Background
Bone is the most common site of metastatic disease associated with breast cancer (BC). Bisphosphonates inhibit osteoclast‐mediated bone resorption, and novel targeted therapies such as ...denosumab inhibit other key bone metabolism pathways. We have studied these agents in both early breast cancer and advanced breast cancer settings. This is an update of the review originally published in 2002 and subsequently updated in 2005 and 2012.
Objectives
To assess the effects of bisphosphonates and other bone agents in addition to anti‐cancer treatment: (i) in women with early breast cancer (EBC); (ii) in women with advanced breast cancer without bone metastases (ABC); and (iii) in women with metastatic breast cancer and bone metastases (BCBM).
Search methods
In this review update, 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 19 September 2016.
Selection criteria
We included randomised controlled trials (RCTs) comparing: (a) one treatment with a bisphosphonate/bone‐acting agent with the same treatment without a bisphosphonate/bone‐acting agent; (b) treatment with one bisphosphonate versus treatment with a different bisphosphonate; (c) treatment with a bisphosphonate versus another bone‐acting agent of a different mechanism of action (e.g. denosumab); and (d) immediate treatment with a bisphosphonate/bone‐acting agent versus delayed treatment of the same bisphosphonate/bone‐acting agent.
Data collection and analysis
Two review authors independently extracted data, and assessed risk of bias and quality of the evidence. The primary outcome measure was bone metastases for EBC and ABC, and a skeletal‐related event (SRE) for BCBM. We derived risk ratios (RRs) for dichotomous outcomes and the meta‐analyses used random‐effects models. Secondary outcomes included overall survival and disease‐free survival for EBC; we derived hazard ratios (HRs) for these time‐to‐event outcomes where possible. We collected toxicity and quality‐of‐life information. GRADE was used to assess the quality of evidence for the most important outcomes in each treatment setting.
Main results
We included 44 RCTs involving 37,302 women.
In women with EBC, bisphosphonates were associated with a reduced risk of bone metastases compared to placebo/no bisphosphonate (RR 0.86, 95% confidence interval (CI) 0.75 to 0.99; P = 0.03, 11 studies; 15,005 women; moderate‐quality evidence with no significant heterogeneity). Bisphosphonates provided an overall survival benefit with time‐to‐event data (HR 0.91, 95% CI 0.83 to 0.99; P = 0.04; 9 studies; 13,949 women; high‐quality evidence with evidence of heterogeneity). Subgroup analysis by menopausal status showed a survival benefit from bisphosphonates in postmenopausal women (HR 0.77, 95% CI 0.66 to 0.90; P = 0.001; 4 studies; 6048 women; high‐quality evidence with no evidence of heterogeneity) but no survival benefit for premenopausal women (HR 1.03, 95% CI 0.86 to 1.22; P = 0.78; 2 studies; 3501 women; high‐quality evidence with no heterogeneity). There was evidence of no effect of bisphosphonates on disease‐free survival (HR 0.94, 95% 0.87 to 1.02; P = 0.13; 7 studies; 12,578 women; high‐quality evidence with significant heterogeneity present) however subgroup analyses showed a disease‐free survival benefit from bisphosphonates in postmenopausal women only (HR 0.82, 95% CI 0.74 to 0.91; P < 0.001; 7 studies; 8314 women; high‐quality evidence with no heterogeneity). Bisphosphonates did not significantly reduce the incidence of fractures when compared to placebo/no bisphosphonates (RR 0.77, 95% CI 0.54 to 1.08, P = 0.13, 6 studies, 7602 women; moderate‐quality evidence due to wide confidence intervals). We await mature overall survival and disease‐free survival results for denosumab trials.
In women with ABC without clinically evident bone metastases, there was no evidence of an effect of bisphosphonates on bone metastases (RR 0.96, 95% CI 0.65 to 1.43; P = 0.86; 3 studies; 330 women; moderate‐quality evidence with no heterogeneity) or overall survival (RR 0.89, 95% CI 0.73 to 1.09; P = 0.28; 3 studies; 330 women; high‐quality evidence with no heterogeneity) compared to placebo/no bisphosphonates however the confidence intervals were wide. One study reported a trend towards an extended period of time without a SRE with bisphosphonate compared to placebo (low‐quality evidence). One study reported quality of life and there was no apparent difference in scores between bisphosphonate and placebo (moderate‐quality evidence).
