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Objectives: Severe hot flash (HF) toxicity due to tamoxifen can compromise compliance. We previously found that HFs did not correlate with endoxifen level or CYP2D6 genotype. In this study, we reduced tamoxifen dose in patients with severe HFs to determine whether HFs were ameliorated whilst maintaining a purported therapeutic endoxifen level of >15 nM., Materials and Methods: Twenty patients with severe HFs on 20 mg TAM had CYP2D6genotype, trough level tamoxifen and metabolites measured with Loprinzi HF scores (HFS) derived before and after DR of tamoxifen to 10 mg. Other data collected included demographics, smoking, alcohol, menstrual and breast cancer history, previous chemotherapies, concurrent medications, BMI and other tamoxifen toxicities., Results: At the 20 mg tamoxifen dose, endoxifen levels were 25.6, 0-91.9 nM (median, range) with HFS 131, 22-1482 (median, range). Upon DR to 10 mg, median endoxifen level fell to 14.1, 0.6-71.9 nM (difference in means p = 0.11, two-tailed T test) with HFS 47, 5-864 (difference in means p = 0.24, two-tailed T test). Despite lacking statistical significance, 85% of patients reported subjective improvement of HFs with DR. After DR, the proportion of patients with endoxifen level <15 nM increased from 20% to 50%. HFS did not correlate with any other parameter., Conclusion: DR of tamoxifen from 20 mg to 10 mg daily resulted in halving of endoxifen levels and subjective improvement of HF. While half the dose-reduced patients were below a potential therapeutic level of endoxifen, other recent studies suggest that low endoxifen levels may not indicate reduced effectiveness of tamoxifen., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Anthracyclines and taxanes are chemotherapeutic agents widely used in a sequential regimen in the adjuvant and neoadjuvant treatment of early breast cancer to reduce the risk of cancer recurrence. Standard practice is to administer anthracycline-based chemotherapy followed by a taxane. Anthracyclines tend to be administered first as they were established before taxanes for treatment of early breast cancer., Objectives: To assess whether the sequence in which anthracyclines and taxanes are administered affects outcomes for people with early breast cancer receiving adjuvant or neoadjuvant therapy., Search Methods: We searched Cochrane Breast Cancer's Specialised Register, CENTRAL, MEDLINE, Embase, the World Health Organization's International Clinical Trials Registry Platform (WHO ICTRP) and ClinicalTrials.gov on 1 February 2018., Selection Criteria: Randomised controlled trials comparing administering a taxane prior to an anthracycline with taxane following anthracycline to people with early breast cancer receiving chemotherapy. The studies needed to have reported on at least one of our outcomes of interest, which included overall survival, disease-free survival, pathological response, treatment adherence, toxicity and quality of life., Data Collection and Analysis: Two review authors independently extracted data, assessed risk of bias and quality of the evidence. The primary outcome measure was overall survival. Secondary outcomes included disease-free survival, pathological response (in the neoadjuvant setting only), adverse events, treatment adherence and quality of life. For time-to-event outcomes of overall survival and disease-free survival, we derived hazard ratios (HRs) with 95% confidence intervals (CI) where possible. For dichotomous outcomes of pathological complete response, treatment adherence and adverse events, we reported the treatment effect as a risk ratio (RR) with 95% CI where possible. We used GRADE to assess the certainty of the evidence separately for the neoadjuvant and adjuvant settings., Main Results: There were 1415 participants in five neoadjuvant studies and 280 participants in four adjuvant studies involving five treatment comparisons. Four of the five neoadjuvant studies collected data for the primary outcome (overall survival) and two studies had data available; one of the four adjuvant studies collected overall survival data.The neoadjuvant studies suggested that the administration of taxanes first probably resulted in little to no difference in overall survival (HR 0.80, 95% CI 0.60 to 1.08; 947 participants; 2 studies; moderate-certainty evidence) and disease-free survival (HR 0.84, 95% CI 0.65 to 1.09; 828 participants; 1 study; moderate-certainty evidence). Administration of taxanes first also resulted in little to no difference in pathological complete response (absence of cancer in the breast and axilla: RR 1.15, 95% CI 0.96 to 1.38; 1280 participants; 4 studies; high-certainty evidence). However, there appeared to be a trend in favour of taxanes first. Studies reported treatment adherence using a range of measures. Administration of taxanes first probably did not increase the likelihood of requiring dose reductions compared to administration of anthracyclines first (RR 0.81, 95% CI 0.59 to 1.11; 280 participants; 1 study; moderate-certainty evidence). There was probably little to no difference in the risk of grade 3/4 neutropenia (RR 1.25, 95% CI 0.86 to 1.82; 280 participants, 1 study; moderate-certainty evidence) or grade 3/4 neurotoxicity (RR 0.95, 95% CI 0.55 to 1.65; 1108 participants; 2 studies; low-certainty evidence) when taxanes were given first. There were no data on quality of life.Only one adjuvant study collected data on overall survival and disease-free survival but did not report data. Administration of taxanes first reduced the risk of grade 3/4 neutropenia (RR 0.62, 95% CI 0.40 to 0.97; 279 participants; 4 studies, 5 treatment comparisons; high-certainty evidence) and appeared to result in little to no difference in grade 3/4 neurotoxicity (RR 0.78, 95% CI 0.25 to 2.46; 162 participants; 3 studies; low-certainty evidence). There was probably little to no difference in the proportions experiencing dose delays when taxanes are given first compared to anthracyclines given first (RR 0.76, 95% CI 0.52 to 1.12; 238 participants; 3 studies, 4 treatment comparisons; moderate-certainty evidence). One study reported on quality of life and indicated that scores (using the Functional Assessment of Cancer Therapy - Breast Cancer (FACT-B) validated questionnaire) were similar in both groups though did not provide numerical data., Authors' Conclusions: In the neoadjuvant setting, there is high- to low-certainty evidence of equivalent outcomes for the sequence in which taxanes are delivered. In the adjuvant setting, none of the studies reported on overall survival or disease-free survival. In most institutions, standard practice would be to deliver anthracycline followed by taxane, and currently available data do not support a change in this practice. We wait for the full-text publication of a relevant neoadjuvant study for women with HER2-negative breast cancer for inclusion in an update of this review.

Background: Studies have reported high tumour response rates for platinum-containing regimens in the treatment of women with metastatic breast cancer. Most of these studies were conducted prior to the 'intrinsic subtype' era, and did not specifically focus on metastatic triple-negative breast cancers (mTNBCs)., Objectives: To identify and review the evidence from randomised trials comparing platinum-containing chemotherapy regimens with regimens not containing platinum in the management of women with metastatic breast cancer., Search Methods: For this review update, we searched the Cochrane Breast Cancer Group's Specialised Register, CENTRAL, MEDLINE, Embase, the World Health Organization's International Clinical Trials Registry Platform and ClinicalTrials.gov on 28 May 2015. We identified further potentially relevant studies from handsearching references of previous trials, systematic reviews, and meta-analyses. Prior to this review update, the most recent search for studies was conducted in May 2003 for the original 2004 review., Selection Criteria: Randomised trials comparing platinum-containing chemotherapy regimens with regimens not containing platinum in women with metastatic breast cancer., Data Collection and Analysis: At least two independent reviewers assessed studies for eligibility and quality, and extracted all relevant data from each study. Hazard ratios (HRs) were derived for time-to-event outcomes, where possible, and fixed-effect models were used for meta-analyses. Objective tumour response rates (OTRRs) and toxicities were analysed as binary (dichotomous) outcomes with risk ratios (RRs) used as measures of effects. Quality of life data were extracted where available. GRADE was used to rate the quality of evidence for survival and tumour response outcomes at the level of subgroups selected and unselected for mTNBC, and for toxicity outcomes based on combining data from selected and unselected populations., Main Results: This update includes 15 new eligible treatment-comparisons from 12 studies. In total, 28 treatment-comparisons, involving 4418 women, from 24 studies are now included in one or more meta-analyses. Of the 28 treatment-comparisons, 19 and 16 had published or provided extractable time-to-event data on overall survival (OS) or progression-free survival/time to progression (PFS/TTP), respectively. All 28 treatment-comparisons provided OTRR data that could be included in meta-analyses. Most women recruited to the studies were not selected on the basis of mTNBC status.In a subgroup of three treatment-comparisons assessing women with mTNBC, platinum-containing regimens may have provided a survival benefit (HR 0.75, 95% CI 0.57 to 1.00; low-quality evidence). In women unselected for intrinsic subtypes such as mTNBC, there was little or no effect on survival (HR 1.01, 95% CI 0.92 to 1.12; high-quality evidence). This effect was similar to the combined analysis of survival data for both populations (HR 0.98, 95% CI 0.89 to 1.07; I 2 =39%, 1868 deaths, 2922 women; 19 trials). The difference in treatment effects between mTNBC women compared with unselected women was of borderline statistical significance (P = 0.05).Data from three treatment-comparisons with mTNBC participants showed that platinum regimens may improve PFS/TTP (HR 0.59, 95% CI 0.49 to 0.72; low-quality evidence). Thirteen treatment-comparisons of unselected metastatic participants showed that there was probably a small PFS/TTP benefit for platinum recipients, although the confidence interval included no difference (HR 0.92, 95% CI 0.84 to 1.01; moderate-quality evidence). Combined analysis of data from an estimated 1772 women who progressed or died out of 2136 women selected or unselected for mTNBC indicated that platinum-containing regimens improved PFS/TTP (HR 0.85, 95% CI 0.78 to 0.93). There was marked evidence of heterogeneity (P = 0.0004; I 2 = 63%). The larger treatment benefit in mTNBC women compared with unselected women was statistically significant (P < 0.0001).There was low-quality evidence of better tumour response in both subgroups of women with mTNBC and unselected women (RR 1.33, 95% CI 1.13 to 1.56; RR 1.11, 95% CI 1.04 to 1.19, respectively). Combined analysis of both populations was closer to the effect in unselected women (RR 1.15, 95% CI 1.08 to 1.22; 4130 women). There was considerable evidence of heterogeneity (P < 0.0001; I 2 = 64%), which may reflect between-study differences and general difficulties in assessing response, as well as the varying potencies of the comparators.Compared with women receiving non-platinum regimens: rates of grade 3 and 4 nausea/vomiting were probably higher among women receiving cisplatin- (RR 2.65, 95% CI 2.10 to 3.34; 1731 women; moderate-quality evidence) but the effect from carboplatin-containing regimens was less certain (RR 0.77, 95% CI 0.47 to 1.26; 1441 women; moderate-quality evidence); rates of grade 3 and 4 anaemia were higher among women receiving cisplatin- (RR 3.72, 95% CI 2.36 to 5.88; 1644 women; high-quality evidence) and carboplatin-containing regimens (RR 1.72, 95% CI 1.10 to 2.70; 1441 women; high-quality evidence); rates of grade 3 and 4 hair loss (RR 1.41, 95% CI 1.26 to 1.58; 1452 women; high-quality evidence) and leukopenia (RR 1.38, 95% CI 1.21 to 1.57; 3176 women; moderate-quality evidence) were higher among women receiving platinum-containing regimens (regardless of platinum agent)., Authors' Conclusions: In women with metastatic breast cancer who do not have triple-negative disease, there is high-quality evidence of little or no survival benefit and excess toxicity from platinum-based regimens. There is preliminary low-quality evidence of a moderate survival benefit from platinum-based regimens for women with mTNBC. Further randomised trials of platinum-based regimens in this subpopulation of women with metastatic breast cancer are required.

