What’s New in Research: September 2019

Study Provides Up-to-Date Estimate of the National Burden of HPV-Positive Oropharyngeal Head and Neck Cancers

Researchers find that about 75 percent of oropharynx cancers are related to sexually transmitted disease; incidence of HPV-related throat cancer is 4.6 per 100,000, peaking at age 60-64

Over the last two decades, there has been a rise in head and neck cancers in the oropharynx, a region in the back of the throat that includes the tonsils and the base of the tongue. The rise of this type of cancer has been linked to the human papillomavirus (HPV), a very common sexually transmitted disease. Investigators from the Dana-Farber/Brigham and Women’s Cancer Center (DF/BWCC) have conducted the largest and most comprehensive study to date on the incidence of HPV-positive oropharyngeal head and neck squamous cell carcinoma (OPSCC) in the U.S. population, finding that 75 percent of oropharynx cancers are related to HPV. They report that the U.S. incidence of HPV-related throat cancer is 4.6 per 100,000 people, peaking in those age 60-64. Their results are published in Cancer Epidemiology, Biomarkers and Prevention. 

“Patients with HPV-related oropharynx cancers are now one of the most common patients we see in the DF/BWCC Head and Neck Oncology Program,” said corresponding author Danielle Margalit, MD, MPH, a radiation oncologist at the DF/BWCC. “Through our study, we now have a clearer picture of the extent to which oropharynx cancer affects Americans. This reinforces just how important it is to educate patients about the HPV vaccine, the importance of quitting smoking as well as safe sex practices — particularly oral sex, which is how we believe oral HPV is mostly contracted.”

HPV-positive OPSCC is distinct from HPV-negative OPSCC in its risk factors and in its prognosis. While risk factors for HPV-negative OPSCC include drinking and smoking, the largest risk factor for HPV-positive OPSCC is having multiple sexual partners, although anyone who is sexually active is at risk of being exposed to HPV. HPV-positive OPSCC tends to be more treatable than HPV-negative OPSCC, and those who have it tend to live longer.

The team, led by first author Brandon Mahal, MD, looked at people within the Surveillance, Epidemiology, and End Results (SEER) Head and Neck with HPV Status database, created by the National Cancer Institute (NCI). This database provides a representative sample of the U.S. population by age and region. The investigators analyzed those with known HPV-positive and known HPV-negative OPSCC, as well as people with OPSCC who had unknown HPV status. They then estimated the incidence of HPV-positive OPSCC for 100,000 people, using software provided by the SEER database. The team also looked at which demographic groups had the highest incidence of HPV-positive OPSCC.

The study found the incidence of HPV-positive OPSCC to be 4.61 cases out of 100,000 people. It was most common in white men under the age of 65, for whom it represents the sixth most common type of cancer. While previous studies have estimated that 70 percent of OPSCC cases were caused by HPV, this study found it to be closer to 75 percent.

The group of OPSCC patients with unknown HPV status in the database provides one limitation to the study, according to the researchers. Also, the data were taken from a 2013-2014 cycle, so the incidence rates might increase or decrease once the database updates.

“From a public health perspective, the best way to address the rise in HPV-positive OPSCC is through preventative measures,” said Margalit. “The HPV vaccine targets the type of HPV that causes the majority of OPSCC and is expected to decrease the cases of HPV-positive OPSCC in the future. The vaccine is recommended for children through age 26 and for some older adults as well. OPSCC requires intensive treatment once it develops, and, unfortunately, we’re not seeing everyone get the vaccines that could prevent it.”

Other authors of this paper include Brandon A. Mahal, Paul J. Catalano, Robert I. Haddad, Glenn J. Hanna, Jason I. Kass, Jonathan D. Schoenfeld and Roy B. Tishler. No conflicts of interest were reported by the authors of this paper. No financial disclosures were reported by the authors of this paper.