In women with BCBM, bisphosphonates reduced the SRE risk by 14% (RR 0.86, 95% CI 0.78 to 0.95; P = 0.003; 9 studies; 2810 women; high‐quality evidence with evidence of heterogeneity) compared with placebo/no bisphosphonates. This benefit persisted when administering either intravenous or oral bisphosphonates versus placebo. Bisphosphonates delayed the median time to a SRE with a median ratio of 1.43 (95% CI 1.29 to 1.58; P < 0.00001; 9 studies; 2891 women; high‐quality evidence with no heterogeneity) and reduced bone pain (in 6 out of 11 studies; moderate‐quality evidence) compared to placebo/no bisphosphonate. Treatment with bisphosphonates did not appear to affect overall survival (RR 1.01, 95% CI 0.91 to 1.11; P = 0.85; 7 studies; 1935 women; moderate‐quality evidence with significant heterogeneity). Quality‐of‐life scores were slightly better with bisphosphonates than placebo at comparable time points (in three out of five studies; moderate‐quality evidence) however scores decreased during the course of the studies. Denosumab reduced the risk of developing a SRE compared with bisphosphonates by 22% (RR 0.78, 0.72 to 0.85; P < 0.001; 3 studies, 2345 women). One study reported data on overall survival and observed no difference in survival between denosumab and bisphosphonate.
Reported toxicities across all settings were generally mild. Osteonecrosis of the jaw was rare, occurring less than 0.5% in the adjuvant setting (high‐quality evidence).
Authors' conclusions
For women with EBC, bisphosphonates reduce the risk of bone metastases and provide an overall survival benefit compared to placebo or no bisphosphonates. There is preliminary evidence suggestive that bisphosphonates provide an overall survival and disease‐free survival benefit in postmenopausal women only when compared to placebo or no bisphosphonate. This was not a planned subgroup for these early trials, and we await the completion of new large clinical trials assessing benefit for postmenopausal women. For women with BCBM, bisphosphonates reduce the risk of developing SREs, delay the median time to an SRE, and appear to reduce bone pain compared to placebo or no bisphosphonate.
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.
The germline BAP1 (BRCA1-associated protein-1) mutation and associated cancer pre-disposition syndrome was first described in 2011. Since then, physicians have considered this diagnosis for patients ...with a characteristic personal or family history of BAP1-associated tumours (mainly uveal and cutaneous melanoma, pleural/peritoneal mesothelioma, renal cell carcinoma and BAP1-deficient melanocytic lesions). However, a positive germline BAP1 mutation detection creates significant uncertainty in terms of appropriate cancer surveillance. A number of groups have proposed surveillance plans but important management dilemmas remain unresolved. The lifetime risk of developing cancer is not known and it is not clear if surveillance would lead to detecting cancer at an earlier stage or change survival outcomes. A consensus monitoring strategy was initially proposed at the Melanoma Institute Australia Melanoma Multidisciplinary Team meeting and later discussed with specialists in the field of cancer genetics, pathology, radiology, medical oncology, ophthalmology and dermatology. The objectives were to facilitate early diagnosis, incorporating where possible, clinically based and low/non-ionising radiation imaging modalities, applying the principles of a good screening test and a multidisciplinary focus.
•A cancer surveillance plan is proposed for germline BAP1 mutation cohorts in the context of discussion about the dilemmas associated with screening this group.•Detailed descriptions of proposed surveillance for the five main tumour types, including radiological discussion, expanding on previous more generalised recommendations.•Broadest interdisciplinary expert collaboration to date, including clinical cancer genetics, oncology, pathology, radiology, ophthalmology and dermatology.
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer associated with shorter survival and a higher likelihood of recurrence. In early TNBC, platinum chemotherapy has been ...shown to improve pathological complete response (pCR); however, its effect on long-term survival outcomes has not been fully elucidated.
Randomised controlled trials examining neoadjuvant or adjuvant platinum chemotherapy for early TNBC were included. Primary outcomes were disease-free survival (DFS) and overall survival (OS). Secondary outcomes were pCR, treatment adherence, grade III or IV toxicity related to chemotherapy, and quality of life.
