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Background: We investigated the outcomes of postmenopausal women with hormone receptor-positive, early breast cancer with special histotypes (mucinous, tubular, or cribriform) enrolled in the monotherapy cohort of the BIG 1-98 trial., Patients and Methods: The intention-to-treat BIG 1-98 monotherapy cohort (5 years of therapy with tamoxifen or letrozole) included 4922 women, of whom 4091 had central pathology review. Histotype groups were defined as: mucinous (N = 100), tubular/cribriform (N = 83), ductal (N = 3257), and other (N = 651). Of 183 women with either mucinous or tubular/cribriform tumors, 96 were randomly assigned to letrozole and 87 to tamoxifen. Outcomes assessed were disease-free survival (DFS), overall survival (OS), breast cancer-free interval (BCFI), and distant recurrence-free interval (DRFI). Median follow-up in the analytic cohort was 8.1 years., Results: Women with tubular/cribriform breast cancer had the best outcomes for all end points compared with the other three histotypes, and had less breast cancer recurrence (97.5% 5-year BCFI) than those with mucinous (93.5%), ductal (88.9%), or other (89.9%) histotypes. Patients with mucinous or tubular/cribriform carcinoma had better DRFI (5-year rates 97.8% and 98.8%, respectively) than those with ductal (90.9%) or other (92.1%) carcinomas. Within the subgroup of women with special histotypes, we observed a nonsignificant increase in the hazard of breast cancer recurrence with letrozole [hazard (letrozole versus tamoxifen): 3.31, 95% confidence interval 0.94-11.7; P = 0.06]., Conclusions: Women with mucinous or tubular/cribriform breast cancer have better outcomes than those with other histotypes, although the observation is based on a limited number of events. In postmenopausal women with these histotypes, the magnitude of the letrozole advantage compared with tamoxifen may not be as large in patients with mucinous or tubular/cribriform disease., Clinicaltrialsgov: NCT00004205., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: In the BIG 1-98 trial objective cognitive function improved in postmenopausal women 1 year after cessation of adjuvant endocrine therapy for breast cancer. This report evaluates changes in subjective cognitive function (SCF)., Methods: One hundred postmenopausal women, randomised to receive 5 years of adjuvant tamoxifen, letrozole, or a sequence of the two, completed self-reported measures on SCF, psychological distress, fatigue, and quality of life during the fifth year of trial treatment (year 5) and 1 year after treatment completion (year 6). Changes between years 5 and 6 were evaluated using the Wilcoxon signed-rank test. Subjective cognitive function and its correlates were explored., Results: Subjective cognitive function and the other patient-reported outcomes did not change significantly after cessation of endocrine therapy with the exception of improvement for hot flushes (P=0.0005). No difference in changes was found between women taking tamoxifen or letrozole. Subjective cognitive function was the only psychosocial outcome with a substantial correlation between year 5 and 6 (Spearman's R=0.80). Correlations between SCF and the other patient-reported outcomes were generally low., Conclusion: Improved objective cognitive function but not SCF occur following cessation of adjuvant endocrine therapy in the BIG 1-98 trial. The substantial correlation of SCF scores over time may represent a stable attribute.

Background: To compare the incidence and timing of bone fractures in postmenopausal women treated with 5 years of adjuvant tamoxifen or letrozole for endocrine-responsive early breast cancer in the Breast International Group (BIG) 1-98 trial., Methods: We evaluated 4895 patients allocated to 5 years of letrozole or tamoxifen in the BIG 1-98 trial who received at least some study medication (median follow-up 60.3 months). Bone fracture information (grade, cause, site) was collected every 6 months during trial treatment., Results: The incidence of bone fractures was higher among patients treated with letrozole [228 of 2448 women (9.3%)] versus tamoxifen [160 of 2447 women (6.5%)]. The wrist was the most common site of fracture in both treatment groups. Statistically significant risk factors for bone fractures during treatment included age, smoking history, osteoporosis at baseline, previous bone fracture, and previous hormone replacement therapy., Conclusions: Consistent with other trials comparing aromatase inhibitors to tamoxifen, letrozole was associated with an increase in bone fractures. Benefits of superior disease control associated with letrozole and lower incidence of fracture with tamoxifen should be considered with the risk profile for individual patients.

