Use Of eGFR Research Articles

Clinical and Economic Impact of Early Diagnosis of Chronic Kidney Disease in General Practice: The Endorse Study.

The underdiagnosis of chronic kidney disease (CKD) remains a significant public health concern. The Early chroNic kiDney disease pOint of caRe Screening (ENDORSE) project aimed to evaluate the clinical and economic implications of a targeted training intervention for general practitioners (GPs) to enhance CKD awareness and early diagnosis. Data on estimated Glomerular Filtration Rate (eGFR) and Urinary Albumin-Creatinine Ratio (uACR) were collected by 53 Italian GPs from 112,178 patients at baseline and after six months. The intervention involved six months of hybrid training provided by 11 nephrologists, which included formal lectures, instant messaging support, and joint visits for complex cases. The results demonstrated a substantial increase in the use of eGFR (+44.7%) and uACR (+95.2%) tests. This led to a 128.9% rise in the number of individuals screened for CKD using the KDIGO classification, resulting in a 62% increase in CKD diagnoses. The intervention's impact was particularly notable in high-risk groups, including patients with type 2 diabetes, hypertension, and heart failure. A budget impact analysis projected cumulative five-year savings of €1.7 million for the study cohort. When these findings were extrapolated to the entire Italian CKD population, potential savings were estimated at €106.6 million, highlighting significant cost savings for the national health service. The clinical simulation assumed that early diagnosed CKD patients would be treated according to current indications for dapagliflozin, which slows disease progression. The ENDORSE model demonstrated that targeted training for GPs can significantly improve early CKD detection, leading to better patient outcomes and considerable economic benefits. This approach shows promise for broader implementation to address the underdiagnosis of CKD on a national and potentially international scale.

Strategies to Guide Preemptive Waitlisting and Equity in Waittime Accrual by Race/Ethnicity.

Use of eGFR to determine preemptive waitlisting eligibility may contribute to racial/ethnic disparities in access to waitlisting, which can only occur when the eGFR falls to ≤20 ml/min per 1.73 m 2 . Use of an alternative risk-based strategy for waitlisting may reduce these inequities ( e.g. , a kidney failure risk equation [KFRE] estimated 2-year risk of kidney failure) rather than the standard eGFR threshold for determining waitlist eligibility. Our objective was to model the amount of preemptive waittime that could be accrued by race and ethnicity, applying two different strategies to determine waitlist eligibility. Using electronic health record data, linear mixed models were used to compare racial/ethnic differences in preemptive waittime that could be accrued using two strategies: estimating the time between an eGFR ≤20 and 5 ml/min per 1.73 m 2 versus time between a 25% 2-year predicted risk of kidney failure (using the KFRE, which incorporates age, sex, albuminuria, and eGFR to provide kidney failure risk estimation) and eGFR of 5 ml/min per 1.73 m 2 . Among 1290 adults with CKD stages 4-5, using the Chronic Kidney Disease Epidemiology Collaboration equation yielded shorter preemptive waittime between an eGFR of 20 and 5 ml/min per 1.73 m 2 in Black (-6.8 months; 95% confidence interval [CI], -11.7 to -1.9), Hispanic (-10.2 months; -15.3 to -5.1), and Asian/Pacific Islander (-10.3 months; 95% CI, -15.3 to -5.4) patients compared with non-Hispanic White patients. Use of a KFRE threshold to determine waittime yielded smaller differences by race and ethnicity than observed when using a single eGFR threshold, with shorter time still noted for Black (-2.5 months; 95% CI, -7.8 to 2.7), Hispanic (-4.8 months; 95% CI, -10.3 to 0.6), and Asian/Pacific Islander (-5.4 months; -10.7 to -0.1) individuals compared with non-Hispanic White individuals, but findings only met statistical significance criteria in Asian/Pacific Islander individuals. When we compared potential waittime availability using a KFRE versus eGFR threshold, use of the KFRE yielded more equity in waittime for Black ( P = 0.02), Hispanic ( P = 0.002), and Asian/Pacific Islander ( P = 0.002) patients. Use of a risk-based strategy was associated with greater racial equity in waittime accrual compared with use of a standard single eGFR threshold to determine eligibility for preemptive waitlisting.

