tbuckley/cabot-search huggingface dataset:
Phase II study of savolitinib in patients (pts) with pulmonary sarcomatoid carcinoma (PSC) and other types of non-small cell lung cancer (NSCLC) harboring MET exon 14 skipping mutations (METex14+).
Authors: Shun Lu, Jian Fang, Xingya Li, Lejie Cao, Jianying Zhou, Qisen Guo, Zongan Liang, Ying Cheng, Liyan Jiang, Nong Yang, Zhigang Han, Jianhua Shi, Yuan Chen, Hua Xu, Helong Zhang, Di Zhang, Jing Li, Linfang Wang, Yongxin Ren, Weiguo Su
Journal: Journal of Clinical Oncology (2020)

9519 Background: There are unmet medical needs for pts with METex14+ NSCLC. PSC is a rare type of NSCLC with high incidence of MET exon 14 mutations and poor prognosis. Savolitinib (AZD6094, HMPL-504, volitinib) is a highly selective oral MET tyrosine kinase inhibitor, and its anti-tumor activity has been shown in combination with osimertinib in pts with EGFR-mutant, MET-amplified NSCLC (Yu H, et al. 2019 AACR, Abstract CT032). Methods: This was a multicenter, multi-cohort, single-arm phase II study (NCT02897479) to evaluate the efficacy, safety, and pharmacokinetics of savolitinib in pts with unresectable or metastatic METex14+ PSC and other NSCLC. MET mutation was tested or retrospectively confirmed by central laboratory. Savolitinib was taken orally, once daily (QD) (600mg for weight ≥50kg or 400mg weight &lt; 50kg) until disease progression or intolerable toxicity. Tumor was evaluated every 6 weeks during the 1 st year and every 12 weeks thereafter. The primary endpoint was independent review committee (IRC) assessed objective response rate (ORR) (RECIST version 1.1). Here we report the results of one cohort of prior MET-treatment naïve patients. Results: As of October 31, 2019, 593 pts were pre-screened/screened, 87 identified with METex14+ and 70 treated. Among treated pts, median age was 68.7 years (range 51.7-85.0), 58.6% pts were male, 92.9% stage IV, 60.0% previously treated, 57.1% with adenocarcinoma, 35.7% with PSC and the rest with other pathological types. Sixty-one pts were efficacy evaluable by IRC assessment (N = 61) (including pts who had at least one measurable lesion at baseline and had ≥1 scheduled post-baseline tumor assessment or evidence of any post-baseline radiological disease progression): ORR was 47.5% (95% CI: 34.6%, 60.7%), disease control rate 93.4% (95% CI: 84.1%, 98.2%) and median duration of response not reached yet. The median progression-free survival was 6.8 months (95% CI 4.2, 13.8) among all treated pts. Efficacy results were consistent with investigators’assessments. The most common (≥20%) treatment-related adverse events (TRAEs) were peripheral edema, nausea, increased AST/ALT, vomiting and hypoalbuminemia. The incidence of ≥ grade 3 TRAEs was 41.4%. TRAEs leading to treatment discontinuation occurred in 14.3% pts, among which liver injury and hypersensitivity were most common (each 2.9%). Conclusions: Savolitinib demonstrated promising anti-tumor activity and acceptable tolerability in METex14+ NSCLC pts. Clinical trial information: NCT02897479 .
Concordance of multispectral immunofluorescence (mIF) with programmed death ligand 1 (PD-L1) and stromal tumor infiltrating lymphocyte (sTILs) clinical assays in early-stage breast cancer (BC).
Authors: Katherine Sanchez, Shu-Ching Chang, Isaac Kim, Maritza Martel, Yaping Wu, William L Redmond, Zhaoyu Sun, Dottie Waddell, Deborah R. Laxague, Brady Bernard, Monil Shah, Walter John Urba, David B. Page
Journal: Journal of Clinical Oncology (2020)