The inflammatory myopathies are a group of immune-mediated inflammatory muscle disorders that typically present with marked proximal muscle weakness. We report four cases of inflammatory myopathies with marked subcutaneous oedema as their main complaint. Three of the four patients had normal or low levels of creatine kinase, an enzyme often markedly elevated in these disorders. Magnetic resonance imaging of the muscles, followed by a muscle biopsy were used to make a definitive diagnosis., (© 2017 Royal Australasian College of Physicians.)

Background: Fulvestrant is a selective oestrogen receptor down-regulator (SERD), which by blocking proliferation of breast cancer cells, is an effective endocrine treatment for women with hormone-sensitive advanced breast cancer. The goal of such systemic therapy in this setting is to reduce symptoms, improve quality of life, and increase survival time., Objectives: To assess the efficacy and safety of fulvestrant for hormone-sensitive locally advanced or metastatic breast cancer in postmenopausal women, as compared to other standard endocrine agents., Search Methods: We searched the Cochrane Breast Cancer Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), and ClinicalTrials.gov on 7 July 2015. We also searched major conference proceedings (American Society of Clinical Oncology (ASCO) and San Antonio Breast Cancer Symposium) and practice guidelines from major oncology groups (ASCO, European Society for Medical Oncology (ESMO), National Comprehensive Cancer Network, and Cancer Care Ontario). We handsearched reference lists from relevant studies., Selection Criteria: We included for analyses randomised controlled trials that enrolled postmenopausal women with hormone-sensitive advanced breast cancer (TNM classifications: stages IIIA, IIIB, and IIIC) or metastatic breast cancer (TNM classification: stage IV) with an intervention group treated with fulvestrant with or without other standard anticancer therapy., Data Collection and Analysis: Two review authors independently extracted data from trials identified in the searches, conducted 'Risk of bias' assessments of the included studies, and assessed the overall quality of the evidence using the GRADE approach. Outcome data extracted from these trials for our analyses and review included progression-free survival (PFS) or time to progression (TTP) or time to treatment failure, overall survival, clinical benefit rate, toxicity, and quality of life. We used the fixed-effect model for meta-analysis where possible., Main Results: We included nine studies randomising 4514 women for meta-analysis and review. Overall results for the primary endpoint of PFS indicated that women receiving fulvestrant did at least as well as the control groups (hazard ratio (HR) 0.95, 95% confidence interval (CI) 0.89 to 1.02; P = 0.18, I 2 = 56%, 4258 women, 9 studies, high-quality evidence). In the one high-quality study that tested fulvestrant at the currently approved and now standard dose of 500 mg against anastrozole, women treated with fulvestrant 500 mg did better than anastrozole, with a HR for TTP of 0.66 (95% CI 0.47 to 0.93; 205 women) and a HR for overall survival of 0.70 (95% CI 0.50 to 0.98; 205 women). There was no difference in PFS whether fulvestrant was used in combination with another endocrine therapy or in the first- or second-line setting, when compared to control treatments: for monotherapy HR 0.97 (95% CI 0.90 to 1.04) versus HR 0.87 (95% CI 0.77 to 0.99) for combination therapy when compared to control, and HR 0.93 (95% CI 0.84 to 1.03) in the first-line setting and HR 0.96 (95% CI 0.88 to 1.04) in the second-line setting.Overall, there was no difference between fulvestrant and control treatments in clinical benefit rate (risk ratio (RR) 1.03, 95% CI 0.97 to 1.10; P = 0.29, I 2 = 24%, 4105 women, 9 studies, high-quality evidence) or overall survival (HR 0.97, 95% CI 0.87 to 1.09, P = 0.62, I 2 = 66%, 2480 women, 5 studies, high-quality evidence). There was no significant difference in vasomotor toxicity (RR 1.02, 95% CI 0.89 to 1.18, 3544 women, 8 studies, high-quality evidence), arthralgia (RR 0.96, 95% CI 0.86 to 1.09, 3244 women, 7 studies, high-quality evidence), and gynaecological toxicities (RR 1.22, 95% CI 0.94 to 1.57, 2848 women, 6 studies, high-quality evidence). Four studies reported quality of life, none of which reported a difference between the fulvestrant and control arms, though specific data were not presented., Authors' Conclusions: For postmenopausal women with advanced hormone-sensitive breast cancer, fulvestrant is at least as effective and safe as the comparator endocrine therapies in the included studies. However, fulvestrant may be potentially more effective than current therapies when given at 500 mg, though this higher dosage was used in only one of the nine studies included in the review. We saw no advantage with combination therapy, and fulvestrant was equally as effective as control therapies in both the first- and second-line setting. Our review demonstrates that fulvestrant is a safe and effective systemic therapy and can be considered as a valid option in the sequence of treatments for postmenopausal women with hormone-sensitive advanced breast cancer.

Purpose: Endoxifen is the major mediator of tamoxifen effect and endoxifen levels <15 nmol/L may be associated with increased risk of breast cancer recurrence. We increased tamoxifen dose in breast cancer patients with low endoxifen levels and assessed the influence of various parameters on reaching 15 nmol/L and 30 nmol/L endoxifen levels., Experimental Design: Tamoxifen dose was increased in those with endoxifen levels below 30 nmol/L. Toxicity, including hot flash score, was measured. CYP2D6 metabolizer status was classified as ultra-rapid (UM), extensive (EM), intermediate (IM), or poor (PM) based genotype of somatic DNA., Results: Dosage was escalated in 68 of 122 participants. On 20 mg tamoxifen, 24% had endoxifen levels below 15 nmol/L and this reduced to 6% following dose escalation. In over 50% of cases, there was no identified cause for low endoxifen. Low baseline endoxifen level, and not CYP2D6 metabolizer status, independently predicted reaching threshold targets for both the 15 nmol/L and 30 nmol/L targets (P = 0.04 and 0.003 respectively). The 15 nmol/L target was reached in all UM/EM and IM patients, 63% of PM patients, and 58% of those with baseline endoxifen of <10 nmol/L. There was no correlation between hot flash score and genotype or any tamoxifen metabolite level including endoxifen (R = 0.07)., Conclusions: Low endoxifen on standard dose tamoxifen was the only independent predictor of failure to achieve potentially therapeutic levels. Trials examining tamoxifen dose escalation and breast cancer outcome should be guided by endoxifen levels alone, without reference to CYP2D6 genotype or presence of hot flashes. Clin Cancer Res; 22(13); 3164-71. ©2016 AACRSee related commentary by Hertz and Rae, p. 3121., (©2016 American Association for Cancer Research.)

