tbuckley/cabot-search huggingface dataset:
The frequency of HER2-low breast cancer among <i>BRCA1</i>, <i>BRCA2</i>, and <i>PALB2</i> mutation carriers.
Authors: Lindsay Goldblatt, Paulina Coutifaris, Payal Deepak Shah
Journal: Journal of Clinical Oncology (2024)

10509 Background: Human epidermal growth factor 2 (HER2) expression in breast cancer (BC) has historically been characterized as negative (0 or 1+ by immunohistochemistry (IHC); 2+ by IHC and not amplified by in-situ hybridization, ISH) or positive (2+ by IHC and amplified by ISH or 3+ by IHC). Recently developed therapies highlight the importance of identifying tumors that are HER2-low (IHC 1+, or 2+ with negative ISH). A minority of BC associated with germline BRCA1, BRCA2( BRCA1/2) or PALB2pathogenic variants (PV) are HER2-positive, but the proportion of BRCA1/2- and PALB2-associated HER2-negative BC that are HER2-low and may benefit from novel HER2-low therapies is unknown.This study aims to retrospectively identify the frequency of HER2-low BC in BRCA1/2 and PALB2 mutation carriers whose cancers were identified as HER2-negative. Methods: We conducted a retrospective chart review of 170 patients diagnosed with HER2-negative BC in the context of a BRCA1/2or PALB2PV at the University of Pennsylvania from 2003 to 2023. Genomic and cancer-specific characteristics including variant classification and receptor status were collected and are descriptively reported. Results: 170 individuals with BRCA1/2 or PALB2 PV developed 190 HER2-negative BC. Forty-seven percent of primary tumors that had been identified as HER2-negative were HER2-low (39% of BRCA1-, 56% of BRCA2-,60% of PALB2-associated BC; see Table). 17 individuals had 17 metastatic site biopsy reports available for review. Of these, 10 (59%) were HER2-low (1 BRCA1-, 8 BRCA2-, and 1 PALB2-associated). 6 of 17 (35%) individuals had discordant HER2 status in primary and metastatic samples; in all cases, the primary tumor was HER2 IHC 0 and the metastatic site was HER2-low. Conclusions: Despite the lower frequency of conventionally HER2-positive BC among individuals with BRCA1/ 2and PALB2PVs, the proportion of these BC that have low HER2 expression is substantial and similar to that of sporadic breast cancer. Discordance in HER2 status between primary and metastatic samples is observed. Individuals with BRCA1/2and PALB2HER2-negative BC may benefit from therapies for HER2-low BC; reevaluation of HER2 status on metastatic samples may identify additional candidates for such therapies. [Table: see text]
Effects of HPV vaccination on the development of HPV-related cancers: A retrospective analysis of a United States-based cohort.
Authors: Jefferson DeKloe, Zachary David Urdang, Ubaldo E. Martinez Outschoorn, Joseph M. Curry
Journal: Journal of Clinical Oncology (2024)

10507 Background: Several studies have shown the efficacy of the Human Papillomavirus (HPV) vaccine in reducing the risk of cervical cancer. Given the recent introduction of the HPV vaccine, there has been limited evidence linking vaccination to a decreased likelihood of developing other HPV-related cancers. Methods: A retrospective cohort study was conducted using a patient population selected from the TriNetX United States Collaborative Network. Patients 9-39 years old attending medical encounters where any vaccine was administered between 1/1/2010 and 12/31/2023 were divided into two cohorts: patients vaccinated for HPV at least five years prior and those no history of HPV vaccination. Outcomes were malignancies at the following sites: Head and Neck (HNC), Cervix, Anus &amp; Anal Canal, Penis, Vulva, and Vagina. Patients with no prior history of cervical dysplasia undergoing Pap smear were observed for atypical cytology. Propensity score matching was performed to match cohorts for age, race/ethnicity, tobacco use, and BMI. Results: Males vaccinated for HPV (n = 760,540) were at decreased odds for HPV-related cancers (odds ratio (OR) = 0.46, 95 % confidence interval (CI) = 0.29-0.72, p-value = 0.001). This finding was