e12589 Background: There is growing need for surrogate immune-based biomarkers in BC to enhance prediction accuracy and to facilitate comparisons of therapeutic activity in the context of clinical trials. We report mIF as a high-dimensional biomarker that is highly concordant with both PD-L1 (SP142) and sTIL clinical assays (H&amp;E), but with greater precision to quantify on-treatment pharmacodynamic effects. We also demonstrate how statistical modeling can be employed to improve precision of PD-L1/sTIL estimates, and reduce sample size requirements for biomarkers-driven comparative clinical trials. Methods: Samples were obtained from a recently-reported pre-surgical cytokine-based phase Ib immunotherapy (IRX-2) clinical trial (NCT02950259). Pre-treatment and resection tissues (n = 30) were analyzed for sTIL score, PD-L1 status, and mIF (PerkinElmer Vectra) using antibodies to quantify BC cells (cytokeratin), immune cells (CD3, CD8, CD163, FOXP3), and per-cell PD-L1 expression. Mixed effects regression models were employed to correct for intratumoral heterogeneity and enhance statistical precision. Monte Carlo simulations were employed to evaluate whether regression modeling could reduce sample size required to detect treatment-related increases in sTIL/PD-L1 in pre-surgical clinical trials. Results: Results: mIF sTIL estimates were highly correlated with H&amp;E sTIL score (pre-treatment samples: r = 0.59, p &gt; 0.001; excisional samples: r = 0.63, p &gt; 0. 001). mIF PD-L1 estimates were highly correlated with the PDL1 SP142 assay, with average densities increasing concordantly according to SP142 IC category (IC0 v. IC1, p = 0.04; IC0 v. IC2/3, p = 0.003). Our regression modeling approach dramatically improved power to demonstrate treatment-related changes in sTIL and PD-L1. The estimated sample size requirement to show the observed effect on sTIL score (1.80 fold change, CV 0.83) was n = 25 with conventional t-testing of means, versus n = 13 with regression modeling. Conclusions: mIF is concordant with SP142 and sTIL prognostic assays, but with increased precision to quantify treatment related changes. Regression modeling can dramatically improve the utility of mIF as a surrogate immune-based biomarker. Our approach is being utilized in ongoing phase II studies to compare the activity of pembrolizumab +/- locoregional cytokines (IRX-2) in triple negative BC, and paclitaxel/trastuzumab +/- pembrolizumab +/- pertuzumab in HER2-positive BC.
Cardiac events and breast cancer survival analysis in caucasians and minorities: A retrospective study in central Illinois.
Authors: Asad Cheema, Ruby Maini, Cameron Koester, Nitin Tandan, Odalys Estefania Lara Garcia, Manjari Rani Regmi, Priyanka Parajuli, Zurain Niaz, Sabree Abedrabo, Hamsa Sahib, Noupama Mirihagalle, Alexander Johnson, Abdisamad M. Ibrahim, Bishal Bhandari, Kristin Delfino, Kathy Robinson, Meghna R. Desai, Abhishek Kulkarni
Journal: Journal of Clinical Oncology (2020)

