bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chapter 7 Post-obduction evolution of New Caledonia
Authors: Sevin B. , Maurizot P. , Cluzel D. , Tournadour E. , Etienne S. , Folcher N. , Jeanpert J. , Collot J. , Iseppi M. , Meffre S. , Patriat M. 
Published: June 2020

Abstract

The post-obduction formations of Grande Terre, New Caledonia, comprise igneous intrusions, regolith cover, and marine and terrestrial sedimentary rocks. Two restricted Late Oligocene granitoid bodies are intruded into the Peridotite Nappe and its substrate in the south of the island. Thick regolith cover developed over the Peridotite Nappe from the Late Oligocene or earlier. The Népoui Group comprises Late Oligocene–Early Miocene mixed marine carbonate and siliciclastic deposits. It mainly reworks the Peridotite Nappe and its regolith cover. Its development pattern is mainly controlled by tectonic uplift and subsidence. The Gwa N'Doro Formation on the eastern coast and the Fluvio-lacustrine Formation in the south are remnants of the Miocene–Present river network. Offshore, thick Oligocene to Neogene sedimentary successions are imaged by seismic surveys on the margins of Grande Terre, although these successions have not been drilled and remain undated. Several dredges have recovered shallow Miocene sedimentary rocks, indicating substantial Neogene subsidence. Quaternary formations are represented inland by aeolianite, vertisols and calcrete and offshore by the large barrier reef–lagoon complex, the onset of which is dated at
c.
400 ka. This chapter discusses the different models proposed for the post-obduction evolution of Grand Terre.
ESR1 Mutations and Overall Survival on Fulvestrant versus Exemestane in Advanced Hormone Receptor–Positive Breast Cancer: A Combined Analysis of the Phase III SoFEA and EFECT Trials
Authors: Turner Nicholas C. , Swift Claire , Kilburn Lucy , Fribbens Charlotte , Beaney Matthew , Garcia-Murillas Isaac , Budzar Aman U. , Robertson John F.R. , Gradishar William , Piccart Martine , Schiavon Gaia , Bliss Judith M. , Dowsett Mitch , Johnston Stephen R.D. , Chia Stephen K. 
Published: June 2020

Abstract

Purpose:
ESR1 mutations are acquired frequently in hormone receptor–positive metastatic breast cancer after prior aromatase inhibitors. We assessed the clinical utility of baseline ESR1 circulating tumor DNA (ctDNA) analysis in the two phase III randomized trials of fulvestrant versus exemestane.

Experimental Design:
The phase III EFECT and SoFEA trials randomized patients with hormone receptor–positive metastatic breast cancer who had progressed on prior nonsteroidal aromatase inhibitor therapy, between fulvestrant 250 mg and exemestane. Baseline serum samples from 227 patients in EFECT, and baseline plasma from 161 patients in SoFEA, were analyzed for ESR1 mutations by digital PCR. The primary objectives were to assess the impact of ESR1 mutation status on progression-free (PFS) and overall survival (OS) in a combined analysis of both studies.

Results:
ESR1 mutations were detected in 30% (151/383) baseline samples. In patients with ESR1 mutation detected, PFS was 2.4 months [95% confidence interval (CI), 2.0–2.6] on exemestane and 3.9 months (95% CI, 3.0–6.0) on fulvestrant [hazard ratio (HR), 0.59; 95% CI, 0.39–0.89; P = 0.01). In patients without ESR1 mutations detected, PFS was 4.8 months (95% CI, 3.7–6.2) on exemestane and 4.1 months (95% CI, 3.6–5.5) on fulvestrant (HR, 1.05; 95% CI, 0.81–1.37; P = 0.69). There was an interaction between ESR1 mutation and treatment (P = 0.02). Patients with ESR1 mutation detected had 1-year OS of 62% (95% CI, 45%–75%) on exemestane and 80% (95% CI, 68%–87%) on fulvestrant (P = 0.04; restricted mean survival analysis). Patients without ESR1 mutations detected had 1-year OS of 79% (95% CI, 71%–85%) on exemestane and 81% (95% CI, 74%–87%) on fulvestrant (P = 0.69).

