Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Division of Medical Oncology, Hospital Sírio-Libanês, Brasilia, Brazil.
Clin Cancer Res. 2020 Jul 1;26(13):3271-3279. doi: 10.1158/1078-0432.CCR-19-3728. Epub 2020 Mar 6.
Evaluate response of mismatch repair-deficient (dMMR) rectal cancer to neoadjuvant chemotherapy.
dMMR rectal tumors at Memorial Sloan Kettering Cancer Center (New York, NY) were retrospectively reviewed for characteristics, treatment, and outcomes. Fifty patients with dMMR rectal cancer were identified by IHC and/or microsatellite instability analysis, with initial treatment response compared with a matched MMR-proficient (pMMR) rectal cancer cohort. Germline and somatic mutation analyses were evaluated. Patient-derived dMMR rectal tumoroids were assessed for chemotherapy sensitivity.
Of 21 patients receiving neoadjuvant chemotherapy (fluorouracil/oxaliplatin), six (29%) had progression of disease. In comparison, no progression was noted in 63 pMMR rectal tumors = 0.0001). Rectal cancer dMMR tumoroids reflected this resistance to chemotherapy. No genomic predictors of chemotherapy response were identified. Of 16 patients receiving chemoradiation, 13 (93%) experienced tumor downstaging; one patient had stable disease, comparable with 48 pMMR rectal cancers. Of 13 patients undergoing surgery, 12 (92%) had early-stage disease. Forty-two (84%) of the 50 patients tested positive for Lynch syndrome with enrichment of germline and mutations when compared with 193 patients with Lynch syndrome-associated colon cancer (, 57% vs 36%; , 17% vs 9%; < 0.003).
Over one-fourth of dMMR rectal tumors treated with neoadjuvant chemotherapy exhibited disease progression. Conversely, dMMR rectal tumors were sensitive to chemoradiation. MMR status should be performed upfront in all locally advanced rectal tumors with careful monitoring for response on neoadjuvant chemotherapy and genetic testing for Lynch syndrome in patients with dMMR rectal cancer.
评估错配修复缺陷（dMMR）直肠肿瘤对新辅助化疗的反应。
回顾性分析纪念斯隆-凯特琳癌症中心（纽约，NY）的 dMMR 直肠肿瘤的特征、治疗和结局。通过免疫组化和/或微卫星不稳定性分析鉴定了 50 例 dMMR 直肠癌患者，与匹配的 MMR 功能正常（pMMR）直肠癌队列比较初始治疗反应。评估了种系和体细胞突变分析。评估了患者来源的 dMMR 直肠肿瘤样体对化疗敏感性。
21 例接受新辅助化疗（氟尿嘧啶/奥沙利铂）的患者中，有 6 例（29%）疾病进展。相比之下，在 63 例 pMMR 直肠肿瘤中未发现进展（=0.0001）。直肠肿瘤 dMMR 肿瘤样体反映了对化疗的这种耐药性。未发现化疗反应的基因组预测因子。在接受放化疗的 16 例患者中，13 例（93%）肿瘤降期；1 例患者疾病稳定，与 48 例 pMMR 直肠肿瘤相似。在接受手术的 13 例患者中，12 例（92%）为早期疾病。在 50 例患者中，有 42 例（84%）检测出林奇综合征阳性，与 193 例林奇综合征相关结肠癌患者相比，种系和 突变丰富（，57%比 36%； ，17%比 9%；<0.003）。
在接受新辅助化疗的 dMMR 直肠肿瘤中，超过四分之一的肿瘤出现疾病进展。相反，dMMR 直肠肿瘤对放化疗敏感。在所有局部晚期直肠肿瘤中应进行 MMR 状态检测，在新辅助化疗中密切监测反应，并对 dMMR 直肠癌患者进行林奇综合征的基因检测。
