tbuckley/cabot-search huggingface dataset:
Programmed death-ligand 1 expression after progressive disease with EGFR-TKI and efficacy of anti-programmed death-1 antibody in non-small cell lung cancer(NSCLC) harboring EGFR mutation.
Authors: Yosuke Dotsu, Atsushi Horiike, Takahiro Yoshizawa, Tomoaki Sonoda, Junji Koyama, Masafumi Saiki, Ryo Ariyasu, Ken Uchibori, Shingo Nishikawa, Satoru Kitazono, Noriko Yanagitani, Hironori Ninomiya, Yuichi Ishikawa, Makoto Nishio
Journal: Journal of Clinical Oncology (2018)

e21232 Background: Several clinical trials have suggested the poorer efficacies of programmed death-1 (PD-1) and PD-ligand 1 (PD-L1) antibodies for NSCLC harboring epidermal growth factor receptor (EGFR) mutations. On the other hand, it suggested that PD-L1 expression levels may be related to the efficacy of PD-1/PD-L1 antibodies for NSCLC, while and EGFR-TKI modulated the expression of PD-L1 in the tumors. The efficacy of PD-1/PD-L1 antibodies and the PD-L1 expression status after progressive disease (PD) with EGFR-TKI have not yet been well examined. Methods: We retrospectively analyzed the correlation between the PD-L1 expression after PD with EGFR-TKI and the efficacy of PD-1 antibodies in NSCLC harboring EGFR mutation. The PD-L1 expression in tumors of re-biopsy specimens after PD with EGFR-TKI was examined by IHC with 28-8 antibody. Results: We identified 15 patients with NSCLC harboring an EGFR mutation (EGFR E19del: n = 4, L858R: n = 2, E19del+T790M: n = 4, L858R+T790M: n = 4, G719X+T790M: n = 1) who were treated with nivolumab (n = 14) or pembrolizumab (n = 1) after PD with EGFR-TKI treatment.Four patients had ≥50% PD-L1 expression in the tumors, while and 6 patients had ≥1% PD-L1 expression. The overall response rate (ORR), the median progression-free survival (mPFS) and the median overall survival (mOS) were 6.7%, 1.5 months and 19.4 months in all patients, respectively. The ORR, mPFS and mOS of the patients with ≥1% PD-L1 expression were 0%, 0.8 months and not reached (NR), respectively. Even in patients with ≥50% PD-L1 expression, the ORR, mPFS and mOS were 0%, 0.8 months and NR, respectively. Conclusions: PD-1 antibodies might be ineffective for NSCLC harboring an EGFR mutation, even after PD with EGFR-TKI and a high PD-L1 expression in the tumor.
Health resource utilization among patients with metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) treated at a tertiary referral center.
Authors: Jie Meng, Jessica J. Jalbert, Roman Casciano, Lauren K. Brais, David Ray, Sonia J. Pulgar, Matthew H. Kulke
Journal: Journal of Clinical Oncology (2018)

e16177 Background: GEP-NETs are receiving increased recognition as important yet underdiagnosed neoplasms. With better understanding of GEP-NETs comes a growing demand to deeper understand real-world health resource utilization (HRU) associated with it. We explored the feasibility of describing HRU among patients with metastatic GEP-NET treated at a tertiary referral center. Methods: We linked research data exported from the Clinical Research Information System database at the gastrointestinal cancer centers of the Dana-Farber Cancer Institute (DFCI) and Brigham and Women’s Hospital to patients’ electronic health records (EHRs) in DFCI and Partners’ institutions. We included patients with well-differentiated, metastatic GEP-NETs diagnosed between July 2003 and May 2015. Patients were considered lost to follow-up if without outpatient visits for > 9 months on treatment or > 3 months off treatment. HRU derived from EHRs was calculated per person-year and stratified by tumor type, year of metastatic diagnosis, and trial enrollment. Results: HRU was highest in pancreatic (pan) NETs across various categories (see table). In stratified analyses, this difference persisted across trial enrollment and was more pronounced in recent years since metastatic diagnosis. Conclusions: Our results indicate that it is feasible to describe HRU in metastatic GEP-NET patients by linking an institutional research database to EHRs and find that panNET patients require more HRU resources than other types of GEP-NETs. One limitation is that different definitions were used to define HRU in DFCI and Partners’ institutions, due to the distinct data structures. HRU per patient-year Pancreatic NET N = 178 Midgut NET N = 290 Other NET N = 172 DFCI EHRs Outpatient visit 18.4 15.6 16.4 Lab test 526.8 443.5 455.3 Diagnostic/imaging test* 0.0 0.0 0.0 Radiology visit* 3.2 2.4 2.8 Specialist visit* 15.7 13.6 14.3 Transfusion* 0.1 0.0 0.1 Treatment* 11.3 10.6 10.6 Partners’ institutions EHRs Inpatient stay 1.9 1.9 1.4 Outpatient visit 7.3 6.9 8.3 Diagnostic test 1.9 2.4 2.1 Transfusion 1.0 0.7 1.0 Lab test 102.0 99.6 84.4 Radiology visit 13.9 10.8 12.3 *derived from outpatient visit
Feasibility and outcome of repeat biopsy upon progression on tyrosine kinase inhibitors in patients with EGFR mutation positive adenocarcinoma of lung-an Indian tertiary cancer centre experience.
