Ghezzi Marco, Garolla Andrea, Magagna Sabina, Šabovich Iva, Berretta Massimiliano, Foresta Carlo, De Toni Luca
Department of Clinical and Experimental Oncology, IOV-IRCCS, Padua, Italy.
Unit of Andrology and Reproductive Medicine, Department of Medicine, University of Padua, Padua, Italy.
Front Oncol. 2020 Mar 5;10:232. doi: 10.3389/fonc.2020.00232. eCollection 2020.
Melanoma is a frequent neoplasm in young adult males in reproductive age, 10% of them degenerating into regional and/or distant metastases (MM). The use of BRAF inhibitors (BRAFi) vemurafenib and dabrafenib is effective in MM patients harboring V600E/K/D mutations. Despite the increased life expectancy in MM patients treated with BRAFi, concerns are raised by the possible side effects and increased risk of gonado- and/or genotoxicity associated with these drugs. However, these aspects are currently under-investigated. Here we report the different fertility outcome in two cases of MM patients, harboring V600E mutation, that received vemurafenib and dabrafenib respectively. The first patient, 36 years at recruitment in 2015 and seeking fatherhood, had an history of relapsing melanoma since 2002 and undergone to numerous interventions and chemotherapy cycles. In November 2011, following detection of V600E mutation, a daily treatment with vemurafenib (1,440 mg) was prescribed with preventive gamete cryopreservation. BRAFi was effective in the clinical stabilization of the disease. In 2015, semen evaluation at follow-up showed sperm parameters within the normal range and no signs of alteration of either sperm function or sperm-DNA. On these bases, no contraindications for fatherhood were given. After a month of free intercourses, the 38-year-old partner achieved spontaneous pregnancy with a regular course, normal male fetal karyotype and a full term birth. The second patient, 39 years at recruitment in 2018 and seeking fatherhood, had an history of melanoma since 2012. In 2018, following the evidence of disease relapse and detection of the V600E mutation, treatment with dabrafenib/trametinib (300 mg/day/2 mg/day) was initiated together with preventive gamete cryopreservation. In 2019, semen evaluation at follow up showed sperm count and motility below the reference values, associated with increased indexes of sperm aneuploidies and sperm DNA fragmentation. Accordingly, access to assisted reproduction technique with cryopreserved spermatozoa was suggested. Differently from dabrafenib that was associated to damage to spermatogenesis, high-dose vemurafenib showed no association with gonadotoxicity and genotoxicity in humans, even at high doses. Although further confirmation are required, our data represent a valued cue in oncofertility counseling to MM patients in addition to preventive cryopreservation.
黑色素瘤是育龄期年轻成年男性中常见的肿瘤，其中10%会恶变为局部和/或远处转移瘤（MM）。使用BRAF抑制剂（BRAFi）维莫非尼和达拉非尼对携带V600E/K/D突变的MM患者有效。尽管使用BRAFi治疗的MM患者预期寿命有所延长，但这些药物可能产生的副作用以及性腺毒性和/或遗传毒性风险增加引发了人们的担忧。然而，目前对这些方面的研究不足。在此，我们报告了两名携带V600E突变的MM患者分别接受维莫非尼和达拉非尼治疗后的不同生育结局。第一名患者于2015年入组时36岁，有生育意愿，自2002年起患有复发性黑色素瘤，接受过多次干预和化疗周期。2011年11月，在检测到V600E突变后，开始每日服用维莫非尼（1440毫克）并进行预防性配子冷冻保存。BRAFi对疾病的临床稳定有效。2015年，随访时的精液评估显示精子参数在正常范围内，精子功能或精子DNA均无改变迹象。基于这些情况，未给出生育禁忌。在一个月的无保护性交后，38岁的伴侣自然受孕，孕期正常，胎儿核型为正常男性，足月分娩。第二名患者于2018年入组时39岁，有生育意愿，自2012年起患有黑色素瘤。2018年，在疾病复发且检测到V600E突变后，开始使用达拉非尼/曲美替尼（300毫克/天/2毫克/天）治疗并进行预防性配子冷冻保存。2019年，随访时的精液评估显示精子数量和活力低于参考值，同时精子非整倍体指数和精子DNA碎片化增加。因此，建议使用冷冻精子进行辅助生殖技术。与达拉非尼对生精功能有损害不同，高剂量维莫非尼在人体中即使高剂量使用也未显示与性腺毒性和遗传毒性有关。尽管需要进一步证实，但我们的数据除了预防性冷冻保存外，还为MM患者的肿瘤生育咨询提供了有价值的线索。
