Articles. Funding US National Cancer Institute and AstraZeneca Pharmaceuticals LP.

Transcription

1 versus tamoxifen in postmenopausal women with ductal carcinoma in situ undergoing lumpectomy plus radiotherapy (NSABP B-35): a randomised, double-blind, phase 3 clinical trial Richard G Margolese, Reena S Cecchini, Thomas B Julian, Patricia A Ganz, Joseph P Costantino, Laura A Vallow, Kathy S Albain, Patrick W Whitworth, Mary E Cianfrocca, Adam M Brufsky, Howard M Gross, Gamini S Soori, Judith O Hopkins, Louis Fehrenbacher, Keren Sturtz, Timothy F Wozniak, Thomas E Seay, Eleftherios P Mamounas, Norman Wolmark Summary Background Ductal carcinoma in situ is currently managed with excision, radiotherapy, and adjuvant hormone therapy, usually tamoxifen. We postulated that an aromatase inhibitor would be safer and more effective. We therefore undertook this trial to compare anastrozole versus tamoxifen in postmenopausal women with ductal carcinoma in situ undergoing lumpectomy plus radiotherapy. Methods The double-blind, randomised, phase 3 National Surgical Adjuvant Breast and Bowel Project (NSABP) B-35 trial was done in 333 participating NSABP centres in the USA and Canada. Postmenopausal women with hormonepositive ductal carcinoma in situ treated by lumpectomy with clear resection margins and whole-breast irradiation were enrolled and randomly assigned (1:1) to receive either oral tamoxifen 20 mg per day (with matching placebo in place of anastrozole) or oral anastrozole 1 mg per day (with matching placebo in place of tamoxifen) for 5 years. Randomisation was stratified by age (<60 vs 60 years) and patients and investigators were masked to treatment allocation. The primary outcome was breast cancer-free interval, defined as time from randomisation to any breast cancer event (local, regional, or distant recurrence, or contralateral breast cancer, invasive disease, or ductal carcinoma in situ), analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT , and is complete. Findings Between Jan 1, 2003, and June 15, 2006, 3104 eligible patients were enrolled and randomly assigned to the two treatment groups (1552 to tamoxifen and 1552 to anastrozole). As of Feb 28, 2015, follow-up information was available for 3083 patients for overall survival and 3077 for all other disease-free endpoints, with median follow-up of 9 0 years (IQR ). In total, 212 breast cancer-free interval events occurred: 122 in the tamoxifen group and 90 in the anastrozole group (HR 0 73 [95% CI ], p=0 0234). A significant time-by-treatment interaction (p=0 0410) became evident later in the study. There was also a significant interaction between treatment and age group (p=0 0379), showing that anastrozole is superior only in women younger than 60 years of age. Adverse events did not differ between the groups, except for thrombosis or embolism a known side-effect of tamoxifen for which there were 17 grade 4 or worse events in the tamoxifen group versus four in the anastrozole group. Interpretation Compared with tamoxifen, anastrozole treatment provided a significant improvement in breast cancerfree interval, mainly in women younger than 60 years of age. This finding means that women will benefit from having a choice of effective agents for ductal carcinoma in situ. Funding US National Cancer Institute and AstraZeneca Pharmaceuticals LP. Introduction With continuous improvements in screening mammography and diagnostic breast imaging during the past three to four decades, ductal carcinoma in situ is now identified more frequently and its management has become an increasingly challenging problem. Originally called early or minimal breast cancer, ductal carcinoma in situ is now classified as stage 0 breast cancer and is regarded by some experts as a precancerous entity. As a result, debate is ongoing as to whether ductal carcinoma in situ should be treated as a malignancy or as a precursor of cancer. Randomised clinical trials of invasive breast cancer have established that breast-conserving surgery and wholebreast irradiation provide the same long-term survival rates as total mastectomy. 1,2 This shift in surgical management has also been adopted for ductal carcinoma in situ, following publication of National Surgical Adjuvant Breast and Bowel Project (NSABP) B-17, 1 a randomised prospective clinical trial of lumpectomy versus lumpectomy and radiotherapy for ductal carcinoma in situ. However, breast-conserving therapy leaves open the chance for a local recurrence, which can manifest itself as another ductal carcinoma in situ or as invasive recurrence. Lancet 2016; 387: Published Online December 10, S (15)01168-X See Comment page 819 See page 857 NRG Oncology/National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh, PA, USA (Prof R G Margolese MD, R S Cecchini PhD, Prof T B Julian MD, Prof P A Ganz MD, J P Costantino DrPH, L A Vallow MD, Prof K S Albain MD, P W Whitworth MD, M E Cianfrocca DO, Prof A M Brufsky MD, H M Gross MD, Prof G S Soori MD, J O Hopkins MD, L Fehrenbacher MD, K Sturtz MD, T F Wozniak MD, T E Seay MD, E P Mamounas MD, Prof N Wolmark MD); Jewish General Hospital, McGill University, Montreal, QC, Canada (Prof R G Margolese); Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA (R S Cecchini, J P Costantino); Department of Surgical Oncology, Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh, PA, USA (Prof T B Julian, Prof N Wolmark); University of California, Los Angeles, CA, USA (Prof P A Ganz); Department of Radiation Oncology, Mayo Clinic, Jacksonville, FL, USA (L A Vallow); SWOG, San Antonio, TX, USA (Prof K S Albain, M E Cianfrocca); Department of Medicine, Loyola University Chicago Stritch School of Medicine, Chicago, IL, USA (Prof K S Albain); Vol 387 February 27,

