Risk of gonadotoxicity with immunotherapy and targeted agents remains an unsolved but crucial issue

In recent years, survivorship has become an area of crucial importance in the care of cancer patients. Breast cancer is the most prevalent malignancy in women, including among premenopausal patients, and the mortality rate is constantly declining.1 Therefore, for ensuring and maximizing the quality of life of cancer survivors, oncology professionals need to take into account and address both potential early and late adverse effects of anticancer therapies. In young women, counteracting the risk and consequences of premature ovarian insufficiency (POI) and subsequent infertility represents a crucial component of their survivorship care.2,3 For hormonally driven tumour such as breast cancer, for many years oncologists have been cautious on the potential detrimental prognostic effect of pregnancy in these survivors.4 Nevertheless, a growing amount of data have recently contributed to dispel these concerns, supporting maternal and foetal safety of pregnancy after breast cancer.5 As suggested by current guidelines, following adequate therapy and period of followup after anticancer treatment completion, patients should not be discouraged anymore on the possibility to conceive.2 Therefore, soon after diagnosis and before the administration of any systemic anticancer therapy, it is now mandatory to discuss the risk of POI.2,3 This represents the first crucial and urgent step in the oncofertility counselling of young cancer patients. Indeed, for informed treatment decisionmaking in young women, current guidelines highlight that it is essential to discuss the potential risk of gonadotoxicity of the proposed therapies and to offer the available strategies for fertility and/or ovarian function preservation.2,3 Estimating the risk of gonadotoxicity and the biological mechanisms behind gonadal damage induced by chemotherapy for breast cancer is relatively well known.2,3 Thus, the gonadotoxicity of anthracyclineand cyclophosphamidebased chemotherapy is well established, and taxanes are also recognized to add to this toxicity. On the contrary, there is no evidence in this regard for immunotherapy and the majority of the available and upcoming targeted agents.2,3 The only partial exception is represented by antiHER2 therapies (Figure 1). Prior exploratory and mostly descriptive analyses of trials investigating different antiHER2 agents have reported the risk of gonadotoxicity with trastuzumab, lapatinib and TDM1. The main results of these analyses have shown that adding trastuzumab to chemotherapy does not appear to increase the risk of posttreatment amenorrhoea,6– 8 without differences when using trastuzumab alone, lapatinib alone or their combination.9 Even if these analyses suggest that trastuzumab and/or lapatinib have no apparent gonadotoxicity, it should be highlighted that most of the patients included in these studies had received prior anthracyclineand cyclophosphamidebased chemotherapy. Two other analyses have reported on posttreatment amenorrhoea rates in premenopausal women receiving antiHER2 therapies without prior exposure to anthracyclineand cyclophosphamidebased chemotherapy. As compared to what is expected for standard breast cancer chemotherapy, lower rates of posttreatment amenorrhoea were observed in premenopausal women who were treated with weekly paclitaxel and trastuzumab in the APT trial10 and in those that received TDM1 alone as adjuvant antiHER2 therapy in the ATEMPT trial.11 Nevertheless, these studies were mostly retrospective analyses characterized by a small sample size, and treatmentinduced gonadotoxicity was assessed using amenorrhoea as marker of ovarian damage, thus preventing an accurate analysis of the real impact of antiHER2targeted agents on patients’ ovarian reserve and subsequent chances of conception. Treatment options in the early breast cancer setting are currently being revolutionized in all disease subtypes. Immunotherapy combined with and following chemotherapy, as well as PARP and CDK4/6 inhibitors administered after the completion of cytotoxic treatment, is becoming standard of care in the (neo)adjuvant setting for selected patients with early breast cancer. In addition, TDM1 is now approved as postneoadjuvant treatment in patients with HER2positive breast cancer without pathological complete response following chemotherapy