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Journal ArticleDOI

Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials.

TL;DR: In 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.
About: This article is published in The Lancet.The article was published on 2012-02-04 and is currently open access. It has received 1647 citations till now. The article focuses on the topics: Epirubicin & Dose-dense chemotherapy.

Summary (2 min read)

Introduction

  • The Early Breast Cancer Trialists’ Collaborative Group was established in 1985 to coordinate individual-patient-level meta-analyses of all random ised trials of adjuvant treatments.
  • 1–4 A previous report1 on the trials that had begun by 1995 reviewed polychemotherapy ver sus no adjuvant chemotherapy and anthracyclinebased chemotherapy (with doxorubicin or epirubicin) versus CMF (cyclophosphamide, methotrexate, fl uorouracil), but did not take dosage into account and did not review taxanes.

Trials

  • Methods of trial identifi cation, data checking, analysis, and involvement of trialists in the interpretation of results are as in previous EBCTCG reports.
  • 1–4 Information about each individual patient was sought during 2005–10 from all randomised trials begun during 1973–2003 of: (1) taxane-based versus non-taxane-based regimens (data for 33 trials, begun in 1994–2003); (2) any anthracyclinebased regimen versus standard or near-standard CMF www.thelancet.com.
  • Trials of intensive chemotherapy with stem-cell rescue or of variation only in dose-density are not included.
  • Otherwise, all main analyses include 99% or more of all relevant patients in closed trials.

Statistical analysis

  • For each main chemotherapy comparison, forest plots describe the separate trials and their results, graphs illustrate absolute risks in various circumstances, and detailed subgroup analyses explore whether proportional risk reductions depend on patient or tumour charac teristics.
  • For, if there is little real heterogeneity between the RRs, this overall χ²₁ (plus the small χ² for heterogeneity between treatment RRs in diff erent subgroups) gets partitioned between the subgroups in approximate proportion to numbers of events, to yield χ²₁ in each.
  • Chemotherapy regimens varied greatly, so real treatment eff ects in diff erent trials could well diff er, even though chance makes it diffi cult to assess this reliably, particularly with short follow-up and some trials not yet available.
  • The fi ndings for recurrence, breast cancer mortality, and overall mortality show a defi nite improvement over CMF.
  • In these trials there was a signifi cant trend towards greater effi cacy with higher cumulative anthracycline dosage (χ²₁=8·0, 2p=0·005; fi gure 4A).

Doxorubicin (A) Epirubicin (E)

  • Most women were aged 55–69 years at entry; results in the few who were older also suggest benefi t (as in the taxane trials), but with wide uncertainty.
  • To help assess any life-threatening acute toxicity.
  • Vol 379 February 4, 2012 Numbers of acute myeloid leukaemia deaths without recurrence were 11 versus one for taxane plus other chemotherapy versus the same, or more, other chemotherapy; fi ve each for anthracycline versus CMF; eight versus none for anthracycline versus nil; and one versus three for CMF versus nil.

Discussion

  • These meta-analyses yield fi ve main fi ndings.
  • Multiplying together breast cancer mortality RRs for the fi rst and third of these fi ndings (standard CMF or standard 4AC vs no chemotherapy, and more eff ective regimens vs either of these; 0·775 × 0·825 = 0·64) would suggest about 36% breast cancer mortality rate reduction for the more eff ective regimens versus no chemotherapy.
  • All writing committee members’ institutions perform some trials sponsored by industry, government, or charity grants, which are under taken and interpreted independently of the funders.
  • Industrial support of trials contributing to EBCTCG meta-analyses is listed in the trial publi cations ; although such sponsorship might delay data from recent studies, it does not otherwise aff ect the analyses.
  • Poor diff erentiation, although not very reproducible between pathologists, is somewhat related to proliferation (and was measured well enough to predict poor prognosis), but in ER-positive disease it did not predict chemosensitivity.

