Growth factor genes and change in mammographic density after stopping combined hormone therapy in the California Teachers Study

The contribution of genetic polymorphisms to the large inter-individual variation in mammographic density (MD) changes following starting and stopping use of estrogen and progestin combined therapy (EPT) has not been well-studied. Previous studies have shown that circulating levels of insulin-like growth factors are associated with MD and cross-talk between estrogen signaling and growth factors is necessary for cell proliferation in the breast. We evaluated single nucleotide polymorphisms (SNPs) in growth factor genes in association with MD changes after women stop EPT use.

We genotyped 191 SNPs in 13 growth factor pathway genes in 284 non-Hispanic white California Teachers Study participants who previously used EPT and collected their mammograms before and after quitting EPT. Percent MD was assessed using a computer-assisted method. Change in percent MD was calculated by subtracting percent MD of an 'off-EPT' mammogram from percent MD of an 'on-EPT' (i.e. baseline) mammogram. We used multivariable linear regression analysis to investigate the association between SNPs and change in percent MD. We calculated P-values corrected for multiple testing within a gene (P_adj).

Rs1983210 in INHA and rs35539615 in IGFBP1/3 showed the strongest associations. Per minor allele of rs1983210, the absolute change in percent MD after stopping EPT use decreased by 1.80% (a difference in absolute change in percent MD) (P_adj= 0.021). For rs35539615, change in percent MD increased by 1.79% per minor allele (P_adj= 0.042). However, after applying a Bonferroni correction for the number of genes tested, these associations were no longer statistically significant.

Genetic variation in growth factor pathway genes INHA and IGFBP1/3 may predict longitudinal MD change after women quit EPT. The observed differences in EPT-associated changes in percent MD in association with these genetic polymorphisms are modest but may be clinically significant considering that the magnitude of absolute increase in percent MD reported from large clinical trials of EPT ranged from 3% to 7%.