bluuebunny/crossref_metadata_2025 huggingface dataset:
A systematic review of evidence for cannabis and cannabinoids as adjuvant therapy in palliative and supportive oncology care.
Authors: Jugl Sebastian , Keshwani Shailina , Adkins Lauren , Heldermon Coy D. , Winterstein Almut , Goodin Amie
Published: May 2020

12091

Background: Medical cannabis use is increasing significantly in the United States as states reduce restrictions. However, ambiguity concerning the evidence for medical cannabis efficacy and safety, especially in the field of oncology, is persistent. Clinicians therefore face challenges in examining benefits and risks of medical cannabis as adjuvant treatment for cancer patients. This study identifies and evaluates the most recent available evidence for the efficacy of cannabis and cannabinoids as adjuvant in supportive and/or palliative use in patients with cancer. Methods: Electronic databases searched included PubMed, Embase, Web of Science, and Cochrane Library to identify studies published following the latest available systematic review, between July 2016 through October 2019. Studies conducted outside the United States, studies not evaluating cannabis or cannabinoids in Oncology care, and preclinical studies were excluded. Findings were organized in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) framework. Lastly, qualitative synthesis was used to generate summary statements about the role of cannabis and cannabinoids as adjuvant in supportive and/or palliative cancer care. Results: We screened 2,267 articles and included 96 studies in our qualitative synthesis. Among those were 2 RCT’s (1 completed), 6 Systematic reviews with Meta-analysis, 4 Systematic reviews without Meta-analysis, 71 other types of reviews and 13 observational studies. The most frequently reported outcomes assessed were efficacy of cannabis and cannabinoids for: pain (40 of 96; 17 indicating improvement), nausea and vomiting (26 of 96; 20 indicating improvement), cachexia (22 of 96; 2 indicating improvement), and utilization patterns of cannabis and/or cannabinoids among cancer patients (8 of 96). Conclusions: Latest available prevalence estimates indicate that a significant proportion of patients in the United States with cancer use cannabis and/or cannabinoids (18.3-40.0%). There is substantial evidence for the effectiveness of cannabis and cannabinoids in treating cancer-related pain; specifically, oromucosal THC/CBD spray. There is conclusive evidence for the effectiveness of cannabis and cannabinoids in relieving chemotherapy-induced nausea and vomiting; specifically, oral THC. There is inconclusive evidence regarding the effectiveness of cannabis and cannabinoids in treating cancer-related cachexia.
Myelopreservation and reduced use of supportive care with trilaciclib in patients with small cell lung cancer.
Authors: Weiss Jared , Goldschmidt Jerome , Zoran Andric , Dragnev Konstantin H. , Pritchett Yili , Morris Shannon R. , Malik Rajesh K. , Daniel Davey B.
Published: May 2020

12096

Background: Chemotherapy (CT) is a mainstay of cancer treatment; however, its side effects, notably myelosuppression, cause significant suffering. Trilaciclib (T) is an IV CDK4/6 inhibitor that protects hematopoietic stem and progenitor cells by preventing proliferation during CT administration. Results from three randomized, double-blind, placebo (P)-controlled phase II trials in patients (pts) with extensive-stage small cell lung cancer (ES-SCLC) have previously been reported. Data from these studies were pooled to understand the effects of T on specific myelosuppression endpoints with greater statistical precision. Methods: All pts received standard CT (etoposide/carboplatin [E/C], E/C/atezolizumab, or topotecan) plus T or P. Analyses were conducted on pooled intent-to-treat datasets from three ES-SCLC studies (NCT02499770; NCT03041311; NCT02514447). Results: 123 pts were treated with T and 119 with P. Median age in both groups was 64 years. Addition of T decreased measures of myelosuppression and the need for supportive care interventions (Table). From the pooled dataset, median OS and PFS (months [95% CI]) were comparable between pts treated with T vs P (OS: 10.6 [9.1, 11.7] vs 10.6 [7.9, 12.8]; PFS: 5.3 [4.6, 6.1] vs 5.0 [4.4, 5.5], respectively). Fewer pts on T had grade 3/4 hematologic events (54 [44.3%]) vs P (91 [77.1%]). Among pts who continued after cycle 1, 11 pts (9.2%) treated with T had ≥1 CT dose reduction vs 36 (30.8%) with P. Conclusions: T significantly and meaningfully reduced both CT-induced myelosuppression and its consequences, with no detrimental effect on PFS or OS, thus improving the patient experience with CT in ES-SCLC. T has potential to become a new standard of care for preventing myelosuppression in SCLC. [Table: see text]
Development and validation of a risk prediction model for poor performance status and severe symptoms among cancer patients.
Authors: Seow Hsien , Tanuseputro Peter , Barbera Lisa Catherine , Earle Craig , Guthrie Dawn , Isenberg Sarina , Juergens Rosalyn A. , Brouwers Melissa C. , Myers Jeffrey , Sutradhar Rinku
Published: May 2020

