bluuebunny/crossref_metadata_2025 huggingface dataset:
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]
What puts physicians and patients discussing cancer screening on the same page?
Authors: Seiden Danielle , Bezuhly Maureen , Aharanoff Gina , Cassano Kelly , Osborne Michael P. , Chadha Manjeet , Talcott James Austin
Published: September 2018

1552

Background: Shared decision making requires effective provider-patient communication. We studied concordance in recalled discussions and factors that affected it. Methods: In a cluster-randomized trial of educational supports for providers (MDs), we are enrolling an age-(30-89 years) and sex-stratified sample of 216 patients (PTs) who underwent a physical examination at 2 urban hospitals, 18 for each of 12 primary care MDs. Screening guideline formatting (colorcoding) and academic detailing were randomly assigned in a 2x2 design. Immediate post encounter surveys recorded PT and MD recall of screening discussions. Results: The first 174 participants were diverse (63% white) and highly educated (77% college degree). PTs and MDs differed in recall of screening discussions, and the differences varied by screening test. When MDs reported a colorectal cancer (CRC) screening discussion, 21% of PTs did not; 20% of MDs disagreed when PTs reported the discussion. The discrepancies were greater for prostate specific antigen (PSA) screening, 29% and 29%, respectively, but much less for mammograms (MAM), 8% and 5%, respectively. Recall of the MD recommendation also differed: 15% of PTs disagreed when their MD reported it, and 33% of MDs when their PT reported it. For PSA, disagreement was 26% and 33%, respectively, and for MAM, disagreement was 17% and 10%, respectively. Overall, agreement between all PTs and MDs on whether screening was recommended was fair for CRC, PSA and MAM: kappa = 0.33, 0.34 and 0.29, respectively. For PTs > 70 agreement was nonexistent on recalled CRC and PSA recommendations (kappa = -0.02 and -0.03, respectively) but preserved for MAM (kappa = 0.39). Sex did not affect CRC agreement. Recall concordance improved when SDM was recalled. For CRC, kappa rose from -0.12 to 0.52 if the MD recalled any MDM element. Conclusions: In a highly educated, diverse patient population, patients and physicians often disagreed on recalled cancer screening discussions. Discordance was greatest with PSA and least with MAM. Discordance was greater in older patients. If MDs recalled any shared decision making, agreement increased significantly. Communication varies by cancer screen, PT age and elements of shared decision making. Clinical trial information: NCT02430948.
Incidence and survival trends of cancers diagnosed in young adults (20-39 years): A population-based study.
Authors: Olga Husson , van der Mark Marianne , Bijlsma Rhode , Westermann Anneke M. , Aben Katja , Van Der Graaf Winette T.A.
Published: September 2018

1567

Background: Cancer in young adults (YAs; 20–39 years) is rare but its incidence is increasing globally. In The Netherlands, care for YA cancer patients is mostly dispersed, in contrast to centralized care for all pediatric cancer patients. Aim of this population-based study was to examine trends in YA cancer incidence and survival. Methods: Data from all YAs diagnosed between 1989-2015 (n = 89,675) were obtained from The Netherlands Cancer Registry. Age-standardized incidence rates with estimated annual percentage of change and five-year relative survival rates were calculated. Results: Cancer incidence in YAs increased significantly from 48 to 67 per 100,000 person years in males (1.7%) and from 78 to 97 per 100,000 person years in females (1.1%). In both males and females, significant rising incidence trends were found for melanoma (2.3%), skin (2.3%) and thyroid cancer (3.2%), CML (7.2%), Hodgkin (1.3%) and Non-Hodgkin lymphoma (0.9%). In females, the incidence of breast cancer increased (1.2%), while it decreased for lung (-1.3%) and ovarian cancer (-4.3%). In males, testicular cancer incidence increased significantly (4.1%). The most common cancers in male YAs were testicular cancer (33%), melanoma (15%), gastrointestinal cancer (8%), Non-Hodgkin and Hodgkin lymphoma (both 7%), whereas in females breast cancer (34%), melanoma (19%), gynecological (14%), thyroid and gastro-intestinal cancer (both 5%) were most frequently diagnosed. Over time, the five-year relative survival increased significantly from 72% to 85%. Survival improved for almost all tumor types, except for pediatric tumors: medulloblastoma (~60%), Ewing sarcoma (~43%) and rhabdomyosarcoma (~41%). A < 80% five-year survival rate was also found for tumors of the lung (36%), gastro-intestinal tract (61%), ALL (60%), AML (65%) and soft tissue sarcomas (77%). Conclusions: Over the last 26 years, a marked increase in the incidence of a diverse spectrum of hematological and solid malignancies, pediatric and adult-type cancers was found for YAs. Survival improved over time, however remains poor for certain tumor types. Our data underpin the importance of knowledge of tumors at YA age to guide centralization of care and clinical research.
Association of dietary fiber intake and gut microbiota in healthy adults.
Authors: Lin Daniel , Peters Brandilyn , Sinha Rashmi , Goedert James J. , Hayes Richard , Ahn Jiyoung
Published: September 2018

