Adjuvant Letrozole Research Articles

Optimal Duration of Extended Adjuvant Endocrine Therapy for Early Breast Cancer; Results of the IDEAL Trial (BOOG 2006-05)

The optimal duration of extended endocrine therapy beyond five years after initial aromatase inhibitor-based adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer is still unknown. Therefore, we conducted a clinical trial to compare two different extended endocrine therapy durations. In the randomized phase III IDEAL trial, postmenopausal patients with hormone receptor-positive breast cancer were randomly allocated to either 2.5 or five years of letrozole after the initial five years of any endocrine therapy. The primary end point was disease free survival (DFS), and secondary end points were overall survival (OS), distant metastasis-free interval (DMFi), new primary breast cancer, and safety. Hazard ratios (HRs) were determined using Cox regression analysis. All analyses were by intention-to-treat principle. A total of 1824 patients were assigned to either 2.5 years (n = 909) or five years (n = 915) of letrozole, with a median follow-up of 6.6 years. A DFS event occurred in 152 patients in the five-year group, compared with 163 patients in the 2.5-year group (HR = 0.92, 95% confidence interval [CI] = 0.74 to 1.16). OS (HR = 1.04, 95% CI = 0.78 to 1.38) and DMFi (HR = 1.06, 95% CI = 0.78 to 1.45) were not different between both groups. A reduction in occurrence of second primary breast cancer was observed with five years of treatment (HR = 0.39, 95% CI = 0.19 to 0.81). Subgroup analysis did not identify patients who benefit from five-year extended therapy. This study showed no superiority of five years over 2.5 years of extended adjuvant letrozole after an initial five years of adjuvant endocrine therapy.

Randomized trial of vitamin D3 to prevent worsening of musculoskeletal symptoms in women with breast cancer receiving adjuvant letrozole. The VITAL trial.

Aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) frequently occur in women being treated for breast cancer. Prior studies suggest high prevalence of vitamin D deficiency in breast cancer patients with musculoskeletal (MS) pain. We conducted a randomized, placebo-controlled trial to determine if 30,000IU vitamin D3 per week (VitD3) would prevent worsening of AIMSS in women starting adjuvant letrozole for breast cancer. Women with stage I-III breast cancer starting adjuvant letrozole and 25(OH)D level ≤40ng/ml were eligible. All subjects received standard daily supplement of 1200mg calcium and 600IU vitamin D3 and were randomized to 30,000IU oral VitD3/week or placebo. Pain, disability, fatigue, quality of life, 25(OH)D levels, and hand grip strength were assessed at baseline, 12, and 24weeks. The primary endpoint was incidence of an AIMSS event. Median age of the 160 subjects (80/arm) was 61. Median 25OHD (ng/ml) was 25 at baseline, 32 at 12weeks, and 31 at 24weeks in the placebo arm and 22, 53, and 57 in the VitD3 arm. There were no serious adverse events. At week 24, 51% of women assigned to placebo had a protocol defined AIMSS event (worsening of joint pain using a categorical pain intensity scale (CPIS), disability from joint pain using HAQ-II, or discontinuation of letrozole due to MS symptoms) vs. 37% of women assigned to VitD3 (p=0.069). When the brief pain inventory (BPI) was used instead of CPIS, the difference was statistically significant: 56 vs. 39% (p=0.024). Although 30,000IU/week of oral vitamin D3 is safe and effective in achieving adequate vitamin D levels, it was not associated with a decrease in AIMSS events based on the primary endpoint. Post-hoc analysis using a different tool suggests potential benefit of vitamin D3 in reducing AIMSS.

Prognostic and predictive importance of the estrogen receptor coactivator AIB1 in a randomized trial comparing adjuvant letrozole and tamoxifen therapy in postmenopausal breast cancer: the Danish cohort of BIG 1-98

PurposeTo evaluate the estrogen receptor coactivator amplified in breast cancer 1 (AIB1) as a prognostic marker, as well as a predictive marker for response to adjuvant tamoxifen and/or aromatase inhibitors, in early estrogen receptor-positive breast cancer.MethodAIB1 was analyzed with immunohistochemistry in tissue microarrays of the Danish subcohort (N = 1396) of the International Breast Cancer Study Group’s trial BIG 1-98 (randomization between adjuvant tamoxifen versus letrozole versus the sequence of the two drugs).ResultsForty-six percent of the tumors had a high AIB1 expression. In line with previous studies, AIB1 correlated to a more aggressive tumor-phenotype (HER2 amplification and a high malignancy grade). High AIB1 also correlated to higher estrogen receptor expression (80–100 vs. 1–79%), and ductal histological type. High AIB1 expression was associated with a poor disease-free survival (univariable: hazard ratio 1.35, 95% confidence interval 1.12–1.63. Multivariable: hazard ratio 1.29, 95% confidence interval 1.06–1.58) and overall survival (univariable: hazard ratio 1.34, 95% confidence interval 1.07–1.68. Multivariable: hazard ratio 1.25, 95% confidence interval 0.99–1.60). HER2 did not seem to modify the prognostic effect of AIB1. No difference in treatment effect between tamoxifen and letrozole in relation to AIB1 was found.ConclusionsIn a subset of the large international randomized trial BIG 1-98, we confirm AIB1 to be a strong prognostic factor in early breast cancer. Hence, although tumor AIB1 expression does not seem to be useful for the choice of tamoxifen versus an aromatase inhibitor in postmenopausal endocrine-responsive breast cancer, AIB1 is an interesting target for new anti-cancer therapies and further investigations of this biomarker is warranted.

