Summary Background Four previously published randomised clinical trials have shown that tamoxifen can reduce the risk of breast cancer in healthy women at increased risk of breast cancer in the first ...10 years of follow-up. We report the long-term follow-up of the IBIS-I trial, in which the participants and investigators remain largely masked to treatment allocation. Methods In the IBIS-I randomised controlled trial, premenopausal and postmenopausal women 35–70 years of age deemed to be at an increased risk of developing breast cancer were randomly assigned (1:1) to receive oral tamoxifen 20 mg daily or matching placebo for 5 years. Patients were randomly assigned to the two treatment groups by telephone or fax according to a block randomisation schedule (permuted block sizes of six or ten). Patients and investigators were masked to treatment assignment by use of central randomisation and coded drug supply. The primary endpoint was the occurrence of breast cancer (invasive breast cancer and ductal carcinoma in situ), analysed by intention to treat. Cox proportional hazard models were used to assess breast cancer occurrence and mortality. The trial is closed to recruitment and active treatment is completed, but long-term follow-up is ongoing. This trial is registered with controlledtrials.com , number ISRCTN91879928. Findings Between April 14, 1992, and March 30, 2001, 7154 eligible women recruited from genetics clinics and breast care clinics in eight countries were enrolled into the IBIS-I trial and were randomly allocated to the two treatment groups: 3579 to tamoxifen and 3575 to placebo. After a median follow up of 16·0 years (IQR 14·1–17·6), 601 breast cancers have been reported (251 7·0% in 3579 patients in the tamoxifen group vs 350 9·8% in 3575 women in the placebo group; hazard ratio HR 0·71 95% CI 0·60–0·83, p<0·0001). The risk of developing breast cancer was similar between years 0–10 (226 6·3% in 3575 women in the placebo group vs 163 4·6% in 3579 women in the tamoxifen group; hazard ratio HR 0·72 95% CI 0·59–0·88, p=0·001) and after 10 years (124 3·8% in 3295 women vs 88 2·6% in 3343, respectively; HR 0·69 0·53–0·91, p=0·009). The greatest reduction in risk was seen in invasive oestrogen receptor-positive breast cancer (HR 0·66 95% CI 0·54–0·81, p<0·0001) and ductal carcinoma in situ (0·65 0·43–1·00, p=0·05), but no effect was noted for invasive oestrogen receptor-negative breast cancer (HR 1·05 95% CI 0·71–1·57, p=0·8). Interpretation These results show that tamoxifen offers a very long period of protection after treatment cessation, and thus substantially improves the benefit-to-harm ratio of the drug for breast cancer prevention. Funding Cancer Research UK (UK) and the National Health and Medical Research Council (Australia).
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Summary Background The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial was designed to compare the efficacy and safety of anastrozole (1 mg) with tamoxifen (20 mg), both given orally every ...day for 5 years, as adjuvant treatment for postmenopausal women with early-stage breast cancer. In this analysis, we assess the long-term outcomes after a median follow-up of 120 months. Methods We used a proportional hazards model to assess the primary endpoint of disease-free survival, and the secondary endpoints of time to recurrence, time to distant recurrence, incidence of new contralateral breast cancer, overall survival, and death with or without recurrence in all randomised patients (anastrozole n=3125, tamoxifen n=3116) and hormone-receptor-positive patients (anastrozole n=2618, tamoxifen n=2598). After treatment completion, we continued to collect data on fractures and serious adverse events in a masked fashion (safety population: anastrozole n=3092, tamoxifen n=3094). This study is registered as an International Standard Randomised Controlled Trial , number ISRCTN18233230. Findings Patients were followed up for a median of 120 months (range 0–145); there were 24 522 woman-years of follow-up in the anastrozole group and 23 950 woman-years in the tamoxifen group. In the full study population, there were significant improvements in the anastrozole group compared with the tamoxifen group for disease-free survival (hazard ratio HR 0·91, 95% CI 0·83–0·99; p=0·04), time to recurrence (0·84, 0·75–0·93; p=0·001), and time to distant recurrence (0·87, 0·77–0·99; p=0·03). For hormone-receptor-positive patients, the results were also significantly in favour of the anastrozole group for disease-free survival (HR 0·86, 95% CI 0·78–0·95; p=0·003), time to recurrence (0·79, 0·70–0·89; p=0·0002), and time to distant recurrence (0·85, 0·73–0·98; p=0·02). In hormone-receptor-positive patients, absolute differences in time to recurrence between anastrozole and tamoxifen increased over time (2·7% at 5 years and 4·3% at 10 years) and recurrence rates remained significantly lower on anastrozole than tamoxifen after treatment completion (HR 0·81, 95% CI 0·67–0·98; p=0·03), although the carryover benefit was smaller after 8 years. There was weak evidence of fewer deaths after recurrence with anastrozole compared with tamoxifen treatment in the hormone-receptor-positive subgroup (HR 0·87, 95% CI 0·74–1·02; p=0·09), but there was little difference in overall mortality (0·95, 95% CI 0·84–1·06; p=0·4). Fractures were more frequent during active treatment in patients receiving anastrozole than those receiving tamoxifen (451 vs 351; OR 1·33, 95% CI 1·15–1·55; p<0·0001), but were similar in the post-treatment follow-up period (110 vs 112; OR 0·98, 95% CI 0·74–1·30; p=0·9). Treatment-related serious adverse events were less common in the anastrozole group than the tamoxifen group (223 anastrozole vs 369 tamoxifen; OR 0·57, 95% CI 0·48–0·69; p<0·0001), but were similar after treatment completion (66 vs 78; OR 0·84, 95% CI 0·60–1·19; p=0·3). No differences in non-breast cancer causes of death were apparent and the incidence of other cancers was similar between groups (425 vs 431) and continue to be higher with anastrozole for colorectal (66 vs 44) and lung cancer (51 vs 34), and lower for endometrial cancer (six vs 24), melanoma (eight vs 19), and ovarian cancer (17 vs 28). No new safety concerns were reported. Interpretation These data confirm the long-term superior efficacy and safety of anastrozole over tamoxifen as initial adjuvant therapy for postmenopausal women with hormone-sensitive early breast cancer. Funding AstraZeneca.
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Summary Background Aromatase inhibitors effectively prevent breast cancer recurrence and development of new contralateral tumours in postmenopausal women. We assessed the efficacy and safety of the ...aromatase inhibitor anastrozole for prevention of breast cancer in postmenopausal women who are at high risk of the disease. Methods Between Feb 2, 2003, and Jan 31, 2012, we recruited postmenopausal women aged 40–70 years from 18 countries into an international, double-blind, randomised placebo-controlled trial. To be eligible, women had to be at increased risk of breast cancer (judged on the basis of specific criteria). Eligible women were randomly assigned (1:1) by central computer allocation to receive 1 mg oral anastrozole or matching placebo every day for 5 years. Randomisation was stratified by country and was done with blocks (size six, eight, or ten). All trial personnel, participants, and clinicians were masked to treatment allocation; only the trial statistician was unmasked. The primary endpoint was histologically confirmed breast cancer (invasive cancers or non-invasive ductal carcinoma in situ). Analyses were done by intention to treat. This trial is registered, number ISRCTN31488319. Findings 1920 women were randomly assigned to receive anastrozole and 1944 to placebo. After a median follow-up of 5·0 years (IQR 3·0–7·1), 40 women in the anastrozole group (2%) and 85 in the placebo group (4%) had developed breast cancer (hazard ratio 0·47, 95% CI 0·32–0·68, p<0·0001). The predicted cumulative incidence of all breast cancers after 7 years was 5·6% in the placebo group and 2·8% in the anastrozole group. 18 deaths were reported in the anastrozole group and 17 in the placebo group, and no specific causes were more common in one group than the other (p=0·836). Interpretation Anastrozole effectively reduces incidence of breast cancer in high-risk postmenopausal women. This finding, along with the fact that most of the side-effects associated with oestrogen deprivation were not attributable to treatment, provides support for the use of anastrozole in postmenopausal women at high risk of breast cancer. Funding Cancer Research UK, the National Health and Medical Research Council Australia, Sanofi-Aventis, and AstraZeneca.
