BACKGROUND: DNA deficient mismatch repair (dMMR) genes are associated with microsatellite instability and good prognosis in early-stage colorectal cancer (CRC). However dMMR is rare in metastatic CRC (mCRC) and little is known about its influence on treatment response rate (RR). The primary objective of this study was to compare the RR of patients with mCRC according to dMMR status. METHODS: This was a retrospective study that compared the RR by Response Evaluation Criteria In Solid Tumors 1.1 criteria in patients with mCRC treated with chemotherapy according to dMMR status. All digital images were retrieved for RR evaluation by a single radiologist blinded to dMMR results. dMMR was defined as loss of immunohistochemistry expression of at least 1 of the MMR genes (MLH1, MSH2, MSH6, or PMS2). Cases were dMMR patients, and controls were proficient MMR (pMMR) patients (1:2 fashion). Based on clinical and molecular features, dMMR patients were classified as probable Lynch or sporadic. RESULTS: From January 2009 to January 2013, 762 out of 1270 patients were eligible and screened for dMMR: n = 27 (3.5%) had dMMR mCRC and n = 735 (96.5%) had pMMR mCRC. Given the rarity, 14 dMMR cases outside the inclusion period were included (total 41 dMMR cases) and 84 controls (pMMR). By intention-to-treat analysis, considering all patients who received at least 1 dose of oxaliplatin-based chemotherapy (N dMMR = 34), those with dMMR had lower RR compared with those with pMMR (RR, 11.7% vs. 28.6%; odds ratio, 0.33; 95% confidence interval, 0.08-1.40; P = .088); patients with probable Lynch-related mCRC presented higher RR than subjects with probable sporadic dMMR (22.2% vs. 0%). dMMR was associated with BRAF mutations and poor prognosis, particularly in the sporadic subgroup (median survival, 29.8 vs. 5.9 months; P = .025). CONCLUSION: This study suggests that the dMMR phenotype is predictive of resistance to oxaliplatin-based chemotherapy. Apparently, such resistance is more pronounced in the sporadic dMMR phenotype, suggesting biological heterogeneity within the dMMR mCRC subgroup.
BACKGROUND: DNA deficient mismatch repair (dMMR) genes are associated with microsatellite instability and good prognosis in early-stage colorectal cancer (CRC). However dMMR is rare in metastatic CRC (mCRC) and little is known about its influence on treatment response rate (RR). The primary objective of this study was to compare the RR of patients with mCRC according to dMMR status. METHODS: This was a retrospective study that compared the RR by Response Evaluation Criteria In Solid Tumors 1.1 criteria in patients with mCRC treated with chemotherapy according to dMMR status. All digital images were retrieved for RR evaluation by a single radiologist blinded to dMMR results. dMMR was defined as loss of immunohistochemistry expression of at least 1 of the MMR genes (MLH1, MSH2, MSH6, or PMS2). Cases were dMMRpatients, and controls were proficient MMR (pMMR) patients (1:2 fashion). Based on clinical and molecular features, dMMRpatients were classified as probable Lynch or sporadic. RESULTS: From January 2009 to January 2013, 762 out of 1270 patients were eligible and screened for dMMR: n = 27 (3.5%) had dMMR mCRC and n = 735 (96.5%) had pMMR mCRC. Given the rarity, 14 dMMR cases outside the inclusion period were included (total 41 dMMR cases) and 84 controls (pMMR). By intention-to-treat analysis, considering all patients who received at least 1 dose of oxaliplatin-based chemotherapy (N dMMR = 34), those with dMMR had lower RR compared with those with pMMR (RR, 11.7% vs. 28.6%; odds ratio, 0.33; 95% confidence interval, 0.08-1.40; P = .088); patients with probable Lynch-related mCRC presented higher RR than subjects with probable sporadic dMMR (22.2% vs. 0%). dMMR was associated with BRAF mutations and poor prognosis, particularly in the sporadic subgroup (median survival, 29.8 vs. 5.9 months; P = .025). CONCLUSION: This study suggests that the dMMR phenotype is predictive of resistance to oxaliplatin-based chemotherapy. Apparently, such resistance is more pronounced in the sporadic dMMR phenotype, suggesting biological heterogeneity within the dMMR mCRC subgroup.
Authors: Andrea Cercek; Melissa Lumish; Jenna Sinopoli; Jill Weiss; Jinru Shia; Michelle Lamendola-Essel; Imane H El Dika; Neil Segal; Marina Shcherba; Ryan Sugarman; Zsofia Stadler; Rona Yaeger; J Joshua Smith; Benoit Rousseau; Guillem Argiles; Miteshkumar Patel; Avni Desai; Leonard B Saltz; Maria Widmar; Krishna Iyer; Janie Zhang; Nicole Gianino; Christopher Crane; Paul B Romesser; Emmanouil P Pappou; Philip Paty; Julio Garcia-Aguilar; Mithat Gonen; Marc Gollub; Martin R Weiser; Kurt A Schalper; Luis A Diaz Journal: N Engl J Med Date: 2022-06-05 Impact factor: 176.079
Authors: Andrea Cercek; Gustavo Dos Santos Fernandes; Campbell S Roxburgh; Karuna Ganesh; Shu Ng; Francisco Sanchez-Vega; Rona Yaeger; Neil H Segal; Diane L Reidy-Lagunes; Anna M Varghese; Arnold Markowitz; Chao Wu; Bryan Szeglin; Charles-Etienne Gabriel Sauvé; Erin Salo-Mullen; Christina Tran; Zalak Patel; Asha Krishnan; Kaitlyn Tkachuk; Garrett M Nash; Jose Guillem; Philip B Paty; Jinru Shia; Nikolaus Schultz; Julio Garcia-Aguilar; Luis A Diaz; Karyn Goodman; Leonard B Saltz; Martin R Weiser; J Joshua Smith; Zsofia K Stadler Journal: Clin Cancer Res Date: 2020-03-06 Impact factor: 12.531