Mismatch Repair–Deficient Rectal Cancer and Resistance to Neoadjuvant Chemotherapy

Abstract

Bristol-Myers Squibb, Kyn Therapeutics, Aduro, and Boehringer Ingelheim. DLR serves on the advisory board of Novartis AAA and has received research funding from Merck and Ipsen Novartis and consulting fees from Lexicon. AV has received research funding from Lilly, Bristol-Myers Squibb, Verastem, BioMed Valley Discoveries, and Silenseed (AV's immediate family member has received research funding from Illumina and reimbursement of travel expenses from Roche). GMN has received meal reimbursement from Intuitive Surgical. JGA has received honoraria from Medtronic, Johnson & Johnson, and Intuitive Surgical. LAD serves on the board of directors of Personal Genome Diagnostics and Jounce Therapeutics; is a paid consultant to Personal Genome Diagnostics, 4Paws, and NeoPhore; is an uncompensated consultant for Merck; has received research funding from Merck; holds licensed patents (with Johns Hopkins University) related to technology for analysis of circulating tumor DNA and mismatch repair deficiency, which are associated with equity and royalty payments; and holds equity in Personal Genome Diagnostics, Jounce Therapeutics, Thrive Earlier Detection, and NeoPhore (LAD's spouse holds equity in Amgen). KG serves on the advisory board of RenovoRX. LBS has received research funding from Taiho. JJS has received travel reimbursement from Intuitive Surgical and has served as a clinical advisor to Guardant Health. ZKS's immediate family member serves as a consultant for Allergan,

Association of mismatch repair status with survival and response to neoadjuvant chemo(radio)therapy in rectal cancer

“…However, their study only included 29 locally advanced rectal cancers and had no comparison with pMMR patients. Furthermore, Cercek et al recently reported chemotherapy resistance for dMMR tumors 23 , which was inconsistent with our findings. The main reasons for the distinction might be that a portion of patients had metastatic disease and a majority of patients underwent NCRT after receiving initial NCT in their study.…”

Immunotherapy for the treatment of colorectal cancer

“…Standard treatment for locally advanced rectal cancer is total neoadjuvant therapy (TNT), in which induction chemotherapy with FOLFOX is followed by chemoradiation (chemoRT) before surgery. While most locally advanced rectal cancers are responsive to chemotherapy, a recent study of patients with dMMR/MSI‐H LARC by our group demonstrated that 29% of patients had local disease progression while receiving FOLFOX 65,66 . In contrast, no patients with pMMR/MSS locally advanced rectal cancer progressed and 89% had tumor downstaging 66 .…”

Cellular Mechanisms Accounting for the Refractoriness of Colorectal Carcinoma to Pharmacological Treatment

“…The dMMR phenotype is also predictive of resistance to oxaliplatin-based chemotherapy in metastatic CRC [ 140 ]. Although, in CRC, the presence of dMMR is associated with a weaker response to neoadjuvant chemotherapy (5-FU/oxaliplatin), these tumors are more sensitive to chemoradiation [ 141 ]. Moreover, in patients with metastatic CRC receiving irinotecan-based chemotherapy as the first-line regimen, a relationship between increased sensitivity to irinotecan and dMMR status has been reported [ 142 ].…”