Immunotherapy With Pembrolizumab for Resectable dMMR/MSI-H Stage III Colon Cancer: A Case of Personalized, Precision Surgery-Sparing Immunotherapy

Abstract

Colorectal cancer (CRC) with deficient mismatch repair (dMMR) and microsatellite instability-high (MSI-H) status represents a highly immunogenic subset that responds well to immune checkpoint inhibitors (ICIs). However, the role of ICIs in resectable, early-stage CRC remains under investigation. We report the case of an 81-year-old woman diagnosed with stage III adenocarcinoma of the right colon, who declined surgery. Immunohistochemistry revealed loss of MLH1 and PMS2, consistent with dMMR. Tumor genomic profiling demonstrated MSI-H, high tumor mutational burden, BRAF V600E, and BRCA2 mutation. Germline testing was negative for BRCA and Lynch syndrome-associated mutations. The patient was treated with neoadjuvant pembrolizumab. After 4 months, mesenteric lymphadenopathy resolved, but focal colonic thickening persisted. The patient again declined surgery. At 10 months of pembrolizumab therapy, PET/computed tomography and colonoscopy showed no residual disease. She developed immune-related adrenal insufficiency, managed with corticosteroids. This case demonstrates complete clinical remission of resectable colon cancer with pembrolizumab alone in a patient with somatic dMMR/MSI-H, BRAF V600E, and BRCA2 mutations. It supports the hypothesis that early use of ICIs—prior to metastatic progression and immune escape—may enhance efficacy. This report highlights the potential for personalized, surgery-sparing treatment strategies in genomically selected CRC patients.

Introduction

Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer-related death globally, accounting for nearly 10% of all cancer diagnoses and fatalities. ¹ Molecular classification of CRC has become increasingly important for prognostication and therapeutic decision-making, particularly with the identification of immunogenic subsets defined by deficient mismatch repair (dMMR) and microsatellite instability-high (MSI-H) status. ²

dMMR/MSI-H tumors result from the inactivation of DNA mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2) either through germline mutations or epigenetic silencing, for example, MLH1 promoter methylation, leading to widespread frameshift mutations, and high tumor mutational burden (TMB).^2,3 These hypermutated tumors generate numerous neoantigens, attracting tumor-infiltrating lymphocytes, and expressing immune checkpoint molecules, thereby creating an inflamed tumor microenvironment (TME).^4,5 This immunogenic phenotype makes dMMR/MSI-H tumors particularly responsive to PD-1 blockade, such as pembrolizumab. ⁶

In metastatic CRC, the phase III KEYNOTE-177 trial demonstrated the superiority of pembrolizumab over chemotherapy in dMMR/MSI-H tumors, leading to its approval as a first-line therapy.^7,8 The therapeutic role of immune checkpoint inhibitors (ICIs) is now being explored in localized CRC. In a landmark study, PD-1 blockade with dostarlimab in dMMR rectal cancer resulted in a 100% complete clinical response rate, allowing all patients to avoid surgery or chemoradiation.^9,10 Likewise, the NICHE and NICHE-2 trials showed that neoadjuvant immunotherapy with ipilimumab and nivolumab in stage II/III dMMR colon cancer achieved major pathological responses in 95% of patients, including complete responses in over 60%.^11,12 Similarly, the NICHE-3 trial demonstrated that neoadjuvant dual immunotherapy with nivolumab and relatlimab (an anti-LAG-3 antibody) for 2 cycles prior to surgery led to pathological responses in all 19 patients treated, with 79% achieving a pathological complete response (pCR). ¹³

Importantly, these responses appear to be enhanced when ICIs are administered early in the disease course before the onset of immune escape mechanisms seen in metastatic disease.^7-14 Neoadjuvant immunotherapy may, therefore, represent an opportunity not only for tumor eradication but also for organ preservation in selected patients with highly immunogenic tumors. ¹¹ Furthermore, these prospective trials are the suggestion that neoadjuvant PD-1-based therapy may represent a definitive approach for dMMR solid tumors enabling organ preservation. ¹⁴

Coexisting molecular alterations may further influence immunotherapy sensitivity. The BRAF V600E mutation, present in about 10% of CRCs, is commonly associated with sporadic MSI-H tumors and right-sided primaries, and typically confers poor prognosis when treated with conventional chemotherapy.^15,16 Similarly, BRCA mutations, though uncommon in CRC, are enriched in dMMR/MSI-H tumors and may signify homologous recombination deficiency (HRD), contributing to enhanced neoantigen formation and immunogenicity. ¹⁷

Herein, we present a rare case of a patient with stage III colon cancer harboring dMMR/MSI-H, BRAF V600E, and BRCA2 mutation who achieved complete clinical remission with pembrolizumab monotherapy after declining surgery. To our knowledge, this is the first reported case of curative immunotherapy in a resectable hypermutated colon cancer with this molecular constellation, underscoring the potential of biomarker-driven, surgery-sparing immunotherapy in selected patients.