Phase 3 randomized study of adjuvant anastrozole (A), exemestane (E), or letrozole (L) with or without tamoxifen (T) in postmenopausal women with hormone-responsive (HR) breast cancer: The FATA-GIM3 trial.

515 Background: Uncertainty still exists regarding the optimal schedule of adjuvant treatment of breast cancer with aromatase inhibitors (AI) and no trial has ever compared all the three AI. Methods: FATA-GIM3 is a multicenter, open label, 2x3 factorial phase 3 randomized study of adjuvant A, E and L upfront (UP - for 5 years) or sequentially (SEQ - for 3 years after 2 years of T) in postmenopausal HR breast cancer pts. Two comparisons were planned: UP vs SEQ and A vs E vs L. DFS (including local or distant relapse, second breast or non-breast cancer, DCIS and death, whichever came first) was the primary end-point; 2% at 5 yrs (corresponding to a HR of 0.79) was defined as the minimum difference required to declare superiority of UP vs SEQ. With two-tailed alfa 0.05, power 80%, 669 events and the enrolment of 3600 patients were planned. Following Data Monitoring Committee advice, final analysis was performed after 5yrs median follow-up. For each comparison a Cox regression model was applied adjusted by stratification factors and stratified by the other treatment factor. Analyses were based on intention-to-treat. Results: from 3/2007 to 7/2012, 3697 patients were enrolled at 76 centres. Median age 64, pT1 69.7% , pN0 64.3%, ER and PgR positive 88.9%, HER2 positive 8.9%, previous chemotherapy 38.3%. At 60 months median follow-up, 401 events were reported. 5yrs DFS was 89.8 with UP and 88.5 with SEQ (delta 1.32%, 95% CI -0.90-3.54; HR 0.89, 95% CI 0.73-1.08; P=0.23). 5yrs DFS was 90.0 with A, 88.0 with E and 89.4 with L (P=0.19). Conclusions: in the FATA-GIM3 trial there is a small non statistically significant DFS advantage for UP vs SEQ. No significant difference is evident among the three AI. Supported by the FARM5K3MEE AIFA grant from the Italian Drug Agency. Clinical trial information: NCT00541086.

A high level of estrogen-stimulated proteins selects breast cancer patients treated with adjuvant endocrine therapy with good prognosis

Background: Adjuvant endocrine therapy has significantly improved survival of estrogen receptor α (ER)-positive breast cancer patients, but around 20% relapse within 10 years. High expression of ER-stimulated proteins like progesterone receptor (PR), Bcl-2 and insulin-like growth factor receptor I (IGF-IR) is a marker for estrogen-driven cell growth. Therefore, patients with high tumor levels of these proteins may have particularly good prognosis following adjuvant endocrine therapy.Patients and methods: Archival tumor tissue was available from 1323 of 1396 Danish breast cancer patients enrolled in BIG 1-98, a randomized phase-III clinical trial comparing adjuvant letrozole, tamoxifen or a sequence of the two drugs. Immunohistochemical staining for ER, HER-2, PR, Bcl-2 and IGF-IR was performed and determined by Allred scoring (ER, PR and Bcl-2) or HercepTest (HER-2 and IGF-IR).Results: Data on all five markers were available from 969 patients with ER-positive, HER-2-negative tumors. These patients were classified in ER activity groups based on the level of PR, Bcl-2 and IGF-IR. High ER activity profile was found in 102 patients (10.5%) and compared with the remaining patients, univariate and multivariate analysis revealed HR (95% CI) and p values for disease-free survival (DFS) of 2.00 (1.20–3.22), 0.008 and 1.70 (1.01–2.84), 0.04 and for the overall survival (OS) of 2.33 (1.19–4.57), 0.01 and 1.90 (0.97–3.79), 0.06, respectively. The high ER activity profile did not disclose difference in DFS or OS according to treatment with tamoxifen or letrozole (p = .06 and .09, respectively).Conclusions: Stratifying endocrine-treated patients in ER activity profile groups disclosed that patient with high ER activity profile (10.5%) had significantly longer DFS and OS, and the profile was an independent marker for DFS. High ER activity is a marker for estrogen-driven tumor growth. We suggest further analyses to disclose whether the ER activity profile or other markers associated with estrogen-driven growth may be used to identify ER-positive high-risk breast cancer patients who can be spared adjuvant chemotherapy.

Abstract P2-09-14: Association between BMI and residual estradiol levels in post-menopausal women using adjuvant letrozole: Results of a prospective study

