Increased Germline Testing Rates Promote Crucial Breast Cancer Care

Susan M. Domchek, MD

A deeper understanding of the prevalence of breast cancer driver mutations across patient subsets is key to standardizing germline testing recommendations and establishing effective therapies for patients with mutations such as BRCA1 and BRCA2, according to Susan M. Domchek, MD.

“Over the past decade, we’ve learned how useful genetic information can be when deciding on a treatment plan for a patient with breast cancer at several stages of the diagnosis,” Domchek said in an interview with OncLive® ahead of the 40th Annual Miami Breast Cancer Conference^®.

In the interview, Domchek highlighted key points related to her presentation on germline testing and breast cancer treatment. These included identifying the patients most at risk for developing BRCA-mutated disease, the relationship between somatic and germline testing, and current efforts to improve germline testing rates in both academic and community settings.

Data from the phase 3 OlympiAD trial (NCT02000622), which evaluated the efficacy of olaparib (Lynparza) vs chemotherapy of physician’s choice in patients with previously treated metastatic BRCA-mutant breast cancer, showed that treatment with olaparib improved patients’ median progression-free survival (PFS) vs chemotherapy at 7.0 months vs 4.2 months, respectively (HR, 0.58; 95% CI, 0.43-0.80; P < .001).¹ Domchek explained how the study data confirmed the benefit of PARP inhibitors in this population. She also highlighted the significance of the findings from the phase 3 OlympiA trial (NCT02032823), in which treatment with adjuvant olaparib led to a 4-year overall survival (OS) rate of 89.8% vs 86.4% with placebo in patients with early-stage, BRCA-mutant breast cancer (Δ 3.4%; 95% CI, –0.1% to 6.8%).²

Domchek is executive director of the Basser Center for BRCA, director of the MacDonald Women’s Cancer Risk Evaluation Center, and the Basser Professor in Oncology at Penn Medicine in Philadelphia, Pennsylvania.

OncLive: What is the significance of understanding which patients could benefit most from germline testing and at what point in their disease should the testing should be done?

Domchek: Our initial data regarding PARP inhibitors were in patients with metastatic breast cancer and showed that PARP inhibitors like olaparib and talazoparib [Talzenna] were effective in treating patients with advanced cancer and were better than chemotherapy in that setting. That was an advance and led to the FDA approval of these medications.

We now understand that in the early-stage setting of high-risk, BRCA-mutant breast cancers, including those with positive lymph nodes, triple-negative breast cancers [TNBCs] over 2 centimeters, or [patients with an incomplete response] to preoperative chemotherapy, a year of olaparib after finishing therapy decreases the chances that the cancer will come back outside the breasts and improves OS. For this reason, it’s important to recognize patients who are good candidates for genetic testing. Those include any patient with TNBC; breast cancer [in patients] under the age of 50 years; or [patients with] a family history of breast cancer, ovarian cancer, metastatic prostate cancer, or pancreatic cancer. Other patients are excellent candidates for genetic testing as well, but those are the ones we want to make sure always get genetic testing.

What clinical trial data have informed these testing practices?

The metastatic setting had 2 [phase 3] studies, OlympiAD and EMBRACA [NCT01945775], where patients with metastatic breast cancer were randomized to receive either a PARP inhibitor, olaparib in [OlympiAD] and talazoparib in [EMBRACA], or standard-of-care [SOC] chemotherapy. In both studies, patients did better on the PARP inhibitor than on standard chemotherapy, with a PFS improvement. That led to the incorporation of these drugs into the SOC.

We’re still trying to do better. That PFS is not as long as we wish it to be, and most patients’ cancers progress after [treatment with] the PARP inhibitor. We’re investigating ways to combine these drugs with others to make those responses last longer.

In the early-stage setting, the key study was OlympiA, where patients with high-risk, early-stage, BRCA-mutated breast cancer were [randomly assigned] to olaparib or placebo [after prior therapy]. This study included 1800 patients from around the world. It was a tour de force of collaboration from companies, cooperative groups, patient advocacy groups, and patients. It was a transformative study, demonstrating that we can improve OS in these patients.

