News Releases Prior Chemotherapies May Impair Ability to Develop Effective CAR T Cells

​PHILADELPHIA — Pediatric patients with solid tumors may have poor quality T cells compared to patients with leukemia, and certain chemotherapies were detrimental to the T cells and their potential to become CAR T cells, according to data presented during a media preview for the AACR Annual Meeting 2018, April 14-18, in Chicago, Illinois.

“The FDA approval of tisagenlecleucel (Kymriah), a CD19-targeted chimeric antigen receptor T-cell therapy (CART), was a landmark moment for childhood cancer therapy,” said David M. Barrett, MD, PhD, assistant professor of pediatrics at Children’s Hospital of Philadelphia. “This therapy takes a patient’s own immune cells, called T cells, and modifies them in the lab to wake them up and recognize that patient’s leukemia.

“In several of the patients with leukemia we first attempted to treat, we noticed the T cells looked exhausted when we first collected them and they either did not survive the lab process to turn them into CAR T cells or did not have enough energy left to work in the patient as a result,” he added.

In order to modify T cells into CAR T cells, the T cells from the patient must be healthy enough to survive in the lab and then have enough energy left once returned to the patient to kill their cancer, Barrett explained. “This is important because these children did not have any other therapies that could potentially cure their cancer and we didn’t even get to try in some of them because their T cells were too poor in quality.”

Barrett and colleagues wanted to understand why some children have poor quality T cells. “We were interested in learning what made good starting material for CAR manufacture, rather than repeating prior work on learning what a good CAR T cell looks like after it has been made.”

The team found that T cells that use glutamine and fatty acid pathways as fuel sources had great CAR T-cell potential while those that depended on glycolysis, another fuel source, were poorly suited to the process of CAR T manufacture.

The researchers collected peripheral blood samples from 157 pediatric patients with acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, Wilms tumor, or Ewing sarcoma, at diagnosis and after each cycle of chemotherapy.

The researchers found that the CAR T-cell potential of the T cells was very poor in all tumor types except ALL and Wilms tumor in the pre-chemotherapy samples, and noticed a decline in CAR T-cell potential with cumulative chemotherapy in all cancer types. They found that the T cells with poor CAR T-cell potential were biased toward using glycolysis as their fuel source instead of using fatty acids.

They also found that certain types of chemotherapy were especially harmful to the “spare respiratory capacity” (SRC) of T cells. “SRC is a measure of the energy reserve of a cell, and is based on how many mitochondria are present and how healthy they are,” said Barrett. Mitochondria are the energy generators of a cell. Having a poor energy reserve means the T cell will die before it has finished killing a patient’s cancer or may not even work at all, he said.

“We have gotten CAR T cells to work for leukemias but not yet been very successful in solid tumors. There are a number of potential reasons for this, but our data suggest poor T-cell starting material may be a key first problem,” Barrett noted.

“The T cells from solid tumor patients may need different manufacturing protocols to be successful,” he added.

The researchers conducted preliminary experiments and demonstrated that it is possible to force the T cells to use fatty acids, the preferred source of fuel, to restore the SRC in chemotherapy-exposed T cells. “These early results give us hope we can exploit this during manufacturing of CAR T cells to make highly active products we otherwise would not have from standard manufacturing approaches,” Barrett said.

A limitation of the study is that the researchers did not make CAR T cells from these patients, but used a surrogate small-scale procedure that correlates with CAR T-cell performance. “We have not yet fully validated the metabolic pathways via complete metabolite analysis, though this is underway,” Barrett said.

This study was supported by the AACR-Stand Up To Cancer (SU2C) Innovative Research Grant, the Doris Duke Charitable Foundation CSDA, the Jeffrey Pride Foundation Research Award, and the St. Baldrick’s Foundation Scholar Award. Barrett declares no potential conflicts of interest.

Press Release Published Date: 3/15/2018 8:05 PM
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Loftus, EileenFri, 16 Mar 2018 12:11:25
Acquired HER2 Mutations Confer Resistance to Hormone Therapy in ER-positive Metastatic Breast Cancer

PHILADELPHIA — Mutations in human epidermal growth factor receptor 2 (HER2) were found to confer resistance to hormone therapy in some estrogen receptor (ER)-positive metastatic breast cancer cases, and resistance could be reversed by dual treatment with the hormone therapy fulvestrant and the HER2 kinase inhibitor neratinib, according to data presented during a media preview for the AACR Annual Meeting 2018, April 14-18, in Chicago, Illinois.

“Despite the reduction in breast cancer recurrence and mortality provided by ER-targeted therapies, resistant ER-positive metastatic breast cancer remains the most common cause of breast cancer death because patients invariably develop resistance and stop responding to these drugs,” said Utthara Nayar, PhD, co-lead author and a research fellow in medicine at Dana-Farber Cancer Institute, Harvard Medical School, Boston.

Prior research has identified activating mutations in the ER in approximately 25-30 percent of patients with ER-positive metastatic breast cancer, Nayar explained. “The goal of our study was to identify additional mechanisms of resistance to help us understand how ER-positive breast cancer develops resistance to commonly used therapeutics, thereby aiding the development of new biomarkers for response as well as novel therapeutic strategies for metastatic breast cancer patients.”

As part of an ongoing project at Dana-Farber, Nayar and Ofir Cohen, PhD, co-lead author, postdoctoral researcher and computational biologist at the Broad Institute and Dana-Farber, and colleagues used whole-exome sequencing to study metastatic tumor biopsies from patients with ER-positive metastatic breast cancer with resistance to hormone therapies. Out of the 168 patients examined, the researchers found HER2 mutations in 12 patients. Of these, eight patients had mutations previously identified to be activating. Nayar and colleagues then examined the available pre-treatment primary biopsies and found that four out of five patients with activating mutations had no evidence of pre-existing HER2 mutations, suggesting the acquisition of these HER2 mutations was a result of hormone therapy.

“It was surprising to discover that HER2 mutations can be acquired in the metastatic setting, suggesting that these tumors evolve,” said Nikhil Wagle, MD, senior author, deputy director of the Center for Cancer Precision Medicine at Dana-Farber and assistant professor of medicine at Harvard Medical School, Boston. “These HER2 mutations seem to be a mechanism of resistance to therapies that target the estrogen receptor, which explains the context in which they are acquired.”

With further analysis, the researchers found that resistance to hormone therapy mediated by HER2 mutations could be overcome with the combination of neratinib and the selective ER degrader fulvestrant in vitro. This dual treatment may be an effective therapeutic strategy for breast cancer patients who are resistant to ER-directed therapies with acquired HER2 mutations, noted Nayar.

“The discovery of the acquired HER2 mutation in one patient’s metastatic biopsy prompted enrollment into a phase II trial of fulvestrant plus neratinib, resulting in a partial response lasting six months, consistent with our in vitro findings showing neratinib-induced resensitization to ER-directed therapy,” said Nayar.

“Our study highlights how important it is to profile resistant metastatic tumors, since these tumors may harbor targetable mechanisms of resistance that were not present in the original tumor biopsy,” said Wagle. “Repeated sequencing of tumors can pinpoint new genetic changes that cause resistance to therapies. This in turn can enable physicians to personalize therapy depending on the specific genetic changes in a patient’s tumor over time.”

Limitations of the study include the small number of patients identified with HER2 mutations and the heterogeneity of the tumor biopsies. “These are real-world samples, so the patients had different stages of cancer initially, received different treatments, and had different tumor features,” noted Wagle. Additionally, because treatment-naïve biopsies for all patients were not available, the researchers need to study additional patients to more accurately determine the percentage of patients with HER2 mutations who have acquired or pre-existing mutations.

This work was supported by the Department of Defense, AACR Landon Foundation, NCI Breast Cancer SPORE grant, Susan G. Komen, The V Foundation, The Breast Cancer Alliance, The Cancer Couch Foundation, Breast Cancer Research Foundation, ACT NOW, Fashion Footwear Association of New York, and Dana-Farber/Harvard Cancer Center SPORE grant.

Wagle is a stockholder in Foundation Medicine. Nayar and Cohen declare no conflicts of interest.

Press Release Published Date: 3/15/2018 8:05 PM
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Loftus, EileenFri, 16 Mar 2018 12:19:24
Vulnerable Populations and the Health Care Providers That Serve Them Lack Information About Clinical Trials and Biobanking

PHILADELPHIA — People in Louisiana communities that experience cancer health disparities would be interested in participating in clinical trials or submitting samples to biobanks if provided information about these opportunities by a trusted physician, but physicians reported lacking appropriate information to give to their constituents, according to data presented during a media preview for the AACR Annual Meeting 2018, April 14-18, in Chicago, Illinois.

“Adults from communities that experience cancer health disparities, such as racial and ethnic minority groups, those with low socioeconomic status, and those who live in rural areas, are underrepresented in clinical trials and biobanks,” said Terry C. Davis, PhD, professor of Medicine and Pediatrics at Louisiana State University Health Sciences Center in Shreveport and at the Feist-Weiller Cancer Center, and director of the Health Literacy Core of the Louisiana Clinical & Translational Science Center. “This issue must be addressed if we are to ensure that new treatments are available and effective for all patients in all segments of the population.”

To learn more about why disparities exist in participation in clinical trials and biobanking, Davis and colleagues conducted focus groups and interviews with adults from racial and ethnic minority groups, those with low socioeconomic status, and those who live in rural areas and the health care providers that serve them.

“By talking to adults from populations that are underrepresented in clinical trials, we found that they are open to participating in clinical trials and biobanking, even if it will not benefit them directly, but that they had never been asked to participate and did not know where to learn about participation,” said Davis. “They all agreed that information would be most effective and actionable if given to them by a trusted physician, but when we talked to health care providers in their community, they said that they lacked information to discuss with their patients.

“Our results show that participation of populations underrepresented in clinical trials and biobanking could be enhanced by developing working relationships with community clinics because community providers are the conduit to patient participation,” added Davis. “Structured methods for delivering useful, plain language information on clinical trials and biobanking need to be created collaboratively with community clinics and the public.”

Davis and her colleague Connie L. Arnold, PhD, held 14 focus groups and seven individual interviews from January 2017 to May 2017 in urban and rural communities in Louisiana. Among the 78 patient and community participants, 78 percent were African-American, 24 percent lived in rural communities, and 70 percent reported having lower income. Among the 25 safety-net health care providers who participated, 10 were physicians, seven clinical research associates, five nurse practitioners, and three behavioral health professionals.

Overall, almost all of the patient and community participants stated that they were open to participating in clinical trials and biobanking. Only the two cancer center patients had been asked to participate by their physician. None of the participants had looked for clinical trials on the internet or social media.

Information on clinical trials and biobanking would be most effective coming from a trusted health care provider, according to the patient and community participants. No one suggested the internet would be a useful place to put information.

All the health care providers were interested in learning more about clinical trials and biobanking and wanted closer ties with researchers. The primary care physicians thought that brief, plain language handouts with talking points to discuss and share with patients, together with contact information of a person to call to get more information about participation in a trial or biobanking, would be effective ways to increase participation.

“These results highlight a huge communication gap between the cancer research community and potential participants in cancer genomics studies as well as their providers,” said Davis. “Enhancing communication is a key priority moving forward. Since a trusted provider is essential for enrollment, these trusted providers and their patients need to have access to clear, culturally appropriate, unbiased information on genomics trials, and their potential risks and benefits. This should happen before anyone is asked to participate in a particular study, not during the consent process.”

According to Davis, a main limitation of the study is that this is a pilot study with a limited number of participants in one state. To strengthen the conclusions of the study, the researchers would need to speak with more people from an even more diverse set of communities, such as additional rural areas and those in Hispanic and non-English speaking communities, she said.

This study was supported by funds from a pilot grant from the Feist-Weiller Cancer Center and in part by 2 U54 GM104940 from the National Institute of General Medical Sciences of the National Institutes of Health, which funds the Louisiana Clinical and Translational Science Center. Davis declares no conflicts of interest.

Press Release Published Date: 3/15/2018 8:05 PM
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Loftus, EileenFri, 16 Mar 2018 12:44:19
Chlamydia Infection is Associated With Increased Risk of Ovarian Cancer

​PHILADELPHIA — An antibody that is present in the blood of women previously infected with the sexually transmitted disease chlamydia is associated with a doubling in ovarian cancer risk, according to data presented during a media preview for the AACR Annual Meeting 2018, April 14-18, in Chicago, Illinois.

“Ovarian cancer is a relatively rare cancer, but women who get it face poor survival rates,” said the study’s lead author, Britton Trabert, PhD, MS, Earl Stadtman Investigator in the Division of Cancer Epidemiology and Genetics at the National Cancer Institute (NCI). “We need to understand more about what causes ovarian cancer so that we can improve screening and treatment, and ultimately, improve survival rates.”

