tbuckley/cabot-search huggingface dataset:
Assessing person-centered care readiness at a cancer system level through a provincial environmental scan in Ontario.
Authors: Lesley Moody, Jorge Navarro, Esther Green, Laura Macdougall, Simron Singh
Journal: Journal of Clinical Oncology (2014)

70 Background: Cancer Care Ontario (CCO) is an Ontario government agency which drives quality and improvement for the Ontario cancer system. Person-Centred Care (PCC) has been an identified goal both from the recent Institute of Medicine (IOM) report and as a corporate strategic priority at CCO. CCO is assessing the degree of PCC practiced in Ontario’s Cancer system to design interventions to improve this aspect of care delivery and design. Currently no established or validated indicators for PCC have been tested and evaluation methodology of PCC is unclear. A baseline of the system’s focus on PCC is required to establish a provincial plan to drive quality improvement. Methods: A series of 14 semi-structured interviews were conducted at Ontario’s regional cancer centers (RCCs) to determine the degree of development of a PCC culture in Ontario’s cancer system. Interviews were conducted with all 14 Regional Cancer Programs (RCPs) including: - 10 Patient and Family Advisors (PFAs); and - 56 RCPs and hospital leaders (Directors, Managers, Physicians, Nursing, Psychosocial Oncology providers). Sixty-six participants (direct interviews/questionnaires) were interviewed; questionnaires were received from 28 organizations (hospitals/RCCs). Results: Although 86% of interviewed organizations reported having a PCC corporate strategy, 41% of hospitals and 73% of RCCs do not have dedicated staff to support the strategy. 53% of organizations work with a Patient and Family Advisory Council (PFAC) and only 43% engage PFAs in decision-making tables with 94% of RCPs expressing a need for guidance on PFA engagement. Key facilitators to promote PCC are: strong and committed leadership and continuous staff engagement/education. Primary barriers include: equity in PFA recruitment, cultural resistance to PCC, and lack of evaluation frameworks. Conclusions: Advancing PCC requires strong provincial direction, training to foster PFA engagement, and measurement and accountability frameworks for cultural change. Clear definitions on accountabilities for PCC roles and expectations for PFAs and staff are also key to supporting PCC regionally.
Clinical outcome of advanced colorectal cancer patients pre- and post-bevacizumab therapy using the SEER database.
Authors: M. Choi, G. Dyson, P. A. Philip, A. F. Shields
Journal: Journal of Clinical Oncology (2011)

6083 Background: Colorectal cancer (CRC) is the second leading cause of death from cancer in United States. Overall survival (OS) for stage IV colon cancer has doubled to 20-24 months with the use of newer active chemotherapy and biologic agents in clinical trials. However there is no current data in population based setting how the biologics have impacted the survival of patients with advanced CRC. Methods: Bevacizumab was approved for advanced CRC patients in February of 2004. Hence we used clinical outcome data in 2003 as pre-biologic era and 2005 as post-biologic era using the SEER database to compare the impact of bevacizumab in patients with stage IV CRC. The primary endpoint was OS. To ensure that each patient had the potential to be followed for 2 years and given that the SEER database is complete until the end of 2007, 2005 was the latest diagnosis year. The Kaplan-Meier method was used to estimate the median survival and log-rank test is used to test the difference in survival curves. Results: We studied 4,895 (12% African American [AA]), and 5,099 (16 % AA) patients diagnosed in 2003 and 2005, respectively. A table detailing the median survival (in months) and confidence intervals is given below. For the comparison of individuals diagnosed in 2003 and 2005, the hazard ratio of dying being an AA patient versus an EA patient was 1.23 (1.16, 1.32) [p-value <0.001] while the hazard ratio of dying being diagnosed in 2003 versus 2005 was 1.12 (1.06, 1.18) [p-value <0.001]. SEER does not have data on chemotherapy treatment for individual patients. However our local Detroit SEER data have shown that only 50% of all advanced CRC patients are treated with chemotherapy. Conclusions: Clinical outcome of advanced CRC patients have modestly improved post introduction of bevacizumab based on population study using the SEER database. However no survival benefit was noted in African American population. Median overall survival for advanced colorectal cancer patients diagnosed in 2003 and 2005 in the SEER database. 2003 2005 Group Median CI Median CI p-value Pooled 9 (8,9) 11 (10,11) <0.001 African Americans 9 (8,11) 9 (7,10) 0.714 European Americans 9 (8,9) 11 (10,11) <0.001
Understanding the mechanism of warfarin-mediated PC prevention.
Authors: Jeremy Jones, Ben Yi Tew, Maya otto-Duessel, Tommy Tong, Markus Kalkum, Teresa Hong, Xueli Liu, Sumanta K. Pal
Journal: Journal of Clinical Oncology (2016)

