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Desmoid tumor is considered a benign neoplasm, yet substantial morbidity can result from local invasion of structures adjacent to the tumor or from complications related to its treatment. We report two patients with extremity desmoid tumor who were each found at MRI to have an unsuspected pseudoaneurysm within their tumor after prior treatments (surgery and systemic therapy in one, surgery alone in the other). Such a pseudoaneurysm probably results from weakening of an arterial wall by adjacent desmoid tumor, as well as from local trauma. Due to the potential risk for life-threatening rupture of a pseudoaneurysm, one patient underwent surgical repair and the other, coil embolization. To our knowledge the presence of pseudoaneurysm has been reported within a few cases of abdominal desmoid tumor but not within an extremity desmoid tumor. This diagnosis has not been reported to have been made at MRI, either.

OBJECTIVE The aim of this study was to identify predictors of desmoid progression during observation. SUMMARY OF BACKGROUND DATA Untreated desmoids can grow, remain stable, or regress, but reliable predictors of behavior have not been identified. METHODS Primary or recurrent desmoid patients were identified retrospectively from an institutional database. In those managed with active observation who underwent serial magnetic resonance imaging (MRIs) with T2-weighted sequences, baseline tumor size was recorded, and 2 radiologists independently estimated the percentage of tumor volume showing hyperintense T2 signal at baseline. Associations of clinical or radiographic characteristics with progression-free survival (PFS; by RECIST) were evaluated by Cox regression and Kaplan-Meier statistics. RESULTS Among 160 patients with desmoids, 72 were managed with observation, and 37 of these had serial MRI available for review. Among these 37 patients, median age was 35 years and median tumor size was 4.7 cm; all tumors were extra-abdominal (41% in abdominal wall). Although PFS was not associated with size, site, or age, it was strongly associated with hyperintense T2 signal in ≥90% versus

Background Although EGFR mutant tumors exhibit low response rates to immune checkpoint blockade overall, some EGFR mutant tumors do respond to these therapies; however, there is a lack of understanding of the characteristics of EGFR mutant lung tumors responsive to immune checkpoint blockade. Patients and methods We retrospectively analyzed de-identified clinical and molecular data on 171 cases of EGFR mutant lung tumors treated with immune checkpoint inhibitors from the Yale Cancer Center, Memorial Sloan Kettering Cancer Center, University of California Los Angeles, and Dana Farber Cancer Institute. A separate cohort of 383 EGFR mutant lung cancer cases with sequencing data available from the Yale Cancer Center, Memorial Sloan Kettering Cancer Center, and The Cancer Genome Atlas was compiled to assess the relationship between tumor mutation burden and specific EGFR alterations. Results Compared with 212 EGFR wild-type lung cancers, outcomes with programmed cell death 1 or programmed death-ligand 1 (PD-(L)1) blockade were worse in patients with lung tumors harboring alterations in exon 19 of EGFR (EGFRΔ19) but similar for EGFRL858R lung tumors. EGFRT790M status and PD-L1 expression did not impact response or survival outcomes to immune checkpoint blockade. PD-L1 expression was similar across EGFR alleles. Lung tumors with EGFRΔ19 alterations harbored a lower tumor mutation burden compared with EGFRL858R lung tumors despite similar smoking history. Conclusions EGFR mutant tumors have generally low response to immune checkpoint inhibitors, but outcomes vary by allele. Understanding the heterogeneity of EGFR mutant tumors may be informative for establishing the benefits and uses of PD-(L)1 therapies for patients with this disease.