Trabert explained that some previous research has shown that pelvic inflammatory disease, which is often caused by sexually transmitted infection, has been associated with ovarian cancer. However, other studies have not found any link between sexually transmitted infections and ovarian cancer. Chlamydia is the most commonly reported sexually transmitted bacterial infection in the United States, so Trabert and colleagues sought to examine possible connections between chlamydia and ovarian cancer. 

The researchers examined data from two different studies: a Polish study of 278 women diagnosed with ovarian cancer between 2000 and 2003, and 556 matched controls; and the NCI-sponsored Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, a nested case-control study with blood draw prior to diagnosis which included 160 women who developed ovarian cancer during follow-up, and 159 matched controls. Using logistic regression, they calculated odds ratios for the association between chlamydia antibodies and ovarian cancer risk.

In both study populations, women who had antibodies against pgp3, a protein considered to be a highly accurate marker of active or prior chlamydia infection, were about twice as likely to have been also diagnosed with ovarian cancer.

Trabert pointed out that the studies also evaluated antibodies against several other infectious agents, including human papillomavirus, herpes simplex virus, hepatitis B, and hepatitis C, and found no association with increased ovarian cancer risk.

“The fact that there were no associations with antibodies against other infectious agents really supports the specificity of the association of chlamydia infection with ovarian cancer,” she said.
Trabert said that the next step is to confirm the findings of this study in larger populations, and to examine whether chlamydia infection is more specifically tied to certain subtypes of ovarian cancer. For example, she said, previous research has shown an association between inflammation, which can be caused by chlamydia infection, and risk for some subtypes of ovarian cancer.

Trabert said the study’s biggest limitation was that the multiplex platform was not able to reliably test for antibodies to Neisseria gonorrhoeae, another known cause of pelvic inflammatory disease.

This study was supported by the NCI Intramural Research Program. Trabert declares no conflicts of interest.  

Press Release Published Date: 3/15/2018 8:05 PM
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Loftus, EileenFri, 16 Mar 2018 12:51:28
AACR Launches Collaborative Initiative to Address Cancer Health Disparities in the African-American Population
PHILADELPHIA — The American Association for Cancer Research (AACR) today announced the launch of a collaborative initiative known as “2020 by 2020”. The initiative will perform genomic sequencing of both tumor and normal tissue from 2,020 consented African-American cancer patients, and aggregate it with clinical data from the patients, by the year 2020, in order to improve our understanding of cancer outcomes in this medically underserved population.

To conduct 2020 by 2020, the AACR is partnering with:
“For all cancers combined, the death rate is 25 percent higher for African-Americans than it is for whites. While there are likely many causes for this, we need to make sure we have tumor DNA sequenced from all patients’ tumors in order to understand these differences in outcomes.” said Michael A. Caligiuri, MD, AACR president, and president of City of Hope National Medical Center in Duarte, California. City of Hope is a member of ORIEN.

To reach the goal, the 2020 by 2020 partners will facilitate the development of an infrastructure for consenting African-American patients to the ORIEN Total Cancer Care Protocol at Morehouse School of Medicine (MSM) in Atlanta. MSM is already a member of ORIEN; the injection of support through the 2020 by 2020 initiative will substantially increase the number of patients that the center can accrue and will allow for the continued collection of material from cancer patients well beyond the year 2020. The data will also be added to the AACR Project GENIE registry, which has already made public 39,600 de-identified genomic records.

AACR Project GENIE and ORIEN will subsequently provide the genomic data generated through the 2020 by 2020 initiative to publicly accessible cancer genome registries for the benefit of academic and industry researchers interested in studying cancer and cancer outcomes in African-American populations. Such research has the potential to deepen our understanding of the causes of cancer health disparities in this population and expedite the development of strategies to address this daunting public health challenge.

“The AACR is extremely proud to lead this very important initiative to help eliminate cancer health disparities,” said Margaret Foti, PhD, MD (hc), chief executive officer of the AACR. “I would like to thank our President, Dr. Caligiuri, for his vision in conceptualizing and spearheading this exciting initiative. We also thank our partners who are contributing vital support to the 2020 by 2020 initiative. By actively collaborating to create this unique, extensive, and freely available data set, they are leading a revolution in cancer health disparities research that holds the promise for significantly enhancing cancer prevention, diagnosis, and treatment in a medically underserved population.”

Press Release Published Date: 3/13/2018 8:00 PM
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Connelly, NancyWed, 14 Mar 2018 01:52:45
Large Variations in Colorectal Cancer Screening Rates Exist Throughout the United States

​PHILADELPHIA — Colorectal cancer (CRC) screening rates varied widely between U.S. states and counties, according to estimates based on 2014 data, which were published in Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research.

“In 2014, nearly 140,000 Americans were diagnosed with colorectal cancer, and over 50,000 Americans died from the disease,” said Zahava Berkowitz, MSPH, MSc, a statistician with the National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention (CDC), Atlanta. “Routine screening for colorectal cancer, starting at age 50, saves lives. However, more than 30 percent of adults have not had recommended colorectal cancer screening.”

The main purpose of the study was to estimate the percentage of adults who are current with colorectal cancer screening in the U.S. at the county level, and to examine geographic patterns in these results. “This analysis can shed light on how close states and counties are to meeting the goal of 80 percent of adults ages 50 and older being regularly screened for colorectal cancer by 2018,” Berkowitz added. The goal of an 80 percent screening rate is shared with the National Colorectal Cancer Roundtable.

Most previous analyses have estimated the prevalence of CRC screening nationally or by state. In this study, Berkowitz and colleagues estimated CRC screening rates in all U.S. counties, which enabled them to identify where CRC screening rates are the lowest.

Using 2014 data from the CDC’s Behavioral Risk Factor Surveillance System (BRFSS), the researchers developed models to estimate CRC screening rates. They used information from 251,360 BRFSS respondents ages 50 to 75 and U.S. Census Bureau population estimates for all 3,142 counties. To be current with screening recommendations, individuals must have completed one of the following: colonoscopy during the past 10 years; fecal occult blood testing (FOBT) during the past year; or sigmoidoscopy during the past five years concurrent with FOBT during the past three years.

Nationwide analysis revealed that 67.3 percent of the adult population ages 50 to 75 was current with CRC screening. Screening varied by ethnicity; 69.2 percent of non-Hispanic whites were current with screening, while only 56.8 percent of Hispanics were current. Colonoscopy was the most popular method of CRC screening, as 63.7 percent of the adult population ages 50 to 75 had undergone the procedure within 10 years.

Model-based state estimates found that Wyoming had the lowest prevalence of any CRC screening (58.9 percent), while Massachusetts had the highest prevalence (75.0 percent).

Model-based county estimates found that the county with the lowest prevalence in any CRC screening was in Alaska (40.1 percent), while the county with the highest prevalence in any CRC screening was found in Florida (79.8 percent). Variability between counties was lowest in Connecticut (a range of 3.6 percent) and highest in South Dakota (a range of 28.6 percent).

“We anticipated county variations of CRC screening rates within the states because we know there are differences between urban and rural areas in adherence to screening recommendations,” noted Berkowitz. “However, we were struck by differences of more than 20 percentage points among counties in some states.

“On a state level, our results identify counties where CRC screening rates are the lowest,” said Berkowitz. “These findings can help guide interventions that could increase CRC screening rates in these areas.”

A limitation of the study is that the data are generated by a model; the results are estimates. “The predicted percentages might be more appropriate for program planning than for program evaluation,” said Berkowitz. “Additionally, our estimates might have overestimated areas with extremely low CRC screening rates and underestimated areas with extremely high CRC screening rates. Lastly, the questions used in the survey did not indicate whether the tests were performed for screening or diagnostic/treatment purposes; the results therefore indicate a measure of CRC test use for any reason.”

The authors declare no conflicts of interest.

Press Release Published Date: 3/1/2018 7:05 PM
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Loftus, EileenFri, 2 Mar 2018 03:53:53
AACR Philadelphia Marathon Celebrates its 25th Anniversary as 2018 Registration Opens

​PHILADELPHIA – City officials announced that registration is now open for the races held during the American Association for Cancer Research (AACR) Philadelphia Marathon Weekend. Runners interested in participating can sign up online

Rated one of the top 10 marathons in the country, the AACR Philadelphia Marathon is celebrating its 25th year as a prime destination for both athletes and history buffs. The weekend begins with the Dietz & Watson Half Marathon, the Rothman 8K run, and the Dunkin’ Munchkin’ Run on Saturday, Nov. 17. The full AACR Philadelphia Marathon will be held on Sunday, Nov. 18, to round out the weekend. Motivated runners can also compete in various challenges by finishing multiple races during the Philadelphia Marathon Weekend. Over 30,000 runners, 60,000 spectators, and thousands of volunteers attend the Philadelphia Marathon Weekend each year. 

“Runners will be able to see some of the most historic and beautiful sights in Philadelphia while running our events,” remarked Leo Dignam, executive director of the Philadelphia Marathon Weekend of Events. He added, “The AACR Philadelphia Marathon is a USATF-certified course and a qualifier for the Boston Marathon.”

The marathon’s title partner, the American Association for Cancer Research (AACR), has introduced a program that enables runners and volunteers to raise funds and awareness for cancer research. The AACR Runners for Research team members will receive VIP entry to the marathon, as well as prizes and free gifts. For more information about the AACR Runners for Research program, contact

“We are excited and humbled to serve as the title partner for the AACR Philadelphia Marathon for the second year in a row—especially as the race celebrates its milestone 25th anniversary,” said Mitch Stoller, AACR Foundation executive director and vice president of philanthropy. “We are determined to make this the largest run in the United States dedicated to cancer research. On behalf of the AACR Foundation, we would be thrilled if you could join our AACR Runners for Research team to truly Make This Run Matter!”

Everyone is encouraged to come to the Philadelphia Marathon Weekend to cheer our runners and enjoy the finish-line festival that features live entertainment, activities for children, Dunkin’ Donuts coffee, Dietz & Watson hot dogs and sausages, and famous Philadelphia food trucks. Stay up-to-date with the latest information. 


Press Release Published Date: 2/26/2018 8:00 AM
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Loftus, EileenMon, 26 Feb 2018 03:13:45
Almost all Adolescents in an Economically Disadvantaged Urban Population Exposed to Tobacco Smoke

PHILADELPHIA — Ninety-four percent of adolescents ages 13 to 19 in an economically disadvantaged, largely minority population in San Francisco had measurable levels of a biomarker specific for exposure to tobacco smoke (NNAL), according to a study published in Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Associ​ation for Cancer Research.

“Exposure of adolescents to secondhand smoke poses a public health challenge because it increases risk for respiratory infections, aggravates asthma, and is linked to an increased likelihood of becoming an active smoker,” said Neal L. Benowitz, MD, professor of medicine and bioengineering and therapeutic sciences, and chief of the Division of Clinical Pharmacology at the University of California, San Francisco (UCSF). “In this study, we set out to assess tobacco smoke exposure among adolescents in an economically disadvantaged population by measuring levels of NNAL in urine samples.

“In a prior study, we showed that 87 percent of this population had evidence of exposure to nicotine, as defined by the presence of cotinine in urine samples,” he added. “Now, using the tobacco-specific biomarker and lung carcinogen NNAL, we find an even higher prevalence of tobacco exposure, which eliminates the possibility that the result with cotinine was due to consumption of nicotine-containing products such as tomatoes, potatoes, eggplant, and black tea.”

Benowitz explained that NNAL is detectable in urine for much longer periods after tobacco exposure compared with cotinine and that it is present only in the urine of people exposed to tobacco. He and his colleagues, therefore, investigated whether NNAL would be a more sensitive biomarker of exposure to secondhand smoke compared with cotinine, more likely to identify adolescents only intermittently exposed.

The researchers measured levels of cotinine and NNAL in urine samples from 465 adolescents who received pediatric care at the Children’s Health Center at Zuckerberg San Francisco General Hospital. Among these adolescents, 91 percent had public health insurance and 8 percent had no health insurance; 53 percent were Latino, 22 percent African-American, 11 percent Asian, and 3 percent white.

Overall, 94 percent of the adolescents had detectable levels of NNAL, compared with 87 percent for cotinine. Thus, using the NNAL biomarker indicated a higher prevalence of tobacco exposure in this population compared with cotinine.

Using a level of more than 30 ng of cotinine per ml of urine as a biomarker of active smoking, which is consistent with prior research, 12 percent of the adolescents were identified as active smokers. Eighty-two percent of the adolescents were identified as nonsmokers who had been exposed to secondhand smoke because they had detectable levels of NNAL but did not have cotinine levels above 30 ng per ml of urine.

The percentage of individuals who were identified as active smokers was highest among the African-American adolescents, 32 percent. In addition, the level of NNAL in the urine of nonsmokers was highest among African-American nonsmokers, suggesting higher levels of secondhand smoke exposure.

“Our data show nearly ubiquitous exposure to tobacco smoke in this population of economically disadvantaged adolescents, which highlights the need for new public health initiatives to reduce exposure,” said Benowitz. “It also suggests that routine urine screening for NNAL or cotinine, with counseling intervention in those screening positive for exposure, could help address this public health challenge.”