primarily driven by a significant reduction in HNC (OR = 0.44, CI = 0.26-0.73, p = 0.0016). Females vaccinated for HPV (n = 945,999) had lower odds for cervical (OR = 0.71, CI = 0.52-0.96, p-value = 0.027) cancers and HPV-related cancers overall (OR = 0.73, CI = 0.57-0.94, p = 0.013). Odds of HNC (OR = 0.67, CI = 0.42-1.1, p = 0.10) and Vulvar/Vaginal cancer (OR = 1.67, CI = 0.81-3.41, p = 0.16) were not significantly different in vaccinated females compared to controls. Vaccinated females were less likely to develop High Grade Squamous Intraepithelial Lesions (HGSIL), (OR = 0.44, CI = 0.30-0.65, p &lt; 0.0001), and Carcinoma In-Situ(OR = 0.422, CI = 0.25-0.72, p = 0.002). Conclusions: These results suggest early evidence of efficacy in the vaccine in preventing the development of several types of malignancies and pre-malignant dysplasia caused by HPV. [Table: see text]
Evaluation of a polygenic risk score as a predictor of early onset triple-negative breast cancer in Black women.
Authors: Holly Jane Pederson, Eudora Hu, Matthew Kucera, Brooke Hullinger, Timothy Simmons, Elisha Hughes
Journal: Journal of Clinical Oncology (2024)

10501 Background: Black women in the U.S. often develop early, biologically aggressive breast cancer (BC). Triple-negative breast cancer (TNBC) is a particularly aggressive type that occurs more frequently in Black than white women and often develops before recommended regular screening. More accurate risk prediction methods are urgently needed to identify young Black women with elevated risk of TNBC. Incorporating polygenic risk scores (PRS) into clinical models can substantially improve risk assessment, but most PRS have demonstrated poor performance among non-European ancestries. We previously described a multiple-ancestry PRS (MA-PRS), based on 56 ancestry-informative and 329 BC-associated single-nucleotide polymorphisms (SNPs), that predicts overall BC risk for diverse populations by characterizing genetic ancestry at each BC SNP and applying ancestry-specific SNP risks and frequencies. Here, we evaluated the extent to which MA-PRS improves upon clinical factors for the prediction of TNBC and early onset ( &lt; 50 years) TNBC in a large, independent cohort of self-reported Black women. Methods: We examined clinical and genetic records from self-reported Black women referred for hereditary cancer testing from 8/22 - 9/23 and negative for pathogenic variants in BC-associated genes. The association of MA-PRS with TNBC was analyzed using multivariable logistic regression adjusted for personal and family cancer history, age and genetic ancestry. Analyses were conducted within the full cohort and the subpopulation of patients &lt; 50 years old. Odds ratios (OR) are reported per standard deviation (SD) with 95% confidence intervals (CI). Results: We identified 14728 Black women who met study eligibility criteria. Nearly 70% (9895/14728) of patients were under the age of 50. In the full cohort, 629 (4.3%) patients were diagnosed with TNBC, and 173 (1.7%) were younger than 50 years old. MA-PRS significantly improved TNBC risk prediction over clinical factors in the full cohort and in the subpopulation of women under 50 (Table). The effect of MA-PRS on risk stratification was comparable to the 1.4 OR per SD reported in current literature for mammographic density, which is widely recognized as an important risk factor. Women in the top 5% of the MA-PRS distribution were at roughly 2-fold increased risk of TNBC (Table). Conclusions: MA-PRS substantially improved upon clinical factors for the prediction of TNBC and early-onset TNBC in a large cohort of Black women. MA-PRS appears to be equally as important for managing risk of early-onset TNBC as mammographic density for overall BC. Incorporation of MA-PRS into BC risk assessment has the potential to improve TNBC survival through more accurate identification of women at high risk. [Table: see text]
Evaluation of cost-effective multiple cancer early detection with extremely low coverage whole genome sequencing from plasma.