12097

Background: Existing cancer predictive tools focus on survival, but few incorporate patient-reported outcomes to predict quality-of-life domains, such as symptoms and performance status. The objective was to develop and validate a predictive cancer model (called PROVIEW) for poor performance status and severe symptoms over time. Methods: We used a retrospective, population-based, cohort study of patients, with a cancer diagnosis, in Ontario, Canada between 2008-2015. We randomly selected 60% of patients for model derivation and 40% for validation. Using the derivation cohort, we developed multivariable logistic regression models with baseline characteristics, using a backward stepwise variable selection process. The primary outcome was odds of having poor performance status six months from index date, as measured by a score < = 30 out of 100 on the Palliative Performance Scale. The index date for each model was diagnosis (Year 0), which was then re-calculated at each of 4 annual survivor marks after diagnosis (up to Year 4). Secondary outcomes included having severe pain, dyspnea, well-being, or depression, as measured by a score of > = 7 out of 10 on the Edmonton Symptom Assessment System. Covariates included demographics, clinical information, current symptoms and performance status, and healthcare utilization. Model performance was assessed by AUC statistics and calibration plots. Results: Our population-based cohort identified 125,479 cancer patients for the performance status model in Year 0. The median diagnosis age was 64 years, 57% were female, and the most common cancers were breast (24%), lung (13%), and prostate (9%). 32% had Stage 3 or 4 disease. In Year 0 after backwards selection, the odds of having a poor performance status in 6 months was increased by more than 10% when the patient had: COPD, dementia, diabetes; radiation treatment; a hospital admission in the prior 3 months; high pain or depression; a current performance status < = 30; any issues with appetite; or received end-of-life homecare. Generally, these variables were also associated with a > 10% increased odds in other years and for the secondary outcomes. The average AUC across all 25 models is 0.7676 which indicates high model discrimination. Conclusions: The PROVIEW model accurately predicts risk of having a poor performance status or severe symptoms over time among cancer patients. It has the potential to be a useful online tool for patients to integrate earlier supportive and palliative care.
Evaluation of the incidence of acute nausea and vomiting after administration of an amino acid solution containing only arginine and lysine with lutetium Lu-177 dotatate.
Authors: Alonzo Nicholas , Seyer Magdalena , Kim Eun-Jeong , Keshavarzi Rawmina , Yee Kathryn , Kunz Pamela L.
Published: May 2020

12113

Background: Lutetium Lu-177 dotatate is used to treat patients with gastroenteropancreatic neuroendocrine tumors, and an amino acid (AA) solution must be administered concurrently to mitigate nephrotoxicity. AA solutions may lead to increased rates of nausea and vomiting (NV) due to the inclusion of unnecessary non-essential and essential AA. Methods: This study is a single academic center retrospective chart review from October 6th, 2015 to December 17th, 2019 evaluating the incidence of acute NV in adult patients after administration of an AA solution containing only arginine 25 grams and lysine 25 grams in 1 liter of normal saline (Arginine-Lysine amino acid [AL AA]) with lutetium Lu-177 dotatate. The incidence of acute NV will be compared to the historical incidence in patients administered Parenteral amino acids 10%, Aminosyn II 10% or Clinisol 15% (commercial AA). Secondary endpoints include the incidence of rescue anti-emetic usage and the percentage of patients that require interruption of the AA infusion. Acute NV are defined as any occurrence of NV within twenty-four hours of the AA infusion. Results: 53 patients received a total of 164 treatments with the AL AA, while 18 patients received a total of 48 treatments with the commercial AA. The AL AA significantly decreased the incidence of acute NV, the mean AA infusion time, the interruption of the AA infusion, and the utilization of rescue anti-emetics compared to the commercial AA (Table) in patients on lutetium Lu-177 dotatate. Conclusions: The study findings support the use of an AL AA to be administered concurrently with lutetium Lu-177 dotatate to minimize commercial AA related acute NV. [Table: see text]
Associations of functional, psychosocial, and medical factors with cognitive impairment in older, chemotherapy-naïve patients with early breast cancer.
Authors: Nakamura Zev , Deal Allison Mary , Nyrop Kirsten A. , Damone Emily , Muss Hyman B.
Published: May 2020

12114

Background: Cognitive decline related to cancer and its treatments is a common concern among patients receiving treatment for cancer. Routine cognitive screening in oncology practice has been limited by the absence of a reliable, cancer-specific cognitive test. The Blessed Orientation Memory Concentration Test (BOMC) [1], has been incorporated in cancer-specific geriatric assessments, but there is no established cutpoint for cancer-related cognitive impairment. Recent research suggests that BOMC scores ≥ 5 may represent cognitive impairment in older patients with cancer. The purpose of this study was to identify cognitive impairment and associated characteristics in chemotherapy-naïve patients with breast cancer. Methods: Women with stage I-III breast cancer were recruited between 2009 and 2018. The BOMC (range 0-28, higher is worse function) was administered prior to chemotherapy. Associations between cognitive dysfunction (BOMC ≥ 5) and functional, psychosocial, medical variable were assessed using log binomial regression analysis. Results: In a sample of 331 women with breast cancer, the mean age was 65.2 years and 68.6% were 65 and older. Twenty-seven percent demonstrated cognitive impairment prior to treatment. Patients with Time Up and Go Test (TUG) ≥ 14 had increased risk of cognitive impairment compared to those with TUG < 14 (44% vs. 23%, p = 0.0002). After controlling for demographic factors, the estimated increase in risk was 66% (RR: 1.66, 95% CI (1.20, 2.31), p = 0.002). For Medical Outcomes Survey (MOS) Physical Function, after controlling for demographic factors, each 1 point increase in physical function (range 0-20, higher is better function) was associated with a 5% decrease in risk of cognitive impairment (p = 0.0004). Conclusions: Using a newly proposed BOMC cutpoint of ≥ 5, our study identified cognitive impairment in over 25% of older, chemotherapy naïve women with breast cancer. This is similar to what has been reported using rigorous neuropsychological testing in comparable populations. Additionally, we found that this degree of cognitive dysfunction was associated with both patient-reported and clinician-assessed impairment in physical function, further supporting the clinical relevance of this new cutpoint. Reference: [1] Katzman et al. Am. J. Psychiatry. 140 (1983) 734–739.
An intervention RCT-study aimed at improving mental health and increasing understanding of fertility preservation with Oncofertility! Psycho-Education And Couple Enrichment (O!PEACE) therapy.
Authors: Suzuki Nao , Koizumi Tomoe , Sugishita Yodo , Matsumoto Hiroshi , Furui Tatsuro , Futamura Manabu , Takai Yasushi , Sugimoto Kohei , Nogi Hiroko , Yamauchi Hideko , Kataoka Akemi , Ohno Shinji , Tsugawa Koichiro , Kawai Kiyotaka , Fukuma Eisuke
Published: May 2020

