tbuckley/cabot-search huggingface dataset:
Association of drug-related polymorphisms with palbociclib-related neutropenia: Pharmacogenetic analysis of PALOMA-2/-3 (P2/3).
Authors: Hiroji Iwata, Olivia Fletcher, Yuan Liu, Yoshiko Umeyama, Zhe Zhang, Patrick Schnell, Jean-Claude Marshall, Jillian G. Johnson, Linda S. Wood, Masakazu Toi, Richard S. Finn, Massimo Cristofanilli, Nicholas C. Turner, Cynthia Huang Bartlett
Journal: Journal of Clinical Oncology (2019)

1060 Background: The most common PAL treatment related adverse event is neutropenia. ABCB1 and ERCC1 variants are associated with increased chemotherapy drug exposure and CYP3A7*1C may be associated with reduced exposure. Pharmacogenetic analyses of these variants in patients (pts) from P2/3 may reveal associations between single nucleotide polymorphisms (SNPs) and early occurrence of grade 3/4 (G3/4) neutropenia. Methods: ABCB1 (rs1045642, rs1128503), ERCC1 (rs3212986, rs11615), and CYP3A7*1C (rs45446698) variants were analyzed in germline DNA from pts with HR+/HER2– advanced breast cancer from P2 (n=584) and P3 (n=442) by TaqMan assay. Association between variants and incidence of G3/4 low absolute neutrophil count (ANC) at Cycle 1 Day 15 (C1D15) was assessed with the exact Cochran-Armitage trend test. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by logistic regression. Results: In total, 652 PAL-treated pts had SNP, race, and C1D15 ANC data. Minor allele frequencies (MAF), incidence rates, and relative risk of G3/4 C1D15 ANC for ABCB1 and ERCC1 variants are given in the Table. CYP3A7*1C was only found in non-Asians (MAF 6%). Conclusions: This is the first comprehensive assessment of pharmacogenetic data from P2/3. ABCB1 and ERCC1 SNP allele frequencies differ between Asians and non-Asians. Despite combining P2/3 data, we lacked power to detect moderate associations; further investigation of these SNPs with G3/4 C1D15 ANC is warranted. Pfizer Clinical trial information: NCT01740427, NCT01942135. [Table: see text]
Genomic analysis of hepatocellular carcinoma (HCC) with active hepatitis B virus (HBV) replication.
Authors: Huat Chye Lim, John Dozier Gordan
Journal: Journal of Clinical Oncology (2019)

e15593 Background: HBV replication contributes to HCC initiation and is associated with worse patient outcomes. Prior tumor genomic studies of HBV-positive and -negative (HBV+/-) HCC have used detection of HBV surface antigen (HBsAg) in serum to annotate HBV status. However, a substantial proportion of HBsAg+ patients lack HBV replication in tumor, suggesting a potentially distinct patient subset. In this study, we determined HBV status by measuring tumor HBV RNA, a proxy for active replication. We then investigated HBV RNA+/- association with somatic mutations, gene sets, homologous recombination deficiency (HRD) and tumor mutation burden (TMB). Methods: RNA-Seq data for 371 HCC tumors were obtained from TCGA. Tumors were classified as HBV RNA+ if they harbored more than 1 HBV RNA read per million human reads, as measured using GATK PathSeq software. Associations between HBV RNA status and somatic mutations, gene sets, HRD and TMB were investigated. HRD score was calculated as the sum of 3 independent HRD measures (large scale state transitions, loss of heterozygosity and telomeric allelic imbalance). Results: HBV RNA+ status was associated with a higher rate of nonsynonymous somatic mutations in multiple genes, including the tumor suppressors TP53, CDKN2A, CHD5 and TET1, as well as AXIN2 and the proto-oncogene BCL11A ( p &lt; 0.05 for all), while HBV RNA- status was associated with a higher rate of nonsynonymous mutations in the chromatin modifier BAP1 ( p = 0.03). In gene set enrichment analysis of normalized RNA-Seq expression data, HBV RNA+ status was associated with increased transcription of DNA repair genes, as well as genes upregulated by mTORC1 and MYC (FDR &lt; 0.03 for all). HBV RNA status was also associated with HRD score (22.19 for HBV RNA+ vs. 15.97 for HBV RNA-, p = 1e-6), but not with TMB. A substantial subset of HBV RNA+ patients (33/100) were not annotated as HBV+ in the TCGA clinical database. Conclusions: HBV status based on tumor HBV RNA detection identifies a genetically distinct subset within all HBV-infected HCC patients that is associated with nonsynonymous somatic mutations in several genes and differential transcription of gene sets, some of which have not been previously reported, as well as with HRD score. These findings suggest potential for differential responsiveness to targeted therapies.
