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Background: The correlation of ERBB2 copy number gain (CNG) from tissue or circulating tumor DNA (ctDNA) by next-generation sequencing (NGS) with standard HER2 tissue evaluation is not well understood., Materials and Methods: We retrospectively identified patients with ERBB2 CNG on commercial NGS. We described their clinical-pathologic features and calculated the positive predictive value (PPV) of ERBB2 CNG by NGS for HER2-positivity by IHC and FISH testing., Results: 176 patients had NGS revealing an ERBB2 CNG (112 by tumor tissue and 91 by ctDNA). The cancer subtypes with the most cases with ERBB2 CNG by NGS were breast ( n = 67), non-small cell lung ( n = 25), colorectal ( n = 18), gastroesophageal ( n = 17), pancreatic ( n = 11), and uterine ( n = 11). The PPV of ERBB2 CNG in determining HER2 positivity by standard IHC/FISH definitions was 88% for tissue NGS ( n = 57) and 80% for ctDNA ( n = 47). The PPV among breast cancer patients for tissue NGS was 97% ( n = 35) and ctDNA was 93% ( n = 39). However, for non-breast cancer cases, the PPV of ERBB2 amplification by tissue NGS dropped to 76% ( n = 22) and by ctDNA to 44% ( n = 7)., Conclusions: ERBB2 CNG by NGS is detected in numerous malignancies for which HER2 testing is not standard. Detection of ERBB2 CNG by tissue NGS and ctDNA has a high PPV for true HER2-positivity by standard IHC and/or FISH testing in breast cancer., Competing Interests: CONFLICTS OF INTEREST ANS reports honorarium from AstraZeneca. AB reports speaker fees from Lilly, Roche, Thermo fisher scientific, and Foundation Medicine., (Copyright: © 2022 Shah et al.)

Background: Early detection of pancreatic ductal adenocarcinoma (PDA) may improve survival. We previously developed a clinical prediction model among patients with new-onset diabetes to help identify PDAs 6 months prior to the clinical diagnosis of the cancer. We developed and internally validated a new model to predict PDA risk among those newly diagnosed with impaired fasting glucose (IFG)., Methods: We conducted a retrospective cohort study in The Health Improvement Network (THIN) (1995-2013) from the UK. Eligible study patients had newly diagnosed IFG during follow-up in THIN. The outcome was incident PDA diagnosed within 3 years of IFG diagnosis. Candidate predictors were factors associated with PDA, glucose metabolism or both., Results: Among the 138 232 eligible patients with initial IFG diagnosis, 245 (0.2%) were diagnosed with PDA within 3 years. The median time from IFG diagnosis to clinical PDA diagnosis was 326 days (IQR 120-588). The final prediction model included age, BMI, proton pump inhibitor use, total cholesterol, low-density lipoprotein, alanine aminotransferase and alkaline phosphatase. The model achieved good discrimination [area under the curve 0.71 (95% CI, 0.67-0.75)] and calibration (Hosmer and Lemeshow goodness-of-fit test P > 0.05 in 17 of the 20 imputed data sets) with optimism of 0.0012662 (95% CI, -0.00932 to 0.0108771)., Conclusions: We developed and internally validated a sequential PDA prediction model based on clinical information routinely available at the initial appearance of IFG. If externally validated, this model could significantly extend our ability to detect PDAs at an earlier stage., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Clinical and genomic data from patients with early-stage breast cancer suggest more aggressive disease in premenopausal women. However, the association between age, disease course, and molecular profile from liquid biopsy in metastatic breast cancer (MBC) is not well characterized., Methods: Patients were classified as premenopausal (< 45 years), perimenopausal (45-55 years), or postmenopausal (> 55 years). Cohort 1 consisted of patients with MBC who consented for prospective serial evaluation of circulating tumor cells (CTCs) using CellSearch™. Cohort 2 included patients who, as part of routine care, had circulating tumor DNA (ctDNA) sequenced by the Guardant360™ assay. Clinicopathologic data were collected from retrospective review to compare disease features between premenopausal and postmenopausal women., Results: Premenopausal women represented 26% of 138 patients in Cohort 1 and 21% of 253 patients in Cohort 2. In Cohort 1, younger patients had a shorter time to metastases and a higher prevalence of lung and brain metastases. Overall, there were similar rates of ≥ 5 CTCs/7.5 mL, HER2 + CTC expression, and CTC clusters between pre- and postmenopausal women. However, for those with triple negative breast cancer, premenopausal women had a higher proportion of ≥ 5 CTCs/7.5 mL. In Cohort 2, premenopausal women had a higher incidence of FGFR1 (OR 2.75, p = 0.022) and CCND2 (OR 6.91, p = 0.024) alterations. There was no difference in the ctDNA mutant allele frequency or the number of detected alterations between these age groups., Conclusions: Our data reveal that premenopausal women diagnosed with MBC have unique clinical, pathologic, and molecular features when compared to their postmenopausal counterparts. Our results highlight FGFR1 inhibitors as potential therapeutics of particular interest among premenopausal women.

