Is chemotherapy necessary for premenopausal women with lower-risk node-positive, endocrine responsive breast cancer? 10-year update of International Breast Cancer Study Group Trial 11-93

Introduction International Breast Cancer Study Group (IBCSG) Trial 11-93 is the largest trial evaluating the role of the addition of chemotherapy to ovarian function suppression/ablation (OFS) and tamoxifen in premenopausal patients with endocrine-responsive early breast cancer. Methods IBCSG Trial 11-93 is a randomized trial comparing four cycles of adjuvant chemotherapy (AC: doxorubicin or epirubicin, plus cyclophosphamide) added to OFS and 5 years of tamoxifen versus OFS and tamoxifen without chemotherapy in premenopausal patients with node-positive, endocrine-responsive early breast cancer. There were 174 patients randomized from May 1993 to November 1998. The trial was closed before the target accrual was reached due to low accrual rate. Results Patients randomized tended to have lower risk node-positive disease and the median age was 45. After 10 years median follow up, there remains no difference between the two randomized treatment groups for disease-free (hazard ratio = 1.02 (0.57–1.83); P = 0.94) or overall survival (hazard ratio = 0.97 (0.44–2.16); P = 0.94). Conclusion This trial, although small, offers no evidence that AC chemotherapy provides additional disease control for premenopausal patients with lower-risk node-positive endocrine-responsive breast cancer who receive adequate adjuvant endocrine therapy. A large trial is needed to determine whether chemotherapy adds benefit to endocrine therapy for this population.     

Role of adjuvant endocrine therapy in early-stage breast cancer

The value of adjuvant endocrine therapy in saving lives of women with estrogen receptor-positive (ER(+)) early-stage breast cancer cannot be disputed. Tamoxifen has proven to be effective in improving relapse-free and overall survival in both pre- and postmenopausal women with ER(+) early-stage breast cancer. In the meta-analysis of the Early Breast Cancer Trialists' Collaborative Group, the proportional reduction in recurrence and mortality for 5 years of tamoxifen therapy was 50% and 28% respectively for patients with ER(+) tumors. These reductions in recurrence and mortality were similar in both lymph node-negative (N(-)) and lymph node-positive (N(+)) patients and translate to an absolute improvement in 10-year survival of approximately 11% in N(+) patients and 6% in N(-) patients. Current data suggest that about 5 years of tamoxifen therapy is the optimal duration of treatment. For women with ER(-)/progesterone receptor-negative (PR(-)) tumors, tamoxifen does not lower the risk of distant metastases or improve survival. In ER(+) patients, the addition of tamoxifen to chemotherapy further lowers the risk of recurrence by about 30% to 40% when compared to chemotherapy alone. In premenopausal women with ER(+) breast cancer, ovarian ablation has proven to be as effective as chemotherapy in improving both relapse-free and overall survival and the potential additive role of ovarian ablation to chemotherapy and/or tamoxifen is presently being explored in clinical trials. The combination of tamoxifen and ovarian ablation is currently being tested and may be superior to tamoxifen alone. In addition, newer, more effective, and less toxic aromatase inhibitors are also being evaluated in clinical trials in the adjuvant setting and have great promise. "Pure" antiestrogens or selective estrogen receptor down-regulators (SERDs) will be studied in adjuvant clinical trials in the near future. Recent data also suggest that molecular markers such as HER-2/neu may predict the response to endocrine therapy, and other predictive factors are currently being evaluated. Lastly, there is renewed interest in neoadjuvant endocrine therapy, a treatment option that may select those patients with early-stage breast cancer most likely to benefit from endocrine therapy.     