According to Benowitz, the main limitations of the study are that it was conducted at a single hospital and that ethnic minorities comprised the majority of the study population, both of which mean the results might not be generalizable to all urban adolescents.

This study was supported by funds from the Flight Attendant Medical Research Institute Bland Lane Center of Excellence on Secondhand Smoke at UCSF, and the National Institute of Health’s National Institute on Drug Abuse and National Center for Research Resources. Benowitz is a consultant to Pfizer and Achieve Life Sciences, which market or are developing medications to aid smoking cessation. He has served as a paid expert witness in litigation against tobacco companies.

Press Release Published Date: 2/22/2018 7:05 PM
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Loftus, EileenFri, 23 Feb 2018 09:23:21
AACR’s Magazine for Patients and Survivors, <i>Cancer Today,</i> Launches a New Website

Cancer Today ( has launched a new website, making it easier for the public to find late-breaking news about cancer research, new cancer therapies, prevention strategies, and clinical trials. Cancer Today, published quarterly by the American Association for Cancer Research (AACR), is the nation’s leading magazine for cancer patients, survivors, and caregivers.

“Through this new website, we expect to become a destination site for anyone who wants to learn more about cancer,” said Kevin McLaughlin, Cancer Today executive editor. “The website will allow us to cover late-breaking news like FDA drug approvals more quickly and offer a platform for more content than is possible in a quarterly magazine. will deliver the same insightful, practical articles that our readers have come to expect from the magazine,” McLaughlin said, “and will extend our mission to serve cancer patients, survivors, and caregivers.”

The Cancer Today website continues to offer the same in-depth analysis of cancer issues, such as off-label prescribing and survivorship concerns, as the printed edition, as well as original stories and videos. The website also provides a filter that readers can use to find what’s relevant to them—advice on their cancer, the latest research updates, or inspiration from reading profiles of cancer survivors and advocates. The site also features Cancer Talk, a blog that lets readers interact with the magazine’s editors and contributors.

“A new and improved Cancer Today website will bolster the AACR’s visibility among the general public,” said Rick Buck, senior director of AACR Communications and Public Relations. “The AACR is the first and largest professional organization in the world dedicated to the prevention and cure of all cancers, and we’ve made a commitment to raise public awareness of the amazing progress being made to help save lives from cancer. The new Cancer Today website will play a vital role in meeting that objective.”

The website’s bold and clear design, created by AAJ Design of Philadelphia, enhances user experience and is easily readable on all platforms. Frequent use of the AACR’s signature green color better integrates the site with the association’s website and the AACR Foundation website. The Cancer Today website was developed by Edgimo, a Boulder, Colorado-based digital strategies firm.

McLaughlin added, “We’re so excited to unveil the new website, and we look forward to continuing to serve the cancer community with timely and accurate news and information about cancer in print and online.”


Press Release Published Date: 2/12/2018 9:00 AM
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Loftus, EileenMon, 12 Feb 2018 02:17:25
The AACR Announces AACR-Johnson & Johnson Lung Cancer Innovation Science Grants

​PHILADELPHIA — The American Asso​ciation for Cancer Research (AACR) is extremely proud to announce the launch of the AACR-Johnson & Johnson Lung Cancer Innovation Science Grants to stimulate research aimed at eradicating this devastating disease. This exciting new funding opportunity, which is supported by the Johnson & Johnson Lung Cancer Initiative, will ignite scientific innovation and transformational advances against lung cancer.

A total of $4.5 million will be made available in research funding in support of meritorious research projects. Three multi-institutional research teams that seek novel approaches to the prevention, interception, and cure of lung cancer will each be awarded up to $1.5 million over a period of three years. The deadline for submission is Wednesday, May 2, at 1 p.m. Eastern Standard Time. Research projects will begin on July 1, 2018.

“Lung cancer is the leading cause of cancer death worldwide, and more research is urgently needed if we are to markedly reduce incidence and mortality from this complex disease. These grants will identify innovative strategies to eliminate behaviors that increase lung cancer risk, devise new ways to intercept a lung cancer-causing process before lung cancer occurs, and develop effective treatments that offer the potential for a cure,” said Margaret Foti, PhD, MD (hc), chief executive officer of the AACR.

Proposals submitted for this important funding opportunity should consider the concepts that lung cancer is often caused by behaviors that lead to: chronic exposure to respiratory carcinogens that produce cellular/genomic damage; chronic inflammation; alterations in innate and adaptive immunity; and changes in the pulmonary microbiome. Consequently, these events may trigger the escape of transformed cells from immune surveillance. Proposals that characterize premalignant lesions or that substantially improve the detection of lung cancer at more curable stages will also be prioritized for funding.

Grant applications will be accepted from multi-institutional teams, composed of principal investigators from at least two, but no more than three, different institutions. Recipients will be notified by June.

Applications must be submitted by 1 p.m. Eastern Standard Time, May 2, 2018, using the proposalCENTRAL website. Further details are available online. Additional inquiries may be directed to the AACR’s Scientific Review and Grants Administration department, at

Press Release Published Date: 2/1/2018 4:10 AM
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Loftus, EileenThu, 1 Feb 2018 09:21:14
American Association for Cancer Research Provides Comments to the FDA on Nicotine Replacement Therapies

​WASHINGTON, D.C.On Friday, January 26, the U.S. Food and Drug Administration (FDA) held a public hearing on the FDA’s approach to evaluating the safety and efficacy of nicotine replacement therapy (NRT) products, including how to promote innovation in these products and how they should be used and labeled. AACR Tobacco and Cancer Subcommittee member Dorothy K. Hatsukami, PhD, Associate Director of Cancer Prevention and Control at the University of Minnesota Masonic Cancer Center, presented a summary of the AACR’s Tobacco and Cancer Subcommittee’s comments to the FDA. The summary of Dr. Hatsukami’s presentation is below.

The AACR Tobacco & Cancer Subcommittee recommends improving the appeal and nicotine delivery of NRT to increase uptake and efficacy of these smoking cessation products. The subcommittee also recommends approving NRT for combination treatments, including use of short-acting and long-acting medications, and considering long-term use of NRT to completely substitute for cigarettes in order to reduce harm to health or to present relapse to smoking. Furthermore, since almost half of smokers who are planning to quit in next 12 months are interested in gradual reduction, the subcommittee recommends that the FDA consider a reduce-to-quit approach with NRT, which has been shown to be more effective than placebo. The AACR is not recommending cigarette reduction that does not lead to complete cigarette cessation as a harm reduction approach. 

Finally, there are significant misperceptions or lack of knowledge among smokers and health care providers regarding the safety of NRT. These misperceptions impact uptake and optimal use of NRT, which ultimately leads to the reduced efficacy of smoking cessation products. Therefore, the Subcommittee recommends adding a simplified label on NRT packages that conveys their relative risk compared to cigarettes, such as “Nicotine replacement therapy is substantially less harmful to health than cigarette smoking,” to clarify these misperceptions and increase smokers’ willingness to use NRT as part of their attempt to quit smoking.

Dr. Hatsukami’s presentation will be archived here. The slides from her presentation to the FDA are available here.

Press Release Published Date: 1/29/2018 4:30 AM
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Loftus, EileenMon, 29 Jan 2018 09:57:18
High Body Fat Levels Are Associated With Increased Breast Cancer Risk in Postmenopausal Women With Normal BMI

​​​Editor’s note: Click here to read the full abstracts for studies featured in the AACR’s press program for the Obesity and Cancer conference.

AUSTIN, Texas — Among postmenopausal women with normal body mass index (BMI), those with higher body fat levels had an increased risk for invasive breast cancer, according to data presented at the American Association for Cancer Research Special Conference Obesity and Cancer: Mechanisms Underlying Etiology and Outcomes, held Jan. 27-30.

"It was previously unknown whether individuals who have a normal BMI but increased body fat have an increased risk of developing cancer," said Neil Iyengar, MD, medical oncologist at Memorial Sloan Kettering Cancer Center. "Our findings show that the risk of invasive breast cancer is increased in postmenopausal women with normal BMI and higher levels of body fat, meaning that a large proportion of the population has an unrecognized risk of developing cancer." Neil Iyengar, MD

"Body fat levels are typically measured via BMI, which is a ratio of weight to height. While BMI may be a convenient method to estimate body fat, it is not an exact way to determine whole body fat levels, as muscle mass and bone density cannot be distinguished from fat mass," said Thomas Rohan, MBBS, PhD, DHSc, professor and chair, Department of Epidemiology and Population Health at Albert Einstein College of Medicine. Dual energy X-ray absorptiometry (DXA) is a technology that can specifically measure for fat content, resulting in a more accurate assessment of total body fat levels, he explained.

The investigators analyzed data from the Women's Health Initiative (WHI), an observational study that follows the health of postmenopausal women ages 50-79. The study included participants who had a normal BMI (between 18.5 to <25.0) with baseline DXA measurements and no history of breast cancer.

During the median 16 years of follow-up, study participants were assessed for the development of invasive breast cancer, and cancer cases were evaluated for estrogen receptor (ER) positivity. Of the 3,460 participants in the study, 182 developed invasive breast cancer during follow-up; 146 of these cases were ER-positive.

In multivariable analysis, compared to women in the lowest quartile of whole body fat mass, women in the highest quartile had approximately a doubling in the risk for ER-positive breast cancer.

Iyengar and colleagues also found that the risk of ER-positive breast cancer increased by 35 percent for each 5-kilogram increase in whole body fat, despite having a normal BMI. "It is also notable that the level of physical activity was lower in women with higher amounts of body fat," said Iyengar. "This suggests that physical activity may be important even for those who are not obese or overweight."

"These findings will probably be surprising to many doctors and patients alike, as BMI is the current standard method to assess the risks for diseases related to body weight," said Andrew Dannenberg, MD, associate director of Cancer Prevention at the Sandra and Edward Meyer Cancer Center of Weill Cornell Medicine. "We hope that our findings will alert women to the possibility of increased breast cancer risk related to body fat, even if they have a healthy weight."

A limitation to the study is that the researchers were unable to analyze how changes in body fat over time related to breast cancer risk. The authors noted that findings from this study are limited to postmenopausal women and are not generalizable to other populations or other cancers.

Several authors of this study are supported by the Breast Cancer Research Foundation. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services. The investigators declare no conflicts of interest.

Press Release Published Date: 1/25/2018 7:05 PM
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Loftus, EileenThu, 25 Jan 2018 03:57:07
Predicted Rise in Canadian Obesity Rate May Lead to Higher Cancer Burden

​​Editor’s note: Click here to read the full abstracts for studies featured in the AACR’s press program for the Obesity and Cancer conference.

AUSTIN, Texas — Reducing the number of overweight and obese Canadians by 50 percent could potentially prevent a cumulative 59,829 cases of cancer by 2042, according to estimates presented at the American Association for Cancer Research Special Conference Obesity and Cancer: Mechanisms Underlying Etiology and Outcomes, held Jan. 27-30.

“Cancer is the leading cause of death in Canada, and several cancer types have strong associations with excess body weight; yet the number of Canadians who are overweight or obese is increasing,” said Darren Brenner, PhD, assistant professor in the departments of Oncology and Community Health Sciences at Cumming School of Medicine, University of Calgary, Alberta, Canada. Darren Brenner, PhD

Brenner is part of a collaborative group from multiple institutions across Canada working together on the Canadian Population Attributable Risk of Cancer Project (ComPARe). The goal of this project is to estimate how many new cases of cancer are caused by 25 different risk factors, including lifestyle factors such as diet, body size, and physical activity, and how many could be avoided over the next 30 years if changes in behaviors were made, Brenner said.

Using population-level data and statistical approaches, Brenner and colleagues first projected the number of Canadians with excess body weight (overweight plus obesity) over the next 30 years. They found that in 2011, the prevalence of overweight and obesity in Canada was 32.7 percent and 17.8 percent, respectively.
“If current trends continue, by 2032, the prevalence of overweight and obesity will be 31.2 percent and 27.9 percent, respectively,” Brenner noted.

Using data from 2012, the researchers estimated that 8,626 cancer cases (3,886 for men and 4,740 for women) were attributable to excess body weight, accounting for 9.4 percent of the 91,373 associated cancer cases (8.8 percent for men and 10.1 percent for women). The researchers then projected that in 2042, 15,747 cancer cases for men and 10,312 cancer cases for women would be attributable to excess body weight, accounting for 10.8 percent of the 146,260 associated cancer cases in men and 11.2 percent of the 92,233 associated cancer cases in women.

“After projecting the future prevalence of excess body weight and cancer incidence attributable to excess body weight, we asked how the trends in excess body weight could be influenced by effective interventions,” said Brenner.

The team studied scenarios of interventions that would reduce the prevalence of excess body weight by 10, 25, and 50 percent by 2042 and then estimated the cancer burden under these new scenarios. “The difference in cancer incidence between our projected data and our ‘prevention’ scenarios would be the future potential for cancer prevention,” Brenner explained. The scenarios were meant to simulate population-level implementation of existing intervention programs, policy changes to impact healthy behavior decision making, or a return to obesity levels in 1990.

