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Abstract

High microsatellite instability (MSI-H)/deficient mismatch repair (dMMR) phenotype is a distinct molecular signature across gastrointestinal cancers characterized by high tumor mutational burden and high neoantigen load. Tumors harboring dMMR are highly immunogenic and heavily infiltrated by immune cells; consequently, they are uniquely vulnerable to therapeutic strategies enhancing immune antitumor response such as checkpoint inhibitors. The MSI-H/dMMR phenotype arose as a powerful predictor of response to immune checkpoint inhibitors with evidence supporting significantly improved outcomes in the metastatic setting. On the other hand, the genomic instability characteristic of MSI-H/dMMR tumors appears to be associated with decreased sensitivity to chemotherapy, and the benefits of standard adjuvant or neoadjuvant chemotherapy approaches in this subtype are being increasingly questioned. Here, we review the prognostic and predictive impact of MMR status in localized gastric and colorectal cancers, and highlight the emerging clinical data incorporating checkpoint inhibitors in the neoadjuvant setting.

Keywords

colorectal cancer gastric cancer microsatellite instability mismatch repair deficiency neoadjuvant therapy

Introduction

The mismatch repair system is a highly conserved DNA repair mechanism protecting the integrity of the genome against mismatching errors arising during DNA replication. Failure to repair mismatching errors leads to the accumulation of frameshift mutations and generation of several abnormal tumor-specific peptides. These immunogenic neoantigens are recognized as ‘non self’ by T-lymphocytes and trigger a host immune antitumor response. Tumors evolve over time under the selective pressure of the immune system and eventually escape immune surveillance through various mechanisms promoting self-tolerance.¹ The discovery of immune checkpoints and the development of immune checkpoint inhibitors (ICIs), namely anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) and anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) monoclonal antibodies, has emerged as an effective strategy to restore antitumoral immunity by ‘removing the brakes’ off the immune system. Checkpoint inhibitors have revolutionized the management of metastatic microsatellite instability (MSI)/deficient mismatch repair (dMMR) tumors across tumor sites.^2,3 MSI is detected in up to 20% of localized gastric cancer (GC) and colorectal cancer (CRC) and presents unique molecular and clinical characteristics calling into question the current standard of care for early-stage disease. The incorporation of ICIs in the armamentarium of cancer therapy in the neoadjuvant setting is an active area of research. In this review, we highlight the opportunities and challenges for novel neoadjuvant strategies, building on retrospective and emerging clinical data incorporating ICIs in the treatment of stage II–III dMMR GC and CRC.

Testing for MSI

Function of the MMR system can be assessed by immunohistochemistry (IHC) or molecular testing, including classic polymerase chain reaction (PCR) and novel next-generation sequencing (NGS) approaches. The four critical genes involved in this pathway (MLH1, MSH2, MSH6, and PMS2) encode proteins functioning as heterodimers.

Under normal circumstances, MSH2 forms a heterodimer with MSH3 or MSH6 to detect and bind single base mismatches or short insertions and deletions. MLH1 partners with PMS2, PMS1, or MLH3 to form a second heterodimer responsible for excision and resynthesis of the corrected DNA bases. Loss of function of any of these genes through mutation or epigenetic silencing results in a failure to repair mismatches and accumulation of mutations. This is reflected in the genome by MSI. Microsatellites are short tandem repeats distributed throughout the genome and identical in all cells from an individual. They are prone to mismatch errors, PCR can detect variability (instability) in the length of these repeated sequences arising as a consequence of dMMR. Alternatively, loss of function of genes involved in the MMR machinery can be easily identified by lack of protein expression on IHC. These two methods are equally valid as initial screening tests and have shown a high degree of concordance.^4,5 IHC is generally recommended as an initial screening test due to its wide availability, lower cost, and rapid turnaround time. NGS is emerging as an alternative molecular method to assess MSI. Its main advantages are the possibility to identify the rare cases of dMMR caused by alternative mechanisms and the possibility to carry a complete biomarker analysis in one test. It has shown high concordance with PCR testing when carried both on tissue and plasma [circulating tumor DNA (ctDNA)] samples.^6,7 However, ctDNA testing for MSI is insensitive if the plasma tumor fraction is below 0.2%.⁷ Despite these promising results, the use of NGS for determination of MSI status requires further validation and should be carried only in centers experienced with these techniques, as recommended by the current European Society of Medical Oncology guidelines.⁸ From now on, we will refer to the state of MMR deficiency or MSI-high using the term dMMR to avoid confusion with testing methods and to refer more generally to the phenotype. Mismatch repair status has major implications as a prognostic and predictive biomarker, and testing should be requested at diagnosis for all colorectal and gastric adenocarcinomas.

Mismatch repair deficiency in GC

GC with MSI is one of the four molecular subtypes described by either The Cancer Genome Atlas or the Asian Cancer Research Group.^9,10 Its prevalence is stage dependent and has been reported in up to 20% of node-negative cases compared to less than 5% in metastatic disease.¹⁰ Mismatch repair in GC is most often caused by acquired epigenetic silencing of the MLH1 promoter,^11–13 thought to be an early event in gastric carcinogenesis.^12,14,15 Methylation events accumulate during GC progression¹⁶ and MLH1 promoter hypermethylation may also rarely occur as a late event in tumor evolution,¹⁷ potentially leading to significant tumor heterogeneity in the dMMR phenotype.¹⁸ In fact, discrepant MMR protein expression between the primary tumor and nodal metastases has been reported¹⁹ and significant MLH1 expression heterogeneity has been reported in 8.9% of dMMR GCs.²⁰ Whether this tumoral heterogeneity impacts clinical outcomes remains unknown. MLH1 promoter hypermethylation is also the leading cause of MMR deficiency in familial cases and cannot be used to differentiate somatic versus germline GC,¹³ unlike CRC. dMMR GCs are enriched with KRAS mutations, they generally lack targetable amplifications (HER2) and are not associated with BRAF V600E mutations.^9,21,22

