Demeestere, Isabelle

Treatment-induced ovarian function loss is a significant concern for many young patients with breast cancer. Accurately predicting this risk is crucial for counselling young patients and informing their fertility-related decision-making. However, current risk prediction models for treatment-related ovarian function loss have limitations. To provide a broader representation of patient cohorts and improve feature selection, we combined retrospective data from six datasets within the FoRECAsT (Infertility after Cancer Predictor) databank, including 2679 pre-menopausal women diagnosed with breast cancer. This combined dataset presented notable missingness, prompting us to employ cross imputation using the k-nearest neighbours (KNN) machine learning (ML) algorithm. Employing Lasso regression, we developed an ML model to forecast the risk of treatment-related amenorrhea as a surrogate marker of ovarian function loss at 12 months after starting chemotherapy. Our model identified 20 variables significantly associated with risk of developing amenorrhea. Internal validation resulted in an area under the receiver operating characteristic curve (AUC) of 0.820 (95% CI: 0.817–0.823), while external validation with another dataset demonstrated an AUC of 0.743 (95% CI: 0.666–0.818). A cutoff of 0.20 was chosen to achieve higher sensitivity in validation, as false negatives—patients incorrectly classified as likely to regain menses—could miss timely opportunities for fertility preservation if desired. At this threshold, internal validation yielded sensitivity and precision rates of 91.3% and 61.7%, respectively, while external validation showed 92.9% and 60.0%. Leveraging ML methodologies, we not only devised a model for personalised risk prediction of amenorrhea, demonstrating substantial enhancements over existing models but also showcased a robust framework for maximally harnessing available data sources.

PURPOSE We investigated time to pregnancy, efficacy and safety of fertility preservation, and assisted reproductive technologies (ARTs) in women with early hormone receptor–positive breast cancer (BC) desiring future pregnancy. PATIENTS AND METHODS POSITIVE is an international, single-arm, prospective trial, in which 518 women temporarily interrupted adjuvant endocrine therapy to attempt pregnancy. We evaluated menstruation recovery and factors associated with time to pregnancy and investigated if ART use was associated with achieving pregnancy. The cumulative incidence of BC-free interval (BCFI) events was estimated according to the use of ovarian stimulation at diagnosis. The median follow-up was 41 months. RESULTS Two hundred seventy-three patients (53%) reported amenorrhea at enrollment, of whom 94% resumed menses within 12 months. Among 497 patients evaluable for pregnancy, 368 (74%) reported at least one pregnancy. Young age was the main factor associated with shorter time to pregnancy with cumulative incidences of pregnancy by 1 year of 63.5%, 54.3%, and 37.7% for patients age <35, 35-39, and 40-42 years, respectively. One hundred and seventy-nine patients (36%) had embryo/oocyte cryopreservation at diagnosis, of whom 68 reported embryo transfer after enrollment. Cryopreserved embryo transfer was the only ART associated with higher chance of pregnancy (odds ratio, 2.41 [95% CI, 1.75 to 4.95]). The cumulative incidence of BCFI events at 3 years was similar for women who underwent ovarian stimulation for cryopreservation at diagnosis, 9.7% (95% CI, 6.0 to 15.4), compared with those who did not, 8.7% (95% CI, 6.0 to 12.5). CONCLUSION In POSITIVE, fertility preservation using ovarian stimulation was not associated with short-term detrimental impact on cancer prognosis. Pregnancy rates were highest among those who underwent embryo/oocyte cryopreservation followed by embryo transfer.

