bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rates of PD-L1 expression testing in U.S. community-based oncology practices (USCPs) for patients with metastatic non-small cell lung cancer (mNSCLC) receiving nivolumab (N) or pembrolizumab (P).
Authors: Khozin Sean , Abernethy Amy Pickar , Nussbaum Nathan C. , Zhi Jizu , Curtis Melissa , Tucker Melisa , Lee Shannon E , Light Dave , Blumenthal Gideon Michael , Pazdur Richard 
Published: September 2018

11596 Background: FDA approved N for previously treated squamous mNSCLC in 3/2015 and non-squamous mNSCLC in 10/2015 regardless of PD-L1 expression. P was approved for previously treated mNSCLC in 10/2015 for patients whose tumors express PD-L1 as determined by an FDA-approved companion diagnostic (CoDx). Post-FDA approval treatment patterns of N and P, including PD-L1 testing patterns, remain unclear. Methods: We conducted a retrospective analysis using de-identified patient-level electronic health record (EHR) data aggregated from USCPs by Flatiron Health in accordance to an institutional review board approved protocol. Data was abstracted using both structured and unstructured EHR content with 10% duplicate abstraction to confirm data quality. All patients in the database with clinically-confirmed mNSCLC diagnosed from 1/1/11 to 3/31/16 and documented order or administration of N or P were included in the analyses. PD-L1 expression testing results were abstracted from unstructured data in EHR documents. Results: Within the first year of FDA approval, 1,362 mNSCLC patients received N or P (96.2% N; 3.3% P, 0.5% N+P). The median duration of treatment was 113 days. Overall, 11.3% of patients were tested for PD-L1 expression, 42.2% of whom tested positive. PD-L1 expression testing increased quarterly (Q) from 3.0% in Q2 2015 to 12.8% in Q1 2016. An FDA-approved CoDx was used 30.5% of the time. Among patients who received N, 90.5% were not tested for PD-L1 expression, 3.2% tested positive, and 4.7% tested negative for PD-L1. Among patients who received P, 32.7% were not tested for PD-L1 expression, 50.0% tested positive, and 1.9% tested negative. Conclusions: We observed low rates of PD-L1 expression testing in USCPs for patients with mNSCLC receiving N or P. Testing rates increased quarterly following FDA-approval. The majority of patients were not tested using FDA-approved CoDx. Most patients who were not tested for PD-L1 expression or tested negative received N. Clinician education will be important as data on optimal PD-L1 testing strategies guiding immunotherapy treatment decisions accumulates.
Genetic variations in semaphorin/neuropilin signaling to predict clinical outcome in patients (pts) with metastatic colorectal cancer (mCRC) receiving bevacizumab-based chemotherapy.
Authors: Miyamoto Yuji , Loupakis Fotios , Zhang Wu , Cao Shu , Okazaki Satoshi , Berger Martin D. , Suenaga Mitsukuni , Schirripa Marta , Soni Shivani , Matsusaka Satoshi , Ning Yan , Yang Dongyun , Gopez Roel , Melendez Elizabeth , Hanna Diana L. , Barzi Afsaneh , Baba Hideo , Falcone Alfredo , Lenz Heinz-Josef 
Published: September 2018

11608 Background: Neuropilin ( NRP) is known to be an important VEGF co-receptor that acts as a key mediator of angiogenesis. Its ligands, semaphorins ( SEMA), compete with VEGF for NRP binding and can themselves have angiogenic activity. Plexins are also receptors of SEMAs, and have the GTPase activating proteins (GAPs) domain for RAS. NRPs are shown to signal through RAS pathways. We aimed to evaluate whether single nucleotide polymorphisms (SNPs) of genes involved in the SEMA/NRPpathways predict clinical outcome in bevacizumab-treated mCRC pts. Methods: Associations between nine SNPs in 7 genes ( SEMA3A, SEMA3D, SEMA3F, NRP1, NRP2, PLXNA1 and PLXND1) and clinical outcomes were evaluated in mCRC patients receiving first-line FOLFIRI-bevacizumab in a