Course Of Routine Clinical Care Research Articles

Decision-Making Confidence of Clinical Competency Committees for Entrustable Professional Activities

A competency-based assessment framework using entrustable professional activities (EPAs) was endorsed by the American Board of Surgery following a 2-year feasibility pilot study. Pilot study programs' clinical competency committees (CCCs) rated residents on EPA entrustment semiannually using this newly developed assessment tool, but factors associated with their decision-making are not yet known. To identify factors associated with variation in decision-making confidence of CCCs in EPA summative entrustment decisions. This cohort study used deidentified data from the EPA Pilot Study, with participating sites at 28 general surgery residency programs, prospectively collected from July 1, 2018, to June 30, 2020. Data were analyzed from September 27, 2022, to February 15, 2023. Microassessments of resident entrustment for pilot EPAs (gallbladder disease, inguinal hernia, right lower quadrant pain, trauma, and consultation) collected within the course of routine clinical care across four 6-month study cycles. Summative entrustment ratings were then determined by program CCCs for each study cycle. The primary outcome was CCC decision-making confidence rating (high, moderate, slight, or no confidence) for summative entrustment decisions, with a secondary outcome of number of EPA microassessments received per summative entrustment decision. Bivariate tests and mixed-effects regression modeling were used to evaluate factors associated with CCC confidence. Among 565 residents receiving at least 1 EPA microassessment, 1765 summative entrustment decisions were reported. Overall, 72.5% (1279 of 1765) of summative entrustment decisions were made with moderate or high confidence. Confidence ratings increased with increasing mean number of EPA microassessments, with 1.7 (95% CI, 1.4-2.0) at no confidence, 1.9 (95% CI, 1.7-2.1) at slight confidence, 2.9 (95% CI, 2.6-3.2) at moderate confidence, and 4.1 (95% CI, 3.8-4.4) at high confidence. Increasing number of EPA microassessments was associated with increased likelihood of higher CCC confidence for all except 1 EPA phase after controlling for program effects (odds ratio range: 1.21 [95% CI, 1.07-1.37] for intraoperative EPA-4 to 2.93 [95% CI, 1.64-5.85] for postoperative EPA-2); for preoperative EPA-3, there was no association. In this cohort study, the CCC confidence in EPA summative entrustment decisions increased as the number of EPA microassessments increased, and CCCs endorsed moderate to high confidence in most entrustment decisions. These findings provide early validity evidence for this novel assessment framework and may inform program practices as EPAs are implemented nationally.

Abstract PO4-14-11: Findings of clinically significant variants (Tier IA) with OmniSeq INSIGHT ® in a breast cancer cohort of 987 patients

Abstract Background: There were an estimated 2.3 million new breast cancer cases worldwide in 2020, with breast cancer now the most diagnosed type of cancer representing 25% of cancer cases and 17% of cancer deaths (1). The GLOBOCAN Cancer Tomorrow prediction tool estimates that incidence will increase by > 45% by 2040 (2). Optimal treatment for breast cancer is increasingly dependent upon knowing a patient’s somatic and germline genomic alteration status. To highlight the importance of these genomic alterations, we provide an overview of the genomic findings in 987 consecutive breast cancer patients tested in the course of routine clinical care. Methods: Comprehensive Genomic and Immune Profiling (CGIP) was performed on 987 qualified breast cancer samples at a CAP/CLIA and NYS CLEP certified reference laboratory with the OmniSeq INSIGHT ® test (3). OmniSeq INSIGHT ® is a next generation sequencing-based laboratory developed test for the detection of genomic variants, signatures, HLA Class I genotypes, and immune gene expression in formalin-fixed paraffin-embedded (FFPE) tumor tissue. DNA is sequenced to detect small variants in the full exonic coding region of 523 genes, copy number alterations in 59 genes (gains and losses), as well as analysis of microsatellite instability (MSI) and tumor mutational burden (TMB). RNA is sequenced to detect fusions and splice variants in 55 genes, in addition to mRNA expression in 64 immune genes. The resultant information, along with PD-L1 protein expression by immunohistochemistry (IHC), is intended for use by qualified health care professionals in accordance with professional guidelines in oncology for management of patients with solid neoplasms. Tier IA variants include variants with strong clinical significance as per AMP–ASCO–CAP recommendations (4). Results: There were 384 Tier IA variants detected in 370 of 987 breast cancer patients (~37.5%) with 251 in PIK3CA (65.3%), 60 in ERBB2 (15.6%), 46 in BRCA2 (11.9%), 19 in BRCA1 (4.9%), 4 in NTRK3 (1.0%), 1 in NTRK1 (0.26%) and 1 in PALB2 (0.26%) including copy number variations (CNV), gene fusion and single nucleotide variants (SNV). At the individual gene level for Tier IA variants, PIK3CA had 251 SNVs detected, ERBB2 had 55 CNVs, 1 gene fusion and 4 SNVs detected, BRCA2 had 39 SNVs and 8 CNVs detected, BRCA1 had 19 SNVs, NTRK3 had 4 gene fusions, NTRK1 had 1 gene fusion and PALB2 had 1 SNV detected. At the variant class level, there were 63 CNVs, 6 gene fusions and 315 SNVs observed. Conclusions: CGIP for breast cancer patients identified one or more clinically significant Tier IA genomic alterations that directs targeted therapy in ~ 37.5% of patients in a cohort of real world patients tested during the standard course of clinical care. This highlights the need for comprehensive genomic testing in breast cancer patients to drive therapeutic decision making.

Referral and Beyond: Restructuring the Kidney Transplant Process to Support Greater Access in the United States

Advocates for improved equity in kidney transplant in the US have recently focused efforts on initiatives to increase referral for transplant evaluation. However, because donor kidneys remain scarce, increased referrals are likely to result in an increasing number of patients proceeding through the evaluation process without ultimately receiving a kidney. Unfortunately, the process of referral and evaluation can be highly resource-intensive for patients, families, transplant programs, and payers. Patients and families may incur out-of-pocket expenses and be required to complete testing and treatments that they might not have chosen in the course of routine clinical care. Kidney transplant programs may struggle with insufficient capacity, inefficient workflow, and challenging programmatic finances and payers will need to absorb the increased expenses of upfront pretransplant costs. Increased referral in isolation may risk simply transmitting system stress and resulting disparities to downstream processes in this complex system. We argue that success in efforts to improve access through increased referrals hinges on adaptations to the pretransplant process more broadly. We call for an urgent reevaluation and redesign at multiple levels of the pretransplant system in order to achieve the aim of equitable access to kidney transplantation for all patients with kidney failure.