2 ALLIANCE/ACOSOG, Chicago, IL, USA (P W Whitworth); Nashville Breast Center, Nashville, TN, USA (P W Whitworth); ECOG/ACRIN, Philadelphia, PA, USA (M E Cianfrocca); Department of Hematology/Oncology, Banner MD Anderson Cancer Center, Gilbert, AZ, USA (M E Cianfrocca); Department of Hematology/Oncology, Magee Womens Hospital/University of Pittsburgh Department of Hematology/Oncology, Pittsburgh, PA, USA (Prof A M Brufsky); Dayton Physicians LLC, Dayton, OH, USA (H M Gross); Missouri Valley Cancer Consortium, Omaha, NE, USA (Prof G S Soori); SCOR NCORP, Winston Salem, NC, USA (J O Hopkins); Department of Hematology/Oncology, Forsyth Regional Cancer Center, Winston Salem, NC, USA (J O Hopkins); Department of Medical Oncology, Kaiser Permanente Northern California Vallejo, CA, USA (L Fehrenbacher); Department of Medical Oncology Colorado Cancer Research Program, Denver, CO, USA (K Sturtz); CCOP, Christiana Care Health Systems, Newark, DE, USA (T F Wozniak); Atlanta Regional Community Clinical Oncology Program, Atlanta, GA, USA (T E Seay); and UF Health Cancer Center at Orlando Health, Orlando, FL, USA (E P Mamounas) Correspondence to: Prof Richard G Margolese, Jewish General Hospital, McGill University, 3755 Côte-Sainte- Catherine Road, Montreal, QC, H3T 1E2, Canada richard.margolese@mcgill.ca Research in context Evidence before this study We did a thorough review of relevant studies of adjuvant endocrine therapy for breast cancer and ductal carcinoma in situ. We searched the MEDLINE database, using the terms DCIS, adjuvant treatment, and hormone therapy for articles published after the year 2000 in English language only. B-35 was based on previous National Surgical Adjuvant Breast and Bowel Project (NSABP) studies B-06, B-17, and B-24. This sequence of studies showed that lumpectomy and radiotherapy was appropriate for the management of ductal carcinoma in situ, and that adjuvant tamoxifen improve d outcomes. In addition to the review of published clinical trials assessing tamoxifen in breast cancer and ductal carcinoma in situ, we did literature surveys annually throughout the duration of this study. These results were interpreted and assessed by the senior authors and incorporated into our annual reports. With the aim to minimise these events, adjuvant treatments were tested. The NSABP B-24 trial 3 was based on previous reports that adjuvant tamoxifen decreased the incidence of tumour recurrence in the affected breast of patients with invasive breast cancer and reduced the rate of new primary tumours in the contralateral breast. This finding suggested that tamoxifen can interfere with the development of primary invasive breast cancer or with the progression from ductal carcinoma in situ to invasive breast cancer. In the NSABP B-24 trial, 1804 women with ductal carcinoma in situ were randomly assigned to receive 5 years of adjuvant tamoxifen or placebo following breastconserving therapy and whole-breast irradiation. At 83 months follow-up, women in the tamoxifen group had fewer breast cancer events than those in the placebo group (10 3% vs 16 9%, p=0 0003). The cumulative incidence of all breast cancers in the tamoxifen group was 4 8% at 7 years: 2 6% in the ipsilateral breast, 1 8% in the contralateral breast, and 0 4% at regional and distant sites. 3 In 2011, Wapnir and colleagues 4 assessed long-term outcomes for ipsilateral breast tumour recurrences in the NSABP B-17 and B-24 studies. Of 490 events, 263 (54%) were invasive. The addition of whole-breast irradiation reduced the risk of recurrence compared with lumpectomy alone (hazard ratio [HR] 0 48 [95% CI ]). Invasive ipsilateral breast tumour recurrence was associated with increased mortality risk (HR 1 75 [95% CI ]), but recurrence of ductal carcinoma in situ was not (0 81 [ ]). In NSABP B-24, lumpectomy and radiotherapy plus tamoxifen reduced invasive ipsilateral breast tumour recurrence by 32% compared with lumpectomy and radiotherapy plus placebo. Despite these benefits, some women still relapsed or had serious side-effects, such as endometrial cancer, Added value of this study Along with IBIS-II DCIS, this study is one of the the first prospective randomised trials to show that anastrozole has additional efficacy for treating ductal carcinoma compared with