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.
Highlights
methyl guanine DNA methyltransferase (MGMT) negative correlates with dacarbazine/temozolomide response31–33; 45% of patients tested have MGMT negative/low regulatory subunit M1 (RRM1) negative correlates with gemcitabine response34; 80% of patients tested have RRM1 negative/low
MGMT negativity correlated with programmed death-ligand 1 (PD-L1) expression but was not significantly correlated with microsatellite instability high status (MSI-H) and TMB-H evaluations
This relationship was found for many tumor types with TMB-H and PD-L1, suggesting that gemcitabine would not benefit most of these patients in combination with checkpoint blockade immunotherapy
Summary
Combinations of immunotherapy and cytotoxic chemotherapy are increasingly being used and tested in clinical trials.[1,2,3] Chemotherapy has the potential to enhance antitumor immune responses[4] by several mechanisms including activation of immune effectors such as monocytic-derived dendritic cells[5] and sensitizing tumor cells to lysis.[6,7] preclinical studies have shown that chemotherapy can deplete immunosuppressive cells, including myeloid-derived suppressor cells[8] and T-regulatory cells.[9,10] It is unclear which cytotoxic chemotherapeutic agents will synergize best with immunotherapy. Protein markers may aid in predicting response or resistance to specific cytotoxic chemotherapeutic agents (Supporting Information Table S1). High thymidylate synthase (TS) was associated with decreased response to capecitabine in metastatic breast cancer,[22] whereas low TS was associated with better response to 5-fluorouracil in colorectal cancer[23] and longer progression-free survival with pemetrexed in nonsmall cell lung cancer.[24,25] Tubulin beta 3 (TUBB3) expression has been linked to resistance to taxanes in ovarian cancer and lower survival in prostate cancer.[26,27,28] Expression of excision repair complementation group 1 (ERCC1) negativity predicts improved response in bladder cancer and longer survival in ovarian and gastric cancers in with the use of platinum agents.[29,30] O-6-methyl guanine DNA methyltransferase (MGMT) deficiency may predict response to dacarbazine in melanoma[31] and temozolomide (glioblastoma and neuroendocrine tumors).[32,33]
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