bluuebunny/crossref_metadata_2025 huggingface dataset:
Whole genome germline sequencing: Its role in general health screening in family practice, the first study in the UK.
Authors: Eeles Ros A. , Sandberg Michael , Pichert Gabriella C. , Side Lucy , Homfray Tessa , Jones Ann-Britt , Hicks Sophie , Bancroft Elizabeth
Published: June 2022

10510

Background: Whole genome sequencing (WGS) is now possible due to improvements in next generation sequencing technology. This gives the opportunity to incorporate genetic data into family practice health screening. The fulfilment of the potential of WGS lies in its future implementation into family practice. This study aimed to set up a model pathway to undertake WGS for actionable findings and assess its potential role in enhancing health screening. Methods: A pilot study comprised of 100 healthy participants from 2020-2022, recruited from a family practice, consented to routine baseline blood tests, cardiac assessment (ECG and echocardiogram), abdominopelvic ultrasound, all performed at the practice. Review of past medical, and family history was done from electronic health records (EHR). Germline genetic testing consisted of 84 cancer and 77 cardiac genes and whole genome sequencing (566 actionable genes reported), including higher penetrance monogenic mutations, recessive carrier alterations and pharmacogenomics. A multidisciplinary clinical team reviewed integrated results through an iterative process, which fed back to participants. Results: Twenty of 100 individuals (20%) had an actionable genetic variant in either cancer (10 individuals), thrombophilia (8) or cardiac rhythm disorder genes (2). Eighty percent of the participants had a variant in an autosomal recessive gene. Pharmacogenomics results yielded significant variants in 30%. Conclusions: The majority of patients had a significant change in management for themselves or their families. Whole genome sequencing as part of health screening in family practice is feasible and is likely to have significant beneficial health management implications. This study is the first of its kind in family practice and shows how this can be implemented.
Cascade testing of first-degree relatives of patients with pancreatic cancer with confirmed germline genetic mutations: A simulation modeling study.
Authors: Peters Mary Linton Bounetheau , Davidi Barak , Seguin Claudia L. , Eckel Andrew , Pandharipande Pari
Published: June 2022

10513

Background: Universal germline genetic testing is recommended for all patients with pancreatic ductal adenocarcinoma (PDAC). In addition to treatment implications for the patient, it is valuable for family members of the PDAC patient to undertake germline testing to understand their familial cancer risk. We evaluated the potential effectiveness of cascade testing of first-degree relatives (FDRs) of PDAC patients to guide MRI-based screening for PDAC. Methods: We used a microsimulation model of PDAC to estimate the potential life expectancy (LE) benefit of cascade genetic testing of FDRs of PDAC patients. Analysis was performed for eight mutations of interest (ATM, BRCA1, BRCA2, PALB2, Lynch, TP53, CDKN2A, STK11) with relative risk of PDAC ranging from 1.6 – 24. FDRs were defined by their sex, age, and information state (not informed, informed but not tested, test negative, or test positive). Family size and composition, communication of genetic testing results, and uptake of cascade testing were based on published studies. For each FDR group, we simulated multiple MRI-based screening strategies, defined by starting age (FDR age at patient diagnosis to age 75) and frequency (once or annual until age 75), and identified the strategy that resulted in the highest LE. Results: Each PDAC patient would have an average of 4.35 living FDRs. 1.32 of these living FDRs would be informed of the patient’s test results but not undergo testing themselves, and 1.03 would test positive for the mutation of interest. For lower risk mutations (ATM, BRCA2, PALB2), FDRs would only undergo screening if they test positive. For Lynch syndrome, not tested FDRs would undergo screening starting at age 65 or 70, whereas FDRs who test positive would start at 50 or 55. For STK11, the highest risk mutation, FDRs would start screening annually as soon as they are informed of the patient’s test results. The total LE gain for cascade testing of FDRs ranged from 0 (BRCA1) to 1.05 years (STK11). Conclusions: For each PDAC patient identified to have a germline genetic mutation, cascade testing of FDRs could add up to a year life expectancy for the family, in addition to the value of the germline information to the PDAC patient’s care. [Table: see text]
Rates of pathogenic variants in common cancer genes among different racial/ethnic groups.
Authors: Beitsch Peter D. , Wernecke Chloe , Cai Steven , Brown Eric Allen , Ortega Krista , Zhu Vicky , Patel Rakesh
Published: June 2022

10515

Withdrawal Notice: Abstract 10151 by Beitsch et al, entitled "Rates of pathogenic variants in common cancer genes among different racial/ethnic groups," was withdrawn by the authors from presentation and publication. As they were preparing for presentation at the meeting, the authors discovered additional data that potentially altered the abstract's conclusions.

