In reply to the letter by Gevaert et al.

Abstract

Dear Sir, Gevaert et al. raised an important issue about the implementation in clinical practice of the 9-gene set for platinum resistance of ovarian cancer patients. They also stated that nonplatinum containing regimens are suboptimal in the treatment of ovarian cancer. In our study we have included specimens of 96 primary ovarian adenocarcinoma patients from 2 Dutch Medical Centres. All patients were treated with platinum-based chemotherapy and 14 patients showed resistance whereas 82 responded to platinumbased chemotherapy. In our search for genes, a discovery set of 24 specimens was profiled in duplicate in which 69 genes were found to be differentially expressed between the nonresponders (n 5 5) and the responders (n 5 19). An algorithm was constructed to identify the predictive genes in this 69-gene discovery set. This resulted in 16 genes, of which 9 genes were confirmed with quantitative (q) RT-PCR. An independent validation was performed using qRT-PCR on a set of 72 specimens (9 nonresponders, 63 responders). The 9-gene set predicted platinum resistance in these 72 tumours with a sensitivity of 89% (95% CI, 0.68–1.09) and a specificity of 59% (95% CI, 0.47–0.71) (OR 5 0.09, p5 0.026). We agree with Gevaert et al. that the specificity is not optimal and that the profile is not yet ready for clinical practice. In fact, we have stated in the Abstract (last line) and Discussion (last paragraph) that further validation, including multicentre (retrospective) studies and prospective clinical trials, are needed before implementation in the clinical practice is warranted. Furthermore we agree with Gevaert et al. that nonplatinum regimens are suboptimal in primary therapy of advanced ovarian cancer (although detailed information seems not to be present in the reference mentioned in their letter). It is certainly not the objective of this study to withhold platinumbased chemotherapy from patients. Rather it is to tailor the treatment of the patients who most likely do not respond to conventional platinum-based chemotherapy. This could be reached by including novel drugs such as angiogenesis inhibitors, Topoisomerase 2a (TOP2A) inhibitors or Aurora kinase A (AURKA) inhibitors to platinum treatment protocols, or by different dosing regimens such as dose-dense therapy. As described in the Results and Discussion, TOP2A and AURKA were shown to be overexpressed in the resistant ovarian carcinomas of our profile and, when validated, the inhibiting drugs might be a good addition to the platinum-based treatment in primary as well as recurrent disease. With this approach none of the sensitive patients will be undertreated whereas patients with resistant tumours will receive a tailored, more effective treatment. In summary we agree with Gevaert et al. that in clinical practice a higher specificity would be more desirable. Besides further validation of the 9-gene set in multicentre (retrospective) studies and prospective clinical trials, tailored platinum containing regimens deserve further investigation in the platinum resistant patients. Yours sincerely, JOZIEN HELLEMAN, MAURICE P.H.M. JANSEN, MARIA E.L. VAN DER BURG AND ELS M.J.J. BERNS