Breast cancer organoids model treatment response of HER2 targeted therapy in HER2-mutant breast cancer

Abstract Background To facilitate cancer precision medicine, breast cancer organoids have recently emerged as a useful pre-clinical model for retaining sufficient fidelity regarding histology, the transcriptome and genome. However, their potential to predict clinical treatment responses remains unclear. Methods We generated breast cancer organoids from breast cancer tissues and performed drug sensitivity test on these organoids based on genomic analysis data. Results A total of 25 fresh breast cancer tissues and biopsies from 22 patients were processed between November 2017 and February 2019. Breast cancer organoids were grown successfully from 10 out of 25 patients (40%). We performed histopathological analysis of H&E stained tissues and organoid sections and confirmed that the phenotypes of organoids matched the original histological breast cancer types. We also performed whole genome DNA sequencing (WGS) and RNA sequencing (RNA-seq) on breast cancer organoids and paired breast cancer tissues. One of these breast cancer organoids had HER2 mutations (previously shown to be an activating mutation) and retained expression of estrogen receptor (ER) and progesterone receptor (PR) (Luminal A subtype). In our previous work, we identified activating HER2 mutations (S310F D769Y V777L 778insGSP) in ER positive/HER2-amplification negative breast cancer, who had developed resistance to multi-line endocrine therapy. Two patients achieved a durable partial response (approximately 1 years) to trastuzumab combined with everolimus. We also showed that HER2 mutations were constitutively active, and T47D and MCF7 overexpressing HER2 mutations were sensitive to HER2 targeted therapies combined with everolimus. Hence, we tested the effects of trastuzumab and everolimus on this HER2-mutant breast cancer organoid in vitro and in vivo. HER2-targeted therapies combined with everolimus produced regression of the HER2-mutated organoid. Conclusions The breast cancer organoids may serve as a high-fidelity platform and recapitulate clinical treatment responses in personalized medicine. These data provide a strong preclinical rationale for combining HER2-targeted therapies with everolimus in HER2-mutant/ HER2-amplification negative breast cancer. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.