Assessment of Molecular Relapse Detection in Early-Stage Breast Cancer
Isaac Garcia-Murillas, Neha Chopra, Iñaki Comino-Méndez, Matthew Beaney, Holly Tovey, Rosalind J Cutts, Claire Swift, Divya Kriplani, Maria Afentakis, Sarah Hrebien, Giselle Walsh-Crestani, Peter Barry, Stephen R D Johnston, Alistair Ring, Judith Bliss, Simon Russell, Abigail Evans, Anthony Skene, Duncan Wheatley, Mitch Dowsett, Ian E Smith, Nicholas C Turner, Isaac Garcia-Murillas, Neha Chopra, Iñaki Comino-Méndez, Matthew Beaney, Holly Tovey, Rosalind J Cutts, Claire Swift, Divya Kriplani, Maria Afentakis, Sarah Hrebien, Giselle Walsh-Crestani, Peter Barry, Stephen R D Johnston, Alistair Ring, Judith Bliss, Simon Russell, Abigail Evans, Anthony Skene, Duncan Wheatley, Mitch Dowsett, Ian E Smith, Nicholas C Turner
Abstract
Importance: Current treatment cures most cases of early-stage, primary breast cancer. However, better techniques are required to identify which patients are at risk of relapse.
Objective: To assess the clinical validity of molecular relapse detection with circulating tumor DNA (ctDNA) analysis in early-stage breast cancer.
Design, setting, and participants: This prospective, multicenter, sample collection, validation study conducted at 5 United Kingdom medical centers from November 24, 2011, to October 18, 2016, assessed patients with early-stage breast cancer irrespective of hormone receptor and ERBB2 (formerly HER2 or HER2/neu) status who were receiving neoadjuvant chemotherapy followed by surgery or surgery before adjuvant chemotherapy. The study recruited 170 women, with mutations identified in 101 patients forming the main cohort. Secondary analyses were conducted on a combined cohort of 144 patients, including 43 patients previously analyzed in a proof of principle study.
Interventions: Primary tumor was sequenced to identify somatic mutations, and personalized tumor-specific digital polymerase chain reaction assays were used to monitor these mutations in serial plasma samples taken every 3 months for the first year of follow-up and subsequently every 6 months.
Main outcomes and measures: The primary end point was relapse-free survival analyzed with Cox proportional hazards regression models.
Results: In the main cohort of 101 female patients (mean [SD] age, 54 [11] years) with a median follow-up of 35.5 months (interquartile range, 27.9-43.0 months), detection of ctDNA during follow-up was associated with relapse (hazard ratio, 25.2; 95% CI, 6.7-95.6; P < .001). Detection of ctDNA at diagnosis, before any treatment, was also associated with relapse-free survival (hazard ratio, 5.8; 95% CI, 1.2-27.1; P = .01). In the combined cohort, ctDNA detection had a median lead time of 10.7 months (95% CI, 8.1-19.1 months) compared with clinical relapse and was associated with relapse in all breast cancer subtypes. Distant extracranial metastatic relapse was detected by ctDNA in 22 of 23 patients (96%). Brain-only metastasis was less commonly detected by ctDNA (1 of 6 patients [17%]), suggesting relapse sites less readily detectable by ctDNA analysis.
Conclusions and relevance: The findings suggest that detection of ctDNA during follow-up is associated with a high risk of future relapse of early-stage breast cancer. Prospective studies are needed to assess the potential of molecular relapse detection to guide adjuvant therapy.
Conflict of interest statement
Conflict of Interest Disclosures: Dr Tovey reported receiving grants from Cancer Research UK during the conduct of the study and grants from Pfizer, Janssen-Cilag Ltd, Merck, AstraZeneca, and Clovis outside the submitted work and having a patent to employees of the Institute of Cancer Research subject to a Rewards to Inventors Scheme, which may reward contributors to a program that is subsequently licensed pending. Dr Bliss reported receiving grants from Cancer Research UK during the conduct of the study and grants and nonfinancial support from AstraZeneca, Merck Sharp & Dohme, Medivation, Puma Biotechnology, Clovis Oncology, Pfizer, Janssen-Cilag, Novartis, and Roche outside the submitted work. Dr Russell reported receiving personal fees from Bayer and Pfizer outside the submitted work. Dr Wheatley reported receiving personal fees from honoraria from Roche, Novartis, Pfizer, and Eli Lilly and Company for advisory board participation and travel grants for American Society of Clinical Oncology/San Antonio Breast Cancer Symposium from Roche. Dr Dowsett reported receiving personal fees from Radius, Myriad, Roche, and GTx; receiving grants from Pfizer; and receiving ICR Rewards for Inventors scheme (Abiraterone) support from the Institute of Cancer Research outside the submitted work. Dr Turner reported receiving advisory board honoraria from AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, Merck Sharp & Dohme, Novartis, Pfizer, Roche/Genentech, Tesaro, and Bicycle Therapeutics and receiving research funding from AstraZeneca, BioRad, Pfizer, Roche/Genentech, Clovis, and Guardant Health. No other disclosures were reported.
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Source: PubMed