Tamoxifen In Early Breast Cancer Research Articles

Treatment adoption and relative effectiveness of aromatase inhibitors compared to tamoxifen in early breast cancer: A multi-institutional observational study

BackgroundSince 2005, aromatase inhibitors (AIs) have been the adjuvant treatment of choice for postmenopausal women with early breast cancer (BC). In this study we characterize the adoption of AIs in Portugal, variables associated with treatment administration, and compare its effectiveness (either in monotherapy or sequential therapy) to tamoxifen monotherapy (TAM). Patients and methodsThis was a retrospective cohort study that included postmenopausal women with stage I-III hormone receptor (HR) positive BC diagnosed from 2006 to 2008 and treated with adjuvant endocrine therapy in four participating institutions. ResultsOf the 1283 eligible patients, 527 (41%) received an AI (16% as monotherapy, 25% as sequential therapy) and 756 (59%) TAM. Patients treated with AI had less differentiated tumors, with higher TNM stage, and were more frequently HER2-positive. Use of AI also differed by center (use range from 33% to 75%, p < 0.001). With a median follow-up of 6.3 years and controlling for clinicopathological and treatment characteristics, treatment with AI had a better overall survival (OS) when compared with TAM (adjusted-HR 0.55, 95% CI 0.37–0.81). ConclusionAIs were successfully introduced as adjuvant treatment for HR-positive BC in Portuguese hospitals. Its use was influenced by tumor and patient characteristics, but also center of care. In this large cohort, AI use was associated with an OS benefit.

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

The optimal ways of using aromatase inhibitors or tamoxifen as endocrine treatment for early breast cancer remains uncertain. 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). 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. 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. Cancer Research UK, Medical Research Council.

Women Commencing Anastrozole, Letrozole or Tamoxifen for Early Breast Cancer: The Impact of Comorbidity and Demographics on Initial Choice

BackgroundAustralian clinical guidelines recommend endocrine therapy for all women with hormone-dependent early breast cancer. Guidelines specify tamoxifen as first-line therapy for pre-menopausal women, and tamoxifen or an aromatase inhibitor (AI) for post-menopausal women depending on the risk of recurrence based on tumour characteristics including size. Therapies have different side effect profiles; therefore comorbidity may also influence choice. We examined comorbidity, and the clinical and demographic characteristics of women commencing different therapies.Patients and MethodsWe identified the first dispensing of tamoxifen, anastrozole or letrozole for women diagnosed with invasive breast cancer in the 45 and Up Study from 2004–2009 (N = 1266). Unit-level pharmacy and medical service claims, hospital, Cancer Registry, and self-reported data were linked to determine menopause status at diagnosis, tumour size, age, comorbidities, and change in subsidy restrictions. Chi-square tests and generalised regression models were used to compare the characteristics of women commencing different therapies.ResultsMost pre-menopausal women commenced therapy with tamoxifen (91%). Anastrozole was the predominant therapy for post-menopausal women (57%), followed by tamoxifen (28%). Women with osteoporosis were less likely to commence anastrozole compared with tamoxifen (anastrozole RR = 0.7, 95% CI = 0.5–0.9). Women with arthritis were 1.6-times more likely to commence letrozole than anastrozole (95% CI = 1.1–2.1). Tamoxifen was more often initiated in women with tumours >1 cm, who were also ≥75 years. Subsidy restriction changes were associated with substantial increases in the proportion of women commencing AIs (anastrozole RR = 4.3, letrozole RR = 8.3).ConclusionsThe findings indicate interplay of comorbidity and therapy choice for women with invasive breast cancer. Most post-menopausal women commenced therapy with anastrozole; however, letrozole and tamoxifen were more often initiated for women with comorbid arthritis and osteoporosis, respectively. Tamoxifen was also more common for women with tumours >1 cm and aged ≥75 years. Subsidy restrictions appear to have strongly influenced therapy choice.

ANZ1001 SORBET: Study of Oestrogen Receptor Beta and Efficacy of Tamoxifen—A single-arm, phase II study of the efficacy of tamoxifen in triple-negative but estrogen receptor beta-positive metastatic breast cancer.