12119

Background: Although ASCO revised Guidelines (2013) recommends referring to psychological professionals if cancer patients show concerns or anxiety about fertility, there is no evidence regarding the efficacy of psychotherapy. The aim of this study is to examine whether the Psycho-Education And Couple Enrichment (O!PEACE) therapy can reduce psychiatric symptoms and improve stress coping and marital relationship in breast cancer patients. Methods: Trial design: multicenter randomized controlled trial, pre-post design. Subjects were women aged 20–39 years with breast cancer before cancer treatment and their husbands. Couples were randomly assigned to receive O!PEACE therapy (n = 37) or not (usual care: n = 37). Assessments of PTSD symptoms, depression and anxiety were made as the primary end points at baseline and at the end of therapy before cancer treatment. Stress coping strategies, resilience, marital relationships, and marital communication were examined as secondary end points. Results: Four participants in O!PEACE therapy and one participant in the usual care withdrew from the trial. Intention-to-treat analyses were conducted using analysis of covariance after multiple imputation by R and SPSS. Series of ANCOVAs were integrated according to Rubin’s rule. A significant decrease was observed in the primary outcome of PTSD symptoms, from baseline to post-intervention, in women who participated in O!PEACE therapy (p = .011, ηp2 = .089). According to post-hoc analyses, for patients with a higher baseline IES-R-J score, O!PEACE therapy resulted in a significantly higher reduction in follow-up assessment IES-R-J score when compared with usual care (U = 172.80, p = .027, r = .258): 59.3% of the women in O!PEACE therapy showed a 5-point or greater reduction, whereas in usual care, 30.0% showed a 5-point or greater reduction. For husbands, the O!PEACE therapy also showed a significant improvement of giving up and blaming others as the stress coping strategy and escape-avoidance coping strategy in their marital communication. For breast cancer patients, the O!PEACE therapy significantly improved support from husbands and the patients’ knowledge level of oncofertility compared with those receiving usual care. Conclusions: Only two counseling sessions of O!PEACE therapy can reduce patients’ distress, improve their husbands’ coping style, and may build a better cooperative relationship for couples in terms of fertility preservation and cancer treatment. Clinical trial information: UMIN000017754 .
Characterization of patients with multiple primary tumors.
Authors: Cadoo Karen Anne , Mukherjee Semanti , Khurram Aliya , Kemel Yelena , Tkachuk Kaitlyn , Liu Ying L , Carlo Maria Isabel , Walsh Michael Francis , Latham Alicia , Dubard-Gault Marianne E , Mandelker Diana , Wang Yuhan , Salo-Mullen Erin E. , Berger Michael F. , Ravichandran Vignesh , Stadler Zsofia Kinga , Joseph Vijai , Robson Mark E. , Seshan Venkatraman E. , Offit Kenneth
Published: May 2020

1502

Background: 17% of patients (pts) with a cancer diagnosis in the U.S. have a prior malignancy. We sought to characterize pts with multiple (≥2) primary cancers (MPC) & identify potential drivers of cancer risk to guide management. Methods: Pts prospectively consented (1/2013-2/2019) to tumor-normal sequencing via custom targeted NGS panel. A subset consented to testing of >76 germline cancer predisposition genes. IARC 2004 rules for defining MPC were applied.Age adjusted gender specific standardized incidence ratios (SIR) for cancer event combinations occurring in at least 5pt were calculated using R statistical package. Results: Of 24417 pts sequenced, 4341 had MPC (18%). (Table) 3465 (80%) had 2, 4% had >4 cancers. Cancer pairs where SIR of 2nd cancer was higher than expected included: colon-colon, prostate-pancreas, bladder-prostate in men & lung-lung, breast-pancreas, thyroid-pancreas in women. 1580 (36%) pts had germline testing; 324 (21%) had 361 pathogenic/likely pathogenic (P/LP) variants (vts). Of these, 157 (48%), 66(20%), pts had high, moderate penetrance vts. The remainder had low penetrance, recessive or vts of uncertain utility. Of pts with high penetrance vt, 132 (84%) had at least one tumor type concordant with germline findings. Conclusions: 18% of pts in this cohort had MPC. There was a significant excess over expected incidence in some cancer combinations. Of pts with germline testing, 21% had a P/LP vt, with most (69%) being high or moderate penetrance. Assessment for loss of heterozygosity in tumor & germline sequencing of the full MPC cohort is ongoing. [Table: see text]
BARCODE 1: A pilot study investigating the use of genetic profiling to identify men in the general population with the highest risk of prostate cancer to invite for targeted screening.
Authors: Eeles Ros A. , ni Raghallaigh Holly ,   The BARCODE1 Study Group
Published: May 2020

