tbuckley/cabot-search huggingface dataset:
Genomic profiling of tumors from patients with germline <i>BRCA</i> mutations.
Authors: Anne-Vibeke Laenkholm, Ida Marie Heeholm Soenderstrup, Maj-Britt Jensen, Jens Ole Eriksen, Mads Thomassen, Anne-Marie Gerdes, Maria Rossing, Heather Ann Brauer, Afshin Mashadi-Hossein, Sean Ferree, Bent Ejlertsen
Journal: Journal of Clinical Oncology (2018)

1533 Background: Gene expression profiling assays are not commonly used for therapy selection for breast cancer patients with germline BRCA mutations but a complete molecular characterization could lead to identification of novel subgroups where therapy modification may be considered. We hypothesized that the PAM50 intrinsic subtypes and ROR score in combination with characterization of the immune response could provide biological insights to guide the next generation of treatment strategies for BRCA-mutated tumors. Methods: The Danish Breast Cancer Group database was used to identify a cohort of 584 BRCA-mutated breast cancer patients diagnosed between 1977 and 2011. Tumor RNA from archived FFPE tissue samples was analyzed on the NanoString platform using a 770-gene Breast Cancer Panel and the PAM50 intrinsic subtypes were determined using the Prosigna gene signature algorithm. The immune response was evaluated with the Tumor Inflammation Signature (TIS) score. Results: Of the 532 samples assessable for PAM50 subtype, 54% were Basal-like, 7% Her2-Enriched, 23% Luminal B, and 16% Luminal A, with significant heterogeneity between BRCA1 and BRCA2 tumors. BRCA1 tumors were primarily Basal-like while BRCA2 tumors were enriched for Luminal subtypes. There was a wide range of Prosigna ROR scores with 15% of the Luminal tumors identified as low-risk (ROR≤40). Similarly, there was a broad spectrum of immune response with BRCA1 tumors demonstrating a higher average TIS score (P < 0.001). However, the heterogeneity of TIS by BRCA mutant was explained by intrinsic subtype with basal-like tumors exhibiting higher inflammation. Conclusions: To our knowledge, this is the largest study of a prognostic signature on BRCA-mutated tumors presented to-date. We observed heterogeneity in the intrinsic subtypes and a wide range of inflammation response with differences between BRCA1 and BRCA2 tumors being explained by intrinsic subtype. Additional analyses are ongoing including evaluation of signatures associated with DNA Damage, immune profile, and HRD as well as association of expression signatures with outcomes. Intrinsic Subtypes: N (%) Basal-like Her2-Enriched Luminal B Luminal A BRCA1 241 (73) 19 (6) 38 (12) 30 (9) BRCA2 48 (24) 18 (9) 84 (41) 54 (26)
Efficacy and safety of low-dosage apatinib monotherapy in advanced lung squamous cell carcinoma.
Authors: Qian Geng, Mengjie Wang, Yingzhi Lu, Wenyu Zhu, Zhiqiang Sun, Hua Jiang
Journal: Journal of Clinical Oncology (2018)

e21170 Background: Lung squamous cell carcinoma (SqCC) is the second most common histology in non-small-cell lung carcinomas (NSCLCs). For advanced lung SqCC, treatment options are still an unmet medical need. Few drugs could be selected when the disease progressed after second-line treatment. This study aimed to preliminarily assess the efficacy and safety of apatinib at a lower dosage (125-500mg/d) in patients with advanced lung squamous cell carcinoma. Methods: Eligible patients should be definitive diagnosed SqCC, who refused chemotherapy or failed first line, second line or even later lines of chemotherapy. Key exclusion criteria included major blood vessel involvement and massive haemoptysis with the amount more than 20ml. Apatinib was given every day, and treatment was continued until disease progression or unacceptable toxic effects. Progression free survival (PFS) was assessed by Kaplan–Meier test. Tumor responses were assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Results: Total 17 patients were enrolled from June 2015 to June 2017. Among them, 10 patients suffered from distant metastases before apatinib administration; 10 patients were with ECOG 2-3. Nine patients (52.9%) received 250mg daily of apatinib, 4 received 125mg, 2 received 425mg and 2 received 500mg daily. One patient failed to evaluate efficacy for personal reason so that 16 patients were eligible for tumor response to apatinib evaluation. The median PFS was 5.3 months (95% CI: 3.0–7.6 months). Three patients achieved partial response (PR) and the objective response rate (ORR) was 18.75% (3/16) and the total disease control rate (DCR) was 75% (12/16). There was no significant associations between the dose of apatinib and efficacy (p = 0.509). The main adverse events were fatigue (47.1%), hypertension (35.3%), hemoptysis (29.4%), proteinuria (23.5%) and loss of appetite (23.5%). No grade 4 adverse event was reported. All the dead events were not drug-related by physician’s judgment. Conclusions: Apatinib monotherapy at a lower dosage might be an optional choice for patients with advanced lung squamous cell carcinoma.
