Estrogen Withdrawal, Increased Breast Cancer Risk and the KRAS-variant

The <i>KRAS</i>-variant is a biologically functional, microRNA binding site variant, which predicts increased cancer risk especially for women. Because external exposures, such as chemotherapy, differentially impact the effect of this mutation, we evaluated the association of estrogen exposures, breast cancer (BC) risk and tumor biology in women with the <i>KRAS-</i>variant. Women with BC (<i>n</i>=1712), the subset with the <i>KRAS-</i>variant (<i>n=</i>286) and <i>KRAS-</i>variant unaffected controls (<i>n</i>=80) were evaluated, and hormonal exposures, <i>KRAS-</i>variant status, and pathology were compared. The impact of estrogen withdrawal on transformation of isogenic normal breast cell lines with or without the <i>KRAS-</i>variant was studied. Finally, the association and presentation characteristics of the <i>KRAS-</i>variant and multiple primary breast cancer (MPBC) were evaluated. <i>KRAS-</i>variant BC patients were more likely to have ovarian removal pre-BC diagnosis than non-variant BC patients (p=0.033). In addition, <i>KRAS-</i>variant BC patients also appeared to have a lower estrogen state than <i>KRAS-</i>variant unaffected controls, with a lower BMI (p&lt;0.001). Finally, hormone replacement therapy (HRT) discontinuation in <i>KRAS-</i>variant patients was associated with a diagnosis of triple negative BC (p&lt;0.001). Biologically confirming our clinical findings, acute estrogen withdrawal led to oncogenic transformation in <i>KRAS-</i>variant positive isogenic cell lines. Finally, <i>KRAS-</i>variant BC patients had greater than an 11-fold increased risk of presenting with MPBC compared to non-variant patients (45.39% vs 6.78%, OR 11.44 [3.42-37.87], p&lt;0.001). Thus, estrogen withdrawal and a low estrogen state appear to increase BC risk and to predict aggressive tumor biology in women with the <i>KRAS-</i>variant, who are also significantly more likely to present with multiple primary breast cancer.