News Releases Elderly Survivors of Three Common Cancers Face Persistent Risk of Brain Metastasis https://www.aacr.org/Newsroom/Pages/News-Release-Detail.aspx?ItemID=1318

PHILADELPHIA — Elderly survivors of breast cancer, lung cancer, and melanoma face risk of brain metastasis later in life, and may require extra surveillance in the years following initial cancer treatment, according to results of a study published in Cancer Epidemiology, Biomarkers, & Prevention, a journal of the American Association for Cancer Research. 

“As cancer treatments have gotten better and more people are surviving a primary cancer diagnosis, it’s important to study secondary cancers, including metastasis to the brain,” said the study’s senior author, Jill S. Barnholtz-Sloan, PhD, Sally S. Morley Designated Professor in Brain Tumor Research, Cleveland Institute for Computational Biology and Department of Population and Quantitative Health Sciences at Case Western Reserve University School of Medicine in Cleveland. “With an aging U.S. population, the number of people with brain metastasis is increasing, although sometimes that metastasis does not occur until many years after the initial cancer diagnosis.”

“As people are living longer after an initial cancer diagnosis, their ‘time at risk’ for metastasis is going up. In addition, the majority of primary cancer diagnoses have no standard of care for brain metastasis screening,” said the study’s first author, Mustafa S. Ascha, MS, a PhD candidate in the Center for Clinical Investigation, Department of Population and Quantitative Health Sciences at Case Western. 

In this study, researchers analyzed rates of synchronous brain metastases (SBM), those diagnosed during the staging workup for the primary cancer, and lifetime brain metastases (LBM), those diagnosed later in life. Primary cancers in this study were lung cancer, breast cancer, and melanoma, which are more likely to metastasize to the brain than many other cancer types.

The researchers linked data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database to Medicare claims data on brain metastases to investigate rates of brain metastasis in elderly patients. Because Medicare is the primary insurer for most patients age 65 or older, the results of SEER-Medicare studies are generalizable to the elderly population, Barnholtz-Sloan explained. Final data included patients diagnosed in 2010 through 2012, with 70,974 lung cancer cases, 67,362 breast cancer cases, and 21,860 melanoma cases. 

The researchers calculated incidence proportion, the ratio of brain metastases counts to the total number of cases, for each primary cancer. 

For primary lung cancer, the incidence proportion of SBM was 9.6 percent and for LBM, 13.5 percent. The highest rates of metastasis were in small-cell and non-small-cell lung carcinoma, compared with adenocarcinoma, a more common type of lung cancer.

For primary breast cancer, the incidence proportion of SBM was 0.3 percent and for LBM, 1.8 percent. The rates of brain metastasis were lowest among patients who had localized breast tumors and highest among those whose cancer had already spread to another part of the body. The rates also varied by molecular subtype, with the highest rates for triple-negative breast cancer.

For melanoma, the incidence proportion of SBM was 1.1 percent and for LBM, 3.6 percent. Rates rose dramatically for patients whose melanoma had already spread at the time of diagnosis; 30.4 percent of those who had distant disease at diagnosis would later develop brain metastasis, compared with 15.2 percent of those who had regional and lymph node involvement, 13.2 percent who had lymph node involvement only, 7.8 percent who had regional tissue involvement, and 2.5 percent among those who had localized disease. 

Barnholtz-Sloan and Ascha said that the results of the study could help clinicians better understand patients’ risk for brain metastasis and could potentially influence screening and surveillance practices. 

“Brain metastases are detected with MRI, which is very expensive,” Barnholtz-Sloan said. “An improved understanding of who is likely to develop a brain metastasis could help determine who should get an MRI.” 

Ascha added that more targeted surveillance could potentially help physicians detect metastases at early stages. “If we can identify brain metastases earlier in their progression, that could allow for earlier treatment and improved outcomes for these patients,” he said.

The authors said the study’s primary limitation is that Medicare data, while providing a comprehensive view of the elderly population, cannot always be generalized to younger patients. Also, the study encompassed four to five years of follow-up, whereas in some cancers, such as breast cancer, brain metastasis can occur decades after the initial cancer, Barnholtz-Sloan said. 

This study was supported in part through support to the Central Brain Tumor Registry of the United States, which receives funding from the American Brain Tumor Association, The Sontag Foundation, Novocure, AbbVie, the Musella Foundation, and the Centers for Disease Control and Prevention. The authors declare no conflicts of interest. 

Press Release Published Date: 5/2/2019 8:05 PM
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Riley, CharmaineFri, 3 May 2019 12:26:08
“Innovation in Collaboration” among Research Teams Rewarded by Grants from Stand Up To Cancerhttps://www.aacr.org/Newsroom/Pages/News-Release-Detail.aspx?ItemID=1317

​PHILADELPHIA – May 2, 2019 – Stand Up To Cancer (SU2C) announced five new awards today drawing on the strengths of existing research activities to explore cross-cutting questions that have the potential of opening new paths to improved cancer treatment, according to the American Association for Cancer Research, SU2C’s Scientific Partner. 

“These new studies bring together outstanding researchers from different teams to make use of the extraordinary talent we have across the SU2C community,” said Arnold J. Levine, PhD, vice chair of the SU2C Scientific Advisory Committee (SAC). “We’re building on previous research at the same time we are tackling tough new questions,” said Levine, who is also professor emeritus of systems biology at the Institute for Advanced Study in Princeton, New Jersey. 

The Phillip A. Sharp Awards for Innovation in Collaboration are named for Phillip A. Sharp, PhD, Nobel laureate and molecular biologist at MIT who serves as chairperson of the SAC, in recognition of his relentless emphasis on collaboration across research institutions and among different teams as a way to bring fresh perspectives to questions in cancer research. 

The grant program is unique in its speed and simplicity. Scientists attending the annual SU2C Scientific Summit in Santa Monica, California, are invited to submit applications consisting of a 250-word outline of their idea. A committee meets the next morning to review the applications, and the preliminary winners are announced that afternoon. Each winning team submits a more detailed application before the grant is confirmed.

“I’ve always believed that it is essential to bring the best minds together, regardless of institutional imperatives, to work together and try to solve the questions that will help us overcome cancer,” Levine said. 

“This is the fastest peer-reviewed grant application process I’ve ever heard of,” Levine said. “But we have been very pleased with the results.” The program is now in its sixth year. 

The leaders of each team cannot be from the same existing SU2C research team. The inclusion of early-career investigators in the team is also encouraged, another distinctive SU2C touch. 

A special award was funded this year by the Emily Whitehead Foundation, named for the first pediatric patient to receive chimeric antigen receptor (CAR) T-cell therapy for leukemia. Emily was 7 years old when she received the groundbreaking treatment in 2011, and is thriving today with no evidence of disease. 

“We are pleased to continue our collaboration with SU2C and fund these extraordinary teams focused on pediatric cancer immunotherapy treatments,” said Tom Whitehead, co-founder of the Emily Whitehead Foundation. “We know collaborative research is essential to lead to successful, less toxic treatments that will give more kids the chance to not only survive their cancer but thrive, healthy and happy.”

Details including the leaders, title of their project, and term and funding for the grant:

  • Alan D’Andrea, MD, Dana-Farber Cancer Institute, leader of a Pancreatic Cancer Collective New Therapies Challenge Research Team: Exploiting DNA-Repair Gene Mutations in Pancreatic Cancer, and Juan Cubillos-Ruiz, PhD, Weill Cornell Medicine, 2016 SU2C Innovative Research Grant recipient: Resistance to PARP inhibitor plus anti-PD1 therapy driven by ER stress and bioactive lipids in ovarian cancer. This team will evaluate gene signatures controlled by phospholipid messengers and ER stress in responding and non-responding patients, and will utilize tumor organoids to test whether pharmacological inhibition of these pathways can render ovarian tumors susceptible to treatment. Two-year grant; total funding $250,000. 
  • Denada Dibra, PhD, The University of Texas MD Anderson Cancer Center, young investigator in the laboratory of SU2C SAC member Guillermina (Gigi) Lozano, PhD, and Peter P. Lee, MD, City of Hope National Medical Center, SU2C Breast Cancer Convergence Research Team: Uncovering mutant TP53 dependencies in spontaneously arising triple-negative breast cancer. This team will use novel mouse models to study how the TP53 tumor suppressor gene may influence the tumor microenvironment, and to characterize both tumor cells and immune cells that may be present within the tumor tissue. One-year grant; total funding $250,000. 
  • Maximilian Diehn, MD, PhD, Stanford University School of Medicine, co-leader of the SU2C-LUNGevity-American Lung Association Lung Cancer Interception Research Team, and Aaron Hata, MD, PhD, Massachusetts General Hospital Cancer Center, investigator on the SU2C-American Cancer Society Lung Cancer Dream Team and a member of the SU2C–National Science Foundation Lung Cancer Convergence Research Team:  Non-invasive monitoring of tumor phenotype by interrogation of plasma cell-free RNA. While circulating tumor DNA (ctDNA) analysis allows non-invasive tumor genotyping, it is unable to assess non-genomic features of tumors such as gene expression. This team seeks to develop a novel method for analyzing cell-free RNA (cfRNA) associated with resistance to tyrosine kinase inhibitors (TKIs) in patients with non-small cell lung cancer, to develop a non-invasive approach to better characterize tumors and detect changes in cancer phenotypes during treatment. Two-year grant; total funding $225,000. 
  • Sarah Tasian, MD, Children's Hospital of Philadelphia, young investigator on the St. Baldrick’s Foundation-SU2C Pediatric Cancer Dream Team, and Kimberly Stegmaier, MD, Dana-Farber Cancer Institute, 2009 Innovative Research Grant recipient, will now team up in this new SU2C Sharp Award: Precision combinatorial immunotherapeutic targeting of thymic stromal lymphopoietin receptor (TSLPR) signaling in pediatric and young adult CRLF2-rearranged ALL. This team will test a novel hypothesis that multi-antigen-specific CAR T cells targeting two or more neoantigens presented by the cancer cells will have superior anti-leukemia efficacy in preclinical models of childhood Down Syndrome-associated ALL and Ph-like ALL, prevent resistance mechanisms observed with single antigen-targeted CAR T cells, and facilitate more durable leukemia remissions in these medically fragile populations. Two-year grant; total funding $250,000. This grant was funded with support from the Emily Whitehead Foundation.
  • Robert H. Vonderheide, MD, DPhil, University of Pennsylvania Abramson Cancer Center, leader of a Pancreatic Cancer Collective New Therapies Challenge Research Team, and Vinod P. Balachandran, MD, Memorial Sloan Kettering Cancer Center, SU2C Pancreatic Cancer Convergence Team co-leader: Antigenicity of mutant KRAS and impact on cancer evolution. The team will combine expertise in immunobiology and computational biology to analyze three unique, clinically curated datasets, including short- and long-term pancreatic cancer survivors, primary resected pancreatic cancers, and mKRAS lung and colon cancers, to investigate how mKRAS immunogenicity may dictate outcomes. Two-year grant; total funding $225,000. 
Press Release Published Date: 5/2/2019 9:00 AM
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Riley, CharmaineThu, 2 May 2019 12:33:56
Quitting Smoking is Associated With Reduced Risk of Bladder Cancer in Postmenopausal Womenhttps://www.aacr.org/Newsroom/Pages/News-Release-Detail.aspx?ItemID=1316

​PHILADELPHIA —A large study of postmenopausal women indicated that quitting cigarette smoking was associated with significantly reduced risk of bladder cancer. The most significant reduction in risk occurred in the first 10 years after quitting, with a modest but continued decline in later years, according to results published in Cancer Prevention Research, a journal of the American Association for Cancer Research.

Although bladder cancer is a fairly rare cancer type, representing an estimated 4.6 percent of new cancer cases in 2019, “it is the most common malignancy of the urinary system, with high recurrence rate and significant mortality,” said the study’s lead author, Yueyao Li, MSPH, MD, a PhD candidate in the Department of Epidemiology and Biostatistics, School of Public Health, Indiana University in Bloomington. 

“Smoking is a well-established risk factor for bladder cancer, but findings on the relationship between duration of smoking cessation and the reduction in bladder cancer risk are inconsistent,” Li continued. She added that while bladder cancer is more common in men, women often have worse outcomes, even when diagnosed at similar stages. 

In this study, Li and colleagues sought to analyze the dose-response relationship between time since quitting smoking and risk of bladder cancer among postmenopausal women, and to investigate whether risk among former smokers ever normalized to the risk faced by those who never smoked. 

The researchers examined data from the Women’s Health Initiative, a long-term national health study of postmenopausal women. They included data from 143,279 women, all of whom had supplied information on whether they had ever smoked cigarettes, how much they had smoked, and whether they were current smokers. In all, 52.7 percent of the women were categorized as “never smokers,” 40.2 percent as former smokers, and 7.1 percent as current smokers. 

As of Feb. 28, 2017, the researchers had identified 870 cases of bladder cancer. The study showed that, in comparison to never smokers, former smokers had twice the risk of bladder cancer, and current smokers had more than three times the risk.

The researchers performed analysis using various statistical models to analyze the association between years since quitting smoking and the risk of bladder cancer, and to account for variables such as education, race/ethnicity, BMI, and dietary factors. They found that the steepest reduction in risk occurred in the first 10 years after quitting smoking, with a 25 percent drop. The risk continued to decrease after 10 years of quitting, but even after 30 or more years since quitting smoking, risk remained higher for women who had smoked than those who never did. 

However, in time-updated models that reflected those who stopped smoking during the study period, the researchers found that compared with women who continued to smoke, those who quit smoking during the follow-up years had a 39 percent decrease in bladder cancer risk, and the risk continued to decline over time.

Li said that while the biological mechanisms of the association between bladder cancer and smoking are not known, the study results indicate that women of any age should be discouraged from smoking, and even those who have smoked for many years stand to benefit from quitting.  

“Our study emphasizes the importance of primary prevention (by not beginning to smoke) and secondary prevention (through smoking cessation) in the prevention of bladder cancer among postmenopausal women,” Li said. “Current smokers should be advised to quit smoking in order to reduce the risk of bladder cancer.” 

Li cautioned that the study was based on postmenopausal women, so results may not be fully generalizable. Also, exposure to smoking was self-reported. 

This study was funded by the National Heart, Lung, and Blood Institute, the National Institutes of Health, and the U.S. Department of Health and Human Services. Li declares no conflicts of interest.