phase III trial: TRIBE ( N= 228). Associations between genotype and RAS mutation status with clinical outcomes was also examined. Main characteristics were the following: male/female = 138/90; median age = 60; RAS-wildtype/mutant = 55/116; median PFS = 9.7 months; median OS = 26.1 months, median follow-up time = 49.3 months. Results: NRP1 rs2228638 Any A ( N= 40) showed a significantly longer PFS compared to G/G variant ( N= 188) in the univariate (11.6 months (M) vs. 9.5 M, HR = 0.64, 95%CI = 0.43-0.95, p = 0.022) and the multivariate analysis (HR = 0.59, 95%CI = 0.38-0.90, p = 0.016). SEMA3F rs12632110 A/A ( N= 20) showed a significantly shorter PFS compared to any G variant (N = 205) in the multivariate analysis (HR = 1.89, 95%CI = 1.02-3.49, p = 0.043). Among RAS-mutant pts, SEMA3F rs12632110, SEMA3F rs1046956, SEMA3D rs7800072, NRP1 rs228638, PLXNA1 rs4679323 and PLXND1 rs2255703 polymorphisms were significantly associated with PFS in the univariate and multivariate analysis. PLXNA1 rs4679323 was also significantly associated with OS in the univariate and multivariate analysis. There was no association between these polymorphisms and outcome in patients with RASwildtype tumors. Conclusions: Genetic variants within SEMA/NRP pathways may be prognostic markers in RAS mutant mCRC patients treated with bevacizumab-based chemotherapy.
Variable DNA mismatch repair-associated gene profiles in colorectal versus uterine cancers.
Authors: Baker Tabari , Deihimi Safoora , Martin Lainie P. , Hall Michael J. , Hampel Heather , El-Deiry Wafik S. 
Published: September 2018

11610 Background: DNA mismatch repair (MMR) plays an important role in maintaining DNA synthesis fidelity in the genome. Mutation in MMR genes occurs in colorectal and uterine cancers and leads to increased mutation burden that is associated with response to immune checkpoint inhibitors. It is unknown if there is an MMR gene-specific mutation signature in MMR-deficient tumors, or whether mutations in MMR genes drive specific mutation patterns. Methods: The study cohort consisted of 1060 uterine cancer (UtCa), and 797 colorectal cancer (CRC) cases consecutively submitted to Caris Life Science for molecular profiling using multiple technologies, including next generation sequencing (NGS), immunohistochemistry (IHC), and in situ hybridization (ISH). Mutation, IHC-positive, and ISH-positive frequencies were compared using Fisher’s exact test (p-value < 0.05 considered significant). Results: In total, 1,857 tumors were examined. Of the 797 CRC cases, 115 (14.4%) had at least one mutation in MLH1, MSH2, or MSH6. Nineteen (19; 2.3%) of the CRC cases had mutations in multiple MMR related genes. Of the 1060 UtCa cases, 52 (4.9%) had at least one mutation in MLH1, MSH2, or MSH6. Twenty-two (22; 2.1%) of the UtCa cases had mutations in multiple MMR related genes. Colorectal cancers that were MLH1, MSH2, and MSH6 mutated enriched for rare, lineage specific co-mutations, including KRAS A146T (4/32 MLH1-mutated cases; 12.5%). Uterine cancers that were MLH1, MSH2, and MSH6 mutated also enriched for several co-mutations, including ARID1A (8/9 MLH1-mutated cases; 88.9%), a SWI-SNF chromatin remodeling complex family member. Further analyses revealed differences in PD-L1 positivity between MMR mutated CRCs versus UtCa (8/131; 6.1% versus 8/51; 15.7%). Tumor mutational load (defined as the total number of non-synonymous mutations per Mb sequenced) was 35 mutations per Mb in CRC and 51 mutations per Mb in UtCa. Conclusions: There are differences in mutation signatures between uterine and colorectal cancer, and possible additional molecular targets for combination with immune checkpoint therapies. Further analysis of MMR gene-specific differences in molecular profiles is ongoing and will be discussed.
HER3-EGFR score to predict clinical outcomes in triple-negative breast cancer.