Prognostic and predictive role of dMMR in GC

dMMR status is associated with improved outcomes in resectable GC compared to microsatellite stable (MSS)/proficient mismatch repair (pMMR). This evidence comes from several post hoc analysis of randomized controlled trials²³ and one meta-analysis of 48 studies.²⁴ More recently, the role of neoadjuvant and adjuvant chemotherapy has been challenged by a few reports assessing the predictive value of MSI status on the efficacy of chemotherapy (Table 1). Post hoc analysis of the CLASSIC,²⁵ MAGIC,²⁶ and D1/D2-CRITICS²⁷ trials have been published. Choi et al. found no improvement in overall survival (OS) with adjuvant chemotherapy with capecitabine and oxaliplatin after R0 resection for the 40 dMMR patients included in the CLASSIC trial. In the MAGIC trial, none of the 12 dMMR patients randomized to perioperative chemotherapy with epirubicin, cisplatin, and fluorouracil showed a pathological response and the 10 dMMR patients treated with surgery alone had an excellent survival (median not reached compared to 20.5 months for MSS patients, hazard ratio (HR) 0.42, p = 0.09). Similarly, post hoc analysis of the D1/D2 and CRITICS trials confirmed the positive prognostic value of the dMMR status and found a poor pathological response [defined as tumor regression grade (TRG) 4, 5 or progression] in 24 of 27 dMMR patients after preoperative chemotherapy with epirubicin, cisplatin or oxaliplatin, and capecitabine (ECX or EOX). The three patients who had a response had substantial mucinous differentiation. Finally, Pietrantonio et al. conducted an individual patient data meta-analysis from four randomized trials (MAGIC, CLASSIC, ARTIST,²⁸ and ITACA-S²⁹) to further clarify the prognostic and predictive value of the dMMR subtype.³⁰ Patients with dMMR GC (n = 121) had superior disease-free survival (DFS) and OS at 5 years but did not appear to benefit from the addition of chemotherapy to surgery, while the pMMR subgroup had improved outcomes with the addition of chemotherapy. Five-year DFS for dMMR patients was 70% with chemotherapy and surgery versus 77% with surgery alone [HR: 1.27; 95% confidence interval (CI): 0.53–3.04] and 5-year OS was 75% versus 83% (HR 1.50; 95% CI: 0.55–4.12). Among these studies, only ITACA-S incorporated a taxane in the experimental arm. The addition of taxanes is now standard of care and appears to improve responses regardless of MSI status. Haag et al. reported a retrospective analysis of 101 patients undergoing perioperative chemotherapy, 58 had received fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) including five of nine dMMR patients.³¹ The rate of poor responders (defined as TRG 2 and 3) did not differ significantly between pMMR and dMMR patients (79.1% versus 88.9%, p = 0.683). Preliminary results from the DANTE phase II trial showed a similar pathological response to FLOT chemotherapy in dMMR and pMMR tumors, with 47% of the 25 dMMR patients achieving a complete or subtotal regression (TRG1 a/b) compared to 44% of the 295 randomized patients.³² Subanalysis of the phase III JACCRO-G7 trial³³ and FLOT4 trial³⁴ has not been published.

Table 1.

Outcomes of patients with dMMR stage II–III GC or GEJ cancer.

Study n (%)	Intervention	Pathological response (becker) (dMMR versus pMMR)	DFS (months) (versus MSS/pMMR)	OS (months) (versus MSS/pMMR)
Retrospective cohort analysis³⁵ 54 (8.8%)	5-FU-based adjuvant CT	–	No difference	–
CLASSIC²⁵ (post hoc) 40 (6.8%)	Adjuvant CAPOX	–	5 years, 83.9 versus 85.7%, p = 0.931	–
CRITICS²⁷ (post hoc) 27 (5.9%)	Preoperative ECX/EOX, Adjuvant CT/CRT	TRG 1–2, 7.4% versus 10.5%	–	5 years, 51.3% versus 36.7%, HR: 0.67, p = 0.14
MAGIC²⁶ (post hoc) 22 (8.7%)	Perioperative ECF	TRG 1–2, 0% versus 14%	–	Median OS, No CT: NR versus 20.5, HR: 0.42 p = 0.09, With CT: 9.6 versus 19.5 m, HR: 2.18 p = 0.03
Meta-analysis³⁰, Individual patient data 121 (7.8%)	Perioperative CT (FLOT not included)	–	5 years, 71.8% versus 52.3%, HR: 0.53 p < 0.001, No benefit from CT for MSI-H/dMMR	5 years, 77.5% versus 59.3%, HR: 0.56 p = 0.008, No benefit from CT for MSI-H/dMMR
Retrospective analysis³¹ 9 (8.9%)	Neoadjuvant CT (FLOT in 57.4%)	TRG 1–2, 11.1% versus 49.5%	Median RFS, NR versus 21.4, p = 0.188	Median OS, NR versus 38.6, p = 0.014
DANTE³² 23 (7.8%)	Perioperative FLOT ± atezolizumab	pCR (TRG 1a), 27 versus* 24%*, 50 versus* 25%**	–	–
NEONIPIGA³⁶ 32 (100%)	Neoadjuvant, Ipilimumab + nivolumab	pCR (TRG 1a) 58.6%	1 year 93.8%	1 year 96.9%

TRG 1a: pCR; TRG 1b: <10% vital tumor; TRG2: 10–50% vital tumor.

Central assessment.

pCR in all randomized patients (295 patients including 25 dMMR patients).

5-FU, 5-fluorouracil; CAPOX, capecitabine and oxaliplatin; CT, chemotherapy; CRT, chemoradiotherapy; DFS, disease-free survival; dMMR, deficient mismatch repair; ECF, epirubicin, cisplatin and fluorouracil; FLOT, fluorouracil, leucovorin, oxaliplatin, and docetaxel; GC, gastric cancer; GEJ, gastro-esophageal junction; HR, hazard ratio; MSS, microsatellite stable; NR, not reached; OS, overall survival; pCR, pathological complete response; pMMR, proficient mismatch repair; RFS, recurrence-free survival.

Taken together, these data suggests that dMMR tumor status is associated with decreased benefit from adjuvant or neoadjuvant chemotherapy, owing to both improved baseline prognosis and decreased sensitivity to chemotherapy compared to patients with pMMR GC. The current recommended standard of care for fit patients with locally advanced (cT2-T4 or N+) GC is either perioperative chemotherapy typically with FLOT or upfront surgery followed by adjuvant chemotherapy; this indication is irrespective of biomarker analysis.^37,38 Knowledge of MMR status adds relevant prognostic information and may be used for individualized therapeutic decision-making. Patients with resected early-stage, node-negative dMMR GC appear to have an excellent prognosis with surgery alone and may potentially avoid chemotherapy after multidisciplinary discussion. While an absence of benefit from neoadjuvant chemotherapy cannot be definitively concluded in view of the limited numbers and retrospective nature of available data, considerable debate remains as to whether patients with stage II-III dMMR GC otherwise eligible for perioperative chemotherapy would be better served by proceeding directly to surgery. Further prospective data are needed to conclusively change the standard of care for stage II-III dMMR GC.

