60P Expression of antibody-drug conjugate targets in metastatic breast cancer

Three Antibody-Drug Conjugates (ADCs), targeting HER2 or TROP2, are approved for metastatic breast cancer (mBC). ADCs targeting another 55 targets are currently being clinically studied in solid tumors. Here, we investigated the expression levels of all 57 targets, their correlation with tumor cellularity, their inter- and intra-patient heterogeneity, their co-expression, and their organ-specificity in primary (P) and metastatic samples (M) from patients enrolled in our rapid autopsy program UPTIDER (NCT04531696). 650 samples (602 M, 48 P) from 20 patients underwent bulk mRNA sequencing. 16 patients had HR+/HER2-, 3 TNBC, and 1 HER2+ primary BC. At the conference, data will be available for 5 additional patients (4 TNBC). Weighted Spearman correlation on median gene expression was used to identify co-expressed/mutually exclusive targets. Associations between gene expression and independent co-variate (sample status: M vs P, M of interest vs all M) were assessed by linear mixed quantile regression with random effect on patient ID. The 5 targets with the highest median expression in M are: FN1, MUC1, HER3, SLC39A6 and CD46 (median range: 7.95-9.83). TROP2 and HER2 had the 7th and 23rd highest expression (median: 4.87 and 7.43). A weak positive or negative correlation of target expression with tumor cellularity was observed for 12 (including HER2 and HER3) and 5 targets, respectively. Intra-patient inter-M heterogeneity, as assessed by interquartile range, was high for FN1, MUC1 and TROP2(median IQR range: 1.47 - 1.52) but relatively low for HER2 and HER3. Reduced and higher expression in M vs P was reported for 15 and 5 targets, respectively. A strong positive correlation (R>0.7) was observed for 10 pairs (ALCAM-HER3, ALCAM-MUC1, EGFR-MET, HER2-HER3…) and a strong negative correlation (R<-0.7) was observed for HER2-GPNMB, HER3-MET, CEACCAM5-PTK7 and SLC34A2-SLC44A4. Organ specific expression was observed for a few genes in intestinal, lung, brain, bone and subcutaneous M but not for M in meninges, lymph nodes or liver. Our study generated novel insights on the current ADC targets and on those under clinical investigation in oncology. Our results can help prioritize ADCs to be evaluated in mBC and guide the development of bispecific ADCs.