Chemotherapy In Premenopausal Women Research Articles

The population-level effects of omitting chemotherapy guided by a 21-gene expression assay in node-positive breast cancer: a simulation modeling study

BackgroundA recent trial showed that postmenopausal women diagnosed with hormone receptor-positive, human epidermal growth factor receptor-2 (HER2)-negative, lymph node-positive (1–3 nodes) breast cancer with a 21-gene recurrence score of ≤ 25 could safely omit chemotherapy. However, there are limited data on population-level long-term outcomes associated with omitting chemotherapy among diverse women seen in real-world practice.MethodsWe adapted an established, validated simulation model to generate the joint distributions of population-level characteristics of women diagnosed with early-stage breast cancer in the U.S. Input parameters were derived from cancer registry, meta-analyses, and clinical trial data. The effects of omitting chemotherapy on 10-year distant recurrence-free survival, life-years, and quality adjusted life-years (QALYs) were modeled for premenopausal and postmenopausal women. QALYs were discounted at 3%. Results were evaluated for subgroups stratified by race and ethnicity. Sensitivity analyses included testing results across a range of inputs. The model was validated using the published RxPONDER trial data.ResultsIn premenopausal women, the 10-year distant recurrence-free survival rates were 85.3% with chemo-endocrine and 80.1% with endocrine therapy. The estimated life-years and QALYs gained with chemotherapy in premenopausal women were 2.1 and 0.6, respectively. There was no chemotherapy benefit in postmenopausal women. There was no variation in the absolute benefit of chemotherapy across racial or ethnic subgroups. However, there were differences in distant recurrence-free survival rates, life-years, and QALYs across groups. Sensitivity analysis showed similar results. The model closely replicated the RxPONDER trial.ConclusionsModeled population-level outcomes show a small chemotherapy benefit in premenopausal women, but no benefit among postmenopausal women. Simulation modeling provides a useful tool to extend trial data and evaluate population-level outcomes.

Final Results of RIGHT Choice: Ribociclib Plus Endocrine Therapy Versus Combination Chemotherapy in Premenopausal Women With Clinically Aggressive Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer.

A head-to-head comparison of efficacy between a cyclin-dependent kinase 4/6 inhibitor plus endocrine therapy (ET) versus combination chemotherapy (CT) has never been reported in patients with clinically aggressive hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC). In this open-label, multicenter, randomized phase II trial, pre/perimenopausal women with clinically aggressive HR+/HER2- ABC were randomly assigned 1:1 to first-line ribociclib (600 mg once daily; 3 weeks on, 1 week off) plus letrozole/anastrozole and goserelin or investigator's choice of combination CT (docetaxel plus capecitabine, paclitaxel plus gemcitabine, or capecitabine plus vinorelbine). The primary end point was progression-free survival (PFS). Among 222 patients randomly assigned to ribociclib plus ET (n = 112) or combination CT (n = 110), 150 (67.6%) had symptomatic visceral metastases, 41 (18.5%) had rapid disease progression per investigator's judgment, and 31 (14.0%) had symptomatic nonvisceral disease. Overall, 106 (47.7%) patients had investigator-assessed visceral crisis. The median follow-up time was 37.0 months. At data cutoff, 31.3% (ribociclib arm) and 15.5% (CT arm) of patients had completed study treatment and transitioned to post-trial access. The median PFS was 21.8 months (ribociclib plus ET; [95% CI, 17.4 to 26.7]) and 12.8 months (combination CT; [95% CI, 10.1 to 18.4); hazard ratio, 0.61 [95% CI, 0.43 to 0.87]; P = .003. The overall response rates and the median time to response in the ribociclib versus CT arms, respectively, were 66.1% and 61.8% and 4.9 months and 3.2 months (hazard ratio, 0.76 [95% CI, 0.55 to 1.06]). Lower rates of symptomatic adverse events were observed in the ribociclib versus CT arm. First-line ribociclib plus ET showed a significant PFS benefit, similar response rates, and better tolerability over combination CT in patients with clinically aggressive HR+/HER2- ABC.

Cost-effectiveness analysis of ovarian function preservation with GnRH agonist during chemotherapy in premenopausal women with early breast cancer.