The use of checkpoint inhibitors in the neoadjuvant setting

Given the impressive efficacy of ICIs in metastatic dMMR GC²³ and previously mentioned caveats with neoadjuvant chemotherapy, it is natural to incorporate these agents at earlier stages. Several trials adding a PD-1/PD-L1 inhibitor to a perioperative chemotherapy backbone are currently open to accrual for patients with gastric or gastro-esophageal junction (GEJ) adenocarcinoma and will include a minority of patients with dMMR tumors. Among these, Al-Batran et al. reported a complete pathological response (TRG1a) rate of 63% (5/8) with the addition of atezolizumab to FLOT in the DANTE trial, compared to 27% (4/15) with FLOT alone.³² A chemotherapy-free approach using dual ICIs was also demonstrated to be feasible and highly effective in the NEONIPIGA and INFINITY phase II trials.^36,39 In total, 32 patients with cT2T4Nx dMMR gastric or GEJ tumors were treated with 12 weeks of neoadjuvant nivolumab and low-dose (1 mg) ipilimumab followed by surgery and an additional 9 months of adjuvant nivolumab in the NEONIPIGA trial. All but one patient underwent surgery, 58.6% achieved a pathological complete response (pCR). Treatment was well tolerated, the rates of surgical complications and adverse events were as expected with 25% grade 3–4 toxicity. At a median follow-up of 12 months, 30 (93.7%) patients remained alive without relapse. Similarly, 15 patients received a single dose of tremelimumab and 12 weeks (3 doses) of neoadjuvant durvalumab followed by surgery in cohort 1 of the INFINITY trial, pCR rate was 60%. Two patients had disease progression after a median follow-up of 13.4 months, one had heterogeneous pMMR/dMMR status.

Is this the dawn of a new surgery-free era?

There is a strong biological rationale to incorporate ICIs in the management of dMMR early-stage GC, preliminary results from ongoing trials are encouraging and truly have the potential to change current standard of care. Surgery has been the cornerstone of potentially curative treatment and the integration of systemic therapy has improved outcomes but has never been considered curative by itself. The unprecedented rates of pCR in the NEONIPIGA trial coupled with the durability of responses observed in the metastatic setting are now challenging the need for surgery for the subset of patients who achieve a complete clinical response, particularly when considering the significant morbidity of gastrectomy and long-term consequences in terms of quality of life. Many questions remain to be answered before this paradigm shift can be implemented in clinical practice. The main caveat for nonoperative management of GC is the suboptimal negative predictive value of preoperative staging and/or surveillance⁴⁰ – the incorporation of ctDNA to surveillance protocols may mitigate this to some extent. Longer follow-up will also be required to determine the durability of response, patterns of recurrence and feasibility of salvage gastrectomy. Cohort 2 of the phase II INFINITY trial (NCT04817826) will help answering these questions by investigating the use of dual checkpoint inhibitor blockade with durvalumab and tremelimumab for resectable dMMR gastric or GEJ adenocarcinomas. The protocol includes a non-operative management strategy for patients achieving clinical complete response (cCR) after 12 weeks of therapy.⁴¹ Finally, the best strategy to achieve response and long-term DFS with or without surgery remains to be explored. Based on a limited number of patients and limited follow-up, response rates to induction chemotherapy with FLOT and anti-PD-1 for 8 weeks appear comparable to a 12-week anti-CTLA4 and anti-PD-1 regimen.^32,36 In the metastatic setting, response rates (70 versus 55%) and OS (not reached versus 38.9 months) favored the combination of ipilimumab and nivolumab over chemotherapy with nivolumab for the 34 dMMR patients treated with ICIs in the phase III trial Checkmate-649.⁴² Table 2 summarizes currently active clinical trials incorporating ICIs in the management of patients with resectable gastric or GEJ adenocarcinoma.

Table 2.

Active trials for patients with stage II–III gastric–GEJ adenocarcinoma.

Trial	Phase	N	Region	Control arm	Experimental arm	Primary outcome
MSI-H/dMMR only
NEONIPIGA37, NCT04006262	II	32	France	–	Ipilimumab + nivolumab	pCR
INFINITY40, NCT04817826	II	31	Italy	–	Durvalumab + tremelimumab	pCR***, 2 year cCR
All comers–perioperative
KEYNOTE 585⁴³, NCT03221426	III	800	International	FP/XP/FLOT + placebo	FP/XP/FLOT + pembrolizumab	pCR, OS, EFS
MATTERHORN⁴⁴, NCT04592913	III	900	International	FLOT + Placebo	FLOT + durvalumab	EFS
DANTE³², NCT03421288	II-III	295	Germany, Switzerland	FLOT	FLOT + atezolizumab	pCR, DFS
IMAGINE, NCT04062656	II	44	Germany	–	Two cycles of nivolumab: Responders: Nivolumab Non-responders: FLOT + nivolumab Nivolumab + relatlimab	pCR
NICE, NCT04744649	II	80	China	XELOX/SOX	XELOX/SOX + S001 (anti-PD-1)	Pathological response
ICONIC⁴⁵, NCT03399071	II	40	UK	–	FLOT + avelumab	pCR
NCT04908566	II	124	China	SOX + anti-PD-1	FOLFIRINOX + anti-PD-1	Pathological response
NCT04354662	II	36	China	–	FLOT + toparlimab	pCR
All comers–adjuvant
ATTRACTION-05*, NCT03006705⁴⁶	III	700	Asia	XELOX/SOX	XELOX/SOX + nivolumab	RFS
VESTIGE**, NCT03443856⁴⁷	II	240	Europe	–	Ipilimumab + nivolumab	DFS

cCR defined as the absence of residual disease on. Radiological examinations, tissue and liquid biopsies, in the absence of salvage gastrectomy.

p Stage III.

yp N+ or R1.

***

pCR and ctDNA negative.

ctDNA, circulating tumor DNA; DFS, disease-free survival; EFS, event-free survival; FLOT, fluorouracil, leucovorin, oxaliplatin, and docetaxel; OS, overall survival; pCR, pathological complete response; PD-1, programmed cell death protein 1; RFS, recurrence-free survival.