Authors: Wendy Wu, Jian Bai, Siqi Wang, Hao Yang, Fuming Sun, Lu Zheng, Di Lu, Xiaoying Dong, Siyang Feng, Kaican Cai, Kezhong Chen, Fan Yang, Hongyang Wang, Lei Chen
Journal: Journal of Clinical Oncology (2024)

10538 Background: Cancer continues to be a significant global health concern, with approximately 19.3 million new cases diagnosed and 10.0 million cancer-related deaths reported in 2020. Multi-cancer early detection (MCED) test using the peripheral blood offers a great opportunity to improve the current cancer screening tests with better performance and benefit-to-harm balance. Methods: Here we introduce a novel MCED test called HIFI-PROF, which utilizes extremely low pass whole-genome sequencing (median coverage of 0.6X) to create a multi-dimensional fragmentation signatures model through machine learning approach. HIFI-PROF was developed to detect and localize six types of cancer (colorectal, pancreas, liver, lung, esophagus and gastric cancer). Results: The study included a total of 1,487 participants, comprising 235 colorectal cancers, 227 pancreatic cancers, 150 liver cancers, 125 lung cancers, 107 esophageal cancers, 106 gastric cancers and 537 healthy volunteers. Most of the cancer cases were I/II stage patients (stage I: 38%, stage II: 35%, stage III: 23%, stage IV: 4%). The participants, stratified by age and clinical status, were divided into two sets: a training set (n=1,079) and a validation set (n=408).HIFI-PROF exhibited an excellent performance in the early detection of multiple cancer types, achieving a sensitivity of 87.58% at a specificity of 99.09% and identifying the tissue of origin (TOO) with an accuracy of 81.99%. The sensitivity rates for detecting cancer at different stages were also promising, with a sensitivity of 84.62% for stage I, 85.59% for stage II, 89.61% for stage III and 92.86% for stage IV. Conclusions: These results highlight the high sensitivity and specificity of HIFI-PROF in identifying cancer cases while maintaining a low rate of false-positive results. The use of HIFI-PROF offers a cost-effective MCED test with excellent performance. Such advancements will contribute to improve strategies for multi-cancer early detection, leading to more effective clinical interventions and better outcomes.
Access for adolescents and young adults with hard-to-cure cancer to PROFYLE: The pan-Canadian precision oncology pipeline.
Authors: Lesleigh S. Abbott, Stephanie Grover, Jan-Willem Henning, Sapna Oberoi, David Malkin
Journal: Journal of Clinical Oncology (2024)

10012 Background: Cancer is the most common cause of disease-related death in children, adolescents and young adults (CAYA). Approximately, 1.5% of patients with cancer in Canada are adolescents and young adults (AYAs) (age 15-29). AYAs often present with advanced disease and limited access to clinical trials including genomic testing. The PRecision Oncology For Young peopLE (PROFYLE) national, collaborative program, was created to provide equitable access to molecular profiling to identify novel targeted treatment options for CAYA with hard-to-cure cancers. The AYA node of PROFYLE aims to enhance the inclusion of AYAs across Canada at pediatric and adult centers while raising awareness of improving cancer outcomes of this underserved population. Methods: Building upon 3 pre-existing regional precision oncology programs, PROFYLE was implemented as the first pan-Canadian precision oncology pipeline. The PROFYLE study is multi-centred, non-randomized, interventional, and qualitative. Inclusion criteria: ≤29y; treatment at a Canadian center; diagnosis of a hard-to-cure cancer. It includes genomic and transcriptomic sequencing of paired germline and cancer fresh/frozen samples. Actionable findings, potential targeted therapy options including available clinical trials, clarification of diagnosis, and genetic counseling recommendations are provided to the clinical care team. Results: To date, &gt; 1,200 CAYA are included from all provinces. Of these, 33% were AYAs. Cancer diagnoses included: 47% sarcoma, 15% leukemia/lymphoma, 13% CNS tumor, 25% other. Of the AYAs enrolled, 53% had ≥1 significant tumour profiling finding (48% specific mutations/fusions; 6% DNA repair defect signature, hypermutation, microsatellite instability, chromosomal instability; 3% predictors of therapeutic resistance; 5% outliers in gene expression). 