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Summary Background Third-generation aromatase inhibitors are more effective than tamoxifen for preventing recurrence in postmenopausal women with hormone-receptor-positive invasive breast cancer. ...However, it is not known whether anastrozole is more effective than tamoxifen for women with hormone-receptor-positive ductal carcinoma in situ (DCIS). Here, we compare the efficacy of anastrozole with that of tamoxifen in postmenopausal women with hormone-receptor-positive DCIS. Methods In a double-blind, multicentre, randomised placebo-controlled trial, we recruited women who had been diagnosed with locally excised, hormone-receptor-positive DCIS. Eligible women were randomly assigned in a 1:1 ratio by central computer allocation to receive 1 mg oral anastrozole or 20 mg oral tamoxifen every day for 5 years. Randomisation was stratified by major centre or hub and was done in blocks (six, eight, or ten). All trial personnel, participants, and clinicians were masked to treatment allocation and only the trial statistician had access to treatment allocation. The primary endpoint was all recurrence, including recurrent DCIS and new contralateral tumours. All analyses were done on a modified intention-to-treat basis (in all women who were randomised and did not revoke consent for their data to be included) and proportional hazard models were used to compute hazard ratios and corresponding confidence intervals. This trial is registered at the ISRCTN registry, number ISRCTN37546358. Results Between March 3, 2003, and Feb 8, 2012, we enrolled 2980 postmenopausal women from 236 centres in 14 countries and randomly assigned them to receive anastrozole (1449 analysed) or tamoxifen (1489 analysed). Median follow-up was 7·2 years (IQR 5·6–8·9), and 144 breast cancer recurrences were recorded. We noted no statistically significant difference in overall recurrence (67 recurrences for anastrozole vs 77 for tamoxifen; HR 0·89 95% CI 0·64–1·23). The non-inferiority of anastrozole was established (upper 95% CI <1·25), but its superiority to tamoxifen was not (p=0·49). A total of 69 deaths were recorded (33 for anastrozole vs 36 for tamoxifen; HR 0·93 95% CI 0·58–1·50, p=0·78), and no specific cause was more common in one group than the other. The number of women reporting any adverse event was similar between anastrozole (1323 women, 91%) and tamoxifen (1379 women, 93%); the side-effect profiles of the two drugs differed, with more fractures, musculoskeletal events, hypercholesterolaemia, and strokes with anastrozole and more muscle spasm, gynaecological cancers and symptoms, vasomotor symptoms, and deep vein thromboses with tamoxifen. Conclusions No clear efficacy differences were seen between the two treatments. Anastrozole offers another treatment option for postmenopausal women with hormone-receptor-positive DCIS, which may be be more appropriate for some women with contraindications for tamoxifen. Longer follow-up will be necessary to fully evaluate treatment differences. Funding Cancer Research UK, National Health and Medical Research Council Australia, Breast Cancer Research Fund, AstraZeneca, Sanofi Aventis.
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Summary Evidence clearly shows a chemopreventive effect for aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) on colorectal cancer and probably other cancer types; however, data on the ...risk–benefit profile for cancer prevention are insufficient and no definitive recommendations can be made. Aspirin has emerged as the most likely NSAID for use in chemoprevention because of its known cardiovascular benefit and available safety and efficacy data. Other traditional NSAIDs, particularly sulindac, and selective COX-2 inhibitors are now given to patients at high risk of colorectal cancer, although these drugs do not provide cardioprotection. More studies of aspirin and cancer prevention are needed to define the lowest effective dose, the age at which to initiate therapy, the optimum treatment duration, and the subpopulations for which the benefits of chemoprevention outweigh the risks of adverse side-effects. Although it might be possible to answer some of these questions with longer follow-up of existing clinical trials, randomised controlled trials with new study designs will be needed. Future projects should investigate the effects of aspirin treatment on multiple organ systems. Cancers of interest are colorectal, breast, prostate, lung, stomach, and oesophageal. The main side-effect of aspirin is peptic ulcers; therefore coadministration of aspirin with a proton-pump inhibitor is an attractive option and is under investigation in the AspECT trial.
