학술논문
Detection of Molecular Residual Disease Using Personalized Circulating Tumor DNA Assay in Patients With Colorectal Cancer Undergoing Resection of Metastases.
Document Type
Academic Journal
Author
Loupakis F; Oncology Unit 1, Department Oncology, Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua, Veneto, Italy.; Sharma S; Natera Inc, San Carlos, CA.; Derouazi M; Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT.; AMAL Therapeutics, Genève, Switzerland.; Murgioni S; Oncology Unit 1, Department Oncology, Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua, Veneto, Italy.; Biason P; Oncology Unit 1, Department Oncology, Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua, Veneto, Italy.; Rizzato MD; Oncology Unit 1, Department Oncology, Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua, Veneto, Italy.; Rasola C; Oncology Unit 1, Department Oncology, Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua, Veneto, Italy.; Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy.; Renner D; Natera Inc, San Carlos, CA.; Shchegrova S; Natera Inc, San Carlos, CA.; Koyen Malashevich A; Natera Inc, San Carlos, CA.; Malhotra M; Natera Inc, San Carlos, CA.; Sethi H; Natera Inc, San Carlos, CA.; Zimmermann BG; Natera Inc, San Carlos, CA.; Aleshin A; Natera Inc, San Carlos, CA.; Moshkevich S; Natera Inc, San Carlos, CA.; Billings PR; Natera Inc, San Carlos, CA.; Sedgwick JD; Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT.; Schirripa M; Oncology Unit 1, Department Oncology, Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua, Veneto, Italy.; Munari G; Oncology Unit 1, Department Oncology, Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua, Veneto, Italy.; Cillo U; Hepatobiliary Surgery and Liver Transplant Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, Italy.; Pilati P; Unit of Surgical Oncology of the Digestive Tract, Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua, Italy.; Dei Tos AP; Unit of Surgical Pathology, Department of Medicine (DIMED), University of Padua, Padua, Italy.; Zagonel V; Oncology Unit 1, Department Oncology, Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua, Veneto, Italy.; Lonardi S; Oncology Unit 3, Department of Oncology, Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Castelfranco Veneto, Veneto, Italy.; Early Phase Clinical Trial Unit, Department of Oncology, Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua, Veneto, Italy.; Fassan M; Unit of Surgical Pathology, Department of Medicine (DIMED), University of Padua, Padua, Italy.; Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padua, Veneto, Italy.
Source
Publisher: American Society of Clinical Oncology Country of Publication: United States NLM ID: 101705370 Publication Model: eCollection Cited Medium: Internet ISSN: 2473-4284 (Electronic) Linking ISSN: 24734284 NLM ISO Abbreviation: JCO Precis Oncol
Subject
Language
English
Abstract
Purpose: More than 50% of patients with stage IV colorectal cancer (metastatic colorectal cancer [mCRC]) relapse postresection. The efficacy of postoperative systemic treatment is limited in this setting. Thus, these patients would greatly benefit from the use of a reliable prognostic biomarker, such as circulating tumor DNA (ctDNA) to identify minimal or molecular residual disease (MRD).
Patients and Methods: We analyzed a cohort of 112 patients with mCRC who had undergone metastatic resection with curative intent as part of the PREDATOR clinical trial. The study evaluated the prognostic value of ctDNA, correlating MRD status postsurgery with clinical outcomes by using a personalized and tumor-informed ctDNA assay (bespoke multiple PCR, next-generation sequencing assay). Postresection, systemic therapy was given to 39.2% of the patients at the discretion of the treating physician.
Results: Postsurgical, MRD positivity was observed in 54.4% (61 of 112) of patients, of which 96.7% (59 of 61) progressed at the time of data cutoff (hazard ratio [HR]: 5.8; 95% CI, 3.5 to 9.7; P < .001). MRD-positive status was also associated with an inferior overall survival: HR: 16.0; 95% CI, 3.9 to 68.0; P < .001. At the time of analyses, 96% (49 of 51) of patients were alive in the MRD-negative arm compared with 52.4% (32 of 61) in the MRD-positive arm. Patients who did not receive systemic therapy and were MRD-negative in the combined ctDNA analysis at two time points had an overall survival of 100%. In the multivariate analysis, ctDNA-based MRD status was the most significant prognostic factor associated with disease-free survival (HR: 5.78; 95% CI, 3.34 to 10.0; P < .001).