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.

This final paper of the proceedings of the recent Eighth St. Gallen Conference 2003 on the Primary Therapy of Early Breast Cancer comments on the Consensus Paper put forth by the international expert panel and emphasizes new information, that has emerged during the 2 years since the seventh such meeting in 2001. More than 3200 breast cancer specialists from various medical fields-coming from 75 countries and all six continents-have attended the meeting and the process of scientific consensus development. Recommendations for patient care are so critically dependent on assessment of endocrine responsiveness that the importance of high-quality steroid hormone receptor determination and standardized quantitative reporting cannot be overemphasized. The Panel modified and simplified the risk categories so that only endocrine receptor-absent status was sufficient to reclassify an otherwise low-risk, node-negative disease into the category of average risk. Absence of steroid hormone receptors was also recognized as indicating endocrine non-responsiveness. Some important areas highlighted especially in the 2003 consensus include: recognition of the separate nature of endocrine non-responsive breast cancer, both invasive cancers and ductal carcinoma in situ (DCIS); improved understanding of the mechanisms of acquired endocrine resistance, offering exciting prospects for extending the impact of successful sequential endocrine therapies; presentation of high-quality evidence indicating that chemotherapy and tamoxifen should be used sequentially rather than concurrently; availability of a potential alternative to tamoxifen for treatment of postmenopausal women with endocrine responsive disease; promise of newly defined prognostic and predictive markers.

Background: Chemotherapy, tamoxifen and ovarian function suppression have all demonstrated their effectiveness for treating women with early breast cancer. Treatment selection for individual patients, however, requires estimates on the magnitude of treatment effects to be achieved from the application of each modality. Unfortunately, information currently available is insufficient to properly tailor adjuvant treatments., Methods: We consider predictive factors to improve our understanding about selection of adjuvant therapies, reassessment of data from previous clinical trials and design of future studies., Results: Estrogen receptor (ER) and progesterone receptor (PgR) are the primary measures available today to tailor adjuvant therapies. Patient age/menopausal status (ability to obtain treatment effects via ovarian function suppression), measures of the metastatic potential of the tumor (such as number of positive axillary lymph nodes), and concurrent use of chemotherapy and tamoxifen are other factors that modify the magnitude of relative effect associated with chemotherapy and endocrine therapies. The Subpopulation Treatment Effect Pattern Plots (STEPP) method displays the patterns of treatment effects within randomized clinical trials or datasets from meta-analyses to identify features that predict responsiveness to the treatments under study without relying on retrospective subset analysis. Confirmation of hypotheses using independent clinical trial databases is recommended., Discussion: All findings from clinical trials and meta-analyses should be presented primarily according to steroid hormone receptor status and patient age. Future studies should be designed as tailored treatment investigations, with endocrine therapies evaluated within populations of patients with endocrine responsive tumors, and chemotherapy questions focused within populations of patients with endocrine nonresponsive disease.

We introduce the subpopulation treatment effect pattern plot (STEPP) method, designed to facilitate the interpretation of estimates of treatment effect derived from different but potentially overlapping subsets of clinical trial data. In particular, we consider sequences of subpopulations defined with respect to a covariate, and obtain confidence bands for the collection of treatment effects (here obtained from the Cox proportional hazards model) associated with the sequences. The method is aimed at determining whether the magnitude of the treatment effect changes as a function of the values of the covariate. We apply STEPP to a breast cancer clinical trial data set to evaluate the treatment effect as a function of the oestrogen receptor content of the primary tumour.