KRAS is the most common oncogenic driver in lung adenocarcinoma (LUAC). We previously reported that STK11/LKB1 (KL) or TP53 (KP) comutations define distinct subgroups of KRAS-mutant LUAC. Here, we examine the efficacy of PD-1 inhibitors in these subgroups. Objective response rates to PD-1 blockade differed significantly among KL (7.4%), KP (35.7%), and K-only (28.6%) subgroups (P < 0.001) in the Stand Up To Cancer (SU2C) cohort (174 patients) with KRAS-mutant LUAC and in patients treated with nivolumab in the CheckMate-057 phase III trial (0% vs. 57.1% vs. 18.2%; P = 0.047). In the SU2C cohort, KL LUAC exhibited shorter progression-free (P < 0.001) and overall (P = 0.0015) survival compared with KRASMUT;STK11/LKB1WT LUAC. Among 924 LUACs, STK11/LKB1 alterations were the only marker significantly associated with PD-L1 negativity in TMBIntermediate/High LUAC. The impact of STK11/LKB1 alterations on clinical outcomes with PD-1/PD-L1 inhibitors extended to PD-L1–positive non–small cell lung cancer. In Kras-mutant murine LUAC models, Stk11/Lkb1 loss promoted PD-1/PD-L1 inhibitor resistance, suggesting a causal role. Our results identify STK11/LKB1 alterations as a major driver of primary resistance to PD-1 blockade in KRAS-mutant LUAC. Significance: This work identifies STK11/LKB1 alterations as the most prevalent genomic driver of primary resistance to PD-1 axis inhibitors in KRAS-mutant lung adenocarcinoma. Genomic profiling may enhance the predictive utility of PD-L1 expression and tumor mutation burden and facilitate establishment of personalized combination immunotherapy approaches for genomically defined LUAC subsets. Cancer Discov; 8(7); 822–35. ©2018 AACR. See related commentary by Etxeberria et al., p. 794. This article is highlighted in the In This Issue feature, p. 781

Purpose Treatment of advanced non–small-cell lung cancer with immune checkpoint inhibitors (ICIs) is characterized by durable responses and improved survival in a subset of patients. Clinically available tools to optimize use of ICIs and understand the molecular determinants of response are needed. Targeted next-generation sequencing (NGS) is increasingly routine, but its role in identifying predictors of response to ICIs is not known. Methods Detailed clinical annotation and response data were collected for patients with advanced non–small-cell lung cancer treated with anti–programmed death-1 or anti–programmed death-ligand 1 [anti-programmed cell death (PD)-1] therapy and profiled by targeted NGS (MSK-IMPACT; n = 240). Efficacy was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and durable clinical benefit (DCB) was defined as partial response/stable disease that lasted > 6 months. Tumor mutation burden (TMB), fraction of copy number–altered genome, and gene alterations were compared among patients with DCB and no durable benefit (NDB). Whole-exome sequencing (WES) was performed for 49 patients to compare quantification of TMB by targeted NGS versus WES. Results Estimates of TMB by targeted NGS correlated well with WES (ρ = 0.86; P < .001). TMB was greater in patients with DCB than with NDB ( P = .006). DCB was more common, and progression-free survival was longer in patients at increasing thresholds above versus below the 50th percentile of TMB (38.6% v 25.1%; P < .001; hazard ratio, 1.38; P = .024). The fraction of copy number–altered genome was highest in those with NDB. Variants in EGFR and STK11 associated with a lack of benefit. TMB and PD-L1 expression were independent variables, and a composite of TMB plus PD-L1 further enriched for benefit to ICIs. Conclusion Targeted NGS accurately estimates TMB and elevated TMB further improved likelihood of benefit to ICIs. TMB did not correlate with PD-L1 expression; both variables had similar predictive capacity. The incorporation of both TMB and PD-L1 expression into multivariable predictive models should result in greater predictive power.

PURPOSE: To evaluate the prevalence of major and ancillary imaging features from liver imaging reporting and data systems (LI-RADS) version 2014 and their interreader agreement when comparing hepatocellular carcinoma (HCC) to intrahepatic cholangiocarcinoma (ICC) and combined tumor (cHCC-CC). METHODS: The Institutional Review Board approved this HIPAA-compliant retrospective study and waived the requirement for patients’ informed consent. Patients with resected HCC (n = 51), ICC (n = 40), and cHCC-CC (n = 11) and available pre-operative contrast-enhanced MRI were included from 2000 to 2015. Imaging features and final LI-RADS category were evaluated by four radiologists. Imaging features were compared by Fisher’s exact test and interreader agreements were assessed by κ statistics. RESULTS: None of the features were unique to either HCC or non-HCC. Imaging features that were significantly more common among HCC compared to ICC and cHCC-CC included washout (76%–78% vs. 10%–35%, p < 0.001), capsule (55%–71% vs. 16%–49%, p < 0.05), and intralesional fat (27%–52% vs. 2%–12%, p < 0.002). Features that were more common among ICC and cHCC-CC included peripheral arterial phase hyperenhancement (40%–64% vs. 10%–14%, p < 0.001) and progressive central enhancement (65%–82% vs. 14%–25%, p < 0.001). The interreader agreement was moderate for each of these imaging features (κ = 0.41–0.55). Moderate agreement was also achieved in the assignment of LR-M (κ = 0.53), with an overall sensitivity and specificity for non-HCC malignancy of 86.3% and 78.4%, respectively. CONCLUSION: HCC and non-HCC show significant differences in the prevalence of imaging features defined by LI-RADS, and are identified by radiologists with moderate interreader agreement. Using LI-RADS, radiologists also achieved moderate interreader agreement in the assignment of the LR-M category.

