Ultimately, measures of global genomic instability like homologous recombination deficiency may have the greatest potential to identify patients who stand to benefit most from a DNA repair defect-targeted approach.
—Melinda L. Telli, MD
The potential of individualizing systemic treatment based on BRCA1/2 status has not yet been realized. BRCA1/2 germline status currently does not factor into systemic therapy decisions,” said Melinda L. Telli, MD, of Standard University School of Medicine, Palo Alto, California, who discussed the triple-negative breast cancer studies presented by Dr. von Minckwitz and Dr. Isakoff.
She noted that poly(ADP-ribose) polymerase (PARP) inhibitors have single-agent activity in advanced BRCA1/2 mutation–associated breast cancer, but no drugs are yet approved. Responses to standard chemotherapy drugs in mutation carriers are not well characterized, and most therapeutic trials do not determine BRCA status, even in patients with triple-negative disease. The role of BRCA mutation testing has been confined to informing recommendations for screening and risk reduction.
“For mutation carriers diagnosed with breast cancer, our treatment approach today is no different from that of a patient with sporadic breast cancer,” Dr. Telli said, but she acknowledged that this practice is poised for change.
With the results of the latest research, she said, “Some 20 years after the cloning of BRCA1, we are moving close to integrating germline BRCA status and markers of genomic instability to individualize therapy.”
In the GeparSixto study, “the finding of a carboplatin benefit among patients with a family history but lacking a germline mutation is fascinating,” she remarked. “It is potentially related to as-yet undiscovered BRCA1/2 mutations, or, on the other hand, to germline mutations in other homologous recombinant DNA repair pathway genes.”
Further Biomarker Evidence
Commenting on Dr. Isakoff’s study, she said the finding of higher homologous recombination deficiency scores in responders is “further evidence of the potential of this biomarker for platinum sensitivity in non-BRCA triple-negative breast cancer.”
In addition, “we have new and important evidence that germline BRCA status does influence systemic treatment response in triple-negative breast cancer, and this has implications for all therapeutic studies in this disease,” Dr. Telli said.
“Looking beyond BRCA, other germline biomarkers associated with therapeutic sensitivity likely exist, and additional studies are needed in this space,” she added.
“Ultimately, measures of global genomic instability like homologous recombination deficiency may have the greatest potential to identify patients who stand to benefit most from a DNA repair defect-targeted approach,” she concluded. ■
Disclosure: Dr. Telli reported no potential conflicts of interest.
Studies in triple-negative breast cancer presented at the 2014 ASCO Annual Meeting sought to determine predictors of response to platinum agents. One identified a subset of responders to neoadjuvant chemotherapy, but prediction proved more elusive in metastatic disease.