Impact of Anti-HER2 Therapy Alone and With Weekly Paclitaxel on the Ovarian Reserve of Young Women With HER2-Positive Breast Cancer

Authors:
Matteo LambertiniSchool of Medicine, University of Genova, Genova, Italy
UOC Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy

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Marcello CeppiIRCCS Ospedale Policlinico San Martino, Genova, Italy

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Richard A. AndersonMRC Centre for Reproductive Health, The Queen’s Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom

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David A. CameronInstitute of Genomics and Cancer, The University of Edinburgh, Edinburgh, United Kingdom

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Marco BruzzoneIRCCS Ospedale Policlinico San Martino, Genova, Italy

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Maria Alice FranzoiGustave Roussy, Villjuif, France

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Claudia MassarottiIRCCS Ospedale Policlinico San Martino, Genova, Italy
University of Genova, Genova, Italy

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Sarra El-AbedBreast International Group, Brussels, Belgium

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Yingbo WangNovartis, Basel, Switzerland

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Christophe LecocqBrEAST Data Centre, Institut Jules Bordet, Brussels, Belgium

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Paolo NuciforoVall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology, SOLTI BC Cooperative Group, Barcelona, Spain

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Rebecca RolyanceNorth Central London Cancer Alliance, London, United Kingdom

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Lajos PusztaiYale School of Medicine, New Haven, Connecticut

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Joohyuk SohnYonsei Cancer Center, Yonsei University Health System, Seoul, Korea

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Maria Maddalena LatoccaSchool of Medicine, University of Genova, Genova, Italy
UOC Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy

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Luca AreccoSchool of Medicine, University of Genova, Genova, Italy
UOC Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy

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Barbara PistilliGustave Roussy, Villjuif, France

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Kathryn J. RuddyMayo Clinic, Rochester, Minnesota

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Alberto BallestreroSchool of Medicine, University of Genova, Genova, Italy
IRCCS Ospedale Policlinico San Martino, Genova, Italy

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Lucia Del MastroSchool of Medicine, University of Genova, Genova, Italy
UOC Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy

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Fedro A. PeccatoriEuropean Institute of Oncology IRCCS, Milan, Italy

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Ann H. PartridgeDana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts

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Cristina SauraVall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology, SOLTI BC Cooperative Group, Barcelona, Spain

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Michael UntchHelios Hospital Berlin-Buch, Berlin, Germany

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Martine PiccartInstitut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium

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Serena Di CosimoFondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

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Evandro de AzambujaInstitut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium

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Isabelle DemeestereFertility Clinic, CUB-Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium

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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.

Background

Chemotherapy plus anti-HER2 therapy is the mainstay systemic treatment for patients with HER2-positive early breast cancer.13 Despite additional anti-HER2 targeted therapies entering clinical practice, trastuzumab remains the standard of care for all patients.13 In patients with node-negative small tumors, chemotherapy burden can be de-escalated by administering weekly paclitaxel for 3 months and concurrent trastuzumab for 1 year.4

Considering its major negative impact on patients’ quality of life, developing treatment-induced premature ovarian insufficiency (POI) is a crucial age-related issue to be discussed with all premenopausal women.5,6 Currently, treatment-induced POI is mostly defined based on amenorrhea after anticancer therapies.7 However, irrespective of menstrual cycle perturbation during treatment and restoration after its completion, anticancer agents may cause direct damage to the primordial follicle pool (ie, the ovarian reserve) that can lead to fertility-related problems and early menopause.5,6 Therefore, the current definition of treatment-induced POI is considered suboptimal and other parameters, including ovarian reserve markers and posttreatment pregnancies, may more properly reflect the impact of anticancer therapies on women’s ovarian reserve and fertility potential.5,6 Produced by granulosa cells of growing follicles, antimüllerian hormone (AMH) is considered an established biomarker of ovarian reserve widely used in women undergoing in vitro fertilization procedures.8,9 It is more sensitive than other hormonal markers and has the advantage of showing little variation during regular menses.810 In patients with cancer, AMH measurement during systemic therapies is considered a promising biomarker for quantifying treatment-induced gonadotoxicity, thus aiding in the diagnosis and prediction of POI.11

With all newly diagnosed premenopausal women, discussing gonadotoxicity risk is the starting point for proper oncofertility counseling.5,6,12,13 However, although the risk and mechanisms of gonadotoxicity with anthracycline/cyclophosphamide-based chemotherapy and their impact on patients’ ovarian reserve are well established,1416 the gonadal effect of anti-HER2 targeted agents remains largely unknown, and limited conflicting evidence exists for taxanes.5,6

In the NeoALTTO (BIG 1-06) trial (ClinicalTrials.gov identifier: NCT00553358), patients with HER2-positive early breast cancer received neoadjuvant treatment with anti-HER2 therapy alone (trastuzumab and/or lapatinib) for 2 cycles (6 weeks total) and then together with weekly paclitaxel for 12 cycles before surgery.17 Considering that AMH level can be an early indicator of gonadotoxicity, with a significant decline in its values within 2 weeks after treatment initiation,18,19 the NeoALTTO trial represented a unique setting to explore for the first time the acute gonadal impact of anti-HER2 therapy alone and in combination with weekly paclitaxel in patients not previously exposed to anthracycline/cyclophosphamide-based chemotherapy.

Patients and Methods

Study Design and Participants

Details of the NeoALTTO trial design were previously reported.17 Briefly, NeoALTTO was a multicenter, open-label, randomized phase III neoadjuvant study in female patients with HER2-positive early breast cancer. Eligible patients were randomly assigned to receive anti-HER2 therapy alone (lapatinib or trastuzumab or their combination) for 6 weeks followed by the addition of weekly paclitaxel for 12 weeks before surgery. After surgery, 3 cycles of 5-fluorouracil + epirubicin + cyclophosphamide was administered followed by 34 additional weeks of the same anti-HER2 therapy received in the neoadjuvant phase.