tamoxifen. Comprehensive quality-of-life analyses were also done because of the high likelihood that participants in both groups of the study would do well and that assessment of adverse effects would be important. Implications of all the available evidence is more effective than tamoxifen in reducing the incidence of invasive cancer. Severe adverse reactions were less frequent with anastrozole. Both drugs have now been shown to be effective, and women with ductal carcinoma in situ who desire adjuvant therapy now have a choice of medication. This decision can be helped by the integration of the efficacy and adverse effect information. vascular complications, and troublesome menopausal symptoms, which affect compliance to treatment. We postulated that the partial agonist properties of tamoxifen and the absence of complete suppression of oestrogen receptor signalling might limit the benefits of such treatment. The advent of third-generation aromatase inhibitors provided the possibility to reduce or eliminate signalling through the oestrogen receptor pathway with treatments that do not have oestrogen agonist effects. In the treatment of oestrogen receptor-positive postmenopausal patients with metastatic disease, the aromatase inhibitor anastrozole has been shown to be superior to tamoxifen in overall response rates and time to progression. 5 Side-effects and toxicities were similar, but anastrozole was associated with fewer throm bo - embolic events than tamoxifen. Results of the ATAC 6 trial for women with early-stage invasive breast cancer also showed superiority for anastrozole over tamoxifen. This multicentre, randomised, double-blind study involved 9366 postmenopausal women randomly assigned to receive anastrozole or tamoxifen, or a combination of both drugs. The results showed a 17% reduction in relative risk of disease recurrence with anastrozole (p=0 0129), and an absolute risk reduction of 2%. In women with confirmed oestrogen receptor-positive tumours, the reduction in risk of recurrence was 22%. No additional benefit was recorded in the combination therapy group. was associated with significantly fewer reports of endometrial cancer, deepvein thrombosis, stroke, and hot flushes, but with more fractures, mainly of the wrist, when compared with tamoxifen. Additionally, anastrozole significantly reduced the risk of developing contralateral breast cancer (odds ratio 0 42 [95% CI ], p=0 007). Based on this rationale, we undertook a double-blind randomised trial in postmenopausal patients with Vol 387 February 27, 2016

3 oestrogen receptor-positive ductal carcinoma in situ. The primary aim of this trial was to compare the effectiveness of 5 years of treatment with anastrozole versus tamoxifen in preventing subsequent occurrence of breast cancer (local, regional, and distant recurrences, and contralateral breast cancer) following lumpectomy and radiotherapy. Methods Study design and participants NSABP B-35 was a randomised, double-blind, phase 3 study, which was undertaken in 333 participating NSABP centres in the USA and Canada. Postmenopausal women with ductal carcinoma in situ or mixed ductal carcinoma in situ and lobular carcinoma in situ who were oestrogen receptor positive or progesterone receptor positive, with no invasive component, were eligible for inclusion. Participants had to have undergone a lumpectomy with clear margins and negative nodes (if biopsied), followed by whole-breast irradiation and no systemic therapy for the current ductal carcinoma in situ. Patients who needed a mastectomy and those with a history of invasive breast cancer, ductal carcinoma in situ, or a cancer not of the breast within 5 years before randomisation were ineligible, apart from those with carcinoma in situ of the cervix, carcinoma in situ of the colon, melanoma in situ, and basal cell and squamous cell carcinoma of the skin. Patients receiving raloxifene, other selective oestrogen receptor modulators, or any sex hormone therapy were ineligible. Patients with a history of thromboembolic disease, cerebral vascular accident or transient ischaemic attack, uncontrolled hypertension, uncontrolled diabetes, or uncontrolled atrial fibrillation were ineligible. All participating clinical centres obtained approval from institutional review boards, and all participants provided written informed consent. Randomisation and masking Eligible patients were randomly assigned in a 1:1 ratio to receive either oral anastrozole 1 mg per day plus an identical placebo for tamoxifen, or oral tamoxifen 20 mg per day plus an identical placebo for anastrozole. Study treatments were administered for 5 years. Because age is a prognostic factor for both breast cancer and other concomitant diseases that affect survival, participants were stratified by age (<60 vs 60 years) to ensure balance between treatment groups. Randomisation was done centrally by the statistical centre (in Pittsburgh, PA, USA) using a web-based minimisation algorithm. Treatment assignment was double-blinded: both