bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of key performance indicator (KPI) for real-time monitoring of treatment of early breast cancer to control socioeconomic and indigenous systemic bias.
Authors: Walpole Euan Thomas , Youl Philippa , Cossio Danica , Morris Michelle Frances , Philpot Shoni 
Published: June 2022

10566 Background: Disparity in outcome for different cancer groups exist particularly for indigenous and poor socioeconomic background. Patient and treatment data on a population basis was examined. Methods: Population data for the state of Queensland, Australia (population 5.2M) collected by Cancer Alliance Queensland as part of government cancer registry roles plus additional linked data available as a gazetted quality assurance committee was examined to find patients with early breast cancer treated with surgery, chemotherapy (CT) and radiotherapy (RT) between 2005-2015. Results: A cohort of 8279 women received treatment with 89.3% having the surgery, CT, RT sequence. Time to completement threshold was 37 weeks using empirical cutpoint estimation in Stata. Overall survival (OS) was 94% at 5 years if < 37 weeks versus 88.5% if not. (p < 0.001). Multivariate analysis of socioeconomic and clinical characteristics for survival was also significant for increasing age, indigenous status, socioeconomic disadvantage, multiple co morbidities and advancing disease stage. Private hospital cases had a better outcome. When delay is analysed between treatments, only time to CT from surgery > 9.5 weeks was significant for OS (HR 1.42 p < 0.001). Indigenous status, socioeconomic status and private facility no longer were significant. Multiple co morbidities and advanced stage were still significantly associated with poorer survival. Funnel plots of treatment centre show the association with public hospital treatment and lower volume centre with delay. Conclusions: This data is retrospective so can inform local service evaluation but implementation of a KPI for delay to adjuvant chemotherapy of 9.5 weeks can provide real time targets for patient care. We measured delay in the recent 5 years (before survival available) which shows consistent delays and it will included as a reporting function of MDT management software. Whilst the increased use of neoadjuvant CT will assist, systematic reporting of this KPI has potential to remove treatment biases for indigenous and lower socioeconomic patients. More recent data will be available for presentation.
Human papillomavirus-associated cancers in Taiwan over the last 18 years: The potential impact of screening, vaccination, and smoking.
Authors: Liao Cheng-I , Feng I-Jung , Johnson Caitlin Ruth , Bin Pin-Jie , Tsai Chun-Teng , Kapp Daniel Stuart , Chan John K 
Published: June 2022

10574 Background: Human papillomavirus (HPV) is a causative agent of many human cancers. This study aims to determine the incidences and trends of HPV-associated cancers in the Republic of China. Methods: HPV-associated cancers included: cervical carcinoma, oropharyngeal squamous cell carcinoma (SCC), anal/rectal, vulvo-vaginal, and penile SCC. Deidentified data were obtained from Taiwan’s National Health Insurance Research Database from 2001 to 2018. SEER*Prep 2.6.0, SEER*Stat 8.3.9.2, and Joinpoint regression program 4.9.0.0 were used to calculate incidences and trends of HPV-associated cancers per 100,000. The age-adjusted incidence was adjusted by the WHO 2000 standard population. Results: A total of 55,248 HPV-associated cancers were identified. Of these, 34,730 (62.9%) were identified in women and 20,518 (37.1%) in men. The majority (60.0%) were cervical followed by oropharyngeal at 37.6%, and other HPV-associated cancers comprised 2.4%. Over the 18-year study, the overall age-adjusted incidence of HPV-associated cancers decreased from 13.41 to 8.92 (per/100,000) with an annual decrease of 2.02% ( P< 0.001). More specifically, cervical cancer incidence decreased from 20.42 to 7.70 per 100,000 with an annual decrease of 5.6% ( P< 0.001). Other cancers, such as vaginal and vulvar, decreased 2.34% ( P< 0.001) and 1.82% ( P< 0.001), respectively. With respect to oropharyngeal SCC, the incidence was over 12-fold higher in men compared to women (8.37 vs. 0.67/100,000) with both sexes increasing at 3.61% ( P< 0.001) and 3.59% ( P< 0.001) annually. Anal/rectal SCC increased at 3.55% ( P< 0.001) whereas penile cancer decreased at 2.52% ( P< 0.001). Of note, all HPV-associated cancers among non-smokers decreased 2.02% ( P< 0.001) annually, whereas they increased in smokers at 1.00% ( P> 0.05) per year. This increase in incidence was particularly evident in oropharyngeal SCC and cervical carcinomas. Conclusions: Women comprised over 60% of HPV related cancers, with cervical cancer being most common followed by oropharyngeal cancer. Over the last 18 years, cervical and vulvovaginal cancers decreased, but the rates of oropharyngeal cancers in men was 12-fold higher than women and continues to increase. Public awareness and education of these trends are needed toward prevention and screening.
Mainstreamed genetic testing of patients with breast cancer: Experience from a single surgeon’s practice in a large U.S. academic center.
Authors: Yin Kanhua , Chai Teresa S , Wooters Mackenzie , Shannon Kristen M , Hughes Kevin S. 
Published: June 2022

