tbuckley/cabot-search huggingface dataset:
Frequent copy number increase of CCND1 or CDK4 in melanomas without mutations in BRAF and RAS genes
Authors: John A. Curtin, Jane Fridlyand, Hetal Patel, Klaus Busam, Heinz Kutzner, Kwang-Hyun Cho, Setsuya Aiba, Eva-Bettina Bröcker, Philip E. Leboit, Toshiro Kageshita, Daniel Pinkel, Boris C. Bastian
Journal: Cancer Research (2005)

1671  The major etiologic factor for malignant melanoma is UV light. However, melanoma most commonly affects intermittently rather than chronically sun-exposed skin, and can also be found in sites that are substantially or completely sun-protected. We hypothesized that this variability could be explained by the existence of biologically and genetically distinct types of melanoma with different etiologic susceptibility to UV-light. We compared the DNA copy number status using array CGH and mutational status in BRAF and RAS genes of 126 primary melanomas arising in four UV exposure groups: skin with (n=30) and without (n=40) chronic sun damage; palms, soles and subungual (acral) sites (n=36); and mucosa (n=20). Using a supervised methodology we found significant differences in the frequencies of regional DNA copy number changes and mutation frequencies in BRAF between the four groups. Based on the copy number changes alone samples could be correctly classified into the four groups with 70% overall accuracy. In two-way comparisons, melanomas arising on skin with and without signs of chronic sun-damage could be correctly classified with 84% accuracy. Similarly acral could be distinguished from mucosal melanoma with 89% accuracy. Mutation in RAS genes occurred exclusively in samples without BRAF mutation and most commonly affected NRAS. Whereas 81% of melanomas on skin without chronic sun-damage had mutations in either BRAF or NRAS, the majority of melanomas in the other groups had mutations in neither gene (acral;67%, mucosal; 84%, CSD; 67%). Melanomas that were wild-type for BRAF and RAS genes showed common copy number increases by array CGH targeting down-stream components of the RAS-BRAF pathway such as CDK4 or CCND1. Amplifications of CDK4 and CCND1 were exclusive of each other. In addition we observed that BRAF but not RAS mutations were frequently paralleled by loss of PTEN, confirming the notion that activation of the PI3-Kinase pathway via PTEN loss or RAS mutation is an independent somatic target in primary melanoma. The divergent patterns of genetic alterations in melanomas of different anatomic sites and sun exposure patterns indicate distinct genetic pathways to melanoma with implications for the design of future clinical and experimental studies. The demonstration of the strong complimentarity of genetic alterations in BRAF, NRAS, CDK4 and CCND1 implicates CDK4 and CCND1 as independent oncogenes in melanomas wild-type for BRAF and NRAS.
Comprehensive Genomic and Transcriptomic Analysis for Guiding Therapeutic Decisions in Patients with Rare Cancers
Authors: Peter Horak, Christoph Heining, Simon Kreutzfeldt, Barbara Hutter, Andreas Mock, Jennifer Hüllein, Martina Fröhlich, Sebastian Uhrig, Arne Jahn, Andreas Rump, Laura Gieldon, Lino Möhrmann, Dorothea Hanf, Veronica Teleanu, Christoph E. Heilig, Daniel B. Lipka, Michael Allgäuer, Leo Ruhnke, Andreas Laßmann, Volker Endris, Olaf Neumann, Roland Penzel, Katja Beck, Daniela Richter, Ulrike Winter, Stephan Wolf, Katrin Pfütze, Christina Geörg, Bettina Meißburger, Ivo Buchhalter, Marinela Augustin, Walter E. Aulitzky, Peter Hohenberger, Matthias Kroiss, Peter Schirmacher, Richard F. Schlenk, Ulrich Keilholz, Frederick Klauschen, Gunnar Folprecht, Sebastian Bauer, Jens Thomas Siveke, Christian H. Brandts, Thomas Kindler, Melanie Boerries, Anna L. Illert, Nikolas von Bubnoff, Philipp J. Jost, Karsten Spiekermann, Michael Bitzer, Klaus Schulze-Osthoff, Christof von Kalle, Barbara Klink, Benedikt Brors, Albrecht Stenzinger, Evelin Schröck, Daniel Hübschmann, Wilko Weichert, Hanno Glimm, Stefan Fröhling
Journal: Cancer Discovery (2021)

