tbuckley/cabot-search huggingface dataset:
Assessment of extracellular matrix and tissue derived metabolites in a liquid biopsy for identifying endotypes of metastatic melanoma patients with differential response to immune checkpoint inhibitor treatment.
Authors: Nicholas Willumsen, Cecilie Liv Bager, Christina Jensen, Morten Asser Karsdal, Daniel Hargbøl Madsen, Morten Hansen, Henrik Schmidt, Inge Marie Svane
Journal: Journal of Clinical Oncology (2019)

e14050 Background: The extracellular matrix (ECM) is a major component of tumors. Several recent findings link ECM composition with outcome in cancer patients treated with immune checkpoint inhibitors (ICIs). The aim here was to explore circulating ECM- and tissue-derived metabolites to enable clustering of patients with metastatic melanoma (MM) into putative endotypes and evaluate patient characteristics and outcome when treated with Ipilimumab accordingly. Methods: Serum was collected from MM patients prior to treatment with Ipilimumab (n = 64). Wards hierarchical clustering of patients was based on 15 ECM- and tissue-derived metabolites measured in serum by ELISA. Identified clusters (endotypes) were compared to clinical characteristics and evaluated for associations with disease control rate (DCR), progression free survival (PFS) and overall survival (OS). Results: Three putative endotypes (cluster A, B, C) were identified including 14, 30 and 20 patients, respectively. Overall a stepwise increase in ECM metabolite median levels were detected from C-B-A with the largest absolute change seen from B-A. There was no difference between A, B, and C according to age, gender, lactate dehydrogenase levels, number of metastasized organs and whether patients were treated previously. At follow-up, the DCR was 0%, 60% and 45% in A, B, and C, respectively. Likewise, patients with endotype A had a median PFS/OS time of 69/85 days versus 174/520 and 165/589 days for endotype B and C. In support, endotype A predicted for poor survival outcomes (PFS AvsB+C :HR = 3.9, 95%CI:2.0-7.6, p = 0.0001; OS AvsB+C :HR:2.5, 95%CI:1.2-4.9, p = 0.0108). Conclusions: Hierarchical clustering of MM patients based on 15 ECM- and tissue-derived metabolites measured in a liquid biopsy identifies 3 putative endotypes. One endotype (A) seems to reflect patients with an overall high and differentiated ECM turnover profile. These patients experience poor outcome when treated with Ipilimumab. If validated, this supports a link between ECM remodeling and outcome in cancer patients treated with ICIs.
Comprehensive analysis of genomic alterations detected by next-generation sequencing-based tissue and circulating tumor DNA assays in Chinese patients with non-small cell lung cancer.
Authors: Hua Yang, Junjie Zhang, Lemeng Zhang, Xiaoping Wen, Yongzhong Luo, Dingquan Yao, Tianli Cheng, Huanqing Cheng, Huina Wang, Feng Lou, Jing Guo, Xiayuan Liang, Shanbo Cao, Jianhua Chen
Journal: Journal of Clinical Oncology (2019)