Objective The aims of this study were to describe the computed tomographic features of organizing pneumonia (OP) in an oncologic patient population and to also identify features associated with lung cancer and patients undergoing hematopoietic stem cell transplant (HSCT). Methods In retrospective computed tomographies from 151 patients with pathologically confirmed OP between January 2009 and September 2014, number of lesions, location, size, margin type, and consistency, as well as volume of lymphadenopathy and the presence and size of pleural effusions, were recorded. Associated malignancy was noted. Results Organizing pneumonia most commonly presented as a diffuse process (n = 62, 41%), frequently occupied both a central and peripheral location (n = 79, 53%), and commonly presented with a solid appearance (n = 67, 44%) or with ground glass opacity (n = 80, 53%). Pleural effusions were seen in 68 patients (45%). Organizing pneumonia less frequently contained air bronchograms, cavitation, necrosis, surrounding ground glass opacity, or adjacent bronchiectasis. In patients with lung cancer (n = 25, 17%), OP more likely presented as discrete lesions and occupied a peripheral location as compared with patients with other malignancies (Ps = 0.025 and 0.002). In HSCT patients (n = 29, 19%), a diffuse process was more commonly seen than in non-HSCT patients (P = 0.038). Conclusions Organizing pneumonia more commonly presents as discrete lesions with a peripheral location in patients with lung cancer and as a diffuse process in patients who had undergone HSCT.

Bone lesions on prostate MRI often raise concern about metastases. This study aimed to evaluate the prevalence of bone metastases on staging prostate MRI and evaluate associations between their MRI features and clinical/pathologic characteristics. Retrospective, IRB-approved study of 3765 patients undergoing prostate MRI for newly diagnosed PCa between 2000 and 2014. The reference standard to calculate the prevalence of bone metastases was bone biopsy and/or ≥1-year follow-up after MRI. In a subsample of 228 patients, the MRI characteristics of bone lesions were recorded by two radiologists independently. Associations between MRI and clinical/pathologic findings, including National Comprehensive Cancer Network (NCCN) risk categories, were calculated. 57/3765 patients (1.5%, 95% CI 1.2–2.0%) had bone metastases. No patient with NCCN low-risk PCa (Gleason

Purpose Treatment with programmed cell death-1 or programmed death ligand 1 (PD-(L)1) inhibitors is now standard therapy for patients with lung cancer. The immunosuppressive effect of corticosteroids may reduce efficacy of PD-(L)1 blockade. On-treatment corticosteroids for treatment of immune-related adverse events do not seem to affect efficacy, but the potential impact of baseline corticosteroids at the time of treatment initiation is unknown. Clinical trials typically excluded patients who received baseline corticosteroids, which led us to use real-world data to examine the effect of corticosteroids at treatment initiation. Methods We identified patients who were PD-(L)1–naïve with advanced non–small-cell lung cancer from two institutions—Memorial Sloan Kettering Cancer Center and Gustave Roussy Cancer Center—who were treated with single-agent PD-(L)1 blockade. Clinical and pharmacy records were reviewed to identify corticosteroid use at the time of beginning anti–PD-(L)1 therapy. We performed multivariable analyses using Cox proportional hazards regression model and logistic regression. Results Ninety (14%) of 640 patients treated with single-agent PD-(L)1 blockade received corticosteroids of ≥ 10 mg of prednisone equivalent daily at the start of the PD-(L)1 blockade. Common indications for corticosteroids were dyspnea (33%), fatigue (21%), and brain metastases (19%). In both independent cohorts, Memorial Sloan Kettering Cancer Center (n = 455) and Gustave Roussy Cancer Center (n = 185), baseline corticosteroids were associated with decreased overall response rate, progression-free survival, and overall survival with PD-(L)1 blockade. In a multivariable analysis of the pooled population, adjusting for smoking history, performance status, and history of brain metastases, baseline corticosteroids remained significantly associated with decreased progression-free survival (hazard ratio, 1.3; P = .03), and overall survival (hazard ratio, 1.7; P < .001). Conclusion Baseline corticosteroid use of ≥ 10 mg of prednisone equivalent was associated with poorer outcome in patients with non–small-cell lung cancer who were treated with PD-(L)1 blockade. Prudent use of corticosteroids at the time of initiating PD-(L)1 blockade is recommended.