Background: It is generally accepted that taxanes are among the most active chemotherapy agents in the management of metastatic breast cancer. This is an update of a Cochrane review first published in 2003., Objectives: The objective of this review was to compare taxane-containing chemotherapy regimens with regimens not containing a taxane in the management of women with metastatic breast cancer., Search Methods: In this review update, we searched the Cochrane Breast Cancer Group Specialised Register, MEDLINE, EMBASE, the World Health Organization's International Clinical Trials Registry Platform (WHO ICTRP), and ClinicalTrials.gov on 14 February 2013 using keywords such as 'advanced breast cancer' and 'chemotherapy'. We searched reference lists of articles, contacted study authors, and did not apply any language restrictions., Selection Criteria: Randomised controlled trials comparing taxane-containing chemotherapy regimens to regimens without taxanes in women with metastatic breast cancer. We included published and unpublished studies., Data Collection and Analysis: Two review authors independently assessed trial quality and extracted data. We derived hazard ratios (HRs) for overall survival, time to progression, and time to treatment failure where possible, and used a fixed-effect model for meta-analysis. We represented objective tumour response rates and toxicity as risk ratios (RRs). We extracted quality of life data where present., Main Results: This review included 28 studies. The updated analysis included 6871 randomised women, while the original review had 3643 women. Of the 28 included studies, we considered 19 studies to be at low risk of bias overall; however, some studies failed to report details on allocation concealment and methods of outcome assessment for those outcomes that are more likely to be influenced by a lack of blinding (for example tumour response rate). Studies varied in the taxane-containing chemotherapy backbone, and the comparator arms and were categorised into three groups: Regimen A plus taxane versus Regimen A (2 studies); Regimen A plus taxane versus Regimen B (14 studies); and single-agent taxane versus Regimen C (13 studies). Thirteen studies used paclitaxel, 14 studies used docetaxel, and 1 study allowed the investigator to decide on the type of taxane; the majority of studies delivered a taxane every 3 weeks. Twenty studies administered taxanes as first-line treatment, and 21 studies involved anthracycline naïve women in the metastatic setting. The combined HR for overall survival and time to progression favoured the taxane-containing regimens (HR 0.93, 95% confidence interval (CI) 0.88 to 0.99, P = 0.002, deaths = 4477; and HR 0.92, 95% CI 0.87 to 0.97, P = 0.002, estimated 5122 events, respectively) with moderate to substantial heterogeneity across trials. If the analyses were restricted to studies of first-line chemotherapy, this effect persisted for overall survival (HR 0.93, 95% CI 0.87 to 0.99, P = 0.03) but not for time to progression (HR 0.96, 95% CI 0.90 to 1.02, P = 0.22). Tumour response rates appeared to be better with taxane-containing chemotherapy in assessable women (RR 1.20, 95% CI 1.14 to 1.27, P < 0.00001) with substantial heterogeneity across studies. Taxanes were associated with an increased risk of neurotoxicity (RR 4.84, 95% CI 3.18 to 7.35, P < 0.00001, 24 studies) and hair loss (RR 2.37, 95% CI 1.45 to 3.87, P = 0.0006, 11 studies) but less nausea/vomiting compared to non-taxane-containing regimens (RR 0.62, 95% CI 0.46 to 0.83, P = 0.001, 26 studies). Leukopaenia and treatment-related death did not differ between the two groups (RR 1.07, 95% CI 0.97 to 1.17, P = 0.16, 28 studies; and RR 1.00, 95% CI 0.63 to 1.57, P = 0.99, 23 studies, respectively). For quality of life measures, none of the individual studies reported a difference in overall or any of quality of life subscales between taxane-containing and non-taxane chemotherapy regimens., Authors' Conclusions: Taxane-containing regimens appear to improve overall survival, time to progression, and tumour response rate in women with metastatic breast cancer. Taxanes are also associated with an increased risk of neurotoxicity but less nausea and vomiting compared to non-taxane-containing regimens. The considerable heterogeneity encountered across studies probably reflects the varying efficacy of the comparator regimens used in these studies and indicates that taxane-containing regimens are more effective than some, but not all, non-taxane-containing regimens.

Purpose: This study aimed to explore differences in physical activity and fitness between women with metastatic breast cancer compared to healthy controls and factors associated with their physical activity levels., Methods: Seventy-one women with metastatic breast cancer, aged (mean (SD)) 57.7 (9.5) and 2.9 (3.1) years after the onset of metastatic disease, and 71 healthy controls aged 55.0 (9.4) years participated. Of those with metastatic disease, 27% had bone-only metastases, 35% visceral-only metastases and 38% bone and visceral metastases. Patient-reported outcomes and physical measures of muscle strength and aerobic fitness assessments were obtained. Participants wore a SenseWear® physical activity monitor over 7 days, and the average steps/day and the time spent in moderate-to-vigorous intensity physical activity were determined., Results: Women with metastases were significantly (i) less aerobically fit than the control group (25.3 (5.4) vs. 31.9 (6.1) mL • kg(-1) • min(-1); P < 0.001); (ii) weaker (e.g. lower limb strength for the metastatic and control groups was 53.5 (23.7) vs. 76.0 (27.4) kg, respectively; P < 0.001); (iii) less active, with the metastatic group attaining only 56% of the mean daily step counts of the healthy women; and (iv) more symptomatic, reporting higher levels of fatigue and dyspnoea (P < 0.001)., Conclusion: Women living in the community with metastatic breast cancer possessed lower aerobic fitness, reduced muscular strength and less daily physical activity compared to healthy counterparts. They also experienced poorer functioning and higher symptom burden., Implications for Cancer Survivors: Women living with metastatic breast cancer may benefit from a physical activity programme to address their physical impairments.

Improvements in the treatment of metastatic HER2-positive breast cancer constitute one of the great advances in breast cancer medicine of the last generation. From being a highly aggressive fatal condition, the use of anti-HER2-targeted therapies, in particular trastuzumab, has led to significant improvements in disease outcomes. There are reports of increasing numbers of patients alive and well more than 5 years from diagnosis of metastatic disease. Nevertheless, there remain many complex and clinically difficult scenarios where there is little in the way of randomized evidence or published guidelines to guide decision making. As a companion piece to our review of HER2-targeted therapies in the metastatic setting, we decided to focus on a series of clinical scenarios that fell outside of the standard trial-based settings and where opinions and guidance from experienced clinicians and experts in the field would be considered useful to help develop safe and effective treatment strategies. The following eight cases were put forward by our panel of experts, voted on by their peers to select the most relevant and interesting cases, and the discussions worked on by teams of two followed by review and commentary by another team of two., (© 2014 Wiley Publishing Asia Pty Ltd.)

Aim: We aimed to systematically review and summarize data from the available clinical trials that examined the treatment of HER2-positive metastatic breast cancer., Methods: We reviewed phase 2 and 3 studies in which an anti-HER2 agent was used in one or both arms of the study. While formal meta-analysis was not possible for such a heterogeneous group of trials, resulting forest plots outline some generalizable findings., Results: There is strong evidence that the addition of an anti-HER2 agent to standard chemo- or endocrine therapy improves clinically relevant measurable outcomes. There is also consistent evidence that initial treatment with trastuzumab alone (and subsequent use of a cytotoxic) is inferior to the initial combination of trastuzumab plus chemotherapy, and that either T-DM1 or dual anti-HER2 agents are superior to single anti-HER2 agent regimens. There is no strong evidence that the use of more than one cytotoxic agent together with an anti-HER2 agent confers any benefit over a single cytotoxic, anti-HER2 combination., Conclusion: This review provides a strong evidence base for current clinical practice with a discussion of treatment in the Australian setting., (© 2014 Wiley Publishing Asia Pty Ltd.)

Background: Combination chemotherapy can cause greater tumour cell kill if the drug dose is not compromised, while sequential single agent chemotherapy may allow for greater dose intensity and treatment time, potentially meaning greater benefit from each single agent. In addition, sequentially using single agents might cause less toxicity and impairment of quality of life, but it is not known whether this might compromise survival time., Objectives: To assess the effect of combination chemotherapy compared to the same drugs given sequentially in women with metastatic breast cancer., Search Methods: We searched the Cochrane Breast Cancer Group Specialised Register, using the search terms "advanced breast cancer" and "chemotherapy", MEDLINE and EMBASE on 31 October 2013. The World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov were also searched (22 March 2012)., Selection Criteria: Randomised controlled trials of combination chemotherapy compared to the same drugs used sequentially in women with metastatic breast cancer in the first-, second- or third-line setting., Data Collection and Analysis: Two authors independently extracted data from published trials. Hazard ratios (HR) were derived from time-to-event outcomes where possible, and a fixed-effect model was used for meta-analysis. Response rates were analysed as dichotomous variables (risk ratios (RR)), and toxicity and quality of life data were extracted where available., Main Results: Twelve trials reporting on nine treatment comparisons (2317 patients randomised) were identified. The majority of trials (10 trials) had an unclear or high risk of bias. Time-to-event data were collected for nine trials for overall survival and eight trials for progression-free survival. All 12 trials reported results for tumour response. In the 12 trials there were 1023 deaths in 2317 women randomised. There was no difference in overall survival, with an overall HR of 1.04 (95% confidence interval (CI) 0.93 to 1.16; P = 0.45), and no significant heterogeneity. This result was consistent in the four subgroups analysed (risk of bias, line of chemotherapy, type of schema of chemotherapy, and relative dose intensity). In particular, there was no difference in survival according to the type of schema of chemotherapy, that is whether chemotherapy was given on disease progression or after a set number of cycles. In the eight trials that reported progression-free survival, 678 women progressed out of the 886 women randomised. The combination arm had a higher risk of progression than the sequential arm (HR 1.16; 95% CI 1.03 to 1.31; P = 0.01) with no significant heterogeneity. This result was consistent in all subgroups. Overall tumour response rates were higher in the combination arm (RR 1.13; 95% CI 1.03 to 1.24; P = 0.008) but there was significant heterogeneity for this outcome across the trials. In the seven trials that reported treatment-related deaths, there was no significant difference between the two arms, although the CIs were very wide due to the small number of events (RR 1.53; 95% CI 0.71 to 3.29; P = 0.28). The risk of febrile neutropenia was higher in the combination arm (RR 1.32; 95% CI 1.06 to 1.65; P = 0.01). There was no statistically significant difference in the risk of neutropenia, nausea and vomiting, or treatment-related deaths. Overall quality of life showed no difference between the two groups, but only three trials reported this outcome., Authors' Conclusions: Sequential single agent chemotherapy has a positive effect on progression-free survival, whereas combination chemotherapy has a higher response rate and a higher risk of febrile neutropenia in metastatic breast cancer. There is no difference in overall survival time between these treatment strategies, both overall and in the subgroups analysed. In particular, there was no difference in survival according to the schema of chemotherapy (giving chemotherapy on disease progression or after a set number of cycles) or according to the line of chemotherapy (first-line versus second- or third-line). Generally this review supports the recommendations by international guidelines to use sequential monotherapy unless there is rapid disease progression.