Addressing Resistance to Therapy in Colorectal Cancer

Addressing Resistance to Therapy in Colorectal Cancer

Variability in Nonvitamin K Oral Anticoagulant Dose Eligibility and Adjustment According to Renal Formulae and Clinical Outcomes in Patients With Atrial Fibrillation With and Without Chronic Kidney Disease: Insights From ORBIT‐AF II

Background Nonvitamin K oral anticoagulants require dose adjustment based on kidney function.The most common estimate of kidney function employed in clinical practice is estimated glomerular filtration rate (eGFR); however, product monographs recommend the use of the Cockcroft-Gault estimated creatinine clearance (eCrCl) for dose adjustment. Methods and Results The authors included patients enrolled in the ORBIT-AF II (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation AF II) trial. Dosing was considered inappropriate when use of eGFR resulted in a lower (undertreatment) or higher (overtreatment) dose than that recommended by the eCrCl. The primary outcome of major adverse cardiovascular and neurological events was a composite of cardiovascular death, stroke or systemic embolism, new-onset heart failure, and myocardial infarction. Among 8727 in the overall cohort, agreement between eCrCl and eGFR was observed in 93.5% to 93.8% of patients. Among 2184 patients with chronic kidney disease (CKD), the agreement between eCrCl and eGFR was 79.9% to 80.7%. Dosing misclassification was more frequent in the CKD population (41.9% of rivaroxaban users, 5.7% of dabigatran users, and 4.6% apixaban users). At 1 year, undertreated patients in the CKD group had significantly greater major adverse cardiovascular and neurological events (adjusted hazard ratio, 2.93 [95% CI, 1.08-7.92]) compared with the group with appropriate nonvitamin K oral anticoagulants dosing (P=0.03). Conclusions The prevalence of misclassification of nonvitamin K oral anticoagulants dosing was high when using eGFR, particularly among patients with CKD. Among patients with CKD, potential undertreatment due to inappropriate and off-label renal formulae may result in worse clinical outcomes. These findings highlight the importance of using eCrCl, and not eGFR, for dose adjustment in all patients with AF receiving nonvitamin K oral anticoagulants.

Variability of estimated glomerular filtration rate and 99m Tc-DTPA glomerular filtration rate: implications for a single time-point sampling regime.

This work aimed to determine the implications of the variability in estimated glomerular filtration rate (eGFR) for the prediction of measured GFR (mGFR) for selection of sampling time-point in single-sample 99m Tc-diethylene-triamine-pentaacetate (DTPA) mGFR. Patient studies were used to compare eGFR and mGFR ( n = 282). The eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration 2009 equation, from serum creatinine values measured in the laboratory ( n = 27) or using a point-of-care testing device ( n = 255). The mGFR was taken as the true value, and the root mean square error (RMS err ) in eGFR was calculated. Receiver operator characteristic curves were generated comparing the sensitivity and specificity of eGFR for the prediction of mGFR within the British Nuclear Medicine Society (BNMS) 2018 guideline ranges. The overall eGFR RMS err was 19.3 mL/min/1.73 m 2 . Use of eGFR to predict mGFR in the ranges specified in the BNMS 2018 guidelines (25-50; 50-70; 70-100; and >100) achieved the following specificity and sensitivity for each individual range (97%, 71%; 92%, 47%; 81%, 48%; and 74%, 90%). For the middle ranges (50-70 and 70-100) the sensitivity is very low, less than 50%; more studies are classified incorrectly on the basis of eGFR in these ranges than correctly. This work shows that serum creatinine eGFR is not sufficiently accurate to predict the optimum single-sample time-point for 99m Tc-DTPA mGFR prior to measurement. It is the recommendation of this study that a single sampling time-point should be chosen for studies eGFR > 40 ml/min/1.73 m 2 as opposed to the use of eGFR to determine the sampling time-point.

Interpretation of Estimated Glomerular Filtration Rate

Glomerular filtration rate (GFR) plays an important role in the clinical evaluation of renal function, classification, prognosis prediction, and drug dosing in patients with acute or chronic kidney disease . Estimated GFR (eGFR) is calculated based on endogenous filtration markers, such as creatinine and cystatin C. These are useful markers, but it is necessary to understand the clinical settings in which eGFR, calculated using creatinine or cystatin C, may be less accurate. Several equations, including the Cockcroft and Gault, modification of diet in renal disease, and chronic kidney disease-epidemiology collaboration (CKD-EPI) equations, are used to calculate eGFR. The latter is most common because it has high accuracy and can predict prognosis. Recently, a new race-omitting CKD-EPI equation has been developed but further studies are required to determine whether it can be applied in clinical practice and research. Furthermore, careful use of eGFR is needed in acute kidney injury, kidney transplantation, and dialysis patients. Drug dosing must be guided by accurate GFR assessment. In addition to medical care, GFR assessment is also important for public health and research. Therefore, further studies are needed to reevaluate and develop the equations for accurate eGFR calculations.

