D. Rea

Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials

BACKGROUND The optimal ways of using aromatase inhibitors or tamoxifen as endocrine treatment for early breast cancer remains uncertain. METHODS We undertook meta-analyses of individual data on 31,920 postmenopausal women with oestrogen-receptor-positive early breast cancer in the randomised trials of 5 years of aromatase inhibitor versus 5 years of tamoxifen; of 5 years of aromatase inhibitor versus 2-3 years of tamoxifen then aromatase inhibitor to year 5; and of 2-3 years of tamoxifen then aromatase inhibitor to year 5 versus 5 years of tamoxifen. Primary outcomes were any recurrence of breast cancer, breast cancer mortality, death without recurrence, and all-cause mortality. Intention-to-treat log-rank analyses, stratified by age, nodal status, and trial, yielded aromatase inhibitor versus tamoxifen first-event rate ratios (RRs). FINDINGS In the comparison of 5 years of aromatase inhibitor versus 5 years of tamoxifen, recurrence RRs favoured aromatase inhibitors significantly during years 0-1 (RR 0·64, 95% CI 0·52-0·78) and 2-4 (RR 0·80, 0·68-0·93), and non-significantly thereafter. 10-year breast cancer mortality was lower with aromatase inhibitors than tamoxifen (12·1% vs 14·2%; RR 0·85, 0·75-0·96; 2p=0·009). In the comparison of 5 years of aromatase inhibitor versus 2-3 years of tamoxifen then aromatase inhibitor to year 5, recurrence RRs favoured aromatase inhibitors significantly during years 0-1 (RR 0·74, 0·62-0·89) but not while both groups received aromatase inhibitors during years 2-4, or thereafter; overall in these trials, there were fewer recurrences with 5 years of aromatase inhibitors than with tamoxifen then aromatase inhibitors (RR 0·90, 0·81-0·99; 2p=0·045), though the breast cancer mortality reduction was not significant (RR 0·89, 0·78-1·03; 2p=0·11). In the comparison of 2-3 years of tamoxifen then aromatase inhibitor to year 5 versus 5 years of tamoxifen, recurrence RRs favoured aromatase inhibitors significantly during years 2-4 (RR 0·56, 0·46-0·67) but not subsequently, and 10-year breast cancer mortality was lower with switching to aromatase inhibitors than with remaining on tamoxifen (8·7% vs 10·1%; 2p=0·015). Aggregating all three types of comparison, recurrence RRs favoured aromatase inhibitors during periods when treatments differed (RR 0·70, 0·64-0·77), but not significantly thereafter (RR 0·93, 0·86-1·01; 2p=0·08). Breast cancer mortality was reduced both while treatments differed (RR 0·79, 0·67-0·92), and subsequently (RR 0·89, 0·81-0·99), and for all periods combined (RR 0·86, 0·80-0·94; 2p=0·0005). All-cause mortality was also reduced (RR 0·88, 0·82-0·94; 2p=0·0003). RRs differed little by age, body-mass index, stage, grade, progesterone receptor status, or HER2 status. There were fewer endometrial cancers with aromatase inhibitors than tamoxifen (10-year incidence 0·4% vs 1·2%; RR 0·33, 0·21-0·51) but more bone fractures (5-year risk 8·2% vs 5·5%; RR 1·42, 1·28-1·57); non-breast-cancer mortality was similar. INTERPRETATION Aromatase inhibitors reduce recurrence rates by about 30% (proportionately) compared with tamoxifen while treatments differ, but not thereafter. 5 years of an aromatase inhibitor reduces 10-year breast cancer mortality rates by about 15% compared with 5 years of tamoxifen, hence by about 40% (proportionately) compared with no endocrine treatment. FUNDING Cancer Research UK, Medical Research Council.

