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Mismatch Repair Deficiency
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This entry is adapted from the peer-reviewed paper 10.3390/cancers13020300

Universal MMR/MSI testing is standard of care for all patients with newly diagnosed CRC based on multi-society guidelines in the United States. Such testing is intended to identify patients with Lynch Syndrome due to a germline mutation in an MMR gene, but also detects those with sporadic dMMR/MSI-high CRCs.

mismatch repair deficiency microsatellite instability colorectal cancer

1. Introduction

Colorectal cancer (CRC) is the second most common cancer diagnosed in women and the third in men worldwide, with more than 1.8 million new cases and approximately 900,000 deaths in 2017 [1]. It is estimated that 147,950 new CRC cases will be diagnosed in the United States with 53,200 deaths in 2020 [2]. Approximately 15% of CRCs show deficient DNA mismatch repair (dMMR) that results in microsatellite instability (MSI). These tumors are frequently poorly differentiated with mucinous features or a medullary growth pattern, although they can also resemble more typical CRCs. CRCs with dMMR have earlier stage at diagnosis compared to proficient MMR (pMMR) tumors [3][4]. Due to the loss of mismatch repair (MMR) function, these tumors accumulate a high mutational burden with abundant mutation-derived neoantigens that attract tumor infiltrating lymphocytes (TILs) [5][6]. Non-metastatic CRCs with dMMR/MSI generally have better stage-adjusted prognosis compared to pMMR tumors, and data suggest that MMR status may also be predictive of tumor responsiveness to different treatments [7][8].

2. The Role of dMMR/MSI in CRC Development

The first multi-step model of CRC carcinogenesis considered adenomatous polyposis coli (APC) gene inactivation as the initial step followed by KRAS gene mutation and chromosome 18q loss of heterozygosity that further promotes the growth of precancerous adenomas. P53 gene inactivation mediates the adenoma-to-carcinoma transition. However, an important alternative pathway was identified where tumors showed microsatellite instability (MSI) due to deficient DNA mismatch repair (dMMR).

MSI is characterized by short sequence repeats (SSRs) or short tandem repeats (STRs) of repeated DNA sequences with various lengths [9]. Microsatellites are widely distributed throughout the genome in a non-random fashion and are prone to mutations during DNA replication [10][11]. In 1993, an analysis of 130 matched CRC tumors and adjacent normal tissues identified differences in polymerase chain reaction (PCR) products whereby 12% of tumors had bands that were shorter in length (band-shift) [12]. Sequencing of these bands by the Perucho lab revealed that they contained simple repetitive sequences termed microsatellites. Further study demonstrated that tumors with this type of mutation had unique characteristics that led to the hypothesis that these tumors could be hereditary. Simultaneously, Thibodeau et al. examined somatic instability in CRCs in human chromosomes 5q, 15q, 17p, and 18q and identified differences between normal tissue and tumor DNA that linked MSI directly with CRC carcinogenesis [13]. MSI was found in association with CRCs arising in hereditary non-polyposis colorectal cancer (HNPCC) including other cancer types, suggesting that cancers developing in HNPCC have a common pathogenesis via MSI [14]. Almost at the same time, Aaltonen’s lab confirmed widespread MSI in familial CRC; however, MSI was also identified in 13% of sporadic CRC cases [15]. This suggested that MSI is a pathogenic pathway shared by both hereditary and sporadic CRC. MSI CRCs are characterized by a large number of mutations at microsatellite sequences, and are commonly located in the proximal colon, have poorly differentiated histology with mucinous features, and appear to have better clinical outcomes [14][16].

