Treatment Of Premenopausal Breast Cancer Research Articles

Single-nucleotide polymorphisms and the effectiveness of taxane-based chemotherapy in premenopausal breast cancer: a population-based cohort study in Denmark

PurposeTaxane-based chemotherapy is the primary treatment for premenopausal breast cancer. Although being inconsistent, research suggests that variant alleles alter pharmacokinetics through reduced function of OATP transporters (limiting hepatic uptake), CYP-450 enzymes (hampering drug metabolism), and ABC transporters (decreasing clearance). Reduced function of DNA repair enzymes may hamper effectiveness through dose-limiting toxicities. We investigated whether single-nucleotide polymorphisms (SNPs) were associated with breast cancer recurrence or mortality in premenopausal women diagnosed with breast cancer.MethodsWe conducted a population-based cohort study of premenopausal women diagnosed with non-distant metastatic breast cancer in Denmark during 2007‒2011, when guidelines recommended adjuvant combination chemotherapy (taxanes, anthracyclines, and cyclophosphamide). Using archived formalin-fixed paraffin-embedded primary tumor tissue, we genotyped 26 SNPs using TaqMan assays. Danish health registries provided data on breast cancer recurrence (through September 25, 2017) and death (through December 31, 2019). We fit Cox regression models to calculate crude hazard ratios (HRs) and 95% confidence intervals (CIs) for recurrence and mortality across genotypes.ResultsAmong 2,262 women, 249 experienced recurrence (cumulative incidence: 13%) and 259 died (cumulative incidence: 16%) during follow-up (median 7.0 and 10.1 years, respectively). Mortality was increased in variant carriers of GSTP1 rs1138272 (HR: 1.30, 95% CI 0.95–1.78) and CYP3A rs10273424 (HR: 1.33, 95% CI 0.98–1.81). SLCO1B1 rs2306283 (encoding OATP1B1) variant carriers had decreased recurrence (HR: 0.82, 95% CI 0.64–1.07) and mortality (HR: 0.77, 95% CI 0.60–0.98).ConclusionDocetaxel effectiveness was influenced by SNPs in GSTP1, CYP3A, and SLCO1B1 in premenopausal women with non-distant metastatic breast cancer, likely related to altered docetaxel pharmacokinetics. These SNPs may help determine individual benefit from taxane-based chemotherapy.

Changes of intestinal microflora of breast cancer in premenopausal women.

Breast cancer is one of the most common malignant tumors in women. More than half of breast cancer patients are not menopausal at the time of diagnosis. The occurrence and development of premenopausal breast cancer are affected by many factors. Intestinal flora, especially SCFA-producing bacteria, participates in the development of various tumors, and there is a lack of in-depth research in premenopausal breast cancer patients. We used 16S rRNA gene sequencing, targeted metabolomics, and cell culture methods to analyze the changes in the intestinal flora and metabolites of premenopausal breast cancer patients. In addition, we treated breast cancer cells with significantly altered propionate and butyrate in vitro to examine their effects on cell activity. This study followed STROBE guidelines. We found that compared with healthy premenopausal women, the composition and symbiosis of intestinal flora in patients with premenopausal breast cancer changed significantly. The abundance of short-chain fatty acid (SCFA)-producing bacteria was significantly reduced, and the key SCFA-producing enzymes were also significantly reduced. Pediococcus and Desulfovibrio could distinguish premenopausal breast cancer patients from normal premenopausal women. The related propionate and butyrate had a certain ability to inhibit breast cancer cell viability in vitro. As SCFA-producing bacteria, Pediococcus and Desulfovibrio showed potential reference value for the diagnosis of premenopausal breast cancer. The ability of propionate and butyrate to inhibit breast cancer cell lines in vitro suggests that the relevant SCFA receptor may be a new target for the treatment of premenopausal breast cancer.

