bluuebunny/crossref_metadata_2025_split huggingface dataset:
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]