bluuebunny/crossref_metadata_2025_split huggingface dataset:
Atezolizumab plus stereotactic ablative therapy for medically inoperable patients with early-stage non-small cell lung cancer.
Authors: Kelly Karen , Daly Megan Eileen , Mirhadi Amin , Lara Frances , Garcia Leslie A , Chen Shuai , Eastham David , Wiegner Ellen Anderson , Riess Jonathan W. , Schalper Kurt A. , Monjazeb Arta 
Published: May 2020

9011 Background: Stereotactic ablative radiation therapy (SABR) is the standard-of-care for medically inoperable, early stage non-small cell lung cancer (NSCLC), but regional and distant failures remain problematic. Based on our in vivo data showing synergy between radiation and immune checkpoint inhibitors (ICI) and the known efficacy and mild toxicity profile of ICI in NSCLC, we conducted a phase I study to determine the maximum tolerated dose of neoadjuvant, concurrent, and adjuvant atezolizumab with SABR for early stage NSCLC patients (pts). Methods: Eligible pts had histologically confirmed T1-3 NSCLC with at least one feature predictive of increased recurrence risk: diameter ≥1 cm, SUV ≥6.2 on PET, or moderately/poorly differentiated histology, were medically inoperable or refused surgery and had a Zubrod PS ≤2. Patients received 6 cycles of atezolizumab. A 3+3 dose finding design was employed with 3 dose levels: 3 mg/kg, 10 mg/kg, and 1200 mg flat dosing. SABR was delivered starting cycle 3 to 50 Gy over 4-5 fractions. Dose limiting toxicity (DLT) was assessed during the first 9 weeks. Results: 20 pts were enrolled, 15 pts in the dose finding and 5 pts at the recommended phase II dose (RP2D). Patient factors: MedIan age 77; 45% male, 85% smoking history, 85% PS 0-1 and 35% squamous. One pt on dose level 2 had a DLT – a grade 3 rash. Atezolizumab 1200 mg flat dosing was the RP2D. Grade 3 pneumonitis was not observed. Partial responses after 2 cycles were seen in 3/17 evaluable pts (18%) and 1 pt had a minor response. No patient progressed on treatment. PD-L1 expression was 0% 8/13 (62%), >1% - 50% 4/13 (31%), >50% 1/13 (8%) in pts with sufficient tissue. Of 5 pts with PD-L1 expression 3 (60%) were responders and 1 (12.5%) of 8 pts with 0% PD-L1 expression responded. Multi-plex Quantitative Immunofluorescence (QIF) using a T cell activation panel demonstrated to correlate with ICI response was performed on 9 samples (including 2 responders, 1 minor responder). The CD3 QIF score was > two-fold higher in the responders compared to non-responders, and the levels of proliferating and activated T cells were likewise > two-fold higher. Comprehensive stool and serial blood analyses have been completed. Correlative endpoints will be reported along with additional efficacy outcomes. Conclusions: Atezolizumab plus SABR is feasible, safe and shows an efficacy signal in medically inoperable early stage NSCLC. This combination will be tested in a randomized phase III trial SWOG/NRG S1914. Funding: This work was supported by the DOD CDMRP W81XWH-15-2-0063 and Genentech. Clinical trial information: NCT02599454.
YAP1 positive small-cell lung cancer subtype is associated with the T-cell inflamed gene expression profile and confers good prognosis and long term survival.
Authors: Owonikoko Taofeek Kunle , Dwivedi Bhakti , Chen Zhengjia , Zhang Chao , Barwick Benjamin , Gilbert-Ross Melissa , Ernani Vinicius , Barwick Benjamin , Zhang Guojing , Carlisle Jennifer W , Khuri Fadlo Raja , Curran Walter J , Lonial Sagar , Ramalingam Suresh S. , Sun Shi-Yong , Waller Edmund K. , Sica Gabriel 
Published: May 2020

9019 Background: The dominant expression of transcription factors ASCL1, NeuroD1, YAP1 or POU2F3 characteristically defines four small cell lung cancer (SCLC) subtypes (SCLC-A, SCLC-N, SCLC-Y and SCLC-P). The clinical validation and biological relevance of these emerging SCLC subtypes is currently lacking. Methods: Using the Illumina TruSeq RNA Exome Kit, we generated RNA-Seq data from 61 cases of SCLC and pulmonary carcinoid to interrogate gene expression differences in SCLC subtypes as well as in survival outliers (top and bottom decile) matched for clinically relevant prognostic factors and treatment. We also assessed YAP1 protein expression in a blinded fashion by immunohistochemistry in 130 SCLC cases. Results: We successfully classified 68% of SCLC into one of the four SCLC subtypes whereas 81.5% of carcinoids did not fit into any of these categories. GSEA for differentially expressed genes between outlier subgroups showed significant upregulation of interferon gamma and interferon alpha response genes in late survivors. Moreover, a previously validated 18-gene T-cell inflamed gene expression profile was upregulated in late survivors and in the SCLC-Y subtype. Furthermore, the SCLC-Y subtype and late survivors showed higher expression of HLA gene family and reduced expression of cancer testis antigens. The median (95%CI) OS was 14 (4.3, 28.8), 16.7 (0.9, NA), 8.1 (2, 9.7) and 20.1 (0.6, 39.5) months respectively, for SCLC-A, N, P and Y subtypes. YAP-1 protein expression was positive in 17 of 130 (13%) SCLC cases. The majority of cases with positive YAP1 expression by immunohistochemistry, 12 of 17 cases (70.6%), were limited stage SCLC at the time of original diagnosis. Conclusions: SCLC subtypes have clinical implication as predictive and prognostic biomarker. SCLC-Y subtype is enriched for T-cell inflamed phenotype and long term survival, and may predict for clinical benefit of immunotherapy.
