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Yayın Comparison of random start controlled ovarian stimulation with kiandard start in letrozole gonadotropin cycles for fertility preservation in women with breast cancer(Elsevier, 2023) Turan, Volkan; Lafuente, Sonia Gayete; Arkfeld, Christopher Ke; Oktay, Kutluk H.Random start controlled ovarian stimulation (RSCOH) was introduced as an option for women with cancer who do not have sufficient time for early follicular start ovarian stimulation protocols for fertility preservation. Our aim was to determine if the outcomes of RSCOH were similar to standard start (early follicular) controlled ovarian hyperstimulation (SSCOH) cycles in women with breast cancer.Yayın Impact of adjuvant chemotherapy or tamoxifen-alone on the ovarian reserve of young women with breast cancer(Springer, 2021) Goldfarb, Shari B.; Turan, Volkan; Bedoschi, Giuliano; Taylan, Enes; Abdo, Nadia; Cigler, Tessa; Bang, Heejung; Patil, Sujita; Dickler, Maura N.; Oktay, Kutluk H.Purpose To determine the longitudinal impact of adjuvant chemotherapy and tamoxifen-only treatments on the reproductive potential of women with breast cancer by using a sensitive ovarian reserve marker anti-Mullerian hormone (AMH) as a surrogate. Methods One-hundred-and-forty-two women with a primary diagnosis of breast cancer were prospectively followed with serum AMH assessments before the initiation, and 12, 18 and 24 months after the completion of adjuvant chemotherapy or the start of tamoxifen-only treatment. The chemotherapy regimens were classified into Anthracycline-Cyclophosphamide-based (AC-based) and Cyclophosphamide-Methotrexate + 5-Fluorouracil (CMF). Longitudinal data were analyzed by mixed effects model for treatment effects over time, adjusting for baseline age and BMI. Results Both chemotherapy regimens resulted in significant decline in ovarian reserve compared to the tamoxifen-only treatment (p < 0.0001 either regimen vs. tamoxifen for overall trend). AMH levels sharply declined at 12 months but did not show a significant recovery from 12 to 18 and 18 to 24 months after the completion of AC-based or CMF regimens. The degree of decline did not differ between the two chemotherapy groups (p = 0.53). In contrast, tamoxifen-only treatment did not significantly alter the age-adjusted serum AMH levels over the 24-month follow up. Likewise, the use of adjuvant tamoxifen following AC-based regimens did not affect AMH recovery. Conclusions Both AC-based regimens and CMF significantly compromise ovarian reserve, without a recovery beyond 12 months post-chemotherapy. In contrast, tamoxifen-only treatment does not seem to alter ovarian reserve. These data indicate that the commonly used chemotherapy regimens but not the hormonal therapy compromise future reproductive potential.Yayın Oocyte cryopreservation with in vitro maturation for fertility preservation in girls at risk for ovarian insufficiency(Springer/Plenum Publishers, 2023) Gayete-Lafuente, Sonia; Turan, Volkan; Oktay, Kutluk H.Purpose To assess the feasibility and outcomes of oocyte cryopreservation with in vitro maturation (IVM) in post-pubertal girls undergoing fertility preservation (FP) for primary ovarian insufciency (POI) risk. Methods Ovarian stimulation was performed with an antagonist protocol or progesterone priming. Ultrasound monitoring was performed transabdominally. Oocytes were retrieved transvaginally under IV sedation. Immature oocytes were subjected to IVM for up to 36 h. All MII oocytes were vitrifed. The main outcome measure was the total number of mature oocytes cryopreserved. The secondary outcome was the increase in the mature oocyte yield after IVM. Results Indications for FP included mosaic Turner syndrome (mTS; n=10), malignancy (n=3), and POI risk (n=2). The mean±SD age, antral follicle count (AFC), and AMH levels were 14.2±1.4 years, 8±5.2 and 1.3±1.3 ng/mL. In girls with mTS, the ovarian reserve was low for age (AFC 7.4±4.7 and AMH 1.4±1.6 ng/mL). Oocyte cryopreservation was possible in all girls with a range of 1–27 mature oocytes obtained, even in those who were previously exposed to chemotherapy or with low ovarian reserve, and no surgical complications were encountered. After IVM, the median mature oocyte yield increased signifcantly from 7.5 to 10.5 (p=0.001). Conclusions Oocyte cryopreservation appears to be feasible and safe in girls as young as 12 years of age at risk for POI The utility of IVM increases the yield of cryopreserved mature oocytes. Prior