Hoskin, Tanya L.

Abstract Background: Endoxifen (Endx) is being developed as a drug for patients with estrogen receptor (ER)+ breast cancer (BC). We previously demonstrated that Endx was superior to TAM in both a letrozole (L) sensitive and resistant MCF7/AC1 model. Tamoxifen (TAM) and its most commonly studied metabolite, 4-hydroxy TAM (4HT), are known to activate critical ER co-regulators such as SRC3, which are oncogenic, and contribute to acquired and de novo endocrine resistance. While both Endx and 4HT are more potent inhibitors of genomic ERα functions compared to TAM, the effects of Endx on non-genomic signaling have not been characterized and its efficacy as an anti-cancer agent compared to RAD001 in AI resistant BC is unknown. Methods: We evaluated the 1 hour in vitro effects of TAM, 4HT, Endx, and L, in terms of activation of multiple signaling cascades using an MCF7/AC1 L-resistant cells and long term estrogen deprived (LTED) cells (MDA 361 and ZR75). Protein Docking studies (shape screening, pharmacophore modeling and ligand-protein docking) for oncogenic kinases, and their associated IC50's were determined for TAM and Endx. The in vivo activity of Endx (50 mg/kg, oral) was determined in MCF/AC1 L-resistant xenograft tumors and compared with L control (10 ug/day, sc), Exemestane (E) (250 ug/d, sc) and E+RAD001 (2.5 mg/kg/d, oral). Results: In MCF7/AC1 L-resistant cells, 1 hr treatment with either TAM (100 nM or 5 uM) or 4HT (100 nM or 5 uM) phosphorylated SRC3 (AIB1) and resulted in downstream activation (phosphorylation) of IGF1R, PDK1, AKT, and p70S6K. In contrast, Endx (100 nM and 5 uM) did not phosphorylate SRC3 nor any downstream kinases but resulted in a dose dependent decrease in AKT phosphorylation. Similar findings were observed in LTED cells MDA 361 and ZR75. Docking studies identified a significant decrease in the binding energy (>2 kcal/mol) of Endx compared to TAM for PKC and PI3K and subsequent kinase profiling demonstrated that Endx more potently inhibits PKCβ1 (IC50 357nM) and PI3KΔ (2.5uM) compared to TAM (IC50 4.8μM and 6.2μM respectively). Therefore, we evaluated the in vivo anti-tumor activity of Endx with E and E+RAD001 in MCF7 L-resistant xenograft tumors. After 9 weeks, the% change in tumor volume relative to baseline was significantly lower for both Endx (median -34%, p = 0.0002) and E+RAD001 (median +1.5%, p = 0.0002) as compared to L controls (median +301%). In contrast, E alone was non-significantly lower (median +172%, (p = 0.09). No significant differences were observed comparing Endx and E+RAD001 (p = 0.56). Conclusions: Endx inhibits PKCβ1 and PI3KΔ at concentrations that are pharmacologically relevant, and unlike TAM and 4HT, does not activate SRC3 nor induce oncogenic signaling pathways in AI resistant cells. Importantly, Endx elicits substantial anti-tumor effects in AI resistant models that are similar to the current standard of care of E+RAD001. These data suggest that Endx may be superior to TAM for the treatment of ER+ BC and may result in clinical benefit for patients with AI resistant disease. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-09-08.

Abstract Purpose: Controversy exists about CYP2D6 genotype and tamoxifen efficacy. Experimental Design: A matched case–control study was conducted using the Austrian Breast and Colorectal Cancer Study Group Trial 8 (ABCSG8) that randomized postmenopausal women with estrogen receptor (ER)-positive breast cancer to tamoxifen for 5 years (arm A) or tamoxifen for 2 years followed by anastrozole for 3 years (arm B). Cases had disease recurrence, contralateral breast cancer, second non–breast cancer, or died. For each case, controls were identified from the same treatment arm of similar age, surgery/radiation, and tumor–node—metastasis (TNM) stage. Genotyping was conducted for alleles associated with no (PM; *3, *4, *6), reduced (IM; *10, and *41), and extensive (EM: absence of these alleles) CYP2D6 metabolism. Results: The common CYP2D6*4 allele was in Hardy–Weinberg equilibrium. In arm A during the first 5 years of therapy, women with two poor alleles [PM/PM: OR, 2.45; 95% confidence interval (CI), 1.05–5.73, P = 0.04] and women with one poor allele (PM/IM or PM/EM: OR, 1.67; 95% CI, 0.95–2.93; P = 0.07) had a higher likelihood of an event than women with two extensive alleles (EM/EM). In years 3 to 5 when patients remained on tamoxifen (arm A) or switched to anastrozole (arm B), PM/PM tended toward a higher likelihood of a disease event relative to EM/EM (OR, 2.40; 95% CI, 0.86–6.66; P = 0.09) among women on arm A but not among women on arm B (OR, 0.28; 95% CI, 0.03–2.30). Conclusion: In ABCSG8, the negative effects of reduced CYP2D6 metabolism were observed only during the period of tamoxifen administration and not after switching to anastrozole. Clin Cancer Res; 19(2); 500–7. ©2012 AACR.

