bluuebunny/crossref_metadata_2025_split huggingface dataset:
Competing mortality (CM) risk in patients with resected stage I and II non-small cell lung cancer (NSCLC): A Surveillance, Epidemiology, and End Results (SEER) analysis.
Authors: Nagaraj Gayathri , Subramanian Janakiraman , Gao Feng , Devarakonda Siddhartha , Govindan Ramaswamy 
Published: March 2020

7563 Background: CM risk has been identified as a potential confounder in the interpretation of treatment effects in head and neck cancer (Rose et al. J Clin Oncol. 2011). Lung cancer patients (pts) are at considerable risk for CM due to their advanced age at diagnosis and smoking related chronic diseases. We plan to identify risk factors for CM in pts with early stage NSCLC and develop a statistical model to estimate the effect of CM on power calculation for lung cancer clinical trials. Methods: Using SEER registry we identified 32104 pts who had undergone surgical resection with or without radiation for stage I and II NSCLC between 1994 and 2006. The data set was split into two groups: training set (75%) and testing set (25%). Risk factors for lung cancer-specific mortality (LCSM) and CM were identified using training data by Gray’s sub-distribution regression of competing risk. Pts from the testing data were then stratified according to CM risk and the impact of this risk on power loss was evaluated. Results: The 5-year cumulative incidence of death from lung cancer, other causes and overall mortality was 32.7%, 14.2% and 46.9% respectively. Risk factors for CM were: age (hazard ratio [HR] 1.05), male gender (HR 1.43), divorced (HR 1.30), widowed (HR 1.23) or single (HR 1.29) marital status, squamous (HR 1.40) or not-otherwise-specified (HR 1.22) histology, stage I NSCLC (HR 1.27) and sublobar resection (HR 1.23). The 5-year cumulative incidence of CM in low, mid and high-risk tertiles was 7%, 14% and 21% respectively. Sample size calculations based on all-cause mortality (ACM) result in over-estimation of power as the risk for CM increases. In order to restore the underestimated power in LCSM, 19% and 35% more pts are required in the mid and high CM risk groups respectively (Table). Conclusions: Our findings indicate that conventional sample size calculation methods can result in significant loss of power and incorporating CM risk models in power estimation should be considered for clinical trials involving early stage NSCLC pts. [Table: see text]
A favorable population among clinical stage IIIA-N2 non-small cell lung cancer: The importance of the location of the primary tumor and involved nodes.
Authors: Matsunaga Takeshi , Suzuki Kenji , Takamochi Kazuya , Oh Shiaki 
Published: March 2020

7575 Background: The number of station of involved N2 nodes has been considered to be one of the most important prognostic factors for lung cancer. However most reports detailed with not clinical nodal status, but pathological nodal status. We investigated the relationship between prognosis and the location of the primary tumor and involved nodes. Methods: A retrospective study was conducted on 1257 patients with primary lung cancer, which was resected between 1996 and 2009. Among them, 79 patients (6.3%) had cN2, c-stage IIIA, pN2 and NSCLC. Mediastinal lymph node with a diameter of 10mm or more in the short axis was diagnosed as metastasis. We defined cN2α as only involvement of upper mediastinal lymph node (UMLN) in main tumor located on upper lobe or as that of lower mediastinal lymph node (LMLN) in main tumor located on lower lobe. And we did cN2β as involvement of LMLN in main tumor located on upper lobe with or without metastatic UMLN or as that of UMLN in main tumor located on lower lobe with or without metastatic LMLN. We analyzed preoperative clinical factors and investigated overall and disease-free survival. Results: The overall 5-year survival rate was 30.2% and median follow-up was 52.8 months. The disease-free 5-year survival rate was 22.2%. The differences in survival between cN2α and cN2β were statistically significant (29.5% vs. 0%, p-value=0.0007), whereas no significant differences was found between cN2 single station and multiple station (23.3% vs. 19.4%, p-value=0.1220). Multivariate analysis with cox’s hazard model disclosed that cN2α was independent good disease-free prognostic factor(HR: 0.426, 95%CI: 0.193-0.941). The sensitivity, specificity and positive predictive value for pN2 single station based on cN2 single station were 71.4%, 49.1% and 34.9% (p=0.1269). Conclusions: Clinical mediastinal lymph node status based on the location of the primary tumor and involved nodes was an important preoperative prognostic factor. Thus this factor should be taken into consideration for planning and evaluating clinical trials. Another fruit of the study was that clinical single nodal N2 was not always pathological single N2 disease.