Is it economically worthwhile to use GnRH agonist (GnRHa) to prevent menopausal symptoms (MS) and protect fertility in premenopausal women with breast cancer (BC) during chemotherapy from the US perspective? It is cost-effective to administer GnRHa during chemotherapy in order to forefend MS in premenopausal patients with BC when the willingness-to-pay (WTP) threshold is $50 000.00 per quality-adjusted life-year (QALY), and to preserve fertility in young patients with BC who undergo oocyte cryopreservation (OC), or no OC, when the WTP thresholds per live birth are $71 333.33 and $61 920.00, respectively. Chemotherapy often results in premature ovarian insufficiency (POI) in premenopausal survivors of BC, causing MS and infertility. Administering GnRHa during chemotherapy has been recommended for ovarian function preservation by international guidelines. Two decision-analytic models were developed, respectively, for preventing MS and protecting fertility over a 5-year period, which compared the cost-effectiveness of two strategies: adding GnRHa during chemotherapy (GnRHa plus Chemo) or chemotherapy alone (Chemo). The participants were early premenopausal women with BC aged 18-49 years who were undergoing chemotherapy. Two decision tree models were constructed: one for MS prevention and one for fertility protection from the US perspective. All data were obtained from published literature and official websites. The models' primary outcomes included QALYs and incremental cost-effectiveness ratios (ICERs). The robustness of the models was tested by sensitivity analyses. In the MS model, GnRHa plus Chemo resulted in an ICER of $17 900.85 per QALY compared with Chemo, which was greater than the WTP threshold of $50 000.00 per QALY; therefore, GnRHa plus Chemo was a cost-effective strategy for premenopausal women with BC in the USA. Probabilistic sensitivity analysis (PSA) results showed an 81.76% probability of cost-effectiveness in the strategy. In the fertility model, adding GnRHa for patients undergoing OC and those who were unable to undergo OC resulted in ICERs of $67 933.50 and $60 209.00 per live birth in the USA, respectively. PSA indicated that GnRHa plus Chemo was more likely to be cost-effective over Chemo when the WTP for an additional live birth exceed $71 333.33 in Context I (adding GnRHa to preserve fertility in young patients with BC after OC) and $61 920.00 in Context II (adding GnRHa to preserve fertility in young patients with BC who cannot accept OC). The indirect costs, such as disease-related mental impairment and non-medical costs (e.g. transportation cost) were not included. All data were derived from previously published literature and databases, which might yield some differences from the real world. In addition, the POI-induced MS with a lower prevalence and the specific strategy of chemotherapy were not considered in the MS model, and the 5-year time horizon for having a child might not be suitable for all patients in the fertility model. When considering the economic burden of cancer survivors, the results of this study provide an evidence-based reference for clinical decision-making, showing that it is worthwhile to employ GnRHa during chemotherapy to prevent MS and preserve fertility. This work was supported by the Natural Science Foundation of Fujian Province [2021J02038]; and the Startup Fund for Scientific Research, Fujian Medical University [2021QH1059]. All authors declare no conflict of interest. N/A.

Abstract P2-11-13: Distinctive clinicopathological features of premenopausal women with intermediate 21-gene recurrence score

Abstract Backgroud Since the results of TAILORx trial were published, it was shown that premenopausal young patients with intermediate Oncotype Dx(ODx) recurrence score(RS) (16-25) may benefit from adjuvant chemotherapy. In secondary analysis of the TAILORx trial, clinicopathological features can provide complementary information in addition to Oncotype Dx results. Although ambiguous benefit of adjuvant chemotherapy in premenopausal women with intermediate risk makes clinical decision difficult, the baseline characteristic may vary depending on menopausal status. This study intends to analyze whether the intermediate-risk group shows differences in characteristics by menopausal status. Materials and Methods 760 early breast cancer patients with ER positive, HER2 negative and lymph node negative patients who have been tested ODx from July 2013 to December 2020 at Severance Hospital were retrospectively reviewed. Results Of the 760 patients, 262 patients were postmenopausal status and 498 patients were premenopausal status. Among 262 postmenopausal patients, 152 patients were in low-risk group(RS 0-20), 43 patients were in intermediate-risk group(RS 21-25), 67 patients were in high-risk group(RS 26-100). Among 498 patients, 353 patients were in low-risk group(RS 0-20), 75 patients were in intermediate-risk group(RS 21-25), 70 patients were in high-risk group(RS 26-100), respectively. In premenopausal patients with intermediate risk, clinical risk group, PR score, and Ki-67 showed a significant difference from the low risk group(p-value 0.003, <0.001 and 0.005, respectively), but no significant difference from the high risk group(p-value 0.242, 0.085 and 0.729, respectively). However, in postmenopausal patients with the intermediate risk, clinical risk group and Ki-67 did not show a significant difference from the low risk group(p-value 1.000 and 0.120, respectively), but showed a significant difference from the high risk group.(p-value 0.009 and 0.001, respectively). Conclusion In this study, some of clinicopathological characteristics of premenopausal patients with intermediate risk were closer to those of high risk group than in the low risk group, unlike postmenopausal patients with intermediate risk. In premenopausal patients with intermediate risk, benefits from adjuvant chemotherapy may be unclear, but when considering the baseline characteristic itself, there is a significant difference with the low risk group when compared with postmenopausal patients. In that point of view, more aggressive treatment decision like adjuvant chemotherapy would be helpful to premenopausal patients with intermediate risk. Keywords: 21-gene recurrence score, premenopausal breast cancer, clinicopathological features Citation Format: Jung Min Park, Jee Hyun Ahn, Soon Bo Choi, Jieon Ko, Jee Ye Kim, Hyung Seok Park, Seung Il Kim, Byeong-Woo Park, Seho Park. Distinctive clinicopathological features of premenopausal women with intermediate 21-gene recurrence score [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 P2-11-13.

