tbuckley/cabot-search huggingface dataset:
Feasibility of using fitness tracker to assess activity level and toxicities in colorectal cancer (CRC) patients (Pts).
Authors: Thomas Holden, Maureen Hill, William Harrell Ward, Caitlin R. Meeker, Elizabeth A. Handorf, Michael J. Hall, Elin R. Sigurdson, Igor A. Astsaturov, Crystal S. Denlinger, Sanjay S. Reddy, Joshua E. Meyer, Matthew R. Zibelman, Efrat Dotan, Jeffrey M. Farma, Namrata Vijayvergia
Journal: Journal of Clinical Oncology (2020)

91 Background: Performance status (PS) is used to predict tolerance and morbidity associated with CRC treatment. Monitoring activity level at the start of therapy using a wearable fitness tracker Fitbit (Fb) may provide a more accurate estimate of a pt’s overall PS and help predict treatment related toxicity (T). Methods: With IRB approval, we prospectively enrolled CRC pts undergoing therapy into 2 cohorts, medical undergoing chemotherapy (M) and surgical undergoing definitive surgery (S). Our objective was to assess feasibility of using Fb to track pt activity level and secondarily correlate with T. After documenting baseline ECOG PS, M and S pts wore Fb for 4 days while receiving chemotherapy or prior to surgery, respectively. Pts’ mean steps per day (SPD) were calculated excluding days Fb was worn &lt;12 hours. To stratify prediction of toxicity risk, a cutoff of 5000 SPD was selected and any post-operative complication (S pts) or ≥grade 3 toxicity (M pts) was counted as T. The study met accrual of 80 pts. Results: On final analysis, 80 pts were evaluated for the primary aim. 68 pts had at least 3 days with ≥12 hours of Fb usage, meeting the 75% feasibility endpoint. 76 pts had at least 1 day with ≥12 hours of Fb usage with data for analysis. SPD correlated with PS and the SPD and active minutes (read by device) for PS 0 and PS 1 pts was 6313 steps and 122 min and 2925 steps and 55 min, respectively (p=0.0003). Rate of T was 25% in pts with PS 0 and 33% in pts with PS 1. With SPD, rate of T was numerically lower in pts with &gt;5000 SPD compared to pts with &lt;5000 SPD (21% vs 32%, p = NS). Conclusions: We observed high rates of compliance with Fb in CRC pts. SPD cutoff of 5000 correlated with ECOG PS 0 vs 1. We observed usefulness of SPD as an identifier for toxicities and suggestion that it may be more reliable compared to PS alone in this small sample of pts. These findings provide rationale to study SPD in conjunction with PS for risk stratification of pts undergoing therapy, and can possibly be incorporated into pre-habilitation selection in high risk groups. [Table: see text]
Patient-reported outcomes (PRO) before and after colorectal cancer (CRC) by race in a national survey.
Authors: Afsaneh Barzi, Xiayu Jiao, Albert John Farias
Journal: Journal of Clinical Oncology (2020)

53 Background: There is significant disparities in the incidence, stage at diagnosis, and survival of CRC by race, however there is little evidence for disparities in patient reported health—an important quality of care metric. The SEER-CAHPS database (A linkage of Surveillance Epidemiology and End Results registry with Consumer Assessment of Healthcare Providers and Systems surveys) was used to explore the impact of CRC diagnosis on PRO. Methods: PRO was assessed by general health (GH) and mental health (MH). Responses of fair &amp; poor to survey questions were classified as “modest”; and responses of excellent, very good, &amp; good as “decent”. The responses were compared for surveys within 4 year window before or after CRC diagnosis. Logistic regression was used to identify variables associated with decline from decent to modest in the GH and MH. Results: The distribution of available surveys and outcome categories are presented in Table. CRC diagnosis was associated with a decline in MH (OR 1.42 95% CI 1.09 – 1.86 p-value &lt; 0.05) and GH (OR 1.40 95% CI 1.17 – 1.67 p-value &lt; 0.01). There was no association between race and decline in GH. However, compared to Whites, Blacks experienced lower odds of decline in MH (OR 0.396, 95% CI 0.185 - 0.848 p-value &lt; 0.05). Hispanics had a trend for more pronounced decline in MH (OR 1.772, p value= 0.098). Tumor stage at diagnosis was a predictor of poorer GH (OR 1.75 95% CI 1.40 - 2.19 p-value &lt; 0.01) and MH (OR 1.37 95% CI 1.00 - 1.87 p value = 0.048). Survey characteristics. Conclusions: Diagnosis of CRC is associated with decline in GH and MH across all racial groups, with worse MH and GH in patients with later stages of disease. Minorities experience gereater declines in MH. [Table: see text]
Prognostication model based on genomic expression in the tumor microenvironment of ER-positive, HER2-negative stage III breast cancer via machine learning.
