ATAC trial update

This study evaluated the cost-effectiveness of anastrozole versus generic tamoxifen for primary adjuvant treatment of postmenopausal women with hormone receptor-positive (HR+) early breast cancer (EBC), from a US healthcare perspective. A probabilistic Markov model was developed using the 5-year completed treatment analysis of the ATAC ('Arimidex', Tamoxifen Alone or in Combination) trial (ISRCTN 18233230) to project outcomes for anastrozole and tamoxifen to 25 years. Resource utilization data were obtained primarily from published literature and a physician survey (including expert opinion from ATAC Steering Committee members). Drug costs were taken from published wholesale acquisition costs (anastrozole $6.56/day, generic tamoxifen $1.33/day). Other unit costs ($US 2003-4) were from standard sources. Utility estimates of relevant health states, used to compute quality-adjusted life-years (QALYs), were collected using the standard gamble technique in a cross-sectional sample of 44 patients. Costs and benefits were discounted 3% annually. In a cohort of 1000 postmenopausal women with HR+ EBC, the model showed anastrozole treatment (versus tamoxifen) would lead to 257 QALYs gained (0.26 QALYs gained per patient), at an additional cost of $5.21 million over 25 years ($5,212 per patient). The estimated incremental cost-effectiveness ratio (ICER) of anastrozole compared with tamoxifen was $20,246 per QALY gained ($23,541 per life-year gained). Cost-effectiveness acceptability curves indicated a >90% probability that the cost per QALY gained with anastrozole would be <$50,000. Results were robust in a sensitivity analysis. Anastrozole is a cost-effective alternative to tamoxifen for the primary adjuvant treatment of postmenopausal women with HR+ EBC.

Background: The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial compared the efficacy and safety of 5 years of anastrozole with tamoxifen as adjuvant treatment for postmenopausal women with localized HR+ breast cancer. At a median follow-up of 10 years, a statistically significant improvement with anastrozole vs. tamoxifen for disease-free survival, time to recurrence and time to distant recurrence was observed. The HOXB13:IL17BR gene expression ratio (H/I) quantifies recurrence risk in ER positive (ER+) breast cancer patients and is predictive of benefit from endocrine therapy. Molecular Grade Index (MGI) is a five-gene index that provides quantitative and objective molecular assessment of tumor grade and proliferative status. Breast Cancer Index (BCI) combines H/I and MGI into a continuous risk model that provides a likelihood of distant recurrence in patients treated with endocrine therapy, and efficacy from neoadjuvant chemotherapy. In the current analysis, evaluation of the prognostic and predictive performance of BCI, H/I and MGI in the ATAC study cohort was conducted. Methods: Under the TransATAC protocol, formalin-fixed, paraffin-embedded (FFPE) blocks of primary tumor were collected from HR+ patients from each monotherapy arm. The current study examined samples collected from the United Kingdom, which constituted 79% of the collection. RNA extracted from 1102 samples from the TransATAC study was amplified, converted to cDNA and subjected to RT-PCR with primers and probes to HOXB13, IL17BR, BUB1A, CENPA, NEK2, RACGAP1 and RRM2. H/I, MGI and BCI were calculated and risk groups were determined using pre-specified cutpoints. Results: Of 1102 tumor specimens assayed, 29 failed QC criteria, leaving 1073 samples for analysis. Detailed results on the prognostic and predictive performance of BCI, H/I and MGI will be presented. Data on whether BCI and its components provided independent prognostic information in the presence of classical variables, their prognostic value for risk of late recurrence, interaction by treatment arms, and comparative performance vs other models will also be discussed. Discussion: The ATAC trial has established the long-term efficacy and safety of anastrozole over tamoxifen as initial adjuvant treatment for post-menopausal early stage breast cancer patients. Continued efforts are needed to improve on quantification of residual risk in patients who were treated with endocrine therapy to guide decision-making in selecting additional adjuvant chemotherapy and/or administering extended endocrine treatment. This study will help to establish the strategy to more effectively select patients for adjuvant therapies. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-15.

