Discordance of immunotherapy response predictive biomarkers between primary lesions and paired metastases in tumours: A systematic review and meta-analysis

Abstract

Background: Several biomarkers predict the efficacy of immunotherapy, which is essential for selecting patients who would potentially benefit. Discordant status of these biomarkers between primary tumours and paired metastases has been increasingly revealed. We aimed to comprehensively summarize the incidence of this phenomenon. Methods: Databases were searched to identify studies reporting primary-to-metastatic conversion of biomarkers, including programmed death ligand-1 (PD-L1), programmed cell death protein-1 (PD-1), PD-L2, tumour-infiltrating lymphocyte (TIL), tumour mutational burden (TMB), and microsatellite instability (MSI). Findings: 56 studies with 2739 patients were included. The pooled discordance rate of PD-L1 was 22%. The percentage of PD-L1 changed from positive to negative was 41%, whereas that from negative to positive was 16%. The discordance rate for PD-1 and PD-L2 was 26% and 22%, respectively. TIL level was found with a discordance rate of 39%, and changes from high to low (50%) occurred more than that from low to high (16%). No significant difference in TMB was observed between two sites in most studies. MSI status discordance was found in 6% patients, with a percentage of 9% from MSI-high to microsatellite instable (MSS) and 0% from MSS to MSI-high. Interpretation: Our study demonstrates that PD-L1, PD-1, PD-L2, and TIL level had high frequency of discordance, while TMB and MSI status were less likely to change between primary tumours and paired metastases. Therefore, evaluating those frequently altered biomarkers of both primary and metastatic tumours is strongly recommended for precise clinical decision of immune checkpoint treatment. Fund: The National Natural Science Foundation of China (81872152).

Discordance of PD-L1 status between primary and metastatic breast cancer: A systematic review and meta-analysis

“…The temporal evolution of the immune microenvironment, which transitions from equilibrium to escape as clinically overt metastatic disease becomes apparent, is well-described [41]. This phenomenon has been previously described by studies demonstrating low tumor infiltrating lymphocyte (TIL) counts at metastatic biopsies [40,42], which is expected considering that PD-L1 and TIL are moderately correlated [14,16,43]. In order to further corroborate the transition from an inflamed although suppressed microenvironment to an immune desert one [44], we identified five of the studies included in the present meta-analysis that also reported TIL data [14,23,32,33,37].…”

“…This meta-analysis is the first, to the best of our knowledge, that provides not only data on PD-L1 positivity rates in primary and metastatic BC, discordance rates of matched tumors and directionality of discordance, but also, crucially due to its clinical utility for TNBC, separate information on expression in different cellular compartments. This was not explored in a previous meta-analysis that reported on discordance of multiple biomarkers, including PD-L1, across human cancers [40]. Exploratory analyses from IMPassion130 have suggested that there is discordance in PD-L1 status between primary tumor and metastasis, as well as greater relative benefit with checkpoint inhibition when PD-L1 is analyzed in the latter [14].…”

The Future of Cancer Diagnosis, Treatment and Surveillance: A Systemic Review on Immunotherapy and Immuno-PET Radiotracers

“…As aforementioned, the selection and the response to immunotherapy is based on several mechanisms that play different roles. ICs expression on tumor cells seems to be a necessary, but not sufficient information to to prove sufficient insights into immune mechanisms related to immunotherapy efficay, to select patients candidate to immunotherapy and to predict the reponse to treatment [ 43 , 44 ].…”

“…For this reason, new criteria for the selection of patients who could benefit from these therapies have been recently evaluated. In particular, the combined positive score (CPS) has been introduced, a composite of ICs (such as PD-L1) tumor proportion score (TPS) and host- and tumor-related parameters, which evaluates the percentage of positive ICs (tumor cells, lymphocytes and macrophages) present in the TME [ 43 , 44 ].…”

Biomarkers in Immunotherapy-Based Precision Treatments of Digestive System Tumors

“…Taking the gut microbiome as an example, its role in modulating adaptive immunity has been reported in CRC before ( 134 ). Moreover, the scholars found a high degree of discordance in primary and metastatic lesions of multiple biomarkers via a multidimensional analysis in 2020 ( 135 ). The discordance rate of PD-L1 (26%) and TIL (39%) between primary metastatic tumors were relatively higher than that in TMB (no significant difference) and MSI status (6%), indicating that the PD-L1expression and TIL are highly heterogeneous and likely to be disturbed by sampling sites.…”