Intergroup Exemestane Study Research Articles

Dissecting the predictive value of MAPK/AKT/estrogen-receptor phosphorylation axis in primary breast cancer to treatment response for tamoxifen over exemestane: a Translational Report of the Intergroup Exemestane Study (IES)\u2014PathIES

PurposeThe prognostic and predictive values of the MAPK/AKT/ERα phosphorylation axis (pT202/T204MAPK, pT308AKT, pS473AKT, pS118ERα and pS167ERα) in primary tumours were assessed to determine whether these markers can differentiate between patient responses for switching adjuvant endocrine therapy after 2–3 years from tamoxifen to exemestane and continued tamoxifen monotherapy in the Intergroup Exemestane Study (IES).MethodsOf the 4724 patients in IES, 1506 were managed in a subset of centres (N = 89) participating in PathIES. These centres recruited 1282 (85%, 1282/1506) women into PathIES of whom 1036 had phospho-marker data. All phospho-markers were analysed by immunohistochemistry staining. Multivariable Cox proportional hazards models of the phospho-markers for disease-free survival (DFS) and overall survival (OS) were adjusted for clinicopathological factors. Treatment effects on the biomarker expression were determined by interaction tests. Benjamini–Hochberg adjustment for multiple testing with a false discovery rate of 10% was applied (pBH).ResultsPhospho-T202/T204MAPK, pS118ERα and pS167ERα were all found to be correlated (pBH = 0.0002). These markers were not associated with either DFS or OS when controlling for the established clinicopathological factors. Interaction terms between the phospho-markers and treatment strategies for either DFS or OS were not statistically significant (pBH > 0.05 for all).ConclusionsThis PathIES study confirmed previously described associations between the phosphorylation site markers of AKT, MAPK and ERα activity in postmenopausal breast cancer patients. No prognostic correlations between the phosphorylation markers and clinical outcome were found, nor were they predictive for clinical outcomes among patients who switched therapy over those treated with tamoxifen alone.

Exploration of tumour-infiltrating lymphocytes as a predictive biomarker for adjuvant endocrine therapy in early breast cancer

PurposeTumour-infiltrating lymphocytes (TILs) have been shown to be prognostic for disease-free survival and predictive for the benefit of chemotherapy in patients with early breast cancer, but have not been studied for endocrine therapy.Experimental designThe number of CD8-positive TILs was assessed in a subcohort of 236 patients in the Intergroup Exemestane Study. AQ After 2–3 years of adjuvant tamoxifen, AQpatients were randomized between the schemes of continuation for 5 years on tamoxifen and switching to exemestane. The numbers of CD8-positive TILs were analysed for correlations with disease-free survival (DFS) and overall survival (OS). A similar analysis was performed on 2596 patients in the TEAM trial who were randomized between the sequential scheme and the exemestane monotherapy.ResultsIn the first cohort, patients with low (below median) numbers of CD8-positive TILs had a univariate hazard ratio (HR) for DFS of 0.27 (95% CI 0.13–0.55) in favour of treatment with exemestane, whereas this benefit was not observed in patients with high numbers of CD8-positive TILs (HR 1.34, 95% CI 0.71–2.50, HR for interaction 5.02, p = 0.001). In the second cohort, patients with low numbers of CD8-positive TILs showed a benefit of exemestane treatment on recurrence-free survival (RFS HR 0.67, 95% CI 0.45–0.99), and not with above-median numbers of CD8-positive TILs (HR 0.86, 95% CI 0.59–1.26, HR for interaction 1.29, p = 0.36).ConclusionsThis study is the first to propose the number of CD8-positive TILs as potential predictive markers for endocrine therapy, with the low presence of CD8-positive TILs associated to benefit for exemestane-inclusive therapy. However, treatment-by-marker interactions were only significant in one cohort, indicating the need for further validation.

