Background: Comprehending the clinical utility of the massively produced BC genomic data remains a challenge. Here, we examined the impact of BC genotypes on patient outcome with respect to clinical (immunohistochemical) tumor subtypes and treatment. Methods: Paraffin DNA from 1664 tumors (556 Luminal A, 439 Luminal B, 291 Luminal-HER2, 157 HER2-enriched and 221 triple-negative [TNBC]) yielded informative results upon targeted parallel sequencing for 58 genes. Patients had operable BC and had been treated in 4 prospective trials with adjuvant anthracycline-based chemotherapy in the pre- and post-trastuzumab (T) era. Analysis was performed in training and validation sets and in the entire cohort. Results: Eligible mutations (mut, n = 3086) were observed in 56 genes and were distributed in various combinations (1 to > 20 mutant genes) in 1043 tumors (63%). PIK3CA mut were found in 466 (44%); TP53 in 420 (40%); GATA3 in 128 (12%); and, CDH1 in 121 (11.5%) tumors. PIK3CA mut were more common in Luminal A/B tumors (49%), while TP53 in HER2-positive (57%) and TNBC (73%) (all p < 0.001). Both PIK3CA and TP53 mut were observed in 7% of all tumors. TP53 mut conferred increased risk for relapse in patients with Luminal A/B (HR = 2.00; 95% CI 1.42-2.82; Wald p < 0.001) and TNBC (HR = 1.82; 95% CI 1.04-3.20; Wald p = 0.037). In the same context, PIK3CA mut were associated with favorable prognosis in the absence of TP53 mut; this effect disappeared in tumors with mut in both genes. In HER2-positive patients in the pre-T era, TP53 mut alone or in combination with PIK3CA mut did not interfere with outcome. By contrast, these mutant genotypes tended to confer decreased risk for relapse in patients treated with T (HR = 0.51; 95% CI 0.23-1.14; Wald p = 0.101). All described effects were equally significant in the training and validation sets. Conclusions: TP53 mutant genotypes are unfavorable prognosticators in Luminal A/B and TNBC patients, but may predict benefit in HER2-positive patients with operable BC treated with T. PIK3CA mut do not seem to interfere with patient outcome in the latter context. If validated in independent large studies, these findings may have important clinical implications.