bluuebunny/crossref_metadata_2025 huggingface dataset:
Aspirin attenuates YAP and β-catenin expression by promoting β-TrCP to overcome docetaxel and vinorelbine resistance in triple-negative breast cancer.
Authors: Ma Ji , Xia Hongwei , Fan Zhenhai , Tang Qiulin , Zhang Tao , Bi Feng
Published: May 2020

e13099

Background: YAP and β-catenin play critical roles in the carcinogenesis of several cancers, but their functions in chemoresistance remain unclear in triple-negative breast cancer (TNBC). Herein, we examined the expression and function of the two proteins in the chemoresistance of TNBC. Methods: We examined the expression levels of YAP and β-catenin in TNBC samples by immunohistochemistry (IHC) and their roles in prognosis. Dynamic changes in the two proteins in TNBC tissues were determined by RT-PCR. CCK-8 assays, colony formation assays, flow cytometry, migration assays and nude mouse models were used to investigate the functions of YAP and β-catenin in drug-resistant TNBC cells. The involved signalling pathways were detected by western blot assays. Results: TNBC patients with high YAP and/or β-catenin expression had a higher risk of relapse or mortality than patients with low YAP and/or β-catenin expression, and changes in the expression of the two proteins might be a promising predictive biomarker for neoadjuvant chemotherapy sensitivity. Inhibition of YAP or β-catenin enhanced the cytotoxicity of the anti-microtubule agents docetaxel and vinorelbine against TNBC cells in vitro and in vivo. Moreover, YAP and β-catenin were upregulated in docetaxel- or vinorelbine-resistant TNBC cells, while inhibition of YAP or β-catenin enhanced the sensitivity of drug-resistant cells. Interestingly, aspirin, a kind of acetylsalicylic acid, reversed the drug resistance of cells and in combination with aspirin and docetaxel or vinorelbine significantly inhibited the growth of drug-resistant TNBC cells. The involved mechanism is that aspirin impaired YAP or β-catenin expression by upregulating the E3 ubiquitin ligase β-TrCP. Conclusions: Both YAP and β-catenin act as key biomarkers of prognosis and anti-microtubule drug resistance in TNBC, and the combined use of aspirin and anti-microtubule drugs inhibits YAP and β-catenin, presenting several promising therapeutic approaches for TNBC treatment.
Role of E2F3 and shugoshin I in epithelial-to-mesenchymal transition and cell invasion in breast cancer.
Authors: Jusino Shirley , Chellappan Srikumar P. , Saavedra Harold I.
Published: May 2020

e13100

Background: Triple-negative breast cancer (TNBC) is the most aggressive and poorly prognostic breast cancer subtype, yet there are currently no biological therapies against this subtype. Our laboratory is finding the sources of novel biological targets in TNBC by studying the E2F transcription factors, which are essential for cellular proliferation and maintenance of genomic stability. While the deregulated Rb/E2F pathway signals the epithelial-to-mesenchymal transition (EMT), the underlining mechanism of how E2Fs drive EMT in TNBC remains unknown. We recently published that the E2F transcriptional activators (E2Fs) are overexpressed in the vast majority of TNBC and that their overexpression upregulates mitotic kinases such as TTK, which we have shown to induce EMT and invasion in TNBC cells. We also demonstrated that the E2Fs maintain genomic integrity in part through Shugoshin I (SGO1), which normally controls chromosome cohesion; however, the role of SGO1 in EMT in breast cancer is unknown. Our hypothesis is that E2F3 and SGO1 are highly expressed in TNBC and that their overexpression modulates EMT genes, thus promoting cell invasion. Methods: To test our hypothesis, we conducted siRNA transfection to knockdown E2F3 and SGO1 in MDA-MB-231 and Hs578t, which are TNBC cells. After 48 hours, we evaluated mRNA levels of EMT-related genes after E2F3 or SGO1 depletion using RT-PCR analysis. We also evaluated the effects of SGO1 depletion in protein localization by immunofluorescence. Furthermore, we evaluated the invasive behavior of MDA-MB-231 and Hs578t cells after SGO1 depletion using a Boyden Chamber Assay. Results: Our results demonstrate that E2F3 and SGO1 depletion decrease MMP3 mRNA levels. Moreover, E2F3 and SGO1 depletion restore E-cadherin expression and localization. Furthermore, E2F3 and SGO1 depletion significantly reduce cell invasion in MDA-MB-231 and Hs578t cells. Conclusions: Our results suggest that SGO1 is a promising drug target for breast cancer metastasis since EMT and invasion are essential early steps in breast cancer metastasis and E2F3 is presently undruggable.
PD-L1 IHC 22C3 pharmdx demonstrates precision and reproducibility in detecting PD-L1 expression in triple negative breast cancer.
Authors: Kulangara Karina , Watts Brittany , Vilardo Monika , La Placa Christopher , Frederick Judith , Tabuena-Frolli Siena , Jansson Malinka , Kersch Kristopher
Published: May 2020