Abstract 9317: Variability in Non-Vitamin K Oral Anticoagulant Dose Adjustment According to Renal Formulae and Clinical Outcomes in Atrial Fibrillation Patients: Insights From ORBIT-AF II

Background: Non-Vitamin K Oral Anticoagulants (NOACs) require dose adjustment based on kidney function. Glomerular filtration rate (eGFR) is most commonly used in clinical practice, but product monographs recommend the use of Cockcroft-Gault creatinine clearance equation (eCrCl) for dose adjustment. We sought to evaluate misclassification of NOAC renal dosing using eGFR versus eCrCl. Methods: We included patients enrolled in the ORBIT-AF II trial. eGFR was calculated using both the MDRD and CKD-EPI formulae. Dose adjustments and eligibility were based on landmark trials. Dosing was considered inappropriate when use of eGFR resulted in a lower (under-treatment) or higher (over-treatment) dose than that recommended by eCrCl. Agreement in NOAC dosing between eCrCl and eGFR was assessed. The primary outcome of major adverse cardiovascular and neurological events (MACNE) was a composite of cardiovascular death, stroke or systemic embolism, and myocardial infarction. Sensitivity analysis was performed for the subgroup of patients with CKD (eCrCl<60 ml/min). Results: Among 8,727 in the overall cohort, agreement between CrCl and eGFR was observed in 93.5-93.8% of patients. Among 2,184 patients with CKD, the agreement between eCrCl and eGFR was 79.9-80.7%. Dosing misclassification was observed in 11.5% of rivaroxaban and 1.1% of dabigatran and apixaban treated patients. Patients receiving an inappropriate NOAC dose had a lower mean eCrCl and eGFR. Undertreated patients were older and of lower body weight compared to overtreated and appropriately dosed patients. Dosing misclassification was more frequent in the CKD population (41.9% of rivaroxaban, 5.7% of dabigatran and 4.6% apixaban patients). At one-year, undertreated patients in the CKD group had significantly greater MACNE [adjusted HR 2.90 (1.09-7.75) compared to appropriate NOAC dosing group p = 0.03]. Conclusions: The prevalence of NOAC dosing misclassification NOACs was high when using eGFR, particularly among those with CKD. Among patients with CKD, potential undertreatment due to inappropriate and off-label renal formulae may result in worse clinical outcomes. These findings highlight the importance of using eCrCl, and not eGFR, for dose-adjustment in all AF patients receiving NOACs.

Quantitative proteomic profiling of esophageal adenocarcinoma tumors to assess prevalence of approved targets and elucidate novel biomarkers.

343 Background: Esophageal adenocarcinoma (EAC) continues to have extremely poor prognosis despite advances in surgical and oncological regimens. Targeted and immune therapy hold promise to improve outcomes in solid tumors including EAC. At present HER-2 and anti-PD-L1 therapies are approved by the FDA for EAC. Additionally, off-label use of EGFR directed therapy has been reported. The aim of this study is to measure expression of 80+ oncoproteins in EAC using multiplexed mass spectrometry to elucidate expression of currently approved-drug targets and explore promising new targets for drug development. Methods: After Institutional Review Board approval (Mayo Clinic and KUMC), EAC patients whose tumors were resected via esophagectomy before chemotherapy and/or radiation were identified. Normal esophageal mucosa samples with no history of EAC were also retrieved for analysis. Tissue sections were microdissected to exclude stroma from adenocarcinoma cells. Isolated EAC cells were solubilized for mass spectrometry-based quantitation of more than 80 clinically relevant tumor markers. Results: 55 EAC tissues were analyzed. HER2, PD-L1 and EGFR were overexpressed only in 16.3%, 0%, and 0% of patients, respectively. New oncoproteins #2 and #6 were noted to have high (7,634.0 and 27,222.6 attomoles/ug) and consistent (98.1% and 94.5%) overexpression in EAC samples. Expression of HER2, oncoproteins #2 and #6 were significantly higher in EAC compared to normal esophageal mucosa. There was no statistical difference in the expression of PD-L1 and EGFR between EAC and normal samples. Conclusions: Mass spectrometry revealed a very low prevalence of target oncoproteins in EAC for currently used drugs. Our study potentially reveals alternate markers which are near universally present at high levels and should be further explored for targeted treatment.[Table: see text]

Limited Evidence for Use of a Black Race Modifier in eGFR Calculations: A Systematic Review.

Commonly used estimated glomerular filtration rate (eGFR) equations include a Black race modifier (BRM) that was incorporated during equation derivation. Race is a social construct, and a poorly characterized variable that is applied inconsistently in clinical settings. The BRM results in higher eGFR for any creatinine concentration, implying fundamental differences in creatinine production or excretion in Black individuals compared to other populations. Equations without inclusion of the BRM have the potential to detect kidney disease earlier in patients at the greatest risk of chronic kidney disease (CKD), but also has the potential to over-diagnose CKD or impact downstream clinical interventions. The purpose of this study was to use an evidence-based approach to systematically evaluate the literature relevant to the performance of the eGFR equations with and without the BRM and to examine the clinical impact of the use or removal. PubMed and Embase databases were searched for studies comparing measured GFR to eGFR in racially diverse adult populations using the Modification of Diet in Renal Disease or the 2009-Chronic Kidney Disease Epidemiology Collaboration-creatinine equations based on standardized creatinine measurements. Additionally, we searched for studies comparing clinical use of eGFR calculated with and without the BRM. Here, 8632 unique publications were identified; an additional 3 studies were added post hoc. In total, 96 studies were subjected to further analysis and 44 studies were used to make a final assessment. There is limited published evidence to support the use of a BRM in eGFR equations.

