Anastrozole versus tamoxifen for the prevention of locoregional and contralateral breast cancer in postmenopausal women with locally excised ductal carcinoma in situ (IBIS-II DCIS): a double-blind, randomised controlled trial

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

A randomized trial to assess the biological activity of short-term (pre-surgical) fulvestrant 500 mg plus anastrozole versus fulvestrant 500 mg alone or anastrozole alone on primary breast cancer

Introduction: Fulvestrant shows dose-dependent biological activity. Greater estrogen-receptor (ER) blockade may feasibly be achieved by combining fulvestrant with anastrozole. This pre-surgical study compared fulvestrant plus anastrozole versus either agent alone in patients with ER-positive breast cancer. Methods: In this double-blind, multicenter trial, 121 patients received: fulvestrant 500 mg on day 1 plus anastrozole 1 mg/day for 14-21 days (F+A); fulvestrant plus anastrozole placebo (F); or fulvestrant placebo plus anastrozole (A), 2-3 weeks before surgery. ER, progesterone-receptor (PgR), and Ki67 expression were determined from tumor biopsies before treatment and at surgery. Results: 103 paired samples were available (F, n = 35; F+A, n = 31; A, n = 37). All treatments significantly reduced mean ER expression from baseline (F: 41%, P = 0.0001; F+A: 39%, P = 0.0001; A: 13%, P = 0.0034). F and F+A led to greater reductions in ER versus A (both P = 0.0001); F+A did not lead to additional reductions versus F. PgR and Ki67 expression were significantly reduced with all treatments (means were 34% to 45%, and 75% to 85%, respectively; all P = 0.0001), with no differences between groups. Conclusions: In this short-term study, all treatments reduced ER expression, although F and F+A showed greater reductions than A. No significant differences were detected between the treatment groups in terms of PgR and Ki67 expression. No additional reduction in tumor biomarkers with combination treatment was observed, suggesting that F+A is unlikely to have further clinical benefit over F alone. Trial registration: Clinicaltrials.gov NCT00259090

Breast cancer management pathways during the COVID-19 pandemic: outcomes from the UK ‘Alert Level 4’ phase of the B-MaP-C study

Abstract: Background: The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions. Methods: This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated ‘standard’ or ‘COVID-altered’, in the preoperative, operative and post-operative setting. Findings: Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had ‘COVID-altered’ management. ‘Bridging’ endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2–9%) using ‘NHS Predict’. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey. Conclusions: The majority of ‘COVID-altered’ management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown

Screening women aged less than 50 years with a family history of breast cancer

Family history is an important breast cancer risk factor and is a common reason for referral to specialist breast clinics for consideration of breast screening. The aims of this study were to determine cancer detection rates and prognostic features of breast cancers identified in women aged less than 50 years at increased risk of breast cancer who attend a Family History Breast Screening Clinic (FHC). Between January 1988 and December 1995, 1371 asymptomatic women aged less than 50 years underwent annual clinical breast examination and biennial mammography due to a family history of breast cancer. A total of 29 cancers (23 invasive and 6 in situ) were detected or presented as interval cancer during a mean follow-up of 22 months (range 0-96 months). This gave a relative risk for invasive breast cancer in this high-risk group of 5 when compared with an age-matched female population in the U.K. The cancer screening detection rates were similar to those of women aged 50 years or over undergoing population screening in the NHS Breast Screening Programme (NHSBSP)--FHC prevalent screen 8 per 1000 screening visits versus NHSBSP 6.5 per 1000, FHC incident screen 3.3 per 1000 screening visits versus NHSBSP 3.8 per 1000. A higher proportion of in situ cancers were detected in the FHC screened group compared with cancers identified in symptomatic patients from an age-matched risk group (21% versus 4%). No differences were demonstrated for invasive tumour size, grade or lymph node stage between symptomatic and screened women. The early results of this study suggests that young women at risk of breast cancer due to a family history may benefit from regular breast screening due to the early detection of in situ lesions

Tumor biomarker changes following pre-surgical treatment with 500 mg Fulvestrant plus Anastrozole Versus 500 mg Fulvestrant Alone and 1 mg Anastrozole Alone [Abstract]