Diagnostic and predictive accuracy of anti-mullerian hormone for ovarian function after chemotherapy in premenopausal women with early breast cancer

PurposeAccurate diagnosis and prediction of loss of ovarian function after chemotherapy for premenopausal women with early breast cancer (eBC) is important for future fertility and clinical decisions regarding the need for subsequent adjuvant ovarian suppression. We have investigated the value of anti-mullerian hormone (AMH) as serum biomarker for this.MethodsAMH was measured in serial blood samples from 206 premenopausal women aged 40–45 years with eBC, before and at intervals after chemotherapy. The diagnostic accuracy of AMH for loss of ovarian function at 30 months after chemotherapy and the predictive value for that of AMH measurement at 6 months were analysed.ResultsUndetectable AMH showed a high diagnostic accuracy for absent ovarian function at 30 months with AUROC 0.89 (96% CI 0.84–0.94, P < 0.0001). PPV of undetectable AMH at 6 months for a menopausal estradiol level at 30 months was 0.77. In multivariate analysis age, pre-treatment AMH and FSH, and taxane treatment were significant predictors, and combined with AMH at 6 months, gave AUROC of 0.90 (95% CI 0.86–0.94), with PPV 0.79 for loss of ovarian function at 30 months. Validation by random forest models with 30% data retained gave similar results.ConclusionsAMH is a reliable diagnostic test for lack of ovarian function after chemotherapy in women aged 40–45 with eBC. Early analysis of AMH after chemotherapy allows identification of women who will not recover ovarian function with good accuracy. These analyses will help inform treatment decisions regarding adjuvant endocrine therapy in women who were premenopausal before starting chemotherapy.

Effects of Gonadotropin-Releasing Hormone Analogs on Ovarian Function Against Chemotherapy-Induced Gonadotoxic Effects in Premenopausal Women With Breast Cancer in China

Studies of the use of gonadotropin-releasing hormone analogs (GnRHa) to protect ovarian function have shown mixed results. To determine whether administering GnRHa during chemotherapy in premenopausal women with breast cancer can reduce ovarian impairment. This randomized clinical trial, conducted at the Shanghai Jiao Tong University Affiliated Shanghai Sixth People's Hospital and Zhejiang Cancer Hospital in China, was an open-label trial involving premenopausal women aged 18 to 49 years with operable stage I to III breast cancer for which treatment with adjuvant or neoadjuvant cyclophosphamide-containing chemotherapy was planned in 2 parallel groups: treatment with chemotherapy with or without GnRHa. Enrollment occurred from September 2015 to August 2017, and follow-up ended December 2020. The data were analyzed in March 2021. A total of 405 patients were enrolled in the study, among whom 27 patients (6.7%) quit participation voluntarily, 33 (8.1%) did not meet the inclusion criteria and were excluded, and 15 (3.7%) were lost to follow-up. Ultimately 330 patients were included in the primary analysis, including 29 patients with baseline anti-Müllerian hormone levels less than 0.5ng/ mL. Eligible patients were randomly assigned (1:1) to receive chemotherapy with (n = 165) or without (n = 165) GnRHa. In patients randomized to receive GnRHa, 3.6 mg of goserelin or 3.75 mg of leuprorelin was injected subcutaneously once every 28 days from 1 to 2 weeks before the first cycle of chemotherapy to 4 weeks after the last cycle of chemotherapy. The primary end point was the rate of premature ovarian insufficiency (POI) at 12 months after chemotherapy. Premature ovarian insufficiency was defined as anti-Müllerian hormone levels of less than 0.5 ng/mL in this study. The secondary end point was overall survival (OS) and tumor-free survival (TFS). A total of 330 eligible patients could be evaluated with complete data, among whom 301 patients (91.2%; GnRHA group: mean [SD] age, 40.6 [6.7] years; control group: mean [SD] age, 40.2 [5.9] years) were eligible for primary end point analysis. At 12 months after the completion of chemotherapy, the POI rate was 10.3% (15 of 146) in the GnRHa group and 44.5% (69 of 155) in the control group (odds ratio, 0.23; 95% CI, 0.14-0.39; P < .001). Anti-Müllerian hormone resumption in the GnRHa group was significantly better than that in the control group (15 of 25 vs 6 of 44; odds ratio, 4.40; 95% CI, 1.96-9.89; P < .001). After a median follow-up of 49 months (range, 25-60 months), the differences in 4-year OS and TFS between the 2 groups were not significant. A post hoc analysis showed that in patients younger than 35 years, the TFS was higher in the GnRHa group than in the control group (93% vs 62%; P = .004; hazard ratio, 0.15; 95% CI, 0.03-0.82; P = .03). This randomized clinical trial found that administering GnRHa in treatment with chemotherapy for premenopausal patients with breast cancer reduces the risk of POI, which promotes the recovery of ovarian function. ClinicalTrials.gov Identifier: NCT02518191.

