bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel proteomic mass spectrometry-based approach to reveal functionally heterogeneous tumor clones in breast cancer metastases and identify clone-specific drug targets.
Authors: Hajjaji Nawale , Abbouchi Mira , Nguyen Lan Anh , Charles Samuel , Leclercq Sarah , Bertin Delphine , Robin Yves-Marie , Fournier Isabelle , Salzet Michel
Published: May 2020

e13063

Background: Breast cancer mortality is expected to rise by almost 30% by 2030 worldwide, mainly due to the occurrence of distant metastases. The development of drugs specifically targeted at tumor drivers has not yet curbed resistance to treatment, which prevents metastases curability. There is a need for new molecular approaches to tackle metastases complex biology, particularly tumor heterogeneity, a main determinant of resistance. The aim of this study was to use a proteomic mass spectrometry-based approach to reveal functionally heterogeneous’ tumor subpopulations in breast cancer metastases, and identify clone specific drug targets. Methods: Metastasis biopsies (n = 21) were collected retrospectively from patients with advanced breast cancer treated at Oscar Lambret Cancer Center (Lille, France). Tumor heterogeneity was analyzed directly on FFPE tissue sections using MALDI mass spectrometry imaging (MSI) on a RapifleX Tissuetyper. Unsupervised spatial segmentation was performed to reveal tumor subpopulations with distinct proteomic profiles within each metastasis. The full proteomic characterization of these tumor clones was further performed with spatially resolved proteomic mass spectrometry. Results: MSI revealed that breast cancer metastases contained 2 to 5 functionally distinct tumor clones (proteomic clones). Although the clone profiles within a metastasis were correlated, unsupervised hierarchical clustering showed a clear distinction between them and specific proteomic signatures. Enrichment analysis showed that differentially expressed proteins were involved in a variety of biological processes or pathways including regulation of histone acetylation, extracellular matrix degradation, DNA repair, NOTCH pathway, estrogen-responsive target genes or exocytosis. The evolution of the proteomic clones profile during disease progression was also determined by comparison of paired biopsies. To identify the candidate treatments best fitted to metastasis heterogeneity, the specific proteomic signatures of the clones were matched against a druggable genome database. It was possible to unveil candidate drug targets personalized to each metastasis functional clone. Conclusions: MALDI mass spectrometry imaging combined with spatially resolved proteomics has the potential to tackle breast cancer metastases heterogeneity, and identify candidate drug targets specific to functional clones to personalize treatments.
Yttrium-90 radioembolization for breast cancer with liver metastases: A focus on mortality, adverse reactions, and radiological response.
Authors: Heckman Patrick , Martinez Brandon , Birhiray Ruemu E.
Published: May 2020

e13065

Background: Breast cancer associated with liver metastases (BCLM) occurs later in the progression of metastatic breast cancer and carries a poorer prognosis than bone or soft tissue metastases (Pagani). As systemic therapy begins to prolong progression, there is an inherent necessity for localized therapy directed at distant metastases. Further, there is some evidence to suggest that interventional techniques can prolong survival and palliate symptoms although data is lacking in this area (Hoe). Here we present findings describing the mortality benefit, adverse effects, and radiological response to Yttrium-90 (Y-90) radioembolization in BCLM patients. Methods: All patients with BCLM who received Y-90 radioembolization at St. Vincent Hospital from 2013-2018 were included in data collection. Digital chart review was utilized for data collection. To be eligible for the study, patients must have image or biopsy proven metastatic breast cancer to the liver, active unresectable disease not appropriate for ablation, ECOG performance status of 0-2, Bilirubin < 2.0 mg/dL, and no other evidence of liver disease. Patients with a life expectancy less than 2 months were excluded. Results: Twenty-five patients with BCLM underwent Y-90 radioembolization of hepatic metastases. Median survival after therapy was 495 days, or 16 months compared to the median survival rate of 4 months for BCLM patients reported by previous studies (Hoe). At 3 month follow up CT, 48% of patients experienced significant reduction in hepatic tumor burden, only 20% had worsening disease. 16% of patients reported abdominal pain. Median increase in bilirubin was 0.1. Median post procedural AST was 47, and ALT 40. Six patients experienced ascites requiring paracentesis, which occurred on average 14.3 months after Y-90 therapy. There were zero cases of pancreatitis and Radioembolization Induced Liver Disease (REILD). Conclusions: In patients with BCLM who undergo Y-90 radioembolization there seems to be a mortality benefit compared to traditional therapies. Further, there is a radiological reduction in tumor burden, and only minimal adverse effects.
Multicenter Italian bone metastasis database: First prospective data on breast cancer patients.
Authors: Bongiovanni Alberto , Foca Flavia , Fantini Manuela , Forcignano Rosachiara , Artioli Fabrizio , Berardi Rossana , Campadelli Enrico , Procopio Giuseppe , Silvestris Francesco , Riva Nada , Gurrieri Lorena , Di Menna Giandomenico , Recine Federica , Fausti Valentina , Debonis Silvia Angela , Mercatali Laura , Spadazzi Chiara , Menis Jessica , Vespignani Roberto , Ibrahim Toni ,   Banca Dati Metastasi Ossee Study Team
Published: May 2020

