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,

Search for other papers by Michael L. Durando in
Current site
Google Scholar
PubMed
Close
 MD, PhD
,
Sanjay V. Menghani Department of Immunobiology, and

Search for other papers by Sanjay V. Menghani in
Current site
Google Scholar
PubMed
Close
 PhD
,
Jessica L. Baumann Department of Pathology, University of Arizona College of Medicine—Tucson, Tucson, Arizona;
Now with Roche Tissue Diagnostics, Tucson, Arizona;

Search for other papers by Jessica L. Baumann in
Current site
Google Scholar
PubMed
Close
 MD
,
Danny G. Robles Banner-University Medical Center Tucson, Tucson, Arizona;
Department of Surgery, University of Arizona College of Medicine—Tucson, Tucson, Arizona;

Search for other papers by Danny G. Robles in
Current site
Google Scholar
PubMed
Close
 MS, MD
,
Tovah A. Day Department of Biology, Northeastern University, Boston, Massachusetts; and

Search for other papers by Tovah A. Day in
Current site
Google Scholar
PubMed
Close
 PhD
,
Cyrus Vaziri Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina.

Search for other papers by Cyrus Vaziri in
Current site
Google Scholar
PubMed
Close
 PhD
, and
Aaron J. Scott Banner-University Medical Center Tucson, Tucson, Arizona;
Division of Hematology and Oncology, Department of Medicine,
University of Arizona Cancer Center,

Search for other papers by Aaron J. Scott in
Current site
Google Scholar
PubMed
Close
 MD
Restricted 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.

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
  • Collapse
  • Expand
  • 1.

    Park VS, Pursell ZF. POLE proofreading defects: contributions to mutagenesis and cancer. DNA Repair (Amst) 2019;76:5059.

  • 2.

    Burgers PM. Polymerase dynamics at the eukaryotic DNA replication fork. J Biol Chem 2009;284:40414045.

  • 3.

    Garg P, Burgers PM. DNA polymerases that propagate the eukaryotic DNA replication fork. Crit Rev Biochem Mol Biol 2005;40:115128.

  • 4.

    Korona DA, Lecompte KG, Pursell ZF. The high fidelity and unique error signature of human DNA polymerase epsilon. Nucleic Acids Res 2011;39:17631773.

  • 5.

    Bermudez VP, Farina A, Raghavan V, et al. Studies on human DNA polymerase epsilon and GINS complex and their role in DNA replication. J Biol Chem 2011;286:2896328977.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Albertson TM, Ogawa M, Bugni JM, et al. DNA polymerase ε and δ proofreading suppress discrete mutator and cancer phenotypes in mice. Proc Natl Acad Sci USA 2009;106:1710117104.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Pachlopnik Schmid J, Lemoine R, Nehme N, et al. Polymerase ε1 mutation in a human syndrome with facial dysmorphism, immunodeficiency, livedo, and short stature (“FILS syndrome”). J Exp Med 2012;209:23232330.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Briggs S, Tomlinson I. Germline and somatic polymerase ε and δ mutations define a new class of hypermutated colorectal and endometrial cancers. J Pathol 2013;230:148153.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Aoude LG, Heitzer E, Johansson P, et al. POLE mutations in families predisposed to cutaneous melanoma. Fam Cancer 2015;14:621628.

  • 10.

    Billingsley CC, Cohn DE, Mutch DG, et al. Polymerase ɛ (POLE) mutations in endometrial cancer: clinical outcomes and implications for Lynch syndrome testing. Cancer 2015;121:386394.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Erson-Omay EZ, Çağlayan AO, Schultz N, et al. Somatic POLE mutations cause an ultramutated giant cell high-grade glioma subtype with better prognosis. Neuro-oncol 2015;17:13561364.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Lindsay H, Scollon S, Reuther J, et al. Germline POLE mutation in a child with hypermutated medulloblastoma and features of constitutional mismatch repair deficiency. Cold Spring Harb Mol Case Stud 2019;5:a004499.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Rohlin A, Zagoras T, Nilsson S, et al. A mutation in POLE predisposing to a multi-tumour phenotype. Int J Oncol 2014;45:7781.

  • 14.

    Kryklyva V, Ter Linden E, Kroeze LI, et al. Medullary pancreatic carcinoma due to somatic POLE mutation: a distinctive pancreatic carcinoma with marked long-term survival. Pancreas 2020;49:9991003.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Hansen MF, Johansen J, Bjørnevoll I, et al. A novel POLE mutation associated with cancers of colon, pancreas, ovaries and small intestine. Fam Cancer 2015;14:437448.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Valle L, Hernández-Illán E, Bellido F, et al. New insights into POLE and POLD1 germline mutations in familial colorectal cancer and polyposis. Hum Mol Genet 2014;23:35063512.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Rayner E, van Gool IC, Palles C, et al. A panoply of errors: polymerase proofreading domain mutations in cancer. Nat Rev Cancer 2016;16:7181.

  • 18.

    Muzny DM, Bainbridge MN, Chang K, et al. Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012;487:330337.

  • 19.

    Kandoth C, Schultz N, Cherniack AD, et al. Integrated genomic characterization of endometrial carcinoma. Nature 2013;497:6773.

  • 20.