e13104

Background: PD-L1 IHC 22C3 pharmDx is an FDA-approved, companion diagnostic assay intended for use in the detection of PD-L1 protein in formalin-fixed paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC), gastric or gastroesophageal junction (GEJ) adenocarcinoma, esophageal squamous cell carcinoma (ESCC), cervical cancer, urothelial carcinoma, and head and neck squamous cell carcinoma (HNSCC) tissues. Methods: Additionally, device precision (inter- and intra-observer, inter-instrument, inter-operator, inter-day, inter-lot, and intra-run) and robustness have been validated at Dako North America for triple negative breast cancer (TNBC) using the Combined Positive Score (CPS) ≥1 cutoff. Device precision (excluding inter- and intra-observer) has also been validated for TNBC using the CPS ≥10 cutoff. External validation studies for TNBC (inter- and intra-site, inter- and intra-observer) were conducted at three CAP-accredited and/or CLIA-licensed laboratories using the CPS ≥1 and CPS ≥10 cutoffs. Results: The precision, robustness, and external validation studies achieved point estimates greater than 85% for positive, negative, and overall percent agreement. Conclusions: Internal and external validation studies demonstrate that PD-L1 IHC 22C3 pharmDx is sensitive, specific, precise, robust, and reproducible in evaluating PD-L1 expression at CPS ≥1 and CPS ≥10 cutoffs using TNBC tissue.
A retrospective single-center study investigating the clinical significance of grade in triple-negative breast cancer.
Authors: Hamm Caroline M.
Published: May 2020

e13108

Background: Triple negative breast cancer is defined as estrogen (ER), progesterone (PR), and human epidermal growth factor receptor (HER-2) proteins negative. The grade is the degree of similarity of tumor cells to normal cells under microscope and is an important biomarker of overall patient outcomes or prognosis with higher grades having a poor prognosis. As recent chemotherapy trials noted moderately undifferentiated grade 2 tumors showing higher rates of relapse, we hypothesize that grade can also be a predictive biomarker or determinant of response to specific treatment. Methods: We reviewed 305 patient charts of triple negative breast cancer patients from 2004-2017 at Windsor Regional Cancer Center analyzing the significance of grade with respect to oncological variables, survival-time, and time to relapse. Statistical analysis was performed using Fleming-Harrington, Pairwise Testing, and COX regression, where applicable. Results: Univariate analysis showed statistically significance difference in chemotherapy type (P = 0.008) and a marginal one in ER & hormone therapy status (P ~0.09) between the grades. The overall survival rates were 90.12%, 64.4%, and 77.2%, for grade 1, 2, 3 respectively. The overall difference in survival among the three groups was statistically significant, based on Fleming-Harrington test (P = 0.019). Comparing only between grade 2 and grade 3, we found that after five years, grade 2 patients had a 5.5-fold increased risk of death (HR = 5.5; 95% CI 1.2-25.6) and 2-folds higher risk of relapse (HR = 1.9; 95% CI 1.1-3.2). Grade 3 does significantly better than grade 2 in time to relapse with relapse rates of 70%, 55.6 %, and 75.6%, respectively for grades 1, 2, and 3 (P = 0.04). Conclusions: Tumor grade has a significant positive predictive value in determining relapse with grade 2 tumors demonstrating poorer disease-free survival as compared to grade 1 & 3, less time to relapse, and increased risk of death. This has implications in stratifying triple negative breast cancer patients by grade in future clinical trials while ongoing research yields new targets for chemotherapy.
Genomic origin and immune-related status of pulmonary sarcomatoid carcinoma.
Authors: Liu Xuewen , Wang Fang , Chen Xinru , Hou Xue , Chang Lianpeng , Xie Zhi , Liu Yongdong , Li Qian , Li Pansong , Guan Yan-Fang , Zhang Xuchao , Wang Sha , Xu Chunwei , Wang Hui , Yi Xin , Zhang Jianjun , Xia Xuefeng , Moran Cesar , Chen Likun
Published: May 2020

e13500

Background: Pulmonary sarcomatoid carcinoma (PSC), composed of sarcomatous component (SaC) and carcinomatous component (CaC), is a rare and generally aggressive subtype of non-small-cell lung cancer (NSCLC). Little is known about the genetic origin, TMB, and PD-L1 status of PSC. Methods: 31 immunohistochemically (IHC) confirmed PSCs were enrolled and tumor samples were subjected to microdissection to obtain SaC and CaC. Different components were subjected to targeted sequencing with a 1021-gene-panel. Somatic mutations were used to assess TMB and construct phylogenetic tree. PD-L1 expression level was determined by IHC. Independent cohorts of 90 lung adenocarcinomas (LUAD) from the Geneplus database and 167 sarcomas from TCGA were used for genomic comparison. Results: 87% of patients (pts) were male, with a median age of 57.0 years. 52% were smokers. The most recurrently mutated genes were TP53 (80%), MET (24%), NF1 (21%), EGFR (21%), and KRAS (21%) in CaC, while TP53 (76%), MAP3K1 (21%), NF1 (21%), MET (21%), and KRAS (21%) in SaC. 55.4% of the variations (SNV, small indels, SV, and CNV) were shared within SaC and CaC. TP53, MET, NF1, and EGFR were mostly frequently found in shared mutations. Overwhelming majority of PSCs (29/30) had common mutations between SaC and CaC implying a monoclonal origin. EGFR were mutated significantly less in adenocarcinoma components (AdC) than LUAD (Fisher Exact test, 4/24 vs 52/90, p < 0.001). High-frequency mutated driver genes in SaC, MET, EGFR, NF1, and ALK, were rarely detected in leiomyosarcomas and uterine sarcomas. The median of TMB in SaC and CaC were both 12.9 mutations/Mb (range, SaC 2.88-33.1, CaC 2.88-47.5), with high correlation between the two components (p < 0.001). PD-L1 expression levels in the two components also had high correlation (p < 0.001). More pts showed high PD-L1 expression ( > = 50%) in SaC rather than CaC (8 versus 3). Conclusions: A majority of PSCs share a monoclonal origin. PSCs with AdC exhibited lower mutated frequency of EGFR than LUAD. SaC and CaC had similar higher TMB status than LUAD. SaC and CaC had similar level of PD-L1expression.
Genomic landscape and clinicopathological characteristics of lung cancer in young Chinese patients.
Authors: Zhang Jiexia , Tong Xiaoling , Bao Hua , Wu Xue , Wang Xiaonan , Shao Yang
Published: May 2020

