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Saura, Cristina

0000-0001-8296-5065

Mayo Clinic

Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.

Citations 8

Imlunestrant, an Oral Selective Estrogen Receptor Degrader, as Monotherapy and in Combination With Targeted Therapy in Estrogen Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer: Phase Ia/Ib EMBER Study
Jhaveri, Komal , Lim, Elgene , Jeselsohn, Rinath , Cynthia, X. , Hamilton, Erika , Osborne, Cynthia R. , Bhave, Manali Ajay, Kaufman, Peter A. , Beck, J. Thaddeus , Manso, Luís , Parajuli, Ritesh , Wang, Hwei-Chung, Tao, Jessica J. , Harnden, Kathleen , Yonemori, Kan , Dhakal, Ajay , Neven, Patrick , Aftimos, Philippe , Pierga, Jean‐Yves , Lu, Yen‐Shen , Larson, Timothy , Jerez, Yolanda , Sohn, Joohyuk , Saura, Cristina , Bardia, Aditya , Sammons, Sarah , Bacchion, Francesca , Li, Yujia , Estrem, Shawn T. , Nguyen, Bastien , Ismail‐Khan, Roohi , Smyth, Lillian M. , Beeram, Muralidhar , Jhaveri, Komal L , Ma, Cynthia , Hamilton, Erika P , Manso Sanchez, Luis , Im, Seock-Ah , Harnden, Kathleen , Yonemori, Kan , Dhakal, Ajay , Neven, Patrick , Aftimos, Philippe , Pierga, Jean-Yves , Lu, Yen-Shen , Larson, Timothy , Sideras, Kostandinos , Sohn, Joohyuk , Kim, Sung-Bae , Saura, Cristina , Bardia, Aditya , Sammons, Sarah L , Li, Yujia , Nguyen, Bastien , Ismail-Khan, Roohi , Smyth, Lillian , Beck, Joseph T , Im, Seock‐Ah , Sideras, Kostandinos , Yuen, Eunice , Rodrik-Outmezguine, Vanessa S.

Journal of Clinical Oncology | September 6, 2024 | Volume: 42 | Issue: 35 | Pages: 4173-4186

10.1200/jco.23.02733 Get It

PURPOSE Imlunestrant is a next-generation oral selective estrogen receptor (ER) degrader designed to deliver continuous ER target inhibition, including in ESR1- mutant breast cancer. This phase Ia/b trial determined the recommended phase II dose (RP2D), safety, pharmacokinetics, and efficacy of imlunestrant, as monotherapy and in combination with targeted therapy, in ER-positive (ER+) advanced breast cancer (ABC) and endometrial endometrioid cancer. The ER+/human epidermal growth factor receptor 2–negative (HER2–) ABC experience is reported here. METHODS An i3+3 dose-escalation design was used, followed by dose expansions of imlunestrant as monotherapy or in combination with abemaciclib with or without aromatase inhibitor (AI), everolimus, or alpelisib. Imlunestrant was administered orally once daily and with the combination partner per label. RESULTS Overall, 262 patients with ER+/HER2– ABC were treated (phase Ia, n = 74; phase Ib, n = 188). Among patients who received imlunestrant monotherapy (n = 114), no dose-limiting toxicities or discontinuations occurred. At the RP2D (400 mg once daily), patients (n = 51) reported grade 1-2 nausea (39.2%), fatigue (39.2%), and diarrhea (29.4%). Patients at RP2D had received previous cyclin-dependent kinase 4/6 inhibitor (CDK4/6i; 92.2%), fulvestrant (41.2%), and chemotherapy (29.4%) for ABC and achieved a median progression-free survival (mPFS) of 7.2 months (95% CI, 3.7 to 8.3). Among patients who received imlunestrant + abemaciclib (n = 42) and imlunestrant + abemaciclib + AI (n = 43), most (69.4%) were treatment-naïve for ABC; all were CDK4/6i-naïve. Patients treated with imlunestrant + everolimus (n = 42)/alpelisib (n = 21) had received previous CDK4/6i (100%), fulvestrant (34.9%), and chemotherapy (17.5%) for ABC. No new safety signals or interactions with partnered drugs were observed. The mPFS was 19.2 months (95% CI, 13.8 to not available) for imlunestrant + abemaciclib and was not reached for imlunestrant + abemaciclib + AI. The mPFS with imlunestrant + everolimus/alpelisib was 15.9 months (95% CI, 11.3 to 19.1)/9.2 months (95% CI, 3.7 to 11.1). Antitumor activity was evident regardless of ESR1 mutation status. CONCLUSION Imlunestrant, as monotherapy or in combination with targeted therapy, had a manageable safety profile with evidence of preliminary antitumor activity in ER+/HER2– ABC.
Fertility Preservation and Assisted Reproduction in Patients With Breast Cancer Interrupting Adjuvant Endocrine Therapy to Attempt Pregnancy
Azim, Hatem A. , Niman, Samuel M. , Partridge, Ann H. , Demeestere, Isabelle , Ruggeri, Monica , Colleoni, Marco , Saura, Cristina , Shimizu, Chikako , Sætersdal, Anna Barbro, Kroep, Judith R. , Mailliez, Audrey , Gombos, Andrea, Kataoka, Akemi, Rousset‐Jablonski, Christine , Borštnar, Simona , Takei, Junko , Walshe, Janice M. , Ruíz-Borrego, Manuel , Bjelic‐Radisic, Vesna , Klar, Natalie , Španić, Tanja, Ruddy, Kathryn J. , Piccart, Martine , Korde, Larissa A. , Goldhirsch, Aron, Gelber, Richard D. , Pagani, Olivia , Borges, Virginia F , Amant, Frederic , Kataoka, Akemi , Rousset-Jablonski, Christine , Takei, Junko , Lee, Jeong Eon , Walshe, Janice M , Ruíz-Borrego, Manuel , Moore, Halle C F , Saunders, Christobel , Susnjar, Snezana , Cardoso, Fatima , Klar, Natalie J , Ruddy, Kathryn J , Piccart, Martine , Goldhirsch, Aron , Gelber, Richard D , Peccatori, Fedro A , Partridge, Ann H , Demeestere, Isabelle , Colleoni, Marco , Saura, Cristina , Warner, Ellen , Borges, Virginia F. , Amant, Frédéric , Gombos, Andrea , Moore, Halle C. F. , Saunders, Christobel , Cardoso, Fátima