Evaluation of applying IHC4 as a prognostic model in the translational study of Intergroup Exemestane Study (IES): PathIES

BackgroundIntergroup Exemestane Study (IES) was a randomised study that showed a survival benefit of switching adjuvant endocrine therapy after 2–3 years from tamoxifen to exemestane. This PathIES aimed to assess the role of immunohistochemical (IHC)4 score in determining the relative sensitivity to either tamoxifen or sequential treatment with tamoxifen and exemestane.Patients and methodsPrimary tumour samples were available for 1274 patients (27% of IES population). Only patients for whom the IHC4 score could be calculated (based on oestrogen receptor, progesterone receptor, HER2 and Ki67) were included in this analysis (N = 430 patients). The clinical score (C) was based on age, grade, tumour size and nodal status. The association of clinicopathological parameters, IHC4(+C) scores and treatment effect with time to distant recurrence-free survival (TTDR) was assessed in univariable and multivariable Cox regression analyses. A modified clinical score (PathIEscore) (N = 350) was also estimated.ResultsOur results confirm the prognostic importance of the original IHC4, alone and in conjunction with clinical scores, but no significant difference with treatment effects was observed. The combined IHC4 + Clinical PathIES score was prognostic for TTDR (P < 0.001) with a hazard ratio (HR) of 5.54 (95% CI 1.29–23.70) for a change from 1st quartile (Q1) to Q1–Q3 and HR of 15.54 (95% CI 3.70–65.24) for a change from Q1 to Q4.ConclusionIn the PathIES population, the IHC4 score is useful in predicting long-term relapse in patients who remain disease-free after 2–3 years. This is a first trial to suggest the extending use of IHC4+C score for prognostic indication for patients who have switched endocrine therapies at 2–3 years and who remain disease-free after 2–3 years.

Long-Term Follow-Up of the Intergroup Exemestane Study.

Purpose The Intergroup Exemestane Study, an investigator-led study of 4,724 postmenopausal patients with early breast cancer (clinical trial information: ISRCTN11883920), has previously demonstrated that a switch from adjuvant endocrine therapy after 2 to 3 years of tamoxifen to exemestane was associated with clinically relevant improvements in efficacy. Here, we report the final efficacy analyses of this cohort. Patients and Methods Patients who remained disease free after 2 to 3 years of adjuvant tamoxifen were randomly assigned to continue tamoxifen or switch to exemestane to complete a total of 5 years of adjuvant endocrine therapy. Given the large number of non-breast cancer-related deaths now reported, breast cancer-free survival (BCFS), with censorship of intercurrent deaths, was the primary survival end point of interest. Analyses focus on patients with estrogen receptor-positive or unknown tumors (n = 4,599). Results At the time of the data snapshot, median follow-up was 120 months. In the population that was estrogen receptor positive or had unknown estrogen receptor status, 1,111 BCFS events were observed with 508 (22.1%) of 2,294 patients in the exemestane group and 603 (26.2%) of 2,305 patients in the tamoxifen group. The data corresponded to an absolute difference (between exemestane and tamoxifen) at 10 years of 4.0% (95% CI, 1.2% to 6.7%), and the hazard ratio (HR) of 0.81 (95% CI, 0.72 to 0.92) favored exemestane. This difference remained in multivariable analysis that was adjusted for nodal status, prior use of hormone replacement therapy, and prior chemotherapy (HR, 0.80; 95% CI, 0.71 to 0.90; P < .001). A modest improvement in overall survival was seen with exemestane; the absolute difference (between exemestane and tamoxifen) at 10 years in the population that was estrogen receptor positive or had unknown estrogen receptor status was 2.1% (95% CI, -0.5% to 4.6%), and the HR was 0.89 (95% CI, 0.78 to 1.01; P = .08). For the intention-to-treat population, the absolute difference was 1.6% (95% CI, -0.9% to 4.1%); the HR was 0.91 (95% CI, 0.80 to 1.03, P = .15). No statistically significant difference was observed in the proportion of patients who reported a fracture event in the post-treatment period. Conclusion The Intergroup Exemestane Study and contemporaneous studies have established that a strategy of switching to an aromatase inhibitor after 2 to 3 years of tamoxifen can lead to sustained benefits in terms of reduction of disease recurrence and breast cancer mortality.