The researchers found that if it is possible to intervene on excess body weight and reduce the prevalence of both overweight and obesity by 10, 25, and 50 percent, it would be possible to prevent 1,660, 4,150, and 8,300 cancer cases in 2042, and a cumulative number of 11,966, 29,914, and 59,829 cancer cases by 2042, respectively.

“Our data provide alarming estimates of the consequences of inaction in Canada,” Brenner said. “The results of this study will inform policymakers, public health officials, and the Canadian population with targets to lower future cancer burden.”

According to Brenner, limitations of the study are that the estimates of overweight and obesity used in this study were based on self-reported data, and that the researchers assumed a latency period of 10 years between exposure to a risk factor and cancer diagnosis, which is a potential over-simplification since the latency period for some exposures is longer.

This study was funded by a Canadian Cancer Society Research Institute Partner Prevention Research Grant. Brenner declares no conflict of interest.

Press Release Published Date: 1/25/2018 7:05 PM
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Loftus, EileenThu, 25 Jan 2018 04:04:32
Quality of Children’s Sleep May Affect Eating Habits and Weight

Editor’s note: Click here to read the full abstracts for studies featured in the AACR’s press program for the Obesity and Cancer conference.

AUSTIN, Texas — Several measures of poor sleep quality were associated with higher body mass index (BMI) in children, according to data presented at the American Association for Cancer Research Special Conference Obesity and Cancer: Mechanisms Underlying Etiology and Outcomes, held Jan. 27-30.

About one in five children between the ages of 6 and 19 is obese, according to recent statistics from the Centers for Disease Control and Prevention. The percentage of U.S. children with obesity has more than tripled since the 1970s, with significant immediate and long-term effects.

“Childhood obesity very often leads to adult obesity,” said the study’s lead author, Bernard Fuemmeler, PhD, MPH, professor and associate director for cancer prevention and control at Virginia Commonwealth University’s Massey Cancer Center. “This puts them at greater risk of developing obesity-related cancers in adulthood.” Bernard Fuemmeler, PhD, MPH

Fuemmeler explained that previous research has shown that sleep patterns play a role in obesity in adults, but most research exploring the connection between sleep and obesity in children has focused on the duration of sleep, rather than the way quality of sleep or circadian patterns affect eating behaviors and weight. 

In this study, Fuemmeler and colleagues enrolled 120 children whose mothers had participated in the Newborn Epigenetic Study, a federally funded project that examines how environmental exposures and nutrition, both pre-birth and during early childhood, affect how genes work. The average age of the children was 8. Researchers controlled for age, sex, race, and maternal education as an indicator of socioeconomic status.

To track the sleep-wake cycle, the children wore accelerometers continuously for 24 hours per day for a period of at least five days. To gauge eating habits, children completed the “eating in the absence of hunger test.” Children ate a meal and reported when they were full; the researchers then tracked how much food they ate once they had reached the point of satiety.

The researchers found:

  • Shorter sleep duration, measured in hours, was associated with a higher BMI z-score (body mass index adjusted for age and sex). Each additional hour of sleep was associated with a .13 decrease in BMI z-score, and with a 1.29 centimeter decrease in waist circumference.
  • More fragmented rest-activity rhythms and increased intradaily variability, a measure of the frequency and extent of transitions between sleep and activity, were also associated with greater waist circumferences.
  • Earlier onset of the most active period during daytime, diurnal activity, was associated with higher intake of calories once the children had reached the point of satiety.

Overall, Fuemmeler said, the study results indicate that while sleep duration is important, examining markers of sleep quality may also be useful in designing childhood obesity prevention strategies.

“Today, many children are not getting enough sleep,” Fuemmeler said. “There are a number of distractions, such as screens in the bedroom, that contribute to interrupted, fragmented sleep. This, perpetuated over time, can be a risk factor for obesity. Because of the strong links between obesity and many types of cancer, childhood obesity prevention is cancer prevention, in my view.”

Fuemmeler said that while further research is necessary to understand more about the way poor sleep affects weight, families would benefit from following guidelines established by the American Academy of Pediatrics.

The study’s primary limitation is that it did not include prospective data that might have helped researchers assess whether sleep quality influences weight gain or weight in children affects their sleep. Fuemmeler said that data will be encompassed in future studies.

Scott Kollins, PhD, and Jessica Lunsford-Avery, PhD, Duke University, also contributed to the development of this work. The study was funded by a grant from the National Institute of Child Health and Human Development. Fuemmeler and co-authors have no conflicts of interest.

Press Release Published Date: 1/25/2018 7:05 PM
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Loftus, EileenThu, 25 Jan 2018 04:16:19
Obese Men May Have Higher Chance of Recurrence Following Radical Prostatectomy

Editor’s note: Click here to read the full abstracts for studies featured in the AACR’s press program for the Obesity and Cancer conference.

AUSTIN, Texas — Among men with prostate cancer who underwent radical prostatectomy (RP), those who were obese had a higher risk of biochemical recurrence, according to data presented at the American Association for Cancer Research Special Conference Obesity and Cancer: Mechanisms Underlying Etiology and Outcomes, held Jan. 27-30.

Biochemical recurrence was defined as two consecutive prostate-specific antigen (PSA) measurements of ≥ 0.2 ng/mL after prostatectomy, which is indicative of recurrent prostate cancer.

“Obesity and metabolic syndrome have become increasingly widespread in our society,” said Arash Samiei, MD, basic scientist and clinical researcher at the Department of Urology at the Allegheny Health Network in Pittsburgh. “Prostate cancer is the most common cancer in men, and up to 30 percent of patients will develop recurrence after RP. We wanted to investigate the association between obesity and metabolic syndrome with the oncological outcome following prostate removal.” Arash Samiei, MD

Samiei explained that previous studies linking high body mass index (BMI) and metabolic syndrome to increased risk of recurrence following RP have been controversial. To build upon previous research, Samiei and colleagues performed a large study with long-term follow-up to conduct a more comprehensive analysis.

Samiei and colleagues conducted a retrospective study of all RPs (1,100 surgeries) performed by two surgeons at Allegheny General Hospital in Pittsburgh between 2003 and 2013. They analyzed Gleason score, pathologic stage, pre-operative PSA, biochemical recurrence time, surgical margin status, and metabolic factors, such as fasting glucose, triglycerides, cholesterol levels, including HDL, pre-operative BMI, and blood pressure.

Patients were categorized as having low-, intermediate-, or high-risk prostate cancer based on pathological staging and grading of the disease. Metabolic syndrome positivity was determined using the World Health Organization (WHO) classification, where at least three out of the following five factors are simultaneously present in an individual – insulin resistance or type 2 diabetes, obesity, high cholesterol or low HDL levels, high triglycerides, and hypertension. The average age of the patient at diagnosis was 60 years, and the average follow-up time was 48 months.

Among the patients studied, 34 percent were obese, as defined by BMI, and 19 percent had metabolic syndrome.

Samiei and colleagues found a higher percentage of obese patients in the high-risk group (41.2 percent of high-risk patients) compared to obese patients in the low/intermediate group (32 percent of low/intermediate risk patients). Additionally, biochemical recurrence was higher in patients with BMI ≥30 (32.4 percent) compared to patients with BMI <30 (16.9 percent). Finally, patients with metabolic syndrome had more than four-fold increased risk of biochemical recurrence compared to those without metabolic syndrome.

“Our study indicates that prostate cancer patients who are obese or have metabolic syndrome undergoing RP may have a higher chance for recurrence of the disease, and these individuals should have more focused follow-up care,” said Samiei. “By preventing metabolic syndrome, men with prostate cancer may have a higher chance of a favorable oncological outcome following surgery.”

Samiei noted that because this was an observational, retrospective study, future work should include the design of large, multi-center prospective studies.

This study was sponsored by the Western Pennsylvania Prostate Cancer Foundation. Samiei declares no conflicts of interest.

Press Release Published Date: 1/25/2018 7:05 PM
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Loftus, EileenThu, 25 Jan 2018 04:23:49
AACR Names Dr. Chi Van Dang as Editor-in-Chief of Cancer Research Journal

PHILADELPHIA — The American Associa​tion for Cancer Research (AACR) is pleased to announce the appointment of Chi Van Dang, MD, PhD, as editor-in-chief of its Cancer Research journal. Published under different titles in its early years, Cancer Research was the first English-language journal to be published in the field of oncology and is arguably the most influential cancer research journal in the world today.

Dang is the scientific director of the Ludwig Institute for Cancer Research, an international, not-for-profit organization of distinguished scientists dedicated to preventing and controlling cancer.  He is also a professor in the Molecular and Cellular Oncogenesis Program at The Wistar Institute in Philadelphia. Dang officially began his term as editor-in-chief of Cancer Research on Jan. 1, and his inaugural editorial can be found here.

“Dr. Dang is a prominent and highly regarded physician-scientist, and the American Association for Cancer Research is thrilled to welcome him in his role as editor-in-chief of Cancer Research,” said Margaret Foti, PhD, MD (hc), chief executive officer of the AACR. “His extensive expertise as a cancer scientist and hematologic oncologist and his 20 years of clinical academic leadership experience at preeminent research institutions will further the success and impact of this important journal and accelerate the pace of progress against cancer.”

Cancer Research publishes original studies, reviews, and opinion pieces spanning the spectrum of cancer research. This semi-monthly journal has a stringent peer review process, accepting only those studies that are novel, timely, and of broad significance in the field.

“I am delighted to assume responsibility for this influential journal at a time when cancer research is providing hope that allows us to begin to use the word ‘cure’ without trepidation,” Dang said. “Together with the newly assembled editorial board, I look forward to promoting major scientific findings that embrace innovative research paradigms and team science.”

Dang is a pioneer in biomedical cancer research. His lab was the first to report a link between an oncogene and altered cancer cell metabolism through the discovery that the oncogenic transcription factor MYC plays a pivotal role in the re-programming of fuel utilization in cancer cells, making cancers addicted to certain fuel sources. Research in the Dang laboratory currently focuses on exploiting metabolic vulnerabilities of cancer cells for therapeutic benefit.

Dang received his bachelor’s degree in chemistry from the University of Michigan, Ann Arbor; PhD in chemistry from Georgetown University, Washington, D.C.; and his MD from the Johns Hopkins University School of Medicine, Baltimore. He has published two books, numerous book chapters, and more than 250 scientific articles. Dang is also the recipient of numerous honors. He was appointed to the Blue Ribbon Panel of former Vice President Joe Biden’s National Cancer Moonshot Initiative, is a fellow of the American Academy of Arts and Sciences, a member of the National Academy of Medicine (Institute of Medicine), and chair of the National Cancer Institute’s Board of Scientific Advisors.

Press Release Published Date: 1/11/2018 5:00 AM
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Loftus, EileenThu, 11 Jan 2018 10:08:04
Female Night Shift Workers May Have Increased Risk of Common Cancers

​PHILADELPHIA — Night shift work was associated with women having an increased risk of breast, skin, and gastrointestinal cancer, according to a meta-analysis published in Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research.

“By systematically integrating a multitude of previous data, we found that night shift work was positively associated with several common cancers in women,” said Xuelei Ma, PhD, oncologist at State Key Laboratory of Biotherapy and Cancer Center, West China Medical Center of Sichuan University, Chengdu, China. “The results of this research suggest the need for health protection programs for long-term female night shift workers.”

Ma explained that because breast cancer is the most diagnosed cancer among women worldwide, most previous meta-analyses have focused on understanding the association between female night shift workers and breast cancer risk, but the conclusions have been inconsistent. To build upon previous studies, Ma and colleagues analyzed whether long-term night shift work in women was associated with risk for nearly a dozen types of cancer.

Ma and colleagues performed a meta-analysis using data from 61 articles comprising 114,628 cancer cases and 3,909,152 participants from North America, Europe, Australia, and Asia. The articles consisted of 26 cohort studies, 24 case-control studies, and 11 nested case-control studies. These studies were analyzed for an association between long-term night shift work and risk of 11 types of cancer. A further analysis was conducted, which looked specifically at long-term night shift work and risk of six types of cancer among female nurses.

Overall, long-term night shift work among women increased the risk of cancer by 19 percent. When analyzing specific cancers, the researchers found that this population had an increased risk of skin (41 percent), breast (32 percent), and gastrointestinal cancer (18 percent) compared with women who did not perform long-term night shift work. After stratifying the participants by location, Ma found that an increased risk of breast cancer was only found among female night shift workers in North America and Europe.

“We were surprised to see the association between night shift work and breast cancer risk only among women in North America and Europe,” said Ma. “It is possible that women in these locations have higher sex hormone levels, which have been positively associated with hormone-related cancers such as breast cancer.”

Among female nurses alone, those who worked the night shift had an increased risk of breast (58 percent), gastrointestinal (35 percent), and lung cancer (28 percent) compared with those that did not work night shifts. Of all the occupations analyzed, nurses had the highest risk of developing breast cancer if they worked the night shift.