Background. Even in view of the recent findings of the MA.17R trial, the impact of prolonged aromatase inhibitor (AI) therapy after prior tamoxifen in hormone receptor-positive early breast cancer remains insufficiently clear. Methods. In this open-label phase III study, we randomly assigned 1912 postmenopausal women with hormone receptor-positive breast cancer after 2-3 years of adjuvant tamoxifen to either 3 or 6 years of anastrozole therapy. The primary endpoint was the adapted disease-free survival (ADFS). This was defined as the DFS beyond 3 years after randomization to AI therapy because initially all patients received the same AI therapy for 3 years. ADFS events included (non-) invasive breast cancer recurrences (local, regional, distant), second primary (non-) invasive (breast) cancers, and death of any cause. The study was designed to detect an increase of the ADFS in the 6-year versus the 3-year anastrozole group corresponding with a hazard ratio (HR) of 0.60. The HRs and the corresponding 95% confidence intervals (CIs) were estimated with stratified Cox proportional-hazard models according to intention-to-treat. Results. Patients were randomized from July 2006 till August 2009. Three years after randomization 1663 patients had no DFS events, with an equal distribution between the treatment arms. The patient and tumor characteristics were well balanced. The median age at randomization was 57 years (P5 = 45 years, P95 = 76 years), the median primary tumor size was 21 mm (P5 = 10 mm, P95 = 50 mm), 67% of the patients had node-positive disease, and in 2% the tumor was HER2-positive (14% unknown); 64% of the patients had received adjuvant chemotherapy and &amp;lt;1% adjuvant trastuzumab. The median adapted follow-up was 4.1 years (P5 = 2.9 years, P95 = 5.8 years). No unexpected safety issues were seen. The 5-year ADFS was 79% in the 3-year and 83% in the 6-year anastrozole treatment group, yielding a HR for ADFS-event of 0.78 (95% CI 0.61 to 1.00; p = 0.0528). In patients with node-positive disease (N = 1117), the HR for ADFS-event was 0.71 (95% CI 0.53 to 0.96; p=0.0232), in N0 disease (N=546) 1.01 (95% CI 0.62 to 1.63; p=0.9817) and in patients with both ER and PR positive breast cancer (N = 1264) 0.68 (95% CI 0.51 to 0.90; p=0.0072). The 5-year adapted overall survival was not different between the treatment groups. Conclusion. These findings do not yet support the use of extended adjuvant AI prescription after 5 years of sequential endocrine therapy for postmenopausal patients with hormone receptor-positive breast cancer, but suggest benefit for a selected group of patients. Continued follow-up is needed to assess long-term efficacy and safety. Funding. Funded by AstraZeneca NL, ClinicalTrials.gov number, NCT00301457. Citation Format: Tjan-Heijnen VC, Van Hellemond IE, Peer PG, Swinkels AC, Smorenburg CH, Van der Sangen M, Kroep JR, De Graaf H, Honkoop AH, Erdkamp F, Van den Berkmortel FW, Kitzen JJ, De Boer M, De Roos WK, Linn SC, Imholz AL, Seynaeve C. First results from the multicenter phase III DATA study comparing 3 versus 6 years of anastrozole after 2-3 years of tamoxifen in postmenopausal women with hormone receptor-positive early breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S1-03.