Mismatch repair deficiency in CRC

Mismatch repair deficiency in CRC arises by one of two distinct mechanisms.⁴⁸ Germline mutation of one of the genes involved in MMR (Lynch syndrome) accounts for approximately 25% of cases, while sporadic cases account for approximately 75% of cases and are attributed to a loss of expression of MLH1 caused by hypermethylation of the MLH1 promoter, associated with the CpG island methylator phenotype and BRAF V600E mutation.⁴⁹ The presence of either of these two molecular features essentially excludes Lynch syndrome. Right-sided tumors tend to be sporadic while rectal tumors tend to be associated with Lynch syndrome. dMMR is found in 15–20% of cases in stage II, 10–15% in stage III, and 4–5% in stage IV colon cancer,^50,51 the prevalence is lower in rectal cancer across all stages (1–10%).^52,53 dMMR is an early event in colorectal carcinogenesis even in sporadic cases and although inter-tumoral heterogeneity of MMR status has been a subject of debate, discordance between primary tumor and metastases seems extremely rare.⁵⁴ dMMR CRC is enriched with mutations in RAS, BRAF, HER2, and NTRK fusions; all are considered mutually exclusive.^55,56

Prognostic and predictive value of dMMR for adjuvant therapy in CRC

A number of retrospective studies and post hoc analysis have evaluated the role of MMR as a prognostic and predictive biomarker in stage II–III CRC,⁵⁷ a complete review would be beyond the scope of this article. The largest evidence comes from two separate pooled individual patient data analysis of the Adjuvant Colon Cancer Endpoint (ACCENT) database,^50,51 results are summarized in Table 3. dMMR confers an improved prognosis at earlier stage, such as N0 (stage II, HR: 0.27, 95% CI: 0.10–0.74, p = 0.011) or N1 disease [1–3 involved nodes, adjusted HR (aHR): 0.65, 95% CI: 0.45–0.93, p = 0.0132], but not for N2 disease (>3 involved nodes, aHR: 1.22, 95% CI: 0.94–1.59, p = 0.1403). The presence of the BRAF V600E mutation does not appear to confer an adverse prognosis for dMMR patients with stage II–III colon cancer,^51,58,59 although it may mitigate the positive prognosis associated with dMMR⁶⁰ in stage III disease. The association between dMMR status and lack of efficacy of 5-fluorouracil (5-FU)-based adjuvant chemotherapy in colon cancer has been a matter of debate for the past decade. In an analysis by Sargent et al.⁶¹ in 2010, 102 patients with dMMR stage II colon cancer had worse survival when treated with adjuvant 5-FU-based adjuvant chemotherapy compared to surgery alone (HR: 2.95, 95% CI: 1.02–8.54, p = 0.04). Subsequent pooled analysis and meta-analyses have confirmed the more favorable prognosis of stage II dMMR colon cancer and lack of benefit from adjuvant chemotherapy; however, no detrimental effect was observed.^50,57 Current guidelines do not support routine adjuvant chemotherapy for patients with stage II dMMR colon cancer while oxaliplatin-based chemotherapy may be considered for high-risk stage II disease. Three to six months of oxaliplatin-based chemotherapy per usual standards is recommended for patients with dMMR stage III colon cancer.^62,63 The addition of oxaliplatin significantly improved OS compared to FP alone (HR: 0.52, 95% CI: 0.28–0.93) in the most recent ACCENT database analysis.⁵¹ Despite optimal management, it is estimated that up to 30% of patients with dMMR colon cancer will experience recurrence. The phase III POLEM⁶⁴ and ATOMIC⁶⁵ trials are investigating the addition of an anti-PD-L1 inhibitor to a chemotherapy backbone as adjuvant therapy for stage III dMMR colon cancer.

Table 3.

Predictive and prognostic value of MSI from two ACCENT pooled analysis.

	Treatment	5-year OS		HR	95% CI	p
	Treatment	dMMR	pMMR	HR	95% CI	p
Stage II
Sargent et al.⁵⁰	Surgery alone (n = 307)	90%	78%	0.27	0.10–0.74	0.011
	5-FU (n = 1155)	88%	87%	0.87	0.61–1.26	0.469
Stage III
Sargent et al.⁵⁰	Surgery alone (n = 264)	59%	54%	0.69	0.35–1.36	0.283
	5-FU (n = 2723)	77%	71%	0.79	0.65–0.97	0.023
Cohen et al.⁵¹	Surgery alone (n = 202)	73%	53%	0.58	0.21–1.63	0.2648
	FP-based (n = 204)	74%	67%	0.60	0.28–1.25	0.1459
	FP + oxaliplatin (n = 4250)
	N1	89.9%	87.1%	0.65	0.45–0.93	0.0132
	N2	69.1%	72.1%	1.22	0.94–1.59	0.1403
	Low risk*	91.6%	88.7%	0.63	0.42–0.95	0.0186
	High risk*	69.8%	72.6%	1.13	0.88–1.45	0.3424
	Surgery ± FP-based	dMMR: 73% versus 74% (n = 49)		1.27	0.34–4.81	0.7218
	FP-based ± oxaliplatin	dMMR: 75.6% versus 85.0% (n = 185)		0.52	0.28–0.93	0.0254

Low risk: T1-3N1, high risk: T4 and/or N2.

95% CI, 95% confidence interval; dMMR, deficient mismatch repair; FP, fluoropyrimidine; HR, hazard ratio; MSI, microsatellite instability; OS, overall survival; pMMR, proficient mismatch repair; 5-FU, 5-fluorouracil.

Evolving treatment landscape in the neoadjuvant setting for CRC

Colon cancer and rectal cancer are distinct entities when it comes to neoadjuvant therapy due to obvious anatomical considerations. Until recently, there has been little interest in neoadjuvant therapy for colon cancer because of the low rates of local recurrence and lower rates of surgical morbidity compared to rectal cancer. Nevertheless, surgery is still associated with complications and quality-of-life deterioration,⁶⁶ especially in elderly or frail patients. The role of neoadjuvant chemotherapy with 6 weeks of FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin) administered preoperatively for locally advanced colon cancer was investigated in the FOXTROT phase III trial,⁶⁷ a total of 6 months of chemotherapy was planned for both arms. Results showed halving of the rate of incomplete resection (5% versus 10%) and decreased 2-year recurrence rate (16.8% versus 21.2%, HR: 0.72, 95% CI: 0.54–0.98, p = 0.037) on updated analysis. Concerns about limitations with clinical staging and the potential for overtreatment with oxaliplatin, especially in frail or elderly patients, have limited clinical applicability and further investigation is ongoing.⁶⁸

Rectal cancer is typically managed with multimodality therapy including radiation, surgery and chemotherapy. Research over the past few years has focused on decreasing long-term treatment morbidity without compromising efficacy. Recommendations for systemic chemotherapy in rectal cancer were traditionally extrapolated from colon cancer with the goal of increasing long-term survival, systemic therapy is now also regarded as an additional tool to maximize downstaging for consideration of organ-sparing nonoperative management. Radiation and resection of the rectum are associated with significant long-term complications and disabilities^69–71 that could potentially be avoided for a subset of patients with earlier use of effective systemic therapy.^72,73 cCR in rectal cancer is increasingly recognized as a surrogate marker for pCR and DFS^74–77 regardless of the strategy used to obtain clinical response. This is highly relevant when considering neoadjuvant strategies for dMMR CRC cancer given their unique response (or lack of response) to radiation, chemotherapy, and immunotherapy. Neoadjuvant therapy in CRC has two main goals: to maximize tumor downstaging to facilitate or avoid resection and to minimize the risks of locoregional and distant recurrence.