High Serum Estradiol Reduces Acute Hepatotoxicity Risk Induced by Epirubicin Plus Cyclophosphamide Chemotherapy in Premenopausal Women with Breast Cancer.

Aim: We evaluated whether acute drug-induced liver injury (DILI) caused by adjuvant chemotherapy with epirubicin plus cyclophosphamide for early breast cancer was associated with estradiol (E2), luteinizing hormone (LH), and follicle-stimulating hormone (FSH). Methods: Reproductive hormone test results of breast cancer patients were collected in the first chemotherapy cycle. E2, LH, and FSH levels were loge-transformed to normally distributed variables and were assessed using Student’s t-test to determine significant differences between the case and control groups. Hormone levels were classified according to the interquartile range and analyzed by logistic regression to determine their association with DILI caused by chemotherapy. Results: Among the 915 enrolled patients (DILI group: 204; control group: 711), menopausal status, along with serum E2, LH, and FSH levels, did not substantially differ between case and control groups. However, in the premenopause subgroup (n = 483), we found a significant difference in the E2 level between the case and control groups (p = 0.001). After adjusting for age and body mass index, premenopausal patients with 152–2,813 pg/mL E2 showed a lower risk of chemotherapy-induced DILI than patients with ≤20 pg/mL E2 (odds ratio: 0.394; 95% confidence interval: 0.207–0.748). The linear trend χ2 test revealed that E2 levels in premenopausal patients with breast cancer were inversely associated with the development of DILI. Conclusion: High serum E2 levels are associated with a reduced DILI risk in premenopausal patients with breast cancer undergoing epirubicin plus cyclophosphamide adjuvant chemotherapy.

258P Goserelin for ovarian protection in premenopausal breast cancer patients receiving cyclophosphamide containing chemotherapy

Globally, breast cancer is the most common female reproductive cancer. Although alkylating chemotherapy is a part of initial treatment in women with curable breast cancer. Premature ovrian insufficiency (POI) is a potential consequence of this treatment and can cause infertility. The current work assessed role of Goserelin in reducing risk of POI in such women. A prospective study was conducted in period between 2017 and 2019 and enrolled 150 women with histologically confirmed breast cancer. Those women were randomly subdivided into two equal groups; Goserelin group where women received chemotherapy regimens with Goserelin and control group where women received chemotherapy regimens without Goserelin. Both groups were followed for one year after end of chemotherapy to assess frequency of POI. Both groups had insignificant differences as regarding baseline data with exception of singnicantly higher negative hormonal receptor among study group. Hot flashes and headache were the most frequent adverse effects in both groups. 12 patients (16%) of Goserelin group and 22 (29%) of the control group developed POI with significant difference (P< 0.05). Median time to resumption of menses was significantly lower among study group in comparison to that control group (5.70 vs. 10.60 months; P= 0.03). Based on the current, older age increased risk to POI while negative hormonal receptors and addition of Goserelin were reducing the frequency of POI. Goserelin co-treatment with regimens of chemotherapy in premenopausal women with breast cancer could reduce the frequency of POI and preserve the fertility among those women.

