Randomized Trial of Letrozole Following Tamoxifen as Extended Adjuvant Therapy in Receptor-Positive Breast Cancer: Updated Findings from NCIC CTG MA.17

Background: Most recurrences in women with breast cancer receiving 5 years of adjuvant tamoxifen occur after 5 years. The MA.17 trial, which was designed to determine whether extended adjuvant therapy with the aromatase inhibitor letrozole after tamoxifen reduces the risk of such late recurrences, was stopped early after an interim analysis showed that letrozole improved disease-free survival. This report presents updated findings from the trial. Methods: Postmenopausal women completing 5 years of tamoxifen treatment were randomly assigned to a planned 5 years of letrozole (n = 2593) or placebo (n = 2594). The primary endpoint was disease-free survival (DFS); secondary endpoints included distant disease-free survival, overall survival, incidence of contralateral tumors, and toxic effects. Survival was examined using Kaplan-Meier analysis and log-rank tests. Planned subgroup analyses included those by axillary lymph node status. All statistical tests were two-sided. Results: After a median follow-up of 30 months (range = 1.5-61.4 months), women in the letrozole arm had statistically significantly better DFS and distant DFS than women in the placebo arm (DFS: hazard ratio [HR] for recurrence or contralateral breast cancer = 0.58, 95% confidence interval [CI] = 0.45 to 0.76; P<.001; distant DFS: HR = 0.60, 95% CI = 0.43 to 0.84; P = .002). Overall survival was the same in both arms (HR for death from any cause = 0.82, 95% CI = 0.57 to 1.19; P = .3). However, among lymph node-positive patients, overall survival was statistically significantly improved with letrozole (HR = 0.61, 95% CI = 0.38 to 0.98; P = .04). The incidence of contralateral breast cancer was lower in women receiving letrozole, but the difference was not statistically significant. Women receiving letrozole experienced more hormonally related side effects than those receiving placebo, but the incidences of bone fractures and cardiovascular events were the same. Conclusion: Letrozole after tamoxifen is well-tolerated and improves both disease-free and distant disease-free survival but not overall survival, except in node-positive patient

Khirbet Nisya 1979-1986: a Report on Six Seasons of Excavation

Problem. This project was an investigation of Khirbet Nisya (near Ramallah/El-Bireh) for six seasons to describe and interpret the excavation evidence. The excavation and analyses of finds were correlated with biblical data to help clarify certain problems relating to the Israelite settlement in the hill country of Palestine. Method. Preliminary studies in the literature were made to determine the proper biblical, geographical, and topographical relationships of the traditional sites for both Bethel and Ai at Beitin and Et-Tell. The archaeological results from both sites were reviewed as to their fit with the biblical data. Patristic evidence was also considered in determining the location of both biblical Bethel and Ai. When new sites seemed advisable, a site for Bethel was sought in El-Bireh, ten miles north of Jerusalem. Excavation was impossible in this thriving, modern city; thus a site for Ai was sought beyond Et-Tawil, the large mountain east of El-Bireh. After locating an ancient ruins, six seasons of excavations (1979-1986) were conducted at this site, Khirbet Nisya. Results. The literature seemed to indicate that both the traditional sites of Bethel and Ai have been wrongly located. Thus, the archaeological results, when applied to the Bible, are misleading. Although the archaeological results fit the biblical data fairly well at Beitin (traditional Bethel), the two are incompatible at Et-Tell (traditional Ai). The intimation is that Bethel and Ai are twin cities in the Bible. Thus, if one is wrongly located, the other must be also. New locations for both Bethel and Ai were suggested at El-Bireh for Bethel and Khirbet Nisya for Ai. The topography, geographical relationships, and patristic evidence all fit at the new locations. Six seasons of excavations and surveys show the following periods present at Khirbet Nisya: Early Bronze (?), Middle Bronze I(?) and II, Late Bronze I, Iron Age I and II, Persian, Hellenistic, Early Roman, Early and Late Byzantine, Umayyad, and Ayyubid/Mamluk/Ottoman. The archaeological profile of the site seems compatible with the situation for biblical Ai. Conclusion. Khirbet Nisya seems to have been an agricultural village or hamlet in most periods. Although, on the basis of the evidence from six seasons of excavation, no claim can be made that it is Ai, it does not seem necessary yet to rule it out, either

Negative Immune Regulator Tim-3 Is Overexpressed on T Cells in Hepatitis C Virus Infection and Its Blockade Rescues Dysfunctional CD4+ and CD8+ T Cells▿

