Fertility Preservation Using Controlled Ovarian Stimulation in Breast Cancer: A Comparative Study of Neoadjuvant and Adjuvant Settings

Fertility Preservation Using Controlled Ovarian Stimulation in Breast Cancer: A Comparative Study of Neoadjuvant and Adjuvant Settings | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Fertility Preservation Using Controlled Ovarian Stimulation in Breast Cancer: A Comparative Study of Neoadjuvant and Adjuvant Settings Moran Shapira, Chen Berkovitz, Myriam Safrai, Jigal Haas, Tal Sella, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6874219/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose: To compare the time to initiation of first oncologic treatment and the outcomes of controlled ovarian stimulation (COS) in breast cancer patients undergoing fertility preservation (FP) in the neoadjuvant chemotherapy (NAC) versus adjuvant chemotherapy (AC) treatment settings. Methods: A retrospective cohort study involving patients with stage 1-3 breast cancer treated with NAC/AC, who underwent FP with random-start COS, between 2015-2023. Baseline, oncologic and COS characteristics and outcomes were collected. Time points related to cancer diagnosis, FP, and first oncologic intervention (surgery or chemotherapy) were calculated. Results: 70 NAC-treated patients were compared to 42 AC-treated patients. Groups were similar in terms of age, marital status, parity and BMI. NAC-treated patients had more advanced disease, more often with lymph node involvement. Median time from diagnosis to FP consult (17 vs 30 days) and to stimulation start (22 vs 59 days) was significantly shorter for NAC-treated patients. Median time from diagnosis to first oncologic intervention was slightly longer for NAC-treated patients (45 vs 41 days, p<0.05). Stimulation characteristics were comparable apart from a less frequent use of hCG trigger among NAC-treated patients (4% vs 16%, p<0.05). First stimulation cycle outcomes such as peak E2 levels, number of retrieved oocytes and fertilization rate were similar, though median number of M2 oocytes was higher in NAC- treated patients (11 vs 8, p<0.05). Conclusion: Expedited patient care at the neoadjuvant setting led to a statistically significant, yet clinically minimal, delay of cancer therapy. Neither oncologic treatment timelines nor FP outcomes were compromised in the NAC setting. Fertility preservation breast cancer neoadjuvant chemotherapy random-start Introduction Breast cancer is the most common malignancy diagnosed in individuals of reproductive age [1, 2]. In this population, the disease more often exhibits biologically aggressive features [3, 4], making chemotherapy a key component of treatment [5]. Beyond the gonadotoxic effects of chemotherapy, the need to postpone pregnancy due to prolonged adjuvant therapies may further impact future fertility [6]. Given that many young breast cancer patients have not yet completed childbearing at the time of diagnosis, FP —typically involving COS followed by oocyte or embryo cryopreservation—is often considered [6, 7]. Since oocyte or embryo cryopreservation must occur before the initiation of chemotherapy [8], the urgency of FP depends on the treatment approach. In cases of adjuvant chemotherapy, fertility preservation is typically performed after the initial treatment (surgery), during the natural interval that occurs as part of the postoperative recovery period before the initiation of chemotherapy. As such, fertility preservation does not dictate the timeline of oncologic treatment. In contrast, in the neoadjuvant chemotherapy setting, fertility preservation must take place before the initial treatment (chemotherapy), meaning that, by necessity, it determines the timing of the oncologic treatment. In recent years, the use of neoadjuvant systemic therapy has increased [9, 10]. Neoadjuvant therapy increases the likelihood of breast-conserving surgery over mastectomy and allows for histologic evaluation of tumor response to systemic therapy, providing valuable prognostic insights. However, concerns regarding potential delays in systemic therapy, or the risk of inadequate FP outcomes due to time limitations, may discourage both oncologists and patients from pursuing FP, particularly in the setting of neoadjuvant systemic therapy [11–13]. In this study, we aimed to assess whether the time from cancer diagnosis to the first oncologic intervention in patients pursuing FP is influenced by the type of chemotherapy (neoadjuvant vs. adjuvant), as well as whether FP outcomes differ when performed prior to neoadjuvant chemotherapy compared to adjuvant chemotherapy Methods Study population This retrospective study included reproductive-aged breast cancer patients who underwent FP at a tertiary medical between 2015 and 2023. All participants had initiated COS for the purpose of oocyte or embryo cryopreservation shortly after their cancer diagnosis and prior to the initiation of chemotherapy. Patients who did not receive chemotherapy or who had missing data were excluded. Exposure groups were defined by the timing of systemic therapy - those who underwent COS prior to receiving neoadjuvant chemotherapy (NAC group), and those who underwent COS prior to adjuvant chemotherapy (AC group). COS protocol COS was initiated as soon as possible after fertility preservation consultation. Antagonist-based protocols were used, and random-start stimulation was performed as a standard, to avoid delay in cancer therapy. Gonadotrophins were administrated in variable doses, depending on patient’s age, BMI, and previous response to stimulation on repeat cycles. Gonadotropin doses were further adjusted according to serum E2 levels and vaginal ultrasound measurement obtained every 2–3 days. In patients with hormone-receptor positive breast cancer cotreatment with Tamoxifen was applied. Tamoxifen (20 mg) was added once a rise of E2 levels was detected and antagonist injections commenced. Final follicular maturation was induced when the leading follicle measured > 17 mm, with either hCG (Ovitrelle 250 mcg, Merck), GnRH- agonist (GnRH-a) (Decapeptyl 0.2 mg) or the dual trigger (Ovitrelle 250 mcg and Decapeptyl 0.2 mg). A transvaginal, ultrasound-guided follicular aspiration was conducted 36 h after triggering. The number of cycle attempts for each patient was determined through a collaborative decision-making process involving the patient, the fertility specialist, and the treating oncologist, with consideration given to the treatment schedule and the outcomes of the initial COS cycle. Data collection Institutional ethics committee approval was obtained for the study (SMC 9383-22). Electronic medical records and pathology reports were reviewed to extract demographic data, germline BRCA1/2 mutation status, tumor grade, estrogen and progesterone receptor-status, human epidermal growth factor receptor (HER-2/neu) status, ki67 score, lymph node involvement and breast cancer stage. In patients treated with adjuvant chemotherapy, tumor size and lymph node status were extracted from pathology reports of surgical specimens. In patients treated with neoadjuvant chemotherapy, tumor size and lymph node status were defined based on pre-treatment clinical evaluation. The following stimulation characteristics and outcomes were extracted for the first stimulation cycle: timing of stimulation initiation (early follicular, late follicular, luteal), initial gonadotropin dose, total gonadotropins dose, number of stimulation days, estrogen co-treatment, type of ovulation trigger, peak E2 levels, number of retrieved oocytes, number of mature (MII) oocytes, fertilization rate. The following data were collected for the entire FP process: number of stimulation cycles per patient, cumulative number of oocytes cryopreserved, and cumulative number of embryos cryopreserved. Several time intervals were calculated. Time to FP consult was defined as the interval from the date of diagnosis (the date of first positive biopsy) to first FP consult. Time to COS was defined as the interval from the date of diagnosis to initiation of COS. Time to first therapeutic intervention was defined as the interval between the date of diagnosis and the initiation of chemotherapy in the NAC group or surgical treatment in the AC group. Statistical analysis Statistical analysis was conducted with the use of SciPy, version 1.0.0. Normality of distribution was evaluated with the use of histograms and Q-Q plots. Continuous variables are presented as mean ± SD or median (IQR) as appropriate. Categoric variables are presented as n (%). Normally distributed continuous variables were compared by means of Student t test, and nonnormally distributed numbers were compared by means of Mann-Whitney test. Categoric variables were compared by means of chi-square. A P value of < .05 was considered statistically significant. A univariate