TPS126 Background: Patients with advanced triple negative breast cancer (BC) have limited treatment options and poor prognosis. At least 20% of triple negative BCs express estrogen receptor (ER) β, the second known isoform of the ER. ERβ binds estrogens and tamoxifen with a similar affinity to ERα and has 5 isoforms, but only ERβ1 is fully functional. There is no standardized method for measuring ERβ. Most published studies used antibodies to total ERβ and ERβ1 with immunohistochemistry (IHC) staining >10-20% or Allred scores to define positive. Two retrospective studies of the relationship between ERβ expression and tamoxifen in early BC have shown ERβ expression was significantly associated with better distant disease free survival and better overall survival in the tamoxifen treated ERα negative patients. This “proof of principle” study will determine the efficacy of tamoxifen in patients with triple negative but ERβ positive metastatic BC. Methods: This single arm phase II study has a Simon’s 2 stage optimal design. The primary end-point is objective response rate (complete and partial responses). Eligible patients have histologically or cytologically confirmed metastatic triple negative BC (ER and PR absent, HER2 ISH negative or IHC 0 or 1) and measureable disease as per RECIST 1.1. Consenting patients undergo central ERβ testing and confirmation of triple negative status on a metastatic biopsy sample. ERβ positive patients (ERβ1 nuclear staining with Allred score >4) are offered trial participation. Consenting patients receive tamoxifen 20mg per oral daily until disease progression, unacceptable toxicity or withdrawal of consent. If there are ≥2 responses in the first stage of 28 patients, an additional 38 patients will be accrued. Tamoxifen will be considered worthy of further research if there are ≥6 responses in the total 66 patients recruited. Progression free survival and clinical benefit rate will also be assessed.

Anastrozole superiority to tamoxifen for early breast cancer confirmed

Anastrozole superiority to tamoxifen for early breast cancer confirmed

Trastuzumab-Related Cardiotoxicity Following Anthracycline-Based Adjuvant Chemotherapy: How Worried Should We Be?

doses of the new selective aromatase inhibitor anastrozole (Arimidex) with megestrol acetate in postmenopausal patients with advanced breast cancer. Eur J Cancer 32A:404-412, 1996 7. Buzdar AU, Jones SE, Vogel CL, et al: A phase III trial comparing anastrozole (1 and 10 milligrams), a potent and selective aromatase inhibitor, with megestrol acetate in postmenopausal women with advanced breast carcinoma: Arimidex Study Group. Cancer 79:730-739, 1997 8. Ward HW: Anti-oestrogen therapy for breast cancer: A trial of tamoxifen at two dose levels. Br Med J 1:13-14, 1973 9. Takatsuka Y, Yayoi E, Inaji H, et al: A comparison of two doses of tamoxifen in patients with advanced breast cancer: 20 mg/day versus 40 mg/day [in Japanese]. Gan To Kagaku Ryoho 16:2093-2097, 1989 10. Tamoxifen for early breast cancer: An overview of the randomised trials—Early Breast Cancer Trialists’ Collaborative Group. Lancet 351:14511467, 1998 11. Lonning PE: Pharmacology of new aromatase inhibitors. The Breast 5:202-208, 1996 12. Goodwin PJ, Ligibel JA, Stambolic V: Metformin in breast cancer: Time for action. J Clin Oncol 27:3271-3273, 2009 13. Ballard-Barbash R, Hunsberger S, Alciati MH, et al: Physical activity, weight control, and breast cancer risk and survival: Clinical trial rationale and design considerations. J Natl Cancer Inst 101:630-643, 2009

Cytochrome P450 2D6 mutation in Turkish women receiving adjuvant tamoxifen.