The present analysis included only female patients aged ≤45 years and with known premenopausal status at randomization, with available serum samples at baseline and at least at 1 additional time point during the neoadjuvant treatment phase.

The NeoALTTO trial was approved by the independent review boards of participating centers, and all included patients provided written informed consent before study entry. The TransALTTO and NeoALTTO Steering Committees approved the present analysis.

Study Procedures

As per the NeoALTTO trial design, all included patients underwent prospective serum sample collection at predefined specific time points. For patients eligible for the present project, serum samples at the following time points were requested for AMH testing: screening/baseline (ie, before administration of any anticancer treatment), week 2 (ie, the “biological window” of anti-HER2 therapy alone), and surgery (ie, the end of 12 cycles of weekly paclitaxel + anti-HER2 therapy and before starting adjuvant chemotherapy).

All frozen serum samples were transferred to the Biobank of Gynecology of Erasmus at the Research Laboratory on Human Reproduction, Université Libre de Bruxelles (ULB) in Brussels, Belgium. Central AMH testing was performed with the Roche Elecsys AMH Plus assay according to manufacturer instructions. The limit of detection was 0.01 ng/mL (0.07 pmol/L).

Study Objectives and Variables of Interest

The primary objective of this analysis was to assess the acute gonadotoxicity of anti-HER2 agents alone or in combination with taxane-only chemotherapy using serum AMH levels as a measure of treatment impact on women’s ovarian reserve.

As secondary objectives, we investigated the impact of the different anti-HER2 agents and of patient age and baseline ovarian reserve (ie, AMH levels) on treatment-induced acute gonadotoxicity.

Statistical Analysis

Sample size calculations and statistical assumptions for the primary endpoint of the NeoALTTO trial were previously described.17 The present analyses focusing on treatment-induced acute gonadotoxicity measured by AMH levels were not preplanned in the protocol and the power of the statistical analyses was not prespecified. Given the highly skewed distribution of AMH levels and the descriptive intent of this analysis, data were summarized using a nonparametric statistical approach. Medians and interquartile ranges (IQRs) were used to summarize AMH levels at each time point. Scatter plots and box plots were used to present AMH dynamics during treatment.

The cumulative variation between AMH levels after 2 weeks and before surgery with respect to AMH levels at baseline was calculated according to the following formula19:

ΔBX=(AMHXAMHB)/(AMHB0.0098)*100,

where AMHB is at baseline, AMHX is at each of the 2 other time points, and 0.0098 is the lowest AMH observed value. The difference between the 2 ΔBX was calculated.

The analyses were first conducted in the overall study population, irrespective of treatment arm. Then, the same analyses were conducted by treatment arm (lapatinib vs trastuzumab vs trastuzumab + lapatinib), by patient age (as categorical variable: <35 vs 35–40 vs 41–45 years) and by pretreatment AMH levels (as categorical variable: first vs second vs third tertile). Kruskal-Wallis tests were used for group comparison at each time point. To compare AMH at 2 different time points, the Wilcoxon matched-pairs signed rank test was applied. The Skillings-Mack test was used to perform an overall comparison between AMH values at each time point.20

The impact of age and pretreatment AMH levels as continuous variables on changes in AMH values during therapy was assessed via the Spearman correlation coefficient, and the Lowess method was applied to visualize the trends.21

Statistical analysis was conducted (M. Bruzzone, M. Ceppi) using Stata, Version 13.1 (StataCorp LP). Statistical tests were 2-sided, and P values <.05 were considered statistically significant.

Results

Of 455 women randomized in the NeoALTTO trial between January 2008 and May 2010, 139 were premenopausal and aged ≤45 years at randomization. Serum samples were not available or could not be tested for AMH level at baseline in 9 patients, resulting in a final cohort of 130 patients (Figure 1).

Figure 1.
Figure 1.

Study flow of participants.

Abbreviation: AMH, antimüllerian hormone.

aTesting for AMH, with prespecified time points of screening/baseline (ie, before administration of any anticancer treatment), week 2 (ie, the “biological window” of anti-HER2 therapy alone), and surgery (ie, the end of 12 cycles of weekly paclitaxel + anti-HER2 therapy and before starting adjuvant chemotherapy).

Citation: Journal of the National Comprehensive Cancer Network 21, 1; 10.6004/jnccn.2022.7065

Median age was 38 years (IQR, 33–42 years), and 86 (66.2%) patients were aged ≤40 years (Table 1). A total of 41 (31.5%), 45 (34.6%), and 44 (33.9%) patients were randomized to the trastuzumab, lapatinib, or trastuzumab + lapatinib arms, respectively.

Table 1.

Patient and Tumor Characteristics

Table 1.

AMH values differed significantly at the 3 time points (P<.001; Figure 2A). At screening/baseline, median AMH levels were 1.29 ng/mL (IQR, 0.56–2.62 ng/mL). After 2 weeks of anti-HER2 treatment alone, a small reduction in AMH levels was observed with a median value of 1.10 ng/mL (IQR, 0.45–2.09 ng/mL; P<.001). At surgery, after paclitaxel and anti-HER2 therapy, a major significant decline in AMH levels was observed with a median value of 0.01 ng/mL (IQR, 0.01–0.03 ng/mL; P<.001).

Figure 2.
Figure 2.

AMH dynamic in the whole study cohort. (A) Evolution of serum AMH levels at the 3 time points (baseline, week 2, and surgery). (B) Cumulative variation of AMH (week 2 vs baseline, surgery vs baseline, and surgery vs week 2).

Abbreviations: AMH, antimüllerian hormone; H0, null hypothesis.