Authors: Ogden Angela , Bhattarai Shristi , Green Andrew R. , Aleskandarany Mohammed A. , Rakha Emad A. , Ellis Ian O. , Li Xiaoxian (Bill) , Krishnamurti Uma , Janssen Emiel A. , Jonsdottir Kristin , Reid Michelle D. , Rida Padmashree C.G. , Aneja Ritu 
Published: September 2018

11612 Background: Limited preclinical evidence suggests that the ErbB family member HER3 may have prognostic value in TNBC. However, HER3 is a pseudokinase that cannot homodimerize, so in order to signal it must bind to other ErbB family members such as HER2 or EGFR. EGFR is frequently overexpressed in TNBC; consequently, it may be necessary to consider HER3 levels in the context of EGFR levels in TNBC to derive clinically meaningful insights. Methods: Towards this end, we tested the prognostic value of a combined immunohistochemical HER3-EGFR score (the sum of the individual H-scores, with the median used as a cutpoint) in a multi-institutional study of n = 510 TNBC patients using Cox proportional hazards regression. We also compared the HER3-EGFR-high and low groups in terms of 105 immunohistochemical biomarkers using Mann-Whitney U tests as well as Ingenuity canonical pathways using gene expression data from RNA-seq. Results: Among chemotherapy-treated TNBC patients, high HER3-EGFR score conferred a 2.30-fold increased risk of dying from breast cancer and a 1.78-fold increased risk of distant metastasis (p = 0.006 and p = 0.041, respectively) after adjusting for age and stage. Individual HER3 and EGFR H-scores were not associated with outcomes in simple or multivariable models. We also found that tumors from chemotherapy-treated TNBC patients with high HER3-EGFR scores exhibited higher immunohistochemical expression of luminal cytokeratins, DNA damage response proteins, and P-cadherin compared with tumors from chemotherapy-treated TNBC patients with low scores (q < 0.25). The top canonical pathway whose components were overexpressed in HER3-EGFR-high TNBCs was Hepatic Fibrosis (p = 0.008), which is linked to distant metastasis, and the top upstream regulator was HNF4A (p = 0.012), a transcription factor for ERBB3 with isoforms that promote liver and gut tumorigenesis. Conclusions: Collectively, our study reveals that HER3-EGFR score may identify chemotherapy-treated TNBC patients at increased risk for distant metastases and death whose tumors may be characterized by fibrotic processes. Our immunohistochemical test thus identifies high-risk TNBCs who may benefit from agents that inhibit HER3-EGFR signaling.
Comparing programmed death ligand-1 expression on tumor cells before and after acquiring resistance to tyrosine kinase inhibitor in EGFR harbouring non-small cell lung cancer.
Authors: Sakdejayont Siwat , Chantranuwat Poonchavist , Poovorawan Nattaya , Sitthideatphaiboon Piyada , Parinyanitikul Napa , Vinayanuwattikun Chanida , Tanasanvimon Suebpong , Sriuranpong Virote 
Published: September 2018

11617 Background: Although anti-PD1/PD-L1-targeting immunotherapy has been successful in the treatment of non-small cell lung cancer (NSCLC) patients, the benefit is unclear in EGFR mutation(mEGFR) NSCLC. To date, there are several clones of anti-PD-L1 antibody which provide different predictive values and the level of expression also dynamically changed after treatment. The study examined changes of PD-L1 expression in mEGFR harbouring NSCLC tissues, comparing between before and after treatment with tyrosine kinase inhibitors(TKIs) using an FDA-approved PD-L1 assay. Methods: We retrospectively reviewed tumor specimen from 24 patients with mEGFR NSCLC who had been treated with gefitinib, erlotinib, afatinib and received second tissue biopsy after acquiring resistance to TKIs. The collected FFPE specimens were stained with commercial anti-PD-L1 22C3 assay monoclonal antibody. Tumor proportion score(TPS) and H-score were measured before and after TKIs. Results: Of the study patients,54.2% patients were exon 19 deletion(n = 13), 41.7% were exon 21 point mutation(L858R) (n = 10), and 1 case was L858R/S761I. After TKIs resistance 10/13 (76.9%) of exon 19del and 8/10 (80%) of L858R revealed presence of +T790M. Pretreatment PD-L1 expression was positive(TPS≥1%) in 6 cases (25%). Mean TPS of positive cases was 34.0% and H-score was 78.2, All except 2 of 6 positive cases had adequate specimens from second biopsy(n = 22). Among 4 positive cases,PD-L1 expression tended to be higher after TKIs; mean TPS changed from 23.9 to 40.9 (p = 0.171) and H-score were from 49.3 to 91.1 (p = 0.172). 18/24 patients with TPS and H-score zero at the beginning remained zero after progression. Median TTP were similar in patients with positive PD-L1 expression and negative,13.8 m vs 14.5 m (n = 24,p = 0.644) with TKIs and 3.9 m vs 2.5 m (n = 14, p = 0.560) with chemotherapy. Conclusions: Prevalence of PD-L1 expression in mEGFR NSCLC was low. PD-L1 expression tended to be higher after TKIs for this with positive cases which may guide the sequences of treatment. Nevertheless no changes of PD-L1 expression for those with negative, hence re-biopsy may not be necessary.