The composition of gut microbiota affects antitumor immune responses, preclinical and clinical outcome following immune checkpoint inhibitors (ICI) in cancer. Antibiotics (ATB) alter gut microbiota diversity and composition leading to dysbiosis, which may affect effectiveness of ICI.We examined patients with advanced renal cell carcinoma (RCC) and non-small-cell lung cancer (NSCLC) treated with anti-programmed cell death ligand-1 mAb monotherapy or combination at two academic institutions. Those receiving ATB within 30 days of beginning ICI were compared with those who did not. Objective response, progression-free survival (PFS) determined by RECIST1.1 and overall survival (OS) were assessed.Sixteen of 121 (13%) RCC patients and 48 of 239 (20%) NSCLC patients received ATB. The most common ATB were β-lactam or quinolones for pneumonia or urinary tract infections. In RCC patients, ATB compared with no ATB was associated with increased risk of primary progressive disease (PD) (75% versus 22%, P 0.01), shorter PFS [median 1.9 versus 7.4 months, hazard ratio (HR) 3.1, 95% confidence interval (CI) 1.4-6.9, P 0.01], and shorter OS (median 17.3 versus 30.6 months, HR 3.5, 95% CI 1.1-10.8, P = 0.03). In NSCLC patients, ATB was associated with similar rates of primary PD (52% versus 43%, P = 0.26) but decreased PFS (median 1.9 versus 3.8 months, HR 1.5, 95% CI 1.0-2.2, P = 0.03) and OS (median 7.9 versus 24.6 months, HR 4.4, 95% CI 2.6-7.7, P 0.01). In multivariate analyses, the impact of ATB remained significant for PFS in RCC and for OS in NSCLC.ATB were associated with reduced clinical benefit from ICI in RCC and NSCLC. Modulatation of ATB-related dysbiosis and gut microbiota composition may be a strategy to improve clinical outcomes with ICI.

Considering retreatment following recovery from an immune-related adverse event (irAE) is a common clinical scenario, but the safety and benefit of retreatment is unknown. We identified patients with advanced non–small cell lung cancer (NSCLC) treated with anti-PD-(L)1 who had treatment held due to irAEs and divided them into two groups: those retreated with anti-PD-(L)1 (retreatment cohort) or those who had treatment stopped (discontinuation cohort). Out of 482 NSCLC patients treated with anti-PD-(L)1, 68 (14%) developed a serious irAE requiring treatment interruption. Of these, 38 (56%) were retreated and 30 (44%) had treatment discontinued. In the retreatment cohort, 18 (48%) patients had no subsequent irAEs, 10 (26%) had recurrence of the initial irAE, and 10 (26%) had a new irAE. Most recurrent/new irAEs were mild (58% grade 1–2) and manageable (84% resolved or improved to grade 1). Two treatment-related deaths occurred. Recurrent/new irAEs were more likely if the initial irAE required hospitalization, but the initial grade and time to retreatment did not influence risk. Among those with no observed partial responses prior to the irAE, progression-free survival (PFS) and overall survival (OS) were longer in the retreatment cohort. Conversely, for those with objective responses prior to the irAE, PFS and OS were similar in the retreatment and discontinuation cohorts. Among patients with early objective responses prior to a serious irAE, outcomes were similar, whether or not they were retreated. Together, data suggest that benefit may occur with retreatment in patients with irAEs who had no treatment response prior to irAE onset. Cancer Immunol Res; 6(9); 1093–9. ©2018 AACR.