Paper cited: Mahal, B. et al. “Incidence and Demographic Burden of HPV-associated Oropharyngeal Head and Neck Cancers in the United States” Cancer Epidemiology Biomarkers and Prevention DOI: 10.1158/1055-9965.EPI-19-0038

Preclinical Study Reveals the Impact of Age on Immunotherapy Treatment for Breast Cancer

Brigham researchers test immunotherapy in young and old mice injected with triple negative breast cancer, find response to treatment varies with age

Recent clinical trials have indicated that immune checkpoint blockade (ICB) therapy, which is designed to unleash a patient’s immune system to attack cancer, has been revolutionary in its implications for breast cancer treatment, especially for its potential to treat patients with triple negative breast cancer (TNBC). Despite the fact that most breast cancer patients are over the age of 60, most clinical trials enroll patients under the age of 60. Age may be an important consideration with respect to ICB, given that aging is associated with profound changes to the immune system, so whether ICB will benefit patients of all age groups is still unknown. In order to understand the influence of aging on the effectiveness of ICB therapy, researchers from Brigham and Women’s Hospital, the Dana Farber Cancer Institute and Harvard Medical School conducted preclinical studies using younger and older mice with TNBC, finding that age affects the efficacy of ICB therapy. The results of this study are published in Cancer Discovery.

“Your immune system changes dramatically as you age, but no one has looked at how age affects the efficacy of this new class of drugs in breast cancer,” said co-first author Greg Goreczny, PhD, a postdoctoral fellow in the Brigham’s Hematology Division. “Because there are so few older patients enrolled in clinical trials, not enough is known about the effect of age on ICB therapy. Our initial question was whether ICB therapy would benefit all ages equally or have a greater benefit to some ages than others.”

The team injected TNBC cell lines into young mice, age 8-12 weeks, and old mice, aged 12 to 15 months. Once the mice formed palpable tumors, the researchers gave them four doses of one of two ICB drugs — anti-PD-L1 or anti-CTLA-4 antibodies. They also injected a group with control antibodies. They then measured the tumor growth over time.

The study revealed that age had a huge effect on response to immunotherapy. The young mice experienced significant reduction in tumor growth and better overall survival rates in response to treatment than those who did not receive the treatment. Immunotherapy treatment did not significantly benefit the aged mice compared to those injected with the control.

The investigators also interrogated the METABRIC database, which includes data on tumor samples from patients with TNBC. Gene markers that predicted responsiveness to ICB in the young mice were prevalent in younger patients, but not in older ones. They also found signs indicative of failure of the innate immune system in the tumors of both aged mice and in samples from older patients with TNBC, implying that this study could be relevant to the treatment of people as well. Those findings led the authors to test a new combination therapy. By combining ICB with a STING agonist, a drug that has immune activation properties, they found that tumors in aged mice now responded to ICB and the mice had improved survival.

“Assessing the immune changes that occur with age could be a new way to think about immunotherapy,” said corresponding author Sandra McAllister, PhD, an associate scientist in the Hematology Division. “Immunological age might not be the same as chronological age. We’re beginning to understand the markers of immunological age, and this opens up the possibility of using it to guide treatment decisions in the clinic.”

Other authors of this paper include Jaclyn Sceneay, Kristin Wilson, Sara Morrow, Molly J. DeCristo, Jessalyn M. Ubellacker, Yuanbo Qin, Tyler Laszewski, Daniel G. Stover, Victor Barrera, John N. Hutchinson, Rachel A. Freedman, and Elizabeth A. Mittendorf.

This work was also supported by funds from the National Institute of Health’s National Cancer Institute (NCI R21CA182614) and the Department of Defense BCMRP Era of Hope Scholar Award (W81XWH-14-1-0191) E.A.M. has received remuneration for participation on advisory boards for Astra-Zeneca, Genetech, Merck, Taplmmune, Sellas Lifebioscience, Peregrine pharmaceuticals and EMD Seroro. EAM has served as the principal investigator on investigator-initiated trials that her previous institution, the University of Texas MD Anderson Cancer Center, received support for from Astra-Zeneca and Genentech. No potential conflicts of interest were reported from the other authors.

Paper cited: Sceneay J et al. “Interferon Signaling is Diminished with Age and is Associated with Immune Checkpoint Blockade Efficacy in Triple-Negative Breast Cancer” Cancer Discovery DOI:10.1158/2159-8290.CD-18-1454

New Study Highlights Sociodemographic Disparities in Oral Cancer Screening Rates

Brigham researchers find lower-income and minority groups less likely to receive recommended cancer screenings at dental visits

Oral cancer accounts for 2 percent of reported malignancies and 1.2 percent of cancer-related deaths in the U.S. Oral cancer screening (OCS), recommended by the American Dental Association since 2010, can help to diagnose the cancer early, and this can significantly improve survival rates. If caught early, the five-year survival rate of oral cancer is 82.8 percent, but once the cancer metastasizes, that rate drops to 28 percent. Researchers at Brigham and Women’s Hospital led a study to examine OCS rates among those who had been to the dentist within two years, looking at whether sociodemographic factors such as income or race predicted differences in these rates. The team found that a significantly higher proportion of minority and low-income individuals reported that they had not received an OCS exam despite a recent dental visit. The results of this study are published in The American Journal of Preventive Medicine.