Initial results from first-in-human study of IPI-549, a tumor macrophage-targeting agent, combined with nivolumab in advanced solid tumors.
Authors: Ryan J. Sullivan, David S. Hong, Anthony W. Tolcher, Amita Patnaik, Geoffrey Shapiro, Bartosz Chmielowski, Antoni Ribas, Les H. Brail, Jennifer Roberts, Lucy Lee, Brenda O'Connell, Jeffrey Lorne Kutok, Suresh Mahabhashyam, Claudio Dansky Ullmann, Michael A. Postow, Jedd D. Wolchok
Journal: Journal of Clinical Oncology (2018)

3013 Background: IPI-549 is a potential first-in-class, oral, selective PI3K-γ inhibitor that in preclinical studies reprograms macrophages from an immune-suppressive to an immune-activating phenotype and can overcome resistance to checkpoint inhibitors. Methods: Ph 1/1b study IPI-549-01 (NCT02637531) is evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunomodulatory activity of IPI-549 to determine its recommended Ph 2 dose (RP2D) and preliminary efficacy, as monotherapy and combined with nivolumab (nivo), in advanced solid tumor pts. Pre- and on-treatment blood samples were obtained for flow cytometry, gene expression, and serum analysis. Results: Initial combination dose-escalation results are reported. 31 pts (30 evaluable), median age 57 yrs and median 4 prior therapies (8 with prior anti PD-(L)1 therapy), received IPI-549 20, 30, and 40 mg QD + nivo 240 mg Q2W in a 6+6 design. IPI-549 PK/PD were unaffected by nivo. The MTD was not reached. Most treatment-emergent adverse events (TEAEs) were Gr 1-2. The most common (≥ 2 pts) treatment-related TEAEs included rash (23%); pruritus (10%); and nausea, anemia, ALT increase, AST increase, and pyrexia (6% each), with no treatment-related deaths. 2 DLTs each occurred at IPI-549 30 mg (Gr 3 rash) and 40 mg QD (Gr 3 rash; Gr 3 ALT/AST increase). 2 pts demonstrated partial responses at first assessment (8 wks): 1 with adrenocortical carcinoma and 1 with microsatellite-stable gallbladder carcinoma receiving IPI-549 30 and 40 mg QD, respectively. 40% of pts (n = 12) remained on study ≥ 12 wks and 6 pts were ongoing at the 05 Feb data cutoff. Based on safety + PK/PD data, the RP2D was IPI-549 40 mg QD + nivo 240 mg Q2W. On-treatment blood samples show evidence of immune activation and reduced immune suppression, including upregulation of IFNg-responsive factors, such as PD-L1 and CXCL9/10, and dose-dependent re-invigoration/proliferation of exhausted PD1+CD8+CD45RA- T cells, evidenced by Ki67 increases. Conclusions: IPI-549 + nivo demonstrates favorable tolerability, early signs of clinical activity, and evidence of immune modulation. Combination expansion cohorts are enrolling at the RP2D. Clinical trial information: NCT02637531.
TCT-401 A Strategy of Percutaneous Coronary Intervention with Drug-Eluting Stents for the Treatment of Cardiac Allograft Vasculopathy May Normalize Survival
Authors: Richard Cheng, Evan Kransdorf, David Chang, Jignesh Patel, Jon Kobashigawa, Babak Azarbal
Journal: Journal of the American College of Cardiology (2018)
Characterization of genomic alterations, tumor mutational burden and PDL1 expression in 181 Chinese hepatocellular carcinomas.
