bluuebunny/crossref_metadata_2025_split huggingface dataset:
ERBB2 amplifications and mutations in 109 advanced breast cancer patients by next-generation sequencing.
Authors: Shah Ami N. , Finkelman Brian , Gerratana Lorenzo , Davis Andrew A. , Katam Neelima , Lin Chenyu , Carroll Kristen , Jacob Saya , Wehbe Firas , Gurley Michael , Lin Fang , Blanco Luis , Vagia Elena , Platanias Leonidas C. , Gradishar William John , Behdad Amir , Cristofanilli Massimo 
Published: May 2020

3565 Background: In advanced breast cancer (ABC) HER2 status is based on ASCO/CAP immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) criteria. Next generation sequencing (NGS) of tissue and blood can detect aberrations in ERBB2 such as copy number gain/amplifications (cng/amp) and mutations. Methods: We retrospectively identified patients (pts) seen at Northwestern University between 2015 and 2019 with ABC and an alteration in ERBB2 identified by tissue and/or circulating tumor DNA (ctDNA) NGS. We included pts with testing by Guardant360, TempusX, and/or FoundationOne platforms. NGS reports were evaluated for non-synonymous mutations and cng/amp. HR and HER2 status were determined based on the most recent pathologic assessment. Mutations were categorized as pathologic if they were consider oncogenic (level 1-2 evidence with direct functional data), likely oncogenic, or predicted oncogenic, based on OncoKB (Chakravarty et al., JCO PO 2017). Results: 109 cases of ABC (6 locally advanced, 103 metastatic) with ERBB2 alterations were identified. Tissue NGS was available from 43%, ctDNA from 72%, and both from 19%. The positive predictive value (PPV) of ERBB2 amp/cng by tissue NGS to predict HER2+ using the gold standard as IHC/FISH was 94% (33/35). The PPV of ERBB2 amp by ctDNA was 93% (40/43). ERBB2 mutations were detected in 52 pts. Of these, 23 pts were considered to harbor pathologic ERBB2 mutations, (19 oncogenic, 2 likely oncogenic, 1 predicted oncogenic) detected by ctDNA and tissue in 4, ctDNA in 16, and tissue in 3 pts. The most frequently detected mutations were V777L and S310. Four pts had co-mutations of ERBB2 V777L and S310F. Disease subtype among those with ERBB2 pathologic mutations was HR+ HER2- in 57%, HER2+ in 26%, and triple negative in 17%. In all patients with serial ctDNA analysis and pathologic ERBB2 mutations, the mutation was detected on the first analysis. Pathologic ERBB2 mutation represented the mutant with the highest mutant allele frequency (MAF) in 30% and top 3 highest MAF in an additional 35%. PIK3CA was co-mutated in 48%. Conclusions: The PPV of ERBB2 amp/cng by tissue and ctDNA NGS was high, and has potential utility for cancers where HER2 IHC/FISH is not standardly assessed or cases where biopsy is challenging. ERBB2 pathologic mutations were found in all breast cancer subtypes. When present, they were identified on the initial ctDNA analysis and often represented a significant clone, supporting its role as a ‘driver mutation’.
Diagnosis of leptomeningeal metastasis (LM) through identification of circulating tumor cells (CTCs) in cerebrospinal fluid (CSF).