Abstract P3-07-35: Tumour immune subtyping as a predictive biomarker for adjuvant endocrine therapy in early breast cancer

Abstract Adjuvant endocrine therapy is one of the mainstays in the treatment of breast cancer. Approximately 75% of all patients is treated with either tamoxifen or an aromatase inhibitor (AI), without any predictive biomarkers besides the estrogen receptor. It is known, that the immune system plays a pivotal role in the treatment of breast cancer. Earlier, subtyping the local immune response has been shown to predict therapy efficacy for chemotherapy. The current study was performed to discover predictive relations between the local immune response and survival in two different cohorts treated with adjuvant endocrine therapy. Tumour tissue was collected from a cohort of 236 Dutch post-menopausal patients from the Intergroup Exemestane Study (IES-trial) who were randomized between 5 years of tamoxifen and 2.5 years of tamoxifen followed by 2.5 years of an AI (switch-scheme). The tumour tissue was stained for infiltration of CD8+ cytotoxic T-cells, FoxP3+ regulatory T-cells and CD68+ macrophages and the expression of different HLA-markers (classical HLA-I, HLA-E, HLA-G). These results were combined into three immune profiles (strong, intermediate, weak), and correlated to survival. Similar analyses were performed on a cohort of 2596 patients participating in the international TEAM trial, who were randomized between 2.5 years of tamoxifen followed by 2.5 years of an AI (switch scheme) and 5 years of an AI. In the IES-cohort, patients with a strong local immune response had a significant better recurrence free survival when treated with 5 years of tamoxifen (5-year RFS 89.5%) compared to the switch scheme (5-year RFS 76.5%) (p=0.003). In patients with a weak local immune response, RFS was improved for patients treated with the switch scheme (5-year RFS 100%) compared to tamoxifen monotherapy (5-year RFS 75.6%) (P=0.003). Similar trends were observed for overall survival, although not statistically significant (p-values of 0.051 and 0.109 respectively). In the TEAM-cohort, no statistical significant differences were observed between both treatments in either immunological subtype (strong immune subtype: 5-year RFS 87.2% for 5-years AI versus 82.8% for the switch scheme (p=0.495), weak immune subtype: 85.9% for 5-year of AI vs 82.2% for the switch scheme (p=0.343)). This study is the first to show combined immunological markers as a predictive marker for endocrine therapy. A strong immune response predicts a benefit for tamoxifen monotherapy, whereas a weak response predicts a benefit for AI-containing therapy. Although the exact mechanism of this effect is not known, we hypothesize that it might be contributed to immunomodulatory capacities of AIs. If the effect observed in the IES- cohort is indeed contributed to the effect of AIs, it would be expected that there is no difference in the TEAM-cohort between both arms since they both contain AIs, which was indeed observed. Future studies will be directed towards validation of these findings in an independent cohort. Citation Format: Blok EJ, Engels CC, Jongste E, Dekker-Ensink G, Kroep JR, Kuppen PJK, van de Velde CJH. Tumour immune subtyping as a predictive biomarker for adjuvant endocrine therapy in early breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-35.

Prognostic and predictive value of ERβ1 and ERβ2 in the Intergroup Exemestane Study (IES)—first results from PathIES