linear regression model was used to assess the individual impact of each potential confounder on 1st stimulation cycle outcomes (number of MII oocytes). Covariates with a p-value < 0.1 in the univariate analysis were included in the final multivariate linear regression model assessing first stimulation outcomes. Results Between 2015 and 2023, 138 women with newly diagnosed early breast cancer underwent COS for FP. Of these, 19 did not receive chemotherapy and 6 had missing data, resulting in a final study cohort of 113 patients with70 undergoing embryo or oocyte cryopreservation prior to neoadjuvant chemotherapy (NAC group), and 43 prior to adjuvant chemotherapy (AC group). Patient and disease characteristics are summarized in Table 1 . NAC and AC groups were comparable in terms of age, body mass index (BMI), marital status, nulliparity rate, and prevalence of germline BRCA1/2 mutations. Patients treated with NAC were characterized by more aggressive disease phenotype, as evidenced by a trend toward higher tumor grade (grade 3, 73.8% vs 55.8%, p < 0.05), a significantly higher rate of lymph node involvement (61.4% vs 30.2%, p < 0.05), and a more advanced stage (stage III, 28.5% vs 9.3%, p < 0.05). In the AC group, 36 patients (83.72%) received FP following surgery, while the remaining 7 patients, initiated FP prior to undergoing surgery. Median time to first FP consult (17 days [IQR 13–28] 30 days [IQR 18–61], p < 0.05) and time to COS (22 days [IQR16-33.25] vs 59 [IQR 39–84], p < 0.05) were significantly shorter for the NAC group. Nonetheless, time to first therapeutic intervention was significantly longer for the NAC group (45 days [IQR 35.75–57.25] vs 41 [IQR 27–53], p < 0.05). Characteristics and outcomes of the first stimulation cycle are presented in Table 2 . The timing of stimulation initiation, duration of stimulation, initial gonadotropin dose, and co-treatment with Tamoxifen were comparable between the groups. A trend toward a higher cumulative gonadotropin dose was observed in the NAC group (3200 [IQR 2350–4050] vs 2950 [IQR 2100–3512], p = 0.09). HCG trigger was more often used in the AC group (4% vs 16%, p < 0.05), while GnRH-a and Dual trigger were more often used in the NAC group (96% vs 84%, p < 0.05). NAC and AC groups did not differ significantly in median peak estradiol levels and number of retrieved oocytes (14 [IQR 8.75-24] vs 13 [IQR 6–18], p = 0.11). However, median number of MII oocytes was significantly higher in the NAC group (11 [IQR 5.5–18]) compared to the AC group (8 [IQR 8–12.5], p = 0.024). Fertilization rates did not differ significantly between the groups. As shown in Table 3 , univariate linear regression analysis was conducted to evaluate the effect of potential confounders on the number of MII oocytes. Only chemotherapy setting and ovulation trigger were significantly associated with MII oocyte number: NAC was linked to a greater number of MII oocytes, while hCG trigger was associated with fewer. After adjusting for trigger type in a multivariate regression analysis, the association between chemotherapy type and MII oocyte count became non-significant. Prior to initiating chemotherapy, 6 patients (8.6%) in the NAC group underwent more than one cycle, compared to 18 patients (41.9%) in the AC group (p < 0.01). After inclusion of repeat cycles, the median cumulative number of MII oocytes was similar between the NAC and AC groups, with 11 (IQR 5–15) and 10.5 (IQR 5–20.25), respectively. Of the total cohort, 48 patients chose embryo storage, 44 opted for oocyte storage, and 16 elected to store both embryos and oocytes. In five cases, COS was attempted but did not result in the storage of any gametes or embryos. When comparing the groups, by the conclusion of the FP process, NAC and AC patients who chose only oocyte cryopreservation stored a similar number of eggs (13.5 [IQR 8.75–21.75] vs. 12 [IQR 7.25–15.5], p = 0.15). Similarly, NAC and AC patients who chose only embryo cryopreservation stored a similar number of embryos (5 [IQR 2.5–8.5] vs. 6 [IQR 4–9], p = 0.41). Discussion The intersection of cancer treatment and FP presents both emotional and clinical challenges. While patients understandably prioritize survival, it is essential that oncologists and fertility specialists convey that parenthood remains a viable option which doesn’t necessarily compromise oncologic outcome[14, 15]. Beyond offering the possibility of future motherhood, FP can also provide a significant psychological benefit, serving as a source of hope and empowerment [16]. For breast cancer patients scheduled to receive adjuvant chemotherapy, integrating FP into the treatment timeline is generally straightforward. FP is typically performed after the initial oncologic intervention—surgery—and therefore does not affect the timing of that intervention or delay the overall oncologic treatment. However, for patients undergoing NAC, the scenario is more complex, as the timing and extent of FP may ultimately postpone the start of first oncologic treatment. In this study of 130 young breast cancer patients undergoing COS prior to chemotherapy, the time to first therapeutic intervention was only slightly longer in the neoadjuvant setting. Chemotherapy was initiated after a median of 45 days after diagnosis in the neoadjuvant group, whereas surgery was performed after a median of 41 days from diagnosis in those treated with adjuvant chemotherapy. Both time frames fall well within the recommended period for initiating the cancer therapy after diagnosis (6–8 weeks) and are unlikely to impair oncologic outcomes [17]. Previous studies have primarily examined treatment timelines in the context of neoadjuvant chemotherapy, reporting a time lapse of approximately 40 days between cancer diagnosis and the initiation of NAC [18–21] a finding consistent with our results The initiation of neoadjuvant chemotherapy after a median of 45 days in the current study was made possible through expedited management, as reflected by significantly shorter intervals from diagnosis to FP consultation and stimulation. In comparison, patients receiving adjuvant chemotherapy reached first intervention (surgery) within a similar timeframe, but without the need for such an accelerated coordination, since chemotherapy followed surgery rather than preceding it. The avoidance of delays in initiating stimulation was further facilitated by the liberal use of the random-start stimulation protocol, which allowed for the immediate initiation of controlled ovarian stimulation (COS), regardless of the timing within the menstrual cycle. This approach potentially reduced the overall FP timeline by 2–4 weeks, while maintaining oocyte retrieval numbers, mature oocyte yield, and fertilization rates [22, 23]. Our findings are consistent with previous studies, which also demonstrate that using the random-start protocol for FP does not cause delays in planned oncologic treatment [19, 20]. It is noteworthy that most patients in the AC group, initiated COS only after surgery, thereby missing the opportunity to utilize the time available between diagnosis and surgery for fertility preservation. This pattern suggests a more “laid-back” approach to management in the adjuvant setting. However, it also highlights that, conceptually, patients in the AC group could have undergone additional COS cycles had FP been initiated earlier. Still, more than half of the AC group were able to complete more than one stimulation cycle, in contrast to the majority of NAC patients, who underwent only a single cycle. Despite this, both groups ultimately stored a similar cumulative number of oocytes or embryos by the end of the FP process. This outcome may be attributed to the first stimulation cycle, during which the NAC group yielded a significantly higher number of mature (MII) oocytes (11 vs. 8, p = 0.024), despite a comparable number of retrieved oocytes. The higher MII yield in the NAC group may be explained by the type of final oocyte maturation trigger. The NAC group more frequently received a GnRH agonist or dual trigger. Among the possible advantages of GnRH agonist for ovulation triggering is the endogenous surge of FSH. The latter has been reported to have several important roles in ovulation and oocyte maturation, leading to improved maturation rate. Indeed, in a univariate linear regression model of the current cohort, GnRH agonist or dual trigger use was positively associated with MII oocyte number [24–26]. As shown in Table 3 , adjusting for trigger type in multivariate analysis rendered the association between chemotherapy type and MII oocyte number non-significant. Several oncologic variables have previously been shown to influence COS outcomes in breast cancer patients. Specifically, hormone receptor–positive status has been associated with a higher number of retrieved [27] and mature oocytes [28]. In our cohort, patients treated with adjuvant chemotherapy were more frequently diagnosed with hormone receptor–positive tumors. However, no association was observed between hormone receptor status and MII oocyte yield (Table 3 ), suggesting that receptor profile could not account for the differences in oocyte yield seen between treatment groups. Few studies have also explored the potential impact of tumor burden on oocyte retrieval outcomes. One study found that a higher cancer grade was associated with a lower baseline AFC and a greater need for gonadotropin during ovarian stimulation [29]. Nonetheless, neither cancer stage nor grade appeared to affect the number of oocytes retrieved or MII oocytes obtained [29, 30]. Similarly, as shown in Table 3 , MII oocyte yield in the current study was not associated with cancer grade, stage, or lymph node involvement. Thus, aside from the difference in ovulation trigger, no clear explanation was identified for the observed difference in MII oocyte yield between the groups. Our study expands current knowledge by offering a broader perspective on both oncologic and reproductive aspects of FP prior to NAC. By adjusting for oncologic and stimulation-related variables, we were able to effectively demonstrate the non-inferiority of FP in the neoadjuvant setting, while also highlighting the feasibility of meeting established oncologic quality standards. Nonetheless, several limitations should be acknowledged. Most notably, the retrospective design of the study poses inherent limitations. Additionally, because our data were drawn from an IVF clinic database, we were only able to include patients who ultimately elected to undergo FP, thus excluding potentially valuable information about those who chose not to pursue FP. Finally, long-term reproductive outcomes, including utilization of stored gametes or embryos and post-treatment pregnancy rates, were not assessed. In conclusion, this study supports the feasibility of COS for FP prior to NAC, specifically with the use of random start COS with GnRH-a or Dural trigger. We could demonstrate that neither treatment timelines nor fertility FP outcomes are compromised compared to the more flexible context of performing FP in the adjuvant setting. The decision to pursue FP should not be determined solely by the timing of planned chemotherapy. Rather, timely coordination between oncology and fertility teams is key to facilitating appropriate and effective care. Declarations Author Contribution MS- conception, design, Interpretation of data, writing of manuscriptCB- acquisition of data, statistical analysisMS- statistical analysis, preparation of tablesJH- Interpretation of data, article revisionTS- Interpretation of data, article revision AA- acquisition of data, preparation of tablesDM- conception and design, Interpretation of data, article revisionRO- conception and design, Interpretation of data, article revision References Xia, C., et al., Global evolution of breast cancer incidence in childbearing-age women aged 15-49 years: a 30-year analysis. J Cancer Res Clin Oncol, 2025. 151 (2): p. 75. Xu, S., et al., Breast Cancer Incidence Among US Women Aged 20 to 49 Years by Race, Stage, and Hormone Receptor Status. JAMA Netw Open, 2024. 7 (1): p. e2353331. Azim, H.A., Jr., et al., Elucidating prognosis and biology of breast cancer arising in young women using gene expression profiling. Clin Cancer Res, 2012. 18 (5): p. 1341-51. 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Tables Table 1 – Baseline and tumor characteristics AC group (n = 43) NAC group (n = 70) P-value Age , years (mean ± SD) 33.07 ± 4.82 32.37 ± 4.48 0.43 Marital status Single, n (%) 21 (48.8) 32 (45.7) 0.39 Married, n (%) 22 (51.2) 35 (50) Divorced, n (%) 0 (0) 3 (4.3) Nulliparity (%) 18 (41.9) 37 (52.9) 0.58 BMI , kg/m 2 (mean ± SD) 22.29 ± 3.13 22.74 ± 3.21 0.58 BRCA positive (%) 17 (50) 25 (41) 0.55 Hormone receptor positive (%) 27 (62.8) 31 (44.3) 0.06 Her 2 positive(%) 5 (11.6) 26 (37.1) < 0.05 Ki67 1 (%) 3 (7.1) 2 (2.9) 0.22 2 (%) 11 (26.2) 11 (16.2) 3 (%) 3 (7.1) 55 (80.9) Grade 1 (%) 0 (0) 0 (0) 0.06 2 (%) 19 (44.2) 16 (26.2) 3 (%) 24 (55.8) 45 (73.8) Axillary lymph nodes involvement (%) 13 (30.2) 43 (61.4) < 0.05 Stage I (%) 19 (44.2) 3 (4.3) < 0.05 II (%) 20 (46.5) 47 (67.1) III (%) 4 (9.3) 20 (28.5) Baseline and tumor features of breast cancer patients who underwent fertility preservation prior to neoadjuvant (NAC) or adjuvant (AC) chemotherapy. Values are presented as mean ± SD or n (%). NAC = neoadjuvant chemotherapy; AC = adjuvant chemotherapy; BMI = body mass index; BRCA = breast cancer gene; HER2 = human epidermal growth factor receptor 2. Table 2 First controlled ovarian stimulation characteristics and outcomes by chemotherapy setting AC group (n = 43) NAC group (n = 70) P-value Stimulation start timing Early follicular (%) 31 (72.1) 42 (60) 0.274 Late follicular (%) 1 (2.3) 6 (8.6) Luteal (%) 11 (25.6) 22 (31.4) Stimulation days (median [Q1, Q3]) 10 [9, 11] 10 [9, 12] 0.421 Gonadotropins initial dose , IU (median [Q1, Q3]) 300 [225, 350] 300 [225, 350] 0.497 Gonadotropins total dose , IU (median [Q1, Q3]) 2950 [2100, 3512] 3200 [2350, 4050] 0.090 Tamoxifen/letrozole co-treatment (%) 22 (51.2) 36 (51.4) 0.978 Ovulation Trigger hCG (%) 7 (16) 3 (4) < 0.05 GnRH-a/Dual (%) 36 (84) 67 (96) Maximal E2 levels , pmol/L (median [Q1, Q3]) 6828 [4192, 11524] 48617 [5119, 14674] 0.19 Retrieved oocytes (median [Q1, Q3]) 13 [6, 18] 14 [8.75, 24] 0.11 MII oocytes (median [Q1, Q3]) 8 [4, 12.5] 11 [5.5, 18] < 0.05 Fertilization rate (mean ± SD) 70.1 ± 20.91 76.43 ± 16.59 0.20 First-cycle ovarian stimulation characteristics and outcomes for patients undergoing fertility preservation prior to neoadjuvant (NAC) or adjuvant (AC) chemotherapy. COS = controlled ovarian stimulation; GnRH-a = gonadotropin-releasing hormone agonist; hCG = human chorionic gonadotropin; MII = metaphase II oocytes; E2 = estradiol; IU = international units. Table 3 Predictors of mature oocyte yield: linear regression models Univariate Analysis Multivariate Analysis β SE P β SE P NAC vs AC 3.65 1.75 0.04 2.84 1.75 0.11 Cumulative dose 0.0004 0.001 0.49 Trigger (hCG vs GnRH-a/Dual) -7.27 2.78 0.01 -6.33 2.81 0.03 Her 2 (positive vs negative) -1.2370 2.059 0.549 Hormone receptors (positive vs negative) 1.4722 1.756 1.756 Grade (3 vs 2) 0.1319 1.841 0.943 Stage (3 vs 2/1) -0.4710 2.209 0.832 Lymph node (positive vs negative) 2.4375 1.743 0.165 Univariate and multivariate linear regression analyses evaluating predictors of the number of mature (MII) oocytes retrieved during the first controlled ovarian stimulation cycle. Abbreviations: β = regression coefficient; SE = standard error; NAC = neoadjuvant chemotherapy; AC = adjuvant chemotherapy; GnRH-a = gonadotropin-releasing hormone agonist. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6874219","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":478184946,"identity":"ad7b9ce8-5c3e-4e6f-8879-69f8d6f7a960","order_by":0,"name":"Moran Shapira","email":"data:image/png;base64,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","orcid":"","institution":"IVF Institute, Obstetrics \u0026 Gynecology department","correspondingAuthor":true,"prefix":"","firstName":"Moran","middleName":"","lastName":"Shapira","suffix":""},{"id":478184947,"identity":"f83392c9-36e1-40f0-87e2-5e359d4ee51c","order_by":1,"name":"Chen Berkovitz","email":"","orcid":"","institution":"Faculty of Medical and Health Science","correspondingAuthor":false,"prefix":"","firstName":"Chen","middleName":"","lastName":"Berkovitz","suffix":""},{"id":478184948,"identity":"e1285131-0b95-4d8d-ab99-d7b6f043f85f","order_by":2,"name":"Myriam Safrai","email":"","orcid":"","institution":"Fertility preservation center, Obstetrics \u0026 Gynecology department","correspondingAuthor":false,"prefix":"","firstName":"Myriam","middleName":"","lastName":"Safrai","suffix":""},{"id":478184949,"identity":"7fc70943-bfac-42f8-8367-d974af7031b1","order_by":3,"name":"Jigal Haas","email":"","orcid":"","institution":"IVF Institute, Obstetrics \u0026 Gynecology department","correspondingAuthor":false,"prefix":"","firstName":"Jigal","middleName":"","lastName":"Haas","suffix":""},{"id":478184950,"identity":"3769bddc-7266-437e-b494-fe5f88f400c2","order_by":4,"name":"Tal Sella","email":"","orcid":"","institution":"Department of Oncology","correspondingAuthor":false,"prefix":"","firstName":"Tal","middleName":"","lastName":"Sella","suffix":""},{"id":478184951,"identity":"927e5021-f021-4268-8859-cac98f22e56d","order_by":5,"name":"Adva Aizer","email":"","orcid":"","institution":"IVF Institute, Obstetrics \u0026 Gynecology department","correspondingAuthor":false,"prefix":"","firstName":"Adva","middleName":"","lastName":"Aizer","suffix":""},{"id":478184952,"identity":"95b2f2bd-ebef-4aa4-963b-ddbdae8e959f","order_by":6,"name":"Dror Meirow","email":"","orcid":"","institution":"Fertility preservation center, Obstetrics \u0026 Gynecology department","correspondingAuthor":false,"prefix":"","firstName":"Dror","middleName":"","lastName":"Meirow","suffix":""},{"id":478184953,"identity":"6daf9408-7653-42af-b1fd-f8154a54f77c","order_by":7,"name":"Raoul Orvieto","email":"","orcid":"","institution":"IVF Institute, Obstetrics \u0026 Gynecology department","correspondingAuthor":false,"prefix":"","firstName":"Raoul","middleName":"","lastName":"Orvieto","suffix":""}],"badges":[],"createdAt":"2025-06-11 18:08:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6874219/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6874219/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":90272530,"identity":"7b9fc38e-7bcc-4996-b81c-bffd8e7f0075","added_by":"auto","created_at":"2025-09-01 01:01:31","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":764885,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6874219/v1/956122ac-b96c-406b-9e96-22189f9f95fb.