THU0150 FINGER JOINT CARTILAGE EVALUATED BY ULTRASOUND IN PATIENTS WITH RHEUMATOID ARTHRITIS AND HEALTHY SUBJECTS
Authors: Takehisa Ogura, Ayako Hirata, Norihide Hayashi, Hideki Ito, Sayaka Takenaka, Yuki Inoue, Takaharu Kagtagiri, Chihiro Imaizumi, Yuto Takakura, Hideto Kameda
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Joint destruction in rheumatoid arthritis (RA) includes both bone and cartilage lesions. Since joint space narrowing (JSN) is not a direct evaluation of cartilage using X-ray, we aimed to examine the validity of ultrasound (US) cartilage evaluation in patients with RA. <h3>Objectives:</h3> <h3>Methods:</h3> The cartilage thickness of bilateral metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints of the 2nd to 5th fingers were visualized from a dorsal view with joints in approximately 90 degrees flexion and measured at the middle portion. Furthermore, one US examiner performed the semiquantitative scoring of the recorded cartilage images in a blinded manner on a scale of 0–2. In addition, the JSN of the corresponding joints was scored using the van der Heijde-modified Sharp method with a hand X-ray. Continuous variables were analysed using the Mann–Whitney U test. The relationships among the total measurement of cartilage thickness, its semi-quantitative score, and the JSN score were assessed using Spearman's rank correlation coefficients. <h3>Results:</h3> One hundred and three patients with RA and 42 healthy subjects were enrolled in this study. The total cartilage thickness was significantly thinner in patients with RA compared to healthy subjects for both the MCP and PIP joints (both p&lt;0.001). The semi-quantitative sum of 16 joints ranged from 2 to 26 (median 8) in patients with RA, which was significantly greater than the 0 to 11 (median 4) seen in healthy subjects (p&lt;0.001). In patients with RA, the semi-quantitative score showed a significant negative correlation with cartilage thickness (rho=−0.64; p&lt;0.001) as well as a significant positive correlation with JSN score (rho=0.66; p&lt;0.001). In addition, in healthy subjects, semi-quantitative score, but not cartilage thickness was significantly correlated with age (rho=0.49; p=0.001 and rho=–0.25; p=0.118, respectively). On the other hand, in RA, these scores showed a significant correlation with RA disease duration but not correlated with age. <h3>Conclusion:</h3> A simplified and direct evaluation of finger joint cartilage damage by semi-quantitative US score is valid and useful for patients with RA. <h3>Disclosure of Interests:</h3> Takehisa Ogura: None declared, Ayako Hirata: None declared, Norihide Hayashi: None declared, Hideki Ito: None declared, Sayaka Takenaka: None declared, Yuki Inoue: None declared, Takaharu Kagtagiri: None declared, Chihiro Imaizumi: None declared, Yuto Takakura: None declared, Hideto Kameda Grant/research support from: AbbVie, Asahi Kasei Pharma, Astellas, Chugai, Eisai, GlaxoSmithKlein, Mitsubishi-Tanabe, Novartis, Consultant for: AbbVie, Eli Lilly, Novartis, Speakers bureau: AbbVie, Asahi Kasei Pharma, Bristol-Myers, Chugai, Eli Lilly, Janssen, Mitsubishi-Tanabe, Novartis, Pfize
Identifying small cell lung cancer resistance mechanisms to cytotoxic T cells in vitro using whole genome CRISPR screening.