Abstract The clinical relevance of comprehensive molecular analysis in rare cancers is not established. We analyzed the molecular profiles and clinical outcomes of 1,310 patients (rare cancers, 75.5%) enrolled in a prospective observational study by the German Cancer Consortium that applies whole-genome/exome and RNA sequencing to inform the care of adults with incurable cancers. On the basis of 472 single and six composite biomarkers, a cross-institutional molecular tumor board provided evidence-based management recommendations, including diagnostic reevaluation, genetic counseling, and experimental treatment, in 88% of cases. Recommended therapies were administered in 362 of 1,138 patients (31.8%) and resulted in significantly improved overall response and disease control rates (23.9% and 55.3%) compared with previous therapies, translating into a progression-free survival ratio &amp;gt;1.3 in 35.7% of patients. These data demonstrate the benefit of molecular stratification in rare cancers and represent a resource that may promote clinical trial access and drug approvals in this underserved patient population. Significance: Rare cancers are difficult to treat; in particular, molecular pathogenesis–oriented medical therapies are often lacking. This study shows that whole-genome/exome and RNA sequencing enables molecularly informed treatments that lead to clinical benefit in a substantial proportion of patients with advanced rare cancers and paves the way for future clinical trials. See related commentary by Eggermont et al., p. 2677. This article is highlighted in the In This Issue feature, p. 2659
Trial in progress: A phase 1-2 multicenter, open-label, dose-escalation and dose-expansion study to evaluate the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of ABN401 in patients with advanced solid tumors.
Authors: Dae Ho Lee, Aflah Roohullah, Byoung Chul Cho, Charlotte Rose Lemech, Paul L. de Souza, Michael Millward, Jun Young Choi, Kyung Eui Park, Minseon Lee, YeongMun Kim, YOUNGKEE Shin, Ji-Youn Han
Journal: Journal of Clinical Oncology (2021)

TPS3157 Background: c-MET (hepatocyte growth factor (HGF) receptor) overexpression, either by gene amplification, or mutation is associated with oncogenic transformation in numerous malignancies including lung, gastric, skin, renal, colorectal, and pancreatic cancers. ABN401 inhibits the activation of c-MET by reversibly interfering with the binding of c-Met tyrosine kinase to adenosine triphosphate (ATP) and blocking the receptor's downstream signaling that has demonstrated efficacy in NSCLC and gastric cancer in mouse xenograft and PDx models. This clinical trial is in progress in patients with advanced cancers. Methods: ABN401 is being evaluated in an open-label, non-randomized, dose-escalation (phase 1) study in patients with advanced solid tumors, and dose-expansion (phase 2) in patients with targeted indications and c-MET biomarker expression (NCT04052971). The phase 1 explores ascending daily doses of oral ABN401 monotherapy in 21-day cycles to identify the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). A preplanned extension (pilot expansion) study has been initiated based on predefined positive efficacy signals at intermediate doses up to 10 NSCLC patients who have c-MET alteration. Once RP2D is determined, the phase 2 expansion of up to 10-29 patients in four specific tumor-type cohorts is planned, utilizing a Simon's optimal two-stage design to evaluate the clinical activity of ABN401. ABN401-001 study began enrolling patients in August 2019 and is ongoing in Korean and Australia. Dose escalation up to cohort 4 has been completed, enrollment to cohort 5 began in November 2020. AEs are assessed according to CTCAE v5. Tumor response is determined according to RECIST 1.1 criteria and safety findings reviewed by the DRC, which will determine the RP2D and MTD. Key Phase 1 eligibility criteria include 1) histological or cytological diagnosis of melanoma or any type of carcinoma or sarcoma and 2) refractory metastatic disease, or refractory locally advanced disease not amenable to local therapy. For the extension (pilot expansion) study, patients must have NSCLC with MET exon 14 skipping, MET amplification and/or c-MET overexpression. An exploratory study is being conducted for co-development of a companion diagnostic (CDx) system including a CTC device and ddPCR kit through liquid biopsy. Clinical trial information: NCT04052971.