The LORIS Trial: Addressing Overtreatment of Ductal Carcinoma In Situ

An unforeseen consequence of the introduction of mammographic breast screening has been the marked increase in the number of women diagnosed with ductal carcinoma in situ (DCIS) [1,2]. In 2009–2010, 2830 women were diagnosed with in situ carcinoma through the National Health Service Breast Screening Programme (NHSBSP) [3]. Screen-detected DCIS now accounts for 20% of ‘cancers’ identified through breast screening. However, the intent of breast screening programmes was to detect early invasive cancer, not to identify DCIS.

Physical activity and breast cancer outcome: a brief review of evidence, current practice and future direction.

There have been several publications of large scale studies with long-term follow up addressing the role of physical activity in the management of breast cancer. Of the twelve studies specifically addressing the effect of physical activity on breast cancer survival, eight showed a statistically significant 50% risk reduction in breast cancer mortality in women who engaged in moderate intensity physical activity before and after their diagnosis of breast cancer. Four smaller studies demonstrated no benefit. Almost all of these observational studies predominantly involved white, professional women from North America and Europe. The positive effects of physical activity were seen for all stages of cancer, with the greatest benefit in steroid receptor positive breast tumours. These studies relied on self-reported questionnaires for recording the levels of physical activity. Despite including thousands of patients, published studies offer no data related to the optimum type, duration and timing of physical activity. Only a few studies provided objective data on physical activity, cardio-respiratory and general fitness. Thus, potential role of physical activity in the management of breast cancer remains far from established. If the beneficial effect of physical activity as demonstrated in the observational studies can be replicated in robust, well designed and well-executed prospective randomised controlled trials, this would provide a tremendous opportunity to enhance adjuvant treatment of breast cancer. By adding physical activity to the spectrum of adjuvant therapies offered to women survival from breast cancer may be enhanced.

Five Years of Exemestane as Initial Therapy Compared to 5 Years of Tamoxifen Followed by Exemestane: The TEAM Trial, a Prospective, Randomized, Phase III Trial in Postmenopausal Women with Hormone-Sensitive Early Breast Cancer.

Background: Exemestane (E) is a steroidal aromatase inhibitor (AI) with an established role in early breast cancer after 2–3 years of tamoxifen (T). Additionally, AIs have shown superiority to T as initial adjuvant therapy. The Tamoxifen Exemestane Adjuvant Multinational (TEAM) study has been prospectively designed to compare the role of E as initial adjuvant therapy with a sequential approach of T followed by E (T→E).Methods: Postmenopausal patients with hormone receptor–positive early breast cancer were randomized to open-label E 25 mg/d or T 20 mg/d. All patients completed surgery and chemotherapy, if indicated. Data were collected and analyzed by the Central Data Center in Leiden, The Netherlands. The trial was initiated in 2001 with the primary objective being a comparison of disease-free survival (DFS) with T vs E. In 2004, TEAM was modified in response to new data; all those initially receiving T were switched to E after 2.5–3 years. An additional 2500 patients were recruited and randomized at diagnosis to E or T→E for 5 years. The modified study design includes 2 coprimary endpoints: (1) DFS of T vs E that was previously reported at 2.75 years median follow-up (Jones S et al, abstract #15 presented at SABCS 2008); and (2) DFS at 5 years of E vs T→E that will be the focus of results presented here.Results: Between 2001 and January 2006, 9775 women were randomized to TEAM. In total, 99% of patients were ER+ and/or PgR+, 50% were node-negative, 44% underwent mastectomy, 68% received radiotherapy, and 36% received chemotherapy. In September 2009, median follow-up will be 5.5 years and the protocol-specified 1285 overall DFS events (locoregional or distant recurrence, second breast cancers, or death without recurrence) will have occurred, allowing for analysis of the second coprimary endpoint. We will present a detailed analysis of the 5-year results from theTEAM trial, the only prospectively powered randomized trial to compare 5 years of an initial AI vs T→AI, 2 commonly received adjuvant therapies for women with hormone receptor–positive early breast cancer. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 11.

Selecting breast cancer patients for chemotherapy: the opening of the UK OPTIMA trial.

