Summary Background The 21-gene recurrence score assay is prognostic for women with node-negative, oestrogen-receptor-positive breast cancer treated with tamoxifen. A low recurrence score predicts ...little benefit of chemotherapy. For node-positive breast cancer, we investigated whether the recurrence score was prognostic in women treated with tamoxifen alone and whether it identified those who might not benefit from anthracycline-based chemotherapy, despite higher risks of recurrence. Methods The phase 3 trial SWOG-8814 for postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer showed that chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil (CAF) before tamoxifen (CAF-T) added survival benefit to treatment with tamoxifen alone. Optional tumour banking yielded specimens for determination of recurrence score by RT-PCR. In this retrospective analysis, we assessed the effect of recurrence score on disease-free survival by treatment group (tamoxifen vs CAF-T) using Cox regression, adjusting for number of positive nodes. Findings There were 367 specimens (40% of the 927 patients in the tamoxifen and CAF-T groups) with sufficient RNA for analysis (tamoxifen, n=148; CAF-T, n=219). The recurrence score was prognostic in the tamoxifen-alone group (p=0·006; hazard ratio HR 2·64, 95% CI 1·33–5·27, for a 50-point difference in recurrence score). There was no benefit of CAF in patients with a low recurrence score (score <18; log-rank p=0·97; HR 1·02, 0·54–1·93), but an improvement in disease-free survival for those with a high recurrence score (score ≥31; log-rank p=0·033; HR 0·59, 0·35–1·01), after adjustment for number of positive nodes. The recurrence score by treatment interaction was significant in the first 5 years (p=0·029), with no additional prediction beyond 5 years (p=0·58), although the cumulative benefit remained at 10 years. Results were similar for overall survival and breast-cancer-specific survival. Interpretation The recurrence score is prognostic for tamoxifen-treated patients with positive nodes and predicts significant benefit of CAF in tumours with a high recurrence score. A low recurrence score identifies women who might not benefit from anthracycline-based chemotherapy, despite positive nodes. Funding National Cancer Institute and Genomic Health.
Summary Background Tamoxifen is standard adjuvant treatment for postmenopausal women with hormone-receptor-positive breast cancer. We assessed the benefit of adding chemotherapy to adjuvant tamoxifen ...and whether tamoxifen should be given concurrently or after chemotherapy. Methods We undertook a phase 3, parallel, randomised trial (SWOG-8814, INT-0100) in postmenopausal women with hormone-receptor-positive, node-positive breast cancer to test two major objectives: whether the primary outcome, disease-free survival, was longer with cyclophosphamide, doxorubicin, and fluorouracil (CAF) given every 4 weeks for six cycles plus 5 years of daily tamoxifen than with tamoxifen alone; and whether disease-free survival was longer with CAF followed by tamoxifen (CAF-T) than with CAF plus concurrent tamoxifen (CAFT). Overall survival and toxicity were predefined, important secondary outcomes for each objective. Patients in this open-label trial were randomly assigned by a computer algorithm in a 2:3:3 ratio (tamoxifen:CAF-T:CAFT) and analysis was by intention to treat of eligible patients. Groups were compared by stratified log-rank tests, followed by Cox regression analyses adjusted for significant prognostic factors. This trial is registered with ClinicalTrials.gov , number NCT00929591. Findings Of 1558 randomised women, 1477 (95%) were eligible for inclusion in the analysis. After a maximum of 13 years of follow-up (median 8·94 years), 637 women had a disease-free survival event (tamoxifen, 179 events in 361 patients; CAF-T, 216 events in 566 patients; CAFT, 242 events in 550 patients). For the first objective, therapy with the CAF plus tamoxifen groups combined (CAFT or CAF-T) was superior to tamoxifen alone for the primary endpoint of disease-free survival (adjusted Cox regression hazard ratio HR 0·76, 95% CI 0·64–0·91; p=0·002) but only marginally for the secondary endpoint of overall survival (HR 0·83, 0·68–1·01; p=0·057). For the second objective, the adjusted HRs favoured CAF-T over CAFT but did not reach significance for disease-free survival (HR 0·84, 0·70–1·01; p=0·061) or overall survival (HR 0·90, 0·73–1·10; p=0·30). Neutropenia, stomatitis, thromboembolism, congestive heart failure, and leukaemia were more frequent in the combined CAF plus tamoxifen groups than in the tamoxifen-alone group. Interpretation Chemotherapy with CAF plus tamoxifen given sequentially is more effective adjuvant therapy for postmenopausal patients with endocrine-responsive, node-positive breast cancer than is tamoxifen alone. However, it might be possible to identify some subgroups that do not benefit from anthracycline-based chemotherapy despite positive nodes. Funding National Cancer Institute (US National Institutes of Health).