Case Presentation

An 81-year-old Caucasian woman with a medical history of hypertension presented with intermittent rectal bleeding. Colonoscopy revealed a large, circumferential mass in the ascending colon. Biopsy confirmed moderately differentiated adenocarcinoma (Figure 1A). Immunohistochemical analysis demonstrated a dMMR phenotype with loss of MLH1 and PMS2 protein expression (Figure 1B).

Figure 1.

(A) Hematoxylin and eosin stain of the colon tumor shows adenocarcinoma (100×). (B) IHC study of the tumor shows negative MLH1 expression in the tumor cells, whereas the internal positive control in the stromal tissue is positive (100×). H&E, hematoxylin and eosin; IHC, immunohistochemical.

Her family history was notable for a mother who died of gastric cancer and a sister with an unspecified malignancy. Baseline carcinoembryonic antigen level was within normal limits at 1.8 ng/mL.

Computed tomography (CT) of the chest, abdomen, and pelvis identified a 6 cm mass in the ascending colon and multiple enlarged regional mesenteric lymph nodes, consistent with stage III colon cancer (Figure 2A–C). No evidence of distant metastasis was observed.

Figure 2.

(A) CT scan shows a concentric tumor mass in the ascending colon (arrows). (B) CT scan showing enlarged mesenteric lymph nodes (arrow). (C) CT scan demonstrating the concentric tumor of the ascending colon spanning at least 6 cm in length (red circle). CT, computed tomography.

Surgical resection (right hemicolectomy) was recommended, but the patient declined the procedure. Comprehensive tumor molecular genomic profiling revealed somatic dMMR, MSI-H, high TMB (63 mutations/Mb), BRAF V600E, and BRCA2 pathogenic variants (Table 1).

Table 1.

IHC and Molecular Genomic Study of the Tumor.

Biomarker	Method	Analyte	Result
Mismatch Repair Status	IHC	Protein	Deficient (loss)
BRAF	Seq	DNA-tumor	Pathogenic variants exon 15|p.V600E
MSI	Seq	DNA-tumor	High
TMB	Seq	DNA-tumor	High, 63 mut/Mb
BRCA2	Seq	DNA-tumor	Pathogenic variant exon 11|p.K1691fs
BRCA2	Seq	DNA-tumor	Pathogenic variant exon 11|p.S2012fs

Abbreviations: IHC, immunohistochemical; MSI, microsatellite instability; Seq, sequencing; TMB, tumor mutational burden.

The tumor was negative for KRAS, NRAS, PD-L1, PIK3CA, NTRK, RET, EGFR, HER2, NF1, and PTEN. A POLE variant of uncertain significance (p.E618K) was detected. Germline testing using peripheral blood was negative for both BRCA mutations and Lynch syndrome-associated MMR gene mutations, confirming the somatic origin of the detected alterations.

Based on the tumor’s highly immunogenic profile, the patient was offered neoadjuvant immunotherapy with pembrolizumab, which she accepted. Pembrolizumab was administered at 200 mg intravenously every 3 weeks for 4 months. Follow-up imaging showed persistent focal thickening of the ascending colon but resolution of mesenteric lymphadenopathy. Surgery was again offered but declined by the patient. Pembrolizumab therapy was continued.

At ~4 months into treatment, the patient developed fatigue and generalized weakness. Laboratory evaluation revealed a low morning serum cortisol level (1.3 µg/dL), consistent with immune-related adrenal insufficiency. She was initiated on oral prednisone (10 mg in the morning and 5 mg in the evening), with subsequent symptom improvement. The maintenance dose was later tapered to 5 mg in the morning and 2.5 mg in the evening.

After 10 months of pembrolizumab therapy, a PET/CT scan showed complete metabolic response with normalization of the right colon and no evidence of residual or metastatic disease (Figure 3). There was no abnormal fluorodeoxyglucose uptake in the colon, peritoneum, lymph nodes, or adrenal glands.

Figure 3.

PET/CT scan performed after 10 months of immunotherapy showed no evidence of hypermetabolic disease, indicating complete clinical response. CT, computed tomography.

A follow-up colonoscopy revealed a normal-appearing mucosa in the ascending colon, and biopsies were negative for malignancy (Figure 4).

Figure 4.

Colonoscopy after 10 months of immunotherapy showed no residual tumor in the ascending colon.

Discussion

This case demonstrates the transformative potential of biomarker-driven immunotherapy in the management of resectable, hypermutated CRC harboring multiple high-risk genomic alterations—dMMR/MSI-H, BRAF V600E, and BRCA2 mutation. The patient achieved complete clinical remission with pembrolizumab monotherapy in the absence of surgery or chemotherapy, illustrating the feasibility of a personalized, immune-based, nonoperative strategy in a carefully selected patient with resectable colon cancer.

