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Systemic Therapies for HER2-Positive Metastatic Breast Cancer Study (SystHERs, NCT01615068) was a prospective, observational disease registry designed to identify treatment patterns and clinical outcomes in patients with HER2-positive metastatic breast cancer (MBC) in real-world treatment settings. SystHERs enrolled patients aged ≥ 18 years with recently diagnosed HER2-positive MBC. Treatment regimens and clinical management were determined by the treating physician. In this analysis, patients were compared descriptively by first-line treatment, age, or race. Multivariate logistic regression was used to examine the associations between baseline variables and treatment selections. Clinical outcomes were assessed in patients treated with trastuzumab (Herceptin [H]) + pertuzumab (Perjeta [P]). Patients were enrolled from June 2012 to June 2016. As of February 22, 2018, 948 patients from 135 US treatment sites had received first-line treatment, including HP (n = 711), H without P (n = 175), or no H (n = 62) (with or without chemotherapy and/or hormonal therapy). Overall, 68.7% received HP + taxane and 9.3% received H without P + taxane. Patients aged

Our aim is to examine the associations between high-sensitivity C-reactive protein (hsCRP) and hemoglobin A1c (HbA1c), common biomarkers of inflammation and insulin resistance, respectively, with breast cancer risk, while adjusting for measures of excess body size. We conducted a nested case–control study within the Alberta’s Tomorrow Project cohort (Alberta, Canada) including 197 incident breast cancer cases and 394 matched controls. The sample population included both pre- and postmenopausal women. Serum concentrations of hsCRP and HbA1c were measured from blood samples collected at baseline, along with anthropometric measurements, general health and lifestyle data. Conditional logistic regression was used to evaluate associations between hsCRP, HbA1c, and breast cancer risk adjusted for excess body size (body fat percentage) and other risk factors for breast cancer. Higher concentrations of hsCRP were associated with elevated breast cancer risk (odds ratio [OR] 1.27; 95% confidence interval [95% CI] 1.03–1.55). The observed associations were unchanged with adjustment for body fat percentage. Higher HbA1c concentrations were not significantly associated with an increased breast cancer risk (OR 1.22; 95% CI 0.17–8.75). These data suggest that hsCRP may be associated with elevated breast cancer risk, independent of excess body size. However, elevated concentrations of HbA1c did not appear to increase breast cancer risk in apparently healthy women.

BACKGROUND: Estrogen receptor beta (ERβ) is the predominant estrogen receptor (ER) expressed in non-small cell lung cancer (NSCLC); however, due to methodological disparities among prior studies, the prognostic value of ERβ expression in NSCLC remains unclear. Our objective was to apply improved detection and analysis techniques to assess the prognostic value of ERβ expression in NSCLC. METHODS: A tissue microarray (TMA) was used which contained resected and biopsy specimens from 299 patients diagnosed at a single center with stages I–IV NSCLC. Sections of this array were stained using high-sensitivity fluorescence immunohistochemistry, with the well-validated PPG5/10 monoclonal antibody. Digital images of the stained array slides were analyzed using software-based image analysis, which reported ERβ expression as a continuous variable in different subcellular domains. RESULTS: There were no differences in ERβ expression between male and female patients. High expression of ERβ was not a prognostic factor, but was significantly associated with stage IV disease in both tumor and stroma (P

Purpose: We report treatments and outcomes in a contemporary patient population with HER2-positive metastatic breast cancer (MBC) by hormone receptor (HR) status from the Systemic Therapies for HER2-positive Metastatic Breast Cancer Study (SystHERs). Experimental Design: SystHERs (NCT01615068) was an observational, prospective registry study of U.S.-based patients with newly diagnosed HER2-positive MBC. Endpoints included treatment patterns and clinical outcomes. Results: Of 977 eligible patients (enrolled from 2012 to 2016), 70.1% (n = 685) had HR-positive and 29.9% (n = 292) had HR-negative disease. Overall, 59.1% (405/685) of patients with HR-positive disease received any first-line endocrine therapy (with or without HER2-targeted therapy or chemotherapy); 34.9% (239/685) received HER2-targeted therapy + chemotherapy + sequential endocrine therapy. Patients with HR-positive versus HR-negative disease had longer median overall survival (OS; 53.0 vs 43.4 months; hazard ratio, 0.70; 95% confidence interval, 0.56–0.87). Compared with patients with high HR-positive staining (10%–100%, n = 550), those with low HR-positive staining (1%–9%, n = 60) received endocrine therapy less commonly (64.2% vs 33.3%) and had shorter median OS (53.8 vs 40.1 months). Similar median OS (43.4 vs 40.1 months) was observed in patients with HR-negative versus low HR-positive tumors (1%–9%). Conclusions: Despite evidence that first-line HER2-targeted therapy, chemotherapy, and sequential endocrine therapy improves survival in patients with HR-positive, HER2-positive disease, only 34.9% of patients in this real-world setting received such treatment. Patients with low tumor HR positivity (1%–9%) had lower endocrine therapy use and worse survival than those with high tumor HR positivity (10%–100%).

Retroperitoneal sarcoma (rps) encompasses a heterogeneous group of malignancies with a high recurrence rate after resection. Neoadjuvant radiotherapy (nrt) is often used in the hope of sterilizing margins and decreasing local recurrence after excision. We set out to compare local recurrence-free survival (lrfs) and overall survival (os) in patients treated with or without nrt before resection. Patients diagnosed with rps from February 1990 to October 2014 were identified in the Alberta Cancer Registry. Patients with complete gross resection of rps and no distant disease were included. Patient, tumour, treatment, and outcomes data were abstracted in a primary chart review. Baseline characteristics were compared using the Wilcoxon nonparametric test for continuous data and the Fisher exact test for dichotomous and categorical data. Survival was analyzed using Kaplan&ndash, Meier curves with log-rank test. Cox regression was performed to control for age, sex, tumour size, tumour grade, date of diagnosis, multivisceral resection, and intraoperative rupture. Resection alone was performed in 62 patients, and resection after nrt, in 40. Use of nrt was associated with multivisceral resection and negative microscopic margins. On univariate analysis, nrt was associated with superior median lrfs (89.3 months vs. 28.4 months, p = 0.04) and os (119.4 months vs. 75.9 months, p = 0.04). On multivariate analysis, nrt, younger age, and lower tumour grade predicted improved lrfs and os, sex, tumour size, date of diagnosis, multivisceral resection, and tumour rupture did not. In this population-based study, nrt was associated with superior lrfs and os on both univariate and multivariate analysis. When feasible, nrt should be considered until a randomized controlled trial is completed.

To examine oncologists’ practice pattern of ordering MA in localized and metastatic GISTs in British Columbia (BC). Patients diagnosed with GIST from January 2008 to December 2017 in BC were identified. Chart review was performed to determine clinical characteristics and the use of MA as part of their oncologic care. The cohort included 411 patients: median age 64 (18–94 years), 49.1% male, primary site included stomach (53%), small intestine (32%), and others (15%). Sixty-nine percent had localized disease, while 13% presented with de novo metastatic disease and 18% had recurrent metastatic disease. MA was ordered in 41% of the patients overall, 28% in localized, and 70% in metastatic settings (63% in de novo metastasis and 78% in recurrent metastasis). Among patients with localized disease, higher MA use rates were observed among those undergoing neoadjuvant/adjuvant treatment (45%) compared to those not receiving systemic therapy (18%). While MA use rates in localized GIST did not change over time (28.5% before 2015 and 28% after 2015), MA use in metastatic disease increased from 54% before 2015 to 79% after 2015. Among all MA ordered for metastatic disease, 82.4% were ordered at the time of de novo metastatic diagnosis, and 77.4% were ordered either at the time of recurrent metastatic diagnosis or earlier when the disease was localized. MA use has remained stable for localized disease but has increased after 2015 in the metastatic setting which may be due to evolving sequencing technology, expansion of metastatic treatment options, and enhanced awareness of MA.

