A word of caution: do not wake sleeping dogs; micrometastases of melanoma suddenly grew after progesterone treatment

Abstract

BackgroundHormonal treatment might affect the immune response to tumor antigens induced in cancer patients who are being vaccinated.Case presentationA 33 years-old woman was diagnosed with cutaneous melanoma in May 2009. Her melanoma was located in the intermammary sulcus, had a Breslow thickness of 4 mm, a Clark’s level IV, it was ulcerated and highly melanotic. The bilateral sentinel node biopsy was negative. She entered into a randomized Phase II/III clinical study comparing a vaccine composed of irradiated melanoma cells plus BCG plus GM-CSF versus IFN-alpha 2b and she was assigned to the vaccine arm. During the two years treatment she remained disease-free; the final CAT scan being performed in August 2011. Between November and December 2011, her gynecologist treated her with three cycles of 200 mg progesterone/day for ten days, every two weeks, for ovary dysfunction. In November 2011 the patient returned to the Hospital for clinical and imaging evaluation and no evidence of disease was found. At the next visit in March 2012 an ultrasound revealed multiple, large metastases in the liver. A CAT scan confirmed the presence of liver, adrenal glands and spleen metastases. A needle biopsy of a liver lesion revealed metastatic melanoma of similar characteristics to the original tumor. We suggest that progesterone treatment triggered proliferation of so far dormant micrometastases that were controlled during CSF470 vaccine treatment.ConclusionThe use of progesterone in patients with melanoma that are under immunological treatments should be carefully considered, since progesterone could modify the balance of pro-inflammatory and Th1 functions to a regulatory and anti-inflammatory profile of the immune system that could have an impact in tumor progression.

Ethinylestradiol and Levonorgestrel as Active Agents in Normal Skin, and Pathological Conditions Induced by UVB Exposure: In Vitro and In Ovo Assessments

“…According to Nurses’ Health Study, the risk to developing melanoma is two times higher among women that have used oral contraception for 10 years or more [ 43 ]. It was also reported that the use of progesterone alone actuated the growth of melanoma micro-metastases [ 44 ]. Another study revealed that only low doses of progesterone (up to 1 µM), similar to the ones used in therapy, are able to stimulate melanoma cell proliferation, while higher doses not only lack such effect but even induce cell cycle arrest and apoptosis [ 40 ].…”

Immunomodulatory Effects of Sex Hormones: Requirements for Pregnancy and Relevance in Melanoma

“…As progesterone promotes a tolerant state in pregnancy, treating a stable melanoma patient with progesterone was found to cause proliferation of dormant micrometastases by tipping the immune system back to a Th2 state. 185 B7-H1 (PD-L1), is a molecule expressed on antigen presenting cells and contributes to tumor evasion and expansion of Tregs. 186,187 In a B7-H1 knockout mouse model of melanoma, it was discovered that females had superior tumor growth resistance compared to males due to estrogen mediated suppression of Treg cells.…”

Progesterone and Melanoma Cells: An Old Story Suspended between Life and Death

“…Others larger multivariate analyses, however, demonstrated that it was equally strong in pre-as well as in post-menopausal groups [20]. Parallely, the literature concerning melanoma progression in pregnancy is also controversial [21][22][23][24], although several recent reports demonstrate that pregnancyassociated melanomas have poorer outcomes than other melanomas [25][26][27][28][29].In vitro progesterone influences melanoma growth [30][31][32][33], but several melanoma cell lines have been studied and very different experimental protocols have been used, so that the results actually available in literature are not univocal. Further research on this topic is thus needed, especially in view of the widespread use of PG in clinical practice.…”

“…In vitro progesterone influences melanoma growth [30][31][32][33], but several melanoma cell lines have been studied and very different experimental protocols have been used, so that the results actually available in literature are not univocal. Further research on this topic is thus needed, especially in view of the widespread use of PG in clinical practice.…”