The abstract was withdrawn on May 13, 2022.
Association of germline genetic testing results with chemotherapy regimens received by women with early-stage breast cancer.
Authors: Kurian Allison W. , Abrahamse Paul , Caswell-Jin Jennifer Lee , Hamilton Ann S. , Hofer Timothy , Ward Kevin C , Katz Steven
Published: June 2022

10518

Background: Germline genetic testing is widespread after breast cancer diagnosis and increasingly informs treatment decisions; however, guidelines do not advise selecting chemotherapy regimens based on genetic testing results. It is unknown whether women with pathogenic variants (PVs) in BRCA1, BRCA2 ( BRCA1/2) or other cancer risk genes receive different chemotherapy regimens than women with negative genetic testing results. Methods: We linked Surveillance, Epidemiology and End Results (SEER) registry records from Georgia and California to clinical germline genetic testing results from four participating laboratories (Ambry, Bioreference/GeneDx, Invitae, and Myriad). For this analysis, we included patients who: 1) were diagnosed with stages I-III breast cancer, either hormone receptor-positive and HER2-negative (HR+HER2-) or triple-negative, in Georgia or California from 2013-2017; 2) received chemotherapy based on SEER records; and 3) linked to a genetic testing result. We further selected cases by genetic testing results: 50% PVs in BRCA1/2 or another cancer risk gene, 25% variant of uncertain significance (VUS) only and 25% negative. We extracted details of chemotherapy regimens from SEER text fields completed by registrars. We categorized regimens by drug classes reported (anthracycline, taxane, platinum, nitrogen mustard, other). We used multivariable models that controlled for age, race/ethnicity, stage, grade, surgical procedure, radiotherapy receipt and geographic site to test whether PV carriers received a more intensive chemotherapy regimen. For HR+HER2-, a more intensive regimen was defined as at least three drugs including an anthracycline and for triple-negative, as at least four drugs including an anthracycline and a platinum (versus fewer drugs). Results: 2,293 women were included, 1,451 with HR+HER2- and 842 with triple-negative disease. On multivariable analysis, receipt of a more intensive chemotherapy regimen was associated with having a BRCA1/2 PV among women with HR+HER2- disease (odds ratio 1.22, p = 0.036), but not among women with triple-negative disease. Moreover, platinum use was elevated in BRCA1/2 PV carriers with HR+HER2- disease (from an adjusted model: BRCA1/2 PV 10.9%, other PV 3.6%, VUS 5.6%, negative 5.7%), while in BRCA1/2 PV carriers with triple-negative disease, platinum use did not vary significantly by genetic results ( BRCA1/2 27.7%, other PV 27.7%, VUS 20.9%, negative 20.7%; p = 0.025 for interaction between genetic result and subtype). Conclusions: Compared to women with negative genetic testing results, women with BRCA1/2 PVs more often received a platinum and/or an anthracycline in chemotherapy regimens for early-stage, HR+HER2- breast cancer. This suggests potential over-treatment. No differences in chemotherapy regimen by genetic testing result were observed in triple-negative disease.
Simulation modeling as a tool to support clinical guidelines and care for breast cancer prevention and early detection in high-risk women.
Authors: Jayasekera Jinani , Lowry Kathryn P. , Yeh Jennifer M , Schwartz Marc D , Wernli Karen J , Isaacs Claudine , Kurian Allison W. , Stout Natasha K.
Published: June 2022