HPV-associated penile cancer: Impact of copy number alterations in miRNA/mRNA interactions and potential druggable targets.

Penile cancer (PeCa) is a rare disease, but its incidence has increased worldwide, mostly in HPV+ patients. Nevertheless, there is still no targeted treatment for this carcinoma. To predict the main signaling pathways involved in penile tumorigenesis and its potential drug targets. Genome-wide copy number profiling was performed in 28 PeCa. Integration analysis of CNAs and miRNAs and mRNA targets was performed by DIANA-TarBase v.8. The potential impact of the miRNAs/target genes on biological pathways was assessed by DIANA-miRPath v.3.0. For each miRNA, KEGG pathways were generated based on the tarbase and microT-CDS algorithms. Pharmaco-miR was used to identify associations between miRNAs and their target genes to predict druggable targets. 269 miRNAs and 2,395 genes were mapped in cytobands with CNAs. The comparison of the miRNAs mapped at these cytobands and the miRNAs that were predicted to regulate the genes also mapped in these regions, resulted in a set of common 35 miRNAs and 292 genes. Enrichment pathway revealed their involvement in five top signaling pathways. EGFR and COX2 were identified as potential druggable targets. Our data indicate the potential use of EGFR and COX2 inhibitors as a target treatment for PeCa patients.

13-LB: Measured vs. Estimated GFR in Young Adults with Uncomplicated T1D

Background: eGFR equations are used to monitor progression of kidney disease, but their performance is incompletely understood in young adults with T1D and preserved GFR. To address this deficit, we compared two eGFR equations (creatinine-based CKD-EPI and modified Schwartz) to mGFR in this population. Methods: GFR based on plasma iohexol clearance was measured in 53 patients (24 males) with T1D, as part of the CAN-SOLVE CKD study Results: Mean age was 20.6±2.1 yrs with mean diabetes duration of 13.1±3.3 yrs. Mean HbA1c and ACR were 8.1±1.3 and 1.6±1.9 mg/mmol, respectively. Mean mGFR was 107.6±15.9 ml/min/1.73 m2. The Schwartz eGFR had a smaller mean bias (5.6 vs. 27.4 ml/min/1.73m2), better accuracy, and overall correlation compared to the CKD-EPI eGFR, while the latter had slightly superior precision. However, both equations were in poor agreement with mGFR. Examination of the Bland Altman plots reveals that, in the lower normal range, the CKD-EPI equation overestimated mGFR. The modified Schwartz equation showed no discernible tendencies. Conclusion: In young adults with T1D and preserved GFR, the modified Schwartz eGFR performed slightly better than CKD-EPI eGFR. Overall, however, both were in poor agreement with mGFR suggesting caution about the use of eGFR as a surrogate outcome in longitudinal studies and emphasizing the need to develop novel equations for this population. Disclosure K. Gaebe: None. C. A. White: None. F. H. Mahmud: Advisory Panel; Self; Insulet Corporation, Lilly Diabetes. J. W. Scholey: None. L. Motran: None. M. Palaganas: None. Y. T. Elia: None. D. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Scientific Affairs, LLC., Lilly Diabetes, Merck & Co., Inc., Mitsubishi-Tanabe, Maze Inc, Prometic, Novo Nordisk, Sanofi. E. B. Sochett: None. Funding Canadian Institutes of Health Research (20R26070); JDRF

Estimated glomerular filtration rate is a marker of mortality in the European Scleroderma Trials and Research Group (EUSTAR) database.