Intergroup Exemestane Study (IES) was a randomised study that showed a survival benefit of switching adjuvant endocrine therapy after 2-3 years from tamoxifen to exemestane. PathIES aimed to assess the potential prognostic and predictive value of ERβ1 and ERβ2 expression in primary tumours in order to determine benefit in the two treatment arms. Primary tumour samples were available for 1256 patients (27% IES population). ERβ1 and ERβ2 expression was dichotomised at the median IHC score (high if ERβ1 ≥ 191, ERβ2 ≥ 164). Hazard ratios (HRs) were estimated by multivariable Cox proportional hazards models adjusting for clinicopathological factors. Treatment effects with biomarker expressions were determined by interaction tests. Analysis explored effects of markers both as a continuous variable and with dichotomised cut-offs. Neither ERβ1 nor ERβ2 were associated with disease-free survival (DFS) or overall survival (OS) in the whole cohort. In patients treated with continued tamoxifen, high ERβ1 expression compared with low was associated with better DFS [HR = 0.38:95% confidence interval (CI) 0.21-0.68, P = 0.001]. DFS benefit of exemestane over tamoxifen (HR = 0.40:95% CI 0.22-0.70) was found in the low ERβ1 subgroup (interaction P = 0.01). No significant difference with treatment was observed for ERβ2 expression in either DFS or OS. In the PathIES population, exemestane appeared to be superior to tamoxifen among patients with low ERβ1 expression but not in those with high ERβ1 expression. This is the first trial of its kind to report a parameter potentially predicting benefit of an aromatase inhibitor when compared with tamoxifen and an independent validation is warranted.

55O_PR - Prognostic and Predictive Value of IHC4 and ERB1 in the Intergroup Exemestane Study (IES) - On Behalf of the Pathies Investigators

55O_PR - Prognostic and Predictive Value of IHC4 and ERB1 in the Intergroup Exemestane Study (IES) - On Behalf of the Pathies Investigators

Long-term assessment of quality of life in the Intergroup Exemestane Study: 5 years post-randomisation

Background:The Intergroup Exemestane Study (IES) (ISRCTN11883920) demonstrated improved survival for postmenopausal women with ER-positive/unknown primary breast cancer who switched to exemestane after 2–3 years tamoxifen, compared with those continuing on tamoxifen to complete 5 years therapy. This was achieved without detriment to on-treatment quality-of-life (QoL). We report on- and post-treatment QoL impact in IES.Methods:A total of 582 patients from 8 countries participated in the QoL substudy. Functional Assessment of Cancer Therapy–Breast (FACT-B) and endocrine symptom subscale (ES) were completed at baseline, 3, 6, 9, 12, 18, 24, 30, 36, 48 and 60 months. The primary endpoint was FACT-B Trial Outcome Index (TOI); secondary endpoints included severity of individual endocrine symptoms.Results:Both the groups showed gradual improvement in overall QoL and lessening of total endocrine symptoms post treatment compared with baseline (P<0.002). There was no evidence of any between-group differences in TOI. Vasomotor complaints remained high on treatment. Vaginal discharge was more frequent (P<0.01) with tamoxifen up to 24 months from baseline. In both the groups, post-treatment libido did not recover to baseline levels.Conclusion:Clinical benefits of switching to exemestane are accompanied by good overall QoL. Although some symptoms persist, the majority of endocrine symptoms improve after treatment completion.

Deep Time: The Long and the Short of Adjuvant Endocrine Therapy for Breast Cancer

Deep Time: The Long and the Short of Adjuvant Endocrine Therapy for Breast Cancer

Carpal tunnel syndrome and musculoskeletal symptoms in postmenopausal women with early breast cancer treated with exemestane or tamoxifen after 2–3 years of tamoxifen: a retrospective analysis of the Intergroup Exemestane Study