From 3972 records, we included 20 published studies. All studies reporting DFS and OS used carboplatin. Inclusion of platinum chemotherapy improved DFS (neoadjuvant: hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.53 to 0.75; adjuvant: HR 0.69, 95% CI 0.54 to 0.88) and OS (neoadjuvant: HR 0.69, 95% CI 0.55 to 0.86; adjuvant: 0.70, 95% CI 0.50 to 0.96). Our analysis confirmed platinum chemotherapy increased pCR rates (risk ratio (RR) 1.44, 95% CI 1.31 to 1.59). There were no differences seen in examined subgroups. Platinum chemotherapy was associated with reduced dose intensity and increased haematological toxicity.
Platinum-based chemotherapy using carboplatin in the adjuvant or neoadjuvant setting improves long-term outcomes of DFS and OS in early TNBC, with no evidence of differences by subgroup. This was at the cost of more frequent chemotherapy delays and dose reductions, and greater haematological toxicity. These findings support the use of platinum-based chemotherapy for people with early TNBC.
•Carboplatin reduces cancer recurrence in early triple negative breast cancer.•Carboplatin chemotherapy improves survival in early triple negative breast cancer.•The benefits are seen if carboplatin is used before or after surgery.•Platinum chemotherapy is associated with increased side effects.•Benefit from carboplatin is seen across examined subgroups.
Routine screening of tumors for DNA mismatch repair (MMR) deficiency (dMMR) in colorectal (CRC), endometrial (EC) and sebaceous skin (SST) tumors leads to a significant proportion of unresolved cases ...classified as suspected Lynch syndrome (SLS). SLS cases (n = 135) were recruited from Family Cancer Clinics across Australia and New Zealand. Targeted panel sequencing was performed on tumor (n = 137; 80×CRCs, 33×ECs and 24xSSTs) and matched blood-derived DNA to assess for microsatellite instability status, tumor mutation burden, COSMIC tumor mutational signatures and to identify germline and somatic MMR gene variants. MMR immunohistochemistry (IHC) and MLH1 promoter methylation were repeated. In total, 86.9% of the 137 SLS tumors could be resolved into established subtypes. For 22.6% of these resolved SLS cases, primary MLH1 epimutations (2.2%) as well as previously undetected germline MMR pathogenic variants (1.5%), tumor MLH1 methylation (13.1%) or false positive dMMR IHC (5.8%) results were identified. Double somatic MMR gene mutations were the major cause of dMMR identified across each tumor type (73.9% of resolved cases, 64.2% overall, 70% of CRC, 45.5% of ECs and 70.8% of SSTs). The unresolved SLS tumors (13.1%) comprised tumors with only a single somatic (7.3%) or no somatic (5.8%) MMR gene mutations. A tumor-focused testing approach reclassified 86.9% of SLS into Lynch syndrome, sporadic dMMR or MMR-proficient cases. These findings support the incorporation of tumor sequencing and alternate MLH1 methylation assays into clinical diagnostics to reduce the number of SLS patients and provide more appropriate surveillance and screening recommendations.
We evaluated study outcomes in patients enrolled in Asian regions in the phase III EMBRACA trial of talazoparib vs. chemotherapy.
Patients with human epidermal growth factor receptor 2-negative ...germline BRCA1/2-mutated advanced breast cancer who received prior chemotherapy were randomized 2:1 to talazoparib 1 mg/day or chemotherapy (physician's choice). Primary endpoint was progression-free survival (PFS) per independent central review in the intent-to-treat (ITT) population. This post-hoc analysis evaluated efficacy/safety endpoints in the ITT population of patients enrolled in Asian regions.
Thirty-three patients were enrolled at Asian sites (talazoparib, n=23; chemotherapy, n=10). Baseline characteristics were generally comparable with the overall EMBRACA population. In Asian patients, median PFS was 9.0 months (95% confidence interval CI, 3.0 to 15.2) for talazoparib and 7.1 months (95% CI, 1.2 to not reached) for chemotherapy (hazard ratio HR, 0.74 95% CI, 0.22 to 2.44). Objective response rate was numerically higher for talazoparib vs. chemotherapy (62.5% 95% CI, 35.4 to 84.8 vs. 25.0% 95% CI, 3.2 to 65.1). Median overall survival was 20.7 months (95% CI, 9.4 to 40.1) versus 21.2 months (95% CI, 2.7 to 35.0) (HR, 1.41 95% CI, 0.49 to 4.05). In Asian patients, fewer grade 3/4 adverse events (AEs), serious AEs (SAEs), grade 3/4 SAEs, and AEs resulting in dose reduction/discontinuation occurred with talazoparib than chemotherapy; for talazoparib, the frequency of these events was lower in Asian patients versus overall EMBRACA population.
