Citations

Mitochondria are dynamic organelles that are able to change their morphology and cellular distribution by either fission or fusion. However, the molecular mechanisms controlling mitochondrial dynamics in vascular endothelial cells (ECs) remain largely unknown. In this study, we observed that knockdown of microtubule‐associated tumor suppressor 1 (MTUS1) in ECs inhibited tube formation and migration, accompanied with decreased promigratory signalings. We showed that MTUS1 was localized in the outer membrane of mitochondria in ECs. Knockdown of MTUS1 disturbed the elongated mitochondrial network and induced the formation of perinuclear clusters of mitochondria. Importantly, mitochondrial motility and fusion were suppressed, whereas generation of reactive oxygen species was increased in MTUS1 knockdown ECs. Mechanistically, we showed that the N‐terminal coiled‐coil domain of MTUS1 interacted with the mitochondrial membrane proteins, mitofusin‐1 and mitofusin‐2, to maintain mitochondrial morphology in ECs. This study illustrated a novel role of MTUS1 in mitochondrial morphology and EC angiogenic responses.—Wang Y., Huang Y., Liu, Y., Li, J., Hao, Y., Yin, P., Liu, Z., Chen J., Wang Y., Wang N., Zhang P., Microtubule associated tumor suppressor 1 interacts with mitofusins to regulate mitochondrial morphology in endothelial cells. FASEB J . 32, 4504–4518 (2018). www.fasebj.org

Abstract Purpose: p95HER2 is a truncated form of HER2 that confers resistance to trastuzumab in vitro, but clinical results have been conflicting to date. Given that p95HER2 levels correlate with total HER2 expression levels, which confer better outcomes, we sought to evaluate the p95HER2/HER2 ratio in the North Central Cancer Treatment Group N0337 and N98-32-52 trials. Experimental Design: The HERmark assay and VeraTag technology (Monogram Biosciences) were used to measure total HER2 and p95HER2 expression levels in 91 patient samples. Results: In the multivariate model, increasing total HER2 level was significantly associated with longer (OS; HR, 0.33; P = 0.002) and decreasing p95HER2 level was significantly associated with longer OS (HR, 4.2; P = 0.01). Total HER2 expression level was significantly associated with longer progression-free survival (PFS) (HR, 0.57; P = 0.04), whereas p95HER2 level was not (HR, 1.7; P = 0.25). However, there was a positive association between p95HER2 and total HER2 expression levels (R2 = 0.48; P < 0.001). Consistent with our hypothesis, the ratio of p95HER2/HER2 was significantly associated with worsening PFS (HR, 1.7; P = 0.04) and OS (HR, 2.8; P = 0.002). Patients with the highest tertile of p95HER2/HER2 values had significantly less favorable PFS (HR, 1.8; P = 0.06) and OS (HR, 2.3; P = 0.02). Conclusions: A high p95HER2/HER2 ratio identified patients with metastatic breast cancer with poor outcomes on trastuzumab-based therapies. Further investigation of the p95HER2/HER2 ratio as a potential prognostic or predictive biomarker for HER2-targeted therapy is warranted. Clin Cancer Res; 24(13); 3053–8. ©2018 AACR.

