Four-Year Disease-Free Remission in a Patient With POLE Mutation–Associated Colorectal Cancer Treated Using Anti–PD-1 Therapy

Authors:
Michael L. Durando Banner-University Medical Center Tucson, Tucson, Arizona;
Division of Hematology and Oncology, Department of Medicine,
University of Arizona Cancer Center,

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 MD, PhD
,
Sanjay V. Menghani Department of Immunobiology, and

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 PhD
,
Jessica L. Baumann Department of Pathology, University of Arizona College of Medicine—Tucson, Tucson, Arizona;
Now with Roche Tissue Diagnostics, Tucson, Arizona;

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Danny G. Robles Banner-University Medical Center Tucson, Tucson, Arizona;
Department of Surgery, University of Arizona College of Medicine—Tucson, Tucson, Arizona;

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Tovah A. Day Department of Biology, Northeastern University, Boston, Massachusetts; and

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Cyrus Vaziri Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina.

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Aaron J. Scott Banner-University Medical Center Tucson, Tucson, Arizona;
Division of Hematology and Oncology, Department of Medicine,
University of Arizona Cancer Center,

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Volume/Issue:
Volume 20: Issue 3
Online Publication Date:
Mar 2022
DOI:
https://doi.org/10.6004/jnccn.2021.7115
Full access

The stability of the human genome depends upon a delicate balance between replication by high- and low-fidelity DNA polymerases. Aberrant replication by error-prone polymerases or loss of function of high-fidelity polymerases predisposes to genetic instability and, in turn, cancer. DNA polymerase epsilon (Pol ε) is a high-fidelity, processive polymerase that is responsible for the majority of leading strand synthesis, and mutations in Pol ε have been increasingly associated with various human malignancies. The clinical significance of Pol ε mutations, including how and whether they should influence management decisions, remains poorly understood. In this report, we describe a 24-year-old man with an aggressive stage IV high-grade, poorly differentiated colon carcinoma who experienced a dramatic response to single-agent checkpoint inhibitor immunotherapy after rapidly progressing on standard chemotherapy. His response was complete and durable and has been maintained for more than 48 months. Genetic testing revealed a P286R mutation in the endonuclease domain of POLE and an elevated tumor mutational burden of 126 mutations per megabase, both of which have been previously associated with response to immunotherapy. Interestingly, tumor staining for PD-L1 was negative. This case study highlights the importance of genetic profiling of both early and late-stage cancers, the clinical significance of POLE mutations, and how the interplay between genetic instability and immune-checkpoint blockade can impact clinical decision-making.

Background

Accurate replication of the human genome is the cornerstone of genetic stability. Any perturbance of the fidelity of DNA replication predisposes to genetic instability and cancer. Human cells contain both accurate, replicative DNA polymerases and error-prone DNA polymerases.1 Selection, recruitment, and activation of the appropriate polymerase to damaged or undamaged DNA ensures accurate replication and preserves genomic integrity.1 High-fidelity replication in human cells is performed primarily by B family DNA polymerases, including the highly conserved DNA Polymerase (Pol) α, ε, and δ.1 Pol α initiates DNA replication, whereas Pols ε and δ propagate DNA replication at the leading and lagging strands, respectively, with high processivity and extremely high fidelity (approximately 1 error per 107 bases).2 The fidelity of both Pol ε and Pol δ is attributed to base selectivity within the catalytic subunit and exonuclease proofreading activity.3

DNA Pol ε comprises 4 subunits, the largest of which is p261 (Pol 2 or Pol ε1), encoded by the POLE1 gene.4 The p261 subunit comprises a 261 kDa protein containing the enzymatically active DNA polymerase and exonuclease domains at its N terminus and the enzymatically inactive C terminus that binds to the 3 smaller Pol ε subunits.5 Mutations in the exonuclease are tumorigenic in mice, in particular causing tumors of gastrointestinal origin.6 In humans, disease-causing dysfunction of Pol ε was first reported as the etiologic cause of facial-dysmorphism, immunodeficiency, livedo, and short stature syndrome.7