Retrospective cohort study of estrogen receptor low positive early breast cancer using real world data.
Authors: Shahla Bari, Hung T. Khong, Brian J. Czerniecki, Ricardo L Costa
Journal: Journal of Clinical Oncology (2021)

525 Background: Estrogen receptor (ER) positive breast cancer (BC) is a heterogeneous disease, with ongoing debate on the optimal cut off point for clinically relevant ER expression. Tumors harboring ≤10% ER expression are associated with poor outcomes. We used a real-world database to assess prognostic and predictive value of an alternative ER expression cut points. Methods: This retrospective cohort study used the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database. During the study period, the de-identified data originated from approximately 280 US cancer clinics (̃800 sites of care). We evaluated the association between ER expression (assessed locally by immunohistochemistry according to ASCO/CAP guidelines) with tumor characteristics, and treatment patterns of patients with early-stage BC (stage I-III) using descriptive statistics. Recurrence free survival and overall survival was defined as time in months from date of surgery until the data of documented cancer recurrence or death respectively. We used Kaplan Myer survival curves to calculate recurrence free (RFS) and overall survival (OS) of patients with ER low, ER intermediate and ER high tumors. To define an alternative ER expression cut point, the data set was divided into 2/3 training and 1/3 test data. A cut point analysis was performed on the training data set to find the optimum cut point of ER+ staining based on correlation with recurrence free survival as the outcome. Results: Among 4,697 ER positive early-stage BC patients, 83 (1.8%) had ER low (ER expression :1-10%) and 36 (0.8%) had ER intermediate BC (11-20%). Median follow up time was 63 months (range 24-84). ER low tumors were associated with higher tumor grade, larger size, and higher axillary tumor burden compared to ER high positive tumors ( &gt; 20% ER expression). African American patients had a higher prevalence of both triple negative and ER low positive BCs compared to ER high tumors- 21%, 22%, and 8% respectively. No significant differences in patient- or tumor-associated characteristics were observed between Low ER and intermediate-ER positive BC patients. Both ER low and intermediate positive tumor patients had survival outcomes similar to patients with TNBC and worse than ER high positive tumors (p &lt; 0.001). No significant correlations between endocrine therapy and RFS or OS were observed among patients with either ER low or intermediate BCs (HR 1.47 and 2.57, p &gt; 0.05; respectively). Sensitivity analysis showed that tumors with ≤ 20% ER expression were associated with worse RFS in both univariate and multivariate analyses (p &lt; 0.05). Conclusions: These findings suggest that patients with ER expression rates ≤ 20% have poor outcomes and derive minimal benefit from endocrine therapies.
IMbrave150: Exploratory efficacy and safety results of hepatocellular carcinoma (HCC) patients (pts) with main trunk and/or contralateral portal vein invasion (Vp4) treated with atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) in a global Ph III study.
