Adjuvant Treatment In Premenopausal Women Research Articles

Adjuvant ovarian function suppression and tamoxifen in premenopausal breast cancer patients: A meta-analysis

Background: The benefit of adding ovarian function suppression (OFS) to tamoxifen in the adjuvant treatment of premenopausal women with breast cancer is uncertain. We conducted a meta-analysis of randomized controlled trials that addressed this question. Methods: Systematic search of PubMed, the web of science, and the meeting library of ASCO, ESMO, and SABCS was conducted using the following keywords: tamoxifen, ovarian suppression, and breast cancer. Eligible studies were those recruiting patients with breast cancer randomized to receive adjuvant tamoxifen and OFS versus tamoxifen alone. Pooled hazard ratio [HR]) for disease-free (DFS) and overall survival (OS) with 95% confidence interval (CI) were calculated using the fixed effect model. Results: We searched a total of 845 records, of which 5 clinical trials, including 7557 patients, were eligible for our analysis. Adding OFS to tamoxifen improved DFS with pooled HR: 0.88 (95% CI: 0.80-0.96, P= 0.004) and OS (pooled HR: 0.87 {95% CI: 0.77-0.98, P= 0.02}) compared to tamoxifen alone. The benefit of the addition of OFS to tamoxifen was mostly observed in patients younger than 40 years where the pooled HRs of DFS was 0.76 (95% CI: 0.63-0.91; P= 0.004), and in those who received adjuvant chemotherapy with pooled HRs of DFS 0.80 (95% CI: 0.65-0.99, P= 0.042). There was an increase in the incidence of all grade musculoskeletal symptoms and high-grade hot flushes with the addition of OFS with risk ratios of 1.12 (95% CI: 1.07-1.17, P< 0.001) and 2.14 (95% CI: 1.01-4.51, P= 0.047) respectively. Conclusion: Our analysis indicates that the addition of OFS to tamoxifen improves DFS and OS. This strategy could be considered in patients in which tamoxifen alone is not deemed sufficient or in case of poor tolerance to OFS with aromatase inhibitors.

Ovarian suppression for adjuvant treatment of hormone receptor-positive early breast cancer.

Ovarian suppression for adjuvant treatment of hormone receptor-positive early breast cancer.

Changes in bone mineral density during 5years of adjuvant treatment in premenopausal breast cancer patients.

Adjuvant treatment for breast cancer in postmenopausal women is a risk factor for bone loss. However, the association between bone mineral density (BMD) changes in premenopausal breast cancer patients and various adjuvant treatment regimens is not well characterized. In this study, we evaluated the changes in BMD according to adjuvant treatment in premenopausal women with breast cancer. Between 2006 and 2010, BMD data of 910 premenopausal women with breast cancer before operation and 1, 2, 3.5, and 5years post-operation were retrospectively analyzed. The patients were divided according to the type of treatment: observation (O), tamoxifen (T), chemotherapy (C), C followed by T (C → T), and gonadotropin-releasing hormone (GnRH) agonist with T (G + T). After 5years of follow-up, BMD changes were similar between the T and O groups (all p > 0.05). Within 1year of treatment, the C group showed the most significant BMD loss. The C → T and G + T groups showed more significant BMD loss in the lumbar spine and femur than the O and T groups (both p < 0.001, both). After 1year of treatment, BMD loss in the lumbar spine was significantly greater in the C → T and G + T groups than in the T group; this tendency was maintained for 5years of treatment (all p < 0.005). Premenopausal women who received adjuvant treatment which induced menopause showed significant bone loss which lasted for 5years. Although no significant difference was observed between the O and T groups, tamoxifen treatment during chemotherapy or GnRH agonist treatment might prevent bone loss.