Purpose: Information on the tolerability and efficacy of adjuvant chemoendocrine therapy for older women is limited. We studied these issues using the data collected as part of the International Breast Cancer Study Group Trial VII., Patients and Methods: Postmenopausal women with operable, node-positive breast cancer were randomized to receive either tamoxifen alone for 5 years (306 patients) or tamoxifen plus three consecutive cycles of classical cyclophosphamide (100 mg/m(2) orally days 1 to 14), methotrexate (40 mg/m(2) intravenous days 1 and 8), and fluorouracil (600 mg/m(2) intravenous days 1 and 8) every 28 days (CMF; 302 patients). The median follow-up was 8.0 years., Results: Among the 299 patients who received at least one dose of CMF, women 65 years of age or older (n = 76) had higher grades of toxicity compared with women less than 65 years old (n = 223) (P =.004). More women in the older age group compared with the younger women experienced grade 3 toxicity of any type (17% v 7%, respectively), grade 3 hematologic toxicity (9% v 5%, respectively), and grade 3 mucosal toxicity (4% v 1%, respectively). Older patients also received less than their expected CMF dose compared with younger postmenopausal women (P =.0008). The subjective burdens of treatment, however, were similar for younger and older patients based on quality-of-life measures (performance status, coping, physical well-being, mood, and appetite). For older patients, the 5-year disease-free survival (DFS) rates were 63% for CMF plus tamoxifen and 61% for tamoxifen alone (hazards ratio [HR], 1.00; 95% confidence interval [CI], 0.65 to 1.52; P =.99). For younger patients, the corresponding 5-year DFS rates were 61% and 53% (HR, 0.70; 95% CI, 0.53 to 0.91; P =.008), but the test for heterogeneity of CMF effect according to age group was not statistically significant. The reduced effectiveness of CMF among older women could not be attributed to dose reductions according to dose received., Conclusion: CMF tolerability and effectiveness were both reduced for older patients compared with younger postmenopausal node-positive breast cancer patients who received tamoxifen for 5 years. The development and evaluation of less toxic and more effective chemotherapy regimens are required for high-risk elderly patients.

The first reported effective adjuvant combination regimen for patients with operable breast cancer comprised oral cyclophosphamide (C) days 1-14 with intravenous methotrexate (M) and fluorouracil (F) on days 1 and 8, repeated every 28 days ('classical' CMF). These drugs have since been extensively used with or without endocrine therapies and/or other cytotoxics, as well as with radiation therapy to the chest wall yielding conflicting results. Although doses and schedules have varied widely, the combination of these three drugs has been generically referred to as CMF. Evidence exists that reducing the dose and/or altering the schedule of CMF ('modified' CMF) have compromised its efficacy in metastatic breast cancer. Reduction below standard dose of a similar regimen also gave inferior results in the adjuvant setting. In fact, the recently reported improved outcome of adding radiation therapy to CMF was only demonstrated in comparisons with a 'modified' CMF. Furthermore, trials in women with estrogen receptor-positive breast cancer, which did not demonstrate any significant benefit for the addition of adjuvant CMF to tamoxifen compared with tamoxifen alone, also used 'modified' CMF. Therefore, adherence to the 'classical' dose and schedule is recommended when CMF is used in adjuvant therapy.

Purpose: Adjuvant cytotoxics prolong disease-free survival (DFS) and overall survival (OS) in patients with operable breast cancer. The first reported effective adjuvant combination regimen consisted of oral cyclophosphamide on days 1 to 14 with intravenous methotrexate and fluorouracil on days 1 and 8, repeated every 28 days (classical CMF). These drugs have since been extensively used with or without endocrine therapies and/or other cytotoxic agents. Although doses and schedules have varied widely, the combination of these three drugs is generically referred to as CMF., Results: Reducing the dose and/or altering the schedule of CMF have compromised its efficacy in metastatic breast cancer. Reduction below standard dose of a similar regimen also gave inferior results in the adjuvant setting., Conclusion: Details of dose and schedule may therefore explain part of the heterogeneity of results observed with CMF. Particular controversy surrounds the contribution of CMF in postmenopausal women who are also receiving tamoxifen (TAM). However, the trials that demonstrated a significant benefit for the addition of CMF to TAM, even in postmenopausal women with estrogen receptor-positive tumors, used classical CMF. Therefore, adherence to the classical dose and schedule is recommended when CMF is used in adjuvant therapy.

