As new treatment options continue to emerge for triple-negative breast cancer (TNBC), sequencing of therapy promises to get ever more complicated.
TNBC had been estimated to account for about 15% of all breast cancer diagnoses, but that proportion shrank with the new HER2-low designation, which accounts for approximately one-third of patients diagnosed with TNBC. An important further subset is those with BRCA-mutant disease.
“Only about 10% to 15% of patients diagnosed with TNBC will also have a BRCA mutation,” said Yuan Yuan, MD, PhD, director of breast oncology at Cedars-Sinai Cancer in Los Angeles.
It is important to identify these patients with BRCA mutation because they may be eligible for additional targeted therapies as part of the disease treatment regimen. For patients with recurrent or stage IV disease, the National Comprehensive Cancer Network (NCCN) currently recommends comprehensive germline and somatic profiling to identify candidates for targeted agents.
“The NCCN just recently removed the age restriction on their guidelines for germline testing for women with TNBC to recommend that all be tested,” said Kelly McCann, MD, PhD, of UCLA Health Jonsson Comprehensive Cancer Center in Los Angeles. “You may only find a handful of people with BRCA mutations, but for that handful it means they may live longer.”
In addition to genetic testing, Yuan said that PD-L1 testing is also an important part of the work-up of patients with TNBC and may help narrow first-line treatment options. That is because patients with TNBC whose tumors express PD-L1 with a combined positive score (CPS) of 10 or more are eligible for treatment with pembrolizumab (Keytruda) plus chemotherapy.
The KEYNOTE-355 trial tested pembrolizumab 200 mg every 3 weeks plus the investigator’s choice of chemotherapy against chemotherapy alone and showed that the addition of pembrolizumab significantly improved overall survival (OS) in patients with a PD-L1 CPS score of 10 or more (HR 0.73, 95% CI 0.55-0.95, P=0.0185).
“Based on those results, patients with tumors that are PD-L1 positive can receive pembrolizumab with a backbone of nab-paclitaxel, paclitaxel, or gemcitabine-carboplatin,” Yuan noted.
For those patients with TNBC and BRCA mutations whose tumors do not express PD-L1, first-line treatment options include platinum-based chemotherapy or one of the two PARP inhibitors approved for this setting. “There are definitely some caveats here, and the best approach is up for debate,” Yuan said. “There is no right or wrong answer.”
The FDA approved olaparib (Lynparza) is based on results from the OlympiAD trial, which tested the PARP inhibitor against physician’s choice of chemotherapy in patients with HER2-negative metastatic breast cancer. Olaparib significantly improved progression-free survival (PFS) compared with chemotherapy (HR 0.58, 95% CI 0.43-0.80, P=0.0009). About half of the patients in the trial had triple-negative disease.
Talazoparib (Talzenna) was approved for HER2-negative locally advanced or metastatic breast cancer based on the EMBRACA trial, which compared talazoparib with physician’s choice of chemotherapy. Here again, treatment with the PARP inhibitor improved PFS compared with chemotherapy (HR 0.54, 95% CI 0.41-0.71, P
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