Impact on disease-free survival of the duration of ovarian function suppression, as postoperative adjuvant therapy, in premenopausal women with hormone receptor-positive breast cancer: a retrospective single-institution study

IntroductionAlthough tamoxifen (TAM) plus ovarian function suppression (OFS) is considered as a standard adjuvant treatment for premenopausal women with hormone receptor-positive breast cancer, the optimal duration of OFS has not yet been established. This retrospective study was designed to assess the duration of OFS and the impact of the duration of OFS on the DFS in these patients.MethodsWe retrospectively reviewed the data of premenopausal patients with breast cancer who received TAM + OFS (goserelin or leuprorelin) as adjuvant therapy between February 2004 and June 2015. The primary analysis was a comparison of the disease-free survival (DFS) between patients who received OFS for 3 years or less (OFS ≤ 3 years group) and those who received OFS for longer than 3 years (OFS > 3 years group).ResultsWe analyzed the data of 215 premenopausal patients diagnosed as having hormone receptor-positive breast cancer. A propensity score-matched model showed the absence of any significant difference in the DFS between the OFS ≤ 3 years group and OFS > 3 years group (6-year DFS rate, 93.2 vs. 94.0%; log-rank test p = 0.767).ConclusionsOur data showed that among premenopausal women with hormone receptor-positive breast cancer who received TAM + OFS as adjuvant endocrine therapy, there was no significant difference in the DFS between the OFS ≤ 3-year group and OFS > 3-year group. A randomized trial is needed to establish the optimal duration of OFS for these patients.

Contribution of ABCB1 and CYP2D6 genotypes to the outcome of tamoxifen adjuvant treatment in premenopausal women with breast cancer.

Recent pre-clinical evidence suggests that the active metabolite of tamoxifen, endoxifen, is a substrate for efflux pump P-glycoprotein. The aim of our study was to evaluate, if the polymoprhisms within ABCB1 gene alter tamoxifen adjuvant treatment efficacy in premenopausal women. Totally 71 premenopausal women with estrogen receptor positive breast cancer indicated for tamoxifen adjuvant treatment were followed retrospectively for median period of 56 months. The gentic polymorphisms of CYP2D6 and ABCB1 were analyzed and potential covariates as tumor grading, staging, age at the diagnosis, comedication, quantitative positivity of ER or PR were also evaluated. Cox proportional-hazards regression model indicated that patients carrying at least one variant allele in ABCB1 rs1045642 had significantly longer time to event survival compared to wild type subjects. Non-significant trend was noted for better treatment outcome of patients carrying at least one variant allele in the SNP rs2032582, while for the CYP2D6 polymorphism poor metabolizer phenotype resulted in worse outcome in comparison to extensive metabolizers subjects with HR of 4.04 (95 % CI 0.31-52.19). Similarly, patients using CYP2D6 inhibitors had non-significantly shorter time-to-event as compared to never users resulting in hazard ratio of 2.06 (95 % CI 0.40-10.63). ABCB1 polymorphisms may affect outcome of tamoxifen adjuvant treatment in premenopausal breast cancer patiens. This factor should be taken into account in addition to the CYP2D6 polymorphism or phenotypic inhibition of CYP2D6 activity.

Picking the optimal endocrine adjuvant treatment for pre-menopausal women

Endocrine treatments are key component of the adjuvant strategy for pre-menopausal patients with luminal tumors. Treatment options should be based not only upon the risk of relapse and level of endocrine responsiveness, but also on co-morbidities, preferences of the patient and degree of side effects. Tamoxifen should still be considered as an appropriate endocrine therapy in a large group of premenopausal patients (e.g. lower risk patient, presence of co-morbidities, patient preference). However, the results of the SOFT and TEXT trials, evaluating the value of ovarian function suppression (OFS) as well as the role of adjuvant aromatase inhibitor (AI), raised questions about the use of tamoxifen alone in selected higher risk patient. In the SOFT study, premenopausal patients did not benefit from the addition of OFS, but for those women at sufficient risk of recurrence to deserve adjuvant chemotherapy and who maintained pre-menopausal estradiol, the addition of OFS to tamoxifen reduced the risk of recurrence. Moreover, in the TEXT trial, adjuvant treatment with exemestane plus OFS, as compared with tamoxifen plus OFS, significantly improved disease-free survival, breast cancer-free interval and distant disease-free survival, thus representing a new treatment option. Recent available information on endocrine options for younger patients with luminal tumors support the use of tailored endocrine treatments. Issues specific for younger patients related to pregnancies desire, family planning, safety, quality of life and subjective side effects should be a priority in the therapeutic algorithm.

Improved adjuvant endocrine therapy for premenopausal women with endocrine responsive disease.