e13622 Background: Breast cancer is the most prevalent malignancy affecting the female population in the United States and poses a significant mortality risk. In central Illinois, our objective was to analyze cardiac events (described as a new diagnosis of heart failure, heart failure hospitalizations, and acute coronary syndrome) in patients diagnosed with breast cancer and overall survival. Methods: A retrospective analysis completed in February 2020 identified patients (n = 1618) based on ICD diagnosis codes with a primary diagnosis of breast cancer. The inclusion criteria comprised of confirmed pathology report with diagnosis of breast cancer between January 2014 and December 2017. A cohort of 478 patients was identified as having met the inclusion criteria. Baseline characteristics and qualitative information were obtained from retrospective chart review. Continuous variables were described with measures of central tendency (mean, median) and dispersion (range, standard deviation). Categorical variables were summarized as frequencies and percentages. Furthermore, comparison between categorical variables were analyzed using Chi-Square test. Survival curves were estimated using kaplan-meier methodology and analyzed with a log rank test. Qualitative variables were analyzed using chi-square test and reported as hazard ratio using SAS software. All significance was assumed at the p &lt; 0.05 level. Results: Of the 478 patients that were included as part of the analysis, 425 (89.6%) were of caucasian background and 49 (10.34%) were minorities (Asian, African American, and Hispanic). In regards to heart failure, our data demonstrated increased heart failure hospitalizations in minorities (7.89%) compared to caucasians (1.22%) which was a significant association (p = 0.026). In the overall survival among caucasian and minority groups there was no statistically significant difference (hazard ratio 0.939 with a 95% CI between 0.218-4.048), however it showed slight trend suggesting improved survival in the caucasian population. Conclusions: Our data illustrates that minorities with breast cancer experienced a higher incidence of heart failure when compared to the caucasian population. This supports closer observation at cardiac risk factors of such patients and medical optimization in an effort to prevent cardiac complications. While we did not see a significant difference in overall survival, further studies may be warranted in such population.
Acquired resistance to PD-1 blockade in NSCLC.
Authors: Adam Jacob Schoenfeld, Hira Rizvi, Danish Memon, Jia Luo, Isabel Ruth Preeshagul, Jennifer L. Sauter, Andrew J. Plodkowski, Chad Vanderbilt, Martin L. Miller, Matthew David Hellmann
Journal: Journal of Clinical Oncology (2020)

9621 Background: Although durability is the trademark characteristic of response to PD-1 blockade, acquired resistance can occur. The frequency, patterns, and survival outcomes of patients with acquired resistance to PD-1 blockade are unknown. Methods: All patients with NSCLC treated with PD-1 blockade at MSKCC were examined. Acquired resistance was defined as initial CR/PR (by RECIST) followed by progression/death. Oligo vs systemic patterns of acquired resistance were defined as progression in ≤ 2 sites of disease or ≥ 3 sites of disease, respectively. Results: Of 1201 patients treated with PD-1 blockade, 243 (20%) achieved initial response and 189 (78%, 95% CI 72-83%) eventually developed acquired resistance (AR). Onset of AR was variable and decreased with longer duration of response (53% within 1 year, 37% 1-2 years, 10% &gt; 2 years). Patients with PD-L1 expression &lt; 50% and TMB &lt; 8mut/Mb were more likely to develop resistance compared those with PD-L1 expression ≥50% and TMB ≥8mut/Mb (OR 5.5, p = 0.02). Unlike organ sites of primary refractory disease, AR commonly occurred in lymph nodes (41%) and infrequently in the liver (6%). Patterns of AR were most commonly oligo rather than systemic (79/141 [56%], 39/141 [28%]); some patients died without radiographic progression (23/141 [16%]). Oligo-AR occurred later (median onset 13 vs 5.6 mo) and associated with improved post-progression survival (median OS 55.2 vs 9.2 mo, HR 6.0, p &lt; 0.001) compared to systemic-AR. Post-progression survival was highest in patients with AR compared to those with initial SD or PD to PD-1 blockade (median 18.9 vs 12.5 vs 4.4, p &lt; 0.001). Of 49 patients treated initially with locally-directed therapy for AR, 28 (57%) remain alive and systemic therapy-free. Conclusions: Acquired resistance to PD-1 blockade is common in NSCLC. Risk of acquired resistance is lower in biomarker-enriched patients and with increased duration of response. Patterns of acquired resistance is commonly oligo in nature, which is amenable to locally-directed therapy and can be associated with improved survival. Differences in organ-site distribution and post-progression survival suggest distinct biology associated with acquired resistance vs primary refractory disease.
A survey of breast cancer patients’ use of cannabis before, during, and after treatment.
Authors: Marisa C. Weiss, Julianne Hibbs, Terri W. McHugh, Meghan Buckley, Sharon Larson, Nancye Green, Virginia G. Kaklamani, Rowan T. Chlebowski, Diana Martinez
Journal: Journal of Clinical Oncology (2020)

