Cancer and IVF: assessing fertility preservation options and associated cancer risks

How I perform fertility preservation in breast cancer patients

Emergency IVF versus ovarian tissue cryopreservation: decision making in fertility preservation for female cancer patients

Introduction Ovarian cancer is a significant health concern worldwide and is the leading cause of death from gynecologic malignancies. While fertility preservation is essential for many young women diagnosed with cancer, concerns have been raised regarding the potential impact of fertility treatments on the risk of ovarian cancer development. 1. Ovarian Cancer Risk Factors Ovarian cancer is a multifactorial disease with various risk factors contributing to its development. A woman has a risk of 1 in 78 of having ovarian cancer in her life time, risk factors include: • Age: Ovarian cancer risk increases with age, with the highest incidence observed in women over 50 years old. About 12.1% of Ovarian Cancer patients are younger than 44 years old. • Family History: Women with a family history of ovarian or breast cancer, especially first-degree relatives, have an increased risk. • BRCA Mutations: Inherited mutations in BRCA1 and BRCA2 genes significantly elevate the risk of ovarian cancer. • Reproductive Factors: Factors such as nulliparity, early menarche, late menopause, and infertility have been associated with an increased risk of ovarian cancer. 2. Fertility Treatments and Ovarian Cancer Risk Understanding the mechanisms underlying ovarian cancer development is crucial for assessing the potential impact of fertility treatments : • Ovulation Hypothesis: The repeated ovulation theory suggests that each ovulatory cycle increases the risk of DNA damage to ovarian epithelial cells, potentially leading to cancer development. The use of fertility drugs to stimulate ovulation, such as clomiphene citrate and gonadotropins, has been studied , the early studies suggested a potential increased risk, more recent evidence has been conflicting, with some studies reporting no association. • In Vitro Fertilization (IVF): Several large-scale studies have investigated the relationship between IVF and ovarian cancer risk found no significant increase in ovarian cancer risk . • Hormonal Influence: Fertility drugs alter hormonal levels, particularly estrogen and progesterone, which may influence ovarian cancer risk. • Selection Bias: Some studies have suggested that the ovarian cancer risk may be confounded by underlying infertility factors rather than the treatments themselves. 3. Clinical Implications and Recommendations • Individual Risk Assessment: Clinicians should assess each patient's individual risk factors for ovarian cancer, including age, family history, and reproductive history, before initiating fertility treatments. • Informed Consent: Patients should be provided with comprehensive information regarding the potential risks and benefits of fertility treatments • Regular Surveillance: Women undergoing fertility treatments should receive regular gynecologic screenings and follow-up care to monitor for any signs or symptoms of ovarian cancer. • Shared Decision Making: Shared decision making between patients and healthcare providers is essential to ensure that treatment decisions align with patients' preferences and values. 4. Fertility Preservation Options • Most therapeutic options for Ovarian Cancer cause infertility, either by premature ovarian failure caused by cytotoxic agents in chemotherapy or surgical approaches that include unilateral or bilateral oophorectomy • In ovarian cancer patients, Oocyte cryopreservation is still the best option and the only one established along with embryo cryopreservation. Fertility preservation surgery can be suggested depending on histology, stage of disease and pre-existing ovarian reserve. • Ovarian tissue cryopreservation will not be an option as long as the risk of reseeding cancer cells is not fully eliminated. 5. Future Directions Advancements in molecular biology and genetics may shed light on the underlying mechanisms of ovarian cancer development and its potential association with fertility treatments. The artificial ovary and in vitro maturation of oocytes is a very attractive option in these patients, but further milestones have to be achieved

Chemotherapy and radiotherapy, among other gonadotoxic treatments, can significantly affect ovarian reserve and function, potentially leading to premature ovarian insufficiency (POI) and sterility. With the increasing survival rates among young female cancer patients, fertility preservation (FP) has become an essential aspect of cancer care. The decision to pursue FP depends on various factors, including patient age, ovarian reserve, the type of treatment, and its gonadotoxic potential. Several FP strategies are available, including oocyte, embryo, and ovarian tissue cryopreservation. While oocyte and embryo cryopreservation are the gold standard techniques, ovarian tissue cryopreservation and in vitro maturation (IVM) present viable alternatives for patients who cannot undergo ovarian stimulation or for whom stimulation is contraindicated. Despite significant advances within the FP practice, challenges remain in ensuring timely FP counseling, equitable access to services, and optimizing long-term reproductive outcomes. Continued research is needed to refine existing FP techniques, explore innovative approaches, and address ethical considerations in FP decision-making. This review explores current FP options, their clinical applications, and future directions to improve reproductive outcomes in young women undergoing gonadotoxic treatments.