Conclusion: This study confirms that in mCRC undergoing resection of metastases, postoperative MRD analysis is a strong prognostic biomarker. It holds promises for being implemented in clinical decision making, informing clinical trial design, and further translational research.
Competing Interests: Fotios Loupakis Consulting or Advisory Role: Amgen, Sanofi, Bayer, Amal Therapeutics Speakers' Bureau: Roche, Sanofi, Bayer, Amgen Research Funding: Roche, Merck Serono, Amgen, Bayer Travel, Accommodations, Expenses: Roche, Amgen, Merck Serono Shruti Sharma Employment: Natera Stock and Other Ownership Interests: Natera Madiha Derouazi Employment: AMAL Therapeutics Leadership: AMAL Therapeutics Travel, Accommodations, Expenses: AMAL Therapeutics Derrick Renner Employment: Natera Stock and Other Ownership Interests: Natera Travel, Accommodations, Expenses: Natera Svetlana Shchegrova Employment: Natera Stock and Other Ownership Interests: Natera Allyson Koyen Malashevich Employment: Natera Stock and Other Ownership Interests: Natera Meenakshi Malhotra Employment: Natera Stock and Other Ownership Interests: Natera Himanshu Sethi Employment: Natera Stock and Other Ownership Interests: Natera Research Funding: Natera Patents, Royalties, Other Intellectual Property: Patents Travel, Accommodations, Expenses: Natera Bernhard G. Zimmermann Employment: Natera Stock and Other Ownership Interests: Natera Honoraria: Natera Patents, Royalties, Other Intellectual Property: Multiple patents and patent applications Alexey Aleshin Employment: Natera Leadership: Natera Stock and Other Ownership Interests: Natera Consulting or Advisory Role: Mission Bio Travel, Accommodations, Expenses: Natera Solomon Moshkevich Employment: Natera, Evidation Health Stock and Other Ownership Interests: Natera Patents, Royalties, Other Intellectual Property: Named as inventor on a patent filed by Natera Inc Travel, Accommodations, Expenses: Natera Paul R. Billings Employment: Natera Leadership: Biological Dynamics, OmniSeq, Alveo Technologies, Mission Bio Stock and Other Ownership Interests: Natera, Trovagene, Biological Dynamics, OmniSeq, Alveo Technologies Consulting or Advisory Role: Bethesda Group, Guidepoint Global Jonathon D. Sedgwick Employment: Boehringer Ingelheim Travel, Accommodations, Expenses: Boehringer Ingelheim Umberto Cillo Consulting or Advisory Role: Springer Health Care, Novartis, Johnson & Johnson, Astellas, Sandoz Speakers' Bureau: Eisai Angelo Paolo Dei Tos Consulting or Advisory Role: Bayer, Roche Vittorina Zagonel Consulting or Advisory Roles: Bristol Myers Squibb, MSD, Eisai, Italfarmaco Speakers' Bureau: Roche, Bristol Myers Squibb, Astellas Pharma, Servier, AstraZeneca, MSD, Jansen, Ipsen Research Funding: Bayer, Roche, Lilly, Astra Zeneca, BMS, Ipsen, Astellas Pharma Travel, Accommodations, Expenses: Bayer, Roche, Servier Sara Lonardi Consulting or Advisory Role: Amgen, Merck Serono, Lilly, Servier, AstraZeneca, Incyte, Daiichi Sankyo, Bristol Myers Squibb Speakers' Bureau: Roche, Lilly, Bristol Myers Squibb, Servier, Merck Serono, Pierre Fabre, GlaxoSmithKline, Amgen Research Funding: Amgen, Merck Serono, Bayer, Roche, Lilly, AstraZeneca, Bristol Myers Squibb Matteo Fassan Consulting or Advisory Role: Astellas Pharma, Tesaro, GlaxoSmithKline, Diaceutics, Diaceutics, Roche Research Funding: Astellas Pharma, QED Therapeutics, Macrophage Pharma No other potential conflicts of interest were reported.Fotios Loupakis Consulting or Advisory Role: Amgen, Sanofi, Bayer, Amal Therapeutics Speakers' Bureau: Roche, Sanofi, Bayer, Amgen