e13520

Background: Approximately 2-3% of lung cancer (LC) was found in very young patients (≤ 45 years old) and they were reported to have different clinical characteristics and genetic profiles when compared to older patients. However, it is still lack of large-scale genomic studies that could provide deep insights into the tumorigenesis, precision treatment and prognosis for this particular population. Methods: Clinically annotated data of targeted next generation sequencing (NGS) on 7858 tumor tissue specimens from LC patients were analyzed. For all specimens, a total of 422 or 425 cancer-related genes were interrogated with a mean coverage depth greater than 500x. Results: Of 7858 LC cases, 814 of them were younger than 45 (age at diagnosis), which were compared to 7044 old LC cases ( > 45 years old). Clinical information showed that young LC are more prevalent in female, to be more advanced disease and to have more adenocarcinoma in histology. Somatic genomic data analysis revealed that compared to old LC, young LC has significantly higher ALK/ROS1/RET fusions, ERBB2 mutations and 5q amplification(FDR < 0.1), but lower mutational frequencies in KRAS, CDKN2A, ERBB4, FAT1, NF1, lower copy number gain (CNG) of PIK3CA, MDM2, FGFR1, and less 5q deletion(FDR < 0.1). Interestingly, in young LC, genetic differences between female and male are not significant, with TP53 and EGFR being most frequently mutated in both sexes. Similarly, the differences between young and old female LC are also limit, with young female LC having more ALK fusions (13.43% vs. 5.1%, FDR < 0.01), less EGFR mutations and MDM2 CNG than old female. On the contrary, male patients demonstrated much wide disparity between young and old LC: young LC was enriched with ALK/ROS1/RET/ERBB2 fusions and mutations in EGFR, ERBB2 and SMAD2, while old LC have more mutations in KRAS, TP53, CDKN2A, and CNG of PIK3CA (all FDR < 0.1). We also found that EGFR exon19 deletion (19del) was significantly enriched in young LC, especially in male, while p.L858R showed preference in old LC. Conclusions: The data suggest that the prevalence of different genetic alterations is both age and sex related. The high level of ALK/ROS1/RET fusions and less CNV in young LC could potentially lead to more effective treatment and better prognosis. We also noted that genomic alterations in young LC were not significantly different across sexes, but the disparity by sex was enormously enlarged in old LC, which might be correlated to their life-long exposures, such as smoking, life styles and sex-affected factors.
Immunofocus-PD-L1 high throughput quantitative next generation sequencing assay.
Authors: Williams Gareth Haydn , Thatcher Robert Paul , Haddow Tiffany Eira , Hardisty Keeda-Marie , Loddo Marco
Published: May 2020

e13521

Background: Immunohistochemical (IHC) assays are presently used as the gold standard predictive tests for immunotherapy but are compromised due to a number of potential variables. Comparative studies have demonstrated differing levels of PD-L1 staining between assays which appears independent of the antibody binding epitope. Secondly, inter-reader reliability even between expert pathologists is problematic particularly for assessment of PD-L1 positive immune cell populations. Methods: To improve predictive testing for anti PD-L1/PD1 immunotherapies we have developed and validated a Next Generation Sequencing Platform, Immunofocus, able to perform high-throughput quantitative PD-L1 gene expression levels in routine diagnostic PWET biopsies. We applied Immunofocus to a cohort of 130 NSCLCs and compared PD-L1 gene expression levels with PD-L1 IHC scores generated using the VENTANA PD-L1 (SP142) Assay. The PD-L1 IHC assessment was carried out double blinded by an independent laboratory. PD-L1 IHC scores were calculated using an algorithm combining tumour proportion score (TPS) with a PD-L1 positive immune cell (IC) score and immune cell area. Results: An exceptionally high degree of correlation was observed between the NGS PD-L1 levels with the combined PD-L1 IHC scores (P < 0.001). Therapeutic cut points for NGS PD-L1 levels were identified corresponding to PD-L1 IHC defined clinical cut points. Notably, ~20% of patients with negative PD-L1 IHC scores showed high NGS PD-L1 expression levels. We hypothesize that these cases represent false negatives and identify a cohort of patients who have shown significant response rates to anti-PD-L1/PD-directed immunotherapies. Conclusions: The Immunofocus NGS PD-L1 assay has potential to greatly improve patient selection for immunotherapy by removing the IHC assay variables and inter-reader variability which compromise current PD-L1 IHC tests while also providing standardized high throughput in the clinical setting. Immunofocus is able to integrate gene expression with somatic mutation analysis allowing capture of networks regulating the immune-checkpoint including for example adaptive and innate resistance pathways, JAK1/2 pathways, differential MHC expression, TEFF gene signature, neoantigen surrogates such as DDR defects and TMB. The integration of NGS PD-L1 expression with other putative biomarkers of response is presently ongoing to further improve prediction of response.
Identification of kinase domain duplications across diverse cancer types in Chinese population by comprehensive genomic profiling (CGP).
Authors: Wang Baohua , Yu Ruoying , Ou Qiuxiang , Bao Hua , Wu Xue , Shao Yang , Zhang Tao
Published: May 2020