Study question When evaluating clinical outcomes for embryo (EC), oocyte (OC) and ovarian tissue cryopreservation (OTC) which fertility preservation strategy is most effective for female cancer patients? Summary answer Return and clinical pregnancy rates were significantly higher with EC compared to OC and OTC. EC and OC strategies ascertained higher live-birth rates than OTC. What is known already Fertility preservation (FP) is essential for female cancer patients to maintain their reproductive potential. Currently, EC, OC and OTC are all considered viable options. Due to the gonadotoxic nature of cancer treatment, optimal practice dictates that FP should be performed prior to treatment. This allows a limited time to consider patient preferences. Hitherto, no network metanalytical data indicates optimal FP strategy, regarding return rate and clinical outcomes in terms of pregnancy and live birth rates. It is imperative that data is reported back to practitioners and patients to conclusively serve the noble goal of informed decision making. Study design, size, duration A systematic search of the literature was performed in the database PubMed/Medline, limited to English-language articles up to December 2024. The search strategy led to the retrieval of 5804 studies. Retrospective and prospective studies and/or cohort study design were considered eligible for inclusion. Included studies should have reported on at least two of the three commonly employed strategies of fertility preservation performed for medical indications, namely oocyte or embryo cryopreservation or ovarian tissue cryopreservation. Participants/materials, setting, methods Included studies reported on female cancer patients undergoing FP prior to gonadotoxic treatments. The outcome measures were clinical pregnancy, live-birth and return rates. Studies with a sample size of one patient returning irrespective of approach in any outcome were excluded from the analysis of the specific outcome. Network meta-analysis was conducted to compare the three approaches. To evaluate the network, estimate direct and indirect effects were assessed. SUCRA score was employed to rank the approaches. Main results and the role of chance A total of 22 studies were included, reporting on a total of 7623 women (EC: 1133, OC: 4957, OTC: 1533). Only one study examined the effects of ex-vivo collection of oocytes from ovarian tissue, and thus it was not included in this meta-analysis. Twenty studies reported results on return rates. Women who had undergone EC were more likely to return to utilize their cryopreserved material compared to OC (RR: 4.25, 95%CI:2.60-6.92, I2=83%) and OTC (RR:6.19, 95%CI:2.45-15.59, I2=0%). No statistically significant difference was observed on return rates between OC and OTC (RR:0.69, 95%CI: 0.29-1.62, I2=51%). Thirteen studies reported results on clinical pregnancy rates. EC presented with higher clinical pregnancy rates compared to both OC (RR:1.33, 95%CI:1.04-1.70, I2=0%) and OTC (RR:1.95, 95%CI:3.20-3.16, I2=0%). Clinical pregnancy rates did not differ between OTC and OC (RR:0.68, 95%CI:0.44-1.06, I2=0%). Thirteen studies reported on live-birth rates. EC and OC presented with higher live-birth rates compared to OTC (EC vs OTC: RR:2.61, 95%CI:1.29-5.98, I2=0%; OC vs OTC: RR:2.09, 95%CI:1.08-4.02, I2=0%). Live-birth rates did not differ between EC and OC (RR:1.25, 95%CI:0.94-1.66, I2=0%). SUCRA score revealed EC as the optimal approach for all outcomes (Return: 1.00, Clinical Pregnancy: 0.99, Live birth: 0.93), followed by OC and OTC. Limitations, reasons for caution The relatively small sample size per group, along with the limited follow-up duration, is the main limitation. Albeit no heterogeneity was recorded, different cryopreservation methods were employed. No obstetric, perinatal, or neonatal outcomes were available. Return rate data should be cautiously interpreted as a number of patients achieved natural conceptions. Wider implications of the findings Our data indicates that EC should be the method of choice for cancer patients’ FP considering clinical outcomes and return rates. Improved clinical outcomes may be attributed to higher embryo survival compared to oocytes. Meanwhile, OTC is a relatively new strategy that merits further investigation into efficacy and clinical significance. Trial registration number No

