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Genetic marker identified cancers responsive to platinum-based chemotherapy
Birkbak NJ. Cancer Disc. 2012;doi:10.1158/2159-8290.CD-11-0206.
A particular genetic marker can predict which aggressive triple-negative breast cancers and ovarian cancers are expected to respond to platinum-based chemotherapies, according to study results published in the journal Cancer Discovery.
Previous findings had identified that triple-negative breast cancers — lacking expression of ERs and PRs or amplification of the HER-2/neu gene — and ovarian cancers with BRCA1 and BRCA2 mutations share a common pattern of genomic abnormalities, including allelic imbalance. Based on these findings, researchers hypothesized that cancers with high allelic imbalance may share sensitivity to platinum-based chemotherapies, as exhibited by BRCA1-linked cancers.
Researchers enrolled 79 preoperative patients in two clinical trials intended to shrink tumor before surgical removal — those administered cisplatin monotherapy alone (n=28) and those administered cisplatin combined with the angiogenesis inhibitor bevacizumab (Avastin, Genentech; n=51). In both clinical trials, approximately 40% of patients had a complete or near-complete disappearance of the cancer after the cisplatin therapy.
Further analysis of the tumor samples demonstrated that patients with triple-negative breast cancer who had higher levels of allelic imbalance extending to the telomere exhibited significant cisplatin sensitivity and pathologic response to preoperative cisplatin treatment. Similarly, in patients with serous ovarian cancer treated with platinum-based chemotherapy, higher numbers of telomeric allelic imbalance predicted better treatment response.
“We found an inverse relationship between BRCA1 expression and [telomeric allelic imbalance] in sporadic [triple-negative breast cancers] and serous ovarian cancers without BRCA1 or BRCA2 mutation. Thus, accumulation of [telomeric allelic imbalance] is a marker of platinum sensitivity and suggests impaired DNA repair,” the researchers said.
Mutations in BRCA genes can inhibit effective DNA repair that predict sensitivity to DNA-damaging agents, such as platinum, according to the researchers. The number of telomeric allelic imbalance, a genomic measure of defective-repaired DNA, could identify patients with cancer expected to benefit from treatments targeting defective DNA repair.
“We currently do not have any targeted therapies for patients with triple-negative breast cancer, so if these laboratory findings are confirmed and an assay is created to predict sensitivity to drugs that target defective DNA repair, it would be a major step forward,” researcher Andrea Richardson, MD, PhD, a surgical pathologist at Brigham and Women’s Hospital and Dana-Farber Cancer Institute, said in a press release.
Disclosure: The researchers report a pending patent application based on this study.