Medline ® Abstracts for References 1-4
of 'Prognostic and predictive factors in early, nonmetastatic breast cancer'
Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials.
Early Breast Cancer Trialists' Collaborative Group (EBCTCG), Peto R, Davies C, Godwin J, Gray R, Pan HC, Clarke M, Cutter D, Darby S, McGale P, Taylor C, Wang YC, Bergh J, Di Leo A, Albain K, Swain S, Piccart M, Pritchard K
Lancet. 2012;379(9814):432. Epub 2011 Dec 5.
BACKGROUND: Moderate differences in efficacy between adjuvant chemotherapy regimens for breast cancer are plausible, and could affect treatment choices. We sought any such differences.
METHODS: We undertook individual-patient-data meta-analyses of the randomised trials comparing: any taxane-plus-anthracycline-based regimen versus the same, or more, non-taxane chemotherapy (n=44,000); one anthracycline-based regimen versus another (n=7000) or versus cyclophosphamide, methotrexate, and fluorouracil (CMF; n=18,000); and polychemotherapy versus no chemotherapy (n=32,000). The scheduled dosages of these three drugs and of the anthracyclines doxorubicin (A) and epirubicin (E) were used to define standard CMF, standard 4AC, and CAF and CEF. Log-rank breast cancer mortality rate ratios (RRs) are reported.
FINDINGS: In trials adding four separate cycles of a taxane to a fixed anthracycline-based control regimen, extending treatment duration, breast cancer mortality was reduced (RR 0·86, SE0·04, two-sided significance [2p]=0·0005). In trials with four such extra cycles of a taxane counterbalanced in controls by extra cycles of other cytotoxic drugs, roughly doubling non-taxane dosage, there was no significant difference (RR 0·94, SE 0·06, 2p=0·33). Trials with CMF-treated controls showed that standard 4AC and standard CMF were equivalent (RR 0·98, SE 0·05, 2p=0·67), but that anthracycline-based regimens with substantially higher cumulative dosage than standard 4AC (eg, CAF or CEF) were superior to standard CMF (RR 0·78, SE 0·06, 2p=0·0004). Trials versus no chemotherapy also suggested greater mortality reductions with CAF (RR 0·64, SE 0·09, 2p<0·0001) than with standard 4AC (RR 0·78, SE 0·09, 2p=0·01) or standard CMF (RR 0·76, SE 0·05, 2p<0·0001). In all meta-analyses involving taxane-based or anthracycline-based regimens, proportional risk reductions were little affected by age, nodal status, tumour diameter or differentiation (moderate or poor; few were well differentiated), oestrogen receptor status, or tamoxifen use. Hence, largely independently of age (up to at least 70 years) or the tumour characteristics currently available to us for the patients selected to be in these trials, some taxane-plus-anthracycline-based or higher-cumulative-dosage anthracycline-based regimens (not requiring stem cells) reduced breast cancer mortality by, on average, about one-third. 10-year overall mortality differences paralleled breast cancer mortality differences, despite taxane, anthracycline, and other toxicities.
INTERPRETATION: 10-year gains from a one-third breast cancer mortality reduction depend on absolute risks without chemotherapy (which, for oestrogen-receptor-positive disease, are the risks remaining with appropriate endocrine therapy). Low absolute risk implieslow absolute benefit, but information was lacking about tumour gene expression markers or quantitative immunohistochemistry that might help to predict risk, chemosensitivity, or both.
FUNDING: Cancer Research UK; British Heart Foundation; UK Medical Research Council.
Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials.
Early Breast Cancer Trialists' Collaborative Group (EBCTCG), Davies C, Godwin J, Gray R, Clarke M, Cutter D, Darby S, McGale P, Pan HC, Taylor C, Wang YC, Dowsett M, Ingle J, Peto R
Lancet. 2011;378(9793):771. Epub 2011 Jul 28.
BACKGROUND: As trials of 5 years of tamoxifen in early breast cancer mature, the relevance of hormone receptor measurements (and other patient characteristics) to long-term outcome can be assessed increasingly reliably. We report updated meta-analyses of the trials of 5 years of adjuvant tamoxifen.
METHODS: We undertook a collaborative meta-analysis of individual patient data from 20 trials (n=21,457) in early breast cancer of about 5 years of tamoxifen versus no adjuvant tamoxifen, with about 80% compliance. Recurrence and death rate ratios (RRs) were from log-rank analyses by allocated treatment.
FINDINGS: In oestrogen receptor (ER)-positive disease (n=10,645), allocation to about 5 years of tamoxifen substantially reduced recurrence rates throughout the first 10 years (RR 0·53 [SE 0·03]during years 0-4 and RR 0·68 [0·06]during years 5-9 [both 2p<0·00001]; but RR 0·97 [0·10]during years 10-14, suggesting no further gain or loss after year 10). Even in marginally ER-positive disease (10-19 fmol/mg cytosol protein) the recurrence reduction was substantial (RR 0·67 [0·08]). In ER-positive disease, the RR was approximately independent of progesterone receptor status (or level), age, nodal status, or use of chemotherapy. Breast cancer mortality was reduced by about a third throughout the first 15 years (RR 0·71 [0·05]during years 0-4, 0·66 [0·05]during years 5-9, and 0·68 [0·08]during years 10-14; p<0·0001 for extra mortality reduction during each separate time period). Overall non-breast-cancer mortality was little affected, despite small absolute increases in thromboembolic and uterine cancer mortality (both only in women older than 55 years), so all-cause mortality was substantially reduced. In ER-negative disease, tamoxifen had little or no effect on breast cancer recurrence or mortality.
