A retrospective study evaluating the impact of scattering radiation from imaging procedures on oocyte quality during ovarian stimulation for fertility preservation in young breast cancer patients

Purpose: Ovarian stimulation for oocyte and embryo cryopreservation is the standard of care for fertility preservation in young breast cancer patients before gonadotoxic chemotherapy. The procedure should be started as soon as possible to avoid delay of treatment; thus, it is often performed concomitantly with tumor staging assessments. However, questions remain regarding the potential negative impact on oocyte quality that may occur due to exposure to scattered ionizing radiation from imaging techniques when staging assessment is conducted at the same time as ovarian stimulation. Methods: We conducted a retrospective study on all breast cancer patients who performed ovarian stimulation for fertility preservation at our center between November 2012 and May 2020. Results: Gynecologic and oncological characteristics were similar between patients exposed (n = 14) or not (n = 60) to ionizing radiation. Exposed patients started the ovarian stimulation sooner after diagnosis than non-exposed patients (11.5 vs 28 days, respectively, P < 0.01). Cycle parameters, including the median number of oocytes collected (10.5 vs 7, P = 0.16), maturation rates (92.5% vs 85.7%, P = 0.54), and fertilization rates (62.2% vs 65.4%, P = 0.70), were similar between groups. Conclusion: This study shows that scattered ionizing radiation due to staging assessment appears to be safe without compromising follicular growth and maturation. Larger studies on fertility and obstetrical outcomes are needed to confirm these preliminary data

Reproductive potential and performance of fertility preservation strategies in BRCA-mutated breast cancer patients

Background: Preclinical evidence suggests a possible negative impact of deleterious BRCA mutations on female fertility. However, limited and rather conflicting clinical data are available. This study assessed the reproductive potential and performance of fertility preservation strategies in BRCA-mutated breast cancer patients. Patients and methods: This was a retrospective analysis of two prospective studies investigating oocyte cryopreservation and ovarian tissue cryopreservation in newly diagnosed early breast cancer patients. In the current analysis, baseline anti-Mullerian hormone (AMH) and performance of cryopreservation strategies were compared between patients with or without germline deleterious BRCA mutations. Results: Out of 156 patients included, 101 had known BRCA status of whom 29 (18.6%) were BRCA-mutated and 72 (46.1%) had no mutation. Median age in the entire cohort was 31 years [interquartile range (IQR) 28-33). Median AMH levels were 1.8 lg/l (IQR 1.0-2.7) and 2.6 \u3bcg/l (IQR 1.5-4.1) in the BRCA-positive and BRCA-negative cohorts, respectively (P=0.109). Among patients who underwent oocyte cryopreservation (N=29), women in the BRCA-positive cohort tended to retrieve (6.5 versus 9; P=0.145) and to cryopreserve (3.5 versus 6; P=0.121) less oocytes than those in the BRCA-negative cohort. Poor response rate (i.e. retrieval of 644 oocytes) was 40.0% and 11.1% in the BRCA-positive and BRCA-negative cohorts, respectively (P=0.147). Among patients who underwent ovarian tissue cryopreservation (N=72), women in the BRCA-positive cohort tended to have a numerically lower number of oocytes per fragment (0.08 versus 0.14; P=0.193) and per square millimeter (0.33 versus 0.78; P=0.153) than those in the BRCA-negative cohort. Two BRCA-mutated patients were transplanted after chemotherapy and one delivered at term a healthy baby. No difference between BRCA1- and BRCA2-mutated patients was observed in any of the above-mentioned outcomes. Conclusion: A consistent trend for reduced reproductive potential and performance of cryopreservation strategies was observed in BRCA-mutated breast cancer patients. Independent validation of these results is needed

Safety of fertility preservation techniques before and after anticancer treatments in young women with breast cancer: a systematic review and meta-analysis

