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Neoadjuvant versus Adjuvant Immunotherapy in MSI-H/dMMR Early Colorectal Cancer: A Value-Conscious Re-examination of Dogma
CC BY 4.0 · Indian J Med Paediatr Oncol 2026; 47(03): 232-235
DOI: DOI: 10.1055/s-0046-1820494
Abstract
The management of early-stage colorectal cancer (CRC) is undergoing a paradigm shift driven by advances in immunotherapy, particularly for tumors characterized by microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR). Representing approximately 15% of non-metastatic CRC, this biologically distinct subgroup is intrinsically resistant to fluoropyrimidine-based chemotherapy yet uniquely sensitive to immune checkpoint inhibition.
This review critically examines the emerging evidence supporting neoadjuvant versus adjuvant immunotherapy strategies in early-stage MSI-H/dMMR colon cancer, drawing on data from FOxTROT, NICHE-2, and ATOMIC. We argue that neoadjuvant immunotherapy is biologically more rational, clinically effective, and value-conscious—particularly relevant in resource-limited settings—while acknowledging that definitive practice change will require randomized comparative trials.
Keywords
early-stage colorectal cancer - immunotherapy - neoadjuvant - adjuvant - fluoropyrimidine resistancePatient Consent
Patient consent is not required due to the retrospective nature of the study.
Publication History
Article published online:
24 April 2026
© 2026. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
Thieme Medical and Scientific Publishers Private Limited
A-13A, Graphix Tower 1, 6th floor, Sector 62, Noida 201309, Uttar Pradesh, India
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Abstract
The management of early-stage colorectal cancer (CRC) is undergoing a paradigm shift driven by advances in immunotherapy, particularly for tumors characterized by microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR). Representing approximately 15% of non-metastatic CRC, this biologically distinct subgroup is intrinsically resistant to fluoropyrimidine-based chemotherapy yet uniquely sensitive to immune checkpoint inhibition.
This review critically examines the emerging evidence supporting neoadjuvant versus adjuvant immunotherapy strategies in early-stage MSI-H/dMMR colon cancer, drawing on data from FOxTROT, NICHE-2, and ATOMIC. We argue that neoadjuvant immunotherapy is biologically more rational, clinically effective, and value-conscious—particularly relevant in resource-limited settings—while acknowledging that definitive practice change will require randomized comparative trials.
Keywords
early-stage colorectal cancer - immunotherapy - neoadjuvant - adjuvant - fluoropyrimidine resistanceIntroduction: When Biology Exposes the Limits of Tradition
For decades, the management of early-stage colorectal cancer (CRC) followed a predictable sequence: diagnosis, surgery, and adjuvant chemotherapy. Even as molecular heterogeneity became increasingly apparent, treatment paradigms remained largely uniform. Microsatellite instability-high (MSI-H)/mismatch repair deficiency (dMMR) CRC represents one of the clearest examples of this discordance between tumor biology and clinical practice.
MSI-H tumors account for approximately 15% of localized CRCs, with nearly 80% arising sporadically and the remainder associated with Lynch syndrome.[1] [2] [3] [4] These tumors are characterized by a high mutational burden, dense lymphocytic infiltration, and increased immune checkpoint expression.[5] Importantly, they are consistently resistant to fluoropyrimidine-based chemotherapy,[6] [7] [8] [9] [10] [11] a finding repeatedly confirmed in randomized trials and pooled analyses.
The advent of immune checkpoint inhibitors has not merely added another therapeutic option; it has challenged the foundational sequencing of treatment.[12] [13] [14] The key question is no longer whether immunotherapy should be used in MSI-H early CRC, but when it should be deployed for maximal benefit.
Stage II MSI-H Colon Cancer: Observation or Missed Opportunity?
Current guidelines[15] [16] recommend observation for stage II MSI-H colon cancer, based on the lack of benefit from adjuvant chemotherapy. While this approach avoids unnecessary toxicity, it leaves approximately 10 to 15% of patients vulnerable to recurrence.
Notably, stage II patients were well represented in the NICHE-2 trial[12] and demonstrated pathological response rates comparable to those observed in stage III disease. This observation suggests that biological behavior, rather than anatomical stage alone, may better predict benefit from systemic therapy.