e20534 Background: While tumor genotyping is the standard treatment for patients with non-small cell lung cancer (NSCLC), spatial and temporal tumor heterogeneity and insufficient specimens can lead to limitations in the use of tissue-based sequencing. Circulating tumor DNA (ctDNA) fully encompasses tumor-specific sequence alterations and offers an alternative to tissue sample biopsies. The aim of the study was to evaluate whether the frequency of multiple genomic alterations observed following ctDNA sequencing was similar to that observed following tissue sequencing in NSCLC. Methods: A total of 99 NSCLC patients were enrolled in this study, including 40 tissue and 59 plasma samples. All kinds of variants of oncogenic drivers in NSCLC were identified by next-generation sequencing (NGS) with Acornmed panel. Results: The frequencies of genetic alterations detected in ctDNA were significantly correlated to those detected via tissue profiling (Spearman’s r = 0.812, P = 0.022). Genomic data revealed significant mutual exclusivity between alterations in epidermal growth factor receptor ( EGFR) and tumor protein 53 ( TP53; P = 0.020) and between those in EGFR and Kirsten rat sarcoma viral oncogene homolog ( KRAS; P = 0.008), as well as potential mutual exclusivity between alterations in EGFR and Erb-B2 receptor tyrosine kinase 2 ( ERBB2; P = 0.059). Furthermore, the EGFR mutant allele frequency (MAF) was strongly correlated with the TP53 MAF in individual tumors (Spearman’s r = 0.773, P = 0.005), and there was a marked difference in the EGFR MAF between patients with and without the TP53 mutation (P = 0.001). Levels of the tumor serum marker CA242 in patients with ctDNA-detectable mutations were higher than those in patients without ctDNA-detectable mutations. Conclusions: This study provides a better understanding of the spectra of genomic alterations detected by tissue and plasma ctDNA assays in Chinese patients with NSCLC. The present data also highlights the importance of tissue and plasma ctDNA screening by NGS to guide personalized therapy and promote the clinical management of NSCLC patients.
Open-label, multicenter, phase I study to assess safety and tolerability of adavosertib plus durvalumab in patients with advanced solid tumors.
Authors: Manish R. Patel, Gerald Steven Falchook, Judy Sing-Zan Wang, Esteban Rodrigo Imedio, Sanjeev Kumar, Pejvack Motlagh, Kowser Miah, Ganesh M. Mugundu, Suzanne Fields Jones, David R. Spigel, Erika Paige Hamilton
Journal: Journal of Clinical Oncology (2019)

2562 Background: Adavosertib (AZD1775; A) is a highly selective inhibitor of WEE1. This Phase I study (NCT02617277) investigated a range of doses and schedules for oral A plus IV durvalumab (DV), a human monoclonal antibody targeting PD-L1, to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) in patients (pts) with advanced solid tumors. Methods: Four 28-day schedules (Sch) were evaluated with pts receiving DV 1500 mg on day (d) 1 of each schedule (Table). Patients continued treatment if they showed clinical benefit in the absence of any discontinuation criteria. Pts received A monotherapy for PK analysis prior to the start of combination therapy in Sch B, C (d –7 to –5) and D (d –9 to –5). MTD was determined using a 3+3 dose-escalation cohort design. Predefined dose-limiting toxicities (DLTs) were evaluated during the first cycle of study treatment. Results: 54 pts received A (most common primary tumor sites: colon, 19%; lung, 13%; breast, 11%). The most common grade ≥3 AEs were fatigue (15%), diarrhea (11%) and nausea (9%). DLTs were nausea (n = 2) and diarrhea (n = 1). 7 pts (13%) had A-related SAEs, including reversible and confounded drug-induced liver injury (Sch B 125 mg and Sch C; 1 each). Disease control rate (DCR) for the total cohort was 36%. Preliminary PK at 150 mg BID suggests adequate coverage for cell kill activity and no drug–drug interaction. Conclusions: The MTD/RP2D was A 150 mg BID (3 d on, 4 d off; treatment d 15–17, 22–24) with DV 1500 mg (d 1 Q4W); safety profile was considered acceptable. Preliminary evidence of antitumor activity was observed. Clinical trial information: NCT02617277. [Table: see text]
Landscape of multilocus inherited neoplasia alleles syndrome in China.
Authors: Quchang Ouyang, Jie Gao, Jun Huang, Pingping Dai, Mingming Zhang, Chen Chen, Yan-Fang Guan, Ling Yang, Xin Yi, Xuefeng Xia
Journal: Journal of Clinical Oncology (2019)

