Biomarkers of outcome to weekly paclitaxel in epithelial ovarian cancer.

We sought to evaluate the role of intrinsic chromosomal aberrations in determining favorable outcome to weekly paclitaxel (WP) in patients with epithelial ovarian cancer (EOC). We evaluated the common genomic aberrations of two patients with EOC and exceptional WP response in the GENIUS study (NCT03740503). We then searched for potential markers of unusual outcomes to WP in a validation cohort. We performed shallow whole genome sequencing (sWGS) in the tumor tissue of women with EOC considered as short-responders (SR; progression with ≤3 cycles) and long-responders (LR; response at ≥8 cycles) to WP monotherapy. We identified two women with exceptional response to WP, lasting over four years, who shared chromosome 8 gain as a common genomic aberration. In order to validate our findings, we reviewed 188 patients with EOC treated with WP and selected 61 women (39 SR, 22 LR) with unusual responses. By sWGS, there was no differential alterations in the copy number changes in chromosome 8, or in genes related to angiogenesis, tubulin superfamily, cell-cycle, apoptosis and paclitaxel metabolism or transportation pathways. Amongst the LR group, we identified six exceptionally long responders (ExLR), with responses lasting over a year. In an exploratory analysis, there was increased amplification of angiogenesis (VEGFB, MMP9), tubulin superfamily (TSC2) and apoptosis related genes (BCL2L1, BAD) in ExLR compared to SR. We identified one patient with a complete response to WP for over 7 years. Molecular profiling identified unique amplifications in interleukin related genes (CXCR1, CXCR2, IL1A, IL1B), not detected in other patients. Intrinsic tumor pathways may impact outcome with weekly paclitaxel monotherapy and further investigations are required.

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Déclaration de conflit d'intérêts

Declaration of Competing Interest Dr. Lheureux reports grants and personal fees from Astra-Zeneca and GSK, personal fees from Merck and Roche, outside the submitted work. Dr. Cescon reports grants from Merck, Pfizer, GSK, and personal fees from Merck, Roche/Genetech, AstraZeneca, GSK, Novartis, Pfizer, Puma, Agendia, Exact Sciences, Dynamo Therapeutics, outside of the submitted work. In addition, Dr. Cescon has a patent in biomarkers of TTK inhibitors pending. Dr. Dhani reports personal fees from Astra Zeneca, grants from Celgene, outside the submitted work. The rest of the authors declare no conflict of interest.