Background: The addition of radiotherapy (RT) following breast conserving surgery (BCS) was first shown to reduce the risk of ipsilateral recurrence in the treatment of invasive breast cancer. Ductal carcinoma in situ (DCIS) is a pre-invasive lesion. Recurrence of ipsilateral disease following BCS can be either DCIS or invasive breast cancer. Randomised controlled trials (RCTs) have shown that RT can reduce the risk of recurrence, but assessment of potential long-term complications from addition of RT following BSC for DCIS has not been reported for women participating in RCTs., Objectives: To summarise the data from RCTs testing the addition of RT to BCS for treatment of DCIS to determine the balance between the benefits and harms., Search Methods: We searched the Cochrane Breast Cancer Group Specialised Register (2 June 2011), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2008, Issue 1), MEDLINE (2 June 2011), EMBASE (2 June 2011) and the World Health Organization's International Clinical Trials Registry Platform (WHO ICTRP; 2 June 2011). Reference lists of articles and handsearching of ASCO (2007), ESMO (2002 to 2007), and St Gallen (2005 to 2007) conferences were performed., Selection Criteria: RCTs of breast conserving surgery with and without radiotherapy in women at first diagnosis of pure ductal carcinoma in situ (no invasive disease present)., Data Collection and Analysis: Two authors independently assessed each potentially eligible trial for inclusion and its quality. Two authors also independently extracted data from published Kaplan-Meier analysis (survival curves) and reported summary statistics. Data were extracted and pooled for four trials. Data for planned subgroups were extracted and pooled for analysis.There were insufficient data to pool for long-term toxicity from radiotherapy., Main Results: Four RCTs involving 3925 women were identified and included in this review. All were high quality with minimal risk of bias. Three trials compared the addition of RT to BCS. One trial was a two by two factorial design comparing the use of RT and tamoxifen, each separately or together, in which participants were randomised in at least one arm. Analysis confirmed a statistically significant benefit from the addition of radiotherapy on all ipsilateral breast events (hazards ratio (HR) 0.49; 95% CI 0.41 to 0.58, P < 0.00001), ipsilateral invasive recurrence (HR 0.50; 95% CI 0.32 to 0.76, p=0.001) and ipsilateral DCIS recurrence (HR 0.61; 95% CI 0.39 to 0.95, P = 0.03). All the subgroups analysed benefited from addition of radiotherapy. No significant long-term toxicity from radiotherapy was found. No information about short-term toxicity from radiotherapy or quality of life data were reported., Authors' Conclusions: This review confirms the benefit of adding radiotherapy to breast conserving surgery for the treatment of all women diagnosed with DCIS. No long-term toxicity from use of radiotherapy was identified.

Background: Chronic inflammation has been recognized to foster tumour development. Whether chemotherapy can be used to neutralize chronic inflammation is unclear., Methods: We evaluated baseline and nadir neutrophils in 111 patients (pts.) with non-small cell lung cancer (NSCLC) and 118 pts. with ovarian cancer (OC) treated with chemotherapy administered with dose-individualization to achieve nadir neutropenia of 1.5. We used predefined baseline neutrophil cut-offs 4.5 × 109/L (NSCLC) and 3.9 × 109/L (OC)., Results: Absence of chemotherapy-induced nadir neutropenia (CTCAE grade 0, neutrophils ≥ LLN) was seen in 23% of OC and 25% of NSCLC pts. Absence of nadir neutropenia was associated with decreased overall survival (OS) compared with presence (>grade 0) of neutropenia (9 vs. 14 months, P=0.004 for NSCLC and 23 vs. 56 months; P=0.01 for OC). Obtaining grade 3/4 neutropenia did not improve survival compared with grade 1/2 neutropenia. In multivariate analyses, baseline neutrophils ≥ 4.5 × 109/L (HR: 2.0; 95% CI: 1.11-3.44;P = 0.02) and absence of nadir neutropenia (HR: 1.6; 95% CI: 1.02-2.65;P = 0.04) for NSCLC and absence of nadir neutropenia (HR: 1.7; 95% CI: 1.04;2.93;P = 0.04) for OC were independently associated with short OS., Conclusions: A neutrophil index comprising elevated baseline neutrophils and absence of neutropenia identified a high risk group of NSCLC and ovarian cancer patients with only modest effect of chemotherapy. New treatment options for this subset of patients are required.

Objectives: To estimate the incidence of metastatic breast cancer (MBC) in Australian women with an initial diagnosis of non-metastatic breast cancer., Design, Setting and Participants: A population-based cohort study of all women with non-metastatic breast cancer registered on the New South Wales Central Cancer Register (CCR) in 2001 and 2002 who received care in a NSW hospital., Main Outcome Measures: 5-year cumulative incidence of MBC; prognostic factors for MBC., Results: MBC was recorded within 5 years in 218 of 4137 women with localised node-negative disease (5-year cumulative incidence, 5.3%; 95% CI, 4.6%-6.0%); and 455 of 2507 women with regional disease (5-year cumulative incidence, 18.1%; 95% CI, 16.7%-19.7%). The hazard rate for developing MBC was highest in the second year after the initial diagnosis of breast cancer. Determinants of increased risk of MBC were regional disease at diagnosis, age less than 50 years and living in an area of lower socio-economic status., Conclusions: Our Australian population-based estimates are valuable when communicating average MBC risks to patients and planning clinical services and trials. Women with node-negative disease have a low risk of developing MBC, consistent with outcomes of adjuvant clinical trials. Regional disease at diagnosis remains an important prognostic factor.

Triple-negative breast cancer (TNBC) is defined by its lack of (or minimal) estrogen receptor and progesterone receptor expression, together with the absence of human epidermal growth factor receptor 2 overexpression or gene amplification. It can be a particularly aggressive form of breast cancer, often characterized by early systemic relapse. This subtype, absent from traditional pathology classifications, has quietly crept into the oncologist's lexicon over the last decade and aroused considerable research interest. Based on tumor pathology, immunohistochemistry and gene profiling studies, TNBC is likely to represent a heterogeneous mix of breast cancer subtypes. This observation will have important implications for the selection of optimal therapies, which are yet to be defined. This article reviews recent insights in the classification and ontogeny of TNBC, current approaches to its management and promising therapeutic targets that are forming the basis for innovative early and late phase clinical trials., (© 2012 Blackwell Publishing Asia Pty Ltd.)

Purpose: To evaluate the effect of different first-line chemotherapy durations in patients with metastatic breast cancer (MBC) on overall survival (OS) and progression-free survival (PFS)., Methods: We searched literature databases to identify randomized controlled trials that compared different chemotherapy durations in the first-line treatment of MBC. Only trials with unconfounded comparisons of additional cycles of chemotherapy were included. The main outcome measures for this analysis were OS and PFS. Published data from retrieved studies were analyzed according to standard meta-analytic techniques., Results: We found 11 randomized clinical trials including 2,269 patients. Longer first-line chemotherapy duration resulted into a significantly improved OS (hazard ratio [HR], 0.91; 95% CI, 0.84 to 0.99; P = .046) and PFS (HR, 0.64; 95% CI, 0.55 to 0.76; P < .001). There were no differences in effects on either OS or PFS between subgroups defined by time of random assignment, study design, number of chemotherapy cycles in the control arm or concomitant endocrine therapy., Conclusion: Longer first-line chemotherapy duration is associated with marginally longer OS and a substantially longer PFS.