10577 Background: Germline genetic testing for cancer susceptibility has proven to be a powerful tool in cancer risk assessment, screening, and prevention but a huge gap exists between the number of germline genetic testing candidates and the number of patients actually tested. This study aimed to evaluate the impact of mainstreamed genetic testing (MGT) model into a single academic breast surgeon’s practice on genetic test completion. Methods: Before September 2019 (pre-MGT phase), a breast surgery practice at Massachusetts General Hospital followed a traditional model of pre-test consultation with a genetic professional. After September 2019 (post-MGT phase), the same practice offered eligible patients with immediate testing in the same visit. We evaluated the appointment completion in the pre-MGT phase and compared the test uptake and test results between the two phases. Results: We identified 204 patients in the pre-MGT phase and 202 patients in the post-MGT phase. In the pre-MGT phase, the median waiting time for genetic counseling was seven days for patients with a newly diagnosed cancer, 211 days for patients with a remote personal history of cancer, and 224 days for non-cancer patients who had a family history. A total of 105 (51.5%) patients completed a genetic counseling appointment (Table). In the post-MGT phase, a significantly higher proportion of patients (88.1%, p < 0.001) consented to genetic testing, while the proportion of patients who tested positive was lower (pathogenic variant: 11.9% vs. 20.0%; variant of uncertain significance: 19.9% vs. 28.0%; p = 0.047). Conclusions: Implementing MGT can reduce the number of clinical visits, significantly shorten patients’ wait time to test initiation, and increase the completion of genetic testing. [Table: see text]
Prevalence and spectrum analysis of germline DICER1 variants of solid tumors: Decoding the mysterious signals of the genome.
Authors: Li Pibao , Han Tiantian , Guo Didi , Luo Ningning , Li Mengmeng , Lu Guanghua , Bu Fanfeng 
Published: June 2022

10578 Background: DICER1 syndrome is a rare genetic condition predisposing to multiple cancer types and causes by germline DICER1 variants. Deleterious mutations identified were mostly located in the RNase III domain. VUSs found in other domains may be also crucial in the inheritance of high-risk neoplasms although there is insufficient evidence. Our study aimed at describing the spectrum of DICER1 variants detected in solid tumors to improve the identification of potentially high-risk DICER1 variants. Methods: Germline mutations including SNV, small INDEL in 448 patients with solid tumors were analyzed by next-generation sequencing (NGS) panel. The pathogenicity of germline mutations was categorized based on American College of Medical Genetics and Genomics (ACMG) guidelines. Results: In total, 3 (0.67%) patients (diagnosed as bladder cancer, schwannoma, and medulloblastoma) were identified harboring truncating pathogenic (P)/likely pathogenic (LP) germline mutations in the RNase III domain. The remaining 445 (99.33%) patients carried 447 uncertain significance (VUS) mutations, of which 416 (92%) were missense mutations lied in different domains and 52% (234/450) located in exon 20-23. The median age was 60 years old with an age range from 0 to 90. The higher frequency cancer type contained lung cancer (35.9%), glioma (10.0%), liver cancer (8.4%). In addition, the two highest frequencies of DICER1 missense variants were c.3334A > G (p. Asn1112Asp, n = 58) and c.3227G > A (p. Ser1076Asn, n = 53), which lied in unknown functional domain of the protein and had been reported in Clinvar. Their clinical significance and pathogenicity remain further study. Conclusions: In our study, DICER1 germline mutations mostly occurred in exon 20-23 and 92% were missense mutations. We reported 3 new cases of tumors associated with DICER1 syndrome, which expanded the DICER1-related tumor spectrum. Understanding the clinical significance of germline DICER1 VUS could improve the identification of potentially high-risk variants. Reclassifying these variants could make them useful for predictive, prognostic, and preventive purposes in clinical practice.
Pathogenic TP53 variant allele frequency across different somatic tissues in two patients with mosaic Li-Fraumeni.
Authors: Tang Tin-Yun , Stearns Duncan , Miron Alexander , Mitchell Anna 
Published: June 2022

