Tumor-agnostic, histology-independent cancer therapy
James Fleck: Anticancerweb 29 (06), 2020
Fortunately, we are at the beginning of a new era in cancer assessment and treatment. Molecular biology has been responsible for a great improvement in the recognition of the microenvironmental characteristics of cancer, which goes far beyond cellular and tissue morphology. High-throughput sequencing studies of human cancer suggest genetic instability as a hallmark of tumor biology, not only in hereditary diseases, but also in a special group of non-hereditary malignancies. High microsatellite instability (MSI-H) / mismatch repair-deficiency (MMR-d) and high tumor mutational burden (TMB-H) are predictive markers for immunotherapy in a wide variety of tumors not necessarily histologically related. The genetic signature of mismatch repair-deficient tumors harbor 10 to 100 times more mutations than mismatch repair-proficient tumors. MMR-d is associated with mutations in repetitive DNA sequences (microsatellites) showing high microsatellite instability. MMR-d is observed in a wide range of histology-independent primary tumors, like endometrial cancer, gastric cancer and colorectal cancer, among others. Mutations, produced mainly by DNA-frame deletions or insertions result in mutant neoantigens. When neoantigens are presented by the major histocompatibility complex, the tumor could be better recognized by the host immune system. In response, trying to protect themselves, the MMR-d / MSI-H tumor cells increase the expression of programmed death ligand-1 (PD-L1). In addition, a greater number of tumor infiltrating lymphocytes (TIL) exhibits upregulated checkpoint proteins, including programmed death-1 (PD-1). Despite the attempt to protect, both phenotypic expressions make these tumors particularly susceptible to immunotherapy with checkpoint inhibitors PD1 / PD-L1.
Recently published in October, 2019 in the Journal of Clinical Oncology, the results of phase II Keynote-158 study demonstrated a RECIST response rate of 34.3% using pembrolizumab (anti-PD-1) in patients with previously treated unresectable or metastatic MMR-d / MSI-H tumors. Approximately, one third of the patients with objective response had a complete response. The median overall survival among 27 MMR-d / MSI-H different tumor types was 23.5 months. Kaplan-Meier analysis showed that more than three quarters of the responders had durable responses, which leads to an estimated 24-months overall survival rate of 48.9%. Immune-mediated adverse events and infusion reactions were reported in 23.2 % of the patients, but most were grade 1 and 2. The results observed in this study supported the tumor-agnostic approval of intravenous pembrolizumab at 200 mg every 3 weeks for the treatment of advanced MSI-H/dMMR cancer. Tumor mutational burden (TMB) has also been used as a prognostic and predictive marker. However, some drawbacks still limit the adoption of TMB for clinical decision making. Target panel sequencing might overestimate TMB due to panel design biases and there is no clear definition of what should be called a high TMB (TMB-H), ranging from 10 to 20 mutations / megabase. Currently, inconsistency has been overcome using whole-exome sequencing (WES) or improving the robustness of the TMB through a new statistical model with a predictive Bayesian structure, called ecTMB (estimation and classification of TMB). Regardless of the method used to assess tumor mutational burden, the microenvironmental phenotype will soon be guiding personalized cancer treatment, further improving cost-benefit ratio.
RECIST = Response Evaluation Criteria in Solid Tumors
1. Aurelien Marabelle, Dung T. Le, Paolo A. Ascierto, et al: Efficacy of Pembrolizumab in Patients with Non-colorectal High Microsatellite Instability/ Mismatch Repair–Deficient Cancer: Results from the Phase II KEYNOTE-158 Study, J Clin Oncol 38:1-10, 2019
2. Lijing Yao, Yao Fu, Marghoob Mohiyuddin & Hugo Y. K. Lam: ecTMB: a robust method to estimate and classify tumor mutational burden, Nature, 10:4983, 2020
3. Photo by National Cancer Institute on Unsplash