Authors: Valeriy Vladimirovich Breder, Arndt Vogel, Philippe Merle, Richard S. Finn, Peter R. Galle, Andrew X. Zhu, Ann-Lii Cheng, Yin-Hsun Feng, Daneng Li, Vincent E. Gaillard, Lindong Li, Alan Nicholas, Riccardo Lencioni
Journal: Journal of Clinical Oncology (2021)

4073 Background: Atezo + bev has been approved in &gt;60 countries for pts with unresectable HCC who have not received prior systemic therapy, based on IMbrave150 (NCT03434379; Finn RS NEJM 2020). Due to their poor prognosis and the hemodynamic changes from increased portal vein pressure, pts with main portal vein tumor thrombus are often excluded from pivotal HCC trials. Here, we report exploratory efficacy and safety results of pts with Vp4 (presence of a tumor thrombus in the main trunk and/or contralateral portal vein) using updated IMbrave150 data (Finn RS ASCO GI 2021). Methods: Pts were randomized 2:1 to atezo 1200 mg IV q3w + bev 15 mg/kg IV q3w or sor 400 mg bid until unacceptable toxicity or loss of clinical benefit per investigator. IMbrave150 enrolled 501 systemic treatment (tx)–naive unresectable HCC pts, ≥1 measurable untreated lesion (RECIST 1.1), Child-Pugh class A liver function and ECOG PS 0/1, including 73 (15%) Vp4 pts. This post hoc exploratory analysis was conducted with a median follow-up of 15.6 mo in ITT pts. Results: Of the Vp4 pts, 48 received atezo + bev and 25 received sor. Median OS (mOS) was 7.6 vs 5.5 mo (HR, 0.62; 95% CI: 0.34, 1.11) and median PFS (mPFS) per independent review facility (IRF)–assessed RECIST 1.1 was 5.4 vs 2.8 mo (HR, 0.62; 95% CI: 0.35, 1.09) with atezo + bev and sor, respectively. ORR per IRF RECIST 1.1 was 23% (11/47) with atezo + bev (2 [4%] pts had CR) vs 13% (3/23) with sor (1 [4%] pt had CR). All-grade variceal bleeding was higher with atezo + bev in Vp4 (13.6%) vs rest of ITT pts (2.5%). See table for further efficacy and safety data. Conclusions: The benefits of atezo + bev over sor in Vp4 pts are consistent with those in ITT pts across all efficacy endpoints, despite the expected disease-intrinsic increase in variceal bleeding in Vp4 vs rest of ITT pts. The overall positive benefit-risk profile supports the use of atezo + bev in pts with Vp4. Clinical trial information: NCT03434379. [Table: see text]
PIT-2: A multicenter phase II trail of S-1 plus cisplatin with concurrent radiotherapy followed by surgery in stage IIIA (N2) lung squamous cell carcinoma.
Authors: Kazuya Takamochi, Masahiro Tsuboi, Morihito Okada, Seiji Niho, Satoshi Ishikura, Shunsuke Oyamada, Takuhiro Yamaguchi, Fumihiro Tanaka, Ichiro Yoshino, Masanori Tsuchida, Satoshi Shiono, Hiroyuki Oizumi, Norihito Okumura, Tomohiro Haruki, Kenji Suzuki
Journal: Journal of Clinical Oncology (2021)

8543 Background: A multicenter phase II study, PIT-2 (Personized Induction Therapy-2), was performed to investigate the efficacy and safety of S-1 plus cisplatin and concurrent thoracic radiation therapy (TRT) followed by surgery in patients with stage IIIA (N2) lung squamous cell carcinoma (LSCC). To date, no clinical trials on the use of induction therapy prior to surgery have focused solely on the treatment of N2 LSCC. Methods: Eligible patients were 20 to 75 years old and had stage IIIA (pathologically proven N2) LSCC, performance status of 0-1, and no prior treatment. The patients received induction therapy consisting of three cycles of S-1 and cisplatin plus concurrent TRT (45 Gy in 25 fractions) followed by surgery. S-1 was administered orally at 40 mg/m 2 twice per day, on days 1 through 14 along with an intravenous infusion of cisplatin (60 mg/m 2 ) on day 1. The treatment cycles were repeated every four weeks. The primary endpoint was 