e13072

Background: Bone Metastases (BM) are still the main cause of morbidity and morbility in cancer patients because of their complications defined as skeletal-related events (SREs).SREs reduce pts quality of life and are associated with an increasing in social and health costs. At present, data concerning BM are mainly obtained retrospectively from monocentric experiences. Methods: We performed a multicentre prospective observational study of patients with BM from breast cancer (BC) with at least 6 month (m)'s follow-up who were registered in a prospective BM database (BMDB). Detailed information on patients at first diagnosis of BM was recorded in a custom-built software system, updated every 6 m by participating centres and reviewed by the coordinator centre.All pts have signed an informed consent. Results: Since October 2014,618 pts with BM from solid tumors were enrolled of whom 220 have BC as primitive site with a 6 m follow-up. Median age was 62 y (range 26-86). Median Follow up was 34 m (6-149). At enrolment 109 (50%) had only BM and 109 (50%) pts had concomitant visceral and BM. Median time to first BM was 47 m (range 0-312) in Bone only disease and 78.6 m in pts with visceral bone metastases. Disease Free interval (DFI) was different according to BC molecular subtypes and stage. The univariate hazard ratio (HR) for visceral or bone metastasis was higher in luminal B tumors (1.56, 95% confidence interval [CI]:1.1-2.3) (p = 0.002), basal-like (2.50, 95% CI:1.1-6.0) (p = 0.043), and HER2-enriched tumors (1.37, 95% CI:0.78-2.4) (p = 0.273). DFI for pts with stage I disease at diagnosis of primary BC was longer than that for stage III pts (median 67.2 m, 95%CI:53.1-96.1, vs. 58.1 m, 95%CI:41.9-73.4), with a HR of 1.84 (95% CI:1.1-3.0) (p = 0.015) for the stage III group, and 0.98 (95% C.I.:0.6-1.5) (p = 0.930) for the stage II group. During BM disease, 98 pts had at least 1 SREs . Zoledronate was used in 69.1% and Denosumab in 28.3% of cases. First line treatment was hormone-based (n = 105, 50.7%) chemo-based therapy (n = 80, 38.7%) and chemo+ormono based (n = 20, 9.7%). During follow up progression disease occurred in 167 pts. Median progression-free (mPFS) and overall survival calculated from metastatic disease diagnosis (mOS) were 15.1 m (95%CI 12.6-18.4) and 66.8 m (95%CI 52.1-79.2),respectively. Conclusions: This study presents prospective data about a cohort of BC pts enrolled at the first BM occurrence and followed over the time, extrapolated by the multicentric observational BMDB in order to better understed the clinical history of breast cancer and bone metastases.
Del-1 and MFG-E8 expression to differentially modulate prognosis of patients with triple-negative breast cancer.
Authors: Lee Soo Jung , Park Ho Yong , Jung Jin Hyang , Lee Jeeyeon , Lee In Hee , Park Ji-young , Chae Yee Soo
Published: May 2020

e13093

Background: Del-1 was previously found to be prognostic biomarker in early breast cancer patients. Del-1 shares both structural and functional homology with Milk fat globule-epidermal growth factor-factor VIII (MFG-E8). To date, the biological functions of Del-1 and MFG-E8 have not been sufficiently compared in side-by-side experiments. MFG-E8 is a secreted glycoprotein from macrophages that promotes clearance of apoptotic cells. In this study, we investigated the function of MFG-E8 and Del-1 and prognosis in a large cohort of EBC patients. Methods: The MFG-E8 levels were measured using a qRT-PCR in breast cancer cells (MDA-MB-231, Hs578T, MCF7, SK-BR3, and T-47D), and tissues from 20 patients with EBC. The effects of MFG-E8 and Del-1 on cell proliferation, migration, and invasion were determined using MTT, wound healing, and Matrigel Transwell assays. The expressions of MFG-E8 and Del-1 protein were detected by immunohistochemical staining in 436 tumor tissues. The relationship between MFG-E8, Del-1 expression levels and clinicopathological features were evaluated. Results: MFG-E8 and Del-1 levels were significantly elevated in MDA-MB-231 and Hs578T cell lines (p < 0.001). Given that MFG-E8 and Del-1 share similar protein structure, we wanted to explore the effect of dual knockdown of MFG-E8 and Del-1 in migration and invasion assay. As expected, knockdown of Del-1 alone decreased cell migration in TNBC cell lines, but dual knockdown of MFG-E8 and Del-1 showed reduction was restored. Dual knockdown of MFG-E8 and Del-1 showed consistent result in invasion assay. Down-regulation of Del-1 inhibited TNBC cells invasion and recovered by the MFG-E8 knockdown. Interestingly, for the 436 patients, Del-1 high- and MFG-E8 low- expression shows correlation with aggressive histologic grade, high Ki-67 (p < 0.001 and p = 0.042, respectively) and shorter survival outcome (distant disease free survival p = 0.028, breast cancer specific survival p = 0.001). Conclusions: Overall, these findings suggest that MFG-E8 and Del-1 protein expression could be a prognostic marker for patients in triple negative breast cancer (TNBC). Thus, MFG-E8 reduction may contributes to tumorigenesis by increasing Del-1. However, functions of Del-1 and MFG-E8 have not yet been thoroughly analyzed, further studies are required.
Physician treatment preferences for metastatic triple negative breast cancer (mTNBC) in an era of immunotherapy.
Authors: Gajra Ajeet , Wojtynek Jeffrey , Dokubo Igoni , Jeune-Smith Yolaine , Kish Jonathan , Feinberg Bruce A.
Published: May 2020