Introduction The aim of this study was to describe the clinical characteristics and radiologic findings in patients with a previous history of malignancy who underwent computed tomography (CT) screening for lung cancer. Methods Patients with a previous history of malignancy and a life expectancy of at least 5 years who were referred for lung cancer screening between May 2, 2011, and September 24, 2014, were included. CT scan features assessed included nodule size, morphologic features, and number. The Lung-CT Reporting and Data System scoring system was retrospectively applied to all studies. Results A total of 139 patients were studied (mean age of 66 years and median smoking history of 50 pack-years). All had a previous history of cancer, most often breast cancer (60 patients [43%]), head or neck cancer (26 patients [19%]), and lung cancer (16 patients [12%]). Of these patients, 42 (30%) had a positive screening study result. Lung cancer was diagnosed in seven patients (5%), and a radiation-induced chest wall sarcoma was diagnosed in one patient (1%); 42 patients (30%) had a positive chest CT scan per the National Comprehensive Cancer Network lung cancer screening nodule follow-up algorithm. Conclusion The rate of diagnosis of lung cancer in our patient population is higher than in several previously published studies. Smokers with a history of malignancy may be a group at particularly high risk for the development of subsequent lung cancer.

9003Background: Treatment with PD-(L)1 inhibitors is now standard therapy for patients with lung cancer. The immunosuppressive effect of steroids may reduce efficacy of PD-(L)1 blockade. On-treatme...

9022Background: The transcendent feature of response to anti-PD-(L)1 therapy is durable, long-term responses, which can last up to years. Much effort in biomarkers has focused exclusively on initia...

9016 Background: Identification of molecular predictors of response to PD-1/PD-L1 inhibitors is critical in order to maximize their therapeutic potential. We previously reported that KRAS-mutant lung adenocarcinomas (LUAC) with co-occurring genetic events in STK11/LKB1(KL) or TP53 (KP) define subgroups with marked differences in immune contexture, including a paucity of CD8+ TILs in KL LUAC. Here, we assess clinical responses to PD-1/PD-L1 therapy in KL and KP subsets, with data assembled under the auspices of the SU2C/ACS Lung Cancer Dream Team. Methods: Patients (pts) with metastatic KRAS-mutant LUAC who received at least one cycle of PD-1/PD-L1 therapy, were alive for ≥14 days thereafter, and had available molecular profiling were identified retrospectively. Efficacy assessment was based on RECIST v1.1. PD-L1 expression was tested using 22C3 pharmDx or E1L3N IHC assays and quantified as percent of staining tumor cell membranes. Isogenic derivatives of the LKR10 KrasLA1/+ murine LUAC cell line with CRISPR/Cas9-mediated Lkb1knockout were used in preclinical experiments. Results: 165 pts with KRAS-mutant LUAC who received PD-1/PD-L1 therapy were included [KL: 27%, KP: 36%, K-only: 37%]. Best overall response differed significantly in the KL (PR: 9.1%, SD: 15.9%, PD: 75%) and KP (PR: 33.3%, SD: 20%, PD: 46.7%) sub-groups (P = 0.005, Fisher’s exact test). PFS was significantly longer in KP compared to KL LUAC (median 12.9 wks vs 8.4 wks, HR = 0.64, 95% CI 0.39-0.95, P = 0.032, log-rank test). ORR in K-only tumors was 21.3% and median PFS 11.4 wks. PD-L1 positivity (≥1%) was more frequent in KP tumors compared to KL (75% vs 22%, P = 0.03, Fisher’s exact test). In syngeneic murine models of KRAS-mutant LUAC, loss of LKB1 promoted resistance to PD-1 inhibitor monotherapy, suggesting a causative role. Conclusions: Mutational inactivation of STK11/LKB1 represents a novel genomic predictor of de novo resistance to immune checkpoint blockade in KRAS-mutant LUAC, whereas TP53 co-mutations are associated with high likelihood of response. Precision immunotherapy will require tailoring to the co-mutation status of individual tumors.