Detection of early-stage lung cancer by exhaled volatile organic compounds using a high-pressure photon ionization time-of-flight mass spectrometry.
Authors: Qiu Mantang , Li Hang , Meng Shushi , Li Qingyun , Zhou Zuli , Wang Jun 
Published: May 2020

9030 Background: Exhaled breath-based test is an attractive option for cancer detection due to its non-invasive nature. Exhaled volatile organic compounds (VOCs) are produced in various biochemical processes and might be sensitive tumor biomarkers. Here, we reported an exploratory study to investigate the performance of exhaled VOCs for detection of early-stage lung cancer using a high-resolution high-pressure photon ionization time-of-flight mass spectrometry (HPPI-TOFMS). Methods: Treatment-naïve patients with pulmonary nodules who received surgery at our department and without history of cancer were enrolled. Exhaled breath samples were collected before surgery and stored in Tedla bags. A CO2 sensor was applicated during sample collection to ensure only “alveolar air” was collected. Exhaled samples were directly detected by HPPI-TOFMS, which has a resolution > 3000. Deep learning algorithm was used to build detection model based on HPPI-TOFMS data. Results: A total of 171 patients were included in this study, including 139 patients with lung cancer (114 of TNM stage I, 14 of stage II, 9 of stage III, and 2 of stage IV) and 32 patients with benign nodules. Mass spectrum peaks with m/z < 500 detected by HPPI-TOFMS were retained and 32500 features were extracted from each exhaled breath samples. Based these extracted features, participants who were pathologically diagnosed as lung cancer could be discriminated from those with benign diseases with an accuracy of 96.19%, sensitivity of 96.43%, and specificity of 84.38%. Discrimination of lung cancer patients with lymph node metastasis (n = 12) from those without lymph node metastasis (n = 127) had an accuracy of 83.23%. Conclusions: Exhaled VOCs as detected by a high-resolution HPPI-TOFMS might be sensitive biomarkers for detection of early-stage lung cancer.
CT and PET radiomic features associated with major pathologic response to neoadjuvant immunotherapy in early-stage non-small cell lung cancer (NSCLC).
Authors: Nakajima Erica C. , Leal Jeffrey P. , Fu Wei , Wang Hao , Chaft Jamie E. , Hellmann Matthew David , Pomper Martin , Forde Patrick M. 
Published: May 2020

9031 Background: An early biomarker of response to immunotherapy (IO) is needed urgently to identify the patients (pts) who will derive benefit. We reported the first clinical trial of neoadjuvant IO (nIO) in resectable non-small cell lung cancer (NSCLC) (NCT02259621). In this study, we investigated whether there was an association between MPR and radiomic features (RF) in [18F]-fluorodeoxyglucose ([18F]-FDG) PET and standard CT images obtained at baseline and after nIO in early stage NSCLC tumors. Methods: Prior to receiving neoadjuvant nivolumab or nivolumab/ipilimumab, patients with Stage I-IIIA NSCLC underwent two [18F]-FDG PET-CTs and/or plain CTs: a baseline scan at enrollment (PRE), and after nIO (POST). After neoadjuvant treatment, tumors were resected and evaluated for MPR. Volumes of interest (VOIs) were drawn around primary tumors on the scans. Using our novel radiomic software, Imager-4D, VOIs were evaluated for 20 RFs assessing [18F]-FDG standard uptake value (SUV) or Hounsfield unit (HU) heterogeneity and spatial distribution in PET and CT images respectively. The baseline, post-treatment, and percent change in RFs before and after nIO were compared between tumors with and without MPR. Wilcoxon test was used for the comparisons. Results: The PRE and POST scans of 24 pts were analyzed. All pts had PRE and POST CTs performed, and 17 pts had PRE and POST [18F]-FDG PET-CT scans. 7 of 24 (29%) had MPR. In the CT scan analysis, HU-based RFs of voxel count, total volume, energy, entropy, homogeneity, contrast, and dissimilarity in POST CT scans each significantly association with MPR. In the PET scan analysis, SUV mean and voxel count RFs in the POST scans, and the percent change in the cluster shade RF between PRE and POST scans were significantly associated with MPR. Conclusions: Collectively, we identified a significant increase in heterogeneity in the POST CT images of NSCLC tumors that had MPR. This association may reflect increased T cell infiltration or tumor necrosis. In contrast, most [18F]-FDG-based RFs did not distinguish MPR vs non-MPR tumors, although the sample size was limited. We will further investigate these HU-based RFs as non-invasive markers of response to IO in conjunction with pathologic markers of IO response and in a larger patient cohort.