In a paper published in JAMA Network in 2022, investigators wrote that although the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology recommend germline testing for BRCA1, BRCA2, PALB, and TP53 mutations in certain patients with breast cancer, studies of universal testing with multigene panels suggest applying these guidelines to all patients with solid tumors and including genes beyond those proved to be associated with breast cancer. How might this statement influence clinical practice?

There’s controversy about who should get genetic testing. Some patients are at higher risk for having important gene mutations than others. Patients at younger ages with a strong family history [of breast cancer], or those who have TNBC or who are of Ashkenazi Jewish descent, are more likely than others to have a BRCA1 or BRCA2 mutation or a mutation in another high-penetrance gene like PALB2 or TP53.

PALB2 is the closest we have to a BRCA3 mutation, and patients who are tested for BRCA1 and BRCA2 should always be tested for PALB2. [Except in] select circumstances where there’s a known mutation in the family, almost all patients [should] have these panel tests.

Some patients are at particularly low risk for mutations in breast cancer susceptibility genes. Patients with estrogen receptor [ER]-positive breast cancer over the age of 65 years with no family history [of breast cancer] who aren’t of Ashkenazi Jewish descent have an exceedingly low risk of having a mutation in BRCA1, BRCA2, or PALB2.

[We can have] a robust and informed discussion about population screening for BRCA1 and BRCA2; in the United States, that is reasonable to discuss. However, we shouldn’t conflate the two. Doing genetic testing in an 80-year-old patient with ER-positive breast cancer is unlikely to yield a finding that significantly changes [their treatment]. However, if a patient is a candidate for a PARP inhibitor because of their high-risk, early-stage or metastatic disease, they should be considered for testing. The guidelines have iteratively lowered the thresholds for testing. Any patient who understands the risks and benefits of testing can consider getting tested.

We should also be careful about gene selection. Many gene panels are huge. If you asked genetics experts [to determine certain genes, explain their risks, and offer treatment options, their answers may not be] 100% correct on an 80-plus gene panel. We need to be careful about why we are testing some of those genes and what we’re trying to do with that information.

Certain genes are particularly problematic. If you test older patients for TP53 mutations, much of the time, if you find an abnormality, that will be related to clonal hematopoiesis and not inherited genetic predisposition [to breast cancer]. Patients need to understand the chances that [their tests will be] positive [for certain mutations], or the prior probability. This is an area of intense debate. Competing guidelines have been confusing to patients and providers alike.

We currently don’t test patients who are at the highest risk [for breast cancer]. [In the future, we should test] them all. Every patient with ovarian cancer or TNBC needs to be tested. These are the patients for which [testing] will have the greatest effect.

Should somatic testing always be done in conjunction with germline testing?

Currently, there’s no indication for somatic testing in patients with early-stage breast cancer. In the metastatic setting, there are many reasons to do somatic testing, [such as] understanding whether an ER-positive cancer has a PIK3CA mutation or whether a patient with a HER2 1+ or 2+ tumor [by immunohistochemistry (IHC)] is eligible for fam-trastuzumab deruxtecan-nxki [Enhertu].

My standard clinical practice in a patient [newly diagnosed] with metastatic breast cancer is a biopsy to [test for] ER-positive, progesterone receptor–positive, and HER2/neu [breast cancer]. I do IHC for mismatch repair because there’s a tumor-agnostic indication by the FDA for immunotherapy in that situation, although it’s not often found in breast cancer. I do somatic sequencing to look for somatic BRCA1, BRCA2, and PALB2 mutations, as well as alterations like PIK3CA and ESR1 mutations to better [determine the most effective therapies].

There are many reasons to do somatic testing beyond [looking for] BRCA1 and BRCA2. If a patient with ER-positive disease with no other risk factors for BRCA1 and BRCA2 has not had germline BRCA1 and BRCA2 mutation testing but has had somatic testing for BRCA1 and BRCA2 ––although somatic testing can miss large genomic rearrangements––[and] has negative somatic testing, the likelihood of a germline BRCA1 or BRCA2 mutation is low.