Authors: Yara Abdou, Jessica Jerez, Andrew Baird, Jillian Dolan, Seongwon Lee, Shinyoung Park, Sunyoung S. Lee
Journal: Journal of Clinical Oncology (2020)

3 Background: Stroma in the tumor microenvironment (TME) is known to impact prognosis and responses to therapy. Few mathematical models exist to prognosticate patients, based on mRNA expressivity in the TME. Methods: Clinical outcomes data and mRNA-seq of 98 patients with stage III estrogen receptor (ER) positive (+) and HER2 negative (-) breast cancer were obtained from TCGA. Twenty six gene groups composed of 191 genes (refer to presentation) enriched in cellular and non-cellular elements of TME, mutational burden (MB), and clinical data were analyzed by Kaplan-Meier (KM) analysis and multivariate nonlinear regression assisted by machine learning to achieve confined optimization with model-data minimization among multiple distribution functions. Results: Prognostication was modeled with higher risk score (RS) representing worse prognosis in stage 3 ER+HER2- breast cancer. Fifteen genes (CD8A, CD8B, FCRL3, GZMK, CD3E, CCL5, TP53, ICAM3, CD247, IFNG, IFNGR1, ICAM4, SHH, HLA-DOB, CXCR3) and five genes (LOXL2, PHEX, ACTA2, MEGF9, TNFSF4) out of 191 genes associated with good and poor prognosis were identified. Genomic expression of the fifteen and five gene groups were labeled as G and P, respectively. RS = 9.3185 – 0.3250 × (Age at diagnosis 0.0001 ) – 8.2979 × (P/G −0.0051 ). Based on RS, patients were clustered into two groups; high and low RS groups, showing two KM curves with P = 0.05, HR = 2.878 (95% CI 1.903 – 3.471), confirming the validity of RS modeling. Analysis of immune profiles in high and low RS groups shows that expression of genes associated with desmoplastic reaction, neutrophils, and immunosuppressive cytokines are higher in high RS groups; and those related to immune system activation are higher in low RS groups (p &lt; 0.05). Conclusions: Machine learning-assisted mathematical modeling of RS and gene analysis identified TME-related genes and gene groups that are strongly associated with worse prognosis in stage 3 ER+HER2- breast cancer. RS could potentially prognosticate patients in the clinic with available genomic profiles.
An investigation of the relationship between tumor location and survival following colon cancer resection.