e13522

Background: Kinase domain duplication (KDD) has recently been recognized as oncogenic and targetable mutations in some cancers. EGFR KDD was identified as an oncogenic driver in lung cancer showing partial response to EGFR TKI. BRAF KDD was reported in diverse tumor types with clinical response to RAF-targeted therapy. We retrospectively investigated the prevalence of KDDs in multiple cancer types of a large Chinese population. Methods: 50742 unique cancer cases were analyzed by comprehensive genomic profiling (CGP). DNA was extracted from formalin-fixed paraffin-embedded specimens (FFPEs), fresh tissue, blood or plasma samples and sequenced with gene panels targeting 400+ cancer-relevant genes. Among them, 53 cases were detected with KDD of various kinases. Results: In this Chinese cohort, KDD was identified in 0.1% of the total population across multiple cancer types including lung cancer (39), breast cancer (5), gastric cancer (3), colorectal cancer (2), mucoepidermoid carcinoma (1), unknown (3). The median age at diagnosis was 54 which was younger than the 60 yrs median age of total population. The distribution of KDDs was in EGFR(34) MET(5), JAK1(2), BRAF(2), FGFR2(2), FGFR1(1), JAK2(1), LYN(1), MAP3K1(1), RAF1(1), RET(1), AKT3(1), and CDK8(1). Thirty-one lung cancer cases were detected with EGFR-KDD, including kinase duplications of exon18-25 (22), exon17-25 (6), exon18-26 (2), exon14-26(1). Three patients with EGFR-KDD exon18-25 showed partial anti-tumor response to target therapy. MET-KDD was exclusively found in lung cancer involving the duplication of MET exon15-21 (2), exon14-17 (1), exon15-16 (1) and exon12-21 (1) while FGFR1/2-KDD was observed only in gastric cancer. Two female patients with breast cancer were detected with JAK1-KDD at age of 45 and 37, respectively. The canonical BRAF-KDD of exon 10-18 was identified in one female patient diagnosed of lung adenocarcinoma at age of 49. Frequently altered genes in patients with KDD were TP53(72%), EGFR (23%), FAT1(13%), BRCA1(10%). MCL1 amplification, a known oncogenic alteration, was identified in fifteen patients (11 EGFR-KDD,2 MET-KDD, 1 BRAF-KDD, 1 JAK2-KDD), representing the most common copy number variation observed. Conclusions: Kinase KDDs were rare but potentially oncogenic mutations in diverse cancer types with clinical outcome of EGFR-KDD to target therapy in lung cancer. Cancer-type specific KDDs were identified including MET-KDD in lung cancer, FGFR1/2-KDD in gastric cancer and JAK1-KDD in breast cancer.
Clinicopathological features of patients with ovarian and breast cancer with BRCA mutation.
Authors: Ozkan Metin , Fırat Sedat Tarık , Coşar Ramazan , Bozkurt Oktay , Inanc Mevlude , Dogan Muhammet Ensar
Published: May 2020

e13524

Background: Breast cancer is the most common cancer and the leading cause of cancer death in women. Ovarian cancer contributes significantly to mortality and morbidity rates. BRCA1 and BRCA2 are the best known genes associated with breast and ovarian cancer, which are important in DNA repair and transcriptional regulation. Methods: In this study, we retrospectively analyzed the clinicopathological features of breast and ovarian cancer patients who were found to have BRCA 1/2 mutations in Erciyes University Medical Oncology between 2009-2019. Results: BRCA mutation was detected in 14 patients with breast cancer and 10 patients with ovarian cancer. The median age of patients with breast cancer was 41 (25-67). Of 14 BRCA mutated patients, 9 (64 %) patients had BRCA2 mutations while 5 (36 %) patients had BRCA1 mutations. All patients had invasive ductal carcinoma. Of 14 patients, 7 patients were grade 3, 6 patients were grade 2, 1 patient was grade 1. At the time of diagnosis, 5 of 14 patients were stage 3 and 5 patients were stage 4. 4 (80%) of 5 patients with stage 4 had BRCA 2 mutation. 5 of 10 patients who received adjuvant therapy after surgery had 4 or more lymph node metastases. Hormone receptor positive / HER2 negative disease was the most common molecular subgroup (8/14, 57%). Five patients were triple negative histology. 4 (80%) of triple negative patients had BRCA1 mutation. Ovarian cancer developed in 2 of 14 patients who had breast cancer with BRCA mutation. Median age of patients with ovarian cancer with BRCA mutation was 52.5 (19-67). 2 of 10 patients with ovarian cancer had germ cell tumors and 8 had epithelial serous carcinoma. Of 10 BRCA mutated patients, 7 (70 %) patients had BRCA2 mutations while 3 (30 %) patients had BRCA1 mutations. Both patients with germ cell tumors were stage 1 at the time of diagnosis, 7 of the patients with epithelial serous carcinoma were stage 3, and 1 was stage 2. While patients with germ cell tumors were followed without recurrence, 6 patients with epithelial serous carcinoma developed recurrence, and all of these patients were platinum sensitive. Breast cancer developed in 1 patient with BRCA1 mutation at follow-up. All patients were alive according to the last control date. Median DFS was 29 months. Conclusions: BRCA-related breast cancer is characterized by a more aggressive phenotype than sporadic breast cancer, BRCA1-associated breast cancer is more frequently high-grade and triple negative histology. BRCA-related ovarian cancer is more sensitive to treatment, especially platinum-based chemotherapy, and is associated with improved prognosis.
YsRNA aberrant expression in colorectal cancer patients.
Authors: Novikova Inna A. , Kutilin Denis S. , Timoshkina Natalya N. , Poluektov Sergey I. , Tolmakh Roman E. , Dashkov Andrey V. , Haragezov Dmitry , Kolesnikov Evgeniy N. , Dontsov Vladimir A. , Soldatkina Natalya V. , Petrov Dmitry S. , Gevorkyan Yuriy A. , Kit Oleg Ivanovich
Published: May 2020

