Monitoring clonal evolution and resistance to EGFR blockade in the blood of metastatic colorectal cancer patients

By G. Siravegna, Benedetta Mussolin, M. Buscarino, G. Corti, A. Cassingena, G. Crisafulli, A. Ponzetti, C. Cremolini, A. Amatu, C. Lauricella and 22 more. Nature Medicine, 2015

997 citations recorded by the source corpus.

Colorectal cancers (CRCs) evolve by a reiterative process of genetic diversification and clonal evolution. The molecular profile of CRC is routinely assessed in surgical or bioptic samples. Genotyping of CRC tissue has inherent limitations; a tissue sample represents a single snapshot in time, and it is subjected to spatial selection bias owing to tumor heterogeneity. Repeated tissue samples are difficult to obtain and cannot be used for dynamic monitoring of disease progression and response to therapy. We exploited circulating tumor DNA (ctDNA) to genotype colorectal tumors and track clonal evolution during treatment with the epidermal growth factor receptor (EGFR)-specific antibodies cetuximab or panitumumab. We identified alterations in ctDNA of patients with primary or acquired resistance to EGFR blockade in the following genes: KRAS, NRAS, MET, ERBB2, FLT3, EGFR and MAP2K1. Mutated KRAS clones, which emerge in blood during EGFR blockade, decline upon withdrawal of EGFR-specific antibodies, indicating that clonal evolution continues beyond clinical progression. Pharmacogenomic analysis of CRC cells that had acquired resistance to cetuximab reveals that upon antibody withdrawal KRAS clones decay, whereas the population regains drug sensitivity. ctDNA profiles of individuals who benefit from multiple challenges with anti-EGFR antibodies exhibit pulsatile levels of mutant KRAS. These results indicate that the CRC genome adapts dynamically to intermittent drug schedules and provide a molecular explanation for the efficacy of rechallenge therapies based on EGFR blockade.

Subfields: Cancer Research, Oncology, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/cd88c8c3c2f23e7dde4ac9f85a599153497dc323

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In Cancer Research

1. C. Alix‐Panabières
2. K. Pantel
3. J. Reis-Filho

In Oncology

1. C. Alix‐Panabières
2. K. Pantel
3. J. Reis-Filho
4. Razelle Kurzrock

In Pathology and Forensic Medicine

1. J. Reis-Filho
2. C. Alix‐Panabières
3. K. Pantel

Citations in the corpus

• ESMO recommendations on the use of circulating tumour DNA assays for patients with cancer: a report from the ESMO Precision Medicine Working Group. (2022, background): “92-94 In this setting, several clinical trials are including ctDNA to guide anti-EGFR rechallenge decision, and the CHRONOS trial has shown clinical bene fi t of anti-EGFR rechallenge in patients with no detection of RAS , EGFR -ECD and BRAF in ctDNA before rechallenge.”
• Liquid biopsy: a step closer to transform diagnosis, prognosis and future of cancer treatments (2022, background): “ctDNA CRC Genomic profiling Tracking clonal variations and therapeutic response [107]”
• Liquid biopsy: current technology and clinical applications (2022, background): “01% with excellent concordance to tissue testing [6] [38, 43].”
• Liquid Biopsy: From Discovery to Clinical Application. (2021, background): “KRAS mutations have been detected on CTCs (115) and then became prime targets for ctDNA analyses in colorectal cancer (116).”