e13027 Background: Comprehensive gene panels are able to identify patients with more than one pathogenic germline mutations. This phenomenon is known as multilocus inherited neoplasia alleles syndrome (MINAS). The frequency and phenotype of double heterozygous carriers in China are still unknown. Methods: A cohort of 12514 unrelated patients with solid tumor were screened using a validated panel. DNA damage repair-associated genes ( BRCA1, BRCA2, PALB2, ATM) and DNA mismatch repair genes ( MLH1, MSH2, MSH6, PMS2, MLH3, MSH3, PMS1) are taken focused on this study. Results: 10 (2.16%) cases harboring two pathogenic/likely pathogenic mutations were identified in 464 patients with germline variant. All patients had at least one high-risk gene mutation except for G10(LC, 73y), which carried 2 ATM variants in the same allele. All patients developed tumors associated with only one of the mutation identified until now. Among 3 patients had PMS2/MSH6 mutation, G6 &amp; G7 did not translated into recognized Lynch Syndrome due to abnormal BRCA1/2(H-risk for BC), while G8 harboring ATM (M-risk for BC) mutation developed to CRC. All of the five patients developed to breast cancer were TNBC molecular subtype. The median ages of diagnosis for BC were similar to single variation patients (44.3 vs 42, p=0.6190). Conclusions: Two double heterozygotes did not appear to have severe or different manifestations than single heterozygote. With the growing implementation of NGS based panel testing, relevant variants in two (or more) genes will be found more frequently. [Table: see text]
“Early impact” of the lung cancer screening in United States population in the SEER Registries.
Authors: Isabel M Emmerick, John M. Varlotto, Maggie M Powers, Feiran Lou, Poliana Lin, Mark Maxfield, Karl Uy
Journal: Journal of Clinical Oncology (2019)

1569 Background: The Lung Cancer Screening Trial (NLST) demonstrated improved overall survival (OS) and lung cancer specific survival (LCSS), likely due to finding early-stage NSCLC. Our study investigates the impact of the NLST publication in 2011 on the lung cancer outcomes in the general US Population by assessing the incidence rates, ratio of early/late stage, and lung cancer mortality in the years immediately prior to and following this publication. Methods: Rate sessions from the SEER18 database were accessed during the years 2008-2015. We analyzed overall lung cancer incidence and mortality rates. The ratio of early/late stage was obtained by dividing the number of stage I and II cases by the number of stage III and IV diagnosed by year. We investigate changes in level and trend using interrupted time series in STATA12, considering 2011 as the intervention. In addition, we performed a T-test for averages ratios comparing the years 2007-2010 to the years 2012-2015 for the entire lung cancer population and for subgroups by median family, ethnicity, Sex, Age and SEER Registry. Results: Although the overall lung cancer rates remained stable during the study period, a significant increase in the ratio of early/late stage was observed following the release of NLST for the overall lung cancer population (p=0.006) and for the screening age group (p= 0.014). The effects of ratio of early/late stage as noted in the overall group persisted for all patient subgroups, except for patients associated with a median income &lt;$40,000, for those there were white, and for the following regions Detroit Metro, Iowa, Greater and Rural Georgia and Louisiana where no association was found between the release of the NLST changes in the ratios of early detection even more, in some cases there was a decrease in late stage detection. There was no impact on lung cancer mortality in the general lung cancer population or in any patient subgroups. Conclusions: Since the publication of the NLST in 2011, there has been no impact on lung cancer mortality or incidence of lung cancer in the general US population. However, favorable increase in the proportion of early stage lung cancers, depending upon median family income, race and location. We expected a greater impact of lung cancer screening after 2015 since CT-screening for lung cancer was adopted by CMS and other insurances during that year.
Progression-free survival (PFS) in unresectable melanoma patients (pts) treated with talimogene laherparepvec (T-VEC) versus granulocyte macrophage colony-stimulating factor (GM-CSF) in OPTiM.
Authors: Mohammed M. Milhem, Kevin J. Harrington, Frances A. Collichio, Thomas Amatruda, Jason Alan Chesney, Sanjiv S. Agarwala, Sumita Bhatta, Min Yi, Mark R. Middleton, Merrick I. Ross, Igor Puzanov
Journal: Journal of Clinical Oncology (2019)