Press Release Published Date: 4/30/2019 8:05 PM
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Riley, CharmaineWed, 1 May 2019 09:21:08
An EGLN Inhibitor Protects Normal Tissues and Enables High-dose Radiation Therapy in a Mouse Model of Unresectable Pancreatic Cancerhttps://www.aacr.org/Newsroom/Pages/News-Release-Detail.aspx?ItemID=1315

​PHILADELPHIA — Administration of the EGLN inhibitor FG-4592 prior to ablative radiotherapy provided protection against fatal gastrointestinal bleeding and improved survival in a mouse model of unresectable pancreatic cancer, according to results published in Cancer Research, a journal of the American Association for Cancer Research.

Surgery is required for the curative treatment of pancreatic cancer, yet the majority of patients with this disease have unresectable tumors, said Cullen Taniguchi, MD, PhD, assistant professor of radiation oncology at The University of Texas MD Anderson Cancer Center. While radiation therapy may be a future alternative to surgery in this patient population, the required dose of radiation to effectively treat the disease can damage the neighboring organs, which can lead to gastrointestinal bleeding and even death, he explained. “This study was conducted to understand if it was possible to protect the bowels from radiation damage in order to give enough radiation to effectively treat unresectable pancreatic cancer,” he said.

“Our proof-of-concept study illustrates that higher doses of radiation therapy can improve outcomes in unresectable pancreatic cancer as long as treatment toxicity is reduced with a radiation protector,” said Taniguchi. “As toxicity is a major limiting factor of cancer treatment, protecting normal tissues from radiation damage is an important concept in the field of oncology that warrants additional attention.”

Hypoxic cells induce a powerful regenerative response, resulting in the protection of tissue, Taniguchi said. “Inhibition of EGLN mimics hypoxia, allowing us to take advantage of the healing response of this phenomenon without actually depriving the cell of oxygen,” he explained. 

Tumor hypoxia is a feature of many cancerous cells that can lead to disease progression and metastasis and is especially prevalent in pancreatic cancer, Taniguchi noted. The researchers found that murine pancreatic tumors were already highly hypoxic and adding FG-4592 did not induce further hypoxia; however, in normal murine tissues, which are not hypoxic, adding the EGLN inhibitor effectively mimicked hypoxia and protected the tissue.  

To determine if administration of FG-4592 could improve survival following ablative radiation therapy, the researchers assigned 70 mice bearing spontaneous, palpable pancreatic tumors one of four treatments: vehicle only, FG-4592 only, vehicle plus radiotherapy, and FG-4592 plus radiotherapy. FG-4592 and vehicle were administered orally, and radiotherapy treatments consisted of 15 fractions to a limited tumor field totaling 75 Gray.

Overall, mice treated with radiotherapy with prior radioprotection via FG-4592 had the highest median overall survival (43 days); no gastrointestinal bleeding was observed. Mice treated with radiotherapy without radioprotection had decreased median overall survival (36 days), and fatal gastrointestinal bleeding was observed in 56 percent of mice in this cohort. The difference in overall survival between these two groups was statistically significant.

Among mice that did not receive radiotherapy, treatment with FG-4592 increased the median overall survival compared to vehicle alone (29 days versus nine days, respectively).

“The fact that treatment with FG-4592 alone increased survival in mice harboring pancreatic cancer was a surprising finding,” said Taniguchi. “We are actively investigating this result, and one preliminary hypothesis is that EGLN inhibition may modulate the immune system and contribute to this therapeutic effect.

“While we utilized EGLN inhibitors in our study, we want to emphasize that radioprotection is not limited to this class of drugs,” noted Taniguchi. “We hope that our results stimulate more research in this area.”

Taniguchi noted that a major limitation in this preclinical mouse study was that no chemotherapy was administered, which would be considered standard of care in humans before the initiation of radiotherapy. “In this preliminary study, we felt that the addition of chemotherapy might complicate the key question of whether we could give an ablative dose of radiation to pancreatic tumors without lethally damaging the small bowel,” Taniguchi explained. “As such, future experiments with clinically relevant chemotherapy, such as FOLFIRINOX or gemcitabine, will need to be conducted in mice before initiating a clinical trial,” he added.

This study was supported by funding from the Cancer Prevention & Research Institute of Texas, the V Foundation, the Sidney Kimmel Foundation, the Sabin Family Foundation Fellowship, the McNair Foundation, and the National Cancer Institute.

Taniguchi declares no conflict of interest.

Press Release Published Date: 4/29/2019 8:05 PM
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Riley, CharmaineTue, 30 Apr 2019 09:16:24
AACR Honors Dr. Elaine Fuchs With 2019 AACR-G.H.A. Clowes Memorial Awardhttps://www.aacr.org/Newsroom/Pages/News-Release-Detail.aspx?ItemID=1314

PHILADELPHIA — The American Association for Cancer Research (AACR) has awarded the 59th AACR-G.H.A. Clowes Memorial Award to Elaine Fuchs, PhD. The award was presented during the AACR Annual Meeting 2019, held March 29-April 3, 2019, in Atlanta.

The AACR and Eli Lilly and Company established the AACR-G.H.A. Clowes Memorial Award in 1961 to honor Dr. G.H.A. Clowes, who was a founding member of the AACR and a research director of Eli Lilly. This prestigious award serves to honor Dr. Clowes’ legacy by recognizing an individual with outstanding recent accomplishments in basic cancer research.

Fuchs was recognized for her paradigm-shifting work dedicated to characterizing how normal skin stem cells maintain homeostasis, participate in wound repair, and contribute to cancer onset and progression. Collectively, her seminal research has greatly contributed to the understanding of mammalian skin, skin stem cells, and skin-related diseases, particularly proinflammatory disorders and cancer. She delivered her award lecture, titled “Stem Cells in Wound Repair, Inflammation and Cancer,” on Monday, April 1, at the Georgia World Congress Center in conjunction with the AACR Annual Meeting 2019. 

Fuchs is the Rebecca C. Lancefield professor and head of the Laboratory of Mammalian Cell Biology and Development at The Rockefeller University in New York, and an investigator of the Howard Hughes Medical Institute.

“Dr. Fuchs is an extraordinary scientist, contributing knowledge not only to cancer research, but to other disciplines including cell biology, genetics, and dermatology,” said Margaret Foti, PhD, MD (hc), chief executive officer of the AACR. “Her pioneering work on the biology of skin stem cells and their behavior in human diseases has had far-reaching implications in these fields, and the AACR is honored to recognize her with this award.”

Fuchs is highly regarded for her studies involving reverse genetics geared toward understanding the fundamental processes governing both normal and abnormal skin development and function. Among her important research discoveries has been the elucidation of the molecular mechanisms underlying the ability of skin stem cells to produce the epidermis and its appendages, including hair follicles as well as sweat and oil glands. She has also extensively defined how normal skin stem cell biology can be deregulated in skin cancers and other hyperproliferative disorders of the skin.

Fuchs was named one of the inaugural Fellows of the AACR Academy in 2013. She has received many additional honors throughout her career, including the McEwen Award for Innovation (2017), the Vanderbilt Prize (2017), the E.B. Wilson Award (2015), the Pezcoller Foundation-AACR International Award for Extraordinary Achievement in Cancer Research (2014), the Kligman-Frost Leadership Award from the Society of Investigative Dermatology (2013), the Pasarow Award for Cancer Research (2013), the March of Dimes Prize (2012), the Albany Prize in Medicine (2011), the AACR-Women in Cancer Research Charlotte Friend Memorial Lectureship (2010), the L’Oréal-UNESCO Award (2010), and the National Medal of Science (2009). She is an elected member of the European Molecular Biology Organization (2010), American Philosophical Society (2005), National Academy of Sciences (1996), Institute of Medicine (1994), and American Academy of Arts and Sciences (1994). 

Fuchs received her bachelor’s degree in chemistry from the University of Illinois at Urbana-Champaign, and her doctorate at Princeton University in Princeton, New Jersey. She was a postdoctoral fellow at the Massachusetts Institute of Technology in Boston. Fuchs was the Amgen professor of basic sciences at the University of Chicago before joining Rockefeller University in 2002. 

Press Release Published Date: 4/29/2019 6:00 AM
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Cohn, SarahMon, 29 Apr 2019 10:22:18
Rates of Physician-Patient Discussions About Lung Cancer Screening Very Low and Declininghttps://www.aacr.org/Newsroom/Pages/News-Release-Detail.aspx?ItemID=1312

​PHILADELPHIA — Low rates of physician-patient discussions about lung cancer screening have declined further since 2012 and were not associated with current smokers’ intents or attempts to quit smoking, according to results published in Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research.

In 2017, the prevalence of patient-physician discussions about lung cancer screening was only 4.3 percent in the general population and 8.7 percent among current smokers, down from 6.7 percent and 12.0 percent respectively in 2012. 

“The low prevalence of discussions about lung cancer screening and lack of association with smokers’ intents and attempts to quit are surprising,” said Jinhai (Stephen) Huo, PhD, MD, MSPH, assistant professor in the Department of Health Services Research, Management and Policy at the University of Florida. “Our results suggest that lung cancer screening is substantially underutilized and not reaching high-risk smokers who would benefit the most.” 

Lung cancer is the leading cause of cancer-related death in women and men in the United States and worldwide. Since 2011, three events in support of lung cancer screening took place: In 2011, the National Lung Screening Trial (NLST), the largest trial of lung cancer screening ever conducted, demonstrated that low-dose computed tomography (CT) scan reduced lung cancer mortality by 20 percent; in 2013, the United States Preventive Services Task Force issued a recommendation for lung cancer screening; and, in 2015, the Centers for Medicare & Medicaid Services released a lung cancer screening policy. 

Huo and colleagues analyzed data from the National Cancer Institute’s Health Information National Trends Survey (HINTS) in 2012, 2014, and 2017, right after the three events. The HINTS survey included questions on whether a respondent had talked with their doctor about having a test to check for lung cancer in the past year and their smoking status. 
 
The researchers analyzed the prevalence of physician-patient discussions about lung cancer screening by age group, smoking status, insurance coverage, and ethnicity. Current smokers were defined as people who had smoked at least 100 cigarettes in their lifetime and were smoking cigarettes every day or some days at the time of the survey; former smokers as those who had smoked previously but did not smoke at the time of the survey; and never smokers as those who had smoked no cigarettes or less than 100 over their lifetime. Huo noted that lung cancer screening is effective in reducing lung cancer mortality in specific populations — current or former heavy smokers ages 55 to 77 with a 30-year history of smoking, or smokers with a 20-pack-year history of smoking and other risk factors for lung cancer, such as a family history of disease or environmental exposure. (A pack-year is calculated by multiplying the number of packs of cigarettes smoked per day by the number of years a person has smoked.) 

Among 9,433 individuals surveyed, the overall prevalence of lung cancer screening discussions was very low and decreased significantly from 6.7 percent in 2012 to 4.3 percent in 2017. Further analysis by age and smoking status revealed that the highest discussion rates in 2017 were for current smokers older than 74 years (22.1 percent), current smokers aged 55 to 74 (17.9 percent), and former smokers older than 74 years (16.3 percent).  Among current smokers, patients more likely to have engaged in discussions with physicians were non-Hispanic Blacks, Hispanics, patients covered by insurance, and those diagnosed with heart or lung disease.  

Multivariable analysis determined that discussions about lung cancer screening were not associated with current smokers’ intents to quit smoking in the next six months or attempts to quit in the past year. 

“More physicians need to initiate a shared decision-making process with their patients who want to have or are eligible for lung cancer screening to reduce the risk of mortality associated with lung cancer,” said Huo. “For eligible high-risk smokers, a low-dose CT scan can reduce the risk of mortality. For moderate- and low-risk smokers, there is no clinical evidence demonstrating that the benefits of screening outweigh the harms. However, smoking cessation discussions should still be taking place as a high priority.” 

The main limitation of the study is that it did not include pack-year smoking history. As a result, the researchers were not able to classify survey respondents by eligibility criteria for lung cancer screening. Other limitations include lack of detail about the content of lung cancer screening discussions, physicians’ knowledge and attitudes about lung cancer screening, and the availability of screening programs where discussions occurred. 

The study was supported by the University of Florida Health Cancer Center Research Pilot Grant through the Florida Consortium of National Cancer Institute Centers Program at the University of Florida. Huo declares no conflicts of interest.

Press Release Published Date: 4/24/2019 8:05 PM
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Riley, CharmaineThu, 25 Apr 2019 09:03:31
Six Factors May Predict Invasive Breast Cancer Recurrence after Ductal Carcinoma in Situ Diagnosishttps://www.aacr.org/Newsroom/Pages/News-Release-Detail.aspx?ItemID=1313

​PHILADELPHIA — Six factors were associated with invasive recurrence of breast cancer after a diagnosis of ductal carcinoma in situ (DCIS), according to data from a meta-analysis published in Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research.

Current guidelines recommend surgical excision of DCIS, often followed by radiotherapy and sometimes endocrine therapy, yet most cases will likely not progress or become life-threatening. As a result, many women are overtreated. “There is a large unmet need to distinguish harmless from potentially hazardous DCIS,” said senior author of the study Jelle Wesseling, MD, PhD, professor of breast pathology in the divisions of diagnostic oncology and molecular pathology at the Netherlands Cancer Institute and Leiden University Medical Center. “We hope our work will help reduce the burden of intensive treatment that thousands of women with low-risk DCIS undergo annually.” 

Wesseling, lead author and PhD student Lindy Visser, and colleagues performed a systematic review of 1,781 studies from the PubMed database from 1970 to June 2018 to assess the risk of ipsilateral (same side) invasive breast cancer recurrence in women primarily diagnosed and treated for DCIS. Forty studies met the eligibility criteria of including at least ten invasive breast cancer events and at least one year of follow-up. 

Next, the researchers used the Quality in Prognosis Studies (QUIPS) tool to assess the studies for risk of bias and identified 17 studies for inclusion in this study. Finally, the researchers performed meta-analyses on all factors associated with the recurrence of invasive breast cancer reported by more than one of these 17 high-quality studies and calculated the average effect size for each factor. 

The number of patients in the included studies ranged from 52 to 37,692, and mean follow-up time ranged from 3.2 to 15.8 years.

Among 26 prognostic factors, Wesseling and colleagues identified six that were associated with a 36 to 84 percent increase in the relative risk of recurrence of invasive disease after DCIS diagnosis: African-American race, premenopausal status, detection by palpation, involved margins, high histological grade, and high p16 protein expression. 