Various factors have recently prompted a re-evaluation of the role of non-anthracycline regimens in early stage breast cancer (ESBC). Since 1990 anthracyclines have been a key component of chemotherapy regimens. However, there is increased understanding of the long-term, irreversible toxicities associated with these therapies, including cardiac failure and secondary leukemia. The development of the taxanes in the 1990s led to new adjuvant chemotherapy regimens and trials of various combinations in an effort to further increase survival and reduce toxicity. Concerns about cardiac toxicity were reinforced with the emergence of trastuzumab for the treatment of HER2-positive breast cancer. Trastuzumab alone causes cardiac toxicity and increases the risk of cardiac toxicity when combined with anthracyclines. These data, combined with recent results demonstrating the efficacy of non-anthracycline regimens in various disease settings, have generated interest in utilizing these therapies in patients with both HER2-positive and -negative tumors. This review outlines the evidence for the use of non-anthracycline adjuvant regimens in ESBC, including cyclophosphamide, methotrexate and 5-fluoruoracil, docetaxel, carboplatin and trastuzumab and docetaxel and cyclophosphamide, which have demonstrated equivalent efficacy and reduced toxicity compared to anthracycline-based regimens in various trials. The review also examines evidence for the use of non-anthracycline regimens in patients who previously had restricted access to these therapies due to their negative lymph node status. The wider availability of these regimens increases options when deciding upon adjuvant chemotherapy for patients with ESBC, especially in patients with a high risk of cardiac toxicity., (© 2010 Blackwell Publishing Asia Pty Ltd.)

Background: The addition of a chemotherapy drug or drugs to an established regimen is one method used to increase the dose and intensity of treatment for metastatic breast cancer., Objectives: To assess the effects of adding one or more chemotherapy drugs to an established regimen in women with metastatic breast cancer., Search Strategy: We searched the Cochrane Breast Cancer Group's Specialised Register (to August 2009) using the codes for "advanced breast cancer" and "chemotherapy". This review is an update of the original Cochrane Review (Issue 3, 2006)., Selection Criteria: Randomised trials with a first line regimen of at least two chemotherapy drugs compared to the same regimen plus the addition of one or more chemotherapy drugs in women with metastatic breast cancer., Data Collection and Analysis: Two authors extracted data independently from published trials. We derived hazard ratios (HR) from time-to-event outcomes where possible, and used a fixed-effect model for meta-analysis. We analysed response rates as dichotomous variables and extracted toxicity data where available., Main Results: We identified 17 trials reporting on 22 treatment comparisons (2674 patients randomised). Fifteen trials (20 treatment comparisons) reported results for tumour response and 11 trials (14 treatment comparisons) published time-to-event data for overall survival. There were 1532 deaths in 2116 women randomised to trials of the addition of a drug to the regimen and control (the regimen alone). There was no detectable difference in overall survival between these patients, with an overall HR of 0.96 (95% confidence interval (CI) 0.87 to 1.07, P = 0.47) and no significant heterogeneity. We found no difference in time to progression between these regimens, with an overall HR of 0.93 (95% CI 0.81 to 1.07, P = 0.31) and no significant heterogeneity. Addition of a drug to the regimen was favourably associated with overall tumour response rates (odds ratio 1.21, 95% CI 1.01 to 1.44, P = 0.04) although we observed significant heterogeneity for this outcome across the trials. Where measured, acute toxicities such as alopecia, nausea and vomiting and leucopenia were more common with the addition of a drug., Authors' Conclusions: The addition of one or more drugs to the regimen shows a statistically significant advantage for tumour response in women with metastatic breast cancer but the results suggest no difference in survival time or time to progression. The positive effect on tumour response was also associated with increased toxicity.

Background: The addition of radiotherapy (RT) following breast conserving surgery (BCS) was first shown to reduce the risk of ipsilateral recurrence in the treatment of invasive breast cancer. Ductal carcinoma in situ (DCIS) is a pre-invasive lesion. Recurrence of ipsilateral disease following BCS can be either DCIS or invasive breast cancer. Randomised controlled trials (RCTs) have shown that RT can reduce the risk of recurrence, but assessment of potential long-term complications from addition of RT following BSC for DCIS has not been reported for women participating in RCTs., Objectives: To summarise the data from RCTs testing the addition of RT to BCS for treatment of DCIS to determine the balance between the benefits and harms., Search Strategy: We searched the Cochrane Breast Cancer Group Specialised Register (January 2008), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2008, Issue 1), MEDLINE (February 2008), and EMBASE (February 2008). Reference lists of articles and handsearching of ASCO (2007), ESMO (2002 to 2007), and St Gallen (2005 to 2007) conferences were performed., Selection Criteria: RCTs of breast conserving surgery with and without radiotherapy in women at first diagnosis of pure ductal carcinoma in situ (no invasive disease present)., Data Collection and Analysis: Two authors independently assessed each potentially eligible trial for inclusion and its quality. Two authors also independently extracted data from published Kaplan-Meier analysis (survival curves) and reported summary statistics. Data were extracted and pooled for four trials. Data for planned subgroups were extracted and pooled for analysis.There were insufficient data to pool for long-term toxicity from radiotherapy., Main Results: Four RCTs involving 3925 women were identified and included in this review. All were high quality with minimal risk of bias. Three trials compared the addition of RT to BCS. One trial was a two by two factorial design comparing the use of RT and tamoxifen, each separately or together, in which participants were randomised in at least one arm. Analysis confirmed a statistically significant benefit from the addition of radiotherapy on all ipsilateral breast events (hazards ratio (HR) 0.49; 95% CI 0.41 to 0.58, P < 0.00001), ipsilateral invasive recurrence (HR 0.50; 95% CI 0.32 to 0.76, p=0.001) and ipsilateral DCIS recurrence (HR 0.61; 95% CI 0.39 to 0.95, P = 0.03). All the subgroups analysed benefited from addition of radiotherapy. No significant long-term toxicity from radiotherapy was found. No information about short-term toxicity from radiotherapy or quality of life data were reported., Authors' Conclusions: This review confirms the benefit of adding radiotherapy to breast conserving surgery for the treatment of all women diagnosed with DCIS. No long-term toxicity from use of radiotherapy was identified.

Aim: To summarise the results of randomised trials testing the addition of radiotherapy (RT) to breast conserving surgery for ductal carcinoma in situ (DCIS); to determine whether there are subsets of women with DCIS who do not benefit from RT; and to determine what the balance may be between reduction in risk of recurrence and long-term toxicity., Methods: We performed a systematic review to resolve these questions, using standard Cochrane methodology to identify, select and appraise relevant randomised trials., Results: Four randomised controlled trials involving 3925 women were identified. All were high quality with minimal risk of bias. Analysis confirmed a statistically significant benefit from the addition of radiotherapy on all ipsilateral breast events (HR=0.49; 95% CI 0.41-0.58, p<0.00001). All subgroups analysed (margin status, age and grade) benefited from the addition of radiotherapy. Nine women require treatment with radiotherapy to prevent one ipsilateral breast recurrence (NNT=9). Deaths due to vascular disease, pulmonary toxicity and second cancers were low and not significantly higher for women who received radiotherapy., Concluding Statement: Radiotherapy was beneficial in all clinically relevant subgroups. Longer follow-up is required to detect any long-term toxicity from use of radiotherapy. To date, no increase in toxicity has been identified.

Background: Combination chemotherapy regimens are frequently favoured over single agents for the treatment of metastatic breast cancer, in an attempt to achieve superior tumour response rates. It is not known however whether giving more intensive chemotherapy regimens results in better health outcomes, when both survival and toxicity are considered, and whether better response rates and rates of progression free survival actually translate to better overall survival., Objectives: To compare single agent with combination chemotherapy for the treatment of metastatic breast cancer., Search Strategy: We searched the Cochrane Breast Cancer Group Specialised Register November 2008. Handsearching of recent conference proceedings was also undertaken., Selection Criteria: Randomised trials of single agent chemotherapy compared to combination therapy in metastatic breast cancer., Data Collection and Analysis: Two authors independently assessed trials for eligibility and quality, and extracted data. Hazard ratios were derived for reported time-to-event outcomes.Response rates were analysed as dichotomous variables. Toxicity and quality of life data were extracted where present., Main Results: Forty three eligible trials (48 comparisons) were identified. These included 9742 women, 55% of whom were receiving first-line treatment for metastatic disease. For overall survival there was a statistically significant difference in favour of the combination regimens with no heterogeneity (HR 0.88, 95% CI 0.83-0.93, p<0.00001). Results were very similar when trials of first-line treatment were analysed, and for analyses where the single agent was also included in the combination regimen. Combination regimens showed a statistically significant advantage for survival over single agent taxane (HR 0.82; 95% CI 0.75-0.89, p<0.00001), but not anthracycline (HR 0.94.86-1.02, p=0.15).Combination regimens were also associated with significantly better time to progression (HR 0.78, 95% CI 0.74 - 0.82, p<0.00001) and response (RR 1.29, 95% CI 1.14 -1.45, p<0.0001) although heterogeneity was statistically significant in both instances and probably due to clinical diversity of the participants and interventions.Women receiving combination regimens experienced a statistically significant detrimental effect on white cell count, increased alopecia and nausea and vomiting., Authors' Conclusions: Combination chemotherapy regimens show a statistically significant advantage for survival, tumor response and time to progression in women with metastatic breast cancer but they also produce more toxicity. An unresolved question is whether combination regimens are more effective than single agents given sequentially.

Aim: To summarise the findings of all randomised trials comparing chemotherapy regimens for metastatic breast cancer that were reported between 2000 and 2007 inclusive., Methods: We searched the specialised register of clinical trials maintained by the secretariat of the Cochrane Breast Cancer Group (CBCG) from 2000 to 2007, and abstracts from the American Society of Clinical Oncology (ASCO) annual scientific meeting (2000-2007)., Results: Eighty reports of 63 trials were identified as eligible for this review. Whilst over 30% of the trials reported a statistically significant difference in response rate or progression free survival, only 8 trials (13%) reported a difference in overall survival. Thirty percent reported quality of life data. Very few trials examined the critical clinical questions of duration and the relative merits of combination versus sequential single agent chemotherapy., Concluding Statement: There is little evidence from trials reported from 2000 to 2007 that major survival differences exist between many commonly employed chemotherapy regimens.