1505

Background: Genetic profiling could be used to target population screening for prostate cancer (PrCa). Approximately 170 single nucleotide polymorphisms (SNPs) have been identified that associate with PrCa development. Although these confer a low to moderate risk of PrCa, the risk is cumulative with increasing number of risk alleles. BARCODE1 is the first study to prospectively investigate the use of a genetic profile in PrCa screening in the UK general population. Methods: A custom Eurek Genomics (EG) SNP assay was developed. Healthy males aged 55-69 were invited to participate via their General Practitioners (GPs). Saliva samples were collected via mailed collection kits. After DNA extraction, genotyping was conducted using the EG assay and a polygenic risk score (PRS) was calculated for each participant. The PRS was calculated using the sum of the weighted alleles for 130 risk loci. Men in the top 10% of the genetic risk profile were invited for prostate MRI and biopsy at the Royal Marsden Hospital (RMH) in London. Results: Invitation letters were sent to 1434 men; overall uptake was 26% (range 13%-47%). 87% of responders were eligible for study entry. DNA was extracted from 303 samples and genotyped. Data were available for 285 men following QC. Mean PRS was 10.33 with a standard deviation of 0.64; twenty-five participants with a PRS above the 90th centile were identified for screening with MRI and prostate biopsy. Of these men (after exclusions due to medical comorbidity/invitations declined) 9 out of 20 had an abnormal MRI (45%) and 18 men underwent biopsy with 7 diagnoses of PrCa (38.8%). All cancers were low-risk with a mean PSA of 1.8 and were managed with Active Surveillance (AS). There were two adverse events following biopsy, both simple lower urinary tract infections managed with oral antibiotics. Average duration of follow-up is 4.5 months (range 1-11). Conclusions: Successful completion of recruitment has shown this community study to be feasible, with an average uptake of 26%. Approximately 70 GP sites have been identified to allow a transition to the full BARCODE-1 study which will recruit 5000 men. The use of genetic profiles to guide PrCa screening is attractive; it requires a one-off test utilising germline DNA which can be assessed for risk loci which are constant, unlike PSA which fluctuates. The results of the BARCODE1 study will be important in defining the role of genetic profiling in targeted PrCa population screening.
Complete human papillomavirus vaccination coverage over a 13-year period in a large population of privately insured U.S. patients.
Authors: Arriaga Yull Edwin , Rosario Bedda L , Scheufele Elisabeth , Rajmane Amol , South Brett , Kefayati Sarah , George Judy , Bullock Timothy , Jackson Gretchen Purcell , Rhee Kyu
Published: May 2020

1511

Background: In the US, Human Papillomavirus (HPV) vaccination coverage is low, particularly in adolescents aged 13-15 years with respect to the Healthy People 2020 goal of 80%. There has been variability in the definition of measuring vaccination coverage in published studies. We examined complete HPV vaccination coverage in a population of privately insured individuals in the US. Methods: This retrospective study used IBM MarketScan Commercial Database, years 2006 to 2018. Inclusion criteria were ages 9 to 45 years and continuous enrollment from age 9 years or from 2006. Complete HPV vaccination coverage was defined as receipt of 2 doses (age 9-15 years) or 3 doses (age 16-45 years) within 12 months and stratified by year, demographics, and US region. Mean vaccination costs per dose were summarized by vaccine brand and health plan type. Results: The table summarizes complete HPV vaccination coverage by selected age groups for 2006 (n=12,221,938), 2010 (n=4,692,633), 2014 (n=2,808,132), and 2018 (n=1,662,148). From 2017 to 2018, the percentage of members who received HPV vaccine increased; for females ages 13-15 by 1% and 16-17 by 5% while for males ages 13-15 by 6% and 16-17 by 15%. In 2018, by region, the highest coverage was in females aged 18-26 at 53% and males aged 16-17 at 43% in the Northeast, and mean cost for each brand was $120 (-6% from 2017), $165 (-3%) and $220 (+5%) for Cervarix (n=151), Gardasil (n=8,201) and Gardasil 9 (n=139,356), respectively. The rate of utilization of Gardasil 9 increased from 33% (2015) to 94% (2018) of all vaccines. The lowest mean HPV vaccine cost by health plan type and brand was with Point-of-Service (POS) and Cervarix at $106, and the highest was with POS with Capitation and Gardasil 9 at $243. Conclusions: In a commercially insured US population, complete HPV vaccination coverage was lower than the Healthy People 2020 goal, but increased over time. Coverage varied according to health plan type and by region. In 2018, Gardasil 9 had the highest mean cost but was the most utilized vaccine, which may be related to broader coverage of HPV types. This study was limited by the transient nature of member enrollment and complexity of measuring complete vaccination coverage. These results should inform policy makers and practicing clinicians about the gap in vaccination coverage. [Table: see text]
The prevalence of germline mutations among patients with solid tumors with genomic alterations identified on tumor testing: Results from a tertiary care academic center molecular tumor board.
Authors: Watson Catherine , Tait Sarah , Soo Lindsay , Plichta Jennifer Kay , Zhang Tian , Castellar Edgardo , Armstrong Andrew J. , Previs Rebecca A. , Strickler John H. , Green Michelle , Datto Michael , Marcom Paul Kelly , Menendez Carolyn S.
Published: May 2020

1516

Background: The proportion of germline versus somatic mutations identified on genomic tumor testing of solid malignancies is not well characterized. We compared somatic and germline testing results in patients with breast, ovarian, pancreatic or prostate cancer with a genomic alteration identified on tumor testing. Methods: Retrospective chart review was performed using a tertiary care academic center’s database of somatic tumor testing results obtained via FoundationOne and Guardant testing. Patients with breast, ovarian, pancreatic or prostate cancer who had a genomic alteration identified on tumor testing, including pathogenic and VUS variants, in BRCA1or BRCA2, CHEK2, ATM, BRIP1, RAD51C, RAD51D, PALB2and CDH1and who had also received germline testing were identified. Analysis was performed to assess prevalence of germline results. The association between mutant allele fraction (MAF) and germline mutation status was also assessed. Results: Results: 124 patients with breast, ovarian, pancreatic or prostate cancer were identified who had a genomic alteration of interest also tested for via germline testing. 54 (32.5%) of tumor mutations were also identified on germline testing. Proportion of genomic results that were germline was wide, ranging from 0-85.7% depending on the gene and variant classification (Table). Germline mutations were present in 36.4% of breast, 25% of ovarian, 53.3% of pancreatic, and 20.9% of prostate cancer patients who had a tumor alteration present. Alterations that were found to be concordant in both somatic and germline testing had an average MAF of 0.54, and alterations identified on somatic testing only had an average MAF of 0.30. Conclusions: Our findings suggest that approximately one-third of genomic alterations on tumor testing will be of germline origin. However, concordance rates may be gene and variant dependent. Higher MAF may be associated with germline alteration status, but further evaluation is needed. Thus, while information provided by genomic tumor testing may be suggestive of a correlating germline mutation, no single alteration type or MAF value is reliably predictive. [Table: see text]
Prevalence and clinical characterization of MMR-D/MSI extra-colonic cancers among germline PMS2 mutation carriers.
Authors: Latham Alicia , Salo-Mullen Erin E. , Catchings Amanda , Ranganathan Megha , Fiala Elise , Kemel Yelena , Konner Jason A. , Soslow Robert A. , Momeni-Boroujeni Amir , Shia Jinru , Mandelker Diana , Birsoy Ozge , Hechtman Jaclyn Frances , Berger Michael F. , Carlo Maria Isabel , Walsh Michael Francis , Robson Mark E. , Offit Kenneth , Stadler Zsofia Kinga , Cadoo Karen Anne
Published: May 2020