Wesseling noted that data obtained using histological grade as a factor needs careful interpretation because of potential differences in evaluation between observers.

The investigators found that insufficient handling of confounding factors, especially treatment for DCIS, and poorly described study groups were the two most frequently occurring biases identified using QUIPS. “We were aware of the high frequency of biases among previous studies. Some biases are inevitable, as it can be difficult to establish fully annotated cohorts, but others are easy to prevent,” said co-senior author of the study Marjanka Schmidt, PhD, genetic epidemiologist at the Netherlands Cancer Institute. “Our goal was to increase awareness and help the research community avoid these biases in the future.

“New studies need to capture information about whether the cancer recurrence was DCIS or a subsequent invasive cancer and whether these are true recurrences or new, primary lesions,” Wesseling added.

The main limitation of the study was that it was not possible to assess all prognostic factors since they were not reported uniformly in all studies. As a result, future research may identify more prognostic factors that help guide treatment decisions for women diagnosed with DCIS, Wesseling said. 

The study was funded by Cancer Research UK and the Dutch Cancer Society. The authors declare no conflict of interest. 


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Riley, CharmaineThu, 25 Apr 2019 09:05:04
A Deep-learning Model May Help Predict Lung Cancer Survival and Outcomeshttps://www.aacr.org/Newsroom/Pages/News-Release-Detail.aspx?ItemID=1311

​PHILADELPHIA — A deep-learning model developed using serial image scans of tumors from patients with non-small cell lung cancer (NSCLC) predicted treatment response and survival outcomes better than standard clinical parameters, according to results published in Clinical Cancer Research, a journal of the American Association for Cancer Research.

“Our research demonstrates that deep-learning models integrating routine imaging scans obtained at multiple time points can improve predictions of survival and cancer-specific outcomes for lung cancer,” said Hugo Aerts, PhD, director of the Computational and Bioinformatics Laboratory at the Dana-Farber Cancer Institute and Brigham and Women’s Hospital, and an associate professor at Harvard University. “By comparison, a standard clinical model relying on stage, gender, age, tumor grade, performance, smoking status, and tumor size could not reliably predict two-year survival or treatment response.” 

Lung cancer is the most common cancer and the leading cause of cancer death worldwide. NSCLC accounts for about 85 percent of all lung cancers. The standard assessment for diagnosis and response to therapy for these patients relies heavily on the measurement of maximum tumor diameter, which is susceptible to variations in interpretation between observers and over time.  

To see if they could extract more predictive insights as cancers evolve, Aerts and colleagues built deep-learning models. They transferred learning from ImageNet, a neural network created by researchers at Princeton University and Stanford University that identifies a wide range of ordinary objects from the most relevant features, and trained their models using serial CT scans of 179 patients with stage 3 NSCLC who had been treated with chemoradiation. They included up to four images per patient obtained routinely before treatment and at one, three, and six months after treatment for a total of 581 images. 

The investigators analyzed the model’s ability to make significant cancer outcome predictions with two datasets: the training dataset of 581 images and an independent validation dataset of 178 images from 89 patients with non-small cell lung cancer who had been treated with chemoradiation and surgery.

The models’ performance improved with the addition of each follow-up scan. The area under the curve, a meaure of the model’s accuracy, for predicting two-year survival based on pretreatment scans alone was 0.58, which improved significantly to 0.74 after adding all available follow-up scans. Patients classed as having low risk for mortality by the model had six-fold improved overall survival compared with those classed as having high risk.

Compared with the clinical model that utilizes parameters of stage, gender, age, tumor grade, performance, smoking status, and clinical tumor size, the deep-learning model was more efficient in predicting distant metastasis, progression, and local regional recurrence.

“Radiology scans are captured routinely from lung cancer patients during follow-up examinations and are already digitized data forms, making them ideal for artificial intelligence applications,” said Aerts. “Deep-learning models that quantitatively track changes in lesions over time may help clinicians tailor treatment plans for individual patients and help stratify patients into different risk groups for clinical trials.” 

The main limitation of this proof-of-principle research is that it needs to be expanded with more data and evaluated in prospective clinical trials, said Aerts. 

The study was supported by grants from the National Institutes of Health. Aerts reports shares from Genospace and Sphera, unrelated to this research.

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Riley, CharmaineMon, 22 Apr 2019 09:50:38
AACR Names New Editor-in-chief of Cancer Epidemiology, Biomarkers & Prevention https://www.aacr.org/Newsroom/Pages/News-Release-Detail.aspx?ItemID=1310

PHILADELPHIA — The American Association for Cancer Research (AACR) is pleased to announce the appointment of Elizabeth A. Platz, ScD, MPH, as editor-in-chief of Cancer Epidemiology, Biomarkers & Prevention, one of eight highly esteemed journals published by the AACR. She officially began her term as editor-in-chief on Jan. 1. 

Cancer Epidemiology, Biomarkers & Prevention (CEBP) publishes original population-based research on cancer etiology, prevention, surveillance, and survivorship.

“The American Association for Cancer Research is happy to welcome Dr. Platz as editor-in-chief of Cancer Epidemiology, Biomarkers & Prevention,” said Margaret Foti, PhD, MD (hc), chief executive officer of the AACR. “With more than 20 years of experience in the field of cancer epidemiology, Dr. Platz has worked extensively to integrate epidemiology and basic science to inform prevention and treatment strategies. Her vision for the journal will build on its past successes and continue to advance its reputation as the top cancer research journal in the area of population science.”

Platz is professor and deputy chair of the Department of Epidemiology at Johns Hopkins Bloomberg School of Public Health and co-leader of the Cancer Prevention and Control Program at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. Her work focuses on the use of molecular and genetic epidemiology approaches in understanding the mechanisms underlying prostate cancer incidence and progression. Also known for her leadership of multidisciplinary prostate cancer research teams, she is at the forefront of epidemiologic research on the role of  inflammation in the development of prostate cancer, and on telomere length as a prognostic marker for poor outcome after treatment for prostate cancer. She was also appointed by the governor to the Maryland State Council on Cancer Control and is a member and former chair of the Maryland Cancer Collaborative, a group charged with prioritizing and implementing strategies from the state’s Comprehensive Cancer Control Plan.

Platz has been an active member of the AACR since 1998, having served as an editorial board member of the AACR journal Cancer Research and, more recently, as a senior editor of Cancer Epidemiology, Biomarkers & Prevention before being named editor-in-chief. She has served on scientific program committees for many AACR meetings, including the AACR Annual Meeting. 

“As an editor, I have always pursued excellence, including ensuring the quality of reviews provided to authors and the timeliness of these reviews,” Platz said. “Editorial excellence benefits authors, CEBP, the AACR, and the entire epidemiologic community.”

Platz received a doctorate in epidemiology at Harvard University and a Master of Public Health at Yale University. She is a member of the American Association for the Advancement of Science, the Society for Epidemiologic Research, and the American Society of Preventive Oncology. She is the recipient of numerous awards and honors, including the Prostate Cancer Mentor of Excellence Award (2013), the Martin D. Abeloff, MD Scholar in Cancer Prevention (2010), and the David H. Bernstein Award for Promising Young Scientists (2000). 

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Cohn, SarahTue, 9 Apr 2019 11:40:57
AACR Names New Editor-in-chief of Molecular Cancer Therapeutics https://www.aacr.org/Newsroom/Pages/News-Release-Detail.aspx?ItemID=1309

PHILADELPHIA — The American Association for Cancer Research (AACR) is pleased to announce the appointment of Beverly Teicher, PhD, as editor-in-chief of Molecular Cancer Therapeutics, one of eight highly esteemed journals published by the AACR. She officially began her term as editor-in-chief of Molecular Cancer Therapeutics on Jan. 1. 

Molecular Cancer Therapeutics publishes the best science in the design, synthesis, discovery, and preclinical study of novel therapeutic agents for the treatment or prevention of cancer. 

“Dr. Teicher is a world-renowned expert in the field of molecular therapeutic research, and the American Association for Cancer Research is thrilled to welcome her as editor-in-chief of Molecular Cancer Therapeutics,” said Margaret Foti, PhD, MD (hc), chief executive officer of the AACR. “With almost 40 years of extensive research experience and contributions to the field, she will enhance the impact of this remarkable journal through her leadership and will further advance our mission to prevent and cure all cancers.”  

Teicher is chief of the Molecular Pharmacology Branch at the National Cancer Institute, focusing on target and drug discovery in the disease areas of sarcoma and small cell lung cancer. She is best known for her work in solid tumor models and physiologic measurements of tumor hypoxia and oxygenation, the study of antiangiogenic agents, and the study of drug combinations with an emphasis on in vivo determination of tumor cell killing along with determination of bone marrow CFU-GM killing in the same host. She has led laboratories and teams that have contributed critical preclinical studies to several approved anticancer agents and several investigational agents currently in clinical trial. 

Teicher has been an active member of the AACR since 1981, having served as a senior editor of Clinical Cancer Research and, more recently, as a senior editor of Molecular Cancer Therapeutics before being named editor-in-chief. She is also a member of the Stand Up To Cancer-Melanoma Research Alliance Joint Scientific Advisory Committee. The AACR is the Scientific Partner of Stand Up To Cancer. 

“I am grateful for the opportunity to lead this journal at a time when improving therapeutics for cancer treatment is essential,” Teicher said. “I look forward to continuing to expand and strengthen its influence within the drug discovery community, as well as within the wider research community.”

Teicher completed a doctorate in bioorganic chemistry at the Johns Hopkins University and postdoctoral training at Yale University School of Medicine. She is active in the international scientific community, having authored or coauthored more than 400 scientific publications and edited eight books. She is a member of the American Chemical Society, the Radiation Research Society, and the American Association for the Advancement of Science. She is the recipient of numerous awards and honors, including the Lilly Research Laboratories President’s Award (2011), the American Cancer Society Junior Faculty Award (1999), and the National Chemistry Honorary (1976). 

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Cohn, SarahTue, 9 Apr 2019 10:21:51
Adults at High Risk for HIV Infection Have Low Rates of Vaccination Against Human Papillomavirushttps://www.aacr.org/Newsroom/Pages/News-Release-Detail.aspx?ItemID=1301

​ATLANTA — Adults who are at high risk of becoming infected with the human immunodeficiency virus (HIV), which causes AIDS, were less likely than the general population to be vaccinated against human papillomavirus (HPV), which can cause anal and cervical cancer, according to results presented at the AACR Annual Meeting 2019, held in Atlanta March 29-April 3. 

HPV infection is common, and in a healthy individual, is often cleared from the body without ever causing disease, said the study’s lead author, Lisa T. Wigfall, PhD, MCHES, assistant professor, Division of Health Education, Department of Health and Kinesiology in the College of Education and Human Development at Texas A&M University in College Station. However, since HIV infection compromises the body’s immune system, an HIV-positive person may be unable to fight off HPV infection and may be more prone to developing some types of cancer, including anal and cervical cancer. 

Since 2006, vaccines have been available that target the HPV strains most likely to cause anal and cervical cancer. The U.S. Centers for Disease Control and Prevention (CDC) recommends that adolescent boys and girls up to 15 years of age receive two doses of the vaccine, beginning at age 11 or 12. Those who start the vaccine series later, at ages 15 through 26, should receive three doses, according to CDC guidelines. 

Uptake of the vaccination has been slower than public health experts would like and is currently far below the nation’s goal of 80 percent. As of 2017, about 49 percent of U.S. adolescents were up-to-date on HPV vaccination, and 66 percent had received the first dose, according to CDC data. Wigfall and colleagues undertook this study to assess HPV vaccination rates for people at high risk of HIV infection.

Researchers used data from the 2016 Behavioral Risk Factor Surveillance System (BRFSS) survey to assess HPV vaccination rates in individuals who reported engaging in one or more high-risk behaviors in the year before the survey. Of 486,303 adults who completed the 2016 BRFSS survey, only 16,507, or 3.39 percent, had used injection drugs and/or engaged in high-risk sexual behavior and were classified as high-risk for HIV infection.

Among that population, only 416 had complete data. In that group, the researchers found that very few people were fully vaccinated against HPV. Vaccination rates varied between high-risk population groups. Some key findings:

  • About one-fourth, or 25.7 percent, of gay/bisexual males aged 18-33 years had initiated the three-dose HPV vaccine series, and 6.2 percent had completed it. 
  • About one-fourth of high-risk heterosexual females aged 18-36 had completed the three-dose HPV series. 
  • Only 11 percent of high-risk heterosexual males aged 18-29 had initiated the three-dose HPV series.
  • None of the transgender men and women and gender-nonconforming individuals had initiated HPV vaccination. 
  • Vaccination rates were much lower among non-Hispanic black respondents than any other racial/ethnic group. “It was alarming that almost all non-Hispanic blacks in the study were unvaccinated, especially given the disproportionate burden of HIV/AIDS among this minority group,” Wigfall said. 

Wigfall said one potential reason for the low rate of vaccination in high-risk populations is that recommendations for people living with HIV were issued several years after the HPV vaccine first became available to the general population.

Previous research has shown that the way physicians talk about the HPV vaccine can influence parents’ decisions on whether to vaccinate their adolescents. Wigfall said that for some high-risk populations in this study, such as gay/bisexual men or transgender individuals, providers may not have addressed connections between high-risk sexual behaviors and HIV/HPV co-infection. 

“Gender and sexual orientation are important topics that should not preclude us from identifying and targeting HPV vaccination efforts among high-risk populations,” Wigfall said.  

Wigfall said that in her opinion, patient-provider communication about the HPV vaccine should be strengthened for high-risk populations, specifically, HIV-positive males or females, as well as HIV-negative gay/bisexual men and transgender individuals. 

In an effort to increase HPV vaccination among high-risk populations, “a necessary first step would be the wide adoption of routine HIV testing for all adolescents and adults, regardless of perceived risk,” she said, noting that the CDC has recommended routine HIV testing since 2006. That recommendation has not been widely followed, leaving thousands of people living with HIV unaware of their HIV-positive status, Wigfall said. 

This study was funded by a career development award from the National Cancer Institute (NCI) under grant number K01CA175239. Wigfall noted that her opinions are her own, and do not necessarily represent the official views of the NCI. 

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Riley, CharmaineTue, 2 Apr 2019 08:00:11
Maintenance Therapy With Rucaparib Shows Clinical Responses in a Subgroup of Patients With Pancreatic Cancerhttps://www.aacr.org/Newsroom/Pages/News-Release-Detail.aspx?ItemID=1302

​ATLANTA — Maintenance treatment with the PARP inhibitor rucaparib (Rubraca) was well tolerated and provided clinical responses among patients with advanced BRCA- or PALB2-mutated pancreatic cancer sensitive to platinum-based chemotherapy, according to results from an interim analysis of an ongoing phase II clinical trial presented at the AACR Annual Meeting 2019, March 29–April 3.