“Nurses that worked the night shift were of a medical background and may have been more likely to undergo screening examinations,” noted Ma. “Another possible explanation for the increased cancer risk in this population may relate to the job requirements of night shift nursing, such as more intensive shifts.”

The researchers also performed a dose-response meta-analysis among breast cancer studies that involved three or more levels of exposure. They found that the risk of breast cancer increased by 3.3 percent for every five years of night shift work.

“Our study indicates that night shift work serves as a risk factor for common cancers in women,” said Ma. “These results might help establish and implement effective measures to protect female night shifters. Long-term night shift workers should have regular physical examinations and cancer screenings.

“Given the expanding prevalence of shift work worldwide and the heavy public burden of cancers, we initiated this study to draw public attention to this issue so that more large cohort studies will be conducted to confirm these associations,” he added.

A limitation of this work is a lack of consistency between studies regarding the definition of “long-term” night shift work, with definitions including “working during the night” and “working at least three nights per month.” Additional limitations include significant between-study heterogeneity and publication bias.

Ma declares no conflict of interest.

Press Release Published Date: 1/7/2018 7:05 PM
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Loftus, EileenFri, 5 Jan 2018 05:09:10
Mutational Signatures May Identify Patients with Breast Cancer Most Likely to Benefit from Platinum-based Chemotherapy

PHILADELPHIA — The presence in advanced breast cancer of mutational signatures characteristic of homologous recombination deficiency (HRD) was associated with improved clinical outcomes to treatment with platinum-based chemotherapy, according to results published in Clinical Cancer Research, a journal of the American Association for Cancer Research.

“Many patients with breast cancer, especially those with the difficult-to-treat triple-negative subtype, are treated with platinum-based chemotherapies like cisplatin, but not all have responses to this treatment,” said Steven J.M. Jones, PhD, head of bioinformatics and codirector of Canada’s Michael Smith Genome Sciences Centre at BC Cancer in Vancouver, British Columbia. “If we could better identify those who are likely to respond to platinum-based chemotherapy, we could optimize patient treatment.

“We found that whole-genome sequencing of breast cancers can reveal mutational patterns characteristic of HRD that identify patients who are likely to respond well to platinum-based chemotherapies,” added Jones. “As whole-genome sequencing becomes more affordable, this presents an opportunity to improve breast cancer treatment.”

Homologous recombination is one of several cellular mechanisms by which normal cells repair damaged DNA. Deficiencies in this pathway occur in many cancers, including the 5 to 10 percent of breast cancers with hereditary BRCA1 and BRCA2 mutations. In cells that are deficient in homologous recombination, the DNA develops signature mutational patterns, said Jones.

Because it is known that platinum-based chemotherapy is particularly effective for patients with BRCA1 or BRCA2 mutations, Jones; Eric Y. Zhao, a graduate student in Jones’ laboratory; and colleagues set out to determine whether genomic mutational patterns characteristic of HRD, which are found in as many as 20 to 40 percent of breast cancers, may also be associated with good responses to platinum-based chemotherapy.

The researchers performed whole-genome sequencing on tumor tissue and matched normal tissue from 93 patients with breast cancer, 33 of whom had been treated with a platinum-based chemotherapy. After analyzing the data for the presence of six HRD-associated mutational signatures, they used a mathematical model called HRDetect, previously shown to predict BRCA1 and BRCA2 deficiency, to calculate an HRDetect score for each breast cancer. Nineteen breast cancers had high HRDetect scores (greater than0.7), 37 had moderate scores (0.005–0.7), and 37 had low scores (less than 0.005).

“Importantly, all seven cancers with pathogenic BRCA1 or BRCA2 mutations had high HRDetect scores,” said Jones. “Thus, our study validated HRDetect using an independent cohort, which is important because whole-genome sequencing protocols can be variable across institutions.”

Further analysis showed that after adjusting for BRCA1/2 mutation status, high HRDetect scores were significantly associated with clinical improvement, as assessed by radiographic tumor shrinkage, following platinum-based chemotherapy. Among the 26 patients who had been treated with a platinum-based chemotherapy and for whom imaging data were available, clinical improvement was observed for eight of the 11 patients whose breast cancers had high HRDetect scores but only two of the 15 patients whose breast cancers had moderate or low HRDetect scores. Three of the eight patients with high HRDetect scores who had clinical improvement had known or likely pathogenic BRCA1 or BRCA2 mutations.

The median total duration on platinum-based chemotherapy and median overall survival was 3 months and 1.3 years longer, respectively, for those with high HRDetect scores compared with those with low HRDetect scores. However, the authors cautioned that these results should be interpreted carefully as they were calculated based on data from a small number of patients.

According to Jones, the main limitation of the study is that it was observational, meaning that the researchers examined a patient cohort for a clinically meaningful correlation, and that it, therefore, does not establish causation. He explained that establishing causation would require a randomized controlled trial but that the findings of their study will likely be helpful in the design of such a trial.

This study was supported by funds from the BC Cancer Foundation. Contributions toward equipment and infrastructure came from the Canada Foundation for Innovation and the BC Knowledge Development Fund. Jones declares no conflicts of interest.

Press Release Published Date: 12/18/2017 10:45 AM
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Beveridge, MichaelMon, 18 Dec 2017 03:36:32
First-in-class ERK1/2 Inhibitor Safe, Shows Early Efficacy in Patients With Advanced Solid Tumors

​PHILADELPHIA — The novel ERK1/2 kinase inhibitor ulixertinib displayed an acceptable safety profile and had clinical activity in patients whose tumors had mutations in the MAPK cell-signaling pathway, according to data from a phase I clinical trial published in Cancer Discovery, a journal of the American Association for Cancer Research.

“A great number of cancers, including melanoma and lung cancers, have mutations in the MAPK/ERK pathway, and while current therapies target proteins in this cascade, many patients develop resistance to current drugs,” said Ryan J. Sullivan, MD, assistant professor of hematology and oncology and member of the Termeer Center for Targeted Therapies at Massachusetts General Hospital. “The common denominator in these failed therapies is that the cancer has found a way to activate ERK. Therefore, the development of ERK inhibitors is a crucial next step to target this aberrant pathway.”

The MAPK/ERK pathway is essential for key cellular processes, and mutations along this pathway may result in uncontrolled cellular growth, which can lead to cancer. The RAS gene, an upstream regulator within the MAPK/ERK cascade, is mutated in roughly 30 percent of human cancers. Mutations in BRAF, another gene in this pathway, often occur at codon V600 in malignant melanoma, where combined BRAF/MEK inhibition is the current standard of care. Atypical BRAF mutations (non-V600) are found in a variety of cancers. There is no targeted therapy for patients with atypical BRAF-mutant cancers, said Sullivan.

The ERK gene is the final regulator in the MAPK/ERK pathway, and when upstream inhibition of this protein cascade fails, ERK signaling is reactivated, resulting in renewed MAPK signaling, Sullivan explained. “Targeting ERK for inhibition may allow the opportunity to thwart resistance from upstream mechanisms,” he noted. Preclinical studies had shown ERK inhibition to overcome resistance to BRAF and MEK inhibitors.

Sullivan and colleagues tested the ERK inhibitor ulixertinib in an open-label, first-in-human study. They enrolled 27 patients in the dose-escalation phase and 108 in the dose-expansion phase. All patients had advanced solid tumors, and more than 65 percent had BRAF-mutant cancers. Of the patients, 24 percent had received prior BRAF and/or MEK therapy and 51 percent had received prior immunotherapy. 

In the dose-escalation phase, the recommended phase II dose (RP2D) of ulixertinib was determined to be 600mg twice daily. The dose-expansion portion of the trial tested the RP2D of ulixertinib in six groups of patients whose tumors had BRAF, NRAS, or MEK mutations, the majority of whom were not treated with prior MAPK-targeted therapy. Partial responses (PR) were seen in 12 percent and 14 percent of evaluable patients in the dose-escalation and dose-expansion cohorts, respectively. PR and/or disease stabilization was seen in all groups, including solid tumors with atypical BRAF mutations.

“It was exciting to see responses in some patients, especially those with non-V600 BRAF mutations,” said Sullivan. “We also saw responses in some patients with BRAF V600 mutant melanoma who had progressed on prior BRAF/MEK inhibitor therapy. ERK inhibition may be a potential way forward for these populations.”

Patients treated at the RP2D had near-complete inhibition of ERK as verified in blood samples. Side effects were comparable to other MAPK inhibitors, and the most common treatment-related adverse event (AE) was rash. No AEs above grade 3 were observed.

“This study shows that ulixertinib is tolerable and has activity in a subset of patients with mutations in the MAPK pathway,” said Sullivan. “The results of this study can be built upon to develop better treatment regimens for these patients.”

Sullivan anticipates that ERK inhibitors will likely be used in combinatorial therapies, and they may supplement pre-existing regimens, such as BRAF/MEK inhibition. “I think we’ll see very complex combinations tailored to specific cancer subtypes, and ERK inhibitors deserve to be part of the repertoire,” Sullivan said.

Based on data from this trial, ulixertinib has received the U.S. Food and Drug Administration’s Fast Track designation.

Limitations of the study include a small pool of expansion cohorts, as is consistent with a phase I trial, and lack of tumor pharmacodynamic analysis.

This study was sponsored by BioMed Valley Discoveries, in which several authors are or were employed. Sullivan declares no potential conflicts of interest.

Press Release Published Date: 12/14/2017 7:05 PM
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Loftus, EileenThu, 14 Dec 2017 04:07:52
Oral Microbiota Indicates Link Between Periodontal Disease and Esophageal Cancer

​PHILADELPHIA — An analysis of bacteria present in the mouth showed that some types of bacteria that lead to periodontal disease were associated with higher risk of esophageal cancer, according to a study published in Cancer Research, a journal of the American Association for Cancer Research.  

Esophageal cancer is the eighth most common cancer and the sixth leading cause of cancer death worldwide, said the study's lead author, Jiyoung Ahn, PhD, an associate professor and associate director for population science at the Laura and Isaac Perlmutter Center at NYU Langone Health in New York. Because the disease is often not discovered until it has reached an advanced stage, five-year survival rates range from about 15 to 25 percent worldwide.

"Esophageal cancer is a highly fatal cancer, and there is an urgent need for new avenues of prevention, risk stratification, and early detection," Ahn said.

Previous research has shown that periodontal disease caused by certain oral microbiota has been associated with several types of cancer, including oral and head and neck cancers.

In order to determine whether oral microbiota were associated with subsequent risk of esophageal adenocarcinoma (EAC) or esophageal squamous cell carcinoma (ESCC), Ahn and colleagues collected oral wash samples from 122,000 participants in two large health studies: the National Cancer Institute Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial and the American Cancer Society Cancer Prevention Study II Nutrition cohort. 

In 10 years of follow-up, 106 participants developed esophageal cancer. In a prospective case-control study, the researchers extracted DNA and sequenced oral wash samples, allowing researchers to compare the oral microbiomes of the esophageal cancer cases and the cancer-free cases.

Certain bacteria types were associated with higher risk of esophageal cancer. For example, higher levels of the Tannerella forsythia bacteria were associated with a 21 percent increased risk of EAC. The bacteria Porphyromonas gingivalis was associated with a higher risk of ESCC. Both species of bacteria are linked with common gum disease, Ahn noted.

The study showed that a few types of oral bacteria were associated with lower risk of esophageal cancer. For example, the Neisseria bacteria was associated with lower risk of EAC. Ahn said this indicates that certain bacteria may have a protective effect, and future research could potentially examine whether these bacteria could play a role in preventing esophageal cancer.

"Our study indicates that learning more about the role of oral microbiota may potentially lead to strategies to prevent esophageal cancer, or at least to identify it at earlier stages," Ahn said. "The next step is to verify whether these bacteria could be used as predictive biomarkers."

Ahn added that the study confirms that good oral health, including regular tooth brushing and dental visits, is an important way to guard against periodontal disease and the growing list of health conditions associated with it.

The study's primary limitation is that the researchers did not have complete information on the participants' oral health. Therefore, they could not determine whether the presence of pathogens was enough to affect esophageal cancer risk, or whether full-blown periodontal disease was the risk factor.

The study was funded by the National Cancer Institute. The Cancer Prevention Study II is funded by the American Cancer Society. Ahn declares no conflicts of interest.

Press Release Published Date: 12/10/2017 7:05 PM
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Loftus, EileenMon, 11 Dec 2017 03:01:34
Lymph Node Surgery May Raise Risk of Arm Morbidity in Younger Women

​SAN ANTONIO — Younger breast cancer patients who underwent axillary lymph node dissection were more likely to experience arm swelling and decreased range of arm motion than patients who received sentinel lymph node biopsies, according to data presented at the 2017 San Antonio Breast Cancer Symposium, held Dec. 5–9.