Reproducible molecular characterization of non-small cell lung cancer from paraffin.
Authors: Wilkerson Matthew , Lai-Goldman Myla , Bernard Philip Seth , Perou Charles M. , Hayes David N. , Grilley-Olson Juneko E. 
Published: March 2020

7576 Background: Recommendations exist to aid the clinically relevant non-small cell lung cancer (NSCLC) classification of squamous (SQ) versus adenocarcinoma (AD), including immunohistochemistry (IHC) for TTF1 and p63. We hypothesize that PCR of RNA gene panels may improve the diagnostic accuracy over IHC. Methods: A multi-institutional cohort of NSCLC patients was abstracted for use of IHC in clinical practice. RNA was isolated from routine paraffin sections and a 54-gene Histology by gene Expression Predictor (HEP) was implemented to distinguish SQ, AD, and other NSCLC variants. IHC for TTF1 and p63 was obtained on a subset of patients in a standardized manner. To compare the reproducibility of PCR diagnostics to morphologic diagnosis, a subset of samples was processed as matched pairs from the same tumor, in blinded manner. Results: 493 clinical samples were analyzed from 419 patients. Pathologists obtained any IHC in 22% of the cases, with TTF1 or p63 in <10% of cases. In the subset of cases where standardized TTF1 and p63 was obtained, the stains were un-evaluable or incompletely obtained in 30% for reasons including technical failure, limited sample, and ambiguous staining (i.e positive for both p63 and TTF1); on this same subset, the HEP technical failure rate was 7%. In cases where staining was successful, both IHC and the HEP agreed with the clinical diagnosis at high rates (93 and 91% respectively). In IHC un-evaluable cases, slides were reviewed by up to 7 additional pathologists. In general such cases failed to produce a consensus diagnosis, suggesting that IHC failure indicates a difficult to diagnose case (kappa statistic <0.5). As another concordance assessment method, we evaluated a second diagnostic property, reproducibility, by taking paired samples from the same case for blinded review. Strikingly, morphologic review in a blinded manner by pathologist generated low agreement with overall agreement of 65% compared to the HEP agreement of 92%. Conclusions: PCR based diagnostics such as the HEP may improve NSCLC diagnostic performance
Antitumor activity in advanced cancer patients with thymic malignancies enrolled in early clinical drug development program (phase I trials) at Institut Gustave Roussy.