A prospective, randomized study of Toremifene vs. tamoxifen for the treatment of premenopausal breast cancer: safety and genital symptom analysis

BackgroundToremifene (TOR) is a selective oestrogen receptor modulator (SERM) and has comparable efficacy to that of tamoxifen (TAM) in breast cancer patients. Herein, we compared the safety of TOR to that of TAM in the adjuvant treatment of premenopausal breast cancer.MethodsThis was a prospective randomized and open-label clinical study. Premenopausal patients with hormonal receptor (HR)-positive early breast cancer were randomly assigned (1:1) to receive TOR) or TAM treatment. The follow-up period was 1 year. The primary end point was the incidence of ovarian cysts, and secondary end points were the incidence of endometrial thickening, changes in female hormones, the incidence of fatty liver, changes in the modified Kupperman index (mKMI) and changes in quality of life.ResultsThere were 92 patients in the final analysis. The incidences of ovarian cysts were 42.6% in the TOR group and 51.1% in the TAM group (p = 0.441). Forty-one patients (87.2%) in the TOR group and 36 patients (80.0%) in the TAM group experienced endometrial thickening (p = 0.348). The proportions of patients with fatty liver were 31.9% in the TOR group and 26.7% in the TAM group (p = 0.581). No significant differences in the mKMI or quality of life were observed between the two groups.ConclusionsTOR and TAM have similar side effects on the female genital system and quality of life in premenopausal early breast cancer patients.Trial registrationClinicalTrials.gov NCT02344940. Registered 26 January 2015 (retrospectively registered).

Comparing Clinicopathologic Features and Surgical Treatment of Premenopausal Breast Cancer across Italy and China: Report from a Medical Exchange Program

Background: This study investigated the differences in clinicopathologic features and surgical treatment between an Italian and a Chinese cohort of premenopausal women with breast cancer, and highlighted the potential advantages of international medical exchange projects. Methods: Premenopausal women who underwent surgical treatment between 2012 and 2016 at one Italian and one Chinese institution participating in a medical exchange program were compared. Factors associated with the probability to receive mastectomy were determined via logistic analysis. Changes in surgical management at the Chinese institution in the period 2018–2019, after the exchange program, were also evaluated. Results: A total of 505 patients, 318 from Italy and 187 from China, were evaluated. The Chinese patients had more frequently advanced-stage tumours, large tumour size (30.9 vs. 18.1 mm, p < 0.01), invasive carcinoma (92.5 vs. 83.3%, p < 0.01), positive axillary lymph nodes (54.5 vs. 27.4%, p < 0.01), Her-2 positivity (36.4 vs. 22.0%, p < 0.01), and high proliferative index (55.1 vs. 30.2%, p < 0.01). Positive oestrogen receptor status and rates of triple-negative breast cancer did not differ (77.0 vs. 69.5%, p = 0.09 and 14.2 vs. 16%, p = 0.56, respectively). Mastectomy rates were higher among Chinese women (85 vs. 41%, p < 0.001), whereas use of sentinel node biopsy was more frequent among Italian women (77 vs. 33%, p < 0.001). Chinese women had more than 4-fold higher risk of receiving mastectomy. In the last 2 years, the rates of breast-conserving surgery and sentinel node biopsy at the Chinese institution increased from 15 to 23%, and from 33 to 42%, respectively. Conclusions: Tumour features and surgical strategies for premenopausal breast cancer may differ significantly between Italy and China. Since the international exchange program, patients from the Chinese institution have been offered more frequently less invasive surgery. International exchange programs can help in designing epidemiological studies which may be useful for strategies to improve breast cancer management and control.

Summary and expectation of the role of GnRHa in the treatment of breast cancer

Gonadotropin-releasing-hormone analogues (GnRHa) are widely used in the treatment of premenopausal breast cancer. The anti-tumor effect of GnRHa is similar to that of surgical castration or chemotherapy, through reversibly inhibiting ovarian function and downregulating the estrogen level in premenopausal female. At the same time, GnRHa can protect the ovarian function, avoiding premature ovarian failure. Also GnRHa can reduce the breast density and endometrial thickness, as a result of which GnRHa may be used to prevent breast cancer in the higher risk population and promote quality of life in breast cancer patients. We here review the clinical roles and research progress of GnRHa in breast cancer.

