Metachronous colorectal cancer risk according to Lynch syndrome pathogenic variant after extensive versus partial colectomy in the Netherlands: a retrospective cohort study.

Background: Extensive colectomy (subtotal or total colectomy) is often advised for carriers of Lynch syndrome with colorectal cancer. However, the risk of metachronous colorectal cancer might differ by Lynch syndrome variant, meaning that partial colectomy, which has better functional outcomes, might be adequate for some patients with low-risk variants. We aimed to assess the risk of metachronous colorectal cancer after partial colectomy and extensive colectomy in carriers of Lynch syndrome with different pathogenic variants.

Methods: For this retrospective cohort study, carriers of Lynch syndrome with colorectal cancer in the Netherlands were identified by linkage of the Dutch Foundation for the Detection of Hereditary Tumors (StOET) database and the Dutch Nationwide Network and Registry of Histopathology and Cytopathology (PALGA) database. Data on demographics, Lynch syndrome variants, colorectal cancers, surgery types, mortality, and surveillance colonoscopies were extracted. Data on colorectal cancer and surveillance colonoscopies were updated until Feb 28, 2022. Data on survival status was updated until Feb 7, 2022. MLH1, MSH2, and EPCAM were classified as high-risk variants and MSH6 and PMS2 as low-risk variants. Patients for whom the type of surgery was unknown were excluded. Cox regression time-to-event analyses were done to assess the risk of metachronous colorectal cancer in four subgroups based on pathogenic variant (high-risk vs low-risk variants) and the extent of surgery (extensive colectomy vs partial colectomy). Sex, age at the time of primary colorectal cancer, primary colorectal cancer stage, performance of surveillance colonoscopies, adherence to the surveillance guidelines, and time period of primary colorectal cancer diagnosis were added to the model as possible confounders. Metachronous colorectal cancer was defined as colorectal cancer diagnosed more than 6 months after the primary colorectal cancer. Patients were censored at time of death or assembly of the database.

Findings: Of 1908 carriers of Lynch syndrome registered in StOET, 532 with a history of colorectal cancer were identified after linkage with PALGA. Five carriers were excluded because of an unknown surgery type, leaving 527 in our sample (mean age at primary colorectal cancer 48·7 years [SD 12·1]; 274 [52%] male and 253 [48%] female). 121 (23%) patients developed metachronous colorectal cancer (median time from primary colorectal cancer to metachronous colorectal cancer 11·0 years [IQR 2·1-17·8]). Metachronous colorectal cancer occurred in 12 (12%) of 97 patients with high-risk variants and extensive colectomy, in 85 (32%) of 267 patients with high-risk variants and partial colectomy, in zero (0%) of 11 patients with low-risk variants and extensive colectomy, and in 24 (16%) of 152 patients with low-risk variants and partial colectomy. Partial colectomy was associated with a higher risk of metachronous colorectal cancer than extensive colectomy in the high-risk variant group (hazard ratio 1·97, 95% CI 1·04-3·73; p=0·039). The risk of metachronous colorectal cancer did not differ between carriers of low-risk variants who had partial colectomy and those of high-risk variants who had extensive colectomy (1·14, 0·55-2·36; p=0·72).

Interpretation: The risk of metachronous colorectal cancer after partial colectomy in carriers of low-risk variants is similar to the risk after extensive colectomy in carriers of high-risk variants. This finding suggests that partial colectomy followed by endoscopic surveillance is an appropriate management approach to treat colorectal cancer in carriers of low-risk Lynch syndrome variants.

Funding: None.