Results from two randomised global trials (SOFT & TEXT) designed to newly define the most effective components of adjuvant endocrine therapy for premenopausal women with endocrine responsive disease, showed that for some, those with high risk of relapse, the use of the aromatase inhibitor exemestane together with ovarian function suppression with GnRH analogue (triptorelin) yielded the most favourable treatment outcome compared with tamoxifen. For women with low risk of relapse, treatment with tamoxifen was similar to ovarian function suppression together with either exemestane or tamoxifen. For women with intermediate risk of relapse, ovarian function suppression added to tamoxifen was not inferior to exemestane, while it resulted in superior outcomes compared to tamoxifen alone. Now, these trials provide critical information for the adjuvant treatment of premenopausal women with endocrine responsive breast cancer and are important for the development of future trials for further improvement of adjuvant endocrine therapies for the younger population.

PG 1.03 Picking the optimal endocrine adjuvant treatment for pre-menopausal women

PG 1.03 Picking the optimal endocrine adjuvant treatment for pre-menopausal women

A randomized controlled study evaluating safety and efficacy of leuprorelin acetate every-3-months depot for 2 versus 3 or more years with tamoxifen for 5 years as adjuvant treatment in premenopausal patients with endocrine-responsive breast cancer.

BackgroundLuteinizing hormone-releasing hormone (LH-RH) agonists provide effective adjuvant treatment for premenopausal women with endocrine-responsive breast cancer. Here, we investigated appropriate treatment durations of an LH-RH agonist, leuprorelin.MethodsWe conducted an open-label, randomized controlled pilot study to evaluate the safety and efficacy of leuprorelin subcutaneously administered every-3-months for 2 versus 3 or more, up to 5 years, together with daily tamoxifen for 5 years in premenopausal endocrine-responsive breast cancer patients. Primary endpoints were disease-free survival (DFS) and safety.ResultsEligible patients (N = 222) were randomly assigned to receive leuprorelin for either 2 years (N = 112) or 3 or more years (N = 110) with tamoxifen for 5 years after surgery. Leuprorelin treatment for 3 or more years provided no significant difference in DFS rate over 2 years: 94.1 versus 91.8 % at 144 weeks (3 years) after the second year (week 96) and 90.8 versus 90.4 % at the fifth year (week 240). The overall survival rate was 100 % for both groups during the third through fifth year study period. There were no significant differences in the incidence of adverse events (AEs) between the 2 groups: most AEs were rated grade 1 or 2.ConclusionsAdjuvant leuprorelin treatment for 3 or more years with tamoxifen showed a survival benefit and safety profile similar to that for 2 years in premenopausal endocrine-responsive breast cancer patients. No new safety signal was identified for long-term leuprorelin treatment. Longer follow-up observation is needed to determine the optimal duration of leuprorelin treatment.

Optimal management of the premenopausal patient with estrogen receptor-positive breast cancer.

Tamoxifen is the standard of care in the adjuvant treatment of premenopausal women with estrogen receptor-positive (ER+) breast cancer. Ovarian suppression (OS) is another method of endocrine therapy and has been shown to decrease the risk of recurrence and confer a survival advantage when used as the sole source of hormone therapy. However, there is no evidence that OS is superior to treatment with tamoxifen. Studies comparing OS with or without tamoxifen compared with chemotherapy have demonstrated comparable effects. There does not appear to be any additional benefit when OS is combined with chemotherapy, although there is a suggestion that there may be an effect in the subgroup of young women (aged younger than 40 years) who are least likely to experience chemotherapy-induced cessation of ovarian function. Interpretation of existing data is hampered by the lack of studies incorporating modern chemotherapy regimens and the absence of molecular analyses that would allow us to better define populations most likely to benefit from endocrine therapy. Last, the role of aromatase inhibitors (AI) in the premenopausal setting remains undefined. Two recent studies, SOFT and TEXT, aim to shed light on the effect of OS and AI in premenopausal ER+ breast cancer and are pending analysis.

