Microsatellite Instability (MSI) as an Independent Predictor of Pathologic Complete Response (PCR) in Locally Advanced Rectal Cancer

Abstract

Objective: The relationship between microsatellite instability (MSI) and response to neoadjuvant chemoradiation in rectal cancer is not well understood. Background: We utilized the National Cancer Database (NCDB) to investigate the association between MSI and pathologic complete response (pCR) in this patient population. Methods: We analyzed 5086 patients between 2010 and 2015 with locally advanced rectal cancer who were tested for MSI and treated definitively with chemoradiation followed by surgery. Primary comparison groups were between 4450 MSI-negative(−) and 636 MSI-positive(+) patients. Multivariable regression analysis was conducted to identify demographic, therapeutic, and clinical characteristics predictive of pCR. Cox proportional-hazard ratios were used for survival. Results: All patients were treated with definitive chemoradiation (median dose 50.4 Gy) followed by resection within 4 months. MSI(+) patients were associated with earlier year of diagnosis and higher-grade tumors (P < 0.05). The overall pCR rate was 8.6%, including 8.9% for MSI(−) and 5.9% for MSI(+) tumors (P = 0.01). Along with lower T stage, MSI(+) cases were significantly associated with a reduced pCR rate (odds ratio 0.65, 95% confidence interval 0.43–0.96) with multivariable analysis. The 5-year survival for patients with pCR was 93% compared with 73% without it (<0.001). Conclusion: Microsatellite instability was independently associated with a reduction in pCR for locally advanced rectal cancer after neoadjuvant chemoradiation in this NCDB-based analysis.

Prognostic Significance of Clinicopathological and Molecular Features After Neoadjuvant Chemoradiotherapy in Rectal Cancer Patients

“…In contrast, other studies have reported that patients with MSI-H or dMMR rectal cancer had higher survival rates (16,30). These contradictory results regarding MSI as a predictive factor may be attributable to the mixed rectal cancer phenotypes with patients harboring various concomitant mutations in different genes such as BRAF, KRAS, or other cancer pathway genes that generally show poor prognosis (15,29). In the meantime, the MSI status from surgically resected specimens after neoadjuvant CRT was not associated with survival outcomes in the present study.…”

“…However, the role of MSI as a predictive factor in rectal cancer has not been confirmed (29). Some studies have reported that MSI-H was independently associated with poor pCR rates after neoadjuvant CRT (15), and had inferior survival outcomes for rectal cancer (14). In contrast, other studies have reported that patients with MSI-H or dMMR rectal cancer had higher survival rates (16,30).…”

“…In addition, microsatellite instability (MSI) caused by the loss of DNAmismatch repair (MMR) function, is known to have a negative predictive effect on survival of colon cancer patients treated with surgery followed by 5-fluorouracil (5-FU)-based adjuvant chemotherapy (12,13). However, the predictive role of MSI after neoadjuvant CRT in rectal cancer remains controversial (14)(15)(16).…”

Association of mismatch repair status with survival and response to neoadjuvant chemo(radio)therapy in rectal cancer

“…For instance, early-stage colorectal adenocarcinomas testing positive for MSI may carry a favorable prognosis and therefore do not require adjuvant chemotherapy [3][4][5] . Some studies suggest that these tumors are more prone to be sensitive to 5-FU chemo(radio)therapy, although this finding is controversial [6][7][8][9][10] . Even if a significantly decreased likelihood of pathologic complete response (pCR) has been demonstrated for dMMR patients after chemoradiation 6 in the largest sample-sized study, no study has been reported to investigate the association of MMR status with survival and response to neoadjuvant radiotherapy (NRT) with a comparison of patients receiving neoadjuvant chemotherapy (NCT) with or without radiotherapy.…”

Microsatellite instability: a review of what the oncologist should know

“…-L1 programmed cell death-Ligand 1, dMMR mismatch repair deficient, MSI-H microsatellite high instability According to the article of Carr et al[41], lifestyle can affect the molecular pathological types of colorectal cancer and statistics show that moderate and high alcohol consumption is associated with an increased risk of MSI-H colon cancer. MSI can be used as a significant molecular marker for prognosis and adjuvant therapy of CRC[42]. MSI has different effects…”