Journal of Clinical Oncology | May 29, 2024 | Volume: 42 | Issue: 23 | Pages: 2822-2832

10.1200/jco.23.02292 Get It

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 GS02-11: Fertility preservation and assisted reproductive technologies (ART) in breast cancer (BC) patients (pts) interrupting endocrine therapy (ET) to attempt pregnancy
Azim, Hatem A. , Niman, Samuel, Ruggeri, Monica , Saura, Cristina , Shimizu, Chikako , Sætersdal, Anna Barbro, Mailliez, Audrey , Gombos, Andrea, Kataoka, Akemi, Borštnar, Simona , Takei, Junko , Lee, Jeong Eon, Borrego, Manuel Ruíz, Bjelic‐Radisic, Vesna , Klar, Natalie , Spanic, Tanya, Ruddy, Kathryn, Piccart, Martine , Korde, Larissa A. , Goldhirsch, Aron, Gelber, Richard D. , Pagani, Olivia , Klar, Natalie J , Saura, Cristina , Partridge, Ann H. , Demeestere, Isabelle , Colleoni, Marco , Kroep, Judith R. , Warner, Ellen , Borges, Virginia F. , Amant, Frédéric , Gombos, Andrea , Rousset‐Jablonski, Christine , Lee, Jeong Eon, Walshe, Janice M. , Moore, Halle C. F. , Saunders, Christobel , Susnjar, Snezana , Cardoso, Fátima , Ruddy, Kathryn J. , Peccatori, Fedro A

Cancer Research | May 2, 2024 | Volume: 84 | Issue: 9_Supplement | Pages: GS02-11-GS02-11

