Reconstructing tumor history in breast cancer: signatures of mutational processes and response to neoadjuvant chemotherapy⋆

•The development of tumors is driven by endogenous and exogenous mutational processes acting over long periods time.•These generate a specific landscape signatures for each individual tumor.•Mutational 405 tumor samples from neoadjuvant clinical trial were correlated with therapy response disease-free survival.•In particular, HRD-, APOBEC-, tobacco-related associated survival.•Analysis outcome based on the genomic history might lead to novel therapeutic approaches. BackgroundDifferent act evolutionary malignant tumor, abnormal DNA editing, mutagens or age-related alterations, among others, tumor. The these can be identified in large datasets. We investigated hypothesis that patterns are behavior breast cancer, particular chemotherapy survival, focus therapy-resistant disease.Patients methodsWhole exome sequencing was carried out pretherapeutic prospective multicenter GeparSepto study. analyzed 11 including biological such as APOBEC-mutagenesis, homologous recombination deficiency (HRD), mismatch repair also tobacco-induced alterations.ResultsDifferent subgroups carcinomas defined mainly differences HRD-related APOBEC-related significant between hormone-receptor (HR)-negative HR-positive well correlations age, Ki-67 immunological parameters observed. could identify linked increased pathological complete rates high significance. In univariate analyses signatures, S3 (HRD, P < 0.001) S13 (APOBEC, = exonic mutation rate (P 0.002) significantly rates. 0.006) S4 (tobacco, 0.011) prognostic reduced survival patients chemotherapy-resistant tumors.ConclusionThe results this investigation suggest tumors, predicted composition an indicator After additional validations, used define future interventions. Different disease. Whole alterations. tumors.