Citation: Journal of the National Comprehensive Cancer Network 21, 1; 10.6004/jnccn.2022.7065

Overall, the percentages of AMH change at week 2 and at surgery differed significantly with respect to baseline (P<.001; Figure 2B). Compared with baseline values, the median cumulative decrease in AMH levels was −12.5% (IQR, −37.6% to 12.4%) at week 2 and −99.9% (IQR −100.0% to −98.7%) at surgery. Compared with week 2 values, the median cumulative decrease in AMH levels at surgery was −80.7% (IQR, −109.5% to −54.8%).

There was no significant difference between treatment arms (trastuzumab vs lapatinib vs trastuzumab + lapatinib) either in the degree of reduction in AMH levels (Figure 3A, supplemental eTable 1, available with this article at JNCCN.org) or in the degree of cumulative decrease in AMH levels (Figure 3B, supplemental eTable 2) at the different time points.

Figure 3.
Figure 3.

AMH dynamic by treatment arm (lapatinib, lapatinib + trastuzumab, and trastuzumab). (A) Evolution of serum AMH levels at the 3 time points (baseline, week 2, and surgery). (B) Cumulative variation of AMH (week 2 vs baseline, surgery vs baseline, and surgery vs week 2).

Abbreviations: AMH, antimüllerian hormone; Lap, lapatinib; Tras, trastuzumab.

Citation: Journal of the National Comprehensive Cancer Network 21, 1; 10.6004/jnccn.2022.7065

At screening/baseline, median AMH levels were 2.76 ng/mL (IQR, 1.40–4.07 ng/mL), 1.33 ng/mL (IQR, 0.95–2.25 ng/mL), and 0.52 ng/mL (IQR, 0.12–1.01 ng/mL) in patients aged <35, 35–40, and 41–45 years, respectively. AMH levels remained significantly different between age groups at all time points (P<.001; Figure 4A, supplemental eTable 3 and eFigure 1). A significant negative correlation was observed between age and AMH levels at baseline (r = −0.609; P<.001; supplemental eFigure 2A), at week 2 (r = −0.617; P<.001; supplemental eFigure 2B), and at surgery (r = −0.500; P<.001; supplemental eFigure 2C).

Figure 4.
Figure 4.

AMH dynamic by age group (ages <35, 35–40, and 41–45 years). (A) Evolution of serum AMH level at the 3 time points (baseline, week 2, and surgery). (B) Cumulative variation of AMH (week 2 vs baseline, surgery vs baseline, and surgery vs week 2).

Abbreviation: AMH, antimüllerian hormone.

Citation: Journal of the National Comprehensive Cancer Network 21, 1; 10.6004/jnccn.2022.7065

The difference between age groups in the degree of reduction in AMH levels (P<.001; Figure 4B, supplemental eTable 4) and the negative correlation between age and degree of decrease in AMH levels (r = −0.326; P<.001; supplemental eFigure 3A–C) were significant only at surgery compared with baseline.

Based on pretreatment AMH levels, the cutoffs to distinguish between the 3 tertiles were <0.74, 0.74 to 1.98, and >1.98 ng/mL. AMH levels remained significantly different between AMH tertile groups at all time points (P<.001; Figure 5A, supplemental eTable 5). A significant positive correlation was observed between AMH tertile groups and AMH levels at week 2 (r = 0.91; P<.001; supplemental eFigure 4A) and at surgery (r = 0.54; P<.001; supplemental eFigure 4B).

Figure 5.
Figure 5.

AMH dynamic by pretreatment AMH tertile groups (1st: <0.74; 2nd: 0.74–1.98; 3rd: >1.98). (A) Evolution of serum AMH level at the 3 time points (baseline, week 2, and at surgery). (B) Cumulative variation of AMH (week 2 vs baseline, surgery vs baseline, and surgery vs week 2).

Abbreviations: AMH, antimüllerian hormone; T, tertile.

Citation: Journal of the National Comprehensive Cancer Network 21, 1; 10.6004/jnccn.2022.7065

The difference between AMH tertile groups in the degree of reduction in AMH levels (P<.001; Figure 5B, supplemental eTable 6) and the positive correlation between AMH tertile groups and the degree of decrease in AMH levels (r = 0.297; P=.002; supplemental eFigure 5A–C) were significant only at surgery compared with baseline.

After repeating the main analyses by including only patients with all 3 samples (screening/baseline, week 2, and surgery) available for AMH testing (n=107), we observed consistent results (supplemental eTables 7–15).

A total of 7 patients had a pregnancy after treatment completion; all were aged <35 years at randomization. Median AMH levels were 3.22 ng/mL (IQR, 1.99–4.61 ng/mL) at screening/baseline, 2.74 ng/mL (IQR, 1.81–3.69 ng/mL) after 2 weeks of anti-HER2 treatment alone, and 0.04 ng/mL (IQR, 0.03–0.04 ng/mL) at surgery after paclitaxel and anti-HER2 therapy.

In patients without subsequent pregnancy and aged <35 years (n=35), median AMH levels were 2.55 ng/mL (IQR, 1.34–4.02 ng/mL) at baseline, 2.15 ng/mL (IQR, 1.24–3.43 ng/mL) at week 2, and 0.04 ng/mL (IQR, 0.01–0.08 ng/mL) at surgery. There were no significant differences in AMH levels at baseline (P=.16), week 2 (P=.463), or surgery (P=.610) in patients with or without subsequent pregnancy.

Discussion

This biomarker analysis of the NeoALTTO trial explored the short-term impact of anti-HER2 therapy alone and then combined with weekly paclitaxel on ovarian reserve measured by AMH levels in premenopausal women with HER2-positive early breast cancer not previously exposed to anthracycline/cyclophosphamide-based chemotherapy. We observed a small reduction in AMH levels during 2 weeks of anti-HER2 treatment alone and then a profound decline to almost undetectable levels in most patients after its combination with weekly paclitaxel. Although type of anti-HER2 targeted agent did not demonstrate any influence, age and pretreatment ovarian reserve had a major impact on the acute risk of treatment-induced gonadotoxicity. This analysis provides novel important information to share with premenopausal patients with breast cancer to improve their oncofertility counseling.