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Fertility Preservation Using Controlled Ovarian Stimulation in Breast Cancer: A Comparative Study of Neoadjuvant and Adjuvant Settings","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBreast cancer is the most common malignancy diagnosed in individuals of reproductive age [1, 2]. In this population, the disease more often exhibits biologically aggressive features [3, 4], making chemotherapy a key component of treatment [5]. Beyond the gonadotoxic effects of chemotherapy, the need to postpone pregnancy due to prolonged adjuvant therapies may further impact future fertility [6]. Given that many young breast cancer patients have not yet completed childbearing at the time of diagnosis, FP \u0026mdash;typically involving COS followed by oocyte or embryo cryopreservation\u0026mdash;is often considered [6, 7].\u003c/p\u003e \u003cp\u003eSince oocyte or embryo cryopreservation must occur before the initiation of chemotherapy [8], the urgency of FP depends on the treatment approach. In cases of adjuvant chemotherapy, fertility preservation is typically performed after the initial treatment (surgery), during the natural interval that occurs as part of the postoperative recovery period before the initiation of chemotherapy. As such, fertility preservation does not dictate the timeline of oncologic treatment. In contrast, in the neoadjuvant chemotherapy setting, fertility preservation must take place before the initial treatment (chemotherapy), meaning that, by necessity, it determines the timing of the oncologic treatment.\u003c/p\u003e \u003cp\u003eIn recent years, the use of neoadjuvant systemic therapy has increased [9, 10]. Neoadjuvant therapy increases the likelihood of breast-conserving surgery over mastectomy and allows for histologic evaluation of tumor response to systemic therapy, providing valuable prognostic insights. However, concerns regarding potential delays in systemic therapy, or the risk of inadequate FP outcomes due to time limitations, may discourage both oncologists and patients from pursuing FP, particularly in the setting of neoadjuvant systemic therapy [11\u0026ndash;13].\u003c/p\u003e \u003cp\u003eIn this study, we aimed to assess whether the time from cancer diagnosis to the first oncologic intervention in patients pursuing FP is influenced by the type of chemotherapy (neoadjuvant vs. adjuvant), as well as whether FP outcomes differ when performed prior to neoadjuvant chemotherapy compared to adjuvant chemotherapy\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy population\u003c/h2\u003e \u003cp\u003eThis retrospective study included reproductive-aged breast cancer patients who underwent FP at a tertiary medical between 2015 and 2023. All participants had initiated COS for the purpose of oocyte or embryo cryopreservation shortly after their cancer diagnosis and prior to the initiation of chemotherapy. Patients who did not receive chemotherapy or who had missing data were excluded. Exposure groups were defined by the timing of systemic therapy - those who underwent COS prior to receiving neoadjuvant chemotherapy (NAC group), and those who underwent COS prior to adjuvant chemotherapy (AC group).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eCOS protocol\u003c/h3\u003e\n\u003cp\u003eCOS was initiated as soon as possible after fertility preservation consultation. Antagonist-based protocols were used, and random-start stimulation was performed as a standard, to avoid delay in cancer therapy. Gonadotrophins were administrated in variable doses, depending on patient\u0026rsquo;s age, BMI, and previous response to stimulation on repeat cycles. Gonadotropin doses were further adjusted according to serum E2 levels and vaginal ultrasound measurement obtained every 2\u0026ndash;3 days.\u003c/p\u003e \u003cp\u003eIn patients with hormone-receptor positive breast cancer cotreatment with Tamoxifen was applied. Tamoxifen (20 mg) was added once a rise of E2 levels was detected and antagonist injections commenced. Final follicular maturation was induced when the leading follicle measured\u0026thinsp;\u0026gt;\u0026thinsp;17 mm, with either hCG (Ovitrelle 250 mcg, Merck), GnRH- agonist (GnRH-a) (Decapeptyl 0.2 mg) or the dual trigger (Ovitrelle 250 mcg and Decapeptyl 0.2 mg). A transvaginal, ultrasound-guided follicular aspiration was conducted 36 h after triggering. The number of cycle attempts for each patient was determined through a collaborative decision-making process involving the patient, the fertility specialist, and the treating oncologist, with consideration given to the treatment schedule and the outcomes of the initial COS cycle.\u003c/p\u003e\n\u003ch3\u003eData collection\u003c/h3\u003e\n\u003cp\u003e Institutional ethics committee approval was obtained for the study (SMC 9383-22). Electronic medical records and pathology reports were reviewed to extract demographic data, germline \u003cem\u003eBRCA1/2\u003c/em\u003e mutation status, tumor grade, estrogen and progesterone receptor-status, human epidermal growth factor receptor (HER-2/neu) status, ki67 score, lymph node involvement and breast cancer stage. In patients treated with adjuvant chemotherapy, tumor size and lymph node status were extracted from pathology reports of surgical specimens. In patients treated with neoadjuvant chemotherapy, tumor size and lymph node status were defined based on pre-treatment clinical evaluation.\u003c/p\u003e \u003cp\u003eThe following stimulation characteristics and outcomes were extracted for the first stimulation cycle: timing of stimulation initiation (early follicular, late follicular, luteal), initial gonadotropin dose, total gonadotropins dose, number of stimulation days, estrogen co-treatment, type of ovulation trigger, peak E2 levels, number of retrieved oocytes, number of mature (MII) oocytes, fertilization rate. The following data were collected for the entire FP process: number of stimulation cycles per patient, cumulative number of oocytes cryopreserved, and cumulative number of embryos cryopreserved.\u003c/p\u003e \u003cp\u003eSeveral time intervals were calculated. Time to FP consult was defined as the interval from the date of diagnosis (the date of first positive biopsy) to first FP consult. Time to COS was defined as the interval from the date of diagnosis to initiation of COS. Time to first therapeutic intervention was defined as the interval between the date of diagnosis and the initiation of chemotherapy in the NAC group or surgical treatment in the AC group.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eStatistical analysis was conducted with the use of SciPy, version 1.0.0. Normality of distribution was evaluated with the use of histograms and Q-Q plots. Continuous variables are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD or median (IQR) as appropriate. Categoric variables are presented as n (%). Normally distributed continuous variables were compared by means of Student \u003cem\u003et\u003c/em\u003e test, and nonnormally distributed numbers were compared by means of Mann-Whitney test. Categoric variables were compared by means of chi-square. A \u003cem\u003eP\u003c/em\u003e value of \u0026lt;\u0026thinsp;.05 was considered statistically significant. A univariate linear regression model was used to assess the individual impact of each potential confounder on 1st stimulation cycle outcomes (number of MII oocytes). Covariates with a p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.1 in the univariate analysis were included in the final multivariate linear regression model assessing first stimulation outcomes.