10.1158/1538-7445.sabcs23-gs02-11 Get It

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.
Abstract GS4-09: Pregnancy Outcome and Safety of Interrupting Therapy for women with endocrine responsIVE breast cancer: Primary Results from the POSITIVE Trial (IBCSG 48-14/BIG 8-13)
Partridge, Ann, Pagani, Olivia , Niman, Samuel M. , Ruggeri, Monica , Azim, Hatem A. , Saura, Cristina , Shimizu, Chikako , Sætersdal, Anna Barbro, Mailliez, Audrey , Gombos, Andrea , Kataoka, Akemi, Borštnar, Simona, Takei, Junko , Borrego, Manuel Ruíz, Bjelic‐Radisic, Vesna , Vilarino, Teresa Ferreiro, Ribi, Karin, Ruddy, Kathryn, Piccart, Martine , Korde, Larissa A. , Goldhirsch, Aron, Gelber, Richard D. , Saura, Cristina , Peccatori, Fedro A , Colleoni, Marco , Kroep, Judith R. , Warner, Ellen , Borges, Virginia F. , Amant, Frédéric , Rousset‐Jablonski, Christine , Lee, Jeong Eon , Walshe, Janice M. , Moore, Halle C. F. , Saunders, Christobel , Susnjar, Snezana , Cardoso, Fátima , Smith, Karen L. , Vilarino, Teresa Ferreiro, Ruddy, Kathryn J. , El-Abed, Sarra

Cancer Research | March 2, 2023 | Volume: 83 | Issue: 5_Supplement | Pages: GS4-09-GS4-09

10.1158/1538-7445.sabcs22-gs4-09 Get It

Abstract Background: Pregnancy after breast cancer (BC) is of substantial importance for many young women at diagnosis and during follow-up. BC treatment including standard endocrine therapy (ET) (5-10 years) may reduce ovarian reserve and the chances of subsequent successful pregnancy, given conception is contraindicated during ET. A temporary interruption of ET to attempt and carry a pregnancy in this population has never been prospectively studied. Methods: POSITIVE is a single-arm, prospective, investigator-initiated, international trial evaluating the safety and pregnancy outcomes of interrupting ET for young women with early-stage hormone-receptor-positive (HR+) BC who desire pregnancy. The primary objective is to assess the risk of BC relapse associated with ET interruption for ~2 years to achieve pregnancy. Women ≤42 years with stage I-III HR+ BC who received adjuvant ET (SERM alone, GnRH analogue plus SERM or AI) for 18 to 30 months and wished to interrupt ET to attempt pregnancy were eligible. The primary endpoint is breast cancer free interval (BCFI) defined as the time from enrollment to the first BC event (local, regional, distant recurrence or a new invasive contralateral BC). Planned sample size was 500 patients. Three interim analyses of BCFI were reviewed by the Data Safety Monitoring Committee (DSMC) to assure a 95% chance of stopping the trial early if the annual BCFI event rate exceeded 4%; with primary analysis triggered after 1600 patient years of follow-up (pyfu) and no more than 46 BCFI events defined as the safety threshold. The DSMC recommended continuing the study following each interim analysis. We now report the primary results. Results: From 12/2014 to 12/2019, 518 women were enrolled. At enrollment, the median age of participants was 37 years (27-43 years); 75.0% were nulliparous, 93.4% had stage I/II disease, 66.3% node-negative. Median time from BC diagnosis to enrollment was 29 months (IQR: 25-32). Tamoxifen alone was the most prescribed ET (41.7%), followed by tamoxifen+ovarian function suppression (35.7%). 62.0% of participants had received neo/adjuvant chemotherapy. At a median follow-up of 41 months (1638 pyfu), 44 participants had experienced a BCFI event, not exceeding the pre-specified safety threshold of 46 events. The 3-year BCFI failure percent was 8.9% (95% CI: 6.3 to 11.6%), similar to the 9.2% (95% CI: 7.6 to 10.8%) calculated in the comparative external control cohort from the SOFT/TEXT trials (Sun et al, Breast 2020). Of 497 women followed for pregnancy status, 368 (74.0%) had at least one pregnancy, 317 (63.8%) had at least one live birth, with a total of 365 babies born. Based on competing risk analysis, 76.3% of patients resumed ET (half within 26 months), 8.3% had BCFI event/death before ET resumption, and 15.4% had not resumed ET yet. Conclusions: The POSITIVE trial demonstrates that for young women with early HR+ BC desiring pregnancy, temporary interruption of ET to attempt pregnancy does not confer a greater short-term risk of recurrence than that observed in a modern historical control group that did not interrupt ET. Most participants have had a live birth. Further follow-up is planned to confirm long-term safety. These results should be considered in counselling BC patients desiring future pregnancy. Citation Format: Ann Partridge, Olivia Pagani, Samuel M. Niman, Monica Ruggeri, Fedro Alessandro A. Peccatori, Hatem A. Azim, Marco Colleoni, Cristina Saura, Chikako Shimizu, Anna Saetersdal, Judith Kroep, Audrey Mailliez, Ellen Warner, Virginia F. Borges, Frédéric Amant, Andrea Gombos, Akemi Kataoka, Christine Rousset-Jablonski, Simona Borstnar, Junko Takei, Jeong Eon Lee, Janice Walshe, Manuel Ruiz Borrego, Halle Moore, Christobel Saunders, Vesna Bjelic-Radisic, Snezana Susnjar, Fatima Cardoso, Karen L. Smith, Teresa Ferreiro Vilarino, Karin Ribi, Kathryn Ruddy, Sarra El-Abed, Martine Piccart, Larissa A. Korde, Aron Goldhirsch, Richard D. Gelber. Pregnancy Outcome and Safety of Interrupting Therapy for women with endocrine responsIVE breast cancer: Primary Results from the POSITIVE Trial (IBCSG 48-14/BIG 8-13) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS4-09.
Impact of Anti-HER2 Therapy Alone and With Weekly Paclitaxel on the Ovarian Reserve of Young Women With HER2-Positive Breast Cancer
Cameron, David , Bruzzone, Marco , Massarotti, Claudia , El-Abed, Sarra , Wang, Yingbo , Lecocq, Christophe, Rolyance, Rebecca, Sohn, Joohyuk , Arecco, Luca , Pistilli, Barbara , Ruddy, Kathryn J. , Saura, Cristina , Piccart, Martine , Cameron, David , El-Abed, Sarra , Sohn, Joohyuk , Saura, Cristina , Bruzzone, Marco , Lambertini, Matteo , Ceppi, Marcello , Anderson, Richard A. , Franzoi, Maria Alice , Nucíforo, Paolo , Pusztai, Lajos , Latocca, Maria Maddalena , Ballestrero, Alberto , Mastro, Lucia Del , Peccatori, Fedro A , Partridge, Ann H. , Untch, Michael , Cosimo, Serena Di , Azambuja, Evandro de , Demeestere, Isabelle