Defining the gonadotoxicity of targeted agents is considered an important unmet clinical need.5,6,22 In patients receiving mostly anthracycline/cyclophosphamide-based chemotherapy, adding trastuzumab to cytotoxic therapy did not seem to increase posttreatment amenorrhea risk,23,24 and no differences were observed when using trastuzumab and/or lapatinib.25 Low rates of posttreatment amenorrhea were observed in premenopausal women receiving trastuzumab and weekly paclitaxel.26 Although these studies suggested no apparent negative gonadotoxic impact of anti-HER2 therapy, all patients received prior or concurrent chemotherapy, and amenorrhea was used as a marker of gonadotoxicity. Hence, the actual impact of anti-HER2 targeted therapy on patients’ ovarian reserve remains undefined.5,6,22 Our data suggest that there could be a possible negative short-term gonadal effect of these agents. Considering that the EGFR signaling pathway has an important role in ovarian function,27 HER2 blockade could theoretically impact the rate of ovarian follicle activation and subsequent follicle growth.27,28 Most serum AMH derives from small antral follicles29; these findings indicate an effect of anti-HER2 blockade on the growing follicles. Due to the short treatment period of 2 weeks and the lack of a recovery period before starting chemotherapy, these data cannot inform on whether anti-HER2 blockade has effects on ovarian primordial follicles, which would translate into a long-term impact on ovarian function. Although significant, the observed reduction in AMH levels after 2 weeks of anti-HER2 treatment alone was small, in marked contrast to what has been observed with chemotherapy over this short 2-week window.18,19 No further reduction in AMH levels was observed with dual anti-HER2 blockade compared with trastuzumab and lapatinib given as single agents. Although it is possible that greater AMH declines would be seen with longer use of anti-HER2 therapy without chemotherapy, it is also plausible that any impact of anti-HER2 therapy on ovarian function may be transient and reversible (similar to the impact on cardiac ejection fraction). Thus, the gonadal effect of these anti-HER2 therapies may have limited clinical impact compared with the subsequent ovarian damage induced by chemotherapy. Considering that other anti-HER2 agents, including antibody–drug conjugates, have entered clinical practice or are in late stages of development in patients with HER2-positive early breast cancer, further efforts in this field are eagerly awaited.22,30

The risk of treatment-induced POI with cyclophosphamide and anthracyclines is well established.5,6 In most patients receiving these agents, AMH levels decline to undetectable values during treatment, with only partial and minimal recovery after therapy completion.19 More limited evidence exists to counsel women receiving taxane-based chemotherapy.14 Adding a taxane to anthracycline/cyclophosphamide-based chemotherapy is associated with a further increased risk of treatment-induced amenorrhea25,31 and a more profound short-term reduction in AMH levels,32 without apparent differences between docetaxel and paclitaxel.25 Compared with sequential regimens, similar rates of treatment-induced amenorrhea are expected with the use of docetaxel combined with cyclophosphamide or carboplatin (+ anti-HER2 therapy).25,33

Considering that weekly paclitaxel + trastuzumab is currently widely used in the clinic,4 the possibility of studying its gonadal impact without prior exposure to or coadministration of cyclophosphamide or anthracyclines is invaluable. In the APT trial, the observed rate of treatment-induced amenorrhea (28%) seemed to be lower than historically expected with cyclophosphamide/anthracycline-based chemotherapy regimens.26 Nevertheless, our analysis suggests that weekly paclitaxel alone has a major acute negative impact on women’s ovarian reserve, leading to a profound decline in AMH levels similar to what was expected with other known gonadotoxic chemotherapy agents. However, it is also possible that concurrent anti-HER2 therapy also contributed to this gonadotoxic effect. A future analysis within the Decrescendo trial (ClinicalTrials.gov identifier: NCT04675827) investigating the potential subsequent recovery of women’s ovarian reserve in the long term is awaited to further characterize the gonadotoxicity of single-agent taxane plus anti-HER2 therapy.

Age and baseline ovarian reserve measured by AMH levels are the most important patient-related factors influencing gonadotoxicity risk.5,6,11 These factors were confirmed in our analysis, showing a clear trend for a more profound reduction in AMH levels in older patients and those with the lowest baseline values. Nevertheless, all women (including the youngest and those with the highest baseline values) had a major acute reduction in AMH levels to very low/undetectable values after treatment using weekly paclitaxel and anti-HER2 agents. Therefore, although most young women with breast cancer, and particularly those aged <35 years and with optimal baseline ovarian reserve, are likely to retain ovarian function after chemotherapy completion and to conceive spontaneously,34,35 such treatments do cause ovarian damage. Hence, all women with breast cancer receiving systemic anticancer treatments should be considered at risk for treatment-induced gonadotoxicity and receive oncofertility counseling, including the possibility of undergoing fertility preservation strategies.5,6

In assisted reproductive technology, AMH is an excellent biomarker for predicting oocyte yield after ovarian stimulation.8,9 However, AMH is a poor predictor of pregnancy, because pregnancy can also occur in women with low/undetectable AMH levels.36 In our analysis, although information on AMH levels at conception or pregnancy attempts was not available, no apparent differences were observed in post-paclitaxel and anti-HER2 treatment values between patients with or without a subsequent pregnancy. Although AMH represents a biomarker of treatment-induced ovarian damage,11 it should not be regarded as a fertility test or a measure of reproductive potential, particularly during or soon after chemotherapy.

Among limitations, this analysis was not preplanned in the study protocol. There were no available serum samples after surgery, and therefore the potential recovery of AMH levels after treatment completion could not be assessed. No information on menstrual function after treatment was registered. Nevertheless, all samples were prospectively collected during study conduction at precise time points and their storage followed strict standard operating procedures. An automated and sensitive AMH assay, which offers improved precision compared with previously available assays, was used to centrally test all samples. The uniqueness of this analysis is represented by the possibility to study the gonadal impact of both anti-HER2 agents alone and weekly paclitaxel without the prior confounding effect of anthracycline/cyclophosphamide-based chemotherapy. Although data on previous gynecologic history, fertility treatments, or reproductive outcomes were not available, data on posttreatment pregnancies were collected, allowing us to obtain additional information on the impact of such therapies on patients’ fertility.

