Female Oncofertility and Immune Checkpoint Blockade in Melanoma: Where Are We Today?

Abstract

The incidence of melanoma among young adults has risen, yet mortality has declined annually since the introduction of immune checkpoint inhibitors (ICI). The utilization of peri-operative ICI has significantly altered the treatment landscape in melanoma, with PD-1 inhibitors showing promising efficacy in improving relapse-free survival rates in high-risk stage II-III disease. With the increasing use of ICI, secondary concerns have emerged regarding the impact of cancer drugs on fertility and reproductive health among women of childbearing potential, especially in early-stage cancer settings. The exclusion of pregnant women from trials contributes to limited human data and clinical uncertainties, such as maternal and fetal toxicities related to ICI exposure during pregnancy, as well as the value of fertility preservation before ICI therapy. Uncertainty persists regarding pregnancy post-adjuvant immunotherapy, given the potential detrimental effects of hormonal and immunological changes during pregnancy on melanoma relapse. There is additional uncertainty about whether pregnancy-associated melanoma (PAM) represents a distinct disease entity that warrants tailored management compared to non-pregnant cases. Our review aims to give an overview of oncofertility practices among female melanoma patients after immunotherapy. We also focus on the literature gap in the published evidence and synthesize summaries regarding ICI toxicities on reproductive health and fetal development, pregnancy planning, and recurrence risks after melanoma treatment.

Keywords: immune checkpoint inhibitors; melanoma; oncofertility; pregnancy.

Figure 1

The PD-1/PD-L1 pathway in the peripheral system and at the maternal-fetal interface during pregnancy. If PD-1 is bound to PD-L1, there is no T-cell activation; thus, maternal immunotolerance towards the fetus is maintained. PD-1 = programmed cell death-1; PD-L1 = programmed cell death ligand-1.

Figure 2

Alterations in the PD-1/PD-L1 pathway in the peripheral system and at the maternal-fetal interface following exposure to immune checkpoint inhibitors. It causes T-cell activation, regulatory T (Treg) cell reduction, and possible fetal rejection. PD-1 = programmed cell death-1; PD-L1 = programmed cell death ligand-1.