Aromatase inhibitors are more effective than is tamoxifen in prevention of breast-cancer recurrence, but at the expense of increased musculoskeletal side-effects, such as carpal tunnel syndrome. The aim of this study was to assess risk factors and the prognostic value of musculoskeletal symptoms during treatment with the steroidal aromatase inhibitor exemestane or with tamoxifen after 2-3 years of tamoxifen. In the Intergroup Exemestane Study, postmenopausal women treated for early invasive breast cancer who remained disease free and on treatment after 2-3 years of tamoxifen were randomised to switch to exemestane or to continue tamoxifen for the remainder of the 5-year period of endocrine treatment. The primary endpoint for this retrospective analysis was occurrence of carpal tunnel syndrome and any musculoskeletal events, analysed in the safety population, which consisted of all patients who had received any trial treatment. As well as case-report forms, questionnaires were distributed retrospectively to gain more details of cases of carpal tunnel syndrome. The relation between musculoskeletal symptoms reported by 6 months from randomisation and survival from 9 months onwards was assessed by Cox proportional hazards models. The trial is registered, number ISRCTN11883920. It has completed accrual and follow-up is continuing for enrolled participants. After a median follow-up of 91·0 months (IQR 83·0-99·2), carpal tunnel syndrome had been reported for 66 (2·8%) of 2319 patients in the exemestane group compared with 13 (0·6%) of 2338 in the tamoxifen group (odds ratio [OR] 5·23, 99% CI 2·39-11·49; p<0·0001). More events occurred during treatment in the exemestane group than in the tamoxifen group (66 [2·8%] vs seven [0·3%], adjusted OR 9·90, 99% CI 3·52-27·82; p<0·0001). There was no significant difference between groups in events in the post-treatment period (ten with exemestane [0·4%] vs seven with tamoxifen [0·3%]; p=0·46). More patients in the exemestane group (1082 of 2319 patients, 46·7%) had musculoskeletal symptoms than in the tamoxifen group (901 of 2338, 38·5%; OR 1·48, 99% CI 1·32-1·67, p<0·0001). More events occurred during treatment in the exemestane group than in the tamoxifen group (984 [42·4%] vs 776 [33·2%], adjusted OR 1·59, 99% CI 1·32-1·91; p<0·0001), with this difference persisting to some extent in the post-treatment period (449 [19·4%] vs 390 [16·7%]; p=0·017). Of 73 on-treatment cases of carpal tunnel syndrome, 58 (79·5%) completed questionnaires were available. 27 patients (46·6%) had bilateral carpal tunnel syndrome and 31 (53·4%) had unilateral disease; 40 (69·0%) underwent surgical release. The disorder greatly affected daily-life activities in 21 (36·2%) cases. Occurrence of musculoskeletal symptoms, including carpal tunnel syndrome, was associated with improved disease-free survival in unadjusted analysis (p=0·023), but not with overall survival (p=0·36). However, after adjustment for possible confounding factors, musculoskeletal symptoms were not associated with disease-free survival (hazard ratio [HR] 0·96, 95% CI 0·82-1·14, p=0·67) or overall survival (HR 1·02, 95% CI 0·84-1·25, p=0·82). Occurrence of carpal tunnel syndrome is higher in patients with breast cancer given exemestane than in those treated with tamoxifen, and surgical release might be necessary in most cases. Development of musculoskeletal symptoms in the first 6 months of treatment is not an independent biomarker of improved disease outcome. Further investigation is warranted into the relation between treatment-emergent musculoskeletal symptoms and clinical outcome in patients with breast cancer receiving hormonal therapy. Pfizer.

Disease-Related Outcomes With Long-Term Follow-Up: An Updated Analysis of the Intergroup Exemestane Study

Disease-Related Outcomes With Long-Term Follow-Up: An Updated Analysis of the Intergroup Exemestane Study

Disease-Related Outcomes With Long-Term Follow-Up: An Updated Analysis of the Intergroup Exemestane Study