Clonal Hematopoiesis and Inflammation in the Vasculature (CHIVE), a Prospective, Longitudinal Clonal Hematopoiesis Cohort and Biorepository

Introduction Clonal hematopoiesis (CH), the expansion of a clonal population of hematopoietic cells, is an age-associated phenomenon leading to increased risk of both hematologic malignancy and non-malignant organ dysfunction. There have been significant advances in our understanding of the underlying pathophysiology of CH in recent years. However, additional studies are needed to better understand clinical trajectories and optimal care of patients with CH. To address this gap, the prospective, longitudinal CHIVE (Clonal Hematopoiesis and Inflammation in the VasculaturE) registry and biorepository was created to support multidisciplinary CH clinics. Methods Adults without active hematological malignancy who were clinically identified to have CH or who were at risk for CH were sequentially enrolled utilizing a multidisciplinary referral approach between October 2020 to April 2023 at Vanderbilt University Medical Center (VUMC). Research samples were procured at the time of routine clinical blood draws or bone marrow biopsies and stored in a newly established biorepository, equipped to store DNA, plasma, and viably cryopreserved cells to enable a spectrum of downstream applications. Specimens were sequenced on a highly cost efficient (~$6/sample) targeted next generation sequencing capture panel that identified mutations residing in the 24 most frequently mutated CHIP genes.The VUMC CH clinic, which serves as a referral pool, were included in Arm A of CHIVE (n=57). We also sought out a population at risk for CH which included patients over 18 years of age with a history of solid tumor, cardiovascular disease, renal disease, rheumatologic disease, or diabetes, who were included in Arm B (n=122). Patients from Arm A or B were included in the CH-positive (CH+) group if they met criteria for CH on the research assay at any time during their enrollment in the study. All other genotyped patients who were not found to have CH by the research assay, regardless of their clinical CH status at study enrollment, were included in the CH-negative (CH-) group.Anthropometric data and clinical assessments, including laboratories and cardiovascular studies obtained in the course of routine clinical care were extracted from the electronic health record, and recorded and maintained in the CHIVE database. Results 261 patients were approached for consent to enroll in CHIVE and 179 were ultimately enrolled. More than one half (54%) of all participants had a CH mutation (CH+) and of those, 49.5% were female. Median age of CH+ patients was 71.9 (IQR 64.0-77.5). DNMT3A (n=44) and TET2 (n=39) were the most commonly mutated genes, while variant allele fractions (VAF) ranged from 2.1 - 79.8% (Figure 1). 246 samples were serial samples collected from 89 patients at regular intervals. Significantly more CH+ patients had a diagnosis of coronary artery disease compared to CH- patients (55.7% vs 32.9%, p=0.004). CH+ patients also had increased rates of hypertension and heart failure compared to the CH- group (p<0.001, 0.035, respectively). Laboratory evaluation showed CH+ patients to have a lower median white blood cell count, hemoglobin, and platelets, and elevated blood urea nitrogen values compared to CH- patients, differences that did not meet statistical significance. 8.2% of the CH+ patients progressed to frank hematologic malignancy over the course of the 2.5-year study (Table 1). Eight of the 97 CH+ and 2 of the 82 CH- patients died over the course of the study period resulting in a trend toward decreased survival in CH+ patients (p=0.112). Conclusions We demonstrate the feasibility of a prospective, observational study of CH patients utilizing a robust referral network to support both clinical care and translational research. A well-genotyped and phenotyped cohort of CH patients will be critical to future translational research efforts and clinical trials - a key function of our study design. Early clinical findings from our cohort recapitulate large scale retrospective datasets where CH patients are at an increased risk of development of hematologic malignancy, end organ damage, and all-cause mortality. Scaling this resource in collaboration with other centers is underway and will ultimately enable the development of clinical guidelines and treatment strategies for this increasingly recognized patient population.

Performance of Liquid Biopsy for Diagnosis and Surveillance of Human Papillomavirus–Associated Oropharyngeal Cancer

There is growing interest in the use of circulating plasma tumor human papillomavirus (HPV) DNA for diagnosis and surveillance of patients with HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). Recent advances in the assays, combining the identification of circulating HPV tumor DNA and tumor DNA fragment analysis (tumor tissue-modified viral [TTMV]-HPV DNA), have been shown to be highly accurate. However, use of these newer techniques has been limited to small cohort studies and clinical trials. To establish the clinical efficacy of plasma TTMV-HPV DNA testing in the diagnosis and surveillance of HPV-associated OPSCC in a contemporary clinical setting. This retrospective observational cohort study included patients with OPSCC who underwent TTMV-HPV DNA testing between April 2020 and September 2022 during the course of routine clinical care. For the diagnosis cohort, patients with at least 1 TTMV-HPV DNA measurement prior to initiation of primary therapy were included. Patients were included in the surveillance cohort if they had at least 1 TTMV-HPV DNA test performed after completion of definitive or salvage therapy. Per-test performance metrics, including sensitivity, specificity, positive predictive value, and negative predictive value, for TTMV-HPV DNA testing. Of 399 patients included in the analysis, 163 were in the diagnostic cohort (median [IQR] age, 63 [56-68.5] years; 142 [87.1%] male), and 290 were in the surveillance cohort (median [IQR] age, 63 [57-70] years; 237 [81.7%] male). Of the 163 patients in the diagnostic cohort, 152 (93.3%) had HPV-associated OPSCC while 11 (6.7%) had HPV-negative OPSCC. The TTMV-HPV DNA sensitivity in pretreatment diagnosis was 91.5% (95% CI, 85.8%-95.4% [139 of 152 tests]), and the specificity was 100% (95% CI, 71.5%-100% [11 of 11 tests]). In the surveillance cohort, 591 tests conducted in 290 patients were evaluated. A total of 23 patients had molecularly confirmed pathologic recurrences. The TTMV-HPV DNA test demonstrated sensitivity of 88.4% (95% CI, 74.9%-96.1% [38 of 43 tests]) and specificity of 100% (95% CI, 99.3%-100% [548 of 548 tests]) in detecting the recurrences. Positive predictive value was 100% (95% CI, 90.7%-100% [38 of 38 tests]), and negative predictive value was 99.1% (95% CI, 97.9%-99.7% [548 of 553 tests]). The median (range) lead time from positive TTMV-HPV DNA test to pathologic confirmation was 47 (0-507) days. This cohort study demonstrated that when evaluated in a clinical setting, the TTMV-HPV DNA assay demonstrated 100% specificity in both diagnosis and surveillance. However, the sensitivity was 91.5% for the diagnosis cohort and 88.4% for the surveillance cohort, signifying that nearly 1 in 10 negative tests among patients with HPV-associated OPSCC was a false negative. Additional research is required to validate the assay's performance and, if validated, then further research into the implementation of this assay into standard clinical practice guidelines will be required.

