ER+ Breast Cancer Treatment Failure : The main factor behind treatment failure in 25% of ER+ breast cancer patients has been identified. After nearly 10 years of research, Indian scientists have discovered the genomic hallmark of endocrine therapy resistance in ER/PR+HER2- breast tumors. 

Reason for ER+ Breast Cancer Treatment Failure : ER+ (ER/PR+HER2)- breast tumors are the most common type of breast cancer worldwide, including in India. Unlike TNBCs (Triple-Negative Breast Cancers), these tumors can be treated with anti-estrogen or aromatase inhibitors. Although endocrine therapy (hormone therapy) is successful, some patients with ER+ breast tumors do not respond to hormone-receptor-specific treatment and face relapse, leading to a lower survival rate.

Genomic causes of therapy resistance

The genomic causes of therapy resistance in ER+ breast tumors are not fully understood. We performed world genome sequencing (WGS) of tumor and normal tissue samples from ER+ breast cancer patients who were resistant to endocrine therapy and who experienced disease relapse after treatment. 

Indicators of endocrine treatment resistance

Additionally, we performed a comparative analysis of WGS data from patients who remained disease-free at least 5 years of follow-up. Our analysis found (a) a resistance signature of three genes (PIK3CA-ESR1-TP53) and (b) disruption of DNA double-strand break repair and homologous recombination pathways to be significantly associated with endocrine-therapy resistance and disease relapse. Genome instability, including copy-number, structural changes, and a high load of telomere-shortening, was identified as an indicator of endocrine treatment resistance. 

Forecast Treatment

Early prediction of endocrine therapy resistance from the genome landscape of breast tumors will help in treatment. Our results also indicate that PARP inhibitors can be repurposed to treat endocrine therapy-resistant breast cancer patients.

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