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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 , but that proportion shrank with the new HER2-low designation, which accounts for approximately 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) 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 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<0.0001). Again, about half of the patients in the trial had triple-negative disease.

"Both trials were done for metastatic disease but in the second- or third-line setting," Yuan said. "Oncologists may choose to start with PARP inhibitors in the front line, though, if the tumor is PD-L1 negative."

The NCCN lists both PARP inhibitors as first-line options for TNBC patients with a PD-L1 CPS of 10 or less and a germline BRCA 1/2 mutation.

"The two PARP inhibitors have never been compared head-to-head, and we can't do cross trial comparisons," Yuan said. "Neither trial yielded any OS benefit, so there is no difference there."

Talazoparib can cause transfusion-dependent anemia. So if the patient is already struggling with low hemoglobin, for example, that may be a reason to choose olaparib, Yuan said.

"Both of them have some myelosuppression, though, and both have gastrointestinal side effects," McCann said. "If I can get my patient through the first month of therapy on these drugs, it tends to even out a bit in terms of gastrointestinal toxicity. I would say though that most physicians are probably more comfortable using olaparib than talazoparib."

There are also no data to inform first-line treatment choice when patients are both BRCA and PD-L1 positive, although both McCann and Yuan said they tend to turn to pembrolizumab plus chemotherapy first in these patients because of the OS benefit.

As patients move to the second-line, there are also numerous treatment options available, but the treatment of choice will likely depend on what the patient was exposed to in first-line. If they have no prior PARP inhibitor exposure, clinicians can reach for either olaparib or talazoparib.

McCann said she will typically always reach for a PARP inhibitor in the second-line before turning to other options like the antibody-drug conjugate (ADC) sacituzumab govitecan (Trodelvy).

The FDA approved sacituzumab govitecan for patients with TNBC who have received two or more prior therapies, at least one of which was in the metastatic setting. In the ASCENT trial, which tested sacituzumab govitecan against physician's choice of single-agent chemotherapy, addition of the ADC improved both PFS (HR 0.43, 95% CI 0.35-0.54, P<0.0001) and OS (HR 0.51, 95% CI 0.41-0.62, P<0.0001) compared with chemotherapy in the full population regardless of brain metastasis.

"Sacituzumab govitecan does have significant bone marrow suppression and gastrointestinal toxicity, so certain patients may want to wait to use it," Yuan said. "Those of us who were involved in the clinical trials have learned how to adapt and care for these patients and are more comfortable handling the side effects. Good patient education and close monitoring of patients on treatment are important."

Systemic chemotherapy is a standard-of-care treatment in second and later lines as well. Yuan also encouraged clinical trial enrollment for the third-line and beyond.

"In clinical trials, we have a few other exciting antibody-drug conjugates being investigated, such as datopotamab deruxtecan, which is a Trop2-targeting drug, and trials looking at HER3 ADCs, such as patritumab deruxtecan (HER3-DXd)," Yuan said. "The results of these trials will be very interesting in the future as we continue to discuss the sequencing question in these patients."

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