A recent study has helped clarify which women with endometrial cancer are likely to benefit from progesterone therapy. Although this treatment can be effective and well-tolerated, it is not widely embraced in clinical practice due to the lack of biomarkers that predict hormone sensitivity and, subsequently, which patients will benefit from progesterone.
Although progesterone has been used as a treatment for endometrial cancer for approximately 50 years, the antitumor mechanisms and site of action for progesterone therapy were unknown, reported Sanaz Memarzadeh, MD, PhD, of the David Geffen School of Medicine at University of California–Los Angeles (UCLA), and colleagues in Cancer Research. In addition, molecular mechanisms underlying progesterone resistance or sensitivity were also poorly understood. Some women with endometrial cancer respond to progesterone, whereas others experience disease progression while on hormonal therapy. Largely because women with hormone-sensitive or resistant disease can’t be prospectively identified, progesterone therapy is not commonly used as a treatment for endometrial cancer.
However, after 3 years of studying a mouse model of endometrial cancer, Memarzadeh and associates have learned that progesterone eliminates cancer cells indirectly by binding to the progesterone receptors in stromal, or connective-tissue, cells residing in the tumor microenvironment. Despite the fact that the stroma is only a minor fraction of the tumor, Memarzadeh’s group discovered that all of the antitumor effects of progesterone are mediated through the stroma.
Deleting the progesterone receptors in the stromal cells in the tumor microenvironment rendered progesterone therapy ineffective. When the receptors were returned to the adjacent cells in the microenvironment of hormone-resistant endometrial cancer, the tumor cells became sensitive to hormone therapy.
“I believe these exciting findings are going to surprise the clinical community and change the way people look at patterns of hormone receptor expression in endometrial tumors,” noted Memarzadeh in a statement from UCLA Health Sciences.
The authors concluded that epigenetic de-repression of stromal progesterone receptor could be a potential therapeutic target for sensitizing hormone-refractory endometrial tumors to progesterone therapy, and that stromal expression of progesterone receptors may emerge as a reliable biomarker in predicting response to hormonal therapy.