In 2013, whole-genome sequencing of patients with familial colorectal carcinoma (CRC) identified germline mutations in DNA Pol ε and δ.8 Since then, POLE mutations have been associated with melanoma,9 endometrial cancer,10 brain cancer,11,12 ovarian cancer,13 pancreatic cancer,14,15 and colorectal and other gastrointestinal cancers.11,15,16 This predisposition to cancer is largely attributed to mutations in the exonuclease subunit proofreading domain of Pol ε17; indeed, the most frequent cancer-associated mutation in POLE is P286R, within this domain.17–19 Data from yeast and mice indicate that this substitution increases mutations to a greater extent than the loss of proofreading activity alone,20,21 likely by sterically blocking the exonuclease site.22 In CRC, a 2016 retrospective cohort study identified POLE mutations in approximately 2% of patients, who were predominantly male and aged <40 years.23 POLE mutations have conferred a significant increase in recurrence- and disease-free survival in early-stage disease and have been associated with a more immunogenic microenvironment, including higher infiltration of CD8+ T lymphocytes and the expression of interferon-responsive cytokines CXCL9 and CXCL10.23

Increasing evidence has supported the efficacy of immune checkpoint inhibition for POLE mutation–associated CRC.24–30 This report presents a patient with stage IV high-grade, poorly differentiated colon carcinoma who rapidly progressed on standard chemotherapy and subsequently experienced a dramatic and durable complete response to single-agent pembrolizumab, which was chosen off-label after molecular analysis of his tumor DNA revealed a P286R POLE mutation and high mutational burden.

Case Report

A 24-year-old man with no significant past medical history presented to the emergency department for a chief complaint of left-sided abdominal pain and emesis. He presented to the emergency department 4 times over a span of 5 months with similar complaints. Chest and abdominal radiographs and CBC counts were unremarkable, except for slight leukocytosis and microcytic anemia on previous visits. On the fifth presentation, CT revealed focal thickening of the descending colon with a 4-cm abscess and possible perforation between the sigmoid and descending colon (Figure 1A). The CEA level was 223 ng/μL and alpha-fetoprotein was undetectable. A CT-guided drain was placed in the abscess and the patient was treated using broad-spectrum antibiotics with plans for a colonoscopy postdischarge. Ten days after discharge (3 weeks after first imaging), the patient again returned with similar complaints. CT revealed resolution of the abscess but persistent and worsening mass-like thickening of the descending colon and new small and large bowel obstructions (Figure 1B). Exploratory laparotomy revealed severe peritoneal inflammation, distended small bowel loops, and a significantly distended transverse and proximal descending colon, which contained a large firm perforated mass that was intensely adhered to the lateral abdominal wall, retroperitoneum, and spleen. Left hemicolectomy, splenectomy, and small bowel resection with end colostomy were performed. Gross examination of the descending colon revealed a 14 × 9 × 8-cm mass with an approximately 5-cm irregular fungating fistulous opening. Hematoxylin-eosin and CDX-2 staining31 showed high-grade, poorly differentiated carcinoma with margin involvement, pathologic stage pT4aN0, and a Ki-67 index >90% (Figure 2), consistent with AJCC stage IIB colon cancer. DNA mismatch repair (MMR) staining revealed intact MLH-1, PMS-2, MSH-2, and MSH-6. The patient had no family history of cancer or carcinogen exposures. He was discharged after surgical recovery with oncology follow-up.

Figure 1.
Figure 1.

