer Center. “The fact that a subgroup of patients were alive and well at the five-year follow-up mark after this combination treatment is remarkable.”

Ribas is the AACR President-Elect for 2019-2020.

The researchers enrolled two cohorts of patients with advanced BRAF V600E-mutant melanoma. The first cohort, which had 63 patients, had not previously been treated with a BRAF-targeted therapeutic and were referred to as BRAF inhibitor-naïve; the second cohort, which had 66 patients, had progressed on prior treatment with vemurafenib monotherapy. The data cutoff for this follow-up study was May 25, 2018.

At the time of the extended follow-up, the median OS in the BRAF inhibitor-naïve cohort was 31.8 months; the OS rate plateaued at roughly four years of follow-up at 39.2 percent. The median OS for patients who had progressed on prior vemurafenib monotherapy was 8.5 months; the OS rate plateaued at 14 percent at roughly three years of follow-up.

Treatment-related adverse events were similar to those previously reported with this drug combination. However, both cohorts had increases in photosensitivity reactions and actinic keratitis due to longer-term exposure.

“A subset of patients derived long-term benefit from this therapeutic strategy, indicating that targeted therapies are a viable option for patients with BRAF-mutant melanoma,” Ribas said. “With the goal of increasing the number of patients with long-term benefit, clinical trials investigating dual BRAF and MEK inhibition in combination with PD-1 or PD-L1 blocking antibodies are currently underway.”

Some patients may have received PD-1 blockade treatments after experiencing progression during this clinical trial and may have derived long-term benefit from such immunotherapy treatments, representing a limitation of this study, Ribas noted.

This study was funded by F. Hoffmann-La Roche Ltd.

Ribas reports institutional research grants from Genentech; honoraria for consultancy from Genentech, Roche, Chugai Pharmaceutical Co., Novartis, Amgen, Merck, and Bristol-Myers Squibb; and personal fees for advisory roles from Arcus Biosciences, Bioncotech Therapeutics, Compugen, CytomX, Five Prime Therapeutics, FLX Bio, ImaginAb, Kite Pharma, Merus, Rgenix, Tango Therapeutics, and PACT Pharma.

Press Release Published Date: 11/14/2019 10:05 PM

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Antibody-Drug Conjugate Shows Early Promise in Patients with Relapsed/Refractory B-cell Non-Hodgkin Lymphoma

Burns, Matthew — Tue, 29 Oct 2019 11:47:35

PHILADELPHIA — ADCT-402, an investigational antibody-drug conjugate, showed signs of clinical activity in patients with relapsed/refractory B-cell non-Hodgkin lymphoma, according to results from a phase I study published in Clinical Cancer Research, a journal of the American Association for Cancer Research.

An aggressive subtype called diffuse large B-cell lymphoma (DLBCL) accounts for roughly one-third of all new non-Hodgkin lymphoma cases. Approximately 30 to 40 percent of patients with DLBCL relapse after first-line treatment. While some patients with relapsed disease benefit from autologous stem cell transplant or chimeric antigen receptor T-cell (CAR-T) therapy, a subset of patients do not respond to these treatments or are ineligible.

“There is a large unmet need for patients with relapsed/refractory DLBCL, particularly for patients who don’t respond to stem cell transplant or CAR-T,” said Brad S. Kahl, MD, a medical oncologist at Washington University School of Medicine in St. Louis. “There are really no attractive options currently available for those patients.”

Kahl and colleagues tested the safety and clinical activity of an antibody-drug conjugate called loncastuximab tesirine, or ADCT-402, in patients with relapsed/refractory B-cell non-Hodgkin lymphoma. ADCT-402 combines a potent DNA-damaging agent called pyrrolobenzodiazepine (PBD) with a monoclonal antibody directed against CD19.

“CD19 is expressed on the surface of virtually all B-cell lymphomas,” explained Kahl. “Employing an antibody-drug conjugate that targets CD19 is an effective way to target a cytotoxic agent to malignant B cells.”

PBD is more potent than traditional cytotoxic agents, and unlike some other cytotoxic agents, it is not associated with peripheral neuropathy. These are important features for patients with relapsed/refractory disease who may have developed resistance to other cytotoxic agents, or who may have existing peripheral neuropathy from previous treatments, said Kahl, who sees patients at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis.

The study enrolled 88 patients, 18 years of age or older, with relapsed/refractory B-cell non-Hodgkin lymphoma who did not respond to or were ineligible for established therapies. Of these patients, 63 had DLBCL.

Patients received one of several test doses of ADCT-402, administered intravenously, every three weeks. Patients were treated until disease progression or patient withdrawal.