The mismatch repair (MMR) system consists of a family of enzymes that detect DNA replication errors (such as mismatches between the two strands of DNA). The MMR system includes MHL1, MSH2, MSH6, and PMS2 genes. Approximately 90% of germline mutations are detected in MLH1 and MSH2 genes. Germline mutations in MLH1 were first identified in multiple familial CRC kindreds [17][18]. Human PMS1 and PMS2 genes were subsequently implicated in familial CRC, although the role of PMS1 in CRC remains unclear [19]. It took longer to confirm the role of MSH6 in MSI CRC due to delayed onset of cancer that obscured the initial effort of discovery [20]. The EpCAM (Epithelial cellular adhesion molecule) gene is located upstream of MSH2, and germline 3′ end deletion of the EpCAM gene leads to hypermethylation of the MSH2 promoter (constitutional epimutation) and MSI [21]. Germline mutations of these genes (MLH1, MSH2, MSH6, PMS2, and EpCAM) lead to HNPCC, also known as Lynch syndrome.

Although progress in recognizing the role of MMR deficiency in MSI CRC is mainly based on the studies in familial CRC (HNPCC) population, these patients represent only 3% of all CRCs [22]. Approximately 12–17% of all CRCs have MSI which indicates the majority of MSI CRCs are sporadic [7][23]. The sporadic MSI CRCs have unique characteristics including later onset of cancer without familial clustering, frequent BRAFV600E mutations, and better clinical outcomes as also found for familial MSI tumors [24][25]. Most sporadic MSI CRCs show loss of MLH1 and PMS2 proteins and the mechanism of MSI in these tumors is due to hypermethylation of the MLH1 gene promoter typically in association with the CpG island methylator phenotype (CIMP) [26]. Approximately 50% of human genes have promotor regions embedded in the clusters of cytosine-guanosine residues called CpG islands, and cytosines in the CpG island can be methylated, thus leading to gene silencing [27]. BRAFV600E occurs exclusively in sporadic dMMR/MSI CRCs in association with hypermethylation of the MLH1 gene promoter, often with the CpG island methylator phenotype (CIMP) [28][29]. However, 2.5–3.9% of patients with MSI CRCs do not have germline mutation or MLH1 methylation and these tumors have been found to have double somatic MMR mutations [22][30][31][32]. These double somatic MSI CRCs have a higher frequency of PIK3CA somatic mutation [33].

Genes containing microsatellites are prone to mutations due to dMMR. Such genes include those regulating cell proliferation (TGFβR2, GRB1, TCF-4, WISP3, IGFIIR), cell cycle or apoptosis (caspase-5, BAX, FAX, PTEN), and DNA repair (CHK1, MLH3, RAS50, MSH3). Mutations in these genes predispose to CRC development [34].

dMMR/MSI CRCs typically harbor increased numbers of both intraepithelial and peritumoral lymphocytes that represent a response to neoantigens generated by the high mutational burden secondary to MSI [6][35][36]. HNPCC-associated CRCs are more commonly seen in men and usually develop at an earlier age than sporadic dMMR/MSI CRCs (average age of cancer onset, 52.9 vs. 70.8 years) [37][38]. HNPCC patients have high risk for synchronous and metachronous CRCs. One study reported that approximately 7% of patients with HNPCC had synchronous CRCs at the time of diagnosis [39]. For HNPCC patients who had a segmental resection of the first colon cancer, 62% developed a metachronous CRC within 30 years of follow-up, suggesting the need of prophylactic total colectomy in this population [40].

