bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vitamin D supplements and marine omega-3 fatty acids and development of advanced cancer.
Authors: Chandler Paulette , Chen Wendy Y. , Ajala Oluremi , Hazra Aditi , Cook Nancy , Bubes Vadim , Lee I-Min , Giovannucci Edward L. , Buring Julie , Manson JoAnn E ,   VITAL Research Group
Published: May 2020

1510 Background: Epidemiologic data suggest that vitamin D supplementation may reduce cancer mortality. We tested whether vitamin D and/or omega-3 supplementation reduces the incidence of advanced stage cancer at diagnosis or lethal cancer, and whether body mass index (BMI) modifies these associations. Methods: The VITamin D and OmegA-3 TriaL (VITAL) is a randomized, placebo-controlled, 2x2 factorial trial of vitamin D3 (cholecalciferol, 2000 IU/day) and marine omega-3 fatty acids (1 g/day) that enrolled men aged ≥50 years and women aged ≥55 years free of cancer and cardiovascular disease at baseline. For this particular analysis, the primary outcome is a composite of metastatic and fatal invasive total cancer. Secondary analyses included examination of BMI (<25, 25-<30, and >= 30 kg/m2) as effect modifiers of the observed associations. Results: VITAL randomized 25,871 participants, among whom 1,617 were diagnosed with invasive cancer over a median 5.3 year intervention period. No significant differences by treatment arm (vitamin D vs placebo: hazard ratio [HR]=0.96; 95% confidence interval, 0.88-1.06; p=0.47; omega-3 vs placebo; HR 1.03 [0.93-1.13]; p=0.56) were observed. However, a significant reduction in advanced cancers (metastatic or fatal) was found for those randomized to vitamin D, compared to placebo (226 assigned to vitamin D and 274 to placebo; HR 0.83 [0.69-0.99]; p=0.036). There was no difference by omega-3 assignment (246 assigned to omega-3 and 254 to placebo: HR 0.97 [0.81-1.15], p=0.72). When stratified by BMI, there was a significant reduction for the vitamin D arm in incident metastatic or fatal cancer among those with normal BMI (BMI<25: HR 0.62 [0.45-0.86], but not among those who were overweight or obese (BMI 25-<30: HR 0.89 [0.68-1.17]; BMI >=30: HR 1.05 [0.74-1.49]); p for interaction by BMI =0.03. There was no effect modification by BMI noted for the omega 3 arm. Conclusions: In a randomized clinical trial, supplementation with vitamin D, but not omega-3s, reduced incidence of advanced (metastatic or fatal) cancer in the overall cohort, with strongest risk reduction in normal weight individuals. Further research is needed to understand these findings. Clinical trial information: NCT01169259.
The impact of poly ADP ribose polymerase (PARP) inhibitors on clonal hematopoiesis.
Authors: Bolton Kelly L , Moukarzel Lea Anne , Ptashkin Ryan , Gao Teng , Patel Minal , Caltabellotta Nicole , Braunstein Lior Zvi , Aghajanian Carol , Hyman David Michael , Berger Michael F. , Diaz Luis A. , Li Bob T. , Abida Wassim , Schram Alison M. , Weigelt Britta , Friedman Claire Frances , Zehir Ahmet , Papaemmanuil Elli , Cadoo Karen Anne , Levine Ross L. 