Abstract Background: Adjuvant aromatase inhibitors (AI) are the standard of care for post-menopausal women with early breast cancer (BC). Some studies have suggested that women with high BMI have less benefit from some AIs (anastrozole, but not letrozole) vs. tamoxifen. Of concern, a positive correlation between BMI and residual estradiol in women using letrozole has been reported (ALIQUOT Study; JCO 2012). These findings have created uncertainty about the use of AIs in overweight and obese women. We conducted a prospective study to measure estrogen levels in post-menopausal women using adjuvant letrozole, with the primary objective of evaluating the relationship between residual E2 and BMI. Methods: Post-menopausal women with early BC taking adjuvant letrozole for at least 3 months were recruited at 4 sites in Toronto, Canada. Fasting blood was collected 24 hours after the prior dose at baseline (Day 1, routine use of own letrozole, including generic) and on Day 29, following 28 days of monitored adherence to a provided supply of Femara 2.5 mg/day (Part A). Participants with BMI>25 were treated for a further 28 days (Part B) with a double dose of Femara (5 mg/day). Estradiol and estrone were measured using a high sensitivity liquid chromatography-tandem mass spectrometry assay. Vitamin D and markers of obesity/inflammation were assayed, and symptom/quality of life questionnaires completed at the same time points. Results: 112 eligible patients were enrolled and completed Part A. Median age was 62 and BMI 24.7 kg/m2 (range 19.0 to 42.2 kg/m2). 68% of participants had received adjuvant chemotherapy. Estradiol levels (mean±SD) were 2.81±1.15 pg/mL at baseline (typical use) and 2.69±1.01 pg/mL at Day 29 following monitored Femara use with near-perfect adherence (p=NS). No significant correlation was observed between estradiol and BMI on either Day 1 or Day 29 (r=0.06, p=NS). As previously reported, letrozole 5 mg/day dose did not affect residual estradiol levels at Day 58 for women with BMI>25. Residual estradiol was not correlated with vitamin D or markers of obesity/inflammation (insulin, leptin, CRP). Conclusion: No association was observed between BMI and residual estradiol in women using letrozole (generic or Femara) at standard doses. These results are consistent with the absence of a treatment-by-BMI interaction in the BIG 1-98 trial and they provide reassurance that letrozole is an appropriate treatment in overweight and obese women. Funded by Hold 'Em For Life (Mount Sinai Hospital, Toronto) and Breast Cancer Research Foundation. Citation Format: Cescon DW, Ennis M, Pritchard KI, Townsley C, Warr D, Elser C, Rao L, Stambolic V, Sridhar S, Goodwin PJ. Association between BMI and residual estradiol levels in post-menopausal women using adjuvant letrozole: Results of a prospective study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-09-14.

Abstract P2-09-05: 12 years' median follow up (MFU) of BIG 1-98: Adjuvant letrozole, tamoxifen and their sequence for postmenopausal women with endocrine responsive early breast cancer

Abstract Background The Breast International Group (BIG) 1-98 study is a randomized, phase 3, double-blind trial that compared five yrs of adjuvant treatment with letrozole, tamoxifen, or their sequence in postmenopausal women with hormone-receptor–positive early breast cancer. The study is conducted by the International Breast Cancer Study Group (IBCSG) on behalf of BIG. 8010 patients (pts) were enrolled between March 1998 and May 2003, and first results demonstrating a significant DFS benefit favoring letrozole compared with tamoxifen were reported in 2005 at 25.8 months' MFU. Subsequent updates showed continuing DFS benefit and updated results published in 2011 at 8.1 yrs' MFU showed OS benefit. Industry-sponsorship of the original BIG 1-98 ended in 2010; IBCSG launched an observational, non-interventional long-term follow-up study (BIG 1-98 LTFU) to collect survival, disease status and adverse events for an additional 5 yrs. We report results from BIG 1-98 LTFU at 12 yrs' MFU. Methods The original trial includes the 8010 patients enrolled. The potential BIG 1-98 LTFU cohort consisted of 148 academic medical centers with a maximum of 6843 pts who were alive and continuing follow-up when the original study ended. Response bias was addressed using weighting class adjustments estimated using multivariable logistic regression. Unadjusted incidence rates are reported here per 1000 pt-yrs with 95% Poisson confidence intervals. An updated abstract will include adjusted incidence rates, as well as estimates of OS and DFS based on a weighted Kaplan-Meier approach. The database will close in July 2016. Results As of May 2016, 81 centers participated in the BIG 1-98 LTFU study, contributing data from approximately 3900 pts (57%) and extending MFU to 12 yrs. Compared with the potential cohort of 6843 pts, the ~3900 in the LTFU analytic cohort were more likely to be under age 65 yrs at enrollment, have node-positive disease, and have tumors that were < 2 cm, PgR positive (≥1%), and with no evidence of peritumoral vascular invasion. Extended adjuvant endocrine therapy for primary BC was continued in 2% of pts. Unadjusted incidence estimates of myocardial infarction increased during LTFU, while incidence of thromboembolic events and osteoporosis decreased (Table). Variations in incidence rates were noted depending on recording mechanism (e.g. registry, clinic visit, telephone, information from family). Unadjusted Incidence Rate/1000 pt-yrs (95% CI)Adverse EventDuring original studyDuring LTFUMyocardial Infarction1.7 (1.4-2.0)3.5 (2.7-4.5)Thromboembolic event6.0 (5.4-6.6)2.5 (1.8-3.3)Osteoporosis23.6 (22.5-24.9)18.2 (16.3-20.3)Bone fractures17.2 (16.2-18.3)15.0 (13.2-16.9) Overall 1845 deaths were reported; the unadjusted incidence of death was lower in the original study compared with during LTFU (21.9 vs. 26.6/1000 pt-yrs); incidence remained relatively stable for pts assigned to tamoxifen (24.9 vs. 25.2/1000 pt-yrs), and increased for pts assigned to letrozole (22.0 vs. 27.1/1000 pt-yrs). Conclusions The BIG 1-98 LTFU study has been successfully conducted. The additional data from the BIG 1-98 LTFU study provides important long-term clinical information about OS, DFS and adverse events. Citation Format: Thürlimann B, Giobbie-Hurder A, Colleoni M, Jensen M-B, Ejlertsen B, de Azambuja E, Neven P, Láng I, Gladieff L, Bonnefoi H, Harvey VJ, Spazzapan S, Tondini C, Price K, Piccart-Gebhart M, Regan MM, Gelber RD, Coates AS, Goldhirsch A. 12 years' median follow up (MFU) of BIG 1-98: Adjuvant letrozole, tamoxifen and their sequence for postmenopausal women with endocrine responsive early breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-09-05.

