Abstract P5-09-09: Functional IGF1R variant predicts preeclampsia protection from invasive breast cancer: Novel California teachers study findings
Authors: Powell M , Von Behren J , Neuhausen S , Reynolds P , Benz C 
Published: March 2017

Many studies have reported lower breast cancer risk in women who develop hypertension in pregnancy with a meta-analysis reporting hazard ratios of 0.86 for preeclampsia and 0.83 for gestational hypertension. Our prior work in the Marin Women's Study (MWS) demonstrated both a lower breast density and a lower risk of breast cancer in women with pregnancy-induced hypertension (PIH) if they possess the TT genotype of IGF1R SNP rs2016347.

Breast cancer in MWS women with PIH by IGF1R genotypers2016347 genotype# with genotype# breast cancer cases% breast cancer casesGG9188.79%GT195147.18%TT8800.00%Fisher's exact = 0.008

The current study was designed to validate and expand upon these findings in the larger California Teachers Study (CTS) which consists of &gt;130,000 female educators. From original participants a case-control study was established in 2012 consisting of all non-Hispanic white women with DNA samples that became cases since entry into the study (N = 2030) and controls without invasive or in situ breast cancer (N = 1552). The current study nests within this case control study. All participants with a self-reported history of preeclampsia were selected (81 cases/56 controls). IGF1R SNP rs2016347 was assessed by Taqman assay.

Results: Women with the TT genotype had an odds ratio (OR) of 0.38 when compared to the GG genotype after adjusting for potential confounders. Stratification by HR+/HR- cases and by age of first birth (AFB) resulted in statistically significant adjusted OR's of 0.26 for HR+ positive cases and 0.15 for women with AFB &lt;30. Both showed significant trend effect for number of T alleles as shown below:

Preeclampsia and breast cancer in CTSrs2016347 genotypeAll cases (N=137)HR+ cases (N=118)AFB &lt;30 (N=106)TT vs GG0.38 (0.13, 1.14)0.26 (0.07, 0.89)*0.15 (0.04, 0.56)*GT vs GG0.53 (0.19, 1.46)0.57 (0.19, 1.74)0.34 (0.12, 1.12)Trend analysisp = 0.09p = 0.03*p = 0.005** p &lt; .05

Overall in the CTS, the adjusted hazard ratio for women with vs without preeclampsia was 0.94 (0.81, 1.08).

Conclusions: These results suggest significant breast cancer protection in women with preeclampsia that possess the TT genotype, specifically in those women with AFB &lt;30, and for the development of HR+ breast cancer. The overall OR for all women with the TT genotype was low at 0.38 but did not reach statistical significance. This analysis in a second cohort again demonstrates a lower risk of breast cancer in women with a hypertensive disorder of pregnancy possessing the same IGF1R variant.

Recent studies have associated the rs2016347 T allele with lower normal tissue expression of IGF1R mRNA, better survival in HR+ breast cancer, and improved pathological response to neoadjuvant chemotherapy. The protective T allele creates a new microRNA (miR-432) binding site within the IGF1R 3'UTR, offering a potential functional explanation for reduced mammary gland expression of this cancer-associated growth factor. This may interact with alterations of growth and metabolic factors characteristic of preeclampsia to imprint the immature gland with a lasting protective effect from later life breast tumorigenesis. If mechanistically substantiated, these findings could lead to a novel breast cancer prevention strategy.

Citation Format: Powell M, Von Behren J, Neuhausen S, Reynolds P, Benz C. Functional IGF1R variant predicts preeclampsia protection from invasive breast cancer: Novel California teachers study findings [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-09-09.