There have been many randomised trials of adjuvant tamoxifen among women with early breast cancer, and an updated overview of their results is presented. In this report, the Early Breast Cancer Trialists' Collaborative Group present their third 5-yearly systematic overview (meta-analysis) of treatment with tamoxifen. Trial identification procedures for the EBCTCG overviews have been described elsewhere. See under "EBCTCG" in the Breast Cancer Collaborative Review Group module. All randomised trials that began before 1990 and compared adjuvant tamoxifen for any duration versus no such treatment for women with early breast cancer. In 1995, information was sought on each woman in any randomised trial that began before 1990 of adjuvant tamoxifen versus no tamoxifen before recurrence. Information was obtained and analysed centrally on each of 37,000 women in 55 such trials, comprising about 87% of the worldwide evidence. Compared with the previous such overview, this approximately doubles the amount of evidence from trials of about 5 years of tamoxifen and, taking all trials together, on events occurring more than 5 years after randomisation. Nearly 8000 of the women had a low, or zero, level of the oestrogen-receptor protein (ER) measured in their primary tumour. Among them, the overall effects of tamoxifen appeared to be small, and subsequent analyses of recurrence and total mortality are restricted to the remaining women (18,000 with ER-positive tumours, plus nearly 12,000 more with untested tumours, of which an estimated 8000 would have been ER-positive). For trials of 1 year, 2 years, and about 5 years of adjuvant tamoxifen, the proportional recurrence reductions produced among these 30,000 women during about 10 years of follow-up were 21% (SD 3), 29% (SD 2), and 47% (SD 3), respectively, with a highly significant trend towards greater effect with longer treatment (2p<0.00001). The corresponding proportional mortality reductions were 12% (SD 3), 17% (SD 3), and 26% (SD 4), respectively, and again the test for trend was significant (2p=0.003). The absolute improvement in recurrence was greater during the first 5 years, whereas the improvement in survival grew steadily larger throughout the first 10 years. The proportional mortality reductions were similar for women with node-positive and node-negative disease, but the absolute mortality reductions were greater in node-positive women. In the trials of about 5 years of adjuvant tamoxifen the absolute improvements in 10-year survival were 10.9% (SD 2.5) for node-positive (61.4% vs 50.5% survival, 2p<0.00001) and 5.6% (SD 1.3) for node-negative (78.9% vs 73.3% survival, 2p<0.00001). These benefits appeared to be largely irrespective of age, menopausal status, daily tamoxifen dose (which was generally 20 mg), and of whether chemotherapy had been given to both groups. In terms of other outcomes among all women studied (ie, including those with "ER-poor" tumours), the proportional reductions in contralateral breast cancer were 13% (SD 13), 26% (SD 9), and 47% (SD 9) in the trials of 1, 2, or about 5 years of adjuvant tamoxifen. The incidence of endometrial cancer was approximately doubled in trials of 1 or 2 years of tamoxifen and approximately quadrupled in trials of 5 years of tamoxifen (although the number of cases was small and these ratios were not significantly different from each other). The absolute decrease in contralateral breast cancer was about twice as large as the absolute increase in the incidence of endometrial cancer. Tamoxifen had no apparent effect on the incidence of colorectal cancer or, after exclusion of deaths from breast or endometrial cancer, on any of the other main categories of cause of death (total nearly 2000 such deaths; overall relative risk 0.99 [SD 0.05]). For women with tumours that have been reliably shown to be ER-negative, adjuvant tamoxifen remains a matter for research. However, some years of adjuvant tamoxifen treatment substantially improves the 10-year survival of women with ER-positive tumours and of women whose tumours are of unknown ER status, with the proportional reductions in breast cancer recurrence and in mortality appearing to be largely unaffected by other patient characteristics or treatments.

A number of trials have studied the value of aromatase inhibitors (AIs) for the adjuvant treatment of early hormone-responsive postmenopausal breast cancer. Three different AIs have been used and they have been compared as initial treatment (two trials) or after 2–3 years of tamoxifen (four trials), in both cases against a standard arm of 5 years of tamoxifen. In addition, two trials have evaluated AIs against no treatment after 5 years of tamoxifen. In all circumstances, the AIs have demonstrated superior efficacy. However, no results are currently available for the key question, that is – is it better to start initially with an AI or use it sequentially after 2 years of tamoxifen? Here, we review the trial results and present two models, which address this issue. The models clearly show that early treatment with an AI is superior to using it after 5 years of tamoxifen. They also favour an upfront strategy to sequencing after 2 years of tamoxifen, but in this case the differences are small and model-dependent. A key question is whether AIs have substantially better efficacy than tamoxifen for ER-positive–PgR-negative tumours, where the data are currently contradictory. A mechanism explaining why greater efficacy might be so is proposed. Further results from ongoing trials will be needed to resolve this issue.

