Dr. Debu Tripathy MD discusses ER, PR and HER2-negative breast cancer (termed triple negative) is a particularly aggressive subtype for which targeted therapies are not effective.
Description: While chemotherapy may be more effective in this subgroup, overall outcomes are worse. Molecular profiling and other biomarker studies suggest that the triple negative subtype is biologically distinct with a high histological grade and proliferation indices, expression patterns showing less differentiation, more stem cell-like properties and specific genes such as EGFR and c-kit – a pattern that is defined as the basal subtype, even though triple negative and basal cases do not represent fully overlapping groups. BRCA 1-related breast cancers tend to be triple negative and fall into the basal group, and there may be an expanded group of “BRCA-like” tumors with normal BRCA 1 sequence testing, but still with abnormalities in the BRCA 1 pathways that are involved in double strand DNA repair. Cells rely on several DNA repair mechanisms, and one of these, primarily single strand DNA repair, is mediated by an enzyme called poly(ADP-ribose) polymerase, or PARP. Cells that already have defective BRCA 1 or 2 function are therefore exquisitely sensitive to PARP inhibitors as this creates what is termed a “synthetic lethal” insult. Early trials with PARP inhibitors suggest that their activity is greatest in BRCA 1 or 2-related cancers. There is also preliminary evidence that DNA damaging agents, particularly platinum drugs, are very active in triple negative or BRCA 1-related breast cancer. A randomized Phase II trial with the PARP inhibitor iniparib (BSI-201) enrolled patients with triple negative advanced breast cancer and compared gemcitabine plus carboplatin alone or with iniparib, and this showed a marked effect of iniparib in improving response rate, disease-free survival and even overall survival. A definitive Phase III trial of the same design has recently been completed. It is likely that PARP inhibitors will soon be approved if these results hold up, and unanswered questions will include which specific chemotherapy agents are the best PARP partners and what patient population derives the greatest benefit – specifically, will it be all triple negative cases, or only BRCA-related or “BRCA-like” tumors.
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Posted on : 08/30/10
Added : 9 years ago