Authors: Qi Ling, Pingzhou Yang, Xiaofeng Tang, Defei Hong, Linlin Qu, Yujie Feng, Yimeng Ou, Yong Li, Yujun Shi, Chunwen Xiao, Yanlin Li, Kai Wang, Weifeng Wang, Hong Bu
Journal: Journal of Clinical Oncology (2018)

e24276 Background: Hepatocellular carcinoma (HCC), the most common hepatic malignancy, is the second leading cause of cancer-related death worldwide. China accounts for more than 50% of new HCC cases and deaths in the world. The genomic profiles of HCC in Chinese patients had not been thoroughly elucidated to facilitate diagnosis and treatment. Methods: FFPE tumor and matched blood samples of 181 Chinese HCC patients, including 152 males (median age of 54) and 29 females (median age of 52), were collected for next-generation sequencing-based 450 genes panel assay. Genomic alterations (including single base substitutions, short and long insertions/deletions, copy number variations, and gene rearrangement in selected genes) and tumor mutational burden were assessed. In addition, the expression of tumor cell PDL1 was also evaluated by FDA-cleared DAKO 22c3 antibody. Results: The most frequently mutated genes in 181 Chinese HCC were TP53 (59.7%), TERT (34.3%), CTNNB1 (21.5%), AXIN1 (12.2%), RB1 (11.0%), STK24 (11.0%), ARID1A (9.9%), CCND1 (7.7%), TSC2 (6.6%) and FGF19 (6.6%). The mutation rates of TERT (p = 0.027) and RB1 (p = 0.016) were significantly higher in patients (pts) with TMB greater than the cohort medium of 7.2 muts/Mb. In addition, loss of function mutation of PBRM1 was found in 2.8% of the pts. About 7% of the patients had TMB value higher than 20 muts/Mb, compared to 1-2% in Western HCC pts, and 31% higher than 10 muts/Mb. Seventy-four patients (median age 54 years; median TMB 6.8 muts/Mb) had tumorous PDL1 expressions assessed by IHC assay. Thirty-six percent of patients were positive of PDL1 (tumor portion score TPS greater than 1%). Only three pts possessed both high TMB and high PDL1 expression (TPS > 50). No correlation was observed between the expression of PDL1 and TMB (r = 0.1). Conclusions: This is the first genomic profiling study of Chinese HCC pts along with TMB and PDL1 expression results. With less actionable gene alterations but more often high TMB and PDL1 expression than their Western counterparts, Chinese HCC pts could potentially benefit more from immune check point inhibitor-based therapies. However, no correlation was observed between the expressions of PDL1 and TMB values.
TCT-738 Incidence And Predictors Of Outcomes After First Definite Stent Thrombosis Event
Authors: Maria Tovar Forero, Thomas Zanchin, Kaneshka Masdjedi, None laurens zandvoort, Felix Zijlstra, Stephan Windecker, Nicolas Van Mieghem, Lorenz Raber, Joost Daemen
Journal: Journal of the American College of Cardiology (2018)
Weekly carfilzomib, lenalidomide, and dexamethasone (KRd) in relapsed or refractory multiple myeloma (RRMM): A phase 1b study.