The choice of systemic adjuvant therapy in receptor-positive early breast cancer

Patients with endocrine-responsive breast cancer represent a distinct population for which tailored adjuvant treatments are needed. Endocrine therapy is mandatory for this population. For premenopausal patients, ovarian ablation or tamoxifen can be recommended; the combination of both, as well as the combination of ovarian ablation and aromatase inhibitors is under investigation. For postmenopausal patients, tamoxifen for 5 years is the 'standard of care'. Anastrozole can be recommended for patients with a contraindication to tamoxifen. The addition of 5 years of letrozole after 5 years of tamoxifen has yielded benefits in terms of disease-free survival. The sequential use of tamoxifen and exemestane was superior to tamoxifen for 5 years. However, in both studies, long-term toxicity is still not fully evaluated. The addition of chemotherapy to endocrine treatment can be recommended for patients at high risk of relapse and in young patients. Chemotherapy should consist of 3-6 cycles of cyclophosphamide, methotrexate, 5-fluorouracil or of an anthracycline-containing regimen. The addition of taxanes cannot be routinely recommended in this population. Endocrine treatment should start after completion of chemotherapy.     

Controversies in adjuvant endocrine treatment of premenopausal women

For patients with hormone receptor-positive breast cancer, some form of endocrine therapy is central to the management of their disease. For premenopausal patients in whom estrogen synthesis occurs primarily in the ovaries, current treatment options include ovarian ablation or suppression and selective estrogen receptor modulators such as tamoxifen and toremifene. Ovarian ablation and tamoxifen have demonstrated their effectiveness in the adjuvant setting, reducing the risk of recurrence and death. However, although some studies suggest ovarian ablation results in an equivalent outcome to chemotherapy alone, studies examining the combination have not demonstrated a clear benefit with the addition of ovarian suppression to standard chemotherapy. Results from trials combining ovarian suppression with tamoxifen have also been inconclusive. Finally, although aromatase inhibitors cannot be used as monotherapy in premenopausal patients, the reduction in the risk of recurrence observed with the integration of these agents into adjuvant regimens in postmenopausal patients when compared with the standard 5 years of tamoxifen has stimulated interest in evaluating the combination of ovarian suppression with an aromatase inhibitor in premenopausal women. Several ongoing trials will investigate these combinations as well as ovarian suppression plus tamoxifen.     

Adjuvant chemoendocrine therapy for early breast-cancer - is it worthwhile - (review)

The overview published in 1999 by the Early Breast Cancer Trialist' Cooperative Group demonstrated that systemic therapy after surgical removal of primary breast tumors prolongs both disease-free and overall survival of patients when compared with no systemic therapy, Specifically, both chemotherapy and ovarian ablation in patients aged less than 50 and tamoxifen in those aged 50 or more achieve a reduction of one-fifth to one-fourth in the annual odds of recurrence or death from any cause. The relative effect of different therapies is independent of the stage of the disease, while the absolute benefit depends not only upon the relative effect of treatment but also upon the baseline prognosis of patients. The overview did not report a direct estimation of the effect of combined chemoendocrine adjuvant therapy. Among the effects that may confound the evaluation of chemoendocrine adjuvant therapy are: (a) the possibility of biological interactions between drugs; (b) the presence on tumor cells of steroid hormone receptors; (c) the suppression of ovarian activity induced by chemotherapy in most premenopausal patients; (d) the scheduling of chemotherapy and endocrine therapy. Based on data of the overview, relevant questions are: (i) does the addition of endocrine therapy (tamoxifen dr ovarian ablation) to chemotherapy improve the outcome of premenopausal patients? (ii) does the addition of chemotherapy to tamoxifen improve the outcome of postmenopausal patients? We have reviewed single randomised trials in an attempt to answer these questions. In premenopausal patients, the addition of tamoxifen to chemotherapy probably induces only small advantages. The addition of ovarian ablation to chemotherapy could improve survival. The relationship between oophorectomy and receptor status has not been extensively studied; however, the addition of oophorectomy, like the addition of tamoxifen, to chemotherapy could be cost effective in cases of estrogen receptor-positive tumors. The effect of tamoxifen in association with ovarian ablation, after chemotherapy, has not yet been studied. In postmenopausal patients the addition of chemotherapy to tamoxifen is debated. The role of receptor status seems to be important in these patients. Most studies found that chemotherapy does not significantly increase the effect of tamoxifen in the subgroup of patients with receptor-positive tumors, while it does increase toxicity. On the contrary, the addition of chemotherapy to tamoxifen, in patients with receptor-negative tumors could significantly improve results.     