“We wanted to look specifically at the population that has access to dental care and report having access to a dentist,” said first author Avni Gupta, a research scientist at the Brigham’s Center for Surgery and Public Health. “Our results indicate that the selection of patients for screening isn’t based on the high-risk profile for oral cancer, but on sociodemographic characteristics. This is not appropriate. All patients should be receiving oral cancer screenings, but providers aren’t screening these groups, and this may be why they are presenting with more advanced cancer.”

The study looked at civilian, non-institutionalized individuals, age 30 and over, that had visited a dentist in the last two years. In three data cycles, from 2011 to 2016, patients self-reported if they had ever had an intra-oral or extra-oral exam, noninvasive procedures that can easily and safely be performed in an out-patient setting by a qualified health professional.

The intra-oral exam, in which a health professional pulls on the tongue and feels around the mouth to detect any premalignant lesions, was the primary outcome of the study. The extra-oral exam, in which the health professional feels the patient’s neck, was a secondary outcome. The patient survey described the intra-oral exam and extra-oral exam in detail so that a patient could easily identify the two types of screenings.

The team found that only 37.6 percent of people who had seen a dental professional reported receiving an intra-oral cancer screening exam while only 31.3 percent reported receiving an extra-oral exam. Adjusting for different risk factors, the team found that OCS rates were much lower among racial minorities, lower-income groups, and those who were uninsured or publicly insured. These disparities were independent of the two major risk factors for oral cancer, smoking and alcohol consumption.

The largest limitation of the study was the use of self-reported data that is subject to recall bias. However, this would only impact the study if these biases had greater influence on some sociodemographic groups than others.

Gupta said that while the previous studies have indicated disparities in access to dental care, she hopes that this study shows that providing access is not enough to get rid of the gaps in OCS rates between different sociodemographic groups.

“Just providing access is not enough – it matters what type of care patients are able to access,” Gupta said. “We talk a lot about disparities in medical care, but the quality of dental care services is important, too. We need to better understand the barriers that dental care providers face in order to ensure that patients get the same level and quality of care regardless of sociodemographic factors.”

Other authors of this paper include Stephen Sonis, Ravindra Uppaluri, Regan W. Bergmark and Alessandro Villa.

No conflicts of interest were reported by the authors of this paper. No financial disclosures were reported by the authors of this paper.

Paper cited: Gupta A et al. “Disparities in Oral Cancer Screening Among Dental Professionals: NHANES 2011–2016” The American Journal of Preventive Medicine DOI: 10.1016/j.amepre.2019.04.026

Novel Combination of Drugs May Overcome Drug-Resistant Cancer Cells

Mathematical modeling and preclinical experiments suggest that time-sensitive administration of glucose-6-phosphate dehydrogenase inhibitors alongside other drugs may thwart resistance in cancer cells

Cancer cells can adapt and develop resistance to chemotherapy drugs, making it difficult to eradicate tumors. A new study led by investigators from Brigham and Women’s Hospital suggests that a combination of three drugs, including a new class of glucose-6-phosphate dehydrogenase inhibitors, could overcome cross-therapy resistance. The results of the study are published today in Science Signaling. 

“We have only recently begun unravelling the full complexities of chemotherapy failure,” said Aaron Goldman, PhD, an instructor of Medicine in the Brigham’s Division of Bioengineering. “The drugs themselves are part of the problem in terms of where resistance is coming from. Resistance is not just intrinsic to cells.”

The investigators used computational modeling, in vitro experiments, in vivo animal models and clinical explant, ex vivo models of human tumors to probe the metabolic processes underlying chemotherapy drug tolerance.

In accordance with the Warburg Effect — a widely accepted paradigm for drug resistance — the investigators observed that the cancer cells took up extra glucose, putting glycolytic pathways into overdrive. But counter to the Warburg Effect, the researchers saw an increase in mitochondrial activity, indicating high levels of cellular oxygen consumption.

Using mathematical modeling, Goldman and his team found that a three-drug combination administered in a time-sensitive progression sensitized the cancer cells. Aside from this new class of drugs, combinations of clinically available drugs could also be used to combat resistance, Goldman said.