Neoadjuvant immunotherapy should not be viewed as a mandate for all stage II MSI-H tumors. Instead, it represents a rational option within clinical trials or shared decision-making frameworks for biologically higher-risk patients.
FOxTROT and the Illusion of Chemotherapy Benefit in MSI-H Disease
The FOxTROT trial[6] established the feasibility of neoadjuvant chemotherapy in operable colon cancer, demonstrating improved downstaging and event-free survival in mismatch repair-proficient tumors. However, outcomes in the MSI-H subgroup were strikingly different.
Pathological tumor regression was observed in only approximately 7% of MSI-H cases, with no meaningful reduction in recurrence. These findings reinforced the biological resistance of MSI-H tumors to fluoropyrimidine-based chemotherapy and should have conclusively discouraged its routine use in this population.
Despite this, oxaliplatin-based adjuvant chemotherapy has continued to be prescribed, reflecting therapeutic inertia rather than evidence-based practice.
Endpoint Selection: Interpreting Early Signals
Several neoadjuvant studies have used 2-year recurrence as a primary endpoint, based on the observation that most relapses in high-risk colon cancer occur within this timeframe. While pragmatic, this endpoint remains a surrogate.
Disease-free survival (DFS) continues to be the globally accepted regulatory endpoint, capturing both recurrence and competing mortality risks. Accordingly, 2-year recurrence should be interpreted as hypothesis-generating rather than practice-defining, underscoring the need for longer-term validation.
Overtreatment Risk and the Imperative of Upfront MMR Testing
A major limitation of chemotherapy-based neoadjuvant strategies is the absence of mandatory upfront MMR testing. Administering neoadjuvant chemotherapy to dMMR tumors delays surgery for a biologically ineffective intervention.
Furthermore, a substantial proportion of patients categorized as “high risk” are ultimately found to have pT3N0 disease, for which chemotherapy is frequently unnecessary. Exposure to avoidable toxicity and surgical delay represents overtreatment rather than therapeutic progress.
This critique applies specifically to chemotherapy-based approaches and highlights why upfront MMR testing must be mandatory rather than optional.
NICHE-2: Proof of Concept for Neoadjuvant Immunotherapy
The NICHE-2 trial[12] evaluated short-course neoadjuvant immunotherapy using ipilimumab and nivolumab in resectable dMMR colon cancer. The results were unprecedented:
Major pathological response: 95%
Pathological complete response: 68%
Timely surgery: 98%
3-year DFS: 100%
Responses were consistent across sporadic and Lynch-associated tumors, reinforcing a biology-driven rather than etiology-driven approach. Although NICHE-2 was a single-arm phase II study conducted at expert centers, the magnitude and consistency of benefit make the signal difficult to dismiss ([Table 1]).
ATOMIC: Adjuvant Immunotherapy's Best-Case Scenario
The ATOMIC trial[13] evaluated adjuvant mFOLFOX6 with or without atezolizumab in resected Stage III dMMR colon cancer. The addition of atezolizumab improved 3-year DFS from 76.6 to 86.4%.
However, this benefit came at the cost of mandatory chemotherapy, increased toxicity, prolonged treatment duration, and persistent recurrence in approximately 13% of patients. Favorable outcomes in the control arm likely reflect the inherently good prognosis of dMMR tumors rather than true chemotherapy sensitivity.
Why Neoadjuvant Immunotherapy Outperforms Adjuvant Approaches
The contrast between NICHE-2 and ATOMIC is best explained by biology rather than pharmacology ([Table 2]). In the neoadjuvant setting, the intact primary tumor serves as a continuous antigen source, facilitating robust T-cell priming and clonal expansion. In the adjuvant setting, this immune amplification is substantially attenuated.
Differences in drug class (PD-1 vs. PD-L1 inhibition) may also contribute, but timing and antigen exposure appear central to the observed disparity.
Why EGFR Antibodies Failed Where Immunotherapy Succeeded
EGFR antibodies have shown limited benefit even in metastatic CRC, largely confined to selected subgroups. In early-stage or micrometastatic disease, their reliance on cytotoxic synergy rather than durable systemic control limits their ability to eradicate residual disease. In contrast, immunotherapy in dMMR tumors exploits intact antigen presentation and immune priming, enabling sustained disease control. This contrast reinforces that treatment success in early-stage CRC is driven by biological context and timing rather than therapeutic escalation.