Abstract Background: Epithelial proliferation in benign breast disease (BBD) is a well-established biomarker of breast cancer risk, and BBD tissues can be used as a platform to assess other biomarkers for breast cancer risk. Lobular involution (the degree of age-related atrophy in lobules) is a new biomarker, with greater degrees of involution associated with lower breast cancer risk. Successful application of tissue biomarkers of risk to breast tissues from normal women would be valuable for risk prediction in the general population. We hypothesized that normal breast tissue samples would differ from BBD tissues in these histologic features of breast cancer risk, with less epithelial proliferation but a similar degree of involution compared to BBD tissues. Methods: Core biopsy samples from the Mayo Benign Breast Disease Cohort Study were compared to core biopsy samples of normal breast tissue obtained from the Susan G. Komen for the Cure Tissue Bank at IU Simon Cancer Center (KTB), a unique resource of breast tissue from donor women without any known breast abnormalities. All core biopsies were assessed histologically by a single breast pathologist for degree of epithelial proliferation (classified as non-proliferative, proliferative without atypia, or atypical hyperplasia) and extent of lobular involution (classified as none, 1-24%, 25-74%, or >75% of lobules). Data were analyzed using chi-square tests and logistic regression. Results: Overall, 318 Mayo BBD and 303 normal (KTB) core breast biopsy samples were evaluated. As anticipated, significantly less epithelial proliferation was present in normal samples compared to BBD samples. Proliferative disease occurred in 9/303 (3%) of normals versus 79/318 (25%) of BBD, and atypical hyperplasia was seen in 2/303 (0.7%) of normal samples versus 24/318 (8%) of BBD core biopsies, p < 0.0001. This difference remained significant after adjusting for age (which was greater overall in the BBD samples). Complete involution was more frequent in normal compared to BBD tissues, although the difference did not reach statistical significance. The age-adjusted odds ratio of complete involution in normal versus BBD tissues was 1.46 (95% CI 0.98-2.17, p = 0.06), suggesting a possible delay or failure of involution in women with BBD. Conclusions: Histologic features of normal breast tissues are different from those of BBD tissues, with less epithelial proliferation and more lobular involution, consistent with a lower risk of breast cancer expected for women with normal breast tissue compared to those with benign breast disease. Normal breast tissues are a valuable and distinct resource that should be considered for biomarker validation studies. Citation Information: Cancer Prev Res 2010;3(12 Suppl):B23.

Purpose Recent changes have occurred in the presurgical planning for breast cancer, including the introduction of preoperative breast magnetic resonance imaging (MRI). We sought to analyze the trends in mastectomy rates and the relationship to preoperative MRI and surgical year at Mayo Clinic, Rochester, MN. Patients and Methods We identified 5,405 patients who underwent surgery between 1997 and 2006. Patients undergoing MRI were identified from a prospective database. Trends in mastectomy rate and the association of MRI with surgery type were analyzed. Multiple logistic regression was used to assess the effect of surgery year and MRI on surgery type, while adjusting for potential confounding variables. Results Mastectomy rates differed significantly across time (P < .0001), and decreased from 45% in 1997% to 31% in 2003, followed by increasing rates for 2004 to 2006. The use of MRI increased from 10% in 2003% to 23% in 2006 (P < .0001). Patients with MRI were more likely to undergo mastectomy than those without MRI (54% v 36%; P < .0001). However, mastectomy rates increased from 2004 to 2006 predominantly among patients without MRI (29% in 2003% to 41% in 2006; P < .0001). In a multivariable model, both MRI (odds ratio [OR], 1.7; P < .0001) and surgical year (compared to 2003 OR: 1.4 for 2004, 1.8 for 2005, and 1.7 for 2006; P < .0001) were independent predictors of mastectomy. Conclusion After a steady decline, mastectomy rates have increased in recent years with both surgery year and MRI as significant predictors for type of surgery. Further studies are needed to evaluate the role of MRI and other factors influencing surgical planning.

A series of 103 acute fractures of the coronoid process of the ulna in 101 patients was reviewed to determine their frequency. The Regan-Morrey classification, treatment, associated injuries, course and outcomes were evaluated. Of the 103 fractures, 34 were type IA, 17 type IB, ten type IIA, 19 type IIB, ten type IIIA and 13 type IIIB. A total of 44 type-I fractures (86%) were treated conservatively, while 22 type-II (76%) and all type-III fractures were managed by operation. At follow-up at a mean of 3.4 years (1 to 8.9) the range of movement differed significantly between the types of fracture (p = 0.002). Patients with associated injuries had a lower Mayo elbow performance score (p = 0.03), less extension (p = 0.03), more pain (p = 0.007) and less pronosupination (p = 0.004), than those without associated injuries. The presence of a fracture of the radial head had the greatest effect on outcome. An improvement in outcome relative to that of a previous series was noted, perhaps because of more aggressive management and early mobilisation. While not providing complete information about the true details of a fracture and its nature, the Regan-Morrey classification is useful as a broad index of severity and prognosis.