Adjuvant treatment of premenopausal women with endocrine-responsive early breast cancer: Design of the TEXT and SOFT trials

ObjectivesIn 2003 the International Breast Cancer Study Group (IBCSG) initiated the TEXT and SOFT randomized phase III trials to answer two questions concerning adjuvant treatment for premenopausal women with endocrine-responsive early breast cancer: 1-What is the role of aromatase inhibitors (AI) for women treated with ovarian function suppression (OFS)? 2-What is the role of OFS for women who remain premenopausal and are treated with tamoxifen? MethodsTEXT randomized patients to receive exemestane or tamoxifen with OFS. SOFT randomized patients to receive exemestane with OFS, tamoxifen with OFS, or tamoxifen alone. Treatment was for 5 years from randomization. ResultsTEXT and SOFT successfully met their enrollment goals in 2011. The 5738 enrolled women had lower-risk disease and lower observed disease-free survival (DFS) event rates than anticipated. Consequently, 7 and 13 additional years of follow-up for TEXT and SOFT, respectively, were required to reach the targeted DFS events (median follow-up about 10.5 and 15 years). To provide timely answers, protocol amendments in 2011 specified analyses based on chronological time and median follow-up. To assess the AI question, exemestane + OFS versus tamoxifen + OFS, a combined analysis of TEXT and SOFT became the primary analysis (n = 4717). The OFS question became the primary analysis from SOFT, assessing the unique comparison of tamoxifen + OFS versus tamoxifen alone (n = 2045). The first reports are anticipated in mid- and late-2014. ConclusionsWe present the original designs of TEXT and SOFT and adaptations to ensure timely answers to two questions concerning optimal adjuvant endocrine treatment for premenopausal women with endocrine-responsive breast cancer.Trial RegistrationTEXT: Clinicaltrials.govNCT00066703SOFT: Clinicaltrials.govNCT00066690

Letrozole plus GnRH analogue as preoperative and adjuvant therapy in premenopausal women with ER positive locally advanced breast cancer

Patients with large ER positive tumors candidate to preoperative chemotherapy may also benefit from a concurrent endocrine intervention, but this issue has been scarcely investigated due to concerns arising from unfavorable results emerged from an adjuvant trial of concurrent tamoxifen and chemotherapy. We retrospectively investigated the activity of letrozole plus GnRH analogue (GnRH-a) administered concurrently with preoperative chemotherapy and as adjuvant treatment in premenopausal women with locally advanced ER positive breast cancer consecutively admitted at the European Institute of Oncology. Results were compared with those of a non-randomized unmatched control group of premenopausal women with locally advanced ER positive breast cancer receiving preoperative chemotherapy, followed by tamoxifen and GnRH-a after surgery. Primary endpoints were pathological complete response (pCR) rate, decrease of Ki67 and disease free survival (DFS). One-hundred and nineteen women constituted the study group, while 95 patients served as controls. The pCR rate was 5.0 vs 1.1% in the study and control group, respectively. A statistically significant greater suppression of Ki67 was observed in patients receiving chemoendocrine therapy as compared with controls (P = 0.003). At a median follow up of 59 months, 26 events occurred in the chemoendocrine group and 48 in the control group. Five-year DFS was 78 vs 41% in the study and in the control group, respectively [adjusted HR 0.46, 95% CI 0.27-0.79, P = 0.0047]. The concurrent administration of letrozole and GnRH-a with preoperative chemotherapy was highly effective in premenopausal women with large ER positive breast cancer in terms of decreased proliferation and of improved DFS. Randomized studies are warranted to establish the role of the addition of endocrine therapy to chemotherapy as standard preoperative approach for ER positive locally advanced breast cancer as well as of letrozole in combination with GnRH-a for the treatment of premenopauasal women with early breast cancer.

LHRH agonists for adjuvant therapy of early breast cancer in premenopausal women.

LHRH agonists for adjuvant therapy of early breast cancer in premenopausal women.