Published: May 2020

1513 Background: Poly (ADP-ribose) polymerase (PARP) inhibitors are an important new class of anti-cancer therapies. Therapy-related myeloid neoplasia (tMN) has been reported following PARPi therapy, and is associated with adverse outcomes. Further insight is required into the risk of tMN conferred by PARPi therapy, independent of germline genetic background and prior therapy. We have shown that oncologic therapy selects for acquired mutations in the blood (clonal hematopoiesis; CH) particularly those in the DNA damage response pathway (DDR) including PPM1D, TP53 and CHEK2 and that CH confers an increased risk of tMN. We hypothesized that characterization of the relationship between CH and PARPi therapy provides insight into its potential for leukemogenesis and may offer opportunities for tMN prevention. Methods: We assessed for CH in the blood of 10,156 cancer patients, including 54 who received PARPi therapy, 5942 who received another systematic therapy or radiation therapy and 4160 untreated prior to blood draw. Results: Patients exposed to PARPi therapy were more likely to have CH (33%) compared to those exposed to other systemic therapies or radiation (18%) or untreated patients (16%). This was particularly pronounced for DDR CH; 25% of PARPi treated patients had DDR CH compared to 2% of untreated patients. In a multivariable model accounting for demographics, exposure to chemotherapeutic agents, radiation therapy and germline BRCA mutation status, exposure to PARPi conferred an increased risk of DDR CH (OR = 3.6, 95% CI 1.5-8.5, p = 0.004). This effect was attenuated after accounting for cumulative exposure to therapy (OR = 2.8, 95% CI 0.97-8.2, p = 0.06) suggesting a multifactorial contribution to the enrichment of CH following PARPi therapy. To characterize this further we performed a prospective collection of patients with CH over a median follow-up time of 58 months. During the follow-up period, 17 patients received PARPi, 360 received cytotoxic therapies or radiation and 232 were untreated or received targeted therapies. The growth rate of DDR CH was significantly higher among those who were exposed to PARPi (median, +2.8% increase in VAF per year) compared to untreated patients (+0.08% per year, p = 0.02) and those exposed to other cytotoxic therapies (+1% per year, p = 0.04). Conclusions: Taken together our data suggests that PARPi therapy promotes the expansion of DDR CH. Future studies should examine the potential of CH to identify individuals at high risk of tMN following PARPi therapy and to develop therapies aimed to prevent tMN in patients with CH.
Clinical conundrums: Developing a strategy for discerning TP53-associated chip and coherent clinical care.
Authors: Weitzel Jeffrey N. , Garber Judy Ellen , Castillo Danielle , Sand Sharon , Mejia Rosa , Cervantes Aleck , Stokes Samantha , Mokhnatkin Janet , Tsang Kar Wing Kevin , Wang Jinhui , Wu Xiwei , Herzog Josef , Nehoray Bita , Slavin Thomas Paul 
Published: May 2020

1514 Background: Germline TP53 mutations are associated with Li-Fraumeni syndrome (LFS). However, approximately 20% of commercial laboratory multigene panel test (MGPT)-detected pathogenic TP53 variants represent aberrant clonal expansion (ACE), rather than a germline finding, and are often detected in individuals that lack classic features of LFS. Clonal hematopoiesis (CH) is a form of ACE, and in the absence of an abnormal hemogram is termed Clonal hematopoiesis of indeterminate potential (CHIP). CHIP is often associated with a pathogenic variant (PV) in hematopoietic pathway gene(s) at a variant allele frequency (VAF) less than expected for a heterozygous germline finding. The prevalence increases with age and exposure to chemotherapy. The presence of a skewed VAF is usually noted in a comment on a genetic test result, however, clinicians without genetic training often lack understanding of the comment and need strategies to discern the difference between germline findings, CHIP, and post-zygotic mosaicism. Our studies illuminate possible strategies for discernment for clinicians. Methods: Among 113 cases with MGPT-detected TP53 PVs, enrolled in the Clinical Cancer Genomics Community Research Network registry, we obtained additional tissues, family history and complete blood count (CBC) reports on 42 cases. DNA extracted from formalin fixed paraffin embedded (FFPE) tumor/normal tissues, blood, saliva, eyebrow plucks, was analyzed using a previously validated custom myeloid and CH gene (n = 79) amplicon-based QIAseq panel. PVs with VAF > 2% were included in analyses. Results: Germline status was confirmed for 6 cases (one with a CH PV), post-zygotic mosaicism was supported for 5 cases and 2 were indeterminant. 12 had results supporting ACE/CH, with additional CH-associated PV(s) identified in 5/12 (41%); n = 2 of each TET2, ATM, TP53; and increasing VAF over time for the driver TP53 PV was noted in 2. Of these 2 one was identified to have a hematopoietic malignancy identified through analysis of the CBCs and bone marrow biopsy in parallel with the increasing VAF. Additional results are pending for 7 cases. Conclusions: With the use of our multi-tissue NGS strategy, serial sampling of suspected ACE/CH cases, family history and CBC analyses we were able to discern the status of most TP53 genetic findings. This work has direct translational impact, refining risk estimation and improving the clinical care of patients with TP53 PVs, while avoiding unnecessary LFS-related care and enabling appropriate care for those with ACE.