10582 Background: The integration of germline genetic testing, frequently from blood, into routine oncological care has increased the frequency at which pathogenic TP53 mutations are found in a variant allele frequency (VAF) range suggestive of either mosaic Li-Fraumeni Syndrome or clonal hematopoiesis of indeterminate potential (CHIP). Mosaic LFS is a rare and poorly described phenomenon wherein a pathogenic TP53 mutation is dispersed in low levels through multiple somatic tissues after stochastically developing during early embryogenesis. In comparison, CHIP is restricted to the bone marrow niche. Germline mosaicism in Li-Fraumeni Syndrome (LFS) is inferred when genomic DNA from a second source recapitulates the exact same TP53 mutation. Given the challenges with sample acquisition, mosaicism has not been previously described in depth in the medical literature. Methods: Two pediatric patients with LFS-associated cancers (glioblastoma, osteosarcoma & ALL respectively) underwent clinical genetics evaluation and were found to have pathogenic TP53 mutations. Initial genetic testing was performed in a CLIA/CAP environment through a send out test or internally. A broad array of somatic tissues was collected at autopsy with subsequent DNA isolation and amplicon sequencing in triplicate to determine the mean VAF of the pathogenic TP53 allele. Results: For both patients, the initial germline test suggesting mosaic LFS had a VAF between 20-30%. Confirmatory intent fibroblast culture in Patient 1 was reported as negative by an external clinical lab and Patient 2’s VAF was much lower. The VAFs for the rest of the somatic tissues as well as in their corresponding cancers are reported below (Table) as means and standard error of the triplicate. Despite the negative fibroblast culture, Patient 1 did demonstrate mutant TP53 in other tissues, confirming mosaicism. Conclusions: The proportion of pathogenic alleles is highly heterogeneous amongst different somatic tissues in mosaic LFS patients. Although CHIP exclusion through germline testing of cultured skin fibroblasts is common, our patients’ skin samples were amongst the tissues with the lowest VAFs. Mosaicism should be highly suspected when tumor sequencing demonstrates an identical mutation to the putative germline mosaic one even with equivocal fibroblast culture results. [Table: see text]
Trends in and determinants of germline BRCA1/2 testing in patients with breast and ovarian cancer.
Authors: Lau-Min Kelsey S. , McCarthy Anne Marie , Nathanson Katherine L. , Domchek Susan M. 
Published: June 2022

