Extended Letrozole Research Articles

Abstract P4-14-03: Influence of competing risks of death on the interpretation of adjuvant endocrine therapy trials for breast cancer

Abstract Background: Early stage, hormone sensitive breast cancer is associated generally with a good prognosis, with only a minority of patients expected to die of breast cancer. Death from causes other than breast cancer can dilute the patients at risk of breast cancer events and result in over-estimation of risk of recurrence and consequently the benefit from breast cancer therapy, a so-called immortal time bias. The MA.17R trial (Goss et al 2016) evaluated the role of extending adjuvant treatment with letrozole from 5 to 10 years. Here we determine the effect of analyzing the MA.17R trial using methods accounting for competing risks. Methods: We compared conventional and competing risk methods for disease-free survival (DFS) and for distant recurrence-free survival (DRFS). In Kaplan-Meier analyses death from any cause was considered an event while cumulative incidence functions (CIFs) assumed death without recurrence to be a competing risk. The complement of the survival function (one minus the survival function) was used to estimate incidence of the primary event of interest. This was compared to estimates obtained using CIFs accounting for the occurrence of competing events. Results: Non-breast cancer death was the most common event defining DFS and DRFS. Over the course of follow-up, there was increasing discrepancy between the risk of disease recurrence measured using Kaplan-Meier and CIF. Among letrozole treated patients the estimated distant recurrence at 5 years of follow-up was 5.4% using CIF and 9.6% using Kaplan-Meier. At 10 years of follow-up, the estimated distant recurrence was 8.4% using CIF and 20.0% using Kaplan-Meier. Similar results were observed for the placebo group (8.5% vs 12.1% at 5 years and 14.8% vs 27.3% at 10 years), and in patients with baseline cardiovascular disease (see Table). Benefit from letrozole on DFS and DRFS was greater when accounting for competing risk (hazard ratio [HR] for DFS 0.66, 95%CI 0.48-0.90; DFRS HR 0.75, 0.50-1.14) compared to the conventional method (DFS HR 0.79, 0.62-0.99; DRFS HR 0.91, 0.70-1.18). In women with baseline cardiovascular risk, the benefits of extended adjuvant letrozole when considering competing risk (DFS HR 0.38, 0.16-0.89; DRFS HR 0.46, 0.16-1.35) were also greater than those observed in the conventional analysis (DFS HR 0.55, 0.32-0.93; DRFS HR 0.59, 0.33-1.04). Treatment with extended letrozole did not influence non-breast cancer death in women who died with disease recurrence (HR 1.06, 0.74 -1.50) or in those with competing risk or censored from the analysis (HR 1.05, 0.73 -1.49). Conclusion: Over the course of follow-up, estimates of DFS and DRFS differ increasingly if measured using Kaplan-Meier or CIF, with CIF estimates of risk being substantially lower. Using a competing risk model, the reduction in distant recurrence at 8 years with extended letrozole is less than 1%. Additional competing risk analyses of the MA.17 (Goss 2006) and MA.27 (Goss 2013) trials are ongoing. Cumulative incidence of disease recurrence in patients with baseline cardiovascular riskTime (years)CIF (%)1-KM (%)Letrozole11.51.534.46.555.813.8Placebo13.53.538.311.8512.520.3 Citation Format: Ethier J-L, Parulekar W, Shepherd L, Summers L, Strasser-Weippl K, Tu D, Amir E. Influence of competing risks of death on the interpretation of adjuvant endocrine therapy trials for breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-14-03.

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.

OT2-02-01: The SOLE Trial: International Breast Cancer Study Group (IBCSG 35–07) and Breast International Group (BIG 1–07) Study of Letrozole Extension.