Evaluation of a mainstream model of genetic testing for men with prostate cancer.
Authors: Scheinberg Tahlia , Goodwin Annabel , Ip Emilia , Linton Anthony , Mak Blossom , Smith David P , Stockler Martin R. , Strach Madeleine Cornelia , Tran Ben , Young Alison Luk , Zhang Alison Yan , Mahon Kate Lynette , Horvath Lisa 
Published: May 2020

1521 Background: In order to identify the ∼12% with inherited cancer predisposition, it is recommended that all men with metastatic prostate cancer (mPC) be offered testing. This has implications for treatment choices and cancer prevention in family. Limited geneticists/genetic counsellors globally present a major barrier to testing. We tested a potential solution, mainstreaming, where testing is performed by the patient’s oncologist. Methods: Men with mPC at three Australian sites were offered germline genetic testing at their medical oncology appointment. Panel testing ( ATM, BRCA1, BRCA2, BRIP1, CHEK2, EPCAM, FANCA, HOXB13, MLH1, MSH2, MSH6, NBN, PALB2, PMS2, RAD51D and TP53) was performed on saliva/blood (Invitae). Primary outcomes were clinician and patient acceptability (modified Royal Marsden Satisfaction Questionnaires). Secondary outcomes included mutation rates and cost-effectiveness. A sample size of 44 provided 90% power, with a one-sided alpha of 5%, to distinguish a proportion of men happy with mainstreaming of 80% vs. 60% or less. Allowing for 25% drop-out, we aimed to recruit 60 men. Results: Of 66 men offered testing from April to November 2019, 63 (95%) accepted. Four pathogenic variants were identified (2 BRCA2, 1 NBN, 1 MSH6). 48 patients and eight clinicians completed questionnaires. Acceptability was high. All (48/48) patients were happy to have been tested, and 45/48 (94%) were happy to have been tested at their oncology appointment. All were happy to receive their results from their oncologist. All clinicians were satisfied mainstreaming and 88% (7/8) felt confident doing so. Mainstreaming was cost-effective, requiring 87% fewer genetic consultations than traditional genetic counselling. Conclusions: This study shows that mainstreaming of men with mPC is feasible, resource efficient and acceptable to both clinicians and patients. Widespread implementation as a new standard of care would facilitate timely access to genetic testing for men with mPC.
Genotype and phenotype correlation of common cancer predisposition syndromes in sarcoma cases.
Authors: Zaheed Milita , Tucker Kathy , Ballinger Mandy L. , Thomas David Morgan ,   International Sarcoma Kindred Study
Published: May 2020

1524 Background: Sarcomas are rare heterogenous cancers affecting a predominantly younger population. The most recognised autosomal dominant contributor being pathogenic TP53 variants associated with Li Fraumeni Syndrome (LFS). When referred, patient eligibility for germline TP53 testing is assessed using classic or Chompret LFS criteria. Other heritable cancer syndromes which can be associated with sarcoma (breast/ovarian, colorectal) are more commonly considered in clinical practice. In some centres germline testing is offered to only those who meet established clinical criteria. Heritable cancer predisposition has several implications including therapy and clinical risk management. Here we report the concordance between clinical criteria and genotypes in sarcoma families. Methods: We included 1,664 sarcoma probands from the International Sarcoma Kindred Study. Eligibility for genetic testing was assessed using internationally accepted clinical criteria for recognised cancer syndromes. Whole genome sequencing was performed on peripheral blood DNA and variants in the ACMG cancer gene list were classified as pathogenic or likely pathogenic using established bioinformatics pipelines. Results: The median age of sarcoma diagnosis in 1664 probands (798 males, 866 Females) was 48 years (range 1-93). The median age of first cancer diagnosis was 46.5 years (0-93) with 291 probands having multiple primary cancers. Of 1504 informative pedigrees, 243 (16%) met criteria for testing; 207 (14%) TP53; 19 (1%) BRCA1/2; 2 (<1%) colorectal cancer (CRC) genes and 15 (1%) familial melanoma. Of 12 TP53 PVs identified, 9 met TP53 testing criteria. Of 13 PVs identified in HR genes (7 BRCA2, 4 PALB2 and 2 BRCA1) only 1 ( PALB2) met BRCA1/2 testing criteria and 2 met Chompret criteria. Both BRCA1 cases were male with a 1st degree relative with ovarian cancer. In CRC genes (1 APC, 2 MSH2, 4 MSH6, 1 PMS2), none met CRC testing criteria but 4 met Chompret criteria. No CDKN2A PVs were identified in melanoma families. Conclusions: In probands with sarcoma, clinical criteria for eligibility for testing for common non-LFS heritable syndromes perform poorly. This should be considered when making decisions regarding germline testing.