“In this interim analysis, we are finding that patients with platinum-sensitive pancreatic cancer appear to benefit from treatment with single agent rucaparib,” said Kim Reiss Binder, MD, assistant professor of medicine in the Division of Hematology Oncology at The Hospital of The University of Pennsylvania. “Several patients had complete or partial responses with rucaparib treatment, suggesting that this therapy has the potential not only to maintain the disease, but also to shrink the tumors in some instances,” she added.

Approximately 6 to 8 percent of patients with pancreatic cancer harbor pathogenic mutations in the genes BRCA or PALB2, noted Reiss Binder. Mutations in these genes often coincide with susceptibility to platinum-based chemotherapies, she added. “While this subgroup of pancreatic cancer patients respond well to platinum-based chemotherapy, prolonged treatment leads to cumulative toxicity, so this approach often becomes unsustainable. We wanted to investigate more tolerable maintenance options, as there are no approved treatments in this setting,” Reiss Binder said.

Rucaparib was approved as a maintenance treatment for patients with recurrent ovarian, fallopian tube, or primary peritoneal cancer who respond to platinum-based chemotherapy. “We wanted to determine if this therapeutic strategy could also be utilized in pancreatic cancer patients with platinum-sensitive tumors,” explained Reiss Binder.

This single-arm, phase II clinical trial is actively enrolling patients with advanced BRCA- or PALB2-mutated pancreatic cancer who have not progressed on prior platinum-based chemotherapy. The patients in the interim analysis had received a median of four months of prior platinum chemotherapy. More than 80 percent of patients were female. 

Patients are treated with 600mg of rucaparib twice daily until disease progression or unacceptable toxicity. The primary endpoint of the study is progression-free survival (PFS). Overall response rate (ORR) is also being evaluated.

Nineteen of the 24 enrolled patients were evaluable for analysis as of Dec. 31, 2018. 

The median PFS at time of analysis was 9.1 months following initiation of rucaparib treatment. The ORR was 37 percent, which included one complete response (CR) and six partial responses (PR). The disease control rate (defined as the sum of PR, CR, and stable disease) was 90 percent for at least eight weeks. Eight patients remained on rucaparib therapy for at least six months, and two patients have remained on rucaparib therapy for more than one year.  

Common adverse events related to the treatment included nausea, dysgeusia (a distortion of the sense of taste), and fatigue. 

“Although this is very preliminary data, the fact that we’re seeing sustained clinical responses in some of these patients is very exciting,” noted Reiss Binder. “Other than the recent tissue-agnostic approval of pembrolizumab for patients with microsatellite instability-high tumors, there really is no other targeted therapy that has shown promise for patients with pancreatic cancer.

“Our results highlight the importance of germline and somatic testing in pancreatic cancer patients,” said Reiss Binder. “The presence of certain mutations can guide treatment strategies, and patients should know to ask their oncologist about getting tested.”

As this was an unplanned interim analysis of an ongoing, small, single-arm study, the results require substantial further validation, noted Reiss Binder.

This study is sponsored by the Abramson Cancer Center and is funded by Clovis Oncology. Reiss Binder receives research funding from Clovis Oncology, Tesaro, Bristol-Myers Squibb, and Lilly Oncology.

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Riley, CharmaineTue, 2 Apr 2019 08:10:05
A Genetic Variant Linked to Increased Risk of Stroke in Childhood Cancer Survivors Treated With Cranial Radiation Therapyhttps://www.aacr.org/Newsroom/Pages/News-Release-Detail.aspx?ItemID=1303

ATLANTA — A common single nucleotide polymorphism (SNP) was associated with increased risk for developing stroke in childhood survivors who received cranial radiation therapy (CRT) for their primary cancer, according to results presented at the AACR Annual Meeting 2019, March 29–April 3.

“We have identified a genetic risk factor that confers a high risk of stroke among childhood cancer survivors treated with cranial radiation therapy,” said Yadav Sapkota, PhD, clinical research scientist at St. Jude Children’s Research Hospital. “Our findings can help better identify survivors who are at the highest risk for developing stroke and formulate intervention strategies to minimize their risk,” he said.

Childhood cancer survivors treated with CRT, or radiation to the brain, for their primary cancer are at an increased risk of developing stroke, said Sapkota. Compared to survivors who do not receive CRT, those who receive between 30 and 50 Gray (Gy) have a six-fold risk for developing stroke, while those who receive more than 50 Gy have an 11-fold risk for developing stroke, according to past studies, he added. “However, the stroke risk seems to vary within the same CRT dose group, even after accounting for other clinical and demographic factors,” Sapkota noted. “This indicated to us that there may be genetic predisposition that influences a CRT-exposed survivor’s risk for developing stroke,” he said.

To identify common SNPs (defined here as occurring in greater than 5 percent of the study population) associated with stroke risk, Sapkota and colleagues analyzed whole-genome sequencing data from 686 childhood cancer survivors treated with CRT for their primary cancer from the St. Jude Lifetime Cohort (SJLIFE) study; all survivors in this analysis were of European descent. Of these survivors, 116 (17 percent) developed clinically diagnosed stroke.

Following multivariable analysis, the authors found that CRT-exposed survivors harboring a common SNP on the 5p15.33 locus were nearly three times as likely to develop a stroke compared to CRT-exposed survivors without the SNP. The dose of radiation appeared to affect the SNP-risk association; survivors treated with 25-50 Gy had nearly five times the risk of developing stroke if they carried the SNP, while patients treated with less than 25 Gy or more than 50 Gy had roughly three times the risk of developing stroke if they carried the SNP.

“We found that the common SNP had the most pronounced effect on the risk for stroke following an intermediate dose of radiation,” noted Sapkota. “While survivors treated with greater than 50 Gy of radiation still have an increased risk of stroke if they carry the SNP, we hypothesize that higher doses of radiation displace the influence of genetics,” he said.

The researchers replicated the finding in two independent groups of survivors from the SJLIFE study, consisting of survivors of African ancestry who received CRT and survivors of European descent who did not receive CRT.  “Results of the replication analysis suggest that a combination of CRT treatment and genetic factors can greatly increase childhood cancer survivors’ risk for developing stroke,” said Sapkota. “Survivors treated with CRT who carry this genetic variant can benefit from being monitored and counseled to minimize their modifiable cardiovascular risk factors,” he added.

A limitation of the study is the small sample size, which will require validation in additional cohorts, Sapkota said. Functional experiments are also needed to gain mechanistic insights underlying the link between the common SNP and risk of stroke among survivors treated with CRT – thereby informing potential intervention-based approaches.

This study was sponsored by the National Cancer Institute and ALSAC, the fundraising and awareness organization of St. Jude. Sapkota declares no conflict of interest.




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Riley, CharmaineTue, 2 Apr 2019 08:12:31
Surgery is Associated With Increased Survival for Patients With HER2+ Stage 4 Breast Cancer https://www.aacr.org/Newsroom/Pages/News-Release-Detail.aspx?ItemID=1304

ATLANTA — Surgery was associated with higher survival rates for patients with HER2-positive (HER2+) stage 4 breast cancer compared with those who did not undergo surgery, according to results presented at the AACR Annual Meeting 2019, March 29-April 3.

Between 20 and 30 percent of all newly diagnosed stage 4 breast cancer cases are HER2+, explained the study’s lead author, Ross Mudgway, a medical student at the University of California, Riverside School of Medicine. This form of breast cancer once had poor outcomes, but in recent years, advances in targeted therapy, such as trastuzumab (Herceptin), have led to improved survival. 

In recent years, most patients with HER2+ breast cancer have been treated with systemic therapy, which could include chemotherapy, targeted therapy, or hormonal therapy, Mudgway said. Surgery is sometimes offered to these patients, but previous research on whether surgery improves survival has yielded mixed results, he said.

Mudgway and senior author Sharon Lum, MD, professor in the Department of Surgery-Division of Surgical Oncology and medical director of the Breast Health Center, Loma Linda University Health, noted that HER2 status has been reported in large registry data sets since the early 2000s, but the impact of surgery on this type of breast cancer has not been well documented across hospital systems. To assess the impact of primary tumor resection on survival in HER2+ stage IV breast cancer patients, they conducted a retrospective cohort study of 3,231 women with the disease, using records from the National Cancer Database from 2010 to 2012. 

Of these women, 89.4 percent had received chemotherapy or targeted therapies, 37.7 percent had received endocrine therapy, and 31.8 percent had received radiation. Overall, 1,130 women, or 35 percent, received surgery.

The researchers found that surgery was associated with a 44 percent increased chance of survival, assuming the majority also had systemic treatment.   

“This suggests that, in addition to standard HER2 targeted medications and other adjuvant therapy, if a woman has stage 4 HER2+ breast cancer, surgery to remove the primary breast tumor should be considered,” said Lum. 

The study also examined factors associated with receipt of surgery and found that women with Medicare or private insurance were more likely to have surgery and less likely to die of their disease than those with Medicaid or no insurance. White women were also more likely than non-Hispanic black women to have surgery and less likely to die of their cancer. 

“These results suggest disparities in health care due to race and socioeconomic factors, and these must be addressed,” Mudgway said.  

Mudgway and Lum said numerous factors may contribute to a physician’s decision on whether to recommend surgery, including comorbidities, response to other forms of treatment, and overall life expectancy. They said these findings should be considered in the context of all other factors. 

“For patients, the decision to undergo breast surgery, especially a mastectomy, can often be life-changing as it affects both physical and emotional health,” Mudgway said. “The patient’s own feelings about whether or not she wishes to have surgery should be considered.” 

Lum noted that this is a retrospective study and may not be fully representative of women facing the decision of whether to have surgery. For example, she noted, doctors may be most willing to operate on women who are healthier overall and are, therefore, more likely to experience a positive outcome. Further research would be needed to confirm the survival benefit suggested by this study. 

This study was self-funded by the Department of Surgery at Loma Linda University. The authors declare no conflicts of interest.




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Riley, CharmaineTue, 2 Apr 2019 08:15:23
Combination of Virotherapy and Radiotherapy Safe, Shows Early Promise in Vulnerable Patients With Esophageal Cancerhttps://www.aacr.org/Newsroom/Pages/News-Release-Detail.aspx?ItemID=1307

ATLANTA — The experimental oncolytic adenovirus telomelysin (OBP-301) in combination with radiotherapy was safe and showed early clinical efficacy in vulnerable patients with esophageal cancer, according to results from a phase I clinical trial presented at the AACR Annual Meeting 2019, March 29–April 3.

“Most standard therapeutic strategies for esophageal cancer, such as surgery and chemoradiotherapy, are relatively invasive and can’t be used in certain patients, including the elderly and those with health complications,” said Toshiyoshi Fujiwara, MD, PhD, professor and chairman in the department of Gastroenterological Surgery at the Okayama University Graduate School of Medicine. “Our combinatorial virotherapy-radiotherapy treatment is less invasive and is applicable for vulnerable patients and has provided extremely encouraging results.”

Many cancer cells overexpress the enzyme telomerase, which enables their replication and proliferation, explained Fujiwara. OBP-301 is a genetically modified virus which selectively replicates in telomerase-positive cells; viral infection is therefore enriched in cancerous cells, causing cell lysis, he added. A prior phase I trial evaluating OBP-301 as a monotherapy found the strategy safe and biologically active in patients with advanced solid tumors.

Because OBP-301 can also disrupt pathways that control DNA repair, Fujiwara and colleagues believe that tumor cells treated with the virotherapy can be rendered sensitive to ionizing radiation, allowing for the synergy of these two therapies. 

In this open-label, phase I dose-escalation trial, the investigators enrolled 13 patients with histologically confirmed esophageal cancer deemed unfit to receive standard surgery or chemotherapy; all patients were elderly and/or those who had complications such as pulmonary disease, cardiovascular disorders, or liver dysfunction, explained Fujiwara. Patients’ median age was 80 years.

Patients received three intratumoral injections of OBP-301 (each injection ranging between 10 billion and 1 trillion viral particles) via endoscope over several weeks with concurrent radiation therapy to a total of 60 Gray. The primary and secondary endpoints were dose-limiting toxicities and objective response rate (ORR), respectively.

In all 13 patients, the ORR was 85 percent, which included eight complete responses (CR) and three partial responses (PR); the clinical CR rate, defined as endoscopically and pathologically confirmed complete disappearance of tumor in the esophagus, was 83 percent and 60 percent for patients with stage 1 and stage 2/3 disease, respectively. No patients had viable malignant cells in post-treatment biopsy specimens.

Common toxicities included fever, esophagitis, pneumonitis, anorexia, constipation, and gastroesophageal reflux. All patients developed transient and self-limiting lymphopenia, and there were no dose-limiting toxicities.

“Not only was our combinatorial therapy safe, but it induced the complete eradication of esophageal tumors in most patients,” said Fujiwara. “These preliminary results indicate that there may be less invasive treatment options available for esophageal cancer patients who are unable to receive standard therapies for their disease.”

Histopathological examination of post-treatment biopsies taken from patients with PR revealed infiltration of CD8-positive T cells, suggesting that this combinatorial therapy may synergize with checkpoint inhibition, Fujiwara noted.

Limitations of this study include small sample size, which is consistent with a phase I dose-escalation trial.

This study was sponsored by the Ministry of Education, Science, and Culture in Japan and by the Japan Agency for Medical Research and Development. Fujiwara is a consultant for Oncolys BioPharma Inc.

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Riley, CharmaineTue, 2 Apr 2019 01:40:36
Prostate Cancer Incidence and Mortality Have Declined in Most Countrieshttps://www.aacr.org/Newsroom/Pages/News-Release-Detail.aspx?ItemID=1308

ATLANTA — Prostate cancer incidence and mortality rates are decreasing or stabilizing in most parts of the world, with the United States recording the biggest drop in incidence, according to results presented at the AACR Annual Meeting 2019, March 29-April 3.

Despite the trend toward declining or stabilizing rates, prostate cancer remains the second most commonly diagnosed cancer and the sixth leading cause of cancer death among men worldwide, said the study's lead author, MaryBeth Freeman, MPH, senior associate scientist, Surveillance Research, at the American Cancer Society in Atlanta.