9524 Background: T-VEC is a modified oncolytic herpes virus designed as an intralesional therapy for unresectable advanced melanoma. OPTiM was a randomized, phase 3 trial that showed improved durable response rate (DRR) with T-VEC vs GM-CSF in pts with unresectable melanoma with regional or distant metastases (16.3% vs 2.1%, p &lt; 0.001). Treatment benefit of T-VEC on DRR and overall survival (OS) was greater in stage IIIB-IVM1a vs IVM1b-IVM1c melanoma. This is the first report of PFS for T-VEC vs GM-CSF. Methods: OPTiM included pts ≥18 yrs with unresectable stage IIIB-IV melanoma; ≥1 injectable cutaneous, subcutaneous (SC), or nodal lesion; ECOG ≤1; LDH ≤1.5 ULN; ≤3 visceral metastases (excluding lung) with none &gt; 3 cm. Pts were randomized 2:1 to receive intralesional T-VEC or SC GM-CSF. The primary endpoint was DRR (partial or complete response continuously for ≥6 mo starting within 12 mo) and reported previously. In this post hoc analysis, PFS was evaluated overall and by disease stage. Results: This analysis included 436 pts: 295 (68%) T-VEC, 141 (32%) GM-CSF; 57% men; 63 yr median age; 57% stage IIIB-IVM1a, 43% stage IVM1b-IVM1c. In the intention to treat set, T-VEC significantly improved PFS (HR: 0.68, 95% CI: 0.54, 0.85, unstratified log-rank p &lt; 0.001). In stage IIIB-IVM1a, PFS favored the T-VEC arm vs the GM-CSF arm (HR: 0.60, 95% CI: 0.44, 0.80, unstratified log-rank p &lt; 0.001). No treatment difference was seen in stage IVM1b-IVM1c (HR: 0.81, 95% CI: 0.57, 1.15, unstratified log-rank p = 0.199). Overall, the 12 mo PFS rate for T-VEC was 14.4% (95% CI: 10.5, 18.8) and GM -CSF was 4.6% (95% CI: 1.6, 10.2). In stage IIIB-IVM1a, the 12 mo PFS rate for T-VEC was 19.9% (95% CI: 14.0, 26.6) and GM-CSF was 3.2% (95% CI: 0.6, 9.9). In stage IVM1b-IVM1c, the 12 mo PFS rate for T-VEC was 7.4% (95% CI: 3.5, 13.2) and GM-CSF was 8.0% (95% CI: 1.9, 20.1). Conclusions: T-VEC demonstrated an improvement in PFS vs GM-CSF, driven primarily by pts with stage IIIB-IVM1a melanoma. This is consistent with previous data showing more pronounced OS benefit with T-VEC and greater efficacy with other immunotherapies in early metastatic disease. Clinical trial information: NCT00769704.
Barriers to accrual and enrollment in brain tumor trials.
Authors: Eudocia Quant Lee, Ugonma Nnenna Chukwueke, Shawn L. Hervey-Jumper, John Frederick De Groot, Jose Pablo Leone, Terri S. Armstrong, Susan Marina Chang, David Arons, Kathy Rose Oliver, Evanthia Galanis, Bret Edward Buckley Friday, Nancy U. Lin, Minesh P. Mehta, Marta Penas-Prado, Michael A. Vogelbaum, Solmaz Sahebjam, Martin J. Van Den Bent, Michael Weller, David A. Reardon, Patrick Y. Wen
Journal: Journal of Clinical Oncology (2019)

2024 Background: A major impediment to improving neuro-oncology outcomes is poor clinical trial accrual. Methods: We convened a multi-stakeholder group including Society for Neuro-Oncology, Response Assessment in Neuro-Oncology, patient advocacy groups, clinical trial cooperative groups, and other partners to determine how we can improve trial accrual. Results: We describe selected factors contributing to poor trial accrual and possible solutions. Conclusions: We will implement strategies with the intent to double trial accrual over the next 5 years. [Table: see text]
Efficacy of quxie capsule in metastatic colorectal cancer: Update of a double-blind, randomized, placebo controlled trial.
Authors: Tong Zhang, Wenting He, Yun Xu, Bin He, Yufei Yang
Journal: Journal of Clinical Oncology (2019)