e13525

Background: Cancer is a disease characterized by uncontrolled cell proliferation. DNA replication is the main driving force behind cell proliferation in both normal development and cancer. Non-coding Y-RNAs are important factors in initiating DNA replication in the nuclei of human cells. Excessive expression of Y-RNA is characteristic of tumors of the bladder, cervix, kidney, lung and prostate. It has also been shown that the level of small RNAs formed from the 3'- and 5'-ends of Y-RNA is significantly higher in patients with certain types of cancer compared to healthy people, therefore, these RNAs may have diagnostic value. However, for colon tumors, data on the expression of Y-RNA/YsRNA obtained in previous studies are ambiguous. The aim of the study was to analyze the differential expression of YsRNA in the tumor and non-tumor tissue of patients with CRC using next generation sequencing (NGS). Methods: For NGS, 10 patients with CRC (colon adenocarcinoma, G2). were selected. Small RNA fractions were isolated using the mirVana miRNA Isolation Kit protocol (Ambion, Life Science Technologies, USA). The library was prepared for sequencing using the TruSeq Small RNASample Preparation Kit (Illumina, USA). Sequencing of the nucleotide sequences of cDNA libraries was performed using a MiSeq (Illumina, USA). The determination of the copy number of Y-RNA fragments (YsRNA, 19-34 bp) was carried out by comparing the nucleotide sequence of the sequenced molecules in each sample with the known nucleotide sequences presented in the databases. In the analysis of differential expression, the edgeR method, implemented in the R language, was used. Results: Several different fractions of YsRNA were detected in tumor and non-tumor tissues: hY3sRNA (the most represented fraction, more than 70%), hY5sRNA and hY1sRNA. In tumor tissue relatively non-tumor, a statistically significant (p < 0.001) increase of 4 and 6 times the number of copies of hY3sRNA and hY5sRNA, respectively, was detected. The function of YsRNA in tumor and normal cells has not yet been established. Conclusions: Thus, in the tumor colon tissue differential expression of 2 YsRNA fractions - hY3sRNA and hY5sRNA, was detected. These YsRNAs can become promising tumor markers and targets for the treatment of CRC, as well as make certain contributions to understanding the mechanisms of carcinogenesis in this nosology.
Comprehensive analysis of advanced-stage solid tumors from TCGA reveal widespread variation of genomics evidence levels across cancer types.
Authors: Weeraratne Dilhan , Ferreira Elisa Napolitano , Mitne Neto Miguel , Huang Hu , Brotman David , Fraga Ana Maria , Ramalho Rodrigo Fernandes , Burger Matheus , Felipe-Silva Aloisio Souza , Snowdon Jane
Published: May 2020

e13547

Background: Improved scalability and affordability of next generation sequencing (NGS) has pivoted cancer care toward genomics-driven treatment decisions. Particularly in advanced-stage or refractory cancer, clinical insights gleaned from NGS have become an integral option as these patients have typically exhausted all lines of available therapy. As precision oncology evolves, NGS is expected to have a differential impact based on the cancer type. In this study, a comprehensive NGS panel was used to determine the strength of clinical evidence in various advanced stage tumor samples from The Cancer Genome Atlas (TCGA). Methods: A hybrid capture panel, Oncofoco, was developed to evaluate SNVs, INDELs, CNVs and TMB in 366 genes. The panel’s utility was validated by interrogating a broader cohort of 2847 TCGA samples (advanced tumors with T3 or T4; or N > = 1; or M > = 1). Watsonä for Genomics, an artificial intelligence offering, was used for variant interpretation and annotation of the 366 genes. A clinical evidence classification system that evaluated the strength of biomarker/drug response associations was used for annotation with level 1/R1 strongest and level 4 weakest from clinical literature, FDA drug labels and guidelines (PMID:28890946). Results: The highest level of evidence for the top nine frequently occurring advanced stage cancers in TCGA is shown in Table. Conclusions: Thyroid cancer and cutaneous melanoma have emerged as the cancer types with the most level 1 evidence (FDA approved drugs) owing to BRAF V600E mutations. Kidney and prostate cancers show no cases with level 1 evidence and also had the largest fraction of unactionable tumors. Over half of colorectal cancer cases had level R1 resistance evidence attributed to KRAS and NRAS mutations. The clinical utility of NGS in late-stage refractory cancer varies widely by tumor type. The presence of level 3 and level 4 evidence in all cancer types bodes well for the development of new targeted drugs. [Table: see text]
Missed opportunities? A retrospective analysis of lung cancer screening utilization among patients with lung cancer.
Authors: Olazagasti Coral , Kohn Nina , Aviles Karen , Ehrlich Matthew , Hoilett Aldane , Seetharamu Nagashree
Published: May 2020