Authors: Kossai Myriam , Duchemann Boris , Caramella Caroline , Boutros Celine , Massard Christophe , Vielh Philippe , Gazzah Anas , Bahleda Rastislav , Angevin Eric , Hollebecque Antoine , Soria Jean-Charles , Besse Benjamin 
Published: March 2020

7604 Background: Thymic epithelial neoplasms (TENs) represent a rare entity with poor prognosis and limited systemic treatment options, particularly in advanced stages and/or in thymic carcinomas (TC). The aim of this study was to assess the clinical benefit, the efficacy and toxicities of agents for patients (pts) with a refractory TEN enrolled in Phase I trials. Methods: We reviewed retrospectively pts with advanced pretreated TEN enrolled in Phase I trials at the Institut Gustave Roussy (SITEP) between 1994 and 2012. Toxicities were reported and scored according to NCI CTCAE version 3.0. Efficacy was assessed using RECIST version 1.1. Results: Twenty-two treated pts were enrolled (14 with TC, 8 with thymomas). The median number of prior systemic therapies was 2 (1-8). The median age was 50 years (range 23-72), and 4 females were treated. Treatment received were mTOR inhibitor (mTORi) in 4 of pts, antiangiogenic agents (AA) in 11 pts, and other targeted therapies in 7 pts. The median follow-up time was 22.1 months (range, 1.25-77.79 months). Autoimmune associated disease (AID) was reported in 6 pts. 18% had grade III/IV toxicity, 54% grade I/II toxicity and no toxic death was reported. AID exacerbated in one patient. One patient experienced a complete response (CR) and 3 a partial response (PR); 16 pts had stable disease (median 6.6 months) and 2 had a progressive disease. Objective response rate (ORR) was 42%, 25.0% for thymoma and 21.4% for TC. The median overall survival was 54.5 months (95% CI 25-75.50 months), 54.5 for thymoma and 62 for TC. The median progression free survival (PFS) was 6.6 months (95% CI 1.35-11.59 months), 5.2 for thymoma and 6.9 for TC. Median PFS was 11.6 months for mTORi, 6.9 for AA, and 6.6 for other targeted therapies. Conclusions: Phase I trials appear as a sound therapeutic option in TENs pts progressing after standard treatments. Use of AA and mTORi seem to yield a good clinical response. Novel targeted therapies might be tested setting in a biology-oriented approach rather than a stochastical one. We are currently offering a molecular profiling in our patients (MOSCATO trial NCT01566019) for a better selection of appropriate Phase I trial.
Molecular analysis-directed, international, phase III trial in patients with advanced non-small-cell lung cancer.
Authors: Bepler Gerold , Williams Charles C. , Schell Michael J. , Chen Wei , Zheng Zhong , Simon George R. , Gadgeel Shirish M. , Zhao Xiuhua , Schreiber Fred James , Brahmer Julie R. , Chiappori Alberto , Tanvetyanon Tawee , Pinder Mary Colleen , Gray Jhanelle Elaine , Haura Eric B. , Antonia Scott J. , Fischer Jurgen R. 
Published: March 2020

8001 Background: ERCC1 (E1) and RRM1 (R1) are predictive markers for platinum agents and gemcitabine (G) respectively. In a phase II trial that utilized E1 and R1 mRNA expression levels for therapeutic decision-making, a response rate of 44%, PFS of 6.6 m, and OS of 13.3 m was achieved. Methods: Pts with advanced, chemo-naive NSCLC, PS 0-1, measurable disease, and a FFPE histological or cell block tumor specimen were eligible. E1 and R1 were analyzed by AQUA and categorized as high or low. Pts were randomized 2:1 to arm A, which received G and carboplatin (Cb) for R1/E1 low, docetaxel (D) and Cb for R1 high and E1 low, G and D for R1 low and E1 high, and D and vinorelbine (V) for R1/E1 high, or arm B, which received GC. Pts received up to 6 cycles. Efficacy was assessed every 6-8 weeks until 1 year from treatment initiation. The primary goal was to improve the 6-m PFS from 38% in arm B (median PFS 4.3 m) to 50% in arm A (median PFS 6.0 m). Secondary goals were improvements in OS (8.0 to 12.0 m) and RR (25% to 50%). Results: Of 275 eligible pts, 183 randomized to arm A. 56 were assigned to GCb, 26 to DCb, 37 to GD, and 64 to DV, which was not significantly different (p=.2) from the expected assignment (30%, 20%, 20%, 30%). In arm B, all 92 pts received GCb. Protein analysis was successful in 91% of pts. The median time from consent to completed gene analysis was 11 days. A tumor rebiopsy for the specific purpose of gene analysis was required in 17% of pts. The 6-m PFS rate and median PFS were 52.0% and 6.1 m in arm A and 56.5% and 6.9 m in arm B (p = 0.18). PFS was not significantly different among the treatment groups in arm A (p = 0.1). A significant survival advantage was found for pts with low E1 and low R1 in arm B compared to the same group in arm A (p = 0.02) although both received GCb therapy. OS and RR were not significantly different between both groups. A comparison between protein and mRNA levels for both genes revealed no significant correlation. Conclusions: This demonstrates that gene expression analysis for therapeutic decision making is feasible in newly diagnosed advanced-stage NSCLC pts. A tumor rebiopsy is safe, required in 17%, and acceptable to 89% pts. The survival results are false negative based on the internal control included in the trial. Clinical trial information: NCT00499109.