Authors: Joseph Hiatt, David MacPherson
Journal: Journal of Clinical Oncology (2019)

e20075 Background: Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine neoplasm associated with high tumor mutation burden (TMB), a paucity of compelling therapeutic options, and very poor survival. In comparison to other malignancies with high TMB, SCLC patients tend to experience lower response rates and shorter response durations with immune checkpoint blockade (ICB) targeting the PD-1 and/or CTLA-4 axes, and chemotherapy with ICB in first line does not exhibit the dramatic synergy seen in non-small cell lung cancer. To identify additional immunosuppressive mechanisms that could serve as novel biomarkers and therapeutic targets in SCLC, we adapted a recently described method to screen for genes that alter the sensitivity of cancer cells to killing by cytotoxic CD8+ T cells. Methods: We introduced Cas9 nuclease and a genome-wide gene inactivation library of ~80,000 single guide RNA (sgRNA) templates into a cell line derived from a genetically engineered murine model of SCLC (mSCLC). In parallel, we isolated and stimulated CD8+ T cells from the OT-I transgenic mouse, which express a rearranged T cell receptor with very high avidity for the ovalbumin (OVA) SIINFEKL peptide presented on H2-K(b) class I MHC. mSCLC cells were loaded with OVA peptide or vehicle and co-cultured with T cells for 24 hours. We collected surviving cells, isolated DNA, and used next-generation DNA sequencing to tabulate the relative representation of sgRNAs in each experimental condition. From these data, we inferred which gene knockouts were protective from, or sensitizing to, killing by CD8+ T cells. Results: We observed expected mediators, including resistance via knockout of antigen presentation machinery and sensitization via knockout of pro-survival pathways ( e.g. NF-kB), and unexpected hits spanning diverse cellular functions. Conclusions: Genome-wide screening for mediators of in vitro killing by CD8+ T cells in a murine model of SCLC is feasible and reveals that both expected and novel pathways may contribute to resistance to immunotherapy in SCLC. Future studies are directed at validating these hits in vitro and in vivo, incorporating new complex gene perturbation libraries, and scaling to additional cell lines.
Thoracic radiotherapy in a cohort study of patients with metastatic small-cell lung neoplasms.
Authors: Anabel Mañes, Josep Jove, Gabriela Antelo, Anna Esteve, Antonio Arellano, Monica Caro, Ernest Luguera, Rosa Ballester, Victoria Tuset, Isabel Planas, Hugo Rosales, Eduardo Baena, Salvador Villà
Journal: Journal of Clinical Oncology (2019)

e20093 Background: Thoracic radiotherapy (TRT) for extensive stage small-cell lung cancer (ES-SCLC) patients is controversial. Slotman et al. (2015) demonstrated a 2-year overall survival (OS) benefit for patients who received TRT after chemotherapy (CT) and prophylactic cranial irradiation (PCI), but obtaining a median OS of 8 months (m). We wanted to confirm results of Slotman’s work in a real-world setting with higher doses of TRT. Methods: We retrospectively reviewed 67 patients with ES-SCLC treated between 1995 and 2015, after completing CT administration. Patients with initial brain metastasis and those who rejected PCI were excluded. All of them received PCI. All patients were followed until death. Disease-specific survival (DSS), disease-free survival (DFS) and OS were analyzed and computed with Kaplan-Meier method, groups were compared with log-rank test. Adjusted hazard risk (HR) of death for TRT was estimated through multivariate Cox model. Results: Patients (59 male, 8 female) with median age 64 years (42-79) had a median Karnofsky performance status (KPS) of 80. Twenty-three patients received high doses TRT (mean dose: 45.4 Gy). No significant differences between groups were found in age, gender, KPS, number of metastatic sites, residual thoracic disease or smoke activity. Non-TRT patients had more metastatic lesions. Median OS for TRT-patients was 19.9 m and 11.2 m for non-TRT patients (p = 0.01). DSS was 23.4 m for TRT-patients and 13.5 m for non-TRT patients (p = 0.007). For TRT-patients and non-TRT patients, median DFS were 15.5 and 8.3 m (p = 0.001), respectively. In the multivariate analysis, TRT (p = 0.003, HR 0.35), KPS (p = 0.012, HR 0.95) and residual thoracic disease (p = 0.02, HR 3.30) were independent prognostic factors for survival. The best benefit was obtained for those patients with consolidative TRT (CTRT): OS of 24.7, DSS of 27.4 and DFS of 15.9 m, compared with 13.4 (p = 0.003), 13.9 (p = 0.003) and 8.5 m (p = 0.007), respectively, for patients not treated with CTRT. Conclusions: TRT impacts positively in OS, DSS and PFS and should be administered to ES-SCLC patients who complete CT and PCI. High TRT doses could achieve better results than those described for low TRT doses.
