Clinical Challenge: BRCA-Mutant Triple-Negative Breast Cancer

The majority of breast cancers are “sporadic,” developing in patients with no associated hereditary mutations. On the other hand, hereditary cancer susceptibility gene mutations, the most common being BRCA1, occur in about 5-10% of patients with breast cancer. Of those women found to have the BRCA1 mutation who develop breast cancer, the vast majority — 60-80% — will have triple-negative breast cancer (TNBC), noted Roberto A. Leon-Ferre, MD, of the Mayo Clinic in Rochester, Minnesota.

The poor prognosis of patients diagnosed with TNBC spurred a major effort to discover treatments for these patients, especially those with potentially targetable mutations like BRCA1/2. Recently, the fruits of these labors have begun to produce results in the form of poly (ADP ribose) polymerase (PARP) inhibitors, immunotherapy agents, and other advances.

Clinicians are now left with challenging questions about which therapies to select and how best to sequence them in this group of patients facing not only their treatment course, but also anxiety about the risk for contralateral or ovarian cancers, as well as the implications of their diagnosis on family members.

Early-Stage Disease

For women with early-stage BRCA-mutant TNBC, the standard first-line treatment continues to be chemotherapy, including taxane-, alkylator-, and anthracycline-based regimens, Leon-Ferre noted.

There has also been a lot of interest in platinum agents in early-stage TNBC, said Banu Arun, MD, of the University of Texas MD Anderson Cancer Center in Houston. The INFORM trial, for which she was a co-author, tested the use of neoadjuvant cisplatin versus doxorubicin-cyclophosphamide in germline BRCA carriers with HER2-negative breast cancer, including 70% of patients with TNBC.

“The results did not show that platinum therapy was better than anthracyclines, but they were also not worse,” Arun said. “Both may be options.”

Subgroup analyses from the BrighTNess and GeparSixto trials showed less pronounced improvements in pathologic complete response with the addition of platinum agents in patients with germline mutations compared with patients without BRCA-mutant disease.

These mixed results make the use of platinum-agents in early-stage disease a controversial topic, especially given that long-term outcomes have also been mixed, said Leon-Ferre.

A meta-analysis evaluating the use of neoadjuvant platinum-based systemic treatment in TNBC showed a statistically significant improvement in pathologic complete response compared with non-platinum-based treatment in women with TNBC. However, those researchers noted, the data may be affected by “moderate heterogeneity among the studies” and that “improvement in pathologic complete response rates may be a result of down-staging of low-volume residual disease, which is not known to translate to lower recurrence rates” and “may not be associated with improved outcomes in BRCA1/2 mutation carriers.”

Leon-Ferre explained that there is also a lot of interest in the just-released results of the OlympiA trial, published in the New England Journal of Medicine and presented during the plenary session of the American Society of Clinical Oncology’s 2021 virtual annual meeting. This phase III trial of early-stage breast cancer evaluated the use of adjuvant olaparib (Lynparza) after neoadjuvant chemotherapy in patients with germline BRCA mutations and high-risk HER2-negative disease.

OlympiA showed that in patients with germline BRCA-mutated, high-risk HER2-negative breast cancer, treatment with olaparib improved the rates of invasive disease and distant-metastasis-free survival. At 3 years, invasive disease-free survival was improved by 8.8%. Overall survival data is trending in the right direction, but more follow-up is needed, Leon-Ferre noted.

“I believe these results will change the standard of care, and that we now have a very compelling reason to test all patients with HER2-negative breast cancer for the presence of BRCA mutations,” he said.

Advanced Disease

The National Comprehensive Cancer Network has included the use of platinum agents (cisplatin and carboplatin) as preferred treatment options for women with recurrent/stage IV breast cancer and germline BRCA1/2 mutations.