Authors: Katrina Knight, Paul G. Horgan, Donald C. McMillan, James Hugh Park, Campbell SD Roxburgh
Journal: Journal of Clinical Oncology (2020)

255 Background: Both tumour location and systemic inflammation (SI) have been related to survival in patients undergoing curative surgery for colon cancer. Recently, right colon cancer (RCC) has been associated with pre-existing cardiovascular disease (CVD). Comorbidity scores such as the Lee Cardiac Risk Index (LCRI) capture symptomatic disease only. Imaging-based assessment of vascular calcification can be used to identify subclinical CVD. We explored the relationship between tumour location, systemic inflammation, cardiac comorbidity and survival in patients undergoing CC resection. Methods: Patients were identified from a prospective cancer database. Clinicopathological characteristics and survival data were abstracted. Aortic calcification (AC) was quantified visually on staging CT images. SI was measured using the modified Glasgow Prognostic Score (mGPS). Results: Of 418 patients, most were female (221, 53%), over 65 (282, 67%), ASA grade II or less (66%) with RCC (230, 55%) and TNM II-III disease (320, 77%). Compared with LCC, RCC was associated with increasing age (59% vs 41%, p = 0.039), greater AC (61% vs 39%, p = 0.013) but not SI (61% vs 39%, p = 0.139). There were no significant differences between LCC with respect to ASA, smoking status or LCRI. Univariate analysis revealed TNM stage (HR 3.55 (95%CI 1.51 - 8.39) p = 0.004) and degree of AC (HR 1.77 (1.04 - 3.00) p = 0.034) were associated with cancer-specific survival (CSS) in RCC while in LCC, only TNM stage was related to CSS (HR 2.30 (0.99 - 5.30) p = 0.05). Multivariate analysis in patients with RCC confirmed AC to be a stage-independent predictor of CSS (HR 1.94 (1.15 – 3.67) p = 0.013). Conclusions: AC is associated with RCC and confers an inferior prognosis, independent of stage. Investigation of underlying mechanisms is required, but impaired perfusion may limit mucosal function, potentiating the effect of carcinogens in the right colon.
SHR-1210 combined with GEMOX as first-line treatment in patients with advanced biliary tract cancer.
Authors: Xiaofeng Chen, Xiaofeng Wu, Hao Wu, Qianwen Shao, Feipeng Zhu, Xiaofeng Qian, Fengjiao Zhao, Weidong Mao, Jing Sun, Jian Wang, Gaohua Han, Changxian Li, Poshita kumari Seesaha, Quanren Wang, Huajun Li, Yang Shao, Yanhong Gu, Xiangcheng Li, Yongqian Shu
Journal: Journal of Clinical Oncology (2020)

535 Background: This study aimed to evaluate the efficacy and safety of SHR-1210 (a humanized anti-programmed cell death receptor 1 antibody) plus gemcitabine and oxaliplatin (GEMOX) as first line treatment in patients (pts) with biliary tract cancer (BTC). Methods: This was a single-arm, single-center, exploratory trial, which included advanced BTC pts. Pts received SHR-1210 (3mg/kg, total dose ≤200mg, ivd, D1/2W) combined with gemcitabine (800 mg/m2, ivd, D1/2W) and oxaliplatin (85mg/m2, ivd, D2/2W). Combined chemotherapy lasted for no more than 12 cycles. Once chemotherapy intolerance occurred or at end of 12-cycle combined chemotherapy, pts with stable disease or objective response would continue to take SHR-1210 as single agent until disease progression or intolerable toxicity. The primary endpoint was the 6-month progression free survival (PFS) rate. Results: From February 2018 to April 2019, 37 eligible pts were enrolled. The median age was 64 (range 41-74) years, male/female was 70.3/29.7%, and bile duct cancer/gallbladder cancer was 59.5/40.5%. All 37 pts were included in the safety analysis. The overall AE incidence rate was 97.3%. The incidence of grade ≥3 AEs was 73.0%, which mainly included increased GGT (gammaglutamyltransferase, 18.9%), hypokalemia (18.9%), and fatigue (16.2%). Particularly, the incidence of fever is 73.0%, in which 2 pts experienced grade 3/4 fever. Among 36 evaluable pts, 19 pts got partial response (PR, 52.8%), 14 pts stable disease (SD, 38.9%), and 3 pts progressive disease (PD, 8.3%) at best. The primary endpoint 6-month PFS rate was 50.0% (95% CI 32.4-65.4), which indicated that the primary endpoint of the study was reached, and mPFS was 6.2 months (95% CI 4.2-7.1). The 12-month overall survival (OS) rate was 50.5% (95% CI 30.6-67.4), and mOS was 12.1 months (95% CI 8.0-NA). Conclusions: This study has reached the pre-defined primary endpoint with a high response rate. Predictive biomarker analysis was reported in another abstract. Further study is needed to validate the efficacy of this combination. Clinical trial information: NCT03486678.