Background: Adjuvant chemotherapy improves survival in pre- and post-menopausal women with early breast cancer. Taxanes are highly active chemotherapy agents in metastatic breast cancer. Their role in early breast cancer was examined in this review., Objectives: To review the randomised evidence comparing taxane containing chemotherapy regimens with non-taxane containing chemotherapy regimens as adjuvant treatment of pre- or post-menopausal women with early breast cancer., Search Strategy: The Cochrane Breast Cancer Group Specialised Register was searched on 9th January 2007 using the codes for 'early breast cancer' and keywords for taxanes. Details of the search strategy used to create the register are described in the Group's module in The Cochrane Library. The reference lists of other related literature reviews and articles were also searched., Selection Criteria: Randomised trials comparing taxane containing regimens with non-taxane containing regimens in women with operable breast cancer. Women receiving neoadjuvant chemotherapy were excluded., Data Collection and Analysis: Data were collected from published trials and abstracts. Studies were assessed for eligibility and quality and the data extracted independently by two review authors. Hazard ratios (HR) were derived for time-to-event outcomes, and meta-analysis was performed using a fixed-effect model. The primary outcome measure was overall survival (OS); disease-free survival (DFS) was a secondary outcome measure. Toxicity and quality of life data were extracted when reported., Main Results: We identified 20 studies, 12 of these (7 full publications, 5 abstracts) had sufficient data published for inclusion (11 for OS and 11 for DFS) in the review. The weighted average median follow up was 60.4 months. All studies fulfilled quality criteria either adequately or well. Amongst 18,304 women with 2483 deaths, the HR for OS was 0.81 (95% CI 0.75 to 0.88, P < 0.00001) favouring taxane containing regimens. Amongst 19,943 women with 4800 events, the HR for DFS was 0.81 (95% CI 0.77 to 0.86, P < 0.00001) favouring taxane containing regimens. There was no statistical heterogeneity for either OS or DFS., Authors' Conclusions: This meta-analysis of studies supports the use of taxane containing adjuvant chemotherapy regimens with improvement of overall survival and disease-free survival for women with operable early breast cancer. The review did not identify a subgroup of patients where taxane containing treatment may have been more or less effective. Dosage and scheduling of the taxane drug is not clearly defined and we await results of the next generation of studies to determine the optimal use of taxanes in early breast cancer.

Purpose: To evaluate local control for patients with locally advanced noninflammatory breast cancer (LABC) managed by selective mastectomy., Methods and Materials: Between 1979 and 1996, 176 patients with LABC were prospectively managed by chemotherapy (CT)-irradiation (RT)-CT without routine mastectomy. All surviving patients were followed for a minimum of 5 years., Results: A total of 132 patients (75%) had a T4 tumor and 22 (12.5%) supraclavicular nodal disease. The clinical complete response rate was 91% (160/176), which included 13 patients who underwent mastectomy and 2 an iridium wire implant. The first site of failure was local for 43 patients (breast +/- axilla for 38); 27 of these patients underwent salvage mastectomy and 11 did not for an overall mastectomy rate of 23% (40/176). If all 176 patients had undergone routine mastectomy (136 extra mastectomies), 11 additional patients may have avoided an unsalvageable first local relapse. The others would have either have not had a local relapse or would have suffered local relapse after distant disease. No tumor or treatment related factor was found to predict local disease at death. Median disease-free and overall survival for all patients was 26 and 52 months, respectively., Conclusions: Selective mastectomy in LABC may not jeopardize local control or survival.

Background: Trastuzumab--a humanised monoclonal antibody against HER2--has been shown to improve disease-free survival after chemotherapy in women with HER2-positive early breast cancer. We investigated the drug's effect on overall survival after a median follow-up of 2 years in the Herceptin Adjuvant (HERA) study., Methods: HERA is an international multicentre randomised trial that compared 1 or 2 years of trastuzumab treatment with observation alone after standard neoadjuvant or adjuvant chemotherapy in women with HER2-positive node positive or high-risk node negative breast cancer. 5102 women participated in the trial; we analysed data from 1703 women who had been randomised for treatment with trastuzumab for 1 year and 1698 women from the control group, with median follow-up of 23.5 months (range 0-48 months). The primary endpoint of the trial was disease-free survival. Here, we assess overall survival, a secondary endpoint. Analyses were done on an intent-to-treat basis. This trial is registered with the European Clinical Trials Database, number 2005-002385-11., Findings: 97 (5.7%) patients randomised to observation alone and 58 (3.4%) patients randomised to 1 year of treatment with trastuzumab were lost to follow-up. 172 women stopped trastuzumab prematurely. 59 deaths were reported for trastuzumab and 90 in the control group. The unadjusted hazard ratio (HR) for the risk of death with trastuzumab compared with observation alone was 0.66 (95% CI 0.47-0.91; p=0.0115). 218 disease-free survival events were reported with trastuzumab compared with 321 in the control group. The unadjusted HR for the risk of an event with trastuzumab compared with observation alone was 0.64 (0.54-0.76; p<0.0001)., Interpretation: Our results show that 1 year of treatment with trastuzumab after adjuvant chemotherapy has a significant overall survival benefit after a median follow-up of 2 years. The emergence of this benefit after only 2 years reinforces the importance of trastuzumab in the treatment of women with HER2-positive early breast cancer.

Background: The addition of a chemotherapy drug or drugs to an established regimen is one method used to increase the dose and intensity of treatment for metastatic breast cancer., Objectives: To identify and review the randomised trial evidence in the first line management of women with metastatic breast cancer that evaluates the addition of one or more chemotherapy drugs to an established regimen., Search Strategy: We searched the specialised register maintained by the Editorial Base of the Cochrane Breast Cancer Group on 3rd August 2004 (updated search on 2nd August 2005) using the codes for "advanced breast cancer" and "chemotherapy". Details of the search strategy applied by the Group to create the register, and the procedure used to code references, are described in the Group's module on the Cochrane Library., Selection Criteria: Randomised trials that evaluated a first line regimen of at least two chemotherapy drugs, and compared it to that same regimen plus the addition of one or more chemotherapy drugs in women with metastatic breast cancer., Data Collection and Analysis: We collected data from published trials and assessed studies for eligibility and quality. Two reviewers extracted data independently. We derived hazard ratios (HR) from time-to-event outcomes where possible, and a fixed effect model was used for meta-analysis. We analysed response rates as dichotomous variables and extracted toxicity data where available., Main Results: We identified 17 trials reporting on 22 treatment comparisons (2674 patients randomised). Fifteen trials (20 treatment comparisons) reported results for tumour response and 11 trials (14 treatment comparisons) published time-to-event data for overall survival. There were 1532 deaths in 2116 women randomised to trials of the addition of a drug to the regimen and control (the regimen alone). There was no detectable difference in overall survival between these patients, with an overall HR of 0.96 (95% CI 0.87 to 1.07, P = 0.47) and no statistically significant heterogeneity. We found no difference in time to progression between these regimens, with an overall HR of 0.93 (95% CI 0.81 to 1.07, P = 0.31) and no statistically significant heterogeneity. Addition of a drug to the regimen was favourably associated with overall tumour response rates (OR 1.21, 95% CI 1.01 to 1.44, P = 0.04) although we observed statistically significant heterogeneity for this outcome across the trials. Where measured, acute toxicities such as alopecia, nausea and vomiting and leukopenia were more common with the addition of a drug., Authors' Conclusions: The addition of one or more drugs to the regimen shows a statistically significant advantage for tumour response in women with metastatic breast cancer but the results suggest no difference in survival time or time to progression. The positive effect on tumour response observed with addition of a drug to the regimen was also associated with increased toxicity.

This seventh article in our series on breast disease will focus on what is new in the management of invasive primary breast cancer. Up-to-date information on the key aspects of breast cancer management is presented, including descriptions of the new technique of sentinel lymph node biopsy and the new hormone treatment, aromatase inhibitors. Current trends in surgery for breast cancer and the adjuvant treatments of chemotherapy and radiotherapy are also discussed.

This study has calculated the potential impact of hormone replacement therapy (HRT) on breast cancer incidence in Australia and has estimated how changes in prescribing HRT to women could affect this risk. The effects of HRT on breast cancer incidence was estimated using the attributable fraction technique with prevalence data derived from the 2001 Australian Health Survey and published rates of breast cancer relative risks from HRT use. In Australia, 12% of adult women were current HRT users and in 2001, 11783 breast cancers were reported. Of these, 1066 (9%) were potentially attributable to HRT. Restricting HRT use to women aged less than 65 years, ceasing HRT prescribing after 10 years or limiting combined oestrogen and progesterone HRT to five years (but otherwise keeping prescription levels to 2001 levels) may reduce the annual breast cancer caseload by 280 (2.4%), 555 (4.7%) or 674 (5.7%), respectively. In conclusion, this study has demonstrated that when HRT prevalence is relatively high, the effect on breast cancer incidence in the population will be significant. A small modification in HRT prescribing practices may impact breast cancer incidence in Australia with associated financial and health care provision implications.