Background: Medial meniscus root tears are a common knee injury and can lead to accelerated osteoarthritis, which might ultimately result in a total knee replacement. Purpose: To compare meniscus repair, meniscectomy, and nonoperative treatment approaches among middle-aged patients in terms of osteoarthritis development, total knee replacement rates (clinical effectiveness), and cost-effectiveness. Study Design: Meta-analysis and cost-effectiveness analysis. Methods: A systematic literature search was conducted. Progression to osteoarthritis was pooled and meta-analyzed. A Markov model projected strategy-specific costs and disutilities in a cohort of 55-year-old patients presenting with a meniscus root tear without osteoarthritis at baseline. Failure rates of repair and meniscectomy procedures and disutilities associated with osteoarthritis, total knee replacement, and revision total knee replacement were accounted for. Utilities, costs, and event rates were based on literature and public databases. Analyses considered a time frame between 5 years and lifetime and explored the effects of parameter uncertainty. Results: Over 10 years, meniscus repair, meniscectomy, and nonoperative treatment led to 53.0%, 99.3%, and 95.1% rates of osteoarthritis and 33.5%, 51.5%, and 45.5% rates of total knee replacement, respectively. Meta-analysis confirmed lower osteoarthritis and total knee replacement rates for meniscus repair versus meniscectomy and nonoperative treatment. Discounted 10-year costs were $22,590 for meniscus repair, as opposed to $31,528 and $25,006 for meniscectomy and nonoperative treatment, respectively; projected quality-adjusted life years were 6.892, 6.533, and 6.693, respectively, yielding meniscus repair to be an economically dominant strategy. Repair was either cost-effective or dominant when compared with meniscectomy and nonoperative treatment across a broad range of assumptions starting from 5 years after surgery. Conclusion: Repair of medial meniscus root tears, as compared with total meniscectomy and nonsurgical treatment, leads to less osteoarthritis and is a cost-saving intervention. While small confirmatory randomized clinical head-to-head trials are warranted, the presented evidence seems to point relatively clearly toward adopting meniscus repair as the preferred initial intervention for medial meniscus root tears.

Abstract Objective In recent years, electronic health record systems have been widely implemented in China, making clinical data available electronically. However, little effort has been devoted to making drug information exchangeable among these systems. This study aimed to build a Normalized Chinese Clinical Drug (NCCD) knowledge base, by applying and extending the information model of RxNorm to Chinese clinical drugs. Methods Chinese drugs were collected from 4 major resources—China Food and Drug Administration, China Health Insurance Systems, Hospital Pharmacy Systems, and China Pharmacopoeia—for integration and normalization in NCCD. Chemical drugs were normalized using the information model in RxNorm without much change. Chinese patent drugs (i.e., Chinese herbal extracts), however, were represented using an expanded RxNorm model to incorporate the unique characteristics of these drugs. A hybrid approach combining automated natural language processing technologies and manual review by domain experts was then applied to drug attribute extraction, normalization, and further generation of drug names at different specification levels. Lastly, we reported the statistics of NCCD, as well as the evaluation results using several sets of randomly selected Chinese drugs. Results The current version of NCCD contains 16 976 chemical drugs and 2663 Chinese patent medicines, resulting in 19 639 clinical drugs, 250 267 unique concepts, and 2 602 760 relations. By manual review of 1700 chemical drugs and 250 Chinese patent drugs randomly selected from NCCD (about 10%), we showed that the hybrid approach could achieve an accuracy of 98.60% for drug name extraction and normalization. Using a collection of 500 chemical drugs and 500 Chinese patent drugs from other resources, we showed that NCCD achieved coverages of 97.0% and 90.0% for chemical drugs and Chinese patent drugs, respectively. Conclusion Evaluation results demonstrated the potential to improve interoperability across various electronic drug systems in China.

93 Background: Tumor mutational load (TML) has been proposed as a biomarker of responsiveness to novel immune checkpoint inhibitors (ICIs) due its association with increased neoantigen formation and tumor immunogenicity. Gastrointestinal cancers (GICs) are generally insensitive to ICIs; therefore the aim of this study was to evaluate the TML, clinically relevant genomic alterations (CRGAs), and PDL-1 status of GIC patients (pts). Methods: We analyzed samples of pts with GICs using a multiplatform profiling tool (Caris Life Sciences, Phoenix, AZ). TML and CRGAs were calculated based on next generation sequencing and mutational load was stratified as high (≥17 mut/Mb), intermediate (8-16 mut/Mb), and low (≤ 7 mut/Mb). PD-L1 status was determined by IHC. Descriptive statistics and simple linear regression were used for analysis. Results: A total of 85 pts with GICs were analyzed. The median pt age was 65. 53% were males and 47% were females. Tumors were colorectal 51%, pancreatic 13%, esophageal 13%, gastric 9%, hepatobiliary 11%, anal canal 4%, and small intestine 1%. 80 cases (94%) had an adequate sample for profiling and TML was available in 59 cases (74%). Cases were 5% TML-high, 56% TML-intermediate, and 39% TML-low. The median TML was 9 mut/Mb and median CRGAs was 3. The most commonly detected CRGAs were TP53 (56%), APC (44%), KRAS (40%), ATM (18%) and PTEN (6%). A positive but very weak correlation was found between TML and number of CRGAs (R2 = 0.3). PD-L1 status was available in 74 cases (93%) with 86% being PD-L1 negative and 14% PD-L1 positive. PD-L1 expression was most commonly seen in esophageal (50%) and anal canal (30%) cancers. Among 57 tumors tested for both biomarkers, no correlation was found between a high TML and PD-L1 expression. Conclusions: TML varies among GICs, and higher TML scores were not associated with PD-L1 expression, but there was a weak correlation between TML and the number of CRGAs. Further analysis by stratification of GIC type and prognostic analysis to assess the correlation between TMB and response to ICIs is warranted.