1569

Background: Increasing evidence has shown that gut microbiota alterations may play a role in colorectal cancer risk. Diet, particularly fiber intake, may modify gut microbiota composition, which may consequently impact cancer risk development. We investigated the relationship between dietary fiber intake and gut microbiota in healthy humans. Methods: Using 16S rRNA gene sequencing, we assessed gut microbiota in fecal samples from 151 healthy adults in two independent study populations: Study A, n = 75 (healthy controls from a colorectal cancer case-control study), and Study B, n = 76 (polyp-free subjects from a cross-sectional colonoscopy study). We calculated energy-adjusted total dietary fiber intake of participants based on food frequency questionnaires. For each study population, we evaluated the relationship between quartiles of higher fiber intake as a continuous ordinal variable, and global gut microbiota community composition (via PERMANOVA of weighted UniFrac distance) and specific taxon abundance (via DESeq2). Results: We found that fiber intake was significantly associated with overall microbial community composition in Study B (p = 0.003) but not Study A (p = 0.68), after adjustment for age, sex, race, body mass index, and cigarette smoking. In a taxonomy-based meta-analysis of these two study populations, higher fiber intake was associated with lower abundance of genus Actinomyces (fold change [FC] = 0.769, p = 0.003), and higher abundance of genera Faecalibacterium (FC = 1.153, p = 0.03), Lachnospira (FC = 1.167, p = 0.04), and SMB53 (FC = 1.201, p = 0.05). A species-level meta-analysis showed an association between higher fiber intake and higher abundance of Faecalibacterium prausnitzii (FC = 1.165, p = 0.03) and lower abundance of Ruminococcus bromii (FC = 0.828, p = 0.08). Conclusions: Our results suggest that higher intake of dietary fiber may alter gut microbiota in healthy adults. Given the potentially modifiable nature of the gut microbiota through diet, these findings warrant further study of diet-microbiota based colorectal cancer prevention strategies.
Does race play a role in genetic screening for hereditary cancer syndromes?
Authors: Chatterjee Sudeshna , Frey Melissa K , Zhou Zhen Ni , Carlson Ann , Caputo Thomas A. , Holcomb Kevin , Chapman-Davis Eloise
Published: September 2018