Background: The non-steroidal reversible aromatase inhibitor (AI), anastrozole (A) is approved as adjuvant monotherapy in hormone receptor (HR) positive early breast cancer (EBC). The steroidal irreversible AI exemestane (E) is approved in sequence after an initial 2-3 years of tamoxifen. MA27 tested the hypothesis that exemestane would have greater efficacy and better end-organ safety than anastrozole for several reasons: E is an irreversible and more potent AI than A; unlike A, E does not induce intra-tumoral aromatase and; through its mild androgenic activity E may exert a second anti-tumor effect and a more favorable bone and lipid metabolism profile than A. Initially the study also tested the role of a cyclooxygenase-2 inhibitor, celecoxib, used in combination with an AI. However, celecoxib was discontinued early in MA27 following identification of cardiovascular toxicity with COX-2 inhibitors. Methods: Postmenopausal women with hormone receptor positive primary breast cancer were randomized after adequate local treatment to 5 years of adjuvant A (1mg/day) or E (25mg/day) with or without celecoxib/placebo (400mg/plac twice daily for 3 years). The primary objective is the comparison of event free survival (EFS) between women treated with A or E. Secondary objectives include overall survival (OS), distant recurrence (DDFS), incidence of contralateral breast cancer (CBC) and safety. Quality of Life in a subset of women has been evaluated, and a very extensive tissue bank created. Stratification included: prior chemotherapy; lymph node status, celecoxib (during use), aspirin use (during randomization to celecoxib), and trastuzumab use (since November 2005). The primary endpoint (EFS) will look for an improvement from 87.5% to 89.9%; HR 0.80, 2-sided 5% level and 80% power, with 644 events required. Results: 7576 women were randomized between June 2003 and July 2008. Celecoxib/placebo, was discontinued 2 years into the trial in December 2004 after 1635 patients had received celecoxib. The number of events required for final analysis was reached April 2010. Patient characteristics were balanced for age (median 64.1yrs); race; ECOG PS; mastectomy; TNM staging and; prior adjuvant chemotherapy. EFS, OS, DDFS, and CBC as well as clinical fractures, cardiovascular events and adverse events will be presented by arm in the final analysis. Conclusions: NCIC CTG MA.27 is the first definitive EBC trial comparing a non-steroidal and steroidal AI as initial adjuvant therapy. Exemestane is not currently approved as initial adjuvant treatment and superiority or equivalence will lead to its inclusion as a first-line option for EBC in postmenopausal HR positive breast cancer. Efficacy, clinical fractures, cardiovascular events and AI related symptoms will help to define the cost-benefit ratios of these two AIs. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S1-1.

ABSTRACTWomen who are diagnosed with early breast cancer remain at considerable risk of recurrence over the next several decades, even if their tumors were small and lymph nodes were negative, and despite receiving standard adjuvant therapy. A majority of breast cancers are hormone (estrogen) receptor-positive and amenable to endocrine therapy, and for those women five years of the selective estrogen receptor modulator tamoxifen is standard therapy. Longer treatment of node-negative patients with tamoxifen may reduce survival benefits, however, possibly due to tamoxifen resistance and emerging receptor agonist activity of that drug. Aromatase inhibitors, which indirectly prevent estrogen stimulation of breast cancer by suppressing whole-body estrogen synthesis in post-menopausal women, are being investigated as alternative, or complementary, therapy to adjuvant tamoxifen in those women: as an alternative to five years of tamoxifen, sequenced with two to three years of tamoxifen, or following five years of tamoxifen. The strategy to extend the benefits of adjuvant therapy beyond a standard course of tamoxifen, using the aromatase inhibitor letrozole, was explored in a large trial, MA.17. Compared with women who received placebo, those who were treated with letrozole experienced a significant 43% reduction in their residual risk of recurrence. This effect was seen regardless of nodal status. Based on the long-term risk of most women with early breast cancer and the MA.17 trial results, the extended adjuvant letrozole may benefit many of those women who are disease-free after five years of tamoxifen.This review is based on a literature search of databases including MEDLINE/PubMed, San Antonio Breast Cancer Symposium, and the Annual Meeting of the American Society of Clinical Oncology, up to and including August 2005, with information selected for its relevance to adjuvant therapy of breast cancer with endocrine therapy only.