Risk factors for locoregional recurrence among breast cancer patients: results from International Breast Cancer Study Group Trials I through VII.

PURPOSE: To explore prognostic factors for locoregional failures (LRF) among women treated for invasive breast cancer within clinical trials of adjuvant therapies. PATIENTS AND METHODS: The study population consisted of 5,352 women who were treated with a modified radical mastectomy and enrolled in one of seven International Breast Cancer Study Group randomized trials. A total of 1,275 women with node-negative disease received either no adjuvant therapy or a single cycle of perioperative chemotherapy, and 4,077 women with node-positive disease received adjuvant chemotherapy of at least 3 months' duration and/or tamoxifen. Median follow-up is 12 to 15.5 years. RESULTS: In women with node-negative disease, factors associated with increased risk of LRF were vascular invasion (VI) and tumor size greater than 2 cm for premenopausal and VI for postmenopausal patients. Of the 1,275 patients, 345 (27%) met criteria for the highest risk groups, and the 10-year cumulative incidences of LRF with or without distant metastases were 16% for premenopausal and 19% for postmenopausal women. For the node-positive cohort, number of nodes and tumor grade were factors for both menopausal groups, with additional prediction provided by VI for premenopausal and tumor size for postmenopausal patients. Of the 4,077 patients, 815 (20%) met criteria for the highest risk groups, and 10-year cumulative incidences were 35% for premenopausal and 34% for postmenopausal women. CONCLUSION: LRFs are a significant problem after mastectomy alone even for some patients with node-negative breast cancer, as well as after mastectomy and adjuvant treatment for some subgroups of patients with node-positive disease. In addition to number of positive lymph nodes, predictors of LRF include tumor-related factors, such as vascular invasion, higher grade, and larger size.     

Randomized adjuvant trial of tamoxifen and goserelin versus cyclophosphamide, methotrexate, and fluorouracil: evidence for the superiority of treatment with endocrine blockade in premenopausal patients with hormone-responsive breast cancer--Austrian Breast and Colorectal Cancer Study Group Trial 5.

PURPOSE: Effective adjuvant treatment modalities in premenopausal breast cancer patients today include chemotherapy, ovariectomy, and tamoxifen administration. The purpose of Austrian Breast and Colorectal Cancer Study Group Trial 5 was to compare the efficacy of a combination endocrine treatment with standard chemotherapy. PATIENTS AND METHODS: Assessable trial subjects (N = 1,034) presenting with hormone-responsive disease were randomized to receive either 3 years of goserelin plus 5 years of tamoxifen or six cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF). Stratification criteria included tumor stage and grade, number of involved nodes, type of surgery, and steroid hormone receptor content. Relapse-free survival (RFS) was defined as time from randomization to first relapse, local recurrence, or contralateral incidence, and overall survival (OS) as time to date of death. RESULTS: With a 60-month median follow-up, 17.2% of patients in the endocrine group and 20.8% undergoing chemotherapy developed relapses. Local recurrences emerged in 4.7% and 8.0%, respectively. RFS and local recurrence-free survival differed significantly in favor of endocrine therapy (P =.037 and P =.015), with a similar trend observed in OS (P =.195). CONCLUSION: Overall, our data suggest that the goserelin-tamoxifen combination is significantly more effective than CMF in the adjuvant treatment of premenopausal patients with stage I and II breast cancer.     