It is critical to identify dMMR/MSI CRCs and currently there are different approaches for detection, including immunohistochemistry (IHC), polymerase chain reaction (PCR)-based methods, and next generation sequencing (NGS). IHC directly evaluates the MMR protein presence/absence in the tumor cells while PCR-based tests use a set of primers (most commonly including two mononucleotide probes (BAT25 and BAT26) and three dinucleotide probes (D2S123, D5D346, D17S250)) to check for PCR products size differences between normal and tumor tissues (band-shift). These two approaches are sensitive and specific with high concordance rate (92–97%) [41][42]. Importantly, there is a small percentage of dMMR CRCs that show intact expression of MMR proteins at IHC, yet have a dysfunctional MMR protein that is due to a missense mutation in an MMR gene. To detect such cases, some experts recommend both IHC and PCR-based tests for dMMR/MSI screening [43][44]. More recently, massive parallel NGS demonstrated the capability of accurately detecting MSI. NGS is able to detect MSI simultaneously in a large number of microsatellite loci. One study evaluated 11,573 solid tumor specimens with NGS and demonstrated a high concordance rate with PCR and IHC results (97%) [45]. Of note, this approach requires specific algorithms and computational methods which can vary with different NGS platforms, although high sensitivity and specificity were confirmed [46][47]. As NGS-guided precision oncology is becoming part of routine clinical practice, this approach is frequently utilized to identify MSI cancers. Liquid biopsy has emerged as a comprehensive approach to characterize the molecular features of tumors by testing cell-free DNA (cfDNA, i.e., fragments of DNA that are shed into the bloodstream from dividing cells during cell proliferation or cell death). One study showed that MSI testing using cfDNA has an overall accuracy of 98.4% [48]. This method is currently incorporated into clinical practice, especially for those patients who have insufficient tumor tissue for IHC, PCR, or NGS tests.

3. Prognostic Value of dMMR/MSI in Non-Metastatic Colorectal Cancer

CRCs with dMMR/MSI are more commonly seen in early stage disease and the incidence is reported to be 20% in stage II, 11% in stage III, and 3.5% in metastatic disease, suggesting that MSI CRCs have a reduced tendency for distant metastasis [49]. Substantial evidence supports that dMMR/MSI is a strong prognostic marker in early stage CRCs with a favorable impact on survival. The quick and simple and reliable (QUASAR) phase III clinical trial evaluated the role of fluorouracil-based adjuvant chemotherapy in stage II colon cancer. In a subsequent analysis, there were 1913 stage II and III CRCs patients, of which 218 (11.4%) patients were found to have MSI tumors and only 10 were stage III patients. The proportion of MSI tumors varied significantly by primary site: 179 of 695 (26%) right-sided colon, 22 of 685 (3%) left-sided colon, and 3 of 407 (1%) rectal cancers. In a subgroup analysis in stage II patients, dMMR/MSI was associated with a significantly decreased risk of tumor recurrence (risk ratio (RR) 0.53, 95% confidence interval (CI): 0.29–0.67, p < 0.001) [50]. In a pooled analysis of 1027 stage II and III colon cancer patients of which 165 (16.1%) showed dMMR/MSI, the presence of dMMR/MSI was associated with significantly improved disease-free survival (DFS) (hazard ratio (HR) 0.51, 95% CI: 0.29–0.89, p = 0.009) and overall survival (OS) (HR 0.47, 95% CI: 0.26–0.83, p = 0.004) in patients who did not receive adjuvant chemotherapy [51]. In the Adjuvant Colon Cancer Endpoint (ACCENT) database analysis that included 17 adjuvant clinical trials, 524 of 2270 (23.1%) stage II colon cancer patients were identified to have dMMR/MSI tumors. dMMR/MSI was associated with improved overall survival (OS) (HR 0.27, p = 0.01) and time to recurrence (TTR) (HR 0.27, p = 0.01) in stage II colon cancer patients following surgical resection compared to patients with MMR proficient (pMMR)/microsatellite stable (MSS) disease [52].