The slippery slopes of advanced reproductive technologies: Presidential address

The slippery slopes of advanced reproductive technologiesPresidential address

Women with cancer undergoing ART for fertility preservation: a cohort study of their response to exogenous gonadotropins

Study question What are the long-term outcomes after fertility preservation (FP) with versus without controlled ovarian stimulation (COS) in women with BC? Summary answer FP with COS was associated with higher rates of post-BC ART-treatment, while the rates of livebirth and all-cause mortality were similar between the two FP-groups. What is known already BC is the most common cancer in women of reproductive age, and the most common indication for female FP in Sweden. FP-methods including cryopreservation of oocytes, embryos and ovarian tissue are offered at Swedish academic centers within the health insurance coverage available to all citizens. A COS treatment is usually completed in 2-3 weeks, while ovarian tissue cryopreservation does not need COS and can be performed within a few days. To date, data on long term reproductive and oncologic outcome in women with BC undergoing FP with vs without COS are scarce. Study design, size, duration Multicenter nationwide cohort study aiming to investigate differences in long-term outcomes of women with BC receiving FP with or without COS at one of the seven regional FP programs in Sweden during 1994 - 2017 (N = 425). Participants/materials, setting, methods During the study period, 367 women received FP with COS (exposed) and 58 women underwent cryopreservation of ovarian tissue (unexposed) at Swedish centers. Reproductive outcomes, including post-diagnosis livebirths and the use of ART, as well as all-cause survival were investigated by linking of individuals in the cohort to several Swedish population-based registers. Outcomes among the women exposed and unexposed to COS were compared using Cox proportional hazard models adjusted for sociodemographic-, disease- and treatment characteristics. Main results and the role of chance Of 367 women exposed to FP with COS, 80 (22%) had at least one post-diagnosis livebirth (mean follow-up 4.3 years), compared to 17 (29%) of 58 women who underwent ovarian tissue cryopreservation (mean follow-up 5.9 years). Rates of ART-use during the follow-up were significantly higher in the group with COS (adjusted hazard ratio, aHR: 3.3, 95% CI:1.0-10.8), while livebirth rates (aHR: 1.1, 95% CI:0.6-2.0) as well as all-cause mortality rates (aHR:1.1, 95% CI:0.4-2.7) were similar between the groups. The five-years and ten-years cumulative incidence of post-BC livebirths was 18.3% and 41.4% among exposed to COS versus 23.7% and 38.9% among women with cryopreservation of ovarian tissue. Limitations, reasons for caution The FP programs in Sweden may differ from those in other countries, however data from population-based registers usually provide diversity. In Sweden, the use of gestational carriers is not permitted, thus individuals in this cohort had to achieve and carry by themselves the pregnancies resulting in post-BC livebirths. Wider implications of the findings The study results provide reassuring real-world reproductive and oncologic data following FP, both with and without COS, in women with BC. Our analyses are adjusted for identified confounders, and provide valuable information for FP-counselling of women with BC in need of FP. Trial registration number not applicable