Study question: Is it safe to perform controlled ovarian stimulation (COS) for fertility preservation before starting anticancer therapies or ART after treatments in young breast cancer patients? Summary answer: Performing COS before, or ART following anticancer treatment in young women with breast cancer does not seem to be associated with detrimental prognostic effect in terms of breast cancer recurrence, mortality or event-free survival (EFS). What is known already: COS for oocyte/embryo cryopreservation before starting chemotherapy is standard of care for young women with breast cancer wishing to preserve fertility. However, some oncologists remain concerned on the safety of COS, particularly in patients with hormone-sensitive tumors, even when associated with aromatase inhibitors. Moreover, limited evidence exists on the safety of ART in breast cancer survivors for achieving pregnancy after the completion of anticancer treatments. Study design, size, duration: The present systematic review and meta-analysis was carried out by three blinded investigators using the keywords 'breast cancer' and 'fertility preservation'; keywords were combined with Boolean operators. Eligible studies were identified by a systematic literature search of Medline, Web of Science, Embase and Cochrane library with no language or date restriction up to 30 June 2021. Participants/materials, setting, methods: To be included in this meta-analysis, eligible studies had to be case-control or cohort studies comparing survival outcomes of women who underwent COS or ART before or after breast cancer treatments compared to breast cancer patients not exposed to these strategies. Survival outcomes of interest were cancer recurrence rate, relapse rate, overall survival and number of deaths. Adjusted relative risk (RR) and hazard ratio (HR) with 95% CI were extracted. When the number of events for each group were available but the above measures were not reported, HRs were estimated using the Watkins and Bennett method. We excluded case reports or case series with <10 patients and studies without a control group of breast cancer patients who did not pursue COS or ART. Quality of data and risk of bias were assessed using the Newcastle-Ottawa Assessment Scale. Main results and the role of chance: A total of 1835 records were retrieved. After excluding ineligible publications, 15 studies were finally included in the present meta-analysis (n = 4643). Among them, 11 reported the outcomes of breast cancer patients who underwent COS for fertility preservation before starting chemotherapy, and 4 the safety of ART following anticancer treatment completion. Compared to women who did not receive fertility preservation at diagnosis (n = 2386), those who underwent COS (n = 1594) had reduced risk of recurrence (RR 0.58, 95% CI 0.46-0.73) and mortality (RR 0.54, 95% CI 0.38-0.76). No detrimental effect of COS on EFS was observed (HR 0.76, 95% CI 0.55-1.06). A similar trend of better outcomes in terms of EFS was observed in women with hormone-receptor-positive disease who underwent COS (HR 0.36, 95% CI 0.20-0.65). A reduced risk of recurrence was also observed in patients undergoing COS before neoadjuvant chemotherapy (RR 0.22, 95% CI 0.06-0.80). Compared to women not exposed to ART following completion of anticancer treatments (n = 540), those exposed to ART (n = 123) showed a tendency for better outcomes in terms of recurrence ratio (RR 0.34, 95% CI 0.17-0.70) and EFS (HR 0.43, 95% CI 0.17-1.11). Limitations, reasons for caution: This meta-analysis is based on abstracted data and most of the studies included are retrospective cohort studies. Not all studies had matching criteria between the study population and the controls, and these criteria often differed between the studies. Moreover, rate of recurrence is reported as a punctual event and it is not possible to establish when recurrences occurred and whether follow-up, which was shorter than 5 years in some of the included studies, is adequate to capture late recurrences. Wider implications of the findings: Our results demonstrate that performing COS at diagnosis or ART following treatment completion does not seem to be associated with detrimental prognostic effect in young women with breast cancer, including among patients with hormone receptor-positive disease and those receiving neoadjuvant chemotherapy. Study funding/competing interest(s): Partially supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC; grant number MFAG 2020 ID 24698) and the Italian Ministry of Health-5 7 1000 funds 2017 (no grant number). M.L. acted as consultant for Roche, Pfizer, Novartis, Lilly, AstraZeneca, MSD, Exact Sciences, Gilead, Seagen and received speaker honoraria from Roche, Pfizer, Novartis, Lilly, Ipsen, Takeda, Libbs, Knight, Sandoz outside the submitted work. F.S. acted as consultant for Novartis, MSD, Sun Pharma, Philogen and Pierre Fabre and received speaker honoraria from Roche, Novartis, BMS, MSD, Merck, Sun Pharma, Sanofi and Pierre Fabre outside the submitted work. I.D. has acted as a consultant for Roche, has received research grants from Roche and Ferring, has received reagents for academic clinical trial from Roche diagnostics, speaker's fees from Novartis, and support for congresses from Theramex and Ferring outside the submitted work. L.D.M. reported honoraria from Roche, Novartis, Eli Lilly, MSD, Pfizer, Ipsen, Novartis and had an advisory role for Roche, Eli Lilly, Novartis, MSD, Genomic Health, Pierre Fabre, Daiichi Sankyo, Seagen, AstraZeneca, Eisai outside the submitted work. The other authors declare no conflict of interest. The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript and decision to submit the manuscript for publication. Registration number: N/A

Circulating Tumor DNA to Interrogate the Safety of Letrozole-Associated Controlled Ovarian Stimulation for Fertility Preservation in Breast Cancer Patients

Background: Current fertility preservation strategies for young breast cancer patients planning a future motherhood include the association of controlled ovarian stimulation with the aromatase inhibitor letrozole (let-COS) to harvest mature oocytes while maintaining low estradiol levels. Despite this is a widely adopted protocol, the safety of let-COS on breast cancer outcomes has been poorly investigated and its use remains off-label. We assessed the safety of let-COS in breast cancer patients using circulating tumor DNA (ctDNA) as a surrogate biomarker of disease recurrence. Methods: BROVALE is an interventional non-randomized prospective study designed to evaluate the efficacy and safety of let-COS for fertility preservation in early breast cancer patients before starting (neo)adjuvant chemotherapy. Letrozole was administered throughout the COS cycle, until ovulation triggering. Safety was a secondary endpoint. Data on oncological outcomes were collected during the follow-up as well as plasma and whole blood for evaluation of ctDNA levels at the time of enrollment (i.e. before starting let-COS) and oocyte retrieval (i.e. 48 hours after the last administration of letrozole). Targeted gene sequencing on the primary tumor samples was performed to identify specific mutations used for ctDNA analysis by digital PCR. DNA extracted from whole blood samples was used to discriminate between somatic and germline mutations. Results: From April 2014 to May 2017, 29 young early breast cancer patients enrolled in the BROVALE study who had available tissue samples participated to the ctDNA substudy. Among them, 15 had at least one validated somatic mutation. ctDNA was undetectable neither before nor after let-COS in 9 of them. Six patients had detectable ctDNA in the plasma samples collected before Let-COS. No change in ctDNA level after let-COS was observed in 3 patients and the level decreased (fold-change 64 0.5) in two women. One patient experienced an increased (fold-change 65 2) in ctDNA level but without disease relapse 34 months after diagnosis. Conclusions: No increase in ctDNA level was observed in 93% (14/15) of the patients receiving let-COS supporting its use as a safe strategy for young women with early breast cancer interested in fertility preservation before chemotherapy