Prenatal hormonal imprinting reflected by anogenital distance and risk of breast cancer: A case-control study of 839 women.

Abstract

10554 Background: Anogenital distance (AGD) is a sexually dimorphic, stable anthropometric marker set during fetal development and widely used as a proxy of prenatal androgen/estrogen balance. We hypothesized that AGD is associated with the risk of developing breast cancer (BC), a hormone-dependent disease. Methods: We conducted a prospective case–control study in Murcia (Spain) including 422 incident BC cases and 417 controls (2022–2024). Two AGD measures were obtained by trained examiners: ano-clitoral (AGDAC, “long”) and ano-fourchette (AGDAF, “short”). Models were adjusted for age and BMI; quintile-based logistic regressions assessed non-linear associations. Stratified analyses were performed by menopausal status. Molecular subtype and Oncotype Recurrence Score (RS) (n=81 luminal tumors) were explored. Results: Compared with controls, BC cases showed longer AGDAC (mean 85.0 vs 81.2 mm; p <0.01) and shorter AGDAF (28.6 vs 29.8 mm; p =0.02). Across AGDAC quintiles, we observed an inverse risk gradient: lowest quintile vs highest, aOR 0.34 (95% CI 0.22–0.54; p <0.001). The association was stronger in premenopausal women (Q1 vs Q5 aOR 0.31; 95% CI 0.16–0.59; p =0.001). AGD was not associated with tumor subtype (luminal A/B, HER2+, triple-negative) nor with genomic risk (RS>25 vs ≤25). Conclusions: AGD, especially AGDAC, emerges as a non-invasive, inexpensive clinical marker of BC susceptibility, independent of molecular subtype and genomic risk. Findings suggest prenatal endocrine programming may prime lifetime BC risk, with a pronounced effect in hormonally active (premenopausal) women. If validated, AGD could enhance risk stratification and early detection pathways in population screening and prevention clinics. Odds ratio (OR) for cases of breast cancer controls according to quintiles of AGD measures, taking the fifth quintile as a reference. Breast cancer (n=422) vs. controls (n=417) AGD in quintiles(Median for each quintile) Cases Controls Odds Ratio a (95%CI) P- trend Odds Ratio b (95%CI) P- trend AGD AF 5 th (38.0 mm) 80 89 1.0 (reference) 1.0 (reference) 4 th (32.1 mm) 75 93 0.90 (0.58-1.4) 0.95 (0.61-1.5) 3 rd (28.5 mm) 84 80 1.2 (0.76-1.8) 1.5 (0.95-2.3) 2 nd (25.3 mm) 87 80 1.2 (0.76-1.8) 1.5 (0.95-2.3) 1 st (21.4 mm) 96 75 1.4 (0.93-2.2) 0.26 1.9 (1.3-3.1) 0.01 AGD AC 5 th (99.0 mm) 114 54 1.0 (reference) 1.0 (reference) 4 th (88.4 mm) 79 88 0.43 (0.27-0.66) 0.40 (0.26-0.63) 3 rd (82.6 mm) 82 87 0.45 (0.29-0.60) 0.42 (0.27-0.66) 2 nd (77.0 mm) 75 92 0.39 (0.25-0.60) 0.37 (0.23-0.58) 1 st (69.3 mm) 72 96 0.36 (0.23-0.55) <0.001 0.34 (0.22-0.54) <0.001 a Unadjusted OR. b OR adjusted by age and BMI. c OR adjusted by. AGDAF: Anogenital distance from the upper verge of the anus to the posterior fourchette AGDAC: Anogenital distance from the upper verge of the anus to the anterior clitoral surface.