Adjuvant endocrine therapies for premenopausal women

Adjuvant endocrine treatment for premenopausal woman remains a controversial area in the therapeutical approach of early stages of breast cancer. Metaanalysis show that ovarian ablation and suppression produce, in a global way, significant benefits in terms of reduction of the risk of recurrence and death. Nevertheless, in the presence of adjuvant chemotherapy, the benefits of ovarian suppression or ablation are clearly reduced, probably in relation to the impact that amenorrhoea induced by chemotherapy. On the other hand, in premenopausal patients, the same metaanalysis show that the use of adjuvant tamoxifen produces benefits in disease-free survival and overall survival very similar to those observed in postmenopausal women. Additionally, the benefits from tamoxifen persist independently of whether or not adjuvant chemotherapy is being received. Thus, some of the questions to answer are: first, is there, in premenopausal women, an additional benefit when ovarian suppression is associated to tamoxifen? Second, it remains controversial if ovarian suppression must be indicated for all patients who receive chemotherapy or only those that have not reached amenorrhoea when adjuvant chemotherapy is completed. Moreover, although in the last decades more than 15,000 premenopausal patients have been included in specific trials of adjuvant endocrine therapy with ovarian suppression or ablation, the best modality of treatment has not been established, and what is more important, the role of its association with tamoxifen has not been completely defined. Many of these aspects remain controversial and the decision about the best therapeutical approach must be individualised in each patient.     

Adjuvant Endocrine Therapy of Perimenopausal and Recently Postmenopausal Women With Hormone Receptor-Positive Breast Cancer

Although 5 years of tamoxifen has been the standard adjuvant endocrine therapy for premenopausal women with hormone receptor-positive breast cancer for more than 2 decades, emerging results suggest that either switching to an aromatase inhibitor after 5 years of tamoxifen when postmenopausal or continuing tamoxifen for an additional 5 years can further decrease relapse risk. As a result, more premenopausal breast cancer patients will be continuing adjuvant endocrine therapy through the menopause transition. In this setting, questions arise regarding continued tamoxifen use through 10 years and/or the timing and appropriateness of switching to an aromatase inhibitor. In addition, it is now recognized that estrogen levels substantially decline for approximately 2 years after the last menstrual period and that chemotherapy and/or tamoxifen-induced amenorrhea preclude reliable ovarian function determination. Because aromatase inhibitors are only effective in a low estrogen environment without ovarian estrogen production, determination of the optimal endocrine adjuvant therapy for perimenopausal women and those recently postmenopausal represent a challenge requiring understanding of current clinical study results and the potential for interactions among therapeutic interventions, ovarian function, and clinical outcome. Available options include tamoxifen for 10 years, tamoxifen for 5 years followed by aromatase inhibitors, tamoxifen with a luteinizing hormone-releasing hormone (LHRH) agonist, aromatase inhibitor with an LHRH agonist or aromatase inhibitor with bilateral oophorectomy. Although completed (Austrian Breast Cancer Study Group [ABCSG]-12) and ongoing (SOFT [Suppression of Ovarian Function Trial], TEXT [Tamoxifen and Exemestane Trial]) clinical trials are addressing some issues, many questions will remain requiring individualized clinical judgement. Rationale supporting the available endocrine therapy options in this setting and recommendations for clinical management follow.     

MMP-2 positivity and age less than 40 years increases the risk for recurrence in premenopausal patients with node-positive breast carcinoma