"Previous studies have indicated significant variation in prostate cancer rates, due to factors including detection practices, availability of treatment, and genetic factors," Freeman said. "By comparing rates from different countries, we can assess differences in detection practices and improvements in treatment."

Researchers examined prostate cancer incidence and mortality patterns across five continents using the most recent cancer incidence data from the International Agency for Research on Cancer and mortality data from the World Health Organization. They examined long-term trends, from 1980 through 2012, for 38 countries that provided "high-quality" data (information assessed as accurate, timely, and complete) and short-term trends for 44 countries with available incidence data and 71 countries with available mortality data. The short-term data encompassed a five-year period that varied slightly among nations, but most often reflected 2008-2012.

Of the 44 countries examined for incidence data, prostate cancer rates during the most recent five-year period increased in four countries, with Bulgaria showing the largest increase. Rates decreased in seven countries, with the United States showing the largest decrease. Rates stabilized in the remaining 33 countries.

Among the 71 countries analyzed for mortality rates, rates decreased in 14 countries, increased in three countries, and remained stable in 54 countries.

Globally, as of 2012, prostate cancer was the most commonly diagnosed cancer among men in 96 countries and the leading cause of death in 51 countries.

Other findings:

  • The highest incidence rates in the most recent five-year period were found in Brazil, Lithuania, and Australia.
  • The lowest incidence rates in the most recent five-year period were found in India, Thailand, and Bahrain.
  • The highest mortality rates in the most recent five-year period were found in the Caribbean, specifically Barbados, Trinidad and Tobago, and Cuba; South Africa; Lithuania; Estonia; and Latvia.
  • The lowest mortality rates in the most recent five-year period were found in Thailand and Turkmenistan.

Freeman said she and colleagues were surprised and pleased to see that so many nations have achieved stability in prostate cancer rates, meaning that rates have not increased during the period examined. In coming years, she said, global health experts would hope for more nations to move from stability toward decreasing incidence and mortality rates. 

Freeman said the study confirmed the impact of prostate-specific antigen (PSA) screening. She explained that in the United States, prostate cancer incidence rates increased from the 1980s to the early 1990s, then declined from the mid-2000s through 2015, largely due to patterns of PSA screening. This type of screening is less available in lower-income nations, contributing to diagnosis at later stages and higher mortality rates, Freeman said.  

Freeman pointed out that some nations plan to scale back recommendations for PSA screening, as it is believed to lead to diagnosis and possible overtreatment of prostate cancer cases that would never become symptomatic. "Overall, patients should be having an informed discussion with their providers about the benefits and harms of PSA testing for detection of prostate cancer," she said. "Future studies should monitor trends in mortality rates and late-stage disease to assess the impact of reduction in PSA testing in several countries."

Freeman said one limitation of the study is the variability in data among different countries. For example, some countries may have only collected data from certain geographic areas, whereas others may have collected data from the whole nation. However, she added that the breadth of data in this study allowed researchers to draw a comprehensive portrait of prostate cancer incidence and mortality around the world.

This study was funded by the American Cancer Society. Freeman declares no conflicts of interest. 

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Riley, CharmaineTue, 2 Apr 2019 01:45:45
HDAC Inhibition May Combat Resistance to Anti-PD-1 Therapy in Patients With Melanoma https://www.aacr.org/Newsroom/Pages/News-Release-Detail.aspx?ItemID=1305

ATLANTA — A combination of the experimental histone deacetylase (HDAC) inhibitor entinostat with the anti-PD-1 therapeutic pembrolizumab (Keytruda) showed clinical responses in patients with melanoma that had progressed on prior anti-PD-1 treatment, according to results from the ENCORE 601 phase Ib/II clinical trial presented at the AACR Annual Meeting 2019, March 29–April 3.

“While a large group of patients have derived benefit from treatment with checkpoint inhibitors, many still develop resistance to these therapies,” said Ryan Sullivan, MD, assistant professor of hematology and oncology at Massachusetts General Hospital Cancer Center. “A number of studies, including this trial, are endeavoring to identify key immunotherapy combinations to overcome resistance to checkpoint blockade immunotherapy.”

HDAC inhibitors can modulate the immune system by suppressing regulatory cells, such as myeloid-derived suppressor cells and regulatory T cells, and by increasing antigen expression on cancerous cells, two mechanisms that may counteract resistance to checkpoint inhibition, explained Sullivan. “Adding HDAC inhibition to anti-PD-1 treatment against tumors that have developed resistance to checkpoint blockade immunotherapy may lead to re-recognition of the tumor by the immune system and down-modulation of immune-suppressive elements in the tumor microenvironment, thereby increasing the efficacy of anti-PD-1 therapy,” he added.

The purpose of the phase II ENCORE 601 trial was to assess the effectiveness of entinostat and pembrolizumab in patients with non-small cell lung cancer, melanoma, and mismatch repair-proficient colorectal cancer. This study reports on patients with unresectable or metastatic melanoma that progressed during or following treatment with anti-PD-1 immunotherapy.

In this single-arm trial, patients were treated with 5mg of entinostat once per week in conjunction with 200mg of pembrolizumab every three weeks until disease progression. The primary endpoint of the study was objective response rate (ORR) as measured by irRECIST.

Fifty-three patients were enrolled in the trial by data cutoff (January 2019). The median duration of prior anti-PD-1 treatment was 4.9 months; 66 percent of patients had no intervening therapy between prior anti-PD-1 treatment and study enrollment. Seventy percent of patients had prior treatment with ipilimumab (Yervoy), and 23 percent of patients had prior treatment with BRAF/MEK inhibitors.

Of the 53 evaluable patients, nine had a partial response and one had a complete response following the combinatorial treatment, resulting in an ORR of 19 percent. At the time of data cutoff, the median duration of response was 12.5 months; five patients had ongoing responses. 

“Our results suggest that this combination may be an active regimen for patients who never responded to or progressed during treatment with PD-1 inhibitors,” said Sullivan. “A key next step will be to identify a biomarker to better determine which patients will respond to this treatment.”

Sullivan noted that prolonged delays and/or intervening therapy between prior anti-PD-1 treatment and trial enrollment may have influenced treatment response, representing a key limitation in the study.

This study was sponsored by Syndax. Sullivan has served as a paid consultant and/or on advisory boards for Merck, Array, Syndax, Compugen, Replimune, Novartis, Bristol-Myers Squibb, and Amgen.


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Riley, CharmaineTue, 2 Apr 2019 08:23:58
Next-generation TRK-targeted Therapeutic, LOXO-195, Shows Early Promise Against Tumors with Acquired Resistance to First-generation Therapeuticshttps://www.aacr.org/Newsroom/Pages/News-Release-Detail.aspx?ItemID=1306

ATLANTA — The investigational anticancer therapeutic LOXO-195 (now known as BAY 2731954), which targets a family of proteins called TRKs, was safe, tolerable, and showed signs of clinical activity in patients who had solid tumors that harbored NTRK gene fusions and had become resistant to other TRK-targeted therapeutics, according to results from patients enrolled in a phase I clinical trial and a U.S. Food and Drug Administration (FDA) expanded access program, which were presented at the AACR Annual Meeting 2019, March 29–April 3.

“NTRK gene fusions, which cause heightened activity of TRK proteins, are detected in a wide range of cancer types,” said David Hyman, MD, chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center in New York. “Although these genetically defined cancers are rare, accounting for about 0.5 percent of all cancer cases diagnosed in the United States, a high percentage of patients respond to treatment with TRK inhibitors, including larotrectinib [Vitrakvi], which was approved by the FDA in November 2018.

“Unfortunately, most tumors that initially respond eventually become resistant to first-generation TRK inhibitors like larotrectinib,” continued Hyman. “This is frequently because the tumor has acquired mutations in NTRK that reduce the ability of the therapeutic to block TRK activity.”

Hyman explained that LOXO-195 is a next-generation TRK inhibitor designed to be able to block TRK activity even if a tumor has acquired NTRK resistance mutations.

“Our preliminary data show that LOXO-195 can cause responses in patients whose NTRK fusion–positive cancers had acquired NTRK resistance mutations during treatment with a prior TRK inhibitor,” said Hyman. “These data suggest that LOXO-195 could eventually be a meaningful treatment for patients whose cancers are resistant to first-generation TRK inhibitors.”

As of Dec. 3, 2018, there were 20 patients who had received LOXO-195 through the phase I clinical trial and 11 patients who had received the second-generation TRK-targeted therapeutic through an FDA expanded access single patient protocol. All the patients, who included seven children and 24 adults, had previously been treated with at least one first-generation TRK-targeted therapeutic.

As of Dec. 3, 2018, 29 of the patients were evaluable for response. Ten of the patients (34 percent) had a confirmed complete or partial response, as assessed by RECIST 1.1 criteria. 

When the researchers analyzed the data based on the mechanisms underlying resistance to the first-generation TRK inhibitors, they found that nine of 20 patients (45 percent) whose tumors were determined to have become resistant by acquiring an NTRK gene mutation had a complete or partial response. None of the three patients whose tumors were determined to have become resistant by TRK-independent mechanisms responded to LOXO-195.

“We were pleased to see that the response data were consistent with what we expected based on our biological understanding of the mechanisms of resistance identified in these patients,” said Hyman. “We saw responses in patients whose tumors had acquired mutations that led the tumors to maintain dependence on TRK for growth and survival and no responses in patients whose tumors had acquired mutations that led the tumors to become independent of TRK.

“Given how promising our early data are, I would encourage patients who have disease progression after treatment with a first-generation TRK inhibitor to seek out a clinical trial testing a next-generation TRK-inhibitor,” added Hyman.

In the phase I clinical trial, a range of doses of LOXO-195, from 32 mg daily to 150 mg twice daily, were tested. Observed toxicities were consistent with the anticipated side effects of TRK inhibition, according to Hyman. The most common adverse events, regardless of investigator attribution, were dizziness/ataxia, nausea/vomiting, anemia, myalgia, abdominal pain, fatigue, and lymphopenia. Dose selection is ongoing in both children and adults.

According to Hyman, the main limitations of the study are the small number of patients treated to date and the fact that some patients were treated through an FDA expanded access single patient protocol, which means that the completeness of data collection for these patients was less than for the patients enrolled in the clinical trial.

This study was funded by Loxo Oncology and Bayer. Hyman has received compensation from Bayer for consultancy work and research funding from Loxo Oncology and Bayer.

Press Release Published Date: 4/1/2019 9:00 AM
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Riley, CharmaineTue, 2 Apr 2019 08:31:22
American Association for Cancer Research Inaugurates New Leadership at 2019 Annual Meetinghttps://www.aacr.org/Newsroom/Pages/News-Release-Detail.aspx?ItemID=1300

ATLANTA — The American Association for Cancer Research (AACR) welcomes Elaine R. Mardis, PhD, as President of the organization for 2019–2020. She was inaugurated during the Annual Business Meeting, held here on April 1, during the AACR Annual Meeting 2019.

Mardis holds the Nationwide Foundation Endowed Chair in Genomic Medicine and is co-executive director of the Institute for Genomic Medicine at Nationwide Children's Hospital in Columbus, Ohio. She also is professor of pediatrics at The Ohio State University College of Medicine.

Mardis is a world-renowned researcher whose work centers on the genomic characterization of cancer and its implications for precision cancer medicine. She has presented keynote addresses and other invited remarks at international conferences on topics including cancer genomics, next-generation sequencing technology, personalized medicine, and cancer immunogenomics.

“I am excited and humbled by my election as President of the AACR, and I am eager to work with Dr. Foti, her amazing staff, and the entire membership to promote basic and translational cancer research toward improved outcomes for cancer patients,” said Mardis.

An active member of the AACR since 2009, Mardis’ contributions to the AACR have been vast and far-reaching. She is currently serving as an AACR Project GENIE Advisory Board member, an AACR Special Conferences committee member, and is a senior editor of the AACR journal Molecular Cancer Research. She previously served on the Board of Directors (2015–2018), as chair of the AACR Annual Meeting 2018 Program Committee, as a committee member for the Pezcoller Foundation-AACR Award (2017), and as a member of the Steering Committee for the AACR Cancer Progress Report 2014. In addition, she was co-chair of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy conference in Salt Lake City, and has served on the organizing committees of several other conferences.

Mardis has received many awards and honors in recognition of her exceptional research accomplishments. She was elected to the 2019 class of Fellows of the AACR Academy, and was the recipient of the Precision Medicine World Congress 2017 Luminary Award, the American Association for Clinical Chemistry Morton K. Schwartz Award for Significant Contributions in Cancer Research Diagnostics (2016), the George Engelmann Interdisciplinary Award (2012), St. Louis Academy of Science (2012), and the Scripps Research Institute Translational Medicine Award (2010).

Mardis received a bachelor’s degree, summa cum laude, and her PhD from the University of Oklahoma. She spent much of her early career at the Washington University School of Medicine in St. Louis, Missouri, as a professor, researcher, and ultimately, co-director of The McDonnell Genome Institute. 

Additionally, Antoni Ribas, MD, PhD, professor of Medicine at the David Geffen School of Medicine at the University of California Los Angeles, was inducted as President-Elect. Elizabeth M. Jaffee, MD, deputy director for the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and associate director of the Bloomberg~Kimmel Institute for Cancer Immunotherapy, now serves as past president.

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Cohn, SarahMon, 1 Apr 2019 09:50:06
Data From Two KEYNOTE Trials Show Pembrolizumab Benefited Patients With Advanced Small Cell Lung Cancerhttps://www.aacr.org/Newsroom/Pages/News-Release-Detail.aspx?ItemID=1296

ATLANTA — The anti-PD-1 monoclonal antibody pembrolizumab (Keytruda) showed promising antitumor activity with durable responses in patients with pretreated, advanced small cell lung cancer (SCLC), according to results from a pooled analysis of the two clinical trials, the phase 1b KEYNOTE-028 and the phase II KEYNOTE-158, presented at the AACR Annual Meeting 2019, March 29–April 3.

“Up to 70 percent of patients with SCLC have advanced disease at diagnosis,” said Hyun Cheol Chung, MD, PhD, professor at Yonsei Cancer Center, Yonsei University College of Medicine in Seoul, Republic of Korea. “Current treatment guidelines specify a variety of first- and second-line treatment options; however, for patients who require third-line therapy, there are no specific recommendations and prognosis is very poor.”