Authors: Fenn Kathleen , Singh Veena M. , Lee Shing Mirn , Cieremans David , Lassman Andrew B. , Hershman Dawn L. , Crew Katherine D. , Accordino Melissa Kate , Trivedi Meghna S. , Iwamoto Fabio Massaiti , Schultz Robbie , Huynh Lan , Sales Edgar V. , Fisher Deanna M , Mayer Julie A , Kreisl Teri Nguyen , Kalinsky Kevin 
Published: May 2020

3567 Background: Diagnosis of LM from solid tumors can be challenging. The TargetSelector (TS) CTC detection assay has demonstrated highly specific and sensitive CTC capture both for epithelial (CK+) and non-epithelial (CK-) subsets. The assay utilizes a ten-antibody (ab) capture cocktail followed by biotinylated secondary abs that bind to CTCs, enriched in a microfluidic device. TS targeted next-generation sequencing (NGS) assay detects somatic mutations in 12 breast cancer-related genes. The aim was to determine whether TS can improve sensitivity in the diagnosis of LM compared to CSF cytology by lumbar puncture (LP). Methods: CSF was collected prospectively from patients (pts) with a prior solid tumor diagnosis and suspicion of LM. CTCs were isolated from CSF using the TS platform. Cells were stained with cytokeratin (CK), CD45, streptavidin and DAPI. CTCs captured in a microchannel were classified as CK + or -. Peripheral blood samples obtained at time of LP underwent similar CTC analysis. Cell-free total nucleic acids (cfTNA) were extracted from plasma and CSF followed by NGS. Data analysis used the Ion Torrent Suite with annotation and report curation by Ion Reporter and Oncomine Knowledgebase Reporter software respectively. Results: There were 14 pts (13 women and 1 man), median age 56 years (range 32-75) with cancers of the breast (10), lung (1), colon (1), CNS lymphoma (1) or glioma (1). Pts had received a median of 2.5 lines of systemic metastatic therapy (range 0-8). CSF cytology was not sent for 1 pt and TS was not performed for 1 pt. TS and standard cytology had 89% agreement in pts with metastatic breast cancer (MBC, 8/9). Of the 6 pts for whom CTCs were detected in CSF by TS, 3 pts had + cytology (all MBC), 2 pts had - cytology and 1 pt with MBC was not tested by cytology. Of the 3 pts with + CSF by cytology (all MBC), all were detected by TS (Table). Among 5 MBC pts with CTCs present in CSF, ER status was concordant in 2 of 5 (40%). HER2 status was concordant in 3 of 4 (75%) evaluable pts and not determined in 1 pt. Analysis of cfDNA from CSF identified somatic mutations in 3 pts (TP53, PIK3CA, CCND1, respectively). In 1 of 3 pts, the mutation identified in the CSF (PIK3CA) in HR+/HER2- MBC was also identified in the blood. Conclusions: TargetSelector is a viable platform for the detection of breast cancer CTCs in the CSF. NGS performed on CSF samples can identify potentially actionable mutations. [Table: see text]
PCR-based comprehensive genomic profiling (PCR-CGP): Feasibility from >20,000 tumor tissue specimens (TTS) and predicted impact on actionable biomarker identification versus hybrid capture (H)-CGP and plasma (P)-CGP.
Authors: Rhodes Dan , Hovelson Daniel H , Suga Jennifer Marie , Anderson Daniel M. , Dees Elizabeth Claire , Koh Han A. , Burkard Mark E. , Khatri Jamil , Safa Malek M. , Matrana Marc Ryan , Yang Eddy Shih-Hsin , Menter Alex R. , Parsons Benjamin Marshall , Slim Jennifer Nadine , Falkner Jayson , Reeder Travis , Vakil Hana , Kwiatkowski Kat , Johnson Bryan , Tomlins Scott A. ,   Strata Network Investigators
Published: May 2020

3574 Background: Tissue-based h-CGP is increasingly utilized for treatment selection in patients with advanced solid tumors but has high tumor surface area [TSA] requirements (≥25mm2 for leading commercial tests). P-CGP is recommended when tissue is insufficient for H-CGP. Here we assessed the feasibility and clinical impact on actionable biomarker identification of PCR-CGP. Methods: We performed a post-hoc, non-prespecified analysis on 21,743 consecutive subjects with advanced solid tumors who sent TTS for PCR-CGP from 5/17-12/19 as part of an ongoing observational trial at > 20 U.S. health systems (NCT03061305). PCR-CGP was performed using StrataNGS, a single-site laboratory developed test assessing all CGP biomarker classes (including microsatellite instability (MSI) status and tumor mutation burden [TMB]). We predicted actionable biomarker identification rates for PCR-CGP, H-CGP and P-CGP if applied to all U.S. patients with advanced solid tumors through incorporating population incidence, biomarker frequencies, test TSA and tumor content requirements (or cfDNA detection rates), and performance characteristics. Actionable biomarkers were the 30 in 11 tumor types from the MolDX p-CGP local coverage determination (L38043), pan-tumor NTRK fusions and MSI, and TMB in lung cancer. Results: Among TTS from 21,734 patients with advanced cancer, 20,493 (94.3%) met TSA requirements for PCR-CGP (≥2mm2) vs. 9,281 (42.7%) for H-CGP. PCR-CGP reported results for 98.0% and 95.0% of patients with large (≥25mm2 TSA) and small (2-24mm2) TS, respectively, in a median of 7 business days. Compared to 1,882 orthogonal actionable biomarker results, PCR-CGP accuracy was 96.6% and 96.5% in large and small TTS, respectively. Actionable biomarker frequency was highly correlated in PCR-CGP tested large vs. small TTS (r2= 0.99), as well as in this PCR-CGP cohort vs. a MSKCC institutional pan-cancer H-CGP cohort (r2= 0.92). If applied to all U.S. patients with advanced solid tumors, PCR-CGP has significantly greater predicted actionable biomarker identification rate (88.5%) compared to P-CGP (77.0%, N-1 chi-squared test, p < 0.0001) or H-CGP (54.3%, p < 0.0001). Conclusions: Half of TTS submitted for PCR-CGP did not meet H-CGP tissue requirements. PCR-CGP is feasible for the vast majority of patients and is predicted to expand the actionable biomarker evaluable proportion of patients with advanced solid tumors compared to H-CGP or P-CGP. Clinical trial information: NCT03061305 .