10583 Background: Germline BRCA1/2 testing (GT) is instrumental in identifying patients with breast and ovarian cancer who may be eligible for biomarker-driven poly ADP ribose polymerase inhibitor (PARPi) therapy. Little is known about recent trends and determinants of GT since PARPi were approved for these patients. Methods: We performed a retrospective cohort study of patients with breast and ovarian cancer who were eligible for GT (diagnosed with breast cancer under age 45, triple negative breast cancer under age 60, male breast cancer or ovarian cancer) between 1/2011 and 3/2020 in the nationwide Flatiron Health EHR-derived deidentified database. Duration of follow-up was at least one year for each patient. Spline regressions estimated the annual prevalence of GT within one year of diagnosis. Multivariable log binomial regressions estimated adjusted relative risks (RR) of GT by patient and tumor characteristics. Multiple imputation with chained equations was conducted for missing data. Results: Among 2,982 eligible patients with breast cancer, 1,682 (56%) underwent GT within one year of diagnosis with a median time of 42 days. GT increased from 37% in 2011 to 68% in 2020, with a significantly higher RR after PARPi were approved for breast cancer in 1/2018 (RR 1.35, 95% CI 1.20-1.51). In multivariable analyses, there were no appreciable differences by sex, race or ethnicity, but there was a negative linear relationship between GT and age (RR 0.93, 95% CI 0.90-0.96 for every 5 years). After adjusting for age, the 87 breast cancer patients with Medicare were also less likely to undergo GT despite being eligible (RR 0.67, 95% CI 0.48-0.95 vs commercial insurance). Among 5,563 eligible patients with ovarian cancer, 1,968 (35%) underwent GT within one year of diagnosis with a median time of 101 days. GT increased from 23% in 2011 to 53% in 2020, with a significantly higher RR after PARPi were approved for ovarian cancer in 12/2014 (RR 2.25, 95% CI 2.01-2.52). Although insurance status was not a significant determinant of GT in patients with ovarian cancer, older age (RR 0.95, 95% CI 0.93-0.97 for every 5 years) and Black race (RR 0.80, 95% CI 0.66-0.98 vs white race) were associated with a lower likelihood of GT in multivariable analyses. All results remained similar in pre-planned sensitivity analyses restricted to the post-PARPi approval period, limiting to patients who remained alive one year after diagnosis and using the non-imputed dataset. Conclusions: GT remains underutilized in patients with breast and ovarian cancer. Although GT has increased since PARPi were approved for this population, significant disparities by age, race and insurance status persist but differ by tumor type. This study is limited by potential misclassification due to missing GT performed outside the Flatiron Health network. Multifaceted patient-, clinician- and system-level strategies are needed to ensure that all eligible patients receive GT.
Retrospective analysis of non-BRCA gene pathogenicity variation in Chinese patients with ovarian cancer.
Authors: Guo Li yuan , Han Tiantian , Guo Didi , Ma Juan , Zhao Yaping , Bu Fanfeng , Chen Siqi , Deng Wanglong , Ding Ran 
Published: June 2022

10584 Background: Ovarian cancer (OC) is the most lethal gynecologic cancer. Pathogenic (harmful) variants（PV) in BRCA1 and BRCA2 are the strongest hereditary risk factors for the development of ovarian cancer. To date, there is little information regarding the frequency of non- BRCA gene PV in Chinese women with OC that undergo genetic cancer risk assessment. In this study we analyzed wild-type BRCA1/2 OC patients (pts) registered in our database. Methods: Peripheral blood of 766 women, diagnosed with ovarian cancer, were taken from the recruited cases with the consent of performing germline genetic testing. Germline mutations including SNV, small INDEL were analyzed by next-generation sequencing (NGS). The pathogenicity of germline mutations was categorized based on American College of Medical Genetics and Genomics (ACMG) guidelines. Results: Of 766 OC pts, 460 pts (60%) underwent BRCA1/2 testing only, while 306 pts (40%) consented in multigene panel testing (MGPT). BRCA1/2 detection rate was 16.8% (129/766), while the detection rate for non- BRCA genes was 7.5% (23/306). There was a significant statistical difference in average age that the non- BRCA gene pathogenicity variation group was higher than the BRCA gene pathogenicity variation group (62 vs. 57, p=0.018). Wild-type B RCA1/2 OC pathogenic variants (PV), were diagnosed in BLM (n=4, 17.4%), ERCC5 (n=2, 8.7%), MUTYH (n=2, 8.7%), RAD51C (n=2, 8.7%), RAD51D (n=2, 8.7%), ATM (n=1, 4.4%), BRIP1 (n=1, 4.4%), CDH1 (n=1, 4.4%), CHEK2 (n=1, 4.4%), ERCC4 (n=1, 4.4%), LZTR1 (n=1, 4.4%), MSH3 (n=1, 4.4%), PALB2 (n=1, 4.4%), PMS2 (n=1, 4.4%), RAD50 (n=1, 4.4%) and SLX4 (n=1, 4.4%) genes. Of all the 23 non- BRAC gene pathogenicity variations, 57% (13/23) lay in the Homologous Recombination Repair (HRR) pathways. Moreover, a 48-year-old woman with ovarian cancer with two pathogenic variants of the [ BRCA2- MUTYH] genes was detected in the retrospective cohort study. Conclusions: BLM, ERCC5, MUTYH, RAD51C and RAD51D genes are the main contributors to hereditary wild-type BRCA1/2 OC in our cohort. The average age of non- BRCA gene pathogenicity variation group was higher than the BRCA gene pathogenicity variation group. Therefore, multi-gene PANEL detection is recommended for ovarian cancer patients, especially for older patients.
NGS analysis of germline mutation profile of patients with hepatocellular carcinoma in China.
Authors: Wu Xiaobing , Guo Didi , Han Tiantian , Zhao Yaping , Ma Juan , Lu Guanghua , Bu Fanfeng , Chen Siqi , Deng Wanglong , Ding Ran 
Published: June 2022