10525

Background: To evaluate the incremental short- and long-term benefits and harms of primary prevention with risk reducing medication in high-risk women receiving screening mammography. Methods: We adapted an established, validated Cancer Intervention and Surveillance Modeling Network (CISNET) breast cancer discrete event microsimulation model developed to synthesize data the impact of using risk-reducing medication and annual mammography among women with a 3% or higher five-year risk of developing breast cancer. We also examined the effects of supplemental MRI. The model follows a simulated cohort of millions of US women from birth to death. We used large observational and clinical trial data to derive input parameters for cohort-specific birth rates, breast cancer risk, incidence and stage, screening performance, survival by age, stage, and subtype, treatment efficacy, and other cause mortality. Breast cancer risk was modeled based on family history, breast density, age and history of past breast biopsy. We compared two strategies, annual 3D mammography alone vs. annual 3D mammography and a 5-year course of risk reducing medication at various starting ages, and adding MRI to each approach. Outcomes included the benefits of risk-reducing drugs (avoiding breast cancer) and screening (stage, breast cancer death). Harms included drug side effects and screening false positives and overdiagnosis. Sensitivity analysis tested the impact of uncertainty in model inputs and assumptions on results. Results: Compared to mammography alone, adding risk reducing medication could decrease invasive breast cancer incidence by 30%, and breast cancer deaths by 30% (Table). However, due to reduction in breast cancer incidence, risk reducing medication could result in a 3% increase in false positive results; adding MRI increases benefits but also increases false-positive results. Benefits and harms of risk reducing medication and breast cancer screening strategies for women at high-risk of developing breast cancer. Conclusions: Risk-reducing mediation reduces the risk of hormone-receptor positive breast cancer, and combining this with mammography (and/or MRI) improves earlier detection. Additional work is ongoing to incorporate adverse effects of therapy. Simulation modeling can be used to provide individualized data to facilitate discussions about breast cancer prevention and early detection among high-risk women seen in clinical practice.[Table: see text]
Molecular alterations associated with rapid progression following CDK4/6 inhibitors (CDKi) in metastatic hormone receptor–positive breast cancer (mHRBC).
Authors: West Malinda T , Goodyear Shaun , Kaempf Andy , Kartika Thomas , Ribkoff Jessica , Hobbs Evthokia , Mitri Zahi Ibrahim
Published: June 2022

1054

Background: Combination of CDKi with endocrine therapy is a key treatment for mHRBC due to survival benefit and favorable safety profile. However, progressive disease inevitably develops and outcomes after CDKi discontinuation (dc) are not well-described. Within our institution, we previously reported clinical characteristics and outcomes for a cohort of 140 mHRBC patients who received CDKi therapy. Median progression-free survival (PFS) and overall survival (OS) post-CDKi dc were 7.0 and 15.4 months, respectively. However, 29% experienced rapid progression or death within 4 months following CDKi dc. Molecular predictors of rapid progression after CDKi are unknown and may help define therapies to improve outcomes. In this study, we sought to identify molecular predictors for rapid disease progression after CDKi dc in mHRBC. Methods: We identified within our cohort 34 patients with mHRBC who progressed on CDKi with next-generation sequencing (NGS) performed on pre-CDKi tissue samples. PFS and OS, measured from CDKi dc, were analyzed with the Kaplan-Meier estimator and log-rank test. Rapid progression was analyzed with logistic regression and Fisher’s exact test to evaluate association between pre-CDKi tumor mutation and rapid progression post-CDKi. Results: NGS of pre-CDKi tumor biopsies found 12 genes ( FGF3, FGF4, FGFR, PIK3CA, PTEN, AKT, RB1, CDKN2A, MYC, CCND1, ESR1, TP53) that were altered in ≥3 of the 34 patients. The six patients (18%) with a PTEN mutation (mut) had a median PFS of 3 months and median OS of 4 mo. In comparison, median PFS and OS of PTEN wild-type (wt) patients were 7 mo. (log-rank p=0.008) and 21 mo. (log-rank p<0.001), respectively. Moreover, those with PTENmut tumors were more likely to experience rapid progression compared to PTENwt (odds ratio = 7.0, 95% CI: 1.1 – 60.5, p=0.048). Notably, in the 10 rapid progression patients with pre-CDKi NGS results, alterations to PI3K pathway constituents were prevalent: PTENmut (40%), FGFRmut (50%), AKTmut (20%) and PIK3CAmut (40%). Conclusions: PI3K pathway alterations are prevalent in mHRBC patients who develop rapid progression post-CDKi dc, with PTENmut being the most significant predictor. These hypothesis-generating findings provide the basis for ongoing investigations to find clinical and molecular biomarkers that can help improve outcomes for mHRBC at risk of rapid progression post-CDKi therapy.[Table: see text]
Multiomic approach to examining gut microbiome sampling methods in breast cancer and control subjects.
Authors: Nowicki Christina Ann , Ray Lucille , Engen Phillip , Madrigrano Andrea , Witt Thomas R. , Lad Thomas E. , Cobleigh Melody A. , Mutlu Ece
Published: June 2022

