1. May, Brandon

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In a new study from the University of Pennsylvania in Philadelphia, researchers have found that patients with breast cancer and a second primary cancer have double the risk of having inherited germline variants in genes other than BRCA1/2, particularly TP53 and MSH6, when compared with patients with a single breast cancer. Findings from this study were presented at the 2018 ASCO Annual Meeting in Chicago (J Clin Oncol 36, 2018 [suppl; abstr 1503]).

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According to the investigators, this study highlights the importance of using a multiple genetic testing panel in risk assessment and prediction of patients who have experienced multiple primary cancers. Kara N. Maxwell, MD, PhD, the leading study author and Assistant Professor of Medicine at the University of Pennsylvania Perelman School of Medicine, Philadelphia, who presented the findings at this year's ASCO event, believes this study also supports the notion that there might exist variables that lead to a higher mutation rate in these at-risk individuals. "Now that we're expanding genetic testing to a larger number of patients, we want to try and hone in on what characters might predict higher mutations, mostly from the standpoint of pre-genetic counseling," Maxwell told Oncology Times.


Studying Genes

In their study, Katherine L. Nathanson, MD, Abramson Cancer Center's Deputy Director, and Susan M. Domchek, MD, Executive Director of the Basser Center for BRCA, led a team of researchers in creating two patient cohorts. The first cohort was comprised of high-risk breast cancer patients with either a single breast cancer (n=464) or breast cancer and an additional primary cancer (n=551). In the second cohort, patients with familial breast cancer (i.e., inherited risk) were also divided into patients with a single breast cancer (n=1,464) or breast cancer and another primary cancer (n=340).


"We hypothesized that if an individual has more than one primary cancer in their lifetime, that could be due to a number of factors, including environmental exposures and genetic predisposition," Maxwell explained. "We looked at several different genes, but we looked at a panel of 15 actionable mutations beyond BRCA that are found on the majority of the more commonly used commercial genetic testing panels."


The genes used in this panel included TP53, PALB2, CDH1, PTEN, STK11, CHEK2, ATM, NBN, MSH6, PMS2, MSH2, MLH1, CDKN2A, MUTYH monoallelic, and CHEK2 Low Risk.


In a total of 891 patients who had a second cancer in addition to breast cancer, their mutation rate was double to that of patients with a single breast carcinoma in cohort one (8.7% vs. 4.1%, respectively; p=0.003) and cohort two (8.2% vs. 4.2%, respectively; p=0.003). Mutation rates also significantly differed between groups in both cohorts.


In the high-risk breast cancer cohort, mutations of the TP53 gene were significantly higher among patients with breast cancer and an additional cancer versus a single breast cancer (2.2% vs. 0.2%, respectively; p=0.005). Mutations in MSH6 were also higher among patients with an additional cancer in this cohort (1.1% vs. 0.0%; p=0.03). Among the patients with familial breast cancer, a significantly greater proportion of patients in the additional breast cancer group had mutations in the MSH6 compared with patients in the single breast cancer arm (0.9% vs. 0.1%, respectively; p=0.02).


Genetic Testing

Overall, the findings from this study indicate that there is twice the risk of inheriting mutations in genes beyond BRCA1/2 in patients with a second primary cancer. The study investigators primarily focused on breast cancer patients as this cohort is where genetic testing is being dynamically pushed, Maxwell explained. Despite the utility of assessing genetic mutations in breast cancer patients, the rate of these mutations in the overall population appear low, even in the Penn Medicine study.


Identifying mutations in individual cancer patients, especially mutations in the TP53 gene, may be helpful during follow-up of minimal residual disease, as well as for comparing between primary and recurrent tumors (J Clin Invest 1997;100(8):2133-2137). Given that TP53 mutations, which were found in a greater amount of patients with a carcinoma in addition to breast cancer, are often associated with poor prognosis in several cancer types (Oncogene 2007;26(15):2157-2165), testing for mutations early is essential for optimizing care in this patient population.


According to Maxwell, the sole reliance on testing for mutations in BRCA1/2 is almost antiquated. "Because of the well-established data on the cancer risks associated with different gene mutations, the vast majority of people coming in for genetic testing don't want to just do a sequential or standard approach," Maxwell commented. "The most common thing we're seeing is that around 95 percent of patients really opt in to having a larger panel of genes tested."


Additionally, in an era where gene medicine and editing has permeated mainstream consciousness, a greater number of patients are feeling comfortable with multiple genetic mutation testing than years prior. Maxwell added, "There's the increasing recognition that germline mutations in genes may have clinical and treatment implications, and most people would like to have that info upfront." Fairly recent data has found, for instance, that mutations in the TP53 gene are associated with a cumulative breast cancer risk of approximately 85 percent by 60 years of age (Cancer 2016;122(23):3673-3681).


Based on research by Katherine Schon, BM BCh, BA, MRCP, of the Cambridge University Hospitals, a risk-reducing bilateral mastectomy or regular breast screening is highly recommended for women without breast cancer who do have a TP53 gene mutation. In an article published with Marc Tischkowitz, PhD, MBChB, of the University of Cambridge, Schon and Tischkowitz write that a "mastectomy rather than lumpectomy is recommended to reduce the risks of a second primary breast cancer and to avoid radiotherapy where possible" in patients with TP53 mutations (Breast Cancer Res Treat 2018;167(2):417-423). In addition, a bilateral mastectomy "should also be considered due to the risk of a contralateral breast cancer" in this patient population.


The greatest concern regarding testing multiple lines of genetic variants and identifying germline mutations in patients at risk for an additional carcinoma, according to Maxwell, is that only about 20 percent of those patients demonstrate these mutations.


"This really suggests that we do not understand why the vast majority of people get one or more cancers in their lifetime or whether they have other factors that we may not know about," Maxwell said. "The field in general needs to start think about other types of changes, including epigenetic changes, or whether there are regions of the genome that we're not looking at yet."


Future research from Maxwell and fellow researchers at Penn Medicine are looking toward larger genetic studies involving international breast cancer cohorts. These larger studies may hopefully enable a greater statistical power for elucidating understanding and supporting the utility of testing genetic mutations for clinical care, risk assessment, and surveillance.


Payal Shah, MD, Assistant Professor of Hematology Oncology at Penn Medicine, told Oncology Times that Penn Medicine cancer researchers are currently pursuing additional genetics research from various angles. "First, we are trying to understand, at an in-depth level, the various cancer risks associated with different mutations in different genes-we know that the story is much more broad than we understood it to be even 5 years ago. Maxwell and Nathanson's work on mutations in patients with multiple primary cancers is an important example of this," Shah explained. "Second, we are looking at the best way to make sure that the right patients have the most appropriate genetic counseling and testing; Dr. Angela Bradbury, for example, studies how telemedicine can play an important role here, especially when delivering results to patients."


In addition to placing a greater focus on developing therapies for patients with inherited and tumor gene mutations, Shah added that Penn research and treatment teams are actively developing and utilizing targeted therapies while "making strong efforts to appropriately test patients and family members so that we can take measures when possible to prevent cancers from ever developing."


Brandon May is a contributing writer.


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