In this subgroup analysis, talazoparib numerically improved efficacy versus chemotherapy and was generally well tolerated in Asian patients, with fewer grade 3/4 treatment-emergent AE (TEAEs), SAEs, and TEAEs leading to dose modification vs. the overall EMBRACA population.
To inform effective genomic medicine strategies, it is important to examine current approaches and gaps in well-established applications. Lynch syndrome (LS) causes 3-5% of colorectal cancers (CRCs). ...While guidelines commonly recommend LS tumour testing of all CRC patients, implementation in health systems is known to be highly variable. To provide insights on the heterogeneity in practice and current bottlenecks in a high-income country with universal healthcare, we characterise the approaches and gaps in LS testing and referral in seven Australian hospitals across three states.
We obtained surgery, pathology, and genetics services data for 1,624 patients who underwent CRC resections from 01/01/2017 to 31/12/2018 in the included hospitals.
Tumour testing approaches differed between hospitals, with 0-19% of patients missing mismatch repair deficiency test results (total 211/1,624 patients). Tumour tests to exclude somatic MLH1 loss were incomplete at five hospitals (42/187 patients). Of 74 patients with tumour tests completed appropriately and indicating high risk of LS, 36 (49%) were missing a record of referral to genetics services for diagnostic testing, with higher missingness for older patients (0% of patients aged ≤ 40 years, 76% of patients aged > 70 years). Of 38 patients with high-risk tumour test results and genetics services referral, diagnostic testing was carried out for 25 (89%) and identified a LS pathogenic/likely pathogenic variant for 11 patients (44% of 25; 0.7% of 1,624 patients).
Given the LS testing and referral gaps, further work is needed to identify strategies for successful integration of LS testing into clinical care, and provide a model for hereditary cancers and broader genomic medicine. Standardised reporting may help clinicians interpret tumour test results and initiate further actions.
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, I2= 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, I2 = 24%, 4105 women, 9 studies, high‐quality evidence) or overall survival (HR 0.97, 95% CI 0.87 to 1.09, P = 0.62, I2 = 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.
Background
Approximately 80% of breast cancers amongst premenopausal women are hormone receptor‐positive. Adjuvant endocrine therapy is an integral component of care for hormone receptor‐positive ...breast cancer and in premenopausal women includes oestrogen receptor blockade with tamoxifen, temporary suppression of ovarian oestrogen synthesis by luteinising hormone releasing hormone (LHRH) agonists, and permanent interruption of ovarian oestrogen synthesis with oophorectomy or radiotherapy. Recent international consensus statements recommend single‐agent tamoxifen or aromatase inhibitors with ovarian function suppression (OFS) as the current standard adjuvant endocrine therapy for premenopausal women (often preceded by chemotherapy). This review examined the role of adding OFS to another treatment (i.e. chemotherapy, endocrine therapy, or both) or comparing OFS to no further adjuvant treatment.
Objectives
To assess effects of OFS for treatment of premenopausal women with hormone receptor‐positive early breast cancer.
Search methods
For this review update, we searched the Specialised Register of the Cochrane Breast Cancer Group, MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 8), the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), and ClinicalTrials.gov on 26 September 2019. We screened the reference lists of related articles, contacted trial authors, and applied no language restrictions.
Selection criteria
We included all randomised trials assessing any method of OFS, that is, oophorectomy, radiation‐induced ovarian ablation, or LHRH agonists, as adjuvant treatment for premenopausal women with early‐stage breast cancer. We included studies that compared (1) OFS versus observation, (2) OFS + chemotherapy versus chemotherapy, (3) OFS + tamoxifen versus tamoxifen, and (4) OFS + chemotherapy + tamoxifen versus chemotherapy + tamoxifen.