Abstract S1-10: Clinical implications of somatic mutations in post-menopausal early-stage estrogen receptor (ER)-positive HER2-negative breast cancer (BC): Results from the BIG 1-98 study

Abstract Background Next generation sequencing (NGS) has revealed that ER+/HER2- BCs have diverse somatic copy number and mutation profiles but thus far the clinical relevance of such findings is unknown. We characterized the molecular alterations in post-menopausal primary BC patients treated in the BIG 1-98 adjuvant letrozole and tamoxifen study and evaluated their associations with prognosis. Materials and Methods NGS was used to genotype DNA from archival primary tumor blocks for 286 cancer-related genes. From 2706 available eligible samples (confirmed ER+, excluding HER2-positivity or neoadjuvant treatment, adequate DNA quality/quantity), a case-cohort design selected 764 samples: all distant relapses and a stratified sampling of non-relapses after 8yr median follow-up. Mutation prevalence and associations with clinicopathological factors (CP) as well as distant recurrence-free interval (DRFS) were analyzed using weighted tests and Cox regression models, with sampling weights to represent the ER+/HER2-negative trial population. Multivariable analyses were adjusted for tumor size, nodal status, grade and age. Results NGS data was available from 538/764 samples (70%), there were 140 (26%) distant relapses. Median sequencing depth was 483x. There was a mean of 11 mutations (1-46) per sample, with 25% having 13 or more mutations and no tumors without a mutation. Overall 28 genes were altered at a frequency of >10%. The most commonly mutated genes were PIK3CA (49.3%), NCOR1 (27.2%), MAP3K1 (23.8%) TP53 (16.6%), CCND1 (17.8%) and GATA3 (17.1%). Alterations that were significantly associated with both Luminal B (Ki67 >14%) and grade 3 included TP53 mutations (p<0.001), FGFR1 (p=0.001) and MYC amplifications (p=0.004). Gene alterations that were significantly associated with shorter DRFS included TP53 (HR:2.16), ARID1A (HR:2.43), CHEK2 (HR:2.54), BRCA2 (HR:1.93), PTEN (HR:2.03), CCND1 (HR:1.82) and FGFR1 (HR:1.78). PIK3CA was significantly associated with lower risk of distant relapse (HR:0.64; 0.43-0.97). Increasing number of total mutations was significantly associated with shorter DRFS (HR:1.04; 95% CI 1.01-1.07; p=0.006). In the multivariable model adjusted for CP factors, ARID1A, BRCA2, CCND1, CHEK2 and PTEN remained independent for shorter DRFS. Greater than 90% of PIK3CA mutations co-existed with another alteration, most common being NCOR1 (29%), MAP3K1 (24%), CDH1 (16%), GATA3 (16%), TP53 (14%) and CCND1 (13%). Patients with a PIK3CA mutation had greater benefit with letrozole over tamoxifen monotherapy (HR 0.32; 0.13-0.8) than those without (HR:0.70; 0.33-1.48) (Pint=0.06). This effect was strongest in the subgroup of PIK3CA mutant patients who were CCND1 and TP53 wild-type (HR:0.24, 0.12-0.48; Pint=0.02) with only 1% relapsing at 5 years. Conclusion: For the first time, we report the prognostic relevance of oncogenic mutations in ER+/HER2- postmenopausal early-stage BCs from a clinical trial. Tumors with PIK3CA mutations derived greater benefit from letrozole over tamoxifen monotherapy, especially if wild-type for CCND1 and TP53. These findings could significantly improve prognostic risk classification and guide future clinical trials of targeted therapies in ER+/HER2- BCs. Citation Format: Loi S, Asher R, Lee CK, Luen S, Savas P, Kammler R, Dell'Orto P, Blasi OM, Demanse D, JeBailley L, Dolan S, Hackl W, Thuerlimann B, Viale G, Regan M, Colleoni MA. Clinical implications of somatic mutations in post-menopausal early-stage estrogen receptor (ER)-positive HER2-negative breast cancer (BC): Results from the BIG 1-98 study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S1-10.

Abstract P2-09-08: Safety assessment of extended adjuvant endocrine therapy with letrozole; results of the randomized phase III IDEAL trial (BOOG 2006-05)