Objectives: This study determined the effects of doxorubicin and/or trastuzumab on diastolic function and the relationship between diastolic function and systolic dysfunction., Background: Doxorubicin and trastuzumab can result in left ventricular ejection fraction (LVEF) declines. However, the effects of these therapies on diastolic function remain incompletely defined., Methods: In a rigorously phenotyped, longitudinal cohort study of 362 breast cancer participants treated with doxorubicin, doxorubicin followed by trastuzumab, or trastuzumab alone, changes in diastolic function were evaluated using linear models estimated via generalized estimating equations. Associations between baseline and changes in diastolic function with LVEF and longitudinal strain were also determined using generalized estimating equations. The Kaplan-Meier estimator derived the proportion of participants who experienced incident diastolic dysfunction. Cox proportional hazards models estimated the associations between participant characteristics and diastolic dysfunction risk, and between diastolic function and cancer therapy-related cardiac dysfunction risk, defined by an LVEF decline of ≥10% to <50%., Results: Over a median of 2.1 years (interquartile range [IQR]: 1.3 to 4.2 years), participants treated with doxorubicin or doxorubicin followed by trastuzumab demonstrated a persistent worsening in diastolic function, with reductions in the E/A ratio, lateral and septal e' velocities, and increases in E/e' (p < 0.01). These changes were not observed with trastuzumab alone. Incident abnormal diastolic function grade occurred in 60% at 1 year, 70% by 2 years, and 80% by 3 years. Abnormal diastolic function grade was associated with a subsequent decrease in LVEF (-2.1%; 95% confidence intervals [CI]: -3.1 to -1.2; p < 0.001) and worsening in longitudinal strain (0.6%; 95% CI: 0.1 to 1.1; p = 0.013) over time. Changes in E/e' ratio were modestly associated with worsening longitudinal strain (0.1%; 95% CI: 0.0 to 0.2; p = 0.022)., Conclusions: A modest, persistent worsening of diastolic function is observed with contemporary breast cancer therapy. Abnormal and worsening diastolic dysfunction is associated with a small risk of subsequent systolic dysfunction. (Cardiotoxicity of Cancer Therapy [CCT]; NCT01173341)., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Cancer therapy-induced cardiomyopathy (CCM) is associated with cumulative drug exposures and preexisting cardiovascular disorders. These parameters incompletely account for substantial interindividual susceptibility to CCM. We hypothesized that rare variants in cardiomyopathy genes contribute to CCM., Methods: We studied 213 patients with CCM from 3 cohorts: retrospectively recruited adults with diverse cancers (n=99), prospectively phenotyped adults with breast cancer (n=73), and prospectively phenotyped children with acute myeloid leukemia (n=41). Cardiomyopathy genes, including 9 prespecified genes, were sequenced. The prevalence of rare variants was compared between CCM cohorts and The Cancer Genome Atlas participants (n=2053), healthy volunteers (n=445), and an ancestry-matched reference population. Clinical characteristics and outcomes were assessed and stratified by genotypes. A prevalent CCM genotype was modeled in anthracycline-treated mice., Results: CCM was diagnosed 0.4 to 9 years after chemotherapy; 90% of these patients received anthracyclines. Adult patients with CCM had cardiovascular risk factors similar to the US population. Among 9 prioritized genes, patients with CCM had more rare protein-altering variants than comparative cohorts ( P≤1.98e-04). Titin-truncating variants (TTNtvs) predominated, occurring in 7.5% of patients with CCM versus 1.1% of The Cancer Genome Atlas participants ( P=7.36e-08), 0.7% of healthy volunteers ( P=3.42e-06), and 0.6% of the reference population ( P=5.87e-14). Adult patients who had CCM with TTNtvs experienced more heart failure and atrial fibrillation ( P=0.003) and impaired myocardial recovery ( P=0.03) than those without. Consistent with human data, anthracycline-treated TTNtv mice and isolated TTNtv cardiomyocytes showed sustained contractile dysfunction unlike wild-type ( P=0.0004 and P<0.002, respectively)., Conclusions: Unrecognized rare variants in cardiomyopathy-associated genes, particularly TTNtvs, increased the risk for CCM in children and adults, and adverse cardiac events in adults. Genotype, along with cumulative chemotherapy dosage and traditional cardiovascular risk factors, improves the identification of patients who have cancer at highest risk for CCM., Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifiers: NCT01173341; AAML1031; NCT01371981.