Interim results of phase II study BRF113928 of dabrafenib in BRAF V600E mutation–positive non-small cell lung cancer (NSCLC) patients.
Authors: Planchard David , Mazieres Julien , Riely Gregory J. , Rudin Charles M. , Barlesi Fabrice , Quoix Elisabeth A. , Souquet Pierre Jean , Socinski Mark A. , Switzky Julie , Ma Bo , Goodman Vicki L. , Carson Stanley W. , Curtis C. Martin , Streit Michael R. W. , Johnson Bruce E. 
Published: March 2020

8009 Background: Activating BRAF V600E mutations in NSCLC are present in < 2% of tumors, primarily adenocarcinoma. The BRAF inhibitor dabrafenib has demonstrated clinical activity in BRAF V600 mutation–positive melanoma. Here we report interim efficacy and safety data obtained in 17 BRAF V600E–mutant NSCLC patients enrolled in dabrafenib phase II study BRF113928. Methods: Single-arm, 2-stage, phase II study in stage IV BRAF V600E mutation–positive NSCLC pts who failed at least 1 line of chemotherapy. Dabrafenib dosed at 150 mg orally twice daily. The primary endpoint was investigator-assessed overall response rate (ORR) per RECIST 1.1 criteria. Results: The median age of the 17 pts was 69 years (range, 51-77 years). Most pts (12/17) were male, all were white with adenocarcinoma, and 13 were former smokers. All pts had failed at least 1 line of prior anticancer therapy, and 5 subjects had failed ≥ 2. At the time of reporting, 11 pts remain on therapy, and 6 have stopped therapy (5 with PD and 1 due to an AE). Thirteen pts were evaluable for efficacy. The best response for these pts included 7 PRs (5 confirmed PRs), 1 SD, and 4 PD; 1 pt discontinued due to an SAE (hypersensitivity reaction) prior to response assessment (ORR, 54%). The median duration of treatment for all 17 pts is approximately 9 weeks (range, 1-69 weeks). Among the 5 pts with confirmed PRs, duration of response was 29 and 49 weeks for the 2 pts who progressed, while the remaining 3 pts were responding for 6+ to 24+ weeks. The safety of dabrafenib in NSCLC pts appears to be generally consistent with what has been previously observed. The most common AEs were decreased appetite, fatigue, asthenia, dyspnea, and nausea, mostly grade 1 or 2. Five pts (29%) had a grade 3 AE, and 1 pt (6%) had a grade 4 SAE (hemorrhage). Conclusions: Dabrafenib shows early antitumor activity in BRAF V600E mutation–positive pretreated NSCLC pts, with an ORR of 54% and with the longest duration of response of 49 weeks thus far. Dabrafenib is generally well tolerated, and the study has met the minimum response rate (≥ 3 of first 20 pts) to continue into the second stage. This study represents the first clinical evidence of BRAF as a therapeutic target in NSCLC. Clinical trial information: NCT01336634.
Detection of EGFR-activating mutations from plasma DNA as a potent predictor of survival outcomes in FASTACT 2: A randomized phase III study on intercalated combination of erlotinib (E) and chemotherapy (C).