Background: It is generally accepted that taxanes are among the most active chemotherapy agents in the management of metastatic breast cancer., Objectives: To identify and review the randomised evidence comparing taxane containing chemotherapy regimens with regimens not containing a taxane in the management of women with metastatic breast cancer., Search Strategy: The specialised register maintained by the Editorial Base of the Cochrane Breast Cancer Group was searched on 2nd May 2003 using the codes for "advanced breast cancer", "chemotherapy". Details of the search strategy applied by the Group to create the register, and the procedure used to code references, are described in the Group's module on the Cochrane Library., Selection Criteria: Randomised trials comparing taxane-containing chemotherapy regimens with regimens not containing taxanes in women with metastatic breast cancer., Data Collection and Analysis: Data were collected from published trials. Studies were assessed for eligibility and quality, and data were extracted, by two independent reviewers. Hazard ratios were derived for time-to-event outcomes where possible, and a fixed effect model was used for meta-analysis. Response rates were analysed as dichotomous variables. Toxicity and quality of life data were extracted where present., Main Results: Twenty one eligible trials were identified of which 12 have published time-to-event data and 16 have reported response data. The quality of randomisation was generally not described. An estimated 2621 deaths in 3643 randomised women demonstrate a statistically significant difference in favour of taxane-containing regimens with a HR for overall survival of 0.93 (95% CI=0.86-1.00, p=0.05) and no statistically significant heterogeneity. If the analysis is restricted to trials of firstline chemotherapy the HR changes to 0.92 and is no longer statistically significant (95% CI 0.84-1.02, p=0.11). There was also a significant difference in favour of taxanes in relation to time to progression (overall HR 0.92, 95%CI 0.85-0.99, p=0.02) and overall response in assessable women (overall OR 1.34, 95%CI 1.18-1.52, p<0.00001) however there was strong statistical evidence of heterogeneity (P<0.00001), probably reflecting the varying efficacy of the comparator regimens used in the trials., Authors' Conclusions: When all trials are considered, taxane-containing regimens appear to improve overall survival, time to progression and overall response in women with metastatic breast cancer. The degree of heterogeneity encountered indicates that taxane-containing regimens are more effective than some, but not all non-taxane-containing regimens.

Background: It is commonly thought that combining chemotherapy agents for treating women with metastatic breast cancer will result in regimens that are more active, offer superior tumour response rates with more time before progression and improve overall survival. However, it is not known whether giving patients more intensive chemotherapy regimens (judged according to some measure eg dose, dose intensity, response rate, or toxicity) results in better health outcomes. One way to investigate the effect of more versus less-intensive chemotherapy is to compare regimens containing a single drug (and hence possibly less active treatment) with regimens containing a greater number of drugs (and hence possibly more active but more toxic), even when adjustments are made to dosages or schedules to account for toxicity., Objectives: To compare use of single chemotherapy agents with regimens containing a combination of agents for the treatment of metastatic breast cancer., Search Strategy: The Specialised Register maintained by the Editorial Base of the Cochrane Breast Cancer Group was searched on 2nd May 2003 using the codes for "advanced breast cancer", "chemotherapy". Details of the search strategy applied by the group to create the register, and the procedure used to code references, are described in the group's module on The Cochrane Library., Selection Criteria: Randomised trials comparing single agent chemotherapy with combination therapy in women with metastatic breast cancer., Data Collection and Analysis: Data were collected from published trials. Studies were assessed for eligibility and quality, and data were extracted by two independent reviewers. Hazard ratios were derived for time-to-event outcomes where possible, and a fixed effect model was used for meta-analysis. Response rates were analysed as dichotomous variables. Toxicity and quality of life data were extracted where present., Main Results: Thirty seven eligible trials were identified of which 28 had published time-to-event data. The quality of randomisation was generally not described. Data, based on an estimated 4220 deaths in 5707 women, show a modest advantage for combination chemotherapy regimens compared with single agents with a hazard ratio (HR) for overall survival of 0.88 (95% CI=0.83-0.94, P<0.0001) and no evident heterogeneity. Results are similar if the analysis is limited to trials in women receiving first-line chemotherapy. Combination regimens are favourably associated with time to progression (overall HR of 0.78 (95% CI=0.73-0.83, P<0.00001) and tumour response rates (OR 1.28, CI=1.15-1.42, P<0.00001) although significant heterogeneity was observed (P=0.002 and P<0.00001 respectively). This probably reflects the varying efficacy of the comparator regimens used in the trials. Women receiving combination regimens experienced a higher toxicity level for leukopenia, hair loss and nausea and vomiting compared with those receiving a single agent, which was statistically significant., Authors' Conclusions: Compared with single-chemotherapy agents, combination regimens show a statistically significant advantage for tumor response and time to progression in women with metastatic breast cancer, a modest improvement in overall survival and significantly worse toxicities.

Background: Antitumour antibiotics are used in the management of metastatic breast cancer. Some of these agents have demonstrated higher tumour response rates than non-antitumour antibiotic regimens, however a survival benefit has not been established in this setting., Objectives: To identify and review the randomised evidence comparing anti-tumour antibiotic containing chemotherapy regimens with regimens not containing an anti-tumour antibiotic in the management of women with metastatic breast cancer., Search Strategy: The specialised register maintained by the Editorial Base of the Cochrane Breast Cancer Group was searched on 2nd May, 2003 using the codes for "advanced breast cancer" and "chemotherapy". Details of the search strategy and coding applied by the Group to create the register are described in the Group's module on The Cochrane Library., Selection Criteria: Randomised trials comparing anti-tumour antibiotic containing regimens with regimens not containing anti-tumour antibiotics in women with metastatic breast cancer., Data Collection and Analysis: Data were collected from published trials. Studies were assessed for eligibility and quality, and data were extracted by two independent reviewers. Hazard ratios (HRs) were derived from time-to-event outcomes where possible, and a fixed effect model was used for meta-analysis. Response rates were analysed as dichotomous variables. Quality of life and toxicity data were extracted where present. A primary analysis was conducted for all trials and by class of antitumour antibiotic., Main Results: Thirty-three trials reporting on 45 treatment comparisons were identified. All trials published results for tumour response and 26 trials published time-to-event data for overall survival. The observed 4084 deaths in 5284 randomised women did not demonstrate a statistically significant difference in survival between regimens that contained antitumour antibiotics and those that did not (HR 0.97, 95% CI 0.91 to 1.03, P = 0.35) and no significant heterogeneity. Antitumour antibiotic regimens were favourably associated with time-to-progression (HR 0.84, 95% CI 0.77 to 0.91) and tumour response rates (odds ratio (OR) 1.34, 95% CI 1.21 to 1.48) although statistically significant heterogeneity was observed for these outcomes. These associations were consistent when the analysis was restricted to the 29 trials that reported on anthracyclines. Patients receiving anthracycline-containing regimens were also more likely to experience toxic events compared to patients receiving non-antitumour antibiotic regimens. No statistically significant difference was observed in any outcome between mitoxantrone-containing and non-antitumour antibiotic-containing regimens., Reviewers' Conclusions: Compared to regimens without antitumour antibiotics, regimens that contained these agents showed a statistically significant advantage for tumour response and time to progression in women with metastatic breast cancer but were not associated with an improvement in overall survival. The favourable effect on tumour response and time to progression observed in anthracycline-containing regimens was also associated with greater toxicity.

The use of taxanes in early breast cancer is increasing. However, there are few mature studies of taxanes in this setting, and their role is uncertain. Our systematic review of randomised trials of adjuvant or neoadjuvant systemic therapy identified ten reported trials comparing a taxane-containing group with a non-taxane-containing control group in women with early breast cancer. Four of five neoadjuvant trials showed higher rates of complete response with taxanes, although differences were not significant. All five adjuvant trials showed improvements in disease-free survival with taxanes, and these improvements were significant in three trials and independent of oestrogen-receptor status. Two trials showed a significant improvement in overall survival. These results support the use of adjuvant taxanes in women with early breast cancer and involved lymph nodes. Longer follow-up of these trials and results from continuing trials are needed to clarify the best use of taxanes in early breast cancer.

