3: Association of hydroxy-delta-5-steroid Dehydrogenase, 3 Beta- and Steroid Delta-isomerase 1 Genetic Inheritance and Distant Metastasis in Post-menopausal Breast Cancer

Introduction:
Inheritance of a single nucleotide polymorphism (1245A >C) in the gene hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 1 (HSD3B1) results in gain-of-function in a key catalytic enzyme (3βHSD1) involved in the conversion of adrenal androgen precursors to estrogen. We hypothesized that inheritance of the HSD3B1 (1245C) allele would negatively impact breast cancer outcomes.



Methods: Germline HSD3B1 was sequenced in 635 post-menopausal women with stage I-III estrogen-receptor positive (ER+), HER2/neu negative (HER2-) breast cancer between 2004-2012 enrolled in a population-based study in western Washington. The primary outcome was cumulative incidence of distant metastatic disease according to genotype. Hazard ratios (HR) were calculated using Fine-Gray regression accounting for competing risks.


Results:
The allelic frequency of HSD3B1 (1245C) was 31%; 47% homozygous wild-type (AA), 44% heterozygous (AC) and 9% homozygous variant (CC). Median follow-up was 58 months. There were no significant differences in age at diagnosis, use of hormone replacement therapy, family history, stage, or use of adjuvant endocrine therapy according to genotype. There was a non-significant trend toward higher frequency of mastectomy (AA and AC 34%, CC 48%, p=0.10) and use of adjuvant chemotherapy (AA 35%, AC 37%, CC 45%, p=.36) with the CC variant. No significant difference in cumulative incidence of distant metastasis was observed between AA and AC (HR, 1.39; 95% CI, 0.42-4.54); however, distant metastatic recurrence was 4.8 times higher (95% CI 1.30-18.16) in women with the CC variant compared to AA (Figure).



Conclusions:
The HSD3B1 (1245C) variant allele is associated with increased cumulative incidence of distant metastatic recurrence in women with post-menopausal ER+/HER2- breast cancer. We also confirmed that the allele frequency is at least equivalent to that reported in the general population. Further research is necessary to understand the effect of excess adrenal androgens and estrogen in promoting breast cancer metastasis, and whether these patients warrant additional therapy.