Endocrine Therapy plus Zoledronic Acid in Premenopausal Breast Cancer

Ovarian suppression plus tamoxifen is a standard adjuvant treatment in premenopausal women with endocrine-responsive breast cancer. Aromatase inhibitors are superior to tamoxifen in postmenopausal patients, and preclinical data suggest that zoledronic acid has antitumor properties. We examined the effect of adding zoledronic acid to a combination of either goserelin and tamoxifen or goserelin and anastrozole in premenopausal women with endocrine-responsive early breast cancer. We randomly assigned 1803 patients to receive goserelin (3.6 mg given subcutaneously every 28 days) plus tamoxifen (20 mg per day given orally) or anastrozole (1 mg per day given orally) with or without zoledronic acid (4 mg given intravenously every 6 months) for 3 years. The primary end point was disease-free survival; recurrence-free survival and overall survival were secondary end points. After a median follow-up of 47.8 months, 137 events had occurred, with disease-free survival rates of 92.8% in the tamoxifen group, 92.0% in the anastrozole group, 90.8% in the group that received endocrine therapy alone, and 94.0% in the group that received endocrine therapy with zoledronic acid. There was no significant difference in disease-free survival between the anastrozole and tamoxifen groups (hazard ratio for disease progression in the anastrozole group, 1.10; 95% confidence interval [CI], 0.78 to 1.53; P=0.59). The addition of zoledronic acid to endocrine therapy, as compared with endocrine therapy without zoledronic acid, resulted in an absolute reduction of 3.2 percentage points and a relative reduction of 36% in the risk of disease progression (hazard ratio, 0.64; 95% CI, 0.46 to 0.91; P=0.01); the addition of zoledronic acid did not significantly reduce the risk of death (hazard ratio, 0.60; 95% CI, 0.32 to 1.11; P=0.11). Adverse events were consistent with known drug-safety profiles. The addition of zoledronic acid to adjuvant endocrine therapy improves disease-free survival in premenopausal patients with estrogen-responsive early breast cancer. (ClinicalTrials.gov number, NCT00295646.)

Leuprorelin Acetate Every-3-Months Depot Versus Cyclophosphamide, Methotrexate, and Fluorouracil As Adjuvant Treatment in Premenopausal Patients With Node-Positive Breast Cancer: The TABLE Study

Ovarian suppression with luteinizing hormone-releasing hormone (LHRH) agonists is an effective adjuvant treatment for premenopausal women with estrogen receptor (ER) -positive breast cancer. Whereas monthly LHRH agonist therapy has been well established, the value of every-3-months (3-monthly) formulations is unclear. This randomized phase III trial was performed to compare the 3-monthly depot LHRH agonist leuprorelin acetate (LAD-3M; n = 299) and chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (CMF; n = 300) in pre- or perimenopausal patients with ER-positive, node-positive breast cancer. With a median follow-up of 5.8 years, recurrence-free survival was similar for patients treated with LAD-3M or CMF (hazard ratio [HR], 1.19; 95% CI, 0.94 to 1.51; P = .15). There was no substantial heterogeneity in the relative treatment effect among subgroups defined by age, progesterone receptor (PR) status, nodal status, hormone levels, or menstrual recovery after treatment. Exploratory overall survival analysis favored LAD-3M (HR, 1.50; 95% CI, 1.13 to 1.99; P = .005). Chemotherapy-related adverse effects such as nausea, vomiting, and alopecia were more common with CMF, whereas symptoms of estrogen suppression such as hot flushes and sweating were initially more pronounced with LAD-3M. The 3-monthly depot LHRH-agonist leuprorelin acetate is an effective adjuvant treatment in premenopausal patients with hormone receptor-positive, node-positive breast cancer that is not inferior to CMF.

Breast cancer, menopause, and long-term survivorship: critical issues for the 21st century

Breast cancer accounts for 33% of all incident cancers in women in North America, and there are an estimated >2 million breast cancer survivors in the United States today. Ovarian hormones are intimately involved in the initiation and promotion of breast cancer development, with targeted endocrine therapies being the most widely used as anticancer treatment. It is not surprising that these treatments frequently cause persistent menopausal symptoms in breast cancer survivors. In addition, adjuvant chemotherapy often induces premature menopause in younger patients with breast cancer. Some women at high risk for the development of breast cancer (e.g., precancerous breast disease, carriers of deleterious hereditary predisposition genes) experience vasomotor symptoms as a result of tamoxifen therapy or preventive oophorectomy. Clinical management of menopausal symptoms in these settings is complicated by the relative prohibition of hormonal therapies and the fact that breast cancer-directed therapies often exacerbate these menopausal symptoms. Thus, this special population of women requires unique management strategies and deserves separate consideration.

