Endocrine-responsive Early Breast Cancer Research Articles

Mechanisms of action of bisphosphonates in oncology: a scientific concept evolving from antiresorptive to anticancer activities

Bisphosphonates are approved for treating malignant bone disease from advanced cancer because they are effective inhibitors of osteoclast-mediated bone resorption. However, there may be a greater role for the use of bisphosphonates than has previously been considered. There is a large body of preclinical evidence showing that bisphosphonates exert a variety of direct and indirect anticancer activities that affect both tumor cells and the surrounding microenvironment, and that stimulate immune reactions. Recent data from clinical trials have shown that adding the bisphosphonate zoledronate to endocrine therapy or chemotherapy improves disease-free survival of patients with endocrine-responsive early breast cancer in a low estrogen environment (that is, following ovarian suppression therapy or in women with established menopause at diagnosis). Adjuvant treatment with the bisphosphonate clodronate also improves disease-free survival in postmenopausal breast cancer. Additionally, zoledronate was found to prolong survival in patients with symptomatic multiple myeloma or other advanced cancers. Here, we present an overview of preclinical and clinical studies that demonstrate anticancer benefits of bisphosphonates, and we discuss potential mechanisms of action that might be responsible for the anticancer activity of bisphosphonates in the clinic.

Zoledronic acid (zoledronate) for postmenopausal women with early breast cancer receiving adjuvant letrozole (ZO-FAST study): final 60-month results

Aromatase inhibitors are the preferred adjuvant endocrine therapy for the majority of postmenopausal women with hormone-responsive early breast cancer. Although generally more effective than tamoxifen, aromatase inhibitor therapy is associated with increased bone loss and fracture risk. Postmenopausal women receiving adjuvant letrozole (2.5 mg/day for 5 years; N = 1065) were randomly assigned to immediate zoledronic acid (zoledronate) 4 mg every 6 months for 5 years, or delayed zoledronate (initiated for fracture or on-study bone mineral density [BMD] decrease). The primary end point was the change in lumbar spine BMD at 12 months. Lumbar spine and total hip BMD at subsequent follow-up, disease-free survival (DFS), and overall survival were assessed as secondary end points. At 60 months (final analysis), the mean change in lumbar spine BMD was +4.3% with immediate zoledronate and -5.4% with delayed intervention (P < 0.0001). Immediate zoledronate reduced the risk of DFS events by 34% (hazard ratio [HR] = 0.66; P = 0.0375) with fewer local (0.9% versus 2.3%) and distant (5.5% versus 7.7%) recurrences versus delayed zoledronate. In the delayed group, delayed initiation of zoledronate substantially improved DFS versus no zoledronate (HR = 0.46; P = 0.0334). Immediate zoledronate in postmenopausal women receiving letrozole preserved BMD and is associated with improved DFS compared with letrozole alone. Clinical Trials Registration No NCT00171340.

Abstract P2-13-04: Superior efficacy of anastrozole to tamoxifen as adjuvant therapy for postmenopausal patients with hormone-responsive breast cancer. Efficacy results of long-term follow-up data from N-SAS BC 03 trial

Abstract Background: Aromatase inhibitors have been shown to be superior to tamoxifen as adjuvant therapy in postmenopausal patients with hormone-responsive breast cancer. Here we report the efficacy results of long-term follow-up data from N-SAS BC 03 trial (UMIN CTRID: C000000056), in which anastrozole was compared to tamoxifen in hormone-responsive postmenopausal early breast cancer patients who had taken tamoxifen for 1—4 years out of a total of 5 years of treatment as adjuvant therapy. Patients and methods: Out of a total of 706 recruited patients, 696 patients (tamoxifen group, n=345; anastrozole group, n=351) were used as the full analysis set for the present study. The log-rank test was used to compare the two groups in terms of disease-free survival (DFS) and relapse-free survival (RFS), Kaplan-Meier estimates were calculated. The treatment effects were estimated by Cox's proportional hazard model and were expressed as hazard ratios, with associated 95% confidence intervals (CIs). Results: After a median follow-up of 76.1 months, (range: 1.3–110 months), the unadjusted hazard ratio was 0.87 (95%Cl 0.60–1.26; log-rank p = 0.457) for DFS and 0.77 (95%Cl 0.49–1.22; log-rank p = 0.266) for RFS, both in favor of anastrozole. The estimated hazard ratio (95%CIs) for DFS and for RFS until each time point (right censored data) was as follows: until 30 months: 0.54 (0.30–0.98) and 0.48 (0.23–0.98), until 42 months; 0.65 (0.40–1.06) and 0.53 (0.29–0.97), until 54 months: 0.77 (0.50–1.19) and 0.63 (0.37–1.06), until 66 months: 0.82 (0.55–1.24) and 0.72 (0.44–1.17), until 78 months: 0.83 (0.57–1.23) and 0.73 (0.46–1.17), respectively. The hazard ratios (95%CIs) for DFS and for RFS until 36 months were 0.72 (95%Cl 0.43–1.22) and 0.58 (95%Cl 0.30–1.12), and those after 36 months were 1.06 (95%Cl 0.62–1.81) and 0.98 (95%Cl 0.51–1.88), respectively. Conclusion: Superior efficacy of anastrozole to tamoxifen in the Japanese population was suggested over a long-term follow-up period. It was the greatest early after switching from tamoxifen and then decreased thereafter. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-13-04.