Conclusions

This NeoALTTO biomarker analysis in premenopausal patients with HER2-positive early breast cancer not previously exposed to anthracycline/cyclophosphamide-based chemotherapy provides evidence on the potential acute impact of anti-HER2 therapy alone (trastuzumab and/or lapatinib) and together with weekly paclitaxel on ovarian reserve measured by AMH levels. These data add to the body of knowledge in the oncofertility field that weekly paclitaxel + anti-HER2 therapy may cause gonadal damage, thus highlighting the importance of oncofertility counseling among premenopausal women receiving this regimen. Age and pretreatment ovarian reserve remain key determinants of treatment-induced gonadotoxicity risk.

References

  • 1.

    Cardoso F, Kyriakides S, Ohno S, et al. Early breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2019;30:1674.

  • 2.

    Denduluri N, Somerfield MR, Chavez-MacGregor M, et al. Selection of optimal adjuvant chemotherapy and targeted therapy for early breast cancer: ASCO guideline update. J Clin Oncol 2021;39:685693.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Korde LA, Somerfield MR, Carey LA, et al. Neoadjuvant chemotherapy, endocrine therapy, and targeted therapy for breast cancer: ASCO guideline. J Clin Oncol 2021;39:14851505.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Tolaney SM, Guo H, Pernas S, et al. Seven-year follow-up analysis of adjuvant paclitaxel and trastuzumab trial for node-negative, human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol 2019;37:18681875.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Lambertini M, Peccatori FA, Demeestere I, et al. Fertility preservation and post-treatment pregnancies in post-pubertal cancer patients: ESMO clinical practice guidelines. Ann Oncol 2020;31:16641678.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Anderson RA, Amant F, Braat D, et al. ESHRE guideline: female fertility preservation. Hum Reprod Open 2020;2020:hoaa052.

  • 7.

    Paluch-Shimon S, Cardoso F, Partridge AH, et al. ESO-ESMO 4th International Consensus Guidelines for Breast Cancer in Young Women (BCY4). Ann Oncol 2020;31:674696.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    La Marca A, Sighinolfi G, Radi D, et al. Anti-Mullerian hormone (AMH) as a predictive marker in assisted reproductive technology (ART). Hum Reprod Update 2010;16:113130.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Dewailly D, Andersen CY, Balen A, et al. The physiology and clinical utility of anti-Mullerian hormone in women. Hum Reprod Update 2014;20:370385.

  • 10.

    Tsepelidis S, Devreker F, Demeestere I, et al. Stable serum levels of anti-Müllerian hormone during the menstrual cycle: a prospective study in normo-ovulatory women. Hum Reprod 2007;22:18371840.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Anderson RA, Cameron D, Clatot F, et al. Anti-Müllerian hormone as a marker of ovarian reserve and premature ovarian insufficiency in children and women with cancer: a systematic review. Hum Reprod Update 2022;28:417434.

    • Search Google Scholar
    • Export Citation
  • 12.

    Razeti MG, Spinaci S, Spagnolo F, et al. How I perform fertility preservation in breast cancer patients. ESMO Open 2021;6:100112.

  • 13.

    Salama M, Lambertini M, Christianson MS, et al. Installing oncofertility programs for breast cancer in limited versus optimum resource settings: empirical data from 39 surveyed centers in Repro-Can-OPEN study part I and II. J Assist Reprod Genet 2022;39:505516.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Zhao J, Liu J, Chen K, et al. What lies behind chemotherapy-induced amenorrhea for breast cancer patients: a meta-analysis. Breast Cancer Res Treat 2014;145:113128.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Fréour T, Barrière P, Masson D. Anti-Müllerian hormone levels and evolution in women of reproductive age with breast cancer treated with chemotherapy. Eur J Cancer 2017;74:18.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Codacci-Pisanelli G, Del Pup L, Del Grande M, et al. Mechanisms of chemotherapy-induced ovarian damage in breast cancer patients. Crit Rev Oncol Hematol 2017;113:9096.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet 2012;379:633640.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Decanter C, Morschhauser F, Pigny P, et al. Anti-Müllerian hormone follow-up in young women treated by chemotherapy for lymphoma: preliminary results. Reprod Biomed Online 2010;20:280285.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Dezellus A, Barriere P, Campone M, et al. Prospective evaluation of serum anti-Müllerian hormone dynamics in 250 women of reproductive age treated with chemotherapy for breast cancer. Eur J Cancer 2017; 79:7280.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Skillings JH, Mack GA. On the use of a Friedman-type statistic in balanced and unbalanced block designs. Technometrics 1981;23:171177.

    • Search Google Scholar
    • Export Citation
  • 21.

    Cleveland WS. Robust locally weighted regression and smoothing scatterplots. J Am Stat Assoc 1979;74:829836.

  • 22.