Enrichment of germline DNA-repair gene mutations in patients with colorectal cancer.
Authors: Aldubayan Saud H , Giannakis Marios , Moore Nathanael , Mu Xinmeng Jasmine , Han G. Celine , Nishihara Reiko , Qian Zhi Rong , Liu Li , Ogino Shuji , Garraway Levi A. , Fuchs Charles S. , Van Allen Eliezer Mendel 
Published: September 2018

1500 Background: Twin studies showed that 30% of all colorectal cancer (CRC) patients have an inherited genetic susceptibility. Several CRC predisposition genes have been described to date. However, mutations in these genes explain the risk in only 5-10% of CRC cases. In this study, we hypothesized that some of the CRC heritability may be explained by excess disruptive germline mutations in DNA repair genes (DRGs). Methods: Exome sequencing data of 716 in the discovery cohort (CanSeq and NHS/HPFS studies) and 1609 CRC patients in the validation cohort (TCGA and NSCCG studies) were used to evaluate germline variants in a pre-selected group of 42 DRGs and 12 known CRC risk genes. Frequencies of disruptive mutations in our cohorts were examined relative to 27173 non-Finnish European cancer-free adults from the ExAC cohort to evaluate for enrichment. Results: Of 716 patients in the discovery cohort, 27 (3.8%) patients harbored germline mutations in APC (n = 11), MSH6 (n = 2), MUTYH (n = 11), CHEK2 (n = 1) and TP53 (n = 2). Interestingly, germline mutations in ATM and PALB2 were significantly enriched in our CRC discovery cohort (OR = 2.7; P = 0.044; and OR = 4.8; P = 0.026, respectively). Evaluation of germline data from another 1609 CRC patients (validation cohort) also showed significantly higher rates of ATM mutations (5; 0.7%; OR = 2.1; P = 0.044), and a trend for enrichment of PALB2 mutations (3; 0.4%; OR = 2.8; P = 0.056). Secondary analysis of actionable germline mutations in a highly penetrant cancer risk gene set ( ATM, BRCA1, BRCA2, BRIP1 and PALB2) suggest a broader enrichment trend in CRC patients for these genes (Discovery: OR = 1.7; P = 0.06; Validation: OR = 2; P = 1.96e-04). Conclusions: Our analysis of germline variants in 2325 CRC patients showed the first robust evidence for germline ATM mutations to confer a higher risk of developing CRC. We also presented evidence to support PALB2 as a potential novel CRC risk gene. Overall, our study shows that mutations in some DRGs may explain some of the missing CRC heritability. It also indicates that a significant percentage of CRC patients, who carry mutations in highly actionable genes where cancer screening recommendations for patients and families do exist, are not captured with current testing recommendations.
Prevalence of homologous recombination deficiency among all tumor types.
