Diet and risk for breast cancer recurrence and survival

Dietary factors may influence the risk for breast cancer and also the prognosis following diagnosis and treatment. The aim of this study was to assess whether self-reported prediagnosis diet or other patient factors associated with breast cancer incidence were predictive of recurrence and survival. Patients (n=149) diagnosed with primary breast cancer between 1989 and 1991 were followed for five or more years. Total energy (hazard ratio (HR)=1.58, 95%, confidence interval (CI)= 1.05, 2.38) as well as total (HR = 1.46, 95% CI = 1.05, 2.01), saturated (HR = 1.79,95% CI = 1.05, 3.04), and monounsaturated (HR = 1.65, 95% CI = 1.09,2.49) fat intakes were associated with increased risk, and energy-adjusted bread and cereal consumption (HR = 0.55, 95% CI = 0.33, 0.93) with decreased risk of recurrence. Both total energy (HR = 1.58, 95% CI = 1.03, 2.43) and polyunsaturated fat (HR = 1.84, 95% CI = 1.09, 3.13) intakes were associated with an increased risk of death. All associations between dietary fat and recurrence and survival attenuated following energy adjustment. Oral contraceptive use (HR = 1.28, 95% CI = 1.03, 1.60), lymph node positive status (HR = 2.36, 95% CI = 1.01, 5.49), and tumor stage (HR = 2.22, 95% CI = 1.02, 4.81) were associated with increased risk of recurrence. Tumor stage (HR = 4.96, 95% CI = 1.86, 13.23), lymph node positive status (HR = 3.31, 95% CI = 1.38, 7.95, and estrogen receptor negative status (HR = 2.46, 95% CI = 1.02, 5.94) were associated with increased risk, and arm muscle circumference (HR = 0.27, 95% CI = 0.09, 0.86) and mammographic utilization (HR = 0.77, 95% CI = 0.61, 0.98) with decreased risk of death. Higher levels of energy, fat intakes, and selected patient characteristics (particularly disease stage and anthropometric indicators of adiposity) appear to increase risk of recurrence and/or shortened survival following the diagnosis of breast cancer.     

Sleep duration and breast cancer risk: A meta‐analysis of observational studies

Studies on the association of short or long sleep duration with breast cancer risk have reported inconsistent results. We quantitatively assessed this association by conducting a meta‐analysis based on the evidence from observational studies. In April 2013, we performed electronic searches in PubMed, EmBase and the Cochrane Library to identify studies examining the effect of sleep duration on breast cancer incidence. The odds ratio (OR) was used to measure any such association in a random‐effects model. The analysis was further stratified by confounding factors that could bias the results. A total of six studies (two case–control and four cohort studies) involving 159,837 individuals were included in our meta‐analysis. Our study did not show an association between either short or long sleep duration and breast cancer risk (short sleep duration data: pooled OR = 1.01, 95% confidence interval (CI) = 0.90–1.14, p = 0.853; long sleep duration data: pooled OR = 0.95, 95% CI = 0.86–1.04, p = 0.251). Moreover, we did not identify any statistically significant association between sleep duration and breast cancer risk in all the subgroup analyses. In conclusion, our findings indicate that sleep duration has no effect on breast cancer risk.     

Diabetes mellitus and risk of breast cancer: a meta-analysis

Diabetes mellitus has been associated with an increased risk of several types of cancers, but its relationship with breast cancer remains unclear. We conducted a meta-analysis of case-control and cohort studies to assess the evidence regarding the association between diabetes and risk of breast cancer. Studies were identified by searching MEDLINE (1966-February 2007) and the references of retrieved articles. We identified 20 studies (5 case-control and 15 cohort studies) that reported relative risk (RR) estimates (odds ratio, rate ratio/hazard ratio, or standardized incidence ratio) with 95% confidence intervals (CIs) for the relation between diabetes (largely Type II diabetes) and breast cancer incidence. Summary RRs were calculated using a random-effects model. Analysis of all 20 studies showed that women with (versus without) diabetes had a statistically significant 20% increased risk of breast cancer (RR, 1.20; 95% CI, 1.12-1.28). The summary estimates were similar for case-control studies (RR, 1.18; 95% CI, 1.05-1.32) and cohort studies (RR, 1.20; 95% CI, 1.11-1.30). Meta-analysis of 5 cohort studies on diabetes and mortality from breast cancer yielded a summary RR of 1.24 (95% CI, 0.95-1.62) for women with (versus without) diabetes. Findings from this meta-analysis indicate that diabetes is associated with an increased risk of breast cancer.     