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Summary Background Tamoxifen and raloxifene reduce the risk of breast cancer in women at elevated risk of disease, but the duration of the effect is unknown. We assessed the effectiveness of ...selective oestrogen receptor modulators (SERMs) on breast cancer incidence. Methods We did a meta-analysis with individual participant data from nine prevention trials comparing four selective oestrogen receptor modulators (SERMs; tamoxifen, raloxifene, arzoxifene, and lasofoxifene) with placebo, or in one study with tamoxifen. Our primary endpoint was incidence of all breast cancer (including ductal carcinoma in situ) during a 10 year follow-up period. Analysis was by intention to treat. Results We analysed data for 83 399 women with 306 617 women-years of follow-up. Median follow-up was 65 months (IQR 54–93). Overall, we noted a 38% reduction (hazard ratio HR 0·62, 95% CI 0·56–0·69) in breast cancer incidence, and 42 women would need to be treated to prevent one breast cancer event in the first 10 years of follow-up. The reduction was larger in the first 5 years of follow-up than in years 5–10 (42%, HR 0·58, 0·51–0·66; p<0·0001 vs 25%, 0·75, 0·61–0·93; p=0·007), but we noted no heterogeneity between time periods. Thromboembolic events were significantly increased with all SERMs (odds ratio 1·73, 95% CI 1·47–2·05; p<0·0001). We recorded a significant reduction of 34% in vertebral fractures (0·66, 0·59–0·73), but only a small effect for non-vertebral fractures (0·93, 0·87–0·99). Interpretation For all SERMs, incidence of invasive oestrogen (ER)-positive breast cancer was reduced both during treatment and for at least 5 years after completion. Similar to other preventive interventions, careful consideration of risks and benefits is needed to identify women who are most likely to benefit from these drugs. Funding Cancer Research UK.
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Summary Background Colorectal cancer is the third most common cancer worldwide and has a high mortality rate. We tested the hypothesis that only one flexible sigmoidoscopy screening between 55 and 64 ...years of age can substantially reduce colorectal cancer incidence and mortality. Methods This randomised controlled trial was undertaken in 14 UK centres. 170 432 eligible men and women, who had indicated on a previous questionnaire that they would accept an invitation for screening, were randomly allocated to the intervention group (offered flexible sigmoidoscopy screening) or the control group (not contacted). Randomisation by sequential number generation was done centrally in blocks of 12, with stratification by trial centre, general practice, and household type. The primary outcomes were the incidence of colorectal cancer, including prevalent cases detected at screening, and mortality from colorectal cancer. Analyses were intention to treat and per protocol. The trial is registered, number ISRCTN28352761. Findings 113 195 people were assigned to the control group and 57 237 to the intervention group, of whom 112 939 and 57 099, respectively, were included in the final analyses. 40 674 (71%) people underwent flexible sigmoidoscopy. During screening and median follow-up of 11·2 years (IQR 10·7–11·9), 2524 participants were diagnosed with colorectal cancer (1818 in control group vs 706 in intervention group) and 20 543 died (13 768 vs 6775; 727 certified from colorectal cancer 538 vs 189). In intention-to-treat analyses, colorectal cancer incidence in the intervention group was reduced by 23% (hazard ratio 0·77, 95% CI 0·70–0·84) and mortality by 31% (0·69, 0·59–0·82). In per-protocol analyses, adjusting for self-selection bias in the intervention group, incidence of colorectal cancer in people attending screening was reduced by 33% (0·67, 0·60–0·76) and mortality by 43% (0·57, 0·45–0·72). Incidence of distal colorectal cancer (rectum and sigmoid colon) was reduced by 50% (0·50, 0·42–0·59; secondary outcome). The numbers needed to be screened to prevent one colorectal cancer diagnosis or death, by the end of the study period, were 191 (95% CI 145–277) and 489 (343–852), respectively. Interpretation Flexible sigmoidoscopy is a safe and practical test and, when offered only once between ages 55 and 64 years, confers a substantial and longlasting benefit. Funding Medical Research Council, National Health Service R&D, Cancer Research UK, KeyMed.