2-year progression-free survival (PFS) rate and key secondary endpoints included overall survival (OS), the objective response rate (ORR) as defined by the Response Evaluation Criteria in Solid Tumors version 1.1, pathological complete remission (pCR) rate, feasibility, and toxicity. Results: Of the 45 patients registered between December 2013 and September 2018, 43 received induction therapy. Of the 43 patients, 39 (91%) underwent surgery (25 lobectomies, 10 bilobectomies, three pneumonectomies, and one wedge resection). The complete resection rate was 95% (37/39). Median follow-up time was 35.7 months. The 2-year PFS and OS rates were 67% (90% CI: 54-78%) and 70% (95% CI: 53-81%), respectively. The ORR and pCR rates were 86% (37/43, 95% CI: 76-96%) and 39% (15/39, 95% CI: 23-54%), respectively. Grade (G) 3 or 4 toxicities during the induction therapy in 43 patients included neutropenia (40%), anemia (9%), thrombocytopenia (7%), and hyponatremia (7%). Severe surgical complications in 39 patients included G3/4 pneumonia (5%), G3 bronchopleural fistula (5%), and G3 pleural effusion (5%). No G3/4 intraoperative adverse events occurred. There was no 30-day postoperative mortality and one 90-day postoperative mortality in a patient who underwent right pneumonectomy and developed pneumonia after discharge. Conclusions: Induction therapy using S-1 plus cisplatin and concurrent TRT followed by surgery is a promising treatment for patients with stage IIIA (N2) LSCC. Clinical trial information: 000012413.
Novel ETV1 mutation in small cell lung cancer transformation resistant to EGFR tyrosine kinase inhibitors.
Authors: Yan Zhou, Hao Bai, Lei Cheng, Baohui Han, Liwen Xiong
Journal: Journal of Clinical Oncology (2021)

e20568 Background: Non-small cell lung cancer (NSCLC) patients harboring mutations in the epidermal growth factor receptor (EGFR) gene dramatically respond to EGFR tyrosine kinase inhibitors (TKIs). However, these patients inevitably developed acquired resistance to TKIs. Among them, small cell lung cancer (SCLC) transformation is a relatively rare mechanism of resistance. However, the mechanism of SCLC transformation is largely unclear. Methods: We performed a 639 cancer-relevant gene panel to detect genetic differences of tissues before and after TKIs resistance caused by SCLC transformation. In vitro experiments were conducted to study the role of ETS variant transcription factor 1 (ETV1) on SCLC transformation and TKIs resistance. Results: We present two EGFR-mutant pulmonary adenocarcinoma (ADC) patients. One with EGFR exon 19 deletion (Ex19del) accepted first-line gefitinib treatment and then received osimertinib(AZD9291) treatment due to acquisition of EGFR-T790M mutation. A novel ETV1 mutation (p.P159S) was detected in SCLC samples after SCLC transformation when not coexisting with T790M. Another patient harbored an EGFR exon 21 mutation (p.L858R) with a long-lasting response to first-line gefitinib and then transformed to SCLC. A previously unreported ETV1 mutation (p.E462Q) was detected in SCLC tissue. In vitro, ETV1 p.E462Q and p.P159S mutations participated in neuroendocrine differentiation by inducing the expression of the neuroendocrine transcription factor, achaete-scute homolog 1 (ASCL1) and promoted H69 cells proliferation. Besides, ETV1 p.E462Q and p.P159S mutations were resistant to first-generation (gefitinib) and third-generation (osimertinib) TKIs after introducing into NCI-H358 cells. Conclusions: Novel ETV1 p.E462Q and p.P159S mutations were found in SCLC tissues of TKIs resistant patients, providing novel understanding of ETV1 involved in acquired resistance to EGFR-TKIs via SCLC transformation.