To investigate how clinical, demographic and treatment-related factors in non-small cell lung cancer (NSCLC) patients impact the risk of mortality in the 30 days following receipt of systemic anti-cancer therapies (SACT), and undertake a comprehensive review of the treatment decisions and experiences of a real-world population.We reviewed NSCLC patients receiving SACT from 2005 to 2014, and captured in the Glans-Look Lung Cancer Database, which contains demographic, clinical, pathological, treatment and outcome data. The 30-day post-SACT mortality rate was calculated, and regimen changes in the last 14 days of life were identified. Univariate analysis and multivariate logistic regression were used to identify demographic, tumor and treatment-related factors that correlated with mortality risk.1044 patients receiving ≥ 1 cycle of SACT in 2005-2014 were identified. 233 (22.3%) deaths occurred ≤ 30 days following SACT receipt; 32 (13.7%) of which had new SACT regimens ≤ 14 days prior to death. Risk of 30-day mortality and regimen changes at the end of life increased in association with being male [OR: 1.48 (1.12-1.95), p = 0.005], advanced disease at diagnosis [OR: 1.85 (1.19-2.88), p = 0.006], palliative-intent treatment [OR: 6.75 (3.88-11.77), p 0.001], and use of EGFR-targeting agents [OR: 4.5 (3.27-6.18) p 0.001]. Risk of early mortality decreased for never-smokers [OR: 0.62 (0.41-0.95), p = 0.028], and those receiving SACT in more recent years (2010-2014) [OR: 0.65 (0.49-0.86), p = 0.002].Our findings identified several factors that affected the risk of early mortality in NSCLC patients following SACT. These results from a representative population provide insights regarding the benefits and risks of SACT and can serve to inform clinical and palliative best practices.

To compare the clinical characteristics and outcomes between relapsed and de novo metastatic non-small cell lung cancer (NSCLC).We reviewed all NSCLC diagnoses between January 1999 and December 2013 in the institutional Glans-Look Lung Cancer Database, which contains demographic, clinical, pathologic, treatment, and outcome information. Patients with distant metastasis at diagnosis (American Joint Committee on Cancer [AJCC] eighth edition, stage IV), the "de novo" cohort, were compared with the "relapsed" cohort, consisting of patients diagnosed with early stage disease (stage I/II) undergoing curative intent treatment and subsequently experiencing metastatic relapse. Survival analysis, along with univariate and multivariable analysis was performed.A total of 185 relapsed and 3039 de novo patients were identified. Significantly different patterns of smoking history, histology, systemic therapy use, and disease extent were observed between the relapsed and de novo cohorts. Median overall survival from time of metastasis was significantly longer in relapsed than in de novo disease (8.9 vs. 3.7 mo, P0.001). Relapsed patients demonstrated significant improvements in outcomes over time. In multivariate analysis, de novo metastatic disease continued to bode a worse prognosis (adjusted hazard ratio [HR], 1.4) as did male sex (HR, 1.2), never-smoking history (HR, 1.2), and presence of extrapulmonary metastases (HR, 1.3). Systemic therapy receipt conferred better outcome (HR, 0.4), although the impact of relapsed versus de novo disease on outcomes persisted regardless of systemic therapy receipt.Relapsed and de novo patients represent significantly different subpopulations within metastatic NSCLC with the latter exhibiting poorer survival. This information facilitates discussions about prognosis with patients and supports screening initiatives aimed at reducing de novo disease.

Background The CHAARTED (ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) and STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) trials showed that the addition of docetaxel (D) to androgen deprivation therapy (ADT) prolonged longevity of men with metastatic hormone-sensitive prostate cancer (mHSPC). However, the impact of upfront D on subsequent therapies is still unexplored. As abiraterone acetate (AA) and enzalutamide (E) are the most commonly used first-line treatment for metastatic castration-resistant prostate cancer (mCRPC), we aimed to assess whether they maintained their efficacy after ADT+D versus ADT alone. Patients and Methods A cohort of patients with mCRPC treated between 2014 and 2017 with first-line AA or E for mCRPC was identified from 3 hospitals’ institutional review board-approved databases. Patients were classified by use of D for mHSPC. This time frame was chosen as ADT+D became a valid therapeutic option for mHSPC in 2014, and it inherently entailed a short follow-up time on AA/E. The endpoints included overall survival from ADT start, overall survival from AA/E start, and time to AA/E start from ADT start. Differences between groups were assessed using the log-rank test. Results Of the 102 patients with mCRPC identified, 50 (49%) had previously received ADT alone, while 52 (51%) had ADT+D. No statistically significant difference in any of the evaluated outcomes was observed between the 2 cohorts. Yet, deaths in the ADT+D group were 12 versus 21 in the ADT alone, after a median follow-up of 24.4 and 29.8 months, respectively. Conclusion In a cohort of ADT/ADT+D-treated patients with mCRPC with short times to first-line AA/E and follow-up, the efficacy of AA/E is similar regardless of previous use of D.

// Aleksi Suo 1 , Allison Childers 2 , Adrijana D’Silva 1 , Lars F. Petersen 2 , Shannon Otsuka 1 , Michelle Dean 2, 3 , Haocheng Li 1, 4 , Emeka K. Enwere 2, 3 , Brant Pohorelic 3 , Alexander Klimowicz 3 , Ivana A. Souza 5 , Jawed Hamid 5 , Gerald W. Zamponi 5 and DGwyn Bebb 1, 2 1 Department of Oncology, Tom Baker Cancer Centre, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada 2 Translational Laboratories, Tom Baker Cancer Centre, University of Calgary, Calgary, AB, Canada 3 Functional Tissue Imaging Unit, Translational Laboratory, Tom Baker Cancer Centre, Calgary, AB, Canada 4 Department of Community Health Sciences, University of Calgary, Calgary, AB, Canada 5 Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada Correspondence to: Aleksi Suo, email: aleksi.suo@albertahealthservices.ca Keywords: T-type VGCC; Cav3.1; NSCLC Received: April 04, 2017 Accepted: December 05, 2017 Published: January 12, 2018 ABSTRACT Introduction : Voltage-gated calcium channels (VGCC) have been found to be differentially expressed in several different tumor types, but their role in tumor growth, malignant invasion, metastases and impact on clinical outcomes has not been clarified. Materials and Methods : From a cohort database of 193 patients with early-stage NSCLC, 163 formalin-fixed paraffin-embedded specimens were available for analysis to construct tissue microarrays. Cav3.1 protein expression was detected using fluorescence immunohistochemistry, and quantified using automated image acquisition and analysis. Results : Among the cohort of 193 NSCLC patients, adenocarcinoma (53.9%) and squamous cell carcinoma (SCC) (30.1%) were the most common histologies. There was no difference between SCC and non-SCC subtypes in overall survival (OS) or relapse-free survival (RFS); 74.2 vs 90.1 months ( p = 0.543) and 48.8 vs 52.6 months ( p = 0.766), respectively. T-type VGCC 3.1 (Cav3.1) overexpression was assessed by tissue microarray immunohistochemistry analysis from 163 available patient samples. Eighteen (11.0%) NSCLC primaries were found to have Cav3.1 overexpression levels, and were significantly associated with SCC histology ( p < 0.001), larger tumor size ( p < 0.001) and later stage disease at diagnosis ( p = 0.019). Median OS was 48.6 vs 106.7 months for Cav3.1 overexpressing and non-overexpressing patients, respectively ( p = 0.032). Regression analysis revealed a significantly negative effect for Cav3.1 overexpression on RFS (Hazard ratio [HR] = 2.02, p = 0.048). Conclusions : Cav3.1 overexpression is a potential biomarker for poorer patient outcomes. These results bring supportive evidence for calcium channels inducing an aggressive phenotype in NSCLC and potentially may serve as a therapeutic target in overexpressing tumors.