Abstract The implementation of adjuvant aromatase inhibitors (AI) has contributed significantly to an ongoing improvement in survival of early breast cancer patients, but the impact of extended AI on toxicity after use in the initial 5 years has not yet been studied. Earlier, it was established that even after 5 years of adjuvant tamoxifen, extended letrozole for 5 years was comparable to the earlier reported toxicities, without an effect on overall quality of life. The aim of the current study is to assess the reported toxicity in the IDEAL trial, investigating extended letrozole after 5 years of endocrine therapy. The Dutch phase III IDEAL trial was designed to study the optimal duration of extended adjuvant letrozole, by randomizing to either 2.5 or 5 years of letrozole after the completion of 5 years of any endocrine therapy. All patients were disease-free at the time of randomization. The primary outcome of this study, disease free survival after extended endocrine therapy, will be reported separately. Toxicity data were collected every 6 months in the first year, and annually thereafter until study completion. 1824 patients were included in the trial, of which 26 patients never started with therapy (n=1798). In total, 3434 adverse events were reported by 1283 patients, causing 360 (20%) patients to stop therapy due to these events. In total, 643 patients randomized to 5 years of therapy reported 1834 AEs (71.2%), whereas 640 patients on 2.5 years of therapy reported 1587 events (71.5%). In the 5 year AI group, 1456 (80%) of the AEs were reported within the initial 2.5 years causing 177 patients to stop therapy in this period, versus 29 patients who stopped due to toxicity after the therapy extension beyond 2.5 years. There was no significant difference in the proportion of grade 3/4 events between both groups (2.5yr: 9.8%, 5yr: 9.7%, X2 p=0.52). Most reported AEs were arthralgia (n=248, 13.8% of all patients , 8.9% grade 3/4), hot flushes (n=215, 12%, 6.5% grade 3/4), osteoporosis (n=181, 10%, 2.2% grade 3/4), fatigue (n=156, 8.7%, 5.1% grade 3/4) and a decrease in joint function (n=114, 6.3%, 3.5% grade 3/4). In total, only one grade 5 AE was reported, which was unrelated to the treatment (bleeding and sepsis after cholecystectomy). Although the toxicity pattern is comparable to regular AI based adjuvant therapy, the percentage of specific adverse events like arthralgia and hot flushes is lower than expected. This observation is possibly a selection bias, since patients who encountered side effects during regular adjuvant therapy could have been less willing to participate in this trial. Remarkably, low numbers of AEs and therapy refusal due to toxicity were reported after therapy extension beyond 2.5 years. In conclusion, extended adjuvant endocrine therapy shows an acceptable toxicity pattern, and therapy extension beyond 2.5 years up to 5 years is well tolerated and safe. Citation Format: Blok EJ, Kroep JR, Meershoek-Klein Kranenbarg EM, Duym-de Carpentier M, Putter H, van den Bosch J, Maartense E, van Leeuwen-Stok AE, Liefers G-J, Nortier JWR, Rutgers EJT, van de Velde CJH. Safety assessment of extended adjuvant endocrine therapy with letrozole; results of the randomized phase III IDEAL trial (BOOG 2006-05) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-09-08.

Comparative Efficacy and Safety of Adjuvant Letrozole Versus Anastrozole in Postmenopausal Patients With Hormone Receptor–Positive, Node-Positive Early Breast Cancer: Final Results of the Randomized Phase III Femara Versus Anastrozole Clinical Evaluation (FACE) Trial

Purpose The Letrozole (Femara) Versus Anastrozole Clinical Evaluation (FACE) study compared the efficacy and safety of adjuvant letrozole versus anastrozole in postmenopausal patients with hormone receptor (HR) -positive and node-positive early breast cancer (eBC). Methods Postmenopausal women with HR-positive and node-positive eBC were randomly assigned to receive adjuvant therapy with either letrozole (2.5 mg) or anastrozole (1 mg) once per day for 5 years or until recurrence of disease. Patients were stratified on the basis of the number of lymph nodes and human epidermal growth factor receptor 2 status. The primary end point was 5-year disease-free survival (DFS), and the key secondary end points were overall survival and safety. Results A total of 4,136 patients were randomly assigned to receive either letrozole (n = 2,061) or anastrozole (n = 2,075). The final analysis was done at 709 DFS events (letrozole, 341 [16.5%]; anastrozole, 368 [17.7%]). The 5-year estimated DFS rate was 84.9% for letrozole versus 82.9% for anastrozole arm (hazard ratio, 0.93; 95% CI, 0.80 to 1.07; P = .3150). Exploratory analysis showed similar DFS with letrozole and anastrozole in all evaluated subgroups. The 5-year estimated overall survival rate was 89.9% for letrozole versus 89.2% for anastrozole arm (hazard ratio, 0.98; 95% CI, 0.82 to 1.17; P = .7916). Most common grade 3 to 4 adverse events (> 5% of patients) reported for letrozole versus anastrozole were arthralgia (3.9% v 3.3%, and 48.2% v 47.9% for all adverse events), hypertension (1.2% v 1.0%), hot flushes (0.8% v 0.4%), myalgia (0.8% v 0.7%), dyspnea (0.8% v 0.5%), and depression (0.8% v 0.6%). Conclusion Letrozole did not demonstrate significantly superior efficacy or safety compared with anastrozole in postmenopausal patients with HR-positive, node-positive eBC.

Preventive effect of zoledronic acid on aromatase inhibitor-associated bone loss for postmenopausal breast cancer patients receiving adjuvant letrozole

BackgroundThis study aims to compare the efficacy and safety between zoledronic acid combined with calcium and calcium alone to prevent aromatase inhibitor-associated bone loss for postmenopausal breast cancer patients receiving adjuvant letrozole.MethodsOne hundred twenty patients were randomly divided into two groups, A and B. Patients in group A (n=60) received modified radical mastectomy or breast-conserving surgery + four cycles of AC followed by T regimen (optional) + radiotherapy (optional) + letrozole 2.5 mg daily + calcium 500 mg twice daily + vitamin D 400 international units daily +4 mg of zoledronic acid every 6 months, while patients in group B (n=60) were not given zoledronic acid and the rest of the treatments of group B were the same as group A. All the patients were followed up for 1 year. The primary endpoint was the intrapatient percentage change in lumbar spine (LS) bone mineral density (BMD) from baseline to month 12. Secondary endpoints included the percentage change in total hip (TH) and femoral neck (FN) BMD, the incidence of osteoporosis, the incidence of a clinically meaningful 5% decline in BMD at 1 year, change of serum N-telopeptide of type 1 collagen (NTX) and bone-specific alkaline phosphatase (BSAP) concentrations.ResultsPatients in group A had a statistically significant higher average change and average percent change in LS, FN, and TH than group B. Group A had a statistically significant lower incidence of a clinically meaningful loss of bone density at the LS, FN, or TH than Group B. The incidence of osteoporosis in group A was significantly lower than group B. The decreases in NTX and BSAP concentrations from baseline to month 12 in patients of group A were significant; in contrast, patients in group B were found to have increases in NTX and BSAP concentrations from baseline. The most common adverse reactions in patients are flu-like symptoms (38%), bone pain (28%), and joint pain (20%).ConclusionAI-associated bone loss can be prevented by concurrent zoledronic acid for postmenopausal breast cancer patients.

