Immunotherapy for deficient mismatch repair (dMMR) pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most challenging cancers to treat due to its late stage at diagnosis in the absence of early signs and symptoms, lack of effective screening or prevention strategies, and overall poor prognosis. More than 50% of patients present with locally advanced or metastatic disease at the time of diagnosis (1,2). In 2022, the American Cancer Society estimated that 62,210 new cases of PDAC will be diagnosed and about 49,380 Americans will die from pancreatic cancer (2). Not surprisingly, PDAC is projected to be the second leading cause of cancer-related death by 2030 in the United States, surpassing prostate, breast and colorectal cancer (3).

Surgical resection is the only curative option for PDAC especially in early stages at initial diagnosis, though careful review should be undertaken to assess for potential locally advanced or metastatic disease. Neoadjuvant chemotherapy with modified FOLFIRINOX (combination 5-fluorouracil, leucovorin, irinotecan, oxaliplatin) (4) or gemcitabine plus nanoparticle albumin-bound (nab)-paclitaxel (5) remain the standards of care by providing an overall survival advantage in locally advanced and metastatic PDAC. In the borderline resectable and locally advanced settings, either regimen is used at times in combination with radiation therapy, to potentially downstage a tumor and achieve a desirable R0 resection. Surgery followed by adjuvant systemic therapy reduces the risk of recurrence though subsequent cycles of treatment are often limited by patient tolerance and toxicity.

In the case reported by Han and Borazanci (6), the authors described a 57-year-old male with metastatic PDAC whose tumor profile revealed a high tumor mutational burden (TMB), microsatellite instability-high (MSI-H), and a non-germline deficient mismatch repair (dMMR) tumor, who ultimately achieved an ongoing response to combination immune checkpoint inhibition (ICI) with ipilimumab and nivolumab. In addition, this case reports detailed a heavily pre-treated tumor which progressed on FOLFIRINOX, gemcitabine/nab-paclitaxel, and clinical trial prior to ICI. Pancreatic tumors characterized by MSI-H or dMMR status, unlike their microsatellite stable and MMR proficient counterparts, are less sensitive to gemcitabine or 5-fluorouracil based regimens (7). Moreover, it is known that dMMR cancers are sensitive to programmed cell death-1 (PD-1) blockade, regardless of tissue of origin, due to the higher number of somatic mutations and potential neoantigens that allow for a more robust and durable anti-tumor response (8). Following the U.S. Food and Drug Administration’s approval of pembrolizumab, a PD-1 inhibitor, for the treatment of MSI-H or dMMR solid tumors, as in this case, knowing the MMR deficiency status can have profound effects on treatment options and it should be tested for in all pancreatic tumors regardless of stage.

The authors described the PDAC in this case report as a manifestation of sporadic MMR deficiency, although the molecular basis for this was not defined. Neither germline pathogenic variants associated with hereditary cancer-predisposing syndromes (including Lynch syndrome) nor somatic mutations of the MMR genes were identified to account for the dMMR noted (on the comprehensive molecular profiling tumor tissue and tumor DNA panel by Caris Life Sciences). Somatic ARID1A mutation, as detected in this patient’s tumor, has been associated with epigenetic inactivation of MLH1 via promoter hypermethylation in other cancer types (9-11). It is therefore possible that the MMR deficiency in this PDAC was associated with MLH1 hypermethylation, although this does not appear to have specifically been tested for. Irrespective of precise molecular mechanism, concordant high TMB and MSI in the absence of a germline pathogenic variant corroborate a sporadic occurrence of MMR deficiency. For patients with dMMR or MSI-H tumors, irrespective of site, it is crucial that germline genetic testing also be performed as this may influence the need for closer surveillance and preventive measures for metachronous cancers, as well as cascade genetic testing in relatives (12). In contrast, one case report of a patient with a pathogenic MSH2 germline mutation and history of Lynch syndrome-type cancers (endometrial, colorectal, urothelial) that lacked MSH2 and MSH6 expression, presented with a PDAC with intact expression of both MSH2 and MSH6, which rendered the patient ineligible for immunotherapy with pembrolizumab (13). This case underscores the importance of testing for MMR gene expression in all tumors of patients with Lynch syndrome especially pancreatic tumors.

Aside from systemic therapy, the biology of pancreatic tumors allows us to explore other therapeutic options. The pathogenesis of PDAC is typically driven by somatic mutations in oncogenes, namely KRAS, and tumor suppressor genes, including CDKN2A, TP53, and SMAD4 (1). Additionally, alterations in the tumor microenvironment by pancreatic neoplastic cells, surrounding desmoplastic stroma, and the presence of other immune cells including carcinoma associated fibroblasts, immunosuppressive myeloid cells, and regulatory T-cells have significant implications for mechanisms of treatment resistance leading to tumor cell proliferation and subsequent metastasis (14). Despite this complexity, there has been progress in identifying new targets including CD40 agonists, focal adhesion kinase inhibitors, vaccines, and combination regimens of standard chemotherapy, radiotherapy, immunotherapy, and targeted agents being studied in clinical trials (14).

In summary, PDAC is challenging to treat but a subset of pancreatic tumors namely those with high TMB, MSI-H, and/or deficient MMR expression appear to have promising results when treated with ICIs, as demonstrated in this case report. Though these tumors are rare, it is highly recommended that all cases of PDAC undergo tumor and germline testing to determine candidacy for immunotherapy or other potential treatment options.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Gastrointestinal Oncology. The article did not undergo external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-23-12/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.

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