Background: Patients (pts) with relapsed/refractory (R/R) follicular lymphoma (FL) remain an unmet need population. Monotherapy with mosunetuzumab (M), a CD20xCD3 bispecific antibody, has demonstrated high and consistent response rates in high-risk R/R FL subsets, with early evidence of response durability and a favorable benefit/risk profile (Assouline et al. ASH 2020). Lenalidomide (Len) is clinically active in pts with FL, and its potent immunomodulatory activity offers the potential for additive/synergistic efficacy when combined with M. Here, we present initial data from an ongoing Phase Ib study (NCT04246086) evaluating the safety and activity of M+Len in R/R FL pts who have received at least one prior line of therapy. Methods: Pts with R/R FL (Grade [Gr] 1-3a) and at least one prior systemic anti-cancer therapy were enrolled to receive 12 cycles of M+Len (cycle duration: Cycle [C] 1, 21 days; C2-12, 28 days). In C1, step-up doses of M (IV infusion) are given on C1 Day (D)1 (1mg) and C1D8 (2mg), with the target dose given on C1D15 (30mg) and on D1 of C2-12. Len (20mg orally) is administered on D1-21 of C2-12. No hospitalization is mandated by the protocol. The primary objective is to evaluate the safety of M+Len; secondary objectives include assessment of response and long-term efficacy outcomes. Cytokine release syndrome (CRS) is reported using ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019). Responses are assessed by investigators with PET-CT using Lugano 2014 criteria (Cheson et al. J Clin Oncol 2014). Results: At data cut-off (May 31, 2021), 27 pts had been enrolled. Median age was 59 years (range: 31-79 years); 12 pts (44%) were male. All pts had an ECOG performance status of 0 (18 pts, 67%) or 1 (9 pts, 33%). Median number of prior lines of therapy was 1 (range: 1-4), and 3 pts (11%) had disease progression (PD) 9 months. All 27 pts were safety evaluable at data cut-off. Twenty pts (74%) experienced ≥1 adverse event (AE) of any Gr; the most common AE was CRS (8 pts, 30%). Gr 3-4 AEs occurred in 8 pts (30%) and serious AEs in 8 pts (30%). No Gr 5 (fatal) AEs were observed. AEs relating to M occurred in 20 pts (74%) and AEs relating to Len occurred in 10 pts (37%). There were no AEs leading to withdrawal of M or Len; 2 pts had M-related AEs leading to M dose delays, 6 pts (22%) had Len-related AEs leading to Len dose interruption and/or reduction. In all pts, CRS events were Gr 1 (7/8 pts) or Gr 2 (1/8 pts). For most pts (6/8), CRS events occurred C1D1-C1D7; 2 pts experienced Gr 1 CRS events in C2. Median time to CRS onset was 1 day after first study drug administration (range: 1-28 days), median CRS duration was 3 days (range: 2-5 days). All CRS events resolved without sequelae. No pt required tocilizumab, ICU admission, high flow oxygen, or vasopressor support. Five pts (19%) reported 14 events of Gr 3-4 neutropenia; all neutropenia events occurred between D41 and D218, with a duration of 6-16 days. All neutropenia events resolved, with 1 patient receiving primary G-CSF prophylaxis and 2 pts receiving G-CSF treatment. No febrile neutropenia events occurred. The efficacy-evaluable population included all pts who had been assessed for response at any time on study, who had withdrawn from treatment or study prior to reaching their first response assessment, or who had been on study long enough to have reached their first scheduled response assessment, planned per protocol for D15-21 of C3. Objective response rate in the 13 pts who were efficacy evaluable at data cut-off was 92%, with complete metabolic response observed in 10 pts (77%), partial metabolic response (PMR) in 2 pts (15%), and stable disease in 1 patient (8%). One pt who initially achieved PMR experienced PD after 8 cycles of treatment. Conclusions: M+Len appears to have an acceptable safety profile in pts with R/R FL who have received at least one prior line of therapy, with encouraging preliminary anti-lymphoma activity observed. These data support initiation of a randomized Phase III study of M+Len versus rituximab+Len. Updated safety, efficacy, and pharmacokinetic data will be presented at the meeting. Disclosures Morschhauser: AstraZenenca: Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria; Janssen: Honoraria; Genmab: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Speakers Bureau; Servier: Consultancy. Bishton: Nottingham University Hospitals NHS Trust: Current Employment; Celltrion: Honoraria; Tevapharma: Honoraria; Bristol-Myers Squibb: Honoraria; Gilead: Honoraria; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees. Eyre: Oxford University Hospitals NHS Foundation Trust: Current Employment; LOXO Oncology: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Speakers Bureau; KITE/Gilead: Consultancy, Honoraria, Speakers Bureau; Secura Bio: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau. Bachy: Kite, a Gilead Company: Honoraria; Novartis: Honoraria; Daiishi: Research Funding; Roche: Consultancy; Takeda: Consultancy; Incyte: Consultancy. Cartron: Roche, Celgene-BMS: Consultancy; Danofi, Gilead, Novartis, Jansen, Roche, Celgene-BMS, Abbvie, Takeda: Honoraria. Ysebaert: AbbVie: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Speakers Bureau. Bobillo: F. Hoffmann-La Roche Ltd: Consultancy, Speakers Bureau; Gilead: Speakers Bureau. Budde: Kite Pharma: Consultancy; Genentech: Consultancy, Research Funding; AstraZeneca: Research Funding. Fox: F. Hoffmann-La Roche Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees. Knapp: F. Hoffmann-La Roche Ltd: Current Employment. Yaqub: Genentech, Inc./F. Hoffmann-La Roche Ltd: Current Employment. Wei: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. O'Hear: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current holder of individual stocks in a privately-held company. Li: F. Hoffmann-La Roche Ltd: Current Employment. Townsend: F. Hoffmann-La Roche Ltd: Consultancy, Honoraria; Celgene (Bristol-Myers Squibb): Consultancy, Honoraria. OffLabel Disclosure: Mosunetuzumab is a CD20xCD3 bispecific antibody that redirects T cells to engage and eliminate malignant B cells. Mosunetuzumab is an investigational agent.

BACKGROUND Understanding the drug development pathway is critical for streamlining the development of effective cancer treatments. The objective of the current study was to delineate the drug development timeline and attrition rate of different drug classes for common cancer disease sites. METHODS Drugs entering clinical trials for breast, colorectal, and non-small cell lung cancer were identified using a pharmaceutical business intelligence database. Data regarding drug characteristics, clinical trials, and approval dates were obtained from the database, clinical trial registries, PubMed, and regulatory Web sites. RESULTS A total of 411 drugs met the inclusion criteria for breast cancer, 246 drugs met the inclusion criteria for colorectal cancer, and 315 drugs met the inclusion criteria for non-small cell lung cancer. Attrition rates were 83.9% for breast cancer, 87.0% for colorectal cancer, and 92.0% for non-small cell lung cancer drugs. In the case of non-small cell lung cancer, there was a trend toward higher attrition rates for targeted monoclonal antibodies compared with other agents. No tumor site-specific differences were noted with regard to cytotoxic chemotherapy, immunomodulatory, or small molecule kinase inhibitor drugs. Drugs classified as “others” in breast cancer had lower attrition rates, primarily due to the higher success of hormonal medications. Mean drug development times were 8.9 years for breast cancer, 6.7 years for colorectal cancer, and 6.6 years for non-small cell lung cancer. CONCLUSIONS Overall oncologic drug attrition rates remain high, and drugs are more likely to fail in later-stage clinical trials. The refinement of early-phase trial design may permit the selection of drugs that are more likely to succeed in the phase 3 setting. Cancer 2017. © 2017 American Cancer Society.

The risk of pregnancy loss in von Willebrand disease (VWD) has been inconsistently reported. Von Willebrand factor (VWF) is a known regulator of angiogenesis, so has the potential to affect placental function. We sought to determine the risk of pregnancy loss and placenta-mediated pregnancy complications in women with VWD, compared with women without VWD. Women with VWD followed in the Southern Alberta Rare Blood and Bleeding Disorders Clinic were invited to participate in a questionnaire (February-June 2014). The same questionnaire was sent to women without VWD identified in a low-risk obstetrical clinic in Calgary, Alberta, Canada. The primary outcome was the proportion of pregnancies that ended in pregnancy loss. Secondary outcomes were preeclampsia, fetal growth restriction, placental abruption, and preterm labor less than 37 weeks gestation. Of the 30 (31.6%) VWD participants that responded, 26 (86.7%) were diagnosed with Type 1 VWD, of which 11 (42.3%) had VWF antigen or activity levels less than 30%. In women with VWD, there were 20 pregnancy losses out of 80 pregnancies [25.0%, 95% confidence interval (CI), 16.81-35.48], compared with eight losses out of 50 pregnancies in the control group (16.0%, 95% CI, 8.34-28.51; P = 0.28). There was no difference in the risk of preeclampsia (1.7 versus 0%, P = 1.00) or preterm labor (16.7 versus 7.1%, P = 0.23) among VWD and control groups. There were no other placenta-mediated pregnancy complications reported. There is no significant difference in pregnancy loss between women with and without VWD; however, a large multicenter study is needed to clarify the risk of pregnancy loss in women with VWD.

