Characterization of rectal cancer in patients with Lynch syndrome

350 Background: Lynch syndrome (LS), resulting from a germline mutation in a DNA mismatch repair (MMR) gene, is associated with ~70% lifetime colorectal cancer (CRC) risk. Although LS-associated colon cancer is associated with both favorable prognosis and lack of efficacy to 5-fluorouracil, clinical features of LS-associated rectal cancer (RC) have not been characterized. Methods: Clinical genetics database review (1998–2012) identified all probands with CRC and a deleterious germline mutation in a MMR gene (MLH1, MSH2, MSH6, PMS2) diagnostic of LS. Probands without identifiable mutations or variants of unknown significance were excluded. Clinical history and pedigree was extracted from medical records and Progeny. Results: Of 119 LS patients with CRC, 16 (13.4%) had RC. Mean age at RC diagnosis was 40.6 (range, 23-56) with 31% having synchronous (n=3) or metachronous (n=2) colon cancer. All RC patients met Revised Bethesda and 63% met Amsterdam II criteria. As opposed to LS-associated colon cancer, the majority of RC patients harbored MSH2 mutations (36% colon vs 69% RC, p value 0.01). 11 tumors were analyzed for MSI or defective MMR protein expression by IHC; results were abnormal and thereby concordant with germline test results in all cases. Of 14 RC patients with clinical data, 5 proceeded directly to surgery (4 stage 0/I; 1 stage II). Nine patients received pre-op treatment for clinical stage II/III (n=7) or IV (n=2) disease, with all receiving chemoradiation and five also receiving pre-op FOLFOX. Downstaging of primary tumor occurred in 66.6% (6/9) and of lymph nodes in 77.7% (7/9) of cases. All nine patients underwent R0 resections; however, pCR was not observed in any of the cases. Notably, one patient with clinical T3N+ disease (by MRI and EUS) had upfront surgery identifying pT2N0 disease with prominent tumor infiltrating lymphocytes. Of 14 patients, mean follow-up of 4.3 years (range, 0.3-13.5), none had disease recurrence; however, one was diagnosed with a new primary colon cancer. Conclusions: Although less common than colon cancer,RC is an important component of LS and may be overrepresented in MSH2 mutation carriers. Given high risk of synchronous or metachronous cancers, appropriate surveillance for second malignancies is necessary.