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Summary Background Biomarkers to improve the risk–benefit of extended adjuvant endocrine therapy for late recurrence in patients with oestrogen-receptor-positive breast cancer would be clinically ...valuable. We compared the prognostic ability of the breast-cancer index (BCI) assay, 21-gene recurrence score (Oncotype DX), and an immunohistochemical prognostic model (IHC4) for both early and late recurrence in patients with oestrogen-receptor-positive, node-negative (N0) disease who took part in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) clinical trial. Methods In this prospective comparison study, we obtained archival tumour blocks from the TransATAC tissue bank from all postmenopausal patients with oestrogen-receptor-positive breast cancer from whom the 21-gene recurrence score and IHC4 values had already been derived. We did BCI analysis in matched samples with sufficient residual RNA using two BCI models—cubic (BCI-C) and linear (BCI-L)—using previously validated cutoffs. We assessed prognostic ability of BCI for distant recurrence over 10 years (the primary endpoint) and compared it with that of the 21-gene recurrence score and IHC4. We also tested the ability of the assays to predict early (0–5 years) and late (5–10 years) distant recurrence. To assess the ability of the biomarkers to predict recurrence beyond standard clinicopathological variables, we calculated the change in the likelihood-ratio χ2 (LR-Δχ2 ) from Cox proportional hazards models. Findings Suitable tissue was available from 665 patients with oestrogen-receptor-positive, N0 breast cancer for BCI analysis. The primary analysis showed significant differences in risk of distant recurrence over 10 years in the categorical BCI-C risk groups (p<0·0001) with 6·8% (95% CI 4·4–10·0) of patients in the low-risk group, 17·3% (12·0–24·7) in the intermediate group, and 22·2% (15·3–31·5) in the high-risk group having distant recurrence. The secondary analysis showed that BCI-L was a much stronger predictor for overall (0–10 year) distant recurrence compared with BCI-C (interquartile HR 2·30 95% CI 1·62–3·27; LR-Δχ2 =22·69; p<0·0001). When compared with BCI-L, the 21-gene recurrence score was less predictive (HR 1·48 95% CI 1·22–1·78; LR-Δχ2 =13·68; p=0·0002) and IHC4 was similar (HR 1·69 95% CI 1·51–2·56; LR-Δχ2 =22·83; p<0·0001). All further analyses were done with the BCI-L model. In a multivariable analysis, all assays had significant prognostic ability for early distant recurrence (BCI-L HR 2·77 95% CI 1·63–4·70, LR-Δχ2 =15·42, p<0·0001; 21-gene recurrence score HR 1·80 1·42–2·29, LR-Δχ2 =18·48, p<0·0001; IHC4 HR 2·90 2·01–4·18, LR-Δχ2 =29·14, p<0·0001); however, only BCI-L was significant for late distant recurrence (BCI-L HR 1·95 95% CI 1·22–3·14, LR-Δχ2 =7·97, p=0·0048; 21-gene recurrence score HR 1·13 0·82–1·56, LR-Δχ2 =0·48, p=0·47; IHC4 HR 1·30 0·88–1·94, LR-Δχ2 =1·59, p=0·20). Interpretation BCI-L was the only significant prognostic test for risk of both early and late distant recurrence and identified two risk populations for each timeframe. It could help to identify patients at high risk for late distant recurrence who might benefit from extended endocrine or other therapy. Funding Avon Foundation, National Institutes of Health, Breast Cancer Foundation, US Department of Defense Breast Cancer Research Program, Susan G Komen for the Cure, Breakthrough Breast Cancer through the Mary-Jean Mitchell Green Foundation, AstraZeneca, Cancer Research UK, and the National Institute for Health Research Biomedical Research Centre at the Royal Marsden (London, UK).