e13095

Background: TNBC accounts for 10-20% of all breast cancer and has poor prognosis. Guidelines now list atezolizumab with nab-paclitaxel (ANP) as preferred for mTNBC w/ PD-L1 expression > 1%. We sought to assess current mTNBC prescribing and sequencing preferences for first-line (1L), second-line (2L), and third-line (3L) therapy among U.S. community oncologists (c-oncs). Methods: C-oncs were presented 4 hypothetical mTNBC clinical scenarios (CS 1-4) via web-based survey. CS differed by PD-L1 expression, menopausal status, prior adjuvant therapy and nature of metastases (bulky liver, lung, bone) but were otherwise uniform in terms of being asymptomatic, BRCA negative, with identical response extent and duration of each line of therapy. Respondents selected their preferred treatment for 1L, 2L, and 3L in each CS in the following categories: single agent (SA) chemotherapy, combination chemotherapy (CC), or ANP. The proportion of c-oncs selecting each treatment approach per CS for each line of therapy was calculated. We describe these preference patterns and how these may deviate from current guidelines. Results: 47 c-oncs participated from across the U.S. (northeast = 23%, midwest = 28%, south = 32%, west = 17%): mean years in practice was 22.7 and mean number of mTNBC patients under treatment was 18.8. The proportion of c-oncs preferring SA, CC or ANP per CS per line of therapy is listed in the table. Deviations from guidelines include preferences for: 1L ANP despite PD-L1 < 1% (26% in CS 1 and 4); 1L CC (45%) in asymptomatic bone only disease (CS1); 2L CC (19-34%) in asymptomatic visceral metastases (CS 2, 3 and 4). The SA 2L (74%)/3L (90%) preferences: capecitabine (36% 2L; 18% 3L) and eribulin (24% 2L; 35% 3L). Gemcitabine + carboplatin was the preferred CC regimen in 2L (50%) and 3L (28%). Conclusions: There is deviation from current guidelines in the treatment preferences for mTNBC patients among c-oncs, specifically the preference for ANP in PD-L1 negative patients and CC in 2L and 3L for asymptomatic patients. [Table: see text]
Economic evaluation of SP142 IHC assay versus 22C3 IHC assay in patients with unresectable locally advanced or metastatic triple-negative breast cancer in the Brazilian private healthcare system.
Authors: Shimabukuro Ho Rodrigo , Mioti Sebastião Mariana , Carvalho Joao , Neves Tomás , Nussbaum Micha
Published: May 2020

e13097

Background: The IMpassion130 trial has demonstrated that atezolizumab plus nab-paclitaxel results in significant clinical benefits for patients with unresectable locally advanced or metastatic (aTNBC). The SP142 IHC assay is a clinically validated and FDA-approved PD-L1 test to identify patients with aTNBC for treatment with atezolizumab plus nab-paclitaxel. A post hoc analysis of IMpassion130 evaluated two other PD-L1 IHC assays, 22C3 and SP263, for analytical and clinical concordance with SP142 and the PD-L1 prevalence by each assay. The prevalence of PD-L1+ per SP142 (tumor-infiltrating immune cells 1%), 22C3 (combined positive score1) and SP263 (tumor-infiltrating immune cells 1%), were 46%, 81% and 75%, respectively. The study compared only SP142 assay with 22C3 assay because patients with SP142 negative and 22C3 positive did not demonstrate a significant clinical benefit for progression-free survival (PFS) and overall survival (OS). Therefore the study aimed to demonstrate the economic impact of these assays in the treatment with atezolizumab plus nab-paclitaxel. Methods: Data of PFS and OS from the post hoc analysis of Impassion130 were extracted to develop a Markov model to simulate the clinical and economic impact of the patient with atezolizumab plus nab-paclitaxel guided by SP142 and 22C3 assays. The analysis considered the cost of atezolizumab+nab-paclitaxel, the cost associated with the management of the adverse events and the cost of the assay. The costs were based on CBHPM (Classificação Brasileira Hierarquizada de Procedimentos Médicos), CMED PF18% (Câmara de Regulação do Mercado de Medicamentos) and local publications. An univariate sensitivity analysis was performed. Results: The study demonstrated that SP142 assay has the potential to save 175,917 BRL (45,595 USD) with atezolizumab plus nab-paclitaxel per patients with aTNBC in three years. Conclusions: The SP142 assay can optimize the use of atezolizumab plus nab-paclitaxel avoiding its use in patient who will not have a significant clinical improvement.
Comprehensive profiling of MDM2/TP53 genomic aberration in Chinese patients with diverse malignancies.
Authors: Zhou Dongkai , Wang Weilin , Yan Sheng , Ye Song , Wu Yingsheng , Ding Yuan , Sun Qiang , Qian Xiaohui , Gao Bingqiang , Kong Yang , Yang Qifan , Ji Weiping , Zheng Zhihai , Zhou Xiumin , Xu Weihua , She Mingjin , Yang Yong , Dong Qiantong , Yu Yaojun , Zhang Shiyue
Published: May 2020

e13508

Background: Murine double minute-2 (MDM2) has increasing clinic relevance as preclinical and early clinical evidences have showed that the MDM2 inhibitors are promising alternative treatments for patients with MDM2-amplified (-amp) and TP53-wild-type (-WT) tumors by preventing TP53 protein degradation. However, exploration into genomic landscape of MDM2/TP53 across various solid tumors in Chinese patients is still limited. Methods: Formalin-fixed, paraffin-embedded (FFPE) tumor samples were collected from 10010 Chinese patients with solid tumors and subjected to a clinical-grade next-generation sequencing (NGS)-based 450 gene panel testing carried out by a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Genomic alterations (GAs) including single base substitutions, short and long insertion/deletions (Indels), copy number variations, gene fusions, and rearrangements were analyzed. Tumor mutational burden (TMB) was measured by a NGS algorithm. Results: Amplification of MDM2 occurred in 3.3% of Chinese patients. MDM2-amp was detected most frequently in soft tissue sarcoma (STS, 11.4 %), melanoma (10.3 %) and osteosarcoma (6.3 %). Notably, MDM2-amp was revealed to be mutually exclusive with TP53-mut in most tumor types other than esophageal carcinoma (93.9 %), head and neck carcinoma (68.4%) and ovarian carcinoma (50 %). Tumors with highest frequencies of MDM2-amp/ TP53-WT were melanoma (100%), osteosarcoma (100%) and urothelial carcinoma (100 %). The most common co-altered genes accompanied with MDM2-amp were FRS2 (84%), CDK4 (38%), EGFR (26%), TP53 (17%) and GLI1 (14%). 82.8% patients who had one or more co-alterations potentially targetable with either FDA-approved or investigational agent. Moreover, TMB of MDM2-amp tumors were significantly lower than that of MDM2-WT and MDM2-mutation (-mut) tumors (median TMB: 3.1 vs. 4.6 vs. 10.8, p < 0.001 respectively). Conclusions: MDM2 amplification was found in 3.3% of 10010 Chinese cancer patients, 83.4% of whom harbored wild-type TP53 that were potentially responsive to MDM2 inhibitors. In addition, 82.8% of the patients with MDM2-amp harbored genomic co-alterations and were potentially therapy targetable. This study provided insights into identifying patients who might potentially benefit from anti-MDM2 therapies.
Association between MUC5B mutation and prognosis across solid tumors.
Authors: Zhao Qun , Zheng Hong , Duan Wei , Li Chengcheng , Xie Wenzhuan , Wang Guoqiang , Zhang Yuzi , Bai Yuezong , Zhou Yingchun
Published: May 2020