Adjuvant therapy for breast cancer with aromatase inhibitors improves survival compared with tamoxifen; however, whether they should be given upfront or sequentially after 2–3 years of tamoxifen in estrogen receptor-positive early breast cancer affecting postmenopausal women is unclear. The Intergroup Exemestane Study looked at 4724 postmenopausal patients with estrogen receptor-positive or unknown breast cancer who had been disease free for 2–3 years on tamoxifen and were randomly assigned to switch to exemestane or to continue tamoxifen for the remainder of a 5-year endocrine treatment period. A significant disease-free survival advantage (p = 0.0001) was seen in favor of exemestane, with an absolute benefit of 3.3% by the end of treatment. This trial is the first to show an overall survival advantage for switching in estrogen receptor-positive breast cancer (p≤ 0.05). In total, 222 deaths occurred in the exemestane group compared with 261 deaths in the tamoxifen group, with a hazard ratio of 0.8 (95% confidence interval: 0.71–1.02; p = 0.08). A retrospective exclusion of patients who had estrogen receptor-negative disease improved the adjusted hazard ratio to 0.85 (0.69–1.0; p = 0.05). Contralateral breast cancer was reduced by 50% both in intention-to-treat and estrogen receptor-positive groups. These results indicate that a similar overall reduction in recurrence can be achieved with a switching or an upfront aromatase inhibitor strategy, but with a reduction in the overall morbidity. The 5% of early breast cancer patients who relapse in the first 2 years of tamoxifen treatment can be identified from 10% of the overall population. The remaining 90% could switch after 2–3 years. Controversy remains regarding whether switching is the optimal strategy and will only be resolved following the results of the Breast International Group 1-98 trial involving sequential therapy. Switching to exemestane for patients who have already had tamoxifen therapy for 2–3 years would appear to be an appropriate strategy for the majority of early breast cancer patients.

Aromatase inhibitors in the management of early breast cancer: Optimizing the clinical benefit

Emerging data from clinical trials on the use of aromatase inhibitors in the management of early-stage, hormone-dependent breast cancer in postmenopausal women are reviewed. Aromatase is the enzyme responsible for the conversion of androgens to estrogens and the only source of estrogens in postmenopausal women. Clinical trials using aromatase inhibitors in the adjuvant treatment of postmenopausal women with breast cancer are few but significant because of their comparative design with tamoxifen given for five years, long regarded as the gold standard for breast cancer treatment. Data from the Anastrozole, Tamoxifen and Combination trial, the MA-17 trial (letrozole compared with placebo), the Italian Tamoxifen Arimidex trial (anastrozole following tamoxifen), and the Intergroup Exemestane Study have shown promising efficacy and safety in the use of these agents. While the optimal aromatase inhibitor for use in the adjuvant setting has not been elucidated, current evidence-based recommendations include using (1) anastrozole as the first adjuvant therapy for five years, (2) tamoxifen for two to three years, then exemestane or anastrozole for the remainder of the five years, and (3) tamoxifen for five years, then letrozole for another five years. While their impact on survival has not been determined, aromatase inhibitors are slowly changing the management of early-stage, hormone-dependent breast cancer in postmenopausal women because of improved disease-free survival rates. Their ultimate role in therapy is unknown, but educating patients about the potential risks and benefits will allow them to make informed decisions regarding these data and their breast cancer care.

BackgroundAromatase Inhibitors (AI) are an important component in adjuvant therapy in postmenopausal women with positive estrogenic receptors in breast cancer. They inhibit the enzyme Cytochrome P450 CYP19, which causes a...