Between 1986 and 2005, 22 patients (mean age, 14.7 years; range, 3-21) with renal hypertension underwent renal artery revascularization for 28 lesions, 23 with open repair (OR) and 5 with percutaneous transluminal renal angioplasty (PTRA). Thirty-day morbidity was 17% (4/23). Hypertension was cured in 13 (57%), improved in 8 (38%), and unchanged in 1 (5%). Renal function worsened in 1. At a mean follow-up of 4.9 years, 1-year patency rate was 94% and maintained for 5 years. Hypertension at 1 year was cured in 6 of 14 patients (43%; OR, 4; PTRA, 2) and improved in 8 (57%; OR, 7; PTRA, 1); hypertension at 5 years was cured in 50% and improved in 50%. Renal function remained unchanged in all patients who were followed. The authors conclude that both OR and PTRA benefit pediatric patients. PTRA for selected patients may be promising as a first line treatment or as a bridge to definitive OR in children with small arteries.

Purpose Studies have suggested good long‐term success rates with bone–patellar tendon–bone (BPTB) autograft and BPTB allograft in anterior cruciate ligament (ACL) reconstruction, but the numbers reported in available prospective studies may be underpowered to elucidate significant differences between the two groups. Here, we present a meta‐analysis to compare the results of BPTB autograft and BPTB allograft in primary ACL reconstruction. Methods A systematic review of prospective trials using BPTB autograft and BPTB allograft tissue for ACL reconstruction with a minimum 2‐year follow‐up was performed. Summary odds ratios (ORs), confidence intervals, and P values were calculated. Results Of 548 studies, 6 fulfilled our inclusion criteria, with 256 patients in the autograft and 278 patients in the allograft group. Allograft patients were more likely to rupture their graft than autograft patients (OR, 5.03; P = .01) and more likely to have a hop test less than 90% of the nonoperative side (OR, 5.66; P < .01). When irradiated and chemically processed grafts were excluded from analysis, no significant differences were found between allograft and autograft patients with respect to graft rupture, rate of reoperation, normal/near normal IKDC scores, Lachman exam, pivot shift exam, patellar crepitus, hop test, or return to sport. Conclusions In this meta‐analysis, ACL reconstruction with BPTB autograft was favored over BPTB allograft for graft rupture and hop test parameters. However, when irradiated and chemically processed grafts were excluded, results were not significantly different between the two graft types. Level of Evidence Level III, systematic review of prospective nonrandomized cohort studies.

Background— The role of valve surgery in left-sided infective endocarditis has not been evaluated in randomized controlled trials. We examined the association between valve surgery and all-cause 6-month mortality among patients with left-sided infective endocarditis. Methods and Results— A total of 546 consecutive patients with left-sided infective endocarditis were included. To minimize selection bias, propensity score to undergo valve surgery was used to match patients in the surgical and nonsurgical groups. To adjust for survivor bias, we matched the follow-up time so that each patient in the nonsurgical group survived at least as long as the time to surgery in the respective surgically-treated patient. We also used valve surgery as a time-dependent covariate in different Cox models. A total of 129 (23.6%) patients underwent surgery within 30 days of diagnosis. Death occurred in 99 of the 417 patients (23.7%) in the nonsurgical group versus 35 deaths among the 129 patients (27.1%) in the surgical group. Eighteen of 35 (51%) patients in the surgical group died within 7 days of valve surgery. In the subset of 186 cases (93 pairs of surgical versus nonsurgical cases) matched on the logit of their propensity score, diagnosis decade, and follow-up time, no significant association existed between surgery and mortality (adjusted hazard ratio, 1.3; 95% confidence interval, 0.5 to 3.1). With a Cox model that incorporated surgery as a time-dependent covariate, valve surgery was associated with an increase in the 6-month mortality with an adjusted hazard ratio of 1.9 (95% confidence interval, 1.1 to 3.2). Because the proportionality hazard assumption was violated in the time-dependent analysis, we performed a partitioning analysis. After adjustment for early (operative) mortality, surgery was not associated with a survival benefit (adjusted hazard ratio, 0.92; 95% confidence interval, 0.48 to 1.76). Conclusions— The results of our study suggest that valve surgery in left-sided infective endocarditis is not associated with a survival benefit and could be associated with increased 6-month mortality, even after adjustment for selection and survivor biases as well as confounders. Given the disparity between the results of our study and those of other observational studies, well-designed prospective studies are needed to further evaluate the role of valve surgery in endocarditis management.