A retrospective evaluation of PD-L1 expression on primary non-small cell lung cancer (NSCLC) samples and associated involved hilar or mediastinal lymph nodes (N1 or N2) (REPLICA).
Authors: Karapanagiotou Eleni , Bille Andrea , Taniere Philippe , Flash Clare , Douiri Abdel , Willis Elizabeth , Kandasamy Srivani , Curinga Domenico , Velamuri Shriram , Nonaka Daisuke 
Published: May 2020

9044 Background: Little is known about the PD-L1 expression in early stage NSCLC as well as the possible heterogeneity of PD-L1 expression in different sites. This study provides information on both PD-L1 expression in stage II and III NSCLC and the relationship between PD-L1 expression in the primary site (lung) and metastatic lymph nodes (LNs) N1 and/or N2. Methods: Samples (primary tumor and N1/N2) from 500 patients who underwent lung resection and lymphadenectomy for NSCLC without prior treatments were collected and analyzed for PD-L1 expression using the 22C3 pharmdx Agilent assay. The tumor proportion score (TPS) is documented for each sample according to the following categories: PD-L1: < 1%, 1-49%, ≥ 50%. PD-L1 stained slides were reviewed by two pathologists independently; for discrepant cases the two pathologists reviewed the stains jointly and the consensus score used for the data analysis. Agreement between the two pathologists was assessed by overall agreement and kappa statistic. The association between PD-L1 expression in the primary tumor and lymph node was assessed by cross-tabulation. Results: A total of 456 tumors and involved LNs were included in the analysis. Pathologist one assessed 435 primary tumor and LN pairs and pathologist 2 assessed 453 tumor and LNs pairs. The overall agreement between pathologists on PD-L1 expression in primary tumor samples was 77%; K = 0.59 (95% CI 0.57 – 0.63) and in LNs 83%; k = 0.62 (95% CI 0.56 – 0.70). Primary tumors showed PD-L1 < 1% in 235/422 (55,6%), PD-L1 1-49% in 146/422 (34,6%) and PD-L1 > = 50% in 41/422 (9.8%). 77% (327/422) showed no heterogeneity in PD-L1 expression between the primary tumor and involved LNs. In tumors with PD-L1 < 1% expression, 94% of the LNs showed PD-L1 < 1% expression and less than 1% showed PD-L1 > = 50%, 6% of the LNs showed PD-L1 1-49%. When the primary tumor was PD-L1 > = 50% nearly half (46%) of the involved LNs showed the same degree of PD-L1 positivity and 10% of them showed PD-L1 < 1%; 44% of the LNs showed PD-L1 1-49%. When the primary tumor showed 1-49% PD-L1 staining, 60% of the LNs showed the same staining pattern, 36% showed PD-L1 < 1% and only 4% showed PD-L1 > = 50% expression. Conclusions: In stage II and III NSCLC, half of the primary tumors show negative PD-L1 expression. Discrepant PD-L1 expression between primary tumors and LN metastases was seen in 23% of the cases, and when present, PD-L1 expression in LN tumors tended to be lower than that in primary tumors.
A mid-chemoradiation dynamic risk model integrating tumor features and ctDNA analysis for lung cancer outcome prediction.