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TL;DR: This review focuses on current approaches and evolving strategies for local and systemic therapy of breast cancer as well as distinct risk profiles and treatment strategies.
Abstract: Importance Breast cancer will be diagnosed in 12% of women in the United States over the course of their lifetimes and more than 250 000 new cases of breast cancer were diagnosed in the United States in 2017. This review focuses on current approaches and evolving strategies for local and systemic therapy of breast cancer. Observations Breast cancer is categorized into 3 major subtypes based on the presence or absence of molecular markers for estrogen or progesterone receptors and human epidermal growth factor 2 (ERBB2; formerlyHER2): hormone receptor positive/ERBB2 negative (70% of patients),ERBB2positive (15%-20%), and triple-negative (tumors lacking all 3 standard molecular markers; 15%). More than 90% of breast cancers are not metastatic at the time of diagnosis. For people presenting without metastatic disease, therapeutic goals are tumor eradication and preventing recurrence. Triple-negative breast cancer is more likely to recur than the other 2 subtypes, with 85% 5-year breast cancer–specific survival for stage I triple-negative tumors vs 94% to 99% for hormone receptor positive andERBB2positive. Systemic therapy for nonmetastatic breast cancer is determined by subtype: patients with hormone receptor–positive tumors receive endocrine therapy, and a minority receive chemotherapy as well; patients withERBB2-positive tumors receiveERBB2-targeted antibody or small-molecule inhibitor therapy combined with chemotherapy; and patients with triple-negative tumors receive chemotherapy alone. Local therapy for all patients with nonmetastatic breast cancer consists of surgical resection, with consideration of postoperative radiation if lumpectomy is performed. Increasingly, some systemic therapy is delivered before surgery. Tailoring postoperative treatment based on preoperative treatment response is under investigation. Metastatic breast cancer is treated according to subtype, with goals of prolonging life and palliating symptoms. Median overall survival for metastatic triple-negative breast cancer is approximately 1 year vs approximately 5 years for the other 2 subtypes. Conclusions and Relevance Breast cancer consists of 3 major tumor subtypes categorized according to estrogen or progesterone receptor expression andERBB2gene amplification. The 3 subtypes have distinct risk profiles and treatment strategies. Optimal therapy for each patient depends on tumor subtype, anatomic cancer stage, and patient preferences.

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References
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Journal ArticleDOI
TL;DR: The 10-year and 15-year effects of various systemic adjuvant therapies on breast cancer recurrence and survival are reported and it is found that the cumulative reduction in mortality is more than twice as big at 15 years as at 5 years after diagnosis.

6,309 citations

Journal ArticleDOI
TL;DR: The recurrence score has been validated as quantifying the likelihood of distant recurrence in tamoxifen-treated patients with node-negative, estrogen-receptor-positive breast cancer and could be used as a continuous function to predict distant recurrent in individual patients.
Abstract: background The likelihood of distant recurrence in patients with breast cancer who have no involved lymph nodes and estrogen-receptor–positive tumors is poorly defined by clinical and histopathological measures. methods We tested whether the results of a reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assay of 21 prospectively selected genes in paraffin-embedded tumor tissue would correlate with the likelihood of distant recurrence in patients with node-negative, tamoxifen-treated breast cancer who were enrolled in the National Surgical Adjuvant Breast and Bowel Project clinical trial B-14. The levels of expression of 16 cancerrelated genes and 5 reference genes were used in a prospectively defined algorithm to calculate a recurrence score and to determine a risk group (low, intermediate, or high) for each patient. results Adequate RT-PCR profiles were obtained in 668 of 675 tumor blocks. The proportions of patients categorized as having a low, intermediate, or high risk by the RT-PCR assay were 51, 22, and 27 percent, respectively. The Kaplan–Meier estimates of the rates of distant recurrence at 10 years in the low-risk, intermediate-risk, and high-risk groups were 6.8 percent (95 percent confidence interval, 4.0 to 9.6), 14.3 percent (95 percent confidence interval, 8.3 to 20.3), and 30.5 percent (95 percent confidence interval, 23.6 to 37.4). The rate in the low-risk group was significantly lower than that in the high-risk group (P<0.001). In a multivariate Cox model, the recurrence score provided significant predictive power that was independent of age and tumor size (P<0.001). The recurrence score was also predictive of overall survival (P<0.001) and could be used as a continuous function to predict distant recurrence in individual patients. conclusions The recurrence score has been validated as quantifying the likelihood of distant recurrence in tamoxifen-treated patients with node-negative, estrogen-receptor–positive breast cancer.

