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Nearly half of metastatic breast cancers (MBC) have genetic aberrations in the PI3K/AKT pathway. To investigate the distinct effect of these aberrations on MBC, 193 MBC patients who progressed after the early line (≤2) salvage treatment voluntarily received next generation sequencing (NGS) for a panel of 1,021 genes. 93 (48%) patients had genetic aberrations in the PI3K/AKT pathway. The number of patients with PIK3CA mutations in kinase domain (KD), helical domain (HD) and other domain (OD), were 36 (18.7%), 26 (13.5%), 10 (5.2%), respectively. 21 (10.9%) patients had mutations in PI3K/AKT pathway genes other than PIK3CA (P/A). Compared to PI3K/AKT-wild type (WT) patients, PIK3CA -HD patients had a significantly shorter progression-free survival (PFS) (Logrank p -value &lt; 0.0001). PIK3CA -KD, PIK3CA -OD and other P/A mutations showed similar PFS to WT patients (Logrank p -value = 0.63). PIK3CA -HD patients had a distinct ctDNA mutation profile to patients with other PI3K/AKT mutations. PIK3CA -HD patients had a higher rate of FGFR and NF1 aberrations. In addition, more PIK3CA -HD carriers were TMB-high. Cox regression analyses suggested that PIK3CA -HD mutations, FGFR aberrations and high TMB were all significant risk factors for poor PFS. In conclusion, future research needs to focus more on the treatment strategies targeting PIK3CA -HD mutations.

aging

PIK3CA gene mutations in the helical domain correlate with high tumor mutation burden and poor prognosis in metastatic breast carcinomas with late-line therapies