Authors: Moding Everett J , Esfahani Mohammad Shahrokh , Nabet Barzin , Liu Yufei , Chabon Jacob J. , He Jianzhong , Qiao Yawei , Xu Ting , Yao Luyang , Gandhi Saumil , Liao Zhongxing X. , Das Millie , Ramchandran Kavitha , Padda Sukhmani Kaur , Neal Joel W. , Wakelee Heather A. , Loo Billy W. , Lin Steven H. , Alizadeh Ash A. , Diehn Maximilian 
Published: May 2020

9046 Background: Circulating tumor DNA (ctDNA) molecular residual disease after curative intent therapy predicts disease progression in localized lung cancer. We hypothesized that integrating pre-CRT features and ctDNA levels during chemoradiation therapy (CRT) can predict patient outcomes earlier to enable response-adapted therapy. Methods: We identified pre-CRT features prognostic of disease progression after CRT for Stage II-III non-small cell lung cancer (NSCLC) in a historical “pre-CRT” training cohort of 109 patients. In addition, we applied CAPP-Seq ctDNA analysis pre-CRT and a median of 21 days into CRT (mid-CRT) to a “ctDNA” training cohort of 42 patients treated at MD Anderson and an independent validation cohort of 21 patients treated at Stanford. Prognostic pre-CRT features and mid-CRT ctDNA concentration were integrated using a Bayesian proportional hazards approach to generate a Continuous Individualized Risk Index (Kurtz et al. Cell 2019) for NSCLC (CIRI-NSCLC) to predict freedom from progression (FFP). Results: Adenocarcinoma histology (HR 2.6, P = 0.0005) and KEAP1 mutation (HR 2.7, P = 0.002) but not stage (P = 0.16), age (P = 0.60), or gender (P = 0.98) were significantly associated with FFP in the pre-CRT training cohort. Mid-CRT ctDNA concentration as a continuous variable was significantly associated with FFP in the ctDNA training cohort (HR 1.6, P = 0.04), and applying an optimal threshold identified in the training cohort (3.2 hGE/ml) significantly stratified FFP in the independent ctDNA validation cohort (HR 4.8, P = 0.02). CIRI-NSCLC enabled individualized real-time updating of the probability of FFP as model features became available over the course of CRT. CIRI-NSCLC outperformed individual model features in the independent validation cohort when compared by C-statistic (CIRI-NSCLC: 0.85; mid-CRT ctDNA: 0.76; histology: 0.66; KEAP1: 0.60). Across the whole cohort, patients with a greater than 66% risk of progression predicted by CIRI-NSCLC (n = 10) had an FFP of 10.0% at 12 months while patients with a less than 33% risk of progression predicted by CIRI-NSCLC (n = 22) had an FFP of 79.7% at 12 months (HR 15.0, P < 0.001). Conclusions: Our results suggest that CIRI-NSCLC can identify patients at very high and low risk of progression. Prospective evaluation will be necessary to test the potential utility of adapting treatment based on CIRI-NSCLC.
Phase II study of olaparib in malignant mesothelioma (MM) to correlate efficacy with germline and somatic mutations in DNA repair genes.
Authors: Hassan Raffit , Mian Idrees , Wagner Cathy , Mallory Yvonne , Agra Maria , Padiernos Emerson , Sengupta Manjistha , Morrow Betsy , Wei Jun S. , Thomas Anish , Steinberg Seth M. , Khan Javed , Ghafoor Azam 
Published: May 2020

9054 Background: BRCA1 associated protein 1 ( BAP1), a nuclear deubiquitinase involved in DNA double-strand break repair is frequently mutated in MM. Because poly(ADP-ribose) polymerase inhibitors (PARPIs) induce synthetic lethality in BRCA1/2 mutant cancers, we sought to evaluate efficacy of olaparib in patients with MM and correlate it with pathogenic germline and somatic mutations in DNA repair genes. Methods: Phase II single-center study (NCT03531840) enrolled patients with advanced pleural or peritoneal mesothelioma who had progressed on prior therapies, age >18 years, ECOG performance status <1, adequate organ and bone marrow function. Olaparib 300mg was given twice daily orally in 3 week cycles until disease progression or toxicity. Efficacy was assessed by CT scan every 6 weeks using RECIST criteria. Whole exome sequencing (WES) was performed on blood and tumor samples to identify pathogenic germline and somatic mutations in DNA repair genes. Primary objective was to determine response rate based on germline or somatic mutation status of DNA repair genes. Results: Between July 2018 to May 2019, 23 patients were enrolled, 15 pleural and 8 peritoneal MM [14 male; median age 63 (range 41-75 years); median number of prior treatments 3 (range 1-5)]. Median olaparib cycles received was 4 (2-21). WES to identify pathogenic mutations in the germline and tumor was performed in 23 and 17 patients respectively. Four patients had germline BAP1, 1 germline MRE11A, and 5 had somatic BAP1 mutations. Of 22 evaluable patients, 1(4%) had partial response (PR), 17 (77%) had stable disease at 6 weeks and 4 (18%) had progressive disease. Patient with PR had a germline mutation in MRE11A. Median progression free survival (PFS) and overall survival (OS) for all patients was 3.4 months (95% CI: 2.7 – 4.8 months) and 8.1 months (95% CI: 4.5 months – not estimable) respectively. Median PFS of germline BAP1 mutant patients (n = 4) was 2.3 months (95% CI: 1.3 – 3.6 months) compared to 4.1 months (95% CI: 2.7 – 5.5 months) for BAP1wild type patients (n = 18;P = 0.026). Median OS was 4.6 months (95% CI: 3.1 – 4.9 months) for patients with germline BAP1 mutation versus not reached for those without germline BAP1 mutation (P = 0.0058). The most common side effects of olaparib were anemia (16%), lymphopenia (24%), nausea (14%), and increased creatinine (9%). Conclusions: Olaparib has limited anti-tumor activity in previously treated MM patients including those with germline or somatic BAP1 mutations. Presence of germline BAP1 mutations was associated with decreased PFS and OS. Clinical trial information: NCT03531840.
