A Case Report of Immunotherapy-Resistant MSI-H Gastric Cancer with Significant Intrapatient Tumoral Heterogeneity Characterized by Histologic Dedifferentiation

We describe a patient with both gastric adenocarcinoma and metastatic squamous cell carcinoma (SCC) of unknown primary site. The possibility of a single malignant clonal process as opposed to differing primaries was supported by the finding of both histologies exhibiting high microsatellite instability. Despite evidence of tumor microsatellite instability, the patient’s disease process did not respond to immune checkpoint inhibition. Our pursuit of whole-exome sequencing and comparing the single-nucleotide variant profiles of both tumors supported a single clonal process with the development of significant intratumoral heterogeneity. High intratumoral heterogeneity has posed a challenge to precision medicine approaches, but we also provide a review of the literature of this phenomenon mediating resistance to immunotherapy strategies.

[1]  S. Szelinger,et al.  Analytic validation and clinical utilization of the comprehensive genomic profiling test, GEM ExTra® , 2021, Oncotarget.

[2]  W. Park,et al.  Determinants of Response and Intrinsic Resistance to PD-1 Blockade in Microsatellite Instability-High Gastric Cancer. , 2021, Cancer discovery.

[3]  A. Jemal,et al.  Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries , 2021, CA: a cancer journal for clinicians.

[4]  Martin L. Miller,et al.  UVB-Induced Tumor Heterogeneity Diminishes Immune Response in Melanoma , 2019, Cell.

[5]  D. Scheinberg,et al.  Rejection of immunogenic tumor clones is limited by clonal fraction , 2018, eLife.

[6]  M. Shah,et al.  Pertuzumab plus trastuzumab and chemotherapy for HER2-positive metastatic gastric or gastro-oesophageal junction cancer (JACOB): final analysis of a double-blind, randomised, placebo-controlled phase 3 study. , 2018, The Lancet. Oncology.

[7]  G. Freeman,et al.  Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response , 2018, Nature Medicine.

[8]  Andrew Dunford,et al.  Genomic Heterogeneity as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma. , 2018, Cancer discovery.

[9]  D. Cunningham,et al.  Rilotumumab plus epirubicin, cisplatin, and capecitabine as first-line therapy in advanced MET-positive gastric or gastro-oesophageal junction cancer (RILOMET-1): a randomised, double-blind, placebo-controlled, phase 3 trial. , 2017, The Lancet. Oncology.

[10]  Y. Bang,et al.  A randomized, open-label study of the efficacy and safety of AZD4547 monotherapy versus paclitaxel for the treatment of advanced gastric adenocarcinoma with FGFR2 polysomy or gene amplification , 2017, Annals of oncology : official journal of the European Society for Medical Oncology.

[11]  M. Shah,et al.  Effect of Fluorouracil, Leucovorin, and Oxaliplatin With or Without Onartuzumab in HER2-Negative, MET-Positive Gastroesophageal Adenocarcinoma: The METGastric Randomized Clinical Trial , 2017, JAMA oncology.

[12]  S. Ou,et al.  Comprehensive Genomic Profiling Aids in Distinguishing Metastatic Recurrence from Second Primary Cancers. , 2017, The oncologist.

[13]  Joon-Oh Park,et al.  Lapatinib in Combination With Capecitabine Plus Oxaliplatin in Human Epidermal Growth Factor Receptor 2-Positive Advanced or Metastatic Gastric, Esophageal, or Gastroesophageal Adenocarcinoma: TRIO-013/LOGiC--A Randomized Phase III Trial. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  M. Loda,et al.  Identification of proteomic biomarkers predicting prostate cancer aggressiveness and lethality despite biopsy-sampling error , 2014, British Journal of Cancer.

[15]  William Pao,et al.  Enabling a genetically informed approach to cancer medicine: a retrospective evaluation of the impact of comprehensive tumor profiling using a targeted next-generation sequencing panel. , 2014, The oncologist.

[16]  I. Rubio,et al.  Changes in Breast Cancer Reports after Pathology Second Opinion , 2014, The breast journal.

[17]  A. Wotherspoon,et al.  Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial , 2013, The Lancet. Oncology.

[18]  Galina Kurteva,et al.  Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. , 2013, The Lancet. Oncology.

[19]  Adam B. Olshen,et al.  Clonality: an R package for testing clonal relatedness of two tumors from the same patient based on their genomic profiles , 2011, Bioinform..

[20]  P. Walsh,et al.  Clinical and cost impact of second-opinion pathology. Review of prostate biopsies prior to radical prostatectomy. , 1996, The American journal of surgical pathology.