1578

Background: Molecular analysis of cancer predisposition genes may influence cancer screening, prevention strategies and options for targeted therapy. We sought to identify ethnic differences in patterns of genetic testing. Methods: Results of all patients with known ancestry who underwent genetic testing at the hereditary breast and ovarian cancer center at a single institution between 7/1/2013-12/31/2016 were reviewed. Race was stratified as Black, White, Asian, and Hispanic. Ashkenazi Jews were excluded from the White subgroup because of their higher rates of testing for deleterious founder mutations. White patients were utilized as the reference population for all statistical analysis. Results: 894 patients were included: 139 Black, 613 White, 33 Hispanic and 108 Asian. Black patients were more likely to undergo genetic testing for a personal history of cancer rather than family history risk assessment compared to White patients (p = 0.002). There was no difference in genetic testing rates based on personal or family history of cancer between Asians or Hispanics and Whites (p = 0.398 ;p = 0.366). Black patients were more likely than White patients to undergo testing with targeted-gene rather than multigene panels (p = 0.026). The use of targeted and multigene panels were not different among Asians or Hispanics ( p = 1.0). Blacks, Asians and Hispanics had a lower rate of known deleterious mutations but a higher rate of variants of unknown significance (VUS) than Whites (15.1% p = 0.048; 22.2% p = .001; 33.3%p = .002 respectively). BRCA1/2 mutations accounted for 100% of identified mutations across all the non-White populations. Among Blacks, BRCA1/2 accounted for 38.1% of VUS compared to 27.9% in Whites ( p = .2114). VUS in the ATM gene accounted for 28.6% in Blacks compared to 8.2% in Whites (p = 0.028). Conclusions: Black patients were less likely to undergo testing based on family history, suggesting a missed opportunity for cancer prevention. They were more likely to undergo targeted testing and100% of identified mutations were in BRCA1/2 genes. Non-white patients had higher rates of VUS, emphasizing the need for improved VUS reclassification in non-White populations.
Patterns of genetic screening for hereditary cancer syndromes: Effect of Supreme Court’s ruling invalidating single gene patent rights.
Authors: Zhou Zhen Ni , Frey Melissa K , Nasioudis Dimitrios , Carlson Ann , Fields Jessica , Holcomb Kevin , Chapman-Davis Eloise
Published: September 2018

1580

Background: In 6/2013 the Supreme Court ruled that isolated DNA sequences found in nature could not be patented, resulting in rapid uptake of multigene panels. We sought to explore trends in genetic testing since this ruling. Methods: Results of all patients undergoing genetic testing and counseling at a single institution between 7/1/13 and 12/31/16 were reviewed. Associations between categorical variables were evaluated by chi-square tests or Fisher's exact tests as appropriate for category size. Results: 1663 patients underwent genetic testing over the study period. The median age was 49 years (range 18-86). Use of multigene panels versus targeted gene testing increased significantly in the years following the Supreme Court ruling (Table 1, P<0.001). While the percentage of patients found to have pathogenic mutations remained stable over the study period (9%), detection of variants of uncertain significance (VUS) increased significantly (Table 1, P<0.001). In 2013 BRCA1/2 mutations accounted for 91% of identified mutations; however this number decreased over time (2014-83%, 2015-70%, 2016-58%, P=0.01). Use of multigene panels detected 71% of mutations in non- BRCA1/2 genes such as CHEK(19), APC(44), MSH6(1), P53(1), and PTEN(1). Patients with a personal history of breast and/or ovarian cancer were more likely to have targeted testing than patients with other cancer types (590, 66% vs. 9, 33%, P=0.001). Conclusions: The uptake of multigene panels has increased since the 2013 Supreme Court ruling. While this technology allowed for the identification of many cancer-related genes that would be missed on targeted BRCA1/2 testing, it also resulted in a significantly increased detection of VUS, a finding with unknown clinical implications. [Table: see text]
VHVT: An ultra-sensitive somatic mutation detection and performance assessment program.
Authors: Liu Jilong , Liu Zu , Cheng Shaomin , Guo Fengming , Tan Meihua , Wang Jingjing , Shao Di , Zhang Pan , Li Zhilong , Liu Han , Li Shiyong , Hu Zhenfei , Hou Yumei , Mao Mao , Ye Mingzhi
Published: September 2018