Background: Adjuvant tamoxifen for early breast cancer provides an improvement in relapse-free (RFS) and overall survival (OS), especially for older women. We carried out a meta-analysis to find out whether the benefit of adding chemotherapy to tamoxifen outweighs its costs in terms of toxic effects for postmenopausal patients., Methods: The meta-analysis of quality-adjusted survival was based on data from 3920 patients aged 50 years or older with node-positive breast cancer randomly assigned in nine trials that compared combination chemotherapy plus tamoxifen with tamoxifen alone. The nine trials were included in the worldwide overview conducted by the early breast cancer trialists' collaborative group (EBCTCG). The quality-adjusted time without symptoms or toxicity (Q-TWiST) method was used to provide treatment comparisons incorporating differences in quality of life associated with subjective toxic effects of treatment and symptoms of disease relapse., Findings: Within 7 years of follow-up the modest benefit of increased RFS and OS for patients who received chemotherapy just balanced the costs in terms of acute toxic side-effects. Chemotherapy-treated patients gained an average of 5.4 months of RFS and 2 months of OS (neither statistically significant), but had to receive cytotoxic treatment for between 2 and 24 months to achieve these gains. No values of preference weights for time spent undergoing chemotherapy and time after relapse gave significantly more Q-TWiST with chemotherapy plus tamoxifen than with tamoxifen alone., Interpretation: Within 7 years of follow-up, adjuvant chemoendocrine therapy did not provide more quality-adjusted survival time than tamoxifen alone for women aged 50 years or older with node-positive breast cancer. Better selection and administration of chemotherapy regimen, different scheduling of chemotherapy and tamoxifen, and appropriate use of patient and tumour characteristics may increase the therapeutic advantage of the combination.

Between 1978 and 1981 we conducted a trial in which adjuvant endocrine therapy consisting of tamoxifen (T = 20 mg/d) and low-dose prednisone (p = 7.5 mg/d) for the duration of one year (p + T), was compared with no adjuvant therapy (observation) in 320 women with operable breast cancer aged 66 to 80 years (median age, 70 years). All patients had axillary lymph node metastases after at least a total mastectomy and axillary clearance. At 96 months median follow-up, 9.1% of the patients died without apparent relapse from cancer. An additional 1.9% had a second malignant neoplastic disease (not breast cancer). The 8-year disease-free survival (DFS) percentages (+/- SE) for the p + T and the observation groups were 36% (+/- 4%), and 22% (+/- 3%), (P = .004). The 8-year overall survival percentages were 49% (+/- 4%) and 42% (+/- 4%), respectively (P = .43). We conclude that despite a large proportion of deaths without relapse of breast cancer, a significant advantage for the p + T group in terms of DFS was demonstrated. We hypothesize that an endocrine therapy of longer duration might have an overall survival benefit in a population of elderly patients.

We evaluated quality of life (QL) and quality-adjusted survival in International Breast Cancer Study Group Trial IX, a randomised trial including 1669 eligible patients receiving tamoxifen for 5 years or three prior cycles of cyclophosphamide, methotrexate and 5-fluorouracil (CMF) followed by 57 months tamoxifen. During the time with CMF toxicity (Tox), without symptoms and toxicity (TWiST), and following relapse (Rel), patients scored their QL indicators and a utility indicator for subjective health estimation between 'perfect' and 'worst' health. Scores were averaged within Tox, TWiST and Rel and transformed to utilities. Mean durations for the three transition times were weighted with utilities to obtain mean quality-adjusted TWiST (Q-TWiST). Patients receiving CMF reported significantly worse scores for most QL domains at month 3, but less hot flushes. After completing chemotherapy, there were no differences by treatment groups. Benefits evaluated by Q-TWiST favoured the additional chemotherapy. CMF provided 3 more months of Q-TWiST for patients with ER-negative tumours, but CMF provided no benefit in Q-TWiST for patients with ER-positive tumours. Q-TWiST analysis based on patient ratings is feasible in large-scale cross-cultural clinical trials. [ABSTRACT FROM AUTHOR]