Previous studies of breast cancer risk after in vitro fertilization (IVF) treatment were inconclusive due to limited follow-up. To assess long-term risk of breast cancer after ovarian stimulation for IVF. Historical cohort (OMEGA study) with complete follow-up through December 2013 for 96% of the cohort. The cohort included 19,158 women who started IVF treatment between 1983 and 1995 (IVF group) and 5950 women starting other fertility treatments between 1980 and 1995 (non-IVF group) from all 12 IVF clinics in the Netherlands. The median age at end of follow-up was 53.8 years for the IVF group and 55.3 years for the non-IVF group. Information on ovarian stimulation for IVF, other fertility treatments, and potential confounders was collected from medical records and through mailed questionnaires. Incidence of invasive and in situ breast cancers in women who underwent fertility treatments was obtained through linkage with the Netherlands Cancer Registry (1989-2013). Breast cancer risk in the IVF group was compared with risks in the general population (standardized incidence ratios [SIRs]) and the non-IVF group (hazard ratios [HRs]). Among 25,108 women (mean age at baseline, 32.8 years; mean number of IVF cycles, 3.6), 839 cases of invasive breast cancer and 109 cases of in situ breast cancer occurred after a median follow-up of 21.1 years. Breast cancer risk in IVF-treated women was not significantly different from that in the general population (SIR, 1.01 [95% CI, 0.93-1.09]) and from the risk in the non-IVF group (HR, 1.01 [95% CI, 0.86-1.19]). The cumulative incidences of breast cancer at age 55 were 3.0% for the IVF group and 2.9% for the non-IVF group (P = .85). The SIR did not increase with longer time since treatment (≥20 years) in the IVF group (0.92 [95% CI, 0.73-1.15]) or in the non-IVF group (1.03 [95% CI, 0.82-1.29]). Risk was significantly lower for those who underwent 7 or more IVF cycles (HR, 0.55 [95% CI, 0.39-0.77]) vs 1 to 2 IVF cycles and after poor response to the first IVF cycle (HR, 0.77 [95% CI, 0.61-0.96] for <4 vs ≥4 collected oocytes). Among women undergoing fertility treatment in the Netherlands between 1980 and 1995, IVF treatment compared with non-IVF treatment was not associated with increased risk of breast cancer after a median follow-up of 21 years. Breast cancer risk among IVF-treated women was also not significantly different from that in the general population. These findings are consistent with absence of a significant increase in long-term risk of breast cancer among IVF-treated women.

Background: Due to their age and life stage, young women with breast cancer (YWBC) encounter distinct challenges related to their diagnosis and treatment. Unmet parity along with potential premature ovarian insufficiency represent a notable concern among this group of patients. Effective strategies to address this issue include fertility preservation techniques, as well as temporary ovarian suppression with gonadotropin-releasing hormone agonists (GnRHa) for ovarian protection during cytotoxic treatments. Here we report a comparative analysis of two prospective studies describing the rates and factors associated with fertility and ovarian function preservation choices in YWBC from two countries. Methods: Women with BC at an age ≤40 years were prospectively accrued in the Joven &amp; Fuerte and PREFER multicenter cohorts in Mexico and Italy, respectively. These studies provide early referrals to fertility and/or ovarian function preservation strategies at diagnosis as needed. This analysis comprised YWBC diagnosed from 2014-2019 whose treatment included chemotherapy (CT) with the objective of identifying their uptake of fertility and ovarian function preservation options. Patients’ characteristics within and across cohorts were compared using chi-squared, Fisher’s exact, and Wilcoxon tests. Simple logistic regression was conducted to calculate the likelihood of undergoing fertility preservation. Results:In total, 485 patients were included: 361 (74%) in Mexico and 124 (26%) in Italy. Median age at diagnosis was 35 years (IQR 32-38) in both cohorts. A higher proportion of Mexican patients had a partner compared to Italian patients (65% vs 59%, p=.04). Patients’ median number of children at diagnosis was also higher in Mexico than in Italy (1 [IQR 0-2] vs 2 [IQR 1-3], p&amp;lt;.001). Patients’ distribution by clinical stage (p&amp;lt;.001), timing of CT (p=.01), hormone receptor status (p=.04), and HER2 status (p=.002) also differed between cohorts: Mexican patients were more frequently diagnosed with stage III BC and received neoadjuvant CT, while Italian patients more commonly had positive hormone receptors or HER2 overexpression. Regarding fertility preservation, a technique was used in 8% and 25% of patients in Mexico and Italy, respectively (p&amp;lt;.001). Methods comprised oocyte (50% in Mexico vs 87% in Italy), embryo (53% vs 0%; this strategy is forbidden by law in Italy), and ovarian tissue cryopreservation (0% vs 16%). GnRHa for ovarian protection were used in nearly all Italian patients (98%) but in a minority of Mexican patients (6%). Not undergoing fertility preservation was mainly due to lack of interest (47-50%), urgency to start treatment (4-6%), and personal reasons (3-5%). Fertility preservation uptake was associated with younger age (OR 1.2, 95%CI 1.1-1.2), unpartnered status (OR 3.4, 95%CI 1.9-5.9), childlessness (OR 21.8, 95%CI 10.0-47.6), private healthcare coverage in Mexico (OR 3.0, 95%CI 1.1-8.1), stage I-II BC (OR 3.1, 95%CI 1.5-6.3), positive hormone receptors (OR 2.3, 95%CI 1.2-4.6), and adjuvant CT (OR 2.4, 95%CI 1.4-4.3). Conclusions: This comparative analysis of two prospective studies in Mexico and Italy showed that a significant distinct proportion of YWBC had access to the available fertility and ovarian function preservation techniques in these countries, possibly reflecting the different social and healthcare contexts. Although all women should receive a complete oncofertility counseling, patients who are younger, unpartnered, childless, and have earlier-stage BC appear to be those who particularly benefit from being offered fertility preservation options. This study underscores the need to enhance awareness and access to oncofertility services in order to provide comprehensive, patient-centered care to this young population. Citation Format: Fernanda Mesa-Chavez, Maria Grazia Razeti, Eva Blondeaux, Alejandra Platas, Virginia Delucchi, Alan Fonseca, Valeria Fontana, Marlid Cruz-Ramos, Paola Anserini, Manuel Rolando García Garza, Edoardo Chiappe, Alejandro Mohar, Laura Orlando, Enrique Bargallo-Rocha, Saverio Cinieri, Lucia Del Mastro, Cynthia Villarreal-Garza, Matteo Lambertini. Fertility and ovarian function preservation in young women with breast cancer: A comparative analysis of two prospective cohort studies in Mexico and Italy [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-03-02.

