AZD9496: An Oral Estrogen Receptor Inhibitor That Blocks the Growth of ER-Positive and ESR1-Mutant Breast Tumors in Preclinical Models.

Fulvestrant is an estrogen receptor (ER) antagonist administered to breast cancer patients by monthly intramuscular injection. Given its present limitations of dosing and route of administration, a more flexible orally available compound has been sought to pursue the potential benefits of this drug in patients with advanced metastatic disease. Here we report the identification and characterization of AZD9496, a nonsteroidal small-molecule inhibitor of ERα, which is a potent and selective antagonist and downregulator of ERα in vitro and in vivo in ER-positive models of breast cancer. Significant tumor growth inhibition was observed as low as 0.5 mg/kg dose in the estrogen-dependent MCF-7 xenograft model, where this effect was accompanied by a dose-dependent decrease in PR protein levels, demonstrating potent antagonist activity. Combining AZD9496 with PI3K pathway and CDK4/6 inhibitors led to further growth-inhibitory effects compared with monotherapy alone. Tumor regressions were also seen in a long-term estrogen-deprived breast model, where significant downregulation of ERα protein was observed. AZD9496 bound and downregulated clinically relevant ESR1 mutants in vitro and inhibited tumor growth in an ESR1-mutant patient-derived xenograft model that included a D538G mutation. Collectively, the pharmacologic evidence showed that AZD9496 is an oral, nonsteroidal, selective estrogen receptor antagonist and downregulator in ER(+) breast cells that could provide meaningful benefit to ER(+) breast cancer patients. AZD9496 is currently being evaluated in a phase I clinical trial. Cancer Res; 76(11); 3307-18. ©2016 AACR.

Comparison of primary and secondary breast cancers in adolescents and young adults.

BACKGROUND: Breast cancer is one of the most common cancers in adolescent and young adult (AYA) patients (ages 15-39) and may develop de novo or in patients previously treated for cancer. This study compares the demographic, tumor, treatment characteristics, and overall survival (OS) of primary versus secondary (SMN) breast cancer in female AYAs. METHODS: All cases of invasive female AYA breast cancer in the 1998-2010 American College of Surgeons National Cancer Database were divided into 2 cohorts according to primary or secondary occurrence. Comparisons using appropriate statistical methods were performed. RESULTS: Of 106,771 patients, 6241 (5.8%) had experienced a prior, histologically distinct malignancy. Breast SMNs were more likely ER-/PR- (OR, 1.24; 95% CI, 1.15-1.34), <1 cm (OR, 1.86; 95% CI, 1.73-1.99) tumors and present at a lower T, N (OR, 1.43; 95% CI, 1.34-1.52), and summary stage but with more distant metastases (OR, 1.42; 95% CI, 1.21-1.67) compared with primary cancers. Adjusted by stage, SMN patients underwent more total mastectomies and received less chemotherapy, radiation, and hormonal therapy. However, SMN patients received definitive surgical treatment almost twice as fast compared with primary cancers (36.12 vs 67.26 days, P < .001). Patients with SMNs had a significantly decreased 3-year OS (79% vs 88.5%, P < .001), with SMN status an independent risk factor for increased mortality (HR, 1.58; 95% CI, 1.41-1.77). CONCLUSIONS: Nonprimary breast cancer in AYAs has different tumor characteristics, presents at a lower stage, and receives less adjuvant therapy than primary cancers. SMN status is an independent risk factor for decreased OS, with an almost 10% decrease at 3 years. Whether the outcome disparity results from previous cancer treatment or differences in biology, environment, or access to care needs further investigation.

Parathyroid carcinoma in more than 1,000 patients: A population-level analysis.