10541

Background: It is well known that estrogen exposure is a major risk factor for breast cancer (BC). Estrogen levels can be affected by the gut microbiome through enterohepatic circulation. No studies regarding gut microbiome changes in BC have examined the colonic mucosal microbiome; and there is no data on which types of gut microbiome studies would be most relevant to the study of the microbiome in BC. Methods: We examined differences in the gut microbiome composition in BC and control subjects using the following sample types: Home-collected stool, endoscopically collected stool, and colonic biopsy samples (for all groups, n=48 total, n=24 BC, n=24 controls). Here, we used both operational taxonomic unit (OTU) and amplicon sequence variant (ASV) based approaches in QIIME2 for 16S rDNA sequencing analysis. Alpha diversity metrics (Chao1, Pielou’s Evenness, Faith PD, Shannon, and Simpson) and beta diversity metrics (Bray-Curtis, Weighted and Unweighted Unifrac) were calculated. LefSe was used to analyze differences in the abundance of various taxa between sample types. Results: Alpha and beta diversity metrics were different between the three sample types when using both OTU or ASV-based analysis, however there were some minor differences between analysis types in these samples. Comparing the 3 sample types, Actinobacteria and Firmicutes (Log10 LDA score >4) were the predominant phyla in home stool samples, while Bacteroidetes and Proteobacteria (Log10 LDA score >4) were higher in abundance in the colonic biopsy samples. Conclusions: Our data shows that alpha and beta diversity metrics differ between sampling methods (home-collected stool, endoscopically collected stool, and colonic biopsies) when looking at the composition of the gut microbiome in BC. Results remained the same regardless of ASV or OTU-based analysis. [Table: see text]
A novel NGS kit solution for multi-cancer early detection using circulating cell free DNA based methylation analysis.
Authors: Zhao Grace Q. , Bao Yun , Wang Heng , Vu Peter , Patel Sandip Pravin , Lin Shengrong
Published: June 2022

10542

Background: Cancer patient survival can be greatly improved by early detection. Cell-free DNA (cfDNA)-based cancer detection using targeted methylation sequencing (TMS) holds great promise. Here, we report the performance of the first cfDNA TMS kit for early cancer detection. Methods: We developed a comprehensive multi-cancer TMS panel, named “Omni1” (900kb) containing ̃3000 cancer specific hypermethylation markers for the detection of the 16 most prevalent solid tumor cancer types in the US. These selected biomarkers all have high signals in cancer, low signals in normal tissue and close to zero background in plasma. The TMS analysis is empowered by Point-n-Seq DNA enrichment and soft bisulfite sequencing technology. Across the different cancer types, the Point-n-Seq Methylation Index (PMI) derived from the Omni1 panel showed over 10 times the difference in the genomic DNA of tumor compared to normal tissues. 8 to 32 early-stage plasma samples from each of the 7 most prevalent cancer types were used for assay testing. cfDNA extracted from each donor was subjected to our Point-n-Seq TMS analysis with the Omni1 panel. The TMS workflow took around five hours, from cfDNA to a sequencing ready library. 6M reads were assigned to each sample resulting in ̃1400X average raw coverage across the target regions. Results: A computational model to calculate the methylation index and the thresholds were established on independent training data sets for each cancer type. For the testing, specificity was set at 89% (CI = 0.81, 0.97, n = 55 self-claimed healthy individuals). The detection rate for stage I (n = 55) and stage II (n = 56) of all 7 cancer types combined is 65% (CI = 0.53,0.78) and 75% (CI = 0.64, 0.86) respectively. Even within this small sample size, it was clear that the detection sensitivity varied among different cancer types, and it increased from stage I to II: colorectal (65%, n = 20; 75%, n = 12), lung (75% n = 8; 92%, n = 12), pancreas (80%, n = 10; 100%, n = 10), ovary (60%, n = 5; 80%, n = 5), breast (40%, n = 7; 100%, n = 3), and prostate cancer (0%, n = 2; 22% n = 9) for stage I and II respectively. A decrease in sensitivity from stage I to II in liver (100%, n = 3; 60%, n = 5) is possibly due to variability from the small sample size. For the cases of CRC, the detection rates obtained from Omni1 are comparable to the stand-alone CRC560 panel (170 kb). Conclusions: In this study we demonstrated that by leveraging an economy-size panel, a robust methylation sequencing kit, and a straightforward analysis methodology, early cancer detection for multiple cancer types can be done with just 1ml plasma. The kit strategy provides an easy-to-use and distributable solution, without the complications of developing a lab-specific test that uses a large methylation panel and a high sequencing cost.
Adapting an evidence-based cancer survivor lifestyle program for cancer prevention and control in African American and Hispanic/Latino communities.
Authors: Kwarteng Jamila L. , Pinsoneault Laura , Manriquez Prado AnaKaren , Aboagye Sophia , Contreras Sandra , Wasserman Erica , Donlevy Derek , Sheean Patricia M. , Tovar Margaret , Vidaver Regina , Kamaraju Sailaja , Stolley Melinda
Published: June 2022