1527

Background: PMS2-associated Lynch syndrome (LS) may have a more modest phenotype than that associated with other mismatch repair (MMR) genes ( MLH1, MSH2, MSH6, EPCAM). Recent studies suggest limited extra-colonic cancers, and modified risk-reducing measures can be provided. Understanding the spectrum of risk is of critical importance as some LS-associated cancers do not have effective screening, requiring risk-reducing surgery (endometrial, ovarian). As MMR-deficiency (MMRD)/ microsatellite instability (MSI) is associated with LS pan-cancer, we sought to characterize PMS2-associated malignancies according to MMR/MSI status. Methods: Review of cancer patients (pts) consented to an IRB-approved protocol of tumor/germline next-generation sequencing (NGS) identified 43 germline heterozygous PMS2 mutation carriers. Tumors were evaluated for MSI via MSIsensor and/or corresponding MMR protein expression via immunohistochemical staining (IHC). Clinical variables were correlated with MMR/MSI status, comparing via Chi-square or standard T-test. Results: There were > 10 tumor types; 69.8% (30/43) were extra-colonic cancers (endometrial (n = 4), ovarian (n = 6), small bowel (n = 3), urothelial (n = 2), pancreas (n = 3), prostate (n = 3), breast (n = 3), brain (n = 3), biliary (n = 1), spindle cell sarcoma (n = 1), and hepatoblastoma (n = 1)). 46.5% (20/43) of tumors were MMRD/MSI. 61.5% (8/13) of colorectal cancers (CRC) were MMRD/MSI, compared to 40% (12/30) of extra-colonic tumors. All endometrial and small bowel cancers were MMRD/MSI. Of 6 ovarian cancers, 3 were clear-cell, 1 endometrioid, and 2 high-grade serous (HGS). The only MMRD/MSI ovary tumor was HGS. 73.9% (17/23) of pts with MMRP/MSS tumors had recurrent/metastatic disease vs 30% (6/20) of pts with MMRD/MSI tumors ( p= 0.004). Mean age at diagnosis did not differ significantly between MMRP/MSS and MMRD/MSI groups (49 vs. 57, respectively, p= 0.146). 11.6% (5/43) of pts had a prior cancer, with only one patient having prior CRC. Pts with extra-colonic tumors were less likely to meet clinical pt and family history LS testing criteria than those with CRC (63.3% (19/30) vs. 7.7% (1/13); p< 0.001). Conclusions: While PMS2-related LS may have a more modest clinical phenotype, in this single-institution study, 60% (12/20) of patients with MMRD/MSI tumors presented with extra-colonic cancers. We caution counseling pts with PMS2-associated LS about reduced extra-colonic risk until more complete information about penetrance, spectrum, and age distribution of cancer is available.
ATM mutation carriers and family history of pancreatic cancer.
Authors: Klavanian Jeannie , Zakalik Dana , Konde Anish S , Rangarajan Tara
Published: May 2020

1529

Background: Multigene panel testing (MGT) is commonly utilized in patients with a personal or family history of cancer. One of the more common gene mutations identified is in the ATM gene, associated with a moderately increased risk of breast and other cancers. There are reports of an association with pancreatic cancer, however the exact risks are unclear. The aim of this study is to describe the family history of pancreatic cancer in a cohort of ATM mutation carriers, and to evaluate possible genotype/phenotype correlation. Methods: Patients who underwent MGT, between ‘13 and ‘19, and tested positive for a pathogenic/likely pathogenic ATM mutation were included in this study. Family history, with a focus on pancreatic cancer, and genetic testing results were analyzed. Results: A total of 114 patients were identified to carry an ATM mutation. Twenty-two (19.3%) individuals had a family history of pancreatic cancer in a close relative, and of those, 13 (11.4%) had an affected first degree relative, and 11 (9.6%) had an affected second degree relative. Among the families with pancreatic cancer, 20 close relatives had a personal history of pancreatic cancer, with the youngest diagnosed at age 40, the oldest diagnosed at age 91, and a mean age of diagnosis of 66.5 years. Thirteen unique variants were identified: 4 splice site, 3 missense, 3 frameshift, 1 nonsense, and 1 silent. Two families had the known high-penetrance ATM mutation, c.7271T > C (p.V2424G). Conclusions: This study describes the association of pancreatic cancer in individuals found to carry pathogenic ATM mutations. A significant proportion (19.3%) of patients had a family history of pancreatic cancer in a close relative, diagnosed as young as age 40. The mean age of diagnosis was slightly younger than the average age in the general population (age 70). As pancreatic cancer screening continues to improve, this information will be an important component to help guide cancer risk assessment and future screening recommendations for ATM mutation carriers. Additional larger studies are needed to further characterize pancreatic cancer risks in patients with ATM gene mutations.
Cancer risk management and family communication of genetic test results among women with inherited breast cancer genes.
Authors: Pal Tuya , Weidner Anne , Tezak Ann , Clouse Kate , Cragun Deborah
Published: May 2020