Abstract 17248: Statin Therapy Increases Coronary Artery Calcification Scores
Authors: Harold Rivner, Rimsky Denis, Fei Tang, George R Marzouka
Journal: Circulation (2018)

Introduction: Coronary artery calcification (CAC) assessment is a noninvasive test to determine atherosclerotic burden. There has been a discordance with the well-known lipid lowering and cardiovascular protection of statins and the progression of CAC in small trials with narrow inclusion criteria. We performed a subgroup analysis of the Multi-Ethnic Study of Atherosclerosis (MESA) dataset to assess the impact of statins on patients with a baseline CAC score of 0. Hypothesis: Statin usage will cause patients to have a higher CAC scores despite lowering LDL and reducing cardiac mortality. Methods: A subgroup analysis (3235 patients) was performed on the MESA dataset to identify patients with a CAC score of 0 at baseline. Statin usage and cholesterol values were reviewed at 4 examination points. Multivariate regression was performed. Results: The number of patients using statins (Table 1) and lipid levels (Table 2) increased throughout the study as expected for an aging population. A consistently larger increase in CAC score was noted in patients receiving statins; this difference was demonstrated in all stratified groups by Framingham score (Table 3). Table 4 shows the results of multivariate linear regression. Excluding gender, statins had the largest impact on CAC; more than any established cardiovascular risk factor. Conclusion: This large subgroup analysis of the MESA dataset demonstrates that statins are associated with increasing CAC score. While this is in contrast to the well-established cardiovascular protection of statin therapy, it adds to the growing literature that statin use is associated with progression of CAC, even in low risk patients with baseline CAC of 0. One hypothesis for this finding is that statins promote coronary atheroma calcification which ultimately results in plaque stabilization and less likelihood for progression to unstable plaques. It is therefore necessary for clinicians to take into account statins when interpreting CAC scores.
Genetic variants involved in bromodomain-containing protein 4 (BRD4) regulating pathway to predict outcomes in patients with metastatic colorectal cancer: Results from FIRE3 and MAVERICC trials.
Authors: Jingyuan Wang, Yi Xiao, Fotios Loupakis, Sebastian Stintzing, Hiroyuki Arai, Francesca Battaglin, Shivani Soni, Wu Zhang, Christoph Mancao, Chiara Cremolini, Volker Heinemann, Alfredo Falcone, Joshua Millstein, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2020)

232 Background: BRD4 plays an important role in transcription, DNA repair and drug resistance. High expression and polymorphisms of BRD4 regulating pathways were reported to be related to worse prognosis in colorectal cancer. Therefore, we hypothesized that genetic variants in BRD4 regulating pathway may predict first-line treatment outcome in mCRC pts. Methods: The impact on outcome of 22 SNPs in 7 genes involved in BRD4 regulating pathway (BRD4, SIPA1, MYC, 53BP1, H2AX, BATF, CD47) was analyzed through the OncoArray, a customized array manufactured by Illumina, on genomic DNA from blood samples of pts enrolled in 2 randomized trials. MAVERICC FOLFIRI/bevacizumab (bev) arm served as discovery cohort (N = 107), FIRE3 FOLFIRI/bev arm as validation (N = 107) and FOLFIRI/cetuximab (cet) arm as control (N = 129). Results: In the discovery cohort, right(R)-sided pts with BRD4 rs4808272 any G allele (N = 46) showed significantly shorter PFS (9.5 vs 18 m) compared to carriers of A/A (N = 21) in both uni- and multi-variable analysis ( p &lt; .01); R-sided pts carrying any T allele of BATF rs7161377 (N = 50) showed longer PFS (12.3 vs 6.8 m) compared to carriers of C/C (N = 14) in univariate analysis ( p &lt; .05) and had a strong trend in multivariable analysis ( p = .06). These findings were all validated in R-sided pts in FIRE3 bev arm (BRD4 rs4808272, PFS 9.8 vs 18.7 m; BATF rs7161377, PFS 15.1 vs 4.2 m) in uni- (both p &lt; .01) and multi-variable ( p = .08 and p &lt; .05 respectively) analysis. No significant association was observed in the control arm. Interestingly, pts carrying CD47 rs3206652 any C allele (N = 13) only showed significant longer PFS (9.0 vs 3.0 m, univariable p &lt; .01 and multivariable p = .07) in the R-sided pts of FIRE3 cet cohort, but no association was observed in the bev-based treatment. Conclusions: Our study demonstrates for the first time that BRD4 and BATF polymorphisms may predict outcomes of bev-based treatment in R-sided mCRC pts; Meanwhile CD47 polymorphism could predict outcomes of cet-based treatment in R-sided mCRC pts. This finding supports a possible role of BRD4 regulating pathway in contributing to resistance to anti-VEGF/EGFR treatment.