Representative axial, coronal, and sagittal plane views (first, second, and third columns, respectively) CT images of the patient (A) at initial presentation with colonic perforation and abscess, (B) approximately 3 weeks later with small and large bowel obstructions before surgical resection, (C) approximately 2 months after resection and 3 weeks after starting CAPOX regimen, (D) approximately 12 weeks after resection after 2 cycles of pembrolizumab, and (E) after approximately 11 months of pembrolizumab therapy. Note that horizontal lines in the axial images correspond to the respective levels in the coronal and sagittal images.

Abbreviation: CAPOX, capecitabine/oxaliplatin.

Citation: Journal of the National Comprehensive Cancer Network 20, 3; 10.6004/jnccn.2021.7115

Figure 2.
Figure 2.

Representative (A) hematoxylin-eosin and (B) CDX-2 staining sections of the resected descending colon mass with increasing magnification. Note the poorly differentiated neoplasm (left) infiltrating the adjacent colonic mucosa (right). Images are 8.5 × 6 cm.

Citation: Journal of the National Comprehensive Cancer Network 20, 3; 10.6004/jnccn.2021.7115

Approximately 1 month postresection, MRI showed a large, vascularized, centrally necrotic mass in the left-upper quadrant (LUQ) measuring 10 × 12 × 11 cm with extension into the left mesocolon mesentery and encasement of the adjacent vasculature (Figure 3A), indicating a rapidly growing, recurrent, stage IV colon cancer. The CEA level at this time was 151 ng/µL. Chemotherapy using capecitabine/oxaliplatin (CAPOX) was initiated 2 weeks later, with the CEA level increasing to 450 ng/µL. Bevacizumab was added in cycle 2, but the patient’s disease markedly progressed after 2 cycles, with the CEA level increasing to 514 ng/µL and the LUQ mass increasing to 15 × 10 × 11 cm as seen on CT (Figure 1C). Caris Molecular Intelligence (Caris Life Sciences, Inc.) profiling of the patient’s resected tumor tissue revealed a high mutational load and a POLE P286R mutation, along with the following mutations: KRAS G13D; PIK3CA C278W; a BRCA1 variant of unknown significance (VUS), R1443Q; and BRCA2 VUS K2191N. After this result, our patient was referred for genetic counseling and germline testing. Analysis via the CancerNext panel (Ambry Genetics) showed no detectable alterations of germline origin, including the POLE, BRCA1, and BRCA2 genes.

Figure 3.
Figure 3.

MRI scans of axial and coronal (first and second columns, respectively) (A) before initiating systemic treatment, (B) after 2 cycles of the CAPOX regimen and 2 doses of pembrolizumab, (C) after 5 doses of pembrolizumab, and (D) after 40 months of pembrolizumab. Note that horizontal lines in the axial sections correspond to the coronal image and vice versa for horizontal lines in the coronal images.

Abbreviation: CAPOX, capecitabine/oxaliplatin.

Citation: Journal of the National Comprehensive Cancer Network 20, 3; 10.6004/jnccn.2021.7115

Considering the genetic profiling consistent with genetic instability (high tumor mutational burden, POLE mutation) and clear progression on CAPOX, the patient was quickly transitioned to immune checkpoint inhibition with monthly infusions of 200 mg intravenous pembrolizumab, which was off-label at the time. The patient experienced 2 gastrointestinal bleeds after the first 2 pembrolizumab infusions, for which he was admitted to the hospital with blood hemoglobin values of 6.5 and 5.6 g/dL, respectively; these bleeds were managed conservatively. His LUQ mass measured 13 × 7 × 7 cm at this point and his CEA level had decreased to 106 ng/µL (see Figures 1D and 3B). The patient then underwent multiple CT-guided biopsies of the mass, all of which revealed severe inflammation and fibrosis without evidence of malignancy. The patient underwent an exploratory laparotomy with resection of the abdominal mass and reversal of the end colostomy 5 weeks after the second dose of pembrolizumab. Extensive inflammation, necrosis, and fibrosis were identified, but there was no evidence of viable tumor cells. Approximately 2 weeks postresection, his CEA level was 3.9 ng/µL and he was given a third dose of pembrolizumab, after which monthly infusions were continued. CT and MRI 5 months after pembrolizumab initiation showed markedly reduced disease burden (Figure 3C) with complete resolution of the mass at 11 months (Figure 1E). Monthly pembrolizumab infusions continued with persistent complete response on interval CT and MRI. An MRI obtained 40 months after initiating pembrolizumab showed no evidence of disease (Figure 3D), and CEA remained within normal limits (Figure 4). The patient remained disease-free 48 months after the first pembrolizumab infusion and was transitioned to annual surveillance follow-up in the clinic.