1532

Background: Identification of inherited breast cancer may guide care, with benefits amplified through family testing. Methods: Females with a pathogenic/likely pathogenic (P/LP) variant in BRCA1/2, PALB2, CHEK2, and/or ATM were surveyed about cancer risk management, family communication of genetic test results, and family testing. Comparisons were made across genes. Results: The 235 participants with P/LP variants (186 BRCA1/2, 28 PALB2, 15 CHEK2, and 6 ATM) had a median age of 54 and 61% had a prior breast cancer diagnosis. For women with P/LP variants in BRCA1/2, PALB2, and ATM/CHEK2, bilateral mastectomy rates were 79%, 61%, and 52%, respectively; and risk-reducing oophorectomy rates were 89%, 30%, and 37%, respectively. All women with PALB2 and ATM/CHEK2 P/LP variants with a bilateral mastectomy had a personal or family history of breast cancer; however, only 27% of those with a risk-reducing oophorectomy had a family history of ovarian cancer. Family communication of genetic test results and family testing rates were higher for those with P/LP variants in BRCA1/2 compared to others. Conclusions: Bilateral mastectomy and risk-reducing oophorectomy were relatively common among women with PALB2 and ATM/CHEK2 P/LP variants in our study, suggesting overtreatment through risk-reducing surgery. Furthermore, strategies to improve family communication of genetic test results and family testing are needed to amplify testing benefits.
Genome Wide Association Study (GWAS) of cognitive impairment after blood or marrow transplantation (BMT) for hematologic malignancy.
Authors: Sharafeldin Noha , Singh Purnima , Bosworth Alysia , Ojesina Akinyemi I , Zhang Jianqing , Chen Yanjun , Patel Sunita K. , Wang Xuexia , Francisco Liton , Forman Stephen J. , Wong F. Lennie , Bhatia Smita ,   NeuroCog-COH
Published: May 2020

1536

Background: Cognitive impairment is prevalent in hematologic malignancy patients treated with BMT (autologous: 18.7%; allogeneic: 35.7%; Sharafeldin JCO; 2018). Given the inter-individual variability in risk of cognitive impairment in this population, we investigated the role of genetic susceptibility using a genome-wide single nucleotide polymorphism (SNP) array platform to identify novel genetic associations. Methods: Discovery: Cognitive function was assessed objectively in 239 adult BMT recipients at pre-specified timepoints: pre-BMT and at 6 mo, 1y, 2y, and 3y post-BMT. A global deficit score (GDS - a summary score of 14 standardized neuropsychological tests) was computed for each patient; a higher score indicated greater cognitive impairment. SNPs passing standard quality control filters ( > 1.4M) were used for analysis. Linear mixed effects models used GDS as the outcome, adjusted for age, sex, BMT type, baseline cognitive reserve, and the first four principal components. We used additive, codominant, and genotype models and an adjusted genome-wide significance threshold of 1.25 x 10−8. Replication: An independent cohort of 544 BMT survivors (192 cases with self-endorsed cognitive problems and 352 controls without) was used for replication. Results: Discovery: Median age at BMT was 51.3y; primary diagnoses: 47% leukemia, 32% lymphoma, 21% multiple myeloma; 57% males; 69% non-Hispanic whites: 50% allogeneic BMT, median GDS score = 0.22 (range 0-2). Forty-four SNPs were significantly associated with increased GDS (additive model: 3 SNPs; codominant model: 20 SNPs; genotype model: 21 SNPs). Estimates ranged from increase in GDS score by 0.28 points for each additional copy of risk allele, p = 1.07 x 10−8 to increase in GDS score by 1.82 points for two copies of risk allele, p = 2.3 x 10−11. Replication: Median age at BMT was 44y; primary diagnoses: 32% leukemia, 49% lymphoma, 19% multiple myeloma; 54% males; 80% non-Hispanic whites: 34% allogeneic BMT. Three SNPs were successfully replicated: rs116334183 resides within lncRNA-SEMA6D-2, which facilitates neuronal migration; rs13286152 86kb downstream of TLE-1, which promotes neuronal survival; and rs12486041 0.36Mb downstream from lncRNA-SPTSSB-1, which regulates sphingolipid production in neuronal axons and 0.36Mb upstream from TOMM22P6 linked to neural repair. Conclusions: In this first GWAS of cognitive impairment post-BMT, we identify 3 SNPs with plausible links to genes implicated in neuronal integrity. Functional studies are currently underway.
Germline alterations other than BRCA in triple negative breast cancer (TNBC) patients who underwent neoadjuvant therapy (NAT) on a prospective clinical trial.
Authors: Arun Banu , Zhao Li , Bassett Roland L. , Thompson Alastair Mark , White Jason B , Layman Rachel M. , Gutierrez Barrera Angelica , Valero Vicente , Ueno Naoto T. , Litton Jennifer Keating , Zhang Jianhua , Ravenberg Elizabeth , Candelaria Rosalind P , Rauch Gaiane M , Tripathy Debu , Moulder Stacy L.
Published: May 2020