Node-positive breast carcinoma is associated with a poor prognosis. Some patients benefit from adjuvant chemotherapy but new treatment modalities should still be developed in order to further increase the cure rate in this patient group. Prognostic factors are needed to define patients for such studies. Here, the prognostic value of matrix metalloproteinase-2 (MMP-2) and age was evaluated in 108 premenopausal, node-positive breast carcinoma patients treated with an adjuvant chemotherapy. Expression of MMP-2 protein was studied in paraffin-embedded tissue sections from primary tumors by using specific MMP-2 monoclonal antibody in an immunohistochemical staining. Age less than 40 years predicted 5-year recurrence free survival (RFS) as unfavorable, being 74% in patients 41-49 years of age and 54% in those under age 40 (p = 0.02). The 5-year RFS rate was 85% in patients with an MMP-2 negative primary tumor while it was 65% in the MMP-2 positive patient group. This difference was not, however, statistically significant (p = 0.07). Correlation between hematogenous metastasis and MMP-2 positivity in breast carcinoma was demonstrated for the first time (p = 0.03). A risk group for a relapse was identified using MMP-2 immunohistochemistry and age. The RFS rate in patients less than 40 years with an MMP-2 positive primary tumor was only 50% while it was 74% in other premenopausal patients (p = 0.007). Young age and MMP-2 positivity may, thus, associate with early relapse in node-positive breast carcinoma.     

Adjuvant chemotherapy therapy of breast cancer]

Six to 12 cycles of CMF is regarded as the standard regimen for adjuvant chemotherapy for breast cancer, producing 10-20% increase in survival for premenopausal and node-positive patients. Tamoxifen combined with CMF has induced an additional reduction in recurrence rate only in postmenopausal patients. Oral administration of 5-FU or its derivatives combined with tamoxifen for as long as 1-2 years is the regimen most widely used in Japan for considerable improvement in survival. But it needs further evaluation in comparison with CMF, and in ultimate duration of treatment and better combination with other drugs. Adjuvant chemotherapy for node-negative patients is advocated in the U.S., where the recurrence rate is as high as 30%. Only 10% of Japanese n0 patients undergo recurrence. Therefore, adjuvant therapy should be given only to high-risk patients.     

Timing of CMF chemotherapy in combination with tamoxifen in postmenopausal women with breast cancer: role of endocrine responsiveness of the tumor.

BACKGROUND: Controversy persists about whether chemotherapy benefits all breast cancer patients. PATIENTS AND METHODS: In the International Breast Cancer Study Group (IBCSG) trial VII, 1212 postmenopausal patients with node-positive disease were randomized to receive tamoxifen for 5 years or tamoxifen plus three concurrent courses of cyclophosphamide, methotrexate and 5-fluorouracil ('classical' CMF) chemotherapy, either early, delayed or both. In IBCSG trial IX, 1669 postmenopausal patients with node-negative disease were randomized to receive either tamoxifen alone or three courses of adjuvant classical CMF prior to tamoxifen. Results were assessed according to estrogen receptor (ER) content of the primary tumor. RESULTS: For patients with node-positive, ER-positive disease, adding CMF either early, delayed or both reduced the risk of relapse by 21% (P=0.06), 26% (P=0.02) and 25% (P=0.02), respectively, compared with tamoxifen alone. There was no difference in disease-free survival when CMF was given prior to tamoxifen in patients with node-negative, ER-positive tumors. CONCLUSIONS: CMF given concurrently (early, delayed or both) with tamoxifen was more effective than tamoxifen alone for patients with node-positive, endocrine-responsive breast cancer, supporting late administration of chemotherapy even after commencement of tamoxifen. In contrast, sequential CMF and tamoxifen for patients with node-negative, endocrine-responsive disease was ineffective.     

Postoperative chemotherapy and chemohormonal therapy in women with node-positive breast cancer