71% had potentially useful findings (15% diagnostic; 9% prognostic; 59% therapeutic; 2% etiologic; 15% cancer predisposition; 2% secondary germline; 0.5% pharmacogenetic). 23% had a pathogenic/likely pathogenic germline variant. 60% had ≥1 potentially actionable somatic alteration. 64% of clinicians indicated that molecular findings impacted clinical management (12% diagnostic; 6% prognostic, 60% therapeutic; 16% germline genetic). 24% indicated a change in treatment planning in response to these findings. Conclusions: The goal of developing a national precision oncology pipeline that provides equitable access to molecular profiling in a clinically relevant timeframe has been realized through the establishment of PROFYLE. Findings demonstrate that the sequencing platform provided medically informative results in the majority of enrolled AYAs. The success of PROFYLE underscores the importance of the continuing efforts to increase the access to this precision oncology initiative for all AYAs with cancer in Canada.
Evaluation of kidney function and body composition in adult survivors of unilateral, non-metastatic, non-syndromic Wilms tumor: A report from the St. Jude Lifetime Cohort Study.
Authors: Daniel M. Green, Kendrick Li, Sue C. Kaste, Kirsten K. Ness, Matthew J. Krasin, Lu Xie, Carmen L Wilson, Deo Kumar Srivastava, Andrew M. Davidoff, Rima S Zahr, Siddhant Taneja, Kyla C. Shelton, Jennifer Q. Lanctot, Stephanie B Dixon, Matthew J. Ehrhardt, Daniel A. Mulrooney, Chelsea Goodliffe Goodenough, Gregory T. Armstrong, Leslie L. Robison, Melissa M. Hudson
Journal: Journal of Clinical Oncology (2024)

10064 Background: The relationships among treatment exposures, body composition and estimated glomerular filtration rate (eGFR) in adult survivors of childhood have not been well studied. Methods: We evaluated body composition with dual energy x-ray absorptiometry (DXA) and eGFR with the Kidney Disease International Global Outcomes (KDIGO) 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease (CKD) in 149 adults previously treated for non-syndromic, non-metastatic, unilateral Wilms tumor at St. Jude Children’s Research Hospital between 1964 and 2004 with chemotherapy and with [(whole abdomen (WA) radiation therapy (RT) – 41 patients; median dose 12.5 Gray (Gy), Interquartile Range (IQR) 12.5 – 20.0 Gy); (hemiabdomen (HA) RT – 30 patients; median dose 12.0 Gy, IQR 10.8 – 20.1 Gy)] or without (78 patients) RT. z-scores for DXA variables were calculated using data from the National Health and Nutrition Survey (1). Results: The study population [56 males (37.6%), 109 whites (73.2%)] was a median of 3.1 years of age at diagnosis (IQR: 1.7-4.3) and 23.4 years at evaluation (IQR: 23.4-35.5). Relative total and relative trunk lean mass, and eGFR were significantly decreased among those who received WART compared to unirradiated patients. Linear regression demonstrated that WART was significantly associated with a lower eGFR (p = 0.012) and higher value of creatinine (p = 0.013). Conclusions: Relative total and relative trunk lean mass, and eGFR are decreased in survivors of unilateral, non-metastatic, non-syndromic WT following WART. Although eGFR was in the normal range, eGFR may be inaccurate due to loss of lean mass. Assessments using non-secreted molecules may more accurately measure the magnitude of kidney function loss among WART treated WT survivors. 1. PLoS ONE 2009;4(9):e7038. [Table: see text]
Precision genome profiling for pediatric leukemia with a software-controlled enrichment method using nanopore sequencer.