Abstract P5-14-11: Rearrangements in CDH1, ESR1, and ERBB2 are commonly observed in breast cancer and may influence diagnosis and treatment

Abstract Background The status of CDH1, ERBB2, and ESR1 is important for the diagnostic and treatment workup for patients with breast cancer. Most alterations in these genes occur in the form of short variants (eg missense and indel alterations) or copy number alterations (eg amplifications of ERBB2 or deletions in CDH1). The prevalence and characteristics of rearrangement events have been understudied. Materials and Methods: Comprehensive genomic profiling using a hybrid-capture based approach was performed on 44,842 breast carcinomas during the course of routine clinical care (FoundationOne® or FoundationOne®CDx) examining all classes of alterations in up to 395 genes, including CDH1, ESR1, and ERBB2. All rearrangements were included in the analysis (known/likely pathogenic and variants of uncertain significance). Estrogen receptor status was extracted from pathology reports for a subset of samples. Results: Rearrangements in CDH1, ESR1, and ERBB2 were observed in 0.26% (115/44842), 0.34% (153/44842), and 1.33% (598/44842) of breast cancer samples, respectively. As expected, CDH1 rearrangements were most common in invasive lobular carcinoma (ILC) (0.64%; 16/2516) though events were observed in samples originally submitted as invastive ductal carcinoma (IDC) (0.16%; 26/15,836), suggesting possible misdiagnosis. CDH1 rearrangements were predominantly loss of function consisting of large deletions, inversions, and truncation events. ESR1 rearrangements were observed at the highest frequency in ER+/HER2- tumors (0.58%) and were never seen in ER-/HER2- and ER-/HER2+ tumors. ESR1 rearrangements were observed with a variety of partners, with recurrent events with CCDC170, SYNE1, RMND1, PLEKHG1, ARMT1, MTHFD1L, and ZBTB2. Consistent with a possible role in therapy resistance, ESR1 rearrangements were enriched in metastatic samples relative to those biopsied from the breast (OR = 2.25; p = 8E-05). ERBB2 rearrangement events were commonly observed in HER2 amplified tumors (13.4%) and rarely in other subtypes (0.12% in ER+/HER2- and 0.28% in ER-/HER2-). Most of the events were intra-chromosomal and typically represented non-fusion duplication fragments that may have generated the ERBB2 amplification. Fusions were much rarer. Out of the 598 rearrangement events, only 18 were predicted to create in-frame and in-strand fusion products retaining the HER2 kinase domain following manual review of the events. Most fusion events were unique, though a fusion with IKZF3 was seen recurrently (n=2). Conclusions Rearrangement events in diagnostically important breast cancer genes (CDH1, ESR1, and ERBB2) were commonly observed in breast cancer with subtype-specific enrichment. Since these alterations have implications in disease diagnosis and therapy response (eg endocrine therapy resistance), comprehensive genomic profiling can provide value in breast cancer care. Citation Format: Ethan Sokol, Dexter Jin, Jeffrey S. Ross, ADRIAN V. LEE, Steffi Oesterreich. Rearrangements in CDH1, ESR1, and ERBB2 are commonly observed in breast cancer and may influence diagnosis and treatment [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-14-11.

Perfusion-only imaging in pregnant women: A comparative reader study with implications for practice patterns.

This study seeks to understand the value of ventilation imaging in pregnant patients imaged for suspected pulmonary embolism (PE). Ventilation-perfusion (VQ) scans in this high-risk population were compared to ventilation-only scans. We hypothesize that in this relatively healthy population, the exclusion of ventilation scans will not impact the rate of scans interpreted as positive. This retrospective blinded comparative reader study on collated VQ scans performed on pregnant patients in the course of routine clinical care in a > 5 year period (03/2012 to 07/2017). Each set of VQ and perfusion only (Q) studies were reviewed by 8 readers (4 nuclear radiology fellows and 4 nuclear medicine faculty) in random order; the Q scans simply omitted the ventilation images. Readers recorded each study as PE, no PE, or non-diagnostic (prospective investigative study of acute PE diagnosis classifications). Logistic mixed effects models were used to test the association between scan type (VQ vs Q). 203 pairs of studies in 197 patients were included (6 patients had 2 scans). Subjects ranged from 14 to 45 years of age, with a median 28 years. A significant association between scan type and positive/negative classification. Q-scans received more positive classifications than VQ-scans (median of 7.6% vs 6.7%). No association was seen between scan type and positive/indeterminate classification, nor between scan type and negative/indeterminate classification. The exclusion of ventilation images in VQ-scans was associated with a higher rate of positive studies, but this difference was small (<1%). Given the overwhelmingly normal percentage of Q-exams (>90% in our study), and the benefits of omitting ventilation imaging, perfusion-only imaging should be considered a reasonable option for imaging the pregnant patient to exclude PE.

Molecular characteristics of advanced colorectal cancer and multi-hit PIK3CA mutations.

3535 Background: Approximately 20% of colorectal cancer (CRC) has an activating mutation in the PIK3CA oncogene. PIK3CA codes for the catalytic subunit of phosphoinositide 3-kinase alpha (PI3Kα), which ultimately activates the AKT and mammalian target of rapamycin (mTOR) pathway. The PI3Kα inhibitor alpelisib has been approved for breast cancer where a single PIK3CA activating mutation is sufficient for response. However, two activating mutations (multi-hit) in the PIK3CA allele substantially increases PI3Kα signaling compared to single hot spot mutations and results in exceptional response to PI3Kα inhibition. We aimed to identify the prevalence of PIK3CA multi-hit mutations in CRC to identify patients potentially susceptible to PI3K inhibitors. Methods: Tissue-based comprehensive genomic profiling (CGP) was performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified, CAP (College of American Pathologists)-accredited laboratory (Foundation Medicine Inc., Cambridge, MA, USA) on all-comers during the course of routine clinical care from 2013-2021. Approval was obtained from the Western Institutional Review Board (Protocol No. 20152817). Hybrid capture was carried out for at least 324 cancer-related genes, including PIK3CA. Results: We identified 48,836 patients with advanced CRC who underwent Foundation Medicine testing and 846 (1.7%) patients with multi-hit PIK3CA mutations. Additional clinical and molecular data was available for 41,154 of these patients of which 710 (1.7%) had multi-hit PIK3CA and 7627 (19%) had any deleterious PIK3CA mutation . The local colon tumor was used for sequencing in 70% of cases and a separate site in 30% of cases. Patients with PIK3CA multi-hit mutations were 53% male with a median age of 60 (interquartile range 50-70). The microsatellite status was available for 697 of 710 patients with multi-hit PIK3CA and 123/697 (18%) were microsatellite instability-high. The Table outlines the genes with cooccurring mutations of &gt;10% prevalence for multi-hit PIK3CA CRC, including the clinically relevant mutations in KRAS (65%) and BRAF (13%). The four most common PIK3CA variants were H1047R (9.8%), E545K (9.2%), E542K (9.0%) and R88Q (7.1%). The most common variant pair was E542K with E545K in 4.7% of multi-hit cases. Conclusions: Double-hit mutations in PIK3CA are seen in 1.7% of advanced CRC patients and may represent a subset of patients that may have enhanced sensitivity to PI3K inhibitors. Given the high prevalence of CRC in the United States and worldwide this represents a clinically meaningful prevalence of multi-hit PIK3CA. Future investigation on the clinical utility of PI3K inhibitors may be warranted in multi-hit PIK3CA CRC.[Table: see text]

Genomic characterization of thymic epithelial tumor from real-world data.

