Novel treatment approaches utilizing antibody-drug conjugates in breast cancer

Abstract

Antibody-drug conjugates (ADCs) are rapidly changing the way we treat patients with breast cancer. Despite this progress, many unanswered questions remain regarding the sequencing of different ADCs with similar payloads, optimal combinations, drug design strategies to limit off-target toxicities, biomarkers to define antigen positivity, and the use of ADCs in the neoadjuvant and adjuvant settings. In this review, we summarize novel ADC approaches in breast cancer treatment, including potential improvements in ADC payloads, linkers, targets, and drug delivery. We also evaluate novel strategies to combine ADCs with other agents, such as targeted drugs and immune checkpoint inhibitors. To improve patient selection, the development of quantitative biomarkers is reviewed, including HER2 mRNA, immunofluorescence-based assays, mass spectrometry, liquid biopsies, digital pathology, and molecular imaging-based approaches. Lastly, we evaluate the potential to incorporate ADCs into the early-stage setting, including evaluating currently published and ongoing clinical trials. This review highlights the potential for ADCs to shift the treatment paradigm in both the advanced and early-stage settings. We further demonstrate the complexity and challenges of improving ADCs to enhance targeting of tumor vulnerabilities while limiting toxicity through rationale drug development strategies to enhance the therapeutic window, linker technology, and payload variability to continue to improve outcomes for patients with breast cancer.

Fig. 1. Ongoing clinical trials in the window of opportunity, neoadjuvant, and adjuvant settings for ADC therapy in early-stage breast cancer with associated primary end points.

*TROPION-Breast04 is both in the neoadjuvant and adjuvant setting. CelTIL a combined biomarker based on tumor cellularity and tumor-infiltrating lymphocytes (TILs), pCR pathologic complete response, ORR objective-response rate, RCB residual cancer burden, ctDNA circulating tumor DNA, iDFS invasive disease-free survival, EFS event-free survival.

Fig. 2. Overview of the novel biomarker approaches in development to aid in tumor characterization for optimization of ADC therapy.

mRNA messenger ribonucleic acid, cfDNA cell-free deoxyribonucleic acid, CTCs circulating tumor cells.