Should the Status of the Pathway Mediated by BRCA1 and BRCA2 be Evaluated Before Selecting Cancer Chemotherapy Drugs?

Abstract

This review brings together evidence to show that chemotherapy agents that cause DNA double strand breaks have increased success in treating model cancers with deficits in the pathway containing BRCA1/2 proteins. In people who do not have BRCA1 or BRCA2 gene mutations, the encoded proteins prevent breast/ovarian cancer. However BRCA1 and BRCA2 proteins have multiple functions including participating in a pathway that mediates error-free repair of DNA double strand breaks. Inactivation of BRCA1, BRCA2 or any other critical protein within this "BRCA pathway" due to a gene mutation should inactivate this error-free repair process. DNA fragments produced by double strand breaks are then left to non-specific processes that rejoin them without regard for preserving normal gene regulation or function, so rearrangements and deletions of DNA segments are more likely. This mechanism contributes to the gross chromosomal rearrangements found in a large majority of human cancers. In many cancers, gene rearrangements and deletions are believed to be critical events so a compromised BRCA pathway increases cancer risk in general. Mutation specifically of the BRCA1 or the BRCA2 gene increases risk as much as about 8 times for subsets of numerous cancers including stomach, pancreas, prostate, colon, etc. as reported in epidemiologic studies. Moreover, inactivating virtually any gene within a model for the BRCA pathway increases risk up to nearly 2000 fold for a subset of leukemias and lymphomas that frequently contain gene rearrangements.In tumor cells, the status of the BRCA pathway may be important during chemotherapy. Some chemotherapy agents cause chromosome breaks as they destroy tumor cells but other types of chemotherapy depend on different mechanisms. A damaged BRCA pathway may make subgroups of tumors unable to correctly repair broken chromosomes. Because normal error-free repairs are no longer assured, sensitivity to chemotherapy drugs that cause DNA double strand breaks should especially increase.The end result specifying tumor resistance vs. tumor sensitivity to chemotherapy is complicated and may be modified by additional mechanisms. Nevertheless this review of the literature shows that the status of the BRCA pathway is a broadly useful criterion in selecting chemotherapy agents for model tumors derived from a variety of different organs. These preclinical models show real gains depending on the chemotherapy regimen selected. If the models are appropriate predictors in cancer patients, then identifying patients more likely to respond to a given chemotherapy agent should minimize serious adverse effects and prolong survival times.