Faculty Bibliography

OBJECTIVE:To investigate the safety and feasibility of performing two consecutive ovarian stimulation cycles with the use of letrozole protocol for fertility preservation in breast cancer patients. DESIGN/METHODS:Retrospective cohort study. SETTING/METHODS:Academic fertility preservation center. PATIENT(S)/METHODS:Seventy-eight women ≤ 45 years, diagnosed with stage ≤ 3 breast cancer, who desired fertility preservation. INTERVENTION(S)/METHODS:Two consecutive cycles versus a single ovarian stimulation cycle with a letrozole-follicle-stimulating hormone (FSH) protocol. MAIN OUTCOME MEASURE(S)/METHODS:Embryo or oocyte cryopreservation outcomes, time interval from surgery to chemotherapy, and breast cancer recurrence rates. RESULT(S)/RESULTS:Sixty-one patients underwent single-cycle stimulation and 17 received two stimulation cycles. The mean total number of oocytes harvested (16.1 ± 13.2 vs. 9.1 ± 5.2) and embryos generated (6.4 ± 2.9 vs. 3.7 ± 3.1) were statistically significantly higher in patients who underwent two cycles versus one cycle. The time interval from surgery to chemotherapy was similar between the two-cycle and single-cycle groups (63.7 ± 7.7 vs. 58.0 ± 12.1 days). After a mean follow-up interval of 58.5 ± 13.6 months, the recurrence rates were similar between the two-cycle (0 of 17) and single-cycle (2 of 49) patients. CONCLUSION(S)/CONCLUSIONS:It appears to be safe and feasible to perform two consecutive ovarian stimulation cycles to increase the oocyte/embryo yield for fertility preservation.

OBJECTIVE:To estimate age-specific probabilities of live birth with oocyte cryopreservation in nondonor (ND) egg cycles. DESIGN/METHODS:Individual patient data meta-analysis. SETTING/METHODS:Assisted reproduction centers. PATIENT(S)/METHODS:Infertile patients undergoing ND mature oocyte cryopreservation. INTERVENTION(S)/METHODS:PubMed was searched for clinical studies on oocyte cryopreservation from January 1996 through July 2011. Randomized and nonrandomized studies that used ND frozen-thawed mature oocytes with pregnancy outcomes were included. Authors of eligible studies were contacted to obtain individual patient data. MAIN OUTCOME MEASURE(S)/METHODS:Live birth probabilities based on age, cryopreservation method, and the number of oocytes thawed, injected, or embryos transferred. RESULT(S)/RESULTS:Original data from 10 studies including 2,265 cycles from 1,805 patients were obtained. Live birth success rates declined with age regardless of the freezing technique. Despite this age-induced compromise, live births continued to occur as late as ages 42 and 44 years with slowly frozen and vitrified oocytes, respectively. Estimated probabilities of live birth for vitrified oocytes were higher than those for slowly frozen. CONCLUSION(S)/CONCLUSIONS:The live birth probabilities we calculated would enable more accurate counseling and informed decisions for infertile women considering oocyte cryopreservation. Given the success probabilities, we suggest that policy makers should consider oocyte freezing as an integral part of prevention and treatment of infertility.

PURPOSE: To update guidance for health care providers about fertility preservation for adults and children with cancer. METHODS: A systematic review of the literature published from March 2006 through January 2013 was completed using MEDLINE and the Cochrane Collaboration Library. An Update Panel reviewed the evidence and updated the recommendation language. RESULTS: There were 222 new publications that met inclusion criteria. A majority were observational studies, cohort studies, and case series or reports, with few randomized clinical trials. After review of the new evidence, the Update Panel concluded that no major, substantive revisions to the 2006 American Society of Clinical Oncology recommendations were warranted, but clarifications were added. RECOMMENDATIONS: As part of education and informed consent before cancer therapy, health care providers (including medical oncologists, radiation oncologists, gynecologic oncologists, urologists, hematologists, pediatric oncologists, and surgeons) should address the possibility of infertility with patients treated during their reproductive years (or with parents or guardians of children) and be prepared to discuss fertility preservation options and/or to refer all potential patients to appropriate reproductive specialists. Although patients may be focused initially on their cancer diagnosis, the Update Panel encourages providers to advise patients regarding potential threats to fertility as early as possible in the treatment process so as to allow for the widest array of options for fertility preservation. The discussion should be documented. Sperm and embryo cryopreservation as well as oocyte cryopreservation are considered standard practice and are widely available. Other fertility preservation methods should be considered investigational and should be performed by providers with the necessary expertise.