Abstract Background: The POSITIVE trial recently demonstrated that temporary interruption of ET to attempt pregnancy does not increase the short-term risk of recurrence in pts with hormone receptor-positive (HR+) BC. Yet, uncertainty exists regarding the safety of ovarian stimulation for embryo/oocyte cryopreservation to preserve fertility in these pts. In addition, very limited data exist regarding safety and efficiency of ART to achieve pregnancy after ET interruption. Methods: POSITIVE is an international, single-arm, prospective trial that enrolled pts ≤ 42 years with stage I-III HR+ BC who had already received 18-30 months of ET prior to enrollment. The use of ART was a predefined 2ry endpoint. We evaluated factors associated with time to pregnancy in a Fine and Gray competing risks model, which included chemotherapy (chemo) ± GnRH analogue (GnRHa), age, prior ET, prior birth, and menstrual status at enrollment. The cumulative incidence of pregnancy at 12 months from enrollment by age was estimated controlling for competing risks. We performed a logistic regression model to evaluate whether ART use was associated with achieving pregnancy, adjusting for age, receipt of chemo ± GnRHa. The cumulative incidence of BCFI events was estimated according to whether or not ovarian stimulation for cryopreservation was performed at diagnosis and prior to enrollment. BC-free interval (BCFI) was defined as the time from enrollment until the first BC event (invasive local, regional, or distant recurrence or contralateral disease). A 24-month landmark analysis was performed to investigate the safety of ART use after enrollment. Median follow-up was 41 months. Results: 497 out of 516 included pts (96%) were followed for at least 6 months and were evaluable for pregnancy status. 368 out of 497 evaluable pts (74%) reported at least one pregnancy. In a multivariable model, young age was the only factor associated with shorter time to pregnancy. The cumulative incidence of pregnancy at 12 months was 64%, 54% and 38% for pts aged &lt; 35, 35-39 and 40-42 years, respectively. 179 pts (36.0%) had undergone ovarian stimulation for embryo/oocyte cryopreservation at diagnosis and prior to enrollment, of whom 68 (37.9%) reported cryopreserved embryo transfer after enrollment. 215 pts (43.3%) reported using any ART after enrollment, of whom 80 (37.2%) underwent ovarian stimulation for in-vitro fertilization (FIVET) or intracytoplasmic sperm injection (ICSI). Other ART used included clomiphene (n=19), intrauterine insemination (n=37) and egg donation (n=17). Pregnancy rates were 82.4% and 67.5% for women who underwent cryopreserved embryo transfer and FIVET/ICSI, respectively. In a multivariate model, cryopreserved embryo transfer was the only ART independently associated with a higher chance of pregnancy (OR:2.41, 95% CI: 1.75-4.95). The cumulative incidence of BCFI events at 3 years was similar for women who underwent ovarian stimulation for cryopreservation at diagnosis and before enrollment, 9.7% (95% CI: 6.0-15.4%), and those who did not, 8.7% (95% CI: 6.0-12.5%). A 24-month landmark analysis showed no impact of ovarian stimulation for FIVET/ICSI after enrollment on BCFI. Conclusions: This is the largest prospective study to investigate fertility preservation and ART in pts with HR+ BC. Young age was the main factor associated with shorter time to pregnancy. Embryo/oocyte cryopreservation at BC diagnosis followed by embryo transfer after ET interruption was the only approach associated with an increased chance of pregnancy. Ovarian stimulation either at BC diagnosis for embryo/oocyte cryopreservation or after enrollment to POSITIVE for FIVET/ICSI did not appear to impact prognosis in the short term. These data are of paramount importance for oncofertility counselling of young BC pts. Citation Format: Hatem Azim, Samuel Niman, Ann Partridge, Isabelle Demeestere, Monica Ruggeri, Marco Colleoni, Cristina Saura, Chikako Shimizu, Anna Saetersdal, Judith Kroep, Audrey Mailliez, Ellen Warner, Virginia Borges, Frédéric Amant, Andrea Gombos, Akemi Kataoka, Christine Rousset-Jablonski, Simona Borstnar, Junko Takei, Jeong Eon Lee, Janice Walshe, Manuel Ruíz - Borrego, Halle Moore, Christobel Saunders, Vesna Bjelic-Radisic, Snezana Susnjar, Fatima Cardoso, Natalie Klar, Tanya Spanic, Kathryn Ruddy, Martine Piccart, Larissa Korde, Aron Goldhirsch, Richard Gelber, Olivia Pagani, Fedro Alessandro Peccatori. Fertility preservation and assisted reproductive technologies (ART) in breast cancer (BC) patients (pts) interrupting endocrine therapy (ET) to attempt pregnancy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS02-11.