Journal of the National Comprehensive Cancer Network | January 11, 2023 | Volume: 21 | Issue: 1 | Pages: 33-41.e16

10.6004/jnccn.2022.7065 Get It

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 PD5-05: 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
Wang, Yingbo , Lecocq, Christophe, Rolyance, Rebecca, Ligato, Jacopo, Pistilli, Barbara , Ruddy, Kathryn J. , Saura, Cristina , Piccart, Martine , Saura, Cristina , Lambertini, Matteo , Ceppi, Marcello , Anderson, Richard A. , Cameron, David , Bruzzone, Marco , Franzoi, Maria Alice , Massarotti, Claudia , El-Abed, Sarra , Nucíforo, Paolo , Pusztai, Lajos , Sohn, Joohyuk , Latocca, Maria Maddalena , Arecco, Luca , Ballestrero, Alberto , Mastro, Lucia Del , Peccatori, Fedro A , Partridge, Ann H. , Untch, Michael , Cosimo, Serena Di , Azambuja, Evandro de , Demeestere, Isabelle

Cancer Research | March 8, 2022 | Volume: 82 | Issue: 4_Supplement | Pages: PD5-05-PD5-05

10.1158/1538-7445.sabcs21-pd5-05 Get It

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.
Pregnancy After Breast Cancer: A Systematic Review and Meta-Analysis
Lambertini, Matteo , Blondeaux, Eva , Bruzzone, Marco , Perachino, Marta , Anderson, Richard A. , Azambuja, Evandro de , Poorvu, Philip D. , Kim, Hee Jeong , Villarreal‐Garza, Cynthia , Pistilli, Barbara , Vaz-Luís, Inês , Saura, Cristina , Ruddy, Kathryn J. , Franzoi, Maria Alice , Sertoli, Chiara, Azim, Hatem A. , Demeestere, Isabelle , Mastro, Lucia Del , Pagani, Olivia , de Azambuja, Evandro , Ceppi, Marcello , Azim, Hatem A , Amant, Frederic , Demeestere, Isabelle , Del Mastro, Lucia , Partridge, Ann H , Peccatori, Fedro A , Lambertini, Matteo , Saura, Cristina , Villarreal-Garza, Cynthia , Bruzzone, Marco , Amant, Frédéric , Partridge, Ann H.

