Background Sex is an important factor in determining response to immune checkpoint inhibitors (ICI) in cancer patients.1 Sex hormones can modulate the immune response in preclinical studies.2 Our study aimed to determine if the pretreatment sex hormone level can predict outcomes in metastatic non-small cell lung cancer (mNSCLC) patients undergoing ICI therapies.
Methods This study included 61 patients with newly diagnosed mNSCLC who received ICI as part of the upfront therapy. Pretreatment plasma and fecal samples were collected before the first ICI infusion, and we measured sex hormone levels using ultra-high-performance liquid chromatography high-resolution mass spectrometry. Sex hormone levels were compared between the clinical benefit and no clinical benefit group. Patients were then divided into high DHEA and low DHEA groups based on the sex-specific median of the cohort. Overall survival (OS) and progression-free survival (PFS) were compared between high DHEA and low DHEA using Kaplan Meier’s methods. A similar analysis was based on the 5-androstenediol level. We used the univariate and multivariate Cox proportional hazards (PH) model to measure hazard ratios (HRs) for PFS and OS.
Results Pretreatment plasma samples were collected from 61 patients, and 31 patients were female (table 1). Among them, 30 plasma samples had measurable DHEA levels, and 46 patients had measurable 5-androstenediol levels (table 2). Patients in the clinical benefit group had significantly higher plasma DHEA levels and 5-androstenediol levels than those in the no clinical benefit group (figure 1)
The high DHEA group had fewer patients with clinical benefits from ICI therapy (27% vs. 87% in the high DHEA and low DHEA groups, respectively) (figure 2). Patients with high DHEA also had shorter OS (mOS: 11.4mo vs. not reached for high DHEA and low DHEA group respectively, p=0.0001) and shorter PFS (mPFS: 4.1mo vs. 22mo for the high DHEA and low DHEA groups, respectively, p<0.0001). High 5-androstenediol also had fewer patients with clinical benefit (46% vs 72% for the high 5-androstenediol and low 5-androstenediol groups, respectively).
Univariate Cox PH analysis confirmed our observation. High DHEA level was associated with poor OS (HR-8.29, 95% CI:2.31–29.79) and PFS (HR=10.23, 95% CI:3.4–30.74). High 5-androstenediol level was associated with shorter PFS (HR=2.26, 95% CI: 1.07–4.75) (table 3).
Conclusions Pretreatment DHEA level and 5-androstenediol level were significantly lower in patients with clinical benefit from ICI. Our study supports the use of pretreatment DHEA as a promising predictive biomarker in patients with metastatic NSCLC receiving ICI therapies.
Klein, S. L. and K. L. Flanagan (2016). Sex differences in immune responses. Nat Rev Immunol 16(10): 626–638.
Ben-Batalla, I., M. E. Vargas-Delgado, G. von Amsberg, M. Janning and S. Loges (2020). Influence of Androgens on Immunity to Self and Foreign: Effects on Immunity and Cancer. Front Immunol 11: 1184.
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