Impact of cannabis (CA) use on chemotherapy (C) treatment and tumor characteristics of patients (pts) with testicular germ cell tumor (TGCT): Experience of the Centre Léon Bérard (CLB).
Authors: Patrick Arnaud-Coffin, Guillaume Moriceau, Marianne Lorcet, Audrey Couillet, Helen Jane Boyle, Aude Flechon
Journal: Journal of Clinical Oncology (2019)

e16054 Background: TGCT are the most frequent cancers in men aged 15-45. This population is increasingly exposed to CA that is illegal in France. Its consequences on treatment and prognosis remain unknown. Methods: The use and the quantity of CA were evaluated for all pts treated by C for a TGCT in the CLB from 01/2016 to 06/2018. Tobacco (T) and alcohol (A) co-addictions were also analyzed. All pts had before starting C pulmonary test with diffusing capacity of the lung for carbon monoxyde (DLCO) evaluation. We searched a link between the use of toxics, contraindication to Bleomycin (B) due to decreased DLCO and tumor characteristics: stage and IGCCCG prognostic groups. Results: One hundred and thirty two pts with a median age of 33.5 years (interval: 17-65) received C for TGCT mainly for NSGCT (n = 97, 73%). Nine pts (7%) were treated in the adjuvant setting (1: 6 or 2 BEP: 3). In metastatic pts, 79 (60%), 30 (23%) and 14 (10%) were considered as good, intermediate and poor prognosis (PG) according to IGCCCG respectively. BEP was given for 3 cycles to 63 pts and 4 to29 and 6 pts received a dose dense regimen according to GETUG13. Eleven pts didn’t received B (5: 4EP, 6: 4VIP) because of DLCO alteration before the beginning of C. Eleven pts treated with B switched to a regimen without B due to a decrease of the DLCO during treatment. CA use was frequent (n = 20, 15%) with 8 pts (6%) having a regular CA consumption (median 5 joints/d). Seventy eight pts (59%) were regular T smokers. Co-addictions for CA consumers were frequent (90% for T and 50% for A). T and CA smokers had more DLCO alteration leading to B contraindication (p = 0.01 and p = 0.04). A quarter (n = 5) of pts using CA didn’t received B, and only 1 pt who didn’t receive B was not a smoker (T and CA). The use of CA was associated with PG, OR 5.46 (CI 95%: 1.35-21.2; p = 008). We could not observe a relationship between relapse and the use of CA (p = 0.34) because of the small number of relapses (n = 8). Half (n = 10) of CA consumers were single men and 25% (n = 5) were unemployed. Conclusions: The use of CA is significantly associated with PG and with a reduction of B use due to adecreased DLCO. The impact of CA intoxication is negative on the quality of treatment (because of more contraindications to B). The association with PG remains unclear, but may be related to social isolation.