Authors: Shota Kato, Aiko Sato-Otsubo, Wataru Nakamura, Masahiro Sugawa, Moe Hidaka, Masahiro Sekiguchi, Kentaro Watanabe, Yuichi Shiraishi, Motohiro Kato
Journal: Journal of Clinical Oncology (2024)

10027 Background: The real-time nature of nanopore sequencing allows for simultaneous basecalling of DNA sequences during sequencing. This unique capability enables adaptive sampling (AS), a software-controlled targeted sequencing method. AS is notable for its ability to rapidly and flexibly enrich multiple genes with long fragment reads and detect various modalities of genetic aberrations in a single run. However, the feasibility and significance of AS for cancer have not been previously reported. Methods: We performed AS on a GridION sequencer using samples from 28 pediatric leukemia patients (10 acute myeloid leukemia, 13 B-cell acute lymphoblastic leukemia, and 5 T-cell acute lymphoblastic leukemia). Target regions were comprised of 466 genes associated with hematologic malignancies and included 30-kilo base pairs of flanking regions. After 3 days of sequencing, single-nucleotide variants (SNVs), structural variations (SVs), and copy number variations (CNVs) were determined. In 21 samples, variant calling accuracy was evaluated using short-read-based whole genome sequencing (WGS). Results: In the on-target regions, mean depth was 21.0× and N50 was 11,191 bps at the median. Of the 13 samples with genetic alterations previously detected through clinical testing for diagnostic classifications, all were reconfirmed by AS. Detecting DUX4 rearrangement needed an additional analysis pipeline because of its structural complexity. Among the 15 remaining samples whose genetic alterations had not been determined by clinical diagnostic testing, AS identified putative driver aberrations in 14 samples. All of these genomic abnormalities were structural variations (SVs) or copy number variations (CNVs), most of which were not encompassed within the genes or regions targeted in clinical diagnostic testing. Detected SVs were described with accurate genomic breakpoints, enabling the efficient detection of gene rearrangements and deletions of the entire region of an exon or a gene. Regarding CNVs, both chromosomal-level CNVs, such as high-hyperdiploid, and focal CNVs, such as CDKN2A deletion, were detectable using genome-wide low-coverage reads in the off-target regions. In the other case with acute myeloid leukemia in which genetic abnormalities were not detected either by clinical testing or AS, WGS identified an NPM1 frameshift deletion located outside of known hotspots. Among variants identified by WGS, AS detected 60.9% of the SNVs, 17.6% of the small indels, and 89.2% of the SVs, with a tendency of poor detection efficiency for variants with low variant allele frequency. Conclusions: AS provides a rapid and precise description of the genomic profile of pediatric leukemia, particularly advantageous for identifying SVs and CNVs, which are difficult to detect by capture-based short-read sequencing.
Demographic factors of prognosis in pediatric neuroblastoma.
Authors: Maya Mathews, Peter T. Silberstein, Michelle Swedek
Journal: Journal of Clinical Oncology (2024)

10041 Background: Neuroblastoma is a rare type of pediatric tumor derived from neural crest progenitor cells. It can arise anywhere along the sympathetic chain but is most commonly found in the retroperitoneum from the adrenal glands. At diagnosis, approximately 50% of patients have hematogenous spread of metastases and so timely, aggressive treatment may be life-saving. The National Cancer Database (NCDB) is an oncology database that collects data from over 1500 cancer centers in the United States. This study will utilize the NCDB to analyze how demographic factors may impact prognosis in patients with pediatric neuroblastoma. Methods: We conducted a retrospective analysis using the National Cancer Database (NCDB) and identified patients diagnosed with pediatric neuroblastoma under the age of 18 between 2004-2020 with ICD code 9500/3 (n = 2323). Multivariate Cox regression analysis was used to calculate hazard ratios (HR) analyzing race, Spanish/Hispanic origin, facility type, education, income, insurance status, age at diagnosis, distance traveled to the facility, and urban characteristics of the facility on prognosis. Results: The median age at diagnosis was one year-old. Patients aged greater than one year-old composed 48% of the sample and had a less favorable prognosis compared to patients younger than one-year old (HR 1.99, 95% CI 1.69-2.35, p &lt; 0.001). The median distance to the facility was 21.4 miles. 50% of the sample patients lived greater than 21.4 miles of their chosen facility and had a poorer prognosis compared to patients who lived closer (HR 1.25, 95% CI 1.06-1.47, p = 0.008). Conversely, patients with private insurance composed 59% of the sample and had a more favorable prognosis (HR 0.54, 95% CI 0.30-0.99, p = 0.046) compared to patients with no insurance. Conclusions: To our knowledge, this study provides the most updated analysis on how demographic factors impact prognosis in patients with pediatric neuroblastoma. We highlight potential barriers to care including age, distance to facility, and insurance. We hope this study may serve as a foundation for further investigation into the systemic barriers that affect patients with pediatric neuroblastoma.