The mortality from breast cancer has improved steadily over the past two decades, in part because of the increased use of more effective adjuvant therapies. Thousands of women are routinely treated with intensive chemotherapy, which can be unpleasant, is expensive and is occasionally hazardous. Oncologists have long known that some of these women may not need treatment, either because they have a low risk of relapse or because they have tumour biology that makes them less sensitive to chemotherapy and more suitable for early adjuvant endocrine therapy. There is an urgent need to improve patient selection so that chemotherapy is restricted to those patients who will benefit from it. Here we review the emerging technologies that are available for improving patient selection for chemotherapy. We describe the OPTIMA trial, which has just opened to recruitment in the UK, is the latest addition to trials in this area, and is the first to focus on the relative cost-effectiveness of alternate predictive assays.

NEAT: National Epirubicin Adjuvant Trial - toxicity, delivered dose intensity and quality of life

The NEAT trial reported considerable benefit for ECMF (epirubicin followed by cyclophosphamide, methotrexate and 5-fluorouracil) of 28% for relapse-free survival (RFS) and 30% for overall survival (OS), when compared with classical CMF in early breast cancer. To assess tolerability, toxicity, dose intensity and quality of life (QoL) analyses were undertaken. All 2021 eligible patients had common toxicity criteria (CTC), delivered chemotherapy and supportive treatments details and long-term morbidities recorded. The QoL substudy used multiple validated measures. ECMF produced low CTC scores, although higher than CMF for nausea, vomiting, alopecia, constipation, stomatitis (P<0.001), infection (P=0.001) and fatigue (P=0.03). Supportive treatments required, however, were similar across randomised treatments. On-treatment deaths were more common with CMF (13) than ECMF(5). Optimal course-delivered dose intensity (CDDI ⩾85%) was received more often by ECMF patients (83 vs 76%: P=0.0002), and was associated with better RFS (P=0.0006). QoL over 2 years was equivalent across treatments, despite minimally worse side effects for ECMF during treatment. ECMF benefit spanned all levels of toxicity, CDDI and QoL. There are no reported acute myeloid leukaemias or cardiac dysfunctions. ECMF is tolerable, deliverable, and significantly more effective than CMF, with no serious long-term toxicity or QoL detriment.

Time to stop operating on breast cancer patients with pathological complete response

Surgery is an obligatory component of treatment for early breast cancer. The last 20 years developments in systemic neoadjuvant therapy have progressively increased pathological complete response (pCR). Pathological complete response is associated with excellent prognosis especially for hormone receptor negative cancers. Therapeutic advances and recognition of the importance of pathological subtype in predicting pCR facilitate identification of subgroups with very high pCR rates. Treatment of HER2 positive hormone receptor negative cancers with combination chemotherapy and multiple targeted anti-HER2 agents results in consistently high pCR rates of 60-83%. Routine surgery in this setting where most patients have no potential to benefit is of questionable value and the option of omitting surgery in these patients should now be explored in a randomized trial. For HER2 positive disease not achieving pCR after neoadjuvant treatment the outcomes are poor. Trials are underway to determine if outcomes for these patients can be improved with alternative targeted therapy.

Chromosome 17 polysomy (Ch17) as a predictor of anthracycline response: emerging evidence from the UK NEA Tadjuvant breast cancer trial