Purpose: The current study was designed to investigate the combined influence of ataxia telangiectasia mutated (ATM) and Ki67 on clinical outcome in early stage hormone receptor positive breast cancer (ES-HPBC), particularly in patients with smaller tumors (< 4 cm) and fewer than four positive lymph nodes. Methods: Formalin-fixed paraffin-embedded specimens of resected primary breast tumors from 532 patients diagnosed with early stage breast cancer were used to construct a tissue microarray. Samples from 297 patients were suitable for final statistical analysis. We detected ATM and Ki67 proteins using immunohistochemistry and quantified their expression with digital image analysis. Data on expression levels were subsequently correlated with clinical outcome. Results: Remarkably, ATM expression was useful to stratify the low Ki67 group into subgroups with better or poorer prognosis. Specifically, in the low Ki67 subgroup defined as having smaller tumors and no positive nodes, patients with high ATM expression showed better outcome than those with low ATM, with estimated survival rates of 96% and 89% respectively at 15 years follow up (p = 0.04). Similarly, low-Ki67 patients with smaller tumors, 1-3 positive nodes and high ATM also had significantly better outcomes than their low ATM counterparts, with estimated survival rates of 88% and 46% respectively (p=0.03) at 15 years follow up. Multivariable analysis indicated that the combination of high ATM and low Ki67 is prognostic of improved survival, independent of tumor size, grade, and lymph node status (p = 0.02). Low Ki67/high ATM expression independently predicts favorable disease survival in a multivariate model in low Ki67 subgroup of ES-HPBC (Stage I-III)Variablesp valueHR (95%CI)Low Ki67/high ATM vs Low Ki67/low ATM0.020.36 (0.15-0.88)ize (T1/2 vs T3/4)0.010.16 (0.04-0.69)LN status (- vs +)0.140.49 (0.20-1.25)LVI (_- vs +)0.160.51 (0.20-1.31)Grade (1/2 vs 3)65)0.010.26 (0.10-0.74) Conclusions: These data suggest that the prognostic value of Ki67 can be improved by analyzing ATM expression in ES-HPBC. Citation Format: Feng X, Li H, Kornarga E, Dean M, Lees-Miller S, Riabowol K, Magliocco A, Morris D, Watson P, Enwere E, Bebb G, Paterson A. Refining the prognostic value of Ki67 biomarker by ataxia telangiectasia mutated (ATM) status in a retrospective study of early stage hormone receptor positive breast cancer [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 P2-05-33.

Background: nab-Paclitaxel (nab-P)–containing regimens have demonstrated efficacy and safety in triple-negative breast cancer (TNBC). In the absence of a standard of care for metastatic (m) TNBC, tnAcity evaluated the efficacy and safety of 3 common chemotherapy combination regimens: nab-P + carboplatin (nab-P/C) or gemcitabine (nab-P/G) vs G/C as first-line treatment (Tx) for patients (pts) with mTNBC based on a ranking algorithm of efficacy and safety. Results of the phase 2 portion are reported here. Methods: Pts with pathologically confirmed mTNBC, no prior cytotoxic chemotherapy for metastatic disease, and no brain metastases were enrolled. Pts received (1:1:1) nab-P 125 mg/m2 + C AUC 2, nab-P 125 mg/m2 + G 1000 mg/m2, or G 1000 mg/m2 + C AUC 2, all given on d 1 and 8 every 3 weeks. The phase 2 primary endpoint was investigator-assessed progression-free survival (PFS); secondary endpoints included overall response rate (ORR), overall survival (OS), percentage of pts initiating cycle 6 receiving doublet therapy, and safety. Results: 191 pts were included in the phase 2 portion. Median age was 55, 53, and 59 years in the nab-P/C, nab-P/G, and G/C groups, respectively. Overall, 98% of pts had an ECOG PS of 0 - 1, 83% were white, and 48% were treated in North America. Most pts (81%) had relapsed disease. Median Tx duration was 25, 18, and 20 weeks, and 47%, 33%, and 52% of pts had ≥ 1 dose reduction for both agents in the nab-P/C, nab-P/G, and G/C groups, respectively. Key efficacy and safety results are summarized in the table. PFS was significantly longer with nab-P/C vs either nab-P/G or G/C (median, 7.4 vs 5.4 mo, P = 0.03 and 7.4 vs 6.0 mo, P = 0.02). Overall, 179 pts discontinued Tx; of these, 55% discontinued due to progression and 16% due to adverse events (AEs). Grade ≥ 3 AEs in ≥ 10% of pts were mainly hematologic. The rank sum of the algorithm for 5 key weighted efficacy and safety endpoints favored nab-P/C. Table 1 nab-P/Cnab-P/GG/CEfficacyn = 64n = 61n = 66PFS, median, mo7.4a5.4b6.0ORR, %71.937.743.9OS, median, mo16.411.913.7Pts initiating cycle 6 with a doublet, %64.155.750.0Safetyn = 64n = 60n= 64Myelosuppression-related events, %c53.141.767.2Pts discontinuing all Tx due to AE, %18.820.021.9Serious TEAEs, %29.736.737.5Grade ≥ 3 AEs, %Neutropenia40.633.348.4Anemia7.88.315.6Thrombocytopenia4.73.314.1Peripheral neuropathy4.75.01.6Deaths due to TEAE, n (%)1 (2)2 (3)2 (3)a P = 0.03 vs nab-P/G; P = 0.02 vs G/C; b P = 0.85 vs G/C; c Including grade ≥ 3 neutropenia, thrombocytopenia, anemia, bleeding, febrile neutropenia, or red blood cell/platelet transfusion. Conclusions: In this phase 2 study, nab-P/C demonstrated a statistically significant longer PFS and a better risk/benefit profile vs nab-P/G or G/C as first-line Tx in pts with mTNBC. These data demonstrate nab-P/C efficacy in mTNBC and address a relevant question around a nab-P/C chemotherapy backbone for this difficult-to-treat tumor type. Further studies are warranted in the context of immunotherapies and targeted agents. NCT01881230. Citation Format: Yardley D, Coleman R, Conte P, Cortes J, Brufsky A, Shtivelband M, Young R, Bengala C, Ali H, Eakel J, Schneeweiss A, de la Cruz Merino L, Wilks S, O'Shaugnessy J, Glück S, Li H, Beck R, Barton D, Harbeck N. nab-paclitaxel + carboplatin or gemcitabine vs gemcitabine/carboplatin as first-line treatment for patients with triple-negative metastatic breast cancer: Results from the randomized phase 2 portion of the tnAcity trial [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 P5-15-03.

While 2/3 of patients with ATRT are less than 3 years at diagnosis, the literature suggests younger children present with more aggressive disease and poorer outcome. However, little data exist on characteristics and outcome of patients diagnosed with ATRT in the first year of life. In particular, it is unclear whether they access similar treatments as do older children. We compared the cohort of patients ≤12 months from the Canadian ATRT registry to all cases extracted from the literature reported between 1996 and 2014 to describe their clinical and treatment characteristics, and potential prognostic factors. Twenty-six (33.7%) patients from the Canadian registry were ≤12 months at diagnosis as were 120 cases identified in the literature. Post-operatively, 46% of the registry's patients underwent palliation as opposed to 10.8% in the literature cohort. Palliative patients were significantly younger than those who received active therapy (3.3 vs. 6.6 months). While the use of high-dose chemotherapy (HDC) was relatively similar in both cohorts (42.9 and 35.5% respectively), radiotherapy (RT) use was significantly lower in the Canadian cohort (14.3 vs 44.9%). Children ≤6 months, who received active therapy, had a worst outcome than older ones. Gross total resection, HDC and adjuvant RT were associated with better outcomes. Eighty percent of the tested patients had evidence of germline mutation of INI1. While 1/3 of ATRT occurs within the first year of life, a large proportion only received palliative therapy. Even when actively treated, children ≤6 months fare worse. Some selected patients benefit from HDC.

There is limited information on how indoor tanning promotes melanoma development. We investigated indoor tanning use in patients with melanomas in sun-exposed skin and studied the clinicopathological and molecular characteristics in relation to indoor tanning exposure. Patients from a multidisciplinary clinic for cutaneous cancers completed standardized questionnaires on risk factors for melanoma as a component of medical history at their initial consultations. For this study, we included patients from December 2013 to May 2015. The 114 patients who reported indoor tanning exposure were younger at diagnosis than the 222 patients who did not (51.5 vs 64.0 years, two-sided P < .001). BRAF V600E genotype was more prevalent in ever-users than in nonusers (42.9% vs 28.3%, two-sided P = .04) and higher in ever-users who initiated indoor tanning prior to age 25 years compared with age 25 years or older (62.2% vs 31.1%, two-sided P = .003). There were more melanomas in intermittently sun-exposed skin in ever-users than nonusers (65.7% vs 51.9%, respectively, two-sided P = .02). Our data suggest indoor tanning may promote melanomas that arise in skin with low-chronic sun-induced damage through BRAF V600E-mediated melanomagenesis.