Chung and colleagues evaluated the safety and efficacy of pembrolizumab as monotherapy in a pooled analysis of the SCLC cohorts from the KEYNOTE-028 and KEYNOTE-158 multicohort trials. All patients included in the analysis had received at least two lines of prior therapy for advanced disease.

“Our findings show that pembrolizumab monotherapy can provide promising antitumor activity with durable clinical benefit and manageable toxicity in patients whose disease has progressed after two or more lines of prior therapy for advanced SCLC,” Chung said.

Of 131 SCLC patients included in the two trials, 83 were eligible for efficacy analyses. Patients from KEYNOTE-028 were required to have PD-L1–positive tumors, but this was not the case for those in KEYNOTE-158.

In the pooled analysis, the objective response rate (ORR) was 19.3 percent, which included two complete responses and 14 partial responses. The median duration of response (DOR) was not reached at the time of this analysis.

Of the 16 responders, nine had responses lasting for at least 18 months.

After a median of 7.7 months of follow-up, the median progression-free survival (PFS) was 2 months and median overall survival (OS) was 7.7 months. At 12 months, PFS and OS were 17 percent and 34 percent, respectively, and at 24 months, PFS and OS were 13 and 21 percent, respectively.

“Our findings are particularly noteworthy given that data show that historically, patients with SCLC in the third-line treatment setting have limited survival benefit, with a median DOR of less than two months and median survival of around two to three months,” Chung said. “Our study shows that pembrolizumab monotherapy can provide durable clinical benefit with manageable toxicity in this hard-to-treat patient population.”

Fourteen of the 16 responders had PD-L1–positive tumors. “Given that the two studies differed slightly in their methods for assessing PD-L1–positivity, we did not seek to evaluate the role of PD-L1 in patient selection in this pooled analysis,” Chung said.

“Overall, the adverse events noted were consistent with the safety profile of pembrolizumab and no new safety signals were identified,” Chung said. He added that 13 patients (10 percent) had a grade 3 or higher treatment-related adverse event. Three patients had grade 5 treatment-related adverse events (intestinal ischemia, pneumonia, encephalopathy), and 21 percent experienced an immune-related adverse event (irAE) or infusion reaction. However, there were no grade 5 irAEs and infusion reactions, Chung noted.

Limitations of the study include that it is a retrospective, exploratory, pooled analysis, and that the two trials were single-arm studies, Chung noted.

Funding for this research was provided by Merck Sharp & Dohme Corp. (MSD), a subsidiary of Merck & Co. Chung has received grants/research support from Eli Lilly, GlaxoSmithKline, MSD, Merck-Serono, and Bristol-Myers Squibb/Ono, Taiho; honoraria from Merck-Serono, and Eli Lilly/Foundation Medicine; and is a consultant to Taiho, Celltrion, MSD, Eli Lilly, Quintiles, BMS, and Merck-Serono.


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Riley, CharmaineMon, 1 Apr 2019 08:18:21
Umbralisib Shows Early Promise for Patients with Marginal Zone Lymphomahttps://www.aacr.org/Newsroom/Pages/News-Release-Detail.aspx?ItemID=1297

ATLANTA — The investigational therapeutic umbralisib, which targets the molecule PI3K-delta, was well tolerated and highly active in patients with relapsed/refractory marginal zone lymphoma, according to early results from the UNITY-NHL phase II clinical trial, which were presented at the AACR Annual Meeting 2019, March 29–April 3.

As of October 20, 2018, 55 percent of patients who had at least six months of follow-up had a partial or complete response following umbralisib treatment. The median duration of response had not been reached. Updated data will be presented at the meeting, according to Nathan H. Fowler, MD, associate professor of medicine and director of clinical research in the Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center in Houston. 

In January 2019, the U.S. Food and Drug Administration (FDA) granted umbralisib breakthrough therapy designation for the treatment of adults with marginal zone lymphoma who have received at least one anti-CD20 treatment. Breakthrough therapy designation is an FDA strategy to expedite assessment of therapeutics for life-threatening diseases such as cancer.

Marginal zone lymphoma is an uncommon, slow-growing type of non-Hodgkin lymphoma,” said Fowler. “Rituximab, either alone or in combination with chemotherapy, has improved outcomes for patients, but in most cases the disease eventually relapses, and these individuals have limited treatment options.

“Umbralisib is a small-molecule inhibitor that targets PI3K-delta, which is a component of a signaling pathway that has a key role in promoting the survival and expansion of many types of cells, and has also been shown to uniquely inhibit CK1 epsilon,” continued Fowler. “Our exciting results suggest that this oral targeted therapeutic has significant activity against relapsed/refractory marginal zone lymphoma and offers hope for patients.”

As of October 20, 2018, 69 patients with relapsed/refractory marginal zone lymphoma had been enrolled on the trial and received 800 milligrams of umbralisib orally once daily until disease progression or unacceptable toxicity. At that time, 38 patients had at least six months of follow-up.

Among the 38 patients, the median follow-up time was 9.6 months. Four had a complete response and 17 had a partial response, as assessed by the investigators, for an overall response rate of 55 percent. An additional 11 patients had stable disease, for a clinical benefit rate (complete response, partial response, and stable disease) of 84 percent. Progression-free survival at 12 months was 71 percent.

The most common adverse event of any grade was diarrhea, which affected 45 percent of the 38 patients. Nausea, fatigue, headache, cough, and decreased appetite affected between 20 percent and 30 percent of patients. The most common grade 3/4 adverse events were neutropenia, febrile neutropenia, and diarrhea, which affected 8 percent, 5 percent, and 5 percent of the 38 patients, respectively. No events of colitis or pneumonitis had been reported.

“All the adverse events we have seen in the trial are to be expected with this class of drugs,” said Fowler. “Moreover, we were able to manage the side effects for the patients, making umbralisib a well-tolerated treatment.

“The adverse event and clinical activity data are highly encouraging at this early timepoint,” added Fowler. “We are excited to continue following patients for a longer time to further establish the long-term activity and side effects of umbralisib. With the results reported so far, umbralisib has the potential to make a real difference for patients with relapsed/refractory marginal zone lymphoma.”

According to Fowler, the main limitations of the data presented are that it was based on a small number of patients and a short follow-up time. 

This study was funded by TG Therapeutics. Fowler serves on scientific advisory boards for TG Therapeutics, Bayer, Gilead Sciences, and Verastem Oncology; he also receives research funding from TG Therapeutics.

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Riley, CharmaineMon, 1 Apr 2019 08:31:19
Cancer Preventive Vaccine Showed Promising Results in Preclinical Model of Lynch Syndromehttps://www.aacr.org/Newsroom/Pages/News-Release-Detail.aspx?ItemID=1298

​ATLANTA — Vaccination with as few as four tumor antigens generated antigen-specific responses, reduced intestinal tumors, and improved survival in a mouse model of Lynch syndrome, suggesting that it may be possible to develop a cancer preventive vaccine for patients with Lynch syndrome, according to data presented at the AACR Annual Meeting 2019, March 29–April 3.

Lynch syndrome is an inherited condition that affects about one in every 280 individuals in the United States,” said Steven M. Lipkin, MD, PhD, the Gladys and Roland Harriman Professor of Medicine, professor of medicine in the Division of Gastroenterology and Hepatology, and vice chair for research in the Weill Department of Medicine at Weill Cornell Medicine in New York; and a geneticist at NewYork-Presbyterian/Weill Cornell Medical Center. “People with Lynch syndrome have a 70 to 80 percent lifetime risk of colorectal cancer, as well as an increased risk for other types of cancer, including small intestine, stomach, endometrial, bladder, and ovarian cancers.

“Currently, frequent screening to detect precancers and early-stage cancer is the main approach used to prevent cancer in people with Lynch syndrome, although some people have risk-reducing surgeries and some take aspirin for colorectal cancer prevention,” continued Lipkin, who is also a member of the Sandra and Edward Meyer Cancer Center and the Caryl and Israel Englander Institute for Precision Medicine at Weill Cornell Medicine. “We are extremely encouraged by our preclinical data, which suggest that rationally designed cancer vaccines may prevent some cancers associated with Lynch syndrome. We are in the process of designing a clinical trial to test this hypothesis.”

The genetic mutations that cause Lynch syndrome prevent the proper repair of damaged DNA, leading to the accumulation of mutations in certain parts of the genome called coding microsatellites, explained Lipkin. The coding microsatellite mutations generate novel or modified proteins called neoantigens, which can be recognized by the patient’s immune system but usually do not yield a sufficiently robust immune response to prevent cancers from developing, he added.

In this study, Lipkin and colleagues investigated whether vaccinating mice with Lynch syndrome–associated neoantigens could stimulate a robust immune response that would have antitumor activity.

One of the first steps the researchers took was to analyze intestinal tumors from Lynch syndrome mice for mutations in the coding microsatellites. They identified 13 coding microsatellites that had at least one mutation that occurred in 15 percent or more of the tumors.

Further analysis was conducted to determine which mutations might generate neoantigens and what the peptide sequences of these neoantigens were. The team then tested how effective the 10 most promising neoantigens were at inducing an immune response in mice. They found four of the neoantigens generated from coding microsatellite mutations induced robust neoantigen-specific immune responses.

Vaccination of Lynch syndrome mice with the four neoantigens induced robust neoantigen-specific immune responses. It also significantly reduced intestinal tumor burden and improved survival compared with nonvaccinated Lynch syndrome mice. In nonvaccinated Lynch syndrome mice, the median intestinal tumor burden was 61 mg and overall survival was 241 days, compared with 31 mg and 380 days, respectively, in vaccinated Lynch syndrome mice.

Combining vaccination and administration of the nonsteroidal anti-inflammatory drug naproxen significantly improved overall survival for the Lynch syndrome mice compared with vaccination alone; in mice receiving the combination treatment, overall survival was 541 days versus 380 days in mice receiving only the vaccine.

“Our preclinical data are very exciting because they provide strong support for continuing the investigation and development of immunoprevention strategies for patients with Lynch syndrome,” said Lipkin.

According to Lipkin, the main limitation of the study is that it is a preclinical study, which means that there is still a lot of work to be done before we can know if this strategy will prevent cancer in patients with Lynch syndrome.

This study was funded by the National Cancer Institute (NCI). Lipkin declares no personal conflicts of interest. Two co-investigators on his NCI grant are employees of the immunotherapy company Nouscom.

Press Release Published Date: 4/1/2019 4:30 AM
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Riley, CharmaineMon, 1 Apr 2019 08:35:11
Gilteritinib Improved Survival for Patients With Acute Myeloid Leukemiahttps://www.aacr.org/Newsroom/Pages/News-Release-Detail.aspx?ItemID=1295

​ATLANTA — Treatment with the FLT3-targeted therapeutic gilteritinib (Xospata) improved survival for patients with relapsed or refractory acute myeloid leukemia (AML) harboring a FLT3 mutation compared with standard chemotherapy regimens, according to results from the ADMIRAL phase III clinical trial presented at the AACR Annual Meeting 2019, March 29–April 3.

Gilteritinib was approved by the U.S. Food and Drug Administration (FDA) for treating adult patients who have relapsed or refractory AML that tests positive for a FLT3 mutation in November 2018.

“The FDA approval of gilteritinib was based on safety data and an interim analysis of the rate of response to gilteritinib in the ADMIRAL trial; it was not based on a comparison of the efficacy of gilteritinib relative to standard chemotherapy,” said Alexander E. Perl, MD, associate professor in the Division of Hematology/Oncology at the Perelman School of Medicine at the University of Pennsylvania, and a member of the Abramson Cancer Center. “We are now presenting the final analysis of the results from the ADMIRAL trial, including data showing that gilteritinib is superior to standard chemotherapy, as measured by improved overall survival.

“These survival data combined with gilteritinib’s relatively low toxicity establish gilteritinib monotherapy as the new standard of care for patients with relapsed or refractory FLT3-mutated AML,” continued Perl. “In addition, the relatively low toxicity of gilteritinib and the fact that it is an oral therapy means physicians can manage patients in the outpatient setting, which is a paradigm shift for the treatment of this disease.”

Perl explained that the FLT3 gene is mutated in about one-third of the AML cases diagnosed in the United States. Patients with relapsed or refractory FLT3-mutated AML have a particularly poor prognosis, with standard chemotherapy regimens yielding low remission rates and any remissions achieved lasting a short duration, he said.

ADMIRAL was a randomized, phase III clinical trial designed to determine whether gilteritinib improved survival for patients with relapsed or refractory FLT3-mutated AML compared with standard chemotherapy regimens, which included investigator’s choice of low-dose cytarabine; azacitidine; mitoxantrone, etoposide, and cytarabine; and fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin.

Of the 371 patients enrolled in the clinical trial, 247 were randomly assigned to gilteritinib and 124 to standard chemotherapy.

At the final analysis, patients assigned gilteritinib were found to have a 36 percent reduction in risk of death compared with those assigned standard chemotherapy. Median overall survival was 9.3 months for those assigned gilteritinib versus 5.6 months for those assigned standard chemotherapy. At 12 months, 37.1 percent of the patients treated with gilteritinib were alive compared with 16.7 percent of those assigned standard chemotherapy.

The combined rate of complete remission (which means a patient has no evidence of disease with full recovery of blood counts) and complete remission with partial hematologic recovery (which means a patient has no evidence of disease with partial recovery of blood counts) was 34.0 percent for those assigned gilteritinib and 15.3 percent for those assigned standard chemotherapy.

“The longest survival in the gilteritinib arm was seen among patients who proceeded to transplant and then resumed gilteritinib thereafter to prevent relapse, but unfortunately long-term survival was very uncommon on either treatment arm,” said Perl. “In an effort to further improve long-term outcomes, clinical trials testing gilteritinib in combination with other therapies for relapsed or refractory FLT3-mutated AML and testing gilteritinib as frontline therapy for newly diagnosed patients have already been launched.”

According to Perl, the main limitation of the study is that the standard frontline treatment for FLT3-mutated AML changed during enrollment to the ADMIRAL trial because the FDA approved the FLT3-targeted therapeutic midostaurin for this indication in April 2017; thus, a small minority of patients in both arms received prior FLT3-targeted therapy. It is possible that leukemias that relapsed after or were refractory to frontline treatment that included midostaurin were less dependent on FLT3 for their growth and therefore had less likelihood of responding to gilteritinib, he explained.