Summary Background Worldwide, many patients with HER2-positive early stage breast cancer do not receive trastuzumab—the standard adjuvant treatment. We investigated the efficacy and safety of ...adjuvant lapatinib for patients with trastuzumab-naive HER2-positive early-stage breast cancer, started at any time after diagnosis. Methods This study was a placebo-controlled, multicentre, randomised phase 3 trial. Women outpatients from 405 centres in 33 countries with HER2-positive early-breast cancer who had previously received adjuvant chemotherapy but not trastuzumab were randomly assigned (1:1) to receive daily lapatinib (1500 mg) or daily placebo for 12 months. Randomisation was done with a computer-generated sequence, stratified by time since diagnosis, lymph node involvement at diagnosis, and tumour hormone-receptor status. Investigators, site staff, and patients were masked to treatment assignment. The primary endpoint was disease-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov , number NCT00374322. Findings Between August, 2006, and May, 2008, 3161 women were enrolled and 3147 were assigned to lapatinib (n=1571) or placebo (n=1576). After a median follow-up of 47·4 months (range 0·4–60·0) in the lapatinib group and 48·3 (0·7–61·3) in the placebo group, 210 (13%) disease-free survival events had occurred in the lapatinib group versus 264 (17%) in the placebo group (hazard ratio HR 0·83, 95% CI 0·70–1·00; p=0·053). Central review of HER2 status showed that only 2490 (79%) of the randomised women were HER2-positive. 157 (13%) of 1230 confirmed HER2-positive patients in the lapatinib group and in 208 (17%) of 1260 in the placebo group had a disease-free survival event (HR 0·82, 95% 0·67–1·00; p=0·04). Serious adverse events occurred in 99 (6%) of 1573 patients taking lapatinib and 77 (5%) of 1574 patients taking placebo, with higher incidences of grade 3–4 diarrhoea (97 6% vs nine <1%), rash (72 5% vs three <1%), and hepatobiliary disorders (36 2% vs one <1%). Interpretation Our data show that there was no significant difference in disease-free survival between groups when analysed in the intention-to-treat population. However, exploratory analyses restricted to patients who had HER2-positive disease confirmed by central fluorescence in-situ hybridisation review suggested marginal benefit with lapatinib in terms of disease-free survival. Thus lapatinib might be an option for women with HER2-positive breast cancer who do not or cannot receive adjuvant trastuzumab. Funding GlaxoSmithKline.
