Relationship between protein biomarkers of chemotherapy response and microsatellite status, tumor mutational burden and PD‐L1 expression in cancer patients

Abstract

Chemotherapy and checkpoint inhibitor immunotherapies are increasingly used in combinations. We determined associations between the presence of anti‐PD‐1/PD‐L1 therapeutic biomarkers and protein markers of potential chemotherapy response. Data were extracted from a clinical‐grade testing database (Caris Life Sciences; February 2015 through November 2017): immunotherapy response markers (microsatellite instability‐high [MSI‐H], tumor mutational burden‐high [TMB‐H], and PD‐L1 protein expression) and protein chemotherapy response markers (excision repair complementation group 1 [ERCC1], topoisomerase 1 [TOPO1], topoisomerase 2 [TOP2A], thymidylate synthase [TS], tubulin beta 3 [TUBB3], ribonucleotide reductase regulatory subunit M1 [RRM1] and O‐6‐methyl guanine DNA methyltransferase [MGMT]). Relationships were determined by the Mantel‐Haenszel chi‐squared test or Fischer's exact tests. Overall, 28,034 patients representing a total of 40 tumor types were assessed. MSI‐H was found in 3.3% of patients (73% were also TMB‐H), TMB‐H, 8.4% (28.3% were also MSI‐H) and PD‐L1 expression in 11.0% of patients (5.1% were also MSI‐H; 16.4% were also TMB‐H). Based on concurrent biomarker expression, combinations of immunotherapy with platinum (ERCC1 negativity) or with doxorubicin, epirubicin or etoposide (TOP2A positivity) have a higher probability of response, whereas combinations with irinotecan or topotecan (TOPO1 positivity), with gemcitabine (RRM1 negativity), and fluorouracil, pemetrexed or capecitabine (TS negativity) may be of less benefit. The potential for immunotherapy and taxane (TUBB3 negativity) combinations is present for MSI‐H but not TMB‐H or PD‐L1‐expressing tumors; for temozolomide and dacarbazine (MGMT negative), PD‐L1 is frequently coexpressed, but MSI‐H and TMB‐H are not associated. Protein markers of potential chemotherapy response along with next‐generation sequencing for immunotherapy response markers can help support rational combinations as part of an individualized, precision oncology approach.

TUBB3 Is Associated with High-Grade Histology, Poor Prognosis, p53 Expression, and Cancer Stem Cell Markers in Clear Cell Renal Cell Carcinoma

“…A recent review reported that PD-L1 is not a reliable predictive biomarker for ICBT in RCC [44]. In the present study, immunohistochemistry showed TUBB3 expression to be correlated with PD-L1 expression in ccRCC, which is consistent with a previous study [26]. However, the mechanism of correlation between TUBB3 and PD-L1 expression has not been fully elucidated.…”

“…A recent report showed that TUBB3 expression is associated with PD-L1 expression in RCC, using immunohistochemistry [26]. However, evaluation of PD-L1 expression by immunohistochemistry is complicated due to many factors [27].…”

Comparison of the biomarkers for targeted therapies in primary extra‐mammary and mammary Paget's disease

“…A single patient in our cohort was included in a basket trial with Pembrolizumab without clinical benefit and a later tumor sample analysis revealed no PD‐L1 positivity, but HER2 amplification was detected and Herceptin therapy was initiated (data not shown). Interestingly, one of the TOP2A ‐amplified cases also exhibited PD‐L1 positivity in IC giving a potential for combination chemotherapy with immune checkpoint inhibitors …”

Microsatellite instability: a review of what the oncologist should know

“…Early findings by researchers showed that most of the MSI cases are sporadic colorectal cancer, which is caused by epigenetic inactivation of gene expression in offspring on account of the methylation of hMLH1 promoter without the gene mutation. Lynch syndrome is an autosomal dominant tumor syndrome caused by mutations in MMR strains, and it can also cause tumors in other parts of the colon and rectum [4].…”