e11098 Background: Despite recent advances in hormonal therapy for breast cancer, tamoxifen remains a major therapeutic option. Polymorphisms in cytochrome P450 2D6 (CYP2D6) gene affect the plasma concentration of tamoxifen active metabolites (endoxifen). Diminished CYP2D6 function, both by genetic variation or concurrent use of pharmacologic inhibitors, can significantly reduce endoxifen plasma concentrations and may lead to reduced TAM effectiveness. Methods: Breast cancer patients who were treated with tamoxifen as adjuvant therapy between November 1989 and November 2009 were included. According to our database 430 patients were analyzed. The mutations were analyzed in all the patients by PCR (C2D6 Vienna LAB, PGX-HIV Strip assay, Austria) from DNA of blood samples and the patients with a genetic variation that ended in an inactive form of P450 2D6 mutations were searched. These mutations were 1795 delT, 1934 G > A and 2637 del A. Results: Of all 430 patients, 18 (4.2%) were detected to have a mutation for CYP2D6 indicating poor metabolizers. Genotype frequency for poor metabolizers were wt/wt 83.5%, *3/*4 (5.5%), *4/*6 (5.5%), and *6/*6 (5.5%). 68.6 % of the patients had wild type genotype and 27.2% had heterozygous indicating normal metabolizer for tamoxifen. Conclusions: CYP2D6 metabolism, as measured by genetic variation and enzyme inhibition, is an independent predictor of breast cancer outcome in post-menopausal women receiving tamoxifen for early breast cancer. In our series frequency of poor metabolizers genetic variations were 4.2% and determination of CYP2D6 genotype may be of value in selecting adjuvant hormonal therapy. No significant financial relationships to disclose.

Bone Quality Test (BQT) scores of fingernails in postmenopausal patients treated with adjuvant letrozole or tamoxifen for early breast cancer

Background The relationship between nail and bone may be measurable, thus making the fingernail a potentially valuable tool for assessing bone health for women receiving treatment for breast cancer. In the BIG 1-98 Fingernail Pilot Substudy, Bone Quality Test (BQT) scores of fingernails were measured at two assessment timepoints. Methods Thirteen eligible patients were enrolled into the substudy during their treatment with tamoxifen (four patients) or letrozole (nine patients). Two fingernails were tested and BQT scores averaged for two assessments six months apart. Results BQT scores collected six months later (second assessment) significantly decreased compared with those at first collection ( p = 0.007) regardless of treatment and prior fracture. Conclusion The reduction of BQT scores observed in the patients of our small exploratory study during exposure to bone-altering breast cancer treatments is an incentive for larger studies using this technique.

WITHDRAWN: Tamoxifen for early breast cancer.

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.

Comparison of the cost-effectiveness of upfront letrozole or anastrozole versus tamoxifen for early breast cancer in hormone receptor positive (HR+) postmenopausal women -the Cypriot perspective

Recently aromatase inhibitors have become a standard care as an adjuvant treatment for many postmenopausal patients with hormone receptor positive early breast cancer. Adjuvant letrozole was made available either immediately postoperative, after 2–3 years of tamoxifen, or as an extended treatment after 5 years of tamoxifen. Between October 2003 and October 2005, we analyzed the subjective tolerance in 185 postoperative early breast cancer patients receiving letrozole outside of a clinical trial. The most prominent toxicity was musculoskeletal pain. In addition hot flushes, increased fatigue, nausea, vomiting, anorexia, mood disturbances, vaginal dryness, hair loss and rash were also recorded.In contrast to the prospective randomized clinical trials, a high drop-out rate of 20% was documented, mainly due to aromatase inhibitor-associated arthralgia syndrome interfering significantly with the daily life of our patients.Although adjuvant aromatase inhibitors have proven to be generally superior to tamoxifen in the adjuvant setting, it is important to focus attention on the tolerance during the adjuvant therapy and to balance this against the potential benefit in individual patients. Alternative options including switching to tamoxifen remain available.