The prognostic value of dMMR/MSI in stage III CRC is less clear compared to stage II and conflicting data exist. In a pooled analysis of 2141 stage II (n = 778) and stage III (n = 1363) colon cancer patients, 344 (16.1%) had dMMR/MSI tumors that were associated with delayed TTR (HR 0.72, 95% CI: 0.56–0.91, p = 0.005) and improved disease-free survival (DFS) (HR 0.80, 95% CI: 0.64–0.99, p = 0.035) and OS (HR 0.79, 95% CI: 0.64–0.99, p = 0.031) vs. pMMR/MSS tumors. Further subgroup analysis showed that the prognostic benefit only achieved statistical significance in stage III cancers for TTR (HR 0.72, 95% CI: 0.54–0.97, p = 0.024) [53]. In the PETACC3 adjuvant study with 1404 stage II and III colon cancer patients, 15% of these patients had dMMR/MSI tumors with 22% being stage II and 12% stage III cancers. Patients with dMMR/MSI cancers had better relapse-free survival (RFS) (HR 0.54, 95% CI: 0.37–0.81, p = 0.003) and OS (HR 0.43, 95% CI: 0.27–0.70, p = 0.001) compared to MSS CRCs by multivariable analysis [54]. In a pooled analysis of stage II and III colon cancer patients from the National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trials C-07 (n = 1836) and C-08 (n = 463), dMMR/MSI tumors were associated with better RFS (HR 0.48, 95% CI: 0.33–0.70, p = 0.0001) and OS (HR 0.64, 95% CI: 0.46–0.89, p = 0.0084) [55]. Furthermore, dMMR/MSI in stage III cancers was also found to be associated with better survival after recurrence (SAR). A pooled analysis of seven phase III clinical trials included 2630 patients who had resected stage III colon cancer with subsequent tumor recurrence. Among these, 271 patients (10.3%) had dMMR/MSI tumors which were associated with better SAR (HR 0.82, 95% CI: 0.69–0.98, p = 0.029) compared to MSS tumors. Of note, BRAFV600E was associated with poorer prognosis in both dMMR/MSI and in pMMR/MSS stage III colon cancers [56].

Other studies found that dMMR/MSI was not prognostic in stage III colon cancer. The prognostic impact of dMMR/MSI was studied in 2580 patients with stage III colon cancer who participated in the phase III adjuvant trial of FOLFOX-based chemotherapy (North Central Cancer Treatment Group (NCCTG) N0147). Among 2580 participants, 314 (12%) patients had dMMR/MSI tumors which made this the largest dMMR/MSI stage III CRC cohort reported to date. This study revealed that dMMR/MSI was not associated with better DFS compared to pMMR/MSS patients which did not change after adjustment for clinical variables, BRAF or KRAS status (HR 0.82, 95% CI: 0.64–1.07, p = 0.14). However, a statistically significant interaction was found between MMR status and disease-free survival (DFS) by primary tumor sidedness. Significantly better DFS was seen in dMMR tumors of the proximal colon (HR 0.71, 95% CI: 0.53–0.94, p = 0.018) but not in the distal colon (HR 1.71, 95% CI: 0.99–2.95, p = 0.056), and these results were validated in an independent cohort (CALGB 89803) [57]. Subsequent analysis of the PETACC3 study revealed that dMMR/MSI status was associated with better RFS (HR 0.48, 95% CI: 0.34–0.69, p < 0.001) and OS (HR 0.47, 95% CI: 0.31–0.72, p < 0.001) in the overall study population. However, the prognostic effect was mainly driven by the benefits seen in stage II disease since only a borderline benefit was seen for RFS in stage III patients [58].

Studies also suggested that other prognostic markers such as node stage (N2 versus N1), and RAS and BRAF mutation status may also contribute to prognosis in dMMR/MSI CRC. One study showed that N2 disease (≥4 positive lymph nodes) among dMMR/MSI stage III CRCs was associated with worse clinical outcomes [57]. Due to the relatively small numbers of dMMR/MSI CRCs included in individual studies, inconsistent results have been reported. In the ACCENT database of 17 adjuvant chemotherapy trials, BRAFV600E was associated with worse SAR (HR 2.65, 95% CI 1.67–4.21, p < 0.0001) in dMMR/MSI CRCs. Although KRAS mutations and BRAFV600E mutation were associated with worse DFS in the NCCTG N0147 study, their prognostic value was limited to pMMR/MSS tumors [57]. This result was confirmed in a pooled analysis of 4411 stage III colon cancer patients from the NCCTG N0147 and PETACC8 studies with 477 dMMR/MSI tumors [59].