e13515

Background: MUC5B encodes Mucin 5B, which is a gel-forming mucin and a major constituent of mucus in the respiratory tract. Previous studies have revealed an increased expression of MUC5B in invasive mucinous adenocarcinoma (IMA) of the lung, indicating it may be involved in the tumorigenesis, and its family member MUC16, which encodes cancer antigen 125 (CA125), a biomarker for tumor diagnosis and the MUC16 mutation was reported to be associated with higher tumor mutation load, and a better survival outcomes in Gastric Cancer. However, the association between MUC5B mutation and prognosis has never been investigated in solid tumors. Methods: Whole-exome sequencing, RNA sequencing and clinical data for 27 types of solid tumors were downloaded from The Cancer Genome Atlas (TCGA). Associations between MUC5B mutation and prognosis were analyzed, and gene set enrichment analysis (GSEA) was used to investigate the underlying mechanism. Results: Among the 27 tumors, MUC5B mutation was associated with a superior disease specific survival (DSS) in Uterine Corpus Endometrial Carcinoma (UCEC) (HR, 0.32; 95% CI, 0.13-0.80; P = 0.01), Bladder Urothelial Carcinoma (BLCA) (HR, 0.43; 95% CI, 0.18-1.05; P = 0.06) and lung adenocarcinoma(LUAD) (HR, 0.44; 95% CI, 0.2-0.95; P = 0.03). MUC5B was also or tended to be associated with longer progression-free survival (PFS) and overall survival (OS) in UCEC (PFS: HR, 0.40; 95% CI, 0.23-0.70; P < 0.001; OS: HR, 0.57, 95% CI 0.31-1.03, P = 0.06), BLCA (PFS: HR, 0.40; 95% CI, 0.19-0.86; P = 0.02; OS: HR 0.42, 95% CI 0.20-0.90, P = 0.02) and LUAD (PFS: HR, 0.63; 95% CI, 0.38-1.06; P = 0.08; OS: HR 0.55, 95% CI 0.31-0.97, P = 0.04). However, MUC5B mutation was associated with poorer OS (HR 1.64, 95% CI 1.03-2.59, P = 0.03) and tended to be associated with poorer PFS (HR 1.56, 95% CI 0.95-2.57, P = 0.08) in Head and Neck squamous cell carcinoma (HNSC). MUC5B mutation was not associated with survival in other tumors. MUC5B mutation was associated with a higher TMB in UCEC, BLCA and LUAD, and GSEA revealed prominent enrichment of signatures related to DNA repair in MUC5B mutation group, compared to MUC5B wide-type group in UCEC (FDR < 0.05), BLCA (FDR < 0.05), and LUAD (FDR < 0.05), but not in HNSC. Conclusions: MUC5B mutation may be a potential predictor for better prognosis in UCEC, BLCA and LUAD, through potentiating DNA damage repair signaling. Identification of MUC5B mutation by genomic profiling provides a potentially novel and convenient approach for these patients to predict the prognosis, and refines patients' management in clinical practice.
Features of iso-miR expression in colon tumor tissue.
Authors: Timoshkina Natalya N. , Kutilin Denis S. , Novikova Inna A. , Poluektov Sergey I. , Tolmakh Roman E. , Dashkov Andrey V. , Haragezov Dmitry , Kolesnikov Evgeniy N. , Dontsov Vladimir A. , Petrov Dmitry S. , Soldatkina Natalya V. , Kit Oleg Ivanovich
Published: May 2020

e13518

Background: With the advent of deep sequencing, enormous variability in miRNA biogenesis was detected, which means that many different sequences can potentially be generated from the same miRNA precursor, potentially having different targets and opposite changes in expression. These variable forms of micro-RNA that differ from the reference sequence are called iso-miR. To date, features of iso-miR expression have not been studied in patients with colorectal cancer (CRC). The aim of the study was to analyze the differential expression of iso-miR in the tumor and normal tissues of patients with CRC. Methods: For iso-miR identification by method of multiple parallel sequencing, 18 patients with CRC (colon adenocarcinoma, G2-3) were selected. The mirVana miRNA Isolation Kit protocol (Ambion, Life Science Technologies, USA) was used to isolate small RNA fractions. The library was prepared 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 iso-miR expression was carried out by comparing the nucleotide sequence of the sequenced molecules in each sample with the known nucleotide sequences of micro-RNA presented in the databases. When analyzing the iso-miR differential expression, the DESeq method implemented in R medium was used. Results: Several iso-miR classes were found (exact, lv3p, mv (multiple variant), nta#T#1 (non-templated T addition)). The most represented is the exact class (corresponding to the canonical miRBase sequence) and lv3pE (3 'extended: it starts from the same position as the canonical sequence, but is longer than the canonical sequence). Statistically significant (p < 0.001) differences in the expression of tumor tissue relative to normal were found for hsa-miR-143 (exact), hsa-miR-26a (exact) and hsa-miR-27b (exact) - a decrease in expression in 3, 32 and 6 times respectively, for hsa-miR-10a (lv3p), hsa-miR-10b (lv3p), hsa-miR-10b (mv) - a decrease of 2 times, for hsa-miR-143 (lv3p) - an increase of 2 times, hsa-miR-143 (nta # T # 1) - a decrease of 5 times, for hsa-miR-192 (lv3p) and (nta # T # 1) - a decrease of 16 and 3 times, respectively. Conclusions: Differential expression of 4 iso-miR classes (exact, lv3p, mv, nta # T) hsa-miR-26a, hsa-miR-27b, hsa-miR-10a, hsa-miR-10b, hsa-miR-143 and hsa-miR-192 was found in patients with CRC, which probably can affect the transcriptional activity of the genes they target. These iso-miRs are also likely to act as potential tumor markers.
An analysis of growth in the genetic counseling profession 2009 to 2019.
Authors: Hooker Gillian , Allain Dawn C. , Buchanan Adam H , Care Melanie , Conway Laura , Cumming Alessandra , Dixon Shannan , Paulyson-Nuñez Kristin , Riordan Sara , Williams Janet
Published: May 2020