Fertility preservation in female sarcoma patients

As a result of treatment innovations, the survival rates of young people with cancer have increased substantially. The cancers most frequently diagnosed in adults aged 25-49years include breast, colorectal and cervical cancer and malignant melanoma (Cancer Research UK, 2009). The 5-year survival rates of over 90% for many malignancies are now reported in young people. But the diagnosis and treatment of cancer often poses a threat to fertility. Methods of fertility preservation are evolving quickly and awareness needs to grow in the medical community regarding these methods. Studies suggest that the ability to have biological children is of great importance to many people. The possible future effects of chemotherapy or radiotherapy on fertility should be discussed with all cancer patients who have reproductive potential. Moreover, fertility preservation should be considered for all young people undergoing potentially gonadotoxic treatment. This article covers the various methods of fertility preserving options in young men and women with respect to the various treatment modalities that they may be subjected to. Sperm banking is a simple and low cost intervention. Embryo cryopreservation is the only established method of female fertility preservation. Oocyte cryopreservation offers a useful option for women without a male partner. Emergency ovarian stimulation and cryopreservation of ovarian tissue (followed by tissue transplantation or in-vitro maturation of oocytes) are experimental techniques for women who require urgent cancer treatment. Large, well-controlled studies are also required to identify any unexpected long-term sequelae of cryopreservation of oocytes and ovarian tissue.

Fertility preservation in men and women: Where are we in 2021? Are we rising to the challenge?

While ovarian tissue cryopreservation has commonly been equated with fertility preservation in cancer patients, there is a range of alternative options to preserve fertility. Based on the type and timing of chemotherapy, the type of cancer, the patient's age and the partner status, a different strategy of fertility preservation may be needed. If the patient has a partner or accepts donor sperm, embryo cryopreservation should be considered first, since this is a clinically well established procedure. Despite relatively low pregnancy rates, when there is time for ovarian stimulation and the patient is single, oocyte cryopreservation may also be preferred to ovarian tissue banking. In breast cancer patients, tamoxifen or aromatase inhibitors can be used for ovarian stimulation prior to oocyte or embryo cryopreservation. In endometrial cancer patients, aromatase inhibitors may be the only choice for ovarian stimulation. When only pelvic radiotherapy is used, ovarian transposition can be performed, but the success rates vary because of scatter radiation and vascular compromise. Lack of FSH and GnRH receptors on primordial follicles and oocytes does not make gonadal suppression an effective strategy of gonadal protection. Fertility preservation should be an integral part of improving the quality of life in cancer survivors; however, it is neither possible nor ethical to recommend the same recipe for every cancer patient.