Hormone therapy for premenopausal women with metastatic breast cancer: combinations with cyclin-dependent kinase inhibitors

This article discusses the problems associated with the search of the most effective treatment strategies for HER2-negative metastatic breast cancer in premenopausal women. Until recently, ovarian suppression and hormone therapy had been the main treatments used in this group of patients. The development of palbociclib, called a “breakthrough therapy”, as well as promising results of trials evaluating the efficacy of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors added to hormone therapy in postmenopausal women suggested a need for the assessment of this treatment regimen in combination with ovarian suppression in younger patients.According to the results of randomized trials and subgroup analysis, the addition of a CDK4/6 inhibitor to ovarian suppression and hormonal therapy significantly increases survival. The safety profile is similar to that of older patients. Randomized trials comparing the efficacy of palbociclib + ovarian suppression + aromatase inhibitor vs. chemotherapy in premenopausal women demonstrated significant benefits of a new treatment strategy: a CDK4/6 inhibitor as a part of combination therapy reduced the risk of progression by 36 % compared to capecitabine.

Survival outcome of combined GnRH agonist and tamoxifen is comparable to that of sequential adriamycin and cyclophosphamide chemotherapy plus tamoxifen in premenopausal patients with early breast cancer.

Survival outcome of ovarian suppression plus tamoxifen has been shown to be comparable with chemotherapy in premenopausal women; however, there are a few previous studies that compared this treatment to the current standard adriamycin and cyclophosphamide (AC) regimen. The aim of the present study was to compare the survival outcome of gonadotropin-releasing hormone (GnRH) agonist plus tamoxifen (GnRH-TAM) and chemotherapy AC plus tamoxifen (AC-TAM) in premenopausal patients with early breast cancer who were hormone receptor-positive. Premenopausal patients with early breast cancer who were treated at The Siriraj Hospital between January 2005 and December 2015 were retrospectively recruited. The inclusion criteria included newly diagnosed breast cancer, size ≤3 cm, node-negative and hormone receptor-positive. All patients received adjuvant systemic therapy and were divided into two groups. In the GnRH-TAM group, the patients received subcutaneous injection of 10.8 mg of goserelin every 3 months for 2-3 years and TAM (20 mg/day) for 5 years. In the AC-TAM group, AC was administered every 3 weeks for 4 cycles followed by TAM (20 mg/day) for 5 years. In total, 40 patients received GnRH-TAM and 130 patients received AC-TAM. The mean age at diagnosis was 44.4±6.3 years while the median follow up time was 77 (36-167) months. There was no mortality in either group and no significant difference in disease-free survival between the two groups. No adverse effect occurred and good compliance was observed in all patients who received GnRH-TAM. Treatment with GnRH-TAM resulted in a comparable survival outcome and better quality of life compared with AC-TAM.

Pretreatment anti-Mullerian hormone-based nomogram predicts menstruation status after chemotherapy for premenopausal women with hormone receptor-positive early breast cancer.

Ovarian function is important for optimizing endocrine treatment in patients with hormone receptor-positive (HR+) early breast cancer (eBC). The aim of the study was to determine whether patients' pretreatment levels of anti-Mullerian hormone (AMH) were associated with menses status after chemotherapy and to build a predictive nomogram model for amenorrhea in women with HR+ eBC. Between August 2013 and December 2014, 120 premenopausal patients with HR+ eBC were included retrospectively. The associations among age, prechemotherapy levels of AMH, follicle-stimulating hormone (FSH),and estradiol (E2) and the 2-year postchemotherapy menses status were analyzed. We determined the cutoff values of hormone levels by using the biostatistical tool (Cutoff Finder). A novel nomogram was established to predict the 2-year amenorrhea status based on the logistic analysis. Concordance index (C-index) was used to validate the capacity. One hundred nine women (90.8%) experienced amenorrhea after chemotherapy. AMH < 0.965ng/ml predicted amenorrhea at 2years (AUC 0.84, sensitivity 74% and specificity 81.8%), independent of age. The predictive nomogram based on age and pretreatment AMH and FSH levels was developed to predict the probability of 2-year postchemotherapy amenorrhea with a C-index of 0.88 (95% CI 0.84-0.91). In premenopausal patients with HR+ eBC, prechemotherapy AMH concentration was associated with the patient's 2-year amenorrhea status, independent of age. The nomogram model based on age and pretreatment AMH and FSH levels accurately predicted the 2-year amenorrhea status.

Another step towards improving oncofertility counselling of young women with Hodgkin's lymphoma.

Another step towards improving oncofertility counselling of young women with Hodgkin's lymphoma.