Association between a glutathione S-transferase A1 promoter polymorphism and survival after breast cancer treatment

Glutathione S-transferase (GST) enzymes detoxify chemotherapeutic drugs, and several studies have reported differences in survival for cancer patients who have variant genotypes for GSTP1, GSTM1 or GSTT1 enzymes. A recently described polymorphism alters hepatic expression of GSTA1, a GST with high activity in glutathione conjugation of metabolites of cyclophosphamide (CP). To consider the possible influence of the reduced-expression GSTA1*B allele on cancer patient survival, we have conducted a pilot study of breast cancer patients treated with CP-containing combination chemotherapy. GSTA1 genotype was determined by polymerase chain reaction and restriction fragment length polymorphism. Kaplan-Meier methods and Cox proportional hazards models were used to evaluate survival in relation to genotype. Among 245 subjects, 35% were GSTA1*A/*A, 49% GSTA1*A/*B and 16% GSTA1*B/*B; the genotype distribution did not differ by ethnic group, age or stage at diagnosis. Among patients who had 0 or 1 GSTA1*B allele, the proportion surviving at 5 years was 0.66 (95% CI = 0.59-0.72), whereas for GSTA1*B/*B subjects the proportion was higher, 0.86 (95% CI = 0.67-0.95). Significantly reduced hazard of death was observed for GSTA1*B/*B subjects during the first 5 years after diagnosis, hazard ratio (HR) = 0.3, 95% CI = 0.1-0.8. The association varied with time, with no survival difference observed for subjects who survived beyond 5 years. These results, although based on a small study population, describe an apparent difference in survival after treatment for breast cancer according to GSTA1 genotype. Further studies should consider the possible association between the novel GSTA1*B variant and outcomes of cancer therapy.     

The SNP rs6500843 in 16p13.3 is associated with survival specifically among chemotherapy-treated breast cancer patients

We have utilized a two-stage study design to search for SNPs associated with the survival of breast cancer patients treated with adjuvant chemotherapy. Our initial GWS data set consisted of 805 Finnish breast cancer cases (360 treated with adjuvant chemotherapy). The top 39 SNPs from this stage were analyzed in three independent data sets: iCOGS (n=6720 chemotherapy-treated cases), SUCCESS-A (n=3596), and POSH (n=518). Two SNPs were successfully validated: rs6500843 (any chemotherapy; per-allele HR 1.16, 95% C.I. 1.08-1.26, p=0.0001, p_(adjusted)=0.0091), and rs11155012 (anthracycline therapy; per-allele HR 1.21, 95% C.I. 1.08-1.35, p=0.0010, p_(adjusted)=0.0270). The SNP rs6500843 was found to specifically interact with adjuvant chemotherapy, independently of standard prognostic markers (p_{(interaction)}=0.0009), with the rs6500843-GG genotype corresponding to the highest hazard among chemotherapy-treated cases (HR 1.47, 95% C.I. 1.20-1.80). Upon trans-eQTL analysis of public microarray data, the rs6500843 locus was found to associate with the expression of a group of genes involved in cell cycle control, notably AURKA, the expression of which also exhibited differential prognostic value between chemotherapy-treated and untreated cases in our analysis of microarray data. Based on previously published information, we propose that the eQTL genes may be connected to the rs6500843 locus via a RBFOX1-FOXM1-mediated regulatory pathway.     

Study on soy isoflavone consumption and risk of breast cancer and survival

Aim: Isoflavones in soy foods are part of a larger class of flayonoid compounds that have have been demonstrated to be potent dietary anti-cancer agents, and the effect of soy intake on the survival of ovarian cancer is conflicting. Therefore, we aimed to explore the whether soy intake is related to the risk of death of breast cancer. Methods: A prospective study was conducted. A total of 256 patients included in this study had breast cancer and were recruited between January 2004 and January 2006. All of them were followed up from since January 2011. A univariate Cox’s regression analysis was used to assess the association between soy intake and survival. Results: The education level, menopausal status, ER/PR status and TNM stage were significant difference in the survival of breast cancer. The highest soy isoflavone was associated with a decreased death risk of breast cancer (OR=0.25, 95% CI=0.09-0.54). Moreover, the higher consumption of soy protein also presented a trend decreased breast cancer risk, and the highest consumption significantly reduced the cancer risk compared with the lowest consumption (OR=0.38, 95% CI=0.17-0.86). Conclusion: The present study suggests soy intake is associated with a significant reduced death risk of breast cancer in Chinese population. Further large sample studies are warranted to confirm the inverse association of soy consumption and breast cancer survival by menopausal status.     