The researchers acknowledge that they do not yet have a clear understanding of the cancer cell plasticity that allows cells to gain new metabolic phenotypes and become drug resistant. In the future, the investigators hope to use mathematical modeling and machine learning to develop increasingly precise drug regimens to inform new cancer therapies.

“We’re mathematically modeling biological frameworks that will allow us to predict drug sequences,” Goldman said. “We’re not just putting drugs together — we’re developing combinations that rationally address resistance.”

This work was supported by a DoD BCRP Breakthrough Award, NIH UO1 (1U01CA214411), Cancer Society Postdoctoral Fellowship (122854-PF-12-226-01-CDD) the Breast Cancer Alliance Young Investigator Award, The Natural Sciences and Engineering Research and the Council of Canada (NSERC) Discovery Grant. Goldman and other authors are employees of Mitra Biotech and hold equity in Mitra Biotech. Another author is an employee of MBLI.

Paper cited: Goldman, A., et al. “Targeting Tumor Phenotypic Plasticity and Metabolic Remodeling in Adaptive Cross-Drug Tolerance.” Science Signaling. DOI: 10.1126/ scisignal.aas8779


No Racial Disparities Found in Quality-of-Care for Coronary Artery Bypass Grafting (CABG) Outcomes for Those Insured by TRICARE

Study provides potential insights into impact of universal insurance, equal-access health care system on racial disparities

Many studies have documented disparities in cardiovascular care for minorities, specifically African Americans compared to white patients. Coronary artery bypass grafting (CABG) is a common procedure in the U.S., and the outcomes and post-surgical care for African Americans tend to be worse. Investigators from Brigham and Women’s Hospital examined whether patients insured through TRICARE — a universal insurance and equal-access system that covers more than 9 million active-duty members, veterans and their families — experienced these disparities. The team found no racial disparities in quality-of-care outcomes, providing insights about the potential impacts of universal insurance and an equal-access health care system.

“In our study, we found a complete absence of racial disparities,” said first author Muhammad Ali Chaudhary, MD, a research fellow at the Center for Surgery and Public Health in the Department of Surgery at the Brigham. “In the military, the color of your uniform matters more than the color of your skin. Here, we have an opportunity to look beyond just the impact of universal insurance. This is a system that may be eliminating other factors that contribute to racial disparities in care such as implicit provider bias, health care segregation, differential access to care and mistrust in the system.”

The study included 8,183 TRICARE patients, age 18-64, who had undergone CABG. The study took its data from TRICARE health care claims from the Military Health System Data Repository for the years of 2006 to 2014.

The primary outcomes for the study were prescription of beta blockers, prescription of statins, and readmission rates within a 30-day period following surgery. All three outcomes are quality-of-care metrics endorsed by the National Quality Forum (NQF) for CABG. African Americans were found to have 10 percent greater odds of beta-blocker prescription than whites and 10 percent lower odds of 30-day readmission, but neither of these findings reached statistical significance. The team found no difference in statin prescription by race. Overall, the study showed no significant difference in quality-of-care metrics for African American and white patients following CABG.

Since the data from the study were taken from a database, researchers could not account for a doctor’s reasoning in choosing to prescribe, or not to prescribe, medication. Since TRICARE is a military insurance, its patients might not accurately model the U.S. population. However, the TRICARE population is socially, geographically and ethnically diverse, and only 20 percent of those covered by TRICARE are actively serving. The rest are veterans and family members of veterans or active-duty members. Unlike Medicare, which provides data for a limited age range, TRICARE covers people of all ages, which may serve as a better model of the American working population.

“It’s one of the hypotheses that we’ve been building for years: Universal health care access and equal access can eradicate racial disparities,” said Chaudhary. “With TRICARE, we have a model that provides a window into the potential impacts of universal insurance and an equal-access health care system.”

Other authors of this paper include Elzerie de Jager, Nizar Bhulani, Nicollette K. Kown, Adil H. Haider, Eric Goralnick, Tracey P. Koehlmoos and Andrew J. Schoenfeld.

This study was funded through a grant from the Henry M. Jackson Foundation for the Advancement of Military Medicine.

Paper Cited: Chaudhary MA et al. “No Racial Disparities In Surgical Care Quality Observed After Coronary Artery Bypass Grafting In TRICARE Patients” Health Affairs DOI: 10.1377/hlthaff.2019.00265



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