Background: Fulvestrant (FaslodexTM) is an estrogen receptor (ER) antagonist with a distinct mode of action. Previous pre-surgical studies have reported dose-dependent reductions in biological tumor markers (ER, progesterone receptor [PgR], and Ki67 levels) with doses of fulvestrant up to 250 mg (approved dose, AD). The NEWEST (Neoadjuvant Endocrine Therapy for Women with Estrogen-Sensitive Tumors) study was the first to indicate that a higher dose of fulvestrant (500 mg) has significantly greater biological activity than AD in the neoadjuvant setting. A greater ER signaling blockade and subsequent anti-cancer effect might be produced by combining fulvestrant with an estrogen-lowering agent such as the aromatase inhibitor anastrozole (ArimidexTM).Objectives: Primary objective: to compare the biological activity of 500 mg fulvestrant plus anastrozole with 500 mg fulvestrant alone and anastrozole alone. Primary endpoints included changes in ER, PgR, and Ki67 index. The secondary objective was to assess tolerability.Methods: This was a Phase II, double-blind, randomized, multicenter trial (9238IL/0057; NCT00259090 ) in postmenopausal women with ER-positive primary breast cancer. Patients were randomized into one of 3 treatment arms: fulvestrant 500 mg plus anastrozole 1 mg once daily (od) for 14 to 21 days (F+A); fulvestrant 500 mg plus anastrozole placebo 1 mg od for 14 to 21 days (F); fulvestrant placebo plus anastrozole 1 mg od for 14 to 21 days (A). Following randomization, treatment, and curative intent surgery, patients were assessed and reviewed for adverse events. Tumor biopsy samples were taken pre-treatment and at surgery to assess changes in ER, PgR, and Ki67 index. Changes in ER index (evaluated by non-automated H-score assessment) are presented.Results: In total, 121 patients were randomized and, to date, 99 paired samples have been analyzed for ER. Treatment with F, F+A, and A each significantly reduced the mean pre-treatment ER index.There was a significant overall treatment effect between therapy arms (p=0.0001). Treatment with F showed a significant decrease in ER index compared with A (p=0.0001), as did F+A vs A (p=0.0004). There was no additional reduction in ER by F+A vs F alone (p=0.2). Ki67 and PgR results are being analyzed. Short-term side effects on treatment were similar for F+A compared with F and A alone.Conclusions: This study is the first to investigate treatment with fulvestrant 500 mg combined with anastrozole. The effects on ER confirm the different mechanisms of action reported experimentally for F and A. F or F+A both significantly decreased ER index, but there was no further significant impact on ER changes by combining F+A vs F. Ongoing analysis of PgR and Ki67 will help determine if there is clinical relevance in the decline in ER level associated with both 500 mg F-containing strategies versus A, and help compare the impact of F+A vs F or A alone on ER function

Evaluation of mammographic surveillance services in women aged 40-49 years with a moderate family history of breast cancer: A single-arm cohort study

Background: Women with a significant family history of breast cancer are often offered more intensive and earlier surveillance than is offered to the general population in the National Breast Screening Programme. Up to now, this strategy has not been fully evaluated. Objective: To evaluate the benefit of mammographic surveillance for women aged 40-49 years at moderate risk of breast cancer due to family history. The study is referred to as FH01. Design: This was a single-arm cohort study with recruitment taking place between January 2003 and February 2007. Recruits were women aged < 50 years with a family history of breast or ovarian cancer conferring at least a 3% risk of breast cancer between ages 40 and 49 years. The women were offered annual mammography for at least 5 years and observed for the occurrence of breast cancer during the surveillance period. The age group 40-44 years was targeted so that they would still be aged < 50 years after 5 years of surveillance. Setting: Seventy-four surveillance centres in England, Wales, Scotland and Northern Ireland. Participants: A total of 6710 women, 94% of whom were aged < 45 years at recruitment, with a family history of breast cancer estimated to imply at least a 3% risk of the disease between the ages of 40 and 50 years. Interventions: Annual mammography for at least 5 years. Main outcome measures: The primary study end point was the predicted risk of death from breast cancer as estimated from the size, lymph node status and grade of the tumours diagnosed. This was compared with the control group from the UK Breast Screening Age Trial (Age Trial), adjusting for the different underlying incidence in the two populations. Results: As of December 2010, there were 165 breast cancers diagnosed in 37,025 person-years of observation and 30,556 mammographic screening episodes. Of these, 122 (74%) were diagnosed at screening. The cancers included 44 (27%) cases of ductal carcinoma in situ. There were 19 predicted deaths in 37,025 person-years in FH01, with an estimated incidence of 6.3 per 1000 per year. The corresponding figures for the Age Trial control group were 204 predicted deaths in 622,127 person-years and an incidence of 2.4 per 1000 per year. This gave an estimated 40% reduction in breast cancer mortality (relative risk = 0.60; 95% confidence interval 0.37 to 0.98; p = 0.04). Conclusions: Annual mammography in women aged 40-49 years with a significant family history of breast or ovarian cancer is both clinically effective in reducing breast cancer mortality and cost-effective. There is a need to further standardise familial risk assessment, to research the impact of digital mammography and to clarify the role of breast density in this population. Trial registration: National Research Register N0484114809