Differential response to immunotherapy in different lesions of MSI-H double primary colorectal cancer: a case report and literature review

Introduction

Colorectal cancer (CRC) is a common gastrointestinal malignancy. The latest statistics for 2022 indicate it as the second most commonly diagnosed cancer and the fifth leading cause of cancer-related mortality in China (1). The early symptoms of CRC are not obvious, and the majority of patients are diagnosed in the advanced stage. With a 5-year survival rate of approximately 14%, the prognosis for advanced metastatic CRC is grim (2). Microsatellite instability (MSI) is the inability to repair replication errors within microsatellite sequences (primarily tandem repetitive DNA sequences of 1–6 nucleotides) due to mismatch repair deficiency (dMMR), leading to error accumulation and microsatellite instability high (MSI-H), which accounts for approximately 5% of metastatic CRC (mCRC) (3,4). The accumulation of DNA mutations in tumor cells of microsatellite instability-high (MSI-H) patients lead to the production of tumor neoantigens that enhance tumor immunogenicity, promote immune cell infiltration, and stimulate anti-tumor immune response (5). As for management of advanced CRC is relies on systemic therapy, including chemotherapy, targeted therapy and immunotherapy (6). For advanced CRC patients with MSI-H/dMMR, the KEYNOTE177 study found that pembrolizumab monotherapy was significantly better than systemic chemotherapy in objective response rate (43.8% vs. 33.1%) and progression-free survival (16.5 vs. 8.2 months). These results suggest that pembrolizumab could be considered as the initial treatment option for advanced CRC patients with MSI-H/dMMR (7,8). Herein, we present a case of double primary CRC. Both lesions were determined as MSI-H by next generation sequencing (NGS). Divergent immunotherapeutic outcomes, were observed, as complete clinical response (cCR) achieved in the rectal lesion, while primary resistance to immunotherapy was considered in the colon lesion. This case study provides a more in-depth analysis of the primary immunotherapy resistance issue and examines a population that could truly benefit from immunotherapy. We present this article in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-24-137/rc).

Case presentation

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

The patient is a 44-year-old woman and previously in good health. She first sought medical attention in May 2022 due to intermittent abdominal pain accompanied by black stools that had been present for over a month. The patient underwent a comprehensive colonoscopy examination in May 2022, revealing an irregular ulcerative lesion with white moss on the periphery of the ascending colon near the hepatic flexure. This resulted in narrowing of the intestinal lumen and the mirror could not be passed. Furthermore, a bulging lesion with a diameter of approximately 1.5 cm × 0.8 cm was observed in the rectum about 8cm from the anus. The central part of the rectal lesion was slightly concave. Pathological analysis of the biopsy suggested adenocarcinoma in both areas of the ascending colon and rectum. The chest-abdomen-pelvis combined enhanced computed tomography (CT) scan suggested thickening of the wall of the ascending colon, indicative of colon cancer; thickening of the wall of the rectum may suggest rectal cancer, while the presence of peritoneal and omental nodules indicating metastases. The diagnosis is a malignant tumor of the colon and rectum with dual primary lesions: cT4bN2M1 adenocarcinoma of the ascending colon and cT2N1M1 adenocarcinoma of the mid-rectum with peritoneal metastasis. Initially, the patient was treated with a first-line regimen combining bevacizumab with XELOX (bevacizumab 400 mg on day 0, oxaliplatin 200 mg on day 1, capecitabine 1.5 g orally twice daily for 14 days) for two treatment cycles. After two cycles of treatment, a follow-up assessment showed stable disease (SD). The patient was subsequently referred to Affiliated Hospital of Hebei University for further enteroscopy and pathology revealed mucinous adenocarcinoma with signet ring cell components in the ascending colon and moderately differentiated adenocarcinoma in the rectum. Immunohistochemistry testing suggested MLH1 (−), PMS2 (−), MSH2 (+), MSH6 (+) in both lesions. In addition, the rectal lesion was sent for the NGS, which showed the presence of KRAS G12D and MSI-H. Considering that the patient was immune beneficiary, she was treated with pembrolizumab (200 mg every 3 weeks) for 5 cycles in the second line treatment. After 5 cycles, a follow-up examination revealed SD in the rectal lesion but progressive disease (PD) in the colonic lesion. Due to the inadequate control of the colonic lesion, a third-line treatment with pembrolizumab in combination with bevacizumab and XELIRI regimen was administered (pembrolizumab 200 mg d0, bevacizumab 500 mg d0, irinotecan 280 mg d1, capecitabine 1.5 g orally twice daily for 14 days). Two cycles later, the colonic lesions were re-evaluated for PD, while the rectal lesions were not observed on imaging (Figure 1). Subsequent enteroscopy revealed an irregular mass with narrowing 65 cm from the anal edge of the ascending colon, 5 cm from the rectal anus, a smooth white scar was visible. Mucinous adenocarcinoma was found in the ascending colon, some of which were signet ring cell components. Furthermore, there was fibroblastic tissue hyperplasia and infiltration of inflammatory cells in the rectum, but no tumor cells were detected. Another NGS test was performed on the colon lesion, revealing it to be Rat sarcoma viral oncogene (RAS) wild type, MSI-H with a total mutation burden (TMB) 28.9 Muts/Mb. The patient’s colon lesion did not demonstrate significant regression, and surgical treatment was advised. However, the patient refused. Consequently, she underwent regular treatment involving pembrolizumab, regorafenib, and celecoxib anti-tumour therapy as fourth-line therapy (Figure 2). Unfortunately, she passed away a month later due to a perforated bowel, which is considered to be related to the primary disease.

Figure 1 Previous imaging review of colonic and rectal lesions of the patient. The colonic (upper line arrows) and rectal lesions (bottom line arrows).