Background Limited data exist describing real‐world treatment of de novo and recurrent HER2‐positive metastatic breast cancer (MBC). Materials and Methods The Systemic Therapies for HER2‐Positive Metastatic Breast Cancer Study (SystHERs) was a fully enrolled (2012–2016), observational, prospective registry of patients with HER2‐positive MBC. Patients aged ≥18 years and ≤6 months from HER2‐positive MBC diagnosis were treated and assessed per their physician's standard practice. The primary endpoint was to characterize treatment patterns by de novo versus recurrent MBC status, compared descriptively. Secondary endpoints included patient characteristics, progression‐free and overall survival (PFS and OS, by Kaplan‐Meier method; hazard ratio [HR] and 95% confidence interval [CI] by Cox regression), and patient‐reported outcomes. Results Among 977 eligible patients, 49.8% (n = 487) had de novo and 50.2% (n = 490) had recurrent disease. A higher proportion of de novo patients had hormone receptor–negative disease (34.9% vs. 24.9%), bone metastasis (57.1% vs. 45.9%), and/or liver metastasis (41.9% vs. 33.1%), and a lower proportion had central nervous system metastasis (4.3% vs. 13.5%). De novo patients received first‐line regimens containing chemotherapy (89.7%), trastuzumab (95.7%), and pertuzumab (77.8%) more commonly than recurrent patients (80.0%, 85.9%, and 68.6%, respectively). De novo patients had longer median PFS (17.7 vs. 11.9 months; HR, 0.69; 95% CI, 0.59–0.80; p < .0001) and OS (not estimable vs. 44.5 months; HR, 0.55; 95% CI, 0.44–0.69; p < .0001). Conclusion Patients with de novo versus recurrent HER2‐positive MBC exhibit different disease characteristics and survival durations, suggesting these groups have distinct outcomes. These differences may affect future clinical trial design. Clinical trial identification number. NCT01615068 (http://clinicaltrials.gov). Implications for Practice SystHERs was an observational registry of patients with HER2‐positive metastatic breast cancer (MBC), which is a large, modern, real‐world data set for this population and, thereby, provides a unique opportunity to study patients with de novo and recurrent HER2‐positive MBC. In SystHERs, patients with de novo disease had different baseline demographics and disease characteristics, had superior clinical outcomes, and more commonly received first‐line chemotherapy and/or trastuzumab versus those with recurrent disease. Data from this and other studies suggest that de novo and recurrent MBC have distinct outcomes, which may have implications for disease management strategies and future clinical study design., The SystHERs breast cancer study was a fully enrolled, prospective registry study that explored contemporary treatment patterns and outcomes in patients with HER2‐positive metastatic breast cancer (MBC), resulting in one of the largest real‐world datasets for this population and providing a unique opportunity to assess patients with de novo and recurrent HER2‐positive MBC. This article reports baseline characteristics, treatment patterns, patient‐reported outcomes, and clinical outcomes in these patient subsets.

Background and aims Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease when aortic rupture occurs, especially for elders. There is an urgent need to understand the mechanisms of AAA formation and development at molecular level. Our previous study showed that disintegrin and metalloprotease 10 (ADAM10) played an important role in abdominal aortic aneurysm formation. In this study, we investigated the effects of another ADAM protein (ADMA9) in AAA formation. Method and results Using AngII treated human aortic smooth muscle cells (HASMCs) and human aortic endothelial cells (hAoECs) as in vitro AAA model and murine AAA model, ADAM9 was overexpressed suggesting that ADAM9 may play important roles in AAA formation. Further investigation showed that ADAM9 induced inflammation leading to increased macrophage infiltration. ADAM9 was also found to induce cell apoptosis. AKT/NF-κB pathway was activated in murine AAA. Bioinformatic analysis showed that the 3’ UTR of ADMA9 was a potential target of miR-126. We investigated the potential of using miR-126 to modulate ADAM9 expression. The expression level of miR-126 was decreased and inversely correlated with the expression of ADAM9 in the in vitro AAA model. Further investigation showed that miR-126 negatively regulated gene expression of ADAM9 and suppressed the production of inflammatory cytokines. miR-126 was also found to improve cell survival and significantly reduce AAA formation in murine AAA. Conclusions Our data revealed a link between ADAM9 and AAA formation, providing an approach to control AAA development using miR-126, possibly through modulation of the expression level of ADAM9.

Aims Due to the rarity and varied natural history of desmoid-type fibromatosis, evidence-based treatment standards for this disease remain lacking. This study evaluated outcomes in patients with desmoid-type fibromatosis managed at a Canadian institution over two decades. Materials and methods Records of 227 patients with desmoid-type fibromatosis referred from 1990 to 2013 were retrospectively reviewed to investigate management strategies including active surveillance, surgery, radiation therapy, cryoablation, and systemic therapy, including tamoxifen and chemotherapy. Results Thirty-two per cent of cases were men, median age 40 years, median tumour size 5.4 cm. Initial treatments were surgery (79%), tamoxifen (13%), radiation therapy (5.0%), chemotherapy (1.8%) and cryoablation (1.2%). Active surveillance was used upfront in 26% of cases, most after 2005. At a median follow-up of 77 months, one patient died of disease, 13 died of unrelated causes and the remainder were alive with no evidence of disease (56%), stable/responding disease (33%) or progressive disease (4%). The recurrence rate was 25% after upfront surgery. Response rates and disease control rates were 40% and 76% for active surveillance; 68% and 96% for radiation therapy; 31% and 67% for tamoxifen; and 53% and 80% for chemotherapy. On univariable analysis, factors associated with a higher recurrence after initial surgery were young age (P = 0.012), male gender (P = 0.012) and extremity location (P = 0.005). On multivariable analysis, only young age was significantly associated with recurrence risk (P = 0.010). Conclusions Active surveillance was associated with spontaneous regression and long-term disease control consistent with other studies. Primary radiation therapy appeared to provide a similar response and disease control compared with systemic treatments and may be a viable option for patients who are not candidates for surgery or active surveillance.

The role of autologous stem cell transplantation (ASCT) in patients with relapsed follicular lymphoma (FL) remains controversial because of a lack of proven overall survival (OS) benefit versus nontransplant strategies. We conducted a comparative effectiveness research study involving 3 tertiary Canadian cancer centers to determine whether the ASCT-based approach used at 1 center improved OS relative to non-ASCT approaches used at the other centers. Of 1082 consecutive patients aged 18 to 60 years and diagnosed with FL from 2001 to 2010, the study population included 355 patients who experienced relapse from chemotherapy (center A = 96, center B = 84, center C = 175). Data were analyzed according to the instrumental variable of treatment center to control for confounding factors. The frequency of using ASCT at first or second relapse was significantly different between the centers (A = 58%, B = 7%, C = 5%, P .001). With a median follow-up of 69.1 months, the actuarial 5-year OS rates after first chemotherapy relapse were 89%, 60%, and 60% for centers A, B, and C respectively (log rank P .0001). Based on instrumental variable analysis, the use of ASCT at relapse 1 or 2 significantly decreased the risk of death from first relapse (HR .127, P = .004) and from initial diagnosis (HR .116, P = .004). In conclusion, for FL patients who relapse after chemotherapy, these results strongly support more frequent use of ASCT at first or second relapse.

Purpose:Patients with HER2-positive metastatic breast cancer (MBC) with central nervous system (CNS) metastasis have a poor prognosis. We report treatments and outcomes in patients with HER2-positive MBC and CNS metastasis from the Systemic Therapies for HER2-positive Metastatic Breast Cancer Study (SystHERs).Experimental Design:SystHERs (NCT01615068) was a prospective, U.S.-based, observational registry of patients with newly diagnosed HER2-positive MBC. Study endpoints included treatment patterns, clinical outcomes, and patient-reported outcomes (PRO).Results:Among 977 eligible patients enrolled (2012–2016), CNS metastasis was observed in 87 (8.9%) at initial MBC diagnosis and 212 (21.7%) after diagnosis, and was not observed in 678 (69.4%) patients. White and younger patients, and those with recurrent MBC and hormone receptor–negative disease, had higher risk of CNS metastasis. Patients with CNS metastasis at diagnosis received first-line lapatinib more commonly (23.0% vs. 2.5%), and trastuzumab less commonly (70.1% vs. 92.8%), than patients without CNS metastasis at diagnosis. Risk of death was higher with CNS metastasis observed at or after diagnosis [median overall survival (OS) 30.2 and 38.3 months from MBC diagnosis, respectively] versus no CNS metastasis [median OS not estimable: HR 2.86; 95% confidence interval (CI), 2.05–4.00 and HR 1.94; 95% CI, 1.52–2.49]. Patients with versus without CNS metastasis at diagnosis had lower quality of life at enrollment.Conclusions:Despite advances in HER2-targeted treatments, patients with CNS metastasis continue to have a poor prognosis and impaired quality of life. Observation of CNS metastasis appears to influence HER2-targeted treatment choice.