A multi-assay liquid biopsy approach to improve detection of bone and soft tissue sarcomas.
Authors: Deena Najjar, LeeAnna Lui, Lauren Battle, Robert Dubin, Elizabeth Zeldin, Mark A. Applebaum, Masanori Hayashi, Daniel A. Weiser
Journal: Journal of Clinical Oncology (2024)

10019 Background: Bone and soft tissue sarcomas are among the most common extra-cranial solid tumors of childhood, yet advances in liquid biopsies lag behind what has been achieved across adult cancers. Solid tumors that lack recurrent genetic mutations or translocations, such as bone and soft tissue sarcomas, are more difficult to detect in circulation using established assays, such as ddPCR. We have developed a pipeline to analyze cell-free DNA (cfDNA) using two molecular profiling techniques that we hypothesized would improve detection of circulating tumor DNA at diagnosis for patients with bone and soft tissue sarcomas. Methods: cfDNA was isolated from plasma of patients with osteosarcoma (OS) (n = 36) and fusion-negative rhabdomyosarcoma (FN-RMS) (n = 7) at multiple timepoints. Methods for detecting tumor DNA in cfDNA included ultra-low coverage whole genome sequencing (ULC-WGS, 0.5x) and ultra-deep targeted sequencing (UDP, ~1000x) using a panel of 11 and 22 tumor-associated genes for OS and FN-RMS, respectively. ULC-WGS data underwent ichorCNA analysis to define percent tumor content of each sample. UDP analysis identified somatic variants through variant callers, Mutect2, Lancet, strelka, and DELLY2, with ClinVar to annotate and define tumor-specific variants in each sample. Combining ULC-WGS and UDP data, an integrated tumor score was developed and assessed in diagnostic samples. Results: 136 OS and 30 FN-RMS cfDNA samples were collected during the patients’ disease courses. Circulating tumor material was detected in 18/23 (78%) OS and7/7 (100%) FN-RMS samples at diagnosis. The most frequent copy number aberrations were seen in the region of chromosome 8q containing the cMYC gene. cMYC amplification was found in 11/23 (48%) of diagnostic OS samples and 2/7 (29%) of diagnostic FN-RMS samples. UDP analysis identified variants in 17/23 (73%) and 7/7 (100%) of diagnostic OS and FN-RMS samples respectively. The most commonly detected variants included TP53, BRCA2, MET, and BRAF. Of the 23 diagnostic OS samples, four had TP53 translocations. The integrated tumor score detected the presence of tumor associated material within diagnostic samples with a sensitivity of 25/30 (83%), compared to the sensitivity of ULC-WGS or UDP alone, which was 15/30 (50%) and 24/30 (80%) respectively. Conclusions: A multi-assay liquid biopsy has promise to improve disease detection and monitoring for patients with solid tumors that lack recurrent driver mutations. We plan to integrate additional molecular profiling technologies to improve the sensitivity and specificity of our cfDNA assays and aim to adapt our pipeline across additional cancers.