Figure 2 Summary of the patient’s treatment from diagnosis to the last follow-up visit. *, colonic lesions; #, rectal lesions. PD, progressive disease; SD, stable disease; CR, complete response; Bev, bevacizumab; Pem, pembrolizumab; Reg, regorafenib.

Discussion

According to the KEYNOTE177 study, the MSI-H arm was the population that benefited from immunotherapy and the comparison of immunotherapy with chemotherapy showed an objective response rate (ORR) of 43.8% versus 33.1% in the first-line treatment of mCRC (7,8). We recognized that this patient would benefit from immunotherapy, so we initiated this treatment as a- second-line option. Subsequently, we observed that despite the patient’s achieving cCR in rectal lesions, the colon lesions continued to progression following third-line treatment. Definitive identification of MSI-H in the patient’s colon lesions via NGS ruled out the possibility of microsatellite stable (MSS) in the context of dMMR (9). We reviewed the literatures to investigate why the patient achieve cCR in the rectal lesion, while the colonic lesion exhibited resistance to immunotherapy despite receiving the same intensity and modality of treatment (10).

The preclinical studies indicate that RAS wild-type is more responsive to immunotherapy (11). Moreover, the results of KEYNOTE177 show that RAS wild, right half, and young women are also potential beneficiaries of this therapy (8). The patient’s colonic lesion was fully consistent with the above characteristics, indicating primary immunoresistance. This suggests that factors other than RAS status plays a role in determining the prognosis of colonic lesion. In left and right half colon cancer, which differ significantly in origin, biological behaviour and prognosis, right half colon cancer relies on activation of different molecular pathways (BRAF mutation and MSI status) compared to left colon cancer (12). Nevertheless, the KEYNOTE177 results also indicated that both left and right colon cancer benefited equally from immunotherapy, with no significant statistical difference (P=0.97) (8). This implies that the tumor’s location was not the primary factor responsible for the resistance observed in the patient’s colon lesion.

Mucinous adenocarcinoma is a rare subtype of CRC that accounts for approximately 10% of all CRCs. It is characterized by the presence of large amounts of mucin proteins on the outside of malignant cells, including MUC1, MUC2 and MUC5AC (13). Previous studies have indicated that mucinous adenocarcinomas have a poor prognosis (14), particularly when signet ring cell components are present (15). Furthermore, mucinous adenocarcinomas are more likely to develop MSI-H (33.3% vs. 10.6%) (16) and peritoneal metastasis (31.8% vs. 5.8%) compared to non-mucinous adenocarcinomas (17). The efficacy of immunotherapy in colorectal mucinous adenocarcinoma remains unclear, given the inconsistent results reported in various studies. Llosa et al. constructed a scoring model using programmed death-ligand 1 (PD-L1) expression and the proportion of extracellular mucus components in a clinical trial (NCT01876511) to further screen for immunotherapy benefit; the study found that patients who benefited from immunotherapy had an increased secretion of extracellular mucus from their tumor cells and an elevated expression of PD-L1, which partly confirms that mucinous adenocarcinoma can benefit from immunotherapy (18). A previous study has shown that the existence of a mucinous component in MSI-H CRC may lead to a negative response to immunotherapy in patients (19). Thus, it remains unclear, based on both theoretical considerations and clinical practice, whether immunotherapy can provide significant benefits to patients with colorectal mucinous adenocarcinoma, including those with MSI-H phenotype.

The most typical feature of colorectal mucinous adenocarcinoma is the presence of a peritumoral mucus pool, which acts as a natural physical barrier, hindering the infiltration of effector T cells or anti-tumor agents (20). Therefore, we have concluded that the difference in prognosis between the patient’s two primary tumors, despite the same treatment modality and intensity, can be attributed to the presence of a pool of mucus surrounding the tumor cells, which acts as a natural barrier to the infiltration of effector T-cells, thereby limiting the efficacy of immunotherapy (10). Further staging is necessary for MSI-H mCRC based on the extent of inflammatory cell infiltration, particularly in the presence of a mucinous adenocarcinoma component (21). At this stage, the tumor appears to have low immune activity and its biological behavior and prognosis is similar to that of an immune desert (22). A combination of immunotherapy and anti-angiogenesis therapy is used to transform a cold tumor into a hot tumor, thereby increasing treatment efficacy (23). Previous research has shown that tumor cells can overexpress COX-2, which promotes an immunosuppressive state (24). The Sixth Affiliated Hospital of Sun Yat-sen University conducted a randomized, single-center phase II clinical trial in locally advanced CRC with MSI-H/dMMR. The results showed that the combination of the PD-1 monoclonal antibody toripalimab and celecoxib significantly increased pCR (pathological complete response) compared to toripalimab alone. The percentage of pCR was 88% with the combination treatment compared to 65% with toripalimab alone (25). Furthermore, the addition of celecoxib reduces the adverse effects associated with regorafenib and enhances its tolerability in patients (26). Therefore, as the subsequent step in the treatment of this patient, we considered the immunotherapeutic combination of regorafenib and a COX-2 inhibitor (celecoxib) as the mainstay of treatment.

Conclusions

We believe that immunotherapy alone might not be sufficient treatment for colorectal mucinous adenocarcinoma even when NGS results indicate MSI-H. Additionally, we recommend that future clinical trials of immunotherapy should stratify by pathology type at the early design stage to clarify the impact of such type on therapeutic efficacy. Early localized treatment for colorectal mucinous adenocarcinoma may represent an enhanced therapeutic approach.

Acknowledgments

Funding: This work was supported by the Foundation Project of the Affiliated Hospital of Hebei University (No. 2023QB09).

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-24-137/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-24-137/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-24-137/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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