Do adjuvant aromatase inhibitors increase the cardiovascular risk in postmenopausal women with early breast cancer

Despite the advantages from using aromatase inhibitors (AIs) compared with tamoxifen for early breast cancer, an unexpectedly greater number of grade 3 and 4 cardiovascular events (CVAE) (as defined by National Cancer Institute of Canada-Common Toxicity Criteria [version 2.0] was demonstrated. Phase 3 randomized clinical trials (RCTs) comparing AI with tamoxifen in early breast cancer were considered eligible for this review. The event-based risk ratios (RRs) with 95% confidence intervals (95% CIs) were derived, and a test of heterogeneity was applied. Finally, absolute differences (ADs) in event rates and the number of patients needed to harm 1 patient (NNH) were determined. Seven eligible RCTs (19,818 patients) reported CVAE results. When considering all RCTs, the AD of the primary endpoint (CVAE) between the 2 arms (0.52%), tamoxifen versus AI, was statistically significant (RR, 1.31; 95% CI, 1.07-1.60; P= .007). This translated into an NNH value of 189 patients; when only third-generation AIs were considered, the difference (0.57%) remained significant (RR, 1.34; 95% CI, 1.09-1.63; P= .0038). Thromboembolic events were significantly more frequent in the tamoxifen arm, regardless of the strategy adopted (RR, 0.53; 95% CI, 0.42-0.65; P< .0001), without significant heterogeneity (P= .21). An AD of 1.17% and an NNH value of 85 patients were observed. According to the results from this meta-analysis, the risk of grade 3 and 4 CVAEs in patients who were receiving AIs was higher compared with the risk in patients who were receiving tamoxifen, and the difference reached statistical significance. However, the AD was relatively low, and from 160 to 180 patients had to be treated to produce 1 event.

Comparison of Menopausal Symptoms During the First Year of Adjuvant Therapy With Either Exemestane or Tamoxifen in Early Breast Cancer: Report of a Tamoxifen Exemestane Adjuvant Multicenter Trial Substudy

Hormonal breast cancer treatment increases menopausal symptoms in women. This study investigated differences between the symptoms associated with either adjuvant tamoxifen or exemestane. Ten common symptoms were assessed by self-report questionnaire administered to 1,614 consecutive patients at baseline and every 3 months during the first year of a double-blind, randomized trial of postmenopausal women with early hormone receptor-positive breast cancer. Symptoms were categorized as none, mild, moderate, or severe. A hot flash score was calculated at each time point. Symptoms were analyzed by repeated-measures analysis of variance. Each time period was tested repeatedly against the baseline; an overall P value was assigned for each reported symptom. Compliance was excellent, with 7,286 questionnaires analyzed. Baseline symptom prevalence ranged from 2% (vaginal bleeding) to 60% to 70% (bone/muscle aches and low energy). There were no significant differences in vaginal bleeding, mood alteration, or low energy. Patients receiving tamoxifen had significantly more vaginal discharge (P < .0001). Exemestane patients reported more bone/muscle aches (P < .0001), vaginal dryness (P = .0004), and difficulty sleeping (P = .03). In both groups, the hot flash score peaked at 3 months and decreased thereafter. At 12 months, patients receiving tamoxifen had a significantly higher mean hot flash score (P = .03), with daily hot flashes increasing from baseline by 33% compared with a 7% increase from baseline with exemestane. At 12 months, exemestane was associated with fewer hot flashes and less vaginal discharge than tamoxifen, but with more vaginal dryness, bone/muscle aches, and difficulty sleeping. Symptoms were common in both groups.

2092 POSTER Comparison of cost-effectiveness of aromatase inhibitors letrozole, anastrozole or exemestane versus tamoxifen for early breast cancer in hormone receptor-positive postmenopausal women: Canadian perspective