The study aim was to evaluate the estimated glomerular filtration rate (eGFR), its association with clinical disease and its predictive ability with respect to mortality in SSc patients from the European Scleroderma Trials and Research Group (EUSTAR) database. SSc patients from the EUSTAR database who had items required for the calculation of eGFR at a baseline visit and a second follow-up visit available were included. A cut-off eGFR value of 60 ml/min was chosen for all SSc patients, and 30 ml/min for those with scleroderma renal crisis (SRC). Cox regression and competing risk analysis were performed to evaluate the use of eGFR as a predictive factor of mortality. A total of 3650 SSc patients were included in this study. The median serum level of creatinine and the mean of eGFR were 0.8 mg/dl (interquartile range = 0.6-0.9) and 86.6 ± 23.7 ml/min, respectively. The eGFR was significantly lower in patients with pulmonary hypertension. Overall survival (OS) was significantly reduced in SSc patients with eGFR < 60 ml/min compared with patients with eGFR ≥ 60 ml/min [OS at 5 years 0.763 (95% CI: 0.700, 0.814) vs 0.903 (95% CI: 0.883, 0.919; P < 0.001)]. In multivariable analysis, OS was associated with male gender (P < 0.01), systolic pulmonary arterial pressure (sPAP) (P < 0.001) and eGFR (P < 0.001). The cumulative incidence of deaths due to SSc was associated with increased sPAP (P < 0.001) and reduced eGFR (P < 0.05). The OS at 5 years of 53 SRC patients was not significantly different between SSc patients with eGFR > 30 ml/min and those with eGFR <30 ml/min. eGFR represents a predictive risk factor for overall survival in SSc. The eGFR, however, does not represent a risk factor for death in SRC.

Association of the Estimated Glomerular Filtration Rate With vs Without a Coefficient for Race With Time to Eligibility for Kidney Transplant

Kidney transplant is associated with improved survival and quality of life among patients with kidney failure; however, significant racial disparities have been noted in transplant access. Common equations that estimate glomerular filtration rate (eGFR) include adjustment for Black race; however, how inclusion of the race coefficient in common eGFR equations corresponds with measured GFR and whether it is associated with delayed eligibility for kidney transplant listing are unknown. To compare eGFR with measured GFR and evaluate the association between eGFR calculated with vs without a coefficient for race and time to eligibility for kidney transplant. This prospective cohort study used data from the Chronic Renal Insufficiency Cohort, a multicenter cohort study of participants with chronic kidney disease (CKD). Self-identified Black participants from that study were enrolled between April 2003 and September 2008, with follow-up through December 2018. Statistical analyses were completed on November 11, 2020. Estimated GFR, measured annually and estimated using the creatinine-based Chronic Kidney Disease-Epidemiology (CKD-EPI) equation with and without a race coefficient. Iothalamate GFR (iGFR) measured in a subset of participants (n = 311) and time to achievement of an eGFR less than 20 mL/min/1.73 m2, an established threshold for kidney transplant referral and listing. Among 1658 self-identified Black participants, mean (SD) age was 58 (11) years, 848 (51%) were female, and mean (SD) eGFR was 44 (15) mL/min/1.73 m2. The CKD-EPI eGFR with the race coefficient overestimated iGFR by a mean of 3.1 mL/min/1.73 m2 (95% CI, 2.2-3.9 mL/min/1.73 m2; P < .001). The mean difference between CKD-EPI eGFR without the race coefficient and iGFR was of smaller magnitude (-1.7 mL/min/1.73 m2; 95% CI, -2.5 to -0.9 mL/min/1.73 m2). For participants with an iGFR of 20 to 25 mL/min/1.73 m2, the mean difference in eGFR with vs without the race coefficient and iGFR was 5.1 mL/min/1.73 m2 (95% CI, 3.3-6.9 mL/min/1.73 m2) vs 1.3 mL/min/1.73 m2 (95% CI, -0.3 to 2.9 mL/min/1.73 m2). Over a median follow-up time of 4 years (interquartile range, 1-10 years), use of eGFR calculated without vs with the race coefficient was associated with a 35% (95% CI, 29%-41%) higher risk of achieving an eGFR less than 20 mL/min/1.73 m2 and a shorter median time to this end point of 1.9 years. In this cohort study, inclusion of the race coefficient in the estimation of GFR was associated with greater bias in GFR estimation and with delayed achievement of a clinical threshold for kidney transplant referral and eligibility. These findings suggest that nephrologists and transplant programs should be cautious when using current estimating equations to determine kidney transplant eligibility.

Early Post-transplant Renal Functions Predict Incidence of Acute Rejection in Kidney Transplantation

