Higher serum PD‐L1 level predicts increased overall survival with lapatinib versus trastuzumab in the CCTG MA.31 phase 3 trial

Abstract

BACKGROUND: The purpose of this retrospective biomarker study of the Canadian Cancer Trials Group (CCTG) MA.31 randomized phase 3 trial (lapatinib vs trastuzumab) of HER2-positive metastatic breast cancer (MBC) was to evaluate the prognostic and predictive biomarker utility of pretreatment serum programmed death ligand 1 (PD-L1) levels. METHODS: CCTG MA.31 accrued 652 HER2positive patients; 387 had serum available (185 in the trastuzumab arm and 202 in the lapatinib arm). The Ella immunoassay platform (ProteinSimple, San Jose, California) was used to quantitate serum PD-L1 levels. Stepwise forward Cox multivariable analyses were performed for progression-free survival and overall survival (OS). RESULTS: In the whole trial population, continuous pretreatment serum PD-L1 levels were not associated with OS. However, within the trastuzumab arm, a higher continuous pretreatment serum PD-L1 level was significant for shorter OS (hazard ratio [HR], 3.85; P = .04), but within the lapatinib arm, pretreatment serum PD-L1 was not associated with OS (P = .37). In the whole trial, in a multivariable analysis for OS, serum PD-L1 (median cut point) remained a significant independent covariate (HR, 2.38; P = .001). There was a significant interaction between treatment arm and continuous serum PD-L1 (bootstrap method; P = .0025): at or above 214.2 pg/mL (the 89th percentile), serum PD-L1 was associated with significantly shorter OS with trastuzumab treatment versus lapatinib treatment. CONCLUSIONS: In the CCTG MA.31 trial, serum PD-L1 was a significant predictive factor: a higher pretreatment serum PD-L1 level was associated with shorter OS with trastuzumab treatment but with longer OS with lapatinib treatment. Immune evasion may decrease the effectiveness of trastuzumab therapy. Further evaluation of elevated serum PD-L1 in advanced breast cancer is warranted to identify patients with HER2-positive MBC who may benefit from novel immune-targeted therapies in addition to trastuzumab. Cancer 2020;126:4859-4866.

Circulating proteins as predictive and prognostic biomarkers in breast cancer

“…Moreover, high serum levels of VEGF and TGF-β1 remain important biomarkers of short OS, either used alone or in combination with other proteins such as Ang-2 and its mediator Tie-2 [ 106 , 107 , 109 ]. Serum PD-L1 appears as an interesting candidate biomarker in cancer immunotherapy, worth further validation [ 122 , 132 , 133 ]. Serum HER2 is also a reliable prognostic biomarker in HER2 + BC, nevertheless tissue HER2 remains more clinically relevant.…”

“…Serum PD-1 and PD-L1 are predictive factors of treatment response in TNBC patients. A recent study evaluated the prognostic and predictive value of serum PD-L1 levels in HER2-positive metastatic breast cancer treated with trastuzumab or lapatinib [ 133 ]. High serum PD-L1 level before treatment was strongly linked to longer OS in the lapatinib group compared to the trastuzumab group.…”

Decreased levels of circulating cytokines VEGF, TNF-β and IL-15 indicate PD-L1 overexpression in tumours of primary breast cancer patients

“…Recently, soluble forms of PD-1 and PD-L1 have been detected in the blood of cancer patients 24 . Based on the published data, soluble PD-L1 may facilitate the prediction of overall survival and treatment response in a specific therapy regimen or the efficacy of neoadjuvant therapy in the specific BC subtypes 25,26 . However, the data providing new clues on their potential as a diagnostic, therapeutic, or prognostic biomarker are added up gradually and especially in BC have not been fully elucidated yet.…”

Challenges in Detection of Serum Oncoprotein: Relevance to Breast Cancer Diagnostics

“…As disease-related biomarkers continue to be discovered at widely varying concentrations within biofluid, the need for signal amplification techniques will become ever more important to meet the challenge of ultra-sensitive detection. Biomarkers such as programmed death-ligand 1 (PD-L1), a transmembrane ligand that suppresses the adaptive immune system through binding to its receptor PD-1, 150 have been implicated in non-small cell lung carcinoma 151 , 152 and breast cancer 153 at sub-ng mL-1 concentrations, below the reliable detection limits of a traditional colorimetric ELISA. Similarly, earlier detection of biomarkers such as cardiac troponin I, which are only detectable in blood during pathological conditions such as acute myocardial infarction, 154–156 are enabled by more sensitive techniques that have lower limits of detection, providing opportunities for earlier intervention and potentially improved clinical outcomes.…”