e13565

Background: Lung cancer (LC) is the leading cause of cancer-related deaths worldwide. Tobacco smoking is implicated as the causative factor in 85% of LC. The U.S. Preventive Services Task Force (USPSTF) and National Comprehensive Cancer Network (NCCN) recommendations for annual low-dose CT chest (LDCT) for LC screening in high risk adults who meet appropriate criteria, which primarily focuses on age and smoking history. Medicare coverage for LC screening for eligible individuals went into effect in February 2015. Despite this, screening rates remain low and patients with LC are typically diagnosed at a later stage. We conducted a single center retrospective analysis of patients with established diagnosis of lung cancer to evaluate if screening guidelines were appropriately followed prior to the cancer diagnosis. Methods: Patients diagnosed with LC between 2016 and 2019 were included in the analysis. Charts were reviewed for demographics, detailed smoking history, as well as histology and stage of LC. Associations between categorical factors and screening and were examined using the chi-square test. Associations between continuous and ordinal factors and screening and were examined using the Mann-Whitney test. Results: A total of 530 charts were reviewed. Of those, 52.5% (278) met NCCN and/or USPSTF criteria and 10.8% (30/278) underwent screening. The median age for those who were screened was 69 years. There was no association between age at diagnosis and screening. There was a significant association between active smoking status and screening (p < 0.0191). An average of 16.8% (16/95) of current smokers and 7.7% (14/183) of former smokers were screened. Patients who had screening CT scans were diagnosed at earlier stages of LC compared to those who were not screened (p < 0.0083) [table]. Conclusions: Our study showed that despite established guidelines for LC screening and insurance coverage, a vast majority of screening-eligible LC patients have never had LDCT. We found that patients who underwent screening as per guidelines were diagnosed at earlier stages of disease compared to those not screened, which goes along with published data. Ongoing efforts to increase awareness and adherence to LC screening guidelines will be of paramount importance in improving early detection and reducing mortality from LC. [Table: see text]
Detect Early Be Safe–Care for Mother (DEBS-CaM) project: School-based interventions to improve awareness and screening for breast cancer among the young mothers of Kerala.
Authors: Warrier Narayanankutty , Sankar Uma V , P S Sreedharan , V Nirmal , K V Sajeevan , Sherif Ajmal
Published: May 2020

e13570

Background: The prognosis rate among the breast cancer patients was less than 50% in India when compared to European countries due to the late diagnosis and most of them diagnosed at an advanced stage of disease. Early detection can reduce the risk of advancement of disease by 30%. There is an immediate need to target both younger population to empower the women with the knowledge on their breast cancer risk and self-breast examination (SBE). So the project aimed to examine the efficacy of a Brief Motivational Intervention (BMI) and Student based Parental intervention (SBPI) based on motivational interviewing as a universal preventive and early diagnosis interventions to fight against breast cancer among the school students using a randomized factorial design. Methods: Daughters and Mothers are always a good dyads for doing an personal health intervention. Since it is a ‘matter of closeness’, a mother and a daughter can easily communicate, intervene and ensure the act of doing in self breast examination.We identified 85 schools (including the Junior high and senior high schools in the northern region of Kerala. The female resource person from the MVR Cancer Centre & Research Institute delivered the awareness session on risk factors of breast cancer breast and SBE. So the attendees demonstrated the SBEs to their mothers and ensure the act of doing monthly. The study utilized a 2 × 2 × 3 factorial design, crossing a BMI; (yes, no) and SBPI (yes, no), with one within-subjects factor (Time; baseline and 10 months). Over 10 months, we recruited cohorts of parent-student dyads and randomize by dyad to one of four experimental conditions: BMI only and BMI and SBPI only. We did the randomization by computer algorithm to ensure that the experimental conditions will balance on prognostic indicators of students and their mother’s on breast cancer risk and including waist to hip ratio, frequency of SBE, healthy dietary intake and physically active. Results: Baseline data collected from students and parents during the summer prior to college matriculation. Follow-ups occurred at 10 months post-baseline for parents in the face to face interview with students at their schools. We found 17% of mothers detected any kind of breast abnormalities and among that, 68% of mothers went for further detailed diagnostic tests. Conclusions: It is an innovative approach incorporating the principles of primary prevention and early detection for the breast cancer among the young mothers of Kerala.
Proximity to oil refineries and risk of cancer: A population-based analysis.
Authors: Williams Stephen B. , Shan Yong , Jazzar Usama , Kerr Preston , Okereke Ikenna , Klimberg V. Suzanne , Tyler Douglas S. , Putluri Nagireddy , Lopez David S , Prochaska John D , Elferink Cornelis , Baillargeon Jacques G. , Kuo Yong-Fang , Mehta Hemalkumar B
Published: May 2020

e13586

Background: Proximity to oil refineries and cancer incidence is largely unknown. We sought to compare the incidence of cancer (bladder, breast, colon, lung, lymphoma, and prostate) according to proximity to an oil refinery in the State of Texas. Methods: A total of 6,302,265 persons aged ≥20 years from January 1, 2001 through December 31, 2014 were identified. We used zero-inflated Poisson regression models to examine the association of proximity to an oil refinery with cancer incidence. Results: We observed that proximity to an oil refinery was associated with a significantly increased risk of incident cancer diagnosis across all cancer types. For example, persons residing within 0-10 (Risk Ratio (RR) 1.16, 95% Confidence Interval (CI) 1.13-1.19) and 11-20 (RR 1.08, 95% CI 1.05-1.11) miles were significantly more likely to be diagnosed with lymphoma than individuals who lived within 21-30 miles from an oil refinery. We also observed differences in stage of cancer at diagnosis according to proximity to an oil refinery. We also found persons residing within 0-10 miles were more likely to be diagnosed with distant metastasis and/or systemic disease than people residing 21-30 miles from an oil refinery. The greatest risk of distant disease was observed in patients diagnosed with bladder cancer living within 0-10 vs. 21-30 miles (RR 1.33, 95% CI 1.06-1.68), respectively. Conclusions: Proximity to an oil refinery was associated with an increased risk of multiple cancer types. We also observed significantly increased risk of regional and distant/metastatic disease according to proximity to an oil refinery.
Impact of the molecular pathology of breast cancer on mortality rates and overall survival in a Haitian cancer clinic.
Authors: Bernard Joseph , Henderson Rebecca , Alexis Lynn Gabrielle , Gilbert Doukens Patrick , Pierre Lenz Sacha Christyl , DeGennaro Vincent A.
Published: May 2020