Efficacy of Different Leuprolide Administration Schedules in Premenopausal Breast Cancer: A Retrospective Review

BackgroundLeuprolide is a safe and effective treatment of estrogen receptor–positive premenopausal breast cancer. Data from the SOFT/TEXT trials solidified leuprolide in combination with an aromatase inhibitor as an effective hormonal treatment for premenopausal breast cancer. However, the efficacy of monthly leuprolide depot compared to leuprolide depot every 3 months in combination with an aromatase inhibitor in this patient population is unclear. Patients and MethodsIn this single center retrospective study, 201 patients were enrolled between January 1, 2015, and October 1, 2016; 100 were included in the 7.5 mg leuprolide monthly injection plus aromatase inhibitor group and 101 in the 22.5 mg leuprolide injection every 3 months plus aromatase inhibitor group. The primary end point was the proportion of patients who experienced ovarian ablation, defined as an estradiol concentration less than 40 pg/mL and a follicle-stimulating hormone concentration of 23 to 116 mU/mL after 3 months of treatment. Significance threshold was P < .05 (2 sided). Secondary end points included disease-free survival and overall survival at 1-year follow-up, as well as adverse events reported during treatment. ResultsAll patients in the monthly leuprolide arm experienced ovarian ablation compared to 100 (99%) of 101 patients in the arm treated every 3 months (P = 1). The disease-free survival rate at 1 year was 95% in the monthly leuprolide arm and 97% in the arm treated every 3 months (P = .75). The overall survival rate at 1 year was 100% in the monthly leuprolide arm and 99% in the arm treated every 3 months (P = 1). The most common treatment-related adverse events between the 2 groups were musculoskeletal pain, hot flashes, fatigue, and insomnia. ConclusionLeuprolide acetate depot administered every 3 months is as efficacious and tolerable as a monthly injection in combination with an aromatase inhibitor for premenopausal patients with hormone receptor–positive breast cancer.

Surgical oophorectomy: a primary option in adjuvant treatment of premenopausal breast cancer

Globally, there are 500,000 annual new cases of hormone-sensitive breast cancer in premenopausal women; 400,000 of these occur in women in low and middle income countries (LMIC). With optimal adjuvant therapy, fully one third more than the half of women who might survive with primary surgery alone-more than 80%, could survive 10 years. Affordability and practicality of treatment profoundly affect global practice and these do not characterize the current standards of care – LHRH agonist plus tamoxifen or an aromatase inhibitor.Surgical oophorectomy plus tamoxifen is a safe, efficient and affordable, patient-centered and equitable adjuvant treatment, long considered equivalent to that from LHRH agonist plus tamoxifen treatment. New data additionally suggest that women, who are in extended follicular phase of their cycles at the time of surgery, benefit much less from this treatment, and women who are in normal progesterone-confirmed follicular or luteal phases, benefit more than unselected or LHRH-treated women. New data also show that surgical oophorectomy plus tamoxifen is associated with no loss of bone mineral density at the hip, and loss for only a year in the lumbar spine.The dominance of a business model for medicine, the narrow perspective and single metric-efficacy focus of guideline creation, and limited understanding of the practice of medicine for poor women worldwide, appear to be contributing to the social injustice of not offering women the option of surgical oophorectomy instead of LHRH treatment. 100,000 women a year could be saved. Further research investigating outcomes associated with the timing of surgical oophorectomy is strongly justified.

Tamoxifen with ovarian function suppression versus tamoxifen alone as an adjuvant treatment for premenopausal breast cancer: a meta-analysis of published randomized controlled trials.