Patients with dMMR CRC appear to have decreased sensitivity to chemotherapy but not to chemoradiation. A systematic review and meta-analysis of nine studies including 5877 patients showed no association between dMMR status and pCR after chemoradiation (10.1% versus 6.6% for dMMR versus pMMR, odds ratio: 1.38, 95% CI: 0.7–2.72).⁷⁸ In a retrospective analysis of 50 patients with dMMR rectal cancer treated with neoadjuvant therapy, 93% of patients (13/16) experienced tumor downstaging after chemoradiation but 29% (6/21) had disease progression while receiving neoadjuvant chemotherapy with fluorouracil and oxaliplatin.⁵³ Similarly, response to 6-week neoadjuvant FOLFOX or CAPOX in the FOXTROT trial was poor with only 7% (8/115) of dMMR patients achieving moderate or greater histological tumor regression. The data suggest incorporating chemotherapy as part of a total neoadjuvant approach may not provide significant downstaging over radiation or chemoradiation alone, and patients should be followed closely given the risk of progressive disease. It is worth emphasizing that patients with stage III dMMR CRC still qualify for oxaliplatin-based chemotherapy per usual recommendations based on improved OS, as discussed previously.

If chemotherapy is not the optimal path to optimize local control and treatment de-escalation, ICIs are showing promising results for patients with dMMR CRC. In the NICHE phase II study,⁷⁹ 32 patients with dMMR colon cancer (81% stage III, 67% sporadic) were treated with a single dose of the anti-CTLA4 ipilimumab and two doses of the anti-PD-1 nivolumab followed by surgery. The observed response rate was 100% with 69% (26/32) achieving pCR and 97% (31/32) achieving major pathological response (<10% viable tumor cells). Poor correlation was noted between radiological assessment and pathological response. All patients are alive and disease-free after a median follow-up of 25 months. In the PICC phase II trial,⁸⁰ 34 patients with locally advanced dMMR colon cancer were randomized to toripalimab with or without celecoxib for 12 weeks followed by surgery and an additional 6 months of adjuvant therapy with the same regimen. pCR rate was 76.5% (26/34), 88% with toripalimab and celecoxib and 65% without celecoxib. All patients are alive and disease-free at a median follow-up of 14.9 months. Sequential use of five cycles of nivolumab after chemoradiation was investigated in the phase II VOLTAGE-A trial⁸¹ for 37 patients with pMMR and 5 patients with dMMR locally advanced rectal cancer (LARC). The addition of nivolumab was safe, two patients had grade 3 immune-related toxicities, one myasthenia, and one interstitial nephritis. Two additional patients had grade 2 toxicity, one colitis, and one peripheral neuropathy. Three of the five patients (60%) with dMMR LARC achieved a pCR. Most recently and to much fanfare, the results from a single-center phase II study investigating the anti-PD-1 agent dostarlimab for 6 months for locally advanced dMMR rectal cancer were recently published in the New England Journal of Medicine.⁸² Patients achieving a cCR (determined both radiographically and endoscopically) were to undergo a watch-and-wait strategy, while those with residual disease were to be treated with standard chemoradiation and surgery or nonsurgical management according to clinical response. At the time of publication, 12 patients have completed treatment with a minimal follow-up of 6 months, with a remarkable complete clinical response rate of 100% and no patient underwent chemoradiation or surgery. Responses were observed early with 81% of patients showing symptomatic improvement by week 9, and most patients achieving at least near complete response at the first assessment at 3 months.

It is not often in the field of medical oncology that we see response rates of 100%. While the follow-up is still limited, there is good reason to believe that these responses will be durable, extrapolating from data in the metastatic setting.^83,84 For the first time, systemic therapy offers the potential for cure without the need for resection or radiation. The safety profile of ICI therapy compares favorably with the morbidity entailed by radiation or surgical resection. There are no new safety signals from the few trials previously mentioned, and the rate of severe or permanent toxicity from ICIs can be expected to be similar to what is observed in the metastatic setting or across tumor sites. Fatal toxicity rate from ICIs is 0.4–1.2%, the rate of chronic immune-related adverse events (irAEs) may be as high as 42.9%, mostly mild endocrinopathies (hypothyroidism) and rheumatological toxicities.⁸⁵ Chronic irAEs are still poorly defined and are the focus of ongoing research, severe permanent disabilities are fortunately rare (<5%). Although very promising, caution is still advised before ICIs become a standard of care in early-stage dMMR CRC: the conclusions are limited by the very small number of patients from a single center, and follow-up is still short. That said, clinicians are now facing a difficult dilemma where the usual standard of care designed for pMMR tumors is suboptimal but the emerging ICI alternative challenges 30 years of evidence-based medicine with available results based on a limited number of patients with minimal follow-up. In the metastatic setting, 29.4% of patients receiving first-line pembrolizumab had disease progression as best response in the landmark Keynote-177 trial.⁸⁴ Some of these events may be accounted for by radiological pseudoprogression⁸⁶; however, there is still a crossing of the survival curves within the first 6 months. No patient experienced primary resistance in the neoadjuvant setting but the small number of patients enrolled cannot provide a reliable estimate. How much evidence is required to safely change practice? At the very least, longer follow-up is needed and results will have to be reproduced in larger multi-center prospective cohorts. Even if randomized clinical trials may not be feasible or required to change standard of care in this case, further evidence is needed to determine the best treatment regimen, optimal duration of treatment, and to provide more information to weigh the risks and benefits of each approach.

Conclusion

In summary, dMMR GC and CRC are distinct entities with unique clinical characteristics and vulnerability to ICIs. Current standards of care were designed to optimize outcomes for pMMR cancers and are imperfectly suited for dMMR cancers. MMR ascertainment is recommended for all early-stage CRC and GC. ICIs demonstrate remarkable activity in the neoadjuvant setting with unprecedented rates of pCR, questioning the need for well-established multimodality approaches including surgery. Although it remains to be seen whether these current exciting results will translate into long-term benefits, neoadjuvant immunotherapy is feasible and offers tremendous promise for patients with dMMR cancers. These data are still considered preliminary – longer follow-up is needed and optimal duration and combination strategies remain to be determined. Hence, caution is advised before de-escalating standard of care treatments with proven survival benefit. Where available, enrollment to ongoing clinical trials is encouraged.