Early improvements in disease-free survival have been noted when an aromatase inhibitor is given either instead of or sequentially after tamoxifen in postmenopausal women with oestrogen-receptor-positive early breast cancer. However, little information exists on the long-term effects of aromatase inhibitors after treatment, and whether these early improvements lead to real gains in survival.4724 postmenopausal patients with unilateral invasive, oestrogen-receptor-positive or oestrogen-receptor-unknown breast cancer who were disease-free on 2–3 years of tamoxifen, were randomly assigned to switch to exemestane (n=2352) or to continue tamoxifen (n=2372) for the remainder of a 5-year endocrine treatment period. The primary endpoint was disease-free survival; overall survival was a secondary endpoint. Efficacy analyses were intention-to-treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN11883920.After a median follow-up of 55·7 months (range 0–89·7), 809 events contributing to the analysis of disease-free survival had been reported (354 exemestane, 455 tamoxifen); unadjusted hazard ratio 0·76 (95% CI 0·66–0·88, p=0·0001) in favour of exemestane, absolute benefit 3·3% (95% CI 1·6–4·9) by end of treatment (ie, 2·5 years after randomisation). 222 deaths occurred in the exemestane group compared with 261 deaths in the tamoxifen group; unadjusted hazard ratio 0·85 (95% CI 0·71–1·02, p=0·08), 0·83 (0·69–1·00, p=0·05) when 122 patients with oestrogen-receptor-negative disease were excluded.Our results suggest that early improvements in disease-free survival noted in patients who switch to exemestane after 2–3 years on tamoxifen persist after treatment, and translate into a modest improvement in overall survival.

2062 POSTER Comparison of the cost-effectiveness of upfront letrozole or anastrozole, or switched exemestane versus tamoxifen for early breast cancer in hormone receptor positive (HR+) postmenopausal women: the UK perspective

2062 POSTER Comparison of the cost-effectiveness of upfront letrozole or anastrozole, or switched exemestane versus tamoxifen for early breast cancer in hormone receptor positive (HR+) postmenopausal women: the UK perspective

Comparison of the cost per distant disease-free year gained for upfront letrozole or anastrozole, or switched exemestane compared to tamoxifen for early breast cancer in hormone receptor-positive postmenopausal women: The UK perspective

557 Background: Due to subsequent poor prognosis, prevention of distant recurrence (DR) is a primary aim of adjuvant hormonal therapy for early breast cancer. Compared to 5 years TAM in hormone receptor positive (HR+) postmenopausal women, DR relative risks are 0.73 (95% CI 0.6 - 0.88) for 5 years letrozole (LET), 0.84 (95% CI 0.7 - 1.0) for 5 years anastrozole (ANA), 0.73 (95% CI 0.59 - 0.9) for 2–3yrs exemestane after 2–3 years (EXE/TAM). This analysis evaluates the incremental cost per distant disease free year gained from a UK NHS perspective of LET, ANA, EXE/TAM versus 5 years TAM using the same health economic model. Methods: A Markov model described pathways through relevant health states over the remaining lifetime of a cohort of HR+ women aged 61 yrs. Probabilities of breast cancer events (contralateral; locoregional; soft tissue, bone, and visceral metastases) adverse events (endometrial cancer, hip and other fractures, cardiovascular disease, thromboembolic events, and arthralgia) were based on the latest early breast cancer overview, published results of the BIG 1–98, ATAC, and IES trials, and UK population-based studies as appropriate. Conservatively, no carry-over effect was assumed for the AIs after therapy discontinuation. Costs (2005 UK£) of breast-cancer care were obtained from a primary costing study in Scotland, and treatment costs for AEs were obtained from published studies. Costs and DR-free years were discounted at 3.5% annually. Results: The mean durations of DDFS were estimated to be 12.81, 12.66, 12.57, and 12.35 years for LET, ANA, TAM/EXE, and TAM, respectively. The incremental cost per distant disease free year gained of LET vs TAM is £10,379 (95% CI £5,286-£17,818), of ANA vs TAM is £11,428 (95% CI £5,071- £48,856), and of TAM/EXE vs TAM alone is £11,020 (95% CI £4,820-£36,947). Conclusion: Compared to 5 years TAM, adjuvant treatment of postmenopausal HR+ women with an AI is a cost-effective use of UK NHS resources. Based on the mean results, LET appears to be the most cost-effective of the three AIs, despite its higher acquisition cost compared to ANA in the UK, though the confidence intervals are wide. [Table: see text]

International comparison of the cost-effectiveness of 5 years letrozole or anastrozole compared to 5 years tamoxifen for early breast cancer in hormone receptor-positive postmenopausal women: Belgium, Canada, UK, and US analyses