Background: Cardiovascular disease in patients with breast cancer is of growing concern. The longitudinal effects of commonly used therapies, including doxorubicin and trastuzumab, on cardiac remodeling and function remain unknown in this population. We aimed to define the changes in echocardiographic parameters of structure, function, and ventricular-arterial coupling, and their associations with left ventricular ejection fraction (LVEF) and heart failure symptoms., Methods: In a longitudinal prospective cohort study of 277 breast cancer participants receiving doxorubicin (Dox), trastuzumab (Tras), or both (Dox+Tras), we obtained 1249 echocardiograms over a median follow-up of 2.0 (interquartile range, 1.0-3.0) years. Left ventricular structure, diastolic and contractile function, and ventricular-arterial coupling measures were quantified in a core laboratory blinded to participant characteristics. We evaluated changes in echocardiographic parameters over time, and used repeated-measures regression models to define their association with LVEF decline and recovery. Linear regression models defined the association between early changes in these parameters and subsequent changes in LVEF and heart failure symptoms., Results: Overall, 177 (64%) received Dox, 51 (18%) received Tras, and 49 (18%) received Dox+Tras. With Dox, there was a sustained, modest decrease in LVEF over the follow-up duration (1-year change in LVEF -3.6%; 95% confidence interval [CI], -4.4% to -2.8%; 3-year change -3.8%; 95% CI, -5.1% to -2.5%). With Tras, a similar LVEF decline was observed at 1 year (-4.5%; 95% CI, -6.0% to -2.9%) and 3 years (-2.8%; 95%CI, -5.3 to -0.4%). Participants receiving Dox+Tras demonstrated the greatest declines at 1 year (-6.6%; 95% CI, -8.2 to -5.0%), with partial recovery at 3 years (-2.8%; 95% CI, -4.8 to -0.8%). LVEF declines and recovery were associated primarily with changes in systolic volumes, longitudinal and circumferential strain, and ventricular-arterial coupling indices, effective arterial elastance (Ea) and the coupling ratio Ea/Ees sb , without evidence for effect modification across therapies. Early changes in volumes, strain, and Ea/Ees sb at 4 to 6 months were associated with 1- and 2-year LVEF changes. Similarly, early changes in strain and Ea were associated with worsening heart failure symptoms at 1 year., Conclusions: Doxorubicin and trastuzumab resulted in modest, persistent declines in LVEF at 3 years. Changes in volumes, strain, and ventricular-arterial coupling were consistently associated with concurrent and subsequent LVEF declines and recovery across therapies., (© 2017 American Heart Association, Inc.)

Background & Aims: Approximately 50% of all patients with pancreatic ductal adenocarcinoma (PDA) develop diabetes mellitus before their cancer diagnosis. Screening individuals with new-onset diabetes might allow earlier diagnosis of PDA. We sought to develop and validate a PDA risk prediction model to identify high-risk individuals among those with new-onset diabetes., Methods: We conducted a retrospective cohort study in a population representative database from the United Kingdom. Individuals with incident diabetes after the age of 35 years and 3 or more years of follow-up after diagnosis of diabetes were eligible for inclusion. Candidate predictors consisted of epidemiologic and clinical characteristics available at the time of diabetes diagnosis. Variables with P values <.25 in the univariable analyses were evaluated using backward stepwise approach. Model discrimination was assessed using receiver operating characteristic curve analysis. Calibration was evaluated using the Hosmer-Lemeshow test. Results were internally validated using a bootstrapping procedure., Results: We analyzed data from 109,385 patients with new-onset diabetes. Among them, 390 (0.4%) were diagnosed with PDA within 3 years. The final model (area under the curve, 0.82; 95% confidence interval, 0.75-0.89) included age, body mass index, change in body mass index, smoking, use of proton pump inhibitors, and anti-diabetic medications, as well as levels of hemoglobin A1C, cholesterol, hemoglobin, creatinine, and alkaline phosphatase. Bootstrapping validation showed negligible optimism. If the predicted risk threshold for definitive PDA screening was set at 1% over 3 years, only 6.19% of the new-onset diabetes population would undergo definitive screening, which would identify patients with PDA with 44.7% sensitivity, 94.0% specificity, and a positive predictive value of 2.6%., Conclusions: We developed a risk model based on widely available clinical parameters to help identify patients with new-onset diabetes who might benefit from PDA screening., (Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.)