Research Funding: Roche, Merck Serono, Amgen, Bayer Travel, Accommodations, Expenses: Roche, Amgen, Merck Serono Shruti Sharma Employment: Natera Stock and Other Ownership Interests: Natera Madiha Derouazi Employment: AMAL Therapeutics Leadership: AMAL Therapeutics Travel, Accommodations, Expenses: AMAL Therapeutics Derrick Renner Employment: Natera Stock and Other Ownership Interests: Natera Travel, Accommodations, Expenses: Natera Svetlana Shchegrova Employment: Natera Stock and Other Ownership Interests: Natera Allyson Koyen Malashevich Employment: Natera Stock and Other Ownership Interests: Natera Meenakshi Malhotra Employment: Natera Stock and Other Ownership Interests: Natera Himanshu Sethi Employment: Natera Stock and Other Ownership Interests: Natera Research Funding: Natera Patents, Royalties, Other Intellectual Property: Patents Travel, Accommodations, Expenses: Natera Bernhard G. Zimmermann Employment: Natera Stock and Other Ownership Interests: Natera Honoraria: Natera Patents, Royalties, Other Intellectual Property: Multiple patents and patent applications Alexey Aleshin Employment: Natera Leadership: Natera Stock and Other Ownership Interests: Natera Consulting or Advisory Role: Mission Bio Travel, Accommodations, Expenses: Natera Solomon Moshkevich Employment: Natera, Evidation Health Stock and Other Ownership Interests: Natera Patents, Royalties, Other Intellectual Property: Named as inventor on a patent filed by Natera Inc Travel, Accommodations, Expenses: Natera Paul R. Billings Employment: Natera Leadership: Biological Dynamics, OmniSeq, Alveo Technologies, Mission Bio Stock and Other Ownership Interests: Natera, Trovagene, Biological Dynamics, OmniSeq, Alveo Technologies Consulting or Advisory Role: Bethesda Group, Guidepoint Global Jonathon D. Sedgwick Employment: Boehringer Ingelheim Travel, Accommodations, Expenses: Boehringer Ingelheim Umberto Cillo Consulting or Advisory Role: Springer Health Care, Novartis, Johnson & Johnson, Astellas, Sandoz Speakers' Bureau: Eisai Angelo Paolo Dei Tos Consulting or Advisory Role: Bayer, Roche Vittorina Zagonel Consulting or Advisory Roles: Bristol Myers Squibb, MSD, Eisai, Italfarmaco Speakers' Bureau: Roche, Bristol Myers Squibb, Astellas Pharma, Servier, AstraZeneca, MSD, Jansen, Ipsen Research Funding: Bayer, Roche, Lilly, Astra Zeneca, BMS, Ipsen, Astellas Pharma Travel, Accommodations, Expenses: Bayer, Roche, Servier Sara Lonardi Consulting or Advisory Role: Amgen, Merck Serono, Lilly, Servier, AstraZeneca, Incyte, Daiichi Sankyo, Bristol Myers Squibb Speakers' Bureau: Roche, Lilly, Bristol Myers Squibb, Servier, Merck Serono, Pierre Fabre, GlaxoSmithKline, Amgen Research Funding: Amgen, Merck Serono, Bayer, Roche, Lilly, AstraZeneca, Bristol Myers Squibb Matteo Fassan Consulting or Advisory Role: Astellas Pharma, Tesaro, GlaxoSmithKline, Diaceutics, Diaceutics, Roche Research Funding: Astellas Pharma, QED Therapeutics, Macrophage Pharma No other potential conflicts of interest were reported.
(© 2021 by American Society of Clinical Oncology.)
Patients and Methods: We analyzed a cohort of 112 patients with mCRC who had undergone metastatic resection with curative intent as part of the PREDATOR clinical trial. The study evaluated the prognostic value of ctDNA, correlating MRD status postsurgery with clinical outcomes by using a personalized and tumor-informed ctDNA assay (bespoke multiple PCR, next-generation sequencing assay). Postresection, systemic therapy was given to 39.2% of the patients at the discretion of the treating physician.