Figure 4.
Figure 4.

CEA level over time, indicating important events (ie, treatment day, scan review) along the disease and treatment course.

Abbreviations: C2D1, cycle 2, day 1; C2D15, cycle 2, day 15; CAPOX, capecitabine/oxaliplatin; CEA, carcinoembryonic antigen; ULN, upper limit of normal.

Citation: Journal of the National Comprehensive Cancer Network 20, 3; 10.6004/jnccn.2021.7115

Discussion

Genomic sequencing continues to revolutionize treatment approaches for different malignancies with a shift to molecular-driven therapy. In 2012, the Cancer Genome Atlas performed molecular characterization of 224 CRCs and identified multiple targetable alterations, including hypermutation in 16% of the tumors. Of the hypermutated tumors, 25% carried somatic mutations in MMR genes or POLE.18 In a 2016 retrospective study of patients with CRC, POLE mutations were identified in 9.8% of those diagnosed at aged ≤45 years compared with 1% in those aged ≥65 years.32 In endometrial cancers, these same mutations are associated with increased immune cell infiltrates and expression of PD-1 and PD-L1, and POLE mutations correlate with antitumor immune response in this population.33 There have been prior reports of positive response to pembrolizumab in patients with CRC with POLE mutations29; however, the response reported was not as complete or durable as we observed in this patient.

The case study presented here describes a young and otherwise healthy patient with high-grade nonmetastatic disease who rapidly recurred and then progressed on initial treatment using standard first-line chemotherapy (CAPOX), as evidenced by increasing CEA levels and tumor burden on imaging (Figure 1A, B), and was then transitioned to off-label single-agent immunotherapy based on genetic profiling of his tumor. The patient’s CEA level reached an apex of 514 ng/µL after 2 cycles of CAPOX but then rapidly decreased to 106 ng/µL after 2 cycles of pembrolizumab and then 2.4 ng/µL after 2 additional cycles (Figure 4). Imaging showed continued complete response 40 months after initiation of pembrolizumab (Figure 3D), with the patient remaining clinically disease-free at 4 years. This is the first patient to show complete and persistent response to anti–PD-1 therapy in sporadic stage IV CRC. Notably, the selection of immune therapy was off-label at the time, and was guided by molecular profiling studies on tumor DNA and the patient’s rapid progression on standard chemotherapy.

Although the exact molecular basis of this patient’s response is impossible to elucidate, the strong associations between immune checkpoint inhibition and genetic instability suggest an explanation for his remarkable sensitivity to immunotherapy. Loss of proofreading function compromises Pol ε catalytic fidelity, leading to a high rate of base substitutions and an exceptionally high mutation burden, termed “ultramutation.”19 For example, POLE-mutated endometrial cancers are associated with an exceptionally high mutational burden and increased T-cell tumor infiltration.33,34 POLE-mutated gliomas and endometrial cancers are associated with better prognoses, thought to result from increased immunogenicity.11,33,34 Indeed, POLE-mutated endometrial cancers with a high mutational burden show an excellent response to immune checkpoint blockade, including after developing resistance to cytotoxic chemotherapy.26 One unresolved question is whether prior treatment of our patient using CAPOX enhanced tumor immunogenicity through increased mutagenesis or an alternative mechanism. To date, POLE-mutated colorectal tumors that responded to pembrolizumab received prior chemotherapy.28,29,35 A possible role for chemotherapy as pretreatment to enhance immunogenicity may warrant future investigation.