Footnotes

Acknowledgements

Not applicable.

Declarations

ORCID iD

Mélina Boutin

References

Dunn

Bruce

Ikeda

, et al. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 2002; 3: 991–998.

André

Shiu

K-K

Kim

, et al. Pembrolizumab in microsatellite-instability–high advanced colorectal cancer. N Engl J Med 2020; 383: 2207–2218.

Marabelle

Ascierto

, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair–deficient cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol 2020; 38: 1–10.

Svrcek

Lascols

Cohen

, et al. MSI/MMR-deficient tumor diagnosis: which standard for screening and for diagnosis? Diagnostic modalities for the colon and other sites: differences between tumors. Bull Cancer 2019; 106: 119–128.

Guyot D’Asnières De Salins

Tachon

Cohen

, et al. Discordance between immunochemistry of mismatch repair proteins and molecular testing of microsatellite instability in colorectal cancer. ESMO Open 2021; 6: 100120.

Shimozaki

Hayashi

Tanishima

, et al. Concordance analysis of microsatellite instability status between polymerase chain reaction based testing and next generation sequencing for solid tumors. Sci Rep 2021; 11: 20003.

Willis

Lefterova

Artyomenko

, et al. Validation of microsatellite instability detection using a comprehensive plasma-based genotyping panel. Clin Cancer Res 2019; 25: 7035–7045.

Luchini

Bibeau

Ligtenberg

MJL

, et al. ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach. Ann Oncol 2019; 30: 1232–1243.

Bass

Thorsson

Shmulevich

, et al. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 2014; 513: 202–209.

10.

Cristescu

Lee

Nebozhyn

, et al. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med 2015; 21: 449–456.

11.

Kim

Bae

, et al. Analysis of microsatellite instability, protein expression and methylation status of hMLH1 and hMSH2 genes in gastric carcinomas. Hepatogastroenterology 2009; 56: 899–904.

12.

von Loga

Woolston

Punta

, et al. Extreme intratumour heterogeneity and driver evolution in mismatch repair deficient gastro-oesophageal cancer. Nat Commun 2020; 11: 139.

13.

Leite

Corso

Sousa

, et al. MSI phenotype and MMR alterations in familial and sporadic gastric cancer. Int J Cancer 2011; 128: 1606–1613.

14.

Sugimoto

Sugai

Habano

, et al. Clinicopathological and molecular alterations in early gastric cancers with the microsatellite instability-high phenotype. Int J cancer 2016; 138: 1689–1697.

15.

Liu

H-Y

Guo

S-H

, et al. Microsatellite instability of gastric cancer and precancerous lesions. Int J Clin Exp Med 2015; 8: 21138–21144.

16.

Oue

Mitani

Motoshita

, et al. Accumulation of DNA methylation is associated with tumor stage in gastric cancer. Cancer 2006; 106: 1250–1259.

17.

Ling

Z-Q

Tanaka

, et al. Microsatellite instability with promoter methylation and silencing of hMLH1 can regionally occur during progression of gastric carcinoma. Cancer Lett 2010; 297: 244–251.

18.

Ottini

Palli

Falchetti

, et al. Microsatellite instability in gastric cancer is associated with tumor location and family history in a high-risk population from tuscany1. Cancer Res 1997; 57: 4523–4529.

19.

Mathiak

Warneke

Behrens

H-M

, et al. Clinicopathologic characteristics of microsatellite instable gastric carcinomas revisited: urgent need for standardization. Appl Immunohistochem Mol Morphol 2017; 25: 12–24.

20.

Kim

Cristescu

Bass

, et al. Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Nat Med 2018; 24: 1449–1458.

21.

van Grieken

NCT

Aoyama

Chambers

, et al. KRAS and BRAF mutations are rare and related to DNA mismatch repair deficiency in gastric cancer from the east and the west: results from a large international multicentre study. Br J Cancer 2013; 108: 1495–1501.

22.

Polom

Das

Marrelli

, et al. KRAS mutation in gastric cancer and prognostication associated with microsatellite instability status. Pathol Oncol Res 2019; 25: 333–340.

23.

Puliga

Corso

Pietrantonio

, et al. Microsatellite instability in gastric cancer: between lights and shadows. Cancer Treat Rev 2021; 95: 102175.

24.

Polom

Marano

Marrelli

, et al. Meta-analysis of microsatellite instability in relation to clinicopathological characteristics and overall survival in gastric cancer. Br J Surg 2018; 105: 159–167.

25.

Choi

Kim

Shin

S-J

, et al. Microsatellite instability and programmed cell death-ligand 1 expression in stage II/III gastric cancer: post hoc analysis of the CLASSIC randomized controlled study. Ann Surg 2019; 270: 309–316.

26.

Smyth

Wotherspoon

Peckitt

, et al. Mismatch repair deficiency, microsatellite instability, and survival: an exploratory analysis of the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial. JAMA Oncol 2017; 3: 1197–1203.

27.

Biesma

Soeratram

TTD

Sikorska

, et al. Response to neoadjuvant chemotherapy and survival in molecular subtypes of resectable gastric cancer: a post hoc analysis of the D1/D2 and CRITICS trials. Gastric Cancer 2022; 25: 640–651.

28.

Lee

Lim

Kim

, et al. Phase III trial comparing capecitabine plus cisplatin versus capecitabine plus cisplatin with concurrent capecitabine radiotherapy in completely resected gastric cancer with D2 lymph node dissection: the ARTIST trial. J Clin Oncol 2011; 30: 268–273.

29.

Bajetta

Floriani

Di Bartolomeo

, et al. Randomized trial on adjuvant treatment with FOLFIRI followed by docetaxel and cisplatin versus 5-fluorouracil and folinic acid for radically resected gastric cancer. Ann Oncol 2014; 25: 1373–1378.

30.

Pietrantonio

Raimondi

Choi

, et al. MSI-GC-01: individual patient data (IPD) meta-analysis of microsatellite instability (MSI) and gastric cancer (GC) from four randomized clinical trials (RCTs). J Clin Oncol 2019; 37: 66.

31.

Haag

Czink

Ahadova

, et al. Prognostic significance of microsatellite-instability in gastric and gastroesophageal junction cancer patients undergoing neoadjuvant chemotherapy. Int J Cancer 2019; 144: 1697–1703.

32.

Al-Batran

S-E

Lorenzen

Thuss-Patience

, et al. Surgical and pathological outcome, and pathological regression, in patients receiving perioperative atezolizumab in combination with FLOT chemotherapy versus FLOT alone for resectable esophagogastric adenocarcinoma: interim results from DANTE, a randomize. J Clin Oncol 2022; 40: 4003.