Objectives: After renal transplantation, a remarkable improvement of impaired patient’s kidney function is often observed. Preserving improved kidney function ensures long-term renal allograft survival. However, there are different risk factors; the acute rejection is the major risk factor. Therefore, the aim of the present study was to examine renal function within the first six months as independent variables in predicting long-term survival and incidence of acute rejection.&#x0D; Methods: Fifty-three patients who underwent kidney transplantation in 2016 and 2017 in King Abdulaziz Medical City- National Guard were evaluated consecutively1 and 2-month pre-transplant up to six months’ post-transplant. Time course of changes in kidney functions; measurements of serum creatinine (Scr), blood urea nitrogen(BUN), albumin, calcium, sodium and potassium were recorded. Estimated glomerular filtration rate (eGFR) and anion gap (AGAP) were also reported. In addition, age, anthropometric factors and causes of ESRD were analyzed.&#x0D; Results: Lower level of calcium was observed in 40% of patient’s two-month pre-transplantation and 69% of patients one month before. Normalization of calcium was achieved in all patients starting from second month post-transplantation. All patients presented elevated serum potassium level in pre-transplant months, however, renal transplant normalize potassium level starting from first month. A remarkable higher level of serum BUN was observed in all pre-transplant patients followed by dramatically decreased after renal transplant for first four months and remain in normal level starting from month 5. Likewise, serum creatinine was highly elevated in all pre-transplant patients. A profound reduction in serum creatinine started from month 1 post-transplant and normalizes at month 4. Moreover, both eGFR and AGAP were kept in normal level immediately after renal transplantation. All patients with early acute rejection during mean follow-up period have a remarkable elevated level of serum creatinine and profound decrease in eGFR starting from first month. While a significant higher level of serum BUN observed in fifth month only and serum albumin in third month.&#x0D; Conclusion: Significant elevation of serum creatinine and reduction in eGFR starting from first month were associated with post-transplanted patients with early acute rejection. The clinical use of eGFR and serum creatinine may aid in predicting incidence of early acute rejection.

Association of socioeconomic status and molecular testing in stage IV colorectal cancer.

e19023 Background: The use of EGFR monoclonal antibodies extends life for patients with advanced colorectal cancers (CRC) whose tumors exhibit wild type KRAS. Research suggests that KRAS testing is underused, denying patients access to targeted therapy. We sought to study the role of socioeconomic factors in the application of KRAS testing. Methods: We identified subjects with stage IV colorectal adenocarcinoma diagnosed between 2010 and 2015 in the Surveillance Epidemiology and End Results (SEER) database. We identified clinical and demographic characteristics, including diagnosis year, race, ethnicity, sex, age, geography, median household income (MHI), insurance coverage, tumor grade, and tumor location. We used multivariable logistic regression models to evaluate associations between these factors and the rate of KRAS testing. We constructed Cox proportional hazard models to assess the impact of KRAS testing on survival. Results: We identified 37,676 patients with stage IV CRC, 31.1% of whom were tested for KRAS mutations. The rate of KRAS testing varied from 23.2% to 56.5% across geographic regions. Patients were more likely to be tested if they were younger (OR 5.10 for age 20-29 vs 80+, 95% CI 3.99-6.54, p &lt; 0.0001), diagnosed more recently (OR 1.92 for 2015 vs 2010, 95% CI 1.77-2.08, p &lt; 0.0001), or lived in an area of high MHI (OR 1.24 for MHI of &gt; $69,311 vs &lt; $49,265, 95% CI 1.14-1.35, p &lt; 0.0001). Patients were less likely to be tested if they had Medicaid (OR 0.83, 95% CI 0.77-0.88, p &lt; 0.0001), were unmarried (OR 0.78, 95% CI 0.75-0.82, p &lt; 0.0001), or had rectal cancer (OR 0.79, 95% CI 0.74-0.84, p &lt; 0.0001). The risk of death was decreased in patients who received KRAS testing (HR 0.77, 95% CI 0.75-0.80, p &lt; 0.0001). The median survival for patients who were tested was 20 months (95% CI 20-21), vs 11 months (95% CI 10-11) for patients not tested (p &lt; 0.001). Conclusions: We found a low rate of KRAS testing overall in CRC patients diagnosed between 2010 and 2015. Testing rates increased over the study period, but, even as of 2015, the majority of patients did not have KRAS testing.We found thatpatients with Medicaid and those who lived in areas of lowest income were less likely to have KRAS testing. Prior studies reported that Medicaid was associated with lower utilization of KRAS testing, but ours represents a more contemporary cohort and is the first to evaluate Medicaid and MHI simultaneously. Ideally Medicaid insurance would increase access to molecular testing for patients with limited resources, but our model suggests that income-based disparities persist despite Medicaid insurance.

Abstract 357: Pan-HER, an antibody mixture simultaneously targeting EGFR, HER2, and HER3, is highly effective in triple negative breast cancer patient-derived xenografts