To assess the impact of location versus number of extra-pulmonary metastatic sites (EPMS) on survival in stage IV non-small cell lung cancer (NSCLC). Retrospective analysis was conducted on patients diagnosed during 1999–2013 with stage IV, M1b (AJCC 7th edition) NSCLC using the large, institutional Glans-Look Database, which contains patient demographic, clinical, pathological, treatment, and outcome information. We assessed the impact of location and number of EPMS and identified correlates of overall survival using the Kaplan–Meier method and Cox regression. We identified a total of 2065 NSCLC patients with EPMS. Median age was 67 (IQR 58–75) years, 52% were men, and 78% were current or former smokers. 60% had one EPMS, and 40% had two or more EPMS. Among those with only one EPMS, most frequent organ involvement included bone (40%), brain (32%), and liver (13%). Median overall survival (mOS) was worst in those with liver metastasis and best in those with adrenal metastasis (2.0 vs. 5.2 months, p = 0.015). However, outcomes based on site of organ involvement were not significantly different in multivariable analysis. Compared to patients with one EPMS, individuals with two or more EPMS experienced worse outcomes (mOS ≤ 2.9 vs. 3.9 months, p

Physical activity (PA) has been shown to improve quality of life and survival in cancer survivors; however, a cancer diagnosis may change PA patterns. We examine determinants of changes in meeting the PA guidelines (150 min/week of moderate aerobic PA) before and after a prostate cancer diagnosis. Eight hundred and thirty prostate cancer survivors who participated in a population-based case–control study between 1997 and 2000 in Alberta, Canada, enrolled in a prospective cohort study. Past year activity levels were self-reported at diagnosis (pre-diagnosis measure) and again 2 years post-diagnosis. Determinants were collected by questionnaires and medical chart abstractions. Four PA patterns were created: non-exercisers (fail to meet guidelines pre-diagnosis and post-diagnosis), adopters (fail to meet guidelines pre-diagnosis, meet guidelines post-diagnosis), maintainers (meet guidelines pre-diagnosis and post-diagnosis) and relapsers (meet guidelines pre-diagnosis, fail to meet guidelines post-diagnosis). Multinomial logistic regression analyses identified that being a non-exerciser compared to maintainer was associated with being employed, rural location, high PSA, smoking status, not attending support groups and less than average physical quality of life (QoL). Being a relapser compared to maintainer was associated with rural location and lack of friend support. Finally, being a non-exerciser compared to adopter was associated with urinary incontinence, smoking status and less than average physical and mental QoL. Demographic, health and lifestyle variables are associated with changes in meeting PA guidelines from pre-diagnosis to post-diagnosis in prostate cancer survivors. Programming should be aimed at offering interventions to help inactive survivors adopt PA and active survivors to maintain PA.

Background: The impact of the change in the neutrophil-to-lymphocyte ratio (NLR) during neoadjuvant chemotherapy (NAC) on outcomes in patients with muscle-invasive bladder cancer (MIBC) is poorly understood.Objective: To evaluate the prognostic impact of the change in NLR during NAC for patients with MIBC.Methods: Patients referred to academic, community, and quaternary referral centres in Alberta, Canada from 2005 to 2015, Ontario, Canada from 2005 to 2013, and Southampton, UK from 2004 to 2010 were evaluated. 376 eligible patients were treated with NAC for clinical T2-4aN0M0 disease, and 296 were evaluable for the change in NLR. A high NLR was defined as being an NLR > 3. Relationships between the change in NLR from baseline to mid-NAC (pre-cycle 3) and outcomes were analyzed using multivariable Cox regression. Kaplan-Meier analysis was used with the log-rank test for group comparisons.Results: Median follow-up was 22.0 months (95% confidence interval [CI]: 14.9-30.0). Patients with a sustained high NLR had a median disease-free survival (DFS) of 12.6 months, compared to 34.8 months for those with a sustained low NLR (log-rank test p = 0.0025; hazard ratio [HR] 0.61 [95% CI: 0.44-0.84]). Median overall survival (OS) was 19.4 months for patients with a sustained high NLR, compared to 44.0 months for patients with a sustained low NLR (log-rank test p = 0.0011; HR 0.54 [95% CI: 0.38-0.77]).Conclusions: A sustained high NLR from baseline to mid-NAC is an independent prognostic factor for patients with MIBC.

Progesterone receptor membrane component 1 (PGRMC1) and Na+/K+‑ATPase α1 subunit (ATP1A1) are two proteins associated with the clinical prognosis of renal cell carcinoma (RCC) and RCC cell proliferation. However, the two proteins have been previously studied independently, and their combined influence on the clinical outcome of RCC remains unclear. The present study suggests that the combined expression levels of PGRMC1 and ATP1A1 (PGRMC1/ATP1A1) are associated with the clinical prognosis of RCC patients. RCC patients with low PGRMC1/positive ATP1A1 levels exhibited the best overall survival (OS) outcomes (103.08±1.85 months). The high PGRMC1/negative ATP1A1 group demonstrated the worst prognosis (73.1±8.87 months). The low PGRMC1/positive ATP1A1 group had the highest 7‑year OS rate (92.3%). The high PGRMC1/negative ATP1A1 group had the lowest 7‑year OS rate (46.7%). Although PGRMC1 and ATP1A1 both act on AKT phosphorylation in RCC cells, their expression levels are independent of each other. Moreover, the synergistic suppressive roles of PGRMC1 downregulation combined with ATP1A1 upregulation exhibit more efficient tumor inhibition potentials on RCC cells. Therefore, combined assessment of the two biomarkers (PGRMC1/ATP1A1) shows enhanced prognostic ability for RCC.

Ki67 is a commonly used marker of cancer cell proliferation, and has significant prognostic value in breast cancer. In spite of its clinical importance, assessment of Ki67 remains a challenge, as current manual scoring methods have high inter- and intra-user variability. A major reason for this variability is selection bias, in that different observers will score different regions of the same tumor. Here, we developed an automated Ki67 scoring method that eliminates selection bias, by using whole-slide analysis to identify and score the tumor regions with the highest proliferative rates. The Ki67 indices calculated using this method were highly concordant with manual scoring by a pathologist (Pearson’s r = 0.909) and between users (Pearson’s r = 0.984). We assessed the clinical validity of this method by scoring Ki67 from 328 whole-slide sections of resected early-stage, hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. All patients had Oncotype DX testing performed (Genomic Health) and available Recurrence Scores. High Ki67 indices correlated significantly with several clinico-pathological correlates, including higher tumor grade (1 versus 3, P

Introduction Only approximately 25% of stage iv non-small-cell lung cancer (nsclc) patients receive systemic therapy. For such patients, we examined factors affecting referral to a cancer centre (cc) and to medical oncology (mo), and use of systemic therapy. Methods Using the Glans–Look Lung Cancer database, we completed a chart review of stage iv nsclc patients diagnosed in Southern Alberta during 2003–2006 and 2010–2011, comparing median overall survival (mos), referral, and treatment in the two cohorts. Results Of the 922 patients diagnosed in 2003–2006 and the 560 diagnosed in 2010–2011, 94% and 82% respectively were referred to a cc, with 22% and 23% receiving traditional chemotherapy (tctx). Referral to a cc or mo and use of tctx correlated with survival ( p < 0.0001): The mos duration was 11.2 months in those receiving tctx and 1.0 months in those not referred to a cc. The overall mos duration was similar in the two cohorts (4.1 months vs. 3.9 months, p = 0.47). Major reasons for lack of referral to mo included poor functional status, rapid decline, and patient wish, which were similar to the reasons for forgoing tctx. In the two cohorts, 87 (9.4%) and 42 (7.5%) patients received epidermal growth factor inhibitors, with a mos duration of 16.2 months. Multivariable analysis showed that male sex [hazard ratio (hr): 1.16; p = 0.008] and pulmonary embolus (hr: 1.2; p = 0.002) correlated with worse survival. In contrast, receipt of chemotherapy (hr: 0.5; p < 0.001) and enrolment in a clinical trial (hr: 0.76; p = 0.049) correlated with better survival. Conclusions Our experience confirms that, over time, uptake of systemic therapy, including tctx and targeted therapy, changed little despite their established efficacy. Most of the factors limiting systemic therapy uptake appear to be non-modifiable at the time of referral. Rapid diagnosis and the availability of well-tolerated drugs for all nsclc patients will likely be the most important factors in increasing systemic therapy uptake in this population.

Introduction: Clinical trial data has shown pazopanib to be noninferior in overall survival (OS) compared to sunitinib as first-line treatment for metastatic renal cell carcinoma (mRCC). The purpose of this study was to evaluate outcomes and compare dose-modifying toxicities of mRCC patients treated with suntinib or pazopanib in the real-world setting.Methods: Data were collected on mRCC patients using the prospective Canadian Kidney Cancer Information System (CKCis) database from January 2011 to November 2015. Statistical analyses were performed using Cox regression adjusted for several risk factors and the Kaplan-Meier method.Results: We identified 670 patients treated with sunitinib (n=577) and pazopanib (n=93). There were no significant differences in International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups (p=0.807). Patients treated with sunitinib had improved OS compared with pazopanib (median 31.7 vs. 20.6 months, p=0.028; adjusted hazard ratio [aHR] 0.60; 95% confidence interval [CI] 0.38‒0.94). Time to treatment failure (TTF) was numerically, but not statistically, improved with sunitinib (medians 11.0 vs. 8.4 months, p=0.130; aHR 0.87; 95% CI 0.59‒1.28). Outcomes with individualized dosing on sunitinib were unavailable for this analysis. Patients treated with sunitinib had a higher incidence of mucositis, hand-foot syndrome, and gastroesophageal reflux disease; patients treated with pazopanib had a higher incidence of hepatotoxicity.Conclusions: In Canadian patients with mRCC, treatment with sunitinib appears to be associated with an improved OS compared to pazopanib in the first-line setting. Patient selection factors and the contemporary practice of individualized dosing with sunitinib may contribute to these real-world outcomes and warrant further investigation.