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eBetween 2015 and 2023, 138 women with newly diagnosed early breast cancer underwent COS for FP. Of these, 19 did not receive chemotherapy and 6 had missing data, resulting in a final study cohort of 113 patients with70 undergoing embryo or oocyte cryopreservation prior to neoadjuvant chemotherapy (NAC group), and 43 prior to adjuvant chemotherapy (AC group). Patient and disease characteristics are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. NAC and AC groups were comparable in terms of age, body mass index (BMI), marital status, nulliparity rate, and prevalence of germline BRCA1/2 mutations. Patients treated with NAC were characterized by more aggressive disease phenotype, as evidenced by a trend toward higher tumor grade (grade 3, 73.8% vs 55.8%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), a significantly higher rate of lymph node involvement (61.4% vs 30.2%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), and a more advanced stage (stage III, 28.5% vs 9.3%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003eIn the AC group, 36 patients (83.72%) received FP following surgery, while the remaining 7 patients, initiated FP prior to undergoing surgery. Median time to first FP consult (17 days [IQR 13\u0026ndash;28] 30 days [IQR 18\u0026ndash;61], p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) and time to COS (22 days [IQR16-33.25] vs 59 [IQR 39\u0026ndash;84], p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) were significantly shorter for the NAC group. Nonetheless, time to first therapeutic intervention was significantly longer for the NAC group (45 days [IQR 35.75\u0026ndash;57.25] vs 41 [IQR 27\u0026ndash;53], p\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003eCharacteristics and outcomes of the first stimulation cycle are presented in Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The timing of stimulation initiation, duration of stimulation, initial gonadotropin dose, and co-treatment with Tamoxifen were comparable between the groups. A trend toward a higher cumulative gonadotropin dose was observed in the NAC group (3200 [IQR 2350\u0026ndash;4050] vs 2950 [IQR 2100\u0026ndash;3512], p\u0026thinsp;=\u0026thinsp;0.09). HCG trigger was more often used in the AC group (4% vs 16%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), while GnRH-a and Dual trigger were more often used in the NAC group (96% vs 84%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). NAC and AC groups did not differ significantly in median peak estradiol levels and number of retrieved oocytes (14 [IQR 8.75-24] vs 13 [IQR 6\u0026ndash;18], p\u0026thinsp;=\u0026thinsp;0.11). However, median number of MII oocytes was significantly higher in the NAC group (11 [IQR 5.5\u0026ndash;18]) compared to the AC group (8 [IQR 8\u0026ndash;12.5], \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.024). Fertilization rates did not differ significantly between the groups.\u003c/p\u003e \u003cp\u003eAs shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, univariate linear regression analysis was conducted to evaluate the effect of potential confounders on the number of MII oocytes. Only chemotherapy setting and ovulation trigger were significantly associated with MII oocyte number: NAC was linked to a greater number of MII oocytes, while hCG trigger was associated with fewer. After adjusting for trigger type in a multivariate regression analysis, the association between chemotherapy type and MII oocyte count became non-significant.\u003c/p\u003e \u003cp\u003ePrior to initiating chemotherapy, 6 patients (8.6%) in the NAC group underwent more than one cycle, compared to 18 patients (41.9%) in the AC group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). After inclusion of repeat cycles, the median cumulative number of MII oocytes was similar between the NAC and AC groups, with 11 (IQR 5\u0026ndash;15) and 10.5 (IQR 5\u0026ndash;20.25), respectively. Of the total cohort, 48 patients chose embryo storage, 44 opted for oocyte storage, and 16 elected to store both embryos and oocytes. In five cases, COS was attempted but did not result in the storage of any gametes or embryos. When comparing the groups, by the conclusion of the FP process, NAC and AC patients who chose only oocyte cryopreservation stored a similar number of eggs (13.5 [IQR 8.75\u0026ndash;21.75] vs. 12 [IQR 7.25\u0026ndash;15.5], p\u0026thinsp;=\u0026thinsp;0.15). Similarly, NAC and AC patients who chose only embryo cryopreservation stored a similar number of embryos (5 [IQR 2.5\u0026ndash;8.5] vs. 6 [IQR 4\u0026ndash;9], p\u0026thinsp;=\u0026thinsp;0.41).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe intersection of cancer treatment and FP presents both emotional and clinical challenges. While patients understandably prioritize survival, it is essential that oncologists and fertility specialists convey that parenthood remains a viable option which doesn\u0026rsquo;t necessarily compromise oncologic outcome[14, 15]. Beyond offering the possibility of future motherhood, FP can also provide a significant psychological benefit, serving as a source of hope and empowerment [16]. For breast cancer patients scheduled to receive adjuvant chemotherapy, integrating FP into the treatment timeline is generally straightforward. FP is typically performed after the initial oncologic intervention\u0026mdash;surgery\u0026mdash;and therefore does not affect the timing of that intervention or delay the overall oncologic treatment. However, for patients undergoing NAC, the scenario is more complex, as the timing and extent of FP may ultimately postpone the start of first oncologic treatment.\u003c/p\u003e\n\u003cp\u003eIn this study of 130 young breast cancer patients undergoing COS prior to chemotherapy, the time to first therapeutic intervention was only slightly longer in the neoadjuvant setting. Chemotherapy was initiated after a median of 45 days after diagnosis in the neoadjuvant group, whereas surgery was performed after a median of 41 days from diagnosis in those treated with adjuvant chemotherapy. Both time frames fall well within the recommended period for initiating the cancer therapy after diagnosis (6\u0026ndash;8 weeks) and are unlikely to impair oncologic outcomes [17]. Previous studies have primarily examined treatment timelines in the context of neoadjuvant chemotherapy, reporting a time lapse of approximately 40 days between cancer diagnosis and the initiation of NAC [18\u0026ndash;21] a finding consistent with our results\u003c/p\u003e\n\u003cp\u003eThe initiation of neoadjuvant chemotherapy after a median of 45 days in the current study was made possible through expedited management, as reflected by significantly shorter intervals from diagnosis to FP consultation and stimulation. In comparison, patients receiving adjuvant chemotherapy reached first intervention (surgery) within a similar timeframe, but without the need for such an accelerated coordination, since chemotherapy followed surgery rather than preceding it. The avoidance of delays in initiating stimulation was further facilitated by the liberal use of the random-start stimulation protocol, which allowed for the immediate initiation of controlled ovarian stimulation (COS), regardless of the timing within the menstrual cycle. This approach potentially reduced the overall FP timeline by 2\u0026ndash;4 weeks, while maintaining oocyte retrieval numbers, mature oocyte yield, and fertilization rates [22, 23]. Our findings are consistent with previous studies, which also demonstrate that using the random-start protocol for FP does not cause delays in planned oncologic treatment [19, 20].\u003c/p\u003e\n\u003cp\u003eIt is noteworthy that most patients in the AC group, initiated COS only after surgery, thereby missing the opportunity to utilize the time available between diagnosis and surgery for fertility preservation. This pattern suggests a more \u0026ldquo;laid-back\u0026rdquo; approach to management in the adjuvant setting. However, it also highlights that, conceptually, patients in the AC group could have undergone additional COS cycles had FP been initiated earlier. Still, more than half of the AC group were able to complete more than one stimulation cycle, in contrast to the majority of NAC patients, who underwent only a single cycle. Despite this, both groups ultimately stored a similar cumulative number of oocytes or embryos by the end of the FP process. This outcome may be attributed to the first stimulation cycle, during which the NAC group yielded a significantly higher number of mature (MII) oocytes (11 vs. 8, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.024), despite a comparable number of retrieved oocytes. The higher MII yield in the NAC group may be explained by the type of final oocyte maturation trigger. The NAC group more frequently received a GnRH agonist or dual trigger. Among the possible advantages of GnRH agonist for ovulation triggering is the endogenous surge of FSH. The latter has been reported to have several important roles in ovulation and oocyte maturation, leading to improved maturation rate. Indeed, in a univariate linear regression model of the current cohort, GnRH agonist or dual trigger use was positively associated with MII oocyte number [24\u0026ndash;26]. As shown in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e, adjusting for trigger type in multivariate analysis rendered the association between chemotherapy type and MII oocyte number non-significant.