8587 Background: Thymic epithelial tumors (TETs), including thymic carcinomas and thymomas, are rare neoplasms arising in the mediastinum. Chemotherapy is still the mainstay of treatment and few therapeutic options are available for patients with advanced or metastatic TETs. Due to their rarity, the sample size in the previous reports about the genomic profiles of TETs was small and the results varied from study to study, which hinders the development of treatment. Herein, we investigated the comprehensive genomic characteristics of TETs evaluated in a large genomic database profiled in a real-world setting. Methods: Tissue biopsy-based comprehensive genomic profiling was performed in the course of routine clinical care. We included data from two different cohorts: Foundation Medicine Inc. (FMI) in the US (Frampton GM, et al. Nat Biotechnol 2013) and the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) in Japan, which is engaged in a national project for collecting genomic analysis and clinical results from patients. Samples profiled at Foundation Medicine were examined for all classes of alterations in 253 genes targeted across all assays. Tumor mutational burden (TMB) and microsatellite instability (MSI) were calculated as previously described (Chalmers ZR, et al. Genome Med 2017. Trabucco, et al. J Mol Diagn 2019). Patients’ background including histology, age, and sex were also investigated, and genetic alteration, TMB, and MSI were stratified by them. Results: A total of 794 patients were collected for our study, including 722 cases from FMI and 72 cases from C-CAT. In the FMI data, 414 cases of thymic carcinoma and 308 cases of thymoma were included. CDKN2A (39.9%), TP53 (30.2%) and CDKN2B (24.6%) were frequently altered in thymic carcinoma, versus TP53 (7.8%), DNMT3A (6.8%), CDKN2A (5.8%) and CDKN2B (4.6%) in thymoma. TMB-High (≥ 10muts/Mb) and MSI-High were present in 7.0% and 2.3% of thymic carcinomas, and 1.6% and 0.3% of thymomas, respectively. Comparison of the thymic carcinoma cohort based on age &lt; 60 vs 60+ years found a significant difference in prevalence of NFKBIA alterations (2.7% age &lt; 60 vs 11.7% age ≥ 60, p = 0.034), while a similar comparison of the thymoma cohort found no significant differences between age groups. An analysis based on sex did not find any significant differences between groups. 55 cases of thymic carcinoma and 17 cases of thymoma were included from C-CAT data. In thymic carcinoma, CDKN2A (27.3%), TP53 (23.6%) and CDKN2B (20.0%) were also frequently altered, while alterations of TSC1 (23.5%) and CD22, LTK, NOTCH1, KMT2A, SETD2, ATM (17.6% each) were found in thymoma. Conclusions: To the best of our knowledge, this is the largest cohort in which genomic alterations, TMB, and MSI status of TETs were investigated. We suggest that several gene mutations, TMB, and MSI status might be potential targets for treatment and lead to therapeutic development opportunities, especially in thymic carcinoma.

Association between TERT promoter mutations and clinical outcome with immune checkpoint inhibitor therapy for advanced urothelial cancer.

561 Background: Recently published data suggests that the presence of a TERT promoter mutation is predictive of superior overall survival (OS) in patients (pts) with advanced/metastatic bladder cancer (mUC) treated with an immune checkpoint inhibitor (ICI) (Kouchkovsky et al, JITC 2021). We aim to validate the results of this study in a large independent cohort. Methods: Pts with mUC treated at two tertiary cancer centers with available genomic data collected in the course of routine clinical care were identified retrospectively. Pts that had received at least one line of ICI therapy in the metastatic setting were selected. Demographic and treatment data were collected, with pts divided into two groups based on the presence or absence of TERT mutation status ( TERTm or TERTwt, respectively). We evaluated OS from diagnosis of at least muscle invasive disease, progression free survival (PFS), and objective response rate (ORR) with ICI therapy across the two groups. OS in our cohort was compared with findings from pts with bladder cancer in The Cancer Genome Atlas (TCGA) database. Results: From our combined data sets, a total of 166 pts had available genomic data, with 64 TERTm pts (52:12 M:F) and 58 TERTwt pts (32:26 M:F) meeting criteria for inclusion. Median age at diagnosis was 67 in both groups. The site of primary disease was bladder in 54 (84%) TERTm vs. 41 (71%) in TERTwt; 10 (16%) and 17 (29%) had upper tract disease, respectively. 47 (73%) TERTm pts and 40 (69%) TERTwt pts had pure urothelial disease; 17 (27%) and 18 (31%) pts had mixed/pure variant histology, respectively. 37 (58%) and 42 (72%) pts received first-line ICI therapy whereas 27 (42%) and 16 (28%) received subsequent-line therapy in TERTm and TERTwt, respectively. At the time of analysis, there were 24 (38%) patients alive in TERTm, and 23 (40%) patients alive in TERTwt. OS was 35 vs. 36 mos (95% CI 0.62-1.51, P=0.66) in TERTm and TERTwt, respectively. PFS on ICI therapy was 4.6 vs. 5.3 mos (95% CI 0.58-1.34, P≥0.99) in TERTm and TERTwt, respectively. ORR was 75% in TERTm and 50% in TERTwt (P=.004). OS in the TCGA database was 35 mos in TERTm and 47 in TERTwt (P=0.19) from a total of 311 and 127 pts, respectively. Conclusions: In contrast to previously published data, our data show no difference in OS and PFS on the basis of TERT mutational status in pts with mUC treated with ICI therapy. Further analysis from larger datasets is needed to reconcile the role of TERT mutations within this patient population.

Association of intra-tumoral microbiome and response to immune checkpoint inhibitors (ICIs) in patients with metastatic renal cell carcinoma (mRCC).

