Mutations in Five Genes Linked to Higher Lifetime Risks for Aggressive Breast Cancer


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USING MULTIGENE hereditary cancer panels to test for mutations in five genes can identify women at high risk for triple-negative breast cancer who may then benefit from more frequent screening, risk management, and potentially targeted therapies as well. A study that looked at multigene panel testing of 10,901 patients with triple-negative breast cancer also found that germline pathogenic variants in those 5 genes—BARD1, BRCA1, BRCA2, PALB2, and RAD51D—were associated with a greater than 20% lifetime risk for overall breast cancer among white women, with similar trends observed among African American women. The results were published in the Journal of the National Cancer Institute.1

Fergus J. Couch, PhD

Fergus J. Couch, PhD

“This is the first study to establish which genes are associated with high lifetime risks of triple-negative breast cancer,”2 according to the study’s corresponding author, Fergus J. Couch, PhD, a geneticist in the Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.

The study has received national press coverage, including USA Today, ABC News, and NBC News. The latter reported that Sandra Swain, MD, FACP, FASCO, Associate Dean of Research Development, Georgetown University, called the study results “significant” and noted, “Triple-negative [breast cancer] is harder to treat when it has recurred and has lower survival rates. It’s really exciting discovering more and more genes that can be targeted for treatment and potentially improve outcomes.”3

Sandra Swain, MD, FACP, FASCO

Sandra Swain, MD, FACP, FASCO

Genes That Make a Difference

RESEARCHERS REVIEWED the results of 8,753 patients with triple-negative breast cancer receiving clinical germline cancer panel testing for 21 genes between March 2012 and June 2016 from a clinical testing laboratory and from a previous study of 2,148 patients with triple-negative breast cancer by a Triple-Negative Breast Cancer Consortium using a 17-gene panel. Both studies included the 5 genes associated with a high risk for triple-negative breast cancer (odds ratio [OR] > 5.0) and 3 other genes (BRIP1, RAD51C, and TP53; associated with moderate risk [OR > 2]).

The genes studied were chosen for evaluation based on the results of previous studies. “We have a fairly good idea of the genes that drive breast cancer and so were able to select the few genes that we were fairly certain are going to make a difference,” Dr. Couch told The ASCO Post. “There are a lot of predisposition genes in the literature (probably 35 or 40), but some of them are very uncertain. We wanted to go with a set that we were fairly confident of, but even so, we came up with some negative results; some genes don’t seem to play a role.”

Similar Trends in African Americans

ALMOST ALL the patients (97.5%) in the smaller, 17-gene study were white. In the clinical cohort study, 62.8% (5,498 patients) were white and 14.5% (1,271 patients) were African American. Pathogenic variants in the genes associated with triple-negative breast cancer were detected in 12.7% of these 1,271 patients, including 3.7% in non-BRCA genes. “No major differences in the pathogenic variant frequencies in genes between African American and white triple-negative breast cancer patients were observed,” the investigators reported.

Dr. Couch said that even though the number of African American individuals in the study was small, the information is useful because it shows the genetics are similar in the white and African American populations and “the same genes are driving the risk in both populations.” The authors noted that triple-negative breast cancer accounts for a higher percentage of overall breast cancer among African American than white individuals (35% vs 15%).

Larger studies of African American patients will be needed to develop more precise risk estimates, the authors acknowledged. Dr. Couch is currently working on one such study, which includes data from the Black Women’s Health Study, the Women’s Circle of Health Study, and the Multiethnic Cohort on 5,000 African American women with breast cancer and 5,000 matched controls. “We hope to publish that this year,” Dr. Couch said. “The number of study participants is much higher than in previously published studies and will provide better estimates of breast cancer in the African American population.”

Expanding Guideline Criteria

“THE NATIONAL Comprehensive Cancer Network® Clinical Practice Guidelines in Oncology (NCCN Guidelines®) currently recommend BRCA1 and BRCA2 testing for individuals with triple-negative breast cancer diagnosed at age 60 years or younger or who meet criteria based on personal and family cancer histories,” the authors noted. “In this study, pathogenic variants in triple-negative breast cancer genes were identified in 4.3% of patients with triple-negative breast cancer from the clinical cohort not meeting the NCCN BRCA1/2 testing criteria. When considering all breast cancer predisposition genes, pathogenic variants were detected in 4.6% of patients. As most of these variants are considered clinically actionable, these findings suggest that testing criteria for patients with triple-negative breast cancer should be expanded to include testing of all breast cancer predisposition genes regardless of age of diagnosis or family history of cancer.”

As a result of these findings, “people may lean more toward testing all triple-negative breast cancer patients now,” Dr. Couch told The ASCO Post. “Our hope is that the NCCN Guidelines, and maybe ASCO as well, will come out with a commentary or a guideline to suggest testing all triple-negative cases so we don’t miss certain people.”