Intergroup Exemestane Study (IES), an investigator-led study in 4,724 postmenopausal patients with early-stage breast cancer has demonstrated clinically important benefits from switching adjuvant endocrine therapy after 2 to 3 years of tamoxifen to exemestane. Now, with longer follow-up, a large number of non-breast cancer-related events have been reported. Exploratory analyses describe breast cancer-free survival (BCFS) and explore incidence and patterns of the different competing events. Patients who were disease-free after 2 to 3 years of adjuvant tamoxifen were randomly assigned to continue tamoxifen or switch to exemestane to complete 5 years of adjuvant endocrine therapy. At this planned analysis, the median follow-up was 91 months. Principal analysis focuses on 4,052 patients with estrogen receptor (ER) -positive and 547 with ER-unknown tumors. In all, 930 BCFS events have been reported (exemestane, 423; tamoxifen, 507), giving an unadjusted hazard ratio (HR) of 0.81 (95% CI, 0.71 to 0.92; P = .001) in favor of exemestane in the ER-positive/ER unknown group. Analysis partitioned at 2.5 years after random assignment showed that the on-treatment benefit of switching to exemestane (HR, 0.60; 95% CI, 0.48 to 0.75; P < .001) was not lost post-treatment, but that there was no additional gain once treatment had ceased (HR, 0.94; 95% CI, 0.80 to 1.10; P = .60). Improvement in overall survival was demonstrated, with 352 deaths in the exemestane group versus 405 deaths in the tamoxifen group (HR, 0.86; 95% CI, 0.75 to 0.99; P = .04). Of these, 222 were reported as intercurrent deaths (exemestane, 107; tamoxifen, 115). The protective effect of switching to exemestane compared with continuing on tamoxifen on risk of relapse or death was maintained for at least 5 years post-treatment and was associated with a continuing beneficial impact on overall survival.

Optimal adjuvant hormonal therapy in postmenopausal women with hormone-receptor-positive early breast cancer: have we answered the question?

Adjuvant endocrine therapy is the most important systemic treatment for postmenopausal women with hormone-receptor-positive early breast cancer following surgery. Most trials have shown that the third-generation aromatase inhibitors, anastrozole, letrozole (LET), and exemestane, significantly prolong disease-free survival compared with tamoxifen. However, an overall survival benefit with aromatase inhibitors was observed in only three trials to date, in retrospective analyses from selected groups of patients: sequential analysis in the Austrian Breast & Colorectal Study Group 8, switch analysis in the Intergroup Exemestane Study, and analysis of initial letrozole in Breast International Group 1-98 study. Although the priming effect observed in preclinical models and breast cancer patients provides a rationale for sequencing adjuvant endocrine treatment with tamoxifen and aromatase inhibitors, the optimal strategy for adjuvant endocrine treatment has yet to be determined. This review discusses aromatase inhibitor monotherapy, sequential adjuvant treatment with tamoxifen followed by an aromatase inhibitor, and sequential adjuvant treatment with an aromatase inhibitor followed by tamoxifen. Available data in support of and against each strategy is evaluated. The safety profiles of tamoxifen and aromatase inhibitors is also examined.

Reversal of skeletal effects of endocrine treatments in the Intergroup Exemestane Study

The adjuvant use of aromatase inhibitors in breast cancer is associated with adverse effects on bone health. We previously reported a decline in bone mineral density (BMD) following the switch from tamoxifen to exemestane in the Intergroup Exemestane Study (IES). Here we report effects of endocrine treatment withdrawal on BMD, bone turnover markers (BTM) and fracture rates. 4,724 patients took part in IES, and 206 patients were included in a bone sub-study. BMD and BTM were assessed pre-randomization, during and after the end of treatment (EOT). To evaluate treatment withdrawal effects, 12- and 24-month post EOT BMD results are available for 122 and 126 patients, respectively. Similar patient numbers had BTM measured post EOT. Following treatment withdrawal, the differences in BMD observed between the two endocrine strategies were partially reversed. At 24 months from EOT, spine BMD increased by 1.53% (95%CI 0.63-2.43; p = 0.001) after stopping exemestane and fell by 1.93% (95%CI -2.91 to 0.95; p = 0.0002) following tamoxifen withdrawal. A similar pattern of changes was observed at the hip. At 2 years post EOT, BMD changes from baseline were similar with both treatment strategies. Corresponding inverse changes in BTM were seen, with an increase following tamoxifen withdrawal and a reduction after exemestane. A higher number of fractures occurred during exemestane treatment, but fracture rates were similar after treatment withdrawal. With the switch strategy used in IES, the on treatment adverse bone effects of exemestane are reversed. Ongoing monitoring of BMD is therefore not routinely required.

