Kathleen I. Pritchard

PURPOSE: To compare the clinical features, natural history, and outcomes for women with "triple-negative" breast cancer with women with other types of breast cancer. EXPERIMENTAL DESIGN: We studied a cohort of 1,601 patients with breast cancer, diagnosed between January 1987 and December 1997 at Women's College Hospital in Toronto. Triple-negative breast cancers were defined as those that were estrogen receptor negative, progesterone receptor negative, and HER2neu negative. The prognostic significance of triple-negative breast cancer was explored. RESULTS: The median follow-up time of the 1,601 women was 8.1 years. One hundred and eighty of 1,601 patients (11.2%) had triple-negative breast cancer. Compared with other women with breast cancer, those with triple-negative breast cancer had an increased likelihood of distant recurrence (hazard ratio, 2.6; 95% confidence interval, 2.0-3.5; P < 0.0001) and death (hazard ratio, 3.2; 95% confidence interval, 2.3-4.5; P < 0.001) within 5 years of diagnosis but not thereafter. The pattern of recurrence was also qualitatively different; among the triple-negative group, the risk of distant recurrence peaked at approximately 3 years and declined rapidly thereafter. Among the "other" group, the recurrence risk seemed to be constant over the period of follow-up. CONCLUSIONS: Triple-negative breast cancers have a more aggressive clinical course than other forms of breast cancer, but the adverse effect is transient.

BACKGROUND: Resistance to endocrine therapy in breast cancer is associated with activation of the mammalian target of rapamycin (mTOR) intracellular signaling pathway. In early studies, the mTOR inhibitor everolimus added to endocrine therapy showed antitumor activity. METHODS: In this phase 3, randomized trial, we compared everolimus and exemestane versus exemestane and placebo (randomly assigned in a 2:1 ratio) in 724 patients with hormone-receptor-positive advanced breast cancer who had recurrence or progression while receiving previous therapy with a nonsteroidal aromatase inhibitor in the adjuvant setting or to treat advanced disease (or both). The primary end point was progression-free survival. Secondary end points included survival, response rate, and safety. A preplanned interim analysis was performed by an independent data and safety monitoring committee after 359 progression-free survival events were observed. RESULTS: Baseline characteristics were well balanced between the two study groups. The median age was 62 years, 56% had visceral involvement, and 84% had hormone-sensitive disease. Previous therapy included letrozole or anastrozole (100%), tamoxifen (48%), fulvestrant (16%), and chemotherapy (68%). The most common grade 3 or 4 adverse events were stomatitis (8% in the everolimus-plus-exemestane group vs. 1% in the placebo-plus-exemestane group), anemia (6% vs. <1%), dyspnea (4% vs. 1%), hyperglycemia (4% vs. <1%), fatigue (4% vs. 1%), and pneumonitis (3% vs. 0%). At the interim analysis, median progression-free survival was 6.9 months with everolimus plus exemestane and 2.8 months with placebo plus exemestane, according to assessments by local investigators (hazard ratio for progression or death, 0.43; 95% confidence interval [CI], 0.35 to 0.54; P<0.001). Median progression-free survival was 10.6 months and 4.1 months, respectively, according to central assessment (hazard ratio, 0.36; 95% CI, 0.27 to 0.47; P<0.001). CONCLUSIONS: Everolimus combined with an aromatase inhibitor improved progression-free survival in patients with hormone-receptor-positive advanced breast cancer previously treated with nonsteroidal aromatase inhibitors. (Funded by Novartis; BOLERO-2 ClinicalTrials.gov number, NCT00863655.).