“Breast cancer is the most common form of cancer in women under the age of 40, but younger breast cancer patients are frequently underrepresented in clinical trials,” said the study’s lead author, Anne Kuijer, PhD, a postdoctoral research fellow at Dana-Farber Cancer Institute/Brigham and Women’s Hospital, and a surgical resident at Diakonessen Hospital Utrecht, Netherlands. “As a result, little is known about optimal treatment strategies and comorbidities, such as arm swelling and decreased range of motion, in younger patients.

“These issues are of particular importance in these patients given their long survivorship period, frequently active lifestyle, and the importance of body image,” Kuijer added.

Many breast cancer patients undergo axillary surgery to determine whether the breast cancer has spread to nearby lymph nodes. Traditionally, women with involved lymph nodes have undergone a more extensive axillary lymph node dissection (ALND). In recent years, studies have shown that the less invasive sentinel lymph node biopsy (SLNB) procedure is safe in selected breast cancer patients with no or limited nodal involvement upon diagnosis.

To assess the incidence of arm morbidity associated with ALND and SLNB, Kuijer and colleagues examined reports from 1,302 women aged 40 or younger who were enrolled in the Young Women’s Breast Cancer Study, a multicenter prospective cohort study that was established to explore biological, medical, and psychosocial issues in young breast cancer patients. Fifty-five percent of the women had undergone an SLNB only, and 41 percent had undergone ALND. In the remaining 4 percent of patients, no axillary surgery was performed. 

Kuijer and colleagues examined the incidence of patient-reported arm swelling or decreased range of motion one year after diagnosis, using criteria from the Cancer Rehabilitation Evaluation System, or CARES-SF. Overall, 13 percent of the women reported arm swelling and 40 percent reported decreased range of motion in the ipsilateral arm—the arm on the same side as the breast tumor—one year after breast cancer diagnosis.

In patients who were treated with breast conserving surgery, the incidence of arm-swelling one year after diagnosis was 6 percent in patients who underwent SLNB and 24 percent in patients who received ALND. For patients who underwent unilateral or bilateral mastectomy, the incidence of arm-swelling was 6 percent and 23 percent for patients who received SLNB or ALND, respectively.

Kuijer said she was surprised by the high rates of self-reported decreased range of motion in the ipsilateral arm one year after diagnosis; 32 percent and 36 percent in patients who received breast conserving surgery combined with a SLNB or ALND respectively, and 28 percent and 44 percent in patients who underwent unilateral or bilateral mastectomy with SLNB or ALND.

Kuijer said the study highlights the importance of de-escalating axillary treatment when appropriate in young breast cancer patients, and illustrates that even conservative surgery has long-lasting effects. “Women should be encouraged to talk to their doctors about all of their options for surgery and the expected outcomes,” Kuijer said.

Kuijer noted that certain patient factors were associated with greater risk of arm morbidity. Being overweight at the time of diagnosis increased the risk for arm-swelling and decreased range of motion. “This is not something patients can influence right away at the time of diagnosis, but it highlights the overall importance of an active and healthy lifestyle,” Kuijer said.

Financial status also played a part; women who described themselves as financially comfortable were less likely to develop arm-swelling. “This highlights the importance of ensuring adequate social support and resources for young patients undergoing breast cancer treatment,” Kuijer added.

Kuijer noted that this study cohort included women who had been treated at some of the largest cancer centers in the Northeast. The study participants may have been of higher socioeconomic status and may have led more active lifestyles than the general population; if so, the incidence of arm morbidity in the general population may be higher. Also, Kuijer said, the study used patient-reported outcomes rather than an objective measure of arm morbidity.

This study was funded by the National Institutes of Health, the Susan G. Komen Foundation, The Pink Agenda, and the Breast Cancer Research Foundation. Kuijer and her colleagues declare no conflicts of interest.

Press Release Published Date: 12/8/2017 5:30 AM
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Loftus, EileenFri, 8 Dec 2017 10:49:47
Older Women with HR-positive Breast Cancer May Receive Similar Benefit from CDK 4/6 Inhibitors as Younger Women

​SAN ANTONIO — Older women with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer who were treated with cyclin-dependent kinase inhibitors 4 and 6 (CDK4/6) achieved progression-free survival at a rate similar to that of younger women, according to data presented at the 2017 San Antonio Breast Cancer Symposium, held Dec. 5–9.

In the past two years, the U.S. Food and Drug Administration (FDA) has approved three CDK4/6 inhibitors: palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio). The drugs work by blocking the function of proteins CDK4 and CDK6, both of which drive cell multiplication, fueling tumor growth. Previous research has shown that for patients with HR-positive metastatic breast cancer, combining a CDK4/6 inhibitor with endocrine therapy improves progression-free survival (PFS) compared to endocrine therapy alone.

“As we approve new drugs to treat cancer, it is important to try to improve our understanding of the efficacy and safety of these drugs in our older patients,” said the study’s lead author, Harpreet Singh, MD, scientific liaison for Cancer in Older Adults and a medical officer in the Office of Hematology and Oncology Products, Center for Drug Evaluation and Research at the FDA. “Older patients traditionally have been underrepresented in oncology clinical trials, so pooling outcomes of older patients across clinical trials in the same drug class allows us to gain insight into how these patients may benefit.”

In this study, Singh and colleagues pooled and analyzed data from prospective, randomized studies of three different CDK4/6 inhibitors in combination with an aromatase inhibitor for the initial treatment of postmenopausal patients with HR-positive metastatic breast cancer. Using Kaplan-Meier estimates and a Cox-proportional hazard model, they explored the effect of age on progression-free survival.

Of 1,334 total patients, 42 percent were 65 or older, and 24 percent were 70 or older. For patients 70 or older who were treated with a CDK4/6 inhibitor in combination with an aromatase inhibitor, the estimated PFS was not reached, compared with an estimated PFS of 18 months for those treated only with an aromatase inhibitor.

For patients under 70 treated with a CDK4/6 inhibitor, the estimated PFS was 23.5 months, compared with an estimated 13.8 months for those treated only with an aromatase inhibitor. 

The researchers also evaluated safety in the patients who had taken at least one dose of CDK4/6 inhibitor. The study showed that the older patients were more likely than the younger patients to discontinue treatment due to side effects: 20 percent of the patients 70 or older discontinued treatment, compared with 17 percent of the patients 65 or older and 8 percent of the patients under age 65. Singh said the most common events that led to discontinuation of treatment across all age groups were infection, fatigue, blood count abnormalities (neutropenia), liver enzyme abnormalities, and diarrhea.

“Our findings suggest that there is no treatment difference across age subgroups in terms of efficacy of CDK4/6 inhibitors,” Singh said. “This is an important piece of information as health care providers and patients weigh their treatment options as new therapies are approved.”

Coauthor Lynn Howie, MD, a medical officer in the same division of the FDA, added that the potential benefit for older breast cancer patients should be weighed against risk of toxicity. In addition to the higher rates of discontinuation of treatment, older patients often required more modification of dosages to help them manage side effects.

“Health care providers should counsel each patient individually on the potential benefit of these therapies as well as the potential risks, taking into account the patient’s disease characteristics, performance status, comorbidities, social support, and treatment preferences,” Howie said.

The authors added that as the population ages, the FDA and other stakeholders are exploring ways to increase the representation of older patients in clinical trials to gain more information on how to treat older adults with cancer.

The study’s primary limitation is the relatively small numbers of older patients enrolled in the clinical trials, particularly those over 75. Singh noted that many older adults who enroll in clinical trials are healthier than their peers, with fewer comorbidities and less frailty, so their results may not be representative of the broader population.

The study was run by the FDA, and the authors have no conflicts of interest.

Press Release Published Date: 12/8/2017 3:30 AM
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Loftus, EileenThu, 7 Dec 2017 04:05:11
Postmenopausal Women Who Lose Weight May Have Reduced Breast Cancer Risk

​SAN ANTONIO — Postmenopausal women who lose weight may have a significantly reduced chance of developing breast cancer, according to data presented at the 2017 San Antonio Breast Cancer Symposium, held Dec. 5–9.

“Breast cancer is among the leading types of cancer and causes of death in American women,” said Rowan Chlebowski, MD, PhD, research professor in the Department of Medical Oncology and Therapeutics Research at City of Hope in Duarte, California. “Obesity rates have been increasing in the United States. We wanted to determine if there was a link between obesity and breast cancer risk.”

Several studies have associated high body mass index (BMI) with increased breast cancer risk, noted Chlebowski. While this risk factor is largely preventable, it is estimated that more than 65 percent of American women are overweight or obese.

“We wanted to determine if weight loss was associated with lower breast cancer incidence, as studies have not been able to consistently show that losing weight reduces the risk of breast cancer,” said Chlebowski. Past studies have been limited to analyses with self-reported measurements, while the prospective study conducted by Chlebowski and colleagues utilizes a short-term, three-year period of measured body weight and height followed by a long period of follow-up.

Chlebowski and colleagues analyzed data from the Women’s Health Initiative (WHI) Observational Study. This program tracks the health of postmenopausal women between the ages of 50 and 79. Participants who had a normal mammogram, no prior breast cancer, and were not underweight (BMI ≥ 18.5) were eligible for enrollment in Chlebowski’s study. Measurements for height and weight were obtained upon enrollment, and measurements were reassessed three years following.

At baseline, 41 percent of women were normal weight, 34 percent were overweight, and 25 percent were obese.

Of the 61,335 patients enrolled in Chlebowski’s study, 3,061 developed invasive breast cancer during an average of 11.4 years of follow-up. Compared to women with stable weight, those who lost weight (≥ 5 percent weight change) were 12 percent less likely to develop breast cancer following multivariable analysis. Weight loss of ≥ 15 percent was associated with a 37 percent reduction in breast cancer risk.  

“In the three-year window of the study, relatively modest weight loss was associated with significant lowering of breast cancer incidence,” said Chlebowski. “From this study, we have evidence that a weight loss strategy can be effective in lowering breast cancer risk in postmenopausal women.”

While weight gain (≥ 5 percent weight change) was not associated with increased overall breast cancer risk, it was associated with more than 50 percent increased risk of triple-negative breast cancer.

The study was supported by the National Institutes of Health (NIH). Chlebowski is a consultant for Novartis, Astra Zeneca, Genentech, and Amgen.

Press Release Published Date: 12/8/2017 3:30 AM
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Loftus, EileenThu, 7 Dec 2017 04:10:30
Circulating Tumor Cells May Predict Late Recurrence in HR-positive Breast Cancer Patients

SAN ANTONIO —Among patients with hormone receptor (HR)-positive HER2-negative stage 2-3 breast cancer without clinical evidence of recurrence, those who had circulating tumor cells (CTC) detected in blood five years after diagnosis had an increased risk for late recurrence of breast cancer, according to data presented at the 2017 San Antonio Breast Cancer Symposium, held Dec. 5–9.

“We found that a single positive CTC assay result five years after diagnosis provides independent prognostic information for late recurrence,” said Joseph A. Sparano, MD, associate director for clinical research, Montefiore Einstein Center for Cancer Care, Albert Einstein Cancer Center, New York. “This provides proof of concept that liquid biopsy-based biomarkers may be used to stratify risk for late recurrence and possibly inform treatment or clinical trial options.”

Despite advances in breast cancer treatment in recent years, many women still have late-recurrent disease five years or more after the initial diagnosis. HR-positive breast cancers, which make up more than half of all breast cancer cases, have an increased risk of late recurrence, noted Sparano. “Biomarkers for late recurrence that may help guide therapy are needed,” he stressed.

Participants of the study, designed and conducted by Sparano and colleagues in the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN), were previously enrolled in ECOG-ACRIN clinical trail E5103, which assessed the addition of bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, to chemotherapy as adjuvant treatment following surgery. Sparano and colleagues measured CTCs in blood samples from patients using the CELLSEARCH CTC assay between 4.5 and 7.5 years after an initial diagnosis of HER2-negative stage 2-3 breast cancer. No patients had clinical evidence of recurrence at the time of enrollment. Of patients with HR-positive breast cancer, 4.5 percent had recurrence of the disease; this compares to a recurrence rate of 0.5 percent in the HR-negative group.

Of the 546 patients enrolled in the study, 4.8 percent had a positive CTC assay result. Among patients with HR-positive breast cancer, 5.1 percent had a positive CTC result; among those with HR-negative disease, 4.3 percent had a positive CTC result. After a median follow-up of 1.6 years, a positive CTC assay result was associated with a nearly 20-fold increased risk of breast cancer recurrence in patients with HR-positive disease. The positive predictive value of a positive CTC assay for recurrence by two years in patients with HR-positive disease was 35 percent, and the negative predictive value for patients in this cohort was 98 percent. A positive CTC assay was not associated with recurrence in the HR-negative group.

Sparano commented that these results were somewhat unexpected. “We were surprised to see that 5 percent of patients had CTCs about five or more years after their initial diagnosis,” he said. “Although we were expecting that CTC-positive patients would have a higher recurrence rate, we weren’t expecting the risk of recurrence to be this high after a relatively short period of time.