BACKGROUND:Germline mutations in BRCA1 and BRCA2 (BRCA1/2) are related to an increased lifetime risk of developing breast and ovarian cancer. Although risk-reducing salpingo-oophorectomy reduces the risk of both cancers, loss of fertility is a major concern. A recent study suggested an association between BRCA1 mutation and occult primary ovarian insufficiency. The objective of the current study was to determine whether BRCA1/2 mutation carriers have an earlier onset of natural menopause compared with unaffected women. METHODS:White carriers of the BRCA1/2 gene (n = 382) were identified within the Breast Cancer Risk Program Registry at the University of California at San Francisco and compared with non-clinic-based white women in northern California (n = 765). The 2 groups were compared with regard to median age at the time of natural menopause before and after adjustment for known risk factors, and the role of smoking within each group was examined using the Kaplan-Meier approach for unadjusted analyses and Cox proportional hazards regression analyses for adjusted analyses. RESULTS:The median age at the time of natural menopause in the BRCA1/2 carriers was significantly younger than among the unaffected sample (50 years vs 53 years; P < .001). The unadjusted hazard ratio for natural menopause when comparing BRCA1/2 carriers with unaffected women was 4.06 (95% confidence interval, 3.03-5.45) and was 3.98 (95% confidence interval, 2.87-5.53) after adjusting for smoking, parity, and oral contraceptive use. For BRCA1/2 carriers who were current heavy smokers (smoking ≥ 20 cigarettes/day), the median age at natural menopause was 46 years versus 49 years for nonsmokers (P = .027). CONCLUSIONS:The BRCA1/2 mutation was associated with a significantly earlier age at natural menopause, and heavy smoking compounded this risk. Because the relationship between menopause and the end of natural fertility is considered to be fixed, these findings suggest the risk of earlier infertility among BRCA1/2 carriers.

The ovaries are susceptible to damage following treatment with gonadotoxic chemotherapy, pelvic radiotherapy, and/or ovarian surgery. Gonadotoxic treatments have also been used in patients with various nonmalignant systemic diseases. Any women of reproductive age with a sufficiently high risk of developing future ovarian failure due to those medical interventions may benefit from embryo cryopreservation though the tools of assessment of such a risk are still not very precise. Furthermore, the risk assessment can be influenced by many other factors such as the delay expected after chemotherapy and the number of children desired in the future. Embryo cryopreservation is an established and most successful method of fertility preservation when there is sufficient time available to perform ovarian stimulation. This publication will review the current state, approach, and indications of embryo cryopreservation for fertility preservation.