PKM1 Exerts Critical Roles in Cardiac Remodeling Under Pressure Overload in the Heart
Authors: Qinfeng Li, Chao Li, Abdallah Elnwasany, Gaurav Sharma, Yu A. An, Guangyu Zhang, Waleed M. Elhelaly, Jun Lin, Yingchao Gong, Guihao Chen, Meihui Wang, Shangang Zhao, Chongshan Dai, Charles D. Smart, Juan Liu, Xiang Luo, Yingfeng Deng, Lin Tan, Shuang-Jie Lv, Shawn M. Davidson, Jason W. Locasale, Philip L. Lorenzi, Craig R. Malloy, Thomas G. Gillette, Matthew G. Vander Heiden, Philipp E. Scherer, Luke I. Szweda, Guosheng Fu, Zhao V. Wang
Journal: Circulation (2021)

Metabolic remodeling precedes most alterations during cardiac hypertrophic growth under hemodynamic stress. The elevation of glucose utilization has been recognized as a hallmark of metabolic remodeling. However, its role in cardiac hypertrophic growth and heart failure in response to pressure overload remains to be fully illustrated. Here, we aimed to dissect the role of cardiac PKM1 (pyruvate kinase muscle isozyme 1) in glucose metabolic regulation and cardiac response under pressure overload.
Real-world outcomes in patients with metastatic clear cell renal cell carcinoma receiving front-line axitinib plus pembrolizumab versus ipilimumab plus nivolumab.
Authors: Kevin Zarrabi, Elizabeth A. Handorf, Benjamin Miron, Matthew R. Zibelman, Fern Anari, Pooja Ghatalia, Elizabeth R. Plimack, Daniel M. Geynisman
Journal: Journal of Clinical Oncology (2021)

4551 Background: Front-line treatment for patients (pts) with metastatic clear cell renal cell carcinoma (mRCC) has undergone rapid advances in the last five years. This evolution has led to uncertainty about the optimal first line combination regimen. Herein, we compare real-world outcomes in pts treated with either axitinib/pembrolizumab (A/P) or ipilimumab/nivolumab (I/N) reported by International Metastatic RCC Database Consortium (IMDC) score. Methods: The nationwide Flatiron Health electronic health records-derived database was used to select pts diagnosed with mRCC and treated with front-line A/P or I/N from 2018-2020. The primary endpoints were overall-survival (OS) and real-world progression free survival (rwPFS). The survival analyses were adjusted using propensity score-based Inverse Probability of Treatment weighting, providing balance on age, gender, insurance, race, IMDC, practice type, and nephrectomy. Survival was assessed from beginning of therapy, and survival by treatment groups was compared using weighted and unweighted Kaplan-Meier curves with log-rank tests and weighted Cox proportional hazards regressions. Disease characteristics between the treatment groups were compared using chi-square and T-tests. Results: 821 pts received frontline A/P (n=259) or I/N (n= 562). Demographics and clinical parameters were similar between the two cohorts. Median age was 66 years, 73% were male, and 54.9% had a nephrectomy. 459 pts had all IMDC criteria factors available, 242 pts had missing factors but enough to define as intermediate/poor risk, 120 pts had unknown IMDC risk. Adjusted median OS was not statistically different: mOS for A/P was not reached (NR) while I/N was 22 mo (95% CI, 19.8-NR; p=0.40). Twelve-month survival was 68.5% for A/P treated pts and 65.8% for I/N treated pts (P=0.41). Twelve-month rwPFS was 41.4% for A/P treated pts and 39.7% for I/N treated pts (P=0.14). No statistical difference in survival was seen within IMDC risk strata (see table). Conclusions: In this retrospective, real-world study of pts treated with front-line A/P or I/N, 12-month survival was not statistically different irrespective of IMDC risk. Longer follow-up will be necessary to discern any significant differences.[Table: see text]
An adventitial painting modality of local drug delivery to abate intimal hyperplasia
Authors: Takuro Shirasu, Nisakorn Yodsanit, Xiujie Xie, Yi Zhao, Yuyuan Wang, Ruosen Xie, Yitao Huang, Bowen Wang, Go Urabe, Shaoqin Gong, Lian-Wang Guo, K. Craig Kent
Journal: Biomaterials (2021)