INTERPRETATION: 5 years of adjuvant tamoxifen safely reduces 15-year risks of breast cancer recurrence and death. ER status was the only recorded factor importantly predictive of the proportional reductions. Hence, the absolute risk reductions produced by tamoxifen depend on the absolute breast cancer risks (after any chemotherapy) without tamoxifen.
FUNDING: Cancer Research UK, British Heart Foundation, and Medical Research Council.
Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials.
Early Breast Cancer Trialists' Collaborative Group (EBCTCG), Darby S, McGale P, Correa C, Taylor C, Arriagada R, Clarke M, Cutter D, Davies C, Ewertz M, Godwin J, Gray R, Pierce L, Whelan T, Wang Y, Peto R
Lancet. 2011 Nov;378(9804):1707-16. Epub 2011 Oct 19.
BACKGROUND: After breast-conserving surgery, radiotherapy reduces recurrence and breast cancer death, but it may do so more for some groups of women than for others. We describe the absolute magnitude of these reductions according to various prognostic and other patient characteristics, and relate the absolute reduction in 15-year risk of breast cancer death to the absolute reduction in 10-year recurrence risk.
METHODS: We undertook a meta-analysis of individual patient data for 10,801 women in 17 randomised trials of radiotherapy versus no radiotherapy after breast-conserving surgery, 8337 of whom had pathologically confirmed node-negative (pN0) or node-positive (pN+) disease.
FINDINGS: Overall, radiotherapy reduced the 10-year risk of any (ie, locoregional or distant) first recurrence from 35·0% to 19·3% (absolute reduction 15·7%, 95% CI 13·7-17·7, 2p<0·00001) and reduced the 15-year risk of breast cancer death from 25·2% to21·4% (absolute reduction 3·8%, 1·6-6·0, 2p=0·00005). In women with pN0 disease (n=7287), radiotherapy reduced these risks from 31·0% to 15·6% (absolute recurrence reduction 15·4%, 13·2-17·6, 2p<0·00001) and from 20·5% to 17·2% (absolute mortality reduction 3·3%, 0·8-5·8, 2p=0·005), respectively. In these women with pN0 disease, the absolute recurrence reduction varied according to age, grade, oestrogen-receptor status, tamoxifen use, and extent of surgery, and these characteristics were used to predict large (≥20%), intermediate (10-19%), or lower (<10%) absolute reductions in the 10-year recurrence risk. Absolute reductions in 15-year risk of breast cancer death in these three prediction categories were 7·8% (95% CI 3·1-12·5), 1·1% (-2·0 to 4·2), and 0·1% (-7·5 to 7·7) respectively (trend in absolute mortality reduction 2p=0·03). In the few women with pN+ disease (n=1050), radiotherapy reduced the 10-year recurrence risk from 63·7% to 42·5% (absolute reduction 21·2%, 95% CI 14·5-27·9, 2p<0·00001) and the 15-year risk of breast cancer death from 51·3% to 42·8% (absolute reduction 8·5%, 1·8-15·2, 2p=0·01). Overall, about one breast cancer death was avoided by year 15 for every four recurrences avoided by year 10, and the mortality reduction did not differ significantly from this overall relationship in any of the three prediction categories for pN0 disease or for pN+ disease.
INTERPRETATION: After breast-conserving surgery, radiotherapy to the conserved breast halves the rate at which the disease recurs and reduces the breast cancer death rate by about a sixth. These proportional benefits vary little between different groups of women. By contrast, the absolute benefits fromradiotherapy vary substantially according to the characteristics of the patient and they can be predicted at the time when treatment decisions need to be made.
FUNDING: Cancer Research UK, British Heart Foundation, and UK Medical Research Council.
Breast and cervical cancer in 187 countries between 1980 and 2010: a systematic analysis.
Forouzanfar MH, Foreman KJ, Delossantos AM, Lozano R, Lopez AD, Murray CJ, Naghavi M
Lancet. 2011 Oct;378(9801):1461-84. Epub 2011 Sep 14.
BACKGROUND: Breast and cervical cancer are important causes of mortality in women aged≥15 years. We undertook annual age-specific assessments of breast and cervical cancer in 187 countries.
METHODS: We systematically collected cancer registry data on mortality and incidence, vital registration, and verbal autopsy data for the period 1980-2010. We modelled the mortality-to-incidence (MI) ratio using a hierarchical model. Vital registration and verbal autopsy were supplemented with incidence multiplied by the MI ratio to yield a comprehensive database of mortality rates. We used Gaussian process regression to develop estimates of mortality with uncertainty by age, sex, country, and year. We used out-of-sample predictive validity to select the final model. Estimates of incidence with uncertainty were also generated with mortality and MI ratios.
FINDINGS: Global breast cancer incidence increased from 641,000 (95% uncertainty intervals 610,000-750,000) cases in 1980 to 1,643,000 (1,421,000-1,782,000) cases in 2010, an annual rate of increase of 3·1%. Global cervical cancer incidenceincreased from 378,000 (256,000-489,000) cases per year in 1980 to 454,000 (318,000-620,000) cases per year in 2010-a 0·6% annual rate of increase. Breast cancer killed 425,000 (359,000-453,000) women in 2010, of whom 68,000 (62,000-74,000) were aged 15-49 years in developing countries. Cervical cancer death rates have been decreasing but the disease still killed 200,000 (139,000-276,000) women in 2010, of whom 46,000 (33,000-64,000) were aged 15-49 years in developing countries. We recorded pronounced variation in the trend in breast cancer mortality across regions and countries.
INTERPRETATION: More policy attention is needed to strengthen established health-system responses to reduce breast and cervical cancer, especially in developing countries.
FUNDING: Susan G Komen for the Cure and the Bill&Melinda Gates Foundation.
Institute for Health Metrics and Evaluation, University of Washington, Seattle, USA.