372 Background: Multiple studies have suggested that the gut microbiome plays a modulatory role in ICI activity and that specific bacteria and/or cumulative microbial diversity may drive response in patients (pts) with mRCC (Routy et al Science 2018; Salgia et al Eur Urol 2020). Even though the tumor microenvironment has substantial bacterial proliferation (Heymann et al Cancer L. 2021), there is a paucity of data assessing the impact of intra-tumoral microbiota in response to ICI therapy. In this study, we sought to explore this association in pts with mRCC. Methods: Pts diagnosed with mRCC who had available RNA sequencing (RNA-seq) data collected in the course of routine clinical care and who were treated with ICIs were retrospectively identified.Intra-tumoral microbiome analysis was performed on formalin-fixed paraffin-embedded samples. Following quality and adapter trimming, RNA-seq reads were mapped to a human genome to filter host reads using the Burrows-Wheeler alignment (BWA) tool. Taxonomic classification was performed using Kraken2 and the absolute abundances of species were estimated using Bracken. The relative abundances among all non-human species were calculated. Statistical testing with Student’s t-test was performed to compare the relative abundance for all species seen within pts who responded to ICIs and those who did not. Results: Among the 28 pts (22:6, M:F) included in this analysis, 24 (86%) had clear cell histology and 20 (71%) were IMDC intermediate/poor risk. All of the samples were collected prior to starting treatment with ICIs and the majority of these (57%) were collected from the primary site. 11 pts (39%) received ICIs as first line treatment and 17 (61%) as second line. Clinical response was seen in 50% of pts included in the study and the most common rendered treatment was nivolumab (17 pts). In the overall cohort, Cutibacterium acne, Moraxella osloensis, and Pasteurella multocida had the highest relative abundances. Additionally, significant differences in relative abundances of specific bacteria were found between ICI responders and non-responders. Among these, Stenotrophomonas maltophilia (p = 0.037) and Corynebacterium sp. zg-917 (p = 0.035) had significantly higher relative abundances in pts who responded to ICIs. Conclusions: This is the first study evaluating the association between intra-tumoral microbiome and response to ICIs in pts with mRCC. Among bacteria associated with response, several have particular relevance – for instance, Corynebacterium spp. have been studied for decades as a possible adjunct to immunotherapeutic agents such as BCG. Efforts are ongoing to validate these findings in a larger cohort.

Abstract P3-08-02: The frequency and somatic mutation landscape of Fibroblast growth factor receptor (FGFR) alterations in breast cancer

Abstract Background: FGFR dysregulation is observed in multiple cancers and targeting FGFR is an emerging therapeutic strategy with FDA approved treatments in bladder and cholangiocarcinoma. Here we examined the prevalence of FGFR mutations, fusions, and high-level amplifications in breast cancer, stratified by receptor subtype and local/metastatic status, in both Foundation Medicine (FM) and institutional Mayo Clinic (MC) cohorts. Methods: For the FM cohort, comprehensive genomic profiling (CGP) examining at least 324 genes for all classes of alterations, including FGFR1-4 was carried out for 32,048 breast cancers during the course of routine clinical care in a Clinical Laboratory Improvement Amendments (CLIA)-certified lab (Foundation Medicine Inc., Cambridge, MA, USA). Tumor mutational burden (TMB) was determined on up to 1.1 Mb, microsatellite instability high (MSI-High) was determined on up to 114 loci and predicted ancestry from &amp;gt;10,000 SNPs. Estrogen receptor (ER) and HER2 status were available for a subset of FM samples. Additionally, 131 patients with metastatic breast cancer from a subset of patients at three Mayo Clinic sites (MC cohort) with clinical characteristics and cancer-panel DNA sequencing data from a CLIA-certified lab (Tempus, Chicago, IL) were included. Results: In the FM cohort, the prevalence of FGFR1-4 high-level amplification (CN≥10) was 10.1%, while mutations (1.5%) and fusions (0.72%) were rare. Most amplifications occurred in FGFR1 (9.2%); most fusions and mutations occurred in FGFR2 (0.46%, 0.77%). FGFR alteration prevalence was highest in ER+/HER2- subtype (14.4%) and lowest in HER2+ disease (7.7%). FGFR alterations were more common in IDC (11.7%) than ILC (7.7%), p&amp;lt;3E-08. FGFR alterations were more prevalent in the metastatic setting relative to breast-biopsied disease (13.6% v 10.1%; OR = 1.4; p=2E-17), especially in the HER2+ (OR =1.9, p=0.004) and ER-/HER2- (OR = 1.9, p = 0.05) disease; no enrichment was seen in the ER+/HER2- metastases (OR =1.0, p = 1). FGFR amplifications were observed at a higher prevalence in patients with predicted East Asian ancestry, relative to patients with European ancestry (12.1% v 10.0%; p = 0.03). Overall, the most common activating mutations in FGFR were FGFR2 N549K (n=85), FGFR1 N546K (n=78), FGFR4 V510M (n=28), FGFR2 K659E (n=28), FGFR4 V510L (n=20), and FGFR2 Y375C (n=15). The most common recurrent fusions were FGFR3:TACC3 (n=36), FGFR2:TACC2 (n=17), FGFR1:TACC1 (n=9), FGFR1:BAG4 (n=6), and FGFR2:ATE1 (n=5). In patients with FGFR amplifications, the most frequently co-occurring alterations were ZNF703 (78.4%), TP53 (51.5%), CCND1 (36.1%), FGF3/4/19 (32.9 - 34.4%), PIK3CA (30.7%), MYC (29.6%), ESR1 (17.2%), EMSY (16.3%), and PTEN (10.6%). Significant co-occurrence was observed for a number of genes including FGF3/4/19, CDK4, and CDK8 (all OR&amp;gt;2, p&amp;lt;1E-07); mutual exclusivity was observed with PIK3R1, BRCA1, and BRCA2 (all OR &amp;lt;0.5, p&amp;lt;4E-13), among other genes. In the 131 metastatic tumors from MC, the prevalence of FGFR1-4 high-level amplifications was 19.8% [FGFR1 (12.4%), FGFR2 (7.4%), and FGFR3 (0.8%)]. The prevalence of high-level FGFR amplifications did not differ by clinical subtypes: HR-/HER2- (7/31), HR+/HER2- (15/79), and HER2+ (2/11), p=0.68. Conclusions: High-level FGFR amplifications are observed in &amp;gt;11% of breast cancers, especially the ER+/HER2- subtype, while mutations/fusions are rare. These data support the ongoing studies evaluating targeted therapies for FGFR amplified ER + breast cancer. Correlations with clinical information (MC cohort) and associations with actionable alterations are ongoing and may inform potential combination strategies. Citation Format: Karthik V Giridhar, Ethan S Sokol, Peter T Vedell, Jason P Sinnwell, Aakash Desai, Tufia C Haddad, Ciara C O’Sullivan, Roberto A Leon-Ferre, Siddhartha Yadav, Kostandinos Sideras, Brenda Ernst, Minetta C Liu, Abe Eyman Casey, Xiaojia Tang, Zoe Fleischmann, Karthikeyan Murugesan, Krishna R Kalari, Matthew P Goetz. The frequency and somatic mutation landscape of Fibroblast growth factor receptor (FGFR) alterations in breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-08-02.