10545

Background: Cancer is the second leading cause of death in Wisconsin with higher mortality rates observed for Black/African American (B/AA) and Hispanic/Latino(a) (Hisp/Lat) communities. Affordable lifestyle interventions targeting healthy nutrition and physical activity patterns tailored to the needs/interests of these communities are critically needed to prevent and control cancer. In this project, we adapted the evidence-based Moving Forward lifestyle program for B/AA breast cancer survivors, which included a program workbook, in-person education/supervised exercise classes, and text messages. We sought to address cancer prevention among B/AA and Hisp/Lat community members in the general population by implementing the program within an urban public recreation system for sustainability. Methods: To help guide the adaptation process, project partners included an academic cancer center, an urban public recreation system, the state department of public health, and a community advisory board. Our approach comprised of focus groups with B/AA and Hisp/Lat residents, surveys collected at community events, and an After-Action Review of a 4-week program pilot. Results: One-hundred community members (58 B/AA and 42 Hisp/Lat) participated in the adaptation phase through eight focus groups (N = 27), 48 surveys, and 25 pilot participants. Seven key program content adaptations were targeted: 1) integrate information on basic cancer biology; 2) explain the association between cancer, nutrition and physical activity; 3) address other diseases besides cancer (heart disease, diabetes); 4) provide cooking demonstrations with culturally relevant tips to facilitate dietary changes; 5) update workbook images and content to reflect race/ethnicity of targeted populations; 6) add information on cancer screening; 7) provide information on local healthy eating and exercise resources. Key adaptations related to conducting the program within a public recreation system included: 1) dividing the program into two 8-week sessions to meet the public recreation system program calendar; 2) eliminating the text message component; 3) providing the program workbook/classes in English and Spanish; and 4) integrating different exercise approaches to meet needs/interests of different age groups, genders, and different fitness levels. Conclusions: Community-academic partnerships and ongoing community engagement led to meaningful adaptations to a cancer prevention and lifestyle program to address cancer disparities in the B/AA and Hisp/Lat communities.
Validation of the PREDICT breast cancer tool in a multiethnic population of U.S. women after a second primary breast cancer.
Authors: Deng Zhengyi , Jones Miranda R , Wang Mei-Cheng , Visvanathan Kala
Published: June 2022