Results: Postsurgical, MRD positivity was observed in 54.4% (61 of 112) of patients, of which 96.7% (59 of 61) progressed at the time of data cutoff (hazard ratio [HR]: 5.8; 95% CI, 3.5 to 9.7; P < .001). MRD-positive status was also associated with an inferior overall survival: HR: 16.0; 95% CI, 3.9 to 68.0; P < .001. At the time of analyses, 96% (49 of 51) of patients were alive in the MRD-negative arm compared with 52.4% (32 of 61) in the MRD-positive arm. Patients who did not receive systemic therapy and were MRD-negative in the combined ctDNA analysis at two time points had an overall survival of 100%. In the multivariate analysis, ctDNA-based MRD status was the most significant prognostic factor associated with disease-free survival (HR: 5.78; 95% CI, 3.34 to 10.0; P < .001).
Conclusion: This study confirms that in mCRC undergoing resection of metastases, postoperative MRD analysis is a strong prognostic biomarker. It holds promises for being implemented in clinical decision making, informing clinical trial design, and further translational research.
Competing Interests: Fotios Loupakis Consulting or Advisory Role: Amgen, Sanofi, Bayer, Amal Therapeutics Speakers' Bureau: Roche, Sanofi, Bayer, Amgen Research Funding: Roche, Merck Serono, Amgen, Bayer Travel, Accommodations, Expenses: Roche, Amgen, Merck Serono Shruti Sharma Employment: Natera Stock and Other Ownership Interests: Natera Madiha Derouazi Employment: AMAL Therapeutics Leadership: AMAL Therapeutics Travel, Accommodations, Expenses: AMAL Therapeutics Derrick Renner Employment: Natera Stock and Other Ownership Interests: Natera Travel, Accommodations, Expenses: Natera Svetlana Shchegrova Employment: Natera Stock and Other Ownership Interests: Natera Allyson Koyen Malashevich Employment: Natera Stock and Other Ownership Interests: Natera Meenakshi Malhotra Employment: Natera Stock and Other Ownership Interests: Natera Himanshu Sethi Employment: Natera Stock and Other Ownership Interests: Natera Research Funding: Natera Patents, Royalties, Other Intellectual Property: Patents Travel, Accommodations, Expenses: Natera Bernhard G. Zimmermann Employment: Natera Stock and Other Ownership Interests: Natera Honoraria: Natera Patents, Royalties, Other Intellectual Property: Multiple patents and patent applications Alexey Aleshin Employment: Natera Leadership: Natera Stock and Other Ownership Interests: Natera Consulting or Advisory Role: Mission Bio Travel, Accommodations, Expenses: Natera Solomon Moshkevich Employment: Natera, Evidation Health Stock and Other Ownership Interests: Natera Patents, Royalties, Other Intellectual Property: Named as inventor on a patent filed by Natera Inc Travel, Accommodations, Expenses: Natera Paul R. Billings Employment: Natera Leadership: Biological Dynamics, OmniSeq, Alveo Technologies, Mission Bio Stock and Other Ownership Interests: Natera, Trovagene, Biological Dynamics, OmniSeq, Alveo Technologies Consulting or Advisory Role: Bethesda Group, Guidepoint Global Jonathon D. Sedgwick Employment: Boehringer Ingelheim Travel, Accommodations, Expenses: Boehringer Ingelheim Umberto Cillo Consulting or Advisory Role: Springer Health Care, Novartis, Johnson & Johnson, Astellas, Sandoz Speakers' Bureau: Eisai Angelo Paolo Dei Tos Consulting or Advisory Role: Bayer, Roche Vittorina Zagonel Consulting or Advisory Roles: Bristol Myers Squibb, MSD, Eisai, Italfarmaco Speakers' Bureau: Roche, Bristol Myers Squibb, Astellas Pharma, Servier, AstraZeneca, MSD, Jansen, Ipsen Research Funding: Bayer, Roche, Lilly, Astra Zeneca, BMS, Ipsen, Astellas Pharma Travel, Accommodations, Expenses: Bayer, Roche, Servier Sara Lonardi Consulting or Advisory Role: Amgen, Merck