Abstract P3-09-10: NTRK1/2/3 fusions are observed in both secretory and non-secretory breast cancers

Abstract Background NTRK1/2/3 kinase fusions are rare oncogenic drivers found in &amp;lt;1% of solid tumors. NTRK fusion-positive (NTRK+) solid tumors have shown meaningful clinical response to small molecule NTRK inhibitors such as entrectinib and larotrectinib, and broad genomic testing will help identify patients (pts) with these rare alterations. NTRK fusions occur more frequently in some cancers than others. For example, NTRK fusions are characteristic of secretory breast cancers (BCa), and it has been posited that non-secretory BCa lack druggable NTRK fusions (PMID: 30707464). However, these conclusions were drawn on limited patient populations. Here we show evidence of NTRK fusions in both secretory and non-secretory breast tumors in the largest real-world cohort of NTRK+ breast tumors reported to date. Methods Comprehensive genomic profiling of at least 324 cancer-related genes, including NTRK1/2/3, was done at Foundation Medicine on de-identified all-comer BCa pts during the course of routine clinical care. Pathology reports and hematoxylin and eosin (H&amp;E) images of NTRK+ breast tumor tissue were examined by a board-certified pathologist for designation of secretory vs. non-secretory phenotype. Results NTRK fusions were identified in 23 BCa specimens. H&amp;E images were available for review in 22 cases, and another was confirmed as secretory via the pathology report. Pathologist review of those 23 cases revealed that NTRK fusions were present in 11 with secretory phenotypes, 11 with non-secretory phenotypes, and 1 with a mixed secretory phenotype. Secretory cases most often harbored a ETV6-NTRK3 fusion (n=7) with additional recurrent fusions seen in TPM3-NTRK1 (n=2) and LMNA-NTRK1 (n=2). Non-secretory breast cancers also harbored ETV6-NTRK3 (n=2), TPM3-NTRK1 (n=1), and LMNA-NTRK1 (n=1) fusions, as well as several unique fusion events that retain the NTRK kinase domain. Conclusions While rare, NTRK fusions occur in a wide variety of tumor types. Within BCa, this includes both secretory and non-secretory phenotypes, with half of the identified alterations occurring in non-secretory BCa. Recurrent events, including ETV6-NTRK3, were observed in both populations. These data support NTRK fusion testing for all BCa pts with both secretory and non-secretory histologic subtypes. Citation Format: Ethan Sokol, Sophia Maund, Jeffrey Ross, Timothy Wilson. NTRK1/2/3 fusions are observed in both secretory and non-secretory breast cancers [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-09-10.

SLCO1B1*5 Allele Is Associated With Atorvastatin Discontinuation and Adverse Muscle Symptoms in the Context of Routine Care.

The SLCO1B1 genotype is known to influence patient adherence to statin therapy, in part by increasing the risk for statin‐associated musculoskeletal symptoms (SAMSs). The SLCO1B1*5 allele has previously been associated with simvastatin discontinuation and SAMSs. Prior analyses of the relationship between SLCO1B1*5 and atorvastatin muscle side effects have been inconclusive due to insufficient power. We now quantify the impact of SLCO1B1*5 on atorvastatin discontinuation and SAMSs in a large observational cohort using electronic medical record data from a single health care system. In our study cohort (n = 1,627 patients exposed to atorvastatin during the course of routine clinical care), 56% (n = 912 of 1,627 patients) discontinued atorvastatin and 18% (n = 303 of 1,627 patients) developed SAMSs. A univariate model revealed that SLCO1B1*5 increased the likelihood that patients would stop atorvastatin during routine care (odds ratio 1.2; 95% confidence interval (CI), 1.1–1.5; P = 0.04). A multivariate Cox proportional hazards model further demonstrated that this same variant was associated with time to atorvastatin discontinuation (hazard ratio 1.2; 95% CI, 1.1–1.4; P = 0.004). Additional time‐to‐event analyses also revealed that SCLO1B1*5 was associated with SAMSs (hazard ratio 1.4; 95% CI, 1.1–1.7; P = 0.02). Atorvastatin discontinuation was associated with SAMSs (odds ratio 1.67; P = 0.0001) in our cohort.

MAJOR DEPRESSIVE DISORDER IS ASSOCIATED WITH TYPE 2 DIABETES IN PATIENTS WITH CHRONIC HEPATITIS C INFECTION.

Major depressive disorder (MDD) is commonly reported in patients with chronic hepatitis C (CHC); however, the factors behind the co-occurrence of these conditions have not been completely clarified yet. We aimed to evaluate the frequency of mental disorders in CHC patients and to investigate variables associated with MDD. CHC patients (n=151) attending a referral Centre for hepatitis were evaluated using the Mini-International Neuropsychiatry Interview and the Cut-Annoyed-Guilty-Eye (CAGE) Questionnaire. Multivariate analysis was used to evaluate independent covariates associated with current MDD. Seventy-six (50.3%) patients had, at least, one current psychiatric diagnosis with MDD (33.1%) being the most common. Current MDD was independently associated with age (≤50 yr.) (OR=2.57; 95%CI=1.25-5.29; P=0.01) and type 2 diabetes mellitus (OR=2.80, 95%CI=1.17-6.70; P=0.02). Cirrhosis was associated with type 2 diabetes mellitus (OR=5.09; 95%CI=1.73-15.04; P=0.03) and current alcohol abuse/dependence (OR=2.54; 95%CI=1.04-6.22; P=0.04). MDD is associated with type 2 diabetes in CHC patients. Even in the direct-acting antivirals (DAAs) era, characterized by great perspectives for the first ample cure of a chronic viral infection, we should ensure that the screening for psychiatric disorders takes place in the course of routine clinical care of patients chronically infected with hepatitis C virus.

Abstract 2233: Landscape of driver mutations in MAPK/PI3K/AKT signaling pathways reveals insights into therapeutic targeting strategies

