Abstract P6-10-02: The KRAS-variant, multiple breast cancer risk, and estrogen withdrawal
Authors: Weidhaas Joanne B , Mcveigh Terri , Pilarski Robert , Miller Nicola , Sweasy Joann , Kerin Michael , Nallur Sunitha , Sadofsky Jackie , Nemec Antonio , Sweeney Karl , Daniel Zelterman 
Published: May 2015

Background: The KRAS-variant is a germ-line, functional microRNA binding site mutation in KRAS that leads to increased risk of premenopausal triple negative breast cancer (TNBC) (1), as well as double primary breast/ovarian cancer in women (2). Evidence of an association with post-menopausal (PM) cancer onset (3), as well as altered BC biology in hormone replacement therapy (HRT) users (4), led us to investigate the hypothesis that estrogen exposure alters BC risk and biology in KRAS-variant individuals.

Methods: Women with a confirmed diagnosis of BC were invited to join a study of the KRAS-variant and hormones, and asked to complete a questionnaire, send in a DNA sample and submit pathologic information. For the study 1712 BC survivors were eligible for inclusion. An additional cohort of unaffected women, positive for the KRAS-variant (n=80), were included from Ohio State University as the control population. Differences were evaluated through 2 tailed t-test and Chi squared analysis. Additionally, isogenic, perfectly matched cell lines +/- or -/- for the KRAS-variant were created to study transformation in vitro.

Results: Of the 1712 study participants, 17.4% (298) had the KRAS-variant. Compared to controls, KRAS-variant BC patients had significantly lower Body Mass Index (BMI) (p&lt;0.0001), were significantly likely to have fewer live births (p=0.0028), and to be older at their first birth (p=0.0070). There was no difference in age of testing between the BC and control KRAS-variant cohorts.

Excluding 68 (3.9%) women with other known BC associated mutations (BRCA1, BRCA2, p53, and PTEN), KRAS-variant BC patients were significantly more likely to be diagnosed with a second, independent BC compared to non-variant BC patients (p=0.0046). No differences were found between the variant and non-variant groups in synchronous versus metachronous presentation, time between first and second breast cancer diagnoses, time between diagnosis and enrollment, or lobular histology.

For women diagnosed when PM in our cohort (n=765), tumor biology in KRAS-variant women was significantly impacted by HRT history. In KRAS-variant PM BC patients that stopped HRT before their BC diagnosis (ex-HRT users), the proportion developing TNBC was significantly higher than for non-variant ex-HRT users (35.5% versus 7.3%, p&lt;0.0001)). The proportion of KRAS-variant ex-HRT users developing TNBC was also significantly higher than for KRAS-variant women who were never on HRT (11.4%, p=0.020) or for those who were on HRT when diagnosed with BC (3.6%, p&lt;0.0001). In addition, KRAS-variant ex-HRT users had significantly higher-grade tumors than non-variant ex-HRT users (p=0.0286).

Finally, cell line studies with isogenic KRAS-variant cell lines demonstrated that estrogen withdrawal led to significantly enhanced cell line growth, and apparent transformation for the KRAS-variant+/- line compared to the non-variant -/- line.

Conclusions: Based on our studies, it appears that estrogen withdrawal may be a risk for breast cancer development and aggressive breast tumor biology for women with the KRAS-variant.

1. Paranjape, et al. (2011). Lancet Oncology. 12(4):377-86. Dec 5.

2. Pilarski, et al. (2012). PLos ONE 7(5): e37891.

3. Ratner, et al. (2011). Oncogene 31(42): 4559-66.

4. Cerne, et al. (2012). BMC Cancer 12(105).

Citation Format: Joanne B Weidhaas, Terri Mcveigh, Robert Pilarski, Nicola Miller, Joann Sweasy, Michael Kerin, Sunitha Nallur, Jackie Sadofsky, Antonio Nemec, Karl Sweeney, Zelterman Daniel. The KRAS-variant, multiple breast cancer risk, and estrogen withdrawal [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-10-02.