e19210 Background: The availability of cannabis is rapidly expanding and cancer is a qualifying condition in all states allowing medical cannabis. However, there are many unknowns with respect to patterns of cannabis use among breast cancer patients. The goal of this study was to better understand how and when cannabis is used among breast cancer patients. Methods: Between 12/16/2019 and 1/19/2020, U.S.-based members of Breastcancer.org and the Healthline communities were invited to participate in a cannabis survey. Subjects confirmed they were age ≥18 and diagnosed with breast cancer within 5 years. After informed consent, data were collected, de-identified and analyzed in aggregate. The study was led by Socanna, conducted by Outcomes Insights, and supported by a grant from Ananda Health/Ecofibre. Results: A total of 3522 persons initiated screening, 832 completed screening, and 725 met eligibility criteria, of whom 612 completed the survey (84%). The results showed that 42% of participants had used medical cannabis products to relieve symptoms, including insomnia (70%), pain (59%), anxiety (57%), stress (51%), and nausea/vomiting (46%). Additionally, cannabis was used prior to treatment in 24%, during treatment in 79%, and after treatment in 54%. Of subjects reporting cannabis use during treatment: 86% used it during chemotherapy, 71% during HER2 therapy, 65% during hormonal therapy, 49% during breast radiation, and 47% during radiation for metastatic sites. Post-surgical use was reported in 51% after mastectomy alone, 40% after lumpectomy, and 38% after mastectomy/reconstruction. An average of 3-4 cannabis products were utilized. Products were sourced from medical dispensaries (54%), family/friends (33%), and recreational sources (27%). Although cannabis using subjects strongly preferred medical sources, 77% had also utilized recreational sources. Conclusions: This survey shows that almost half of breast cancer patients reported using cannabis to help relieve common symptoms from breast cancer or its treatments. Of those, 79% used cannabis during active treatment, which can impact efficacy and safety. To date, studies have not investigated drug interactions between cannabis and these therapeutic agents. Furthermore, there is a concern regarding contaminants. Although most medical cannabis is tested for pathogens and contaminants, this is not the case for cannabis obtained from other sources. The results of this study highlight the need for research regarding cannabis for medical purposes, including safety and interaction studies.
Development and validation of natural language processing (NLP) algorithm for detection of distant versus local breast cancer recurrence and metastatic site.
Authors: Yasmin Karimi, Douglas W. Blayney, Allison W. Kurian, Daniel Rubin, Imon Banerjee
Journal: Journal of Clinical Oncology (2020)

2043 Background: Electronic health records (EHR) are used for retrospective cancer outcomes analysis. Sites and timing of recurrence are not captured in structured EHR data. Novel computerized methods are necessary to use unstructured longitudinal EHR data for large scale studies. Methods: We previously developed a neural network-based NLP algorithm to identify no recurrence vs. metastatic recurrence cases by analyzing physician notes, pathology and radiology reports in Stanford’s breast cancer database, Oncoshare (Cohort A). To validate this algorithm for local vs. distant recurrence, we identified a distinct Oncoshare cohort (Cohort B). Cases were manually curated for longitudinal development of local or distant recurrence and metastatic sites. A two-sided t-test was used to compare mean probabilities between local and distant recurrence cases. Next, we combined cases in Cohorts A and B to train and validate a novel NLP classifier that identifies metastatic site. The combined cohort was randomly divided into training and validation sets. Sensitivity and specificity were calculated for the NLP algorithm’s ability to detect metastatic sites compared to manual curation. Results: In Cohort B: 350 metastatic cases were identified. Mean probability for local and distant recurrence was 0.43 and 0.79, respectively and differed significantly for patients with local vs. distant recurrence (p&lt;0.01). In Cohorts A and B: 632 metastatic cases were used for determination of sites. Sensitivity and specificity were highest for detection of peritoneal metastasis followed by liver, lung, skin, bone and central nervous system (table). Conclusions: This NLP algorithm is a scalable tool that uses unstructured EHR data to capture breast cancer recurrence, distinguishing local from distant recurrence and identifying metastatic site. This method may facilitate analysis of large datasets and correlation of outcomes with metastatic site. [Table: see text]
Clinical characteristics of ischemic bowel disease in elderly patients
Authors: Xianmin Liu, Yu Zhang, Yanli Bai
Journal: BMJ (2018)

Objective
To analyze the clinical characteristics of ischemic bowel disease in elderly patients.