Authors: Saurabh Zanwar, Vanita Noronha, Amit Joshi, Vijay Maruti Patil, Anuradha Chougule, Amit Janu, Rajiv Kumar, Kumar Prabhash
Journal: Journal of Clinical Oncology (2017)

e20628 Background: A repeat biopsy at the time of progression is important to evaluate the mechanism of resistance to tyrosine kinase inhibitors (TKIs) in EGFR mutation positive adenocarcinoma (ADC) of lung and dictates decisions for further therapy. Being an invasive procedure, a rebiopsy is not always possible and presents various hindrances. Methods: Between January 2012 and November 2016, EGFR mutation positive ADC of Lung treated with TKIs were evaluated for and offered a repeat biopsy at the time of progression on TKI. Feasibility of rebiopsy was done by a team of experienced interventional radiologists. Proportion of patients undergoing a rebiopsy, reason for inability to undergo a rebiopsy, histopathology findings including any small cell transformation and adequacy of tissue for further molecular testing were assessed. Results:154 patients were offered a repeat biopsy out of which 119 patients (77.3%) underwent a repeat biopsy. There was no evidence of malignancy in 17.6% (21/119) patients on the rebiopsy specimen and tumor was inadequate for molecular testing in 9 out of 98 patients (9.2%) in whom malignancy was detected on the repeat biopsy specimen. Small cell transformation was seen in 3.3% (4/119) patients who underwent a repeat biopsy. Amongst the 34 patients who could not undergo rebiopsy, patient unwillingness for the procedure was the most common reason, accounting for 47% cases (16/34) followed by a technically difficult biopsy as per judgement of the interventional radiology team in 32.3% (11/34). 5 out of 34 patients were not subjected to a rebiopsy a poor performance status and 3 patients were not subjected to rebiopsy as per treating clinician’s discretion. Thus, out of 154 patients, adequate tissue was not available for molecular testing in 41.5% patients who progressed on TKI due to various reason as elaborated above. Molecular testing is planned on the remaining biopsy specimens. Conclusions: Conventional invasive rebiopsy upon progression on TKIs fails to collect adequate tissue for molecular testing in almost 40% cases due to various reasons making liquid biopsy a very important tool in this setting.
GGNBP2 to suppress tumor growth and cancer stem cell load of triple negative breast cancer by controlling STAT3 pathway.