BackgroundOvarian function suppression (OFS) significantly downregulates the concentration of plasma estrogens. However, it is unclear whether it offers any survival benefits if combined with adjuvant tamoxifen treatment in premenopausal women. This meta-analysis was designed to assess data from previous studies involving adjuvant tamoxifen treatment plus OFS in premenopausal breast cancer.MethodsElectronic literature databases (PubMed, Embase, the Web of Science, and the Cochrane Library) were searched for relevant randomized controlled trials published prior to February 1, 2015. Only randomized controlled trials that compared tamoxifen alone with tamoxifen plus OFS for premenopausal women with breast cancer were selected. The evaluated endpoints were disease-free survival and overall survival.ResultsFour randomized controlled trials comprising 6,279 patients (OFS combination, n=3,133; tamoxifen alone, n=3,146) were included in the meta-analysis. There was no significant improvement in disease-free survival or overall survival with addition of OFS in either the whole population or the hormone receptor-positive subgroup. The risk of distant recurrence was not reduced with the addition of OFS in the whole population. A subgroup analysis showed that addition of OFS significantly improved overall survival in patients who were administered chemotherapy.ConclusionBased on the available studies, concurrent administration of OFS and adjuvant tamoxifen treatment for premenopausal women with breast cancer has no effect on prolonging disease-free survival and overall survival, excluding patients who were administered chemotherapy. It should not be widely recommended, except perhaps for women who were hormone-receptor positive and who were also administered adjuvant chemotherapy.

Premature ovarian failure is a major risk factor for cancer-related sexual dysfunction.

Premature ovarian failure is a major risk factor for sexual dysfunction in women who receive treatment for premenopausal breast cancer. Women should be counseled on prevention of vulvovaginal dryness and atrophy when chemotherapy is initiated.

The role of hormonal ovarian ablation in adjuvant treatment of premenopausal breast cancer

Breast cancer is the most frequent malignant disease in women with about 25% compared to all malignant tumours. Chemotherapy, antiestrogen and ovarian ablation/ supression present effective adjuvant approach for premenopausal women diagnosed with hormonal depended, operable breast cancer. To evaluate benefits of combined chemo/hormonal therapy that is undutiful, but optimal application has not yet been clearly determined. Thirty-six women were divided into three therapy groups. The first group (13 women) was treated with six cycles of adjuvant FAC chemotherapy followed by regular check-ups; the second group (13 women) after six cycles of adjuvant FAC chemotherapy continued treatment with a two-year application of goserelin given by subcutaneous injections (FAC-Z); the third group (10 women), after six cycles of adjuvant FAC chemotherapy continued with once per month application of gorselin for two years and a daily application of 20 mg tamoxifen for five years (FAC-Z-T). The length of overall disease free period and survival were analyzed in all three groups. The benefit of LH-RH analogues in premenopausal women with hormone-dependent breast cancer was found to be low, and probably limited to smaller subgroups of patients, possibly such as those with either both steroid receptors positive (ER and PR) or those with an extremely high level of steroid receptors. In our paper, analyses of such subgroups could not been performed due to a small sample of patients. The effect of therapy is better in patients, who developed amenorrhoea, regardless of the type of later hormonal therapy. Ovarial ablation, whatever the method, should be probably applied as early as possible within the treatment of early breast cancer, especially in patients in whom chemotherapy induced amenorrhoea is not expected, i.e. in very young female patients.

Abstract P3-11-04: Prediagnosis Hysterectomy and Estrogen Therapy in Relation to Mortality after Breast Cancer