e15030 Background: To verify the efficacy of Quxie Capsule in patients with metastatic colorectal cancer (mCRC). Methods: This is a update of a randomized, double-blind, placebo-controlled trial. Between April 2014 and July 2015, 121 patients were enrolled in the study. Sixty patients were eligible and randomized to the two groups at a 1:1 ratio. Treatment group received conventional therapy and Chinese herbal medicine combined with Quxie Capsule for 3 months. Control group received conventional therapy and Chinese herbal medicine combined with placebo for 3 months. Main outcome measures were overall survival (OS) and progression-free survival (PFS). As of Dec 31st 2018, one patient in the control group was still alive, and all the other patients reached the main clinical endpoint. Median follow-up time was 19.4 months. Bo Ao Tong (Beijing) Medical Technology Co. Ltd. was responsible for the protocols of blind and block randomization. Results: The median OS were 23.9 months in the treatment group [95% confidence interval (CI) 15.9–28.5] vs. 14.3 months in the control group (95% CI 11.3–21.4) (Kaplan–Meier, Log-rank P=0.032), hazard ratio (95%CI)= 0.55 (0.31, 0.95), P=0.04. In the subgroups of left-sided colon, RAS wild type, non-targeted therapy, colon cancer and ≥second-line therapy, the median OS of the treatment group and the control group were respectively: 20.9 vs 12.2m, 17.4 vs 14.4m, 20.8 vs 12.0m, 25.1 vs 18.5m, 25.1 vs 12.0m ( P=0.037, 0.019, 0.022, 0.018, 0.007). There were no significant differences between the two groups in PFS. Conclusions: Quxie Capsule showed good efficacy, can reduce the risk of death and prolong the OS of patients with mCRC. Clinical trial information: ChiCTR-IOR-16009733.
Case 7-1978
Authors: Richard C. Cabot, Robert E. Scully, James J. Galdabini, Betty U. McNeely, Bernard R. Aserkoff, James J. Galdabini
Journal: New England Journal of Medicine (1978)

Presentation of CaseA 22-year-old automobile mechanic was admitted to the hospital because of jaundice.He was well until six years earlier, when he began to pass fresh blood per rectum intermittently after bowel movements. Three years before admission he began to have occasional bouts of diarrhea, with the passage of up to five loose stools daily, and a lowgrade fever and pain in the left calf occurred. Sigmoidoscopic examination at another hospital was reported to show ulcerative colitis. A barium-enema examination (Fig. 1) revealed marginal serrations, haustral thickening and mucosal granularity in the transverse and descending colon. A stool . . .
Incidence of severe late toxicities of head and neck squamous cell cancer (HNSCC) treatment in the era of intensity modulated radiotherapy (IMRT).
Authors: Akaolisa Samuel Eziokwu, Shlomo A. Koyfman, Chandana A. Reddy, Brian Matia, Neil McIver Woody, Nikhil Purushottam Joshi, Brian B. Burkey, Joseph Scharpf, Eric Lamarre, Brandon Prendes, Robert Lorenz, Jamie Ku, David J. Adelstein, Jessica Lyn Geiger
Journal: Journal of Clinical Oncology (2019)