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #45 Background: The role of HER2 and Topoisomerase IIα (TOPO2α) as predictors of anthracycline sensitivity remains controversial. To address this we conducted an analysis of HER2, Topoisomerase IIα amplification (TOPO2α-amp) and deletion (TOPO2α-del), chromosome 17 polysomy (C17) and Ki67 as prognostic and predictive markers in the UK National Epirubicin Adjuvant Trial ( NEAT ) which compared classical CMF with Epirubicin followed by CMF (NEJM 2006;355:1851-62). Methods: TMAs constructed with 1638/2021 tumors from patients in the NEAT study were analysed for HER2/TopoIIα gene alterations, C17 polysomy, and Ki67. Log-rank analyses explored the prognostic value of markers on relapse-free survival (RFS) and overall survival (OS). Cox-regression models tested independent prognostic value on RFS and OS in the presence of treatment, age, type of surgery, tumor size, nodal status, ER status and grade, and marker x treatment interactions for RFS and OS. Results: Of 1625 NEAT samples analysed, 806(50%) received anthracycline-containing treatment; 985(61%) were ≤50 years old; 1114(69%) had nodal involvement; 791 (49%) were ER+ve; 961(59%) had G3 tumours; and 893 (56%) had tumour size >2cm. 19% were HER2-amp, 9% were TOPO2α-amp, 9% were TOPO2α-del, 18% were polysomic for C17 and 62% had high Ki67 (>13.0%). HER2-amp and TOPO2α-del were significant poor prognostic factors (P<0.001) for RFS and OS, and were independent variables in multivariate analyses. Other factors did not reach significance at the 1% level. No significant treatment interaction with anthracyclines was seen for HER2-amp (OS p=0.25, RFS p=0.51). Polysomy C17 was not prognostic but exhibited a significant treatment interaction with anthracyclines (RFS p=0.02, HRs 0.96 95%CI 0.73-1.26 vs 0.56 95%CI 0.33-0.97, OS p=0.06, HRs 0.97 95%CI 0.72-1.30 vs 0.60 95%CI 0.33-1.08). Patients with C17 polysomic tumours had significantly greater benefit from anthracyclines. Conclusions: Analysis of samples from the NEAT trial, which for the first time included HER2, TOPO2α, Ki67 and C17, strongly suggest that the most powerful predictor of benefit from adjuvant anthracyclines is chromosome 17 polysomy, perhaps as a marker of chromosomal instability, with a weak effect for HER2-amp. No effect was observed for differing TOPO2α status. Given the lack of consistency seen in previous studies with respect to HER2 and TOPO2α, we suggest that polysomy C17 could be the unifying predictive marker of anthracycline sensitivity, particularly as these data are confirmed by data from a separate meta-analysis of MA5 and BR9601 trials (SABCS2008). Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 45.

Abstract S2-3: The Impact of Body Mass Index (BMI) on the Efficacy of Adjuvant Endocrine Therapy in Postmenopausal Hormone Sensitive Breast Cancer (BC) Patients; Exploratory Analysis from the TEAM Study

Background: Obesity is associated with an increased risk of breast cancer (BC) recurrence and decreased survival, also in case of adjuvant endocrine therapy. It is still not clear whether the activity of aromatase inhibitors and tamoxifen (T) given as adjuvant therapy is affected by body mass index (BMI), although both drugs are widely prescribed. In this analysis, we explored the outcome of TEAM patients (pts) treated with exemestane (E) versus T (2.75 yrs), and with E versus T followed by E (T/E) (5 yrs) in relation to BMI. Patients and Methods: The TEAM trial is a randomized, international phase III study in postmenopausal hormone sensitive early BC pts comparing the activity and safety of adjuvant E (25 mg daily) or the sequence of T (20 mg daily) followed by E (T/E), both regimens given for five years. WHO BMI definitions were used: normal 18.5-24.9 kg/m2, overweight 25-30 kg/m2, obese >30 kg/m2. Disease-free survival (DFS) and overall survival (OS) were calculated by Kaplan-Meier method; results were compared by using the log-rank test and Cox proportional hazard modelling adjusted for country. Results: Weight and height was known in 4741 pts. Mean BMI was 26.9 kg/m2 (SD 4.9); 39% had a normal BMI, 36.9% overweight, and 23.3% of pts was obese. Underweight pts (n=41, 0.9%) were excluded from further analysis. At 2.75 yrs (E vs T) disease relapse in normal weight, overweight and obese pts using E was observed in 8.1%, 6.8% and 7.5% respectively (p=0.57), and in 9.1%, 8.8%, and 12.5%, respectively (p=0.06) of pts using T. The hazard ratio (HR for risk of relapse on E vs T) in the three subgroups was 0.91 (95%CI 0.66-1.24), 0.78 (95%CI 0.55-1.089), and 0.57 (95%CI 0.39-0.84, p=0.004), respectively. At a median follow-up of 5.1 years, disease relapse in normal weight, overweight and obese pts using E occurred in 14.8%, 15.1% and 15.1%, respectively; and in pts using T in 17.0%, 16.9%, and 18.3%, respectively. Regarding DFS, the HR in normal weight, overweight, and obese pts was 0.87 (95%CI 0.69-1.10), 0.88 (95%CI 0.70-1.11), and 0.75 (95%CI 0.56-1.01, p=0.058), respectively, and with respect to OS 0.87 (95%CI 0.65-1.15, p= 0.32), 0.89 (95%CI 0.67-1.18, p= 0.43), and 0.71 (95% CI 0.51-1.01, p= 0.053), respectively. Conclusions: After 2.75 years more disease events were observed in obese women using tamoxifen, which was not seen in obese exemestane users, whereas at 5 years these differences in disease recurrences disappeared in this group. In contrast to recent reports, there seems to be a difference regarding the influence of a high BMI on recurrence rate between tamoxifen and the aromatase inhibitor exemestane. Further research on this topic is warranted. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S2-3.