Abstract Total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAHBSO) can reduce breast cancer incidence by up to 50%, but less is known about its effects on breast cancer-specific and total mortality. Ovarian suppression is an accepted treatment for premenopausal breast cancer that may improve disease-free and overall survival. Prediagnosis TAHBSO may similarly reduce breast cancer mortality rates. However, all-cause mortality among women with breast cancer could be adversely affected by increases in deaths due to heart disease, stroke, or bone fracture that may be associated with TAHBSO. To examine associations between prediagnosis TAHBSO, estrogen therapy, and mortality after breast cancer, we analyzed data from a cohort of 9,215 women ages 50-79 who were diagnosed with invasive breast cancer during 1989-2003 in Wisconsin, Massachusetts, or New Hampshire. Causes and dates of death through 2006 were obtained from the National Death Index. To account for non-breast cancer deaths as competing events, we fit proportional cumulative incidence associated subhazards regression models for breast cancer-specific mortality. Cox proportional hazards regression was used to calculate multivariate hazard ratios (HR) and 95% confidence intervals (CI) for all-cause mortality. Cox regression models were stratified on study center, year of interview, and age at diagnosis and adjusted for body mass index, smoking status, family history of breast cancer and stage at diagnosis as potential confounders. Over an average 8.3 years of follow-up, 2,715 deaths were observed, including 1,507 breast cancer deaths. In total, 1,718 women (18.6%) reported TAHBSO prior to breast cancer diagnosis; while 5,937 women (64.4%) had an intact uterus and ovaries at diagnosis. Compared to women with an intact uterus and ovaries who never used postmenopausal hormones, the subhazard ratio for breast cancer-specific mortality was 0.92 for women who had intact uterus and ovaries and reported using estrogen therapy (95% CI: 0.66, 1.28), 0.71 for women who reported TAHBSO and never used hormones (95% CI: 0.54, 0.95), and 0.93 for women who reported TAHBSO and estrogen use (95% CI: 0.75, 1.16). In contrast, a reduction in all-cause mortality associated with TAHBSO was observed for women who reported estrogen therapy use. Compared to women with an intact uterus and ovaries who never used estrogens, the HR for all-cause mortality among estrogen users who had not undergone TAHBSO was 0.92 (95% CI: 0.73, 1.16), 0.87 for women who reported TAHBSO but no hormone use (95% CI: 0.74, 1.04), and 0.77 among women who reported TAHBSO and estrogen use (95% CI: 0.64, 0.92). Limitations to this analysis included missing information on hormone receptor status and treatment regimens. In these data, prediagnosis TAHBSO was associated with reduced breast cancer-specific mortality among women who never used hormones, and reduced all-cause mortality among estrogen users. Figure available in online version. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-11-04.

Adjuvant endocrine therapy of premenopausal women with early breast cancer: an overview

Tamoxifen is currently the standard of care for premenopausal women with hormone receptor-positive early breast cancers. However, endocrine strategies in premenopausal women include not only estrogen receptor blockade with tamoxifen but also temporary suppression of ovarian estrogen synthesis by luteinizing hormone-releasing hormone (LHRH) agonists, or permanent interruption of ovarian estrogen synthesis with oophorectomy or radiotherapy. Luteinizing hormone-releasing hormone agonists have proven to be as effective as surgical oophorectomy in adjuvant treatment of premenopausal breast cancer. The addition of LHRH agonists compared to no therapy reduces the annual odds of recurrence and death in premenopausal women aged less than 50 years with estrogen receptor-positive tumors. Luteinizing hormone-releasing hormone agonists alone or in combination with tamoxifen have shown disease-free survival rates similar to chemotherapy with CMF (cyclophosphamide/methotrexate/5-fluorouracil) and other second-generation chemotherapies. The role of aromatase inhibitors in combination with ovarian suppression is still not established, especially as a large phase III randomized study (Austrian Breast and Colorectal Cancer Study Group Trial 12) did not show superior efficacy compared with ovarian suppression plus tamoxifen in premenopausal early stage disease. Patients currently continue to receive ovarian suppression and tamoxifen. CYP2D6 status may become an important discriminator for the type of endocrine therapy for the premenopausal patient in the future.

Adjuvant goserelin and ovarian preservation in chemotherapy treated patients with early breast cancer: results from a randomized trial

The purpose of this randomized study was to examine if goserelin concomitant to CMF-chemotherapy as adjuvant treatment for premenopausal breast cancer, protects the ovaries from premature failure. A total of 285 premenopausal breast cancer patients, in a randomized adjuvant trial (Zoladex in premenopausal patients (ZIPP)), were assigned to a study on ovarian function. Node positive patients were assigned to CMF-(cyclophosphamide, methotrexate and 5-fluorouracil) chemotherapy in addition to endocrine therapy. All patients were randomly assigned to receive 2 years of goserelin, goserelin plus tamoxifen, tamoxifen alone or no endocrine treatment. We studied, if menses were affected in the treatment groups, up to 36 months after randomization. One year after completed CMF- and endocrine therapy, 36% of the women in the goserelin group reported menses, compared to 7% in the goserelin plus tamoxifen group, 13% in the tamoxifen group and 10% of the controls. Among women treated with goserelin, there was a statistically significant increase in the proportion of menstruating women, 1 year after completed treatment compared to at 24 months of treatment (P = 0.006), in contrast to all other treatment groups, who were unchanged or more often amenorrheic. In our study, there is some evidence of protective effect of goserelin on ovarian function in CMF treated women. This effect was not observed in the combined tamoxifen and goserelin treatment.