Authors: Mok Tony , Wu Yi Long , Lee Jin Soo , Yu Chong-Jen , Sriuranpong Virote , Wen Wei , Tsai Julie , Truman Matt , Klughammer Barbara , Wu Lin 
Published: March 2020

8021 Background: Biomarker analysis of tumor from FASTACT 2 confirmed predictive power of EGFR mut on the benefit of intercalated combination of E and C as 1st line in advanced NSCLC (T. Mok, ESMO 2012). However, only limited tumor were available. Recent development allowed us to detect EGFR mut in cell-free DNA from plasma (pEGFRmut). In this study, we studied the concordance between pEGFRmut and EGFR mut in tumor (tEGFRmut), and the role of pEGFRmut as predictor of PFS and OS. Methods: Retrospective EGFR mut testing of FFPET and plasma from FASTACT 2 were performed with two allele-specific PCR assays, cobas EGFR_FFPET test and cobas EGFR_blood test (in development). Both tests are designed to detect EGFR activating mut (exon 19 deletions, L858R, G719X). One FFPET section was used for tissue test and 2-ml plasma was used for blood test. Results: Among 268 tumors from 451 enrolled pts, 90% (241/268) were analyzable. 40% (96/241) harbored at least one activating EGFR mut. All 427 plasmas from 451 enrolled pts were analyzable. 32% (136/427) were positive for EGFR activating mut. The concordance of two tests from 224 matched tissue and plasma samples was summarized below. Using tissue as comparator, the sensitivity of plasma test was 76% (68/89) and the specificity of plasma test was 96% (130/135) respectively. Positive and negative predictive values for EGFR activating mut were 93% (68/73) and 86% (130/151) respectively. Median PFS of patients with pEGFRmut treated with intercalated combination versus chemotherapy alone was 13.8 vs. 6.1 m (HR=0.21 p<0.0001), and for pEGFR wild-type, 6.7 vs. 6.0 m (HR=0.80, p=0.06). Median OS of patients with pEGFRmut treated with intercalated combination versus chemotherapy alone was 32.4 vs. 19.0 m (HR=0.51, p=0.0035), and for pEGFR wild-type, 16.1 vs 13.3 m (HR=0.89, p=0.39). Conclusions: cobas EGFR_blood test can be used to reliably detect EGFR mutations in plasma. pEGFRmut is a potent predictor of survival outcomes in FASTACT 2. Clinical trial information: NCT00883779/ MO22201/CTONG0902. [Table: see text]
Patterns of metastasis and survival in patients with PI3K pathway-driven stage IV squamous cell lung cancers (SQCLC).
Authors: Paik Paul K. , Moreira Andre L. , Wang Lu , Won Helen H. , Hasanovic Adnan , Rekhtman Natasha , Sima Camelia S. , Ladanyi Marc , Berger Michael F. , Kris Mark G. 
Published: March 2020

8022 Background: The majority of actionable drivers in SQCLCs occur in the PI3K (30%) and FGFR1 (20%) pathways. The biologic behaviors and natural histories of these oncogenic subtypes are not well characterized. Methods: As of October 2011, all patients with SQCLCs at MSK have undergone prospective, multiplex testing of their FFPE tumors for FGFR1 amplification (FISH), PIK3CA mutations (Sequenom), PTEN loss (IHC), and PTEN mutations (exon sequencing), among others. Patient characteristics, outcomes, and metastatic sites were identified. Survival probabilities were estimated using the Kaplan-Meier method. Group comparisons were performed with log-rank tests and Cox proportional hazards methods. Results: 68 stage IV SQCLC patients were analyzed. 39 had tissue sufficient for next-gen sequencing. Genotypes were: FGFR1 amplified (16%); PTEN loss (24%), PIK3CA mutant (7%), PTEN mutant (13%). Events were non-overlapping save for 2 cases with PTENnonsense mutations and PTEN loss. The sole significant clinical difference (KPS, age, sex, lines of tx) was sex (women in PI3K group 52% vs. in others 23%, p=0.02). Metastatic patterns vs. other are shown in the Table. Median OS for PI3K vs. other: 10mo (95%CI:6.5-14.3) vs. 14mo (95%CI:9.6-36.7), p=0.02. Median OS for FGFR1 vs. others: 19mo (95%CI:9-NR) vs. 10mo (95%CI:6.5-14.3), p=0.3. Multivariate analysis for OS: PI3K vs. other, HR death=2.3 (95%CI:1.1-4.8, p=0.03); Age ≥65, HR=1.3 (95%CI:0.6-2.9, p=0.6); KPS≥70, HR=0.5 (95%CI:0.2-1.7, p=0.3); Male sex, HR=0.7 (95%CI:0.3-1.4, p=0.3). Conclusions: Patients with stage IV PI3K-aberrant SQCLCs have poorer survival compared to other patients with SQCLCs. Brain metastases occurred exclusively in patients with PI3K-aberrant tumors. These data suggest that PI3K pathway activation confers a distinct biology, and that targeting this in SQCLC patients with brain metastases may be an effective therapeutic strategy. [Table: see text]
Efficacy and safety of crizotinib in patients with advanced ROS1-rearranged non-small cell lung cancer (NSCLC).