Abstract Alterations in the signaling cascade of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K) pathways are common mechanisms of cancer initiation and progression. RAS proteins (KRAS/HRAS/NRAS), a crucial component of this cascade, are often found to be activated in cancer cells. Recent advancements in RAS targeting offer new treatment strategies for patients, however studies suggest that the clinical responses may be tissue-dependent. Thus, understanding the landscape of RAS alterations and the concomitant mutations observed in their effector pathways may be crucial in developing appropriate disease-specific therapeutic strategies for effectively addressing this biology. In this study, we utilized comprehensive genomic profiling data from 282,792 cancer patients across 77 tumor types, tested in the course of routine clinical care (FoundationOne) to assess the landscape of gene alterations within this signaling cascade. RAS alterations were identified in 27% of the cohort. Mutations in PI3K and PTEN were also frequent (&amp;gt;10%); alterations in FGFR1-4, EGFR, RAF (ARAF/BRAF/RAF1) and ERBB2 were each identified in over 5% of samples. A closer inspection of non-small cell lung carcinomas (NSCLC, n=55,893), colorectal carcinomas (CRC, n=35,104) and pancreatic cancers (PC, n=17,447), revealed distinct mutational spectrums. RAS alterations, particularly KRAS, exhibited varying prevalence: PC (85%), CRC (54%) and NSCLC (32%). In NSCLC, 35% of the KRAS alterations were identified to be G12C. In contrast, the predominant KRAS alterations in CRC and PC were G12D (29% CRC, 41% PC) and G12V (20% CRC, 30% PC). Further, only CRCs exhibited a high rate of KRAS G13D (16% of all KRAS alterations); KRAS G12R was found exclusively to PC (15%) and KRAS amplifications were most frequently identified in NSCLC (11%). Distinct patterns were also observed in genes upstream and downstream of the RAS proteins. Alterations in ALK, EGFR, STK11 and MET were significantly more prevalent in NSCLC (P &amp;lt; 10−5); whereas gene alterations in PI3K, RAF, MTOR and ERBB2 were more frequently identified in CRC (P &amp;lt; 10−5). In contrast, PC showed a predominant presence of RAS mutations, with limited mutations in other genes of the signaling cascade. Of note, PI3K alterations were identified at a much lower prevalence in PC (4%) compared to NSCLC (11%) and CRC (19%). Our findings suggest a tissue-dependent spectrum of driver mutations exist across the MAPK/PI3K/AKT signaling pathways. The observed mutational profiles may explain some of the efficacy differences observed by targeting RAS across these diseases and have implications on acquired resistance mechanisms in a tissue-specific manner. Additional insights may be gleaned by investigating immunotherapy related biomarkers with these alterations to suggest combination strategies for effectively targeting the RAS signaling cascade. Citation Format: Smruthy Sivakumar, Ethan S. Sokol, Garrett M. Frampton, Priti S. Hegde, David Fabrizio. Landscape of driver mutations in MAPK/PI3K/AKT signaling pathways reveals insights into therapeutic targeting strategies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2233.

Abstract LB196: Comparison of whole exome sequencing and targeted sequencing in patients with advanced bladder cancer

Abstract Background: Next generation sequencing (NGS) to identify genomic alterations (GAs) in tumor samples are increasingly used in clinical practice. Targeted sequencing (TS) or whole exome sequencing (WES) are used by various commercially available platforms. Differing methods often result in poor inter-reproducibility, even when testing the same tissue. Bladder cancer has substantial genetic heterogeneity as compared to many other malignancies. The purpose of this study is to compare WES and TS in bladder cancer. Methods: Patients with advanced bladder cancer who had undergone tissue WES (GEM ExTra®) or TS (FoundationOne CDx® [FMI]) in the course of routine clinical care were assessed. Genes with at least one detected GA were selected, with others excluded. All detected GAs were classified as being detected on TS only, WES only, concordant (detected on both platforms), or partially concordant (different GAs detected within the same gene). Variants of uncertain significance were excluded for this study. Results: In our series, 25 patients had WES and 42 patients had TS - 14 patients (21%) had both tests performed. A total of 88 genes were detected to have at least one GA across all samples. Of all detected GAs, 66/162 (41%) were concordant, with 45/162 (28%) and 51/162 (31%) of GAs detected exclusively by WES and TS, respectively. The genes with the highest proportion of concordance when detected, were TERT (70%), TP53 (85%) and ARIDA1A (50%). SOX4 and E2F3 were detected on WES only, while RBM and CHEK2 were detected on TS only. Notably, six TP53 GAs were detected exclusively on TS. TP53, TERT, MLL2/KMT2D, ERBB2 were each partially concordant on one occasion. The difference in the rate of concordant GAs in samples from the same collection site and date (41%), as compared to those in which both differed (35%) were not statistically significant (p=0.54). Conclusions: Although the majority of GAs identified were concordant, each platform exclusively identified GAs with varying clinical significance. SOX4 and E2F3 mutation, shown to correlate with invasive potential in bladder cancer, were detected exclusively on WES. In contrast, RBM and CHEK2 (of known significance in melanoma and breast cancer) were found exclusively on TS. Larger series are needed to further establish the concordance of these approaches. Citation Format: Neal Shiv Chawla, Zeynep Zengin, Ameish Govindarajan, Sumanta K. Pal. Comparison of whole exome sequencing and targeted sequencing in patients with advanced bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB196.

Genomic alterations for novel targeted therapies in pancreatobiliary cancers from real-world data.

4124 Background: Cancers of the pancreas and biliary tract remain one of the unfavorable malignant tumors with few driver genomic alterations. Tumor-agnostic approaches are promising for cancers with poor prognosis, with some potentially actionable alterations, such as BRCA1/2 mutations, ERBB2 amplification, MSI-High, or tumor mutational burden (TMB)-High. However, co-existing alterations, clinical significance of other genomic alterations, or frequency of alterations by clinical and genomic background are unclear. Here we investigated the genomic profile in a large cohort of advanced pancreatobiliary cancers to help refine and discover new targets for improved cancer therapies. Methods: Comprehensive genomic profiling was performed at Foundation Medicine, on patients with RWD tested during the course of routine clinical care. Hybrid capture was carried out on up to 395 cancer-related genes and select introns from up to 31 genes frequently rearranged in cancer. 16,913 pancreatic cancer (PC) patients and 3,031 biliary tract cancer (BTC) patients were available for analyses and were stratified by age (≥40/ &lt; 40), MSI status, TMB status (High ≥10/Low &lt; 10 Muts/Mb), and select gene alterations. Using a chi-square test with Yate’s correction, frequencies of genetic alterations were analyzed according to clinical or genomic background. Results: KRAS (84.8%), TP53 (73.3%), CDKN2A (51.2%), CDKN2B (26.5%), and SMAD4 (23.2%) were frequently altered in PC patients, versus TP53 (60.6%), CDKN2A (33.5%), KRAS (27.1%), CDKN2B (20.6%) and SMAD4 (16.9%) in BTC patients. The frequency of MSI-High and TMB-High in BTC was 1.2% and 5.7%, respectively, while these were lower in PC (0.48% and 2.1%, respectively). In PC patients, the KRAS alteration rate was significantly lower in both MSI-High (57.3%, P&lt; 0.001) and TMB-High populations (51.3%, P&lt; 0.001). In BTC patients, the rate of ERBB2 amplification was 6.4% in TMB-High and 8.6% in TMB-Low population. Interestingly, CDK12 rearrangement was observed in BTC patients with ERBB2 amplified tumors but not in those without ERBB2 amplified tumors. In patients of pediatric/adolescents and young adults ( &lt; 40 years old), the mutation rate of KRAS/ TP53/ CDKN2A/ SMAD4 was lower, and FGFR2 rearrangement (4%) was observed in PC patients; GATA6 amplification (11.1%) and rearrangement of BRAF (2.8%), FGFR2 (5.6%) were observed in BTC patients. Conclusions: A large real-world dataset showed differences in genomic landscape according to clinical or genomic background, and some potential targets for the development of novel drugs in advanced pancreatobiliary cancers. These findings may lead to the improvement of cancer therapies in PC and BTC patients with poor prognosis.