556 Background: The BIG1–98 and ATAC trials have proven the effectiveness of 5 years letrozole (LET) and anastrozole (ANA), respectively, compared to 5 years tamoxifen (TAM) for the treatment of postmenopausal women with hormone receptor positive (HR+) early stage breast cancer. This analysis uses similar assumptions to those used in the NICE appraisal in the UK, and country specific input data to estimate the cost-effectiveness of LET vs TAM and ANA vs. TAM from the Belgian, Canadian, UK, and US health care perspective (8 analyses). Methods: The same Markov model was used to estimate the incremental cost per quality-adjusted life year (QALY) gained (ICQ) across the 8 analyses in postmenopausal women with HR+ early stage breast cancer. Model events and assumptions were based on the analysis undertaken by the NICE appraisal team in the UK. Probabilities of breast cancer events (contralateral; locoregional; and metastases) were based on the latest early breast cancer (Lancet) overview. Country-specific cost, utility, and adverse event parameter values were informed by relevant population-based studies. LET and ANA effects were informed by published results of the BIG 1–98 and ATAC trials, which were assumed to cease after therapy discontinuation (other than fracture risk that continued for 5 further years). Costs and QALYs were estimated over the remaining lifetime of a cohort of HR+ women aged 60 yrs, discounted at 3.5% annually. Conclusion: Compared to TAM, adjuvant treatment of postmenopausal HR+ women with LET or ANA for 5 years is a cost-effective use of resources in all of the countries included in this analysis. Based on the model assumptions used by the NICE appraisal team in the UK, the mean results indicate that LET is more cost-effective than ANA, though the confidence intervals are wide. [Table: see text] No significant financial relationships to disclose.

P179 Comparison of the cost per distant disease free year gained of upfront letrozole or anastrozole, or switched exemestane versus tamoxifen for early breast cancer in hormone receptor positive (HR+) postmenopausal women: the UK perspective

P179 Comparison of the cost per distant disease free year gained of upfront letrozole or anastrozole, or switched exemestane versus tamoxifen for early breast cancer in hormone receptor positive (HR+) postmenopausal women: the UK perspective

The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen

Tamoxifen is biotransformed to the potent anti-estrogen, endoxifen, by the cytochrome P450 (CYP) 2D6 enzyme. CYP2D6 genetic variation and inhibitors of the enzyme markedly reduce endoxifen plasma concentrations in tamoxifen-treated patients. Using a North Central Cancer Treatment Group adjuvant tamoxifen trial, we performed a comprehensive evaluation of CYP2D6 metabolism by assessing the combined effect of genetic variation and inhibition of the enzyme system on breast cancer recurrence and death. Medical records were reviewed at each randomizing site to determine whether CYP2D6 inhibitors were co-prescribed with tamoxifen. Extensive metabolizers were defined as patients without a *4 allele (i.e., wt/wt) who were not co-prescribed a CYP2D6 inhibitor. Patients with decreased CYP2D6 metabolism were classified as intermediate or poor metabolizers (PM) based on the presence of one or two CYP2D6*4 alleles or the co-administration of a moderate or potent CYP2D6 inhibitor. The association between CYP2D6 metabolism and clinical outcome was assessed using Cox modeling. Medication history was available in 225/256 eligible patients and CYP2D6*4 genotype in 190 patients. Thirteen patients (6%) were co-prescribed a CYP2D6 inhibitor [potent (n = 3), moderate (n = 10)], resulting in the following CYP2D6 metabolism: extensive (n = 115) and decreased (n = 65). In the multivariate analysis, patients with decreased metabolism had significantly shorter time to recurrence (p = 0.034; adj HR = 1.91; 95% CI 1.05-3.45) and worse relapse-free survival (RFS) (p = 0.017; adj HR = 1.74; 1.10-2.74); relative to patients with extensive metabolism. Cox' modeling demonstrated that compared to extensive metabolizers, PM had the most significant risk of breast cancer relapse (HR 3.12, p = 0.007). CYP2D6 metabolism, as measured by genetic variation and enzyme inhibition, is an independent predictor of breast cancer outcome in post-menopausal women receiving tamoxifen for early breast cancer. Determination of CYP2D6 genotype may be of value in selecting adjuvant hormonal therapy and it appears CYP2D6 inhibitors should be avoided in tamoxifen-treated women.