1588

Background: NGS as a high throughput technique is particular valuable for cancer given its ability to detect multiple driver mutations. While reads contain SNVs and short InDels can be mapped to the right position using gatk-like programs, a program designed for germline mutation detection, reads contain long InDels such as EGFR EX19 deletions often wrongly mapped especially when deletions near the ends of the reads. Thus, gatk would not recognize these reads, consequently underestimate the mutation allelic frequency, and even missed out InDels when supporting reads were rare. Methods: Here we present a variation hotspot validation toolkit (VHVT), a validation based method to precisely detect the ultra-low frequency somatic mutations. As far as we know, it is the first specialized somatic mutation detection software. First, reference sequences aimed at the hotspot mutations were assembled, then reads were be mapped to the new assembled reference to precisely distinguish the supporting reads. Moreover, log odds (LOD) and Poisson mathematical model were integrated to control sequencing error, as a result, VHVT can achieve a limitation of detection at 0.01% with sensitivity and specificity above 95% and 99% respectively. In addition, we developed a method to quantitatively assess the performance of variation detection program using standard reference data. By mapping to the reconstructed reference, all supporting reads will be detected in sequencing data, and comparing theses with the number of supporting reads delivered by a program we can define recognition ratio of supporting reads. Results: Our reference standard data showed that VHVT can recognize average 30% more support reads than gatk for EGFR EX19 deletions. In a total 498 NSCLC clinical samples test, VHVT detected actionable mutations in 289 samples. 243 positive mutations were verified (168 by SANGER sequencing, 75 by ddPCR) with concordance rate at 100%. Conclusions: Taken all together, our results demonstrated the robust performance of VHVT for somatic mutation detection and program assessment and thus facilitate the development of personalized cancer therapy.
Randomized, double-blind, phase III trial of a personalized peptide vaccination for human leukocyte antigen-A24-positive glioblastoma multiforme patients refractory to temozolomide-based therapy.
Authors: Terasaki Mizuhiko , Narita Yoshitaka , Arakawa Yoshiki , Sugiyama Kazuhiko , Aoki Tomokazu , Kanamori Masayuki , Nagane Motoo , Kumabe Toshihiro , Hirose Yuichi , Ichikawa Tomotsugu , Fujimaki Takamitsu , Kobayashi Hiroyuki , Goto Hisaharu , Takeshima Hideo , Ueba Tetsuya , Abe Hiroshi , Tamiya Takashi , Sonoda Yukihiko , Kakuma Tatsuyuki , Nishikawa Ryo
Published: September 2018

2000

Background: To establish whether personalized peptide vaccination (PPV) is clinically beneficial for human leukocyte antigen (HLA)-A24-positive glioblastoma multiforme (GBM) patients refractory to temozolomide (TMZ)-based therapy. Methods: From January 2012 to March 2016, 88 HLA-A24-positive GBM patients refractory to TMZ-based therapy from 20 Japanese hospitals were randomly assigned to receive PPV treatment (n = 58) or best supportive care (BSC) (n= 30) at a 2 to 1 ratio. Four peptides chosen from 12 peptide candidates based on pre-vaccination IgG levels specific to each peptide or 4 corresponding placebos were injected subcutaneously once weekly for 12 times at the first course followed by biweekly vaccinations until disease progression. The primary endpoint was overall survival (OS). Results: The primary endpoint was not met in this clinical trial. Unfavorable prognostic factors were performance status (PS) 3, higher plasma levels of pre-vaccination granulocyte macrophage-colony stimulating factor (GM-CFS), and PPV containing SART2-derived peptides. Therefore, 78 patients with PS of 0 to 2 (50 with PPV and 28 with BSC) were provided for the subgroup analysis. Among them, the median OS of 39 PPV patients (10.4 months, 95% CI, 7.8-12.0 months) who had either lower levels of GM-CSF ( < 0.9 pg/mL) or 4 peptide vaccinations that did not include SART2-derived peptides was significantly (p = 0.03) longer than that of the corresponding 19 BSC patients (6.8, 4.6-12.7). In contrast, the median OS of 10 PPV patients (4.1, 1.1-8.3) who had both higher levels of GM-CSF ( > 0.9 pg/mL) and 4 peptide vaccinations containing SART2-derived peptides was significantly (p = 0.01) shorter than that of the corresponding 9 BSC patients (not reached, 1.6-not reached). A single grade 3 adverse event was the only PPV-related adverse event of grade > 3 in this study. Conclusions: PPV monotherapy could be a new treatment modality for HLA-A24-positive GBM patients refractory to TMZ-based therapy, since this approach showed clinical benefit and safety under precision medicine-based pre-vaccination selection of appropriate patients. Clinical trial information: UMIN000006970.
Final results of the EORTC Brain Tumor Group randomized phase II TAVAREC trial on temozolomide with or without bevacizumab in 1st recurrence grade II/III glioma without 1p/19q co-deletion.
Authors: Van Den Bent Martin J. , Klein Martin , Smits Marion , Reijneveld Jaap C. , Idbaih Ahmed , Clement Paul , De Vos Filip Yves Francine Leon , Wick Wolfgang , Mulholland Paul James , Taphoorn Martin J.B. , Lewis Joanne , de Heer Iris , Kros Johan M , Verschuere Tina , Golfinopoulos Vassilis , Gorlia Thierry , French Pim ,   EORTC Brain Tumor Group
Published: September 2018