Moving Research From Bench to Bedside to Community: There Is Still More to Do

Third-generation aromatase inhibitors (AIs), including letrozole, are now standard therapy for initial adjuvant endocrine treatment of postmenopausal women with early breast cancer. The International Breast Cancer Study Group's Breast International Group (BIG) 1-98 trial is examining efficacy and safety of letrozole or tamoxifen, whether used upfront or sequentially, for postmenopausal with hormone receptor-positive breast cancer. Women in the BIG 1-98 trial were randomized to either 5 years' monotherapy with tamoxifen or letrozole (trial arms A and B, respectively), or to 5 years' sequential therapy with 2 years of tamoxifen followed by 3 years of letrozole, or 2 years of letrozole followed by 3 years of tamoxifen (arms C and D, respectively). Results of the primary core analysis (PCA) of BIG 1-98, at a median follow-up of 25.8 months, showed a significant improvement in disease-free survival for patients treated with initial adjuvant letrozole relative to those on tamoxifen (P=0.003). Of interest, there was an important reduction in distant metastases, the most common and ultimately fatal type of early recurrence, for patients allocated to initial letrozole compared with initial tamoxifen. Since the PCA, there have been further analyses of BIG 1-98 with variations in the cohorts analyzed and follow-up period. The first and largest central pathology review in an adjuvant AI trial to date was also performed in the BIG 1-98 trial. In light of the impending sequence analysis, expected in late 2008, the goal of this article is to describe and summarize the breadth of information learned to date and highlight the key findings regarding the efficacy and safety of letrozole in the initial adjuvant setting.

341 POSTER Letrozole is cost-effective versus tamoxifen as adjuvant therapy in postmenopausal women with early breast cancer: BIG-1-98

Abstract #12 Background: Meta-analyses (EBCTCG, Lancet 2005; 365:2687) have established in estrogen receptor (ER) positive breast cancer (BC) that 5 yrs of adjuvant tamoxifen (Tam) substantially reduces recurrence and mortality. The aromatase inhibitors (AIs) anastrozole, exemestane and letrozole have been studied in prospective trials in postmenopausal patients (pts) in comparison with Tam either as initial monotherapy (Cohort 1) or after 2 to 3 years of Tam in a switching strategy (Cohort 2); both to a total of 5 years (yrs) of endocrine therapy.&amp;#x2028; Methods: Outcomes data submitted to EBCTCG were used in separate meta-analyses of Cohort 1 (trials: ATAC, BIG 1-98/IBCSG 18-98) and of Cohort 2 (trials: ABCSG 8, ARNO 95, IES/BIG 2-97, ITA). The primary analysis involved pts with tumors reported to be ER positive with endpoints of BC recurrence (all, local only, contralateral BC only, distant), death with and without recurrence, any death. Subgroup analyses included progesterone receptor (PgR) status, age, tumor grade and nodal status. All p-values were 2-sided.&amp;#x2028; Results: Highlights include: Cohort 1: 9,856 pts with 50,000 woman-years of follow-up. At 5 yrs, AI therapy was associated with an absolute 2.7% (standard error [SE] 0.7) decrease in BC recurrence (10.7% vs 13.4%, relative decrease 20% [SE 5], p=0.00004). There appeared to be greater proportional decreases in isolated local recurrence (30% [SE 10], p=0.003) and in contralateral disease (38% [SE 12], p=0.003) than in distant recurrence (12% [SE 6], p= 0.04). AIs yielded an absolute 1.0% (SE 0.5) decrease in BC mortality (5.5% vs 6.5%, relative decrease 7% [SE 7], p=0.28). Cohort 2: 9,015 pts with 33,000 woman-years of follow-up. At 6 yrs from treatment divergence (i.e., 8-9 yrs from diagnosis), AI therapy was associated with an absolute 3.5% (SE 1.1) decrease in BC recurrence (12.6% vs 16.1%, relative decrease 29% [SE 6], p&amp;lt;0.00001). There appeared to be greater proportional reductions in isolated local recurrence (40% [SE 13], p=0.002) and in contralateral disease (35% [SE 16], p=0.03) than in distant recurrence (24% [SE 7], p= 0.001). AIs yielded an absolute 1.6% (SE 0.8) decrease in BC mortality (6.3% vs 8.0%, relative decrease 22% [SE 9], p=0.02). Subset analyses with respect to PgR status, age, tumor grade and nodal status revealed no apparent heterogeneity between the proportional reductions in recurrence and no indication of an increase or decrease in non-breast deaths with AIs in either cohort 1 or 2.&amp;#x2028; Conclusions: In 2 separate meta-analyses considering both the initial monotherapy setting and the switching setting after 2 to 3 yrs of Tam, AIs produced significantly lower BC recurrence rates compared with Tam. Additional follow-up data will provide important information on long-term survival. Meta-analyses can be helpful even in the era of relatively large clinical trials. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 12.