    Lambertini M, Marrocco C, Spinaci S, et al. Risk of gonadotoxicity with immunotherapy and targeted agents remains an unsolved but crucial issue. Eur J Clin Invest 2022;52:e13779.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Abusief ME, Missmer SA, Ginsburg ES, et al. The effects of paclitaxel, dose density, and trastuzumab on treatment-related amenorrhea in premenopausal women with breast cancer. Cancer 2010;116:791798.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Ruddy KJ, Schaid DJ, Batzler A, et al. Antimullerian hormone as a serum biomarker for risk of chemotherapy-induced amenorrhea. J Natl Cancer Inst 2021;113:11051108.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    Lambertini M, Campbell C, Bines J, et al. Adjuvant anti-HER2 therapy, treatment-related amenorrhea, and survival in premenopausal HER2-positive early breast cancer patients. J Natl Cancer Inst 2019;111:8694.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Ruddy KJ, Guo H, Barry W, et al. Chemotherapy-related amenorrhea after adjuvant paclitaxel-trastuzumab (APT trial). Breast Cancer Res Treat 2015;151:589596.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Richani D, Gilchrist RB. The epidermal growth factor network: role in oocyte growth, maturation and developmental competence. Hum Reprod Update 2018;24:114.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Kim K, Lee H, Threadgill DW, et al. Epiregulin-dependent amphiregulin expression and ERBB2 signaling are involved in luteinizing hormone-induced paracrine signaling pathways in mouse ovary. Biochem Biophys Res Commun 2011;405:319324.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Jeppesen JV, Anderson RA, Kelsey TW, et al. Which follicles make the most anti-Mullerian hormone in humans? Evidence for an abrupt decline in AMH production at the time of follicle selection. Mol Hum Reprod 2013;19:519527.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Anderson RA, Clatot F, Demeestere I, et al. Cancer survivorship: reproductive health outcomes should be included in standard toxicity assessments. Eur J Cancer 2021;144:310316.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31.

    Silva C, Caramelo O, Almeida-Santos T, et al. Factors associated with ovarian function recovery after chemotherapy for breast cancer: a systematic review and meta-analysis. Hum Reprod 2016;31:27372749.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Lambertini M, Olympios N, Lequesne J, et al. Impact of taxanes, endocrine therapy, and deleterious germline BRCA mutations on anti-Müllerian hormone levels in early breast cancer patients treated with anthracycline- and cyclophosphamide-based chemotherapy. Front Oncol 2019;9:575.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33.

    Ejlertsen B, Tuxen MK, Jakobsen EH, et al. Adjuvant cyclophosphamide and docetaxel with or without epirubicin for early TOP2A-normal breast cancer: DBCG 07-READ, an open-label, phase III, randomized trial. J Clin Oncol 2017;35:26392646.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34.

    Poorvu PD, Gelber SI, Zheng Y, et al. Pregnancy after breast cancer: results from a prospective cohort of young women with breast cancer. Cancer 2021;127:10211028.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35.

    Lambertini M, Blondeaux E, Bruzzone M, et al. Pregnancy after breast cancer: a systematic review and meta-analysis. J Clin Oncol 2021;39:32933305.

  • 36.

    Steiner AZ, Pritchard D, Stanczyk FZ, et al. Association between biomarkers of ovarian reserve and infertility among older women of reproductive age. JAMA 2017;318:13671376.

    • PubMed
    • Search Google Scholar
    • Export Citation

Submitted May 29, 2022; final revision received August 9, 2022; accepted for publication August 9, 2022.

Previous presentation: A summary of these results was presented in abstract form at the 2022 ASCO Annual Meeting; June 4, 2022; Chicago, Illinois (J Clin Oncol 2022:40[Suppl]:Abstract 12084).

Author contributions: Conception and design: Lambertini, de Azambuja, Demeestere. Administrative support: Lambertini, Ceppi, Anderson, Cameron, Bruzzone, Franzoi, Massarotti, El-Abed, Wang, Lecocq, Rolyance, Pusztai, Sohn, Latocca, Arecco, Pistilli, Ruddy, Ballestrero, Del Mastro, Peccatori, Partridge, Saura, Untch, Piccart, Di Cosimo, de Azambuja. Collection and assembly of data: All authors. Data analysis and interpretation: Lambertini, Ceppi, Anderson, Bruzzone, de Azambuja, Demeestere. Manuscript writing: All authors.

Data availability statement: Qualified researchers can request access to individual patient-level data of the NeoALTTO trial by submitting a research project proposal to the Breast International Group. Further details on the Breast International Group’s Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents are available online.

Disclosures: Dr. Lambertini has disclosed serving as a scientific advisor for Roche, Lilly, Novartis, AstraZeneca, MSD, Seagen, Gilead, Pfizer, and Exact Sciences; receiving honoraria from Roche, Lilly, Novartis, Pfizer, Sandoz, Takeda, Knight, Libbs, and Ipsen; and receiving a travel grant from and grant/research support from Gilead. Dr. Anderson has disclosed serving as a consultant for Roche. Dr. Cameron has disclosed receiving grant/research support from Novartis; and serving as a consultant for Roche, Pfizer, and Novartis. Dr. El-Abed has disclosed receiving grant/research support from Novartis, Roche/Genentech, AstraZeneca, and Pfizer. Dr. Wang is employed by Novartis and holds stock. Dr. Nuciforo has disclosed receiving grant/research support from Novartis, Roche/Genentech, MSD, Bayer, and Targos. Dr. Pusztai has disclosed serving as a consultant for and receiving honoraria from Seagen, Pfizer, AstraZeneca, Merck, Novartis, Bristol Myers Squibb, Genentech, Athenex, Radius, Clovis, and Roche; receiving grant/research support from Seagen, AstraZeneca, Merck, Pfizer, and Bristol Myers Squibb. Dr. Pistilli has disclosed serving as a scientific advisor for Puma Biotechnology, Novartis, Myriad Genetics, and Pierre Fabre; receiving personal fees from Novartis, AstraZeneca, MSD, and Pfizer; and grant/research support from Daiichi, Puma Biotechnology, Novartis, Merus, Pfizer, and AstraZeneca. Dr. Peccatori has disclosed serving as a consultant for Ipsen and Roche Diagnostics. Dr. Saura has disclosed serving as a consultant and scientific advisor for and receiving travel grants from AstraZeneca, Byondis B.V., Daiichi Sankyo, Eisai, Exact Sciences, Exeter Pharma, F. Hoffmann–La Roche Ltd., MediTech, Merck Sharp & Dohme, NovarQs, Pfizer, Philips, Pierre Fabre, PintPharma, Puma, Roche Farma, Sanofi-Aventis, SeaGen, and Zymeworks; and receiving grant/research support from AstraZeneca, Daiichi Sankyo, Eli Lilly and Company, Genentech, Immunomedics, Macrogenics, Merck Sharp & Dohme, Novartis, Pfizer, Piqur Therapeutics, Puma, Roche, Byondis B.V., and Zenith Pharma. Dr. Piccart has disclosed serving as a consultant and scientific advisor for and receiving honoraria from Roche and Novartis. Dr. Di Cosimo has disclosed serving as a consultant and scientific advisor for Pierre-Fabre, AstraZeneca, IQVIA, and MEDSIR. Dr. de Azambuja has disclosed receiving honoraria from and serving as a scientific advisor for Roche/Genentech, Novartis, Seattle Genetics, Zodiacs, Libbs, Pierre Fabre, and Lilly; receiving travel grants from Roche/Genentech and GlaxoSmithKline/Novartis; and receiving grant/research support from Roche/Genentech, AstraZeneca, Genentech/Novartis, and Servier. Dr. Demeestere has disclosed serving as a scientific advisor for and receiving grant/research support from Roche, receiving honoraria from Novartis, and receiving personal fees from Theramex and Ferring. The remaining authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.