Summary Background Prediction of response to anthracycline-based therapy for breast cancer is challenging. We aimed to assess the value of HER2 and TOP2A as predictive markers of response to ...anthracycline-based adjuvant therapy in patients with early breast cancer. Methods We did a meta-analysis of individual patient data from five randomised adjuvant trials that compared anthracycline-based regimens with cyclophosphamide, methotrexate, and fluorouracil (CMF) regimens. We assessed the status of HER2 and TOP2A genes with fluorescent in-situ hybridisation. Tumour samples were submitted to an external laboratory for validation. We calculated hazard ratios (HR) to compare event-free survival (EFS) and overall survival in patients receiving anthracycline-based treatment with those receiving CMF in two HER2 cohorts ( HER2 amplified and non-amplified tumours) and in three TOP2A cohorts (normal, amplified, and deleted tumours). Findings We analysed data for 3452 patients for HER2 and 3102 patients for TOP2A . For EFS, HRs were 0·89 (95% CI 0·79–1·01) for HER2 non-amplified patients and 0·71 (0·58–0·86) for HER2 -amplified patients (pinteraction =0·0485); for overall survival, HRs were 0·91 (95% CI 0·79–1·05) for HER2 non-amplified patients and 0·73 (0·59–0·89) for HER2 -amplified patients (pinteraction =0·0718). In analysis of TOP2A status, HRs for EFS were 0·88 (0·78–1·00) for normal, 0·63 (0·46–0·87) for deleted, and 0·62 (0·43–0·90) for amplified (pinteraction =0·0513); HRs for overall survival were 0·89 (0·78–1·03) for normal, 0·68 (0·49–0·95) for deleted, and 0·67 (0·46–0·98) for amplified (pinteraction =0·1608). When patients with TOP2A -deleted and TOP2A -amplified tumours were grouped together (altered cohort) and compared with data from patients with normal TOP2A tumours, HRs for EFS were 0·64 (0·50–0·81) for altered and 0·88 (0·78–1·00) for normal (pinteraction =0·0183); HRs for overall survival were 0·67 (0·52–0·86) for altered and 0·89 (0·78–1·03) for normal (pinteraction =0·0455). Interpretation Although HER2 amplification and combined TOP2A amplification and deletion may have some value in the prediction of responsiveness to anthracycline-based chemotherapy, our findings do not support the use of anthracyclines only in patients with HER2 -amplified or TOP2A -aberrated tumours. Funding Associazione Italiana Ricerca Cancro, Academy of Finland, Belgian Federation Against Cancer, Cancer Research UK, Les Amis de l'Institut Bordet, Scottish Breast Cancer Trials Group, NCIC Clinical Trials Group, Canadian Cancer Society Research Institute, Danish Council for Strategic Research, Pharmacia-Upjohn (now Pfizer), and Abbott Laboratories.
Summary Background Treatment of breast cancer with aromatase inhibitors is associated with damage to bones. NCIC CTG MA.27 was an open-label, phase 3, randomised controlled trial in which women with ...breast cancer were assigned to one of two adjuvant oral aromatase inhibitors—exemestane or anastrozole. We postulated that exemestane—a mildly androgenic steroid—might have a less detrimental effect on bone than non-steroidal anastrozole. In this companion study to MA.27, we compared changes in bone mineral density (BMD) in the lumbar spine and total hip between patients treated with exemestane and patients treated with anastrozole. Methods In MA.27, postmenopausal women with early stage hormone (oestrogen) receptor-positive invasive breast cancer were randomly assigned to exemestane 25 mg versus anastrozole 1 mg, daily. MA.27B recruited two groups of women from MA.27: those with BMD T-scores of −2·0 or more (up to 2 SDs below sex-matched, young adult mean) and those with at least one T-score (hip or spine) less than −2·0. Both groups received vitamin D and calcium; those with baseline T-scores of less than −2·0 also received bisphosphonates. The primary endpoints were percent change of BMD at 2 years in lumbar spine and total hip for both groups. We analysed patients according to which aromatase inhibitor and T-score groups they were allocated to but BMD assessments ceased if patients deviated from protocol. This study is registered with ClinicalTrials.gov , NCT00354302. Findings Between April 24, 2006, and May 30, 2008, 300 patients with baseline T-scores of −2·0 or more were accrued (147 allocated exemestane, 153 anastrozole); and 197 patients with baseline T-scores of less than −2·0 (101 exemestane, 96 anastrozole). For patients with T-scores greater than −2·0 at baseline, mean change of bone mineral density in the spine at 2 years did not differ significantly between patients taking exemestane and patients taking anastrozole (−0·92%, 95% CI −2·35 to 0·50 vs −2·39%, 95% CI −3·77 to −1·01; p=0·08). Respective mean loss in the hip was −1·93% (95% CI −2·93 to −0·93) versus −2·71% (95% CI −4·32 to −1·11; p=0·10). Likewise for those who started with T-scores of less than −2·0, mean change of spine bone mineral density at 2 years did not differ significantly between the exemestane and anastrozole treatment groups (2·11%, 95% CI −0·84 to 5·06 vs 3·72%, 95% CI 1·54 to 5·89; p=0·26), nor did hip bone mineral density (2·09%, 95% CI −1·45 to 5·63 vs 0·0%, 95% CI −3·67 to 3·66; p=0·28). Patients with baseline T-score of −2·0 or more taking exemestane had two fragility fractures and two other fractures, those taking anastrozole had three fragility fractures and five other fractures. For patients who had baseline T-scores of less than −2·0 taking exemestane, one had a fragility fracture and four had other fractures, whereas those taking anastrozole had five fragility fractures and one other fracture. Interpretation Our results demonstrate that adjuvant treatment with aromatase inhibitors can be considered for breast cancer patients who have T-scores less than −2·0. Funding Canadian Cancer Society Research Institute, Pfizer, Canadian Institutes of Health Research.