e13588

Background: Breast cancer in the most common malignancy among women in Haiti and is mostly diagnosed at an advanced stage. While it is well known that molecular subtype is a prognostic factor, it needs to be investigated among Haitian patients with breast cancer. This study aimed to evaluate the impact of molecular classification of breast cancer on the survival of patients managed in Haiti’s largest cancer clinic. Methods: A retrospective study was conducted on the breast cancer patients of Innovating Health International (IHI) in Port-au-Prince, Haiti from January 2014 to December 2018. Chart review included all patients with breast cancer and tested for molecular classification. Data on variables such as date of admission, age, TNM staging, molecular classification, outcome and date of death were collected for the analysis. Mortality rate and median overall survival (OS) were estimated as of December 31st, 2019 and stratified according to molecular subtypes. Results: Among the 948 breast cancer cases diagnosed for the study period, 234 (24.7%) of them had a complete molecular classification. The mean age was 51.5 years [range: 23-94]. 55.1% of the patients were ER-positive, among them 33.7% ER+/PR+/HER2-, 15.4% ER+/PR-/HER2-, 2.1% ER+/PR-/HER2+ and 3.8% ER+/PR+/HER+ (triple positive). There were overall 25.6% of luminal A and 29.5% of luminal B cases. 44.9% were ER-negative, among them 14.1% ER-/PR-/HER2+ (HER2-enriched) and 29.1% ER-/PR-/HER2- (triple-negative). 92.2% of the patients had advanced breast cancer (stages IIB to IV). 29.5% had metastatic breast cancer, 22.8% for luminal A cases, 27.0% for luminal B, 36.7% for HER2-enriched and 32.8% for TNBC. Overall mortality rate was 42.3%, respectively 33.3% for luminal A cases, 37.7% for luminal B, 42.4% for HER2-enriched cases and 55.9% for TNBC. Median OS was not yet reached for luminal A, luminal B and HER2-enriched breast cancer, with a respective mean survival of 52.4 months, 51.3 months and 51.6 months. However, OS was 30.6 months for triple-positive breast cancer and 23.7 months for TNBC. Conclusions: Patients with luminal A breast cancer were less likely to have metastatic disease and thus had lower mortality rate and better overall survival. This was likely due to its less aggressive biology and the availability of hormone therapy. Poor availability and inaccessibility of HER2-targeted drugs were the main cause of the higher mortality rate among HER2-enriched patients. TNBC remains the most aggressive subtype.
Can body size explain the excess cancer risk in men?
Authors: Radkiewicz Cecilia , Sjölander Arvid , Benyi Emelie , Lambe Mats , Dickman Paul , Sävendahl Lars , Edgren Gustaf
Published: May 2020

e13593

Background: Men are at increased risk of a majority of malignancies affecting both sexes. Since tall stature is associated with elevated cancer risk and since men are taller than women, we decided to investigate to what extent body stature, as a proxy for stem cell number within tissue, can explain the excess cancer risk in men. Methods: We performed a population-based cohort study investigating the association between male sex and cancer, accounting for body height. The analyses included all Swedish men and women with an adult height registration in either the Swedish Passport Register, the Conscription Register, and/or the Medical Birth Register (n = 6,156,659). Height data was linked to the Swedish Cancer Register where we observed 285,778 non-sex-specific cancer cases, diagnosed in 1960-2012. We applied contemporary causal mediation analysis methodology to assess the relative effect of male sex on lifetime cancer risk mediated by body height. Results: A vast majority of the investigated cancer sites were significantly associated with male sex (33 of 39) and height (27 of 39). The proportion of the excess cancer risk in men explained by sex differences in body height ranged from 0.5% (laryngeal) to 100% (salivary glands, colon, melanoma, and AML). The effect of body height and the mediated effect through height on cancer risk was most consistent and pronounced in malignancies with weak, few, or no known risk factors. Conclusions: A large proportion of the excess cancer risk in men is explainable by height. There is no known, height-associated cancer risk factor strong enough to provide an alternative pathway. Our findings supports the notion that a substantial proportion of cancer cases arise stochastically rather than are caused by underlying hereditary and/or environmental factors.
Lung cancer gender differences: An analysis of 1599 patients diagnosed between 1996 and 2018.
Authors: Seifi Sharareh , Khosravi Adnan , Salimi Babak , Esfahani Monfared Zahra
Published: May 2020

e13596

Background: Several studies showed disparities in terms of gender in lung cancer pattern. As we know, there is limited available data from lung cancer trends by gender in Iran and information reported in previous Iranian studies has become outdated. Methods: This observational study included data of Lung Cancer which were obtained from National Institute of Tuberculosis and Lung Disease (NRITLD), Masih Daneshvari Hospital,from January 1, 1996 to June 1, 2018. Overall survival (OS) and progression free survival (PFS) were estimated for each gender at several time points by the Kaplan-Meier method. Results: Characteristics of 1599 patients are shown in Table. Adenocarcinoma was most prevalent pathology in both sex and incidence of this histology increased in men during all study periods except 2002-2006. Notably, Adenocarcinoma has an increasing pattern especially after 2006 in women. Most prevalent Stage was advanced stages in both sex. Mean OS were 9.84±0.56 and 10.27±0.91 months in male and female respectively (P = 0.769). Also, mean PFS was non-significantly longer in men than women (7.6±0.49 vs 7.4±0.39, P = 0.903).Cox regression multivariate analysis showed only significant effect for advanced/extensive stages on OS(P = 0.015). Conclusions: The findings highlight important characteristics of the lung cancer epidemic; women are diagnosed at younger age and were less smoker than men. It is necessary for all chealthcare systems to assess the cancer burden periodically and gender differences should be considered for screening guidelines, preventive strategies, and Treatment. [Table: see text]
Prevalence of pathogenic non-BRCA1/2 gene variants in patients with suspected hereditary breast and ovarian cancer at a referral hospital in northeastern Brazil.
Authors: Sant'Ana Rosane Oliveira , Picanço-Albuquerque Clarissa Gondim , Silva-Fernandes Isabelle Joyce de Lima , Silva Paulo Goberlanio de Barros , Bezerra Maria Júlia Barbosa , Luciano Maria Claudia dos Santos , Lima Marcos Venício Alves
Published: May 2020