Abstract OT2-3-01: The LORIS trial: A multicentre, randomized phase III trial of standard surgery versus active monitoring in women with newly diagnosed low risk ductal carcinoma in situ

Background: The independent review of the UK National Health Service Breast Screening Programme reported recently on the benefits and harms of breast screening (The Lancet, Volume 380, Issue 9855, Pages 1778 - 1786, 17 November 2012). This concluded that breast screening saves lives but acknowledged the existence of overtreatment. Consequently, randomized trials were recommended to elucidate the appropriate treatment of screen-detected ductal carcinoma in situ (DCIS) and to gain a better understanding of its natural history. The LORIS trial will address these issues in low and low/intermediate grade screen detected (low risk) DCIS. Trial Design: LORIS is a phase III, multicentre, 2 arm study, with a built in 2 year feasibility phase, in women confirmed by central pathology review to have low risk DCIS. Comprehensive site training will be complimented by a patient friendly DVD designed to ensure consistent and appropriate use of terminology. Patients will be randomised between standard surgery and active monitoring with annual mammography. Follow-up will be for a minimum of 10 years. Eligibility Criteria: 1) Female, age ≥ 46 years 2) Screen-detected or incidental microcalcification (with no mass lesion clinically or on imaging) 3) Low risk DCIS on large volume vacuum-assisted biopsy, confirmed by central pathology review 4) Patient fit to undergo surgery 5) No previous breast cancer or DCIS diagnosis 6) Written informed consent Specific Aims: The LORIS Trial aims to establish whether patients with newly diagnosed low risk DCIS can safely avoid surgery without detriment to their wellbeing (psychological and physical) and whether those patients who do require surgery can be identified by pathological and radiological means. Primary endpoint: Ipsilateral invasive breast cancer free survival rate at 5 years Secondary endpoints: Overall survival; mastectomy rate; time to mastectomy; time to surgery; patient reported outcomes; health resource utilisation and assessment of predictive biomarkers. A digital image data repository and tissue bank will provide a prospective resource for both translational and imaging studies. Statistical Methods: A total of 932 patients will be randomized to a non-inferiority design to test the null hypothesis that active monitoring of women diagnosed with low risk DCIS is not non-inferior in terms of 5 year ipsilateral invasive breast cancer free survival (iiBCFS) rate compared to treatment with surgery. The iiBCFS rate will be compared across the two arms on a per protocol and intent-to-treat basis, using a 1-sided (α = 0.05) log-rank test for non-inferiority. The iiBCFS rate is assumed to be 97.5% in the surgery arm giving 80% power to exclude a difference of more than 2.5% in the active monitoring arm at 5 years. Present Accrual and Target Accrual: 20 UK sites have been identified to contribute to the feasibility phase of the trial. Enrolment of the first patient is expected in late 2013/early 2014. A further 40 sites will be recruited upon successful completion of the feasibility phase. For further information, please contact the LORIS Trial Office LORIS@trials.bham.ac.uk. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-3-01.