5 Background: Triple-negative breast cancer (TNBC) is an immunogenic breast cancer subtype, with a greater percentage of tumors containing tumor-infiltrating lymphocytes (TILs) compared to non-TNBC. TILs are prognostic for recurrence and predictive for chemotherapy benefit in TNBC, but not in estrogen receptor (ER)-positive tumors. A subset of TNBC expresses the androgen receptor (AR), and resembles ER-positive breast cancer in terms of demographics (older age) and clinical course (later recurrences that tend to involve bone). However, little is known regarding the association between TILs and AR expression in TNBC. Methods: From a cohort of 9982 women with surgically-treated non-metastatic breast cancer, patients who met criteria for TNBC (ER/PR < 1% and HER2-negative) by centralized-pathology review were included as previously published [Leon-Ferre et al, Breast Cancer Res Treat 2017]. Stromal TILs in these tumors were quantified on full-face hematoxylin and eosin sections from the surgical specimen, following the 2014 TIL Working Group recommendations [Salgado et al, Ann Oncol 2014]. The expression of AR [EPR1535(2), Abcam] was scored as a continuous variable (1% increments), and categorized as absent (0%), low (1-25% ), low-moderate (26-50%) moderate (51-75%) and high (> 75%) and correlated with TIL density. Results: 605 patients met criteria for TNBC. The median age was 56 years. Most tumors were T1-2 (95%), N0-1 (86%), and high grade (88%). The median stromal TIL content was 20% (0-90%). Tumor tissue was available for AR staining in 509/605 patients. 165 (32%) tumors expressed AR as follows: low: 12%, low-moderate: 7%, moderate: 5%, and high: 8%. Apocrine tumors (n = 30) expressed AR most frequently (86%) and at higher levels (AR high: 50%). For all 509 tumors, the median stromal TIL content according to AR expression was AR absent: 20%, AR low: 20%, AR low-moderate: 15%, AR high: 10%. AR and stromal TILs (both as continuous variables) demonstrated a weak inverse correlation (correlation coefficient -0.1064, p = 0.017). Conclusions: AR expression in TNBC is associated with lower levels of stromal TILs. Additional data correlating the AR, stromal TILs and outcomes in this cohort will be presented at the meeting.