10551

Background: PREDICT is a widely used clinical tool to estimate prognosis based on treatment after a diagnosis of early-stage breast cancer (BC). However, it has not been validated for use in women diagnosed with a second primary BC. Methods: Women diagnosed with one or two BCs between 2000-2013 were identified from the US Surveillance, Epidemiology, and End Results (SEER) program. Validation analyses were conducted separately among women with one and two BCs. For each group, absolute and relative differences in predicted (P) and observed (O) 5-year BC-specific mortality were estimated stratified by estrogen receptor (ER) status. For women with two BCs, mortality prediction was based on demographic and tumor characteristics of their second BCs. Model discrimination was evaluated by receiver-operator curve (ROC) and area under the curve (AUC). Results: 6,729 women diagnosed with a second BC and 357,204 women with only one BC were included. Among women with one ER-positive BC, the predicted (P) and observed (O) BC mortality were comparable [absolute difference (P-O): -0.22%, 95%CI: -0.29%, -0.15%]. For women diagnosed with a second ER-positive disease, the model largely underestimated the BC mortality (P-O: -6.24%, 95%CI: -6.96%, -5.49%). An underestimation of 3%-15% in absolute BC mortality was observed in subgroup analyses based on age, race/ethnicity [P-O for Non-Hispanic (NH) White, NH Black, and Hispanic were -5.63%, -9,3%, and -9.24%], chemotherapy (P-O: -9.06, 95%CI: -10.79, -7.4), radiation therapy (P-O: -5.06, 95%CI: -6.29, -3.93) and tumor characteristics. PREDICT overestimated BC mortality for women diagnosed with one ER-negative BC (P-O: 4.54%, 95%CI: 4.27%, 4.86%) but it performed well for women diagnosed with a second ER-negative BC (P-O: -1.69%, -3.99%, 0.16%). However, in subgroup analyses among women with two BCs the tool underestimated mortality for women with a second ER-negative disease if their first cancer was diagnosed before age 50 years (P-O: -3.27, 95%CI: -6.48, -0.06), was poorly differentiated (P-O: -4.08, 95%CI: -7.09, -1.2), or ER-negative (P-O: -4.68, 95%CI: -7.62, -1.39). The overall AUCs for first and second ER-positive and ER-negative BCs ranged between 0.73 and 0.82. Conclusions: The PREDICT tool largely underestimated the 5-year BC-specific mortality in women diagnosed with a second ER-positive breast cancer and in many subgroups of women diagnosed with a second ER-negative cancer. Novel prognostic tools are needed for women diagnosed with a second breast cancer.
Trends in oncological disease burden: A comparative study between higher and lower-middle-income countries.
Authors: Hanbury Georgina Helen , Jani Chinmay , Abdallah Nour , Shalhoub Joseph , Salciccioli Justin D , Marshall Dominic C
Published: June 2022

10560

Background: Cancer is a major cause of morbidity and mortality worldwide. Ten million cancer-related deaths were recorded in 2020, a rise of 66% over the preceding two decades. Malignancies of the breast, lung, prostate and colon account for over 40% of new cancer diagnoses worldwide. This study observes trends in oncological disease burden among higher (HIC’s) and lower-middle-income countries (LMIC’s) between 2000 and 2019. Methods: Mortality to incidence ratios (MIR) were calculated using the Global Burden of Disease database by extracting age standardized mortality and incidence rates per 100 000 for breast, lung, prostate and colorectal cancer for the years 2000-2019. The European Union (EU) 15+ countries were taken to represent HIC’s. 8 of the LMIC’s in the World Bank group were included as their data quality rating was 3/5 or higher. This cohort comprised Egypt, Sri Lanka, Ukraine, El Salvador, Republic of Moldova, Philippines, Kyrgyzstan and Nicaragua. Breast, lung, colorectal and prostate cancer were included as the tumor types with highest global incidence. Median MIR (with interquartile range) were computed for each LMIC and EU15+ groups for males and females for each of the four tumor types. Results: Between 2000 and 2019 median MIR for the LMIC group was higher than for EU15+ group for all four cancer types in males and females. Wilcoxon rank sum of the 2019 data showed a statistically significant difference (p <0.001) in MIR between HIC’s and LMIC’s (table 1). For breast, prostate and colorectal cancer the difference in median MIR between LMIC group and EU15+ decreased over the observation period, for lung cancer the difference increased. Conclusions: Globally there are wide geographical variations in MIR. Cancer outcomes appear consistently worse in LMIC’s compared to HIC’s. Availability of cancer screening, access to treatment and risk-factor prevalence may contribute to the above trends. Identifying these regional disparities provides an opportunity to target resource allocation to regions that would derive the greatest benefit. [Table: see text]
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.