Objective:To determine the referral rate to radiation oncologist (RO), use of postoperative radiotherapy (PORT) and the impact of a clinical practice guideline (CPG) on patients with atypical meningioma (AM).Methods:A retrospective review of meningioma patients (n=526) treated between 2003 and 2013 was undertaken. Patients’ characteristics, extent of surgical resection (EOR), RO referral, PORT, date and treatment of first recurrence were collected for all patients >18 years with a new diagnosis of AM after surgical resection (n=83). Progression free survival (PFS) and overall survival (OS) according to EOR were assessed by the Log-Rank test of Kaplan-Meier survival.Results:Median age was 57 years. EOR was gross total (GTR) in 44 patients, subtotal (STR) in 36 patients and 3 patients had unknown EOR. RO referral rate was 26.5% (n=22); 5 patients initially had GTR and 17 had STR. Only 7 patients received PORT. At a median follow up time of 29 months, recurrences occurred in 28 patients, 4 had GTR, 21 had STR and 3 had an unknown EOR. With PORT, 2 patients developed recurrence. 5-year PFS was 62% after GTR and 33% after STR (P=0.002). 5-year OS was 92% after GTR and 83% after STR (P=0.45).Conclusion:In this cohort with AM, RO referral rate was low and was not influenced by the CPG. Use of PORT was also low. Given the lack of conclusive evidence supporting PORT in such patients, a multidisciplinary approach, including RO consultation, is needed to provide patients with optimal and individualised care.

The present study was designed to investigate the role of circulating miRNA-21 (miR-21) in vascular restenosis of lower extremity arterial occlusive disease (LEAOD) patients after interventional therapy. A total of 412 LEAOD patients were enrolled randomly in the present study. According to computed tomography angiography (CTA) and ankle-brachial index (ABI), patients were assigned into the restenosis group and the non-restenosis group. miR-21 expression was detected with quantitative real-time PCR (qRT-PCR) before and after patients underwent interventional therapy. A follow-up period of 6 months was achieved. A receiver operating characteristic (ROC) curve was drawn and the area under the curve (AUC) was calculated to assess the predictive value of miR-21 in vascular restenosis. Patients were older in the restenosis group than in the non-restenosis group. The percentages of patients with diabetes and hypertension were higher in the restenosis group than in the non-restenosis group, and the Fontaine stage exhibited a significant difference between the two groups. miR-21 expression was higher in the restenosis group than in the non-restenosis group. miR-21 expression level was related to age, diabetes and hypertension in the restenosis group. Using miR-21 to predict vascular restenosis yielded an AUC of 0.938 (95% confidence interval (CI): 0.898–0.977), with Youden index of 0.817, sensitivity of 83.5% and specificity of 98.2%. Logistic regression analysis revealed that diabetes and miR-21 expression were the major risk factors for vascular restenosis of LEAOD. miR-21 can be used as a predictive indicator for vascular restenosis of LEAOD after interventional therapy.

To evaluate the association of high sensitivity C-reactive protein (hsCRP) with the presence of abdominal aortic aneurysm (AAA).Medline, Cochrane, Embase, and Google Scholar databases were searched until 22 June 2016 using the keywords predictive factors, biomarkers, abdominal aortic aneurysm, prediction, high sensitivity C-reactive protein, and hsCRP. Prospective studies, retrospective studies, and cohort studies were included.Twelve case-control studies were included in the meta-analysis with a total of 8345 patients (1977 in the AAA group and 6368 in the control group). The pooled results showed that AAA patients had higher hsCRP value than the control group (difference in means = 1.827, 95% CI = 0.010 to 3.645, p = .049). Subgroup analysis found AAA patients with medium or small aortic diameter (50 mm) had higher hsCRP plasma levels than the control group (difference in means = 1.301, 95% CI = 0.821 to 1.781, p .001). In patients with large aortic diameter (≥50 mm), no difference was observed in hsCRP levels between the AAA and control groups (difference in means = 1.769, 95% CI = -1.387 to 4.925, p = .272). Multi-regression analysis found the difference in means of hsCRP plasma levels between AAA and control groups decreased as aortic diameter increased (slope = -0.04, p .001), suggesting that hsCRP levels may be inversely associated with increasing aneurysm size.Our findings suggest that hsCRP levels may possibly be used as a diagnostic biomarker for AAA patients with medium or small aortic diameter but not for AAA patients with large aortic diameter. The correlation between serum hsCRP level and AAA aneurysm is not conclusive due to the small number of included articles and between-study heterogeneity.

Background: Phase III trials in metastatic colorectal cancer (mCRC) have collectively led to progressive advancements in patient outcomes over the past decades. This study characterizes the evolution of mCRC phase III trials through assessing the value of cancer therapy, as measured by the ASCO Value Framework. Methods: Phase III trial results of systemic therapy for mCRC published between 1980 and 2015 were identified, and their outcome, statistical significance, journal impact factor, and citation by the 2016 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for CRC were recorded. For each trial, the net health benefit (NHB) score was calculated using the June 2015 (original) and May 2016 (revised) ASCO Value Framework: Advanced Disease. Results: There were 114 mCRC phase III trials eligible for calculation of the NHB score. Using the revised framework, the median NHB score was 4.6 (range, -30 to 43.5); 12% of trials received bonus points. Trials with statistically significant results had higher NHB scores compared with nonsignificant trials (median NHB score, 21.6 vs 2.9; P

Introduction: Extragonadal germ cell tumours (EGCTs) are a heterogeneous group with distinct natural history and responses to treatmentmodalities. We sought to evaluate characteristics and survival outcomes in men with EGCTs.Methods: We performed a retrospective analysis on a consecutive list of men diagnosed with EGCT in two Albertan cancer centres between 1990 and 2013. Demographic characteristics and outcomes, stratified by primary site, were evaluated.Results: Sixty-nine cases were identified. The median age was 29 (range 15–76) and 48 cases (70%) were non-seminomatous. Twenty-four (35%) belonged to International Germ Cell Cancer Collaborative Group (IGCCCG) favourable risk group, 14 (20%) to intermediate, and 31 (45%) to poor. Thirty (43%) had mediastinal primary (MPs); 29 were treated with first-line bleomycin, etoposide,and cisplatin (BEP). Seventeen (57%) relapses occurred, of which three patients achieved long-term survival. Seventeen (25%) had a central nervous system (CNS) primary, with eight (47%) classic germinoma. Seven (41%) received primary chemotherapy alone; 5 (29%) received primary radiotherapy alone, and 5 (29%) received both. Nineteen (28%) had a retroperitoneal primary (RPs) and received first-line chemotherapy; all but two received BEP and eight (42%) had surgical resection. Three (5%) had other or unknown primary. Five-year overall survival (OS) and disease-free survival for all patients were 56% and 44%, respectively; for MPs, 44% and 34%; for CNS primary, 76% and 53%; for RPs, 58% and 53%. Factors that correlated with decreased OS were elevated alpha fetoprotein (AFP) (p