Background: Studies have reported high tumour response rates for platinum-containing regimens in the treatment of women with metastatic breast cancer., Objectives: To identify and review the evidence from randomised trials comparing platinum-containing chemotherapy regimens with regimens not containing platinum in the management of women with metastatic breast cancer., Search Strategy: The specialised register maintained by the editorial base of the Cochrane Breast Cancer Group was searched on 2nd May 2003 using the codes for "advanced breast cancer", "chemotherapy". Details of the search strategy applied to create the register, and the procedure used to code references, are described in the Cochrane Breast Cancer Group module on The Cochrane Library., Selection Criteria: Randomised trials comparing platinum-containing chemotherapy regimens with regimens not containing platinum in women with metastatic breast cancer., Data Collection and Analysis: Studies were assessed for eligibility and quality, and data (from published trials) were extracted by two independent reviewers. Hazard ratios were derived for time-to-event outcomes, where possible, and a fixed effect model was used for meta-analysis. Response rates were analysed as dichotomous variables. Toxicity and quality of life data (not available) were extracted where present., Main Results: Thirteen eligible trials were identified, of which 12 had published time-to-event data. The quality of randomisation was generally not described.Data, based on an estimated 987 deaths in 1377 women, was unable to show a statistically significant difference in favour of platinum-containing regimens. The hazard ratio (HR) for overall survival was 1.00 (95% confidence interval (CI) 0.88 to 1.15, p=0.96), with minor heterogeneity. Results were similar when the analysis was limited to trials in women receiving first line chemotherapy. There was no statistically significant difference in favour of platinum-containing regimens for time to progression (overall HR of 1.06 (95% CI 0.95 to 1.19, p=0.31) although there was marked evidence of heterogeneity (p< 0.0001). There was a statistically significant difference in overall response in favour of platinum-containing regimens (OR 1.47; 95% CI 1.23 to 1.76, p=0.0001). However, there was strong statistical evidence of heterogeneity (p < 0.00010) probably reflecting the varying efficacy of the comparator regimens used in the trials. Heterogeneity may also reflect the differences, and difficulties, in assessing response. Women receiving platinum-containing regimens experienced statistically significant greater toxicity levels for leukopenia, hair loss, nausea and vomiting and anaemia compared with those receiving non-platinum regimens., Reviewers' Conclusions: In view of the significant excess toxicity, lack of progression or survival benefit and the availability of less toxic active agents it is difficult to justify the use of platinum-containing regimens, particularly as first line treatment for women with metastatic breast cancer in routine clinical practice. Ongoing trials are examining the possibility of synergy between platins and trastuzamab, a monoclonal antibody treatment. No randomised trials containing oxalplatin were identified for the present review.

Background: Both chemotherapy and endocrine therapy can be used as treatments for metastatic breast cancer., Objectives: To review the evidence and determine whether chemotherapy or endocrine therapy has the most beneficial effect on treatment outcomes (survival, response rate, toxicity and quality of life)., Search Strategy: The specialised register maintained by the Editorial Base of the Cochrane Breast Cancer Group was searched on 16th September 2002 using the codes for "advanced breast cancer", "chemotherapy" and "endocrine therapy". Details of the search strategy applied by the Group to create the register, and the procedure used to code references, are described in the Group's module on the Cochrane Library., Selection Criteria: Randomised trials comparing the effects of chemotherapy alone with endocrine therapy alone on pre-specified endpoints in metastatic breast cancer., Data Collection and Analysis: Data were collected from published trials. Hazard ratios were derived for survival analysis and a fixed effect model was used for meta-analysis. Response rates were analysed as dichotomous variables. Toxicity and quality of life data were extracted where present., Main Results: The primary analysis of overall effect using hazard ratios derived from published survival curves involved six trials (692 women). There was no significant difference seen (HR=0.94, 95%CI 0.79-1.12, p=0.5). A test for heterogeneity was p=0.1. A pooled estimate of reported response rates in eight trials involving 817 women shows a significant advantage for chemotherapy over endocrine therapy with RR=1.25 (1.01-1.54, p=0.04). However the two largest trials showed trends in opposite directions, and a test for heterogeneity was p=0.0018. There was little information available on toxicity and quality of life. Six of the seven fully published trials commented on increased toxicity with chemotherapy, mentioning nausea, vomiting and alopecia. Three of the seven mentioned aspects of quality of life, with differing results. Only one trial formally measured quality of life, concluding that it was better with chemotherapy., Reviewer's Conclusions: In women with metastatic breast cancer and where hormone receptors are present, a policy of treating first with endocrine therapy rather than chemotherapy is recommended except in the presence of rapidly progressive disease.

Metastatic breast cancer is incurable but often responsive to treatment. There is little evidence-based consenus on when to use which treatments, in what combination and for how long. Systematic reviews were performed on 12 prospectively defined, clinically relevant research questions to support the development of evidence-based clinical practice guidelines. A comprehensive search of Medline from 1966 to 1996 identified over 1800 controlled trials. Eligibility and data extraction were performed independently by two blinded reviewers. Trial results were summarised by ratios of median survivals (RMS) and P -values for survival curve comparisons with meta-analysis by weighted combination of these statistics. Sixty-five publications reporting 97 treatment comparisons were included. There was moderate evidence that more rather than fewer cycles of chemotherapy improved survival (RMS:1.23, P -0.01). The evidence did not support: higher rather than lower doses of chemotherapy (or of endocrine therapy); any one class of endocrine agent over all others; multiple endocrine agents over a single agent; or, combined chemotherapy and endocrine therapy over either single modality. Only six trials assessed quality of life revealing better quality of life with more rather than fewer cycles of chemotherapy and with standard rather than lower doses of chemotherapy. These systematic reviews reveal counterintuitive evidence useful to everyday practice, in particular that more rather than fewer cycles of chemotherapy lead to better quality of life and longer survival., (Copyright 2000 Harcourt Publishers Ltd.)

The development of endocrine resistance in previously sensitive, estrogen receptor-positive breast cancers is a major limitation in the treatment of breast cancer. Because antiestrogens have a cell cycle-specific action on breast cancer cells and influence the expression and activity of several cell cycle-regulatory molecules, the development of aberrant cell cycle control mechanisms is a potential mechanism by which cells might develop resistance to antiestrogens. We postulated that overexpression of cyclin D1, which is a common feature of breast cancer, may confer antiestrogen resistance. We addressed this question in vitro by testing the ability of ectopic cyclin D1 overexpression to overcome the growth-inhibitory effects of tamoxifen and the pure steroidal antiestrogens, ICI 164384 and ICI 182780, in T-47D and MCF-7 human breast cancer cells. In cells stably transfected with a human cyclin D1 cDNA under the control of a metal-inducible metallothionein promoter, cyclin D1 expression was increased 2-4-fold following treatment with zinc. Despite the continued presence of antiestrogen, cyclin D1 induction resulted in the formation of active cyclin D1/Cdk4 complexes, concurrent hyperphosphorylation of the retinoblastoma protein, and entry into S phase of cells previously arrested in G1. Elevated cyclin D1 protein levels were first detected 3 h after treatment with zinc, and the proportion of cells in S phase began to increase 6 h later. The S-phase fraction increased 2-3-fold from 13 to 17% in cells treated with antiestrogen alone, to a peak of 33-38% 15 h after zinc treatment. Both the cyclin D1 protein level and the proportion of cells in S phase increased with increasing concentrations of zinc. We conclude that the ectopic overexpression of cyclin D1 reverses the growth-inhibitory effect of antiestrogens in estrogen receptor-positive breast cancer cells, providing a potential mechanism for clinical antiestrogen resistance.

Both retinoids and anti-estrogens inhibit breast cancer cell proliferation with accumulation of cells in the G1 phase of the cell cycle, but the effect of retinoids is delayed compared to that of anti-estrogens. To determine whether this temporal difference is due to a simple delay in the action of retinoids on a common site or to different sites of action within the G1 phase, we studied the cell cycle effects of retinoic acid (RA) and the anti-estrogen ICI 164384 (ICI) in T-47D cells partially synchronized by mevalonic acid rescue of lovastatin-induced cell cycle arrest. We found that cells entering the cell cycle semi-synchronously after mevalonic acid rescue of lovastatin treatment were immediately susceptible to ICI but not RA. This suggests that RA may act at a point up-stream and ICI at a point down-stream of lovastatin action. Consistent with this, cells recommencing cell cycle progression after RA treatment were susceptible to the effects of lovastatin, while cells pre-treated with ICI then rescued with estradiol were not. In addition, cells rescued from cell cycle arrest induced by either RA, ICI or lovastatin entered S phase with the same kinetics. Our findings suggest, first, that within G1, RA acts before and ICI acts after the point of lovastatin action and, second, that despite these differences in the initiation of cell cycle arrest, the final nature of the cell cycle arrest is similar. Hence, retinoids and anti-estrogens may be expected to target different cell cycle-regulatory molecules to initiate cell cycle arrest, while overcoming this arrest may be accomplished by the activation of a common molecular pathway.

Retinoids have antiproliferative effects in human breast cancer cells and share some characteristics with antiestrogens, although the molecular targets involved have yet to be identified in either case. Using T-47D human breast cancer cells, we compared the effects of retinoic acid (RA) and the antiestrogen ICI 164384 on cell cycle phase distribution and the expression of genes with known functions in cell cycle control. Both RA and ICI 164384 inhibited cell cycle progression in G1 phase, but the RA effect was delayed by 16 h. This delay in action was also seen with 9-cis RA and other retinoids. Administration of 17 beta-estradiol abolished the effects of ICI 164384 but was without effect in RA-treated cells. Antiestrogen treatment caused a rapid inhibition of c-myc and cyclin D1 gene expression and reduced Cdk2 activity by more than 50% at 24 h. RA, however, did not affect c-myc or cyclin D1 gene expression, nor did it significantly change the mRNA or protein levels of cyclins D3 or E or cyclin-dependent kinases (CDK) Cdk2 or Cdk4. RA-induced reduction in Cdk2 activity was modest and occurred after %S phase declined, while Cdk4 activity was reduced, coincident with cell cycle changes. However, following either RA or ICI 164384, there was a reduction in the amount of hyperphosphorylated pRB, first apparent well before cell cycle changes were seen. These data demonstrate that: (a) the mechanisms of action of antiestrogens and retinoids are different but converge at pRB; and (b) RA can affect CDK activity without reducing cyclin or CDK levels.