Background: Estrogen Receptor 1 (ESR1) aberrations may be associated with expression of estrogen receptor (ER) or progesterone receptor (PgR), human epidermal growth factor receptor-2 (HER2) or Ki-67 labeling index and prognosis. Patients and methods: ESR1 was assessed in 1129 (81%) of 1396 postmenopausal Danish women with early breast cancer randomly assigned to receive 5 years of letrozole, tamoxifen or a sequence of these agents in the Breast International Group 1-98 trial and who had ER ≥1% after central review. Results: By FISH, 13.6% of patients had an ESR1-to-Centromere-6 (CEN-6) ratio ≥2 (amplified), and 4.2% had ESR1-to-CEN-6 ratio <0.8 (deleted). Deletion of ESR1 was associated with significantly lower levels of ER (P < 0.0001) and PgR (P = 0.02) and more frequent HER2 amplification. ESR1 deletion or amplification was associated with higher-Ki-67 than ESR1-normal tumors. Overall, there was no evidence of heterogeneity of disease-free survival (DFS) or in treatment effect according to ESR1 status. However, significant differences in DFS were observed for subsets based on a combination of ESR1 and HER2 status (P = 0.02). Conclusions: ESR1 aberrations were associated with HER2 status, Ki-67 labeling index and ER and PgR levels. When combined with HER2, ESR1 may be prognostic but should not be used for endocrine treatment selection in postmenopausal women with endocrine-responsive early breast cancer. [ABSTRACT FROM PUBLISHER]

Background: On average, aromatase inhibitors are better than tamoxifen when used as initial or sequential therapy for postmenopausal women with endocrine-responsive early breast cancer. Because there may be contraindications to their use based on side-effects or cost, we investigated subgroups in which aromatase inhibitors may be more or less important.Patients and methods: Breast International Group 1-98 trial randomized 6182 women among four groups comparing letrozole and tamoxifen with sequences of each agent; 5177 (84%) had centrally confirmed estrogen receptor (ER) positivity. We assessed whether centrally determined ER, progesterone receptor (PgR), human epidermal growth factor receptor 2, and Ki-67 labeling index, alone or in combination with other prognostic features, predicted the magnitude of letrozole effectiveness compared with either sequence or tamoxifen monotherapy.Results: Individually, none of the markers significantly predicted differential treatment effects. Subpopulation treatment effect pattern plot analysis of a composite measure of prognostic risk revealed three patterns. Estimated 5-year disease-free survival for letrozole monotherapy, letrozole→tamoxifen, tamoxifen→letrozole, and tamoxifen monotherapy were 96%, 94%, 93%, and 94%, respectively, for patients at lowest risk; 90%, 91%, 93%, and 86%, respectively, for patients at intermediate risk; and 80%, 76%, 74%, and 69%, respectively, for patients at highest risk.Conclusion: A composite measure of risk informs treatment selection better than individual biomarkers and supports the choice of 5 years of letrozole for patients at highest risk for recurrence. [ABSTRACT FROM AUTHOR]