Effect of detection of epigenomic changes in plasma-derived cell-free DNA on multicancer classification.
Authors: Bergamaschi Anna , Haan David , Ku Jeremy , Ning Yuhong , Ellison Chris , Guler Gulfem , Phillips Tierney , McCarthy Erin , Antoine Michael , Nguyen Albert , Scott Aaron , Lloyd Paul , Ashworth Alan , Bethel Kelly , Levy Samuel 
Published: May 2020

1539 Background: Epigenomic changes in DNA methylation patterns are more precisely delineated by active demethylation events as marked by 5-hydroxymethylation (5hmC) of cytosine residues. 5hmC appears to be dynamically modulated in tumor tissues and can be employed as a cancer biomarker. Strategies which interrogate 5hmC genome-wide patterns in a liquid biopsy context may provide efficient and precise technology for early cancer screening and detection. In this study we identified genome-wide 5hmC changes in plasma based circulating free DNA (cfDNA) from breast, colorectal, lung, pancreatic and prostate cancer patients versus non-cancer individuals. Methods: cfDNA was isolated from plasma, enriched for the 5hmC fraction using novel click-chemistry protocol for labelling followed by sequencing and alignment to a reference genome to construct features sets of 5hmC patterns. Regularized classification models were constructed to classify cancer samples apart from non-cancer. Results: > 500 non-cancer individuals and > 500 cancer patients across five cancer types (breast, colorectal, lung, pancreas and prostate) were included in this study. About 60% of the cancer samples were early stage disease (I or II). The ability to classify non-cancer versus cancer patients was evaluated by 5-fold cross validation of our trained prediction models. Our models were able to classify all breast cancer with a test auROC of 0.86 while prediction model classification for ER negative samples had an auROC of 0.92. Colorectal performance auROC was 0.9; lung auROC = 0.92, pancreatic auROC = 0.97 and prostate auROC = 0.91. Overall sensitivity range, when allowing 2% false positive, was between 85% and 52%. Further using 5hmC signal in blood we were able to identify several signaling pathways specifically relevant to the biology of the cancers investigated. Conclusions: These findings further demonstrate that 5hmC changes in cfDNA enable non-invasive detection of breast, colorectal, lung pancreatic, and prostate cancers. Further, 5hmC signals enabled the identification of a suite of cancer signaling pathways differentially enriched in cancers versus non-cancers. These data suggest that dynamic changes in tumor cell methylation, detectable through 5-hydroxymethylation, are contained in the circulating blood and signal active disease biology.
A sensitive and quantitative multimodal blood test for the detection of colorectal adenomas and cancer: Correlation with size and number of polyps.