Recently, a systematic review and meta-analysis included 51 studies with 28,331 stage II and III CRC patients. The 16.4% of patients found to have dMMR/MSI CRCs had improved DFS (HR 0.67, 95% CI: 0.59–0.75, p < 0.001) and OS (HR 0.74, 95% CI: 0.68–0.82, p < 0.001) and importantly, the observed DFS and OS benefits were similar in both stage II and stage III disease [60]. However, another meta-analysis was performed that included only stage III CRCs from 36 studies consisting of both randomized clinical trials (RCT) and non-RCTs. This study found that dMMR/MSI had no prognostic impact for OS, DFS, and disease specific survival (DSS) [61]. The discrepancies among these studies are likely multifactorial and include data from non-randomized and non-study cohorts, different adjuvant chemotherapy regimens, small numbers of dMMR/MSI CRC patients enrolled in each study, and other factors contributing to heterogeneity of the patient populations. One observation appears consistent, which is that the prognostic impact of dMMR/MSI declines with regional and distant metastatic disease such that a favorable prognosis exists in stage II CRC while the effects diminish in stage III disease.

Why does the prognostic value of dMMR/MSI decrease in stage III CRC? It is believed that the prognostic benefits from dMMR/MSI rely on the immunological reaction associated with dMMR/MSI tumors. Enhanced lymphocytic infiltration with an immunoreaction is detected in dMMR/MSI CRCs and this leads to increased host anti-tumor immunity to suppress tumor metastasis [62]. The observed decreased incidence of dMMR/MSI CRCs with advancing disease stage is consistent with this hypothesis. It is speculated that with disease progression and development of metastasis, mechanisms of immune evasion develop that enable dMMR/MSI tumors to evade immune surveillance with loss of a prognostic advantage. This is seen in stage IV CRCs with dMMR/MSI where no prognostic advantage was found [63]. Table 1 lists the recent studies evaluating prognostic value of dMMR/MSI in CRC.

Table 1. Recent studies evaluating the prognostic value of dMMR/MSI in colorectal cancer.

Table
Study Name Year of Publication Disease Stage Patient Number dMMR/MSI Patients Endpoint HR (95% CI) p Value
QUASAR study [50] * 2011 II 636 167 RR 0.44 (0.29–0.67) <0.001
Pooled analysis [51] 2010 II, III 1027 165 DFS 0.51 (0.29–0.89 0.009
OS 0.47 (0.26–0.83) 0.004
ACCENT analysis [52] 2014 II 2270 524 OS 0.27 (0.10–0.74) 0.01
TTR 0.27 (0.10–0.75) 0.01
Pooled analysis [53] 2010 II, III 2141 344 DFS 0.80 (0.64–0.99) 0.035
OS 0.79 (0.64–0.99) 0.031
TTR 0.72 (0.56–0.91) 0.005
PETACC3 [54] 2012 II, III 1404 210 RFS 0.54 (0.37–0.81) 0.003
OS 0.43 (0.27–0.70) 0.001
NSABP C-07/08 [55] 2012 II, III 2299 207 TTR 0.48 (0.33–0.70) 0.0001
OS 0.64 (0.46–0.89) <0.01
SAR 1.60 (1.07–2.41) 0.02
ACCENT analysis [56] 2019 III 2630 271 SAR 0.82 (0.69–0.98) 0.029
NCCTG N0147 [57] 2013 III 2580 314 DFS 0.82 (0.64–1.07) 0.14
DFS Proximal 0.71 (0.53–0.94) 0.053
DFS Distal 1.71 (0.99–2.95) 0.056
PETACC3 [58] 2015 II 309 86 RFS 0.26 (0.10–0.65) NR
OS 0.16 (0.04–0.64) NR
III 755 104 RFS 0.67 (0.46–0.99) NR
OS 0.70 (0.44–1.09) NR
PETACC-8 and NCCTG N0147 [59] ** 2017 III 4411 477 TTR KRAS mutant 1.04 (0.57–1.90) 0.91
OS KRAS mutant 1.07 0.57–2.02) 0.84
TTR BRAFV600E 0.94 (0.58–1.51) 0.80
OS BRAFV600E 1.26 (0.78–2.04) 0.35
Systemic review and meta-analysis [60] 2019 II, III 17065 2337 OS 0.74 (0.68–0.82) <0.001
23195 3264 DFS 0.67 (0.59–0.75) <0.001
III 7481 907 OS 0.71 (0.63–0.81) <0.001
10714 1198 DFS 0.69 (0.60–0.80) <0.001
Meta-analysis [61] 2019 III RCT NR NR OS 0.96 (0.75–1.23) NR
DFS 0.83 (0.65–1.07) NR
III non-RCT NR NR OS 0.89 (0.62–1.28) NR
DFS 0.83 (0.65–1.07) NR
DSS 1.07 (0.68–1.69) NR