Importance of evaluation of ovarian function in women with breast cancer when using endocrinotherapy

The randomized clinical trials showed the effectiveness of the addition of ovarian suppression to tamoxifen or to aromatase inhibitors after adjuvant chemotherapy in women younger or older than 35 years, but with at least one high-risk factor for recurrence.However, the lack of clear criteria for evaluating the ovarian function after gonadotoxic chemotherapy, especially in women in the perimenopause, significantly complicates the choice of the right tactics for endocrine therapy. Despite proven efficacy of aromatase inhibitors as part of the adjuvant breast cancer therapy in women with preserved ovarian function in SOFT and TEXT trials, this tactic requires a more differentiated approach, according to many experts.The relative factors (STRAW criteria, age, gonadotoxicity of chemotherapy) for determining the probability of restoration of ovarian function after the chemotherapy were determined using the characteristics of the menstrual cycle in women with hormone-sensitive breast cancer based on the international trials available in the literature. The introduction of these methods for evaluating the ovarian function after chemotherapy in premenopausal women into the clinical guidelines for the adjuvant management of early breast cancer may make the choice of ovarian suppression more appropriate not only from the clinical, but also from the physiological point of view.

Concurrent and sequential initiation of ovarian function suppression with chemotherapy in premenopausal women with endocrine-responsive early breast cancer: an exploratory analysis of TEXT and SOFT

Recent breast cancer treatment guidelines recommend that higher-risk premenopausal patients should receive ovarian function suppression (OFS) as part of adjuvant endocrine therapy. If chemotherapy is also given, it is uncertain whether to select concurrent or sequential OFS initiation. We analyzed 1872 patients enrolled in the randomized phase III TEXT and SOFT trials who received adjuvant chemotherapy for hormone receptor-positive, HER2-negative breast cancer and upon randomization to an OFS-containing adjuvant endocrine therapy, initiated gonadotropin-releasing-hormone-agonist triptorelin. Breast cancer-free interval (BCFI) was compared between patients who received OFS concurrently with chemotherapy in TEXT (n = 1242) versus sequentially post-chemotherapy in SOFT (n = 630). Because timing of trial enrollment relative to adjuvant chemotherapy differed, we implemented landmark analysis re-defining BCFI beginning 1 year after final dose of chemotherapy (median, 15.5 and 8.1 months from enrollment to landmark in TEXT and SOFT, respectively). As a non-randomized treatment comparison, we implemented comparative-effectiveness propensity score methodology with weighted Cox modeling. Distributions of several clinico-pathologic characteristics differed between groups. Patients who were premenopausal post-chemotherapy in SOFT were younger on average. The median duration of adjuvant chemotherapy was 18 weeks in both groups. There were 231 (12%) BC events after post-landmark median follow-up of about 5 years. Concurrent use of triptorelin with chemotherapy was not associated with a significant difference in post-landmark BCFI compared with sequential triptorelin post-chemotherapy, either in the overall population (HR = 1.11, 95% CI 0.72-1.72; P = 0.72; 4-year BCFI 89% in both groups), or in the subgroup of 692 women <40 years at diagnosis (HR = 1.13, 95% CI 0.69-1.84) who are less likely to develop chemotherapy-induced amenorrhea. Based on comparative-effectiveness modeling of TEXT and SOFT after about 5 years median follow-up, with limited statistical power especially for the subgroup <40 years, neither detrimental nor beneficial effect of concurrent administration of OFS with chemotherapy on the efficacy of adjuvant therapy that includes chemotherapy was detected. NCT00066690 and NCT00066703.

P019 - The timing of ovarian function suppression (OFS) with chemotherapy in premenopausal women with endocrine-responsive HER2-negative early breast cancer: a secondary analysis of TEXT and SOFT

P019 - The timing of ovarian function suppression (OFS) with chemotherapy in premenopausal women with endocrine-responsive HER2-negative early breast cancer: a secondary analysis of TEXT and SOFT

Factors associated with ovarian function recovery after chemotherapy for breast cancer: a systematic review and meta-analysis.