exposure to chemotherapy or low ovarian reserve should not be an automatic reason to exclude these girls from FP consideration.Yayın Outcomes of random-start letrozole protocol with PGT-A in women with breast cancer undergoing fertility preservation(Springer/Plenum Press, 2023) Turan, Volkan; Gayete-Lafuente, Sonia; Bang, Heejung; Oktay, Kutluk H.PURPOSE : To compare the cycle characteristics and outcomes of random-start-controlled ovarian stimulation (RSCOS) protocols to the outcomes of standard-start-controlled ovarian stimulation (SSCOS) cycles and to report the utility of PGT-A in these cycles. Methods: One hundred and seventeen who underwent SSCOS and 39 who underwent RSCOS for oocyte and/or embryo cryopreservation before breast cancer chemotherapy were retrospectively evaluated. Mean number of embryos and blastocyst euploidy rates were the main outcome measures. Results: A majority of RSCOS cycles were initiated in the luteal phase (66.6% luteal vs. 33.3% follicular). While the total dose of gonadotropins was significantly higher in the RSCOS (3720.8 ± 1230.0 vs. 2345.1 ± 803.6 IU; P < 0.001), the mean number of mature oocytes and embryos was similar to SSCOS. However, there was a trend for a higher number of mean embryos with luteal start RSCOS (6.9 ± 2.7 in late follicular start vs. 9.4 ± 4.2 in luteal start, P = 0.08). PGT-A was performed in 48% of the cases that underwent embryo cryopreservation in RSCOS (12 women, mean age = 35.3 ± 4.1; 87 blastocysts), revealing a euploidy rate of 36.2 ± 22.3% per patient. This rate was comparable to a 45% aneuploidy rate from similarly aged published data. Of the 7 RSCOS patients who returned for frozen embryo transfer, 5 delivered and one has an ongoing pregnancy, while in SSCOS, 18 out of 40 cycles resulted in live birth. Conclusion: Our data suggests that RSCOS fertility preservation cycle outcomes are similar to those with SSCOS and result in age-appropriate euploidy rates.Yayın Ovarian stimulation and oocyte cryopreservation in females with cancer(Lippincott Williams & Wilkins, 2023) Oktay, Kutluk H.; Turan, VolkanPurpose of review: We reviewed the most recent developments including the safety and effectiveness data and success rates in individualized ovarian stimulation protocols for adult and postpubertal females with cancer. Recent findings: In women with breast cancer, aromatase inhibitor- and tamoxifen-supplemented stimulation protocols increase the margin of safety by limiting estrogen exposure. The outcomes of ovarian stimulation appear similar between cancer and noncancer populations, even with the recently developed random-start protocols, which allow initiation of ovarian stimulation anytime during the menstrual cycle. Based on lower anti-Mullerian hormone levels and primordial follicle density, carriers of BRCA pathogenic variants (BRCApv) have decreased ovarian reserve in comparison to women without those variants and may lose larger portion of their ovarian reserve post chemotherapy. Oocyte cryopreservation is also emerging as a suitable fertility preservation approach for selected postpubertal girls as young as 12 years of age. Summary: Individualized ovarian stimulation approaches combined with improvements in cryopreservation techniques increased the success and safety margin to preserve fertility with oocyte freezing. Women with BRCApv, on the other hand, may be at disadvantage as they have lower ovarian reserve and may lose larger portion of their ovarian reserve post chemotherapy compared to women who do not carry these variants.Yayın Presence of BRCA mutations and a pre-chemotherapy AMH level of < 2NG/ML strongly predict risk of amenorrhea in women with breast cancer(Elsevier, 2023) Oktay, Kutluk H.; Turan, Volkan; Bedoschi, Giuliano; Goldfarb, Shari; Bang, HeejungThe likelihood of post-chemotherapy (ChT) amenorrhea is still empirically determined. Breast cancer is the most prevalent malignancy among the women of reproductive age. Our aim was to determine the predictors of amenorrhea risk post-ChT in women with breast cancer (ca). As acute amenorrhea (<12mo post-ChT) can be temporary, we used amenorrhea status 12- and 18-months post-ChT as the primary endpoint.Yayın A prospective longitudinal analysis of the predictors of amenorrhea after breast cancer chemotherapy: Impact of BRCA pathogenic variants(Wiley, 2023) Oktay, Kutluk H.; Turan, Volkan; Bedoschi, Giuliano; Abdo, Nadia; Bang, Heejung; Goldfarb, ShariBackground: Better tools for post-chemotherapy amenorrhea risk