Background: The potential gonadotoxicity of anti-HER2 agents remains largely unknown, and limited, conflicting evidence exists for taxanes. Antimüllerian hormone (AMH) is an established biomarker of ovarian reserve that may aid in quantifying anticancer treatment–induced gonadotoxicity. Patients and Methods: The present biomarker analysis of the randomized phase III neoadjuvant NeoALTTO trial included premenopausal women aged ≤45 years at diagnosis of HER2-positive early breast cancer with available frozen serum samples at baseline (ie, before anticancer treatments), at week 2 (ie, the “biological window” of anti-HER2 therapy alone), and/or at the time of surgery (ie, after completing paclitaxel + anti-HER2 therapy, before starting adjuvant chemotherapy). Results: The present analysis included 130 patients with a median age of 38 years (interquartile ratio [IQR], age 33–42 years). AMH values at the 3 time points differed significantly (P<.001). At baseline, median AMH levels were 1.29 ng/mL (IQR, 0.56–2.62 ng/mL). At week 2, a small but significant reduction in AMH levels was observed (median, 1.10 ng/mL; IQR, 0.45–2.09 ng/mL; P<.001). At surgery, a larger significant decline in AMH levels was observed (median, 0.01 ng/mL; IQR, 0.01–0.03 ng/mL; P<.001). Although the type of anti-HER2 treatment (trastuzumab and/or lapatinib) did not seem to impact the results, age and pretreatment ovarian reserve had a major influence on treatment-induced gonadotoxicity risk. Conclusions: This NeoALTTO biomarker analysis showed that anti-HER2 therapies alone had limited gonadotoxicity but that the addition of weekly paclitaxel resulted in marked AMH decline with possible negative implications for subsequent ovarian function and fertility.

Abstract Background: Knowledge regarding risk of treatment-induced premature ovarian insufficiency (POI) is crucial for appropriate oncofertility counseling. While the gonadotoxicity of anthracycline- and cyclophosphamide-based chemotherapy (CT) in young breast cancer (BC) patients (pts) is well established, the impact of anti-HER2 agents remains largely unknown and limited conflicting evidence exists for taxanes. Anti-Mullerian hormone (AMH) is an established biomarker of ovarian reserve; its measurements during systemic therapies may aid in diagnosis and prediction of POI. The NeoALTTO trial represented a unique setting to explore the acute gonadotoxicity of anti-HER2 therapy alone and in combination with weekly paclitaxel in pts not previously exposed to any other potentially gonadotoxic anticancer treatment. Methods: NeoALTTO (NCT00553358) is a multicenter, open-label, randomized phase III neoadjuvant trial in HER2-positive early BC pts randomized to receive lapatinib (L), trastuzumab (T), or their combination (L+T) alone for 6 weeks followed by the addition of paclitaxel for 12 weeks before surgery.The present analysis included only premenopausal women aged ≤45 years with available frozen serum samples at baseline (i.e. before administering any anticancer treatment), at week 2 (i.e. “biological window” of anti-HER2 therapy alone) and/or at surgery (i.e. after completion of paclitaxel plus anti-HER2 therapy). Central AMH testing was performed at Erasme Hospital (Brussels, Belgium) with the Roche Elecsys® AMH Plus assay (LoD=0.010 ng/ml). AMH levels during anti-HER2 therapy alone and then combined with paclitaxel were assessed as a measure of treatment impact on ovarian reserve. The impact of different anti-HER2 agents (T and/or L), pts’ age and baseline AMH levels on treatment gonadotoxicity were also investigated. Results: The present analysis included 130 pts with a median age of 38 years (IQR: 33-42 years), of whom 86 (66.2%) were ≤40 years. At baseline, median AMH levels were 1.29 ng/mL (IQR 0.56 - 2.62 ng/mL). At week 2, a small but significant reduction in AMH levels was observed (median value: 1.10 ng/mL, IQR 0.45 - 2.09 ng/mL, p&lt;0.001; median cumulative decrease: -12.5%, IQR -37.6% - 12.4%). At surgery, there was a large significant decline in AMH levels (median value: 0.01 ng/mL, IQR 0.01 - 0.03 ng/mL, p&lt;0.001; median cumulative decrease: -99.9%, IQR -100.0% - -98.7%). Type of anti-HER2 