Abstract Background The SOLE trial tests the hypothesis that treatment-free intervals during the course of five years of extended adjuvant letrozole will improve disease-free survival (DFS). The hypothesis is based on the observation in animal models that intermittent letrozole withdrawal will permit some estrogenic stimulation which makes residual resistant disease susceptible to letrozole reintroduction. Trial Design Randomized, Phase III trial comparing 5 years of continuous letrozole vs. 5 years of intermittent letrozole. The intermittent group receives letrozole daily for the first 9 months (followed by a 3-month gap) years 1–4, and 12 months year 5. Stratification factors are institution and prior endocrine therapy (SERM, AI or both). Major Eligibility Criteria -Postmenopausal -Disease-free -Received 4–6 years of prior adjuvant endocrine therapy (SERM and/or AI) -Randomized within 12 months of last dose of prior endocrine therapy -Endocrine-responsive breast cancer at diagnosis -Node-positive breast cancer at diagnosis Specific Aim To compare continuous and intermittent letrozole given for a five year period for postmenopausal women who are disease-free following 4–6 years of prior adjuvant endocrine therapy with SERM(s) and/or AI(s) for endocrine-responsive node-positive operable breast cancer. Statistical Methods The primary analysis will be undertaken with the intention-to-treat population of all randomized patients. The primary endpoint DFS will be compared between treatment arms using a two-sided stratified logrank test with an overall experiment-wise alpha level equal to at most 0.05. For the eligible population of patients with node positive disease at initial diagnosis, we assume 90% of patients who receive continuous extended letrozole will be alive and disease-free at 4 years from randomization (based on results of MA.17). The sample size was determined to provide 80% power to detect a 20% reduction in the risk of an event defining DFS associated with intermittent letrozole compared with continuous letrozole (hazard ratio = 0.80; increase in 4-year DFS from 90% to 91.917%) using a two-sided 0.05 level test of significance. Present and Target Accrual Target: 4800; Present: 2655 (June 1, 2011) Related Research The SOLE-EST Substudy focuses on the changes in estrogen levels that occur on letrozole and during the three month treatment gap without letrozole; and relationships between changes in patient-reported musculoskeletal symptoms, grip strength and QL. The target accrual goal is 100 patients (75 intermittent and 25 continuous). The SOLE Quality of Life Substudycompares differences in patient-reported symptoms and QL between continuous letrozole for 5 years and intermittent letrozole over a 2-year period. The target accrual goal is 834 patients. Central Pathology Review for all patients of histology, grade, ER, PgR, HER2, and Ki-67 is ongoing. Contact Information The SOLE trial is a worldwide collaboration among cooperative groups and large institutions primarily through the Breast International Group (BIG). Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT2-02-01.

Extended high dose letrozole regimen versus short low dose letrozole regimen as an adjuvant to gonadotropin releasing hormone antagonist protocol in poor responders undergoing IVF-ET*

Objective. To compare the efficacy and cost-effectiveness of extended high dose letrozole regimen/HPuFSH-gonadotropin releasing hormone antagonist (GnRHant) protocol with short low dose letrozole regimen/HPuFSH-GnRHant protocol in poor responders undergoing IVF-ET.Methods. In this randomized controlled trial, 136 women who responded poorly to GnRH agonist long protocol in their first IVF cycle were randomized into two equal groups using computer generated list and were treated in the second IVF cycle by either extended letrozole regimen (5 mg/day during the first 5 days of cycle and 2.5 mg/day during the subsequent 3 days) combined with HPuFSH-GnRHant protocol or short letrozole regimen (2.5 mg/day from cycle day 3–7) combined with HPuFSH-GnRHant protocol.Results. There were no significant differences between both groups with regard to number of oocytes retrieved and clinical pregnancy rate (5.39 ± 2.08 vs. 5.20 ± 1.88 and 22.06% vs. 16.18%, respectively).The total gonadotropins dose and medications cost per cycle were significantly lower in extended letrozole group (44.87 ± 9.16 vs. 59.97 ± 14.91 ampoules and 616.52 ± 94.97 vs. 746.84 ± 149.21 US Dollars ($), respectively).The cost-effectiveness ratio was 2794 $ in extended letrozole group and 4616 $ in short letrozole group.Conclusion. Extended letrozole regimen/HPuFSH-GnRHant protocol was more cost-effective than short letrozole regimen/HPuFSH-GnRHant protocol in poor responders undergoing IVF-ET.