Abbreviations: HR: hazard ratio; CI: confidence interval; QUASAR: Quick and Simple and Reliable; RR: recurrence rate; ACCENT: Adjuvant Colon Cancer Endpoint database; OS: overall survival; TTR: time to recurrence; DFS: disease free survival; PETACC: Pan-European Trial in Alimentary Tract Cancer; RFS: recurrence free survival; NSABP: National Surgical Adjuvant Breast and Bowel Project; SAR: survival after recurrence; NCCTG: North Central Cancer Treatment Group; RCT: randomized controlled trials; DSS: disease specific survival. * Only reported the right-sided colon cancer. ** Only listed analysis for dMMR/MSI population

4. Predictive Value of dMMR/MSI for Adjuvant Chemotherapy in Non-Metastatic Colorectal Cancer

Initial retrospective small studies suggested that fluorouracil (5-FU)-based adjuvant chemotherapy was beneficial for stage II and III CRC cancer irrespective of the MMR status [64][65][66]. A retrospective study including 891 consecutive stage III CRC with median follow-up of 54 months suggested that adjuvant chemotherapy significantly improved survival in patients with dMMR/MSI cancers [67]. This study only used one microsatellite marker to identify MSI disease and there were only 63 dMMR/MSI patients included in the study.

Ribic et al. studied specimens from prospective, randomized trials of 5-FU-based adjuvant chemotherapy to further evaluate the predictive utility of dMMR/MSI [68]. The study included 570 patients with 95 (16.7%) dMMR/MSI stage II and III colon cancer patients, and 287 patients (42 dMMR/MSI) who did not receive adjuvant treatment. MSI status was determined by a PCR-based assay with multiple probes. dMMR/MSI was associated with a better 5-year survival rate among patients who did not receive adjuvant chemotherapy (HR 0.31, 95% CI: 0.14–0.72, p = 0.004). However, 5-FU-based adjuvant chemotherapy did not improve 5-year OS (HR 1.07, 95% CI: 0.62–1.86, p = 0.80) in patients with dMMR/MSI tumors while it seemed to benefit those with pMMR/MSS tumors (HR 0.72, 95% CI 0.53–0.99, p = 0.04). The lack of benefit seemed to be similar in both stage II and stage III dMMR/MSI cancers in a subgroup analysis.