treatment (L vs. L vs. T+L) did not impact the results: there was no significant difference between treatment arms in degree of reduction in AMH levels at week 2 (p=0.763) or at surgery (p=0.700). Age and pre-treatment ovarian reserve had a major impact on treatment-induced gonadotoxicity risk, with a more profound decrease in AMH levels observed for older pts (p&lt;0.001) and those with lower baseline AMH levels (p&lt;0.001). Among pts aged &lt;35 years, there was no significant difference in AMH levels between those with (n=7) or without (n=35) a subsequent pregnancy at baseline (p=0.316), week 2 (p=0.463) or at surgery (p=0.610). Conclusions: This biomarker analysis of the NeoALTTO trial showed for the first time the potential acute gonadal damage induced by anti-HER2 therapies alone and with the addition of weekly paclitaxel. We observed a small but significant reduction in AMH levels during T and/or L alone and then a profound reduction to almost undetectable levels following the addition of weekly paclitaxel, without differences by specific anti-HER2 regimen. Age and pre-treatment AMH levels strongly impacted gonadotoxicity risk. While this analysis is limited by lack of AMH measurement in longer term follow-up, findings have important implications for future research and oncofertility counseling of premenopausal women with HER2-positive BC. Citation Format: Matteo Lambertini, Marcello Ceppi, Richard A. Anderson, David A. Cameron, Marco Bruzzone, Maria Alice Franzoi, Claudia Massarotti, Sarra El-Abed, Yingbo Wang, Christophe Lecocq, Paolo Nuciforo, Rebecca Rolyance, Lajos Pusztai, Joohyuk Sohn, Jacopo Ligato, Maria Maddalena Latocca, Luca Arecco, Barbara Pistilli, Kathryn J. Ruddy, Alberto Ballestrero, Lucia Del Mastro, Fedro A. Peccatori, Ann H. Partridge, Cristina Saura, Michael Untch, Martine Piccart, Serena Di Cosimo, Evandro de Azambuja, Isabelle Demeestere. Impact of anti-HER2 therapy alone and in association with weekly paclitaxel on the ovarian reserve of young women with HER2-positive early breast cancer: Biomarker analysis of the NeoALTTO trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD5-05.

PURPOSE Many patients and physicians remain concerned about the potential detrimental effects of pregnancy after breast cancer (BC) in terms of reproductive outcomes and maternal safety. This systematic review and meta-analysis aimed at providing updated evidence on these topics. METHODS A systematic literature review was conducted to identify studies including patients with a pregnancy after BC (PROSPERO number CRD42020158324). Likelihood of pregnancy after BC, their reproductive outcomes, and maternal safety were assessed. Pooled relative risks, odds ratios (ORs), and hazard ratios (HRs) with 95% CIs were calculated using random effects models. RESULTS Of 6,462 identified records, 39 were included involving 8,093,401 women from the general population and 112,840 patients with BC of whom 7,505 had a pregnancy after diagnosis. BC survivors were significantly less likely to have a subsequent pregnancy compared with the general population (relative risk, 0.40; 95% CI, 0.32 to 0.49). Risks of caesarean section (OR, 1.14; 95% CI, 1.04 to 1.25), low birth weight (OR, 1.50; 95% CI, 1.31 to 1.73), preterm birth (OR, 1.45; 95% CI, 1.11 to 1.88), and small for gestational age (OR, 1.16; 95% CI, 1.01 to 1.33) were significantly higher in BC survivors, particularly in those with previous chemotherapy exposure, compared with the general population. No significantly increased risk of congenital abnormalities or other reproductive complications were observed. Compared to patients with BC without subsequent pregnancy, those with a pregnancy had better disease-free survival (HR, 0.66; 95% CI, 0.49 to 0.89) and overall survival (HR, 0.56; 95% CI, 0.45 to 0.68). Similar results were observed after correcting for potential confounders and irrespective of patient, tumor, and treatment characteristics, pregnancy outcome, and timing of pregnancy. CONCLUSION These results provide reassuring evidence on the safety of conceiving in BC survivors. Patients' pregnancy desire should be considered a crucial component of their survivorship care plan.