The dMMR/MSI-H phenotype defines a unique molecular subset of CRC characterized by a high TMB, increased neoantigen load, and a T-cell-inflamed TME.^2-5 These tumors are particularly sensitive to ICIs, notably PD-1 blockade. The KEYNOTE-177 trial established pembrolizumab, a PD-L1 inhibitor, as the standard first-line therapy for metastatic MSI-H/dMMR CRC, demonstrating superior progression-free survival and more durable responses compared to conventional chemotherapy, which led to its subsequent approval by the U.S. Food and Drug Administration.^7,8

Emerging evidence suggests that the timing of ICI administration may significantly influence therapeutic outcomes. In early-stage CRC, the TME may be more immunologically intact, and the absence of metastatic immune escape mechanisms may facilitate a more robust antitumor response. ¹⁴ The NICHE, NICHE-2, and NICHE-3 trials demonstrated that short-course neoadjuvant immunotherapy in resectable dMMR colon cancer achieved major pathological responses in over 90% of patients, with pCRs in 67% to 79%.^11-13 Similarly, neoadjuvant PD-1 blockade with dostarlimab in dMMR rectal cancer resulted in a 100% complete clinical response rate, eliminating the need for chemoradiation or surgery in all treated patients.^9,10 These findings support the hypothesis that early administration of ICIs—prior to metastatic progression—maximizes therapeutic efficacy and may create opportunities for organ preservation.

This patient’s tumor harbored a rare combination of somatic dMMR/MSI-H, BRAF V600E, and BRCA2 mutation.

Although the BRAF V600E mutation is generally associated with poor prognosis and resistance to standard chemotherapy, ~30% of BRAF-mutated colorectal tumors exhibit MSI-H status, typically due to MLH1 promoter hypermethylation, and respond to ICIs as effectively as BRAF wild-type counterparts. ¹⁵ In fact, the coexistence of BRAF mutation and MSI-H status creates an immunologically active TME, that is, highly responsive to PD-1 blockade.^2,16

About 1% of CRC patients have BRCA mutation. ¹⁷ The concurrent BRCA2 mutation is particularly noteworthy. Although BRCA2 alterations are uncommon in CRC, a recent study with 9321 CRC specimen has shown that they occur more frequently in dMMR/MSI-H tumors, with an incidence of 23.8%. ¹⁸ This suggests a possible link between HRD and the hypermutated, immunogenic phenotype. HRD may act synergistically with dMMR to further increase genomic instability and neoantigen load, potentially enhancing sensitivity to ICIs. ¹⁹ While the clinical implications of BRCA mutations in CRC are still evolving, their co-occurrence with dMMR/MSI-H may represent a biomarker for heightened immunotherapy responsiveness.

To our knowledge, this is the first reported case of resectable stage III colon cancer with concurrent dMMR/MSI-H, BRAF V600E, and BRCA2 mutations achieving complete clinical remission with pembrolizumab monotherapy.

The estimate the percentage of CRC patients that would have the phenotype of our patient (dMMR + BRAF V600E mutation + BRCA2 mutation) may be calculated by multiplying the individual probabilities: 15% have dMMR, ² 10% have BRAF 600E mutation, ¹⁶ and 1% have BRCA mutation. ¹⁷ Then 0.015% of all CRCs are estimated to have all 3 features. However, we could not find any CRC cases having all 3 features like our patient.

Current National Comprehensive Cancer Network guidelines recommend neoadjuvant immunotherapy for colon cancer only in cases deemed unresectable or inoperable. ²⁰ However, this case supports expanding the therapeutic paradigm to consider non-operative management in patients with highly immunogenic, molecularly defined tumors who are either unwilling or unable to undergo surgery.

Another key point illustrated in this case is the importance of monitoring for immune-related adverse events. The patient developed adrenal insufficiency, a known toxicity of PD-1 inhibitors, which was promptly recognized and effectively managed with corticosteroid replacement, allowing continuation of therapy.

Looking ahead, this case exemplifies the growing momentum toward precision oncology in CRC, where treatment decisions are increasingly guided by molecular and immunologic features rather than solely by anatomical staging. The convergence of dMMR/MSI-H, BRAF mutation, and BRCA2-associated HRD represents a unique immunogenic signature that may warrant curative-intent immunotherapy without surgery in selected patients. However, significant questions remain, including the optimal duration of immunotherapy, long-term durability of response, and the risk of late recurrence.

Prospective studies are needed to evaluate immune checkpoint inhibition as definitive therapy for hypermutated, resectable CRC. Future trials should aim to refine predictive biomarkers, including TMB thresholds, HRD signatures, and spatial immune profiling, to better stratify patients who may benefit from surgery-sparing, curative immunotherapy. Ultimately, this evolving approach may transform the standard of care in immunogenic CRC, enabling personalized, less invasive, and durable treatments that preserve organ function and improve quality of life.

Conclusion

This case demonstrates that neoadjuvant pembrolizumab can induce complete remission in resectable, hypermutated stage III colon cancer with dMMR/MSI-H, BRAF V600E, and BRCA2 mutations without surgery or chemotherapy. It underscores the potential of early immunotherapy, before metastatic progression and immune evasion, in achieving durable responses in genomically selected patients.

The co-occurrence of dMMR/MSI-H, BRAF, and BRCA2 alterations may confer synergistic immunogenicity, supporting immunotherapy as a curative, organ-preserving option. The optimal duration of therapy remains uncertain.

This case highlights the promise of personalized, precision surgery-sparing immunotherapy, and supports further trials to define its role in early-stage CRC.