Immune checkpoint inhibitor in microsatellite stable, POLE-mutated, tumor mutational burden-high metastatic colon cancer—a case report

Introduction

Colorectal cancer (CRC) is the fourth most common cancer and the second most common cause of cancer-related death in the United States. Although surgical resection alone can be curative in early-stage CRC, locally advanced or metastatic disease requires systemic therapy. Recently, there has been growing focus on the role of genetic testing, molecular profiling, and immunotherapy in CRC management. Microsatellite instability-high (MSI-H) tumors are targetable through immune checkpoint inhibitors (ICIs) in several types of solid tumors, including CRC. André et al. showed greater progression-free survival with pembrolizumab, a human monoclonal immunoglobulin G (IgG)4 antibody against programmed death-1 (PD-1), compared to chemotherapy in metastatic MSI-H/defective mismatch repair (dMMR) CRC as first-line therapy (1). In addition to MSI, other mutations may present novel targets for ICI in CRC. DNA polymerase epsilon (POLE) is involved in nucleotide and base excision repair. Pathogenic mutations in POLE have been found to respond to ICI (2). Tumor mutational burden (TMB), a measure of somatic mutations within a certain coding area of a tumor genome, may also assist in the selection of immunotherapy. The KEYNOTE-158 study demonstrated the effectiveness of pembrolizumab in many different types of unresectable/metastatic cancers with TMB-high (TMB-H) status (3). We present a case of complete response of metastatic microsatellite stable (MSS), POLE-mutated positive, KRAS and BRAF wildtype, TMB-H CRC to neoadjuvant pembrolizumab. We present this article in accordance with the CARE reporting checklist (available at https://amj.amegroups.com/article/view/10.21037/amj-24-13/rc).

Case presentation

A 31-year-old male presented with left lower quadrant abdominal pain and intermittent hematochezia. Medical history was notable for iron-deficiency anemia, depression, and previous alcohol use disorder. Physical exam revealed some left lower quadrant tenderness with computed tomography (CT) imaging revealing a 13 cm mass in the sigmoid colon with invasion of adjacent small bowel loops and the abdominal wall musculature (Figure 1), in addition to enlarged left mesenteric common iliac and external iliac lymph nodes. A 1.4 cm metastatic soft tissue nodule in the left peritoneum was also seen. Biopsy of the colonic mass revealed moderately differentiated invasive adenocarcinoma and he was diagnosed with stage IV colon adenocarcinoma. Mismatch repair testing by immunohistochemistry showed no loss of nuclear expression of MMR proteins. Molecular profiling via CARIS revealed KRAS-wildtype, BRAF-wildtype, programmed cell death-ligand 1 (PD-L1) negative, POLE-mutated positive (pathogenic EXON14 pA.456P), and elevated TMB of 133 mutations/megabase.

Figure 1 Pre-treatment contrast-enhanced CT scan. (A) Axial CT image demonstrating a tumor in the sigmoid colon with invasion of the abdominal and left psoas muscle. (B) Sagittal CT image demonstrating invasion of the abdominal wall. (C) Axial CT image demonstrating a metastatic nodule in the left retroperitoneum. (D) Coronal CT image demonstrating the sigmoid tumor with invasion of the iliacus muscle laterally and adjacent small bowel loops medially. CT, computed tomography.

The patient was started on neoadjuvant chemotherapy with FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) at full dose for his body size. Carcinoembryonic antigen (CEA) was 18.7 ng/mL preceding chemotherapy. However, after two cycles he developed severe abdominal pain and was found to have developed a new coloenteric fistula extending into the primary colonic mass and evidence of small bowel obstruction. Given his poor tolerance of cytotoxic chemotherapy and progressive disease, the decision was made to pursue pembrolizumab based on his POLE and TMB status. After completing six cycles of pembrolizumab, CT imaging showed impressive tumor treatment response with a significant decrease in size of the sigmoid mass, decreased invasion of abdominal wall and resolution of the retroperitoneal nodule (Figure 2). CEA normalized to 0.6 ng/mL on immunotherapy. After 12 cycles of pembrolizumab 200 mg every 3 weeks, the patient underwent ex-lap with sigmoid colectomy and adjacent excision of abdominal and pelvic wall musculature with abdominal wall reconstruction. Surgical pathology (Figure 3). revealed a complete pathologic response and was negative for residual viable tumor and negative for metastatic carcinoma in 16 lymph nodes. A small residual colonic mass in the pathologic specimen demonstrated necrosis, calcification, and fibrosis. Repeat imaging has been negative for recurrent disease and the patient remains recurrence-free now 37 months after completing immunotherapy.

Figure 2 Post-ICI/pre-operative contrast-enhanced CT scan. Axial (A) and sagittal (B) CT images demonstrating significant decrease in size of the colonic tumor with decreased invasion of the abdominal wall musculature. (C) Axial CT image demonstrating resolution of the nodule in the left retroperitoneum. (D) Coronal CT image demonstrating decreased size of the sigmoid tumor, no invasion of the iliacus muscle laterally with intervening fat plane, and resolution of the small bowel invasion medially. CT, computed tomography; ICI, immune checkpoint inhibitor.