\u003c/p\u003e\n\u003cp\u003eSeveral oncologic variables have previously been shown to influence COS outcomes in breast cancer patients. Specifically, hormone receptor\u0026ndash;positive status has been associated with a higher number of retrieved [27] and mature oocytes [28]. In our cohort, patients treated with adjuvant chemotherapy were more frequently diagnosed with hormone receptor\u0026ndash;positive tumors. However, no association was observed between hormone receptor status and MII oocyte yield (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e), suggesting that receptor profile could not account for the differences in oocyte yield seen between treatment groups. Few studies have also explored the potential impact of tumor burden on oocyte retrieval outcomes. One study found that a higher cancer grade was associated with a lower baseline AFC and a greater need for gonadotropin during ovarian stimulation [29]. Nonetheless, neither cancer stage nor grade appeared to affect the number of oocytes retrieved or MII oocytes obtained [29, 30]. Similarly, as shown in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e, MII oocyte yield in the current study was not associated with cancer grade, stage, or lymph node involvement. Thus, aside from the difference in ovulation trigger, no clear explanation was identified for the observed difference in MII oocyte yield between the groups.\u003c/p\u003e\n\u003cp\u003eOur study expands current knowledge by offering a broader perspective on both oncologic and reproductive aspects of FP prior to NAC. By adjusting for oncologic and stimulation-related variables, we were able to effectively demonstrate the non-inferiority of FP in the neoadjuvant setting, while also highlighting the feasibility of meeting established oncologic quality standards. Nonetheless, several limitations should be acknowledged. Most notably, the retrospective design of the study poses inherent limitations. Additionally, because our data were drawn from an IVF clinic database, we were only able to include patients who ultimately elected to undergo FP, thus excluding potentially valuable information about those who chose not to pursue FP. Finally, long-term reproductive outcomes, including utilization of stored gametes or embryos and post-treatment pregnancy rates, were not assessed.\u003c/p\u003e\n\u003cp\u003eIn conclusion, this study supports the feasibility of COS for FP prior to NAC, specifically with the use of random start COS with GnRH-a or Dural trigger. We could demonstrate that neither treatment timelines nor fertility FP outcomes are compromised compared to the more flexible context of performing FP in the adjuvant setting. The decision to pursue FP should not be determined solely by the timing of planned chemotherapy. Rather, timely coordination between oncology and fertility teams is key to facilitating appropriate and effective care.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eMS- conception, design, Interpretation of data, writing of manuscriptCB- acquisition of data, statistical analysisMS- statistical analysis, preparation of tablesJH- Interpretation of data, article revisionTS- Interpretation of data, article revision AA- acquisition of data, preparation of tablesDM- conception and design, Interpretation of data, article revisionRO- conception and design, Interpretation of data, article revision\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eXia, C., et al., \u003cem\u003eGlobal evolution of breast cancer incidence in childbearing-age women aged 15-49 years: a 30-year analysis.\u003c/em\u003e J Cancer Res Clin Oncol, 2025. \u003cstrong\u003e151\u003c/strong\u003e(2): p. 75.\u003c/li\u003e\n\u003cli\u003eXu, S., et al., \u003cem\u003eBreast Cancer Incidence Among US Women Aged 20 to 49 Years by Race, Stage, and Hormone Receptor Status.\u003c/em\u003e JAMA Netw Open, 2024. \u003cstrong\u003e7\u003c/strong\u003e(1): p. e2353331.\u003c/li\u003e\n\u003cli\u003eAzim, H.A., Jr., et al., \u003cem\u003eElucidating prognosis and biology of breast cancer arising in young women using gene expression profiling.\u003c/em\u003e Clin Cancer Res, 2012. \u003cstrong\u003e18\u003c/strong\u003e(5): p. 1341-51.\u003c/li\u003e\n\u003cli\u003eChollet-Hinton, L., et al., \u003cem\u003eBreast cancer biologic and etiologic heterogeneity by young age and menopausal status in the Carolina Breast Cancer Study: a case-control study.\u003c/em\u003e Breast Cancer Res, 2016. \u003cstrong\u003e18\u003c/strong\u003e(1): p. 79.\u003c/li\u003e\n\u003cli\u003eGraham, E., et al., \u003cem\u003eYoung Age as a Predictor of Chemotherapy Recommendation and Treatment in Breast Cancer: A National Cancer Database Study.\u003c/em\u003e J Surg Res, 2024. \u003cstrong\u003e296\u003c/strong\u003e: p. 155-164.\u003c/li\u003e\n\u003cli\u003ePaluch-Shimon, S., et al., \u003cem\u003eESO-ESMO fifth international consensus guidelines for breast cancer in young women (BCY5).\u003c/em\u003e Ann Oncol, 2022. \u003cstrong\u003e33\u003c/strong\u003e(11): p. 1097-1118.\u003c/li\u003e\n\u003cli\u003eGanz, P.A., J.E. Bower, and A.L. Stanton, \u003cem\u003eSpecial Issues in Younger Women with Breast Cancer.\u003c/em\u003e Adv Exp Med Biol, 2015. \u003cstrong\u003e862\u003c/strong\u003e: p. 9-21.\u003c/li\u003e\n\u003cli\u003eChung, K., et al., \u003cem\u003eEmergency IVF versus ovarian tissue cryopreservation: decision making in fertility preservation for female cancer patients.\u003c/em\u003e Fertil Steril, 2013. \u003cstrong\u003e99\u003c/strong\u003e(6): p. 1534-42.\u003c/li\u003e\n\u003cli\u003eJackson, I., et al., \u003cem\u003eTreatment Patterns, Trends, and Outcomes of Neoadjuvant Chemotherapy Use Among Patients With Early-Stage Invasive Triple-Negative Breast Cancer.\u003c/em\u003e JCO Oncol Pract, 2025: p. OP2400871.\u003c/li\u003e\n\u003cli\u003eGraham, P.J., et al., \u003cem\u003eNeoadjuvant Chemotherapy for Breast Cancer, Is Practice Changing? A Population-Based Review of Current Surgical Trends.\u003c/em\u003e Ann Surg Oncol, 2015. \u003cstrong\u003e22\u003c/strong\u003e(10): p. 3376-82.\u003c/li\u003e\n\u003cli\u003eHershlag, A., C. Mullin, and S.L. Bristow, \u003cem\u003eIs Fertility Preservation Feasible and Safe With Neoadjuvant Therapy for Breast Cancer?\u003c/em\u003e JCO Glob Oncol, 2020. \u003cstrong\u003e6\u003c/strong\u003e: p. 356-359.\u003c/li\u003e\n\u003cli\u003eKappy, M., et al., \u003cem\u003eFertility preservation for cancer patients: treatment gaps and considerations in patients\u0026apos; choices.\u003c/em\u003e Arch Gynecol Obstet, 2021. \u003cstrong\u003e303\u003c/strong\u003e(6): p. 1617-1623.\u003c/li\u003e\n\u003cli\u003eKim, J., et al., \u003cem\u003eWhich patients pursue fertility preservation treatments? A multicenter analysis of the predictors of fertility preservation in women with breast cancer.\u003c/em\u003e Fertil Steril, 2012. \u003cstrong\u003e97\u003c/strong\u003e(3): p. 671-6.\u003c/li\u003e\n\u003cli\u003eAnderson, R.A., et al., \u003cem\u003eSurvival after breast cancer in women with a subsequent live birth: Influence of age at diagnosis and interval to subsequent pregnancy.\u003c/em\u003e Eur J Cancer, 2022. \u003cstrong\u003e173\u003c/strong\u003e: p. 113-122.\u003c/li\u003e\n\u003cli\u003ePartridge, A.H., et al., \u003cem\u003eInterrupting Endocrine Therapy to Attempt Pregnancy after Breast Cancer.\u003c/em\u003e N Engl J Med, 2023. \u003cstrong\u003e388\u003c/strong\u003e(18): p. 1645-1656.\u003c/li\u003e\n\u003cli\u003ePoorvu, P.D., et al., \u003cem\u003ePregnancy after breast cancer: Results from a prospective cohort of young women with breast cancer.\u003c/em\u003e Cancer, 2021. \u003cstrong\u003e127\u003c/strong\u003e(7): p. 1021-1028.\u003c/li\u003e\n\u003cli\u003eRubio, I.T., et al., \u003cem\u003eEUSOMA quality indicators for non-metastatic breast cancer: An update.\u003c/em\u003e Eur J Cancer, 2024. \u003cstrong\u003e198\u003c/strong\u003e: p. 113500.\u003c/li\u003e\n\u003cli\u003eSellami, I., et al., \u003cem\u003eOocyte vitrification for fertility preservation following COS does not delay the initiation of neoadjuvant chemotherapy for breast cancer compared to IVM.\u003c/em\u003e J Assist Reprod Genet, 2023. \u003cstrong\u003e40\u003c/strong\u003e(3): p. 473-480.\u003c/li\u003e\n\u003cli\u003eLetourneau, J.M., et al., \u003cem\u003eRandom start ovarian stimulation for fertility preservation appears unlikely to delay initiation of neoadjuvant chemotherapy for breast cancer.