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BRCAness Correlates with Chemotherapy Responsiveness and Clinical Outcome in Ovarian Cancer
Abstract & Commentary
By Robert L. Coleman, MD, Professor, University of Texas; M.D. Anderson Cancer Center, Houston, is Associate Editor for OB/GYN Clinical Alert.
Dr. Coleman reports no financial relationship to this field of study.
Synopsis: A BRCAness gene expression profile derived from ovarian cancer patients was independently validated with respect to chemosensitivity and survival in two cohorts of sporadic ovarian cancer. This is an important step in the clinical utility of a tool, which may be leveraged to indicate which patients without a genetic mutation in the BRCA genes may benefit from use of a PARP inhibitor.
Source: Konstantinopoulos PA, et al. Gene expression profile of BRCAness that correlates with responsiveness to chemotherapy and with outcome in patients with epithelial ovarian cancer. J Clin Oncol 2010 Jun 14; Epub ahead of print.
The primary purpose of this study was to develop a gene expression profile of BRCA dysfunction ("BRCAness"), which could be used to discriminate sporadic ovarian cancer patients with or without dysfunction to the homologous repair pathway and correlate whether this profile would describe sensitivity to platinum-based chemotherapy and pharmacological inhibition of poly-ADP ribose polymerase (PARP).
To do this, the investigator interrogated a publicly available microarray dataset, which included 34 ovarian cancer patients with confirmed germline BRCA1/2 mutations and 27 ovarian cancer patients without mutation (sporadic). The resulting gene profile included 60 genes, which had 94% accuracy in discriminating these two cohorts. To address the applicability of the test, they applied the profile pre-clinically and clinically against independent samples. Preclinically, they demonstrated high fidelity prediction of platinum sensitivity/resistance and inducement of RAD51 loci (a marker of homologous recombination and PARP sensitivity) following ionizing radiation in pancreatic cancer cell lines. Further, the profile accurately predicted sensitivity to PARP inhibition in all 4 samples. Clinically, they assessed the profile for BRCAness against a set of previously described paired human tissue samples from 4 patients with known germline BRCA mutation, where sensitive initial biopsies were matched with biopsies from resistant tumors following therapy. In each of these cases, resistance was heralded by BRCA reversion mutations restoring BRCA function. In 6 of these 8 specimens, the profile accurately predicted BRCA status and chemosensitivity profile.
Next, they studied the profile in 70 patients with sporadic ovarian cancer (35 test negative for BRCA mutation and 35 untested but without a significant family history or ethnicity for germline mutation). Despite being similar for all known prognostic factors, the patients with a BRCA-ness profile had a significantly better disease-free and overall survival, and positive trends to increasing response to platinum therapy.
The authors concluded that the genomic profile of BRCAness correlates with responsiveness to platinum and PARP inhibitors and identifies a subset of sporadic patients with improved outcome. Additional evaluation of this profile as a predictive tool in patients with sporadic EOC is warranted.
In recent issues of the OB/GYN Clinical Alert, I have focused on the impact defining this population could have for effective therapeutic interventions. Last year this month, Fong et al published the results of a phase I clinical trial of olaparib, a PARP inhibitor, in patients with known germline mutations in BRCA 1/2. The remarkable response rate, even in patients with known refractory disease, offered hope for very personalized medicine with an agent associated with few adverse events. In June's Special Feature, I profiled a study that demonstrated the improvements in capturing patients at high risk for carrying BRCA mutations that occurred as a result of a policy change at a major cancer center. In both situations, the target has centered on patients with a known mechanistic opportunity to respond to a novel class of agents and in whom appropriate counseling would be of great value to their care.
The burgeoning availability of PARP inhibitors and the data from the current report would suggest this audience may be greatly expanded as up to one-third of patients with ovarian cancer may fit a profile that could benefit from this targeted therapy. While the proof of principle has yet to be validated in the clinic, the availability of this profile is poised to enter a clinical trial where allocation of treatment may be directed by the tumor profile or at least correlated with response to therapy in post-hoc analyses.