What established germline testing processes are in place at Penn Medicine?

Currently, we actively monitor how good we are at testing patients with certain cancers. For instance, in ovarian cancer, we try to achieve 100% testing. We’re not there, but we’re at over 80%. Sometimes, patients don’t want germline testing, but we’re working on that. We’re [testing at similar rates in] TNBC and pancreatic cancer. Any patient with pancreatic cancer or metastatic prostate cancer is eligible for germline testing.

When we have a discrete entity, it’s easier to keep track of our metrics, which is important. Otherwise, we adhere to NCCN guidelines [regarding germline testing in] breast cancer, and those guidelines will continue to evolve.

Can testing processes from larger academic centers be scaled down and replicated in the community setting to improve testing rates?

[Several movements] are going on. Angela R. Bradbury, MD, at Penn Medicine has a National Institutes of Health–funded trial, [eReach (NCT04353973)], investigating digital health platforms vs telegenetics to help community practices across the country with genetic testing. Her genetic counselors are licensed in all 50 states. We’re trying different models to make genetic testing easier for providers.

We have also instituted point-of-care testing for pancreatic cancer and metastatic prostate cancer, which involves a 7-minute video. That’s been a successful model.

There’s not 1 way to do this. It needs to fit the institution and the provider. Some providers are comfortable doing pretest education for patients and disclosing those results. That’s great. [However], we’re busy, and it can be challenging. [Providers may have questions] like: What panel should we send? Which insurance does a patient have? Which lab should we send the testing to? Our role in the Basser Center for BRCA is to serve as a resource and help providers strategize what might be best at their institution.

There are many ways to do this. The key is to be able to measure it. We’ve spent much time at Penn Medicine using our electronic health record to capture this. We have HL7 integration with several labs. Our genetic testing information comes in as discrete entities, and we can tell if a patient has been tested. In most electronic health records, if a PDF has been scanned into the file and marked “lab,” it’s hard for providers to figure out whether genetic testing has been done. I encourage all institutions to figure out a way to keep track of who’s getting tested, because that’s the only way to know whether you’re achieving your goals.

How can pathologists and medical oncologist better work together to improve patient care?

Pathologists are critical to anything we do in oncology. Pathologists make the diagnosis of cancer. We have a regular tumor board where pathologists, radiologists, medical radiation oncologists, and surgical oncologists are all on the phone together. Looking at the pathology and radiology is critical.

Patients with breast cancer have said to me that it’s amazing [that when they’re] diagnosed with breast cancer, they gain 3 doctors. I try to correct them [and say they’ve] gained at least 5 doctors. They sometimes forget to include their radiologists and pathologists, but we all work together as a team. It’s critically important.

What ongoing breast cancer research at Penn Medicine may push the needle forward?

We’re interested in pushing ahead in cancer interception to prevent carcinogenesis at the earliest stages. [We want to] use patients with inherited cancer susceptibility, specifically BRCA1- and BRCA2-mutation carriers, to investigate that.

We have several ongoing studies. One open international study is the [phase 3] BRCA-P trial [NCT04711109], which is led in the United States by Judy E. Garber, MD, MPH, [of Dana-Farber Cancer Institute in Boston, Massachusetts], investigating denosumab to decrease the risk of breast cancer in BRCA carriers.

We are also interested in vaccine approaches or immuno-prevention. We have an open vaccine [trial] where we have treated a cohort of BRCA1- and BRCA2-mutation carriers with a prior cancer diagnosis. We are soon to vaccinate our first BRCA carrier without a prior cancer history.

We are trying to prevent patients from developing cancer in the first place. This is an important area because although we treat patients with cancer, we’d much rather prevent the cancer from developing in the first place.

References

1. Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377(6):523-533. doi:10.1056/NEJMoa1706450
2. Geyer CE Jr, Garber JE, Gelber RD, et al; OlympiA Clinical Trial Steering Committee and Investigators. Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer. Ann Oncol. 2022;33(12):1250-1268. doi:10.1016/j.annonc.2022.09.159