e17570 Background: IMRT for HNSCC limits exposure to critical nearby structures thereby reducing toxicities. Real world data on toxicities after long term follow-up post IMRT for HNSCC are lacking. This study assessed the incidence of late toxicities in patients with HNSCC within 5 years post-treatment with definitive IMRT (d-IMRT). Methods: This is a retrospective, IRB approved, single-institution review of patients (pts) with stage I-IVB HNSCC treated with d-IMRT +/- chemotherapy between 2009 and 2013. The primary outcomes were incidence of severe late toxicities (dysphagia requiring esophageal stricture dilation, physician-reported grade 2 or worse neck fibrosis and xerostomia) occurring 3 months or more after completion of IMRT; feeding tube (FT) dependence within 1st year of IMRT completion, and FT dependence beyond 1st year post IMRT. Toxicities were deemed acute if they occurred during IMRT and up to 90 days post IMRT. Results: 274 pts, median age 59 years (38 – 82.9), were identified. 67.6% were HPV positive, 10.5% HPV negative and HPV status was unknown in 21.9%. Site of disease was oropharynx in 70%, larynx in 25% and hypopharynx in 4%. 206 pts (75.2%) received d-IMRT alone, 37 (13.5%) had definitive concurrent chemoradiation – mostly with cisplatin (58%), and 31 (11.3%) received adjuvant IMRT. Of the 243 pts treated with d-IMRT +/- chemotherapy, 80 (32.9%) required FT during RT due to grade 2 or worse acute dysphagia. Excluding 11 pts with disease recurrence or new HNSCC diagnosis, FT dependence at any time from 3 months to one year post IMRT occurred in 22 of 232 pts (9.48%), while FT dependence beyond 1st year post IMRT occurred in 8 pts (3.4%). 11 pts (4.7%) required stricture dilation for late dysphagia. Late grade 2 or worse fibrosis and xerostomia occurred in 7 (3.0%) and 89 (38.4%) pts, respectively. Conclusions: Our study suggests that except for xerostomia, severe late toxicities after definitive IMRT for HNSCC is likely uncommon. Prospective studies with late IMRT toxicities and their impact on quality of life (QoL) as endpoints are warranted.
Outcomes after adjuvant radiotherapy in breast cancer patients with and without germline mutations: A large, single-institutional experience.
Authors: Bhavana Sree Vangara Chapman, Diane D. Liu, Shane Richard Stecklein, Angelica Gutierrez Barrera, Wendy A. Woodward, Gabriel O Sawakuchi, Banu Arun, Simona Flora Shaitelman
Journal: Journal of Clinical Oncology (2019)

1502 Background: Women with germline mutations in DNA repair pathways are at an increased risk of developing breast cancer. We posit that tumors arising in these patients may be more sensitive to radiotherapy and, therefore, patients may experience improved locoregional control and survival outcomes following adjuvant radiotherapy as compared to patients without DNA repair pathway mutations. Methods: We evaluated the records of 2,221 women with stage 0-III de novo primary breast cancer treated with surgery and adjuvant radiotherapy who all underwent genetic testing at our institution from 1993 to 2018. Mutations were categorized as pathogenic variant, variant of unknown significance (VUS), or negative. The Kaplan-Meier method was used to estimate the locoregional recurrence rate (LRR), rate of distant metastasis (DM), disease-free survival (DSS), and overall survival (OS) from the time of surgery. Results: The median age at diagnosis was 45 years (range 19-84). Median follow-up time was 7 years (95% confidence interval 6.6-7.4). Among 1,960 patients with evaluable radiation records, 752 (38.4%) received breast only radiation, 12 (0.6%) received chest wall only radiation, and 1,196 (61.0%) received breast/chest wall and regional nodal radiation. A total of 255 (11.4%) and 162 (7.3%) patients had a pathogenic variant mutation and a VUS only, respectively. Pathogenic variant and VUS in BRCA1/2 mutations were detected in 216 (9.7%) and 82 (3.7%) patients, respectively. Perturbations in ATM, CHEK2, MLH, MSH2/6, MUTYH, PALB2, RAD50/51, and/or TP53 were detected in 71% (85/119) of patients who tested positive for a non- BRCA1/2 pathogenic variant or VUS. On univariate analysis, there was no significant association between BRCA1/2 mutation status or any genetic mutation and rate of LRR or DM, DSS, or OS ( p &gt; 0.10 for all). Clinicopathological features including advanced stage and lymphovascular invasion were associated with higher cumulative incidence of LRR and DM as well as shorter DFS and OS ( p &lt; 0.01 for all). Conclusions: Herein we report on the largest cohort of women with breast cancer treated with adjuvant radiotherapy at a single institution who have undergone germline testing. Our findings suggest that the overall prognosis of breast cancer treated with adjuvant radiotherapy in patients with germline BRCA1/2 or other genetic predisposition is similar to patients with sporadic breast cancer. Further investigation to evaluate acute or late toxicities and secondary cancers as a result of radiotherapy is warranted.