Changes in TROP2 expression in lung cancer patients receiving anticancer treatments.
Authors: Shota Omori, Hirotsugu Kenmotsu, Koji Muramatsu, Takuya Kawata, Haruki Kobayashi, Kazuhisa Nakashima, Kazushige Wakuda, Akira Ono, Tateaki Naito, Haruyasu Murakami, Takashi Sugino, Toshiaki Takahashi
Journal: Journal of Clinical Oncology (2019)

e14732 Background: Human trophoblast cell surface glycoprotein (TROP2) is expressed on the cell surface of trophoblasts and various solid cancer cells. Recently, an antibody-drug conjugate (ADC) targeting TROP2 has been developed. The objective of this retrospective study is to evaluate the prevalence of TROP2 expression in the specimen of lung cancer and its changes during anticancer treatments. Methods: TROP2 expression was evaluated prior to and following anticancer treatment by immunohistochemical (IHC) analysis using an anti-TROP2 antibody (SP295). IHC scores were graded from 0 to 3 and grade ≥2 was considered to be positive. Pre- and post-treatment IHC scores of TROP2 expression were compared by Wilcoxon signed rank test. Results: Among 160 patients with evaluable tissue samples, median age was 65 (range, 39-89) years with 69% in stage III-IV. Histological diagnosis included 81% adenocarcinoma (Ad), 12% squamous cell carcinoma (Sq), 5% neuroendocrine carcinoma (NEC), and others. Among 130 Ad patients, 59% had EGFR mutations. Anticancer treatments included cytotoxic chemotherapy (77%), targeted therapy (42%), and radiotherapy (19%). TROP2 was expressed in 143 (89%) and 139 (87%) in pre- and post-treatment samples, respectively. Pre-treatment TROP2 positive expression were more frequently observed in Ad (92%) or Sq (100%) than NEC histology (25%, p &lt; 0.001). There was no significant change in TROP2 expression after treatment (p = 0.509). Conclusions: TROP2 was commonly observed in the specimen of lung cancer especially in non-NEC histology regardless of anticancer treatments. TROP2-targeted ADC might have a therapeutic potential to be tested in TROP2-expressing lung cancer. [Table: see text]
Efficacy and safety of a novel topical minocycline foam for the treatment of moderate to severe acne vulgaris: A phase 3 study
Authors: Tooraj Joseph Raoof, Deirdre Hooper, Angela Moore, Martin Zaiac, Tory Sullivan, Leon Kircik, Edward Lain, Jasmina Jankicevic, Iain Stuart
Journal: Journal of the American Academy of Dermatology (2019)

FMX101 4% topical minocycline foam has been shown to be an effective and safe treatment for acne vulgaris (AV).To further evaluate the efficacy and safety of FMX101 4% in treating moderate to severe acne vulgaris.A 12-week, multicenter, randomized (1:1), double-blind, vehicle-controlled study was conducted. Coprimary end points were the absolute change in inflammatory lesion count from baseline and the rate of treatment success (Investigator's Global Assessment score of 0 or 1 with a ≥2-grade improvement).There were 1488 participants in the intent-to-treat population. The FMX101 4% group had significantly greater reductions in the number of inflammatory lesions from baseline (P < .0001) and a greater rate of treatment success based on Investigator's Global Assessment (P < .0001) versus the foam vehicle group at week 12. FMX101 4% was generally safe and well tolerated.The efficacy and safety of FMX101 4% were not characterized in participants with mild AV.FMX101 4% topical minocycline foam was effective and safe for the treatment of moderate to severe AV.
Influenza and mortality for non-small cell lung cancer.