Authors: Jin Zhang, Yunhui Hu, Zhenmin Lei
Journal: Journal of Clinical Oncology (2017)

e23003 Background: Gametogenetin binding protein 2 (GGNBP2) is encoded in human chromosome 17q12-q23, a region known as a breast and ovarian cancer susceptibility locus. GGNBP2 has a single C2H2 zinc finger and a consensus LxxLL nuclear receptor (NR) binding motif. We have reported that GGNBP2 suppresses ERα-positive breast tumorigenesis by acting as a nuclear receptor co-repressor to restrain ERα activity. However, the detailed molecular mechanisms of GGNBP2 and its role in triple negative breast cancer (TNBC) remain largely unclear. Methods: A human breast cancer tissue array containing 138 human breast tumor tissues were utilized to examine GGNBP2 expression in breast cancer samples by IHC. To address the potential anti-breast tumor activity of GGNBP2 in vitro, we expressed exogenous GGNBP2 in TNBC cells, including MDA-MB-231 and Cal51 cell lines. Cell proliferation and cell cycle were assessed by cell growth curve/EdU assays and flow cytometry after propidium Iodide staining. Apoptosis was determined by flow cytometry after annexin V staining, by caspase 3/7 and caspase 9 activity assays. Cancer stem cell properties were determined by expression of CD44/CD24/ALDH1 markers. The levels of phosphorylated STAT3 and total STAT3 were determined by western blot. Quantitative PCR and Western blot were carried out to evaluate the effects of GGNBP2 overexpression on STAT3 target genes, CCND1, Mcl-1, survivin, bax and bim expression. Results: GGNBP2 expression is down-regulated in TNBC cells and patient tumors. GGNBP2 down-regulated expression is associated with poor patient survival. Overexpression of GGNBP2 significanly induces cell cycle G0/G1 phase arrest and apoptosis in TNBC cell lines. Expression of cancer stem cell markers also decreased in GGNBP2-overexpressed TNBC cells. GGNBP2 reduces the expression levels of CCND1, Mcl-1 and survivin, promotes the expression levels of bax and bim proteins. Importantly, overexpression of GGNBP2 inhibits STAT3 phosphorylation and STAT3 downstream target gene expression, including CCND1, Mcl-1 and survivin. Conclusions: GGNBP2 serves as a critical nuclear negative regulator of STAT3-mediated gene expression and tumorigenesis in TNBC.
Abstract 16153: The Association of Quality of Life and Race in Peripheral Arterial Disease Following Percutaneous Vascular Intervention: The Q-PAD Registry
Authors: Anwar Zaitoun, Saif Al-Najafi, Thaer Musa, Susan Szpunar, Dawn Light, Hiroshi Yamasaki, Thoams Lalonde, Rajendra H Mehta, Howard S Rosman
Journal: Circulation (2016)

Introduction: Black patients (pts) with peripheral arterial disease (PAD) are known to have higher prevalence, greater extent and severity, and worse outcomes compared to white pts with PAD. Yet, t...
Repurposing tin mesoporphyrin as a novel immune checkpoint therapy in the treatment of cancer: A preclinical evaluation.
Authors: James N. Arnold, Tamara Muliaditan, James W. Opzoomer, Jonathan Caron, Mary Okesola, Paris Kosti, Sharanpreet Lall, Mieke Van Hemelrijck, Francesco Dazzi, Andrew Tutt, Anita Grigoriadis, Cheryl Gillett, Stephen F. Madden, Joy M Burchell, Shahram Kordasti, Sandra S. Diebold, James F. Spicer
Journal: Journal of Clinical Oncology (2018)

e15129 Background: Unprecedented clinical outcomes have been achieved in a variety of cancers by targeting the immune checkpoint molecules PD-1 and CTLA-4. However, as a significant number of patients is unresponsive, or only responds transiently to current therapies, it suggests that further important immune regulators in the tumor microenvironment exist. Heme oxygenase-1 (HO-1) is an enzyme that is responsible for the breakdown of heme to generate biliverdin, ferrous iron and the immune suppressive molecule carbon monoxide. In this preclinical study we evaluate HO-1 as an innate immune checkpoint target. An HO-1 inhibitor, tin mesoporphyrin (SnMP), has previously demonstrated tolerability and efficacy in the clinic for the treatment of hyperbilirubinemia, and we evaluate repurposing SnMP as a novel immune checkpoint therapeutic. Methods: We studied HO-1 in an aggressive spontaneous murine model of mammary adenocarcinoma (MMTV-PyMT) using chemotherapy to stimulate an anti-tumor immune response. We use patient survival data and RNA-sequencing analyses to support the clinical relevance of our conclusions. Results: In MMTV-PyMT mice, inhibiting HO-1 using SnMP synergized with chemotherapy to permit immunological control of tumor growth. HO-1 was primarily expressed by tumor associated macrophages, and genetic inactivation of the gene in myeloid cells paralleled the observations of SnMP treatment with chemotherapy. We discovered a striking clinical parallel, where high HO-1 expression was associated with poor prognosis in cancer patients receiving chemotherapy. Single-cell RNA sequencing analysis of a breast cancer patient dataset also suggested that the myeloid lineage was a significant source of HO-1 expression in human cancer, and was co-expressed with the immune checkpoints PD-L1/2. We compared the efficacy of PD-1 blockade to that of SnMP, and in the MMTV-PyMT model, SnMP was more efficacious than PD-1 blockade alongside chemotherapy, highlighting the potential importance of HO-1 as an immune checkpoint target. Conclusions: Our data support the clinical evaluation of SnMP as a novel immune checkpoint therapeutic in cancer within chemotherapy regimens.