Funding: The NeoALTTO trial received financial support from GlaxoSmithKline (until January 2015) and Novartis Pharma AG (as of January 2015). Research reported in this publication was supported by the Italian Association for Cancer Research under award number MFAG 2020 ID 246989 (M. Lambertini) and the Italian Ministry of Health (5x1000 funds 2017; M. Lambertini).

Disclaimer: The financial sponsors of the study had no role in the study design, data collection, analysis, interpretation, or writing of the report, and they had no access to the data. All authors had full access to the data and had final responsibility for the decision to submit for publication.

Correspondence: Matteo Lambertini, MD, PhD, Department of Medical Oncology, UOC Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, University of Genova, Largo Rosanna Benzi 10, 16132 Genova, Italy. Email: matteo.lambertini@unige.it

Supplementary Materials

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  • Expand
  • View in gallery
    Figure 1.

    Study flow of participants.

    Abbreviation: AMH, antimüllerian hormone.

    aTesting for AMH, with prespecified time points of screening/baseline (ie, before administration of any anticancer treatment), week 2 (ie, the “biological window” of anti-HER2 therapy alone), and surgery (ie, the end of 12 cycles of weekly paclitaxel + anti-HER2 therapy and before starting adjuvant chemotherapy).

  • View in gallery
    Figure 2.

    AMH dynamic in the whole study cohort. (A) Evolution of serum AMH levels at the 3 time points (baseline, week 2, and surgery). (B) Cumulative variation of AMH (week 2 vs baseline, surgery vs baseline, and surgery vs week 2).

    Abbreviations: AMH, antimüllerian hormone; H0, null hypothesis.

  • View in gallery
    Figure 3.

    AMH dynamic by treatment arm (lapatinib, lapatinib + trastuzumab, and trastuzumab). (A) Evolution of serum AMH levels at the 3 time points (baseline, week 2, and surgery). (B) Cumulative variation of AMH (week 2 vs baseline, surgery vs baseline, and surgery vs week 2).

    Abbreviations: AMH, antimüllerian hormone; Lap, lapatinib; Tras, trastuzumab.

  • View in gallery
    Figure 4.

    AMH dynamic by age group (ages <35, 35–40, and 41–45 years). (A) Evolution of serum AMH level at the 3 time points (baseline, week 2, and surgery). (B) Cumulative variation of AMH (week 2 vs baseline, surgery vs baseline, and surgery vs week 2).

    Abbreviation: AMH, antimüllerian hormone.

  • View in gallery
    Figure 5.

    AMH dynamic by pretreatment AMH tertile groups (1st: <0.74; 2nd: 0.74–1.98; 3rd: >1.98). (A) Evolution of serum AMH level at the 3 time points (baseline, week 2, and at surgery). (B) Cumulative variation of AMH (week 2 vs baseline, surgery vs baseline, and surgery vs week 2).

    Abbreviations: AMH, antimüllerian hormone; T, tertile.

  • 1.

    Cardoso F, Kyriakides S, Ohno S, et al. Early breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2019;30:1674.

  • 2.

    Denduluri N, Somerfield MR, Chavez-MacGregor M, et al. Selection of optimal adjuvant chemotherapy and targeted therapy for early breast cancer: ASCO guideline update. J Clin Oncol 2021;39:685693.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Korde LA, Somerfield MR, Carey LA, et al. Neoadjuvant chemotherapy, endocrine therapy, and targeted therapy for breast cancer: ASCO guideline. J Clin Oncol 2021;39:14851505.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Tolaney SM, Guo H, Pernas S, et al. Seven-year follow-up analysis of adjuvant paclitaxel and trastuzumab trial for node-negative, human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol 2019;37:18681875.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Lambertini M, Peccatori FA, Demeestere I, et al. Fertility preservation and post-treatment pregnancies in post-pubertal cancer patients: ESMO clinical practice guidelines. Ann Oncol 2020;31:16641678.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Anderson RA, Amant F, Braat D, et al. ESHRE guideline: female fertility preservation. Hum Reprod Open 2020;2020:hoaa052.

  • 7.

    Paluch-Shimon S, Cardoso F, Partridge AH, et al. ESO-ESMO 4th International Consensus Guidelines for Breast Cancer in Young Women (BCY4). Ann Oncol 2020;31:674696.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    La Marca A, Sighinolfi G, Radi D, et al. Anti-Mullerian hormone (AMH) as a predictive marker in assisted reproductive technology (ART). Hum Reprod Update 2010;16:113130.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Dewailly D, Andersen CY, Balen A, et al. The physiology and clinical utility of anti-Mullerian hormone in women. Hum Reprod Update 2014;20:370385.