A randomized trial (MA.17R) of extending adjuvant letrozole for 5 years after completing an initial 5 years of aromatase inhibitor therapy alone or preceded by tamoxifen in postmenopausal women with early-stage breast cancer.

LBA1 Background: Five years of aromatase inhibitor (AI) therapy either as up-front treatment or after 2-5 years of tamoxifen has become the standard of care for postmenopausal women with hormone receptor positive early breast cancer. Extending treatment with an AI to 10 years may further reduce the risk of breast cancer recurrence. Methods: We conducted a double-blind, placebo-controlled trial (Canadian Cancer Trials Group MA.17R) to test the efficacy of extending AI treatment for an additional five years using letrozole. The primary endpoint was disease-free survival. Results: A total of 1,918 women with early stage breast cancer were enrolled (median follow-up 75 months, 6.3 years). A total of 165 disease-free survival (DFS) events (67 on letrozole and 98 on placebo) occurred, of which 42 versus 53 were distant recurrences on letrozole and placebo, respectively. There were 200 deaths (100 in each treatment group). The 5 year DFS was respectively 95% for patients receiving letrozole versus 91% for those on placebo (HR 0.66; P = 0.01) from a two-sided log-rank test stratified by nodal status, prior adjuvant chemotherapy, interval between last dose of AI therapy and randomization, and duration of prior tamoxifen at randomization. The 5 year overall survival was respectively 93% for subjects on letrozole and 94% on placebo with a HR of 0.97 (P = 0.83). The annual incidence rate of contralateral breast cancer was 0.21% for subjects on letrozole versus 0.49% on placebo (P = 0.007). Conclusions: Compared to 5 years of AI treatment as initial therapy or preceded by 2-5 years of tamoxifen, extending AI treatment to 10 years significantly improves disease-free survival. Further analyses will provide a comprehensive picture of toxicities and QOL. Clinical trial information: NCT00754845.

Patient-reported outcomes from MA.17R: A randomized trial of extending adjuvant letrozole for 5 years after completing an initial 5 years of aromatase inhibitor therapy alone or preceded by tamoxifen in postmenopausal women with early-stage breast cancer.

LBA506 Background: MA.17R is a Canadian Cancer Trials Group (CCTG) led phase III randomized controlled trial comparing letrozole to placebo after 5 years of aromatase inhibitor (AI) as adjuvant therapy for hormone-receptor positive breast cancer. The primary endpoint was disease-free survival. Quality of life (QOL) was a secondary endpoint. Methods: QOL was measured with the SF-36 (2 summary scores and 8 domains) and menopause-specific QOL (MENQOL) (4 symptom domains) at baseline and every 12 months (mo) up to 60 mo. QOL assessment was mandatory for CCTG centres but optional to centres in other groups. Mean change scores from baseline were calculated at 12 and 36 mo. Between-arm differences were assessed with the Wilcoxon test. Results: 1918 patients were randomized and 1428 patients completed the baseline QOL assessment. Compliance with QOL measures was over 85%. Baseline summary scores for SF-36 physical (PCS, 47.5 for letrozole and 47.9 for placebo) and mental (MCS, 55.5 for letrozole and 54.8 for placebo) were close to population norms (50). No differences were seen between groups in mean change scores for the SF-36 PCS and MCS and the other 8 QOL domains. Patients randomized to letrozole reported worse vasomotor symptoms (12 mo p = 0.02, 36 mo p = 0.03) and worse sexual functioning (12 mo p = 0.01, 36 mo p = 0.01). Further analyses with follow up to 60 months will be presented. Conclusions: No differences were seen in overall QOL measured by the SF 36 summary measures between letrozole and placebo groups. Differences existed for vasomotor symptoms and sexual functioning which were worse in the letrozole group and attributed to improvements in mean scores seen for women randomized to placebo. The data indicate that continuation of AI therapy after 5 years prior treatment is not associated with a deterioration of overall QOL. Treatment related vasomotor and sexual functioning alterations occur with ongoing treatment. Clinical trial information: NCT00754845.

Patient-reported outcomes from MA.17R: A randomized trial of extending adjuvant letrozole for 5 years after completing an initial 5 years of aromatase inhibitor therapy alone or preceded by tamoxifen in postmenopausal women with early-stage breast cancer.

Patient-reported outcomes from MA.17R: A randomized trial of extending adjuvant letrozole for 5 years after completing an initial 5 years of aromatase inhibitor therapy alone or preceded by tamoxifen in postmenopausal women with early-stage breast cancer.

A randomized trial (MA.17R) of extending adjuvant letrozole for 5 years after completing an initial 5 years of aromatase inhibitor therapy alone or preceded by tamoxifen in postmenopausal women with early-stage breast cancer.

A randomized trial (MA.17R) of extending adjuvant letrozole for 5 years after completing an initial 5 years of aromatase inhibitor therapy alone or preceded by tamoxifen in postmenopausal women with early-stage breast cancer.