33.

Yoshida

Kodera

Kochi

, et al. Addition of docetaxel to oral fluoropyrimidine improves efficacy in patients with stage III gastric cancer: interim analysis of JACCRO GC-07, a randomized controlled trial. J Clin Oncol 2019; 37: 1296–1304.

34.

Al-Batran

S-E

Homann

Pauligk

, et al. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a ra. Lancet 2019; 393: 1948–1957.

35.

Kim

Cheong

, et al. Microsatellite instability in sporadic gastric cancer: its prognostic role and guidance for 5-FU based chemotherapy after R0 resection. Int J Cancer 2012; 131: 505–511.

36.

Andre

Tougeron

Piessen

, et al. Neoadjuvant nivolumab plus ipilimumab and adjuvant nivolumab in patients (pts) with localized microsatellite instability-high (MSI)/mismatch repair deficient (dMMR) oeso-gastric adenocarcinoma (OGA): the GERCOR NEONIPIGA phase II study. J Clin Oncol 2022; 40: 244.

37.

Ajani

D’Amico

Bentrem

, et al. Gastric cancer, version 2.2022, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Netw 2022; 20: 167–192.

38.

Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 2021 (6th edition). Gastric Cancer 2023; 26: 1–25.

39.

Pietrantonio

Raimondi

Lonardi

, et al. INFINITY: a multicentre, single-arm, multi-cohort, phase II trial of tremelimumab and durvalumab as neoadjuvant treatment of patients with microsatellite instability-high (MSI) resectable gastric or gastroesophageal junction adenocarcinoma (GAC/GEJAC). J Clin Oncol 2023; 41: 358.

40.

Berlth

Chon

S-H

Chevallay

, et al. Preoperative staging of nodal status in gastric cancer. Transl Gastroenterol Hepatol 2017, 2: 8.

41.

Raimondi

Palermo

Prisciandaro

, et al. Tremelimumab and durvalumab combination for the non-operative management (NOM) of microsatellite instability (MSI)-high resectable gastric or gastroesophageal junction cancer: the multicentre, single-arm, multi-cohort, phase II infinity study. Cancers (Basel) 2021; 13: 2839.

42.

Janjigian

Shitara

Moehler

, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet 2021; 398: 27–40.

43.

Bang

Y-J

Van Cutsem

Fuchs

, et al. KEYNOTE-585: phase III study of perioperative chemotherapy with or without pembrolizumab for gastric cancer. Futur Oncol 2019; 15: 943–952.

44.

Janjigian

Van Cutsem

Muro

, et al. MATTERHORN: efficacy and safety of neoadjuvant-adjuvant durvalumab and FLOT chemotherapy in resectable gastric and gastroesophageal junction cancer—a randomized, double-blind, placebo-controlled, phase 3 study. J Clin Oncol 2021; 39: TPS4151.

45.

Mansukhani

Davidson

Gillbanks

, et al. Iconic: peri-operative immuno-chemotherapy in operable oesophageal and gastric cancer. J Clin Oncol 2018; 36: TPS4139.

46.

Terashima

Kim

Y-W

Yeh

T-S

, et al. ATTRACTION-05 (ONO-4538-38/BMS CA209844): a randomized, multicenter, double-blind, placebo- controlled phase 3 study of nivolumab (nivo) in combination with adjuvant chemotherapy in pStage III gastric and esophagogastric junction (G/EGJ) cancer. Ann Oncol 2017; 28: v266–v267.

47.

Smyth

Peeters

Knoedler

, et al. EORTC 1707 VESTIGE: adjuvant immunotherapy in patients with resected gastric cancer following preoperative chemotherapy with high risk for recurrence (ypN+ and/or R1)—an open-label randomized controlled phase II study. J Clin Oncol 2021; 39: TPS4156.

48.

André

Cohen

Salem

. Immune checkpoint blockade therapy in patients with colorectal cancer harboring microsatellite instability/mismatch repair deficiency in 2022. Am Soc Clin Oncol Educ Book 2022; 42: 1–9.

49.

Evrard

Tachon

Randrian

, et al. Microsatellite instability: diagnosis, heterogeneity, discordance, and clinical impact in colorectal cancer. Cancers (Basel) 2019; 11: 1567.

50.

Sargent

Shi

Yothers

, et al. Prognostic impact of deficient mismatch repair (dMMR) in 7,803 stage II/III colon cancer (CC) patients (pts): a pooled individual pt data analysis of 17 adjuvant trials in the ACCENT database. J Clin Oncol 2014; 32: 3507.

51.

Cohen

Taieb

Fiskum

, et al. Microsatellite instability in patients with stage III colon cancer receiving fluoropyrimidine with or without oxaliplatin: an ACCENT pooled analysis of 12 adjuvant trials. J Clin Oncol 2020; 39: 642–651.

52.

Ostwal

Pande

Engineer

, et al. Low prevalence of deficient mismatch repair (dMMR) protein in locally advanced rectal cancers (LARC) and treatment outcomes. J Gastrointest Oncol 2019; 10: 19–29.

53.

Cercek

Dos Santos Fernandes

Roxburgh

, et al. Mismatch repair-deficient rectal cancer and resistance to neoadjuvant chemotherapy. Clin Cancer Res 2020; 26: 3271–3279.

54.

Evrard

Messina

Sefrioui

, et al. Heterogeneity of mismatch repair status and microsatellite instability between primary tumour and metastasis and its implications for immunotherapy in colorectal cancers. Int J Mol Sci 2022; 23: 4427.

55.

Xiao

Huang

, et al. A next-generation sequencing-based strategy combining microsatellite instability and tumor mutation burden for comprehensive molecular diagnosis of advanced colorectal cancer. BMC Cancer 2021; 21: 282.

56.

Svrcek

Colle

Cayre

, et al. Prevalence of NTRK1/3 fusions in mismatch repair-deficient (dMMR)/microsatellite instable (MSI) tumors of patients with metastatic colorectal cancer (mCRC). J Clin Oncol 2021; 39: e15537.

57.

Jin

Sinicrope

. Prognostic and predictive values of mismatch repair deficiency in non-metastatic colorectal cancer. Cancers (Basel) 2021; 13: 300.

58.

Taieb

Zaanan

Le Malicot

, et al. Prognostic effect of BRAF and KRAS mutations in patients with stage III colon cancer treated with leucovorin, fluorouracil, and oxaliplatin with or without cetuximab: a post hoc analysis of the PETACC-8 trial. JAMA Oncol 2016; 2: 643–653.

59.

Roth

Tejpar

Delorenzi

, et al. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J Clin Oncol 2009; 28: 466–474.