282P - Evaluation of Bone Mineral Density (BMD) in Early Breast Cancer (EBC) Patients Treated With Up-Front or Switch Schedules of Aromatase Inhibitors (AIS): Results of a Single Centre Retrospective Study

ABSTRACT Background Aromatase inhibitors (AIs) are the standard adjuvant treatment of hormone responsive early breast cancer (EBC) in postmenopausal women. AIs are well tolerated but are associated with specific toxicities, including effect on bone (accelerated bone loss, bone fracture, osteoporosis) and musculoskeletal symptoms (ostealgia, arthralgia, myalgia) Aim: The present observational study investigated the effect of BMD in postmenopausal women with EBC scheduled to receive AIs up-front or switch treatment after standard 2-3 years of adjuvant Tamoxifen (TAM-AIs). Patients and methods We reviewed data for 89 patients with hormone receptor-positive EBC: 64 postmenopausal women received up-front AIs for 5 years; 25 patients received TAM-AIs. BMD were assessed at baseline and during hormonal treatment once a year. Osteopenic patients received Calcium and vitamin D; osteoporotic patients received also oral biphosphonates. Results No patient with a normal baseline BMD (T-score >-1) became osteoporotic during 5 years of follow-up. However, it was noted that more women receiving AIs up-front became osteopenic, as compared with TAMaAI treated women (AIs = 58% vs. TAM-AIs = 26%, p= Conclusion The data suggest that only those women with a T-score of less than -1.5 are at risk of developing osteoporosis during the AIs adjuvant therapy. This cut-off value might reduce the costs both for BMD monitoring and supplementary comedications. Finally, the correct management of treatment-related symptoms might improve patient's compliance and the adherence to treatment. Disclosure All authors have declared no conflicts of interest.

A risk score based on histopathological features predicts higher risk of distant recurrence in premenopausal patients with lymph node-negative endocrine-responsive breast cancer

PurposeTo develop a Risk Score (RS) to predict distant recurrence among premenopausal women with node-negative endocrine-responsive early breast cancer. MethodsThe Cox model was used to develop the RS using clinical and histopathological features from 378 women participating in the IBCSG Trial VIII who received endocrine therapy alone or following chemotherapy. The performance of the resulting model was validated on a cohort of 1005 patients from a single institution who received endocrine therapy alone. ResultsIn a multivariable analysis, the risk of distant recurrence was associated with tumor size, ER, Ki-67 and peritumoral vascular invasion. In the validation cohort, patients with high RS were at greater risk of distant recurrence compared to patients with low RS (HR, 17.41; 95% CI, 5.72–52.95). ConclusionIn premenopausal women with node-negative endocrine-responsive early breast cancer, the RS identifies patients at higher risk of distant recurrence.

Estrogen receptor alpha (ESR1) gene amplification status and clinical outcome in tamoxifen-treated postmenopausal patients with endocrine-responsive early breast cancer: An analysis of the prospective ABCSG-6 trial.

10501 Background: Estrogen receptor alpha (ERα) expression is a prognostic parameter in breast cancer and predicts response to endocrine therapy. One of the factors important for protein expression is amplification of its encoding gene ESR1. We have investigated the value of ESR1 amplification in predicting the long-term clinical outcome in tamoxifen-treated postmenopausal women with endocrine-responsive breast cancer. Methods: 394 patients who had been randomized into the tamoxifen-only arm of the prospectively designed endocrine ABCSG-06 trial and in whom FFPE tumor tissue was available were included in this analysis. Immunohistochemical ERα expression was evaluated both locally and centrally using the Allred score, while ESR1 gene amplification status was evaluated by FISH analysis using the ESR1/CEN6 ratio. Results: ESR1 copy number gains were detected in 187 of 394 (47%) tumor specimen and was associated with favorable clinical outcome. At a median follow-up of 10 years, women with intratumoral ESR1 copy number gains had a significantly longer distant recurrence-free survival (adjusted HR for relapse 0.48; 95% CI 0.28-0.83; p=0.009) and breast cancer-specific survival (adjusted HR for death 0.46; CI 0.46-0.71; p=0.006) when compared to women with normal ESR1 copy numbers. Immunohistochemical ERα protein expression, evaluated by Allred score, was significantly correlated with ESR1 copy number alterations (p&lt;0.0001; Chi-Square test), but did itself not allow to discriminate between patients with poor and good prognosis. Conclusions: ESR1 amplification status is an independent and powerful predictor for long-term distant recurrence-free and breast cancer-specific survival in postmenopausal women with endocrine-responsive early-stage breast cancer who received 5 years of tamoxifen.