Highly accurate automated tissue classification using deep learning on digital pathology images: A novel tool for resolving conflicts in diagnosis.
Authors: Benz Stephen Charles , Beziaeva Liudmila , Jaber Mustafa , Rabizadeh Shahrooz , Szeto Christopher 
Published: May 2020

3578 Background: Pathologist inspection of biopsy slides is the gold-standard for diagnosis and is crucial for effective therapy decisions. However, expert shortage is resulting in turnaround times exceeding College of American Pathologists’ (CAP) standards (Alshieban, 2015). Further, discrepancy between diagnoses can exceed 4% (Mukhopadhyay, 2018), and 2% of cases are designated as ‘carcinoma of unknown primary’ (CUP) negatively affect outcomes due to difficulty selecting therapies (Rassy, 2020). Here we sought to aid in diagnosing patients from whole-slide images (WSIs) using deep neural networks. Methods: > 6.3K high-resolution H&E-stained diagnostic WSI of formalin-fixed paraffin-embedded (FFPE) tumor block slices were selected from TCGA sources. Slide images were obtained from 30 different cancer subtypes including 368 Breast (5.6%), 324 Colon (5.12%), 287 Lung Adenocarcinoma (LUAD) (4.5%), Lung Squamous-Cell carcinoma (LUSC) (4.5%), and Stomach Adenocarcinoma (4.3%). Local regions containing tumor tissue were automatically identified by training an Inception V3 deep-learning network as previously presented. A separate Inception V3 network was trained to classify the primary tissue of 200mm2 tumor regions in 60% of the images, which was validated in the remaining 40% testing cohort. Results: The proposed deep-learning model was 92.7% accurate in identifying the primary tissue within the test set of WSIs. As expected, most misclassification occurred in highly-related tissue-types: Rectal cancers misclassified as colon (25%) and vice versa (4.8%), uveal melanomas misclassified as cutaneous melanomas (18.6%), cholangiocarcinomas as hepatocellular carcinomas (8.6%), and LUSC misclassified as LUAD (6.0%) and vice versa (3.4%). Combining related tissues, the classifier achieves 94.6% accuracy across 24 primary types. Unexpectedly, cutaneous melanomas samples were misclassified as breast (9.1%) and LUSC (5.6%), suggestive of related molecular phenotypes. Conclusions: By focusing machine-vision attention on tumor regions, the automated system approaches pathologist accuracy. Used in conjunction with molecular profiling, rates of CUP or misdiagnosis can feasibly be minimized to improve patient care. This system is currently being validated in an external set of > 4K unselected clinical cases from the NantHealth database.
Selpercatinib (LOXO-292) in patients with RET-fusion+ non-small cell lung cancer.
Authors: Goto Koichi , Oxnard Geoffrey R. , Tan Daniel Shao-Weng , Loong Herbert H. F. , Bauer Todd Michael , Gainor Justin F. , McCoach Caroline Elizabeth , Gautschi Oliver , Besse Benjamin , Cho Byoung Chul , Peled Nir , Weiss Jared , Kim YuJung , Ohe Yuichiro , Horiike Atsushi , Park Keunchil , Huang Xin , Olek Elizabeth , Subbiah Vivek , Drilon Alexander E. 