2009

Background: Although bevacizumab (BEV) is frequently used in recurrent grade II and III glioma without 1p/19q co-deletion, this use is without evidence from randomized trials. Methods: The TAVAREC trial (NCT01164189) is a randomized phase II study in locally diagnosed non-1p/19q co-deleted grade II or III glioma, with a first and contrast-enhancing recurrence after initial radiotherapy. Prior chemotherapy was allowed provided patients were at least 6 months off treatment. Patients were treated with either 200mg/m2 temozolomide (TMZ) day 1-5 every 4 weeks for a maximum of twelve cycles, or with the same TMZ regimen in combination with BEV 10 mg/kg every 2 weeks until progression. Response, Quality of Life (QOL, using the EORTC QOL C30/BCM20 questionnaire) and neurocognitive function (NCF) using a standardized test battery with Hopkins Verbal Learning, Trail Making test A/B and Controlled Oral Word Association were evaluated every 3 months. Primary endpoint is the Overall Survival (OS) rate at 12 months (OS12). Tumor samples were centrally analyzed for MGMT status (Illumina methylation arrays) and IDH1/2 mutations ( IDHmt). Results: Between 8/2/2011 and 31/7/2015, 155 patients were randomized; median age was 44 years, 88 (70%) of 125 tested tumors showed an IDHmt, 27% of patients had received prior chemotherapy. OS12 was 61% in the TMZ arm and 55% in the TMZ+BEV arm, with overlapping OS and progression free survival (PFS) Kaplan Meier curves and similar response rates (TMZ: 42%; TMZ + BEV: 49%). Post-progression, 33% of the TMZ and 17% of the TMZ + BEV patients received BEV. OS was longer in IDHmt tumors compared to IDH wild type tumors (15 mo vs 10.7 mo, p = 0.001) but PFS was clinically similar (6.7 mo vs 5.1 mo, p = 0.056). IDH mutational status was not predictive for benefit to BEV. Compliance to NCF testing and QOL was above 60% in the 1st year. At the group level, NCF was similar in the TMZ and in the TMZ+BEV patients. QOL and MGMTresults will be presented at the meeting. Conclusions: The addition of BEV to TMZ does not improve OS, PFS, or cognitive function in recurrent grade II and III 1p/19q intact gliomas; regardless of IDH mutational status. Clinical trial information: NCT01164189.
Identification of novel therapeutic targets in glioblastoma with functional genomic mRNA profiling.
Authors: Brahm Cyrillo Gerardo , Walenkamp Anna Maria Elisabeth , Van Linde Myra Ellen , Verheul Henk M.W. , Fehrmann Rudolf Stephan Nicolaas
Published: September 2018