Prognostic and predictive role of ESR1 status for postmenopausal patients with endocrine-responsive early breast cancer in the Danish cohort of the BIG 1-98 trial

Estrogen Receptor 1 (ESR1) aberrations may be associated with expression of estrogen receptor (ER) or progesterone receptor (PgR), human epidermal growth factor receptor-2 (HER2) or Ki-67 labeling index and prognosis. ESR1 was assessed in 1129 (81%) of 1396 postmenopausal Danish women with early breast cancer randomly assigned to receive 5 years of letrozole, tamoxifen or a sequence of these agents in the Breast International Group 1-98 trial and who had ER ≥ 1% after central review. By FISH, 13.6% of patients had an ESR1-to-Centromere-6 (CEN-6) ratio ≥ 2 (amplified), and 4.2% had ESR1-to-CEN-6 ratio <0.8 (deleted). Deletion of ESR1 was associated with significantly lower levels of ER (P < 0.0001) and PgR (P = 0.02) and more frequent HER2 amplification. ESR1 deletion or amplification was associated with higher-Ki-67 than ESR1-normal tumors. Overall, there was no evidence of heterogeneity of disease-free survival (DFS) or in treatment effect according to ESR1 status. However, significant differences in DFS were observed for subsets based on a combination of ESR1 and HER2 status (P = 0.02). ESR1 aberrations were associated with HER2 status, Ki-67 labeling index and ER and PgR levels. When combined with HER2, ESR1 may be prognostic but should not be used for endocrine treatment selection in postmenopausal women with endocrine-responsive early breast cancer.

Early discontinuation of tamoxifen intake in younger women with breast cancer: Is it time to rethink the way it is prescribed?

BackgroundTamoxifen is the main recommended adjuvant hormonal treatment for premenopausal women with hormone-responsive early breast cancer. Little data is available on compliance and persistence to tamoxifen intake in younger women. MethodsUsing the French National Health Insurance System database, we constituted a cohort of 288 women who were diagnosed with breast cancer and received at least one supply of tamoxifen for breast cancer between September 2005 and July 2011. Medical records and mailed questionnaires provided complementary sources of data. Time to treatment discontinuation and associated predictors were studied using techniques for censored data. ResultsAmong women who received a prescription of tamoxifen, 6.1% (16) did not fill any prescription. After 2years of tamoxifen intake, 29.7% (95%confidence interval (CI) 24.1–36.4) had discontinued their treatment; after 3years this percentage increased to 39.5% (95%CI 32.9–47.0). The risk of treatment discontinuation rose sharply during the 1st year of treatment and remained approximately constant in the second year. After multivariate adjustment, tamoxifen discontinuation increased significantly with low social support (Hazard Ratio (HR)=2.1; 95%CI 1.2–3.4), and self-reporting of non-compliance behaviour (HR=2.2; 95%CI 1.3–3.7). ConclusionThe consequences of high treatment discontinuation rates in younger women with long potential life expectancy may be significant. There is an urgent need to acknowledge and tackle compliance issues in the field of oncology, unless we are willing to accept inefficient prescriptions of efficacious drugs.

Tamoxifen and Anastrozole As a Sequencing Strategy: A Randomized Controlled Trial in Postmenopausal Patients With Endocrine-Responsive Early Breast Cancer From the Austrian Breast and Colorectal Cancer Study Group