The association between stressful life events and breast cancer risk: a meta-analysis

Breast cancer is the most prevalent cancer in women in Western societies. Studies examining the relationship between stressful life events and breast cancer risk have produced conflicting results. The purpose of this meta-analysis was to identify studies on this relationship, between 1966 and December 2002, to summarize and quantify the association and to explain the inconsistency in previous results. Summary odds ratios and standard errors were calculated, using random effect meta-regression analyses, for the following categories: stressful life events, death of spouse, death of relative or friend, personal health difficulties, nonpersonal health difficulties, change in marital status, change in financial status and change in environmental status. The presence of publication bias has been explored, and sensitivity analyses were performed to identify heterogeneity, using calculation of the percentage of variability due to heterogeneity, meta-regression analyses and stratification. Only the categories stressful life events (OR = 1.77, 95% CI 1.31-2.40), death of spouse (OR = 1.37, 95% CI 1.10-1.71) and death of relative or friend (OR = 1.35, 95% CI 1.09-1.68) showed a statistically significant effect. Publication bias was identified in both stressful life events (p = 0.00) and death of relative or friend (p = 0.02). Sensitivity analyses resulted in the identification of heterogeneity in all categories, except death of spouse. The results of this meta-analysis do not support an overall association between stressful life events and breast cancer risk. Only a modest association could be identified between death of spouse and breast cancer risk.     

Cardiac glycosides and breast cancer risk: A systematic review and meta‐analysis of observational studies

Cardiac glycosides are phytoestrogens and have been linked to the risk of estrogen sensitive cancers such as uterus cancer. However, the association between use of cardiac glycosides and risk of breast cancer remains unclear. We investigated the association between cardiac glycosides use and the risk of breast cancer by systematically reviewing the published literature and performing meta‐analyses. A comprehensive literature search was performed using MEDLINE, EMBASE, Web of Science and SCOPUS to identify all relevant articles published up to November 2015. Risk estimates, and accompanying standard errors, for the association between cardiac glycoside use and breast cancer were extracted from identified studies. Meta‐analysis models were used to calculate a combined hazard ratio (HR), and 95% confidence interval (CI), and to investigate heterogeneity between studies. In total, nine studies were identified investigating cardiac glycosides use and risk of developing breast cancer. Overall, there was evidence to suggest an association between cardiac glycosides use and breast cancer risk (HR = 1.34; 95% CI 1.25, 1.44; p < 0.001) with little variation in the association between studies (I² = 16%, p for heterogeneity = 0.30). Results were little altered when analysis was restricted to studies with high quality scores or cohort studies. Overall, there was a 34% increase in breast risk with use of cardiac glycosides but it is unclear whether this association reflects confounding or is causal. Further observational studies are required to examine this association particularly for estrogen receptor positive breast cancer and to explore the role of potential confounding variables.     

Influence of education level on breast cancer risk and survival in Sweden between 1990 and 2004

On account of limited recent data regarding the role of education in breast cancer risk and prognosis, we conducted this study to assess the association between education level and in situ and invasive breast cancer risk and invasive breast cancer survival, using the 2006 update of the Swedish Family-Cancer Database. Cox's proportional hazards models were used to calculate the hazard ratio (HR) and 95% confidence interval (CI) adjusted for age, time-period, parity, age at first birth, county of residence, and family history of breast cancer. Compared to women completing less than 9 years of education, university graduates were more likely to be diagnosed with in situ (HR = 1.44, 95% CI: 1.28-1.63) and invasive (HR = 1.28, 95% CI: 1.20-1.36) breast cancer, and the lack of homogeneity between these two HRs was statistically significant, p = 0.007. Further stratification revealed that the lack of homogeneity was greatest for breast cancers diagnosed before age 50. Compared to women completing less than 9 years of education, university graduates were associated with the highest survival following a breast cancer diagnosis (lowest fatality hazard ratio), HR = 0.68, 95% CI: 0.61-0.75. Further research is warranted to elucidate possible behaviors or characteristics associated with education that could explain the differences in incidence and survival, such as compliance with cancer screening.     