A number of emerging molecules and pathways have been implicated in mediating the T-cell exhaustion characteristic of chronic viral infection. Not all dysfunctional T cells express PD-1, nor are they all rescued by blockade of the PD-1/PD-1 ligand pathway. In this study, we characterize the expression of T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) in chronic hepatitis C infection. For the first time, we found that Tim-3 expression is increased on CD4+ and CD8+ T cells in chronic hepatitis C virus (HCV) infection. The proportion of dually PD-1/Tim-3-expressing cells is greatest in liver-resident T cells, significantly more so in HCV-specific than in cytomegalovirus-specific cytotoxic T lymphocytes. Tim-3 expression correlates with a dysfunctional and senescent phenotype (CD127low CD57high), a central rather than effector memory profile (CD45RAnegative CCR7high), and reduced Th1/Tc1 cytokine production. We also demonstrate the ability to enhance T-cell proliferation and gamma interferon production in response to HCV-specific antigens by blocking the Tim-3-Tim-3 ligand interaction. These findings have implications for the development of novel immunotherapeutic approaches to this common viral infection

Late extended adjuvant treatment with letrozole improves outcome in women with early-stage breast cancer who complete 5 years of tamoxifen.

PURPOSE: The National Cancer Institute of Canada Clinical Trials Group MA.17 trial examined the efficacy of letrozole (LET) started within 3 months of 5 years of adjuvant tamoxifen in postmenopausal hormone receptor-positive early-stage breast cancer. When the trial was unblinded, patients who received placebo (PLAC) were offered LET. PATIENTS AND METHODS: This cohort analysis describes the outcomes of women assigned PLAC at the initial random assignment after unblinding. Efficacy outcomes of women who chose LET (PLAC-LET group) were compared with those who did not (PLAC-PLAC group) by the hazard ratios and by P values calculated from Cox models that adjusted for imbalances between the groups. Toxicity analyses included only events that occurred after unblinding. RESULTS: There were 1,579 women in the PLAC-LET group (median time from tamoxifen, 2.8 years) and 804 in the PLAC-PLAC group. Patients in the PLAC-LET group were younger; had a better performance status; and were more likely to have had node-positive disease, axillary dissection, and adjuvant chemotherapy than those in the PLAC-PLAC group. At a median follow-up of 5.3 years, disease-free survival (DFS; adjusted hazard ratio [HR], 0.37; 95% CI, 0.23 to 0.61; P < .0001) and distant DFS (HR, 0.39; 95% CI, 0.20 to 0.74; P = .004) were superior in the PLAC-LET group. More self-reported new diagnoses of osteoporosis and significantly more clinical fractures occurred in the women who took LET (5.2% v 3.1%, P = .02). CONCLUSION: Interpretation of this cohort analysis suggests that LET improves DFS and distant DFS even when there has been a substantial period of time since the discontinuation of prior adjuvant tamoxifen.Clinical Trial, Phase IIIJournal ArticleMulticenter StudyRandomized Controlled TrialResearch Support, N.I.H. ExtramuralResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17.

BACKGROUND: Most recurrences in women with breast cancer receiving 5 years of adjuvant tamoxifen occur after 5 years. The MA.17 trial, which was designed to determine whether extended adjuvant therapy with the aromatase inhibitor letrozole after tamoxifen reduces the risk of such late recurrences, was stopped early after an interim analysis showed that letrozole improved disease-free survival. This report presents updated findings from the trial. METHODS: Postmenopausal women completing 5 years of tamoxifen treatment were randomly assigned to a planned 5 years of letrozole (n = 2593) or placebo (n = 2594). The primary endpoint was disease-free survival (DFS); secondary endpoints included distant disease-free survival, overall survival, incidence of contralateral tumors, and toxic effects. Survival was examined using Kaplan-Meier analysis and log-rank tests. Planned subgroup analyses included those by axillary lymph node status. All statistical tests were two-sided. RESULTS: After a median follow-up of 30 months (range = 1.5-61.4 months), women in the letrozole arm had statistically significantly better DFS and distant DFS than women in the placebo arm (DFS: hazard ratio [HR] for recurrence or contralateral breast cancer = 0.58, 95% confidence interval [CI] = 0.45 to 0.76; P < .001; distant DFS: HR = 0.60, 95% CI = 0.43 to 0.84; P = .002). Overall survival was the same in both arms (HR for death from any cause = 0.82, 95% CI = 0.57 to 1.19; P = .3). However, among lymph node-positive patients, overall survival was statistically significantly improved with letrozole (HR = 0.61, 95% CI = 0.38 to 0.98; P = .04). The incidence of contralateral breast cancer was lower in women receiving letrozole, but the difference was not statistically significant. Women receiving letrozole experienced more hormonally related side effects than those receiving placebo, but the incidences of bone fractures and cardiovascular events were the same. CONCLUSION: Letrozole after tamoxifen is well-tolerated and improves both disease-free and distant disease-free survival but not overall survival, except in node-positive patients.Clinical TrialJournal ArticleRandomized Controlled TrialResearch Support, N.I.H. ExtramuralResearch Support, Non-U.S. Gov'tResearch Support, U.S. Gov't, P.H.S.info:eu-repo/semantics/publishe

