Citations

Abstract Purpose: To determine if the degree of estrogen suppression with aromatase inhibitors (AI: anastrozole, exemestane, letrozole) is associated with efficacy in early-stage breast cancer, and to examine for differences in the mechanism of action between the three AIs. Experimental Design: Matched case–control studies [247 matched sets from MA.27 (anastrozole vs. exemestane) and PreFace (letrozole) trials] were undertaken to assess whether estrone (E1) or estradiol (E2) concentrations after 6 months of adjuvant therapy were associated with risk of an early breast cancer event (EBCE). Preclinical laboratory studies included luciferase activity, cell proliferation, radio-labeled ligand estrogen receptor binding, surface plasmon resonance ligand receptor binding, and nuclear magnetic resonance assays. Results: Women with E1 ≥1.3 pg/mL and E2 ≥0.5 pg/mL after 6 months of AI treatment had a 2.2-fold increase in risk (P = 0.0005) of an EBCE, and in the anastrozole subgroup, the increase in risk of an EBCE was 3.0-fold (P = 0.001). Preclinical laboratory studies examined mechanisms of action in addition to aromatase inhibition and showed that only anastrozole could directly bind to estrogen receptor α (ERα), activate estrogen response element-dependent transcription, and stimulate growth of an aromatase-deficient CYP19A1−/− T47D breast cancer cell line. Conclusions: This matched case–control clinical study revealed that levels of estrone and estradiol above identified thresholds after 6 months of adjuvant anastrozole treatment were associated with increased risk of an EBCE. Preclinical laboratory studies revealed that anastrozole, but not exemestane or letrozole, is a ligand for ERα. These findings represent potential steps towards individualized anastrozole therapy.

Abstract BACKGROUND Perioperative steroid protocols for patients undergoing transsphenoidal surgery (TSS) for pituitary pathology vary by institution. OBJECTIVE To assess the safety of withholding glucocorticoids in patients undergoing TSS. METHODS Patients with an intact hypothalamic-pituitary-adrenal (HPA) axis undergoing TSS for a pituitary tumor at the same academic institution between 2012 and 2015 were randomized to either receive 100 mg of intravenous hydrocortisone followed by 0.5 mg of intravenous dexamethasone every 6 h for 4 doses (STER, n = 23) or to undergo surgery without steroids (NOSTER, n = 20). Postoperative cortisol levels were then used to determine the need for glucocorticoids after surgery. Data regarding postoperative cortisol levels, hospital stay length, and complications were collected. RESULTS Mean postoperative 8 am cortisol levels were higher in the NOSTER group compared to the STER group (745 ± 359 nmol/L and 386 ± 193 nmol/L, respectively, P = .001) and more patients were discharged on glucocorticoids in the STER group (42% vs 12%, P = .07). There was no difference in the incidence of postoperative complications, including hyperglycemia, diabetes insipidus, or permanent adrenal insufficiency. Permanent adrenal insufficiency occurred in 8% of patients. CONCLUSION Perioperative steroids can be safely withheld in patients with an intact HPA axis undergoing TSS. Although administration of perioperative glucocorticoids does not appear to increase the risk of complications, it may interfere with assessment of the HPA axis after surgery.

Abstract Musculoskeletal injuries have been and remain a significant issue for sonographers. Despite its importance, the topic of musculoskeletal injury in sonographers has received little attention in the radiology literature. Our goal is to bring this extremely important issue to the forefront, with the hope of initiating conversations and actions leading to improved workplace practices for sonographers.

Abstract Background Celecoxib and low-dose aspirin might decrease risk of breast cancer recurrence. Methods In the Canadian Cancer Trials Group MA.27, postmenopausal hormone receptor–positive breast cancer patients were randomly assigned (2 × 2) to adjuvant exemestane or anastrozole, and celecoxib or placebo. Low-dose aspirin of 81 mg or less was a stratification factor. Due to concerns about cardiac toxicity, celecoxib use was stopped in December 2004, while stratification by aspirin use was removed through protocol amendment. We examined the effects of celecoxib and low-dose aspirin on event-free survival (EFS), defined as time from random assignment to time of locoregional or distant disease recurrence, new primary breast cancer, or death from any cause; distant disease–free survival (DDFS); and overall survival (OS). All statistical tests were two-sided. Results Random assignment to celecoxib (n = 811, 50.0%) or placebo (n = 811, 50.0%) was discontinued after 18 months (n = 1622). At a median of 4.1 years’ follow-up, among 1622 patients, 186 (11.5%) patients had an EFS event: 80 (4.9%) had distant relapse, and 125 (7.7%) died from any cause. Celecoxib did not statistically significantly impact EFS, DDFS, or OS in univariate analysis (respectively, P = .92, P = .55, and P = .56) or multivariable analysis (respectively, P = .74, P = .60, and P = .76). Low-dose aspirin use (aspirin users n = 476, 21.5%; non–aspirin users n = 1733, 78.5%) was associated in univariate analyses with worse EFS (hazard ratio [HR] = 1.48, 95% confidence interval [CI] = 1.12 to 1.96, P = 0.006) and worse OS (HR = 1.87, 95% CI = 1.35 to 2.61, P < .001). After adjusting for baseline characteristics and treatment arm, aspirin use showed no statistical association with EFS (P = .08) and DDFS (P = .82), but was associated with statistically worse OS (HR = 1.67, 95% CI = 1.13 to 2.49, P = .01). Conclusion Random assignment to short-term (≤18 months) celecoxib as well as use of low-dose aspirin showed no effect on DDFS and EFS in multivariable analysis. Low-dose aspirin increased “all-cause” mortality, presumably because of higher preexisting cardiovascular risks.

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.

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.