乳腺癌保乳术后不同放疗方式的疗效及不良反应

目的:回顾性分析早期乳腺癌保乳术后不同放疗方式对局部正常器官的影响,观察不同放疗方式与生存率的关系。方法:收集我院1998-2010年保乳术后接受不同放疗方式治疗的乳腺癌患者121例,其中37例接受常规二维放疗,80例接受三维放射治疗,放疗采用6MV-X线全乳腺放疗50Gy,瘤床电子线外照射加量10Gy或同步加量至60Gy,4例未接受放疗,雌、孕激素受体阳性的患者加用内分泌治疗。治疗结束后每三个月复查至2年,每半年复查至5年,以后每年复查,放射性不良反应按照RTOG评价标准进行评价。结果:全组3年生存率为97.0％,5年生存率为95.0％,5年无瘤生存率为95.0％,局部复发率为0％。二维放疗放射性肺损伤的发生率明显高于三维放疗（P=0.010）。左侧乳腺癌放射性心脏损伤发生率稍高于右侧,但无明显统计学差异（P=0.210）,二维放疗放射性心脏损伤的发生率明显高于三维放疗（P=0.007）。二维放疗引起II°及III°急性放射性皮肤损伤发生率明显高于三维放疗（P=0.003）。美容效果与放射性皮肤反应相关,发生II°及以上皮肤反应的乳腺外观美容效果差于I°及以下皮肤反应的美容效果（P=0.030）。保乳术后接受局部放疗的患者3年生存率为98.0%,5年生存率为98.0%,T1与Ｔ2患者1、3、5年生存率分别为100%与97%、100%与94%、100%与94%,差异具有统计学意义（P=0.014）。结论:保乳术后行局部放疗明显延长生存时间,三维放疗与二维放疗相比5年生存优势未体现,但在保护肺、心脏、皮肤及美容效果方面明显好于二维放疗。     

Do adjuvant aromatase inhibitors increase the cardiovascular risk in postmenopausal women with early breast cancer

BACKGROUND: Despite the advantages from using aromatase inhibitors (AIs) compared with tamoxifen for early breast cancer, an unexpectedly greater number of grade 3 and 4 cardiovascular events (CVAE) (as defined by National Cancer Institute of Canada-Common Toxicity Criteria [version 2.0] was demonstrated. METHODS: Phase 3 randomized clinical trials (RCTs) comparing AI with tamoxifen in early breast cancer were considered eligible for this review. The event-based risk ratios (RRs) with 95% confidence intervals (95% CIs) were derived, and a test of heterogeneity was applied. Finally, absolute differences (ADs) in event rates and the number of patients needed to harm 1 patient (NNH) were determined. RESULTS: Seven eligible RCTs (19,818 patients) reported CVAE results. When considering all RCTs, the AD of the primary endpoint (CVAE) between the 2 arms (0.52%), tamoxifen versus AI, was statistically significant (RR, 1.31; 95% CI, 1.07-1.60; P= .007). This translated into an NNH value of 189 patients; when only third-generation AIs were considered, the difference (0.57%) remained significant (RR, 1.34; 95% CI, 1.09-1.63; P= .0038). Thromboembolic events were significantly more frequent in the tamoxifen arm, regardless of the strategy adopted (RR, 0.53; 95% CI, 0.42-0.65; P< .0001), without significant heterogeneity (P= .21). An AD of 1.17% and an NNH value of 85 patients were observed. CONCLUSIONS: According to the results from this meta-analysis, the risk of grade 3 and 4 CVAEs in patients who were receiving AIs was higher compared with the risk in patients who were receiving tamoxifen, and the difference reached statistical significance. However, the AD was relatively low, and from 160 to 180 patients had to be treated to produce 1 event.     

Effect of chemotherapy on survival in metastatic breast cancer

Summary In order to assess the impact of modern combination chemotherapy on overall survival of metastatic breast cancer patients, we retrospectively analysed survival data of those patients who presented with breast cancer and developed metastases at our clinic from 1971–78 inclusive. Our results indicate a trend towards improved survival from onset of first distant metastasis after 1975. Assessment of survival by treatment modality revealed significantly longer survival from first metastasis for those patients receiving predominantly endocrine treatment compared to chemotherapy, median survival being 32.5 versus 23 months for endocrine therapy and chemotherapy respectively. Patients receiving adriamycin in combination with other drugs, had longer survival from first metastasis than those patients receiving chemotherapy without adriamycin (median survival being 25 versus 18.5 months respectively). These differences are most probably due to patient selection. On the basis of these results it would appear that chemotherapy may be improving short-term survival in some patients, but is making no major impact on long-term survival. Address for reprints: Dr. A.H.G. Paterson, Dept. of Medicine, Cross Cancer Institute, 11560 University Avenue, Edmonton, Alberta, Canada T6G 1Z2.     