Another pooled analysis combined five randomized adjuvant clinical trials with 457 stage II and III colon cancer patients and confirmed the lack of benefit of 5-FU as adjuvant therapy in dMMR/MSI tumors [51]. Seventy dMMR/MSI patients were included in the study and 5-FU-based adjuvant treatment failed to improve DFS (HR 1.39, 95% CI: 0.46–4.15, p = 0.56) although it significantly improved DFS for pMMR/MSS patients (HR 0.67, 95% CI: 0.48–0.93, p = 0.02). To further evaluate the stage-specific predictive utility of dMMR/MSI, the study combined these patients with the previously reported dataset [68] that resulted in 1027 stage II and III patients with 165 dMMR/MSI cases. Although adjuvant chemotherapy showed a DFS benefit in stage III pMMR/MSS patients (HR 0.64, 95% CI: 0.48–0.84, p = 0.001), it did not lead to a DFS benefit in either stage II (HR 2.30, 95% CI 0.29–0.89, p = 0.09) or stage III (HR 1.01, 95% CI 0.26–0.83, p = 0.98) dMMR/MSI colon cancers. Interestingly, there was a detrimental effect on OS observed from receipt of adjuvant chemotherapy in stage II dMMR/MSI colon cancer patients (HR 2.95, 95% CI: 1.02–8.94, p = 0.04). A Korean study including 860 stage II colon cancer patients with 126 (14.7%) dMMR/MSI cases also confirmed that adjuvant chemotherapy did not improve DFS (HR 0.557, p = 0.254) in this patient population, although OS seemed to be improved (HR 0.288, p = 0.033) [69].

Analysis of 1913 stage II CRCs from the QUASAR study including 218 dMMR/MSI cases, showed that MMR status is prognostic but is not predictive for the outcome of adjuvant chemotherapy (odds ratio (OR) 0.81, 95% CI: 0.29–2.22) [50]. However, this study had a very small number of events (only 15) which makes it difficult to interpret the findings. Another study pooled data from two adjuvant trials (CALGB 9581 and 89803) that included 1852 patients of which 330 were dMMR/MSI and included 199 (21.1%) stage II and 131 (14.3%) stage III CRC patients. MMR status was found to be prognostic but not predictive of outcome of adjuvant treatment consisting of infusional 5-FU with an irinotecan-based regimen) [70].

Another study evaluated the predictive utility of dMMR/MSI in 2141 stage II and III colon cancer patients of which 344 were dMMR/MSI and were treated with 5-FU-based adjuvant chemotherapy [53]. This study found that 5-FU-based adjuvant treatment was associated with a reduced 5-year recurrence rate (22% versus 37%, p = 0.044) especially at distant sites (11% versus 29%, p = 0.011), including the liver (22% versus 56%, p = 0.005). The benefit of adjuvant chemotherapy was limited to stage III disease. A subgroup analysis suggested that the benefit of 5-FU-based adjuvant treatment among dMMR/MSI stage III tumors was limited to patients with suspected hereditary, but not sporadic dMMR/MSI CRCs.

Adjuvant treatment for CRC evolved and fluorouracil, leucovorin, and oxaliplatin (FOLFOX) became the standard of care after the landmark MOSAIC study (multicenter international study of oxaliplatin/5-fluorouracil/Leucovorin (LV) in the adjuvant treatment of colon cancer) which showed benefits in DFS and OS for the addition of oxaliplatin to the 5-FU/leucovorin regimen [71].

A small retrospective study of 233 stage III colon cancer patients included 32 dMMR/MSI cases. Patients had either 5-FU/LV (n = 20) or FOLFOX (n = 12) as adjuvant treatment [72]. The addition of oxaliplatin was associated with improved DFS in dMMR/MSI patients compared to 5-FU/LV only treatment (HR 0.17, 95% CI: 0.04–0.68, p = 0.01). In an update of the MOSAIC study with 9.5 years median follow-up, 95 dMMR/MSI stage II/III CRC cases were identified among 1008 patients. FOLFOX as adjuvant treatment was associated with a trend toward improved DFS (HR 0.48, 95% CI: 0.21–1.12, p = 0.088) and OS (HR 0.41, 95% CI: 0.16–1.07, p = 0.069) among patients with dMMR/MSI tumors [73]. A retrospective study known as AGEO included 433 dMMR/MSI stage II and III colon cancer patients and evaluated the impact of adjuvant 5-FU or FOLFOX treatment [74]. In the study population, oxaliplatin-based adjuvant chemotherapy was associated with a trend toward improved DFS (HR 0.13 95% CI 0.02–1.05, p = 0.06) while 5-FU/LV alone did not show a DFS benefit. A subgroup analysis showed that the DFS benefit from oxaliplatin-based adjuvant treatment was limited to stage III colon cancers (HR 0.41, 95% CI: 0.19–0.87, p = 0.02). Most recently, a pooled analysis of C-07 and MOSAIC trial including 1625 stage III colon cancer patients with 185 dMMR/MSI cases revealed that the addition of oxaliplatin to fluoropyrimidine adjuvant treatment significantly improved OS (HR 0.52, 95% CI: 0.28–0.93) and DFS (HR 0.47, 95% CI: 0.27–0.82) compared to fluoropyrimidine alone treatment. Interestingly, the survival benefit from oxaliplatin based adjuvant treatment seemed to be more prominent in dMMR/MSI patients [75]. These data suggested dMMR/MSI stage III CRC patients benefit from oxaliplatin-based adjuvant treatment.