Long-term endometrial effects in postmenopausal women with early breast cancer participating in the Intergroup Exemestane Study (IES)—a randomised controlled trial of exemestane versus continued tamoxifen after 2–3 years tamoxifen

BackgroundThe antiestrogen tamoxifen may have partial estrogen-like effects on the postmenopausal uterus. Aromatase inhibitors (AIs) are increasingly used after initial tamoxifen in the adjuvant treatment of postmenopausal early breast cancer due to their mechanism of action: a potential benefit being a reduction of uterine abnormalities caused by tamoxifen. Patients and methodsSonographic uterine effects of the steroidal AI exemestane were studied in 219 women participating in the Intergroup Exemestane Study: a large trial in postmenopausal women with estrogen receptor-positive (or unknown) early breast cancer, disease free after 2–3 years of tamoxifen, randomly assigned to continue tamoxifen or switch to exemestane to complete 5 years adjuvant treatment. The primary end point was the proportion of patients with abnormal (≥5 mm) endometrial thickness (ET) on transvaginal ultrasound 24 months after randomisation. ResultsThe analysis included 183 patients. Two years after randomisation, the proportion of patients with abnormal ET was significantly lower in the exemestane compared with tamoxifen arm (36% versus 62%, respectively; P=0.004). This difference emerged within 6 months of switching treatment (43.5% versus 65.2%, respectively; P=0.01) and disappeared within 12 months of treatment completion (30.8% versus 34.7%, respectively; P=0.67). ConclusionSwitching from tamoxifen to exemestane significantly reverses endometrial thickening associated with continued tamoxifen.

Disease Related Outcome with Long Term Follow-Up: An Updated Analysis of the Intergroup Exemestane Study (IES).

Abstract Background: IES is an investigator-led study in 4724 postmenopausal patients with early breast cancer (sponsored by Pfizer Ltd; ISRCTN11883920) that has already demonstrated significant, clinically important benefits from switching adjuvant endocrine therapy after 2-3 years tamoxifen (T) to exemestane (E) (NEJM 2004, Lancet 2007). With longer follow-up the sensitivity of a disease free survival analysis may be reduced by the increasing number of non breast cancer-related deaths. Analysis of breast cancer free survival (BCFS), censoring intercurrent deaths, provides a sensitive estimate of the true impact of an adjuvant intervention on breast cancer outcome.Materials and methods: Patients who were disease-free after 2-3 years of adjuvant T, were randomized to continue T or switch to E to complete a total of 5 years of adjuvant endocrine therapy. At the time of this planned analysis in June 2009, the median follow-up was 91 months, and 91% of surviving patients had ≥6 years followup. The analysis focuses on 4052 pts known to be ER positive (+) and 547 with ER unknown (unk) tumors. The remaining 125 patients now known to be ER negative are excluded from this analysis.Results: 933 BCFS events have been reported (E=425 T=508) giving an unadjusted hazard ratio (HR) of 0.81 (95%CI: 0.71, 0.92); p=0.001 in favor of E in the ER+ and ER unk groups. With mature follow-up, the benefits of E appear similar in the ER unk and ER+ sub-groups (HR=0.85 95%CI (0.60, 1.20); p=0.36 and HR=0.80 95%CI (0.70, 0.92); p=0.002 respectively). Similarly, all other prognostic subgroups show consistency with the overall BCFS effect. An analysis partitioned at 2.5 years post randomization showed the on-treatment BCFS benefit of switching to E (HR=0.60 95%CI (0.48, 0.75); p&amp;lt;0.0001) was maintained post-treatment (HR=0.94 95%CI (0.80, 1.10); p=0.46). Continuing improvement in OS was demonstrated, with E=352 versus T=405 deaths (HR=0.86, 95%CI (0.75, 0.99); p=0.04). Of these, 219 were reported as intercurrent deaths (E=105, T=114).Conclusions: The protective effect of switching to E, compared with continuing on T, on relapse rate is maintained for at least 5 years post treatment completion. Associated with this is a continuing benefit on overall survival. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 12.