Methods
The clinical data of 83 patients with ischemic bowel disease, including 48 patients aged ≥ 60 years (elderly group) and 35 patients aged <60 years (control group), admitted in our hospital from January 2011 to June 2016 were retrospectively analyzed. The clinical characteristics, underlying diseases, examination methods and treatment were compared between the two groups.


Results
There were no significant differences in gender, occupation, urban or rural origin between the two groups (P>0.05). The incidence of acute mesenteric ischemia (AMI) in elderly group was significantly higher than that in the control group [22.9% (11/48) vs. 5.7% (2/35), χ2=4.534, P=0.033]; while the incidence of ischemic colitis (IC) in control group was higher than that in the elderly group [94.3% (33/35) vs. 70.8% (34/48), χ2=7.154, P=0.007]. Elderly group was more prone to misdiagnosis as compared with the control group [58.3% (28/48) vs. 34.3% (12/35), χ2=4.688, P=0.030]. Abdominal pain, diarrhea and hematochezia were the most common clinical manifestations of the two groups. Moderate pain and dull pain were the main symptoms of the elderly group accounting for 75.0% (36/48), while colic was the main symptoms of the control group accounting for 65.7% (23/35). The proportion of elderly patients with hypertension, coronary heart disease and cerebral infarction was higher than that of the control group [70.8%(34/48)vs. 25.7%(9/35), 62.5%(30/48)vs. 20.0%(7/35), 16.7%(8/48)vs. 0(0/35), χ2=16.504, 14.798, 4.684, all P<0.05]. The number of patients receiving colonoscopic examination was lower in the elderly group than that in the control group [52.1% (25/48) vs. 94.3% (33/35), χ2=17.127, P=0.000]. The overall effective rate of medical treatment for elderly patients was 90.2%(37/41), mostly of them were chronic mesentery ischemia (CMI) and IC patients; while 11 cases of AMI patients had poor outcomes of medical and surgical treatment including 5 fatal cases.


Conclusions
The incidence and mortality of AMI in elderly patients with ischemic bowel disease are higher, while CMI and IC have good prognosis. Timely diagnosis, appropriate treatment may improve the cure rate and reduce mortality for elderly patients with AMI.


Key words: 
Aged; Ischemic bowel disease; Clinical features
Co-mutations of KRAS/BRAF and TP53 or the high tumor mutation burden to predict survival in patients with biliary tract carcinoma.
Authors: Lingling Guo, Xiaoxia Kou, Panpan Song, Xiaoyu Zhang, Hongjuan Zhang, Jinrong Qiu
Journal: Journal of Clinical Oncology (2020)