Separate trials for premenopausal and postmenopausal (less than or equal to 65 yr of age) patients with node-positive breast carcinoma were initiated by the Eastern Cooperative Oncology Group in 1978 to evaluate adjuvant chemotherapy and chemohormonal therapy approaches. Postoperative patients were stratified by degree of axillary nodal involvement and estrogen receptor (ER) status prior to randomization. Premenopausal patients received 12 monthly cycles of intermittent cyclophosphamide, methotrexate, and 5-fluorouracil (CMF), CMF plus prednisone (CMFP), or CMFP plus continuous tamoxifen (CMFPT). Postmenopausal patients received either observation or 12 monthly cycles of CMFPT or CMFP. The median follow-up for the analyzed patients is 54 months for the 553 premenopausal patients and 59 months for the 223 postmenopausal patients. The premenopausal trial has not demonstrated any significant differences between the regimens for either relapse-free or overall survival. The relapse-free survival in the postmenopausal trial has demonstrated a trend for CMFPT over observation (P = .07). Both CMFP and CMFPT are associated with an improved relapse-free survival over observation alone in ER-negative patients (P = .01) and in progesterone receptor-negative patients (P = .01). However, the relapse-free survival advantages have not translated to survival. Side effects were significantly increased with the addition of P to CMF in the premenopausal trial. The addition of T to CMFP was associated with an increased incidence of edema and hot flashes in premenopausal patients; however, the latter was decreased in postmenopausal patients relative to CMFP.(ABSTRACT TRUNCATED AT 250 WORDS)     

Impact of Adjuvant Chemotherapy Cycles on Prognosis of Resectable Stomach Cancer: A Retrospective Analysis

Aims: The aim of this study was to investigate the effects of adjuvant chemotherapy cycles on the prognosisof patients with post-operative stomach cancer through retrospective analysis. Methods: A total of 128 patientswith gastric cancer who underwent gastrectomy, followed by adjuvant chemotherapy consisting of epirubicin,cisplatin or oxaliplatin, leucovorin, and 5-fluorouracil, according to a defined schedule, were divided into threegroups according to the number of chemotherapy cycles: Group I (<6 cycles); Group II (6 cycles); and GroupIII (>6 cycles). Results: The 5-year overall survival (OS) was 20.8% in Group I, 45.0% in Group II, and 42.9%in Group III, with a median follow-up of 43 months. The 5-year relapse-free survival (RFS) was 15.1% in GroupI, 40% in Group II, and 40% in Group III. The OS and RFS in Groups II and III were significantly betterthan in Group I (OS, p = 0.002 and p=0.003; RFS, P<0.001 and P=0.002). There was no difference in OS (p =0.970) or in RFS (p = 0.722) between Groups II and III. Multivariate Cox hazard analysis determined that thenumber of adjuvant chemotherapy cycles was an independent factor that influenced OS and RFS. Conclusion:Six cycles of adjuvant chemotherapy gave encouraging outcomes in patients with resectable gastric cancer.Further prospective randomized controlled investigations are warranted in a multi-center setting.     

Goserelin (Zoladex)--its role in early breast cancer in pre- and perimenopausal women

Current standard adjuvant therapies for premenopausal women with early breast cancer include ovarian ablation by surgery or irradiation, chemotherapy and tamoxifen. The value of ovarian ablation in prolonging the survival of premenopausal patients with early breast cancer was clearly established by the analyses performed by the Early Breast Cancer Trialists' Collaborative Group in 1996. More recently, the value of ovarian suppression using the luteinizing hormone releasing hormone analogue goserelin as adjuvant therapy in pre-/perimenopausal women with early breast cancer has been confirmed in a series of studies involving over 8000 patients. The results from these studies provide evidence that goserelin, alone or in combination with tamoxifen, is at least as effective as cytotoxic chemotherapy in patients with hormone receptor-positive tumours and is effective when used after adjuvant chemotherapy. The use of goserelin in the management of early breast cancer presents an option which can avoid the side-effects experienced with cytotoxic chemotherapy and may offer unique benefits to premenopausal patients. The consolidation of these emerging results should help in defining the optimal role for goserelin in pre-/perimenopausal patients with early breast cancer.     

