Molecular differences between younger versus older ER-positive and HER2-negative breast cancers

The RxPONDER and TAILORx trials demonstrated benefit from adjuvant chemotherapy in patients age <= 50 with node-positive breast cancer and Recurrence Score (RS) 0-26, and in node-negative disease with RS 16-25, respectively, but no benefit in older women with the same clinical features. We analyzed transcriptomic and genomic data of ER+/HER2- breast cancers with in silico RS < 26 from TCGA (n = 530), two microarray cohorts (A: n = 865; B: n = 609), the METABRIC (n = 867), and the SCAN-B (n = 1636) datasets. There was no difference in proliferation-related gene expression between age groups. Older patients had higher mutation burden and more frequent ESR1 copy number gain, but lower frequency of GATA3 mutations. Younger patients had higher rate of ESR1 copy number loss. In all datasets, younger patients had significantly lower mRNA expression of ESR1 and ER-associated genes, and higher expression of immune-related genes. The ER- and immune-related gene signatures showed negative correlation and defined three subpopulations in younger women: immune-high/ER-low, immune-intermediate/ER-intermediate, and immune-low/ER-intermediate. We hypothesize that in immune-high cancers, the cytotoxic effect of chemotherapy may drive the benefit, whereas in immune-low/ER-intermediate cancers chemotherapy induced ovarian suppression may play important role.

Automated summary

The RxPONDER and TAILORx trials showed the benefits of adjuvant chemotherapy in patients under 50 with positive lymph nodes and Recurrence Score (RS) 0-26, and in node-negative disease with RS 16-25. However, no benefits were observed in older women with the same clinical features. Transcriptomic and genomic data analysis revealed that younger patients had lower mRNA expression of ESR1 and ER-associated genes, higher expression of immune-related genes, and a different mutation burden compared to older patients.