Authors: Connor J Kinslow, Yuankun Wang, Yi Liu, Konstantin M. Zuev, Tony J. C. Wang, Ciro M. Donalek, Michael Amori, Simon Cheng
Journal: Journal of Clinical Oncology (2019)

e13114 Background: Lung cancer is the leading cause of cancer deaths in the United States and worldwide. While influenza illness is known to be particularly dangerous for frail and elderly patients, the relationship between influenza illness and outcomes in cancer patients remains largely unknown. Methods: Monthly mortality rates for all patients at risk, as well as newly diagnosed patients, with non-small cell lung cancer (NSCLC) diagnosed between 2009 and 2015 were compared during high and low flu months using data from the Surveillance, Epidemiology, and End Results (SEER) Program and the Center for Disease Control and Prevention (CDC) website. Influenza severity was determined by the percentage of outpatient visits to healthcare providers for influenza-like illness (ILI). CDC ILI activity levels were matched with SEER data by month and state. State-months with an ILI activity level of 8 or higher were considered to be high flu months, as defined by the CDC. Results: 195,038 patients with NSCLC from 13 states were included in the analysis. 52 out of 1,081 state-months (5.1%) had high flu activity. Monthly mortality rates for low and high flu months were 4.9 and 5.7%, respectively (p = .001). The monthly mortality rate for newly diagnosed patients was also significantly higher during high flu months (9.4 vs. 10.2%, p = .01). When the analysis was limited to winter months only, monthly mortality rates for low and high flu months were 4.7 and 5.3%, respectively (p = .02). The relationship between flu severity and mortality was also observed at the individual state level. Conclusions: Increased influenza severity is associated with higher mortality rates for NSCLC patients. Future research should elucidate the relationship between vaccination and survival in lung cancer patients.
Utility of concurrent immunoradiation for locally advanced and/or medically inoperable melanoma and Merkel cell carcinoma.
Authors: Joyson Poulose, Megan Wheelden, Heath B. Mackley, Carla Schmeck, Junjia Zhu, Colette Pameijer, Rogerio Izar Neves, Todd Schell, Carol Mallon, Joseph J. Drabick
Journal: Journal of Clinical Oncology (2019)

e21053 Background: Melanoma and Merkel Cell Carcinoma (MCC) are aggressive cutaneous malignancies with poor responses to cytotoxic chemotherapy. The use of immune checkpoint inhibitors (ICI) has substantially improved outcomes in metastatic disease and in the neoadjuvant setting. Addition of concurrent radiation therapy (RT) can augment the response of ICI, however there are little data on this combined approach as a neoadjuvant or non-operative strategy. Methods: We retrospectively analyzed outcomes of patients who received RT combined with an ICI against PD1, PD-L1, CTLA-4, or dual targets as neoadjuvant or definitive non-operative management for non-polymetastatic disease at our center from 2012 to 2018. Results: This study analyzed 14 patients, 7 males and 7 females, with a median age of 75 years. There were 10 patients with melanoma and 4 patients with MCC. Among them, 9 patients had stage III disease and 5 patients had oligometastatic disease. Prior treatments included surgery (71%), radiation (21%), and immunotherapy (21%) comprising interferon alpha (1), intralesional BCG (1), and Nivolumab (1). The ICI used were Pembrolizumab (5), Nivolumab (2), Avelumab (2), Ipilumumab (4) and Ipilumumab + Nivolumab (1). Immune related adverse events were seen in 8 patients and included endocrine (5), skin (4), and gastrointestinal (2) toxicity, majority of which were grade 1. Both grade 3 dermatitis and colitis were seen in 2 patients, and 1 patient had grade 3 colitis. There was 1 patient with grade 1 radiation dermatitis. Following concurrent ICI + RT, 4 patients who did not achieve a complete response (CR) at the irradiated site underwent surgical resection with no postoperative complications. An objective response at the irradiated site was seen in 13 (93%) patients, and 12 (86%) patients achieved a CR outside the radiated field. At the time of last follow up, 10 patients remain alive, of which 8 patients are in sustained complete remission. Conclusions: Concurrent use of ICI + RT was a safe approach in patients with locally advanced or medically inoperable melanoma and MCC with potential for durable complete remissions in the majority. Prospective studies are warranted to further validate this approach.