A randomized study of adjuvant treatments for operable breast cancer patients stratified by estrogen receptor and menopausal status

According to estrogen receptor (ER) and menopausal status, operable breast cancer patients were randomized for adjuvant endocrine therapy with tamoxifen (TAM) in premenopausal patients, after oophorectomy (OVEX), chemotherapy, CHEM (mitomycin C+ oral cyclophosphamide), or chemo-endocrine therapy (TAM + CHEM). Some 1579 patients were entered in the trial between 9, 1978 and 12, 1991, with a median follow-up of 10 years. In ER-positive, premenopausal patients there were no significant differences in relapse-free (RFS) or overall survival (OS) among the OVEX + TAM, CHEM, and CHEM + TAM arms. On the contrary, in ER-positive, post-menopausal patients, the chemoendocrine therapy showed a significantly better OS (p = 0.0254) with a trend of better RFS (p = 0.0674), as compared with TAM or CHEM groups. ER-negative, premenopausal patients showed no significant differences in RFS or OS between CHEM and CHEM + TAM arms. In ER-negative, postmenopausal patients, there was a non-significantly better RFS (p = 0.0888) and a significantly better OS (p = 0.0332) in CHEM + TAM group than in the CHEM alone group. These results suggest that ER and menopausal status are important criteria to select early breast cancer patients for adjuvant treatments.     

Postoperative adjuvant chemotherapy followed by adjuvant tamoxifen versus nil for patients with operable breast cancer: a randomised phase III trial of the European Organisation for Research and Treatment of Cancer Breast Group

BackgroundThe contribution of adjuvant tamoxifen in breast cancer patients after receiving adjuvant chemotherapy is not fully established. We investigated the impact of tamoxifen, given sequentially after completion of adjuvant chemotherapy in patients with operable breast cancer.Patients and methodsBetween March 1991 and June 1999, 1863 women with stages I–IIIA operable breast cancer who had undergone surgery and completed six cycles of adjuvant combination chemotherapy with either CMF, CAF, CEF, FAC or FEC were randomised to receive either tamoxifen 20 mg daily for 3 years or no further treatment. Irrespective of menstrual status and hormone receptor content of the primary tumour, patients were stratified by institute, chemotherapy scheme and age (above 50 years or younger). The main end-point was to detect a 5% increase in the 5 year survival (from 80% to 85%) in favour of antioestrogen therapy. Secondary end-points were relapse free survival (RFS), local control, incidence of second primary breast cancer and correlation of results with hormone receptor content.ResultsAfter exclusion of all patients from three sites because of inadequate documentation, a total of 1724 patients (93%) were analysed (Tam 861 and Control 863). At a median follow-up of 6.5 years, 5-year RFS on tamoxifen was 73% versus 67% in controls (p = 0.035). No difference was seen in overall survival. The benefit of tamoxifen therapy was mainly seen in the subgroup of patients with histologically documented positive axillary nodes (5-year RFS on tamoxifen 71% versus 64% in the control group, p = 0.044) and in patients with tumours expressing the ER and PR positive phenotype (5-year RFS on tamoxifen 77% versus 70% in the control group, p = 0.014).ConclusionsTamoxifen administered for 3 years after completion of adjuvant chemotherapy in this otherwise unselected group of patients for endocrine sensitivity had a limited impact on relapse and had no detectable effect on overall survival. The beneficial effect of tamoxifen is mainly confined to the subgroup of patients with node-positive disease and to patients with tumours expressing the ER and PR positive phenotype.     

Chemoendocrine therapy for premenopausal women with axillary lymph node-positive, steroid hormone receptor-positive breast cancer: results from INT 0101 (E5188).