patients and investigators were masked to treatment group. Procedures or tamoxifen therapy was to begin within 30 days following randomisation and to end 5 years from the date of first dose, irrespective of any missed doses. Both treatments were administered orally. All patients received whole-breast irradiation (50 Gy after surgery). Patients were followed up via physical examinations every 6 months for the first 5 years and every 12 months thereafter. Patients also received annual bilateral mammograms. Outcomes The primary endpoint was breast cancer-free interval, defined as the time from randomisation to any breast cancer event including local, regional, or distant recurrence, or contralateral breast cancer, invasive disease, or ductal carcinoma in situ. It was censored for deaths. Disease-free survival was a secondary endpoint, defined as time to any recurrence (excluding lobular carcinoma in situ), second primary cancer (excluding basal cell or squamous cell carcinoma of the skin, or various carcinomas in situ), and death from any cause. Other secondary endpoints were ipsilateral breast cancer, contralateral breast cancer, non-breast second primary cancers, osteoporotic fractures, and overall survival. All endpoints were analysed by intention to treat. The study also included quality-of-life components (the results of which are reported separately). 7 Statistical analysis The expected rate of breast cancer events was per person-year of follow-up, based on the observed rate in the NSABP B-24 tamoxifen group in those who were 50 years of age or older at study entry. The study was designed to need a sample size of at least 3000 patients to provide at least 80% power to detect a 33% reduction in breast cancer event rates, which required 199 breast cancer-free interval events to be recorded before final analysis. Three pre-planned interim analyses were done, when 49, 99, and 149 events were observed. To account for α spending and preserve the overall type I error rate at 0 05, the adjusted two-sided significance level for the final analysis was All analyses followed the intention-to-treat principle and included all at-risk women with available follow-up information. We estimated distributions of time to any breast cancer and disease-free and overall survival for each treatment group using the Kaplan-Meier method and did comparisons between treatments by log-rank tests stratified by age. We calculated hazard ratios (HRs) and 95% CIs for any breast cancer, disease-free survival, and overall survival from Cox models stratified by age. As prespecified in the protocol, we did tests for interactions between treatment and specific covariates including age group, comedo necrosis, and palpable mass at presentation. Significant interactions prompted separate tests within each covariate group. We compared invasive and non-invasive breast cancers, ipsilateral recurrence, and contralateral breast cancers using Cox models controlling for age to obtain HRs, 95% CIs, and p values. We compared non-breast second primary cancers and osteoporotic fractures by calculating average annual rates and risk ratios (RRs). We computed CIs for RRs Vol 387 February 27,

4 Figure 1: Trial profile 3104 patients enrolled and randomly assigned 1552 assigned to tamoxifen 1552 assigned to anastrozole 9 withdrew before having any follow-up 12 withdrew before having any follow-up 1543 analysed for survival 1540 analysed for survival 5 excluded because only follow-up was by telephone 1 excluded because only follow-up was by telephone 1538 analysed for disease-free survival 1539 analysed for disease-free survival See Online for appendix assuming a Poisson distribution and conditioning on the total number of events and person-years at risk. SAS version 9.4 was used for all analyses. This study is registered with ClinicalTrials.gov, number NCT Role of the funding source The funders of the study had no role in the design or conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the report; or the decision to submit for publication. RGM and RSC had full access to all the data in the study and take responsibility for the integrity of the data, the accuracy of the data analysis, and for the work as a whole, from inception to published article. Results Between Jan 6, 2003, and June 15, 2006, 3104 patients were enrolled into the trial and randomly assigned to tamoxifen (n=1552) or anastrozole (n=1552; figure 1 and appendix p 1). The present analysis used data collected up to Feb 28, A total of 3083 (99%) of 3104 patients had follow-up information available for survival, with 3077 (99%) also having follow-up information for all other disease-free endpoints. Median duration of follow-up was 9 0 years (IQR ). All baseline patient and tumour characteristics were well balanced across the treatment groups (table 1). Treatment compliance did not differ between the tamoxifen and anastrozole groups, with about 64% of participants in each group completing 5 years of therapy (appendix p 1). The