Targeted sequencing of postmenopausal ER+/HER2+ breast cancer
Present study illustrates a genomic landscape of 21 patients with postmenopausal Estrogen receptor (ER)-positive and Human epidermal growth factor receptor-2 (HER-2)-positive (ER+HER2+) breast cancer (BC) treated with chemo-free, neoadjuvant combination of letrozole and lapatinib using our previous phase II study, Neo-ALL IN cohort. As expected, TP53(61.9%) and PIK3CA (57.1%) were two most frequent mutations, which were inter-correlated (p=0.026) and associated with unfavorable clinical outcomes. Of our notice, patients who experienced progression after neoadjuvant treatment all harbored PIK3CA mutations at exon 9 in helical domains. More importantly, MLL2 was highlighted in the study, which was negatively associated with somatic mutations in TP53 or PIK3CA, and was predominantly observed in patients with low KI-67 level and the absence of initial nodal involvement. Accordingly, patients with MLL2 mutations showed more favorable ORR and 5-year EFS rate compared to those with the wild-type. Collectively, our analyses suggest PIK3CA hotspot mutations at exon 9 as a potential negative predictor in ER+HER2+ BC treated with neoadjuvant letrozole and lapatinib, and MLL2 somatic mutation as a potential predictor epigenetically conferring therapeutic benefit in these patients. It might particularly add its value for it is the first exploration in Asian cohort.