Summary Patients with breast cancer positive for human epidermal growth-factor receptor type 2 (HER2) are an important subgroup for consideration in the Asian context. Rationally designed, anti-HER2 ...targeted agents that can substantially improve treatment outcomes have become commercially available, but are still too costly for some groups in developed countries and for underdeveloped and developing nations. This review discusses the available evidence for optimum management of HER2-positive early and advanced breast cancer, and how this evidence can be applied to Asian countries with different levels of health-care resources and economic development—using framework provided by the Breast Health Global Initiative. We provide a brief overview of HER2 testing and discuss management of early and advanced HER2-positive breast cancer, and formulate a consensus statement for the management of breast cancer in the context of basic, limited, enhanced, and maximum health-care resource availability.
Summary Background Treatment with adjuvant trastuzumab for 1 year improves disease-free survival and overall survival in patients with human epidermal growth factor receptor 2 (HER2)-positive early ...breast cancer. We aimed to assess disease-free survival and overall survival after a median follow-up of 4 years for patients enrolled on the Herceptin Adjuvant (HERA) trial. Methods The HERA trial is an international, multicentre, randomised, open-label, phase 3 trial comparing treatment with trastuzumab for 1 and 2 years with observation after standard neoadjuvant, adjuvant chemotherapy, or both in patients with HER2-positive early breast cancer. The primary endpoint was disease-free survival. After a positive first interim analysis at a median follow-up of 1 year for the comparison of treatment with trastuzumab for 1 year with observation, event-free patients in the observation group were allowed to cross over to receive trastuzumab. We report trial outcomes for the 1-year trastuzumab and observation groups at a median follow-up of 48·4 months (IQR 42·0–56·5) and assess the effect of the extensive crossover to trastuzumab. Our analysis was by intention-to-treat. The HERA trial is registered with the European Clinical Trials Database, number 2005-002385-11. Findings The HERA trial population comprised 1698 patients randomly assigned to the observation group and 1703 to the 1-year trastuzumab group. Intention-to-treat analysis of disease-free survival showed a significant benefit in favour of patients in the 1-year trastuzumab group (4-year disease-free survival 78·6%) compared with the observation group (4-year disease-free survival 72·2%; hazard ratio HR 0·76; 95% CI 0·66–0·87; p<0·0001). Intention-to-treat analysis of overall survival showed no significant difference in the risk of death (4-year overall survival 89·3% vs 87·7%, respectively; HR 0·85; 95% CI 0·70–1·04; p=0·11). Overall, 885 patients (52%) of the 1698 patients in the observation group crossed over to receive trastuzumab, and began treatment at median 22·8 months (range 4·5–52·7) from randomisation. In a non-randomised comparison, patients in the selective-crossover cohort had fewer disease-free survival events than patients remaining in the observation group (adjusted HR 0·68; 95% CI 0·51–0·90; p=0·0077). Higher incidences of grade 3–4 and fatal adverse events were noted on 1-year trastuzumab than in the observation group. The most common grade 3 or 4 adverse events, each in less than 1% of patients, were congestive cardiac failure, hypertension, arthralgia, back pain, central-line infection, hot flush, headache, and diarrhoea. Interpretation Treatment with adjuvant trastuzumab for 1 year after chemotherapy is associated with significant clinical benefit at 4-year median follow-up. The substantial selective crossover of patients in the observation group to trastuzumab was associated with improved outcomes for this cohort. Funding F Hoffmann-La Roche, Michelangelo Foundation.
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