e13602

Background: Breast cancer (BC) is associated with several hereditary syndromes (HS). Patients with clinical criteria for hereditary breast and ovarian cancer (HBOC) should be evaluated for the presence of pathogenic BRCA1/2 variants, although the absence of BRCA1/2 variants does not rule out HS. The purpose of this study was to evaluate the prevalence of pathogenic non- BRCA1/2 variants in patients with suspected HBOC. Methods: Suspected HBOC (NCCN criteria) patients (n = 267) from a Northeastern Brazilian referral cancer hospital were submitted to NGS 31-gene painel. Individuals testing negative for BRCA1/2 mutation (n = 210) remained in the present presentation. Data were analized by the chi-squared test and Fisher’s test ( p< 0.05; SPSS 20.0). Results: Pathogenic/likely pathogenic (P/LP) non- BRCA1/2 variants were detected in 13.3% (n = 28/210) of the patients, all of whom had BC. The most prevalent variant was PALB2 (31%), followed by ATM and MUTYH (14.2%), and TP53 and PMS2 (10.7%). Among these patients 10.7% (n = 3/28) had triple negative tumors. Other gene variants ( BARD1, CHEK2, MLH1, MSH2, PMS1 and XRCC2) were observed at lower frequencies (3.5% each). DNA mismatch repair (MMR)/Lynch syndrome (LS) mutated genes were identified in 4/24 patients with BC. Rare microdeletions were identified in PALB2 (chr16:23652431-23652678 [exons 1-10] and TP53 (chr17:7.573.927-7.579.891 [exons 2-10]) , to our knowledge for the first time in the medical literature (ClinVar). In addition, one patient displayed a double pathogenic variant in ATM (c.67C > T: p.[Arg23*]) and PALB2 (chr16:23652431-23652678 [exons 1-10]). Patients with and without P/LP did not differ with regard to clinical-pathological parameters or therapeutic profile. Conclusions: Patients with suspected HBOC should be evaluated for non- BRCA1/2 variants, including MMR. We also suggest considering BC among the malignancies associated with LS.
Contribution of family history of gynecologic cancers to associated risk-factors and screening: Analysis of an Internet-based risk assessment tool.
Authors: O'Keefe Ryan M. , Lariviere Michael Joseph , Vachani Carolyn , Hampshire Margaret K. , Bach Christina , Arnold-Korzeniowski Karen , Healy Marisa , Metz James M. , Hill-Kayser Christine E.
Published: May 2020

e13605

Background: Well-established risk-factors exist for gynecologic cancers (GC): estrogen exposure increases risk of endometrial cancer (EC); HPV infection and smoking are associated with cervical cancer (CC); oral contraceptive (OCP) use may be associated with an increased risk of CC but a reduced risk of EC and ovarian cancer (OC). Women with a family history (FH) of cancer are more likely to receive regular CC screening, but the association between FH of GC and other risk factors has not been investigated. Methods: Reduce My Risk is an Internet tool created in 2009 to provide personalized information regarding cancer risk, available at OncoLink.org. Voluntary participants were asked about risk factors and risk-associated behaviors. Differences between female respondents with v. without FH of GC were analyzed using chi-square test. Results: Among 16,878 female respondents, 841 (5.0%) had FH of CC, 345 (2.0%) EC, 1,117 (6.6%) OC, and 92 (0.5%) vulvar/vaginal (VC) cancer. Those with FH of any GC showed no difference in alcohol consumption compared to those without FH. Those with FH of CC, EC, OC, and VC were more likely to be obese (34.1% v. 24.7%; 37.2% v. 24.9%; 31.4% v. 24.7%, 43.7% v. 25%, p < 0.001 for all). Those with FH of CC were more likely to have first sexual intercourse before age 18 (69.2% v. 57.8%, p < 0.001) and to have > 10 sexual partners (24.0% v. 16.7%, p < 0.001). This group was also more likely to be current smokers (19.3% v. 11.7%, p < 0.001), and to smoke > 1 pack/day (6.5% v. 2.8%, p < 0.001). They were more likely to receive regular CC screening (91.2% v. 86.8%, p = 0.09), though the difference was not statistically significant. Women < 35 y with a FH of CC showed no differences in HPV vaccination rate (37.0% v. 39.3%, p = 0.29). Those with FH of EC were more likely to have menarche before age 12 (39.3% v. 32.0%, p = 0.005), and to have taken post-menopausal HRT for ≥2 y (77.6% vs. 66.8%, p < 0.001). Those with FH of EC, and OC were more likely to have taken OCPs (77.6% v. 66.8%; 71.9% v. 66.7%, p < 0.001 for both). Conclusions: Many with a FH of GC have increased likelihood of both modifiable and non-modifiable risk factors that are associated with the development of cancer. FH of CC did not increase likelihood of regular screening or HPV vaccination, but was associated with smoking, early intercourse, and multiple sexual partners. Future work should explore targeted intervention for those with FH of GC as a teachable opportunity for the benefits of weight reduction, smoking cessation, pap screening, and HPV vaccination.