e13526

Background: Genetic counselors (GCs) are health care professionals who provide support to patients and physicians navigating the rapidly changing landscape of genetic testing and the genetic underpinnings of disease. Increased demand for genetic counseling services prompted an analysis of changes in the workforce over the last decade. Methods: To quantify the growth in the GC profession in the U.S and Canada in the last decade, we acquired data from the American Board of Genetic Counseling, National Society of Genetic Counselors, Canadian Association of Genetic Counselors, Accreditation Council for Genetic Counseling and Association of Genetic Counseling Program Directors. Results: Between 2009 and 2019, the workforce more than doubled, growing from 2,205 ABGC-certified GCs to 5,172. In Canada, the number of CAGC-certified GCs has grown from 211 in 2009 to 327 in 2019. Growth is striking in cancer genetic counseling; the proportion of GCs providing direct patient care in North America who report cancer as a primary specialty has increased from 25% in 2008 to 50% in 2019. Similar growth has been seen in training opportunities for GCs. The number of accredited graduate programs has increased from 33 in 2009 to 51 in 2019, with several more in development. Combined, these programs had 464 training slots in 2019, up from 223 in 2009. In 2019, 1569 applicants registered for the applicant match for training. Training opportunities and clinical genetic counselors are concentrated in large metropolitan areas, with over half of GCs working in 28 metro regions. GC services in rural areas are increasingly provided remotely via telemedicine, with 59% of GCs in direct patient care in 2018 reporting providing services by phone and 19% using web or video services to deliver care. In cancer genetics, about 50% of GCs nationwide reported in 2018 their 3rd next available appointment for new patients was within 14 days. Conclusions: The past decade has seen significant growth in the numbers of GCs and more patients have access to GCs than a decade ago. Reimbursement for services remains a significant barrier to access. Further research is warranted to understand additional political, administrative and logistical facilitators and barriers to providing care to all who need genetics services.
Association of CEP72 rs924607 with vincristine-induced peripheral neuropathy (PN) in patients with diffuse large B-cell lymphoma on CALGB 50303 (Alliance).
Authors: Hertz Daniel Louis , Larson Nicholas Bradley , Pierpont Timothy , Bartlett Nancy L. , Zelenetz Andrew David , Wilson Wyndham Hopkins , Leonard John Paul , Jung Sin-Ho , Riska Shaun M. , Richards Kristy L.
Published: May 2020

e13535

Background: Pediatric patients (pts) receiving long-term vincristine treatment for acute lymphoblastic leukemia (ALL) who carry two variant alleles of CEP72 rs924607 experience more severe peripheral neuropathy (PN) at lower cumulative vincristine doses. The objective of this retrospective pharmacogenetic analysis was to determine if pts homozygous for rs924607 have increased PN risk when receiving short-term vincristine treatment for diffuse large B-cell lymphoma (DLBCL). Methods: Caucasian pts with DLBCL randomized to either of two vincristine-containing regimens (R-CHOP or DA-EPOCH-R) on the CALGB 50303 (Alliance) trial were genotyped for germline rs924607 via TaqMan. Vincristine was administered intravenously 1.4 mg/m2 (2 mg cap) on day 1 of each R-CHOP cycle (1.4 mg/m2/cycle) or 0.4 mg/m2/day (no cap) on days 1-4 of each DA-EPOCH-R cycle (1.6 mg/m2/cycle). Dosing was repeated every 21 days for 6 treatment cycles, for a maximum cumulative vincristine dose of 8.4 (R-CHOP) or 9.6 (DA-EPOCH-R) mg/m2 over 18 weeks. The primary analysis compared risk of NCI CTCAE grade 3 or higher PN in rs924607 homozygous variant pts versus wild-type allele carriers using multivariable Cox proportional hazards regression adjusted for treatment received (R-CHOP vs. DA-EPOCH-R), age (continuous), and sex (male vs. female). A secondary analysis was conducted only in pts assigned to the DA-EPOCH-R arm. Results: Of 307 pts included in the analysis, 32 (10.4%) experienced grade 3+ PN. PN occurrence was nominally lower in homozygous pts (5/59 = 8.5%) than wild-type carriers (27/248 = 10.9%). In the primary analysis, homozygous pts did not experience PN earlier in treatment (Hazard ratio (HR) = 1.04, (95% confidence interval: 0.39-2.75), one-sided p-value = 0.47). There was no significant difference between groups in dose-at-PN occurrence (homozygous (n = 5): 8.81 mg/m2 vs. wild-type carrier (n = 27):6.74 mg/m2, p > 0.05). The secondary analysis in pts on the DA-EPOCH-R arm (n = 147), in which the majority of PN events occurred (n = 27/32 = 84%), homozygous pts (n = 26) did not have significantly increased PN risk (HR = 1.30, p = 0.56). Conclusions: This retrospective analysis of the prospective CALGB 50303 trial did not find that pts homozygous for CEP72 rs924607 had increased PN risk during short-term vincristine treatment for DLBCL. Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org . ClinicalTrials.gov Id: NCT00118209.
The prevalence of targetable genomic alterations is substantially high in rare tumors.
Authors: Wang Shuhang , Li Ning , Chen Rongrong , Yu Yue , Fang Yuan , Gu Dejian , Yi Xin , Huang Huiyao , Wu Dawei , Fang Hong , Bai Ying , Sun Chao , Qi Anqi , Fan Qi , Zhou Ying
Published: May 2020