BACKGROUND: The recurrence score based on the 21-gene breast cancer assay predicts chemotherapy benefit if it is high and a low risk of recurrence in the absence of chemotherapy if it is low; however, there is uncertainty about the benefit of chemotherapy for most patients, who have a midrange score. METHODS: We performed a prospective trial involving 10,273 women with hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, axillary node-negative breast cancer. Of the 9719 eligible patients with follow-up information, 6711 (69%) had a midrange recurrence score of 11 to 25 and were randomly assigned to receive either chemoendocrine therapy or endocrine therapy alone. The trial was designed to show noninferiority of endocrine therapy alone for invasive disease-free survival (defined as freedom from invasive disease recurrence, second primary cancer, or death). RESULTS: Endocrine therapy was noninferior to chemoendocrine therapy in the analysis of invasive disease-free survival (hazard ratio for invasive disease recurrence, second primary cancer, or death [endocrine vs. chemoendocrine therapy], 1.08; 95% confidence interval, 0.94 to 1.24; P=0.26). At 9 years, the two treatment groups had similar rates of invasive disease-free survival (83.3% in the endocrine-therapy group and 84.3% in the chemoendocrine-therapy group), freedom from disease recurrence at a distant site (94.5% and 95.0%) or at a distant or local-regional site (92.2% and 92.9%), and overall survival (93.9% and 93.8%). The chemotherapy benefit for invasive disease-free survival varied with the combination of recurrence score and age (P=0.004), with some benefit of chemotherapy found in women 50 years of age or younger with a recurrence score of 16 to 25. CONCLUSIONS: Adjuvant endocrine therapy and chemoendocrine therapy had similar efficacy in women with hormone-receptor-positive, HER2-negative, axillary node-negative breast cancer who had a midrange 21-gene recurrence score, although some benefit of chemotherapy was found in some women 50 years of age or younger. (Funded by the National Cancer Institute and others; TAILORx ClinicalTrials.gov number, NCT00310180 .).

BACKGROUND: There have been many randomised trials of adjuvant prolonged polychemotherapy among women with early breast cancer, and an updated overview of their results is presented. METHODS: In 1995, information was sought on each woman in any randomised trial that began before 1990 and involved treatment groups that differed only with respect to the chemotherapy regimens that were being compared. Analyses involved about 18,000 women in 47 trials of prolonged polychemotherapy versus no chemotherapy, about 6000 in 11 trials of longer versus shorter polychemotherapy, and about 6000 in 11 trials of anthracycline-containing regimens versus CMF (cyclophosphamide, methotrexate, and fluorouracil). FINDINGS: For recurrence, polychemotherapy produced substantial and highly significant proportional reductions both among women aged under 50 at randomisation (35% [SD 4] reduction; 2p<0.00001) and among those aged 50-69 (20% [SD 3] reduction; 2p<0.00001); few women aged 70 or over had been studied. For mortality, the reductions were also significant both among women aged under 50 (27% [SD 5] reduction; 2p<0.00001) and among those aged 50-69 (11% [SD 3] reduction; 2p=0.0001). The recurrence reductions emerged chiefly during the first 5 years of follow-up, whereas the difference in survival grew throughout the first 10 years. After standardisation for age and time since randomisation, the proportional reductions in risk were similar for women with node-negative and node-positive disease. Applying the proportional mortality reduction observed in all women aged under 50 at randomisation would typically change a 10-year survival of 71% for those with node-negative disease to 78% (an absolute benefit of 7%), and of 42% for those with node-positive disease to 53% (an absolute benefit of 11%). The smaller proportional mortality reduction observed in all women aged 50-69 at randomisation would translate into smaller absolute benefits, changing a 10-year survival of 67% for those with node-negative disease to 69% (an absolute gain of 2%) and of 46% for those with node-positive disease to 49% (an absolute gain of 3%). The age-specific benefits of polychemotherapy appeared to be largely irrespective of menopausal status at presentation, oestrogen receptor status of the primary tumour, and of whether adjuvant tamoxifen had been given. In terms of other outcomes, there was a reduction of about one-fifth (2p=0.05) in contralateral breast cancer, which has already been included in the analyses of recurrence, and no apparent adverse effect on deaths from causes other than breast cancer (death rate ratio 0.89 [SD 0.09]). The directly randomised comparisons of longer versus shorter durations of polychemotherapy did not indicate any survival advantage with the use of more than about 3-6 months of polychemotherapy. By contrast, directly randomised comparisons did suggest that, compared with CMF alone, the anthracycline-containing regimens studied produced somewhat greater effects on recurrence (2p=0.006) and mortality (69% vs 72% 5-year survival; log-rank 2p=0.02). But this comparison is one of many that could have been selected for emphasis, the 99% CI reaches zero, and the results of several of the relevant trials are not yet available. INTERPRETATION: Some months of adjuvant polychemotherapy (eg, with CMF or an anthracycline-containing regimen) typically produces an absolute improvement of about 7-11% in 10-year survival for women aged under 50 at presentation with early breast cancer, and of about 2-3% for those aged 50-69 (unless their prognosis is likely to be extremely good even without such treatment). Treatment decisions involve consideration not only of improvements in cancer recurrence and survival but also of adverse side-effects of treatment, and this report makes no recommendations as to who should or should not be treated.