Authors: Heeke Arielle Lutterman , Baker Tabari , Lynce Filipa , Pishvaian Michael J. , Isaacs Claudine 
Published: September 2018

1502 Background: Triple negative breast and ovarian cancer are known to have a high frequency of homologous recombination deficiencies (HRDef). The prevalence of HRDef among all tumors is unknown. Methods: Molecular profiles of 48,733 tumors obtained from pts with bladder, breast, ovarian, pancreas, prostate, thyroid, cervical, hepatobiliary, colorectal (CRC), endometrial, gastric/esophageal (GE), head/neck, renal, non-small cell lung (NSCLC), small cell lung (SCLC), GIST, glioma, melanoma, sarcoma and unknown 1° cancers were reviewed to identify somatic pathogenic mutations (mut) in HR genes ATM, ATRX, BARD1, BLM, BRCA1/2, BRIP1, FANCA/C/D2/E/F/G/L, MRE11A, NBN, PALB2, PTEN, RAD50, RAD51, RAD51B, or WRN. Molecular profiles were generated from tumors submitted to Caris Life Sciences using multiple technologies including next generation sequencing (average read depth 500X). Results: Overall frequency of HR mut among all tumors is 11.61% (5658/48733). Cancer lineages with highest frequency of HR mut are endometrial (38.08%, 1956/5137), glioma (15.90%, 265/1667), ovarian (12.99%, 1151/8862), prostate (11.21%, 77/687), cervix (10.06%, 79/785) & breast (9.66%, 562/5818). Least commonly mutated lineages include GIST (1.50%, 3/200), sarcoma (3.12%, 55/1763), head/neck (3.70%, 24/648), hepatobiliary (4.72%, 39/827) & pancreas (5.05%, 102/2022). Frequencies of HR gene mutations are depicted in Table 1. Conclusions: HR mutations were seen in 11.61% of tumors. While the percentage of HRDef in pancreatic cancer pts is lower than what has been seen in other datasets, the percentage in breast and ovarian cancer, as well as the percentage of other tumors with HRDef, provide a path to employ HRDef-directed therapies such as platinums, but especially PARP inhibitors and newer agents such as ATRX inhibitors. [Table: see text]
Routine tumor next-generation sequencing (NGS) to identify rare germline lung cancer risk mutations in EGFR and ERBB2.
Authors: Chen Ruthia , Koeller Diane R. , Sholl Lynette M. , Rabin Michael S. , Yurgelun Matthew B. , Chittenden Anu B. , Garber Judy Ellen , Oxnard Geoffrey R. 
Published: September 2018

1513 Background: New insights into lung cancer genomics has required a new look at genetic determinants of inherited lung cancer risk. There are now four germline mutations in lung cancer oncogenes (EGFR T790M, V843I, R776H; and ERBB2 G660D) which have been reported in kindreds with a high prevalence of lung cancer in nonsmokers. We hypothesized that routine tumor NGS could be used to find rare kindreds with inherited lung cancer risk. Methods: An institute-wide database of tumor NGS results was queried for cases positive for one of the reported germline risk alleles in EGFR or ERBB2. At our center, tumor NGS is performed using a hybrid-capture platform spanning exons and key introns of ~400 cancer related genes, and is available for patients (pts) with consent to a research protocol. For living pts with a mutation detected at an allelic fraction (AF) > 25%, and excluding acquired T790M, genetic counseling and CLIA germline testing was provided. For pts with EGFR T790M, testing was performed on the INHERIT EGFR study (NCT01754025; ALCMI). Results: 51 cases were identified from a total of 13,488 cancers with NGS results: 45 with EGFR T790M (all lung cancer), 4 with EGFR R776H (NSCLC, endometrial cancer, and 2 glioma), 2 with ERBB2 G660D (NSCLC and glioblastoma). 34 pts with T790M detected after EGFR inhibitor were excluded, leaving 17 pts of interest. Germline testing was performed on 9 living pts with > 25% AF on NGS, and was positive in 8; 6 of these had germline EGFR T790M. Additionally, germline EGFR R776H was found in a never-smoker with metastatic endometrial cancer; she had a prior a history of NSCLC, and family history was notable for multiple members with lung, breast, and colon cancer. Germline ERBB2 G660D was found in a young never-smoker with metastatic NSCLC and a family history significant for lung cancer in multiple first-degree relatives. Conclusions: Rare germline lung cancer risk mutations in EGFR and ERBB2 can be identified on routine tumor NGS, and may indicate a risk of inherited lung cancer. Our study includes the second known report of a germline EGFR R776H or ERBB2 G660D mutations. Commercial germline NGS assays could be expanded to cover these rare but potentially high-penetrance variants.
Pathogenic germline mutations in emerging cancer genes: What happens after panel testing?
Authors: Hall Evan Thomas , Ahuja Parikh Divya , Gupta Tanya , Caswell Jennifer Lee , Mills Meredith , Kingham Kerry , Koff Rachel , Ford James M. , Kurian Allison W. 
Published: September 2018

1528 Background: Next-generation sequencing technology enables more comprehensive germline genetic testing, including genes whose cancer risks are less well-characterized (particularly among patients with less striking family histories). Little is known about patient outcomes, particularly adherence to risk-reducing recommendations and family testing. Methods: We attempted a phone interview ≥3 times with each adult patient who had a germline pathogenic or likely pathogenic mutation found in an emerging cancer gene (defined as any gene other than BRCA1/2 or the Lynch Syndrome genes MLH1, MSH2/6, PMS2) at a single academic cancer genetics clinic from January 2013-July 2016. Results: Of 143 eligible patients, 53 (37%) were successfully contacted and all consented to participate. Median follow-up was 677 days (range 247–1401) and age was 52 years (21-82). Two-thirds (68%) had personal cancer history and 93% had a first-degree relative with cancer. Mutations in genes associated with named syndromes ( APC=5 , CDH1=3 , TP53=3, PTEN=2) were found in 23% (many of whom lacked family history typical of these syndromes) whereas 77% had mutations in less well-characterized genes ( MYH=10, CHEK2=10, ATM=6, PALB2=6 , NBN=3, RAD51C=2, RAD51D=2, SDHB=1, CDKN2A=1, MRE11A=1, RAD50=1, FLCN=1). Conclusions: Two years after panel testing, patients with germline mutations in less well-characterized genes reported high rates of adherence to recommendations, family communication and testing. Limitations include a relatively low response rate and a single academic center; this may bias toward a “best-case” scenario. Larger, population-based studies will be crucial to understand the real-world outcomes of germline multiple-gene panel testing and its contribution to precision oncology. [Table: see text]
Breast cancer risk assessment and chemoprevention use among VA primary care.
Authors: Merriman Joseph , Bidassie Balmatee , Kovach Amanda , Vallette Marissa , Park Yeun-Hee Anna , Aggarwal Anita , Colonna Sarah Violet 
Published: September 2018

1543 Background: Despite recommended guidelines and available medicationsto reduce breast cancer risk by up to 50-65%, <5% of the 10 million eligible women are offered chemoprevention in the U.S. The comfort level, practice patterns, and barriers to breast cancer risk assessment and chemoprevention use within the VA have not been reported. Methods: We assessed VA primary care providers using a REDcap survey. We obtained provider demographics, use and comfort level with breast cancer risk models and chemoprevention and knowledge about chemoprevention. Data was analyzed with Fishers exact or chi-square tests. Results: Of the 200 survey respondents, 167 were included for analysis. Overall, 30% used the Gail model monthly or more often, and 1.5 % prescribed chemoprevention in the last 2 years. Fewer than 30% correctly answered chemoprevention knowledge questions. Designated women's health providers were more comfortable with risk assessment and chemoprevention (p<.046, p<.004) and used risk models more often (p<.045). 63% expressed interest in education about breast cancer prevention. Conclusions: Breast cancer risk assessment and chemoprevention use by VA primary care is limited by lack of comfort and familiarity. Women's health providers are more comfortable and knowledgeable about breast cancer risk models and chemoprevention, offering an opportunity for partnership with high-risk oncologists to improve breast cancer risk assessment and chemoprevention use among female Veterans.[Table: see text]