Premature Ovarian Failure and Its Consequences: Vasomotor Symptoms, Sexuality, and Fertility

Premature ovarian failure is a common consequence of systemic treatment for premenopausal breast cancer. Vasomotor symptoms and sexual dysfunction occur frequently in women who have an abrupt menopause from chemotherapy or ovarian suppression. However, current fertility may be impaired even in women who are menstruating after chemotherapy, and survivors are at high risk for permanent ovarian failure at a young age. Hot flashes can be managed with venlaxafine, gabapentin, or-potentially-stress management. Providing advice on treating vaginal dryness and brief sexual counseling can often alleviate sexual dysfunction. Options for fertility preservation remain limited but are improving rapidly. Distress about interrupted childbearing has a long-term impact on the quality of life.

Current NCI-sponsored Cooperative Group trials of endocrine therapies in breast cancer

Over several decades, investigators working through National Cancer Institute-sponsored Cooperative Groups have contributed to major advances in the endocrine treatment of breast cancer. Accomplishments include the benefit of tamoxifen therapy for early stage invasive and noninvasive breast cancer, the benefit of raloxifene and tamoxifen for prevention of breast cancer, the improved efficacy of tamoxifen after chemotherapy as opposed to concurrent administration, and the ability of letrozole administered after 5 years of tamoxifen to improve disease-free survival. Most recently, Cooperative Group studies have contributed to the development of a molecular profiling test, Oncotype Dx, which identifies women who have an excellent prognosis with hormonal therapy alone. Ongoing phase 3 clinical trials address the following questions: Is prolonged duration of aromatase inhibitor (AI) therapy beneficial? What is the efficacy and toxicity of steroidal versus nonsteroidal AIs in adjuvant treatment? Is combination hormonal therapy with an estrogen receptor down-regulator (fulvestrant) and an AI superior to an AI alone in the treatment of metastatic breast cancer? Does ovarian suppression offer superior benefit to standard therapy in the treatment of premenopausal breast cancer? What is the role of chemotherapy for early stage breast cancer selected via molecular profiling analysis? How can targeted therapies be used effectively in combination? Studies in subsets of patients defined by molecular profiling will be necessary to fully define breast cancer subtypes and realize the promise of personalized medicine. Close research partnerships that promote large-scale translational research are essential to the continuation of rapid achievements in this field.

Use of luteinising-hormone-releasing hormone agonists as adjuvant treatment in premenopausal patients with hormone-receptor-positive breast cancer: a meta-analysis of individual patient data from randomised adjuvant trials

Several trials have been done to assess treatment of premenopausal breast cancer with luteinising-hormone-releasing hormone (LHRH) agonists, but results have been inconclusive, especially for patients with hormone-receptor-positive cancer. We collected individual patients' data from published trials and did analyses focused on women with tumours positive for oestrogen receptor, progesterone receptor, or both. The main endpoints were recurrence and death after recurrence. We obtained data for 11 906 premenopausal women with early breast cancer randomised in 16 trials. When used as the only systemic adjuvant treatment, LHRH agonists did not significantly reduce recurrence (28.4% relative reduction, 95% CI consistent with 50.5% reduction to 3.5% increase, p=0.08) or death after recurrence (17.8%, 52.8% reduction to 42.9% increase, p=0.49) in hormone-receptor-positive cancers. Addition of LHRH agonists to tamoxifen, chemotherapy, or both reduced recurrence by 12.7% (2.4-21.9, p=0.02); and death after recurrence by 15.1% (1.8-26.7, p=0.03). LHRH agonists showed similar efficacy to chemotherapy (recurrence 3.9% increase, 7.7% reduction to 17.0% increase; death after recurrence 6.7% reduction, 20.7% reduction to 9.6% increase; both not significant). No trials had assessed an LHRH agonist versus chemotherapy with tamoxifen in both arms. LHRH agonists were ineffective in hormone-receptor-negative tumours. LHRH agonists provide an additional class of agents for treatment of premenopausal women with hormone-receptor-positive breast cancer. Optimum duration of use is unknown.

