Fertility preservation and management of pregnancy in melanoma patients requiring systemic therapy

Abstract

Melanoma is one of the most common cancers in adolescents and adults at fertile age, especially in women. With novel and more effective systemic therapies that began to profoundly change the dismal outcome of melanoma by prolonging overall survival, the wish for fertility preservation or even parenthood has to be considered for a growing portion of melanoma patients—from the patients' as well as from the physicians' perspective. The dual blockade of the mitogen-activated protein kinase pathway by B-Raf proto-oncogene serine/threonine kinase and mitogen-activated protein kinase inhibitors and the immune checkpoint inhibition by anti-programmed cell death protein 1 and anti-cytotoxic T-lymphocyte-associated protein-4 monoclonal antibodies constitute the current standard systemic approaches to combat locally advanced or metastatic melanoma. Here, the preclinical data and clinical evidence of these systemic therapies are reviewed in terms of their potential gonadotoxicity, teratogenicity, embryotoxicity and fetotoxicity. Recommendations for routine fertility and contraception counseling of melanoma patients at fertile age are provided in line with interdisciplinary recommendations for the diagnostic work-up of these patients and for fertility-protective measures. Differentiated recommendations for the systemic therapy in both the adjuvant and the advanced, metastatic treatment situation are given. In addition, the challenges of pregnancy during systemic melanoma therapy are discussed.

Uncomplicated pregnancy and delivery under ongoing nivolumab therapy for metastatic melanoma

“…Although ICI does not appear to induce teratogenic effects, the use of immunotherapy, nevertheless, may present huge challenges for pregnancy because of activated immune responses may result in miscarriages, restricted fetal growth, or cause of immune-related adverse events (irAE) in the fetus or mother [1][2][3]. Sporadic clinical evidence is available in the form of case reports [4,5], describing both favorable and unfavorable outcomes of ICI as well as targeted therapy in pregnant melanoma patients.…”

“…The clinical implications of the finding of tetrasomy 3 and 8 on FISH analysis are difficult to interpret. Extrapolating from other malignancies, tetrasomy 8 has been found rarely in patients with acute myeloid leukaemia, a Choroidal melanoma is a rare, potentially lethal cancer with up to 50% of patients developing fatal metastases [1]. The two most important factors determining the metastatic potential of a tumour are its dimensions and cytogenetics [1].…”

“…Extrapolating from other malignancies, tetrasomy 8 has been found rarely in patients with acute myeloid leukaemia, a Choroidal melanoma is a rare, potentially lethal cancer with up to 50% of patients developing fatal metastases [1]. The two most important factors determining the metastatic potential of a tumour are its dimensions and cytogenetics [1]. Copy number aberrations in chromosomes 1, 3, 6 and 8 can be used to predict survival, with the changes that occur in chromosomes 3 and 8 being the best described [1].…”

Melanoma During Pregnancy as a Complicated Medical Problem

“…MEK inhibitors can have teratogenic effects, and bexarotene, IFN-α, dacarbazine, cyclophosphamide, and imatinib are also contraindicated. 67,78 Treatment of melanoma in pregnant women is a complex problem that requires careful discussion of treatment options with the patient, and therapeutic decisions should be individualized taking into account the health of both mother and fetus. Guidelines published in 2018 by the American Academy of Dermatology suggest a 2-to 3-year delay of planned pregnancy in women with stage II melanoma.…”

Potential ovarian toxicity and infertility risk following targeted anti-cancer therapies

“…To the best of our knowledge to date, there have been no published preclinical or clinical studies that have independently investigated the potential effects of this class of inhibitors on female fertility. However, consistent with these likely effects, the European Medicines Agency summary of product characteristics for dabrafenib, trametinib, and cobimetinib states that a reduced number of ovarian corpora lutea was observed in female rats, though no detailed ovarian follicle data were provided ( Hassel et al 2021 ).…”