Anastrozole (ANA) alone delivers significant disease-free survival benefits over tamoxifen (TAM) monotherapy in postmenopausal women with early estrogen receptor-positive breast cancer. The ABCSG-8 (Austrian Breast and Colorectal Cancer Study Group 8) study is a large phase III clinical trial addressing the sequence strategy containing ANA in comparison with 5 years of TAM in a low- to intermediate-risk group of postmenopausal patients. Endocrine receptor-positive patients with G1 or G2 tumors were eligible. After surgery, patients were randomly assigned to 5 years of TAM or 2 years of TAM followed by 3 years of ANA. Adjuvant chemotherapy and G3 and T4 tumors were exclusion criteria. Intention-to-treat and censored analyses of on-treatment recurrence-free survival (RFS) were performed, and exploratory survival end points and toxicity were investigated. Information from 3,714 patients, including 17,563 woman-years, with a median of 60 months of follow-up was available for this analysis. Median age was 63.8 years, 75% were node negative, and 75% had T1 tumors. Sequencing of ANA after identical 2-year treatment with TAM in both arms did not result in a statistically significant improvement of RFS (hazard ratio [HR], 0.80; 95% CI, 0.63 to 1.01; P = .06). Exploratory analyses of distant relapse-free survival indicated a 22% improvement (HR, 0.78; 95% CI, 0.60 to 1.00). On-treatment adverse events and serious adverse events were consistent with known toxicity profiles of ANA and TAM treatment. Despite a low overall rate of recurrence in a population with breast cancer at limited risk of relapse, the a priori sequence strategy of 2 years of TAM followed by 3 years of ANA led to small outcome and toxicity benefits.

Recognizing menopause in women with amenorrhea induced by cytotoxic chemotherapy for endocrine-responsive early breast cancer

Cytotoxic anticancer treatment may induce amenorrhea or menopause to a variable extent. These side effects may not only impair or impede fertility but also cause sexual dysfunction, bone loss, and menopausal symptoms, with a strikingly negative effect on quality of life in many women. Aromatase inhibitors (AIs) are a recommended adjuvant endocrine treatment option in postmenopausal patients affected by early breast cancer (EBC) but are contraindicated in premenopausal women and in those with residual ovarian function. Women over 40 years of age with chemotherapy-induced amenorrhea (CIA) and routine hormonal levels consistent with menopause may receive an AI as adjuvant endocrine treatment. For these women, the tools available to identify menopause do not appear to be completely reliable. This review focused on the pathophysiology of ovarian toxicity induced by cytotoxic agents and on potentially useful methods to diagnose chemotherapy-induced menopause in patients treated with adjuvant chemotherapy for endocrine-responsive EBC. Moreover, practical approaches are proposed to distinguish true menopausal women, who would benefit from AIs, from those with transient or persistent CIA.

P4-02-02: The Natural Fetal Estrogen Estetrol (E4), Causes Anti-Estrogenic Effects in Women with Endocrine-Responsive Positive Early Breast Cancer.

Abstract Background: Estetrol (E4) is a natural fetal estrogen which exerts estrogenic effects on reproductive organs and on the bone, and effectively reduces menopausal smyptoms. In contrast to other estrogens, however, E4 has estrogen-antagonistic effects on breast cancer cell lines in vitro and in the rat DMBA model, which would make it a suitable Hormone Replacement Therapy (HRT) in breast cancer patients, particularly in women who are being treated with aromatase inhibitors. Patients and Methods: We have investigated the effect of 14 days preoperative treatment with 20 mg E4 per day on tumor proliferation, apoptosis, ER-receptors, PgR receptor and several endocrine parameters in a prospective, randomised, double-blind, placebo-controlled, neo-adjuvant study in 15 pre- and 14 postmenopausal women with estrogen-receptor positive early breast cancer. Results: Estetrol induced a significant increase of SHBG, a significant decrease of FSH in postmenopausal women and no increase of gonadotrophins in premenopausal women. Estetrol had no effect on Ki67 expression and on apoptosis-related Bax and Bcl-2, but the apoptosis index in tumor tissue increased significantly. Systemic IGF-1 levels decreased significantly. Surprisingly the intratumoral epithelial ER-alpha expression decreased significantly, whereas the ER-beta expression showed a trend to increase. Conclusion: Our data suggest that E4 may be suitable and safe for HRT in women with spontaneous or induced menopausal symptoms, since apoptosis increases, IGF-1 decreases and no unfavourable effects are observed on Ki67, Bax and Bcl-2. The decrease of ER-alpha and the increase of ER-beta suggest a mechanism of action, explaining why the natural fetal estrogen E4 has estrogen-antagonistic effects on breast cancer tissue. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-02-02.

S1-2: Long-Term Follow-Up in ABCSG-12: Significantly Improved Overall Survival with Adjuvant Zoledronic Acid in Premenopausal Patients with Endocrine-Receptor–Positive Early Breast Cancer.

