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The correlation of genetic alterations with response to neoadjuvant chemotherapy (NAC) has not been fully revealed. In this study, we enrolled 247 breast cancer patients receiving anthracycline‐taxane‐based NAC treatment. A next generation sequencing (NGS) panel containing 36 hotspot breast cancer‐related genes was used in this study. Two different standards for the extent of pathologic complete response (pCR), ypT0/isypN0 and ypT0/is, were used as indicators for NAC treatment.  TP53  mutation (n = 149, 60.3%),  PIK3CA  mutation (n = 109, 44.1%) and  MYC  amplification (n = 95, 38.5%) were frequently detected in enrolled cases.  TP53  mutation ( P  =   0.019 for ypT0/isypN0 and  P  =   0.003 for ypT0/is) and  ERBB2  amplification ( P  <   0.001 for both ypT0/isypN0 and ypT0/is) were related to higher pCR rates.  PIK3CA  mutation ( P  =   0.040 for ypT0/isypN0) and  CCND2  amplification ( P  =   0.042 for ypT0/is) showed reduced sensitivity to NAC. Patients with MAPK pathway alteration had low pCR rates ( P  =   0.043 for ypT0/is). Patients with  TP53  mutation (−)  PIK3CA  mutation (−)  ERBB2  amplification (+)  CCND1  amplification (−),  TP53  mutation (+)  PIK3CA  mutation (−)  ERBB2  amplification (+)  CCND1  amplification (−) or  TP53  mutation (+)  PIK3CA  mutation (+)  ERBB2  amplification (+)  CCND1  amplification (−)had significantly higher pCR rates ( P  <   0.05 for ypT0/isypN0 and ypT0/is) than wild type genotype tumors. Some cancer genetic alterations as well as pathway alterations were associated with chemosensitivity to NAC treatment. Our study may shed light on the molecular characteristics of breast cancer for prediction of NAC expectations when breast cancer is first diagnosed by biopsy.

Somatic alterations of TP53 , ERBB2 , PIK3CA and CCND1 are associated with chemosensitivity for breast cancers