Authors: Noa Biran, David Samuel DiCapua Siegel, Jesus G. Berdeja, Noopur S. Raje, Robert F. Cornell, Melissa Alsina, Tibor Kovacsovics, Belle Fang, Amy Kimball, Carl Ola Landgren
Journal: Journal of Clinical Oncology (2018)

8022 Background: KRd is approved for treatment of RRMM patients (pts). Under the approved KRd regimen, carfilzomib is given twice weekly (20/27 mg/m2; 10-min IV infusion). Here we present updated results from a dose-finding study assessing weekly KRd. Methods: This study consisted of a dose-evaluation component and a dose-expansion component in both RRMM and newly diagnosed MM. Results for RRMM pts are presented here. Two dose levels were evaluated: carfilzomib 56 mg/m2 and carfilzomib 70 mg/m2. All pts received carfilzomib (30-min IV infusion on days [D] 1, 8, and 15; 20 mg/m2 on C1D1), lenalidomide 25 mg (D1–21), and dexamethasone 40 mg (D1, 8, 15, and 22) on a 28-day cycle (dexamethasone was not given on D22 for cycles 9+). Pts in the expansion arm received the selected KRd regimen on the same schedule used for dose evaluation. Response was assessed by investigators. Results: Twenty-two RRMM pts were enrolled in the dose-evaluation part and received study drug (56 mg/m2, n = 10; 70 mg/m2, n = 12). The maximum tolerated dose of carfilzomib was not reached; the 70 mg/m2 dose was selected for dose expansion and 34 additional RRMM pts received this dose. Results are presented for pts who received carfilzomib 56 mg/m2 during dose evaluation (n = 10; median 2 prior regimens [range 1-3]) and for pts who received carfilzomib 70 mg/m2 during dose evaluation or expansion (n = 46; median 1 prior regimen [range 1-5]). Median (mean) average carfilzomib dose was 53.2 (52.8) mg/m2 in the 56 mg/m2 group and 62.4 (61.3) mg/m2 in the 70 mg/m2 group. Pt incidence of grade ≥3 adverse events was 70.0% (56 mg/m2) and 71.7% (70 mg/m2). Pt incidence of carfilzomib discontinuation due to adverse events was 20.0% (56 mg/m2) and 17.4% (70 mg/m2). There were three total deaths in the 70 mg/m2 group (one each due to cardiac arrest, cardiac disorder, and progressive disease). Overall response rates were 90.0% (56 mg/m2) and 89.1% (70 mg/m2); 20.0% (56 mg/m2) and 30.4% (70 mg/m2) of pts achieved a complete response (CR) or stringent CR. Conclusions: Once weekly KRd was effective and had manageable toxicity in pts with RRMM. As a weekly carfilzomib dosing regimen could offer pts greater convenience, these results support further clinical evaluation. Clinical trial information: NCT02335983.
The impact of health related quality of life (HRQoL) on short term survival of recurrent ovarian cancer patients: Analysis of pooled data from the North-Eastern German Society of Gynecological Oncology (NOGGO) meta data base.
Authors: Jalid Sehouli, Radoslav Chekerov, Maren Keller, Gulten Oskay-Oezcelik, Elena Ioana Braicu, Rolf Richter
Journal: Journal of Clinical Oncology (2018)

5539 Background: The goal of this analysis is a predictive score (recurrent ovarian cancer survival score, NOGGO-ROCSurv score) using HRQoL and other risk factors to estimate the risk of 1-year mortality in recurrent ovarian cancer patients. Methods: The data of recurrent patients with baseline HRQoL assessment using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 were selected from the NOGGO data base. ROC analysis were used to evaluate the predictive value of the risk factors and to find cut off values. Multivariable stepwise logistic regression models for 1-year mortality were performed to identify risk factors and their weights for a risk score. Results: Out of 972 patients 808 (83.1%) had 1st, 145 (14.9%) 2nd, and 19 (2.0%) 3rd recurrence, most patients (814, 83.8%) with advanced tumor stage at first diagnosis, 918 (94.4%) with good performance status (PS). The median age was 61 years (range 25-84 years). 1-year survival rate was 67.1%. Nearly all HRQoL scales except cognitive functioning, sleep disturbance, financial difficulties and diarrhea showed predictive value for short term survival with an area under the curve (AUC) up to 62.6% for global quality of life (gQoL). The risk score included chemo therapy free interval (CTFI) < 1 year, PS > 1, gQoL < 25, fatigue > 70, Nausea > 25, age ≥ 75 years, appetite loss > 25 and pre-existing cardiovascular disease (ordered from most to least important). The AUC for the risk score was 0.744 (95% CI 0.708 – 0.780), and the high risk group showed a positive predictive value of 84.5%, a negative predictive value of 72.5%, a sensitivity of 22.3%, and a specificity of 98.0%. Conclusions: HRQoL combined with other risk factors is predictive for 1-year survival. This risk score may help decision making for therapy and may be useful for stratification in randomized trials. But the identified patient group under risk is only small. So an improvement of the score is reasonable and a validation necessary.
