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Risk of metachronous colon cancer following surgery for rectal cancer in mismatch repair gene mutation carriers.

ABSTRACT: Despite regular surveillance colonoscopy, the metachronous colorectal cancer risk for mismatch repair (MMR) gene mutation carriers after segmental resection for colon cancer is high and total or subtotal colectomy is the preferred option. However, if the index cancer is in the rectum, management decisions are complicated by considerations of impaired bowel function. We aimed to estimate the risk of metachronous colon cancer for MMR gene mutation carriers who underwent a proctectomy for index rectal cancer.This retrospective cohort study comprised 79 carriers of germline mutation in a MMR gene (18 MLH1, 55 MSH2, 4 MSH6, and 2 PMS2) from the Colon Cancer Family Registry who had had a proctectomy for index rectal cancer. Cumulative risks of metachronous colon cancer were calculated using the Kaplan-Meier method.During median 9 years (range 1-32 years) of observation since the first diagnosis of rectal cancer, 21 carriers (27 %) were diagnosed with metachronous colon cancer (incidence 24.25, 95 % confidence interval [CI] 15.81-37.19 per 1,000 person-years). Cumulative risk of metachronous colon cancer was 19 % (95 % CI 9-31 %) at 10 years, 47 (95 % CI 31-68 %) at 20 years, and 69 % (95 % CI 45-89 %) at 30 years after surgical resection. The frequency of surveillance colonoscopy was 1 colonoscopy per 1.16 years (95 % CI 1.01-1.31 years). The AJCC stages of the metachronous cancers, where available, were 72 % stage I, 22 % stage II, and 6 % stage III.Given the high metachronous colon cancer risk for MMR gene mutation carriers diagnosed with an index rectal cancer, proctocolectomy may need to be considered.

SUBMITTER: Win AK

PROVIDER: S-EPMC4041733 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Risk of metachronous colon cancer following surgery for rectal cancer in mismatch repair gene mutation carriers.

Win Aung Ko AK Parry Susan S Parry Bryan B Kalady Matthew F MF Macrae Finlay A FA Ahnen Dennis J DJ Young Graeme P GP Lipton Lara L Winship Ingrid I Boussioutas Alex A Young Joanne P JP Buchanan Daniel D DD Arnold Julie J Le Marchand Loïc L Newcomb Polly A PA Haile Robert W RW Lindor Noralane M NM Gallinger Steven S Hopper John L JL Jenkins Mark A MA

Annals of surgical oncology 20130129 6

<h4>Background</h4>Despite regular surveillance colonoscopy, the metachronous colorectal cancer risk for mismatch repair (MMR) gene mutation carriers after segmental resection for colon cancer is high and total or subtotal colectomy is the preferred option. However, if the index cancer is in the rectum, management decisions are complicated by considerations of impaired bowel function. We aimed to estimate the risk of metachronous colon cancer for MMR gene mutation carriers who underwent a procte ...[more]

PMID: 23358792

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Project description:The aim of this study was to investigate immune response and its prognostic significance in colon carcinomas using the previously described Immunoscore (IS). A population-based series of 779 colorectal cancers, operated on between 2000 and 2010, were classified according to tumour, node, metastasis (TNM) status, mismatch repair (MMR), and BRAF mutation status. Rectal cancer cases (n = 203) were excluded as a high proportion of these patients received preoperative neoadjuvant chemoradiotherapy. Tissue microarray (TMA) samples collected from the tumour centre and invasive front were immunostained for CD3 and CD8. Lymphocytes were then digitally calculated to categorize IS from grade 0 to 4. Samples adequate for IS were available from 510 tumours. IS was significantly associated with AJCC/UICC stage, T stage, lymph node and distant metastases, perineural and lymphovascular invasion, MMR status, and BRAF mutation status. For IS0, IS1, IS2, IS3 and IS4, respectively, the 5-year disease-free survival (DFS) rates were 59, 68, 78, 83 and 94% (p < 0.001); 5-year disease-specific survival (DSS) rates were 47, 55, 75, 80, and 89% (p < 0.001); and 5-year overall survival (OS) rates were 40, 44, 66, 61, and 76% (p < 0.001). IS was also prognostic for DFS, DSS, and OS within subsets of microsatellite-stable (MSS) and microsatellite-instable (MSI) disease. Multivariable analysis showed that IS, AJCC/UICC stage, lymphovascular invasion, and lymph node ratio in AJCC/UICC stage III disease were independent prognostic factors for DFS, DSS, and OS. Age was an independent prognostic factor for DSS and OS. Gender and BRAF mutation were independent prognostic factors for OS. In conclusion, IS differentiated patients with poor versus improved prognosis in MSS and MSI disease and across AJCC/UICC stages. IS, AJCC/UICC stage, lymphovascular invasion, and lymph node ratio in AJCC/UICC stage III disease were independent prognostic factors for DFS, DSS, and OS.

Project description:BackgroundNeoadjuvant chemotherapy and radiation followed by surgical resection of the rectum is a standard treatment for locally advanced rectal cancer. A subset of rectal cancer is caused by a deficiency in mismatch repair. Because mismatch repair-deficient colorectal cancer is responsive to programmed death 1 (PD-1) blockade in the context of metastatic disease, it was hypothesized that checkpoint blockade could be effective in patients with mismatch repair-deficient, locally advanced rectal cancer.MethodsWe initiated a prospective phase 2 study in which single-agent dostarlimab, an anti-PD-1 monoclonal antibody, was administered every 3 weeks for 6 months in patients with mismatch repair-deficient stage II or III rectal adenocarcinoma. This treatment was to be followed by standard chemoradiotherapy and surgery. Patients who had a clinical complete response after completion of dostarlimab therapy would proceed without chemoradiotherapy and surgery. The primary end points are sustained clinical complete response 12 months after completion of dostarlimab therapy or pathological complete response after completion of dostarlimab therapy with or without chemoradiotherapy and overall response to neoadjuvant dostarlimab therapy with or without chemoradiotherapy.ResultsA total of 12 patients have completed treatment with dostarlimab and have undergone at least 6 months of follow-up. All 12 patients (100%; 95% confidence interval, 74 to 100) had a clinical complete response, with no evidence of tumor on magnetic resonance imaging, 18F-fluorodeoxyglucose-positron-emission tomography, endoscopic evaluation, digital rectal examination, or biopsy. At the time of this report, no patients had received chemoradiotherapy or undergone surgery, and no cases of progression or recurrence had been reported during follow-up (range, 6 to 25 months). No adverse events of grade 3 or higher have been reported.ConclusionsMismatch repair-deficient, locally advanced rectal cancer was highly sensitive to single-agent PD-1 blockade. Longer follow-up is needed to assess the duration of response. (Funded by the Simon and Eve Colin Foundation and others; ClinicalTrials.gov number, NCT04165772.).

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Risk of metachronous colon cancer following surgery for rectal cancer in mismatch repair gene mutation carriers.

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Risk of metachronous colon cancer following surgery for rectal cancer in mismatch repair gene mutation carriers.

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