Which factors related to patient, treatment or disease are associated with ovarian function recovery after chemotherapy in premenopausal women with breast cancer? Younger age and GnRH agonist (GnRHa) administration during chemotherapy were significantly associated with menses recovery, but this recovery was less likely in patients exposed to taxanes. To date, published meta-analyses have only assessed GnRHa administration as a possible factor for ovarian function recovery, and their results were conflicting. Current guidelines present distinct recommendations regarding the use of GnRHa for fertility preservation (FP) in women with breast cancer. A systematic review and meta-analysis of published studies in the English, Portuguese, French or Spanish languages (1990-2015), ongoing trials or completed trials (1990-2015) and conference proceedings (2000-2015) were performed. We searched the MEDLINE, Embase, LILACS, Scielo, Toxline and DART databases, online trial registries and conference proceedings. Studies were eligible if they included premenopausal women with early breast cancer treated with chemotherapy, reported ovarian function recovery data and identified factor(s) associated with recovery. Two authors independently screened the studies, extracted data and assessed the risk of bias. An odds ratio (OR) was estimated from the number of recovery events. A meta-analysis was conducted using a random-effects model. Fifteen articles were included. Five different factors were analysed: younger age and baseline levels of anti-Müllerian hormone (patient-related factors), co-administration of GnRHa, addition of taxanes to anthracycline-based chemotherapy and addition of endocrine therapy to chemotherapy (treatment-related factors). Menses recovery was the most used marker. Younger age (≤40 years) and exposure to GnRHa were positively associated with menses recovery (OR 6.07 and 2.03, respectively) but exposure to taxanes adversely affected recovery (OR 0.49). Significant heterogeneity among studies was found. A general limitation of the included studies is the use of menses as the main recovery marker. Regarding GnRHa, the substantial heterogeneity and conflicting results limit the interpretation of our results. Studies that use additional markers and have a longer follow-up are needed. The decision for using chemotherapy regimens with taxanes must take into account their potential adverse effects on female fertility. Considering the conflicting results regarding GnRHa agonist use, other fertility preservation strategies should also be considered. No external funding was received. There are no conflicts of interest to declare. This review was registered at PROSPERO (CRD42015013494).

Efficacy and safety of goserelin combined with adjuvant chemotherapy in premenopausal women with breast cancer

&lt;p class="Abstract"&gt;This study aims to evaluate the efficacy and safety of goserelin combined with chemotherapy for premenopausal women with breast cancer. Literatures were extracted from databases including Excerpta Medica Database, Springer, Pubmed, China National Knowledge Infrastructure and Chinese Biological Medicine from their inception up to May 2014. The main efficacy measures were 5 years overall survival (OS), 10 years OS, 5 years disease free survival and 5 years progress free survival. Ten randomized comparison clinical trials were eligible in this study. The result showed that goserelin combined with chemotherapy group can improve the survival rate and decrease the incidence of arthralgia in postmenopausal breast cancer patients, respectively, compared to the control group. However, they can increase the occurrence of vomiting during the chemotherapy process. Compared with the simple chemotherapy, goserelin combined with chemotherapy can provide benefits for premenopausal women with breast cancer on improving the survival rate and reducing arthralgia.&lt;/p&gt;&lt;p&gt; &lt;/p&gt;

Utility of gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage in premenopausal women with breast cancer: a systematic review and meta-analysis.

BackgroundPremature ovarian failure and infertility following chemotherapy are major concerns for premenopausal women with breast cancer. A potential ovarian function preservation strategy is administration of gonadotropin-releasing hormone (GnRH) agonists during adjuvant chemotherapy; however, studies of the clinical efficacy of GnRH agonists to protect chemotherapy-induced ovarian damage have shown mixed results.ObjectiveThis meta-analysis study was designed to estimate the efficacy of GnRH agonists administered concurrently with chemotherapy to prevent chemotherapy-induced ovarian damage in premenopausal women with breast cancer.MethodsElectronic literature databases (PubMed, EMBASE, MEDLINE, Cochrane Library databases searching, China National Knowledge Infrastructure, Web of Science, and the Wanfang Data) were searched for relevant randomized controlled trials (RCTs) published until September 2015. Only RCTs that examined the effect of GnRH agonists for chemotherapy-induced ovarian failure in premenopausal women with breast cancer were selected. The rate of spontaneous resumption of menses and spontaneous pregnancy were collected. All data were analyzed by RevMan 5.3 (Cochrane Collaboration, Copenhagen, Denmark) and Stata 12.0 (StataCorp, College Station, TX, USA).ResultsEleven RCTs with a total of 1,062 participants (GnRH agonists administered concurrently with chemotherapy, n=541; chemotherapy alone, n=521) were included in the meta-analysis. A significantly greater number of women treated with GnRH agonist experienced spontaneous resumption of menses after the adjuvant chemotherapy, yielding a pooled odds ratio of 2.57 (versus chemotherapy alone, 95% confidence interval (CI)=1.65, 4.01; P<0.0001). A subgroup analysis showed that addition of GnRH agonists significantly improved the resumption of menses rate in patients who were hormone-insensitive. However, the two treatment groups experienced similar spontaneous pregnancy (odds ratio =0.177; 95% CI=0.92, 1.40; P=0.09).ConclusionGnRH agonists cotreatment with chemotherapy in premenopausal women with breast cancer plays a beneficial role in resumption of ovarian function, with a higher rate of resumption of menses. However, treatment with GnRH agonists does not appear to exhibit its protective effects in fertility.