Safety and tolerability of oxaliplatin based pressurized intraperitoneal aerosol chemotherapy (PIPAC) for patients with peritoneal carcinomatosis: A phase I dose-finding study in Asian patients.
Authors: Raghav Sundar, Guo Wei Kim, Hon Lyn Tan, Lingzhi Wang, Koy Min Chue, Chia Hui Tai, Siok Chin Teo, Clarisse Jang, Corissa Chee, Bettina Lieske, Cheng Ean Chee, Asim Shabbir, Jimmy Bok Yan So, Wei-Peng Yong
Journal: Journal of Clinical Oncology (2020)

360 Background: PIPAC is a novel, laparoscopic intraperitoneal chemotherapy delivery technique which aims to improve on hyperthermic intraperitoneal chemotherapy (HIPEC), ameliorating drug distribution and tissue penetration. Thus far, PIPAC has been conducted with oxaliplatin chemotherapy in Europe, at an arbitrary dose of 92mg/m 2 ; 150mg/m 2 was found to be intolerable. We conducted a dose-escalation phase 1 study to establish the safety, tolerability and recommended phase 2 dose (RP2D) for PIPAC in Asian patients. Methods: This phase 1 study of oxaliplatin administered via PIPAC was designed as a traditional 3+3 dose escalation study for patients with predominant peritoneal metastasis from a gastrointestinal primary tumor, after failure of standard therapies. Dose levels were planned at 45, 60, 90 and 120mg/m 2 . Repeat doses of PIPAC were permitted, 6 weeks apart. Dose limiting toxicities (DLT) were defined as any clinically relevant grade 3 adverse events occurring within 28 days after PIPAC. Results: This study included 16 patients (25 PIPAC procedures; 8 gastric, 4 colorectal and 1 gallbladder, pancreas and appendix cancer each). Median age was 62 years, with a median peritoneal carcinomatosis index (PCI) score of 17 (range 1 - 39). Two patients developed pancreatitis (grade 2 and 3) on day 6 and day 9 after PIPAC administration at the dose cohort of 45mg/m 2 , necessitating cohort expansion to 6 patients. One patient was noted to have asymptomatic grade 3 hyperamylasemia (90mg/m 2 cohort). There were no other DLTs and all 3 patients in the highest dose cohort (120mg/m 2 ) tolerated PIPAC well. Nine patients who underwent a 2 nd PIPAC procedure had a decrease in PCI score from 18.4 to 15.5; one patient at 120mg/m 2 had an improvement in PCI from 30 to 12. Conclusions: The RP2D of PIPAC with oxaliplatin is 120mg/m 2 . Single agent PIPAC is well tolerated, and future studies with PIPAC must consider a bi-directional approach with the incorporation of systemic therapy, with either chemotherapy or immunotherapy to improve efficacy. Clinical trial information: NCT03172416.
Phase II study of nivolumab and relatlimab in advanced mismatch repair deficient (dMMR) cancers resistant to prior PD-(L)1 inhibition.