PURPOSE: Chemotherapy, tamoxifen, and ovarian ablation/suppression (OA/OS) are effective adjuvant approaches for premenopausal, steroid hormone receptor-positive breast cancer. The value of combined therapy has not been clearly established. PATIENTS AND METHODS: Premenopausal women with axillary lymph node-positive, steroid hormone receptor-positive breast cancer (1,503 eligible patients) were randomly assigned to six cycles of cyclophosphamide, doxorubicin, and fluorouracil (CAF), CAF followed by 5 years of monthly goserelin (CAF-Z), or CAF followed by 5 years of monthly goserelin and daily tamoxifen (CAF-ZT). The primary end points were time to recurrence (TTR), disease-free survival (DFS), and overall survival (OS) for CAF-Z versus CAF, and CAF-ZT versus CAF-Z. RESULTS: With a median follow-up of 9.6 years, the addition of tamoxifen to CAF-Z improved TTR and DFS but not OS. There was no overall advantage for addition of goserelin to CAF. CONCLUSION: Addition of tamoxifen to CAF-Z improves outcome for premenopausal node-positive, receptor-positive breast cancer. The role of OA/OS alone or with other endocrine agents should be studied more intensely.     

Resumption of menses with initiation of letrozole after five years of amenorrhea on tamoxifen: caution needed when using tamoxifen followed by aromatase inhibitors

Background: Randomized trials in postmenopausal women have shown a benefit to substituting aromatase inhibitors for tamoxifen or using them sequentially following a full course of tamoxifen. The aromatase inhibitor letrozole has also been utilized for ovarian induction in premenopausal women. Case Report: A premenopausal woman with early stage breast cancer became amenorrheic with adjuvant chemotherapy, and remained so during 5 years of daily tamoxifen. After discontinuing tamoxifen, laboratory studies confirmed an apparent postmenopausal state. Menses resumed following a 2-week course of letrozole. Conclusion: Aromatase inhibitors need to be used with caution in women who stop menstruating following adjuvant chemotherapy or tamoxifen.     

Direct comparisons of adjuvant endocrine therapy, chemotherapy, and chemoendocrine therapy for operable breast cancer patients stratified by estrogen receptor and menopausal status

Based on estrogen receptor (ER) and menopausal status, operable breast cancer (UICC stage I, II, III-a) patients were randomized for adjuvant endocrine therapy, chemotherapy, and chemoendocrine therapy, and the effects on the relapse-free survival (RFS) and overall survival (OS) were compared. Tamoxifen (TAM) 20 mg/day was administered orally for 2 years after mastectomy as an adjuvant endocrine therapy in postmenopausal patients. In premenopausal patients, oophorectomy (OVEX) was performed before TAM administration. In the chemotherapy arm (CHEM), patients were given 0.06 mg/kg of body weight of mitomycin C (MMC) intravenously, followed by an oral administration of cyclophosphamide (CPA) 100 mg/day in an administration of a 3-month period and a 3-month intermission. This 6-month schedule was repeated 4 times in 2 years. The chemoendocrine arm (CHEM + TAM) was composed of TAM with MMC + CPA chemotherapy. The patients were randomized according to ER and menopausal status. ER-positive patients were randomized to three arms: OVEX ± TAM, CHEM, and CHEM + TAM. For ER-negative patients there were two arms: CHEM and CHEM + TAM. 1579 patients entered the trial between September 1978 and December 1991, with median follow-up of 8.2 years. In ER-positive, premenopausal patients, there were no significant differences in RFS or OS among OVEX ± TAM, MMC + CPA, TAM + MMC + CPA arms. On the contrary, in ER-positive, postmenopausal patients, the chemoendocrine therapy showed a significantly higher RFS (p = 0.0400) and OS (p=0.0187) as compared with TAM to chemotherapy alone. There were no significant differences in RFS or OS by addition of TAM on the chemotherapy, in both pre- and post-menopausal ER-negative patients. It was concluded that in ER-positive premenopausal breast cancer, endocrine therapy alone may be equivalent in prolonging RFS and OS to chemotherapy or chemoendocrine therapy, and that ER-positive postmenopausal breast cancer may be better controlled with the combination of TAM and chemotherapy, as compared to TAM or chemotherapy alone. The importance of stratification of operable breast cancer by ER and menopausal status, as well as the direct comparisons of different treatments, were stressed.This revised version was published online in October 2005 with corrections to the Cover Date.