250P - Development and validation of a 19-feature classifier that predicts response to neoadjuvant trastuzumab emtansine (T-DM1) in breast cancer patients

Background

Antibody-drug conjugates (ADCs) have expanded the therapeutic arsenal for breast cancer (BCa). Since ADCs may be effective in patients that have low or no expression of the antigen target, biomarkers for optimal patient stratification remain elusive. Identifying novel biomarkers beyond the antigen target that consider other ADC-markers such as the cytotoxin target and pathways involved in ADC processing may provide unique insights into treatment response.

Methods

We first characterized the expression of 70 genes and 32 gene signatures related to ADC processing including antigen/payload targets, endocytosis, lysosomal function, and resistance pathways in a cohort of 1,082 breast tissues, comparing expression within intrinsic molecular subtypes and their association with survival. Then we re-analyzed the trastuzumab emtansine (T-DM1) arm (n=52) and two control arms (paclitaxel and trastuzumab, n=31; paclitaxel, pertuzumab, and trastuzumab, n=44) of the I-SPY2 trial to determine whether combinations of ADC-processing markers would predict response to T-DM1.

Results

ADC-markers showed high inter-individual variability, subtype enrichment, and associations with survival, which could inform effective patient selection. Using I-SPY2 microarray data, we conducted univariate and multivariate logistic regression using elastic net on 71 prespecified ADC-markers to derive a 19-feature classifier that displayed superior predictive utility compared to ERBB2 mRNA alone (ROC AUC of 0.99 vs 0.87). The T-DM1 predictor only had less predictive utility in the trastuzumab/pertuzumab and chemotherapy control arms (ROC AUC of 0.78 and 0.62), underlining its specificity to T-DM1 rather than anti-Her2 targeted therapies.

Conclusions

These data create a foundation for ADC patient selection by tailoring gene signatures to key features of the ADC: antigen/payload target (topoisomerase, microtubule, or DNA), cleavable (enzyme or acid labile) or noncleavable (lysosome processing) linker, and mechanisms of resistance (ABC transporters, glucuronidation enzymes). An important next step will be to validate this signature as a prespecified, qualified biomarker in a larger external cohort.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors were responsible for the governance, coordination, and running of the study.

Funding

This project was funded by MultiplexDX s.r.o. and the European Union's Horizon 2020 research and innovation programme under an EIC Accelerator grant (agreement No 946693) awarded to MultiplexDX s.r.o. (Pavol Cekan as PI).

Disclosure

F. Pareja: Financial Interests, Personal, Advisory Board: MultiplexDX; Financial Interests, Personal, Advisory Role: AstraZeneca. E.D. Paul: Financial Interests, Personal, Full or part-time Employment: MultiplexDX; Financial Interests, Personal, Stocks/Shares: MultiplexDX; Financial Interests, Personal, Funding: MultiplexDX; Non-Financial Interests, Member: ASCO. B. Huraiová; N. Valková; N. Matyašovská; D. Gábrišová; S. Gubová; H. Ignačáková; T. Ondris; S. Bendíková; D. Lovíšek; M. Gala: Financial Interests, Personal, Full or part-time Employment: MultiplexDX; Financial Interests, Personal, Funding: MultiplexDX. I. Comino-Mendez: Financial Interests, Personal, Speaker’s Bureau: Menarini; Financial Interests, Personal, Other: Menarini. J.N. Kather: Financial Interests, Personal, Invited Speaker: Fresenius, Eisai, MSD, Bayer, BMS, Roche Diagnostics International Ltd, Pfizer, AstraZeneca, Janssen; Financial Interests, Personal, Advisory Board: Owkin, DoMore Diagnostics, Panakeia, London, UK, Repare Therapeutics USA, MultiplexDX; Financial Interests, Personal, Stocks/Shares: StratifAI; Financial Interests, Personal, Advisory Role: Scailyte, Cancilico, Mindpeak, Histofy; Financial Interests, Personal, Funding: GSK. P. Cekan: Financial Interests, Personal, Full or part-time Employment: MultiplexDX; Financial Interests, Personal, Leadership Role: MultiplexDX; Financial Interests, Personal, Stocks or ownership: MultiplexDX; Financial Interests, Personal, Funding: MultiplexDX; Non-Financial Interests, Member: ASCO.