Figure 3 Pathology post-immunotherapy and surgical resection. (A) Necrosis of tumor cells with dystrophic calcification of the necrotic material (H&E staining, 100×). (B,C) Islands and nodules of necrotic tumor surrounded by dense fibrosis. Inflammatory infiltrate composed of an inner rim of histiocytes and an outer rim of lymphocytes and plasma cells (H&E staining, 200×). H&E, hematoxylin and eosin.

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 and its subsequent amendments. Written informed consent was obtained from the patient for 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.

Discussion

Metastatic CRC remains a challenging malignancy to manage despite many therapeutic options, including chemotherapy, vascular endothelial growth factor (VEGF) inhibitors, targeted therapies such as epidermal growth factor receptor (EGFR) inhibitors, and immunotherapy, owing in part to its heterogeneous genomic structure. In the appropriate MSI-H/dMMR patient, response rates to PD-1 inhibitors are promising but variable (3). These dMMR tumors contain thousands of mutations which can encode mutant proteins that are able to be potentially recognized by the immune system. In a Phase III open-label clinical trial involving 307 patients with metastatic MSI-H CRC, André et al. showed greater progression-free survival using PD-1 inhibitor pembrolizumab at a dose of 200 mg every 3 weeks compared to chemotherapy as first-line therapy (1). Largely due to this study, immunotherapy treatment has become a first-line National Comprehensive Cancer Network (NCCN) category 1 recommendation for MSI-H CRC.

Currently, only 3.5–5% of patients with stage IV CRC are MSI-H. It therefore remains crucial to identify other markers in MSS CRC that may be targetable by immunotherapies. DNA POLE is involved in 3'→5' exonuclease proofreading. Mutations in POLE, the largest subunit of DNA polymerase , are relatively uncommon, constituting 3% of CRC cases (4). They are more common in younger age patients and males (5). POLE-mutated malignancies are associated with microsatellite stability, but also have high levels of single-nucleotide substitutions (SNSs) and TMB-H which can create neoantigens that may be targets for ICI. Pathogenic variants of POLE mutations have been shown to respond to ICI: Garmezy et al. (2) showed greater progression-free survival (15.1 vs. 2.2 months) and overall survival (29.5 vs. 6.8 months) in patients with solid tumors, including CRC, that were treated with ICI in combination with or absence of cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitors. TMB can also be beneficial for predicting positive response to ICI in various cancers. Yarchoan et al. demonstrated a correlation between higher level of TMB and objective response rate to ICI but showed a lower predicted response in CRC (6). POLE-mutated CRC has also been shown to respond to ICI. Roussea et al. showed greater median overall survival in TMB-H vs. TMB-low CRC treated with ICI (43 vs. 12 months) (7). However, after cohort stratification, this benefit was only present in CRC with POLE-mutated or evidence of dMMR. Wang et al. showed that TMB was higher in pol-d mutated cancers, including CRC, and that POLE-mutated cancers also had greater overall survival when treated with ICI (8). Gong et al. reported a case of recurrent CRC with an elevated TMB (122 mutations/megabase) and mutations in POLE (V411L) and RAF1R (256S) that had clinical response with reduction in tumor size after just two cycles of pembrolizumab which was sustained after eight cycles (9).

Patient perspective: per patient and his mother: “The key is remembering to fight. Accept what God brings you in life but never lose hope”.

Conclusions

Despite our patient’s cancer having intact mismatch repair, he responded to ICI. However, he had a significantly elevated TMB, as well as pathogenic POLE mutation. To the best of our knowledge, our case is the first to demonstrate complete pathologic response in MSS, TMB-H, POLE-mutated tumor 37 months post-completion of neoadjuvant pembrolizumab. Our findings warrant consideration of further investigation of the role of neoadjuvant ICI in MSS, TMB-H, POLE-mutated CRC in a prospective setting.

Acknowledgments

Many thanks to our patient and his mother who provided full consent to have this case shared with the world in the hope that other patients might benefit from this observation in the future.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://amj.amegroups.com/article/view/10.21037/amj-24-13/rc

Peer Review File: Available at https://amj.amegroups.com/article/view/10.21037/amj-24-13/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://amj.amegroups.com/article/view/10.21037/amj-24-13/coif). J.S. received payments made to him for expert testimony in unrelated cases. S.W. received consulting fees from Clario as an oncologic imaging consultant and payments from Eisai for lectures. J.K. received grants from NRG Oncology Pilot Grant, UCCC Pilot Award, and UC College of Medicine Innovation Award. D.S. has ongoing consulting agreements with Regeron and Elevar, which were not related to this article. The other 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 and its subsequent amendments. Written informed consent was obtained from the patient for 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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