Estrogen withdrawal, increased breast cancer risk and the KRAS-variant

In addition, KRAS -variant BC patients also appeared to have a lower estrogen state than KRAS -variant unaffected controls, with a lower BMI ( P < 0.001). Finally, hormone replacement therapy (HRT) discontinuation in KRAS -variant patients was associated with a diagnosis of triple negative BC ( P < 0.001). Biologically confirming our clinical findings, acute estrogen withdrawal led to oncogenic transformation in KRAS -variant positive isogenic cell lines.

Finally, KRAS -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 < 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 KRAS -variant, who are also significantly more likely to present with multiple primary breast cancer.