e635 Background: Multi-institution retrospective trials have shown that prolonged use of warfarin reduces the risk of prostate cancer (PC), an effect that is not observed for other cancers. The anti-coagulant warfarin prevents the gamma-carboxylation (gla) of target proteins by interfering with the vitamin K cycle through its inhibition of the vitamin K epoxide reductase (VKOR). Most known gla proteins are found in the clotting cascade, but here we investigate the role of gla of the androgen receptor (AR) and other warfarin-mediated effects in the prevention of PC by warfarin. Methods: We treated mice with warfarin and performed RNA-seq on prostate tissues. We used immunoprecipitation (IP) followed by mass spec sequencing to identify gla sites on AR. We used cell culture models to investigate the role of AR-gla and other pathways identified by RNA-seq data in the mechanism of action of warfarin. Finally, we sequenced a SNP in VKOR and performed IHC to detect VKOR expression in prostatectomy tissues in an institutional series. Results: RNA-seq data show alteration of several pathways in warfarin-treated mouse prostates, including AR signaling, hormone and lipid synthesis, and genes known to affect PC (e.g. SPINK1). Mass spec shows that AR is gla’d at amino acid 2E, which is known to be mutated in partial androgen insensitivity syndrome patients. Warfarin inhibits AR conformation change and transcriptional activity in benign (non-cancerous) prostate cells. VKOR knock-down recapitulates effects of warfarin treatment, suggesting an on target effect of the drug. Mutation of the AR-gla site has modest effects in benign prostate cells. In a small series of patients, we found that one allele of a VKOR SNP is found at a significantly higher rate in PC patients than expected. We also found that VKOR is highly expressed in normal human prostate epithelia but is lost in cancerous tissue, a pattern of expression that is unique to PC. Conclusions: Warfarin, likely through its ability to control AR-gla, inhibits AR transcriptional activity. The relative contribution of modest AR inhibition and the effect on other pathways must be investigated to determine how warfarin reduces the risk of PC and to identify optimal drug targets for development of chemopreventative therapeutics.
Phase I and pharmacokinetics/pharmacodynamics (PK/PD) study of MEK inhibitor, RO4987655, in Japanese patients with advanced solid tumors.
Authors: Yasuhide Yamada, Hiroshi Nokihara, Noboru Yamamoto, Yutaka Fujiwara, Yosuke Tamura, Hiroshi Wakui, Kazunori Honda, Shinji Nakamichi, Hajime Asahina, Yuko Tanabe, Satoru Kitazono, Hidenori Mizugaki, Naoya Yamazaki, Shigenobu Suzuki, Junichi Sasaki, Mieko Matsuoka, Tomohide Tamura
Journal: Journal of Clinical Oncology (2014)