Abstract Background: Pregnancy-related issues are a priority for young breast cancer (BC) patients. Increasing evidence has shown that pregnancy after prior BC diagnosis is feasible. Nevertheless, few BC survivors conceive following anticancer treatment completion and many physicians remain concerned about the potentially detrimental effects of pregnancy after BC in terms of fetal/obstetrical outcomes and maternal prognosis. This systematic review and meta-analysis aims at providing updated and solid evidence on these important issues. Methods: A systematic literature review up to January 31, 2020 with no language restriction was conducted to identify studies including patients with a pregnancy after prior BC diagnosis. Chances of pregnancy after BC, fetal and obstetrical outcomes, disease-free survival (DFS) and overall survival (OS) were assessed. Pooled relative risks (RRs), hazard ratios (HRs) or odds ratio (ORs) with 95% confidence intervals (CI) were calculated using the random effects models. The study is registered with the PROSPERO registration number CRD42020158324. Results: Overall, 39 studies were included. Out of the 8,265,713 young women included in these studies, 8,093,401 were from the general population, 57,739 had cancers other than BC, 114,573 had BC. Among the 114,573 BC patients, 7,505 had a pregnancy after BC diagnosis and 107,068 did not. Compared to women from the general population, BC patients had 60% reduced chances of having a pregnancy following anticancer treatment completion (RR 0.40, 95% CI 0.32-0.49). Among other cancer patients, only women with prior cervical cancer had lower pregnancy rates (RR 0.33, 95% CI 0.31-0.35) than BC patients. Compared to the general population, BC survivors had significantly increased risks of low birth weight (OR 1.50, 95% CI 1.31-1.73), small for gestational age (OR 1.16, 95% CI 1.01-1.33), preterm delivery (OR 1.45, 95% CI 1.11-1.88) and caesarean section (OR 1.14, 95% CI 1.04-1.25). No significant increased risk of congenital abnormalities (OR 1.63, 95% CI 0.89-2.98) or other pregnancy or delivery complications (spontaneous or induced abortion, gestosis, antepartum or postpartum hemorrhage) was observed. Prior chemotherapy exposure or short pregnancy interval (defined as &lt;2 or &lt;5 years after BC diagnosis) were not associated with additional increased risk of complications. Pregnancy after BC was not associated with a negative impact on patients’ outcomes. Compared to BC patients without subsequent pregnancy, those with pregnancy after BC had better OS (HR 0.56, 95% CI 0.46-0.67) and DFS (HR 0.73, 95% CI 0.56-0.94). Similar results were observed in the studies correcting for the potential “healthy mother effect” (OS: HR 0.52, 95% CI 0.42-0.65; DFS: HR 0.74, 95% CI 0.58-0.96). No detrimental prognostic effect of pregnancy after BC was observed in patients with hormone-receptor positive disease (DFS: HR 1.10, 95% CI 0.73-1.66), while better outcomes were observed for those with hormone-receptor negative disease (DFS: HR 0.72, 95% CI 0.55-0.95). The safety of pregnancy after BC was observed irrespective of BRCA status, nodal status, previous chemotherapy exposure, pregnancy interval and pregnancy outcomes. Conclusions: This large meta-analysis provides solid evidence on the safety of pregnancy after prior BC diagnosis. The increased risk of fetal and obstetrical complications (but not of congenital abnormalities) calls for ensuring a closer monitoring of these pregnancies. The significantly reduced chances of conceiving as compared to the general population and other cancer patients should raise further awareness on the need to improve the oncofertility counseling of young BC patients wishing to complete their family planning following anticancer treatment completion. Citation Format: Eva Blondeaux, Marta Perachino, Marco Bruzzone, Richard A. Anderson, Evandro De Azambuja, Philip D. Poorvu, Hee Jeong Kim, Cynthia Villarreal-Garza, Barbara Pistilli, Ines Vaz-Luis, Cristina Saura, Kathryn J. Ruddy, Maria Alice Franzoi, Chiara Sertoli, Marcello Ceppi, Hatem A. Azim, Jr., Frederic Amant, Isabelle Demeestere, Lucia Del Mastro, Ann H. Partridge, Olivia Pagani, Fedro A. Peccatori, Matteo Lambertini. Chances of pregnancy after breast cancer, reproductive and disease outcomes: A systematic review and meta-analysis [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS3-09.