10585 Background: Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death worldwide with very poor prognosis. Many studies have focused on oncogene characteristics, however, the germline landscape of Chinese HCC patients has not been fully clarified. The purpose of this study is to assess the inherited genetic factors regarding germline mutations in Chinese HCC patients. Methods: Genetic mutations were reviewed in 1670 Chinese HCC patients who underwent hybridization capture based next-generation sequencing (NGS). The pathogenicity of germline mutations was categorized based on American College of Medical Genetics and Genomics (ACMG) guidelines. Results: Of 1670 patients with HCC, 110 (6.7%) patients were identified to carry 111 pathogenic variants(P) or likely pathogenic variants(LP) in 112-cancer predisposition gene panel, and there was no age difference between P/LP group and non-P/LP group (average age: 57 vs 56, p = 0.64). The most frequently germline mutated genes were BRCA1/2 (11.7%), followed by ATM(4.5%), BLM(4.5%), ERCC2(4.5%), ERCC3(4.5%) and BRIP1(3.6%), ERCC4(3.6%), FANCD2(3.6%), MUTYH(3.6%), RAD50(3.6%). Of all the 111 germline mutations, 47% (n = 52) lay in the Homologous Recombination Repair (HRR) pathways. Both in P/LP group and non-P/LP group, the most frequently somatic mutated genes were TP53, TERT and MUC16. 7/110(6.4%)of patients in P/LP group were high TMB(≥10 mutations/megabase) and 131/1560(8.5%) in non-P/LP group. There was no statistical difference in TMB between P/LP and non-P/LP group. Conclusions: Taken together, we have presented the spectrum of pathogenic germline mutations in Chinese HCC patients. P/LP germline variants in cancer predisposition genes were detected in 6.7% of those patients, and predisposition genes associated with HCC risk needs further investigation. Inherited genetics should not be overlooked in HCC as there are important implications for precision treatment, future risk of cancers, and familial cancer risk.
Oncologist knowledge of cost of genetic testing.
Authors: Weiner Shayna , Austin Sarah , Carr Grant , Kidwell Kelley M. , Resnicow Ken , Stoffel Elena Martinez , Griggs Jennifer J. 
Published: June 2022

10591 Background: Genetic testing allows patients and their families to identify hereditary cancer syndromes. Financial barriers to genetic testing are a major concern for patients offered genetic risk assessment. The cost of germline genetic testing has decreased substantially over the last several years. It is not clear, however, that oncologists are knowledgeable about the cost of genetic testing. The purpose of this study was to investigate oncologists’ knowledge of genetic testing costs. Methods: We deployed a survey to all oncologists who are members of the Michigan Oncology Quality Consortium, a physician-led quality improvement collaborative whose members represent 95% of the oncologists in Michigan. The modified Dillman method was used to achieve the maximum response rate. Responses were collected from December 2020 through May 2021. The responses to the question, “If a patient were to ask you how much it would cost for them to have clinical genetic testing for hereditary cancer syndromes, what would you tell them?” were independently coded by three investigators into one of three categories – correct and helpful, correct and not helpful, or incorrect and not helpful. We investigated associations between the number of years in practice and how important was cost as a barrier to genetic risk assessment. Results: The response rate to the survey was 61.2% (194/317). Only 25% of respondents provided an answer that was deemed to be both correct and helpful to a patient, for example “approximately $250 if out of pocket.” Nearly 40% of respondents gave an answer that was correct but was non-specific and would not help a patient decide about pursuing genetic testing. This category included responses such as deferring to a genetic counselor or that cost varies based on insurance. About 28% gave an incorrect response, such as “several thousand dollars” or responded, “I don’t know.” No associations were found between cost response category, number of years in practice, or reported responses that financial barriers play a role in referral patterns. Conclusions: The majority of oncologists in our statewide sample do not have an accurate understanding of the cost of germline genetic testing. Lack of precise information about the costs of testing may lead patients to believe that genetic testing is either not important or not within reach. Furthermore, providing incorrect information can have a downstream effect and prevent patients and their families from pursuing genetic counseling. Improving oncologists’ knowledge about the cost of testing may decrease barriers to uptake of genetic risk assessment. [Table: see text]