\u003c/em\u003e Hum Reprod, 2017. \u003cstrong\u003e32\u003c/strong\u003e(10): p. 2123-2129.\u003c/li\u003e\n\u003cli\u003eChien, A.J., et al., \u003cem\u003eFertility preservation with ovarian stimulation and time to treatment in women with stage II-III breast cancer receiving neoadjuvant therapy.\u003c/em\u003e Breast Cancer Res Treat, 2017. \u003cstrong\u003e165\u003c/strong\u003e(1): p. 151-159.\u003c/li\u003e\n\u003cli\u003eShapira, M., et al., \u003cem\u003eLong-term safety of controlled ovarian stimulation for fertility preservation before chemotherapy treatment in patients with breast cancer.\u003c/em\u003e Fertil Steril, 2025. \u003cstrong\u003e123\u003c/strong\u003e(3): p. 477-487.\u003c/li\u003e\n\u003cli\u003eMarklund, A., et al., \u003cem\u003eEfficacy and safety of controlled ovarian stimulation using GnRH antagonist protocols for emergency fertility preservation in young women with breast cancer-a prospective nationwide Swedish multicenter study.\u003c/em\u003e Hum Reprod, 2020. \u003cstrong\u003e35\u003c/strong\u003e(4): p. 929-938.\u003c/li\u003e\n\u003cli\u003eEsmaeilian, Y., et al., \u003cem\u003eIVF characteristics and the molecular luteal features of random start IVF cycles are not different from conventional cycles in cancer patients.\u003c/em\u003e Hum Reprod, 2023. \u003cstrong\u003e38\u003c/strong\u003e(1): p. 113-124.\u003c/li\u003e\n\u003cli\u003eBen-Haroush, A., et al., \u003cem\u003eDoes \u0026apos;Dual Trigger\u0026apos; Increase Oocyte Maturation Rate?\u003c/em\u003e J Obstet Gynaecol, 2020. \u003cstrong\u003e40\u003c/strong\u003e(6): p. 860-862.\u003c/li\u003e\n\u003cli\u003eHaas, J., et al., \u003cem\u003eGnRH agonist and hCG (dual trigger) versus hCG trigger for final follicular maturation: a double-blinded, randomized controlled study.\u003c/em\u003e Hum Reprod, 2020. \u003cstrong\u003e35\u003c/strong\u003e(7): p. 1648-1654.\u003c/li\u003e\n\u003cli\u003eOrvieto, R., \u003cem\u003eTriggering final follicular maturation for IVF cycles.\u003c/em\u003e Reprod Biol Endocrinol, 2025. \u003cstrong\u003e23\u003c/strong\u003e(Suppl 1): p. 12.\u003c/li\u003e\n\u003cli\u003eSii, S., et al., \u003cem\u003eControlled ovarian hyperstimulation in breast cancer patients: Does oestrogen receptor status make a difference?\u003c/em\u003e Aust N Z J Obstet Gynaecol, 2023. \u003cstrong\u003e63\u003c/strong\u003e(6): p. 774-779.\u003c/li\u003e\n\u003cli\u003eBalayla, J., et al., \u003cem\u003eOutcomes of ovarian stimulation and fertility preservation in breast cancer patients with different hormonal receptor profiles.\u003c/em\u003e J Assist Reprod Genet, 2020. \u003cstrong\u003e37\u003c/strong\u003e(4): p. 913-921.\u003c/li\u003e\n\u003cli\u003eCioffi, R., et al., \u003cem\u003eDo stage and grade of malignancy impact fertility preservation in breast cancer patients?\u003c/em\u003e J Gynecol Obstet Hum Reprod, 2021. \u003cstrong\u003e50\u003c/strong\u003e(10): p. 102215.\u003c/li\u003e\n\u003cli\u003eWald, K., et al., \u003cem\u003eBreast cancer grade and stage do not affect fertility preservation outcomes.\u003c/em\u003e J Assist Reprod Genet, 2022. \u003cstrong\u003e39\u003c/strong\u003e(5): p. 1155-1161.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003e\u0026ndash; Baseline and tumor characteristics\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAC group (n\u0026thinsp;=\u0026thinsp;43)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNAC group (n\u0026thinsp;=\u0026thinsp;70)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge\u003c/strong\u003e, years (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33.07\u0026thinsp;\u0026plusmn;\u0026thinsp;4.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32.37\u0026thinsp;\u0026plusmn;\u0026thinsp;4.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.43\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003eMarital status\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSingle, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21 (48.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32 (45.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003e0.39\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMarried, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22 (51.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35 (50)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDivorced, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (4.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eNulliparity (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18 (41.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37 (52.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.58\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eBMI\u003c/strong\u003e, kg/m\u003csup\u003e2\u003c/sup\u003e (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22.29\u0026thinsp;\u0026plusmn;\u0026thinsp;3.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22.74\u0026thinsp;\u0026plusmn;\u0026thinsp;3.21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.58\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eBRCA positive (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17 (50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25 (41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.55\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eHormone receptor positive (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27 (62.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e31 (44.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eHer 2 positive(%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (11.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26 (37.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003eKi67\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (7.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003e0.22\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11 (26.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11 (16.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (7.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e55 (80.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003eGrade\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19 (44.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16 (26.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24 (55.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e45 (73.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAxillary lymph nodes involvement (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13 (30.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e43 (61.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003eStage\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eI (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19 (44.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (4.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eII (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20 (46.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e47 (67.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIII (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (9.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20 (28.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eBaseline and tumor features of breast cancer patients who underwent fertility preservation prior to neoadjuvant (NAC) or adjuvant (AC) chemotherapy. Values are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD or n (%). NAC\u0026thinsp;=\u0026thinsp;neoadjuvant chemotherapy; AC\u0026thinsp;=\u0026thinsp;adjuvant chemotherapy; BMI\u0026thinsp;=\u0026thinsp;body mass index; BRCA\u0026thinsp;=\u0026thinsp;breast cancer gene; HER2\u0026thinsp;=\u0026thinsp;human epidermal growth factor receptor 2.\u003c/p\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eFirst controlled ovarian stimulation characteristics and outcomes by chemotherapy setting\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAC group (n\u0026thinsp;=\u0026thinsp;43)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNAC group (n\u0026thinsp;=\u0026thinsp;70)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003eStimulation start timing\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEarly follicular (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e31 (72.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e42 (60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003e0.274\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLate follicular (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (2.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (8.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLuteal (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11 (25.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22 (31.