PURPOSE/OBJECTIVE:BRCA gene mutations and elevated serum estradiol (E(2)) are well-known risk factors for breast cancer. The aim of this study was to investigate the association between BRCA gene mutations and serum E(2) level. METHODS:We measured baseline (menstrual cycle day 2-3) E(2) levels of 96 women with breast cancer who underwent BRCA testing. RESULTS:The mean age, parity, and age at menarche did not differ between women with and without BRCA1/2 mutations. Basal serum E(2) level was significantly higher in women with BRCA2 mutations compared to women with BRCA1 mutations or without BRCA mutations (71.7 ± 41.6 vs. 45.5 ± 20.7 vs. 38.5 ± 12.6 pg/ml in BRCA2 mutation carriers, BRCA1 mutation carriers, and non-carriers, respectively, p value = 0.03). Women with BRCA2 mutations had 3.1 times as great risk for high basal E(2) level (>48 pg/ml) as women without BRCA mutations after adjusting for age and BMI (95 % confidence interval: 1.3, 7.6). BRCA mutation carriers with high serum E(2) level were significantly younger than the carriers with low serum E(2) level (31.4 ± 3.1 vs. 34.7 ± 4.9 years, p = 0.04). CONCLUSIONS:In this pilot study, we found an association between high basal serum E(2) levels and BRCA2 mutations. Our results suggest that increased production of E(2) may have a role in the pathogenesis of BRCA2-mutation-related breast cancer.

The underlying mechanism behind age-induced wastage of the human ovarian follicle reserve is unknown. We identify impaired ATM (ataxia-telangiectasia mutated)-mediated DNA double-strand break (DSB) repair as a cause of aging in mouse and human oocytes. We show that DSBs accumulate in primordial follicles with age. In parallel, expression of key DNA DSB repair genes BRCA1, MRE11, Rad51, and ATM, but not BRCA2, declines in single mouse and human oocytes. In Brca1-deficient mice, reproductive capacity was impaired, primordial follicle counts were lower, and DSBs were increased in remaining follicles with age relative to wild-type mice. Furthermore, oocyte-specific knockdown of Brca1, MRE11, Rad51, and ATM expression increased DSBs and reduced survival, whereas Brca1 overexpression enhanced both parameters. Likewise, ovarian reserve was impaired in young women with germline BRCA1 mutations compared to controls as determined by serum concentrations of anti-Müllerian hormone. These data implicate DNA DSB repair efficiency as an important determinant of oocyte aging in women.

OBJECTIVE:Ovarian and testicular tissue cryopreservation are the only fertility preservation options for sexually immature individuals. Because of their experimental nature, it is important to determine safety and possible bundling with other medicallyindicated procedures. STUDY DESIGN/METHODS:Prospective observational. RESULTS:Cryopreservation indications included cancer in 75 % of females and 50 % of males, while non-cancer indications included various hematological conditions. Similar numbers of females (12/28) and males (3/9) underwent prior chemotherapy. Females underwent laparoscopic (27/28) or robotic (1/28) approaches while incisional biopsy was used in males. Bundling of ovarian and testicular harvesting with other medicallyindicated procedures was performed in 42 % and 22 %, respectively. The operative time inclusive of bundled procedures was similar (1.6 ± 0.1 vs. 0.9 ± 0.3 h) but the discharge time was significantly longer for females than males (10.4 ± 0.6 vs. 4.6 ± 0.6 h, p<0.05) due to frequent bundling of medically-indicated procedures in females. All procedures were successfully completed without complications or significant blood loss. CONCLUSIONS:Pediatric gonadal tissue cryopreservation can be combined with other medically-indicated procedures to minimize the potential inconvenience, additional anesthetic risks, and costs.

Breast cancer is the most common malignancy diagnosed in women in the United States. Many breast cancer survivors are concerned that cancer treatment will compromise their reproductive potential. Despite this concern, most women receive limited information addressing preservation of fertility before initiating adjuvant chemotherapy. Historically, the supraphysiologic levels of estrogens associated with ovarian stimulation have precluded the use of assisted reproductive technologies in the presence of breast cancer. In an effort to mitigate the potential effects of elevated estrogen levels during ovulation induction, we developed a novel ovarian stimulation protocol for women with breast cancer, with the use of aromatase inhibitors. Our studies suggest that in the short term, aromatase inhibitors plus gonadotropins are safe and effective agents for ovarian stimulation in fertility preservation cycles. In this review, we outline the data supporting the use of aromatase inhibitors for ovarian hyperstimulation in women with breast cancer before initiating adjuvant chemotherapy.