Do selective estrogen receptor modulators treat cervical precancer and cancer? Time to pool data from relevant trials

Abstract

Dear Editor,Based on the nearly absolute etiologic link between carcinogenic human papillomavirus (HPV) and cervical cancer, two new approaches for the prevention of cervical cancer have emerged: (1) HPV vaccination for primary HPV prevention in younger women and (2) carcinogenic HPV detection for secondary prevention via identifying and treating cervical precancer and early cancers. Both have demonstrated high degrees of efficacy with maximum effectiveness guided by an understanding of the causal model and application of these technologies in an age appropriate manner. 1 Despite the advent of these promising prevention tools, there is a real need to develop nonsurgical methods for treating cervical precancerous lesions and even early cancer for three reasons. First, current HPV vaccines are prophylactic and do not treat pre-existing HPV infections. 1 Second, surgical excision of screen-detected precancerous lesions, while a highly efficacious (90-95%) treatment 1 increases the risk of preterm delivery and infant morbidity and mortality. 2 Third, most women who screen positive by a Pap and/or HPV do not have clinically actionable disease, yet these women are at risk of cervical precancer and cancer in the future and must be followed up intensively. In addition, in the low-resource settings, surgical methods are not commonly available and cryotherapy, while moderately efficacious when its use is limited to smaller lesions, causes significant watery discharge and requires sexual abstinence for several weeks to permit healing of treated epithelium.Despite the knowledge that HPV infection is the obligate cause of cervical cancer, targeted immunological approaches for therapy such as therapeutic vaccines have been unsuccessful. 3 Chung and Lambert 4 present a novel approach of using estrogen receptor antagonists (selective estrogen receptor modulators or SERMs) to treat cervical precancer and cancer. As noted by the authors, there are strongly supportive laboratory 5 and epidemiological data 6,7 that estrogen plays contributing role in cervical carcinogenesis. In this study, Chung and Lambert 4 successfully treated 7 E6/E7 transgenic mice that spontaneously manifested cervical cancer with Raloxifene, an estrogen receptor antagonist that reduces the risk of breast cancer.To investigate whether Raloxifene might reduce the incidence of cervical cancer and its immediate precursor, carcinoma in situ (CIS), previously unpublished data on these outcomes from two randomized clinical trials to evaluate two SERMs, tamoxifen and raloxifene, for breast cancer risk reduction were analyzed. The NSABP (National Surgical Adjuvant Breast and Bowel Project), an NCI funded Cooperative Group, has designed and conducted the two large breast cancer prevention trials, Breast Cancer Prevention Trial P-1 (BCPT-P1) 8 and Study of Tamoxifen vs. Raloxifene (STAR). 9 While both tamoxifen and raloxifene are estrogen receptor antagonists in breast tissue, raloxifene is an estrogen receptor antagonist whereas tamoxifen is an agonist in the huma...

Endogenous Sex Steroids and Risk of Cervical Carcinoma: Results from the EPIC Study

“…Estrogens have a profound influence on the cervical squamous-columnar junction from which ICC arises in mice and in humans (28), and the estrogen receptor a has been shown to be necessary for cervical cancer to arise in mice (11). Drugs that interfere with the function of estrogen receptor a (e.g., raloxifene) have been shown to prevent the onset or induce the regression of ICC in transgenic mice (11) but corresponding data in humans are scant (29).…”

“…ICC can be effectively prevented through screening and HPV vaccination programs, and treated with surgery and radiotherapy (37). Elucidating the dependence of cervical lesions on sex steroid hormones (29,30) may allow, however, the discovery of hormone modulators that could further improve ICC control by, for example, decreasing recurrences of cancerous and precancerous lesions.…”

Human papillomavirus oncogenes reprogram the cervical cancer microenvironment independently of and synergistically with estrogen

“…Furthermore, treatment with estrogen-signaling inhibitors promotes regression of cervical cancer and precancerous lesions in these mice (23,24). While caution is reasonable in extrapolating the efficacy of drugs in murine models to therapeutic treatment of human disease (25), human population-based data do correlate long-term antiestrogen use with lower risk of cervical neoplasia (26).…”

Functional association of oestrogen receptors with HPV infection in cervical carcinogenesis

“…ERα supporting CC during the time of initiation of carcinogenic events indicate that ERα antagonists are a good therapeutic option at the onset of cervical carcinogenesis or the late maintenance of stromal ERα, which needs to be targeted with a suitable SERM inhibitor. Although studies with animal models have demonstrated that SERMs are good candidates for treatment of CC, the current SERMs yielded inconclusive results (Chung et al 2010, Castle 2011, Munger 2014) that limit their use because of a lack of evidence from controlled clinical trials. Hence, the efficacy and acceptance of SERMs as a therapeutic option in the precancer or invasive cervical carcinoma is largely unpredictable.…”