Complete preoperative chemotherapy regimen FLOT: Evaluating the safety and histopathologic results in gastric cancer (GC).
Authors: Luis Villanueva, Jaime Anabalon, Olga Barajas, Carlos Gallardo, Jose Luis Leal, Mauricio Mahave, Luis Matamala, Angelica Molina, Felipe Reyes, Pamela Salman, Jean M Butte, Roberto Charles, Nicolas Devaud, Sebastian Hoefler, Sergio Enrique Panay, Elizabeth Milla, Maria Alejandra Muñoz, Christian Caglevic
Journal: Journal of Clinical Oncology (2018)

e16016 Background: The perioperative regimen FLOT has been associated with a better outcome in GC and a higher chance of having pathological complete response (pCR), Thus, giving all cycles of chemotherapy before surgery might improve pCR and having a positive impact on survival. The aim of this study is to evaluate the histological and safety results of FLOT regimen administrated before the surgery in patients (pts) of our institution. Methods: Retrospective study that evaluates pts with diagnosis of GC (T1-4, N+, M0) confirmed by biopsy, categorized according to preoperative images and post operative surgical procedures. They were presented to oncological committee joint of Instituto Oncologico FALP between november 2016 and september 2017 and received complete preoperative regimen FLOT. They were analyzed by demographic, clinical, safety and histopathologic variables. Results: There were 19 pts. 11 men (57,9%) and 8 women (42,1%) with median age of 65 years (32-80 years). Most of pts presented ECOG 0 (73,7%). Principal histopathologic diagnosis were adenocacinoma NOS (33%) and tubular adenocarcinoma (33%). Nine pts (47,4%) had a clinical IIB stage before the treatment. The mean of cycles was 7,4 (3-8 cycles). Ten pts required diminishing or suspending doses. Adverse events G3 or G4 occurred in 47,3%. Neutropenia G3-4 was the most frequent complication. Fifteen pts had been operated on. Three pts are pending surgery and 1 patient was not operated because presented progressive disease. All resected pts were undergone gastrectomy and D2 dissection. Three pts (20%) achieved pCR and 4 (26,6%) cases had metastatic disease (peritoneal carcinomatosis). No 30-day mortality occurred. Conclusions: Our data suggests that intensive and complete preoperative FLOT chemotherapy is feasible, safety and effective in GC. Most of pts received all the cycles of FLOT before surgery. The achievement of pCR was similar to other docetaxel-based chemotherapy trials, although our sample size is small. We had a high rate of metastatic patients perhaps an optimal staging is necessary before starting treatment.
FOLFIRINOX plus cetuximab (CET) or bevacizumab (BEV) in patients (pts) with initially unresectable colorectal liver metastases (CRLM) with BRAF mutated (mut) tumors: A subgroup analysis of the UNICANCER PRODIGE 14-ACCORD 21 (METHEP2) trial.