median duration of treatment was 46 8 months (IQR ) in the tamoxifen group and 59 8 months ( ) in the anastrozole group. As of Feb 28, 2015, we recorded a total of 212 breast cancer-free interval events, of which 122 were in the tamoxifen group and 90 were in the anastrozole group. resulted in an overall statistically significant decrease in breast cancer-free interval events compared with tamoxifen (HR 0 73 [95% CI ], p=0 0234; (n=1552) (n=1552) Age, years < (47%) 731 (47%) (53%) 821 (53%) Race White 1352 (87%) 1361 (88%) Black 135 (9%) 124 (8%) Pacific Islander 6 (<1%) 6 (<1%) Asian 39 (3%) 34 (2%) Native American/Alaskan 3 (<1%) 5 (<1%) Multiracial 4 (<1%) 5 (<1%) Unknown 13 (1%) 17 (1%) Ethnic origin Non-Hispanic 1407 (91%) 1421 (92%) Hispanic or Latino 51 (3%) 45 (3%) Unknown 94 (6%) 86 (6%) Tumour evident on mammogram Yes 1488 (96%) 1513 (98%) No 59 (4%) 33 (2%) Unknown 5 (<1%) 6 (<1%) Comedo necrosis Absent 728 (47%) 669 (43%) Present 592 (38%) 669 (43%) Unknown 232 (15%) 214 (14%) Tumour palpable Yes 135 (9%) 121 (8%) No 1412 (91%) 1425 (92%) Unknown 5 (<1%) 6 (<1%) Pathological tumour size (cm) < (36%) 528 (34%) (24%) 389 (25%) Unknown 626 (40%) 635 (41%) Body-mass index (kg/m 2 ) < (26%) 376 (24%) (33%) 503 (32%) (41%) 673 (43%) Data are n (%). Table 1: Baseline characteristics figure 2, table 2). The 5-year breast cancer-free interval rates were 96 3% (95% CI ) in the tamoxifen group and 96 3% ( ) in the anastrozole group. The estimated percentage of patients with a 10-year breast cancer-free interval was 89 1% ( ) in the tamoxifen group and 93 1% ( ) in the anastrozole group. As the Kaplan-Meier curves (figures 2 and 3) show, a divergence occurs after the first 60 months (5 years). This divergence was a statistically significant time-bytreatment interaction (p=0 0410). We also recorded a statistically significant interaction between treatment and age group categorised as younger than 60 years versus 60 years and older (p=0 0379). Table 3 shows the number of breast cancer events, HRs, CIs, and p values by age Vol 387 February 27, 2016

5 group. The beneficial effect of anastrozole is significant only in women younger than 60 years of age. Table 2 shows the rates for the individual events contributing to breast cancer-free interval events. The rate of all invasive breast cancers was significantly higher in the tamoxifen group than in the anastrozole group (table 2). was also associated with a significant reduction in contralateral breast cancer and in invasive contralateral breast cancer (table 2). The other endpoints did not differ significantly between the treatment groups. In total, 495 disease-free survival events were recorded, of which 260 were in the tamoxifen group and 235 were in the anastrozole group (figure 3). The 5-year estimates for disease-free survival rate were 91 6% (95% CI ) in the tamoxifen group and 91 5% ( ) in the anastrozole group. The 10-year estimates for disease-free survival were 77 9% (95% CI ) in the tamoxifen group and 82 7% ( ) in the anastrozole group. Although this difference is not statistically significant, a trend similar to that noted for breast cancer-free interval does seem to exist in which the Kaplan-Meier curves separate in the second half of the study but at a later point in time (at around 8 years [96 months]). Again, we noted a statistically significant interaction between treatment group and age (p=0 0331), with a significant effect recorded only in women aged younger than 60 years (table 3). 209 patients (102 in the tamoxifen group and 107 in the anastrozole group) had a non-breast second primary cancer as their first event (table 4). Inspection of the individual sites of second primary cancers showed no notable differences by treatment group (table 4). A total of 186 deaths occurred during the study: 88 in the tamoxifen group and 98 in the anastrozole group (data not shown); there was no significant difference between the groups in the number of deaths (HR 1 11 [95% CI ], p=0 48). The 5-year estimates for overall survival were 98 0% (95% CI ) for the tamoxifen group and 97 9% ( ) for the anastrozole group. The 10-year estimates for overall survival were 92 1% (95% CI ) for the tamoxifen group and 92 5% ( ) for the anastrozole group. We recorded no statistically significant interaction between treatment and age group for overall survival (p=0 38). Eight deaths from breast cancer occurred in the tamoxifen group and five in the anastrozole group. Information about adverse events was available for 3070 (99%) randomised patients (1535 in each treatment group; table 5). Except for thrombosis or embolism, which are known side-effects of tamoxifen (overall incidence 2 7% in the tamoxifen group vs 0 8% in the anastrozole group, with 17 grade 4 or worse events in the tamoxifen group vs four in the anastrozole group), our results showed no notable differences by treatment group overall or for any specific type of adverse event reported. Women in the Event-free survival (%) Number at risk Figure 2: Breast cancer-free interval HR=hazard ratio. Patients alive and disease-free (%) Treatment Time since randomisation (months) 100 Number at risk Figure 3: Disease-free survival HR=hazard ratio. Treatment Patients (n) Patients (n) Events (n) Events (n) anastrozole group had slightly more cases of arthralgia and myalgia, but the percentages were similar between the treatment groups. However, these adverse events underestimate the difference in severity of patient-reported symptoms for both treatments, as is described in more detail in our report of the quality-of-life outcomes. Discussion This trial can be viewed as part of a stepwise evaluation by the NSABP of new treatments for patients with ductal carcinoma in situ. The NSABP B-17 1,2 trial established that lumpectomy and whole-breast irradiation was an appropriate, optional treatment for ductal carcinoma in situ. The NSABP B-24 trial 3 subsequently showed that the addition of adjuvant tamoxifen following lumpectomy and whole-breast irradiation resulted in fewer recurrences of cancer (invasive or non-invasive), in either breast, HR 0 73 (95% CI ), p= HR 0 89 (95% CI ), p= Time since randomisation (months) Vol 387 February 27,

6 (n=1538) (n=1539) Hazard ratio (95% CI) p value All breast cancers Total ( ) Invasive ( ) Ductal carcinoma in situ ( ) 0 52 Ipsilateral recurrence Total ( ) 0 34 Invasive ( ) 0 39 Ductal carcinoma in situ ( ) 0 59 Contralateral breast cancer Total ( ) Invasive ( ) Ductal carcinoma in situ ( ) 0 73 Breast cancer at distant sites ( ) 0 37 Breast second primary cancer* 0 1 *Angiosarcoma in the ipsilateral breast. Table 2: Breast cancer first events Patients (n) (n=1538) (n=1539) Hazard ratio (95% CI) p value Breast cancer-free interval events <60 years ( ) years ( ) 0 78 Disease-free survival events <60 years ( ) years ( ) 0 79 Table 3: Breast cancer-free interval and disease-free survival events by age group compared with placebo. The results of NSABP B-35 now show that, compared with tamoxifen, anastrozole resulted in further improvement in breast cancer-free interval, especially in younger post menopausal patients. The recorded difference in breast cancer-free interval in this trial was almost entirely attributable to the younger postmenopausal patients. No obvious biological explanation exists for this difference between younger and older postmenopausal women. Study drug compliance, body-mass index, tumour characteristics, and deaths from other causes were reviewed and were not found to contribute to this result. The difference between the treatments did not become apparent until after 5 years (60 months) of follow-up, which could be explained by the low rate of breast cancer events in both groups. No significant difference in ipsilateral cancer, either invasive or non-invasive, occurred. This finding might be a result of radiotherapy to the ipsilateral breast, but overall recurrence rates for both were low. The adverse events common to these drugs were similar to those reported in previous studies. The incidence of thromboembolic events was higher with tamoxifen than with anastrozole. 17 cases of uterine cancer were reported (n=1538) (n=1539) Risk ratio* (95% CI) Non-breast second ( ) primary cancer Uterine cancer ( ) Osteoporotic fractures ( ) *Risk ratio for women in the anastrozole group compared with those in the tamoxifen group. Table 4: Non-breast cancer events (n=1535) (n=1535) Overall toxicity Grade 0/1 312 (20%) 318 (21%) Grade (50%) 771 (50%) Grade (25%) 384 (25%) Grade 4 59 (4%) 50 (3%) Grade 5 (death) 13 (1%) 12 (1%) Thromboembolic events Grade 0/1 (none/superficial thrombosis) 1494 (97%) 1522 (99%) Grade 2 (deep-vein thrombosis) 4 (<1%) 1 (<1%) Grade 3 (uncomplicated pulmonary 20 (1%) 8 (1%) embolism) Grade 4 (life-threatening pulmonary 17 (1%) 3 (<1%) embolism) Grade 5 (death) 0 1 (<1%) Arthralgia Grade 0/1 (none/mild pain) 1177 (77%) 1031 (67%) Grade 2 (moderate pain) 302 (20%) 427 (28%) Grade 3 (severe pain) 55 (4%) 77 (5%) Grade 4 (disabling) 1 (<1%) 0 Myalgia Grade 0/1 (none/mild pain) 1367 (89%) 1317 (86%) Grade 2 (moderate pain) 150 (10%) 187 (12%) Grade 3 (severe pain) 18 (1%) 30 (2%) Grade 4 (disabling) 0 1 (<1%) Table 5: Adverse events by treatment group in the tamoxifen group and eight in the anastrozole group, which is similar to the results of the B-24 trial, although B-24 also included premenopausal women. Grade 2 or worse arthralgias were reported in 23 32% of patients, with higher severity in the anastrozole group. Myalgias were reported less frequently in the anastrozole group, but were more severe in this group than in the tamoxifen group. These findings are similar to adverse events for these symptoms reported in previous studies. 6 However, observer rating of these symptoms and others is known to underestimate the severity experienced by patients. One of the strengths of our study is the systematic patient selfassessment with standardised questionnaires, as is reported in our companion paper. 7 Specifically, musculoskeletal pain severity was significantly worse in the anastrozole group than in the tamoxifen group (p=0 001) Vol 387 February 27, 2016