Given the favorable prognosis of dMMR/MSI in stage II CRC and lack of clear evidence of a survival benefit from 5-FU-based adjuvant treatment, the current guidelines do not recommend adjuvant treatment for stage II dMMR/MSI colon cancer. For stage III CRC with dMMR/MSI, oxaliplatin-based adjuvant treatment is considered standard of care due to the diminished prognostic benefit for dMMR/MSI in these tumors and evidence of survival benefit from oxaliplatin-based treatment. Table 2 lists recent studies evaluating predictive utility of dMMR/MSI for adjuvant chemotherapy.

Table 2. Recent studies evaluating the predictive value of dMMR/MSI in colorectal cancer.

Table
Study Details Year Publication Disease Stage Patient Number dMMR/MSI pts Adjuvant Chemo Endpoint HR (95% CI) p Value
Pooled analysis 2003 II, III 570 95 5-FU OS (no adjuvant) 0.31 (0.14–0.72) 0.004
OS (with adjuvant) 1.07 (0.62–1.86) 0.80
II 312 58 5-FU OS (with adjuvant) 3.28 (0.86–12.48) NR
III 258 37 OS (with adjuvant) 1.42 (0.36–5.56) NR
Pooled analysis 2010 II and III 457 70 5-FU DFS (with adjuvant) 1.10 (0.42–2.91) 0.85
1027 165 DFS, stage II (with adjuvant) 2.30 (0.85–6.24) 0.09
DFS stage III (with adjuvant) 1.01 (0.41–2.51) 0.98
OS stage II (with adjuvant) 2.95 (1.02–8.94) 0.04
Korean study 2015 II 860 126 5-FU DFS (with adjuvant) 0.557 0.254
OS (with adjuvant) 0.288 0.033
QUASAR 2011 II 1913 218 5-FU OR (for recurrence) 0.81 (0.29–2.22) NR
Pooled analysis 2011 II and III 2141 344 5-FU 5-year recurrence rate * NR 0.044
Distant recurrence * NR 0.011
Liver recurrence * NR 0.005
Retrospective study 2010 III 233 32 FOLFOX vs. 5-FU/LV DFS 0.17 (0.04–0.68) 0.01
MOSAIC subgroup study 2015 II and III 1008 95 FOLFOX vs. 5-FU/LV DFS 0.48 (0.21–1.12) 0.088
OS 0.41 (0.16–1.07) 0.069
AGEO study 2016 II and III 433 433 FOLFOX vs. 5-FU/LV vs. surgery alone DFS ** 0.41 (0.19–0.87) 0.02

Abbreviations: HR: hazard ratio; CI: confidence interval; 5-FU: Fluorouracil; OS: overall survival; NR: not reported; DFS: disease free survival; QUASAR: Quick and Simple and Reliable; OR: odds ratio; FOLFOX: Fluorouracil, Leucovorin, and oxaliplatin. * Only listed stage III cancers (1183 patients with 180 dMMR/MSI cases). ** Only for stage III disease

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