Authors: Katherine M. Bever, Hao Wang, Jennifer N. Durham, Susan Petrie, Jessica Hoare, Cara Wilt, William Howard Sharfman, Nilofer Saba Azad, Daniel A. Laheru, Robert A Anders, Drew M. Pardoll, Suzanne Louise Topalian, Elizabeth M. Jaffee, Dung T. Le
Journal: Journal of Clinical Oncology (2020)

TPS839 Background: Cancers deficient in DNA mismatch repair (dMMR) are highly immunogenic tumors exhibiting high rates of response to immune checkpoint inhibitors targeting the programmed cell death-1 (PD-1)/PD-1 ligand (PD-L1) interaction. These tumors are characterized by high levels of microsatellite instability (MSI-H) and an exceptionally high tumor mutation burden, thought to underlie responsiveness to immunotherapy, with higher predicted immunogenicity of mutation-associated neoantigens. However, primary and acquired resistance are observed and diversity in responses is not fully explained by variations in mutation burden. Other immune checkpoints may be acting in parallel with PD-1/PD-L1. In particular, lymphocyte activation gene 3 (LAG3) mediates exhaustion of activated T cells and may have a role in resistance to PD-(L)1 inhibitors (PD-(L)1i); therefore, we hypothesized that the addition of LAG3 inhibitor (relatlimab) to the PD-1i nivolumab may overcome resistance in these tumors. Methods: Patients with advanced dMMR/MSI-H cancer who have progressive disease (by RECIST 1.1) during or within 6 months of PD-(L)1i containing therapy, and after at least 12 weeks of therapy, and meet other eligibility will be enrolled. All patients will receive nivolumab 480mg + relatlimab 160mg every 4 weeks until intolerance or progression, or up to a maximum of 2 years. The primary endpoint is objective response rate. Key secondary endpoints include safety, progression free and overall survival, and other response endpoints as measured by RECIST 1.1 and iRECIST criteria. Exploratory objectives will include analysis of the tumor microenvironment on biopsies obtained at baseline and on-treatment, analysis of T cell populations in the tumor and in the periphery and functional characterization of mutation-associated neoantigen-specific T cells. Studies of the microbiome will be conducted on stool and oral wash samples. Enrollment of 21 patients is planned. Clinical trial information: NCT03607890.
Is D2 surgery necessary for clinical T1 gastric cancer with nodal swelling?
Authors: Takeyuki Wada, Takaki Yoshikawa, Ayako Kamiya, Keichi Date, Tsutomu Hayashi, Sho Otsuki, Yukinori Yamagata, Hitoshi Katai, Toshirou Nishida
Journal: Journal of Clinical Oncology (2020)

288 Background: D2 surgery is required for clinical T1 gastric cancer with nodal swelling, however, D2 has a higher risk for morbidity than D1/D1+. Moreover, previous study demonstrated that the false positive rate for nodal diagnosis in clinical T1 was very high. To select optimal surgery with high probability, we explored risk factors for false positivity in clinical T1 disease. Methods: Patients who underwent radical gastrectomy for clinical T1 gastric cancer between April 2015 and June 2019 were enrolled. Accuracy, sensitivity, specificity, positive predictive value, and negative predictive values for nodal diagnosis were retrospectively investigated. The risk factors for false positivity were also analyzed by the following factors; age, sex, histological type, tumor size, tumor depth, location, tumor type, presence of ulcer, and timing of CT that is (1) the patients who underwent primary endoscopic mucosal dissection (ESD) but resulted in non-curative resection, then received CT to proceed to surgery (delayed CT group) or (2) the other patients who had received CT before primary surgery or before non-curative ESD (primary CT group). Results: A total of 679 patients were examined in the present study. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were 83.5% (567/679), 14.3% (13/91), 94.2% (554/588), 27.7% (13/47), and 87.7% (554/632), respectively. The false positive rate was 72.3% (34/47). In univariate analysis, differentiated tumor ( p= 0.012) and delayed CT (p &lt; 0.001) were associated with the false positivity. Multivariate analysis revealed that delayed CT (OR, 4.534; p &lt; 0.001) was a sole significant risk factor for false positivity. False positive rate was 100% (13/13) in the delayed CT group and 61.8% (21/34) in the primary CT group ( p= 0.009). Conclusions: False positive rate was high in clinical T1 disease, especially when the patients received delayed CT after non-curative ESD. D2 surgery would be unnecessary even though nodal swelling was detected in CT after non-curative ESD.