e16650 Background: Biliary tract carcinoma (BTC), including cholangiocarcinoma and gallbladder carcinoma, is the second most common type of hepatobiliary cancer. Patients with BTC always show poor prognosis, here we revealed the molecular landscape of BTC in the Chinese population and evaluated the role of different mutations in informing prognosis. Methods: Formalin-Fixed Paraffin-Embedded (FFPE) or freshly-sampled tumor tissues from 59 BTC patients were conducted next-generation sequencing of 620 genes related to oncogenesis. Tumor mutation burden (TMB) value represents the number of non-synonymous mutations per mega base pairs in each sample. Kaplan-Meier survival curves were generated and compared using the log-rank test. Results: Altogether, 59 patients have mutations mainly in TP53, Ras/Raf, PI3K, CDK signaling pathways and SWI/SNF complex. The most frequently mutated gene was TP53(53%), followed by KRAS(23%), ARID1A(17%), ATM(12%), CDKN2A(10%), SMAD4(8%), BRCA2(8%), STK11(7%), BRAF(5%), IDH1(5%) and FGFR3 (3%). Noticeably, only one patient with FGFR2 fusion was detected. The Median TMB of these patients is 2.80 Muts/Mbp (0-36.52 Muts/Mbp). Existing data showed that KRAS/BRAF alterations were associated with a worse overall survival (OS) (median OS 166d vs. 294d, p= 0.063). Further analysis indicated that RAS/BRAF mutations were often co-current with TP53 alternations. And patients with coaltered RAS/BRAF and TP53 demonstrated the worst prognosis (media OS 123d vs. 294d, p= 0.087). In addition, a higher TMB ( &gt; 2.80 Muts/Mb) was also associated with a worse survival (median OS 174d vs. 355d, p= 0.085). Conclusions: We identified KRAS/BRAF, or co-mutations with TP53 and high TMB could predict poor prognosis in BTC patients. These findings will be useful for clinical decision making in patients with refractory biliary tract cancer and for risk stratification of patients in future clinical studies.
Value of clinical treatment score post-5 years (CTS5) for late relapse risk assessment in patients with early-stage HER2+ breast cancer (BC) in the north central cancer treatment group (NCCTG) N9831 (Alliance) trial.
Authors: Tanmayi Pai, Angelica Gil, Yaohua Ma, Zhuo Li, Pooja Advani, Alvaro Moreno-Aspitia, Gerardo Colon-Otero, Edith A. Perez, E Aubrey Thompson, Saranya Chumsri
Journal: Journal of Clinical Oncology (2020)

529 Background: Multiple prognostic models exist to predict late relapse risk in early stage hormone receptor-positive (HR+) breast cancer (BC). The CTS5 is one such model that has been validated in HR+ HER2-negative BC. The value of this model in HR+ HER2+ has not been established. Here, we assessed CTS5 in patients (pts) with early stage HER2+ BC treated in the NCCTG N9831 (Alliance) trial. Methods: Pts with stage I-III HER2+ HR+ BC who survived ≥ 5 years were included. The online CTS5 calculator was used to determine CTS5 score and risk group (low, intermediate, and high) based on age, tumor size, grade, and number of involved nodes. Kaplan-Meier (KM) estimates, Cox regression models, and C index were used for analysis. Results: From 3,130 pts, 1,204 pts met the criteria and were included. Median age was 49 (22-79) years and median tumor size was 2.4 (0.1-12) cm. 63.6% had grade 3 tumors, 33.6% grade 2, and 2.8% grade 1. Median follow up was 10.89 (5.01-15.32) years. Based on CTS5, 821 (68.2%) pts were classified as high risk, 289 (24%) as intermediate risk, and 94 (7.8%) as low risk. Overall, using univariate Cox regression analysis, there was no statistically significant difference in recurrence free survival (RFS) among pts with intermediate vs. low (HR 0.47 95%CI 0.18-1.22, p = 0.12) and high vs. low (HR1.23 95%CI0.57-2.67, p = 0.6) with the C index of 0.58. Among pts who received concurrent trastuzumab (H) with HR+ BC, there was also no statistical difference in RFS between high vs. low (HR 0.68 95%CI0.24-1.97, p = 0.48) with the C index of 0.55. Paradoxically, pts with intermediate risk had better RFS than low risk (HR 0.18 95%CI0.03-0.97, p = 0.05). As a continuous variable, there is also no significant improvement in RFS per 1 unit increase in CTS5 score (HR 1.19 95%CI 0.73-1.96, p = 0.49) with the C index of 0.54. After 5 years, 7.06% (n = 30/425) of HR+ pts treated with concurrent H recurred. Conclusions: The CTS5 model is not prognostic in pts with early stage HR+ HER2+ BC receiving adjuvant H. While most HR+ HER2+ pts are classified as high risk by CTS5, the recurrence between years 5-10 was low in pts who received adjuvant H. This study highlights the need to develop a new predictive model for risk of late relapse in this specific group of pts to enable clinicians to determine which pts would benefit from extended adjuvant endocrine therapy. Support: BCRF-19-161, U10CA180821, Genentech. https://acknowledgments.alliancefound.org Clinical trial information: NCT00005970 .