  • 10.

    Tsepelidis S, Devreker F, Demeestere I, et al. Stable serum levels of anti-Müllerian hormone during the menstrual cycle: a prospective study in normo-ovulatory women. Hum Reprod 2007;22:18371840.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Anderson RA, Cameron D, Clatot F, et al. Anti-Müllerian hormone as a marker of ovarian reserve and premature ovarian insufficiency in children and women with cancer: a systematic review. Hum Reprod Update 2022;28:417434.

    • Search Google Scholar
    • Export Citation
  • 12.

    Razeti MG, Spinaci S, Spagnolo F, et al. How I perform fertility preservation in breast cancer patients. ESMO Open 2021;6:100112.

  • 13.

    Salama M, Lambertini M, Christianson MS, et al. Installing oncofertility programs for breast cancer in limited versus optimum resource settings: empirical data from 39 surveyed centers in Repro-Can-OPEN study part I and II. J Assist Reprod Genet 2022;39:505516.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Zhao J, Liu J, Chen K, et al. What lies behind chemotherapy-induced amenorrhea for breast cancer patients: a meta-analysis. Breast Cancer Res Treat 2014;145:113128.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Fréour T, Barrière P, Masson D. Anti-Müllerian hormone levels and evolution in women of reproductive age with breast cancer treated with chemotherapy. Eur J Cancer 2017;74:18.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Codacci-Pisanelli G, Del Pup L, Del Grande M, et al. Mechanisms of chemotherapy-induced ovarian damage in breast cancer patients. Crit Rev Oncol Hematol 2017;113:9096.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet 2012;379:633640.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Decanter C, Morschhauser F, Pigny P, et al. Anti-Müllerian hormone follow-up in young women treated by chemotherapy for lymphoma: preliminary results. Reprod Biomed Online 2010;20:280285.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Dezellus A, Barriere P, Campone M, et al. Prospective evaluation of serum anti-Müllerian hormone dynamics in 250 women of reproductive age treated with chemotherapy for breast cancer. Eur J Cancer 2017; 79:7280.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Skillings JH, Mack GA. On the use of a Friedman-type statistic in balanced and unbalanced block designs. Technometrics 1981;23:171177.

    • Search Google Scholar
    • Export Citation
  • 21.

    Cleveland WS. Robust locally weighted regression and smoothing scatterplots. J Am Stat Assoc 1979;74:829836.

  • 22.

    Lambertini M, Marrocco C, Spinaci S, et al. Risk of gonadotoxicity with immunotherapy and targeted agents remains an unsolved but crucial issue. Eur J Clin Invest 2022;52:e13779.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Abusief ME, Missmer SA, Ginsburg ES, et al. The effects of paclitaxel, dose density, and trastuzumab on treatment-related amenorrhea in premenopausal women with breast cancer. Cancer 2010;116:791798.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Ruddy KJ, Schaid DJ, Batzler A, et al. Antimullerian hormone as a serum biomarker for risk of chemotherapy-induced amenorrhea. J Natl Cancer Inst 2021;113:11051108.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    Lambertini M, Campbell C, Bines J, et al. Adjuvant anti-HER2 therapy, treatment-related amenorrhea, and survival in premenopausal HER2-positive early breast cancer patients. J Natl Cancer Inst 2019;111:8694.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Ruddy KJ, Guo H, Barry W, et al. Chemotherapy-related amenorrhea after adjuvant paclitaxel-trastuzumab (APT trial). Breast Cancer Res Treat 2015;151:589596.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Richani D, Gilchrist RB. The epidermal growth factor network: role in oocyte growth, maturation and developmental competence. Hum Reprod Update 2018;24:114.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Kim K, Lee H, Threadgill DW, et al. Epiregulin-dependent amphiregulin expression and ERBB2 signaling are involved in luteinizing hormone-induced paracrine signaling pathways in mouse ovary. Biochem Biophys Res Commun 2011;405:319324.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Jeppesen JV, Anderson RA, Kelsey TW, et al. Which follicles make the most anti-Mullerian hormone in humans? Evidence for an abrupt decline in AMH production at the time of follicle selection. Mol Hum Reprod 2013;19:519527.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Anderson RA, Clatot F, Demeestere I, et al. Cancer survivorship: reproductive health outcomes should be included in standard toxicity assessments. Eur J Cancer 2021;144:310316.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31.

    Silva C, Caramelo O, Almeida-Santos T, et al. Factors associated with ovarian function recovery after chemotherapy for breast cancer: a systematic review and meta-analysis. Hum Reprod 2016;31:27372749.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Lambertini M, Olympios N, Lequesne J, et al. Impact of taxanes, endocrine therapy, and deleterious germline BRCA mutations on anti-Müllerian hormone levels in early breast cancer patients treated with anthracycline- and cyclophosphamide-based chemotherapy. Front Oncol 2019;9:575.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33.

    Ejlertsen B, Tuxen MK, Jakobsen EH, et al. Adjuvant cyclophosphamide and docetaxel with or without epirubicin for early TOP2A-normal breast cancer: DBCG 07-READ, an open-label, phase III, randomized trial. J Clin Oncol 2017;35:26392646.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34.

    Poorvu PD, Gelber SI, Zheng Y, et al. Pregnancy after breast cancer: results from a prospective cohort of young women with breast cancer. Cancer 2021;127:10211028.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35.

    Lambertini M, Blondeaux E, Bruzzone M, et al. Pregnancy after breast cancer: a systematic review and meta-analysis. J Clin Oncol 2021;39:32933305.

  • 36.

    Steiner AZ, Pritchard D, Stanczyk FZ, et al. Association between biomarkers of ovarian reserve and infertility among older women of reproductive age. JAMA 2017;318:13671376.

    • PubMed
    • Search Google Scholar
    • Export Citation
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