Lifetime Breast Cancer Risks

THE STUDY report noted that “absolute risks for triple-negative breast cancer in the general population are low,” 1.19% in the white population, but pathogenic variations in triple-negative breast cancer predisposition genes “substantially increased breast cancer risk. Absolute risk models accounting for risks of different subtypes of breast cancer identified five triple-negative breast cancer predisposition genes (PALB2, BRCA1, BRCA2, RAD51D, and BARD1) with greater than 20% lifetime risks for overall breast cancer,” the researchers reported.

“Although NCCN guidelines already recommend additional breast cancer screening via magnetic resonance imaging for women with PALB2, BRCA1, and BRCA2 pathogenic variants, the results from the current study provide evidence to support similar screening for patients with pathogenic variants in RAD51D and BARD1,” the authors noted. “Continued study of gene-specific risks for breast cancer subtypes may lead to tailored medical management recommendations for pathogenic variant carriers. Consistent with this hypothesis, initial studies evaluating intensified screening in high-risk women have suggested that a decrease in mortality from triple-negative breast cancer can be achieved.”

“When you look at our data, you see that we basically brought forward a couple of new genes, BARD1 and RAD51D,” Dr. Couch said. Coincidentally, “NCCN issued a new update for breast and ovarian cancer testing and now actually recommends BARD1 for this magnetic resonance imaging–based screening.” That recent recommendation, however, was mostly “based on smaller studies and expert opinions,” Dr. Couch added. “We have clearly shown that our model pushes BARD1 over the 20%” threshold for lifetime risk of breast cancer. The current recommendations do not, however, include RAD51D. “We very much hope that based on the data we just published, the next time the NCCN Breast Cancer panel meets, it will consider these data and include that gene in its recommendation.”

Targeted Therapeutic Approaches

MULTIGENE PANEL testing of all patients with triple-negative breast cancer may not only improve cancer risk assessment, but also further “the ongoing development of targeted therapeutic approaches for triple-negative breast cancer patients with mutations in predisposition genes,” the authors concluded. Clinical trial investigators are well aware of the potential of genetic testing to identify individuals who may benefit from targeted therapeutic strategies, Dr. Couch noted.

“We start testing everyone for these genes; it is unclear how we can effectively screen for first-time cases.”
— Sandra Swain, MD, FACP

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Currently, the focus of targeted therapy is on the poly (ADP-ribose) polymerase (PARP) inhibitors, Dr. Couch said. “They work really well in the BRCA1 and BRCA2 population. There are numerous trials published now showing they are particularly effective. They are broadly approved in the metastatic setting for breast and ovarian cancers now,” he noted, but not in an adjuvant setting. “That means if you are diagnosed with primary breast cancer alone, you can’t receive those drugs, unless you get an exception.”

Mutations in BRCA1 and BRCA2, and perhaps in other genes such as PALB2 and BARD1, may “hypersensitize tumors to PARP inhibitors,” Dr. Couch said. New trials are underway studying PARP inhibitors in combinations with other agents that can be used in the adjuvant setting. “You put the two together and hopefully the patient will benefit,” he added.

Population-Based Studies

IN HER COMMENTS to NBC News about the triple-negative breast cancer study,3 Dr. Swain noted, “We start testing everyone for these genes; it is unclear how we can effectively screen for first-time cases.”

Using genetic testing to screen for triple-negative breast cancer “gets tricky,” admitted Dr. Couch. Most clinicians would probably not want to “test for just a subtype of breast cancer,” such as triple-negative breast cancer, he said. “They really would want to test for all possible risks for breast cancer.”

Population-based genetic testing studies being conducted by the research team at Mayo and other groups around the world with unselected people, not necessarily having any family history of cancer, “are finding that quite a high proportion of those individuals, over 5%, have mutations on these genes, and so they are at an elevated risk,” Dr. Couch said. “I can’t say their level of risk is the same as somebody who has an extensive family history. The point is they are at increased risk, and should they be benefiting from this as well?” Dr. Couch predicted that the guidelines will be revised accordingly over the next 1 to 2 years, as the data from these population-based studies are published. ■

DISCLOSURE: Dr. Couch is a consultant/advisor to AstraZeneca, has received research funding from GRAIL, and has an unspecified relationship with Ambry Genetics. Dr. Swain has received travel reimbursement from Caris Life Sciences.

REFERENCES

1. Shimelis H, LaDuca H, Hu C, et al: Triple-negative breast cancer risk genes identified by multigene hereditary cancer panel testing. J Natl Cancer Inst. August 7, 2018 (early release online).

2. Dangor J: Mayo-led research team identifies genes that increase risk for triple-negative breast cancer. Mayo Clinic News Network, August 7, 2018. Available at https://newsnetwork.mayoclinic.org/discussion/mayo-led-research-team-identifies-genes-that-increase-risk-for-triple-negative-breast-cancer/. Accessed September 6, 2018.

3. Scher A: Researchers discover gene mutations linked with aggressive breast cancer. NBC News, August 6, 2018. Available at https://www.nbcnews.com/ health/health-news/researchers-discover-gene-mutations-linked-aggressive-breast-cancer-n898111. Accessed September 6, 2018.


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