Platinum resistance in gynecologic malignancies: Response, disease free and overall survival are predicted by biochemical signature: A metabolomic analysis

Author(s):Show less -

D'Amora, Paulo ^{[1, 2, 3]} ; Silva, Ismael Dale C. G. ^{[1, 3]} ; Tewari, Krishnansu S. ^{[4, 5]} ; Bristow, Robert E. ^{[4, 5]} ; Cappuccini, Fabio ^{[4, 5]} ; Evans, Steven S. ^{[2, 3]} ; Salzgeber, Marcia B. ^[1] ; Addis-Bernard, Paula J. ^[2] ; Palma, Anton M. ^[6] ; Marchioni, Dirce M. L. ^[7] ; Carioca, Antonio A. F. ^[8] ; Penner, Kristine R. ^[9] ; Alldredge, Jill ^[10] ; Longoria, Teresa ^[11] ; Nagourney, Robert A. ^{[2, 3, 4, 5]}

Affiliation:Show less -

^[1] Fed Univ Sao Paulo EPM UNIFESP, Coll Med, Gynecol Dept, Mol Gynecol & Metabol Lab, Rua Pedro Toledo, 781-4o Andar Frente, BR-04039032 Sao Paulo, SP - Brazil

^[2] Nagourney Canc Inst, g, 750 East 29th St, Long Beach, CA 90806 - USA

^[3] Metabolomycs Inc, 750 East 29th St, Long Beach, CA 90806 - USA

^[4] Todd Canc Inst, Mem Med Ctr Long Beach, 2810 Long Beach Blvd, Long Beach, CA 90806 - USA

^[5] Univ Calif Irvine UCI, Sch Med, Dept Obstet & Gynecol, 101 City Dr South, Orange, CA 92868 - USA

^[6] Univ Calif Irvine UCI, Inst Clin & Translat Sci ICTS, 843 Hlth Sci Rd, Irvine, CA 92697 - USA

^[7] Univ Sao Paulo, Sch Publ Hlth, Nutr Dept, Sch Med FMUSP, Av Dr Arnaldo 715, BR-01246904 Sao Paulo, SP - Brazil

^[8] Univ Fortaleza UNIFOR, Nutr Dept, Av Washington Soares 1321, BR-60811905 Fortaleza, Ceara - Brazil

^[9] Kaiser Permanente South Bay Med Ctr, 25825 S Vermont Ave, Harbor City, CA 90710 - USA

^[10] Univ Colorado, Canc Ctr, UCHlth Canc Care Anschutz Med Campus, 1665 Aurora, Aurora, CO 80045 - USA

^[11] Scripps Clin, John R Anderson V Med Pavil, 9898 Genesee Av, La Jolla, CA 92037 - USA

• Document type: Journal article
• Source: GYNECOLOGIC ONCOLOGY; v. 163, n. 1, p. 162-170, OCT 2021.
• Web of Science Citations: 0

Abstract

Objective. Platinum resistance, defined as the lack of response or relapse within six months of platinum-based chemotherapy, is an important determinant of survival in gynecologic cancer. We used quantitative Mass Spectrometry to identify metabolic signatures that predict platinum resistance in patients receiving chemotherapy for gynecologic cancers. Methods. In this study 47 patients with adenocarcinoma of the ovary or uterus who were candidates for carboplatin plus paclitaxel submitted blood for quantitation of metabolites and surgical specimens for the isolation 3-dimensional organoids used to measure individual patient platinum resistance, ex vivo. Results were correlated with response, time to progression and survival. Results. Of 47 patients, 27 (64.3%) achieved complete remission with a mean time to progression of 1.9 years (+/- 1.5), disease-free survival of 1.7 years (+/- 1.4) and overall survival of 2.6 years (+/- 1.6) and a mean cisplatin lethal concentration 50% (LC50) = 1.15 mu g/ml (range 0.4-3.1). Cisplatin LC50's correlated with a non-significant decrease in complete remission (RR {[}95% CI] =0.76 {[}0.46-1.27]), diminished disease-free survival (median: 1.15 vs. 2.99 years, p = 0.038) and with biochemical signatures of 186 metabolites. Receiver operating curves (ROC) of lipid ratios, branched chain amino acids and the tryptophan to kynurenine ratio identified patients at the highest risk of relapse and death (AUC = 0.933) with a sensitivity of 92.0% and specificity of 86.0% (p < 0.001). Conclusions. Metabolic signatures in gynecologic cancer identify patients at the highest risk of relapse and death offering new diagnostic and prognostic tools for management of the advanced gynecologic tumors. (c) 2021 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). (AU)

• FAPESP's process: 14/19171-2 - A study to correlate the activity of first-line chemotherapy with response, time to progression and overall survival in patients with advanced epithelial ovarian cancer
• Grantee: Paulo D'Amora
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 15/16921-3 - A study to correlate the activity of first-line chemotherapy with response, time to progression and overall survival in patients with advanced epithelial ovarian cancer
• Grantee: Paulo D'Amora
• Support Opportunities: Scholarships in Brazil - Young Researchers