Background: The benefit of adjuvant chemotherapy in postmenopausal patients with estrogen receptor (ER)-positive lymph node-negative breast cancer is being reassessed.Patients and methods: After stratification by ER status, 1669 postmenopausal patients with operable lymph node-negative breast cancer were randomly assigned to three 28-day courses of ‘classical’ CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy followed by tamoxifen for 57 months (CMF→tamoxifen) or to tamoxifen alone for 5 years.Results: ERs were positive in 81% of tumors. At a median follow-up of 13.1 years, patients with ER-positive breast cancers did not benefit from CMF [13-year disease-free survival (DFS) 64% CMF→tamoxifen, 66% tamoxifen; P = 0.99], whereas CMF substantially improved the prognosis of patients with ER-negative breast cancer (13-year DFS 73% versus 57%, P = 0.001). Similarly, breast cancer-free interval (BCFI) was identical in the ER-positive cohort but significantly improved by chemotherapy in the ER-negative cohort (13-year BCFI 80% versus 63%, P = 0.001). CMF had no influence on second nonbreast malignancies or deaths from other causes.Conclusion: CMF is not beneficial in postmenopausal patients with node-negative ER-positive breast cancer but is highly effective within the ER-negative cohort. In the future, other markers of chemotherapy response may define a subset of patients with ER-positive tumors who may benefit from adjuvant chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Invasive lobular carcinoma (ILC) is mostly hormone receptor-positive (ER+) and associated with higher risk of late relapse (> 5 years after diagnosis) when compared to invasive ductal carcinoma (IDC). In this analysis we investigate the magnitude of benefit of endocrine treatment (tamoxifen [tam] or letrozole [let]) and the patterns of relapse over time in patients with ILC (classical subtype) or IDC enrolled in the monotherapy arms of BIG 1-98 study (12-year update). Material and methods: BIG 1-98 was a randomized, phase III study that compared five years of tam or let (monotherapy arms), or their sequences in post-menopausal women with ER+ early BC. There were 4922 patients enrolled in the monotherapy arms of BIG 1-98. This analysis includes patients who had centrally-reviewed histology data (n = 4080) and classified as IDC and ILC (n = 3660). Centrally-defined ER, PgR, Ki-67 were used to defined ER+ subtypes (n = 2923). ER+ subtypes were defined as Luminal A (ER+ and/or PR+ HER2-- and Ki67<14%) or Luminal B (ER+ and/or PR+, HER2-- and Ki6714%) for both ILC and IDC. Follow-up in the tam arm was censored at the time of selective crossover for women who chose to switch to let. Results: In the IDC subset, 1436 (44%) and 1163 (36%) were classified as Luminal A and Luminal B, while in the ILC subset 237 (59%) and 87 (22%) were classified as Luminal A and Luminal B, respectively. The 5-year DFS and OS estimates (±SE) for IDC and ILC are described in the table. I n multivariate models for DFS adjusted for classic clinicopathological features, significant interactions between treatment and histology (ILC or IDC), (p = 0.01) and treatment and subgroups (Luminal B or A), (p = 0.01) were observed. The DFS HRs for let vs tam were 0.51 (95% CI, 0.33 to 0.79) for ILC Luminal A and 0.35 (95% CI, 0.21 to 0.56) for ILC Luminal B. The DFS HRs for let vs tam were 0.93 (95% CI, 0.74 to 1.77) for IDC-Luminal A and 0.64 (95% CI, 0.52 to 0.78) and IDC-Luminal B. In the models for OS, the data suggest that the effect of letrozole varies by histology (interaction p = 0.053). The OS HRs for let vs tam was 0.39 (95% CI, 0.23 to 0.68) for ILC and 0.70 (95% CI, 0.57 to 0.86) for IDC. The hazards of DFS and OS events increased between 30 and 60 months after diagnosis among ILC pts treated with tam. In contrast, comparable hazard rates were observed for ILC pts treated with let and IDC pts treated with either let or tam. Conclusions: The magnitude of benefit of adjuvant let varies by histology and ER-subgroup. Greater reduction in risk of a DFS event is noted in women with Luminal B for both IDC and ILC. There is a trend for OS favoring let in women with ILC. ILC pts treated with let have similar patterns of relapse over time when compared to IDC. The biologic underpinnings of these observations should be explored. [ABSTRACT FROM AUTHOR]