Authors: Friedland Shai , Pan Jennifer Y. , Watson Drew , Chen Yu , Nimgaonkar Ashish , Gulzar Zulfiqar , Gupta Pratyush , Lucas Julian , Atkins Alex , Lai Jr-Ming , Hsieh Ben , Su Stephen , Lim Austin , Ciu Iris , Setthasap Ploy , Sninsky John J. , Mei Rui 
Published: May 2020

1555 Background: Colonoscopic polypectomy is the primary reason for declining colorectal cancer incidence and mortality. Epidemiological evidence has ordered the timing and risk of pre-cancerous adenomas, localized and invasive cancer along a 7-10 year continuum. The increased size and number of index polyps are correlated with an increased probability of progression to cancer and informs surveillance colonoscopies. Methods: A single-center, IRB-approved, prospective, blinded study was conducted at the VA Palo Alto Health Care System. Results for 354 patients with no prior diagnosis of CRC who were scheduled for colonoscopy are presented. Indications for colonoscopy were 86% asymptomatic and 14% with symptoms or positive-FIT. Patients had blood drawn immediately prior to colonoscopy. The test analyzes three biomarkers: circulating gastrointestinal epithelial cells (CEC), validated somatic mutations, and methylation (SEPTIN9) of cell-free DNA and uses incident risk to calculate a CMx Score, scaled from 0 to 100. Multivariate regression methods were used to assess the degree of association between the pre-defined CMx Scores and polyp sizes and number, adjusting for both DNA mutation and DNA methylation status. Results: There is a significant association between CMx Scores and polyp size (F value = 5.80, p-value = 0.017). DNA mutation (F value = 1.29, p-value = 0.263) and methylation status (F value = 0.34, p-value = 0.560) were non-significant. Similarly, there is a significant association between CMx Scores and number of polyps (F value = 23.71, p-value < 0.0001). Again, DNA mutation (F value = 1.57, p-value = 0.210) and methylation status (F value = 1.34, p-value = 0.248) were non-significant. These results suggest that CMx Scores, which incorporate CEC, are providing predictive information of polyp sizes and number above and beyond DNA mutation and methylation status alone. Conclusions: A novel noninvasive multimodal blood-based assay that analyzes cell-free DNA for somatic mutations and methylation, CEC and integrates SEER incidence risk is significantly associated with polyp size and number. The opportunity to track progression and potentially inform colonoscopy interval is notable. [Table: see text]
Breast cancer events in women with atypical ductal hyperplasia who do not undergo surgical excision.
Authors: Kilgore Lyndsey Jo , Yi Min , Bevers Therese Bartholomew , Coyne Robin , Lazzaro Marita , Lane Deanna L , Albarracin Constance T. , Bedrosian Isabelle 
Published: May 2020

1562 Background: Atypical ductal hyperplasia (ADH) found on core needle biopsy is associated with an upgrade to carcinoma in 10-30% of women, thus surgical excision remains the standard of care. We sought to review the incidence of breast cancer in women with ADH managed by either observation or surgical excision over a 15 year period. Methods: Our prospectively maintained registry was reviewed to identify patients with ADH diagnosed by core needle biopsy between 1/2004 and 10/2018. Observed patients were deemed low risk for upgrade after multidisciplinary review confirmed adequate sampling, limited atypia and concordance between imaging and histology. Surgical patients were excluded if upstaged to carcinoma following excision. Patients with < 1 year follow-up were excluded. Subsequent breast cancer was classified as ipsilateral or contralateral to the previous ADH and was further classified as index site if the new cancer was identified in the same quadrant as prior ADH. Multivariate logistic regression models were used to assess potential predictors of subsequent breast cancer events. Results: Four hundred and seventy-eight women with 483 ADH lesions met criteria; 305 were observed and 173 underwent excision. Median follow-up was 5.2 years, range 1.1-15.3. At the time of ADH diagnosis, 91 women had a personal history of breast cancer. Age < 50 was the only statistically significant difference between the groups (24.6% vs. 33.3%, p = 0.04). Race, receipt of chemoprevention, prior breast cancer history and median follow-up were not significant between the groups. Prior history of breast cancer was associated with subsequent breast cancer risk in multivariate analysis (OR 2.25, 95% CI 1.04-4.87, p = 0.04). After excluding patients with a history of breast cancer, multivariate analysis demonstrated no association of age, race, use of chemoprevention or surgical excision with future cancer risk. Among the 387 patients without a prior breast cancer history, 21 patients developed a subsequent cancer; 10 in the surgical group and 11 in the observed group (7.3% vs. 4.4% respectively, p = 0.2). Two cancers were identified at the index site in the surgery group (2/137, 1.5%) and three in those observed (3/250, 1.2%). Conclusions: Observation, rather than surgical excision, is safe in selected women that have a core biopsy diagnosis of ADH. Index site failures are rare and are superseded by cancer risk elsewhere in the breast. National screening and diagnosis recommendations should consider recommending observation for this select group of patients with ADH.