The greatest responses were observed in patients treated at a dose of 120 µg/kg or higher. Of these patients, 40.6 percent had a complete response, and 18.8 percent had a partial response. Of the 51 evaluable patients with DLBCL treated at a dose of 120 µg/kg or higher, 37.3 percent had a complete response, and 17.6 percent had a partial response. Among patients with complete responses, the median duration of response was not reached after a median follow-up of 7.5 months.

“With most of the established treatments, we typically see response rates around 30 percent for DLBCL patients,” said Kahl. “To have a therapy with a higher response rate and some durability would be a great advancement for the field and for these patients. We’re hopeful that ADCT-402 will ultimately prove to be a good addition for this patient population.”

Eighty-seven of the 88 enrolled patients experienced at least one treatment-emergent adverse event (TEAE). The most common TEAEs were low blood cell counts, fatigue, liver-test abnormalities, nausea, rash, shortness of breath, and tissue swelling. Sixty-five of the 88 patients experienced a TEAE of grade 3 or higher, including low blood cell counts, liver test abnormalities, fatigue, and shortness of breath. Seven patients had a TEAE with a fatal outcome due to disease progression, according to Kahl.

Based on the results of this phase I study, a dose of 150 µg/kg was selected for an ongoing phase II trial, which recently completed enrollment. In an attempt to mitigate some of the TEAEs, patients in the phase II study will receive fewer doses and will be pre-medicated with a low-dose steroid to reduce inflammation, explained Kahl.

A limitation to the phase I study was that each dose cohort contained a relatively small number of patients, said Kahl.

This study was funded by ADC Therapeutics. Kahl has received support from ADC Therapeutics and has consulted for Seattle Genetics and Genentech.

Press Release Published Date: 11/3/2019 10:05 PM

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AACR Applauds Nomination of Stephen M. Hahn, MD, as FDA Commissioner

Burns, Matthew — Fri, 1 Nov 2019 09:38:42

PHILADELPHIA — The American Association for Cancer Research (AACR), the world’s first and largest cancer research organization dedicated to the prevention and cure of cancer, congratulates Stephen M. Hahn, MD, on his nomination as Commissioner of the U.S. Food and Drug Administration (FDA). Hahn is a renowned expert in radiation oncology and research, an experienced and highly effective administrator, and an innovative leader.

“I have seen firsthand Dr. Hahn’s extraordinary dedication and commitment to cancer patients, and the AACR is extremely confident that he will be an outstanding leader for the FDA,” said Margaret Foti, PhD, MD (hc), chief executive officer of the AACR. “Dr. Hahn, who is board certified in both radiation and medical oncology, is esteemed for the breadth and depth of his scientific knowledge and expertise, and he has consistently advocated for a drug review process at the FDA that is both science-directed and patient-focused.”

Hahn has been a member of the AACR since 1999. He served as an inaugural member of the AACR Radiation Science and Medicine Working Group Steering Committee and the AACR Radiation Oncology Task Force. Hahn has also served as a member of other AACR committees. He served with distinction in 2018 as cochair of the Workshop on Clinical Development of Drug-Radiotherapy Combinations held in partnership with the FDA, the AACR, and the American Society for Radiation Oncology (ASTRO).

“The unprecedented research opportunities that exist today, coupled with our rapidly improving ability to translate these scientific advances into improved treatments for patients, require an experienced and visionary leader at the FDA,” said AACR President Elaine R. Mardis, PhD, co-executive director of the Institute for Genomic Medicine at Nationwide Children's Hospital. “Dr. Hahn’s impressive qualifications make him ideally positioned to succeed at the FDA, and the AACR looks forward to working with him upon his confirmation.”

Hahn is currently chief medical executive of The University of Texas MD Anderson Cancer Center in Houston and was formerly chair of radiation oncology at the University of Pennsylvania School of Medicine in Philadelphia. He is the author of more than 200 peer-reviewed journal articles and other publications.

“For several years, I served with Dr. Hahn on a National Cancer Institute study section, and I always found him to be an extremely thoughtful and science-oriented grant reviewer,” said AACR President-Elect Antoni Ribas, MD, PhD, professor of Medicine at the David Geffen School of Medicine at the University of California Los Angeles. “He has always put the interests of patients first, by embracing the importance of regulatory science to truly inform and improve the way new cancer medicines are evaluated for safety and efficacy.”

“As acting commissioner, Dr. Sharpless served skillfully in this capacity, and the entire scientific and patient care community owes him a tremendous debt of gratitude for his outstanding oversight of the FDA,” said Foti.

Press Release Published Date: 11/1/2019 10:50 AM

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