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Unmet fertility and pregnancy-related issues in young breast cancer patients

par Lambertini, Matteo
Président du jury Melot, Christian
Promoteur Ignatiadis, Michail
Co-Promoteur Demeestere, Isabelle
Publication Non publié, 2018-11-26

Thèse de doctorat

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Résumé :

Survival from breast cancer has significantly improved over the past years. Therefore, survivorship issues are an area of crucial importance to be addressed as early as possible by all health care providers dealing with breast cancer patients. Fertility and pregnancy-related issues represent a priority area of concern for young women with breast cancer. Despite a growing attention towards these issues has been given over the past years and is currently provided to young breast cancer patients, several grey zones persist in many domains of this field and some physicians are still uncomfortable to deal with this topic. In this thesis, we aimed at providing evidence on several unmet fertility and pregnancy-related issues faced by young breast cancer patients with the ultimate goals to further improve their quality of life and to help physicians during the oncofertility counseling of these women.In Chapter 1 of this thesis, we addressed questions related to the factors with a potential negative or protective impact on the ovarian function of young breast cancer patients. First, we assessed the influence of carrying a germline BRCA mutation on the reproductive potential of young breast cancer patients and the performance of fertility preservation strategies in this setting. We conducted a retrospective analysis within two prospective studies that involved young women with newly diagnosed breast cancer who underwent oocyte cryopreservation or ovarian tissue cryopreservation for fertility preservation at CUB-Hôpital Erasme in Brussels (Belgium) between January 2006 and December 2016. A total of 101 patients were included, of whom 29 had germline deleterious BRCA mutations. We observed a consistent trend for reduced reproductive potential and performance of both oocyte and ovarian tissue cryopreservation in BRCA-mutated patients.Second, we evaluated the gonadotoxicity of anticancer treatments focusing particulary on the risk of treatment-related amenorrhea (TRA) with the addition of taxanes to anthracycline-based chemotherapy and with the administration of chemotherapy plus the anti-human epidermal growth factor receptor 2 (HER2) agents trastuzumab and/or lapatinib. This analysis was conducted in 2,862 premenopausal patients with early-stage HER2-positive breast cancer enrolled in the ALTTO randomized trial (NCT00490139) by assessing menopausal status at week 37 visit following the initiation of anti-HER2 treatment. Addition of taxanes to anthracycline-based chemotherapy led to a statistically significantly higher risk of TRA. No difference in TRA rates was observed between the four anti-HER2 treatment arms (trastuzumab alone, lapatinib alone, their sequence or their combination); the absence of higher TRA rates in the dual blockade arm as compared to single agent arms may suggest the gonadal safety of these agents. TRA was associated with statistically significant improved disease-free survival (DFS) and overall survival (OS) in patients with hormone receptor-positive/HER2-positive disease. Third, we provided evidence on the efficacy and safety of temporary ovarian suppression with gonadotropin-releasing hormone agonists (GnRHa) during chemotherapy as an option for ovarian function preservation in young breast cancer patients undergoing (neo)adjuvant chemotherapy. We performed a meta-analysis including individual patient-level data from the 5 major trials (PROMISE-GIM6, POEMS/SWOG S0230, Anglo Celtic Group OPTION, GBG-37 ZORO, Moffitt-led trial) that investigated the role of this strategy. A total of 873 breast cancer patients were included. Concurrent administration of GnRHa and chemotherapy significantly reduced the risk of developing chemotherapy-induced premature ovarian insufficiency (POI), and was associated with a higher number of subsequent pregnancies. Similar DFS and OS were observed between groups irrespective of the estrogen receptor (ER) status of the disease suggesting the safety of administering GnRHa concurrently with chemotherapy.In Chapter 2 of this thesis, we aimed to address questions related to the safety of pregnancy following prior history of breast cancer including the impact of timing of pregnancy, induction of abortion or breastfeeding, as well as to investigate the pregnancy outcomes in these patients. First, we assessed if there were differences in survival outcomes between patients who conceived following breast cancer diagnosis as compared to those who did not have a subsequent pregnancy with a particular focus to women with ER-positive tumors. In addition, we investigated the potential impact of timing of pregnancy, induction of abortion and breastfeeding on patients’ prognosis. For this purpose, a multicenter retrospective case-control study was conducted. A total of 1,207 breast cancer patients with known ER status were included in the analysis, of whom 333 conceived after prior breast cancer and 874 had no subsequent pregnancies. Long-term results from this study confirmed that pregnancy after breast cancer can be considered safe irrespectively of ER status and should not be discouraged. This was observed independently of pregnancy outcome, pregnancy interval, and breastfeeding status. Second, we assessed the safety of pregnancy following prior history of HER2-positive breast cancer, and the pregnancy outcomes in women who conceived during or after chemotherapy plus anti-HER2 treatment. We collected all the pregnancy events that occurred in the NeoALTTO (NCT00553358) and ALTTO (NCT00490139) trials. These are two randomized studies that explored the role of trastuzumab and/or lapatinib in patients with HER2-positive early breast cancer as neoadjuvant and adjuvant treatment, respectively. A total of 92 patients had at least one pregnancy after inclusion in the two trials, of whom 12 patients conceived during anti-HER2 targeted therapy (exposed group) while 80 after the end of treatment (unexposed group). We observed that having a pregnancy after prior history of HER2-positive early breast cancer did not appear to impact on DFS. A high rate of induced abortion was observed among women in the exposed group; nevertheless, despite only 5 live births being described in this group, unintentional exposure to trastuzumab and/or lapatinib during gestation did not seem to affect newborn outcomes. Patients in the unexposed group appeared to have normal pregnancy outcomes. Therefore, overall, having a pregnancy following completion of chemotherapy plus anti-HER2 therapy showed to be safe without compromising fetal outcome or maternal prognosis.In conclusion, taken together, we believe that our findings can serve as a rational basis to improve the oncofertility counseling of young breast cancer patients facing concerns related to TRA risk, preservation of ovarian function and/or fertility as well as for those willing to consider a future pregnancy. Several ongoing and upcoming projects from our group have been started based on the results presented in this thesis and are expected to provide further evidence on these crucial topics.