116 Background: RO4987655 is an oral and selective inhibitor of MEK, a key enzyme of the MAPK signaling pathway. This was a phase I, non-randomized, open-label, dose-escalation study in Japanese patients (pts) with advanced solid tumors. Primary objectives were determination of maximum tolerated dose (MTD) based on dose-limiting toxicities (DLTs), safety evaluation and PK analysis. Secondary objectives were PD analysis and exploratory analysis of RO4987655’s anti-tumor activity according to the RECIST 1.0 criteria. Methods: Patients received an oral single dose of RO4987655 (1, 2, 4, 5, and 6.5 mg) (Cycle 0) followed by continuous once daily dosing (QD, 1, 2, and 4 mg/day) then twice daily dosing (4, 5, and 6.5 mg BID, total daily dose: 8, 10 and 13 mg/day) in 28-day cycles. A 3 + 3 dose-escalation design was used. Blood samples for PK analysis were collected in Cycle 0 (Day 1, 2 and 3) and in Cycle 1 (Day 1, 8, 15 and 22). PD was evaluated by pERK inhibition in peripheral blood mononuclear cells (PBMCs) using FACS analysis. Results: In dose-escalation, 25 pts were enrolled. After the MTD was defined, 6 pts were added to the MTD dose for further confirmation of safety profile. Tumor types included esophageal (n=8), colorectal (n=8) and non-small cell lung cancer (NSCLC) (n=4). MTD was defined as 8 mg/day due to 4 DLTs of Grade 3 creatine phosphokinase (CPK) elevation. Most commonly related adverse events included dermatitis acneiform, CPK elevation, and eye disorders, particularly macular edema and visual impairment. Plasma concentration of RO4987655 appeared to increase in a dose-proportional manner with a plasma half-life of 4.32 to 21.1 hours. After multiple dose administration, steady-state conditions were reached by Cycle 1 Day 8. The inhibitory effects of RO4987655 on pERK in PBMCs increased in a dose-dependent manner. An esophageal cancer pt confirmed partial response with over 50% shrinkage and 6 pts including NSCLC noted as stable disease ≥16 weeks by independent assessment. Conclusions: RO4987655 is tolerable with a favorable PK/PD correlation in Japanese pts with advanced solid tumors. Exploratory analysis of biomarker is ongoing. Clinical trial information: JapicCTI-111490.
Improving breast-conserving surgery: A focus on margins.
Authors: Freya Ruth Schnabel, Shira Schwartz, Deirdre Kiely, Jennifer Chun
Journal: Journal of Clinical Oncology (2013)

127 Background: Inadequate lumpectomy margins are associated with an increased risk of ipsilateral recurrence in patients undergoing breast conserving surgery for cancer. Multiple procedures are often required to achieve acceptable margins, increasing the burden to the patient and the health care system, and potentially delaying other adjuvant treatments. A novel device for intraoperative assessment of lumpectomy margins (MarginProbe) has been associated with a 25% reduction in the rate of positive margins at the conclusion of primary lumpectomy surgery. Our aim was to establish a baseline re-excision rate among surgeons and to initiate a follow up study to assess the impact of incorporating this new technology for intraoperative margin assessment. Methods: The NYU Langone Medical Center Breast Cancer Database was queried for patients who underwent breast conserving surgery including ≥ 1 re-excision procedure from 1/2010-1/2013. Variables of interest included re-excision rates, stage of disease, and additional margins taken at primary lumpectomy surgery. Statistical analyses included descriptive analyses and Pearson’s Chi-Square. Results: During the study period 957 patients had breast conserving surgery and 229 required ≥ 1 re-excision procedures (24%). Re-excision rates varied widely among surgeons (10-36%). Stage 0 disease (ductal carcinoma in situ) was associated with an increased frequency of re-excisions (p&lt;0.0001). These parameters will be re-evaluated in patients undergoing breast conserving surgery with adjunctive intraoperative use of the MarginProbe device. Re-excision rates and the accuracy of intraoperative assessment of lumpectomy margins will be compared with the historical cohort. Conclusions: The necessity for multiple surgical procedures to complete breast conserving surgery results in an added burden to the patient and the health care system. Improved intraoperative assessment of lumpectomy margins represents an opportunity to improve the quality of breast cancer surgery. A critical analysis of the impact of a new device on re-excision rates will be important to understand its potential benefit to the conduct of breast conserving surgery.
Early breast cancer response to neoadjuvant chemotherapy: Defining the optimal timing and response rate using clinical tumor measurement.
Authors: Dominique Boudreau, Fabiano Santos, Andre Robidoux, Jean-Francois Boileau
Journal: Journal of Clinical Oncology (2015)