Goserelin for Ovarian Protection During Breast-Cancer Adjuvant Chemotherapy

ABSTRACTPremature ovarian failure is a devastating long-term toxic effect of chemotherapy for premenopausal women. The survival benefit of adjuvant chemotherapy in young women with operable hormone receptor–negative breast cancer is well known, but concern over becoming infertile may influence the c

Abstract OT2-1-02: A phase 2 study of neoadjuvant goserelin and letrozole for premenopausal women with estrogen receptor positive HER2 negative stage 2 and 3 breast cancer

Abstract Background: More than half of premenopausal women with breast cancer have tumors that are estrogen receptor (ER) positive. Despite this, there has been limited utilization of neoadjuvant endocrine therapy in that setting. Trial Design: A Phase 2 study in premenopausal women (Age&amp;gt;18) with tumor size&amp;gt;2cm and locally advanced tumor, ER positive (Allred 6-8), HER2 negative, breast cancer who are not considered candidates for breast conservation surgery (BCS) or are borderline for BCS. Patients will be treated with a LHRH-A in combination with letrozole for a period of 4 weeks. At the end of 4 weeks, patients will undergo biopsy of the tumor for Ki67 assessment along with a serum estradiol (E2) level to confirm adequate hormone suppression. Patients will then fall into one of 3 groups: 1. Postmenopausal (E2&amp;lt;10pg/ml) and Ki67≤10% These patients will remain on letrozole for 16-18 weeks followed by definitive surgery. Patients with a PEPI-0 and continued estradiol suppression will be offered surgical oophorectomy, continued letrozole and no chemotherapy (CT). 2. Postmenopausal (E2&amp;lt;10pg/ml) and Ki67&amp;gt;10% These patients will be designated endocrine therapy resistant and be offered neoadjuvant CT. Patients who decline neoadjuvant CT should be offered immediate surgery. 3. Premenopausal (E2≥10pg/ml) There is a failure of the LHRH-A to fully suppress estradiol levels at one month, treatment decisions will be individualized. Specific aims 1. To determine the pathological complete response (pCR) rate to CT in patients with a Ki67&amp;gt;10% at one month, despite a fully suppressed estradiol level. 2. To determine the PEPI-0 rate in patients whose estradiol is fully suppressed at both 4 weeks and 16 weeks and whose 4 week tumor Ki67&amp;lt;10%. 3. In patients with a PEPI-0 tumor to determine the acceptability of management with surgical oophorectomy with continued oral letrozole and no CT. Statistical methods:The study design was chosen assuming the expectation for the efficacy of neoadjuvant CT in premenopausal women with ER+ breast cancer is low, with a pCR rate in the range of 5%.Our hypothesis is that patients with tumors resistant to endocrine therapy will be enriched for sensitivity to CT to a level typical of patients with ER negative disease (20%). Thus, the trial was designed so that at a 0.1 significance level, there would be a 90% chance of detecting a pCR rate &amp;gt;20% when the true pCR rate &amp;gt;5%. A 90% binomial confidence interval (CI) for the true pCR rate will be constructed. We anticipate approximately 20% of patients will have a 4 week Ki67 &amp;gt; 10%. A sample of 235 eligible patients will be required to obtain 35 with a 4-week post treatment Ki67 value &amp;gt;10 % and estradiol level &amp;lt;10 pg/ml who are willing to switch to neoadjuvant CT. We anticipate that 75% of patients will have a 4-week Ki67 &amp;lt;10% along with estradiol &amp;lt;10pg/ml. Based upon the sample size needed, there would be 175 patients who complete 16 weeks of neoadjuvant endocrine therapy. We estimate at least 20% of the patients with a Ki67 &amp;lt;10% at 4 weeks will be in the PEPI 0, Stage 0/1 group after surgery. A 90% binomial CI will be constructed for the proportion of these who choose to forego CT. Accrual: Open June 2014. Target=235. Citation Format: Andre Mattar, Rodrigo Goncalves, Matthew J Ellis, Roberto Hegg. A phase 2 study of neoadjuvant goserelin and letrozole for premenopausal women with estrogen receptor positive HER2 negative stage 2 and 3 breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT2-1-02.