Journal of Clinical Oncology | July 1, 2021 | Volume: 39 | Issue: 29 | Pages: 3293-3305

10.1200/jco.21.00535 Get It

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 1998: Predictive and prognostic role of T- and B-cell receptor repertoire in HER2-positive breast cancer: An analysis of the NeoALTTO clinical trial
Rediti, Mattia , Venet, David , Rothé, Françoise , Qing, Tao , Maetens, Marion , Bradbury, Ian , Izquierdo, Miguel , Bajji, Mohammed, Chia, Stephen , Liu, Minetta C. , Saura, Cristina , Huober, Jens , Salgado, Roberto , Saura, Cristina , Cosimo, Serena Di , Hilbers, Florentine , Harbeck, Nadia , Untch, Michael , Rimm, David L. , Nucíforo, Paolo , Loi, Sherene , Pusztai, Lajos , Sotiriou, Christos P.

Cancer Research | September 4, 2020 | Volume: 80 | Issue: 16_Supplement | Pages: 1998-1998

10.1158/1538-7445.am2020-1998 Get It

Abstract Background: Disease relapse is observed in a significant proportion of HER2-positive breast cancer (BC) patients with residual disease (RD) after neoadjuvant treatment, as well as in a subgroup of those achieving pathological complete response (pCR). As the host immune response plays a key role in modulating the activity of anti-HER2 agents, we investigated the association of T- and B-cell receptor (TCR and BCR) repertoires with pCR and event-free survival (EFS) in the NeoALTTO phase 3 trial. Methods: RNA sequencing (RNAseq) data from baseline tumor biopsies were available for 254 patients out of the 455 enrolled in the study. Among those, 166 did not achieve a pCR defined as ypT0/is. Matched RNAseq data from RD samples were available for 43 cases. TCR/BCR repertoires were extracted from RNAseq data using the MiXCR software. TCR and BCR read counts, number of clones, evenness, Shannon entropy, Gini index, length of the complementarity determining region 3, top and second top clone proportion were evaluated. Survival analysis was performed using univariate and multivariate (adjusted for tumor size, nodal status, grade, estrogen receptor [ER] status, age and treatment arm) Cox proportional hazard models, while logistic regressions were used for pCR. False discovery rate (FDR) was obtained using Benjamini & Hochberg method. Results: Baseline TCR top (odds ratio [OR]=0.63 [95% CI 0.46-0.87], FDR=0.021) and second top (OR=0.57 [0.41-0.79], FDR=0.004) clone proportion were significantly associated with a lower probability of achieving pCR in the multivariate analysis. BCR evenness (hazard ratio [HR]=1.5 [1.2-2], FDR=0.015) and Gini index (HR=0.66 [0.52-0.85], FDR=0.015) were significantly associated with EFS in the multivariate analysis. In residual disease, BCR evenness and Gini index showed a similar trend in the EFS univariate analysis, while TCR read counts, number of clones, and entropy were associated with lower HR (P&lt;0.05), although FDR were borderline significant (0.05&lt;FDR&lt;0.1). A model to predict EFS including baseline BCR evenness, ER status, stromal tumor-infiltrating lymphocyte level, and pCR was able to identify 3 groups with good, intermediate and poor prognosis (Kaplan-Meier 5-year EFS rates of 95%, 80% and 58%, respectively). Of note, about 63%, 45% and 12% of the patients achieved a pCR in the three prognostic groups, respectively. Conclusions: In the NeoALTTO trial, the presence of an evenly distributed BCR repertoire was associated with worse EFS. A model integrating baseline immune-related and clinical features was able to identify patients with excellent prognosis despite RD or, conversely, with poor prognosis after pCR. We envision that our model has the potential to allow the personalization of post-operative treatment strategies after both pCR and RD in HER2-positive BC. Further validation of our findings is warranted. Citation Format: Mattia Rediti, David Venet, Françoise Rothé, Tao Qing, Marion Maetens, Ian Bradbury, Miguel A. Izquierdo, Serena Di Cosimo, Florentine Hilbers, Mohammed Bajji, Nadia Harbeck, Michael Untch, David L. Rimm, Stephen Chia, Minetta C. Liu, Cristina Saura, Jens Huober, Paolo Nuciforo, Roberto Salgado, Sherene Loi, Lajos Pusztai, Christos Sotiriou. Predictive and prognostic role of T- and B-cell receptor repertoire in HER2-positive breast cancer: An analysis of the NeoALTTO clinical trial [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1998.