121 Background: Breast cancer pathological complete response (pCR) following neoadjuvant therapy (NAT) is associated with better survival in some tumor subtypes. There is interest in identifying methods to increase early prediction of pCR during NAT. A simple and inexpensive technique such as early clinical breast examination has been shown to correlate with pCR during NAT in some studies. However, the optimal timing of the measurement and the best tumor response (TR) rate to predict pCR still need to be defined. Methods: We conducted a retrospective cohort study of patients prospectively enrolled in the following NSABP trials in one academic center (Montreal, Canada): B-40, B-41, FB-AX-003, FB-4, FB-5 and FB-6. Patients with T4 disease or disease progression were excluded. Clinical tumor measurements were recorded before each cycle of NAT. TR was measured as the percentage decrease in the largest tumor diameter. ROC curves for TR measurements at each time point were generated, comparing areas under the curve using the DeLong method. P-value ² 0.05 was considered significant. Results: We analyzed data of 155 patients recruited from Aug. 2005 to May 2011. Results are presented in Table 1. The best time point to predict pCR was after cycle 2. At this time point, a TR of 46% was the best cutoff value to predict for pCR. Among hormone receptor positive (HR+) and HER-2 positive (HER-2+) breast cancer patients, a TR of 47% after cycle 2 was significantly predictive for pCR. These findings were similar using a 50% TR cutoff after 2 cycles. Conclusions: Observing a 50% reduction in largest tumour diameter on clinical breast examination after cycle 2 of NAT is predictive for pCR in HR+ and HER-2+ breast cancer patients. We recommend using this definition of clinical response in future trials evaluating novel methods to improve early prediction of pCR during NAT. [Table: see text]
Racial differences in the pattern of hematologic toxicity in the treatment of colorectal cancer.
Authors: Olalekan O. Oluwole, William Wu, Steven N. Wolff, Kenneth R. Hande
Journal: Journal of Clinical Oncology (2012)

679 Background: 5-fluorouracil (5-FU), a synthetic fluoropyrimidine, is a critical component of chemotherapy in many cancers. Its metabolites inhibit Thymidylate Synthetase (TS) causing cessation of DNA synthesis and are misincorporated into DNA and RNA causing ineffective DNA repair and faulty mRNA splicing. The rate limiting step in the catabolism of 5-FU is by the Dihydropyrimidine Dehydrogenase enzyme (DPD) which catabolizes over 80% of 5-FU. Patients with near total DPD enzymatic deficiency develop life threatening toxicity after a single administration and those with less severe deficiency will have delayed elimination of 5-FU and slowly accumulate active metabolites leading to toxicities. Methods: We conducted a pilot retrospective cohort study of African American (AA) and Caucasian patients treated for colorectal cancer over a 9 year period, 2000 – 2008, in this IRB approved study. The primary outcome of interest was the rate of development of grade 3 or 4 neutropenia (Absolute Neutrophil Count &lt;1000/uL = grade 3 and &lt;500/uL = grade 4). Descriptive and univariate analysis were done. To test for differences between AA and Caucasians, we computed independent t-test for continuous and Fisher’s exact test for categorical variables. Relative Risk (RR) and p-values were computed. All statistics were done with SPSS v19 software. Results: There were 66 evaluable patients (40 men, 26 women), 40 AA, 24 Caucasians and 2 of other races. Thirty-eight patients (15 Caucasians and 23 AA) received 5-FU containing chemotherapy. The two groups were comparable in baseline characteristics. AA were more likely to develop grade 3-4 hematological toxicity. Nine of 23 AA (39.1%) and one of 15 Caucasians (6.7%) developed grade 3-4 hematological toxicity. RR 8.56, 95% confidence interval 0.95 – 421.06 (p-value of 0.0561) Conclusions: These results suggest that AA were more likely than Caucasians to have severe hematologic toxicity with the use of 5-FU containing chemotherapy. This difference did not meet statistical significance due to small sample size and few numbers of events in the Caucasian arm. A larger prospective study is needed to further evaluate the observed difference.
Circulating microRNAs associated with docetaxel-resistant castration resistant prostate cancer.
Authors: Lisa Horvath, Hui-Ming Lin, Lesley Castillo, Kate Lynette Mahon, Karen Chiam, Brian Yong Lee, Quoc Nguyen, Wenjia Qu, Michael J. Boyer, Martin R. Stockler, Nick Pavlakis, Gavin M. Marx, Girish Mallesara Hiriyanna Gowda, Howard Gurney, Susan J. Clark, Alex Swarbrick, Roger J. Daly
Journal: Journal of Clinical Oncology (2014)