e13539

Background: Comprehensive Genomic Profiling may be informative for novel treatment strategies and to improve outcome for patients with rare solid tumors. This study aims to discover opportunities for use of targeted therapies currently in routine practice in patients with rare tumors. Methods: Solid tumors with an incidence lower than 2.5/100,000 per year was defined as rare tumors in China after comprehensive analysis based on epidemiology data and current availability of standardized treatment. Genomic data of rare tumors from the public database cBioPortal was compared with that of Chinese population for targetable genomic alterations (TGAs). TGAs was defined as mutations of ALK, ATM, BRAF, BRCA1, BRCA2, CDKN2A, EGFR, ERBB2, FGFR1,2,3, KIT, MET, NF1, NTRK1,2,3, PIK3CA, PTEN, RET, and ROS1 with level 1 to 4 of evidence according to OncoKB knowledge database. Results: Genomic data of 4901 patients covering 63 subtypes of rare tumor from cBioportal was obtained as the western cohort. Data of next generation sequencing (NGS) of 1312 patients from across China covering 67 subtypes was summarized as the Chinese cohort. Forty-one subtypes were overlapped between the two cohorts. The accumulative prevalence of TGAs was 20.40% (1000/4901) in cBioportal cohort, and 53.43% (701/1312) in Chinese cohort (p < 0.001). Among those 41 overlapping subtypes, it was still significantly higher in Chinese cohort compared with cBioportal cohort (54.1%% vs. 26.1%, p < 0.001). Generally, targetable mutations in BRAF, BRCA2, CDKN2A, EGFR, ERBB2, KIT, MET, NF1, ROS1 were ≥3 times more frequent in Chinese cohort compared with that of cBioportal cohort. Cancer of unknown primary tumor type, gastrointestinal stromal tumor, gallbladder cancer, intrahepatic cholangiocarcinoma, and sarcomatoid carcinoma of the lung were the top 5 tumor types with highest TGAs. Conclusions: The incidence of TGAs in rare tumors was substantially high worldwide and was even higher in Chinese rare tumor population. Comprehensive genomic profiling may offer novel treatment paradigms to address the limited options for patients with rare tumors.
Family cancer patterns and variation by race and ethnicity among individuals with pathogenic variants in multi-gene cancer predisposition panels at a large urban comprehensive cancer center.
Authors: Tatineni Sushma , Purrington Kristen , Assad Hadeel , Abdallah Nadine , Tarockoff Meri , Surapaneni Malini , Petrucelli Nancie , Reagle Rachel , Simon Michael S.
Published: May 2020

e13540

Background: The identification of pathogenic variants and variants of unknown significance (VUS) in multi-gene cancer predisposition testing raises new questions regarding cancer risk and management. We evaluated the personal and family cancer patterns and variation by race and ethnicity, among individuals positive for pathogenic variants in non-BRCA1/ 2 cancer predisposing genes. Methods: The Karmanos Cancer Institute (KCI) Cancer Genetics database was queried from May 13, 2013 through December 31, 2018. There were 3,544 unrelated individuals evaluated for hereditary cancer predisposition of whom 1,868 had 18-gene panel testing at 6 sites across Michigan. Data was collected on personal and family cancer history including ages at diagnosis utilizing a 3-generation pedigree, self-identified race and ethnicity and results of genetic testing. We describe the prevalence of pathogenic variants by proband cancer diagnosis, family history, race, and ethnicity. Results: The race/ethnic distribution of the tested cohort included 67.5% non-Hispanic White (NHW), 24.4% African American (AA), 2.1% Arab, 1.8% Ashkenazi Jewish (AJ), 1.0% Hispanic, and 3.4% other. The distribution of cancer diagnoses included 40.6% breast, 5.5% ovarian, 4.1% colon, 3.5% endometrial, 2.0% pancreas and 39.7% unaffected. Pathogenic variants were seen in 151 (8.1%) individuals and VUS in 309 (16.5%). The five most common pathogenic variants were CHEK2 (40), MUTYH (22), ATM (20), and PALB2 (18). The most common pathogenic variants by race and ethnicity were CHEK2 (NHW), RAD51C (AA), PALB2 (Arab), CHEK2, MSH6 (AJ), and none in Hispanics. Variants associated with the four most common cancer types were breast ( CHEK2 ), ovarian ( CHEK2, MUTYH, BRIP1), colon ( ATM), and endometrial ( MSH6, PALB2). Of 40 individuals with CHEK2 variants, 92.5% were NHW, and 34 (85%), 31 (78%), 10 (25%), 1 (2.5%) had family history of breast cancer, breast cancer before age 50, ovarian, and colon cancer, respectively. Of 20 with ATM variants, 95% were NHW, 13 had family history data and 10 (76.9%), 8 (61.5%), 2 (15.4%), 1 (7.7%) had family history of breast, breast cancer before age 50, ovarian, and colon cancer, respectively. Conclusions: Pathogenic variants seen using multigene panel testing differ by race, ethnicity and personal/family history of cancer. This data will inform genetic counseling strategies in regards to cancer risk and management. Data on additional genes updated through 2019 will be presented.
Pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) for advanced breast cancer patients with high risk for Hereditary Breast and Ovarian Cancer Syndrome (HBOC).
Authors: Sant'Ana Rosane Oliveira , Silva-Fernandes Isabelle Joyce de Lima , Luciano Maria Claudia dos Santos , Silva Paulo Goberlanio de Barros , Lima Marcos Venício Alves
Published: May 2020