Abstract As a heterogeneous disease, breast cancer is clinically classified taking into account the expression of estrogen receptor alpha (ERα), progesterone (PR), and the presence/amplification status of the oncogenic human epidermal growth factor receptor 2 (HER2). Triple negative breast cancer (TNBC) represents ~10-20% of all cases, and displays poor prognosis and aggressive clinical course. EGFR is more often overexpressed in TNBC than in other breast cancer subtypes, providing cancer cells with compensatory signals that greatly contribute to the development of resistance and survival in response to therapy. This characteristic has made HER family members potentially important therapeutic targets. The present study was designed to investigate the effects of Pan-HER, a novel mixture of six monoclonal antibodies directed against members of the human epidermal growth factor receptor (HER) family EGFR, HER2, and HER3, in a preclinical trial of TNBC patient-derived xenografts (PDXs). Fifteen low passage TNBC PDX tumor samples were transferred and engrafted into the right mammary fat pad of mice for engraftment. When tumors reached an average size of 150-200 mm3, mice were randomized (n ≥ 3 per group), and treated following three, one-week cycles, consisting of 3 times/week intraperitoneally (IP) injection of either formulation buffer (Vehicle control) or Pan-HER (50 mg/kg). At the end of treatment, tumors were collected for western blot, RNA and immunohistochemistry analyses. All 15 TNBC PDXs were responsive to Pan-HER treatment, showing significant reductions in tumor growth consistent with Pan-HER-mediated tumor down-modulation of EGFR and HER3 protein levels and significantly decreased activation of associated HER family signaling pathways including AKT, ERK and NF-κB. Tumor regression was observed in five of the models, which corresponded to those PDX tumor models with the highest level of HER family activation. This observation may provide a plausible explanation for the response of TNBC tumors to Pan-HER as an indication of the potential use of EGFR and associated signaling expression as biomarkers for selecting patients that may benefit of targeting these proteins. In summary, this preclinical TNBC PDX trial with Pan-HER provides strong justification for further biomarker-guided studies in TNBC. The finding that tumors were affected rapidly and effectively, with long-lasting results, offers exciting perspectives to treat this aggressive form of breast cancer, for which available treatment options are currently limited. Citation Format: Roberto R. Rosato, Don S. Choi, Wei Qian, Wen Chen, Johan Lantto, Ivan D. Horak, Michael Kragh, Jenny C. Chang. Pan-HER, an antibody mixture simultaneously targeting EGFR, HER2, and HER3, is highly effective in triple negative breast cancer patient-derived xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 357.

A novel proteotoxic combination therapy for EGFR+ and HER2+ cancers.

While HER2 and EGFR are overexpressed in breast cancers and multiple other types of tumors, the use of EGFR and/or HER2 inhibitors have failed to cure many cancer patients, largely because cancers acquire resistance to HER2/EGFR-specific drugs. Cancers that overexpress the HER-family proteins EGFR, HER2, and HER3 are uniquely sensitive to agents that disrupt HER2 and EGFR protein folding. We previously showed that disruption of disulfide bond formation by Disulfide Disrupting Agents (DDAs) kills HER2/EGFR overexpressing cells through multiple mechanisms. Herein, we show that interference with proline isomerization in HER2/EGFR overexpressing cells also induces cancer cell death. The peptidyl-prolyl isomerase inhibitor Cyclosporine A (CsA) selectively kills EGFR+ or HER2+ breast cancer cells in vitro by activating caspase-dependent apoptotic pathways. Further, CsA synergizes with the DDA tcyDTDO to kill HER2/EGFR overexpressing cells in vitro and the two agents cooperate to kill HER2+ tumors in vivo. There is a critical need for novel strategies to target HER2+ and EGFR+ cancers that are resistant to currently available mechanism-based agents. Drugs that target HER2/EGFR protein folding, including DDAs and CsA, have the potential to kill cancers that overexpress EGFR or HER2 through the induction of proteostatic synthetic lethality.

Variability in Non–Vitamin K Antagonist Oral Anticoagulants Dose Adjustment in Atrial Fibrillation Patients With Renal Dysfunction: The Influence of Renal Function Estimation Formulae

BackgroundNon–vitamin K antagonist oral anticoagulants (NOACs) require renal dose adjustment. The most common estimates of renal function in clinical practice are derived from estimated glomerular filtration rate (eGFR; Modified Diet in Renal Disease [MDRD] or the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]). However, the landmark stroke prevention trials and product monographs recommend the use of the Cockcroft-Gault creatinine clearance equation (eCrCl) for drug eligibility and dose adjustment. We sought to evaluate the agreement in NOAC dosing between these 3 equations in a large population of patients with atrial fibrillation and moderate chronic kidney disease. MethodsWe identified 831 patients with non–dialysis-dependent chronic kidney disease and atrial fibrillation (CHA2DS2-VASc 3.9). For each patient, eCrCl, MDRD eGFR, and CKD-EPI eGFR were prospectively calculated. Eligibility criteria for NOAC medications were evaluated by comparing the eGFR as estimated by MDRD or CKD-EPI equation with the eCrCl as estimated by Cockcroft-Gault, with the latter regarded as the "gold standard." ResultsThe use of eGFR resulted in significant misclassification with respect to NOAC dosing. Compared with eCrCl, the MDRD eGFR and CKD-EPI eGFR misclassified 36.2% and 35.8% of patients, respectively. The misclassification resulted in undertreatment (eg, inappropriate dose reduction; 26.9% MDRD, 28.8% CKD-EPI), and to a lesser extent overtreatment (eg, inappropriate use of standard dose; 9.3% MDRD, 7.0% CKD-EPI). ConclusionsMDRD and CKD-EPI eGFR fail to correctly identify a significant proportion of patients who require NOAC dose adjustment, limiting their clinical utility. Cockcroft-Gault eCrCl should be calculated for all patients in whom a NOAC is being prescribed.

Pragmatic Use of Kidney Function Estimates for Drug Dosing: The Tide Is Turning.

Creatinine clearance has been the most common method of estimating kidney function for the purpose of drug dosing for decades. The availability and extensive clinical use of estimated glomerular filtration rate (eGFR) now provides clinicians a potential alternative. Currently, data demonstrating the validity of eGFR-based drug dosing is limited, but proof of principle has been established and the tide related to use of eGFR for drug dosing appears to be turning. Use of the same kidney function estimate for management of kidney disease, drug development and dosing, and harmonization in all clinical arenas would be ideal. Use of multiple equations can lead to differences in kidney function estimates and corresponding drug dosing regimens, which necessitates clinical judgment and a pragmatic approach when rendering drug dosing decisions. Careful consideration of the risk-benefit ratio of individual drugs and dosing regimens within each patient is warranted. Going forward, FDA guidance will likely incentivize pharmaceutical manufacturers to generate eGFR-based dosing recommendations in addition to creatinine clearance for inclusion in the label of newly approved drugs. However, dosing information for currently approved drugs will continue to be based on creatinine clearance alone, so clinicians must be vigilant in the assessment of kidney function in order to provide optimal pharmacotherapy.

Abstract 410: Identifying ovarian cancer specific targeted drugs using high-throughput drug sensitivity profiles of primary cancer cells

Abstract Ovarian cancer (OvCa) is the sixth most common cancer in women and leading cause of death from gynecologic diseases. Poor prognosis in OvCa is due to late diagnosis and acquired resistance to the commonly used platinum-based regimens. A significant setback for OvCa treatment is the lack of reliable biomarkers and effective targeted therapies. In order to discover novel therapeutic opportunities with approved and emerging drugs for OvCa, we have established primary cultures using ascites or tumor tissue samples from chemo-refractory ovarian cancer patients for ex vivo Drug Sensitivity and Resistance Testing (DSRT) and genomic profiling. In addition, we have performed DSRT with 31 established OvCa cell lines. Comparison of the drug sensitivity profiles of ten primary cancer cell cultures and 31 OvCa cell lines revealed previously unanticipated cancer selective drug vulnerabilities. Several drug groups were identified suggesting that the sensitive samples were addicted to the corresponding signaling networks. For example, in a 53-year old chemorefractory low grade serous OvCa patient, genomic and transcriptomic analyses revealed a fusion gene of NRG-1, a target that was recently reported to involve the NRG1/ERBB3 activation loop in OvCa. We found high expression of ERBB2 and ERBB3 by RNA-seq as well as high levels of phospho-ERBB3, phospho-ERBB2 and phospho-EGFR by immunohistochemistry. In agreement with the molecular mechanism, DSRT analysis identified significant sensitivity of primary cancer cells to EGFR inhibitors, such as erlotinib and to dual EGFR and Her2 inhibitor afatinib. The patient has received combination therapy of gemcitabine and erlotinib during nine months, followed by afatinib monotheraphy that has lead to complete remission after six months treatment. We have detected activated NRG1/ERBB3 activation loop also in several additional ovarian cancer patient cases, highlighting the importance of this signaling pathway in ovarian cancer pathogenesis. Our study reveals that a subset of serous ovarian cancer patients with activating NRG1/ERBB3 signaling loop have clinical benefits from repurposing dual EGFR/Her2 inhibitor afatinib, providing a basis for the clinical use of EGFR and dual EGFR/Her2 tyrosine kinase inhibitors in clinical treatment. In conclusion, DSRT technology together with molecular profiling provides a powerful strategy to identify tumor driver signals and select clinically actionable inhibitors. Hence, this type of systems medicine approach can significantly improve the power of mainly genomics-oriented personalized medicine approaches. Citation Format: Astrid Murumägi, Akira Hirasawa, Suleiman Khan, Daniela Ungureanu, Mariliina Arjama, Teijo Pellinen, Samuli Eldfors, Riitta Koivisto-Korander, Arto Leminen, Ralf Bützow, Tero Aittokallio, Olli Kallioniemi. Identifying ovarian cancer specific targeted drugs using high-throughput drug sensitivity profiles of primary cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 410. doi:10.1158/1538-7445.AM2017-410