Conclusion
MSI-H/dMMR CRC is uniquely resistant to chemotherapy and uniquely sensitive to immunotherapy. Accumulating evidence supports neoadjuvant immunotherapy as the most biologically rational, clinically effective, and value-conscious strategy in early-stage disease.
While randomized comparative trials are still needed, the burden of proof increasingly rests with proponents of prolonged adjuvant approaches. For MSI-H/dMMR colon cancer, the question is no longer whether immunotherapy should be used—but whether delaying it represents a missed opportunity.
|
Feature |
FOxTROT (neoadjuvant chemotherapy) |
NICHE-2 (neoadjuvant IO) |
|---|---|---|
|
Response of MSI-H |
Poor |
Exceptional (95% major pathological response, 67% pathological complete response) |
|
MSI-low included |
Yes |
No |
|
Safety and feasibility |
Acceptable |
Excellent |
|
Trial phase |
Phase III |
Phase II |
|
DFS (disease-free survival) |
No definitive DFS improvement reported in available publications |
100% 3-y DFS |
|
HR (hazard ratio) |
Not reported |
Not estimable (no events) |
|
Feature |
NICHE-2 (Neoadjuvant IO) |
ATOMIC (Adjuvant IO) |
|---|---|---|
|
Timing of IO |
Before surgery |
After surgery |
|
Pathological response |
95% major pathological response, 67% pathological complete response |
DFS improvement |
|
Chemotherapy included |
No |
Yes |
|
CRC stage included |
I–III |
III only |
|
Trial phase |
Phase II |
Phase III |
|
DFS (disease-free survival) |
100% 3-y DFS |
Significant DFS improvement |
|
HR (hazard ratio) |
Not estimable (no events) |
0.58 |
Conflict of Interest
None declared.
Patient Consent
Patient consent is not required due to the retrospective nature of the study.
References
- Boland CR, Goel A. Microsatellite instability in colorectal cancer. Gastroenterology 2010; 138 (06) 2073-2087.e3
- Sinicrope FA. Lynch syndrome-associated colorectal cancer. N Engl J Med 2018; 379 (08) 764-773
- Eikenboom EL, van der Werf-'t Lam AS, Rodríguez-Girondo M. et al. Universal immunohistochemistry for Lynch syndrome: a systematic review and meta-analysis of 58,580 colorectal carcinomas. Clin Gastroenterol Hepatol 2022; 20 (03) e496-e507
- Jenkins MA, Hayashi S, O'Shea AM. et al; Colon Cancer Family Registry. Pathology features in Bethesda guidelines predict colorectal cancer microsatellite instability: a population-based study. Gastroenterology 2007; 133 (01) 48-56
- Casak SJ, Marcus L, Fashoyin-Aje L. et al. FDA approval summary: pembrolizumab for the first-line treatment of patients with MSI-H/dMMR advanced unresectable or metastatic colorectal carcinoma. Clin Cancer Res 2021; 27 (17) 4680-4684
- Morton D, Seymour M, Magill L. et al; FOxTROT Collaborative Group. Preoperative chemotherapy for operable colon cancer: mature results of an international randomized controlled trial. J Clin Oncol 2023; 41 (08) 1541-1552
- Taieb J, Svrcek M, Cohen R, Basile D, Tougeron D, Phelip JM. Deficient mismatch repair/microsatellite unstable colorectal cancer: diagnosis, prognosis and treatment. Eur J Cancer 2022; 175: 136-157
- Taieb J, Gallois C. Adjuvant chemotherapy for stage III colon cancer. Cancers (Basel) 2020; 12 (09) 2679
- Hause RJ, Pritchard CC, Shendure J, Salipante SJ. Classification and characterization of microsatellite instability across 18 cancer types. Nat Med 2016; 22 (11) 1342-1350
- Llosa NJ, Cruise M, Tam A. et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov 2015; 5 (01) 43-51
- Le DT, Durham JN, Smith KN. et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017; 357 (6349) 409-413
- Chalabi M, Verschoor YL, Tan PB. et al. Neoadjuvant immunotherapy in locally advanced mismatch repair-deficient colon cancer. N Engl J Med 2024; 390 (21) 1949-1958
- Sinicrope FA, Ou F-S, Arnold D. et al. Randomized trial of standard chemotherapy alone or combined with atezolizumab as adjuvant therapy for patients with stage III deficient DNA mismatch repair (dMMR) colon cancer (Alliance A021502; ATOMIC). J Clin Oncol 2025; 43 (Suppl. 17) LBA1