Radiomic features of renal cell carcinoma primary and metastatic sites as predictors of TERT and BAP1 mutations.

282 Background: TERT and BAP1 mutations are associated with poor clinical outcome in patients (pts) with metastatic renal cell carcinoma (mRCC) (Dizman et al JITC 2020; Joseph et al J Urol 2016). In this study we explore radiogenomics as a non-invasive method to identify these alterations. Methods: Pts with mRCC who had genomic testing in the course of routine clinical care were included in the current analysis. Pts were assessed with the GEM Extra assay, a CAP-accredited, CLIA-certified test encompassing paired tumor-normal whole exome sequencing (WES) and tumor whole transcriptome sequencing (TGen; Phoenix, AZ). Pts underwent CT imaging; radiomic analysis was performed on the segmented metastatic and primary lesions. Features were independently correlated with TERT and BAP1 mutation status to generate Pearson correlation values (PCVs). Results: 92 pts (65:27 M: F) were included in the analysis; of these, the majority of pts (84%) had clear cell histology. Alterations in the TERT gene were seen in 12 pts. In these pts 1,325 radiomic features of the primary tissue were examined and 251 features correlated with a PCV ≥ |0.2|. Of these, 42 features were correlated with a PCV ≥ |0.3|. Highest correlation with TERT mutation was seen with Gray Level Cooccurrence Matrix (GLCM) and First Order Features (FOF). 9 pts had BAP1 mutation with 5 detected in primary tumor and 4 in metastatic sites. Analysis of primary tumor imaging yielded no significant associations between radiomic features and BAP1 mutation. However, out of approximately 1,500 radiomic features noted in metastatic sites, 111 features correlated with BAP1 mutation with a PCV ≥ 0.2. Of these, 15 features correlated with a PCV ≥ 0.3. The radiomic features with the highest correlation with BAP1mt were Gray Level Dependence Matrix (GLDM) and GLCM. Conclusions: By identifying a correlation between radiomic features of TERT mutation in primary tumors and BAP1 mutation in metastatic sites, our work may ultimately yield a non-invasive method of discerning mutational status in patents with mRCC. Efforts are ongoing to validate our findings within The Cancer Imaging Archive.

Nonvisualized palpable bowel endometriotic satellites.

STUDY QUESTIONWhat is the prevalence of laparoscopically nonvisualized palpable satellite bowel nodules at or near the planned stapler site in women undergoing segmental bowel resection for endometriosis?SUMMARY ANSWEROverall, 13 (25.5%) of 51 patients who underwent resection had nonvisualized palpable satellite lesions as small as 2 mm, including seven (14%) who had nonvisualized palpable lesions at or beyond the planned stapler site.WHAT IS KNOWN ALREADYBoth laparoscopy and laparotomy for bowel resection are standard of care in Europe and the USA. Reoperation rates after laparoscopic bowel procedures are 1–16%. Endometriotic lesions at the stapler margin of bowel resections are associated with increased repeat surgery. Nodules of 0.1 mm to 1 cm in size were not recognized during laparoscopic bowel surgery but were recognized on histological examination. Up to 20 nodules not visualized at laparoscopy have been recognized and excised at laparotomy. Tenderness is found at up to 27 mm from a recognized lesion. The size of a lesion does not always predict its symptoms or behavior.STUDY DESIGN, SIZE, DURATIONThis single-arm, observational study focused on the presence of nonvisualized palpable satellite lesions of the bowel. Fifty-one patients scheduled for laparoscopic-assisted bowel resection for deep infiltrating endometriosis with suprapubic incision for placement of the stapler’s anvil and removal of the specimen in the course of routine clinical care were included. There were no additional inclusion or exclusion criteria.PARTICIPANTS/MATERIALS, SETTING, METHODSLaparoscopic-assisted segmental bowel resection for endometriosis was performed in a private referral center on women aged 24–49 years.MAIN RESULTS AND THE ROLE OF CHANCEForty-nine (96.1%) of the 51 patients underwent segmental resection of the sigmoid or rectum, and 14 (27.5%) underwent segmental resection of the ileum for large nodule(s) recognized on MRI. Twelve patients underwent both procedures. Eleven (22.4%) of the 49 patients with recognized sigmoid or rectal lesions and 5 (35.7%) of the 14 patients with recognized ileal lesions had nonvisualized, palpable, satellite lesions. All the large lesions and none of the satellite lesions had been recognized preoperatively on MRI. Five (10%) of 49 patients with lesions of the large bowel and 4 (28.6%) of the 14 patients with lesions of the ileum had nonvisualized palpable satellite lesions at or beyond the planned stapler site. Lesions as small as 2 mm were palpable.LIMITATIONS, REASONS FOR CAUTIONThis is an observational study. It is not known if the small lesions of this study contributed to the symptoms or were progressive, stable or regressive. This study analyzed lesions in the bowel segment proximal to the primary large bowel lesion, but not in the distal segment as that would have required a change in standard of care surgical technique. This study protocol did not include shaving or disk resection or patients in whom no lesions were visualized. The use of additional techniques for recognition, such as hand-assisted laparoscopy or rectal probes, was not investigated.WIDER IMPLICATIONS OF THE FINDINGSThis study confirms that some nonvisualized satellite lesions as small as 2 mm are palpable and that an increased length of resection can be used to remove lesions recognized by palpation and to avoid lesions at and beyond the stapler site. This may decrease recurrent surgery in 1–16% of the women undergoing surgery for bowel endometriosis. Knowledge of the occurrence of these small lesions may also be particularly useful in plans for repeat surgery or for women with clinically significant bowel symptoms and no visible lesions at laparoscopy. Moreover, small lesions are considered to be important as there is no current technique to determine whether a large primary lesion, smaller lesions, an associated adjacent tissue reaction or a combination of those cause symptoms.STUDY FUNDING/COMPETING INTEREST(S)This CIRENDO cohort was supported by the G4 Group (the University Hospitals of Rouen, Lille, Amiens and Caen) and the ROUENDOMETRIOSE association. No specific funding was received for the study. H.R. reports receiving personal fees from Plasma Surgical Inc., Ethicon Endosurgery, Olympus and Nordic Pharma for presentations related to his experience with endometriosis surgery. D.C.M. reports being given access to Lumenis Surgical CO2 Lasers’ lab at a meeting. None of the other authors have conflicts of interest to disclose.TRIAL REGISTRATION NUMBERN/A