Genomic landscape and immune phenotype of malignant pleural mesothelioma.
Authors: Patel Meera , Elliott Andrew , Liu Stephen V. , Kim Chul , Raez Luis E. , Feldman Rebecca , Pai Sachin Gopalkrishna , Wozniak Antoinette J. , Nagasaka Misako , Lopes Gilberto , Spira Alexander I. , Kim Edward S. , Korn Wolfgang Michael , Mamdani Hirva 
Published: May 2020

9056 Background: Malignant pleural mesothelioma (MPM) is a relatively uncommon malignancy with poor prognosis and no major therapeutic breakthroughs over the past decade. Better understanding of the genomic landscape and distribution of immune biomarkers in this disease has the potential to enable development of novel therapies. Methods: We analyzed molecular profiles of 222 MPM tumors using next-generation sequencing of 592 genes utilizing Caris Life Sciences platform. Genes were grouped into pathways: DNA damage repair (DDR) ( ATM, BRCA2, BRIP1, BAP1, CHEK2, ERCC2, FANCA/D2/E/L, MLH1, MSH6, MUTYH, NBN, PMS2, RAD50/51B, WRN), cell cycle regulation including TP53 ( RB1,CCNE1, CDKN2A, CCND1, CCND3, CDKN1B), chromatin remodeling (CR) ( ARID2, ASXL1, DNMT3A, EP300, EZH2, KDM6A, KMT2C, KMT2D, NSD3, PBRM1, SMARCB1/A4, SETD2), RAS/MAPK ( KRAS, MAP2K1, NF1, NF2), and PI3K/AKT ( AKT, PIK3CA, PIK3R1/R2, PTEN, RICTOR, TSC1, TSC2, ZNF703). Tumor mutational burden (TMB), PD-L1 expression (SP142 IHC, tumor staining), and MSI/MMR were analyzed. Seventy-two cases also had whole transcriptome sequencing data. Differences in alterations were compared for age, gender, and pathways. Results: Median age of patients (pts) was 72 yr (range, 37-90), 73% were male. Gene pathway alterations were seen in 81% of cases. DDR, specifically homologous recombination (HR), was the most commonly mutated pathway (36.9%), followed by RAS (25.2%) and CR (18.9%). Genes mutated in ≥5% of cases included BAP1 (26.3%), NF2 (23.5%), TP53 (15.5%), SETD2 (10.2%). PD-L1 was high (≥50% tumor cells positive) in 11.4% (n = 24), intermediate (1-49%) in 31.4% (n = 66), and negative ( < 1%) in 57.1% (n = 120) pts. TMB was high (≥10 mutations/Mb) in 9.6% of tumors (n = 20). None of the tumors were dMMR/MSI-H. HR gene BAP1 and CR gene SETD2 mutations trended to be more prevalent in pts ≥70 yo (p = 0.02). CR trended to be more commonly mutated in females (p = 0.02). No other significant differences were found in specific gene/pathway alterations, PD-L1 expression, or TMB in the context of age and gender. Distribution of PD-L1 expression was not different among various pathways. No highly recurrent, targetable fusion isoforms were seen among the 85 identified (mean 1.1 fusions/tumor), which have not yet been characterized for pathogenicity. Conclusions: The majority of MPM tumors harbor alteration in one of the key cellular pathways. HR pathway mutations are the most common. The majority of tumors were PD-L1 negative and carry low TMB indicating low immunogenicity. No age and gender specific differences exist except for BAP1 and SETD2 mutations.