Breast Cancer

Breast cancer is the most frequently diagnosed cancer in women, accounting for about 30% of all new cancer cases, and its incidence is increasing. ^[1] Globally it is both the most commonly occurring cancer and the commonest cause of cancer death among women, with incidence and mortality declining in high-resource countries but increasing in low-resource countries. ^[2] Among US women it is the second most common cancer and the second most common cause of cancer death, with an estimated 43 170 deaths in 2023. ^[3] Breast cancer is classified into molecular subtypes (luminal A, luminal B, HER2 and triple negative/basal-like), and associations with risk factors vary by subtype. ^{[4] [5]} Triple-negative breast cancer accounted for 12% of breast cancers diagnosed in the United States from 2012 to 2016, with a 5-year survival 8% to 16% lower than hormone receptor-positive disease. ^[6] Survival depends on both stage and molecular subtype. ^[2]

The development of breast cancer is a multi-step process involving multiple cell types. ^[7] Approximately 5-10% of breast cancer is considered hereditary, typically with an early age of onset. ^[8] BRCA1 and BRCA2 act as tumor suppressor genes that regulate DNA repair through homologous recombination, and their mutations account for the majority of hereditary breast and ovarian cancer. ^[9] Endogenous estrogen exposure, proliferative benign breast disease, breast density and family history may indicate increased breast cancer risk, and incidence increases with age. ^[10] In observational studies, later age at menarche and breastfeeding were consistently associated with decreased risk across all subtypes, while later age at menopause, later first childbirth and nulliparity or low parity were associated with increased risk of luminal A, luminal B and HER2 subtypes. ^[4]

In its current recommendation statement, the US Preventive Services Task Force recommends biennial screening mammography for women aged 40 to 74 years (B recommendation), replacing its 2009 recommendation of biennial screening at 50 to 74 years with selective screening at 40 to 49 years. ^{[3] [12]} The European Society of Breast Imaging (EUSOBI) keeps regular mammography as the mainstay of screening and advises high-risk women to start earlier with yearly breast MRI, supplemented by yearly or biennial mammography from 35-40 years old. ^[1] The American College of Radiology Appropriateness Criteria (2025 update) recommend mammography and digital breast tomosynthesis in all risk categories and, in high-risk patients, breast MRI starting as early as 25 to 30 years of age. ^[13] A systematic review of 23 international guidelines issued between 2010 and 2021 found that most recommend annual or biennial mammography between 40 and 74 years for average-risk women, with 50-69 years regarded as the optimal age group, but ages and intervals are not identical across guidelines. ^[14] In a meta-analysis of mammography trials, relative risks for breast cancer mortality were 0.86 for women aged 50 to 59 years and 0.67 for those aged 60 to 69 years, whereas estimates for women aged 39 to 49 years (0.92) and 70 to 74 years (0.80) were not statistically significant, and all-cause mortality was not reduced with screening.

In prospective cohort studies, sufficient physical activity (RR 0.90), breastfeeding (RR 0.87) and fruit and vegetable consumption (RR 0.87) were associated with lower breast cancer risk; these are observational associations, not trial results. ^[11] In randomized trials, conjugated equine estrogens plus medroxyprogesterone acetate increased breast cancer risk by approximately 1 excess event/1000 person-years compared with placebo, whereas low-dose conjugated estrogens plus bazedoxifene was not associated with increased risk. ^[17] Combined estrogen/progestogen hormone therapy, but not estrogen alone, increases breast cancer risk with longer-term use, and in cohort data ever-use of estrogen/progesterone was associated with an RR of 1.60. ^{[18] [11]} The Endocrine Society clinical practice guideline on menopausal symptoms advises screening women for breast cancer