This study was funded by Astellas Pharma US Inc. In the past two years, Perl has received honoraria for serving on advisory boards for AbbVie, Actinium Pharmaceuticals, Agios, Astellas, Daiichi Sankyo, Jazz Pharmaceuticals, Novartis, NewLink Genetics, and Takeda; has received consultancy fee from Astellas, Daiichi Sankyo, Arog, AbbVie; and his institution has received research funding for him to conduct multi-institutional clinical trials from Actinium Pharmaceuticals, Astellas, Bayer, BioMed Valley Discoveries, Daiichi Sankyo, FujiFilm, and Novartis.

Press Release Published Date: 4/1/2019 4:25 AM
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Riley, CharmaineMon, 1 Apr 2019 08:02:22
Emil J Freireich Honored With AACR Award for Lifetime Achievement in Cancer Researchhttps://www.aacr.org/Newsroom/Pages/News-Release-Detail.aspx?ItemID=1290

​PHILADELPHIA — The American Association for Cancer Research (AACR) recognized Emil J Freireich, MD, FAACR, with the 2019 AACR Award for Lifetime Achievement in Cancer Research during the AACR Annual Meeting 2019, held March 29-April 3 in Atlanta.

Freireich, who retired as professor in the Department of Leukemia, Division of Cancer Medicine, and director of the Adult Leukemia Research Program, The University of Texas MD Anderson Cancer Center, Houston, was honored for his work in establishing combination chemotherapy and neoadjuvant therapy as powerful weapons in treating childhood acute lymphoblastic leukemia (ALL). His discovery that multiple drugs given simultaneously, both during the initial course of treatment and for a year after the patient was in remission, helped transform childhood leukemia into a type of cancer that can often be cured. Today, Freireich’s discoveries are still used in clinical practice, and survival rates for childhood leukemia exceed 90 percent.  

“Dr. Freireich is a remarkable physician-scientist who transformed his understanding of the biological mechanisms behind pediatric leukemia into lifesaving cures,” said Margaret Foti, PhD, MD (hc), chief executive officer of the AACR. “His innovations in combining therapies and finding new ways to avoid relapse changed the course of clinical research and saved the lives of entire generations of children. He is deeply deserving of this special honor.”

The AACR Award for Lifetime Achievement in Cancer Research was established in 2004 to honor individuals who have made significant fundamental contributions to cancer research, either through a single scientific discovery or a collective body of work. These contributions, whether they have been in research, leadership, or mentorship, must have had a lasting impact on the cancer field and must have demonstrated a lifetime commitment to progress against cancer.

Freireich’s contributions to the treatment of leukemia began in the 1950s when he developed a new strategy to end bleeding in his young patients. He proved that fresh blood rich in platelets was more effective in preventing hemorrhages than older blood that came from blood banks. This discovery changed protocols in hospitals around the country and effectively ended bleeding as a cause of death. 

Freireich then launched clinical trials to test whether combining chemotherapeutic agents was more effective than giving the drugs sequentially. He ultimately developed a four-drug regimen to treat pediatric leukemia, and he continued that regimen for a year after remission to kill any residual disease. This strategy, known as early intensification, is still used today.  

Later, Freireich became the first to perform leukocyte transfusion and show that peripheral blood stem cells could be engrafted, thus leading to allogeneic bone marrow grafts. He also developed the first continuous-flow blood cell separator. 

Freireich earned his bachelor’s degree and his medical degree from the University of Illinois in Chicago. He practiced medicine at Chicago hospitals, then did a fellowship in hematology at Mass Memorial Hospital in Boston. In 1953, he was drafted into the U.S. Army but was allowed to serve by working at the National Institutes of Health. There, he conducted his earliest groundbreaking research on ALL. 

In 1965, he joined The University of Texas MD Anderson Cancer Center, where he went on to a remarkable 50-year career. In addition to his research, Freireich became a renowned educator, overseeing the physician-scientist training program and helping develop the curriculum. He retired in 2015 but has remained involved in MD Anderson’s medical education program. 

Freireich was inducted as a Fellow of the AACR Academy in 2014. He has been recognized with countless career awards, including the Albert Lasker Basic Medical Research Award in 1972; the David A. Karnofsky Memorial Award and Lecture in 1976; the de Villiers International Achievement Award from the Leukemia and Lymphoma Society in 1979; the Jeffrey A. Gottlieb Memorial Award from MD Anderson Cancer Center in 1981; the Charles F. Kettering Prize from the General Motors Cancer Research Foundation in 1983; and the First NIH Distinguished Alumni Award in 1990. 

He won the Medical Oncology Fellows Outstanding Teacher Award from MD Anderson Cancer Center and the Return of the Child Award from the Leukemia Society of America in 1996; the Charles A. LeMaistre Outstanding Achievement Award in 2000; the Cino del Duca Award, 11th International Congress on Anti-Cancer Treatment in 2001; the Pollin Prize for Pediatric Research from Columbia University in 2003; the Gerald P. Bodey Sr. Distinguished Award in 2005; and the Paul Ehrlich Magic Bullet Lifetime Achievement Award in 2008. 

Freireich was recognized at the Opening Ceremony of the AACR Annual Meeting.

Press Release Published Date: 3/31/2019 11:00 AM
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Cohn, SarahSun, 31 Mar 2019 08:40:34
Excess Body Weight Before age 50 is Associated With Higher Risk of Dying From Pancreatic Cancerhttps://www.aacr.org/Newsroom/Pages/News-Release-Detail.aspx?ItemID=1299

​ATLANTA —Excess weight before age 50 may be more strongly associated with pancreatic cancer mortality risk than excess weight at older ages, according to results of a study presented at the AACR Annual Meeting 2019, March 29–April 3.

Pancreatic cancer is relatively uncommon, accounting for just over 3 percent of all new cancer cases. However, it is an extremely deadly type of cancer, with a five-year survival rate of just 8.5 percent, according to the National Cancer Institute’s Surveillance, Epidemiology, and End Results database. In the United States, pancreatic cancer is the third leading cause of cancer death, after lung and colorectal cancer, and is expected to cause about 46,000 deaths in 2019. 

“Pancreatic cancer rates have been steadily increasing since the early 2000s,” said the study’s lead author, Eric J. Jacobs, PhD, senior scientific director of Epidemiology Research at the American Cancer Society in Atlanta. “We’ve been puzzled by that increase because smoking—a major risk factor for pancreatic cancer—is declining.

“Increased weight in the U.S. population is a likely suspect, but previous studies have indicated that excess weight is linked with only a relatively small increase in risk, which doesn’t look large enough to fully explain recent increases in pancreatic cancer rates,” Jacobs continued.  

Jacobs said, however, that most previous studies on the link between weight and pancreatic cancer were based on weight measured in older adulthood, which may be less informative because it could reflect body fat gained too late in life to influence risk of pancreatic cancer during a typical lifespan. In this study, researchers sought to find out if excess weight measured earlier in adulthood might be more strongly linked to pancreatic cancer risk than excess weight measured at older ages.

Researchers examined data from 963,317 U.S. adults with no history of cancer who enrolled in the American Cancer Society’s Cancer Prevention Study II, a nationwide study of cancer mortality that began in 1982 and followed participants through 2014. All participants reported their weight and height just once, at the start of the study, when some were as young as 30 while others were in their 70s or 80s. The researchers used this information to calculate body mass index (BMI), a measure of weight relative to height, as an indicator of excess weight.

During the follow-up period, 8,354 participants died of pancreatic cancer. As expected, higher BMI was linked with increased risk of dying of pancreatic cancer, but this increase in risk was largest for BMI assessed at earlier ages. An increase of five units of BMI, about 32 pounds for a 5-foot, 7-inch adult, was associated with 25 percent increased risk in those who had their BMI assessed between ages 30 and 49; 19 percent increased risk in those assessed between 50 and 59; 14 percent increased risk in those assessed between ages 60 and 69; and 13 percent increased risk in those assessed between ages 70 and 89. Jacobs noted that while the study only had information on deaths from pancreatic cancer, the disease is nearly always fatal, so results are expected to be similar to those for new diagnoses of pancreatic cancer.

Jacobs said the study results indicate that excess weight could increase risk of death from pancreatic cancer more than previously believed. Furthermore, Jacobs noted that recent generations are reaching early middle age with more excess weight than earlier generations did. Therefore, he anticipates that excess weight will explain a larger proportion of pancreatic cancer risk in the future as newer and heavier generations reach the older ages when pancreatic cancer typically occurs. For example, he estimates that 28 percent of pancreatic cancer deaths in Americans born between 1970 and 1974 will be attributable to excess weight, compared to only 15 percent of pancreatic cancer deaths among Americans born in the 1930s, a group that was much less likely to be obese in early middle age. 

“Our results strongly suggest that to stop and eventually reverse recent increases in pancreatic cancer rates, we will need to do better in preventing excess weight gain in children and younger adults, an achievement which would help prevent many other diseases as well,” Jacobs said. 


This study was funded by the American Cancer Society. Jacobs declares no conflicts of interest. 


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Riley, CharmaineMon, 1 Apr 2019 09:05:33
Mesothelin-targeted CAR T-cell Therapy Safe, Shows Early Promise in Patients With Advanced Solid Tumorshttps://www.aacr.org/Newsroom/Pages/News-Release-Detail.aspx?ItemID=1291
ATLANTA — A chimeric antigen receptor (CAR) T-cell therapy that targets the protein mesothelin showed no evidence of major toxicity and had antitumor activity in patients with malignant pleural disease from mesothelioma, according to results from a phase I clinical trial presented at the AACR Annual Meeting 2019, March 29–April 3.

“Patients with advanced-stage solid tumors, such as mesothelioma, and lung and breast cancers, that are metastatic to the chest cavity have poor outcomes despite treatment,” said Prasad S. Adusumilli, MD, deputy chief of thoracic surgery at Memorial Sloan Kettering Cancer Center (MSK). “Treatment with CAR T cells results in dramatic successes in blood cancers; however, results have been disappointing to date for solid tumors.”

Adusumilli, senior author of the study Michel Sadelain, MD, PhD, and colleagues engineered the mesothelin-targeted CAR T cells called IcasM28z using completely human components, which includes the Icaspase-9 safety “suicide” switch that can be activated to kill all CAR T cells in a patient’s body in case of an unexpected toxicity.

“The novelty of our study is that the CAR T cells target the cancer cell-surface protein, mesothelin, which is expressed on the majority of cancer cells, and they are delivered directly to the tumor site using regional delivery techniques,” Adusumilli said. “If this approach is successful, 2 million patients with mesothelin-expressing solid tumors per year in the United States will be eligible for this treatment.”

The investigators recruited 21 patients with malignant pleural disease (19 with malignant pleural mesothelioma, one with metastatic lung cancer, and one with metastatic breast cancer); 40 percent of them had received three or more lines of prior therapy. After cyclophosphamide preconditioning, IcasM28z CAR T cells were injected directly into the pleural cavity using an interventional radiology procedure.

The investigators evaluated multiple clinical, radiological, and laboratory parameters in the patients who received the CAR T cells and found no evidence of toxicity at the doses tested. CAR T cells were found to be persistent in the peripheral blood of 13 patients during the 38-week evaluation, and their presence was associated with more than 50 percent decrease in the levels of a mesothelin-related peptide in the blood and evidence of tumor regression on imaging studies.

One patient with mesothelioma underwent curative-intent surgery followed by radiation therapy to the chest. “Twenty months from diagnosis, the patient is doing well, with no further treatment,” Adusumilli noted.

Fourteen patients went on to receive anti-PD1 checkpoint blockade agents. In preclinical studies, the researchers found that in large tumors, the CAR T cells became functionally exhausted even while residing in the tumor. Treatment with anti-PD-1 agents could reactivate the exhausted CAR T cells and eradicate the tumors in a proportion of mice. “On the basis of these published observations, in some patients who received CAR T cells, we administered anti-PD-1 agents off-protocol as next line of therapy,” Adusumilli said.

After up to 21 cycles of treatment with an anti-PD1 agent, two patients had complete metabolic response on PET scans at 60 and 32 weeks, respectively, and these responses are ongoing at the time of this reporting; five patients had partial response; and four had stable disease.

“Combining rationally developed strategies—such as interventional radiology, T-cell genetic engineering, and newer immunotherapy agents—has produced encouraging results and provides rationale to further investigate this approach in aggressive, therapy-resistant cancers such as mesothelioma, for which the currently available treatment options are not optimal,” Adusumilli noted.

A limitation to the study is that this is a phase I trial, and the long-term efficacy of this approach has not yet been established, Adusumilli noted.

Preclinical research leading to this clinical trial and the clinical trial are partly supported by awards from the National Cancer Institute, the Department of Defense, a Stand Up To Cancer (SU2C)-Cancer Research Institute Cancer Immunology Dream Team grant (the AACR is the Scientific Partner of SU2C), and Baker Street Foundation. MSK has licensed mesothelin CARs to Atara Biotherapeutics. MSK has received license fees and has the potential to receive royalties under the license. Adusumilli and Sadelain are inventors and will receive a share of the license income. Adusumilli’s and Sadelain’s labs receive sponsored research funding from Atara Biotherapeutics.

Press Release Published Date: 3/31/2019 7:00 AM
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Riley, CharmaineSun, 31 Mar 2019 11:25:16
HER2-targeted CAR T-cell Therapy Safe, With Promising Antitumor Activity in Patients With Advanced Sarcomahttps://www.aacr.org/Newsroom/Pages/News-Release-Detail.aspx?ItemID=1292

​ATLANTA — A combination of chemotherapy and chimeric antigen receptor (CAR) T cells designed to target the protein HER2 was found to be safe and showed clinical responses in pediatric and adult patients with advanced HER2-positive sarcoma, according to results from a phase I clinical trial presented at the AACR Annual Meeting 2019, March 29–April 3.


“Children and adults with recurrent or refractory sarcomas have limited treatment options,” said Shoba Navai, MD, assistant professor of pediatrics at the Center for Cell and Gene Therapy at Baylor College of Medicine, Texas Children’s Hospital, and Houston Methodist Hospital in Houston. “Depending on the specific type of sarcoma, curative salvage chemotherapy regimens are available, but the chance of success is low and the therapies can be quite toxic.”

Navai is a co-investigator on the trial who presented the work on behalf of a team led by Meenakshi Hegde, MD, assistant professor of pediatrics - hematology and oncology at the Center for Cell and Gene Therapy at Baylor College of Medicine, Texas Children’s Hospital, and Houston Methodist Hospital.