Authors: Evelyne Lopez-Crapez, Antoine Adenis, Simon Thezenas, Eric Assenat, Eric Francois, Rosine Guimbaud, Marion Chauvenet, Faiza Khemissa, Franck Audemar, Etienne Suc, Michel Rivoire, FranÃ§ois Ghiringhelli, Anne Mercier-Blas, Laurent Mineur, Yves Becouarn, Philippe Houyau, Trevor Stanbury, Claire Jouffroy-Zeller, Olivier Bouche, Marc Ychou
Journal: Journal of Clinical Oncology (2018)

3548 Background: The treatment of metastatic colorectal cancer (mCRC) pts with BRAF-mut tumors is a major challenge for physicians. They account for < 10% of mCRC, correlate with poor prognosis, and respond poorly to standard first-line regimens including chemotherapy doublets (2-CT) plus a targeted agent. Guidelines suggest treating BRAF-mut mCRC with a triplet CT regimen (3-CT; fluorouracil, irinotecan, and oxaliplatin combination) plus BEV, based on a subgroup analysis of the TRIBE study. In this analysis of 16 mCRC pts with BRAF-mut tumors, median PFS (mPFS) and OS (mOS) were 7.5 and 19 months (mo), respectively. Since the impact of 3-CT plus CET on outcomes in pts with BRAF-mut tumors is largely unexplored, we aimed to assess this subpopulation in the METHEP2 trial. Methods: This trial assessed whether 3-CT (FOLFIRINOX) compared to 2-CT (FOLFOX or FOLFIRI), combined with CET or BEV (by KRAS exon 2/RAS status), would increase R0/R1 liver resection rates in pts with initially CRLM. As an exploratory analysis, we assessed the outcome of the subset of BRAF-mut mCRC pts. Results: 256 pts were included. KRAS exon 2 and RAS (KRAS/NRAS: exon 2, exon 3, exon 4) were mutated in 91/256 pts (35.5%) and in 109/218 pts (50%), respectively. The R0/R1 liver resection rate was 57% in the 3-CT arm vs. 48% in the 2-CT arm. mPFS was 12.8 mo in the 3-CT arm vs. 11.5 mo in the 2-CT arm (HR, 1.05; 95%CI, 0.79-1.39). mOS was 42.9 mo in the 3-CT arm vs. 37.6 mo in the 2-CT arm (HR, 0.80; 95%CI, 0.56-1.16). Nine out of 230 (3.9%) mCRC pts were BRAF-mut: 8/9 pts received CET and 1 (in the 2-CT arm) received BEV as the targeted agent. Efficacy results in the 2-CT (n = 4) vs. the 3-CT (n = 5) arms were as follows: objective tumor response, 0/4 vs. 4/5; R0/R1 resection, 0/4 vs. 2/5; mPFS, 1.8 vs. 6.1 mo; and mOS, 6.6 vs. 21.3 mo. Conclusions: In this small series, pts with BRAF-mut tumors treated with 3-CT plus a targeted agent had better PFS and OS than those treated with 2-CT plus a targeted agent. Moreover, intent-to-treat survival outcomes with 3-CT plus CET are in the same range than those with 3-CT plus BEV from TRIBE. Clinical trial information: NCT01442935.
Value of innovation in oncology: The position of European cancer patients on access to innovative treatments.
Authors: Francesco Florindi, Francesco De Lorenzo, Kathi Apostolidis, Jana Pelouchova, Andrew Winterbottom, Szymon Chrostowski, Dan Cimpoeru, Natacha Bolanos, Anna Rek, Isabelle Manneh-Vangramberen, Jiska Bolhuis, Lydia Makaroff
Journal: Journal of Clinical Oncology (2017)

e18021 Background: The paper presents the position of the European Cancer Patient Coalition (ECPC), in partnership with Interel, on the value of innovation in oncology today, focusing on issues that would benefit most from the direct involvement of patients.The objective of the paper is to present key factors affecting access to innovation in oncology in Europe and to propose key recommendations on how to improve equity in access and to actively involve patients in decision-making. Methods: The document was produced under the supervision of the ECPC Board of Directors, and the contribution of the ECPC General Assembly, which was consulted in June 2016 during the Annual General Meeting.The paper is based also on a systemic literature review. Results: The paper analyses the main systems barriers to access to innovation, which affect all European cancer patients: low level fo health expenditure on cancer; high cost of innovative treatments; complex regulatory and reimbursement pathways; lack of enabling environments; limited patient involvement in decision making. The paper goes on identifying 40 key policy recommendations in 10 pivotal areas (see Table). Conclusions: Innovative healthcare technologies, strategies, and services offer the potential to improve the lives of many people living with cancer. Ensuring that effective innovations are accessible and affordable to all patients is a challenge facing all cancer stakeholders. The successful development and implementation of new cancer care modalities stems from putting the needs of patients at the centre of the innovation process. Patients are the ultimate beneficiaries and users of cancer diagnosis, treatment, and care. They have unique knowledge, perspectives, and experiences that improves and encourages innovation in oncology. Optimal innovation can only be obtained by understand the diverse needs and preferences of cancer patients, and integrating patient-centred approaches into the regulatory and healthcare system. [Table: see text]