Data collection and analysis
Two review authors independently extracted data and assessed risk of bias and certainty of evidence using the GRADE approach. Hazard ratios (HRs) were derived for time‐to‐event outcomes, and meta‐analysis was performed using a fixed‐effect model. The primary outcome measures were overall survival (OS) and disease‐free survival (DFS). Toxicity, contralateral breast cancer, and second malignancy were represented as risk ratios (RRs), and quality of life data were extracted when provided.
Main results
This review update included 15 studies involving 11,538 premenopausal women with hormone receptor‐positive early breast cancer; these studies were conducted from 1978 to 2014. Some of these treatments are not current standard of care, and early studies did not assess HER2 receptor status. Studies tested OFS versus observation (one study), OFS plus chemotherapy versus chemotherapy (six studies), OFS plus tamoxifen versus tamoxifen (six studies), and OFS plus chemotherapy and tamoxifen versus chemotherapy and tamoxifen (two studies). Of those studies that reported the chemotherapy regimen, an estimated 72% of women received an anthracycline. The results described below relate to the overall comparison of OFS versus no OFS.
High‐certainty evidence shows that adding OFS to treatment resulted in a reduction in mortality (hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.78 to 0.94; 11 studies; 10,374 women; 1933 reported events). This treatment effect was seen when OFS was added to observation, to tamoxifen, or to chemotherapy and tamoxifen. The effect on mortality was not observed when OFS was added to chemotherapy without tamoxifen therapy (HR 0.95, 95% CI 0.82 to 1.09; 5 studies; 3087 women; median follow‐up: range 7.7 to 12.1 years). The addition of OFS resulted in improved DFS (HR 0.83, 95% CI 0.77 to 0.90; 10 studies; 8899 women; 2757 reported events; high‐certainty evidence). The DFS treatment effect persisted when OFS was added to observation, to tamoxifen, and to chemotherapy and tamoxifen. The effect on DFS was reduced when OFS was added to chemotherapy without tamoxifen therapy (HR 0.90, 95% CI 0.79 to 1.01; 5 studies; 2450 women). Heterogeneity was low to moderate across studies for DFS and OS (respectively).
Evidence suggests that adding OFS slightly increases the incidence of hot flushes (grade 3/4 or any grade; risk ratio (RR) 1.60, 95% CI 1.41 to 1.82; 6 studies; 5581 women; low‐certainty evidence, as this may have been under‐reported in these studies). Two other studies that could not be included in the meta‐analysis reported a higher number of hot flushes in the OFS group than in the no‐OFS group. Seven studies involving 5354 women collected information related to mood; however this information was reported as grade 3 or 4 depression, anxiety, or neuropsychiatric symptoms, or symptoms were reported without the grade. Two studies reported an increase in depression, anxiety, and neuropsychiatric symptoms in the OFS group compared to the no‐OFS group, and five studies indicated an increase in anxiety in both treatment groups (but no difference between groups) or no difference overall in symptoms over time or between treatment groups. A single study reported bone health as osteoporosis (defined as T score < ‐2.5); this limited evidence suggests that OFS increases the risk of osteoporosis compared to no‐OFS at median follow‐up of 5.6 years (RR 1.16, 95% CI 1.10 to 28.82; 2011 women; low‐certainty evidence).
Adding OFS to treatment likely reduces the risk of contralateral breast cancer (HR 0.75, 95% CI 0.57 to 0.97; 9 studies; 9138 women; moderate‐certainty evidence).
Quality of life was assessed in five studies; four studies used validated tools, and the fifth study provided no information on how data were collected. Two studies reported worse quality of life indicators (i.e. vaginal dryness, day and night sweats) for women receiving OFS compared to those in the no‐OFS group. The other two studies indicated worsening of symptoms (e.g. vasomotor, gynaecological, vaginal dryness, decline in sexual interest, bone and joint pain, weight gain); however these side effects were reported in both OFS and no‐OFS groups. The study that did not use a validated quality of life tool described no considerable differences between groups.
Authors' conclusions
This review found evidence that supports adding OFS for premenopausal women with early, hormone receptor‐positive breast cancers. The benefit of OFS persisted when compared to observation, and when added to endocrine therapy (tamoxifen) or chemotherapy and endocrine therapy (tamoxifen). The decision to use OFS may depend on the overall risk assessment based on tumour and patient characteristics, and may follow consideration of all side effects that occur with the addition of OFS.
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.
PDF