Pre-menopausal breast cancer and aromatase inhibitors: treating a new generation of women

Aromatase inhibitors have revolutionized the treatment of post-menopausal women with hormone receptor positive breast cancer. However, approximately 22% of all cases of breast cancer in North America are diagnosed in women below the age of 50 and a substantial proportion of these women are pre-menopausal. In the pre-menopausal population with hormone receptor positive disease, research on the use of aromatase inhibitors is only beginning to emerge. In this review, the mechanism of action of aromatase inhibitors and the history of endocrine treatment for pre-menopausal breast cancer is briefly presented. Available research to date regarding efficacy and toxicity of aromatase inhibitors in the treatment of pre-menopausal breast cancer and future research directions are also discussed.

Premenopausal breast cancer: chemotherapy and endocrine therapy.

Modern treatment of premenopausal breast cancer is based on well-established prognostic and predictive factors for disease outcome such as nodal status, hormone receptor expression, tumour size, tumour grading and patient age. The development of strategies according to such individual risk profiles has resulted in significant improvements both in overall and disease-free survival. An abundant number of new prognostic and predictive factors in addition to those already mentioned may help to increase our understanding of the biology of breast cancer and to individualize therapy in premenopausal patients. Although less than 10% of patients directly benefit, it is estimated that approximately each year the life of more than 4000 women in Germany will be saved or prolonged by adjuvant treatment. Whether dose intensive modifications and new antineoplastic drugs can improve disease outcome will be clarified when ongoing studies have increased observation time. At present, hormone ablation via surgical, radiotherapeutical or drug-induced castration in addition to selective estrogen response modifiers (SERM), such as tamoxifen, with or without chemotherapy remains the cornerstone of adjuvant treatment in premenopausal patients with breast cancer. In advanced disease, new highly effective hormonal and other target-oriented antineoplastic agents with few adverse effects have been recently introduced. However, overall survival in metastatic disease remains poor, even when intensive or high-dose chemotherapy is used. Special attention must be given to longer follow up and potential toxic long-term adverse effects of therapy when new regimens are applied in clinical trials.

The role of LH-RH analogues in the adjuvant and palliative treatment of breast cancer.

Ovarian ablation has a long-standing history in the treatment of metastatic breast cancer. At the end of the past century, several reports appeared on the beneficial effect of surgical removal of the ovaries in premenopausal women with advanced breast cancer. Subsequently, this treatment became the standard systemic hormone therapy for such patients. However, the disadvantage is that only a minority of patients respond, and the remainder suffer unnecessary treatment morbidity. In a random premenopausal patient population, oophorectomy produced an average 33% objective response rate. In the search for alternatives, analogues of luteinizing hormone-releasing hormone (LH-RH) have been thoroughly investigated in pre- and postmenopausal women. The results obtained have established a place for LH-RH agonists in the treatment of premenopausal women with metastatic breast cancer. In addition, these substances have replaced oophorectomy where indicated in the adjuvant hormonal treatment of premenopausal breast cancer.

Adjuvant treatment of premenopausal breast cancer with zoladex and tamoxifen: results from randomised trials by the Cancer Research Campaign (CRC) Breast Cancer Trials Group, The Stockholm Breast Cancer Study Group, the South East Sweden Breast Cancer Group and Gruppo Interdisciplinare Valutazione Intervention Oncologia (GIVIO)

Adjuvant treatment of premenopausal breast cancer with zoladex and tamoxifen: results from randomised trials by the Cancer Research Campaign (CRC) Breast Cancer Trials Group, The Stockholm Breast Cancer Study Group, the South East Sweden Breast Cancer Group and Gruppo Interdisciplinare Valutazione Intervention Oncologia (GIVIO)