2009 ECCO15/ESMO34 conference

Upfront exemestane improves disease-free survival (DFS) in patients with postmenopausal early breast cancer compared with upfront tamoxifen, according to an analysis from the TEAM trial. Cornelis van de Velde (Leiden, the Netherlands) and colleagues randomly assigned 9779 patients to receive either exemestane for 5 years or tamoxifen for 2·5–3 years with a subsequent switch to exemestane. The switch was proposed after the Intergroup Exemestane Study ( 2007; 599–70) established this switch to exemestane was better than treatment with tamoxifen alone for 5 years. 754 patients on tamoxifen switched to exemestane in the TEAM analysis. After 2·75 years, 740 DFS events were noted; hazard ratio [HR] 0·89 (95% CI 0·77–1·03; p=0·12). When events were censored, the HR was 0·83 (0·71–0·97; p=0·022). Fracture rates did not differ between groups, but the exemestane group had more arthralgia. 2009 NCRI conferenceInhibitors of the proto-oncogene MET are showing promise as anti-angiogenics. Shahneed Sandhu (Sutton, UK) presented findings from a phase 1 trial of the oral MET inhibitor, ARQ197, in 29 patients with advanced solid tumours. The drug was well tolerated, with only three patients exhibiting dose-limiting toxicities, and a phase 2 dose of 300 mg twice daily was recommended. MRI of tumours in 12 patients showed a reduction in tumour permeability sustained over 56 treatment days, suggesting an anti-angiogenic response. Full-Text PDF

5010 Survival and safety post study treatment completion: an updated analysis of the Intergroup Exemestane Study (IES) – submitted on behalf of the IES Investigators

5010 Survival and safety post study treatment completion: an updated analysis of the Intergroup Exemestane Study (IES) – submitted on behalf of the IES Investigators

0131 Survival & safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment: A number needed to treat analysis based on the intergroup exemestane study (IES)

0131 Survival & safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment: A number needed to treat analysis based on the intergroup exemestane study (IES)

Phase 3 Trials of Aromatase Inhibitors for Breast Cancer Prevention

The third-generation aromatase inhibitors (AIs), anastrozole, exemestane, and letrozole are potential agents for preventing estrogen receptor (ER)-positive breast cancer (BC) in high-risk postmenopausal women. No AI has yet been fully evaluated for prevention. Each AI is incorporated into the design of a phase 3 randomized BC prevention trial based on hypothesis-generating contralateral breast cancer (CLBC) data from a corresponding adjuvant trial. Arimidex, tamoxifen alone or in combination (ATAC) pitted anastrozole against tamoxifen for 5 years as "initial adjuvant" therapy, showing at 33.3 months fewer CLBCs with anastrozole versus tamoxifen (odds ratio [OR] 0.42 overall; OR 0.29 ER-positive BCs), offering the hypothesis on which IBIS-II (International Breast Cancer Intervention Study) is based. "High-risk" IBIS-II compares anastrozole to placebo for the primary prevention of BC in 6000 postmenopausal women. IES (Intergroup Exemestane Study) compared exemestane to tamoxifen following 2-3 years of adjuvant tamoxifen in 4742 postmenopausal women with ER-positive BCs. The benefit from "switching" to exemestane in reducing CLBCs (HR 0.44 at 30.6 months) underlies MAP.3 (Mammary Prevention 3), which compares exemestane to placebo for primary BC risk reduction in 4560 postmenopausal women. MA.17 showed reduced CLBC incidence (HR 0.57) at 2.4 years in postmenopausal women with receptor-positive tumors receiving "extended adjuvant" letrozole compared to placebo following 5 years of tamoxifen. The Study of Letrozole and Raloxifene (STELLAR), using as the control raloxifene, the new U.S. standard drug for BC prevention, would complete the trio of AI prevention trials, but STELLAR is currently on hold.