Conclusions:
Detection of ESR1 mutations in baseline ctDNA is associated with inferior PFS and OS in patients treated with exemestane versus fulvestrant.
Predictive Value of Molecular Subtypes in Premenopausal Women with Hormone Receptor–positive Early Breast Cancer: Results from the ABCSG Trial 5
Authors: Bago-Horvath Zsuzsanna , Rudas Margaretha , Singer Christian F. , Greil Richard , Balic Marija , Lax Sigurd F. , Kwasny Werner , Hulla Wolfgang , Gnant Michael , Filipits Martin 
Published: June 2020

Abstract

Purpose:
To assess the predictive value of molecular breast cancer subtypes in premenopausal patients with hormone receptor–positive early breast cancer who received adjuvant endocrine treatment or chemotherapy.

Experimental Design:
Molecular breast cancer subtypes were centrally assessed on whole tumor sections by IHC in patients of the Austrian Breast and Colorectal Cancer Study Group Trial 5 who had received either 5 years of tamoxifen/3 years of goserelin or six cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF). Luminal A disease was defined as Ki67 &lt;20% and luminal B as Ki67 ≥20%. The luminal B/HER2-positive subtype displayed 3+ HER2-IHC or amplification by ISH. Recurrence-free survival (RFS) and overall survival (OS) were analyzed using Cox models adjusted for clinical and pathologic factors.

Results:
185 (38%), 244 (50%), and 59 (12%) of 488 tumors were classified as luminal A, luminal B/HER2-negative and luminal B/HER2-positive, respectively. Luminal B subtypes were associated with poor outcome. Patients with luminal B tumors had a significantly shorter RFS [adjusted HR for recurrence: 2.22; 95% confidence interval (CI), 1.41–3.49; P = 0.001] and OS (adjusted HR for death: 3.51; 95% CI, 1.80–6.87; P &lt; 0.001). No interaction between molecular subtypes and treatment was observed (test for interaction: P = 0.84 for RFS; P = 0.69 for OS).

Conclusions:
Determination of molecular subtypes by IHC is an independent prognostic factor for recurrence and death in premenopausal women with early-stage, hormone receptor–positive breast cancer but is not predictive for outcome of adjuvant treatment with tamoxifen/goserelin or CMF.
See related commentary by Hunter et al., p. 5543
Statins Reduce Intratumor Cholesterol Affecting Adrenocortical Cancer Growth
Authors: Trotta Francesca , Avena Paola , Chimento Adele , Rago Vittoria , De Luca Arianna , Sculco Sara , Nocito Marta C. , Malivindi Rocco , Fallo Francesco , Pezzani Raffaele , Pilon Catia , Lasorsa Francesco M. , Barile Simona N. , Palmieri Luigi , Lerario Antonio M. , Pezzi Vincenzo , Casaburi Ivan , Sirianni Rosa 
Published: June 2020

Abstract
Mitotane causes hypercholesterolemia in patients with adrenocortical carcinoma (ACC). We suppose that cholesterol increases within the tumor and can be used to activate proliferative pathways. In this study, we used statins to decrease intratumor cholesterol and investigated the effects on ACC growth related to estrogen receptor α (ERα) action at the nuclear and mitochondrial levels. We first used microarray to investigate mitotane effect on genes involved in cholesterol homeostasis and evaluated their relationship with patients' survival in ACC TCGA. We then blocked cholesterol synthesis with simvastatin and determined the effects on H295R cell proliferation, estradiol production, and ERα activity in vitro and in xenograft tumors. We found that mitotane increases intratumor cholesterol content and expression of genes involved in cholesterol homeostasis, among them INSIG, whose expression affects patients' survival. Treatment of H295R cells with simvastatin to block cholesterol synthesis decreased cellular cholesterol content, and this affected cell viability. Simvastatin reduced estradiol production and decreased nuclear and mitochondrial ERα function. A mitochondrial target of ERα, the respiratory complex IV (COXIV), was reduced after simvastatin treatment, which profoundly affected mitochondrial respiration activating apoptosis. Additionally, simvastatin reduced tumor volume and weight of grafted H295R cells, intratumor cholesterol content, Ki-67 and ERα, COXIV expression and activity and increase terminal deoxynucleotidyl transferase dUTP nick end labeling–positive cells. Collectively, these data demonstrate that a reduction in intratumor cholesterol content prevents estradiol production and inhibits mitochondrial respiratory chain–inducing apoptosis in ACC cells. Inhibition of mitochondrial respiration by simvastatin represents a novel strategy to counteract ACC growth.
A Novel Approach to Safer Glucocorticoid Receptor–Targeted Anti-lymphoma Therapy via REDD1 (Regulated in Development and DNA Damage 1) Inhibition
Authors: Lesovaya Ekaterina A. , Savinkova Alena V. , Morozova Olga V. , Lylova Evgeniya S. , Zhidkova Ekaterina M. , Kulikov Evgeny P. , Kirsanov Kirill I. , Klopot Anna , Baida Gleb , Yakubovskaya Marianna G. , Gordon Leo I. , Readhead Ben , Dudley Joel T. , Budunova Irina 
Published: June 2020