Analyses Adjusting for Selective Crossover Show Improved Overall Survival With Adjuvant Letrozole Compared With Tamoxifen in the BIG 1-98 Study

Among postmenopausal women with endocrine-responsive breast cancer, the aromatase inhibitor letrozole, when compared with tamoxifen, has been shown to significantly improve disease-free survival (DFS) and time to distant recurrence (TDR). We investigated whether letrozole monotherapy prolonged overall survival (OS) compared with tamoxifen monotherapy. Of 8,010 postmenopausal women with hormone receptor-positive, early breast cancer enrolled on the Breast International Group (BIG) 1-98 study, 4,922 were randomly assigned to 5 years of continuous adjuvant therapy with either letrozole or tamoxifen. Of 2,459 patients enrolled in the tamoxifen treatment arm, 619 (25.2%) selectively crossed over to either adjuvant or extended letrozole after initial trial results were presented in January 2005. To gain better estimates of relative treatment effects in the presence of selective crossover, we used inverse probability of censoring weighted (IPCW) modeling. Weighted Cox models, by using IPCW, estimated a statistically significant, 18% reduction in the hazard of an OS event with letrozole treatment (hazard ratio [HR], 0.82; 95% CI, 0.70 to 0.95). Estimates of 5-year OS on the basis of IPCW were 91.8% and 90.4% for letrozole and tamoxifen, respectively. The HRs of DFS and TDR events by using IPCW modeling were 0.83 (95% CI, 0.74 to 0.94) and 0.80 (95% CI, 0.67 to 0.94), respectively (P < .05 for DFS, OS, and TDR). Median follow-up was 74 months. Adjuvant treatment with letrozole, compared with tamoxifen, significantly reduces the risk of death, the risk of recurrent disease, and the risk of recurrence at distant sites in postmenopausal women with hormone receptor-positive breast cancer.

Effectiveness of a Letter Notification Program for Women With Early-Stage Breast Cancer Eligible for Extended Adjuvant Letrozole

After National Cancer Institute of Canada trial MA.17 demonstrated benefits with letrozole after 5 years of tamoxifen, oncologists needed to identify and offer therapy to patients in community follow-up who were eligible for extended adjuvant hormone therapy. In British Columbia (BC), letters about extended letrozole therapy were sent to eligible BC women, their primary care physicians (PCPs), and their oncologists. We evaluated the effectiveness of this communication strategy. Eight hundred eighty-five women with stage I-III breast cancer who completed 4 to 6 years of tamoxifen in 2004 with no documented recurrence were sent letters describing extended adjuvant letrozole in February 2005. Treatment uptake and characteristics for women who did or did not receive a subsequent letrozole prescription were described. Among 838 eligible women, 305 (36%) received a letrozole prescription before April 2006. More women in the letrozole cohort had tumors larger than 2.0 cm (44.2% v 30.8%); node-positive disease (52.5% v 22.5%); prior radiotherapy (71.1% v 58.5%); and prior chemotherapy (51.5% v 20.8%; all P <or= .001). Among women younger than 70 years with node-positive disease, 65% received letrozole (122 of 188). Most prescribing physicians were oncologists (57.0%) or PCPs (30.8%). A significant increase in letrozole prescriptions was observed after the letter mail-out. In this population-based setting, extended adjuvant letrozole was more common among younger women with higher risk disease and more prior therapy but underutilized overall. The reasons for extended therapy underutilization and the role of the letter mail-out strategy in informing breast cancer survivors of new available treatments in other health systems warrant further study.

Method to Test Whether Late Extended Letrozole, Rather Than Self- Selection, Improves the Outcome in Patients With Breast Cancer Who Have Completed 5 Years of Tamoxifen

TO THE EDITOR: Using an analysis of just one arm of the MA-17 trial, Goss et al conclude in the title of their article that late extended letrozole improves outcome in women in early-stage breast cancer who complete 5 years of tamoxifen. However, the presented data cannot justify the title or the conclusion. It is well recognized that women from a better socioeconomic background, those who choose to have earlier investigations and prompt treatment—the healthy women—fare better than others. This major unexplained confounding factor cannot be completely compensated by any of the means, statistical or otherwise, employed by the authors and could contribute significantly toward the difference in the outcomes of those who chose to switch from placebo to letrozole and those who chose not to switch. A simple study that could test whether this difference is because of self-selection. Just ask all the women who were in the other arm—the letrozole arm of the study— to first imagine that they were receiving the placebo in the original random assignment. Then, ask them the exact question that was posed to the women in the placebo arm, including the exact information sheet about the benefit of letrozole, asking them whether they would want to switch or not. Then, compare the outcome of those women who would have wanted to switch with those who would not or could not decide (as the latter would have just maintained status quo and remained on the placebo). If there is no difference in the outcome of these two groups, then we could take the conclusions of the latest article more seriously. If there is a difference, then the benefit of extended letrozole could be estimated from the comparison of the differences in each arm. The principle is explained in Figure 1.