e13549

Background: Local Advanced Breast Cancer (LABC) is associated with high risk of death. NAC is a safe and effective approach for these populations. pCR is a proven prognostic factor in several studies of NAC. HBOC is associated to high risk of breast cancer usually in young age and especially for BRCA1 mutations with a basal phenotype. The aim of this study was to evaluate the influence of BRCA mutational status on frequence of pCR. Methods: this is part of a retrospective, observational study of prevalence of HBOC among patients admitted for cancer therapy in our institution. Since August, 2018 over 300 pte suspected for HBOC (by NCCN criteria) have been screened for NGS with a 31-gene painel. Statistical analysis performed Person X2/Fisher and logistic regression ( p< 0.05; SPSS 20.0). Results: Most pte were women (80%), with median age of 38y (22-72y), most tumors were (80%) stage III, Luminal B (23%) and TNBC (36%). Pathogenic mutations were identified in 34%(n = 28) of the sample ( BRCA1 50%, BRCA2 16.7%, PALB2 16.7%, follow by TP53, PMS2, XRCC2, MUTYH, BARD1 and ATM with 2.8% each).The majority of patients had more than 1 NCCN criteria: age < 45y (83%), family member with BC < 50y (24%) or TNBC (33%) the most common. TNBC tumors had stronger association with germline mutation ( p< 0.001). Regarding response rate there were 13 stable disease (SD), 5 progressive disease (PD), 43 pCR and 39 pathological partial response (pPR). There were no differences in pRC among mutated or no mutated pte, p= 0,170. However, among mutated TNBC there were strong correlation with more pCR, p< 0,006. There was no difference on pCR rate related to mutation status (BRCA vs Non-BRCA), p = 0,84. Conclusions: the present study corroborates other data about the impact of germline mutation status over pCR after NAC for LABC, except for mutated TNBC population, whose seems to be more NAC sensitive.
Outcome of mammography examination among asymptomatic women.
Authors: Kolade-Yunusa Hadijat Oluseyi
Published: May 2020

e13558

Background: Early detection of breast cancer is important in reducing mortality, morbidity and high socio-economic burden associated with it. Mammography is currently the primary imaging modality used as a screening tool to detect early breast cancer in women experiencing no symptoms as they are most curable in the early stage. The aim of the study is to determine the mammographic outcome in asymptomatic women who presented for mammographic breast examination in Abuja,Nigeria. Methods: This descriptive cross-sectional study comprises of 113 asymptomatic women who presented for mammographic examination at the Radiology department of University of Abuja Teaching Hospital, Gwagwalada from March 2015 to December 2018. Two basic views (craniocaudal and mediolateral views) of the breast were obtained using EXR-650 machine.Additional views were obtained when necessary. Images of the breast were review by radiologist. Results: The mean age of study population was 40.72 ±10.45years with age range of 35 and 65 years. The mammographic outcome among asymptomatic women who had mammographic examination was negative in 69(61.1%) women and positive in 44(38.9%). The differences observed between the positive and negative mammographic outcome was statistically significant p = 0.01. The positive outcome noted in mammograms of women examined were: benign mass in 18(15.9%) women; 9(8.0%) had benign calcification; 7(6.2%) showed architectural distortion; 5(4.4%) was inconclusive; focal asymmetry in 3(2.6%); and suspicious mass in 2(1.8%). Conclusions: Mammogram is an important tool for screening and diagnoses of breast pathologies. In this study, screening of women reveals various benign and malignant breast changes which necessitate early interventions. Early detection of breast cancer save lives. [Table: see text]
Relationship between nutritional status and length of hospital stay in oncological surgery.
Authors: Meissner Carl , Otto Ronny , Fahlke Joerg , Mueller Mathias , Ridwelski Karsten
Published: May 2020

e13591

Background: In Germany, a serious illness is the main cause of malnutrition. Various studies have already shown that the length of time in hospital for various diseases and operations in malnourished patients increases. This leads to a deterioration in the quality of life of the patient and results in considerable costs for the health care system. Methods: In order to investigate the relationship between nutritional status and length of hospital stay, a patient group of 363 patients who had a tumor with the primary tumor in the gastrointestinal tract was first identified. All patients had an NRS score of 3 or greater and a meaningful laboratory with regard to protein and albumin levels and / or results of a bioelectrical impedance analysis. The average length of stay for these patients was determined depending on the various parameters. Results: The present study shows that malnourished patients have to stay in the hospital for between 2 and 11.1 days longer. When evaluating the NRS score, the protein and albumin level as well as the BCM and the ECM / BCM index, a longer hospital stay of malnourished patients compared to those who were not malnourished was demonstrated. The BMI is an insufficient parameter to describe the nutritional status. An extension of the length of hospital stay cannot be demonstrated only on the basis of the BMI. Conclusions: Since an inadequate nutritional status obviously affects the length of hospital stay in oncological patients, they should be examined early for malnutrition. The length of stay can be shortened through nutritional therapy measures, which also leads to a significant reduction in costs.
Role of CD8+ T-cell infiltration in breast tumors of Black women compared to White women.
Authors: Abdou Yara , Attwood Kristopher , Yao Song , Cheng Ting-Yuan David , Bandera Elisa , Zirpoli Gary , Payne Ondracek Rochelle , Stein Leighton , Bshara Wiam , Khoury Thaer , Ambrosone Christine B. , Omilian Angela
Published: May 2020