Abstract Background: We have previously reported significantly improved disease-free survival (DFS) in premenopausal patients with endocrine-responsive early breast cancer receiving adjuvant zoledronic acid (ZOL) in ABCSG-12 (Gnant M, et al. NEJM. 2009;360:679–91). Other trials, such as ZO-FAST and the postmenopausal (&amp;gt;5 yr) subset analysis of AZURE, have demonstrated similar anticancer effects with ZOL. Now with &amp;gt;6 yr of follow-up in ABCSG-12, we report an overall survival (OS) benefit and preplanned subgroup analyses that more precisely define interactions between the ZOL benefit and patient/tumor characteristics. Methods: Premenopausal women with endocrine-receptor-positive early stage breast cancer (N = 1,803) were randomized to ovarian function suppression with goserelin (3.6 mg q28d) and tamoxifen (TAM; 20 mg/d) or anastrozole (ANA; 1 mg/d) ± ZOL (4 mg q6mo) for 3 yr. Endpoints included DFS and OS, both analyzed using logrank test and Cox models. Results: At median follow-up of 76 mo, patients receiving ZOL had a significant 27% reduction in the risk of DFS events (HR = 0.73; Cox P = .022) and a significant 41% reduction in the risk of death (HR = 0.59; Cox P = .027) vs no ZOL. Multivariate analyses showed a strong interaction between ZOL and patient age, but did not show any interactions between ZOL and ANA/TAM or any classic tumor parameter (eg, T, N, grade, ER). Among patients &amp;gt; 40 yr of age (n = 1,390) with presumed complete ovarian blockade, ZOL significantly reduced the risk of DFS events by 34% (HR = 0.66; Cox P = .014) and the risk of death by 49% (HR = 0.51; Cox P = .020); however, there were no significant DFS or OS benefits in patients &amp;lt;40 yr of age. Currently, all patients have completed 3 yr of ZOL and are in the follow-up phase with no reported cases of osteonecrosis of the jaw or renal failure. Additional analyses at a median follow-up of approximately 84 mo are planned for late 2011 and will be presented, providing additional insights into disease recurrence patterns with and without ZOL. Conclusions: Long-term follow-up of ABCSG-12 (76 months) confirms and extends previous results seen at 48 mo and 62 mo follow-up, and suggests that anticancer benefits of adjuvant ZOL result in highly significant DFS and OS benefits mainly in patients with a low-estrogen environment (ie, ovarian suppression and age &amp;gt;40 yr). These results are consistent with the significant DFS and OS improvements seen in the postmenopausal (&amp;gt;5 yr) cohort of the AZURE trial, and suggest that both estrogen deprivation and reduction of bone-turnover-derived growth factors in the bone marrow microenvironment are needed for sufficient suppression of dormant micrometastases. Taken together with the previously demonstrated bone-protective effects of ZOL, these DFS and OS benefits strongly suggest that adding ZOL to adjuvant endocrine therapy should be considered for premenopausal women with endocrine-receptor-positive early breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S1-2.

Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8·1 years median follow-up

Postmenopausal women with hormone receptor-positive early breast cancer have persistent, long-term risk of breast-cancer recurrence and death. Therefore, trials assessing endocrine therapies for this patient population need extended follow-up. We present an update of efficacy outcomes in the Breast International Group (BIG) 1-98 study at 8·1 years median follow-up. BIG 1-98 is a randomised, phase 3, double-blind trial of postmenopausal women with hormone receptor-positive early breast cancer that compares 5 years of tamoxifen or letrozole monotherapy, or sequential treatment with 2 years of one of these drugs followed by 3 years of the other. Randomisation was done with permuted blocks, and stratified according to the two-arm or four-arm randomisation option, participating institution, and chemotherapy use. Patients, investigators, data managers, and medical reviewers were masked. The primary efficacy endpoint was disease-free survival (events were invasive breast cancer relapse, second primaries [contralateral breast and non-breast], or death without previous cancer event). Secondary endpoints were overall survival, distant recurrence-free interval (DRFI), and breast cancer-free interval (BCFI). The monotherapy comparison included patients randomly assigned to tamoxifen or letrozole for 5 years. In 2005, after a significant disease-free survival benefit was reported for letrozole as compared with tamoxifen, a protocol amendment facilitated the crossover to letrozole of patients who were still receiving tamoxifen alone; Cox models and Kaplan-Meier estimates with inverse probability of censoring weighting (IPCW) are used to account for selective crossover to letrozole of patients (n=619) in the tamoxifen arm. Comparison of sequential treatments to letrozole monotherapy included patients enrolled and randomly assigned to letrozole for 5 years, letrozole for 2 years followed by tamoxifen for 3 years, or tamoxifen for 2 years followed by letrozole for 3 years. Treatment has ended for all patients and detailed safety results for adverse events that occurred during the 5 years of treatment have been reported elsewhere. Follow-up is continuing for those enrolled in the four-arm option. BIG 1-98 is registered at clinicaltrials.govNCT00004205. 8010 patients were included in the trial, with a median follow-up of 8·1 years (range 0-12·4). 2459 were randomly assigned to monotherapy with tamoxifen for 5 years and 2463 to monotherapy with letrozole for 5 years. In the four-arm option of the trial, 1546 were randomly assigned to letrozole for 5 years, 1548 to tamoxifen for 5 years, 1540 to letrozole for 2 years followed by tamoxifen for 3 years, and 1548 to tamoxifen for 2 years followed by letrozole for 3 years. At a median follow-up of 8·7 years from randomisation (range 0-12·4), letrozole monotherapy was significantly better than tamoxifen, whether by IPCW or intention-to-treat analysis (IPCW disease-free survival HR 0·82 [95% CI 0·74-0·92], overall survival HR 0·79 [0·69-0·90], DRFI HR 0·79 [0·68-0·92], BCFI HR 0·80 [0·70-0·92]; intention-to-treat disease-free survival HR 0·86 [0·78-0·96], overall survival HR 0·87 [0·77-0·999], DRFI HR 0·86 [0·74-0·998], BCFI HR 0·86 [0·76-0·98]). At a median follow-up of 8·0 years from randomisation (range 0-11·2) for the comparison of the sequential groups with letrozole monotherapy, there were no statistically significant differences in any of the four endpoints for either sequence. 8-year intention-to-treat estimates (each with SE ≤1·1%) for letrozole monotherapy, letrozole followed by tamoxifen, and tamoxifen followed by letrozole were 78·6%, 77·8%, 77·3% for disease-free survival; 87·5%, 87·7%, 85·9% for overall survival; 89·9%, 88·7%, 88·1% for DRFI; and 86·1%, 85·3%, 84·3% for BCFI. For postmenopausal women with endocrine-responsive early breast cancer, a reduction in breast cancer recurrence and mortality is obtained by letrozole monotherapy when compared with tamoxifen montherapy. Sequential treatments involving tamoxifen and letrozole do not improve outcome compared with letrozole monotherapy, but might be useful strategies when considering an individual patient's risk of recurrence and treatment tolerability. Novartis, United States National Cancer Institute, International Breast Cancer Study Group.

Which patients benefit most from adjuvant aromatase inhibitors? Results using a composite measure of prognostic risk in the BIG 1-98 randomized trial

BackgroundOn average, aromatase inhibitors are better than tamoxifen when used as initial or sequential therapy for postmenopausal women with endocrine-responsive early breast cancer. Because there may be contraindications to their use based on side-effects or cost, we investigated subgroups in which aromatase inhibitors may be more or less important. Patients and methodsBreast International Group 1-98 trial randomized 6182 women among four groups comparing letrozole and tamoxifen with sequences of each agent; 5177 (84%) had centrally confirmed estrogen receptor (ER) positivity. We assessed whether centrally determined ER, progesterone receptor (PgR), human epidermal growth factor receptor 2, and Ki-67 labeling index, alone or in combination with other prognostic features, predicted the magnitude of letrozole effectiveness compared with either sequence or tamoxifen monotherapy. ResultsIndividually, none of the markers significantly predicted differential treatment effects. Subpopulation treatment effect pattern plot analysis of a composite measure of prognostic risk revealed three patterns. Estimated 5-year disease-free survival for letrozole monotherapy, letrozole→tamoxifen, tamoxifen→letrozole, and tamoxifen monotherapy were 96%, 94%, 93%, and 94%, respectively, for patients at lowest risk; 90%, 91%, 93%, and 86%, respectively, for patients at intermediate risk; and 80%, 76%, 74%, and 69%, respectively, for patients at highest risk. ConclusionA composite measure of risk informs treatment selection better than individual biomarkers and supports the choice of 5 years of letrozole for patients at highest risk for recurrence.

Current Opinion of Aromatase Inhibitor-induced Arthralgia in Breast Cancer in the UK

Aims Aromatase inhibitors are now a standard of care in the management of hormone-responsive early breast cancer in postmenopausal women. The troublesome side-effect of arthralgia remains a distinct clinical problem, with limited data on its aetiology and management. The aim of this questionnaire study was to evaluate the opinion of UK breast cancer clinicians on the importance of this treatment side effect. Materials and methods In 2009, a questionnaire was sent to 772 breast surgeons and oncologists who manage breast cancer within the UK. The questionnaire evaluated the importance, investigation, management and the need for guidelines for aromatase inhibitor-induced arthralgia (AIA). Results Four hundred and sixteen (54%) returned questionnaires were suitable for analysis. By specialty, 234 (56%) were completed by breast surgeons, 134 (32%) by clinical oncologists, 45 (11%) by medical oncologists and one by a general surgeon. Three hundred and eighty-three (92%) specialists graded the importance of AIA as either very important or important; 211 (51%) did not know the aetiology of AIA; 280 (68%) did not perform bloods; 254 (61%) did not request radiology and 251 (60%) felt management was the responsibility of the oncologists. Three hundred and forty-nine (84%) considered that their practice would benefit from national guidelines. Conclusion This questionnaire has highlighted that AIA is a major patient concern. Further research, educational initiatives and guidance are needed to improve the management of this treatment complication.