The phase III TNT trial evaluated the use of first-line docetaxel with carboplatin in 376 women with TNBC. In an unselective group of patients, carboplatin was no more active than docetaxel; however, in patients with germline BRCA1/2 mutations, carboplatin resulted in a significantly better response than docetaxel. Progression-free survival was also improved with carboplatin, but there was no difference in overall survival.

Arun said the most exciting new treatment option for women with BRCA-mutant TNBC are PARP inhibitors. She pointed to two recent landmark studies showing that PARP inhibitors result in better outcomes compared with conventional chemotherapy:

• Another assessment of the OlympiAD trial compared olaparib with physician’s choice of non-platinum chemotherapy and showed improvement in progression-free survival with the PARP inhibitor in all subtypes of patients with germline BRCA mutations

• EMBRACA compared talazoparib (Talzenna) with physician’s choice of single-agent chemotherapy and showed longer progression-free survival in patients with germline BRCA mutations, but not in overall survival

Despite these advances, there are some remaining questions about how to combine or sequence PARP inhibitors with platinum chemotherapy in this setting, Arun said. “For example, it is unknown whether if a patient is resistant to one they might be resistant to another. There are also questions about whether to start with platinum and then add a PARP, or start with a PARP and add a platinum, or do the combination with PARP inhibitor maintenance. It remains to be investigated in a clinical setting.”

BRCA versus PD-L1

Patients with metastatic BRCA-mutant TNBC can also have PD-L1 positive tumors. In 2019, the FDA approved the combination of atezolizumab (Tecentriq) plus nab-paclitaxel (Abraxane) for women with advanced TNBC that tests positive for PD-L1.

“As it stands today, we generally prefer to start with immunotherapy and chemotherapy in those patients because atezolizumab has shown an improvement in overall survival in those patients in the first-line setting,” Leon-Ferre explained. “Immunotherapy appears to be most effective when used as first-line therapy. In contrast, PARP inhibitors have been shown to control cancer longer than chemotherapy but have not yet shown that they make people live longer.”

However, he added, some patients may still prefer the ease and convenience of the oral PARP inhibitor, and this was particularly evident during the COVID-19 pandemic.

“I saw patients who had both options and some decided that they would rather stay away from the hospital and take the oral drug,” Leon-Ferre said. “It is important to have a conversation about all the options, and for well-informed patients, I think it is reasonable to use a PARP inhibitor first.”

Sacituzumab

A new player in the treatment of TNBC is the antibody-drug conjugate sacituzumab govitecan (Trodelvy), which gained FDA approval in April 2020 for unresectable locally advanced or metastatic TNBC in women who had two or more prior systemic therapies. The drug was approved based on results of the ASCENT trial that included women with TNBC.

“The approval is for TNBC with no mention of BRCA status,” Arun noted.

At the virtual 2020 San Antonio Breast Cancer Symposium, results of a biomarker evaluation of the ASCENT study were presented that suggested better survival outcomes compared with placebo in patients regardless of BRCA1/2 status, although the number of patients with germline BRCA1/2-positive disease was small.

“Sacituzumab would be an option for patients with and without BRCA mutations, as both derived benefit in the ASCENT study,” Leon-Ferre said. “In these women, it is best reserved for later lines of therapy — definitely after use of a PARP inhibitor.”

Additional Considerations

Finally, he said that even with these many new treatment options, women with BRCA-mutant breast cancer remain clinically challenging to treat because of the nature of the cancer-predisposition mutation.

“One of the main challenges remains the risk of other cancers,” he explained. “There is a risk of having new breast cancer even when the first is cured, the consideration of undergoing bilateral mastectomies, and the risk for ovarian cancer that have to be considered.”

In addition, many people with BRCA mutations develop cancer at a younger than average age, which has implications for overall health and fertility, Leon-Ferre said. “Given the younger age of onset, fertility preservation is top of mind for many patients diagnosed with breast cancer in the context of a BRCA mutation. This requires careful planning and promptness.”

“We have many exciting treatment options, but we have to work together to make decisions quickly to line up everything that is needed and not delay treatment initiation,” he concluded.