    Kane DP, Shcherbakova PV. A common cancer-associated DNA polymerase ε mutation causes an exceptionally strong mutator phenotype, indicating fidelity defects distinct from loss of proofreading. Cancer Res 2014;74:18951901.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Li HD, Cuevas I, Zhang M, et al. Polymerase-mediated ultramutagenesis in mice produces diverse cancers with high mutational load. J Clin Invest 2018;128:41794191.

  • 22.

    Parkash V, Kulkarni Y, Ter Beek J, et al. Structural consequence of the most frequently recurring cancer-associated substitution in DNA polymerase ε. Nat Commun 2019;10:373.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Domingo E, Freeman-Mills L, Rayner E, et al. Somatic POLE proofreading domain mutation, immune response, and prognosis in colorectal cancer: a retrospective, pooled biomarker study. Lancet Gastroenterol Hepatol 2016;1:207216.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Eng C. POLE mutations in colorectal cancer: a new biomarker? Lancet Gastroenterol Hepatol 2016;1:176177.

  • 25.

    Picard E, Verschoor CP, Ma GW, et al. Relationships between immune landscapes, genetic subtypes and responses to immunotherapy in colorectal cancer. Front Immunol 2020;11:369.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Santin AD, Bellone S, Buza N, et al. Regression of chemotherapy-resistant polymerase ε (POLE) ultra-mutated and MSH6 hyper-mutated endometrial tumors with nivolumab. Clin Cancer Res 2016;22:56825687.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Stenzinger A, Pfarr N, Endris V, et al. Mutations in POLE and survival of colorectal cancer patients—link to disease stage and treatment. Cancer Med 2014;3:15271538.

  • 28.

    Chen J, Lou H. Complete response to pembrolizumab in advanced colon cancer harboring somatic POLE F367S mutation with microsatellite stability status: a case study. Onco Targets Ther 2021;14:17911796.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Gong J, Wang C, Lee PP, et al. Response to PD-1 blockade in microsatellite stable metastatic colorectal cancer harboring a POLE mutation. J Natl Compr Canc Netw 2017;15:142147.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Kim JH, Kim SY, Baek JY, et al. A phase II study of avelumab monotherapy in patients with mismatch repair-deficient/microsatellite instability-high or POLE-mutated metastatic or unresectable colorectal cancer. Cancer Res Treat 2020;52:11351144.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31.

    Bayrak R, Haltas H, Yenidunya S. The value of CDX2 and cytokeratins 7 and 20 expression in differentiating colorectal adenocarcinomas from extraintestinal gastrointestinal adenocarcinomas: cytokeratin 7-/20+ phenotype is more specific than CDX2 antibody. Diagn Pathol 2012;7:9.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Kothari N, Teer JK, Abbott AM, et al. Increased incidence of FBXW7 and POLE proofreading domain mutations in young adult colorectal cancers. Cancer 2016;122:28282835.

  • 33.

    van Gool IC, Eggink FA, Freeman-Mills L, et al. POLE proofreading mutations elicit an antitumor immune response in endometrial cancer. Clin Cancer Res 2015;21:33473355.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34.

    McConechy MK, Talhouk A, Leung S, et al. Endometrial carcinomas with POLE exonuclease domain mutations have a favorable prognosis. Clin Cancer Res 2016;22:28652873.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35.

    Wang C, Gong J, Tu TY, et al. Immune profiling of microsatellite instability-high and polymerase ε (POLE)-mutated metastatic colorectal tumors identifies predictors of response to anti-PD-1 therapy. J Gastrointest Oncol 2018;9:404415.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36.

    Shlien A, Campbell BB, de Borja R, et al. Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers. Nat Genet 2015;47:257262.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37.

    Campbell BB, Light N, Fabrizio D, et al. Comprehensive analysis of hypermutation in human cancer. Cell 2017;171:10421056.e10.

  • 38.

    Hodel KP, de Borja R, Henninger EE, et al. Explosive mutation accumulation triggered by heterozygous human Pol ε proofreading- deficiency is driven by suppression of mismatch repair. eLife 2018;7:e32692.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39.

    Hodel KP, Sun MJS, Ungerleider N, et al. POLE mutation spectra are shaped by the mutant allele identity, its abundance, and mismatch repair status. Mol Cell 2020;78:11661177.e6.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40.

    Huang F, Tanaka H, Knudsen BS, et al. Mutant POLQ and POLZ/REV3L DNA polymerases may contribute to the favorable survival of patients with tumors with POLE mutations outside the exonuclease domain. BMC Med Genet 2020;21:167.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41.

    Strickland KC, Howitt BE, Shukla SA, et al. Association and prognostic significance of BRCA1/2-mutation status with neoantigen load, number of tumor-infiltrating lymphocytes and expression of PD-1/PD-L1 in high grade serous ovarian cancer. Oncotarget 2016;7:1358713598.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42.

    Ahn SM, Ansari AA, Kim J, et al. The somatic POLE P286R mutation defines a unique subclass of colorectal cancer featuring hypermutation, representing a potential genomic biomarker for immunotherapy. Oncotarget 2016;7:6863868649.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 24917 342 33
PDF Downloads 1974 181 13
EPUB Downloads 0 0 0