While it is not known what percentage of sarcomas express HER2 on the tumor surface, osteosarcoma, one of the most common types of sarcoma, has been reported to be HER2-positive in up to 40 percent of patients, and HER2-positivity is associated with a higher likelihood of tumor metastasis, Navai explained. Prior clinical studies have shown that HER2-targeted antibodies such as trastuzumab are not effective for these patients. “Our group has previously shown in the laboratory that HER2-directed CAR T cells are better at targeting low levels of HER2 on tumor cells compared with trastuzumab, so these CAR T cells may have antitumor activity in patients with sarcoma even when HER2-antibody therapies do not,” she added.

“Our study shows that HER2-targeted CAR T-cell therapy given in combination with lymphodepletion chemotherapy is safe, and though very early, it shows promising antitumor activity in some patients with advanced HER2-positive sarcomas,” Navai said.

In this trial, Navai, Hegde, and colleagues treated 10 patients, ages 4 to 54, with refractory/metastatic HER2-positive sarcoma (five with osteosarcoma, three with rhabdomyosarcoma, and one each with Ewing sarcoma and synovial sarcoma). Patients had received up to five prior salvage therapies.

Patients received up to three infusions of HER2-targeted CAR T cells after lymphodepletion with either fludarabine or fludarabine and cyclophosphamide; those who had responses to this initial treatment received up to an additional five infusions of CAR T cells without lymphodepletion.

The investigators found that the CAR T cells expanded in all but two patients with a median peak expansion on day 7, and that they could detect the CAR T cells in all patients six weeks after infusion.

One pediatric patient whose rhabdomyosarcoma had metastasized to the bone marrow had a complete response (CR) for 12 months, but relapsed later; retreatment with CAR T cells resulted in a CR that has been ongoing for 17 months. Analysis of this patient’s blood at multiple time points showed antibody responses against several intracellular proteins involved in the cell cycle, cell growth, cell signaling, and in tumor processes such as invasion and metastasis, Navai said. 

“Some antibodies in this patient’s blood were newly detected and maintained after CAR T-cell infusions, suggesting that in addition to the expected direct effect of the CAR T cells targeting HER2 on the tumor, they may have engaged the patient’s own immune system,” she added. “Further studies are needed to identify the specificities and functional significance of these responses.”

One pediatric patient with osteosarcoma that had metastasized to the lungs has an ongoing CR for 32 months. Three patients had stable disease, and five had progressive disease.

Navai noted that overall, the patients on this study had limited treatment-related toxicities. All patients had expected decreases in their blood counts following chemotherapy that subsequently improved, and none developed infections secondary to low blood counts, she added. 

“Importantly, no patients experienced decreased heart function, which has been reported with other types of HER2-targeted therapies. We also did not observe any pulmonary toxicities in our patients despite expansion of the infused CAR T cells,” Navai said.

A limitation to the study is that this is a small phase I trial, and further testing of the HER2-specific CAR T cells in larger cohorts of patients is warranted to define efficacy and optimal dosage, Navai said.

This study was funded by a St. Baldrick’s-Stand Up to Cancer (SU2C) Dream Team Translational Research Grant (the AACR is the Scientific Partner of SU2C), Cookies for Kids’ Cancer, and Cancer Prevention and Research Institute of Texas. Alex’s Lemonade Stand Foundation provided travel and housing for patients enrolled in the study. Navai and Hegde declare no conflicts of interest.



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Riley, CharmaineSun, 31 Mar 2019 11:33:10
Immune Checkpoint Inhibitor Combination Efficacious For Patients With High-grade Neuroendocrine Carcinomahttps://www.aacr.org/Newsroom/Pages/News-Release-Detail.aspx?ItemID=1293

ATLANTA — A combination of the anti-CTLA-4 immunotherapeutic ipilimumab (Yervoy) and the anti-PD-1 immunotherapeutic nivolumab (Opdivo) showed clinical benefit among patients with rare, high-grade neuroendocrine carcinoma, according to results from the DART phase II clinical trial presented at the AACR Annual Meeting 2019, March 29–April 3.


“Rare tumor types, as an aggregate, represent nearly a quarter of all cancers,” said Sandip Patel, MD, associate professor of medicine at the University of California San Diego School of Medicine in La Jolla. “Our study highlights the feasibility of performing clinical trials among patients with rare cancers, and hopefully will help dispel the belief that clinical trials are not feasible for this patient population.

“We were pleased to see that patients with high-grade neuroendocrine carcinoma derived benefit from a combination of the two immune checkpoint inhibitors in the DART trial,” said Patel, who is also a medical oncologist with Moores Cancer Center at UC San Diego Health. “Given that current treatment options for patients with high-grade neuroendocrine carcinoma are generally limited to aggressive chemotherapy regimens, this is an exciting finding for this patient population.”

The aim of the Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART) trial is to evaluate the combinatorial efficacy of ipilimumab (1mg/kg every six weeks) and nivolumab (240mg every two weeks) in patients with rare tumor types. This study summarizes the findings from 33 patients with neuroendocrine tumors, with patients with pancreatic neuroendocrine cancers currently being studied in a separate ongoing cohort of DART. The primary endpoint was overall response rate (ORR); secondary endpoints included progression-free survival (PFS) and overall survival (OS). 
The most common tumor sites were gastrointestinal (15 patients) and lung (six patients); 58 percent (19 patients) had high-grade disease. Patients had received a median of two lines of therapy prior to enrollment in the trial.

In this neuroendocrine cohort, the ORR was 24 percent, which included one complete response (CR) and seven partial responses (PR). All patients who had a CR or PR had high-grade disease. 
“We only observed complete and partial responses among patients with high-grade carcinoma, and one preliminary hypothesis for this finding is that high-grade neuroendocrine carcinomas may have a higher tumor mutational burden, which is an indicator of better response to immunotherapy,” said Patel. “We are planning to verify these results, specifically in patients with high-grade neuroendocrine carcinoma, later this year, as a separate cohort in the DART trial.” 

The six-month PFS was 30 percent, and the median OS was 11 months. The most common toxicities included fatigue (30 percent of patients) and nausea (27 percent of patients). The most common immune-related adverse event (irAE) was grade 3-4 abnormal liver function; no grade 5 irAEs were observed.

Patel noted that an advantage of the DART trial was that patients could be treated at local centers, which was convenient for participants and facilitated their accrual. However, due to this design, there was no central pathology review, which represents a key limitation of the study, he added.

The SWOG Cancer Research Network, part of the National Cancer Institute’s National Clinical Trials Network, created DART and is managing the trial. The DART study is funded by the National Institutes of Health through National Cancer Institute grant awards and in part by Bristol-Myers Squibb.

Patel reports receiving grants from Bristol-Myers Squibb and personal fees from Bristol-Myers Squibb during the conduct of the study; grants from Eli Lilly, Incyte, AstraZeneca/MedImmune, Merck, Pfizer, Roche/Genentech, Xcovery, Fate Therapeutics, Genocea, and Iovance; and personal fees from AstraZeneca, Illumina, Tempus, and Novartis.


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Riley, CharmaineSun, 31 Mar 2019 11:35:41
Adding the MET Inhibitor Savolitinib to Osimertinib was Beneficial for Certain Pretreated Lung Cancer Patients in TATTON Trial https://www.aacr.org/Newsroom/Pages/News-Release-Detail.aspx?ItemID=1294

ATLANTA — Adding the investigational MET inhibitor savolitinib to the EGFR inhibitor osimertinib (Tagrisso) yielded clinical responses in patients who had EGFR-mutant non-small cell lung cancer (NSCLC) that had developed resistance to prior EGFR-targeted therapies through MET-gene amplification, according to interim results from two expansion cohorts of the phase Ib clinical trial TATTON, presented at the AACR Annual Meeting 2019, March 29–April 3.

“To date, targeted therapy for lung cancer patients with EGFR mutations has consisted solely of monotherapy with various EGFR tyrosine kinase inhibitors (TKIs), though we have known for more than 10 years that a proportion of resistance to EGFR TKIs results from activation of the MET bypass pathway,” said Lecia V. Sequist, MD, MPH, a thoracic medical oncologist and director of the Center for Innovation in Early Cancer Detection at Massachusetts General Hospital Cancer Center.

Prior research has shown that MET amplification is a bypass pathway observed in about 5 to 10 percent of patients whose disease has progressed after treatment with first- or second-generation EGFR TKIs and in about 25 percent of those whose disease has progressed after treatment with third-generation EGFR TKIs, Sequist explained.

Prior clinical trials of combinations of EGFR- and MET-targeted therapeutics have not been successful, partly due to the drug combinations studied, and largely because patients were not chosen based on appropriate biomarkers, Sequist said. “In the TATTON trial, newer TKIs that have increased specificity for EGFR and MET are used, and patients with EGFR-mutant NSCLC are required to have documented MET-driven resistance,” she added.

Interim results from two distinct expansion cohorts are presented here. In the first cohort, a combination of osimertinib and savolitinib was tested in patients with EGFR-mutant lung cancer with acquired resistance driven by MET amplification after treatment with a first- or second-generation EGFR TKI; these patients’ tumors were also negative for T790M mutation. In the second cohort, the same combination was tested in patients with EGFR-mutant lung cancer with acquired resistance driven by MET amplification after treatment with osimertinib or another experimental third-generation EGFR TKI.

“Data from the TATTON trial demonstrate for the first time the benefit of adding a MET inhibitor to an EGFR inhibitor in patients with EGFR-mutant NSCLC and with MET-driven acquired resistance,” Sequist said. “The study has shown efficacy of combination targeted therapy in a patient population for whom chemotherapy is the current primary treatment option.

“This finding illustrates the value of careful patient selection in studies of targeted therapies,” Sequist said, adding, “These clinically meaningful responses also demonstrate that as different heterogeneous resistance clones come up, they can in turn be brought under control by tailoring therapy.”

In the cohort of 46 patients who had received prior first- or second-generation EGFR TKI, treatment with osimertinib plus savolitinib yielded an objective response rate (ORR) of 52 percent, with 24 partial responses. The median duration of response (DOR) was 7.1 months.

In the cohort of 48 patients who had received prior third-generation EGFR TKI, treatment with osimertinib plus savolitinib yielded an ORR of 28 percent, with 12 partial responses. The median DOR was 9.7 months.

“Overall the regimen was tolerable, though there was added toxicity with the combination of osimertinib and savolitinib compared to osimertinib given alone, and we saw that some patients discontinued treatment due to toxicity,” Sequist said. The most frequent adverse events were nausea, diarrhea, and lowered numbers of leukocytes and platelets. 

One patient, who had brain metastases, died from kidney failure a few days after starting the combination treatment. The treating investigator considered that this serious adverse event was difficult to evaluate with respect to relation to the study drugs, Sequist said. “Our understanding of the adverse event profile of the osimertinib-savolitinib combination, and how to manage the adverse events, is improving,” she added.

Since the initiation of the TATTON trial, osimertinib was approved for treatment in first-line setting for patients with EGFR-mutant NSCLC. Because of this, only a subset of patients in the trial had received prior first-line osimertinib and had developed MET-driven resistance. “The newly opened phase II SAVANNAH study will further explore the combination of osimertinib plus savolitinib in patients whose disease has progressed on osimertinib and is MET-positive,” Sequist said.

These are early-phase trials and the findings need confirmation in larger trials, Sequist noted.

The TATTON trial was funded by AstraZeneca. Sequist reports consulting agreements with Genentech, Merrimack Pharmaceuticals, AstraZeneca, and Blueprint Medicines; and receiving honorarium from AstraZeneca. Her institution receives research funding on her behalf from AstraZeneca, Novartis, Boehringer Ingelheim, Merrimack Pharmaceuticals, Blueprint Medicines, and LOXO Oncology.

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Riley, CharmaineSun, 31 Mar 2019 11:42:01
Dr. Cornelis J.M. Melief Honored With 2019 AACR-CRI Lloyd J. Old Award in Cancer Immunologyhttps://www.aacr.org/Newsroom/Pages/News-Release-Detail.aspx?ItemID=1289

PHILADELPHIA – The American Association for Cancer Research (AACR) will recognize Cornelis J.M. Melief, MD, PhD, with the seventh AACR-CRI Lloyd J. Old Award in Cancer Immunology during the AACR Annual Meeting 2019, held March 29-April 3 in Atlanta.

Melief is an emeritus professor at the Leiden University Medical Center in the Netherlands, as well as chief scientific officer at ISA Pharmaceuticals. 

He is being recognized for his discovery of mechanisms of immune recognition of cancer antigens and activation of antitumor responses, and for his role in the development of innovative immunotherapies, including a vaccine against the human papillomavirus (HPV), a leading cause of cervical cancer. He currently focuses on developing new immunotherapies and improving their effectiveness through combination therapies.

“Dr. Melief has brought tremendous insight to basic immunology, enhancing our understanding of how the immune system could be used to fight cancer and leading to the development of lifesaving treatments,” said Margaret Foti, PhD, MD (hc), chief executive officer of the AACR. “He is also renowned for his ability to translate his scientific discoveries into clinical practice. Dr. Melief is considered a luminary in the field of cancer immunology, and we are thrilled to honor his brilliant career with this award.” 

Melief has been a member of numerous scientific organizations throughout Europe and the United States. As a member of the AACR, he served as a member of the Immunology Advisory Committee from 2005 to 2011, and as a member of the editorial board of the AACR journal Cancer Research.  

Melief has been recognized with many scientific honors, including the SOFI Prize Leiden in 1986, the AkzoNobel Prize in 1995, the European Federation of Immunological Societies Lecture Award in 2007, the Ceppellini Lecture from the European Society of Immunogenetics in 2009, the William B. Coley Award from the Cancer Research Institute in 2009, and the Queen Wilhelmina Research Prize from the Dutch Cancer Society in 2010. 

Melief earned his doctorate in 1967 and his medical degree in 1970, both from the University of Amsterdam. He conducted postdoctoral research at the Central Laboratory of the Netherlands Red Cross Blood Transfusion Service (CLB) and New England Medical Center Hospital and Dana-Farber Cancer Center. He went on to serve as a scientific staff member of the CLB Amsterdam, leading a newly formed Department of Experimental Tumor Immunology. He then became head of the Division of Immunology at the Netherlands Cancer Institute, then went on to lead the Department of Immunohematology and Blood Transfusion at Leiden University Medical Center. Through the course of his career, he has authored more than 450 peer-reviewed publications and is credited with more than 30 patents or patent applications.

Melief will deliver a lecture titled “Adventures in Cancer Immunology” on Tuesday, April 2, at the Georgia World Congress Center.

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Cohn, SarahSun, 31 Mar 2019 07:29:25