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eStimulation days\u003c/strong\u003e (median [Q1, Q3])\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 [9, 11]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 [9, 12]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.421\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eGonadotropins initial dose\u003c/strong\u003e, IU (median [Q1, Q3])\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e300 [225, 350]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e300 [225, 350]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.497\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eGonadotropins total dose\u003c/strong\u003e, IU (median [Q1, Q3])\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2950 [2100, 3512]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3200 [2350, 4050]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.090\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eTamoxifen/letrozole co-treatment (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22 (51.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36 (51.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.978\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003eOvulation Trigger\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ehCG (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGnRH-a/Dual (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36 (84)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e67 (96)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eMaximal E2 levels\u003c/strong\u003e, pmol/L (median [Q1, Q3])\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6828 [4192, 11524]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e48617 [5119, 14674]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.19\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eRetrieved oocytes\u003c/strong\u003e (median [Q1, Q3])\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13 [6, 18]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14 [8.75, 24]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eMII oocytes\u003c/strong\u003e (median [Q1, Q3])\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 [4, 12.5]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11 [5.5, 18]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eFertilization rate\u003c/strong\u003e (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e70.1\u0026thinsp;\u0026plusmn;\u0026thinsp;20.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e76.43\u0026thinsp;\u0026plusmn;\u0026thinsp;16.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003cp\u003eFirst-cycle ovarian stimulation characteristics and outcomes for patients undergoing fertility preservation prior to neoadjuvant (NAC) or adjuvant (AC) chemotherapy. COS\u0026thinsp;=\u0026thinsp;controlled ovarian stimulation; GnRH-a\u0026thinsp;=\u0026thinsp;gonadotropin-releasing hormone agonist; hCG\u0026thinsp;=\u0026thinsp;human chorionic gonadotropin; MII\u0026thinsp;=\u0026thinsp;metaphase II oocytes; E2\u0026thinsp;=\u0026thinsp;estradiol; IU\u0026thinsp;=\u0026thinsp;international units.\u003c/p\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003ctable id=\"Tab3\" border=\"1\" class=\"fr-table-selection-hover\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003ePredictors of mature oocyte yield: linear regression models\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eUnivariate Analysis\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eMultivariate Analysis\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026beta;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026beta;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNAC vs AC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCumulative dose\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.0004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTrigger (hCG vs GnRH-a/Dual)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-7.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-6.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHer 2 (positive vs negative)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-1.2370\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.059\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.549\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHormone receptors (positive vs negative)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.4722\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.756\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.756\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGrade (3 vs 2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.1319\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.841\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.943\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStage (3 vs 2/1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.4710\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.209\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.832\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLymph node (positive vs negative)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.4375\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.743\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.165\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003cp\u003eUnivariate and multivariate linear regression analyses evaluating predictors of the number of mature (MII) oocytes retrieved during the first controlled ovarian stimulation cycle. Abbreviations: \u0026beta;\u0026thinsp;=\u0026thinsp;regression coefficient; SE\u0026thinsp;=\u0026thinsp;standard error; NAC\u0026thinsp;=\u0026thinsp;neoadjuvant chemotherapy; AC\u0026thinsp;=\u0026thinsp;adjuvant chemotherapy; GnRH-a\u0026thinsp;=\u0026thinsp;gonadotropin-releasing hormone agonist.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Fertility preservation, breast cancer, neoadjuvant chemotherapy, random-start","lastPublishedDoi":"10.21203/rs.3.rs-6874219/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6874219/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose: \u003c/strong\u003eTo\u003cstrong\u003e \u003c/strong\u003ecompare the time to initiation of first oncologic treatment and the outcomes of controlled ovarian stimulation (COS) in breast cancer patients undergoing fertility preservation (FP) in the neoadjuvant chemotherapy (NAC) versus adjuvant chemotherapy (AC) treatment settings.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e A retrospective cohort study involving patients with stage 1-3 breast cancer treated with NAC/AC, who underwent FP with random-start COS, between 2015-2023. Baseline, oncologic and COS characteristics and outcomes were collected. Time points related to cancer diagnosis, FP, and first oncologic intervention (surgery or chemotherapy) were calculated.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003e70\u003cstrong\u003e \u003c/strong\u003eNAC-treated patients were compared to 42 AC-treated patients. Groups were similar in terms of age, marital status, parity and BMI. NAC-treated patients had more advanced disease, more often with lymph node involvement. Median time from diagnosis to FP consult (17 vs 30 days) and to stimulation start (22 vs 59 days) was significantly shorter for NAC-treated patients. Median time from diagnosis to first oncologic intervention was slightly longer for NAC-treated patients (45 vs 41 days, p\u0026lt;0.05). Stimulation characteristics were comparable apart from a less frequent use of hCG trigger among NAC-treated patients (4% vs 16%, p\u0026lt;0.05). First stimulation cycle outcomes such as peak E2 levels, number of retrieved oocytes and fertilization rate were similar, though median number of M2 oocytes was higher in NAC- treated patients (11 vs 8, p\u0026lt;0.05).\u003c/p\u003e\n\u003cp\u003e\u003cu\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e\u003c/u\u003e\u003cstrong\u003e \u003c/strong\u003eExpedited patient care at the neoadjuvant setting led to a statistically significant, yet clinically minimal, delay of cancer therapy. Neither oncologic treatment timelines nor FP outcomes were compromised in the NAC setting.\u003c/p\u003e","manuscriptTitle":"Fertility Preservation Using Controlled Ovarian Stimulation in Breast Cancer: A Comparative Study of Neoadjuvant and Adjuvant Settings","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-02 09:45:39","doi":"10.21203/rs.3.rs-6874219/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ac66ef2c-24b0-46a6-9ab2-97210610ed40","owner":[],"postedDate":"July 2nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-09-01T00:53:19+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-02 09:45:39","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6874219","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6874219","identity":"rs-6874219","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}