Other genetic deficiencies can complement POLE mutations to influence the mutagenesis phenotype. Several studies have shown that MMR deficiency amplifies mutagenesis caused by POLE mutations.10,36–38 In contrast, it has been shown that cancer-associated POLE alleles are capable of generating a hypermutator phenotype even when MMR is functional.39 Somatic or germline POLE P286R mutations are rarely seen with deficient MMR.39 In keeping with this trend, our patient’s tumor was MMR-proficient, indicating that mutation accumulation can be attributed primarily to POLE P286R. Interactions with other polymerase activities may also be relevant to the phenotype of POLE mutation. A recent study showed that mutations in POLQ and REV3L synergize with POLE mutations to further enhance mutation rates and immune cell infiltration40; however, it is unknown how POLQ and REV3L mutations influence response to treatment. Similarly, although BRCA1/2 deficiencies are associated with higher mutational burden, increased tumor immunogenicity, and improved survival, it remains unknown whether the BRCA1/BRCA2 VUS in our patient’s tumor altered mutagenesis patterns and/or therapeutic response.41

Genetic testing on this patient revealed that 46% of tumor cells harbored the P286R mutation in the exonuclease proofreading domain of POLE. This particular POLE mutation has been shown to cause a mutator phenotype20 and has been suggested as a possible indicator of response to immune therapy.42 Indeed, this patient’s tumor showed an extremely elevated mutation load of 126 mutations/megabase. Interestingly, the tumor stained negative for PD-L1, contrary to other recent reports of patients with CRC who experienced positive response to immune checkpoint inhibition.28,29 Based on the literature and this patient’s response to single-agent PD-1 blockade, it is reasonable to postulate that his POLE mutation–associated genetic instability conferred sensitivity to immune checkpoint inhibition. Of note, at the time of writing, there were a number of ongoing and recently concluded clinical trials of POLE-mutated tumors and immune checkpoint blockade as monotherapy or in combination with traditional chemotherapies (see ClinicalTrials.gov identifiers: NCT03810339, NCT03150706, NCT03435107, and NCT03827044). Additional studies will be necessary to determine whether POLE mutations, tumor mutational burden, or a combination of the 2 may serve as bona fide biomarkers to predict response to immunotherapy in colorectal and other malignancies.

Conclusions

Sporadic CRC in young patients (aged <50 years) is 10 times more likely to be associated with POLE mutations than in those diagnosed through screening.10 POLE mutations contribute to a hypermutated phenotype, which correlates with anti–PD-1 therapy response. This case study highlights how genomic profiling identified a POLE mutation associated with genetic instability and guided the selection of anti–PD-1 therapy, which elicited a complete and durable response. Further research is warranted to determine whether immuno-oncology therapy should be considered as a first-line treatment for patients with cancer harboring POLE mutations.

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Submitted August 21, 2021; final revision received November 17, 2021; accepted for publication November 18, 2021.

Michael L. Durando, MD, PhD, and Sanjay V. Menghani, PhD, contributed equally to this study.

Disclosures: The authors have disclosed that they have not received any financial considerations from any person or organization to support the preparation, analysis, results, or discussion of this article.

Funding: Dr. Durando’s training was supported by the Training Program in Immunobiology of Normal and Neoplastic Lymphocytes funded by the NCI of the NIH under award number T32-CA-009140. Dr. Menghani’s training was supported by the National Institute of General Medical Sciences of the NIH under award number 1F30GM139246-01A1.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Correspondence: Aaron J. Scott, MD, Division of Hematology and Oncology, Department of Medicine, University of Arizona College of Medicine—Tuscon, P.O. Box 245054, 1515 North Campbell Avenue, Tucson, AZ 85724-5024. Email: ajscott@email.arizona.edu
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    Figure 1.

