Arun Highlights Importance of Identifying BRCA1/2 Mutations in Metastatic Breast Cancer

Banu Arun, MD

Banu Arun, MD

Two PARP inhibitors are currently approved for patients with HER2-negative advanced or metastatic breast cancer who areBRCA1orBRCA2positive. Pivotal trials led to a 3-month improvement in progression-free survival (PFS) with these agents compared to standard-of-care chemotherapy, underlying the importance of identifying these mutations.

Olaparib (Lynparza) was approved based on data from the phase III OlympiAD trial, in which patients randomized to receive the PARP inhibitor experienced a PFS of 7.0 months versus 4.2 months with chemotherapy. Talazoparib (Talzenna) was also approved for patients with locally advanced or metastatic disease based on data from the phase III EMBRACA trial where patients had a median PFS of 8.6 months in the talazoparib arm versus 5.6 months with chemotherapy.

These 2 PARP inhibitors vary in terms of toxicities and how they are administered, but both agents are approved for patients with metastatic breast cancer harboring a germlineBRCAmutation. These mutations can be identified through genetic testing; criteria have been outlined in the National Comprehensive Cancer Network (NCCN) guidelines and are updated annually.

As other targeted therapies become available for these patients, the role of genetic testing becomes increasingly important. Other hereditary genes that could potentially have a role in making treatment considerations includePALB,ATM, andCHEK2mutations.

In an interview withTargeted Oncology, Banu Arun, MD, co-medical director of breast medical oncology in The Clinical Cancer Genetics Program at The University of Texas MD Anderson Cancer Center, discussed the role of genetic testing in patients with metastatic breast cancer. She highlighted the importance of identifying various mutations, includingBRCA1/2mutations in light of the approval of PARP inhibitors. In addition, she spoke to how the role of genomic testing is evolving in this field with the development of new targeted agents.

TARGETED ONCOLOGY:What is the current role of genetic testing in breast cancer?

Arun:Germline testing for hereditary breast cancer has made its practice into 1 of the important tests for breast cancer treatment. There are already guidelines for hereditary genetic testing forBRCA1andBRCA2. Most of us follow the NCCN guidelines; that criteria includes testing all patients before age 45 or all patients with triple-negative breast cancer before the age of 60. Outside those age ranges, there is also criteria for patients with family history of breast cancer, ovarian cancer, any individual with pancreas cancer or any individual with metastatic prostate cancer is eligible.

TARGETED ONCOLOGY:What are the implications of genetic testing?

Arun:There are multiple implications for genetic testing in breast cancer. First, for the patient with breast cancer, it can help to determine, for example if there is aBRCAmutation, the risk of contralateral breast cancer. At the time of deciding for surgery, the patient could opt for double mastectomy to prevent contralateral breast cancer. This approach should be discussed though in detail with the patient and her surgeon.

It also has therapeutic implications. Now that PARP inhibitors are FDA approved for metastatic breast cancer with germlineBRCAmutations, physicians could use PARP inhibitors for their patients with metastaticBRCA-positive breast cancer. The response rate is about 60% for these agents. We also know the platinums induce an up to 60% response rate in patients who are BRCA mutation carriers for metastatic breast cancer. Therefore, platinums could be considered for treatment as well.

The other implications for patients besides treatment is also for screening. We know that ovarian cancer risk is up to 45% inBRCA1and up to 25% inBRCA2carriers. Doing preventable oophorectomy is recommended per the guidelines for patients in their late thirties or early forties.

There are also family implications. Once you find a mutation in the patient, each first-degree relative, has a 50% risk of carrying the mutation; ideally these family members should consider genetic testing (what we call predicative testing).  If they are positive, then they would do risk management interventions, such as adding MRI to their breast screening, considering double mastectomy, ovarian screening, or oophorectomy. If it’s a BRCA2mutation carrier, they should do pancreas screening, screening for melanoma, prostate screening, amongst others.

There are also other genes that are related to hereditary breast cancers such asPALB2mutations,ATM, andCHEK2. Those tests can be ordered all together withBRCA1andBRCA2on panels. If patients are positive, it might not have immediate therapeutic implications at this  time as we do not have sufficient data. For example, we don’t have enough data to recommend bilateral mastectomy, however, for unaffected family members, it can have screening implications, such as adding MRIs to the screening or screening for other cancers.

TARGETED ONCOLOGY:Could you speak to the importance of detecting aBRCAmutation in these patients?

Arun:Patients withBRCA1-andBRCA2-mutated metastatic breast cancer are eligible to be treated with PARP inhibitor therapies and targeted agents based on 2 prospective randomized trials comparing PARP inhibitors to standard-of-care chemotherapy. The response rate was almost doubled with PARP inhibitors, and the duration of response was statistically significantly prolonged by about 3 months in both of the studies. The FDA approved these agents for the treatment of patients with metastatic breast cancer withBRCAmutations. Also, platinums can be used in these patients as well. PARP inhibitors and platinums induce a up to 60% response rate.

TARGETED ONCOLOGY:What tests do you use for genetic testing in breast cancer?

There are several CLIA-certified companies that offer germline testing in the blood. These are commercially available tests covered by the patient’s insurance if they fit the criteria.

TARGETED ONCOLOGY:How frequently is genetic testing being used in breast cancer clinical trials?

Arun:There are multiple clinical trials looking at PARP inhibitors in combinations. This requires that the patients undergo germline genetic testing forBRCAmutations. Some of the trials also include other hereditary mutations, such asPALB2. Again, if patients are found to have those mutations, they may be eligible for clinical trials.

We, for example, are about to open a study with using PARP inhibitors plus other targeted agents for patients with metastatic breast cancer withBRCAmutations. The availability of these treatments as well as clinical trials will increase BRCA testing for patients with breast cancer.

TARGETED ONCOLOGY:What advice would you like to share with community oncologists in regard to genetic testing for patients with breast cancer?

Arun:My message would be to see whether the patient fits criteria for genetic testing forBRCA1andBRCA2, usually using the NCCN guidelines and updates. For the other genes, I think they have to pay attention to family history. If they have a patient with, for example, breast and uterine cancer, and a family history of thyroid cancer, maybe the patient is a candidate forPTENmutation testing. Some patients with breast cancer have family members with colon cancer and ovarian cancer, therefore checking for Lynch syndrome mutations might be helpful. Taking into account personal history of cancer, age of onset is important, as well as considering any family history of different types of cancer.

TARGETED ONCOLOGY:Is there anything else the community should be aware of with genetic testing in this population?

Arun:The 1 thing that healthcare providers should be aware of is that when a limited panel of genetic tests is ordered, for example if you only look atBRCA1andBRCA2, you might get a 5% to 6% variant of uncertain significance (VUS), which means we get a test result where we don’t know what it means clinically yet. If you expand the test to, say, a 90-gene panel, then more than 30% of the patients will have a VUS. Be aware that the more genes that are ordered, the higher the likelihood of finding mutations where we don’t know what it means for the patient and family members.

Finally, with the increased availability of targeted agents, genomic testing (testing the tumor for mutations) is also increasing in breast cancer. Genomic testing can lead to the incidental findings ofBRCA