Advances in Advanced TNBC
Currently, TNBC is predominantly treated with chemotherapy.
Clinical management of patients with TNBC is challenging, and genetic characterization has defined molecular subtypes, each of which responds differently to chemotherapy.11-13 Pathological and molecular characterization is important in the management of patients with TNBC, which harbor several hallmark mutations, including TP53, PI3KCA, PTEN, BRCA1, and BRCA2, and loss of RB1 and BRCA1.
The subset of BRCA-associated breast cancer, or “BRCAness,” is characterized by a heightened sensitivity to damage from DNA cross-linking, which may explain why platinum salts are effective in these tumors.
Olaparib, a poly ADP-ribose polymerase (PARP) inhibitor, may be an effective treatment for BRCA-mutant tumors. PARP inhibitors have been shown to target single-stranded DNA repair with homologous recombination that arise in this setting.
Ongoing clinical trials are evaluating PARP inhibition. These include olaparib in the OlympiAD study (ClinicalTrials.gov Identifier: NCT02000622), niraparib in BRAVO (ClinicalTrials.gov Identifier: NCT01905592), and talazoparib in EMBRACA (ClinicalTrials.gov Identifier: NCT01945775).
The presence of tumor-infiltrating lymphocytes and the overexpression of PD-L1 supports the evaluation of checkpoint inhibitors in TNBC.
KEYNOTE-119 (ClinicalTrials.gov Identifier: NCT02555657) is a phase 3 trial evaluating single-agent pembrolizumab vs single-agent chemotherapy for metastatic TNBC.
The phase 3 KEYNOTE-355 trial (ClinicalTrials.gov Identifier: NCT02819518) will compare pembrolizumab plus chemotherapy vs chemotherapy alone among patients with previously untreated, locally recurrent, inoperable or metastatic TNBC. This study is still accruing patients. Identifying biomarkers of response will be important for identifying patients who are likely to benefit from immunotherapy.
Data with checkpoint inhibitors are, however, not mature and were not available at the ASCO meeting, Dr Mayer indicated.
Novel drugs and combinations are helping oncologists overcome resistance to endocrine and HER2-targeted therapies. The management of TNBC, while still challenging, has also seen significant advances, and molecular profiling in these tumors will help personalize treatment for patients.
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