Interpreting breast international group (BIG) 1-98: a randomized, double-blind, phase III trial comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive, early breast cancer

The Breast International Group (BIG) 1-98 study is a four-arm trial comparing 5 years of monotherapy with tamoxifen or with letrozole or with sequences of 2 years of one followed by 3 years of the other for postmenopausal women with endocrine-responsive early invasive breast cancer. From 1998 to 2003, BIG -98 enrolled 8,010 women. The enhanced design f the trial enabled two complementary analyses of efficacy and safety. Collection of tumor specimens further enabled treatment comparisons based on tumor biology. Reports of BIG 1-98 should be interpreted in relation to each individual patient as she weighs the costs and benefits of available treatments.Clinicaltrials.gov ID: NCT00004205.

Overall survival with adjuvant zoledronic acid in patients with premenopausal breast cancer with complete endocrine blockade: Long-term results from ABCSG-12.

520 Background: Adjuvant zoledronic acid (ZOL) significantly improved disease-free survival (DFS) in premenopausal patients (pts) with endocrine-responsive early breast cancer in ABCSG-12 (Gnant et al. NEJM 2009). The ZOL anticancer effect was confirmed in other prospective trials, such as ZO-FAST and the postmenopausal (> 5 yrs) cohort of AZURE. Long-term follow-up of ABCSG-12 (> 6 yr) now allows pre-planned subgroup analyses that more precisely identify the ZOL benefit, and interactions with pt and tumor characteristics. Methods: Premenopausal pts with early breast cancer (N = 1,803) were randomized to ovarian function suppression with goserelin (3.6 mg q28d) and tamoxifen (TAM; 20 mg/d) or anastrozole (ANA; 1 mg/d) ± ZOL (4 mg q6mo) for 3 yr. Endpoints included DFS and overall survival (OS), both analyzed using log-rank test and Cox models. Preplanned subgroup analyses included subpopulation treatment effect pattern plot (STEPP). Results: At 68 mo median follow-up, ZOL significantly reduced the risk of DFS events by 32% vs no ZOL (HR = 0.68; P = .009); in addition, there was a strong trend toward reduced risk of death (HR = 0.66; P = .08) with ZOL vs no ZOL. Multivariate analyses showed no interaction between ZOL benefit and ANA/TAM or any classic tumor parameter (eg, T, N, grade, ER). However, a strong interaction between ZOL and pt age was demonstrated. Pts > 40 yr of age (n = 1,390) derived significant DFS benefits from ZOL (HR = 0.58; 0.40-0.83; P = .003), whereas there was no apparent benefit in pts < 40 yr of age. ZOL reduced the risk of death by 42% in pts > 40 yr of age (P = .05), with presumed complete ovarian blockade. In several age subgroups > 40 yr, HRs < 0.5 were observed for both DFS and OS. Conclusions: ABCSG-12 long-term follow-up at 68 mo suggests that anticancer benefits of adjuvant ZOL mainly occur in pts with a low-estrogen environment. As in the postmenopausal (> 5 yrs) cohort of AZURE, ZOL leads to highly significant DFS and OS benefits. This suggests that both estrogen deprivation and reduction of bone-turnover–derived growth factors in the bone marrow microenvironment are needed for sufficient suppression of dormant micrometastases.

62-Month follow-up of ABCSG-12: Adjuvant endocrine therapy, alone or in combination with zoledronic acid, in premenopausal patients with endocrine-responsive early breast cancer

62-Month follow-up of ABCSG-12: Adjuvant endocrine therapy, alone or in combination with zoledronic acid, in premenopausal patients with endocrine-responsive early breast cancer

Abstract P5-11-02: The Carry-Over Effect of Adjuvant Zoledronic Acid: Comparison of 48- and 62-Month Analyses of ABCSG-12 Suggests That the Benefits of Combining Zoledronic Acid with Adjuvant Endocrine Therapy Persist Long after Completion of Therapy