1546

Background: Previous studies have related germline BRCA mutations to pathologic complete response (pCR) in TNBC cohorts. However, prospective data is lacking on the frequency of non- BRCA germline mutations and pCR in TNBC patients who received neoadjuvant therapy (NAT). The aim of this study was to describe germline alterations in comparison with pCR in a prospective cohort of TNBC receiving NAT. Methods: Pre-NAT blood was drawn from patients enrolled in a clinical trial of genomically tailored NAT (ARTEMIS: NCT: 02276443, per eligibility patients had to have negative clinical BRCA tetsing). Germline DNA was extracted and sequenced on a HiSeq4000 sequencer (Illumina, coverage 60X). Reads were aligned to human reference hg19. Variants were filtered against public databases of normal cohorts: esp6500, 1000 genome, ExAC with a frequency cutoff at 1% in any ethnicity. Two integrative scores were used to evaluate the deleteriousness of the missense variants and the variants predicted to be damaging by both scores were included in the analyses. A 105 pan-cancer susceptibility gene panel was selected based on literature data and commercially available gene panels. NAT included anthracycline and taxane based chemotherapy +/- targeted therapy based on tumor genomic expression. Univariate logistic regression models were used to fit pCR for individual mutations, excluding genes mutated in fewer than three patients. All statistical analyses were performed using R version 3.6.1. with a significance of p=0.05. Results: Germline results and pCR were available for 152 patients. Median age was 55 yrs (range: 24-77). 7.9% were stage (st) I, 65.8% st II, 26.3% st III. 55 pts (36%) had pan-cancer associated germline mutations, whereas 33 (21%) had a breast-cancer associated mutation. Greater than 1% mutations were seen in seventeen genes (Table). There was no significant difference in pCR rate after NAT among pts with different germline mutations versus without mutation. Conclusions: Breast cancer related germline mutations other than BRCA in TNBC are relatively common supporting at least a breast panel (not only BRCA1/2) testing. Treatment implications of different germline mutations and their impact on pCR is ongoing on an extended series. [Table: see text]
Mediation of black/white disparities in triple negative breast cancer by socioeconomic position, reproductive factors and diabetes in the Nurses’ Health Study Cohorts I & II.
Authors: Marcus Lydia , Dookeran Keith A.
Published: May 2020

1565

Background: The higher rates of triple negative (TN) breast cancer (BC) observed among black compared to white women may be attributable to social and reproductive factors, as well as biological conditions like diabetes mellitus type 2. We examine the extent to which the black/white race disparity in TNBC is transmitted through these factors. Methods: Data are from the Nurses’ Health Study I and II prospective cohorts and include non-Hispanic (nH) black (n = 97) and nH white (n = 8,876) women aged 25-55 years at enrollment with invasive BC diagnoses. Participant characteristics are self-reported or drawn from medical records. We estimated average controlled direct associations (ACDA) using logistic regression with model-based standardization to evaluate the age/body mass index (BMI)-adjusted prevalence difference for TN versus luminal A/B type BC by race, and performed a series of ACDA (with comparison of rescaled coefficients (RC)) controlling for diabetes, mean family income before diagnosis (cont.), husband’s education ( < college, college, graduate school), parental ownership of participant’s childhood home (yes/no), age at menarche (cont.), age at first birth (cont.), parity (integer), and breastfeeding (BF) (parous/never BF, parous/ever BF). Results: Compared to nH whites, nh black women had higher prevalence of TNBC (24.5% v. 45.4%; p < 0.01), higher prevalence of diabetes (5.5% v. 11.3%; p = 0.01), lower prevalence of BF (59.2% v. 46.6%; p = 0.02), higher mean BMI (26.1 v. 29.9; p < 0.01), and lower mean family income ($17,304 v. 15,750; p < 0.01). BMI, age, and menopause were positively associated with prevalence of diabetes. In the age/BMI adjusted model, nH black women were 20%-points more likely than nH whites to have TNBC (95% Confidence Interval (CI): 0.11, 0.29). This disparity was reduced to 18.1% after also adjusting for BF (95% CI: 0.09, 0.28), to 13.7% after additionally adjusting for socioeconomic indicators (95% CI: 0.02, 0.25), and to 13.3% after adjusting for all potential mediators (95% CI: 0.01, 0.26). Based on the method of RC, socioeconomic indicators accounted for the largest fraction of mediated effects and BF accounted for most of main effect attenuation associated with reproductive factors; diabetes accounted for negligible effect. Conclusions: Our findings support the hypothesis that observed racial differences in TNBC diagnoses may be at least partially mediated by differences in socioeconomic position and reproductive patterns, namely breastfeeding.
Malignancies associated with DPP4 inhibitors and GLP1 receptor agonists: Data from a large real-world database.
Authors: Wang Jiasheng , Kim Chang H.
Published: May 2020

1567

Background: DPP44 inhibitors (DPP4i) and GLP1 receptor agonists (GLP1Ra) control type 2 diabetes (T2DM) by promoting GLP-1 pathway; its activation can lead to dysplasia or tumor inhibition based on tissue types. Moreover, DPP4 can act as a tumor suppressor or activator. Few studies have looked at the risk of DPP4i and GLP1Ra on various types of cancer. Methods: We inquired an aggregated electronic health record database, Explorys (IBM, NY). Patients (Pts) diagnosed with T2DM from 1/05 to 6/19 were included and followed for 5 years after starting DPP4i, GLP1Ra, or metformin. Odds ratio (OR) were calculated after 6mo of lag time. Results: We identified 344,550, 112,000, and 1,245,930 pts in the DPP4i, GLP1Ra, and metformin group, respectively. The three groups were well balanced except pts in the GLP1Ra group had higher BMI. Within 5 years, 24,260 pts (9.5%) in DPP4i, 5,580 (8.7%) in GLP1Ra, and 57,490 (9.3%) in metformin group developed any types of cancer. When adjusted for sex, age, smoking status, alcohol abuse history, hemoglobin A1C (≤9.0% vs > 9.0%) and BMI ( < 30 vs ≥30 kg/m2) around initiation of antidiabetic agents, the aOR was 1.01 (95%CI .94-1.08) for DPP4i and 1.06 (95%CI .93-1.20) for GLP1Ra, comparing with the metformin group. For specific cancer types, DPP4i users were associated with significantly higher risk of bladder, kidney, liver cancer and melanoma; while the risk of breast, lung and prostate cancer were reduced. GLP1Ra users were associated with higher risk of thyroid cancer; while the risk of bladder, colon, lung, and prostate cancer were reduced. Conclusions: DPP4i and GLP1Ra were not associated with increased cancer risk overall. However, they were associated with increased or decreased risk of specific cancer types. [Table: see text]
Metabolic syndrome, metabolic comorbid conditions, and risk of early-onset colorectal cancer.
Authors: Chen Hanyu , Li Zitong , Zheng Xiaobin , Hur Jinhee , Zong Xiaoyu , Chapman William , Nickel Katelin B. , Tipping Andrew , Colditz Graham A. , Olsen Margaret A. , Giovannucci Edward L. , Fields Ryan , Cao Yin
Published: May 2020