60.

Chouhan

Sammour

Thomas

, et al. The interaction between BRAF mutation and microsatellite instability (MSI) status in determining survival outcomes after adjuvant 5FU based chemotherapy in stage III colon cancer. J Surg Oncol 2018; 118: 1311–1317.

61.

Sargent

Marsoni

Monges

, et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol 2010; 28: 3219–3226.

62.

Baxter

Kennedy

Bergsland

, et al. Adjuvant therapy for stage II colon cancer: ASCO guideline update. J Clin Oncol 2021; 40: 892–910.

63.

Argilés

Tabernero

Labianca

, et al. Localised colon cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2020; 31: 1291–1305.

64.

Lau

Kalaitzaki

Church

, et al. Rationale and design of the POLEM trial: avelumab plus fluoropyrimidine-based chemotherapy as adjuvant treatment for stage III mismatch repair deficient or POLE exonuclease domain mutant colon cancer: a phase III randomised study. ESMO Open 2020; 5: e000638.

65.

Sinicrope

F-S

Zemla

, et al. Randomized trial of standard chemotherapy alone or combined with atezolizumab as adjuvant therapy for patients with stage III colon cancer and deficient mismatch repair (ATOMIC, alliance A021502). J Clin Oncol 2019; 37: e15169.

66.

Group* 2015 European Society of Coloproctology Collaborating. Predictors for anastomotic leak, postoperative complications, and mortality after right colectomy for cancer: results from an international snapshot audit. Dis Colon Rectum 2020; 63: 606–618.

67.

Seligmann

and FOxTROT Collaborative Group. FOxTROT: neoadjuvant FOLFOX chemotherapy with or without panitumumab (Pan) for patients (pts) with locally advanced colon cancer (CC). J Clin Oncol 2020; 38: 4013.

68.

ISRCTN Registry. A trial assessing preoperative chemotherapy in patients with locally advanced but resectable colon cancer. ISRCTN Registry website, 2023. https://doi.org/10.1186/ISRCTN83842641

69.

Peeters

KCMJ

van de Velde

CJH

Leer

JWH

, et al. Late side effects of short-course preoperative radiotherapy combined with total mesorectal excision for rectal cancer: increased bowel dysfunction in irradiated patients—a dutch colorectal cancer group study. J Clin Oncol 2005; 23: 6199–6206.

70.

Attaallah

Ertekin

Tinay

, et al. High rate of sexual dysfunction following surgery for rectal cancer. Ann Coloproctol 2014; 30: 210–215.

71.

Ridolfi

Berger

Ludwig

. Low anterior resection syndrome: current management and future directions. Clin Colon Rectal Surg 2016; 29: 239–245.

72.

Kennecke

Brown

Loree

, et al. CCTG CO.28 primary endpoint analysis: Neoadjuvant chemotherapy, excision and observation for early rectal cancer, the NEO trial. J Clin Oncol 2021; 39: 3508.

73.

Garcia-Aguilar

Patil

Gollub

, et al. Organ preservation in patients with rectal adenocarcinoma treated with total neoadjuvant therapy. J Clin Oncol 2022; 40: 2546–2556.

74.

Park

You

Agarwal

, et al. Neoadjuvant treatment response as an early response indicator for patients with rectal cancer. J Clin Oncol 2012; 30: 1770–1776.

75.

Habr-Gama

Perez

Nadalin

, et al. Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results. Ann Surg 2004; 240: 711–718.

76.

Smith

Strombom

Chow

, et al. Assessment of a watch-and-wait strategy for rectal cancer in patients with a complete response after neoadjuvant therapy. JAMA Oncol 2019; 5: e185896.

77.

Fernandez

São Julião

Figueiredo

, et al. Conditional recurrence-free survival of clinical complete responders managed by watch and wait after neoadjuvant chemoradiotherapy for rectal cancer in the international watch & wait database: a retrospective, international, multicentre registry study. Lancet Oncol 2021; 22: 43–50.

78.

O’Connell

Reynolds

McNamara

, et al. Microsatellite instability and response to neoadjuvant chemoradiotherapy in rectal cancer: a systematic review and meta-analysis. Surg Oncol 2020; 34: 57–62.

79.

Verschoor

van den Berg

Beets

, et al. Neoadjuvant nivolumab, ipilimumab, and celecoxib in MMR-proficient and MMR-deficient colon cancers: final clinical analysis of the NICHE study. J Clin Oncol 2022; 40: 3511.

80.

Kang

Zhang

, et al. Neoadjuvant PD-1 blockade with toripalimab, with or without celecoxib, in mismatch repair-deficient or microsatellite instability-high, locally advanced, colorectal cancer (PICC): a single-centre, parallel-group, non-comparative, randomised, phase 2 trial. Lancet Gastroenterol Hepatol 2022; 7: 38–48.

81.

Yuki

Bando

Tsukada

, et al. Short-term results of VOLTAGE-A: nivolumab monotherapy and subsequent radical surgery following preoperative chemoradiotherapy in patients with microsatellite stable and microsatellite instability-high locally advanced rectal cancer. J Clin Oncol 2020; 38: 4100.

82.

Cercek

Lumish

Sinopoli

, et al. PD-1 blockade in mismatch repair–deficient, locally advanced rectal cancer. N Engl J Med 2022; 386: 2363–2376.

83.

Lenz

H-J

Van Cutsem

Luisa Limon

, et al. First-line nivolumab plus low-dose ipilimumab for microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: the phase II CheckMate 142 study. J Clin Oncol 2021; 40: 161–170.

84.

Diaz

Shiu

K-K

Kim

T-W

, et al. Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study. Lancet Oncol 2022; 23: 659–670.

85.

Johnson

Nebhan

Moslehi

, et al. Immune-checkpoint inhibitors: long-term implications of toxicity. Nat Rev Clin Oncol 2022; 19: 254–267.

86.

Colle

Radzik

Cohen

, et al. Pseudoprogression in patients treated with immune checkpoint inhibitors for microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer. Eur J Cancer 2021; 144: 9–16.

Controversies and management of deficient mismatch repair gastrointestinal cancers in the neoadjuvant setting

Abstract

Keywords

Introduction

Testing for MSI

Mismatch repair deficiency in GC

Prognostic and predictive role of dMMR in GC

The use of checkpoint inhibitors in the neoadjuvant setting

Is this the dawn of a new surgery-free era?

Mismatch repair deficiency in CRC

Prognostic and predictive value of dMMR for adjuvant therapy in CRC

Evolving treatment landscape in the neoadjuvant setting for CRC

Conclusion

Footnotes

Acknowledgements

Declarations

ORCID iD

References