Abstract Background: ABCSG-12 examined the efficacy of ovarian suppression using goserelin combined with tamoxifen (TAM) or anastrozole (ANA) ± zoledronic acid (ZOL) in premenopausal patients with endocrine-responsive early breast cancer. Results at 48 months and at 62 months show that adding ZOL significantly improved disease-free survival (DFS) and reduced disease recurrence. Methods: Premenopausal patients with endocrine-responsive early breast cancer (N = 1,803) were randomized to goserelin (3.6 mg q28d) and TAM (20 mg/d) or ANA (1 mg/d) ± ZOL (4 mg q6mo) for 3 years. Endpoints included DFS and overall survival, both analyzed using log-rank test and Cox models. Results: At 48 months’ median follow-up, ZOL significantly reduced the risk of DFS events by 36% versus no-ZOL (hazard ratio [HR] = 0.64; P = .01); this was maintained at 62 months’ follow-up (HR = 0.68; P = .009). In addition, the trend toward reduced risk of death with ZOL was maintained at both 48 months (HR = 0.60; P = .11) and 62 months (HR = 0.66; P = .10) compared with no-ZOL. Patients receiving ZOL also had fewer distant recurrences compared with no-ZOL: 29 versus 41 events at 48 months, and 44 versus 56 events at 62 months. No significant renal adverse events or confirmed cases of osteonecrosis of the jaw (ONJ) have been reported. Conclusions: Comparisons of 48- and 62-month data suggest a possible carry-over of the ZOL anticancer benefit 2 years after treatment completion. Additional analyses will be presented, including disease outcomes during therapy and after treatment, as well as overall survival analyses. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-11-02.

Abstract S1-8: Outcome According to CYP2D6 Genotype among Postmenopausal Women with Endocrine-Responsive Early Invasive Breast Cancer Randomized in the BIG 1-98 Trial

Abstract Background: Available endocrine therapies, tamoxifen or aromatase inhibitors (AIs), are effective on average for the large population of postmenopausal women with steroid hormone-receptor positive early breast cancer, but many patients still relapse and die of their disease. Treatment selection may be improved by determining patient and disease features that suggest one or another endocrine therapy regimen is better for the individual patient. Recent clinical studies have presented conflicting evidence about whether postmenopausal women receiving adjuvant tamoxifen who carry genetic variants associated with low or absent CYP2D6 activity have a worse disease outcome. BIG 1-98 is a double-blind randomized trial comparing five years of the AI letrozole (Letx5), tamoxifen (Tamx5) and sequences of Let and Tam as adjuvant endocrine therapy for postmenopausal women with endocrine-responsive breast cancer. BIG 1-98 enrolled 8010 patients between 1998 and 2003. Results at 6 years median follow-up showed that, on average, Let was superior to Tam for disease-free and overall survival, and for time to distant recurrence. The sequential arms (Tamx2 → Letx3; Letx2 → Tamx3 had similar results compared with Let. Genotyping is underway using DNA extracted from tumor blocks of patients in trial BIG 1-98 to elucidate genetic determinants of interindividual variability in efficacy and side effects of adjuvant endocrine therapies. We hypothesize that variants of CYP2D6 are associated with shorter breast cancer-free interval on tamoxifen monotherapy, and that the relation will not be observed with letrozole monotherapy as a control. The association with sequential therapies is unknown and will be explored. Methods: Formalin-fixed, paraffin-embedded primary tumor specimens were reviewed in the IBCSG Central Pathology Laboratory and DNA isolated from one or two 1mm cores. Single nucleotide polymorphisms (SNPs) of CYP2D6 {including CYP2D6*4, *2, *3A, *6, *7, *10, *17, *41} were genotyped on the Beckman SNPstream or the ABI 7900 TaqMan system. The association of CYP2D6 variants with breast cancer-free interval and onset of hot flashes/night sweats will be investigated. The role of adjuvant chemotherapy, which was administered in about one-third of trial patients prior to randomization to adjuvant endocrine therapy, will also be investigated. Results: At this time, CYP2D6*4 has been genotyped from FFPE material of 2000 patients, with a success rate greater than 75%. The frequency of homozygous and heterozygous CYP2D6*4 was 8% and 18%, respectively, which is in line with anticipated allele frequency in a predominantly Caucasian population. Genotyping of additional CYP2D6 alleles is ongoing for these patients, as well as full genotyping for up to another 2000 patients. Conclusions: Trial BIG 1-98 provides a large, homogeneously-treated and followed cohort of patients treated with tamoxifen and other endocrine therapy regimens with available material for genotyping. Results of CYP2D6 genotyping (8 alleles) for all available patients will be presented at the meeting. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S1-8.