1571

Background: The etiology and contributors to the rising incidence of early-onset colorectal cancer (CRC diagnosed under age 50), driven largely by distal and rectal cancer, remain largely unknown. Metabolic syndrome is associated with higher risk of CRC diagnosed at older ages; however, its association with early-onset CRC remains unclear. Methods: We conducted a nested case-control study among participants aged 18-50 years with ≥2 years of enrollment and prescription drug coverage in the IBM MarketScan Commercial Databases (2006-2015). Incident CRC cases were identified using ICD-9-CM diagnosis codes. Controls without any cancer were identified using frequency matching on age, sex, geographical region, and duration of insurance enrollment. Metabolic syndrome was defined using either ICD-9-CM diagnosis codes or the presence of at least 3 of the following: obesity, hypertension, hyperlipidemia, and hyperglycemia/type 2 diabetes. In addition to ICD-9-CM codes, hypertension, hyperlipidemia, and hyperglycemia/type 2 diabetes were also defined based on regular use of medications. Multivariable logistic regressions were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Results: A total of 4,673 early-onset CRC and 40,832 controls were included. Metabolic syndrome was associated with increased risk of early-onset CRC (OR: 1.33, 95% CI 1.16-1.52), after adjusting for a range of potential confounders. The number of metabolic comorbid conditions was positively associated with risk of early-onset CRC in a dose-response fashion. Compared to individuals without any conditions, individuals with 1, 2, ≥3 metabolic conditions had a 13% (OR: 1.13, CI 1.04-1.22), 18% (OR: 1.18, CI 1.07-1.31), and 40% (OR: 1.40, CI 1.22-1.61) higher risk of early-onset CRC (Ptrend<0.001), respectively. These associations were driven by proximal (OR for ≥2 vs 0 metabolic comorbid conditions: 1.40, CI 1.15-1.69) and distal colon cancer, OR ≥2 vs 0: 1.25, CI 1.03-1.53), but not rectal cancer (OR≥2 vs 0: 1.07, CI 0.92-1.24). Conclusions: Metabolic syndrome and metabolic comorbid conditions were associated with increased risk of early-onset CRC, largely driven by proximal and distal colon cancer. Metabolic dysregulations may contribute to the rising incidence of early-onset CRC.
Geographic disparity of outcome in patients with cancer over decades: The surveillance, epidemiology, and end results.
Authors: Sakurai Kenichi , Kantarjian Hagop M. , Sasaki Koji , Jabbour Elias , Ravandi Farhad , Konopleva Marina , Borthakur Gautam , Wierda William G. , Daver Naval Guastad , Takahashi Koichi , Naqvi Kiran , Dinardo Courtney Denton , Bravo Guillermo Montalban , Issa Ghayas C. , Jain Preetesh , Pierce Sherry A. , Soltysiak Kelly A , Garcia-Manero Guillermo , Tingen Martha S , Cortes Jorge E.
Published: May 2020

1574

Background: Improvements in prevention, early detection and therapy of cancer have decreased cancer related mortality yet health disparities continue to exist. We investigated the impact of such disparities in cancer survival. Methods: In the Surveillance, Epidemiology, and End Results, we identified 784,341 patients with cancer from 1990 to 2016 in Georgia; 68,493 in 1990-1999, 371,353 in 2000-2009, and 322,932 in 2010-2016. We assessed overall survival (OS) of patients with all cancers, chronic myeloid leukemia (CML), and lung cancer given the dramatic improvement in patient outcomes in CML since 2000 compared to the consistently poor outcome in lung cancer. We assessed distance from each county to the one National Cancer Institute-designated cancer center (NCI-CC) in Georgia. Results: The 5-year OS of patients with any cancer was 55% with median OS 80 months; the 5-y OS of each county ranged from 33% to 82% (interquartile range[IQR], 51%-65%)(P < 0.001). The improvement of OS was minimal over decades: 5-year OS was 52%, 55%, and 55% in 1990-1999, 2000-2009, and 2010-2016, respectively; the median was 69 months, 80 months, not reached, respectively (P < 0.001). In patients with lung cancer and CML, the 5-year OS was 15% and 52% with the median of 9 months and 67 months, respectively. The geographic difference between counties was relatively small and constant over time in patients with lung cancer, represented by the width in the range and IQR: range 5%-17%, IQR 9%-13%, median 13% in 1990-1999; range 2%-24%, IQR 10%-14%, median 14% in 2000-2009; and range 4%-24%, IQR 12%-17%, median 17% in 2010-2016. However, the geographic difference was more prominent in patients with CML and widened after introduction of modern therapy: range 20%-42%, IQR 26%-34%, median 32% in 1990-1999; range 14%-83%, IQR 38%-64%, median 53% in 2000-2009; and range 14%-80%, IQR 40%-57%, median 57% in 2010-2016. Multivariate Cox regression showed age (hazard ratio[HR],1.040;95% confidence interval[CI],1.039-1.040;P < 0.001), median county income (HR,0.919;95% CI,0.916-0.921;P < 0.001), African American (HR,1.021;95% CI,1.210-1.227;P < 0.001), and distance to NCI-CC (each 100 kilometers) (HR,1.021;95% CI,1.017-1.025;P < 0.001) as predictive factors. Conclusions: The disparity of cancer care exists between geographic locations. The geographic difference of survival seems more prominent when highly effective therapies are available.