44 Background: Despite a range of new treatments, docetaxel (DTX) remains the first-line chemotherapy for castration-resistant prostate cancer (CRPC). However, only 50% of patients respond to docetaxel at the cost of potentially significant toxicity. Therefore, there is a need for new biomarkers to identify early response to therapy. This study aims to determine if circulating microRNAs are associated with DTX chemotherapy outcome in CRPC. Methods: Global microRNA profiling was performed on DTX-resistant and sensitive cell lines to identify candidate circulating microRNA biomarkers. Custom Taqman Array MicroRNA cards measured the levels of 46 candidate microRNAs in plasma/serum from 97 CRPC patients, collected pre- and three weeks post-cycle one of DTX. Responses were defined by the PCWG1 serum prostate-specific antigen (PSA) response criteria; partial response (PR), stable disease (SD), progressive disease (PD). Multiple T-test, Mann-Whitney U, Kaplan-Meier, Receiver Operating Characteristic (ROC), and Cox regression analyses were used to assess the associations between microRNA levels and clinical outcomes. Results: Eighteen microRNAs were associated with PSA response or overall survival (p&lt;0.05). DTX non-responders (PD+SD) and patients with shorter survival had high pre-DTX levels of miR-200 family members (miR-200a, miR-200b, miR-200c, miR-429; p&lt;0.05), or decreased/unchanged post-DTX levels of miR-17 family members (miR-19b, miR-20a, miR-20b; p&lt;0.05). The combined levels of miR-20a, miR-146a, miR-200b, miR-200c, miR-222, and miR-301b predicted PSA response (ROC AUC 0.74, 95% CI 0.64-0.84). Pre-DTX miR-200a levels (HR 3.0, 95%CI 1.6-5.8; p=0.001) and post-DTX change in miR-20a (HR 3.4, 95%CI 1.8-6.3; p=0.0002) were independent predictors of overall survival when modeled with hemoglobin levels (HR 2.6, 95%CI 1.4-5.1; p=0.02), PSA response (HR 2.1, 95%CI 1.1-3.9; p=0.03), and visceral metastases (HR 2.0, 95%CI 1.1-3.5; p=0.03). Conclusions: Circulating microRNAs are potential early predictors of DTX chemotherapy outcome and may be useful in stratifying patients in future clinical trials. These microRNAs may also be involved in DTX resistance and represent potential therapeutic targets.
Screening for EGFR, KRAS, and PIK3CA mutations in well-characterized, immunohistochemically confirmed squamous cell carcinoma of lung.
Authors: N. Rekhtman, P. K. Paik, M. E. Arcila, L. J. Tafe, M. F. Zakowski, G. J. Riely, V. A. Miller, M. G. Kris, M. Ladanyi
Journal: Journal of Clinical Oncology (2011)

e21143 Background: The occurrence of EGFR and KRAS mutations in squamous cell carcinoma (SQCC) of lung is controversial due in part to very limited pathology data in many published studies, and the prevalence of other mutations is not established. We hypothesized that full pathologic and immunohistochemical (IHC) characterization of genotyped SQCC cases could help resolve these uncertainties. Methods: Fifty resected SQCC with IHC confirmation (TTF1-/p63+) were screened for hot-spot point mutations in EGFR, KRAS, PIK3CA, AKT1, BRAF, ERBB2, and MAP2K1 by Sequenom and EGFR exon 19 deletions by standard methods. In addition, 15 SQCC found to harbor EGFR (n=9) or KRAS (n=6) mutations on routine clinical testing underwent a detailed clinicopathologic and IHC reassessment. Results: No EGFR or KRAS mutations were found in 50 pure resected SQCC (0% observed incidence; 95% CI 0-7%), whereas PIK3CA and AKT1 mutations were identified in 6% (95% CI 1-17%) and 2% (95% CI 0-11%) of cases, respectively. Reassessment of 15 SQCC with EGFR/KRAS mutations revealed that none could be confirmed to represent pure SQCC. Seven of 15 (47%) cases were small biopsy/cytology specimens showing SQCC but specimens from other sites (metastatic or primary) revealed adenocarcinoma (ADC) or adenosquamous carcinoma (AD-SQC) harboring mutations identical to those in SQCC (when other-site mutation data was available). One case (7%) was a small biopsy showing SQCC but subsequent same-site resection revealed AD-SQC. Six cases (40%) were re-classified as solid ADC after IHC. Conclusions: EGFR/KRAS mutations do not occur in pure SQCC, and when detected in specimens reported as “SQCC” they may represent a component of AD-SQC or solid ADC. These findings highlight the importance of IHC for the accurate diagnosis of SQCC, which is essential for interpreting molecular data. For pure SQCC in resection specimens, routine EGFR mutation testing is not indicated. Because small specimens may not distinguish SQCC from AD-SQC, testing should be guided by clinical parameters as further addressed by Paik et al (abstract submitted, ASCO 2011). Low-frequency PIK3CA/AKT1 mutations in SQCC are of interest as potential therapeutic targets.