7 The number of fractures reported did not differ significantly between the two groups. Osteoporosis was not an eligibility issue. One possible limitation of our study is our unexplained report of fewer fractures than in other reports. All fractures were reported by participating institutions and were defined as fractures of the hip, spine, and wrist. This could cause under-reporting compared with patients self-reporting on standard questionnaires. However, in view of the overall pattern of serious adverse events and uterine cancer, anastrozole seems to have a preferable safety profile to tamoxifen for serious adverse events. was more effective than tamoxifen in postmenopausal women younger than 60 years of age and would be the preferred treatment for those patients. For women aged 60 years and older, there was no evidence of a significant difference in outcomes. Therefore, decisions for adjuvant therapy in this age group should be based on the safety profile of each drug. should be avoided in women with a history of deep-vein thrombosis or uterine problems. Women with osteoporosis would probably be more safely treated with tamoxifen than anastrozole. Based on our findings, women who develop adverse events or uncomfortable symptoms on one drug would have the option of treatment with the other agent without compromising efficacy. One of the most notable findings in our trial was the reduction of contralateral invasive breast cancer with anastrozole. Previous studies showed that women with a history of ductal carcinoma in situ were at substantial risk for future invasive breast cancer; ductal carcinoma in situ has long been recognised as a precursor of invasive cancer. 8,9 Therefore, this finding suggests a role for anastrozole in preventing breast cancer. Examination of these findings against the background of the Breast Cancer Prevention Trial (P-1) 10 supports this view. If ductal carcinoma in situ is a risk factor for future breast cancer, then intervention for the prevention of future invasive breast cancer might be the most useful aspect of treatment with anastrozole. In the P-1 study, tamoxifen reduced the incidence of breast cancer by 48% compared with placebo. In B-35, anastrozole further significantly reduced the rate of contralateral invasive cancer compared with tamoxifen. However, this study was not a trial of cancer prevention in high-risk women. Although ductal carcinoma in situ is one risk factor for the future development of breast cancer, a group of women at high risk would also include those with a strong family history or those with previous biopsies showing atypical hyperplasia. These findings cannot be extrapolated to all high-risk patients based on cross-protocol comparisons, but, in the absence of a direct trial, the choice could reasonably be made on an individualised basis. Further support comes from the IBIS-II trial, 11 which compared anastrozole versus placebo for cancer prevention in high-risk women. Participants treated with anastrozole were 53% less likely to develop breast cancer than those receiving placebo (40 vs 85 cases). The results of IBIS-II DCIS, comparing anastrozole to tamoxifen in women with ductal carcinoma in situ, are expected imminently. 12 The results of the present study confirm the excellent overall prognosis for women treated for ductal carcinoma in situ. Eight deaths from breast cancer occurred in the tamoxifen group and five in the anastrozole group. A recent Surveillance, Epidemiology, and End Results (SEER) data analysis 13 of patients with ductal carcinoma in situ concluded that radiotherapy did not improve overall survival. However, a local recurrence of invasive cancer in either breast carries an increased risk of death 3 and is, at the very least, a serious event, usually leading to further breast and possibly axillary surgery and additional adjuvant systemic therapies. The SEER data analysis did not include a comparison of patients who received hormone therapy, which was shown in protocol B-24 to provide a significant benefit. With modern treatments, the outcomes for patients with ductal carcinoma in situ have improved. In protocol B-17, there was a 25% incidence of any breast cancer event in the lumpectomy-alone group. 7 For patients treated with whole-breast irradiation, this rate fell to 13%, and for those receiving tamoxifen in B-24 it was 8%. 