A Q&A With Richard Finn, MD: Targeted Therapies for Breast Cancer
Publishded Online: Mar 19, 2014
Richard Finn, MD
Targeted Therapies: How might poly(ADP-ribose) polymerase (PARP) inhibition be able to restore DNA repair processes?
Finn: The theory is that tumors that carry defects in BRCA (the breast cancer susceptibility gene), which is part of the DNA repair cascade, are at risk for single- strand DNA breaks, and repairs of those breaks depend on a complex that includes the PARP protein. By inhibiting PARP in the context of inherent DNA repair defects, you set up the cell for developing double-strand DNA defects, and then a catastrophic death from irreparable DNA damage.
Because many BRCA-mutated cancers are triple negative, it was rational to evaluate PARP inhibitors for triple-negative breast cancer. The challenge is that most triple-negative breast cancers are not BRCA, even though the converse might be true. The idea of PARP inhibitors outside of BRCA mutations is also an interesting idea, but it still needs to be evaluated in the context of knowing whom to treat or how to select them, or the best combinations.
There also might be potential synergy between DNA-damaging agents and a compound that blocks DNA repair, such as a PARP inhibitor. That led to a randomized, phase II study with iniparib in triple-negative breast cancer that looked very promising, with significant improvement in overall survival with iniparib, platinum, and gemcitabine versus platinum and gemcitabine alone.1 However, in a larger, randomized, phase III study, that benefit was lost, which was a big setback to the PARP field.2
There may be a role for these drugs, but you really need to have a predictive marker for response. Potentially, the best predictive marker we have is BRCA-mutated status, but not all BRCA mutations are the same.
Targeted Therapies: What is the standard treatment now to prevent the recurrence of HER2+, node-negative tumors?
Finn: We know that HER2 amplification is a negative prognosticator in breast cancer. Historically, HER2-amplified breast tumors have one of the worst outcomes. We know that, even in the setting of nodenegative disease, HER2 amplification is a marker for increased risk of relapse and recurrence, and, while there are other characteristics of the tumor that might come into play, many of us feel that these patients should receive trastuzumab. My opinion would be that the TCH (taxane/platinum/trastuzumab) regimen offers the best risk-benefit ratio for adjuvant therapy for these women. Specifically, it decreases the risk of anthracycline-associated cardiotoxicity without compromising any disease-control benefits.