中国乳腺癌全人群生存率分析研究进展*

乳腺癌是女性最常见的恶性肿瘤之一,在我国乃至全球乳腺癌居女性恶性肿瘤发病率首位,严重影响女性的健康。人群为基础的癌症生存分析能够反映某一国家或地区癌症预防、诊断、治疗的整体水平,为有针对性地制定卫生政策提供基础数据支持。在世界范围内由于人种、社会经济文化、基础医疗保健、诊疗水平等多方面存在差异,不同国家或地区乳腺癌生存率差距较大。乳腺癌生存率与肿瘤分期、受体状态、治疗方式等密切相关,通过深入比较相关因素与乳腺癌生存率的关系,为预测乳腺癌预后、提高临床诊疗水平提供帮助。本文着重概述国内外乳腺癌生存现状,并针对目前我国癌症监测工作提供相关参考建议。      

Meta-analysis of clodronate and breast cancer survival

Clinical trials have reported conflicting results on whether oral clodronate therapy improves survival in breast cancer patients. This study was undertaken to evaluate further the effect of oral clodronate therapy on overall survival, bone metastasis-free survival and nonskeletal metastasis-free survival among breast cancer patients. An extensive literature search was undertaken for the period 1966 to July 2006 to identify clinical trials examining survival in breast cancer patients who received 2 or 3 years of oral clodronate therapy at 1600 mg day(-1) compared with those without therapy. Meta-analyses were carried out separately for patients diagnosed with advanced breast cancer and early breast cancer. Our meta-analysis found no evidence of any statistically significant difference in overall survival, bone metastasis-free survival or nonskeletal metastasis-free survival in advanced breast cancer patients receiving clodronate therapy or early breast cancer patients receiving adjuvant clodronate treatment compared with those who did not receive any active treatment.     

Association studies on 11 published colorectal cancer risk loci

Background:

Recently, several genome-wide association studies (GWAS) have independently found numerous loci at which common single-nucleotide polymorphisms (SNPs) modestly influence the risk of developing colorectal cancer. The aim of this study was to test 11 loci, reported to be associated with an increased or decreased risk of colorectal cancer: 8q23.3 (rs16892766), 8q24.21 (rs6983267), 9p24 (rs719725), 10p14 (rs10795668), 11q23.1 (rs3802842), 14q22.2 (rs4444235), 15q13.3 (rs4779584), 16q22.1 (rs9929218), 18q21.1 (rs4939827), 19q13.1 (rs10411210) and 20p12.3 (rs961253), in a Swedish-based cohort.

Methods:

The cohort was composed of 1786 cases and 1749 controls that were genotyped and analysed statistically. Genotype–phenotype analysis, for all 11 SNPs and sex, age of onset, family history of CRC and tumour location, was performed.

Results:

Of eleven loci, 5 showed statistically significant odds ratios similar to previously published findings: 8q23.3, 8q24.21, 10p14, 15q13.3 and 18q21.1. The remaining loci 11q23.1, 16q22.1, 19q13.1 and 20p12.3 showed weak trends but somehow similar to what was previously published. The loci 9p24 and 14q22.2 could not be confirmed. We show a higher number of risk alleles in affected individuals compared to controls. Four statistically significant genotype–phenotype associations were found; the G allele of rs6983267 was associated to older age, the G allele of rs1075668 was associated with a younger age and sporadic cases, and the T allele of rs10411210 was associated with younger age.

Conclusions:

Our study, using a Swedish population, supports most genetic variants published in GWAS. More studies are needed to validate the genotype–phenotype correlations.     