    Representative axial, coronal, and sagittal plane views (first, second, and third columns, respectively) CT images of the patient (A) at initial presentation with colonic perforation and abscess, (B) approximately 3 weeks later with small and large bowel obstructions before surgical resection, (C) approximately 2 months after resection and 3 weeks after starting CAPOX regimen, (D) approximately 12 weeks after resection after 2 cycles of pembrolizumab, and (E) after approximately 11 months of pembrolizumab therapy. Note that horizontal lines in the axial images correspond to the respective levels in the coronal and sagittal images.

    Abbreviation: CAPOX, capecitabine/oxaliplatin.

  • Figure 2.
    View in gallery
    Figure 2.

    Representative (A) hematoxylin-eosin and (B) CDX-2 staining sections of the resected descending colon mass with increasing magnification. Note the poorly differentiated neoplasm (left) infiltrating the adjacent colonic mucosa (right). Images are 8.5 × 6 cm.

  • Figure 3.
    View in gallery
    Figure 3.

    MRI scans of axial and coronal (first and second columns, respectively) (A) before initiating systemic treatment, (B) after 2 cycles of the CAPOX regimen and 2 doses of pembrolizumab, (C) after 5 doses of pembrolizumab, and (D) after 40 months of pembrolizumab. Note that horizontal lines in the axial sections correspond to the coronal image and vice versa for horizontal lines in the coronal images.

    Abbreviation: CAPOX, capecitabine/oxaliplatin.

  • Figure 4.
    View in gallery
    Figure 4.

    CEA level over time, indicating important events (ie, treatment day, scan review) along the disease and treatment course.

    Abbreviations: C2D1, cycle 2, day 1; C2D15, cycle 2, day 15; CAPOX, capecitabine/oxaliplatin; CEA, carcinoembryonic antigen; ULN, upper limit of normal.

Figure 1.

Representative axial, coronal, and sagittal plane views (first, second, and third columns, respectively) CT images of the patient (A) at initial presentation with colonic perforation and abscess, (B) approximately 3 weeks later with small and large bowel obstructions before surgical resection, (C) approximately 2 months after resection and 3 weeks after starting CAPOX regimen, (D) approximately 12 weeks after resection after 2 cycles of pembrolizumab, and (E) after approximately 11 months of pembrolizumab therapy. Note that horizontal lines in the axial images correspond to the respective levels in the coronal and sagittal images.

Abbreviation: CAPOX, capecitabine/oxaliplatin.
Figure 2.

Representative (A) hematoxylin-eosin and (B) CDX-2 staining sections of the resected descending colon mass with increasing magnification. Note the poorly differentiated neoplasm (left) infiltrating the adjacent colonic mucosa (right). Images are 8.5 × 6 cm.
Figure 3.

MRI scans of axial and coronal (first and second columns, respectively) (A) before initiating systemic treatment, (B) after 2 cycles of the CAPOX regimen and 2 doses of pembrolizumab, (C) after 5 doses of pembrolizumab, and (D) after 40 months of pembrolizumab. Note that horizontal lines in the axial sections correspond to the coronal image and vice versa for horizontal lines in the coronal images.

Abbreviation: CAPOX, capecitabine/oxaliplatin.
Figure 4.

CEA level over time, indicating important events (ie, treatment day, scan review) along the disease and treatment course.

Abbreviations: C2D1, cycle 2, day 1; C2D15, cycle 2, day 15; CAPOX, capecitabine/oxaliplatin; CEA, carcinoembryonic antigen; ULN, upper limit of normal.
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Copyright:
Copyright © 2022 by the National Comprehensive Cancer Network 2022
Page Numbers:
6
Article Category:
Research Article
Received:
21 Aug 2021
Accepted:
18 Nov 2021
Print Publication Date:
01 Mar 2022
Online Publication Date:
Mar 2022
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