BRAF with or without MEK inhibition plus PD-1 checkpoint blockade for the treatment of metastatic melanoma.
Authors: Michelle Rohlfs, Roland L. Bassett, Carol Lacey, Natalie McQuail, Urvi Mehta, Ida John, Rinata Simien, Stephanie Tupue, Tina Karin Dett, Isabella Claudia Glitza, Adi Diab, Rodabe Navroze Amaria, Hussein Abdul-Hassan Tawbi, Michael A. Davies, Wen-Jen Hwu, Patrick Hwu, Sapna Pradyuman Patel
Journal: Journal of Clinical Oncology (2016)

9548 Background: The treatment (tx) of metastatic melanoma (MM) has met with considerable advances with the use of targeted therapy such as BRAF and MEK inhibitors (BRAFi, MEKi) and anti-PD1 (aPD1) checkpoint agents, pembrolizumab (PEMBRO) and nivolumab (NIVO). The combination (combo) of these two therapeutic classes has previously been studied with ipilimumab and is currently being studied with PEMBRO (KEYNOTE-022). Given the commercial availability of these agents, many providers have begun combining these agents for clinical use. Thus, we evaluated our use of combo BRAFi +/- MEKi with aPD1 agents PEMBRO or NIVO to determine the tolerability and efficacy of these combined tx. Methods: We performed a single-center IRB-approved retrospective review of patients (pts) with BRAF-positive mm who received tx with the combo of BRAFi +/- MEKi plus PEMBRO or NIVO. Pts could have received prior tx with either class of agents, and have a run-in with BRAFi +/- MEKi or with aPD1 drugs of any duration before concurrent combo tx. Toxicity via adverse event (AE) documentation and efficacy via PFS were captured. Results: Between June 2014 and December 2015, 38 pts were treated with the combo BRAFi +/- MEKi plus aPD1. The median age was 54, 52% were male, 68% had M1c disease and 24% had elevated LDH at the time of combo tx. Run-in consisted of BRAFi +/- MEKi in 63%, 34% had a run-in with aPD1; one pt started the combo tx concurrently. Eight pts (21%) had a run-in period of 4 wks or less, 12 pts (32%) of 6 wks or less. 58% received BRAFi + aPD1 while 42% received BRAFi + MEKi + aPD1. Mean number of doses of aPD1 was 10, with majority of pts (79%) receiving PEMBRO. Median follow-up was 4.9 mos and median PFS from start of combo tx was 7.6 mos (doublet tx 8.5 mos and triplet tx 7.2 mos). AEs were noted in 28 pts (74%). The majority were Grade (G) 1-2, commonly fatigue. G3-4 AEs were seen in 4 pts (11%) as a result of rash, nausea/vomiting, fever and chills. No pts had tx held for hepatotoxicity; there have been no G5 AEs with this combo, and all pts remain alive at last follow-up. Conclusions: The addition of aPD1 to a targeted therapy regimen of BRAFi +/- MEKi appears safe and well-tolerated in BRAF-positive MM. Results of the prospective KEYNOTE-022 will further our understanding of this combo.
HER2 overexpression and amplification in patients with colorectal cancer: a large-scale retrospective study in Chinese population.