Abstract
Glucocorticoids are widely used for therapy of hematologic malignancies. Unfortunately, chronic treatment with glucocorticoids commonly leads to adverse effects including skin and muscle atrophy and osteoporosis. We found recently that REDD1 (regulated in development and DNA damage 1) plays central role in steroid atrophy. Here, we tested whether REDD1 suppression makes glucocorticoid-based therapy of blood cancer safer. Unexpectedly, approximately 50% of top putative REDD1 inhibitors selected by bioinformatics screening of Library of Integrated Network-Based Cellular Signatures database (LINCS) were PI3K/Akt/mTOR inhibitors. We selected Wortmannin, LY294002, and AZD8055 for our studies and showed that they blocked basal and glucocorticoid-induced REDD1 expression. Moreover, all PI3K/mTOR/Akt inhibitors modified glucocorticoid receptor function shifting it toward therapeutically important transrepression. PI3K/Akt/mTOR inhibitors enhanced anti-lymphoma effects of Dexamethasone in vitro and in vivo, in lymphoma xenograft model. The therapeutic effects of PI3K inhibitor+Dexamethasone combinations ranged from cooperative to synergistic, especially in case of LY294002 and Rapamycin, used as a previously characterized reference REDD1 inhibitor. We found that coadministration of LY294002 or Rapamycin with Dexamethasone protected skin against Dexamethasone-induced atrophy, and normalized RANKL/OPG ratio indicating a reduction of Dexamethasone-induced osteoporosis. Together, our results provide foundation for further development of safer and more effective glucocorticoid-based combination therapy of hematologic malignancies using PI3K/Akt/mTOR inhibitors.
Abstract A06: Multiplatform analysis of early-stage cancer signatures in blood
Authors: Li Bingsi , Wang Chenyang , Xu Jiayue , Fang Shuai , Qiu Fujun , Su Jing , Chu Huiling , Han-Zhang Han , Mao Xinru , Liu Hao , Liu Xianling , Zhang Wei , Zhao Heng , Zhang Zhihong 
Published: June 2020

Abstract
Background: Detection of cancer in its early stages is likely to be the most effective way to improve clinical outcome. In patients with cancer, a portion of cell-free DNA (cfDNA) in the blood stream is tumor derived, providing an opportunity to analyze the cancer genome in real time noninvasively. MERMAID is a retrospective multicenter case-control study to investigate early tumor signatures in blood using different platforms.
Methods: The study was conducted among 452 surgery-resectable patients with lung cancer (N=180), colorectal cancer (N=210), liver cancer (N=62), and 290 age-/sex- matched non-cancer controls. Patients who were recognized to have anemia, autoimmune diseases, treated with neoadjuvant therapy were excluded from the study. The non-cancer controls were recruited with the criteria of showing no clinical symptoms or history of cancer at time of administration. The participants were divided into subgroups and analyzed by ultra-deep mutation sequencing (HS-UMI), droplet digital PCR (ddPCR), and deep methylation sequencing (ELSA-seq) singly or in combination.
Results: Overall, the highest accuracy was achieved using ELSA-seq and will be reported in full. Highly similar classification results were obtained in training and test sets, with the area under the curve (AUC) value ranging from 0.90-0.97. The specificity for each cancer type ranged from 96-99%, and the average sensitivities with 95CI were lung cancer (61%, 53-70%), colorectal cancer (82%, 76-87%), and hepatocellular cancer (91%, 80-96%). Moreover, incorporation of somatic variants and epigenetic alterations improved the overall accuracy.
Conclusions: This study highlighted the potential of machine learning-aided deep methylation sequencing as a sensitive ctDNA profiling approach for early cancer detection. Further investigation in large-scale clinical studies is ongoing.
Citation Format: Bingsi Li, Chenyang Wang, Jiayue Xu, Shuai Fang, Fujun Qiu, Jing Su, Huiling Chu, Han Han-Zhang, Xinru Mao, Hao Liu, Xianling Liu, Wei Zhang, Heng Zhao, Zhihong Zhang. Multiplatform analysis of early-stage cancer signatures in blood [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A06.
Abstract A17: Pan-solid tumor comparison of variant detection in paired liquid and tissue biopsies
Authors: Assaf Zoe June F. , Sivakumar Smruthy , Jin Dexter X. , Maund Sophia L. , Lyalina Svetlana , Walia Guneet , Sokol Ethan S. , Trabucco Sally E. 
Published: June 2020

