Prognosis of Microsatellite Instability and/or Mismatch Repair Deficiency Stage III Colon Cancer Patients After Disease Recurrence Following Adjuvant Treatment

Results of an ACCENT Pooled Analysis of Seven Studies

J. Taieb; Q. Shi; L. Pederson; S. Alberts; N. Wolmark; E. Van Cutsem; A. de Gramont; R. Kerr; A. Grothey; S. Lonardi; T. Yoshino; G. Yothers; F. A. Sinicrope; A. Zaanan; T. André

Disclosures

Ann Oncol. 2019;30(9):1466-1471. 

In This Article

Abstract and Introduction

Abstract

Background: Microsatellite instable/deficient mismatch repair (MSI/dMMR) metastatic colorectal cancers have been reported to have a poor prognosis. Frequent co-occurrence of MSI/dMMR and BRAF V600E complicates the association.

Patients and methods: Patients with resected stage III colon cancer (CC) from seven adjuvant studies with available data for disease recurrence and MMR and BRAF V600E status were analyzed. The primary end point was survival after recurrence (SAR). Associations of markers with SAR were analyzed using Cox proportional hazards models adjusted for age, gender, performance status, T stage, N stage, primary tumor location, grade, KRAS status, and timing of recurrence.

Results: Among 2630 patients with cancer recurrence (1491 men [56.7%], mean age, 58.5 [19–85] years), multivariable analysis revealed that patients with MSI/dMMR tumors had significantly longer SAR than did patients with microsatellite stable/proficient MMR tumors (MSS/pMMR) (adjusted hazard ratio [aHR], 0.82; 95% CI [confidence interval], 0.69–0.98; P = 0.029). This finding remained when looking at patients treated with standard oxaliplatin-based adjuvant chemotherapy regimens only (aHR, 0.76; 95% CI, 0.58–1.00; P = 0.048). Same trends for SAR were observed when analyzing MSI/dMMR versus MSS/pMMR tumor subgroups lacking BRAF V600E (aHR, 0.84; P = 0.10) or those harboring BRAF V600E (aHR, 0.88; P = 0.43), without reaching statistical significance. Furthermore, SAR was significantly shorter in tumors with BRAF V600E versus those lacking this mutation (aHR, 2.06; 95% CI, 1.73–2.46; P < 0.0001), even in the subgroup of MSI/dMMR tumors (aHR, 2.65; 95% CI, 1.67–4.21; P < 0.0001). Other factors associated with a shorter SAR were as follows: older age, male gender, T4/N2, proximal primary tumor location, poorly differentiated adenocarcinoma, and early recurrence.

Conclusions: In stage III CC patients recurring after adjuvant chemotherapy, and before the era of immunotherapy, the MSI/dMMR phenotype was associated with a better SAR compared with MSS/pMMR. BRAF V600E mutation was a poor prognostic factor for both MSI/dMMR and MSS/pMMR patients.

Introduction

Surgery alone or combined with adjuvant chemotherapy remains the cornerstone of treatment of non-metastatic colorectal cancer (CRC).[1–8] Chromosomal instability and microsatellite instability (MSI) are distinct, well-described pathways of colorectal carcinogenesis that confer a different prognosis.[9] MSI/deficient DNA mismatch repair (MSI/dMMR) is considered a favorable prognostic factor in non-metastatic patients (stage I to III) tumors;[9] however, its prognostic role in metastatic CRC (mCRC) patients remains controversial.

A recent meta-analysis suggested that MSI/dMMR is a poor prognostic factor in patients eligible for the first-line treatment of non-resectable mCRC.[10] In this analysis, however, number of patients in each subgroup were limited which precluded definitive conclusions. Moreover, MSI/dMMR CRCs are often mutated for BRAF V600E , an established poor prognostic factor in mCRC that complicates the picture.

Clinical trials testing immunotherapy for MSI/dMMR mCRC patients, and targeted treatment of BRAF V600E mCRC patients, have yielded promising results. Having a clearer picture of the prognosis of each of these molecular subgroups is important given that approaches to their treatment is rapidly changing.

Among patients treated in seven phase III trials of adjuvant chemotherapy, we analyzed overall survival after disease recurrence in relationship to MMR and BRAF V600E status.

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