“This study provides strong evidence of the clinical validity of the CTC assay as a prognostic biomarker for late recurrence in HR-positive breast cancer, which accounts for about one-half of all recurrences,” Sparano said. “Utilizing the CTC assay for prognostic analysis may aid in a more accurate identification of patients who would most benefit from extended adjuvant endocrine therapy or other treatment options,” he noted.

Next steps include studying how a single negative CTC test or serial negative tests could serve as a negative predictive marker that may allow sparing of extended adjuvant endocrine therapy beyond five or more years.

Limitations of the study include short follow-up after the CTC assay, with an average time of 1.6 years. Sparano noted that additional follow-up is required, and that further study will be necessary to determine the clinical utility of the CTC assay in this setting.

ECOG-ACRIN received funding for this study from the Breast Cancer Research Foundation, Susan G. Komen, and the National Cancer Institute. Sparano declares no conflicts of interest.

Press Release Published Date: 12/8/2017 3:30 AM
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Loftus, EileenThu, 7 Dec 2017 04:15:50
Phase III EMBRACA Trial Meets Primary Endpoint

​SAN ANTONIO — Patients with advanced HER2-negative breast cancer with germline BRCA mutations had significantly prolonged progression-free survival (PFS) when treated with the PARP inhibitor talazoparib compared with those who received chemotherapy of physician’s choice, according to data from the phase III trial, EMBRACA, presented at the 2017 San Antonio Breast Cancer Symposium, held Dec. 5–9.

“We are very pleased that the phase III EMBRACA trial—the largest randomized clinical trial conducted in this group of patients with hereditary breast cancer—met its primary efficacy endpoint of progression-free survival,” said Jennifer Litton, MD, associate professor in the Department of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center.

Talazoparib is a dual mechanism PARP inhibitor that inhibits the PARP enzyme and also traps PARP on DNA, thus preventing DNA damage repair, leading to death in BRCA1/2-mutated cells, Litton explained. Prior studies had shown that talazoparib’s unique structural properties make it more effective in trapping PARP-DNA complexes. This therapeutic had yielded promising results in preclinical studies and previous phase I and II clinical trials.

“In EMBRACA, talazoparib demonstrated superior clinical benefit in all subsets of patients, regardless of receptor subtype (HR-positive or triple-negative breast cancer), number of prior lines of chemotherapy, BRCA mutation type and central nervous system metastasis,” noted Litton.

The U.S. Food and Drug Administration has approved three PARP inhibitors so far—olaparib (Lynparza), rucaparib (Rubraca), and niraparib (Zejula)—to treat certain ovarian cancers, including those with BRCA gene mutations.

EMBRACA is an open-label, randomized, phase III trial to compare the efficacy and safety of 1 mg/day talazoparib with standard single-agent physician’s choice of therapy (PCT) (capecitabine, eribulin, gemcitabine, or vinorelbine) in patients with advanced breast cancer and a germline BRCA1/2 mutation. Patients were randomly assigned (2:1) to talazoparib (287) or PCT (144).

The primary objective was PFS, assessed by blinded independent central review, and secondary objectives were overall survival (OS), overall response rate (ORR) and clinical benefit rate at 24 weeks (CBR24), and safety. Patient-reported outcomes were also measured. 

The median PFS was 8.6 months for patients in the talazoparib arm, versus 5.6 months for those in the PCT arm, and this difference was statistically significant. Patients in the talazoparib arm were 45.8 percent less likely to have disease progression, compared with those in the PCT arm.

ORR and CBR24 showed a statistically significant improvement for those in the talazoparib arm compared with those in the PCT arm: The ORR was 62.6 percent for patients in the talazoparib arm, versus 27.2 percent for those in the PCT arm. Twelve complete responses were observed in the study, all in the talazoparib arm. The CBR24 was 68.6 percent for patients in the talazoparib arm, versus 36.1 percent for those in the PCT arm.

An interim analysis of overall survival was also conducted; although data are not yet mature, a positive trend favoring talazoparib was observed, with a 24 percent reduction in the risk of death. Survival data will continue to be monitored and final OS estimates reported once the data matures, Litton said.

Quality-of-life measurements revealed that in the talazoparib arm, patents had a significant delay in the time to deterioration in health compared with patients in the PCT arm, using the EORTC QLQ-C30 questionnaire.

“Most notable for this study was not only the improvement to date of PFS, but the time to clinical deterioration, which was 24.3 months for patients on talazoparib, versus 6.3 months for those on standard-of-care chemotherapy,” Litton noted.

Fifty-five percent of patients in the talazoparib arm experienced grade 3-4 hematologic adverse events, versus 39 percent of those in the PCT arm. Talazoparib was associated with fewer grade 3-4 gastrointestinal disorders and skin/subcutaneous tissue disorders than PCT. Grade 3-4 serious adverse events were observed in 26 percent and 25 percent of patients in talazoparib and PCT arms, respectively. Adverse events resulting in death occurred in 2.1 percent and 3.2 percent of patients in talazoparib and PCT arms, respectively. 

“Overall, once-daily oral talazoparib was well tolerated in comparison to chemotherapy, with improvements in progression-free survival and clinical responses, providing a significant option for patients with BRCA mutations and metastatic breast cancer. We look forward to following the OS results as those data mature,” said Litton.

This study was funded by Pfizer. Litton has research funding with EMD Serono, AstraZeneca, Pfizer, Genentech, and GlaxoSmithKline, and serves on advisory boards for Pfizer and AstraZeneca, all uncompensated.

Press Release Published Date: 12/8/2017 3:30 AM
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Loftus, EileenFri, 8 Dec 2017 08:31:03
Two Years of Extended Anastrozole Therapy Proved as Effective as Five Years in Clinical Trial

SAN ANTONIO — Postmenopausal women with hormone-receptor positive (HR-positive) breast cancer who took the aromatase inhibitor anastrozole for two years after an initial five years of adjuvant endocrine therapy received an equal benefit to those who took the drug for five additional years. The trial results suggest that a shorter duration of treatment may provide sufficient benefits while protecting women from harmful side effects, according to data from the ABCSG-16 phase III trial presented at the 2017 San Antonio Breast Cancer Symposium, held Dec. 5–9.

“In early-stage HR-positive breast cancer, the risk of relapse persists despite many advances in treatment,” said Michael Gnant, MD, FACS, director and chairman of the Department of Surgery, Comprehensive Cancer Center, at the Medical University of Vienna. “Adjuvant treatment with aromatase inhibitors has been demonstrated to improve disease-free survival of postmenopausal women with this subtype of breast cancer. However, the optimal duration of extended AI has previously been unknown. Because this treatment leads to prolonged side effects and impacts quality of life, it is important to establish how long the treatment should be given.”

In this trial, between February 2004 and June 2010, 3,484 postmenopausal women with HR-positive early-stage breast cancer were randomized in 71 centers in Austria to receive either two years or five years of extended adjuvant therapy. All had undergone an initial five years of adjuvant endocrine treatment, either tamoxifen or other regimens containing aromatase inhibitors.

The trial’s primary endpoint was disease-free survival. Secondary endpoints included overall survival, contralateral breast cancer (cancer in the opposite breast), fractures, and toxicity.

As of June 30, 2016, 78 percent of women in both trial arms were alive without recurrence; 757 women experienced recurrence, relapse, or other disease-free survival events: 377, or 22 percent, of women in the two-year group and 380, or 22 percent, of women in the five-year group.

There was also no significant difference in overall survival or time to contralateral breast cancer. Bone fractures were more likely in years three to five after randomization, suggesting that a longer duration of anastrozole treatment may be a risk factor for fractures. 

Gnant said the trial results suggest that clinicians should consider a two-year course of anastrozole sufficient for most patients.

“I believe that these trial results should be implemented into daily practice at once,” Gnant said. “There is simply no rationale to keep most patients on extended AI for longer than two years. This result can help save a lot of unnecessary side effects for many women around the world.”

In addition to bone fractures, other side effects of prolonged AI therapy include bone fractures, hot flashes, arthralgia, sexual dysfunction, and hair loss.

Gnant cautioned that researchers cannot rule out benefits for some patients who take anastrozole for longer periods. He said future translational research using data and biomaterial from the patients in the ABCSG-16 trial could be useful to characterize potential molecular factors that influence patients’ response to anastrozole.

The study was funded by AstraZeneca. Gnant has received honoraria, travel or accommodations funding, and research funding from AstraZeneca.

Press Release Published Date: 12/7/2017 3:30 AM
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Loftus, EileenThu, 7 Dec 2017 08:25:43
Phase III Trial Data Support Current Standard 12-month Adjuvant Trastuzumab for HER2-positive Breast Cancer

​SAN ANTONIO — Disease-free survival (DFS) after nine weeks of adjuvant trastuzumab and standard chemotherapy was not comparable to DFS after 12 months of adjuvant trastuzumab and standard chemotherapy for women with early-stage HER2-positive breast cancer, supporting the current practice of extended trastuzumab treatment, according to data from the phase III Synergism or Long Duration (SOLD) clinical trial, presented at the 2017 San Antonio Breast Cancer Symposium, held Dec. 5–9.

The study, however, found no substantial difference in the secondary endpoints of distant disease-free survival (DDFS) and overall survival (OS) between the 12-month trastuzumab arm and the nine-week trastuzumab arm.

“The choice for one-year duration of trastuzumab administration in patients with HER2-positive breast cancer was arbitrary, and not based on research data,” said Heikki Joensuu, MD, professor in the Department of Oncology at the Helsinki University Hospital and University of Helsinki in Finland.

In all four large randomized trials that established the current standard treatment (chemotherapy plus trastuzumab), trastuzumab was given for one year and, therefore, the one-year duration became the standard, Joensuu explained. In two randomized trials with relatively limited statistical power, there was no statistical difference in DFS or OS between those who received nine weeks versus 12 months of trastuzumab.

“The current standard treatment is lengthy, costly, and occasionally associated with cardiac adverse events,” Joensuu said. While trastuzumab is well tolerated in general, the most important adverse effect is congestive heart failure (CHF). CHF occurred in less than 3 percent of the patients treated in the pivotal clinical trials, but the risk for trastuzumab-related CHF is likely higher in elderly patients who have pre-existing risk for CHF, he added.

Joensuu and colleagues studied whether it is sufficient to administer trastuzumab with chemotherapy only for a brief period of time (nine weeks) instead of the standard practice of administering trastuzumab both during chemotherapy (for nine weeks) and then as a single agent after stopping chemotherapy (for 12 months).

“We could not demonstrate that the experimental treatment [nine weeks of trastuzumab] is similar in efficacy as the standard treatment [12 months of trastuzumab] in terms of DFS,” said Joensuu. “There was, however, not much difference between the groups in two other important clinical endpoints, DDFS and OS, which were secondary objectives of the study.”

In SOLD, the investigators randomly assigned (1:1) 2,176 patients with early-stage HER2-positive breast cancer to the nine-week trastuzumab arm or the 12-month trastuzumab arm.

Patients in both arms received three cycles of docetaxel (80 mg/m2 or 100 mg/m2) and trastuzumab three times a week, followed by three cycles of chemotherapy. Patients in the nine-week arm received no further treatment while those in the 12-month arm received trastuzumab every three weeks for 14 cycles. Patients with estrogen receptor-positive cancer received appropriate endocrine treatment and radiation therapy per guidelines.

In the 12-month arm, DFS was 90.5 percent, compared with 88 percent in the nine-week arm. There was no substantial difference in DDFS and OS between the two arms: five-year DDFS was 93.2 percent in the nine-week arm and 94.2 percent in the 12-month arm; five-year OS was 94.7 percent in the nine-week arm and 95.9 percent in the 12-month arm.

“Interestingly, we detected a significant interaction between the dose of docetaxel given concomitantly with trastuzumab in preplanned subgroup analyses,” noted Joensuu.

Among patients who received 100 mg/m2 docetaxel, DFS in the nine-week arm was similar to the DFS in the 12-month arm, but among those who received 80 mg/m2 docetaxel, 12 months of trastuzumab yielded superior DFS than nine weeks, suggesting that the dose of docetaxel administered with trastuzumab may influence survival outcomes. “This, and brief dual inhibition of HER2 with trastuzumab and pertuzumab, each given with an adequate dose of a taxane, warrant further studies,” he said.

“The shorter trastuzumab treatment was safer to the heart than the longer treatment,” added Joensuu. Cardiac failure occurred in 3 percent and 2 percent of patients in the 12-month and nine-week arms, respectively. Patients in the nine-week arm had significantly higher cardiac left ventricle ejection fractions (LVEFs) than patients in the 12-month arm, but the absolute differences were small, and the LVEFs mostly returned to the baseline level within three years after the date of randomization, Joensuu said.

A limitation of the study is that because of cancer characteristics and some logistical issues, including not being able to reach the planned number of DFS events within a reasonable time frame, the study had lower statistical power than planned.