Serono, Lilly, Servier, AstraZeneca, Incyte, Daiichi Sankyo, Bristol Myers Squibb Speakers' Bureau: Roche, Lilly, Bristol Myers Squibb, Servier, Merck Serono, Pierre Fabre, GlaxoSmithKline, Amgen Research Funding: Amgen, Merck Serono, Bayer, Roche, Lilly, AstraZeneca, Bristol Myers Squibb Matteo Fassan Consulting or Advisory Role: Astellas Pharma, Tesaro, GlaxoSmithKline, Diaceutics, Diaceutics, Roche Research Funding: Astellas Pharma, QED Therapeutics, Macrophage Pharma No other potential conflicts of interest were reported.Fotios Loupakis Consulting or Advisory Role: Amgen, Sanofi, Bayer, Amal Therapeutics Speakers' Bureau: Roche, Sanofi, Bayer, Amgen Research Funding: Roche, Merck Serono, Amgen, Bayer Travel, Accommodations, Expenses: Roche, Amgen, Merck Serono Shruti Sharma Employment: Natera Stock and Other Ownership Interests: Natera Madiha Derouazi Employment: AMAL Therapeutics Leadership: AMAL Therapeutics Travel, Accommodations, Expenses: AMAL Therapeutics Derrick Renner Employment: Natera Stock and Other Ownership Interests: Natera Travel, Accommodations, Expenses: Natera Svetlana Shchegrova Employment: Natera Stock and Other Ownership Interests: Natera Allyson Koyen Malashevich Employment: Natera Stock and Other Ownership Interests: Natera Meenakshi Malhotra Employment: Natera Stock and Other Ownership Interests: Natera Himanshu Sethi Employment: Natera Stock and Other Ownership Interests: Natera Research Funding: Natera Patents, Royalties, Other Intellectual Property: Patents Travel, Accommodations, Expenses: Natera Bernhard G. Zimmermann Employment: Natera Stock and Other Ownership Interests: Natera Honoraria: Natera Patents, Royalties, Other Intellectual Property: Multiple patents and patent applications Alexey Aleshin Employment: Natera Leadership: Natera Stock and Other Ownership Interests: Natera Consulting or Advisory Role: Mission Bio Travel, Accommodations, Expenses: Natera Solomon Moshkevich Employment: Natera, Evidation Health Stock and Other Ownership Interests: Natera Patents, Royalties, Other Intellectual Property: Named as inventor on a patent filed by Natera Inc Travel, Accommodations, Expenses: Natera Paul R. Billings Employment: Natera Leadership: Biological Dynamics, OmniSeq, Alveo Technologies, Mission Bio Stock and Other Ownership Interests: Natera, Trovagene, Biological Dynamics, OmniSeq, Alveo Technologies Consulting or Advisory Role: Bethesda Group, Guidepoint Global Jonathon D. Sedgwick Employment: Boehringer Ingelheim Travel, Accommodations, Expenses: Boehringer Ingelheim Umberto Cillo Consulting or Advisory Role: Springer Health Care, Novartis, Johnson & Johnson, Astellas, Sandoz Speakers' Bureau: Eisai Angelo Paolo Dei Tos Consulting or Advisory Role: Bayer, Roche Vittorina Zagonel Consulting or Advisory Roles: Bristol Myers Squibb, MSD, Eisai, Italfarmaco Speakers' Bureau: Roche, Bristol Myers Squibb, Astellas Pharma, Servier, AstraZeneca, MSD, Jansen, Ipsen Research Funding: Bayer, Roche, Lilly, Astra Zeneca, BMS, Ipsen, Astellas Pharma Travel, Accommodations, Expenses: Bayer, Roche, Servier Sara Lonardi Consulting or Advisory Role: Amgen, Merck Serono, Lilly, Servier, AstraZeneca, Incyte, Daiichi Sankyo, Bristol Myers Squibb Speakers' Bureau: Roche, Lilly, Bristol Myers Squibb, Servier, Merck Serono, Pierre Fabre, GlaxoSmithKline, Amgen Research Funding: Amgen, Merck Serono, Bayer, Roche, Lilly, AstraZeneca, Bristol Myers Squibb Matteo Fassan Consulting or Advisory Role: Astellas Pharma, Tesaro, GlaxoSmithKline, Diaceutics, Diaceutics, Roche Research Funding: Astellas Pharma, QED Therapeutics, Macrophage Pharma No other potential conflicts of interest were reported.
(© 2021 by American Society of Clinical Oncology.)