Authors: Ou Sai-Hong Ignatius , Bang Yung-Jue , Camidge D. Ross , Riely Gregory J. , Salgia Ravi , Shapiro Geoffrey , Solomon Benjamin J. , Engelman Jeffrey A. , Kwak Eunice Lee , Clark Jeffrey W. , Tye Lesley , Wilner Keith D. , Stephenson Patricia , Varella-Garcia Marileila , Bergethon Kristin , Iafrate Anthony John , Shaw Alice Tsang 
Published: March 2020

8032 Background: ROS1 receptor tyrosine kinase rearrangements define a subset of NSCLC sensitive to the small-molecule tyrosine kinase inhibitor crizotinib, approved multinationally for the treatment of advanced ALK-positive NSCLC. Updated efficacy and safety data are presented for crizotinib in patients with advanced ROS1-rearranged NSCLC. Methods: ROS1 status was determined by break-apart FISH assays, and patients were enrolled into an expansion cohort of an ongoing phase 1 crizotinib study (NCT00585195). Patients received crizotinib 250 mg BID. Responses were assessed using RECIST v1.0. The disease control rate (DCR; % stable disease [SD] + partial response [PR] + complete response [CR]) was evaluated at weeks 8 and 16. Results: At the data cut-off, 33 patients with ROS1-positive NSCLC had enrolled, and 31 had received crizotinib, with 25 evaluable for response. Median age was 51 years (range 31–72), 79% of patients were never-smokers and 97% had adenocarcinoma histology. The median number of prior treatments for advanced disease was 1 (range 0–7). The objective response rate (ORR) was 56% (95% CI: 24.4–65.1), with 2 CRs, 12 PRs and 8 SDs. 8-week and 16-week DCRs were 76% and 60%, respectively. Median PFS has not been reached, with ~60% of patients still in follow-up for PFS; 6-month PFS probability was 71% (95% CI: 45.6–86.0). Median treatment duration was 24 weeks (range 2.3–112), and 24 patients were on treatment at the data cut-off; 5 patients died (all disease-related). 91% of patients had treatment-related adverse events (AEs): most commonly visual impairment (82%), nausea (36%) and diarrhea (33%). Most AEs were grade 1 in severity. Peripheral edema and elevated transaminases were also reported, similar to the previous experience of crizotinib. There were no treatment-related serious AEs or treatment-related permanent discontinuations. Accrual of patients with ROS1-positive NSCLC is ongoing. Conclusions: As observed in ALK-positive NSCLC, crizotinib had dramatic antitumor activity with a high ORR (56%) in patients with ROS1-positive NSCLC and a generally tolerable and manageable AE profile. These findings indicate that crizotinib is an effective therapy for advanced ROS1-positive NSCLC. Clinical trial information: NCT00585195.