BACKGROUND: Parathyroid carcinoma (PC) is a rare malignancy with a moderate prognosis. The staging system, prognostic indicators, and optimal surgical management are still under debate. This large cohort explores prognostic factors for PC. METHODS: 1,022 cases of PC in the 1998-2011 National Cancer Data Base that underwent surgery were examined for predictors of lower overall survival (OS) and relative risk (RR) of death at 5 years. RESULTS: The 5-year OS was 81.1% in 528 patients with ≥ 60 months of follow-up. The overall cohort was mainly non-Hispanic (96.5%), white (77.4%), and insured (94.3%), with a median age of 57 years. Mean OS was lower and RR of death greater in older (P < .001), black (P = .007) patients with a secondary malignancy (P = .015) and ≥ 2 comorbidities (P = .005), whose surgical specimen had positive surgical margins (P = .026) or positive lymph nodes (P < .001). Multivariate cox regression demonstrated that positive lymph nodes (hazard ratio [HR], 6.47; 95% CI, 1.81-23.11) and older age (HR, 2.35; 95% CI, 1.25-4.43) were associated with lower OS. CONCLUSION: PC is a rare malignancy with a 5-year OS of 81.1%. Positive lymph nodes and older age predict lower OS and an increased risk of death.

Risk estimator for adrenal tumor functionality.

BACKGROUND: Adrenal lesions are a common imaging finding with a prevalence approaching 10%. Although guidelines recommend dedicated laboratory tests to rule out tumor functionality, many patients never undergo this workup. This study investigates the use of demographic and clinical variables to create an easy scoring system for predicting adrenal tumor functionality (functional adrenal tumors, or FATs). METHODS: Altogether, 2,807 patients in the NSQIP 2005-2010 database underwent adrenalectomy as their principal operation and had a postoperative diagnosis consistent with an adrenal lesion/disorder. Patients were divided into two groups based on a postoperative diagnosis consistent with tumor functionality. Univariate and multivariate logistic regression analyses were performed to identify specific predictors of FATs and for Cushing's, Conn's, or pheochromocytoma. RESULTS: Overall, 13.2% (n = 402) of adrenalectomies performed were for FATs. Patients with a FAT were younger (age <40, p < 0.01), overweight (BMI > 30 kg/m(2), p < 0.01), hypertensive (p < 0.001). They also had elevated white blood cells (WBC > 11, p < 0.001), serum creatinine (Cr > 1.25 mg/dl, p < 0.001), and sodium (Na > 143 mmol/L, p < 0.001). On multivariate regression, patients with these characteristics were 20.53 times (CI 15.79-25.27) more likely to have a FAT (model c-statistic 0.634, CI 0.605-0.663; Hosmer-Lemeshow test (H-L), p = 0.035). Patients who were younger (p < 0.001), female (p < 0.001), diabetic (p = 0.07), overweight (p = 0.027), with elevated WBCs (p < 0.001) and lower Cr (p < 0.001) were 63.62 times (CI 58.03-69.21) more likely to have Cushing's (model c-statistic 0.685, CI 0.648-0.722; H-L p = 0.954). CONCLUSIONS: After external validation, this risk estimator might be used to quantify the probability of tumor functionality in patients with incidental adrenal masses. Although predictive power may be limited, it helps identify patients at high risk for FATs that need more urgent referral to a specialist.

Induction of heart valve lesions by small-molecule ALK5 inhibitors.

Aberrant signaling by transforming growth factor-ß (TGF-ß) and its type I (ALK5) receptor has been implicated in a number of human diseases and this pathway is considered a potential target for therapeutic intervention. Transforming growth factor-ß signaling via ALK5 plays a critical role during heart development, but the role of ALK5 in the adult heart is poorly understood. In the current study, the preclinical toxicology of ALK5 inhibitors from two different chemistry scaffolds was explored. Ten-week-old female Han Wistar rats received test compounds by the oral route for three to seven days. Both compounds induced histopathologic heart valve lesions characterized by hemorrhage, inflammation, degeneration, and proliferation of valvular interstitial cells. The pathology was observed in all animals, at all doses tested, and occurred in all four heart valves. Immunohistochemical analysis of ALK5 in rat hearts revealed expression in the valves, but not in the myocardium. Compared to control animals, protein levels of ALK5 were unchanged in the heart valves of treated animals. We also observed a physeal dysplasia in the femoro-tibial joint of rats treated with ALK5 inhibitors, a finding consistent with a pharmacological effect described previously with ALK5 inhibitors. Overall, these findings suggest that TGF-ß signaling via ALK5 plays a critical role in maintaining heart valve integrity.