2018

Background: Glioblastoma (GBM), the most common primary brain tumor in adults, universally recurs and has a dismal prognosis. Therefore, there is an unmet need for new and more effective treatment strategies. Here, we aim to discover new therapeutic targets by identifying upregulated genes in GBM with known antineoplastic drug interactions. Methods: Publicly available, raw microarray expression data of patient-derived GBM samples and normal brain tissue were collected from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). Subsequently, we applied functional genomic mRNA profiling (FGmRNA-profiling), a method that is able to correct the gene expression profile of an individual tumor for physiological and experimental factors, which are considered not to be relevant for the observed tumor phenotype. Next, the FGmRNA-profiles of healthy brain tissue and glioblastoma were used to perform a class comparison analysis. Significantly upregulated genes in GBM were prioritized based on: known interaction with antineoplastic agents and the current status of clinical evaluation in humans. Results: After FGmRNA-profiling 66 normal brain tissue samples and 1280 patient-derived GBM samples, class comparison identified 712 significantly upregulated genes. Of all significantly upregulated genes, 27 genes interacted with antineoplastic drugs. 17 out of these 27 druggable genes, including EGFR and VEGFA, have already been clinically evaluated in GBM, and had limited efficacy. Out of the 10 remaining druggable genes, we prioritized RRM2, MAPK9 and XIAP, as these genes are associated with biologic pathways involved in the carcinogenesis of GBM and are therefore considered as novel potential therapeutic targets. Conclusions: Based on data-driven prioritization, we identified three potential therapeutic druggable targets, which have not yet been explored in the context of glioblastoma. Further preclinical and clinical research on the inhibition of these druggable genes is necessary and may lead to an improvement of treatment outcomes for patients with GBM.
NCCTG N1174: Phase I/comparative randomized phase (Ph) II trial of TRC105 plus bevacizumab versus bevacizumab in recurrent glioblastoma (GBM) (Alliance).
Authors: Galanis Evanthia , Anderson S. Keith , Butowski Nicholas A. , Hormigo Adilia , Schiff David , Tran David Dinh , Omuro Antonio Marcilio Padula , Jaeckle Kurt A. , Kumar Shaji , Kaufmann Timothy J. , Buckner Jan C. , Twohy Erin , Giannini Caterina , Wen Patrick Y.
Published: September 2018

2023

Background: TRC105 is a humanized antibody targeting CD105 (endoglin), a member of the TGFβ receptor superfamily. CD105 is expressed in glioma stem cells and circulating endothelial cells (CECs) in GBM patients (pts), increasing following VEGF inhibition. N1174 was conducted in recurrent bevacizumab (bev) naïve GBM pts to investigate the hypothesis that CD105 blockade+bev can delay development of bev resistance. Methods: After a ph I cohort (15 pts) established the ph II dose of TRC105 as 10 mg/kg IV over 4 hours every 7 days in combination with standard dose bev, the ph II trial used 1:1 randomization with 90% power and 0.10 type I error to detect a 3 month (mo) difference in progression-free survival (PFS) between the two arms. CECs including CD105 positive subsets were measured by flow cytometry at baseline and multiple time points. Results: Based on 101 evaluable ph II pts, there was no significant difference in PFS between TRC105+bev and bev only (2.9 vs 3.2 mo, respectively; HR=1.14, 95% CI 0.73-1.77, p=0.57), or overall survival (10.0 vs 7.4 mo; HR 1.02 95% CI 0.63-1.65, p=0.93). Response rate (complete or partial) was 12.2% (6/49) for TRC105+bev and 11.6% (5/43) for bev only. Overall incidence of grade (gr) 3+ toxicity was higher for TRC105+bev (67.3% vs 32.7%, p<0.001) mainly due to 14 pts with gr 3 anemia in the TRC105+bev arm vs 0 in the bev only pts. Gr 3+ non-heme toxicities were higher in pts receiving TRC105+bev vs bev only (50% vs 30.6%, p=0.07), mainly due to headache (6 vs 1 pts) and hyperglycemia (3 vs 0 pts). CECs remained stable in combination treated pts, suggesting a possible impact of the anti-CD105 blockade, but increased at progression in the bev only arm. There was no association between PFS and initial changes in CEC values, independent of treatment received. Conclusions: TRC105 plus bev did not prolong median PFS vs single agent bev in recurrent GBM pts, although it was associated with a non-significant prolongation of OS. These data and associated correlative analysis of CECs from study pts point against endoglin being a clinically significant factor for the development of bev resistance. Support: U10CA180821, U10CA180882. Clinical trial information: NCT01648348.