Authors: Shujuan Ni, Junjie Peng, Dan Huang, Midie Xu, Lei Wang, Cong Tan, Hui SUN, Sanjun Cai, Weiqi Sheng
Journal: Journal of Clinical Oncology (2017)

e15099 Background: Recent studies have shown that human epidermal growth factor receptor 2 (HER2) overexpression or amplification may be a potentially predictive factor for anti-HER2 response and anti-EGFR resistance in colorectal cancer (CRC). However, the prevalence of HER2 positivity in CRC patients and its correlation with clinicopathologic features are not clear. Methods: HER2 expression was tested by immunohistochemistry (IHC) in 4,913 consecutive patients with CRC treated with surgical resection of primary tumor during 2011-2014 in our institution. The formalin-fixed, paraffin-embedded samples of the primary tumors were used. Dual color silver-enhanced in situ hybridization (DISH) was performed in all IHC 3+/2+ cases and randomly selected IHC 1+/0 cases subsequently. The scoring criteria of HER2 status in gastric cancer was used. Results: HER2 positivity was found in 160 (3.3%) out of 4,913 cases of CRC. Among them, 68 cases were IHC 3+, while 92 cases were IHC 2+ and DISH+. 157 cases (3.2%) were HER2 amplified determined by DISH, including 66 (97.1%, 66/68) IHC 3+ and 92 (35.6%, 92/258) IHC 2+ cases. None of the 50 cases of IHC 1+/0 was HER2 amplified. HER2 positivity was correlated with perineural invasion, vascular invasion, lymph node metastases, and higher TNM stage. HER2 positivity was more common in younger patients ( &lt; 60 year old). Only one HER2 positive case had mismatch repair protein (MMR) deficiency. HER2 positivity was found not related to tumor location. Conclusions: To our knowledge, this is the largest study of HER2 status in Asian patients with CRC. HER2 overexpression or amplification of tumor cells occurred in a small number of patients with CRC. HER2 positivity was related to unfavorable prognostic factors, more common in younger patients and rare in MMR deficiency cases. The further study of molecular heterogeneity of HER2 expression or amplification in patients with CRC was ongoing.
Comparison of survival outcomes and demographic trends of uterine sarcomas between a single institution and the National Surveillance Epidemiology &amp; End Result database (SEER) from 2002-2012.
Authors: Indumathy Varadarajan, Sukhdeep Kaur, Ankit Shah, Daniel Kyung, Wereuche Nze, Hareesha R. Chakunta, Maneesh Rajiv Jain, Kristine Marie Ward, Pamela A. Crilley, David Lane Topolsky, Stephanie King, Michael Styler
Journal: Journal of Clinical Oncology (2016)

e18140 Background: Uterine sarcomas (US) represent 3-7% of uterine cancers, are pathologically heterogeneous, behave aggressively & portend poor prognosis. We compared the demographics & survival outcomes in patients (pts) with US from our institution to SEER from 2002-2012. Methods: 60 pts with US were treated at Hahnemann University Hospital (H) from 2002-2012.Incidences of the 4 major subtypes, grade, mean age & stage of presentation were noted. Survival analyses were performed by Kaplan- Meier method. Number of pts that received Lymph node dissection (LND) & adjuvant XRT were noted. This information was compared to data from SEER. Results: SEER lists 13,273 pts from 2002-2012; incidence rate of endometrial stromal sarcoma (ESS) was 0.4, adenosarcoma (AS) 0.2, uterine carcinosarcoma (CS) 1.4 & leiomyosarcoma (LMS) 1.7 per 100,000. In the H series, adj chemo was administered to 40% of the CS, 60% of the LMS, & 50% of the ESS. Carboplatin/ paclitaxel was the major choice in CS and gemcitabine /docetaxel in LMS. Adj chemo data were not obtainable from SEER. Conclusions: Mean age of presentation, grade & stage distribution among the US subtypes were comparable between our pts & SEER. LMS & ESS pts presented at later stage in our series & survival was higher in LMS. In both CS & ESS the 5yr survival was lower in H pts. This may be due to the higher % of ESS pts with Stage IV. Improved survival in our LMS group may be due to routine LND, adjuvant XRT & chemo. Further studies are essential to improve survival outcomes. CS LMS ESS AS H SEER H SEER H SEER H SEER Mean Age (yr) 70 67.3 56 58.7 62 54.1 62 56.8 Total Pts (%) 31 (51.7) 4908 (37) 15 (25) 6100 (46) 12 (20) 1536 (11.6) 2 (3.3) 729 (5.5) Survival (%) 1 year 42 67.6 75 77.2 51 80.9 ~ 91.3 3 year 26 40.9 65 52.5 34 71.6 ~ 80.2 5 year 9 33.6 63 40.9 17 69.1 ~ 72.8 Stage (%) I 26 28.1 37 24.9 36 39 100 56.2 II 13 8.5 7 8.3 9 6.1 0 6 III 32 24.1 13 11.9 9 8.2 0 2.6 IV 19 19.5 33 17.5 36 15.1 0 3.6 Unk 9 19.5 20 37.1 18 31.5 0 31.4 Grade (%) Well Diff 0 4 13 11 32 49 100 27 Poorly Diff 48 59 46 45 42 34 0 19 Unk 52 37 40 44 25 17 0 53 LND (%) Y 73 51.9 33 21.4 58 33.7 100 46.4 N 22 36.6 60 66.5 42 54.4 0 43.1 Unk 10 11.5 6 12 0 11.8 0 10.5 Adj XRT (%) Y 58 29 60 24 25 21 100 18 N 29 69 26 74 75 78 0 81 Unk 13 2 13 2 0 1 0 1
Lenvatinib + pembrolizumab in patients with advanced endometrial cancer: Updated results.