Published: May 2020

3584 Background: Selpercatinib (LOXO-292) is a highly selective and potent small molecule RET kinase inhibitor. Here we report an update on the efficacy and safety of selpercatinib in RET-fusion+ non-small-cell lung cancer (NSCLC). Methods: Patients with RET-fusion+ NSCLC were enrolled to the Phase 1/2 LIBRETTO-001 trial (NCT03157128), a global, multicenter trial (16 countries, 89 sites). Following the Phase 1 dose escalation portion of the trial, patients received the recommended dose of 160 mg orally twice daily. Each cycle was 28 days. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Secondary endpoints included duration of response (DoR) and safety. Per health authority agreement, the primary analysis set was defined as the first 105 consecutively enrolled patients previously treated with platinum-based chemotherapy. Treatment-naïve patients were analyzed separately. All analyses were based on a 16-Dec-2019 data cutoff date. Results: In the primary analysis set of platinum-treated patients (median of 3 prior systemic regimens; range 1-15), the ORR by investigator assessment was 70% (95% CI 59.8–78.1, n = 73/105). Responses did not differ by fusion partner or number or type of prior therapies, including anti-PD-1/PD-L1 agents and off-label multikinase inhibitor use. The median DoR was 20.3 months (95% CI 15.6–24.0) with 45 of 73 (62%) responders censored at a median follow-up of 14.8 months. Among 39 treatment-naïve patients, the ORR by investigator assessment was 90% (95% CI 75.8–97.1, n = 35/39, including 2 responses pending confirmation). Median DoR was not reached with 27 of 33 (82%) confirmed responses ongoing at a median follow-up of 7.4 months. In the safety analysis set consisting of all selpercatinib dosed patients (N = 702), the most common treatment-related adverse events (TRAEs) that occurred in ≥15% of patients were dry mouth (33.3%), increased AST (24.5%), increased ALT (23.8%), hypertension (23.2%), diarrhea (19.7%), and fatigue (16.8%). Only 2% (14 of 702) of patients discontinued selpercatinib for TRAEs. Conclusions: Selpercatinib achieved marked and durable antitumor activity in patients with RET-fusion+ NSCLC. Selpercatinib was well tolerated. Efficacy data assessed by independent review committee based on the 16-Dec-2019 data cutoff date will be presented. Clinical trial information: NCT03157128 .
A phase I, first-in-human, open-label, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of oral TP-3654 administered daily for 28 days to patients with advanced solid tumors.
Authors: Garrido-Laguna Ignacio , Dillon Patrick Michael , Anthony Stephen Patrick , Janat-Amsbury Margit , Ashenbramer Nissa , Warner Steven L , Mouritsen Lars , Wade Mark L. , Whatcott Clifford , Bearss David , Fu Siqing 
Published: May 2020

3586 Background: TP-3654 is an oral, second generation, potent PIM-1 kinase inhibitor with activity against PIM 2, 3 and favorable selectivity against other kinases. These cytoplasmic serine/threonine kinases are highly expressed in many cancers and their oncogenic potential has been largely attributed to supressing apoptosis downstream of stimuli including inflammatory cytokines and other immune effectors. TP-3654 has efficacy in various hematologic and solid tumor models inducing stromal Pim-1 also has been shown to mediate various aspects of the tumor microenvironment. Thus, Pim kinases are attractive targets for the treatment of many human malignanices. Methods: A first in human, multicenter, phase 1, dose escalation study using a standard 3+3 design with a modified Fibonacci scheme to examine the safety and clinical activity of TP-3654 in patients with advanced solid tumors. Results: Ten patients were enrolled between 30Apr and 31Dec2019 receiving 480, 720, and 1080 mg respectively. Grade 3 AEs were scrotum wound infection, altered mental status, anemia, fall, and lower extremity edema, none were related to study drug and all were manageable with supportive care. There were no Grade 4 or 5 AEs and no DLTs. Median duration of SD was 5.5 months (6/10) and with prolonged SD > 16wks (4/10). One CRC patient with 4 lines of prior therapy had a 22% reduction in tumor volume (SD > 5+ mos). TP-3654 plasma PK values (Cmax, AUC) continuously increased through all 3 cohorts. Average Cmax (ng/mL) and AUC0-24 (ng*hours/mL) were 195, 1965 (480mg); 357, 3310 (720mg); 735, 6922 (1080mg), respectively. PK values increased linearly with higher doses without reaching saturation. Peripheral Blood Mononuclear Cells were isolated from subjects prior and up to 24hours after treatment. Western Blot from protein lysates revealed a decrease in phosphorylation of BAD and p70s6K proteins, both regulated by PIM-1 kinase. Conclusions: These findings suggest that TP-3654 is tolerated as a monotherapy in patients with heavily pretreated, relapsed, and resistant solid tumors warranting further clinical development in selected indications.
Correlation between overall response rate and progression-free survival/overall survival in comparative trials involving targeted therapies in molecularly enriched populations.
Authors: Solomon Benjamin J. , Loong Herbert H. F. , Summers Yvonne J. , Thomas Zachary M , French Pearl Plernjit , Lin Boris K. , Sashegyi Andreas , Wolf Juergen , Yang James Chih-Hsin , Drilon Alexander E. 