IGF-I and breast cancer: a meta-analysis

IGFs are peptide hormones involved in the regulation of cell proliferation, differentiation and apoptosis. IGFs are regulated by endocrine and paracrine mechanisms; however, their action in tissue is determined by circulating levels and local production of IGFs and IGF-binding proteins (IGFBPs). Some, but not all, epidemiologic studies have associated high circulating levels of IGF-I with increased risk of breast cancer among premenopausal women. To evaluate the overall association of IGF-I and IGFBP-3 levels with breast cancer risk, we performed a meta-analysis on 16 publications of epidemiologic and clinical studies. Analyses were performed for all women as well as for pre- and postmenopausal women separately. Hedges' standardized mean differences (HSMDs) and odds ratios (ORs) were used to estimate the effect of IGF-I and IGFBP-3. Data analysis showed that circulating levels of IGF-I were not significantly higher in breast cancer patients than in controls for all women and for the postmenopausal group (HSMD = 0.024 and 0.035, respectively; p > 0.40) but were significantly higher (HSMD = 0.170, p < 0.001) for the premenopausal group. ORs for breast cancer risk were 1.05 (95% CI 0.94-1.17), 0.93 (95% CI 0.80-1.10) and 1.39 (95% CI 1.16-1.66). The HSMD of IGFBP-3 was 0.18 (p < 0.001), and the OR for breast cancer was 1.42 (95% CI 1.15-1.74) for premenopausal women. Our results support the suggested association between high IGF-I and IGFBP-3 levels and increased risk of breast cancer in premenopausal women.     

Selection bias influences reported contralateral breast cancer incidence and survival in high risk non-BRCA1/2 patients

Summary Purpose The results of studies comparing survival in familial and sporadic breast cancer (BC) are inconsistent. A higher incidence of contralateral breast cancer (CBC) has been reported in familial BC. Ascertainment bias may influence both the reported familial CBC and survival. Design We assessed CBC incidence, distant disease free (DDFS) and overall survival (OS) in 327 BC patients who had ≥3 breast and/or ovarian cancers in the family but no BRCA1/2 gene mutation (non-BRCA1/2). They were matched to 327 sporadic controls for year and age at detection. To correct for ascertainment bias, we analyzed also separately the results (1) Of the 250 non-BRCA1/2 patients with DNA testing performed before diagnosis or within 2 years (‘unselected’) and (2) Of the 77 with testing ≥2 years after diagnosis (late-tested). Results Median follow-up of non-BRCA1/2 patients was 6.1 yrs. Ten years CBC incidence was 11% in non-BRCA1/2 versus 6% in sporadic patients (p=0.002). At multivariate analysis CBC incidence was increased in late-tested non-BRCA1/2 (HR 4.6; p=0.001) not in ‘unselected’ (HR 1.8; p=0.1). Increased CBC occurred in non-BRCA1/2 patients mainly before genetic testing, suggesting ascertainment bias. Tumors were ≤T1 in 62% of non-BRCA1/2 versus 50% of sporadic patients (p=0.003), node-negative in 55% versus 52% respectively (p=0.5). After correction for stage and therapy, OS did not differ between ‘unselected’ non-BRCA1/2 and sporadic patients (HR 0.8; p=0.3), but was improved in late-tested non-BRCA1/2. Conclusion Overall survival and contralateral breast cancer incidence were similar in ‘unselected’ non-BRCA1/2− and sporadic patients. Reports of higher CBC incidence and better survival in non-BRCA1/2 patients may substantially be caused by DNA testing selection-bias.     

Specialisation and breast cancer survival in the screening era

It is recommended that specialist surgeons treat all breast cancer, although the limited evidence to support this is based on treatment patterns prior to the introduction of screening. Whether a specialist survival advantage exists in the post-screening era is uncertain, as referral and treatment patterns may have changed, in addition to the effect of screening on the natural history of breast cancer. Our aim was to determine the impact of screening on the caseload and case-mix of specialist surgeons, to determine if the survival advantage associated with specialist care is maintained with longer follow-up and persists after the introduction of screening. Using the West of Scotland Cancer Registry, all 7197 women treated for breast cancer in a 15-year time period (1980-1994) in a geographically defined cohort were followed up for an average of 9 years, and pathological stage and socioeconomic status were linked with mortality data. We show that the caseload of specialists has increased substantially (from 11 to 59% of the total workload) and that smaller cancers have been selectively referred. However, even after allowing for pathological stage, socioeconomic status and method of detection, specialist treatment was associated with a significantly lower risk of dying (prescreening: relative risk of dying=0.83, 95% CI=0.75-0.92; post-screening: relative risk of dying=0.89, 95% CI=0.78-1.00). We conclude that this survival benefit is most consistent with effective surgical management rather than selective referral, the influx of screen-detected cancers or adjuvant therapies.