New onset vasomotor symptoms but not musculoskeletal symptoms associate with clinical outcomes on extended adjuvant letrozole – Analyses from NCIC CTG MA.17

PurposeNew onset symptoms on adjuvant aromatase inhibitors for hormone receptor positive early breast cancer may associate with clinical outcomes. We performed this exploratory analysis of the association of new onset musculoskeletal (MSK) and vasomotor (VM) symptoms with clinical outcomes in the NCIC CTG MA.17 trial 5 years of extended adjuvant endocrine therapy with letrozole after tamoxifen. MethodsSymptoms were collected at baseline, 1, 6, and every 12 months on study. Multivariate Cox Models adjusting for age, nodal status, duration of tamoxifen and prior chemotherapy were used to compare disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) based on data collected before, and after, the unblinding between women with VM or MSK symptoms and those without. ResultsData post-unblinding showed new VM symptoms on extended letrozole significantly improved DFS and DDFS when occurring 1 month (DFS HR 0.52, 95% CI, 0.28–0.96; p = 0.04; DDFS HR 0.49, 95% CI, 0.24–0.99; p = 0.046) and 6 months (DFS HR 0.43, 95% CI, 0.24–0.78; p = 0.006; DDFS HR 0.44, 95% CI, 0.22–0.85; p = 0.02) after treatment initiation. Those with new VM symptoms at 12 months also had a significantly better DFS (HR 0.47, 95% CI 0.26, 0.84; P = 0.01) and a trend in improved DDFS. Only a trend to improved OS was found for those with VM symptoms 6 month after treatment. No significant improvement was found for those with new MSK symptoms at any time point or for any endpoint. ConclusionsNew onset VM symptoms with extended letrozole may be useful in predicting treatment benefit.

Prognostic and predictive effects of diabetes, hypertension, and coronary artery disease among women on extended adjuvant letrozole: NCIC CTG MA.17

BackgroundWomen with breast cancer and diabetes mellitus (DM) have poorer survival. Mechanisms include insulin dysregulation and/or DM related co-morbidities (CM). In MA.17 adjuvant letrozole (LET) after 5 years of tamoxifen (TAM) reduced the risk of recurrence and improved survival. We evaluated DM, hypertension (HTN), and coronary artery disease (CAD) as prognostic and predictive factors in MA.17. Patients and methodsDisease free survival, distant disease free survival (DDFS) and overall survival (OS) were compared using Cox regression model adjusting for other prognostic factors: in women treated by placebo (PLAC) based on the presence or absence of baseline DM (n = 462), HTN (n = 1627), CAD (n = 604) or any one of these CM (n = 2049), and between LET and PLAC groups in each CM. Analyses based on nodal status were performed. ResultsDM was neither prognostic nor predictive for women on extended LET. Women with one CM had similar outcomes on LET compared to women free of CM. For node positive women, the difference between LET and PLAC in DDFS was greater among women with one CM (hazard ratio [HR] = 0.30 [0.15–0.60], p = 0.001) compared to those without CM (HR = 0.72 [0.45–1.16], p = 0.17, p interaction = 0.04). Women on PLAC with HTN trended towards lower DDFS (HR = 1.50 [0.98–2.3], p = 0.06) and OS (HR = 1.61 [0.95–2.72], p = 0.08) than non-HTN women. HTN women had better DDFS on LET than non-HTN women. Women with one CM on PLAC had lower OS (HR = 2.10 [1.26–3.51], p = 0.004) than those free of CM. ConclusionsDM was not prognostic or predictive of outcomes. Women with CM who remain disease free after 5 years of TAM should be offered LET. HTN trended towards a negative prognosticator and outcomes among this group were improved on LET. More studies are needed to assess impact of adrenergic stimulation as a possible link to poorer breast cancer outcomes.

Association of Variants in Candidate Genes with Lipid Profiles in Women with Early Breast Cancer on Adjuvant Aromatase Inhibitor Therapy

Aromatase inhibitors can exert unfavorable effects on lipid profiles; however, previous studies have reported inconsistent results. We describe the association of single-nucleotide polymorphisms (SNP) in candidate genes with lipid profiles in women treated with adjuvant aromatase inhibitors. We conducted a prospective observational study to test the associations between SNPs in candidate genes in estrogen signaling and aromatase inhibitor metabolism pathways with fasting lipid profiles during the first 3 months of aromatase inhibitor therapy in postmenopausal women with early breast cancer randomized to adjuvant letrozole or exemestane. We performed genetic association analysis and multivariable linear regressions using dominant, recessive, and additive models. A total of 303 women had complete genetic and lipid data and were evaluable for analysis. In letrozole-treated patients, SNPs in CYP19A1, including rs4646, rs10046, rs700518, rs749292, rs2289106, rs3759811, and rs4775936 were significantly associated with decreases in triglycerides by 20.2 mg/dL and 39.3 mg/dL (P < 0.00053), respectively, and with variable changes in high-density lipoprotein (HDL-C) from decreases by 4.2 mg/dL to increases by 9.8 mg/dL (P < 0.00053). Variants in CYP19A1 are associated with decreases in triglycerides and variable changes in HDL-C in postmenopausal women on adjuvant aromatase inhibitors. Future studies are needed to validate these findings, and to identify breast cancer survivors who are at higher risk for cardiovascular disease with aromatase inhibitor therapy.