5,685 citations

Journal ArticleDOI
TL;DR: A testing algorithm that relies on accurate, reproducible assay performance, including newly available types of brightfield ISH, is proposed and strongly recommends validation of laboratory assay or modifications, use of standardized operating procedures, and compliance with new testing criteria to be monitored.
Abstract: Purpose To develop a guideline to improve the accuracy of human epidermal growth factor receptor 2 (HER2) testing in invasive breast cancer and its utility as a predictive marker. Methods The American Society of Clinical Oncology and the College of American Pathologists convened an expert panel, which conducted a systematic review of the literature and developed recommendations for optimal HER2 testing performance. The guideline was reviewed by selected experts and approved by the board of directors for both organizations. Results Approximately 20% of current HER2 testing may be inaccurate. When carefully validated testing is performed, available data do not clearly demonstrate the superiority of either immunohistochemistry (IHC) or in situ hybridization (ISH) as a predictor of benefit from anti-HER2 therapy. Recommendations The panel recommends that HER2 status should be determined for all invasive breast cancer. A testing algorithm that relies on accurate, reproducible assay performance, including newly...

4,560 citations

Journal ArticleDOI
TL;DR: The RS assay not only quantifies the likelihood of breast cancer recurrence in women with node-negative, estrogen receptor-positive breast cancer, but also predicts the magnitude of chemotherapy benefit.
Abstract: Purpose The 21-gene recurrence score (RS) assay quantifies the likelihood of distant recurrence in women with estrogen receptor‐positive, lymph node‐negative breast cancer treated with adjuvant tamoxifen. The relationship between the RS and chemotherapy benefit is not known. Methods The RS was measured in tumors from the tamoxifen-treated and tamoxifen plus chemotherapy‐ treated patients in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B20 trial. Cox proportional hazards models were utilized to test for interaction between chemotherapy treatment and the RS. Results A total of 651 patients were assessable (227 randomly assigned to tamoxifen and 424 randomly assigned to tamoxifen plus chemotherapy). The test for interaction between chemotherapy treatment and RS was statistically significant (P .038). Patients with high-RS ( 31) tumors (ie, high risk of recurrence) had a large benefit from chemotherapy (relative risk, 0.26; 95% CI, 0.13 to 0.53; absolute decrease in 10-year distant recurrence rate: mean, 27.6%; SE, 8.0%). Patients with low-RS ( 18) tumors derived minimal, if any, benefit from chemotherapy treatment (relative risk, 1.31; 95% CI, 0.46 to 3.78; absolute decrease in distant recurrence rate at 10 years: mean, 1.1%; SE, 2.2%). Patients with intermediate-RS tumors did not appear to have a large benefit, but the uncertainty in the estimate can not exclude a clinically important benefit.

2,390 citations

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TL;DR: The absolute risk reductions produced by tamoxifen depend on the absolute breast cancer risks (after any chemotherapy) without tamox ifen, so all-cause mortality was substantially reduced.

2,347 citations

Related Papers (5)
Frequently Asked Questions (6)
Q1. What contributions have the authors mentioned in the paper "Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100 000 women in 123 randomised trials" ?

Peto et al. this paper reviewed the preliminary taxane trial results and updated the other chemotherapy trial results, assessing the relevance of scheduled drug dosage and investigating whether any of the available patient or tumor characteristics ( eg, age, nodal status, tumour diff erentiation, oestrogen receptor [ ER ] status, use of tamoxifen ) aff ect the proportional reductions with modern chemotherapy in breast cancer recurrence and death. 

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). 

10-year overall mortality diff erences paralleled breast cancer mortality diff erences, despite taxane, anthracycline, and other toxicities. 

In all meta-analyses involving taxane-based or anthracycline-based regimens, proportional risk reductions were little aff ected by age, nodal status, tumour diameter or diff erentiation (moderate or poor; few were well diff erentiated), oestrogen receptor status, or tamoxifen use. 

In trials adding four separate cycles of a taxane to a fi xed anthracycline-based control regimen, extending treatment duration, breast cancer mortality was reduced (RR 0·86, SE 0·04, two-sided signifi cance [2p]=0·0005). 

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.