Background: Mutations in the leucine rich repeat kinase 2 ( LRRK2) gene are among the most common genetic causes of Lewy body Parkinson’s disease (PD). However, LRRK2 mutations can also lead to a variety of pathological phenotypes other than typical PD, including relatively pure nigrostriatal cell loss without alpha-synuclein-positive Lewy bodies or Lewy neurites, progressive supranuclear palsy (PSP), and multiple system atrophy (MSA). The mechanisms behind this remarkable pleomorphic pathology are currently unclear. Objective: To genetically and pathologically characterize a case with a LRRK2, p.Ile1371Val rare variant and pathologically proven MSA. Methods: From the brain donation program at the Parkinson’s Institute and Clinical Center, we selected 26 brains with family history and a with clinicopathological diagnosis of PD ( n = 20), MSA ( n = 4), or PSP ( n = 2). We performed neuropathological evaluation, including alpha-synuclein and tau immunohistochemistry and sequenced 188 genes that have been reported as causative for or associated with neurodegenerative diseases. Results: We identified a known LRRK2, p.Ile1371Val genetic variant in a case with clinically diagnosed and pathologically proven MSA. Neuropathology revealed that the olivopontocerebellar system was more affected than the striatonigral system. Conclusions: Our data suggest that genetic variants in the LRRK2 gene can present clinically and neuropathologically as MSA. One other LRRK2 genetic variant ( LRRK2, p.Ile2020Thr) has been reported with a neuropathological diagnosis of MSA. Interestingly, the LRRK2 variant ( LRRK2, p.Ile1371Val) identified here has been reported previously in a postmortem case with Lewy body PD. Future studies are critical to discover the mechanisms leading to different neurodegenerative trajectories both in neuronal and glial cell populations.

Abstract Background: Pembrolizumab (P), an anti-PD-1 immune checkpoint inhibitor, has been approved for treatment of microsatellite instability-high and mismatch repair deficient cancers. In I-SPY 2, patients were randomized to receive standard chemotherapy alone or in combination with an experimental agent. P was one of the experimental agents evaluated in HER2- patients in I-SPY 2 and graduated in the TN, HR+HER2-, and HER2- signatures. We hypothesize that a combination of two signatures predicting response to veliparib/carboplatin therapy in I-SPY 2 [MammaPrint High2 (MP2)/PARPi7-high] and reflecting DNA damage repair deficiency, may also predict response to P. In addition, we also tested 9 gene expression signatures reflecting different aspects of DNA damage and repair: FA, MMR, BER, HR, TLS, NER, NHEJ, DR, and DNA damage sensing (DDS) pathways. Methods: Data from 249 patients (P: 69 and controls: 180) were available. Pre-treatment biopsies were assayed using Agilent gene expression arrays. All I-SPY 2 qualifying biomarker analyses follow a pre-specified analysis plan. We used logistic modeling to assess biomarker performance. A biomarker is considered a specific predictor of P response if it associates with response in the P arm but not the control arm, and if the biomarker x treatment interaction is significant (likelihood ratio test, p&lt;0.05). This analysis is also performed adjusting for HR status as a covariate, and within receptor subsets, sample size permitting. For successful biomarkers, we use Bayesian modeling to estimate the pCR rates of 'predicted sensitive' patients in each arm. Our statistics are descriptive rather than inferential and do not adjust for multiplicities of other biomarkers outside this study. Results: MP2 status associates with pCR in P (OR=7.7; p=0.00021), but also to a lesser extent in the control arm (OR=2.4:p=0.045), with an OR ratio of 3.3 which trends toward significance, even after adjusting for HR status (LR p=0.083). A majority of TN patients are MP2; and TN/MP2 patients have an estimated pCR rate of 67% in P (vs. 23% in control). Although only ~30% of HR+HER2- patients were MP2, their estimated pCR rate in P is 61%, compared to 29% in unselected HR+/HER2- patients. PARPi7 predicted response in the P arm only in the HR+HER2- group (LR p= 0.025), but not in the population as a whole or the TN subtype. Combining MP2 and PARPi7 into MP2/PARPi7-high did not improve performance over MP2 as a single biomarker. Of the 9 DDR pathway signatures tested, both BER and DDS associate with pCR in P, but only DDS (which includes ATM, ATR, CHEK1-2) associates with pCR in the P arm (LR p=0.00029), and not the control arm (LR p=0.53), with a significant interaction with treatment (LR p=0.0064) that retains significance in a model adjusting for HR status. When dichotomized to optimize the biomarker x treatment interaction, the estimated pCR rate is 75% in P vs 18% in control, in the DDS+ subset. Conclusion: In this small study, MP2 status and a DNA damage sensing pathway but not the PARPi7 or other repair pathways show promise as predictive biomarkers for immune checkpoint inhibition therapy in breast cancer. Citation Format: Yau C, Wolf D, Brown-Swigart L, Hirst G, Sanil A, Singhrao R, I-SPY 2 TRIAL Investigators, Asare S, DeMichele A, Berry D, Esserman L, van 't Veer L, Nanda R, Liu M, Yee D. Analysis of DNA repair deficiency biomarkers as predictors of response to the PD1 inhibitor pembrolizumab: Results from the neoadjuvant I-SPY 2 trial for stage II-III high-risk breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD6-14.