assessment are needed for fertility preservation decision-making. Our aim was to determine the predictors of amenorrhea risk at 12 and 18 months post-chemotherapy in women with breast cancer. Methods: 142 women with breast cancer were longitudinally followed for their menstrual changes at 6, 12, and 18 months after the completion of adjuvant chemotherapy with an Anthracycline-Cyclophosphamide-based (AC-based) or Cyclophosphamide-Methotrexate +5-Fluorouracil regimen. Pre- and/or post-chemo AMH levels, age, BMI, tamoxifen use, regimen type, and germline BRCA pathogenic variant (gBRCApv) status were evaluated for the prediction of amenorrhea at 6-18 months. Results: In multivariable-adjusted logistic regression, age (p = 0.03) and AMH (p = 0.03) at 12 months, and gBRCApv status (p = 0.03) at 18 months were significant predictors of amenorrhea (areas under the ROC curve of 0.77 and 0.76, for 12 and 18 months, respectively) among 102 evaluable subjects. An undetectable AMH immediately post-chemotherapy was predictive of amenorrhea with <18 month follow-up. In longitudinal analysis estimating time trends, baseline AMH and gBRCApv status was associated with the risk of amenorrhea over 6-18 months; the AMH >2.0 ng/mL group showed attenuated time-trend risk of amenorrhea versus AMH ≤2.0 group (ratio of ORs = 0.91, 95% CI = 0.86-0.97, p = 0.002), while the gBRCApv + showed a steeper time trend, versus the controls (ratio of ORs = 1.12, 95% CI = 1.04-1.20, p = 0.003). Conclusions: In addition to the pre- and post-treatment AMH levels, gBRCApv status is a novel potential predictor of amenorrhea at 12 and 18 months after chemotherapy. The higher likelihood of amenorrhea in women gBRCApv suggests that they are more prone to losing their fertility post-chemotherapy.Yayın Trends and regional differences for fertil ity preservation procedures in women with breast cancer(Elsevier, 2024) Turan, Volkan; Bedoschi, Giuliano; Lee, Dong-Yun; Barbosa, Caio Parente; Oliveira, Renato de; Saçıntı, Koray Görkem; Sönmezer, Murat; Lambertini, Matteo; Massarotti, Claudia; Schaub, Amelia; Wang, Erica; Gayete-Lafuente, Sonia; Dunlop, Cheryl; Anderson, Richard A.; Bang, Heejung; Oktay, Kutluk H.Introduction : Breast cancer is the most common malignancy in women of reproductive age and chemotherapy protocols impair fertility, frequently necessitating fertility preservation (FP) referral. Embryo, oocyte, or ovarian tissue cryopreservation are established FP modalities in women with breast cancer but there are few data on their uptake over time. In this study our aim was to determine the regional time trends and utility differences for fertility preservation methods of reproductive tissue cryopreservation. Methods : This multicenter study included 1,623 women diagnosed with breast cancer from seven tertiary centers in six countries (Brazil, Italy, Scotland, South Korea, Turkey, USA). Participant centers provided the details of FP cryopreservation approaches broken down annually from 2012 to 2021. Women with newly diagnosed breast cancer, aged 18-45 years who were referred for FP at participating centers and had normal ovarian function at the time were included. Results : We found a mean increase of 7% per year (p=0.002, adjusting for centers) in the number of women referred for FP. Of those who were referred (n=1623), a mean 38.7% underwent FP (n=629), with a range of 12% in South Korea) to 95% in Brazil. The number of women undergoing ovarian stimulation for FP continually increased until 2021, with oocyte cryopreservation being the most common procedure throughout the study period (p=0.014 for time trend). The proportion of random start ovarian stimulation cycles increased each year from 58.3% in 2012 to 86.8% in 2021, (p=0.005 for time trend, and p=0.04 for 2012 vs. 2021). Conclusions : The utility of FP has steadily increased for young women with breast cancer over the last decade, although regional differences significantly influence FP practices. The findings of our study could have value for policy making in FP care for young women with breast cancer at the local, regional, or global level. Micro abstract Breast cancer is the most common malignancy in women of reproductive age and chemotherapy protocols impair fertility, frequently necessitating fertility preservation referral. The utility of fertility preservation has steadily increased for young women with breast cancer over the last decade, although regional differences significantly influence fertility preservation practices.