Causes and prevention of tamoxifen-induced accumulation of triacylglycerol in rat liver

Tamoxifen can induce hepatic steatosis in women. In this study, we wanted to elucidate the mechanism behind the tamoxifen-induced accumulation of triacylglycerol in liver in female rats, and we hoped to prevent this development by combination treatment with the modified fatty acid tetradecylthioacetic acid (TTA). The increased hepatic triacylglycerol level after tamoxifen treatment was accompanied by decreased acetyl-coenzyme A carboxylase (ACC) and FAS activities, increased glycerol-3-phosphate acyltransferase (GPAT) activity, and a tendency to increased diacylglycerol acyltransferase (DGAT) activity. The activities and mRNA levels of enzymes involved in beta-oxidation, ketogenesis, and uptake of lipids from liver were unaffected by tamoxifen, whereas the uptake of lipoproteins was unchanged and the uptake of fatty acids was decreased. Combination treatment with tamoxifen and TTA (Tam+TTA) normalized the hepatic triacylglycerol level and increased the activities of ACC, FAS, GPAT, and DGAT compared with tamoxifen-treated rats. The activities and mRNA levels of enzymes involved in beta-oxidation, ketogenesis, and uptake of lipids were increased after Tam+TTA treatment. In conclusion, tamoxifen increased the hepatic triacylglycerol level, probably as a result of increased triacylglycerol biosynthesis combined with unchanged beta-oxidation. The tamoxifen-induced accumulation of triacylglycerol was prevented by cotreatment with TTA, through mechanisms of increased mitochondrial and peroxisomal beta-oxidation.

Potential clinical and economic impact of switching U.S. women to exemestane following 2–3 years of therapy with tamoxifen for early breast cancer

6109 Background: Switching postmenopausal women with early breast cancer to exemestane after 2–3 years of tamoxifen therapy has been reported to increase disease-free survival. However, the potential impact of this management strategy on the U.S. health-care system is unknown. The objective of this study was to estimate the 10-year clinical and economic consequences that would accrue if all eligible U.S. patients in 2006 were switched from tamoxifen to exemestane. Methods: A Markov model with a 10-year time horizon was used to predict patients’ transitions across various health states based on treatment strategy (continuing tamoxifen versus switching to exemestane), breast cancer status (no recurrence, local or distant recurrence, contralateral breast cancer), and other related health events (osteoporosis, endometrial cancer, death). Disease- and treatment-related events were estimated using data from the Intergroup Exemestane Study (IES); survival and medical-care costs by type of recurrence were estimated using SEER-Medicare data and published literature. The switch-eligible cohort was defined to be consistent with IES selection criteria and its size in 2006 estimated based on SEER-Medicare and market research data. Costs incurred in future years were discounted at 3% annually. Results: We estimate that 71,800 U.S. women would be eligible to switch from tamoxifen to exemestane in 2006. Doing so would be expected to prevent 3,000 cases of recurrence (21,100 vs 24,100) and 2,000 breast cancer deaths (12,800 vs 14,800) over 10 years. The net budgetary impact over 10 years is projected to be $320M ($992M vs $672M), reflecting a $336M increase in costs of adjuvant hormonal therapy ($500M vs $164M), a $32.1M increase in costs of monitoring and treatment of adverse events ($73.7M vs. $41.6M), and a $47.4M reduction in recurrence-related treatment costs ($419M vs $466M). Conclusion: Switching all eligible U.S. breast cancer patients from tamoxifen to exemestane in 2006 would increase medical-care costs by $4,460 per patient but reduce breast cancer recurrences by 12% and breast cancer deaths by 14% over 10 years. [Table: see text]