- Cercek A, Lumish M, Sinopoli J. et al. PD-1 blockade in mismatch repair–deficient, locally advanced rectal cancer. N Engl J Med 2022; 386 (25) 2363-2376
- Argilés G, Tabernero J, Labianca R. et al; ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org. Localised colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2020; 31 (10) 1291-1305
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Colon Cancer. Version 1. 2025 . Plymouth Meeting, PA: National Comprehensive Cancer Network; published March 2025. Accessed February 1, 2026
Address for correspondence
Publication History
Article published online:
24 April 2026
© 2026. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
Thieme Medical and Scientific Publishers Private Limited
A-13A, Graphix Tower 1, 6th floor, Sector 62, Noida 201309, Uttar Pradesh, India
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References
- Boland CR, Goel A. Microsatellite instability in colorectal cancer. Gastroenterology 2010; 138 (06) 2073-2087.e3
- Sinicrope FA. Lynch syndrome-associated colorectal cancer. N Engl J Med 2018; 379 (08) 764-773
- Eikenboom EL, van der Werf-'t Lam AS, Rodríguez-Girondo M. et al. Universal immunohistochemistry for Lynch syndrome: a systematic review and meta-analysis of 58,580 colorectal carcinomas. Clin Gastroenterol Hepatol 2022; 20 (03) e496-e507
- Jenkins MA, Hayashi S, O'Shea AM. et al; Colon Cancer Family Registry. Pathology features in Bethesda guidelines predict colorectal cancer microsatellite instability: a population-based study. Gastroenterology 2007; 133 (01) 48-56
- Casak SJ, Marcus L, Fashoyin-Aje L. et al. FDA approval summary: pembrolizumab for the first-line treatment of patients with MSI-H/dMMR advanced unresectable or metastatic colorectal carcinoma. Clin Cancer Res 2021; 27 (17) 4680-4684
- Morton D, Seymour M, Magill L. et al; FOxTROT Collaborative Group. Preoperative chemotherapy for operable colon cancer: mature results of an international randomized controlled trial. J Clin Oncol 2023; 41 (08) 1541-1552
- Taieb J, Svrcek M, Cohen R, Basile D, Tougeron D, Phelip JM. Deficient mismatch repair/microsatellite unstable colorectal cancer: diagnosis, prognosis and treatment. Eur J Cancer 2022; 175: 136-157
- Taieb J, Gallois C. Adjuvant chemotherapy for stage III colon cancer. Cancers (Basel) 2020; 12 (09) 2679
- Hause RJ, Pritchard CC, Shendure J, Salipante SJ. Classification and characterization of microsatellite instability across 18 cancer types. Nat Med 2016; 22 (11) 1342-1350
- Llosa NJ, Cruise M, Tam A. et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov 2015; 5 (01) 43-51
- Le DT, Durham JN, Smith KN. et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017; 357 (6349) 409-413
- Chalabi M, Verschoor YL, Tan PB. et al. Neoadjuvant immunotherapy in locally advanced mismatch repair-deficient colon cancer. N Engl J Med 2024; 390 (21) 1949-1958
- Sinicrope FA, Ou F-S, Arnold D. et al. Randomized trial of standard chemotherapy alone or combined with atezolizumab as adjuvant therapy for patients with stage III deficient DNA mismatch repair (dMMR) colon cancer (Alliance A021502; ATOMIC). J Clin Oncol 2025; 43 (Suppl. 17) LBA1
- Cercek A, Lumish M, Sinopoli J. et al. PD-1 blockade in mismatch repair–deficient, locally advanced rectal cancer. N Engl J Med 2022; 386 (25) 2363-2376
- Argilés G, Tabernero J, Labianca R. et al; ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org. Localised colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2020; 31 (10) 1291-1305
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Colon Cancer. Version 1. 2025 . Plymouth Meeting, PA: National Comprehensive Cancer Network; published March 2025. Accessed February 1, 2026