e13608

Background: Literature regarding racial differences in tumor immune responses in breast cancer remains sparse. To address this research gap, we assessed CD8+ T-cells in breast tumor samples from the Women’s Circle of Health Study (WCHS) population of predominantly Black breast cancer patients. We characterized and compared the density of CD8+ T cells, their prognostic value and their association with pharmacologic beta-blockers. Prior studies suggest that reducing adrenergic signaling through beta blockers can stimulate CD8+ T-cells. Methods: Tumor-infiltrating CD8+ T-cells were assessed by IHC staining of tissue microarray cores from 688 breast cancer patients, including 550 Blacks and 138 Whites. CD8+ T cells were scored with digital image analysis. Comparisons of demographic and clinical variables (including CD8+ T cell density) were made using the Mann-Whitney U or Kruskal-Wallis and Fisher’s exact tests. Associations with overall survival (OS) and disease-specific (DSS) survival were evaluated using the log-rank test of Cox regression. Analyses were performed in the overall sample and by disease sub-type. Results: Higher CD8+ T cell density was seen in Black women compared to White, with mean values of 756.2/mm2 and 292.4/mm2 respectively (p < 0.001). Within the overall population and in black women, CD8+ T cell density was significantly higher in younger patients, patients with high grade, and ER negative tumors. No significant associations were observed between CD8+ T cell density and OS or DSS. However, when stratified by subtype, Black patients with triple negative breast cancer and high CD8+ T cell density showed a trend towards improved OS in comparison to patients with low CD8+ T cell density (p = 0.065). 170 patients with information on beta blocker usage were analyzed. No significant associations were noted between CD8+ T cell density and beta blocker use. Conclusions: We observe a significantly higher CD8+ T cell density in Blacks compared to Whites, but this does not confer a survival advantage. Additionally, beta-blockers did not seem to enhance CD8+ T cell infiltration in tumors from Black patients. Our data raise the possibility that distinct mechanisms of immune cell action may occur in different racial groups. Future studies are needed to determine the functional properties of CD8+ T cells in Black women and to characterize additional immune cell subtypes that may also play a role.
Trends in gender-based disparity in incidence, mortality and survival for major digestive disease cancers in the U.S. (2000-2016).
Authors: Sada Yvonne , Zafeiropoulou Efthalia , Richardson Peter , Kramer Jennifer , Christie Israel , Jiao Li , Liu Yanhong , Chiao Elizabeth , White Donna
Published: May 2020

e13621

Background: Males have excess risk of most digestive cancers; whether cancer mainly due to virus (stomach), lifestyle including obesity/alcohol (colon/esophagus), or both (liver). We evaluated for secular trends in gender-specific incidence, mortality and survival for these cancers in the U.S. Methods: We used official U.S. Cancer Statistics [USCS] data (2000-2016) to calculate annual age-adjusted incidence and mortality rates (IR/MR). It covers >98% population/all states (vs. SEER-10 statewide registries, covers <1/3rd African-Americans/Whites). We calculated mortality-to-incidence rate ratios (MIR), an established 5-year survival proxy. We used Joinpoint to assess trends in average annual percentage change (AAPC). Results: Table shows age-adjusted IRs and MRs for colon, esophagus and stomach cancer decreased for men and women (all AAPCs negative, all significant but stomach IR women), with both liver IR/MR significantly increasing in both genders. Gender differences in relative burden were seen (e.g., MRs in colon>esophagus>liver>stomach in men vs. colon>stomach>liver>esophagus in women), with greatest male excess in esophagus (e.g., 4.4-fold IR). MIRs suggested less favorable survival (higher=worse) for men for esophagus/colon. Conclusion: Substantial gender disparity persists in digestive cancers, with male excess gap decreasing for colon and increasing for liver. [Table: see text]
Breast cancer frequency and survival by molecular subtype in central Illinois.
Authors: Sahib Hamsa , Abedrabo Sabree , Niaz Zurain , Koester Cameron , Maini Ruby , Lara Garcia Odalys Estefania , Tandan Nitin , Parajuli Priyanka , Regmi Manjari Rani , Cheema Asad , Mirihagalle Noupama , Ibrahim Abdisamad M. , Bhandari Bishal , Johnson Alexander , Delfino Kristin , Robinson Kathy , Desai Meghna R. , Kulkarni Abhishek
Published: May 2020

e13631

Background: Breast cancer is the most common female malignancy. In 2019, it is estimated that there were 268,000 new cases of female breast cancer. The most common subtype was HR+/HER2 based on 2012-2016 cases, a much higher rate than triple negative breast cancer. Best survival rates are found among women with HR+/HER2- subtype followed by HR+/HER2+ and HR-/HER+ subtypes. Triple negative subtype comparatively had a poorer survival.Our objective was to determine breast cancer rate and survival by molecular subtype in the central Illinois population. Methods: A cohort of 478 patients diagnosed with breast cancer between January 2014 and December 2017 was identified by using ICD codes. Eligibility criteria included pathology confirmed breast cancer.Categorical variables were summarized as frequencies and percentages. Predictors of survival were assessed with Cox proportional hazards regression analyses.All significance was assumed at the p < 0.05 level. Results: Luminal A breast cancer was the most common type in our population. In the cohort of 478 patients, 208 patients (74%) were found to have Luminal A. whereas, 37 patients (13.21%) had Basal subtype, 20 patients (7.14%) had Luminal B and 13 patients (5.36%) had Her2 enriched subtype. However, there was no statistical difference in survival between the subtypes. Conclusions: Although the frequency of cancer subtypes in our population is comparable to the national epidemiology data,we observed that there is no statistical difference in survival as compared to NCI SEERS data. This could be due to optimum care and patient’s adherence to chemo-radiation or due to small sample size. This could be an important area of future research to investigate if we can increase survival of poor prognosis subtypes (as triple negative) by following the same measures. Long term follow up for the patients in the study might also be necessary.