Same gain, less pain: potential patient preferences for adjuvant treatment in premenopausal women with early breast cancer

The aim of this study was to determine the treatment preferences (adjuvant goserelin or cyclophosphamide, methotrexate and fluorouracil (CMF) chemotherapy) of healthy premenopausal women should they hypothetically develop oestrogen-receptor (ER) positive early breast cancer. Two hundred pre or peri-menopausal women read two scenarios describing goserelin or chemotherapy. Information included: How and where treatments were administered, side-effects, their likely persistence and impact on fertility. Women stated their unprompted initial and final preferences with reasons for the choices made. Respondents showed an overwhelming preference for goserelin. 156 (78%) women favoured goserelin, 22 (11%) chemotherapy and 22 (11%) remained undecided ( P < 0.0001). Primary reasons for preferring goserelin for were 105 (71%) avoidance of chemotherapy side-effects, especially hair loss, perceived convenience and less disruption to normal life 54 (36%). The minority who preferred chemotherapy, valued the treatment finishing more quickly. These results together with clinical trial data showing equivalence of goserelin with CMF regimens suggest that premenopausal women with ER-positive tumours should at least be offered the choice of either adjuvant hormone therapy or chemotherapy.

Ovarian ablation in the adjuvant treatment of premenopausal and perimenopausal breast cancer.

Ovarian ablation has been employed in the treatment of breast cancer for many decades and, more recently, its value as an adjuvant treatment for premenopausal women with early-stage disease has been clearly demonstrated. This review examines the different methods of achieving ovarian ablation and assesses the relevance of ovarian suppression as a treatment aim. Medline searches were used to identify recent key articles relating to the adenoma-carcinoma sequence. Further relevant articles were obtained by manual scanning of the reference lists of selected papers. Ovarian ablation has historically been achieved by surgical or radiological intervention. Although beneficial in premenopausal disease, these methods produce permanent ablation that results in a premature menopause, which may be associated with long-term adverse events. A series of trials have recently demonstrated the benefits of luteinizing hormone releasing hormone (LHRH) agonists, such as goserelin and leuprorelin, as adjuvant treatment for premenopausal hormone-sensitive disease. LHRH agonists produce a reliable suppression of ovarian oestrogen production of equivalent efficacy to adjuvant chemotherapy in hormone-sensitive disease. Effective ovarian suppression is marked by amenorrhoea, but studies have suggested that permanent amenorrhoea is not necessary to confer benefit in the treatment of early breast cancer. LHRH agonists therefore represent a beneficial therapeutic option for premenopausal patients with hormone-sensitive early disease.

Breast cancer.

Several interesting aspects of breast cancer were covered at this year's American Society of Clinical Oncology meeting. Sentinel lymph node (SN) mapping is now in widespread use, in concert with the general trend toward trying to decrease the morbidity of breast cancer surgery. With every advance, however, comes new challenges, and there was a timely presentation from Giuliano's group addressing the controversial issue of how to interpret the presence of cells in the SN seen only with keratin stains but not by routine hematoxylin and eosin stains. Two abstracts addressed the issue of whether for certain women with invasive breast cancer radiation therapy could be omitted after lumpectomy. Another interesting topic related to hormonal issues in the adjuvant treatment of premenopausal women. An analysis from the ZIPP-TRIAL reported on bone marrow density studies in young women given two years of ovarian suppression in the adjuvant setting: it seems that the loss of bone density may be reversible and, more interestingly, may be prevented with concurrent tamoxifen. Two other presentations looked at the prognostic significance of drug-induced amenorrhea in young women treated with adjuvant chemotherapy and at the efficacy of ovarian suppression during chemotherapy in preserving fertility. In an unpublicized presentation, Mary-Claire King presented very interesting results from the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial suggesting that tamoxifen may be an effective chemopreventive drug for women with BRCA2, but not BRCA1, mutations. Two important presentations re-analyzed the outcome of the pivotal trials using Herceptin to treat metastatic breast cancer and nicely show that FISH analysis of HER-2 overexpression is a more accurate indicator of response to Herceptin than immunohistochemical staining. Finally, there were two interesting presentations related to tamoxifen resistance which may be relevant clinically, pertaining to subsequent raloxifene use and the interaction of the estrogen receptor and EGF receptor pathways, respectively.

Uracil-ptegafur (UFT) + Prednimustine (P) as an oral adjuvant treatment for premenopausal women with node positive breast cancer

Uracil-ptegafur (UFT) + Prednimustine (P) as an oral adjuvant treatment for premenopausal women with node positive breast cancer