SOLD was funded by Pharmac (New Zealand), Sanofi, Novartis, the Academy of Finland, the Cancer Society of Finland, Helsinki University Hospital research funds, Sigrid Juselius Foundation, and Jane and Aatos Erkko Foundation. Joensuu is a scientific advisor for Neutron Therapeutics, has received consultation fees from Orion Pharma, and has stock ownership interest in Orion Pharma, Faron Pharmaceuticals, and Sartar Therapeutics.

Press Release Published Date: 12/7/2017 3:30 AM
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Loftus, EileenThu, 7 Dec 2017 08:30:56
Temporary Ovarian Suppression With Hormone Analog May Preserve Fertility During Breast Cancer Chemotherapy

SAN ANTONIO — Meta-analysis of individual patient data from five randomized clinical trials provided a high level of evidence that treatment with a gonadotropin-releasing hormone analog (GnRHa) could safely and effectively protect ovarian function and potentially preserve fertility in premenopausal women receiving chemotherapy for early-stage breast cancer, according to a study presented at the 2017 San Antonio Breast Cancer Symposium, held Dec. 5–9.

“Temporary ovarian suppression obtained by administering GnRHa during chemotherapy is a medical intervention with the potential to preserve ovarian function and fertility in premenopausal breast cancer patients; however, to date, the role of this option remains controversial and it is still considered an experimental technique by the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO),” said Matteo Lambertini, MD, medical oncologist and ESMO fellow at the Institut Jules Bordet in Brussels, Belgium.

The possibility that anticancer treatments will cause premature ovarian insufficiency (POI) and subsequent infertility are prevalent concerns affecting young women diagnosed with breast cancer, which adds significant anxiety and emotional strain as they make treatment decisions, explained Lambertini.

Temporary ovarian suppression with GnRHa during chemotherapy was primarily developed as a strategy to reduce the risk of developing treatment-induced POI than as a fertility-preserving procedure; therefore, the majority of the trials that investigated this strategy had a very short follow-up and did not report on post-treatment pregnancies, Lambertini said. Further, different randomized clinical trials that investigated the efficacy of this approach showed conflicting results, and some of these trials included very few patients, making it difficult to draw solid conclusions based on the results of individual studies, he added.

Lambertini and team aimed to provide more conclusive clinical evidence on this topic by conducting an individual patient data meta-analysis of five randomized clinical trials in which premenopausal women with early-stage breast cancer were randomly assigned to receive chemotherapy alone (437 women) or with concurrent GnRHa (436 women).

The study found that the POI rate in the GnRHa group was 14.1 percent, versus 30.9 percent in the control group; patients in the GnRHa group had 62 percent less risk to develop POI as compared to those treated with chemotherapy alone. Treatment effect was homogeneous among the different patient subgroups.

Patients in the GnRHa group had one- and two-year amenorrhea (absence of menstrual periods) rates of 36.8 percent and 18.2 percent, respectively. One- and two-year amenorrhea rates in the control group were 40.4 percent and 30 percent, respectively.

“Although the absolute numbers remain low, we observed a doubling in the number of post-treatment pregnancies in patients in the GnRHa group compared with those treated with chemotherapy alone. This suggests that GnRHa during chemotherapy is not only a strategy to preserve ovarian function but may also potentially improve future fertility,” Lambertini said.

Thirty-seven patients in the GnRHa group had at least one post-treatment pregnancy during the follow-up period, versus 20 patients in the control group.

There were no significant differences in disease-free survival and overall survival between the two groups; this suggests that administering GnRHa during chemotherapy can be considered safe in breast cancer patients, he said.

“Our study adds important evidence on both the efficacy and the safety of temporary ovarian suppression with GnRHa during chemotherapy, not only in patients with estrogen receptor [ER]-negative disease but also in women with ER-positive tumors, who account for the majority of new cases of breast cancer in young women,” Lambertini commented.

“This study provides solid evidence on this specific topic,” Lambertini said. “We believe that the results of our study would serve as the reference evidence for updating the international ASCO and ESMO guidelines on the use of this strategy.”

The five clinical trials studied were PROMISE-GIM6, POEMS/SWOG S0230, Angelo Celtic Group OPTION, GBG-37 ZORO, and a Moffitt Cancer Center-led trial.

Limitations of the study include the impossibility of including all the randomized clinical trials on this topic, the lack of data on the extent of ovarian function preservation using more sensitive biomarkers, and limited information on patients’ wish to have a pregnancy, according to Lambertini.

This study was partly funded by the Italian Association for Cancer Research. Lambertini does not have any relevant conflicts of interest to disclose.

Press Release Published Date: 12/7/2017 3:30 AM
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Loftus, EileenThu, 7 Dec 2017 08:36:56
Acupuncture Reduced Joint Pain Caused by Aromatase Inhibitor Treatment in a Randomized, Phase III Clinical Trial

​SAN ANTONIO — Acupuncture significantly reduced joint pain for postmenopausal women with early-stage breast cancer receiving treatment with an aromatase inhibitor compared with both sham acupuncture and no treatment, according to data from the randomized, phase III SWOG S1200 clinical trial presented at the 2017 San Antonio Breast Cancer Symposium, held Dec. 5–9.

“Aromatase inhibitors are among the most common and most effective treatments for postmenopausal women diagnosed with hormone receptor–positive breast cancer; however, many patients suffer from side effects that cause them to miss treatments or stop treatment altogether,” said Dawn L. Hershman, MD, leader of the Breast Cancer Program at the Herbert Irving Comprehensive Cancer Center at NewYork-Presbyterian/Columbia University Medical Center. “We need to identify strategies to control these side effects, the most common of which is debilitating joint pain and stiffness.

“The data from this randomized, phase III clinical trial indicate that health care practitioners should discuss the possibility of acupuncture with patients experiencing aromatase inhibitor–related joint pain and stiffness because it has the potential to improve their quality of life,” continued Hershman, who is also a vice chair of SWOG, the global cancer clinical trials network funded by the National Cancer Institute (NCI). “We hope that by reducing the debilitating side effects of aromatase inhibitor treatment, acupuncture may improve adherence to treatment and thereby outcomes, but we need to conduct further studies to determine if this is indeed the case.”

Hershman explained that many patients don’t want to take more medications to relieve symptoms caused by aromatase inhibitor treatment. Acupuncture is a traditional Chinese method of medical treatment involving the insertion of fine, single-use, sterile needles in defined acupoints. A number of small, single-institution studies have suggested that it may provide an alternative approach to reducing aromatase inhibitor–related joint pain and stiffness.

Therefore, Hershman and colleagues designed and conducted a multicenter, randomized, blinded trial evaluating whether acupuncture could reduce aromatase inhibitor–related joint symptoms in postmenopausal women diagnosed with early-stage, hormone receptor–positive breast cancer.

The researchers enrolled 226 patients in the trial: 110 were randomized to true acupuncture; 59 to sham acupuncture, which involves superficially inserting needles in nonacupoints; and 57 to waitlist control, which meant no treatment. Patients receiving true acupuncture or sham acupuncture had twice-weekly sessions for six weeks followed by one session per week for six more weeks. Patients reported on their pain before, during, and after treatment using various methods, including the Brief Pain Inventory–Short Form (BPI), a self-administered 14-item questionnaire used to evaluate the severity of a patient's pain on a 0 to 10 scale, where higher scores indicate more pain, and the impact of this pain on the patient's daily functioning.

After six weeks, patients in the true acupuncture treatment arm reported significantly lower BPI worst pain scores compared with those in the sham acupuncture and the waitlist control arms. The mean BPI worst pain for the true acupuncture arm was 0.92 points lower than the mean BPI worst pain for the sham acupuncture arm and 0.96 points lower than the mean BPI worst pain for the waitlist control arm. In addition, the proportion of patients who had a large reduction in BPI worst pain, a reduction of two or more points, was significantly greater in the true acupuncture arm than in the sham acupuncture and the waitlist control arms: 58 percent compared with 33 percent and 31 percent, respectively. The differences remained statistically significant when assessed at 24 weeks, even though the intervention was 12 weeks.

The most common adverse event reported among those receiving true and sham acupuncture was bruising.

“We were very pleased to see acupuncture had durable beneficial effects with no significant side effects in a large, rigorous clinical trial,” said Hershman. “We hope that these data will not only encourage health care practitioners to discuss acupuncture as a complementary therapy for patients receiving aromatase inhibitors, but that they will also enhance payers’ willingness to reimburse these patients for acupuncture.”

This study was supported by grant R01AT006376 from the National Institutes of Health (NIH) National Center for Complementary and Integrative Health and the Office of Research on Women’s Health; and grant UG1CA189974 and legacy grant U10CA37429 from the NIH/NCI/Division of Cancer Prevention. Hershman declares no conflicts of interest.

Press Release Published Date: 12/7/2017 3:30 AM
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Loftus, EileenThu, 7 Dec 2017 08:43:10
Common Genetic Fusion Event May be Associated with Low-risk Prostate Cancer

​PHILADELPHIA — Establishing the way in which a genetic alteration called a TMPRSS2-ERG gene fusion forms in a prostate cancer, rather than the presence of the gene fusion itself, could help identify patients with prostate cancer with a low risk of spreading, which might determine the best course of treatment for the patient, according to results published in Cancer Research, a journal of the American Association for Cancer Research.

“Active surveillance is a common approach to caring for patients with a Gleason score of 6, because this score indicates the prostate cancer has a low risk of spreading,” said John C. Cheville, MD, professor of pathology at the Mayo Clinic in Rochester, Minnesota. “Men on active surveillance receive no treatment and are followed. Some of these men are later found to have clinically significant disease that requires treatment.”

A Gleason score provides information on how aggressive a prostate cancer is. It is calculated when a prostate needle biopsy specimen is examined under a microscope. Depending on how normal or abnormal the cancer looks, it is assigned a number from 1 to 5, with 5 being the most abnormal and most aggressive. Different areas of a tumor may have different patterns, and the two highest patterns are added together to give the Gleason score. Most prostate cancers are Gleason score 6 (composed entirely of pattern 3) and men with Gleason score 6 are considered at low risk of having their tumors progress.

“Identifying a biomarker that, in addition to Gleason score, distinguishes men at increased risk for disease progression from those whose prostate cancer never becomes a clinically significant problem could help improve patient care,” said Cheville.

To look for genetic biomarkers of clinically significant or insignificant disease, Cheville and colleagues used whole-genome mate pair sequencing to study gene fusions in prostate cancer tissue samples obtained from 133 patients who underwent a radical prostatectomy at the Mayo Clinic. The prostate cancers were divided into four groups: 53 low volume Gleason 6 tumors were classed as very low risk for progression; 26 high volume Gleason 6 tumors were classed as low risk for progression; 29 Gleason 7 tumors were classed as intermediate risk for progression; and 25 Gleason 8 or higher tumors were classed as high risk for progression.

The researchers detected TMPRSS2-ERG fusions in 45 percent of the prostate cancers analyzed, which is consistent with prior studies, according to Cheville. Fusions were detected in 43 percent, 49 percent, 52 percent, and 24 percent in the very-low risk, low-risk, intermediate-risk, and high-risk groups, respectively.

Among the 60 prostate cancers with TMPRSS2-ERG fusions, 39 had deleted the interstitial genes between TMPRSS2 and ERG during the fusion event and 21 had retained these genes. Eighteen of the 21 prostate cancers that had retained the interstitial genes during TMPRSS2-ERG gene fusion were in the very-low risk and low-risk groups.

“Our data support results from other studies in that the presence or absence of a TMPRSS2-ERG gene fusion was not predictive of outcome,” Cheville said. “But how the gene fusion formed was important; the retention of interstitial genes during the fusion event was more common in very- low risk and low-risk cancers, and there may be genes in this region that suppress or limit tumor growth. There is potential utility for determining the status of interstitial genes in stratifying men with prostate cancer into more well-defined risk groups, but this will require further study before it can be incorporated into clinical practice.”

Information on whether a patient went on to have a biochemical recurrence was available for 34 patients who had prostate cancer with a TMPRSS2-ERG gene fusion with interstitial gene deletion and 22 patients who had prostate cancer with a TMPRSS2-ERG gene fusion with interstitial gene retention. In univariate, but not multivariate, analysis, biochemical recurrence was significantly lower if the prostate cancer had a TMPRSS2-ERG gene fusion with interstitial gene retention compared with those that had interstitial gene deletion.

“The loss or retention of interstitial genes was tied closely to Gleason score, and we did not have enough cases to determine whether or not the type of fusion was an independent marker for biochemical recurrence,” said Cheville. “We need to look at many more samples and also look at patients with higher Gleason scores to determine the extent to which loss of interstitial genes is associated with disease progression.”

According to Cheville, the main limitation of the study is the relatively small number of patients analyzed in each group.

This study was supported by James and Dorothy Nelson Benefactor Funds and the Mayo Clinic Center for Individualized Medicine. Cheville declares no conflicts of interest.

Press Release Published Date: 12/6/2017 7:05 PM
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Loftus, EileenThu, 7 Dec 2017 11:53:08