Impact of smoking on subtypes and molecular profile of breast cancer: a systematic review

Background: Breast cancer encompasses heterogeneous pathological and molecular subtypes with distinct aetiologies and clinical outcomes. Although cigarette smoking is an established carcinogenic exposure, its subtype-specific associations and molecular effects in breast cancer remain insufficiently clarified. This systematic review synthesizes epidemiological, molecular, and prognostic evidence on how active cigarette smoking influences the risk of specific breast cancer subtypes. Methods: We conducted a systematic review, including observational and translational human studies that assessed active cigarette smoking in relation to breast cancer subtypes defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status, or by intrinsic molecular classifications. We also included studies evaluating smoking-associated molecular alterations within breast tumors. Results: Nineteen studies met the eligibility criteria. Epidemiological evidence suggested a possible modest increase in the risk of luminal/ER-positive breast cancer, particularly among women with longer smoking duration, heavier cumulative exposure, or smoking initiation before first full-term pregnancy; however, the pooled meta-analysis for current vs. never smoking was not statistically significant. No meaningful association was identified for triple-negative breast cancer (TNBC), and findings for HER2-positive breast cancer were heterogeneous. Molecular studies were associated with smoking-related changes in promoter DNA methylation, higher overall mutational burden, increased genomic instability, altered immune-cell infiltration within the tumor microenvironment, and conversion of receptor phenotype—especially toward HER2 positivity—suggesting a potential association with more aggressive tumor characteristics. Prognostic studies generally showed poorer overall survival and a higher risk of disease recurrence among smokers. Discussion: Active cigarette smoking may be associated with a possible modest increase in the risk of luminal/ER-positive breast cancer, while being associated with molecular alterations linked to more aggressive tumor phenotypes and poorer clinical outcomes.