Authors: Vicky Makker, Drew W. Rasco, Nicholas J. Vogelzang, Mark Messing, Marcia S. Brose, Allen Lee Cohn, Carol Aghajanian, Daniel E. Stepan, Corina E. Dutcus, Emmett V. Schmidt, Matthew Guo, Pallavi Sachdev, Robert Charles Shumaker, Matthew H. Taylor
Journal: Journal of Clinical Oncology (2018)

5596 Background: Lenvatinib (LEN) is an inhibitor of VEGFR 1−3, FGFR 1−4, and other kinases. Pembrolizumab (PEM) is an anti-PD-1 antibody. We report updated interim results from a phase 1b/2 study evaluating LEN + PEM in patients (pts) with advanced endometrial cancer (EC) (NCT02501096). Methods: In this multicenter, open-label study, pts with histologically confirmed EC irrespective of microsatellite instability (MSI) or mismatch repair (MMR) status and measurable disease per immune-related RECIST (irRECIST) received LEN (20 mg PO QD) plus PEM (200 mg IV Q3W). Tumor assessments were performed by investigators using irRECIST. The primary phase 2 endpoint was objective response rate at 24 weeks (ORRWK24), calculated only for evaluable pts who had 24 weeks of follow up or discontinued treatment or died prior to 24 weeks. Secondary endpoints included ORR (full analysis set), progression-free survival (PFS), and duration of response (DOR). Results: At data cutoff of Aug 1 2017, 54 pts were enrolled [endometrioid: Gr 1 (7), Gr 2 (12), Gr 3 (5); serous (18); others (8); unknown (4)]. Three (6%) pts were MSI-high (MSI-H); 43 (80%) were non-MSI-H/proficient MMR (MMRp); 8 (15%) were not done/unknown. Median follow-up for PFS was 4.0 months (95% confidence interval [CI], 2.7–7.6). ORRWK24 was 50.0% (95% CI, 32.4–67.6), and all responses were confirmed. ORR was 36.7% (95% CI, 23.4–51.7), which reflects the short follow-up time for pts with later enrollment. Median DOR has not yet been reached (not estimable [NE], 95% CI, 4.1–NE) and median PFS was 10.1 months (95% CI, 5.3–NE). Of the 3 MSI-H pts, 1 achieved partial response, 1 had stable disease, and 1 had progressive disease. For non-MSI-H/MMRp pts, ORRWK24 was 50.0% (95% CI, 29.9–70.1). Grade 3 treatment-related adverse events (TRAEs) occurred in 32 (59%) pts; there were no Grade 4 TRAEs. 3 (6%) pts discontinued treatment due to a TRAE. The most common TRAEs were hypertension (59%), fatigue (50%), diarrhea (44%), hypothyroidism (35%), and stomatitis (33%). Conclusions: Combination LEN + PEM demonstrated encouraging activity in advanced EC regardless of MSI/MMR status, with no new safety signals identified. A randomized, international, 2-arm, phase 3 study in recurrent EC is planned. Clinical trial information: NCT02501096.