Abstract
Comprehensive genomic profiling (CGP) of circulating tumor DNA (ctDNA) provides an opportunity to noninvasively monitor a patient’s tumor burden via liquid biopsy. Liquid biopsies can assess a patient’s mutational landscape through time and provide information on treatment response and relapse. It has become increasingly common to have paired genomic data analysis between liquid and tissue biopsies from the same patient. However, the impact of clinical, temporal, and biologic factors on percentage of positive agreement (PPA) of variant detection between these biopsies is unclear. For our study, we leveraged two databases containing CGP data from paired liquid and tissue biopsy specimens tested by Foundation Medicine (FMI): the FMI database (&gt;1700 paired samples) and the Flatiron Health-Foundation Medicine Clinico-Genomic Database (CGDB). The CGDB is a subset of the FMI database linked with the Flatiron Health nationwide de-identified EHR-derived database, which includes demographic, treatment, and clinical outcomes information (&gt;500 paired samples). We report pan-solid tumor and per-indication prevalence and PPA for variants commonly assayed in both liquid and tissue tests. We found that PPA depended on the tumor DNA concentration in plasma and tissue biopsies, as well as the amount of time between tests. We also investigated the effect of treatments administered in the time between liquid and tissue tests on the detected variants and observed some well-described resistance alterations at a higher frequency in liquid samples, including a higher prevalence of ESR1 point mutations in breast cancer, more EGFR T790M alterations in lung cancer, and frequent KRAS Q61H alterations in colorectal cancer. Liquid biopsies can also contain DNA shed from multiple metastatic sites. We observed evidence of this in the form of polyclonal resistance alterations, which may also account for differences in PPA over time. Our findings indicate that while PPA is generally high between samples, it may be influenced by factors such as intervening therapies, resistance, therapy efficacy, and polyclonality of liquid samples.
Citation Format: Zoe June F. Assaf, Smruthy Sivakumar, Dexter X. Jin, Sophia L. Maund, Svetlana Lyalina, Guneet Walia, Ethan S. Sokol, Sally E. Trabucco. Pan-solid tumor comparison of variant detection in paired liquid and tissue biopsies [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A17.
Abstract A18: Plasma circulating tumor DNA is scarce and confounded by clonal hematopoiesis in metastatic renal cell carcinoma
Authors: Bacon Jack V. W. , Annala Matti , Soleimani Maryam , Lavoie Jean-Michel , So Alan I. , Gleave Martin E. , Fazli Ladan , Chi Kim N. , Kollmannsberger Christian K. , Wyatt Alexander W. , Nappi Lucia 
Published: June 2020

Abstract
Despite the recent implementation of novel targeted therapies, the 5-year survival rate for metastatic renal cell carcinoma (mRCC) remains dismal. Prognostic and predictive biomarkers are urgently required to avoid unnecessary patient morbidity and financial toxicity. Exploratory studies leveraging archival primary tumor tissue are considered suboptimal in this setting due to the considerable heterogeneity of metastatic lesions. Circulating tumor DNA (ctDNA) permits the noninvasive characterization of metastatic cancers using a simple blood draw. In this study, we sought to establish the utility of a ctDNA-based assay as a tool to profile the somatic genome of patients with mRCC. We collected whole blood from 55 progressing mRCC patients. All patients were systemic therapy naïve at the time of sample collection. Plasma cell-free DNA (cfDNA) and matched leukocyte DNA were subjected to targeted sequencing across 981 cancer-associated genes. Matched tumor tissue from 14 patients was also analyzed. The median cfDNA sequencing depth for this cohort was 938x. 33% of patients had evidence for RCC-derived ctDNA above 1% of total cfDNA; this was significantly lower than prostate or bladder cancer patients analyzed using the same approach. Among ctDNA-positive patients, ctDNA fraction averaged only 3.9% and showed no association with clinical variables or cfDNA yield. In these patients, the most commonly mutated genes were VHL, BAP1, and PBRM1, and matched tissue concordance was 77%. Evidence of somatic expansions unrelated to RCC, such as clonal hematopoiesis of indeterminate potential (CHIP), was detected in 43% of patients. Pathogenic germline mutations in DNA repair genes were detected in 11% of patients. Patients with ctDNA above 1% had shorter overall survival and progression-free survival on first-line therapy. Patients with evidence of CHIP but not ctDNA had an intermediate prognosis compared to ctDNA-positive and ctDNA-negative patients. CfDNA sequencing enables characterization of the somatic RCC genome in only a minority of metastatic RCC patients. Due to low ctDNA abundance and presence of non-RCC derived somatic clones in circulation, cfDNA sequencing may not be a simple pan-patient alternative to tissue biopsy in metastatic RCC.
Citation Format: Jack V. W. Bacon, Matti Annala, Maryam Soleimani, Jean-Michel Lavoie, Alan I. So, Martin E. Gleave, Ladan Fazli, Kim N. Chi, Christian K. Kollmannsberger, Alexander W. Wyatt, Lucia Nappi. Plasma circulating tumor DNA is scarce and confounded by clonal hematopoiesis in metastatic renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A18.
Abstract A37: Early change in circulating tumor DNA as a potential predictor of response to chemotherapy in patients with metastatic colorectal cancer
Authors: Zembutsu Hitoshi , Osumi Hiroki , Shinozaki Eiji , Yamaguchi Kensei 
Published: June 2020

