Abstract 2690: Expression profiles of antibody drug conjugate (ADC) targets in breast and lung cancer subtypes and in new HER2 subgroups with their PD-L1 status

Abstract Antibody drug conjugates (ADCs) are transforming the treatment of breast cancer as well as lung, ovarian, and several other cancer indications. ADCs targeting HER2 and TROP2 are currently approved in breast and lung cancer subgroups. Some HER2-targeted therapies are efficacious in breast cancer in newly defined HER2-low and -ultralow subgroups. There has been recent interest and some successes combining ADC’s with immune checkpoint inhibitors. Despite these successes, tumors still develop resistance through both target-dependent and independent mechanisms. Previously we investigated which ADC’s may be expressed in HER2-positive versus negative breast cancers and adeno versus squamous NSCLC histological subtypes. We have now extended these analyses to explore which ADC’s show the highest relative expression levels in these cancers, co-expression with PD-L1 and expression in HER2-low and -ultralow breast cancer subgroups. Optimized IHC assays for B7-H3, B7-H4, Nectin-4, TROP2, PD-L1 and HER2 on Ventana or Dako automated staining platforms were applied to treatment naïve tumor samples from ER+ BC (n=60), TNBC (n=52) and NSCLC (n=134; adeno and squamous) in tissue microarray format (1mm cores). ADC targets were scored by pathologist-assisted digital image analysis to deliver H-Scores and frequencies of positivity at high, moderate, low and negative expression levels. Diagnostic visual scoring methods were employed for analysis of PD-L1 and HER2 (including addition of ultra-low score for HER2). We demonstrate that immune positivity for PD-L1 (CPS >10) was most frequent in HER2-low TNBC compared with HER2-ultralow or negative samples, and that B7-H3 and Nectin-4 H-Scores were higher in TNBC compared with ER+ BC, regardless of PD-L1+ status suggesting potential for immunotherapy combinations in TNBC and especially HER2-low subtype. Furthermore, B7-H4 H-Scores were higher in HER2-low, ultralow and negative ER+ BC compared with HER2 positive samples, while the inverse was observed for B7-H3 revealing potential opportunities for therapies that may overcome resistance to HER2-targeted therapies in this cancer subtype. Squamous NSCLC displayed higher B7-H3 and B7-H4 H-Scores and percent positive cells compared with adeno subtype, and B7-H3 and B7-H4 H-Scores were higher in PD-L1 positive samples (TPS≥1%) supporting ADC therapy for these targets in combination with PD-1/PD-L1 immunotherapies. Taken together, these data may aid the future selection of targets for upcoming therapeutics that can overcome target-independent resistance and provide rationale for immunotherapy combinations. Citation Format: Marie Cumberbatch, Woo Ho Kim, Milan Bhagat, John Cogswell. Expression profiles of antibody drug conjugate (ADC) targets in breast and lung cancer subtypes and in new HER2 subgroups with their PD-L1 status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2690.