Published: May 2020

3588 Background: Randomized trials involving agents targeting oncogene addicted tumors have greatly increased over the past decade. Whether clinical response rates can predict or correlate with efficacy measures such as progression-free survival (PFS) or overall survival (OS) has not been established in molecularly enriched patient populations. In this meta-analysis, we investigated whether improvements in objective response rate (ORR) in comparative trials using targeted agents could serve as a potential surrogate endpoint for improvements in PFS or OS in populations with oncogene addicted cancer. Methods: CT.gov and MEDLINE databases were queried (using commercial text mining software I2E) for randomized, phase 3 clinical trials based on the following prospectively defined criteria: (1) use of agents targeting EGFR activating mutations (erlotinib, gefitinib, afatinib, dacomitinib, osimertinib), ALK and ROS1 rearrangements (crizotinib, ceritinib, alectinib), BRAF V600E or V600K mutations (dabrafenib), and BCR-ABL fusion protein (imatinib, dasatinib, nilotinib, ponatinib); (2) must include molecularly enriched trial populations (biomarker subgroup data included if available); (3) control arms should not include targeted agents directed towards those molecularly enriched populations. ORR, OS, and PFS data were manually extracted from the relevant studies and correlative analyses (weighted Pearson correlation) were performed. Results: 61 trials were identified with 15 ultimately meeting the prespecified criteria. ORR effect size (both the ORR difference and log odds ratio) and the log PFS hazard ratio were strongly correlated (-0.78, p-value = 0.0007). No significant correlation was found between ORR and OS. Conclusions: In our analyses, a strong correlation between ORR and PFS was found in randomized clinical trials investigating agents targeting oncogene-driven cancers. Establishing a correlation between ORR and OS was limited, most probably due to confounding factors such as treatment cross-over following progression, number of subsequent therapies and long post-progression survival in this setting. These findings further warrant the use of ORR as a surrogate for PFS in biomarker-driven studies.
RICTOR amplification as a novel therapeutic target for lung cancer brain metastases.
Authors: Cheng Haiying , Fan Ni , Sokol Ethan , Wang Feng , Zou Yiyu , Feng Monica , Frampton Garrett M. , Bhagat Tushar , Verma Amit , Halmos Balazs , Perez-Soler Roman 
Published: May 2020

3597 Background: Approximately 20% to 50% of patients with advanced lung cancer develop brain metastases, which are associated with debilitating neurologic impairment and a dismal prognosis. There have been very limited studies investigating the genomics of brain metastases in lung cancer. Methods: We comprehensively investigated the frequency of PI3K/AKT/RICTOR/mTOR pathway aberrations in primary and metastatic sites using an extensive database of 11845 cases of lung adenocarcinoma by NGS (FoundationOne). The potential roles of RICTOR amplification in the development of brain metastases were studied both in vitro and in vivo in orthotopic mouse models. Results: Compared to the primary tumor, PI3K/AKT/mTOR gene alterations were more frequent in metastatic sites, with particular enrichment noted in brain metastases. RICTOR amplification alone accounted for the observed higher frequency both in brain metastases (brain vs. primary: 9.73% vs 3.50%, P = 2.6E-14; brain vs. other mets: 9.73% vs. 7.3%, P = 0.03) and other metastatic sites (other mets vs. primary: 7.3% vs.3.5%, P = 10E-15), whereas the frequency of PTEN, AKT1, PK3CA or mTOR genetic alterations was not different in the primary tumor, brain and other metastatic sites. In vitro, inducible RICTOR knockdown in H23 lung cancer cells (parental line with RICTOR amplification) was associated with reduced cell migration and invasion, whereas upregulation of RICTOR in HCC827 lung cancer cells (parental line with normal RICTOR copy numbers) was associated with an increase of both processes. These results were confirmed with pharmacological inhibition using mTOR1/2 inhibitors with known CNS penetration. In vivo, both inducible ablation of RICTOR and the mTOR1/2 inhibitor TAK228 (Sapanisertinib) significantly inhibited lung cancer H23-R4-Luc tumor growth in the brain, including a number of near complete responses. Mechanistic studies suggest that RICTOR may regulate the brain metastasis process through AKT and CXCL12 chemokine-CXCR4 axis. Conclusions: RICTOR amplification is the first identified actionable target that is markedly enriched in brain metastases. Our study provides a strong rationale for the development of RICTOR-targeted therapeutic strategies for the treatment and/or prevention of these major causes of lung cancer morbidity and mortality.