Abstract
The impact of the change in ctDNA levels after chemotherapy on the clinical outcomes of patients with metastatic colorectal cancer (mCRC) remains unclear. The present study evaluated the clinical implications of the early change in ctDNA levels as a predictor of objective response and the clinical outcome in mCRC patients who received chemotherapy. We investigated the effects of after/before ratio of ctDNA levels 2 and 8 weeks after initiation of second-line chemotherapy on objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). ctDNA was detected using amplicon-based deep sequencing with a molecular barcode that includes &gt;240 hotspot mutations in 14 colon cancer-related genes. Patients with lower ctDNA level (≤ 50%) 8 weeks after initiation of chemotherapy compared to baseline showed significantly longer PFS and OS than the patients with higher (&gt; 50%) ctDNA level in multivariate analysis. In patients achieving partial response or stable disease, the after/before ratio of ctDNA level 8 weeks after initiation of chemotherapy was significantly lower than those in patients with progressive disease. The present study suggests that an early change in the ctDNA level might serve as a biomarker to predict the chemotherapeutic efficacy and clinical outcomes in patients with mCRC.
Citation Format: Hitoshi Zembutsu, Hiroki Osumi, Eiji Shinozaki, Kensei Yamaguchi. Early change in circulating tumor DNA as a potential predictor of response to chemotherapy in patients with metastatic colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A37.
Abstract A52: Role of circulating tumor DNA (ctDNA) from liquid biopsy in early-stage NSCLC resected lung tumor investigation (LIBERTI)
Authors: Morgensztern Daniel , Green Emma , King Jennifer C. , Sable-Hunt Alicia , Erwin Richard , Moore Amy , Addario Tony , Morris Clive , Govindan Ramaswamy 
Published: June 2020

Abstract
The detection of ctDNA after cancer surgery with curative intent may indicate the presence of minimal residual disease and a higher risk for relapse. The Addario Lung Cancer Medical Institute (ALCMI) has launched a multicenter study to evaluate the role of ctDNA in patients with completely resected stage II to III non-small cell lung cancer (NSCLC) using a highly sensitive assay developed by Inivata. This molecular residual disease (MRD) personalized assay is used to detect tumor-specific variants in plasma DNA from patients with NSCLC. The study will enroll 500 patients across three cohorts, with the initial ctDNA collection prior to neoadjuvant therapy (cohort 1), prior to surgery (cohort 2), or between the surgery and initiation of adjuvant chemotherapy (cohort 3). We will conduct an initial evaluation of ctDNA results after enrollment of 100 eligible patients. All patients will be followed for survival and recurrence for a maximum of 60 months from the date of surgery. The primary objective is to correlate the presence of ctDNA following complete surgical resection with disease-free survival.
Citation Format: Daniel Morgensztern, Emma Green, Jennifer C. King, Alicia Sable-Hunt, Richard Erwin, Amy Moore, Tony Addario, Clive Morris, Ramaswamy Govindan. Role of circulating tumor DNA (ctDNA) from liquid biopsy in early-stage NSCLC resected lung tumor investigation (LIBERTI) [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A52.