Project 2: Improving the Endocrine Management of Premenopausal ER+/HER2- Breast Cancer
Breast cancer is the most commonly diagnosed cancer in women before menopause worldwide, and its incidence is increasing in developed countries. Breast tumors arising before menopause are more likely to be of an aggressive intrinsic subtype, of higher grade and at an advanced stage compared with tumors after menopause.
Breast cancer that is both estrogen receptor (ER) positive and HER2 negative also is known as ER+/HER2- breast cancer. Women who haven't undergone menopause and have this type of breast cancer are commonly treated with chemotherapy, endocrine therapy and ovarian function suppression.
Meta-analyses of adjuvant trials have demonstrated that aromatase inhibitors plus ovarian function suppression improve disease-free survival compared with tamoxifen plus ovarian function suppression. However, this approach has yet to improve overall survival.
Endoxifen as an alternative endocrine strategy
Premature menopause is known to be associated with higher rates of cardiac disease, hypertension, diabetes, hyperlipidemia, osteoporosis and death. Therefore, alternative endocrine strategies for women with ER+/HER2- breast cancer before menopause are critically needed, especially for women who can't tolerate ovarian function suppression.
Endoxifen is an active tamoxifen metabolite. We led the development of endoxifen as a novel endocrine therapy for ER positive breast cancer. Through completion of phase 1 and 2 clinical trials, we demonstrated that endoxifen is safe and well tolerated, has substantial oral bioavailability, and is superior to tamoxifen in endocrine therapy-resistant disease. We also identified a novel mechanistic basis for the superior anticancer effects of endoxifen — the novel endoxifen target PKCβI.
Hypotheses
We hypothesize that:
- Endoxifen is a superior endocrine therapy in part due to its ability to dually target both the estrogen receptor and PKCβI.
- The optimal treatment of women with ER+/HER2- breast cancer before menopause can be achieved using endoxifen monotherapy without the need for ovarian function suppression.
Project aims
This project has three aims:
- Aim 1: Develop endoxifen for women with ER+/HER2- breast cancer before menopause. This clinical trial, called (Z)-Endoxifen for the Treatment of Premenopausal Women With ER+/HER2- Breast Cancer, is open and recruiting participants. Get details about this trial.
- Aim 2: Elucidate the mechanisms by which PKCβI contributes to endoxifen responsiveness in endocrine-sensitive disease.
- Aim 3: Determine the predictive and prognostic value of PKCβI in ER+/HER2- breast cancer treated with tamoxifen and endoxifen.