Efficacy of letrozole extended adjuvant therapy according to estrogen receptor and progesterone receptor status of the primary tumor: National Cancer Institute of Canada Clinical Trials Group MA.17.

PURPOSE: Controversy exists regarding estrogen (ER) and progesterone (PgR) receptor expression on efficacy of adjuvant endocrine therapy. In the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial, the benefit of anastrozole over tamoxifen was substantially greater in ER+/PgR-than ER+/PgR+ tumors. In BIG 1-98 (Breast International Group), the benefits of letrozole over tamoxifen were the same in ER+ tumors irrespective of PgR. MA.17 randomized postmenopausal women after 5 years of tamoxifen, to letrozole or placebo. We present outcomes according to tumor receptor status. PATIENTS AND METHODS: Disease-free survival (DFS) and other outcomes were assessed in subgroups by ER and PgR status using Cox's proportional hazards model, adjusting for nodal status and prior adjuvant chemotherapy. RESULTS: The DFS hazard ratio (HR) for letrozole versus placebo in ER+/PgR+ tumors (N = 3,809) was 0.49 (95% CI, 0.36 to 0.67) versus 1.21 (95% CI, 0.63 to 2.34) in ER+/PgR-tumors (n = 636). ER+/PgR+ letrozole patients experienced significant benefit in distant DFS (DDFS; HR = 0.53; 95% CI, 0.35 to 0.80) and overall survival (OS; HR = 0.58; 95% CI, 0.37 to 0.90). A statistically significant difference in treatment effect between ER+/PgR+ and ER+/PgR-subgroups for DFS was observed (P = .02), but not for DDFS (P = .06) or OS (P = .09). CONCLUSION: These results suggest greater benefit for letrozole in DFS, DDFS, and OS in patients with ER+/PgR+ tumors, implying greater activity of letrozole in tumors with a functional ER. However, because this is a subset analysis and receptors were not measured centrally, we caution against using these results for clinical decision making.Comparative StudyJournal ArticleRandomized Controlled TrialResearch Support, N.I.H. ExtramuralResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Duration of letrozole treatment and outcomes in the placebo-controlled NCIC CTG MA.17 extended adjuvant therapy trial.

PURPOSE: MA.17 was a double-blind placebo-controlled trial involving 5187 postmenopausal women that established letrozole to be of value in reducing recurrence of breast cancer when given in the extended adjuvant therapy setting after about 5 years of tamoxifen. Analyses were conducted to examine the relationships between duration of treatment on MA.17 and outcomes. METHODS: The final MA.17 database that included all events up to the date of unblinding of the study was interrogated. A non-parametric kernel smoothing method was used to estimate the hazard rates for disease-free survival (DFS), distant DFS (DDFS) and overall survival (OS) at 6, 12, 24, 36 and 48 months of follow-up and the hazard ratios (HRs) of letrozole to placebo were determined. The trend in HRs over time was tested based on a Cox model with a time-dependent covariate. RESULTS: Considering all patients, HRs for events in DFS and DDFS progressively decreased over time, favoring letrozole, with the trend being significant (p < 0.0001 and p = 0.0013, respectively) whereas the trend for OS was not significant. Considering the 2360 patients with node-positive status, the HRs for DFS, DDFS and OS all decreased over time with tests for trend all showing significance (p = 0.0004, 0.0005 and 0.038, respectively). Considering the 2568 patients with node-negative status, the HRs for DFS decreased over time with the test for trend being significant (p = 0.027) whereas the HRs for DDFS and OS showed no significant change over time. CONCLUSION: These analyses suggest that, at least out to about 48 months, longer duration of letrozole treatment is associated with greater benefit in the extended adjuvant therapy setting.Journal ArticleMulticenter StudyRandomized Controlled TrialResearch Support, N.I.H. ExtramuralResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe