Citations

Significance Statement Soluble urokinase plasminogen activator receptor (suPAR), a marker of inflammation, is also an independent marker for incidence and progression of renal diseases. Mechanistically, it has been shown to activate podocytes in glomerular diseases. In this study, the authors provide the first description linking suPAR levels with disease progression for a major genetic renal disease that mainly affects the extraglomerular compartment, autosomal dominant polycystic kidney disease (ADPKD). They found an association between suPAR levels and height-adjusted total kidney volume, independent of age, sex, race, hypertension, and eGFR. In addition, patients with suPAR levels >2.82 ng/ml had a 3.38-fold increase in risk of incident ESRD. These findings suggest that suPAR levels may be useful for early identification of patients with ADPKD at high risk of disease progression. Background Levels of soluble urokinase plasminogen activator receptor (suPAR), an inflammation marker, are strongly predictive of incident kidney disease. Patients with autosomal dominant polycystic kidney disease (ADPKD) experience progressive decline in renal function, but rates of decline and outcomes vary greatly. Whether suPAR levels are predictive of declining kidney function in patients with ADPKD is unknown. Methods We assessed suPAR levels in 649 patients with ADPKD who underwent scheduled follow-up for at least 3 years, with repeated measurements of height-adjusted total kidney volume and creatinine-derived eGFR. We used linear mixed models for repeated measures and Cox proportional hazards to characterize associations between baseline suPAR levels and follow-up eGFR or incident ESRD. Results The median suPAR level was 2.47 ng/ml and median height-adjusted total kidney volume was 778, whereas mean eGFR was 84 ml/min per 1.73 m 2 . suPAR levels were associated with height-adjusted total kidney volume ( β =0.02; 95% confidence interval, 0.01 to 0.03), independent of age, sex, race, hypertension, and eGFR. Patients in the lowest suPAR tertile (<2.18 ng/ml) had a 6.8% decline in eGFR at 3 years and 22% developed CKD stage 3, whereas those in the highest tertile (suPAR>2.83 ng/ml) had a 19.4% decline in eGFR at 3 years and 68% developed CKD stage 3. suPAR levels >2.82 ng/ml had a 3.38-fold increase in the risk of incident ESRD. Conclusions suPAR levels were associated with progressive decline in renal function and incident ESRD in patients with ADPKD, and may aid early identification of patients at high risk of disease progression.

e20639 Background: Multiple randomized controlled trials (RCTs) have shown a robust benefit of immunotherapy with immune checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC). We did a meta-analysis to examine the benefit of ICI in various subgroups. Methods: PubMed was searched up to Jan 15, 2019 for RCTs comparing overall survival (OS) between ICI and control (without ICI) arms. Pooled hazard ratio (HR) and 95% confidence interval (CI) was calculated for each subgroup. Interaction tests were done to compare relative benefit between opposed subgroups of interest (eg. men vs women; reported as Pheterogeneity). All analyses were performed with a random effects model in Comprehensive Meta Analysis (v2). Results: Twelve phase 2/3 RCTs involving 7244 patients were included. A significant OS benefit of ICI was found in both squamous and non-squamous histology. Current/former smokers, EGFR wild-type, and KRAS mutant patients had a significant OS benefit from ICI, but never smokers, EGFR mutant, and KRAS wild-type patients did not. An OS benefit of ICI was found in patients with or without baseline brain metastasis, PD-L1 < 1% or ≥1%, men or women, age < 65 or ≥65, and ECOG PS 0 or ≥1. No significant difference of relative benefit from ICI over control was found in patients with different PD-L1 expression, sex, age, or ECOG PS (Table). Conclusions: OS benefit of ICI in NSCLC was associated with a smoking history, wild-type EGFR or KRAS mutation. However, the OS benefit of ICI was seen regardless of histology, PD-L1 expression, sex, age, and ECOG PS. [Table: see text]

6592 Background: Sex, age and ECOG performance status (PS) may affect immune response and the efficacy of cancer immunotherapy with immune checkpoint inhibitors (ICI). We did a meta-analysis to assess the potential sex, age and ECOG PS differences of immunotherapy efficacy in advanced cancer. Methods: PubMed was searched up to January 15, 2019 for randomized controlled trials (RCT) comparing overall survival (OS) in patients with advanced cancer treated with ICI immunotherapy vs control therapy (without ICI). For sex difference analysis, pooled hazard ratio (HR) of death for men and women was calculated separately, and the heterogeneity between the two estimates was assessed using an interaction test by pooling study-specific interaction HR. Age ( < 65 vs ≥65) and ECOG PS (0 vs ≥1) difference was analyzed similarly. Subgroup analysis by cancer type and line of therapy (frontline vs subsequent) was explored. All analyses were done in Comprehensive Meta Analysis (v2) with random effects models. Results: Thirty phase 2/3 RCTs involving 17,728 patients were included. An OS benefit of immunotherapy was found for both men (HR 0.75, 95% confidence interval [CI] 0.69-0.81, P < 0.01) and women (HR 0.79, 95% CI 0.69-0.90, P < 0.01); for both younger ( < 65; HR 0.75, 95% CI 0.68-0.83, P < 0.01) and older (≥65; HR 0.76, 95% CI 0.69-0.83, P < 0.01) patients; and for both ECOG PS 0 (HR 0.78, 95% CI 0.69-0.89, P < 0.01) and PS ≥1 (HR 0.77, 95% CI 0.71-0.84, P < 0.01) patients. No significant difference of relative benefit from immunotherapy over control therapy was found in patients with different sex ( P = 0.283), age ( P = 0.906) or ECOG PS ( P = 0.783). In melanoma RCTs, compared with women (HR 0.77, 95% CI 0.64-0.94, P < 0.01), men (HR 0.56, 95% CI 0.42-0.76, P < 0.01) had more OS benefit from immunotherapy ( P = 0.037). No significant difference was found in other subgroup analyses by cancer types or line of therapy. Conclusions: Overall we found no evidence of association of sex, age, or ECOG PS with cancer immunotherapy efficacy. However, in melanoma, men might benefit more from immunotherapy than women.

4521 Background: The MTAP gene encodes an essential enzyme for the salvage pathway of nucleotide synthesis and is frequently deleted in UBC. Anti-folate agents such as pemetrexed can effectively inhibit the de novo pathway of nucleotide synthesis and as a result, create a synthetic lethality in MTAP deficient UBC. We hypothesize that MTAP gene loss correlates with enhanced response to pemetrexed in UBC. Methods: We investigated MTAP gene deletion rates in the TCGA database and determined MTAP protein loss rates by immunohistochemistry (IHC) using a UBC tissue microarray (TMA) from 151 patients (pts). We then performed in vitro and in vivo studies using MTAP proficient and MTAP deficient bladder cancer cell lines. At the clinical level, we performed a retrospective analysis based on MTAP status of pts treated with pemetrexed as 2nd line at our institution between 2014 and 2018. We are now enrolling pts in a single-arm, open-label, phase II clinical trial (NCT02693717) with pemetrexed in pts with MTAP deficient UBC. Results: Per our TCGA and TMA IHC analyses, MTAP deficiency rate was 25.9% and 27.8%, respectively. MTAP deficient UBC cell lines were at least 40 times more sensitive to pemetrexed than MTAP proficient lines. Knockdown of the MTAP gene increased apoptosis rate by pemetrexed from approximately 20% to 60%. Additionally, pemetrexed significantly inhibited the growth of MTAP deficient or knockdown xenograft tumors but not MTAP proficient tumors. Retrospective analysis of 12 pts using RECIST criteria indicated that all 4 MTAP deficient UBC pts responded to pemetrexed whereas only 1 of 8 (12.5%) MTAP proficient UBC pts responded. Of the 6 pts enrolled on the clinical trial, 3 (50%) had complete or partial response, 1 had stable disease, 1 was not evaluable and 1 had disease progression. Combined analysis of the entire experience demonstrates a higher response rate in MTAP deficient UBC (70%) as compared to MTAP proficient UBC (12.5%). Conclusions: Our preclinical and clinical data demonstrate that MTAP loss in UBC leads to a state of synthetic lethality when treated with pemetrexed and should be further investigated as a novel biomarker to predict response to anti-folate agents.

1562 Background: In Caucasian-predominant populations, overweight or obese NSCLC pts (BMI≥25-kg/m2) have better prognosis while underweight (BMI≤18.5-kg/m2) pts have a worse prognosis. A large pooled sample allowed us to evaluate the role of ethnicity in this BMI-NSCLC OS relationship. Methods: Using individual data, survival analysis was performed on 15 ILCCO studies, assessing the interactions between ethnicity and BMI on overall survival (OS). Adjusted Hazard Ratios (aHR) from Cox models and adjusted penalized smoothing spline plots were generated. Results: Among 13416 (77%) Caucasian, 2975 (17%) Asian, and 935 (5%) Black NSCLC pts analyzed, we confirmed that for all pts, being underweight at NSCLC diagnosis was associated with worse OS (aHR=1.68, CI 1.5-1.8, p<0.001), while overweight/obese pts had improved survival (aHR 0.89, CI 0.8-0.9, p<0.001), when compared to pts with normal BMI. In general, Black pts had poorer OS than Caucasian pts (aHR 1.26 CI 1.1-1.4, p<0.001). However, the BMI-OS relationship differed according to ethnicity (BMI-ethnicity interaction, p=0.009): Caucasian underweight pts had poorer OS (aHR 1.67, CI 1.5-1.8, P<0.001) while overweight/obese pts had improved OS (aHR 0.89, CI 0.8-0.9, P<0.001). In Asian pts, these two associations were aHR 1.15, CI 0.8-1.5, P=0.33, and aHR 0.91, CI 0.7-1.1, P=0.32, respectively. In Black pts, these two associations were aHR 1.06, CI 0.7-1.5, p=0.73 and 0.75, CI 0.6-0.8 p<0.001, respectively. For overweight/obese patients, as BMI rises from 25-kg/m2 through 45-kg/m2, the prognosis worsens for Caucasian pts, remains stable for Asian pts, but improves for Black pts. Conclusions: InCaucasian pts, being underweight had a greater negative impact on OS than for Asian or Black pts, while being obese had a greater beneficial impact in Blacks than in other ethnic groups. These ethnic differences likely reflect genetically-informed muscle/adipose tissue distributions, where Black pts may have less sarcopenic obesity than other ethnicities. In future prognostic studies, BMI relationships must account for ethnic differences.

Background Patients with symptomatic severe aortic stenosis and a history of chest radiation therapy represent a complex and challenging cohort. It is unknown how transcatheter aortic valve replacement ( TAVR ) compares with surgical aortic valve replacement in this group of patients, which was the objective of this study. Methods and Results We retrospectively reviewed all patients with severe aortic stenosis who underwent either TAVR or surgical aortic valve replacement at our institution with a history of mediastinal radiation (n=55 per group). End points were echocardiographic and clinical outcomes in‐hospital, at 30 days, and at 1 year. Inverse propensity weighting analysis was used to account for intergroup baseline differences. TAVR patients had a higher STS score than surgical aortic valve replacement patients (5.1% [3.2, 7.7] versus 1.6% [0.8, 2.6], P <0.001) and more often ( P <0.01 for all) a history of atrial fibrillation (45.5% versus 12.7%), chronic lung disease (47.3% versus 7.3%), peripheral arterial disease (38.2% versus 7.3%), heart failure (58.2% versus 18.2%), and pacemaker therapy (23.6% versus 1.8%). Postoperative atrial fibrillation was less frequent (1.8% versus 27.3%; P <0.001) and hospital stay was shorter in TAVR patients (4.0 [2.0, 5.0] versus 6.0 [5.0, 8.0] days; P <0.001). The ratio of observed‐to‐expected 30‐day mortality was lower after TAVR as was 30‐day mortality in inverse propensity weighting–adjusted Kaplan–Meier analyses. Conclusions In patients with severe aortic stenosis and a history of chest radiation therapy, TAVR performs better than predicted along with less adjusted 30‐day all‐cause mortality, postoperative atrial fibrillation, and shorter hospitalization compared with surgical aortic valve replacement. These data support further studies on the preferred role of TAVR in this unique patient population.

BackgroundEsophageal carcinoma is the eighth most common cancer in the world. Volumetric‐modulated arc therapy (VMAT) is widely used to treat distal esophageal carcinoma due to high conformality to the target and good sparing of organs at risk (OAR). It is not clear if small‐spot intensity‐modulated proton therapy (IMPT) demonstrates a dosimetric advantage over VMAT. In this study, we compared dosimetric performance of VMAT and small‐spot IMPT for distal esophageal carcinoma in terms of plan quality, plan robustness, and interplay effects.Methods35 distal esophageal carcinoma patients were retrospectively reviewed; 19 patients received small‐spot IMPT and the remaining 16 of them received VMAT. Both plans were generated by delivering prescription doses to clinical target volumes (CTVs) on phase‐averaged 4D‐CT's. The dose‐volume‐histogram (DVH) band method was used to quantify plan robustness. Software was developed to evaluate interplay effects with randomized starting phases for each field per fraction. DVH indices were compared using Wilcoxon rank‐sum test. For fair comparison, all the treatment plans were normalized to have the same CTVhigh D95% in the nominal scenario relative to the prescription dose.ResultsIn the nominal scenario, small‐spot IMPT delivered statistically significantly lower liver Dmean and V30Gy[RBE], lung Dmean, heart Dmean compared with VMAT. CTVhigh dose homogeneity and protection of other OARs were comparable between the two treatments. In terms of plan robustness, the IMPT and VMAT plans were comparable for kidney V18Gy[RBE], liver V30Gy[RBE], stomach V45Gy[RBE], lung Dmean, V5Gy[RBE], and V20Gy[RBE], cord Dmax and , liver Dmean, heart V20Gy[RBE], and V30Gy[RBE], but IMPT was significantly worse for CTVhigh D95%, , and D5%‐D95%, CTVlow D95%, heart Dmean, and V40Gy[RBE], requiring careful and experienced adjustments during the planning process and robustness considerations. The small‐spot IMPT plans still met the standard clinical requirements after interplay effects were considered.ConclusionsSmall‐spot IMPT decreases doses to heart, liver, and total lung compared to VMAT as well as achieves clinically acceptable plan robustness. Our study supports the use of small‐spot IMPT for the treatment of distal esophageal carcinoma.

BackgroundInducible co-stimulator (ICOS) is a CD28-related molecule exclusively expressed on activated T cells and plays a critical role in modulating the immune response in breast cancer. The blockage of ICOS pathway has been shown to inhibit the activity of Type 2 T helper cells, thus potentially protecting against cancer growth. The current study aims to investigate the correlation between inducible co-stimulator ligand (ICOSL) expression in tumor tissues and the prognoses of patients with invasive breast cancer.MethodsTumor samples from 562 Chinese patients with invasive breast carcinomas were collected between 2003 and 2010. The expression of ICOSL on breast tumor and adjacent non-cancerous tissue was determined via immunohistochemistry. The overall survival (OS) of patients with positive and negative ICOSL expression were described using Kaplan–Meier curves, respectively. Parametric correlation method was used to analyze the correlation between ICOSL expression and other clinicopathological parameters. ICOSL was selected as a dependent variable for multivariate analysis.ResultsPositive ICOSL expression was identified on the plasma membrane in both cytoplasm and the nucleus of breast cancer cells. Membrane-expressed ICOSL is determined as an independent prognostic factor for OS in breast cancer but without significantly correlating with other clinicopathologic parameters such as age, menopausal status, depth of invasion, lymph node metastasis status, histologic classification, etc.ConclusionOur study suggests that the up-regulated expression of ICOSL protein in breast tumor cells can be associated with poor prognoses in invasive breast carcinomas.

Abstract Background: Patients achieving a pathologic complete response (pCR) following neoadjuvant therapy have significantly improved event-free survival relative to those who do not; and pCR is an FDA-accepted endpoint to support accelerated approval of novel agents/combinations in the neoadjuvant treatment of high risk early stage breast cancer. Previous studies have shown that recurrence risk increased with increasing burden of residual disease (as assessed by the RCB index). As well, these studies suggest that patients with minimum residual disease (RCB-I class) also have favorable outcomes (comparable to those achieving a pCR) within high risk tumor subtypes. In this study, we assess whether integrating RCB with MRI functional tumor volume (FTV), which in itself is prognostic, can improve prediction of distant recurrence free survival (DRFS); and identify a subset of patients with minimal residual disease with comparable DRFS as those who achieved a pCR. Imaging tools can then be used to identify the subset that will do well early and guide the timing of surgical therapy. Method: We performed a pooled analysis of 596 patients from the I-SPY2 TRIAL with RCB, pre-surgical MRI FTV data and known follow-up (median 2.5 years). We first assessed whether FTV predicts residual disease (pCR or pCR/RCB-I) using ROC analysis. We applied a power transformation to normalize the pre-surgical FTV distribution; and assessed its association with DRFS using a bi-variate Cox proportional hazard model adjusting for HR/HER2 subtype. We also fitted a bivariate Cox model of RCB index adjusting for subtype; and assessed whether adding pre-surgical FTV to this model further improves association with DRFS using a likelihood ratio (LR) test. For the Cox modeling, penalized splines approximation of the transformed FTV and RCB index with 2 degrees of freedom was used to allow for non-linear effects of FTV and RCB on DRFS. Result: Pre-surgical MRI FTV is significantly associated with DRFS (Wald p&lt;0.00001), and more effective at predicting pCR/RCB-I than predicting pCR alone (AUC: 0.72 vs. 0.65). Larger pre-surgical FTV remains associated with worse DRFS adjusting for subtype (Wald p &lt;0.00001). The RCB index is also significantly associated with DRFS adjusting for subtype (Wald p&lt;0.00001). Adding FTV to a model containing RCB and subtype further improves association with DRFS (LR p=0.0007). RCB-I patients have excellent DRFS (94% at 3 years compared to 95% in the pCR group). Efforts are underway to identify an optimal threshold for dichotomizing pre-surgical FTV and FTV change measures for use in combination with pCR/RCB-I class to generate integrated RCB (iRCB) groups as a composite predictor of DRFS. Conclusion: Pre-surgical MRI FTV is effective at predicting minimal residual disease (RCB0/I) in the I-SPY 2 TRIAL. Despite the association between FTV and RCB, FTV appears to provide independent added prognostic value (to RCB and subtype), suggesting that integrating MRI volume measures and RCB into a composite predictor may improve DRFS prediction. Citation Format: Hylton NM, Symmans WF, Yau C, Li W, Hatzis C, Isaacs C, Albain KS, Chen Y-Y, Krings G, Wei S, Harada S, Datnow B, Fadare O, Klein M, Pambuccian S, Chen B, Adamson K, Sams S, Mhawech-Fauceglia P, Magliocco A, Feldman M, Rendi M, Sattar H, Zeck J, Ocal I, Tawfik O, Grasso LeBeau L, Sahoo S, Vinh T, Yang S, Adams A, Chien AJ, Ferero-Torres A, Stringer-Reasor E, Wallace A, Boughey JC, Ellis ED, Elias AD, Lang JE, Lu J, Han HS, Clark AS, Korde L, Nanda R, Northfelt DW, Khan QJ, Viscusi RK, Euhus DM, Edmiston KK, Chui SY, Kemmer K, Wood WC, Park JW, Liu MC, Olopade O, Tripathy D, Moulder SL, Rugo HS, Schwab R, Lo S, Helsten T, Beckwith H, Haugen PK, van't Veer LJ, Perlmutter J, Melisko ME, Wilson A, Peterson G, Asare AL, Buxton MB, Paoloni M, Clennell JL, Hirst GL, Singhrao R, Steeg K, Matthews JB, Sanil A, Berry SM, Abe H, Wolverton D, Crane EP, Ward KA, Nelson M, Niell BL, Oh K, Brandt KR, Bang DH, Ojeda-Fournier H, Eghtedari M, Sheth PA, Bernreuter WK, Umphrey H, Rosen MA, Dogan B, Yang W, Joe B, I-SPY 2 TRIAL Consortium, Yee D, Pusztai L, DeMichele A, Asare SM, Berry DA, Esserman LJ. Refining neoadjuvant predictors of three year distant metastasis free survival: Integrating volume change as measured by MRI with residual cancer burden [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-07-03.