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Summary Background Initial results of the UK/ANZ DCIS (UK, Australia, and New Zealand ductal carcinoma in situ) trial suggested that radiotherapy reduced new breast events of ipsilateral invasive and ...ductal carcinoma in situ (DCIS) compared with no radiotherapy, but no significant effects were noted with tamoxifen. Here, we report long-term results of this trial. Methods Women with completely locally excised DCIS were recruited into a randomised 2×2 factorial trial of radiotherapy, tamoxifen, or both. Randomisation was independently done for each of the two treatments (radiotherapy and tamoxifen), stratified by screening assessment centre, and blocked in groups of four. The recommended dose for radiation was 50 Gy in 25 fractions over 5 weeks (2 Gy per day on weekdays), and tamoxifen was prescribed at a dose of 20 mg daily for 5 years. Elective decision to withhold or provide one of the treatments was permitted. The endpoints of primary interest were invasive ipsilateral new breast events for the radiotherapy comparison and any new breast event, including contralateral disease and DCIS, for tamoxifen. Analysis of each of the two treatment comparisons was restricted to patients who were randomly assigned to that treatment. Analyses were by intention to treat. All trial drugs have been completed and this study is in long-term follow-up. This study is registered, number ISRCTN99513870. Findings Between May, 1990, and August, 1998, 1701 women were randomly assigned to radiotherapy and tamoxifen, radiotherapy alone, tamoxifen alone, or to no adjuvant treatment. Seven patients had protocol violations and thus 1694 patients were available for analysis. After a median follow-up of 12·7 years (IQR 10·9–14·7), 376 (163 invasive 122 ipsilateral vs 39 contralateral, 197 DCIS 174 ipsilateral vs 17 contralateral, and 16 of unknown invasiveness or laterality) breast cancers were diagnosed. Radiotherapy reduced the incidence of all new breast events (hazard ratio HR 0·41, 95% CI 0·30–0·56; p<0·0001), reducing the incidence of ipsilateral invasive disease (0·32, 0·19–0·56; p<0·0001) as well as ipsilateral DCIS (0·38, 0·22–0·63; p<0·0001), but having no effect on contralateral breast cancer (0·84, 0·45–1·58; p=0·6). Tamoxifen reduced the incidence of all new breast events (HR 0·71, 95% CI 0·58–0·88; p=0·002), reducing recurrent ipsilateral DCIS (0·70, 0·51–0·86; p=0·03) and contralateral tumours (0·44, 0·25–0·77; p=0·005), but having no effect on ipsilateral invasive disease (0·95, 0·66–1·38; p=0·8). No data on adverse events except cause of death were collected for this trial. Interpretation This updated analysis confirms the long-term beneficial effect of radiotherapy and reports a benefit for tamoxifen in reducing local and contralateral new breast events for women with DCIS treated by complete local excision. Funding Cancer Research UK and the Australian National Health and Medical Research Council.
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Summary Background When the mechanism of action behind treatment toxicity reflects the intended effect on the treatment target, the toxicity might be a useful marker for efficacy. During endocrine ...treatment of breast cancer, the occurrence of symptoms related to oestrogen depletion or oestrogen blockade might thus be a predictor of treatment effectiveness. In this retrospective analysis, the relation between the reported incidence of vasomotor or joint symptoms and breast cancer recurrence in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial is assessed. Methods Women with hormone-receptor-positive tumours who reported vasomotor or joint symptoms at the first follow-up visit (3 months) in the ATAC trial, (which assessed tamoxifen or anastrozole for adjuvant treatment of postmenopausal breast cancer), were compared with women without these symptoms to see if there was a relation between these symptoms and subsequent recurrence. The ATAC trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN18233230. Findings 1486 of 3964 (37·5%) eligible women reported newly emergent vasomotor symptoms at the 3-month follow-up visit and had lower subsequent recurrence than those who did not report these symptoms (223 during 10 752 women-years of follow-up vs 366 during 11 573 woman-years of follow-up, respectively; hazard ratio HR 0·84 95% CI 0·71–1·00, p=0·04; adjusted for age, body-mass index, previous hormone-replacement therapy, nodal status, tumour size, and tumour grade). A greater decrease in breast-cancer recurrence was seen for the 1245 of 3964 (31·4%) eligible women who reported new joint symptoms at the 3-month follow-up visit compared with those not reporting these symptoms (158 during 9242 women-years of follow-up vs 366 during 11 573 women-years of follow-up; adjusted HR 0·60 0·50–0·72, p<0·0001). Interpretation The appearance of new vasomotor symptoms or joint symptoms within the first 3 months of treatment is a useful biomarker, suggesting a greater response to endocrine treatment compared with women without these symptoms. Awareness of the relation between early treatment-emergent symptoms and beneficial response to therapy might be useful when reassuring patients who present with them, and might help to improve long-term treatment adherence when symptoms cannot be alleviated effectively. Funding Cancer Research UK and AstraZeneca.
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