Abstract Background: Patients with previously untreated mTNBC typically receive cytotoxic chemotherapy as first-line therapy for metastatic disease. However, efficacy and safety are suboptimal. KEYNOTE-086 (NCT02447003) is a multicohort, single-arm, phase 2 study of pembrolizumab monotherapy for mTNBC. In cohort B, we assessed the safety and antitumor activity of pembrolizumab as first-line therapy for patients with PD-L1-positive mTNBC. Methods: Key eligibility criteria for cohort B were age ≥18 y, centrally confirmed TNBC, no prior systemic anticancer therapy for metastatic disease, ECOG performance status 0-1, measurable disease per RECIST v1.1 by central review, no radiographic evidence of brain metastases, and a tumor PD-L1 combined positive score (CPS) ≥1. Pembrolizumab 200 mg was given once every 3 wk for 24 mo or until disease progression, intolerable toxicity, or investigator or patient decision. Tumor imaging was performed every 9 wk for 12 mo and every 12 wk thereafter. Clinically stable patients with radiologic progression could remain on pembrolizumab until progression was confirmed on subsequent assessment. Primary end point was safety. Secondary end points included ORR, duration of response, and PFS (all RECIST v1.1 by central review) and OS. Results: Of the 206 patients with tumors evaluable for PD-L1 expression, 128 (62%) had PD-L1 CPS ≥1. Of these, 84 met all eligibility criteria and enrolled. All patients were women, median age was 52.5 y, 29 (35%) had ECOG PS 1, 40 (48%) had elevated LDH, 55 (65%) had visceral ± nonvisceral metastases, and 73 (87%) received prior (neo)adjuvant therapy. All patients received ≥1 pembrolizumab dose, and after median follow-up of 10.6 mo, 18 (21%) remained on pembrolizumab. Treatment-related AEs occurred in 53 (63%) patients and were of grade 3-4 severity in 7 (8%); no patients died or discontinued pembrolizumab because of treatment-related AEs. The most common treatment-related AEs were fatigue (26%), nausea (13%), and diarrhea (12%). No grade 3-4 treatment-related AE occurred in &gt;1 patient. The most common immune-mediated AE was hypothyroidism (10%). Three patients had complete response and 16 had partial response for an ORR of 23% (95% CI 15-33). Of the 11 patients with a best response of stable disease, 1 had stable disease for ≥24 wk, leading to a disease control rate of 24% (95% CI 16-34). 12 of 19 (63%) responses were ongoing at data cutoff, and median duration of response was 8.4 mo (range 2.1+ to 13.9+). Median PFS was 2.1 mo (95% CI 2.0-2.2), with an estimated 6-mo PFS rate of 26%. Median OS was 16.1 mo (95% CI 11.3-NR), with an estimated 6-mo OS rate of 83%. Conclusions: Pembrolizumab monotherapy continues to demonstrate a favorable safety profile and robust, durable antitumor activity in patients with PD-L1-positive, previously untreated mTNBC. Citation Format: Adams S, Loi S, Toppmeyer DL, Cescon DW, De Laurentiis M, Nanda R, Winer EP, Mukai H, Tamura K, Armstrong AC, Liu MC, Iwata H, Ryvo L, Wimberger P, Rugo HS, Tan A, D'Aquanno C, Ding Y, Karantza V, Schmid P. KEYNOTE-086 cohort B: Pembrolizumab monotherapy for PD-L1–positive, previously untreated, metastatic triple-negative breast cancer (mTNBC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD6-10.