Lifetime exposure to high estrogens levels and deregulation of enzymes of estrogen biosynthetic and metabolic pathway are considered breast cancer risk factors. Our research team has previously evaluated, in women with hormone-dependent breast cancer, NRF2 and KEAP1 polymorphisms (alone or in association), with breast cancer prognosis, in cases with GSTM1-present genotype. We identified that GSTM1*1/0 genotype and cumulative presence of at least one allele mutated in KEAP1 and/or NRF2 polymorphisms might be associated with worse prognosis. Moreover, older women were carriers of both GSTM1 null and CYP1B1Val genotypes, similar results were found for the cumulative presence of GSTT1 null and CYP1B1Val genotypes and for MTHFR C677T and GSTT1 null polymorphism. These results lead us to genotype other enzymes involved in estrogen biosynthetic/metabolic pathways, namely: CYP17A1 T27C, CYP19A1 codon 39 Trp/Arg, COMT Val158Met, CYP1A1 Ile462Val, GSTP1 Ile105Val, ERα PvuII and XbaI polymorphisms and TP53 Arg72Pro (DNA damage signalling and repair pathway) polymorphism. The genotyping analysis was evaluated, alone or in association, with breast cancer prognosis and with age at breast cancer diagnosis, we found no association (p-value>0.05). These results emphasize that polymorphisms in NRF2/KEAP1 complex and the null polymorphisms of GSTM1/GSTT1 should be further investigated as targets for breast cancer therapy. In addition, polymorphisms related to inefficient estrogen detoxification might be a trigger to hormone-dependent breast cancer development at later ages, and should be considered in breast cancer risk assessment models.