// Xiaolan Feng 1,2,3 , Haocheng Li 3,4 , Elizabeth N. Kornaga 5,6 , Michelle Dean 5,6 , Susan P. Lees-Miller 7 , Karl Riabowol 7 , Anthony M. Magliocco 8 , Don Morris 3,6 , Peter H. Watson 9 , Emeka K Enwere 5,6 , Gwyn Bebb 3,6 and Alexander Paterson 3 1 Department of Oncology, BC Cancer Agency-Vancouver Island Center, Victoria, British Columbia, Canada 2 Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada 3 Department of Oncology, Tom Baker Cancer Centre and University of Calgary, Cumming School of Medicine, Calgary, Alberta, Canada 4 Department of Community Health Science, TRW Building, University of Calgary, Calgary, Alberta, Canada 5 Functional Tissue Imaging Unit, Translational Research Laboratory, Tom Baker Cancer Centre, Calgary, Alberta, Canada 6 Translational Research Laboratory, Tom Baker Cancer Centre, Calgary, Alberta, Canada 7 Department of Biochemistry and Molecular Biology, Health Science Building, University of Calgary, Alberta, Canada 8 Department of Anatomic Pathology, H. Lee Moffitt Cancer Center, Tampa, FL, USA 9 Department of Pathology, BC Cancer Agency-Vancouver Island Center, Victoria, British Columbia, Canada Correspondence to: Xiaolan Feng, email: // Keywords : ATM, Ki67, early stage hormone receptor positive breast cancer, automated quantitative immunofluorescence analysis, disease specific overall survival Received : August 26, 2016 Accepted : October 05, 2016 Published : October 12, 2016 Abstract Introduction: This study was designed to investigate the combined influence of ATM and Ki67 on clinical outcome in early stage hormone receptor positive breast cancer (ES-HPBC), particularly in patients with smaller tumors (< 4 cm) and fewer than four positive lymph nodes. Methods: 532 formalin-fixed paraffin-embedded specimens of resected primary breast tumors were used to construct a tissue microarray. Samples from 297 patients were suitable for final statistical analysis. We detected ATM and Ki67 proteins using fluorescence and brightfield immunohistochemistry respectively, and quantified their expression with digital image analysis. Data on expression levels were subsequently correlated with clinical outcome. Results: Remarkably, ATM expression was useful to stratify the low Ki67 group into subgroups with better or poorer prognosis. Specifically, in the low Ki67 subgroup defined as having smaller tumors and no positive nodes, patients with high ATM expression showed better outcome than those with low ATM, with estimated survival rates of 96% and 89% respectively at 15 years follow up ( p = 0.04). Similarly, low-Ki67 patients with smaller tumors, 1-3 positive nodes and high ATM also had significantly better outcomes than their low ATM counterparts, with estimated survival rates of 88% and 46% respectively ( p = 0.03) at 15 years follow up. Multivariable analysis indicated that the combination of high ATM and low Ki67 is prognostic of improved survival, independent of tumor size, grade, and lymph node status ( p = 0.02). Conclusions: These data suggest that the prognostic value of Ki67 can be improved by analyzing ATM expression in ES-HPBC.

The goal of the work described here was to determine whether deep inspiration breath-hold (DIBH) produces a clinically meaningful reduction in pulmonary dose compared with free breathing (FB) during locoregional radiation for right-sided breast cancer.Four-field, modified-wide tangent plans with full nodal coverage were developed for 30 consecutive patients on paired DIBH and FB CT scans. Nodes were contoured according to European Society for Radiotherapy and Oncology guidelines. Plan metrics were compared using Wilcoxon signed-rank testing.In 21 patients (70%), there was a ≥5% reduction in ipsilateral lung V20Gy with DIBH compared with FB. The mean decrease in ipsilateral lung V20Gy was 7.8% (0%-20%, P.001). The mean lung dose decreased on average by 3.4 Gy with DIBH (-0.2 to 9.1, P.001). The mean reduction in liver volume receiving 50% of the prescribed dose was 42.3 cmDIBH reduced ipsilateral lung V20Gy by ≥5% in the majority of patients. For some patients, the volume of liver receiving a potentially toxic dose decreased with DIBH. DIBH should be available as a treatment strategy to reduce ipsilateral lung V20Gy prior to compromising internal mammary chain nodal coverage for patients with right-sided breast cancer during locoregional radiation therapy if the V20Gy on FB exceeds 30%.

Background Hemorrhagic cystitis (HC) is a complication of allogeneic stem cell transplantation (SCT), associated with factors such as BK polyomavirus reactivation, age, conditioning regimen, and presence of graft-versus-host disease (GVHD). The incidence and impact of HC in patients receiving fludarabine (Flu), busulfan (Bu), and anti-thymocyte globulin (ATG) conditioning is unknown. Methods We conducted a case-control study of patients undergoing SCT at our center between January 1, 2003 and Dec 31, 2012, to determine the incidence of HC and its effect on patient outcomes including overall survival (OS), relapse, non-relapse mortality, GVHD, and healthcare resource use. Results In total, 94 cases of HC were identified and matched to controls based on age, donor type, disease type, and disease status at transplantation. The total incidence of HC was 17.7% (117 of 661 patients). Cases had a higher rate (43.6% vs 27.1%, P=.0394) of acute GVHD (Grade II-IV), and chronic GVHD requiring systemic steroids (34.9% vs 18.6%, P=.004). Male gender was found to be a risk factor (HR=1.725, P=.017). OS and progression-free survival (PFS) did not differ between cases and controls (OS HR=1.128, 95% confidence interval [CI] 0.7807-1.639; PFS HR=0.8809, 95% CI 0.6320-1.234), however the rate of non-relapse mortality was higher in cases (HR=1.632, 95% CI 1.007 to 2.830). Median length of hospitalization was longer for patients with HC than matched controls (65.5 days vs 40.5 days, P

468 Background: Recent analysis using CKCis, a prospective database, showed that mRCC patients receiving first-line sunitinib (S) had better survival than patients receiving pazopanib (P) and greater than expected absolute survival in the real world setting. We conducted further analyses to see if an individualized approach (treatment starting at standard dose/schedule with subsequent schedule/dose alterations based on toxicity) using S results in better outcomes in mRCC patients. Methods: Patients within CKCis diagnosed with clear cell mRCC treated with first-line S or P between January 2011 to December 2015 were analyzed by three treatment groups: 1) S as per individualized approach (SI), 2) S as per product monograph (SS), or 3) P as per product monograph (PS). Overall survival (OS) and time-to-treatment failure (TTF) were calculated. Cox regression analysis allowed for adjustment of International Metastatic RCC Database Consortium (IMDC) criteria with age as a continuous variable. Results: A total of 573 patients were identified, 261 patients in SI, 201 patients in SS, and 111 patients in PS. Differences in baseline characteristics were noted (Table). Median OS was improved in SI vs. SS (40.8 vs. 22.6 months (m), p

687 Background: Phase III trials (P3T) in metastatic colorectal cancer (mCRC) have collectively led to incredible advancements in patient outcomes over the past thirty years. It is unknown how many of these trials have led to clinically relevant improvements based on clinical benefit, toxicity and cost. Our objective was to characterize the evolution of mCRC P3T with the ASCO Value Framework. Methods: P3T of systemic therapy for mCRC published between 1980 and 2015 were identified. Data regarding the trial sample size, journal year of publication, statistical significance, journal impact factor, and citation by the 2015 mCRC National Comprehensive Cancer Network (NCCN) guidelines were extracted. For each trial, the Net Health Benefit (NHB) score was calculated using the June 2015 (original) and May 2016 (revised) ASCO Value Advanced Disease Frameworks. Data were analyzed to identify associations using the Chi-square, Kruskal-Wallis, and t-tests. Results: There were 108 mCRC P3T eligible for calculation of the original and revised NHB score. Median NHB score was 4.1, range -30 to 43.5, using the revised framework. Only 13% of trials received at least 10 bonus points for palliation, quality of life, or tail of the curve. The revised framework demonstrated moderate correlation with the original framework (Pearson correlation coefficient = 0.63, p

468 Background: The neutrophil-to-lymphocyte ratio (NLR), an inflammatory marker, has been associated with a poor prognosis in several solid malignancies. In muscle-invasive bladder cancer (MIBC), an elevated pre-cystectomy NLR has been shown to predict for poor survival; however, its role in prognostication for patients being treated with neoadjuvant chemotherapy (NAC) is unknown. We evaluated the baseline NLR as an independent prognostic factor in patients with MIBC treated with NAC. Methods: Patients with MIBC treated with NAC in Alberta from 2005 to 2015, and at the Princess Margaret Hospital in Ontario from 2005 to 2013 were evaluated. All 290 patients treated with NAC were included; 272 were evaluable for NLR and outcomes. Patient, disease, and treatment-related factors were evaluated. NLR was examined prior to initiation of preoperative chemotherapy. The prognostic role of NLR on overall survival (OS) and progression-free survival (PFS) was determined using Cox proportional hazard regression analysis. Results: The median age of patients was 66 years (range 36-87). The majority of patients (77%) were male. Median baseline NLR at diagnosis was 2.9. NLR > 3.0 at baseline was independently associated with PFS and OS after adjustment for age, gender and stage (Table). Patients with an NLR > 3 had a median PFS of 14.1 months compared to 25.1 months in those patients with a baseline NLR ≤ 3 (HR 0.63, p = 0.01). Similarly, OS was 19.4 months in patients with a baseline NLR > 3 compared to 33.4 months in those with a baseline NLR ≤ 3 (HR 0.65, p = 0.04). Conclusions: NLR is an independent prognostic factor for patients with MIBC undergoing NAC. [Table: see text]

e15573 Background: The benefits of routine use of prophylactic G-CSF with first-line chemotherapy in patients with MT-GCT are unclear. We evaluated patterns of G-CSF use and correlated with patient...