3,7 This decrease is a 77% reduction in all events with the combined treatment. In the present trial, we report a further decrease in events, especially contralateral invasive breast cancer, in postmenopausal women younger than 60 years of age. With the main concern in treating ductal carcinoma in situ being the prevention of invasive cancer with the possibility of metastases and death, adjuvant hormone treatment following ductal carcinoma in situ can be regarded as an important prevention issue because of this demonstration that invasive cancer incidence is reduced. The recent SEER data analysis suggests that younger women and African American women with ductal carcinoma in situ are at an increased risk for invasive cancer compared with other women in North America. Future research should focus on identifying molecular or genetic subgroups that would or would not benefit from adjuvant treatments. Treatment of patients with ductal carcinoma in situ with anastrozole provides a significant decrease in breast cancer events and the unwanted treatments that would follow. NSABP B-35 documents the potential adverse events and toxicities so that women and their doctors can make appropriate choices for treatment of ductal carcinoma in situ. Our companion report 7 on patient-reported quality of life and symptoms provides a more detailed evaluation of the comparative symptom profiles of these two therapies and highlights differences in symptom patterns by age group and treatment, allowing integration of outcome results and adverse effects analysis to help decision making. At present, the use of anastrozole provides a distinct benefit for the treatment of ductal carcinoma in situ and should be offered as a treatment option when appropriate. Vol 387 February 27,

8 Contributors RGM contributed to the literature search, study design, data interpretation, writing of the report, and final approval. RSC contributed to study conception and design; acquisition, analysis, and interpretation of data; critical drafting and revision of the report for important intellectual content; final approval of the version to be published; and agrees to be accountable for all aspects of the work. TBJ contributed to study conception and design; acquisition, analysis, and interpretation of data; revision of the report; final approval of version to be published; and agrees to be accountable for all aspects of the work. PAG and JPC contributed to study design, data collection, data interpretation, and writing of the report. LAV contributed to acquisition of data, drafting and revision of the report, and final approval, and agrees to be accountable for aspects of the work. KSA contributed to study design on behalf of SWOG Breast Committee, patient accrual, and review and approval of the report. PWW contributed to acquisition of data and revisions to the report. MEC made substantial contributions to the acquisition of data, reviewed the draft of the report, approved the version to be published, and agrees to be accountable for all aspects of the work. AMB contributed to acquisition and analysis of data and patients, drafting of work, and final approval of the report. HMG contributed to study design, data analysis and interpretation, patient accrual, and editing of the report. GSS contributed to acquisition and analysis of data and patients, drafting of work, and final approval of the report. JOH contributed to the study design, reviewed intellectual content, gave final approval of the version to be published, and agrees to be accountable for all aspects of the work. LF contributed to acquisition, analysis, and interpretation of work; critical revision of the draft of the report including intellectual content; approval of the final version; and agrees to be accountable for all aspects of the work. KS contributed to patient accrual, data collection, and local study research oversight. TFW participated in the Breast Cancer Committee and Prevention Trial implementation; promoted patient enrolment at the Christiana Care CCOP as local Principal Investigator; contributed the majority of patients from the Christiana Care CCOP for this trial and the preceding trial that was the basis for the control group in the study; reviewed and approved the final report for publication; and accepts accountability for accuracy and integrity of the work. TES helped with acquisition of data with patient enrolment, contributed to review of work, gave final approval of the version to be published, and agrees with data interpretation, conclusions, and recommendations. EPM contributed to study design, data collection, data interpretation, and writing and approval of the final report. NW contributed to the conception and design of the work, helped to revise it, gave final approval of the version to be published, and agrees to be accountable for all aspects of the work. Declaration of interests MEC has received research support from Novartis, fees from Biotheranostics Advisory Board, and fees from Roche and Abbvie outside of the submitted work. All other authors declare no competing interests. Acknowledgments This clinical trial was supported by grants from the National Cancer Institute (grant numbers U10CA , , , , and ) and AstraZeneca Pharmaceuticals LP. References 1 Fisher B, Costantino J, Redmond C, et al. Lumpectomy compared with lumpectomy and radiation therapy for the treatment of intraductal breast cancer. N Engl J Med 1993; 328: Fisher B, Dignam J, Wolmark N, et al. 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