Abstract P3-07-20: A validated test for neoadjuvant clinical response to endocrine therapy in breast cancer that estimates accurately recurrence-free and overall survival

Abstract Background: Aromatase inhibitors (AIs) have an established role in the treatment of estrogen receptor alpha positive post-menopausal breast cancer. Recently we have developed and validated a microarray-derived 4-gene test (Edinburgh EndoResponse4) to predict response to AIs in the neoadjuvant setting. We have also demonstrated the translational potential of this test in predicting accurately clinical response when mRNA is measured for these genes by polymerase chain reaction (PCR) or the gene protein is measured by immunohistochemistry (IHC). There is a major clinical need for biomarkers to predict which patients are likely to recur on adjuvant endocrine therapy so alternative or additional treatments can be provided to reduce recurrence and improve outcome. The aim of this study was to determine if Endoresponse4 and IHC of these gene proteins could do this. Methods: The original microarray assay used pre- and on-treatment (14-days) biopsies from 73 post-menopausal women with ER-rich breast cancer receiving 3 months of neoadjuvant letrozole prior to surgery with 10 years follow-up after adjuvant letrozole. Matched formalin-fixed paraffin embedded (FFPE) tissue sections from 42 of these patients were used for IHC and antibodies were optimised against 3 of the 4 proteins (where validated antibodies were available) using Envision technology. The ability of our test to estimate recurrence-free (RFS) and breast cancer specific overall survival (OS) using both PCR and IHC was then tested in a unique validation cohort of 140 post-menopausal women with ER-rich breast cancer treated with 2 weeks of neoadjuvant letrozole or anastrozole prior to surgery followed by adjuvant endocrine therapy and 10 years of follow up.. Results: Within our training cohort (n=73) using Kaplan-Meier analysis our 4-gene test predicted neoadjuvant clinical response and demonstrated a significant association with both RFS (P=0.029) and OS (P=0.009). This approach predicts outcomes within 2-weeks rather than 4-months of treatment required in other studies such as P024. Using IHC in the training cohort (n=42), two gene markers in combination (IL6ST at diagnosis and MCM4 after 2-weeks treatment) predicted both RFS (P=0.017) and OS (P=0.009) with great accuracy. The 140 patient group is being analysed and the findings are so far are consistent with the initial training cohort and indicate a significant association with outcomes. Conclusion: • A 4 gene model with clinical potential has been developed and validated to predict response to neoadjuvant aromatase inhibitors. • This 4 gene model predicts for response and also predicts relapse free and overall survival. • Proteins encoded by 2 of these 4 genes measured by IHC in an initial test set of 42 patients predict accurately both EFS and OS • A validation cohort (n=140) with over 10-years of follow-up will be available at SABCS 2015 to determine if this 2 biomarker test can predict outcome on adjuvant endocrine therapy. Citation Format: Turnbull AK, Arthur LM, Webber V, Thomas J, Uddin S, Webb H, Dunbier A, Dowsett M, Renshaw L, Sims AH, Dixon JM. A validated test for neoadjuvant clinical response to endocrine therapy in breast cancer that estimates accurately recurrence-free and overall survival. [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 P3-07-20.

Abstract PD2-01: Randomized phase 3 trial of adjuvant letrozole versus anastrozole in postmenopausal patients with hormone receptor positive, node positive early breast cancer: Final efficacy and safety results of the femara versus anastrozole clinical evaluation (Face) trial

Abstract Background The FACE trial was designed to evaluate the efficacy and safety of adjuvant letrozole (LET) versus anastrozole (ANA) in postmenopausal patients with hormone receptor-positive (HR+), node-positive breast cancer. Materials and methods In this phase 3b, open-label, multicenter trial, postmenopausal women with HR+ and lymph node positive breast cancer were randomized 1:1 to receive either LET (2.5 mg) or ANA (1 mg) daily for 5 years in the adjuvant setting. Randomization was stratified by the number of lymph nodes (1-3 versus 4+) and HER2 status (positive versus negative). Patients with stage IIA, IIB or IIIA invasive cancer were eligible. Treatment continued for 5 years or until disease recurrence. The primary endpoint was disease free survival (DFS) at 5 years. Key secondary endpoints were safety and overall survival (OS). Results Between Dec 2005 and Mar 2008, 4170 patients were randomized to receive LET (n = 2076) or ANA (n = 2094). Baseline characteristics were generally balanced between the two arms. Median age was 62 years; 71.4% of pts had 1-3+ lymph nodes, and 8.7% of cancers were HER2+. Median duration of exposure was 60 months in both arms. With 709 of the protocol-planned 959 DFS events, 5-yr estimated DFS rate was 84.9% for LET vs. 82.9% for ANA (HR = 0.93 [95% CI: 0.80 – 1.07]; p = 0.3150). 5-yr estimated OS rate was 89.9% for LET vs. 89.2% for ANA (HR = 0.98 [95% CI: 0.82 – 1.17]; p = 0.7916). Primary reasons for treatment discontinuation in the LET versus ANA arms were AEs (15.1% vs. 14.3%) and disease progression (9.5% vs. 10.4%). Safety profiles were similar between treatment arms. The most common adverse events (AEs) in the LET versus ANA arms were arthralgia (48.2% vs. 47.9%), hot flushes (32.5% vs. 32.3%) and fatigue (16.8% vs. 16.6%). Suspected drug-related grade 3/4 AEs were reported in 9.5% of patients in the LET arm versus 8.1% of patients in the ANA arm; suspected drug-related AEs leading to discontinuation were reported in 14.0% vs. 12.9% of patients in LET vs. ANA arms, respectively. Preplanned and exploratory subgroup analyses will be presented. Conclusions Treatment with LET did not demonstrate DFS efficacy difference over ANA in postmenopausal patients with HR+, node-positive breast cancer. (Funded by Novartis; ClinicalTrials.gov number NCT00248170). Citation Format: O'Shaughnessy J, Yardley DA, Burris HA, De Boer R, Amadori D, McIntyre K, Ejlertsen B, Gnant M, Jonat W, Pritchard KI, Dowsett M, Hart L, Poggio S, Valagussa P, Salomon H, Wamil B, Smith I. Randomized phase 3 trial of adjuvant letrozole versus anastrozole in postmenopausal patients with hormone receptor positive, node positive early breast cancer: Final efficacy and safety results of the femara versus anastrozole clinical evaluation (Face) trial. [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 PD2-01.