Publications by authors named "Stephen Fox"

342 Publications

ROS1 rearrangements in non-small cell lung cancer: screening by immunohistochemistry using proportion of cells staining without intensity and excluding cases with MAPK pathway drivers improves test performance.

Pathology 2021 Oct 8. Epub 2021 Oct 8.

Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Vic, Australia.

Therapeutically actionable ROS1 rearrangements have been described in 1-3% of non-small cell lung cancer (NSCLC). Screening for ROS1 rearrangements is recommended to be by immunohistochemistry (IHC), followed by confirmation with fluorescence in situ hybridisation (FISH) or sequencing. However, in practise ROS1 IHC presents difficulties due to conflicting scoring systems, multiple clones and expression in tumours that are wild-type for ROS1. We assessed ROS1 IHC in 285 consecutive cases of NSCLC with non-squamous histology over a nearly 2-year period. IHC was scored with ROS1 clone D4D6 (n=270), clone SP384 (n=275) or both clones (n=260). Results were correlated with ROS1 break-apart FISH (n=67), ALK status (n=194), and sequence data of EGFR (n=178) and other drivers, where possible. ROS1 expression was detected in 161/285 cases (56.5%), including 13/14 ROS1 FISH-positive cases. There was no ROS1 expression in one ROS1 FISH-positive case in which sequencing detected an ALK-EML4 fusion, but not a ROS1 fusion. The other 13 ROS1 FISH-positive cases showed moderate to strong staining with both IHC clones. However, one case with a TPM3-ROS1 fusion would have been scored as negative with SP384 and D4D6 clones by some previous criteria. ROS1 expression was also detected in 58/285 cases (20.4%) that had driver mutations in genes other than ROS1. A sensitivity of 100% for detecting a ROS1 rearrangement by FISH was achieved by omitting intensity from the IHC scoring criteria and expression in >0% cells with D4D6 or in ≥50% cells with SP384. Excluding cases with driver events in any MAPK pathway gene (e.g., in ALK, EGFR, KRAS, BRAF, ERBB2 and MET) substantially reduced the number of cases proceeding to ROS1 FISH. Only 15.9% of MAPK-negative NSCLC would proceed to FISH for an IHC threshold of >0% cells with D4D6, with a specificity of 42.4%. For a threshold of ≥50% cells with SP384, only 18.5% of MAPK-negative cases would proceed to FISH, with a specificity of 31.4%. Based on our data we suggest an algorithm for screening for ROS1 rearrangements in NSCLC in which ROS1 FISH is only performed in cases that have been demonstrated to lack activating mutations in any MAPK pathway gene by comprehensive sequencing and ALK IHC, and show staining at any intensity in ≥50% of cells with clone SP384, or >0% cells with D4D6.
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http://dx.doi.org/10.1016/j.pathol.2021.07.006DOI Listing
October 2021

Future-Proofing Startups: Stress Management Principles Based on Adaptive Calibration Model and Active Inference Theory.

Authors:
Stephen Fox

Entropy (Basel) 2021 Sep 2;23(9). Epub 2021 Sep 2.

VTT Technical Research Centre of Finland, FI-02150 Espoo, Finland.

In this paper, the Adaptive Calibration Model (ACM) and Active Inference Theory (AIT) are related to future-proofing startups. ACM encompasses the allocation of energy by the stress response system to alternative options for action, depending upon individuals' life histories and changing external contexts. More broadly, within AIT, it is posited that humans survive by taking action to align their internal generative models with sensory inputs from external states. The first contribution of the paper is to address the need for future-proofing methods for startups by providing eight stress management principles based on ACM and AIT. Future-proofing methods are needed because, typically, nine out of ten startups do not survive. A second contribution is to relate ACM and AIT to startup life cycle stages. The third contribution is to provide practical examples that show the broader relevance ACM and AIT to organizational practice. These contributions go beyond previous literature concerned with entrepreneurial stress and organizational stress. In particular, rather than focusing on particular stressors, this paper is focused on the recalibrating/updating of startups' stress responsivity patterns in relation to changes in the internal state of the startup and/or changes in the external state. Overall, the paper makes a contribution to relating physics of life constructs concerned with energy, action and ecological fitness to human organizations.
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http://dx.doi.org/10.3390/e23091155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8468633PMC
September 2021

Transcriptome of Male Breast Cancer Matched with Germline Profiling Reveals Novel Molecular Subtypes with Possible Clinical Relevance.

Cancers (Basel) 2021 Sep 8;13(18). Epub 2021 Sep 8.

Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy.

Male breast cancer (MBC) is a rare and understudied disease compared with female BC. About 15% of MBCs are associated with germline mutation in BC susceptibility genes, mainly and . Hereditary MBCs are likely to represent a subgroup of tumors with a peculiar phenotype. Here, we performed a whole transcriptome analysis of MBCs characterized for germline mutations in the most relevant BC susceptibility genes in order to identify molecular subtypes with clinical relevance. A series of 63 MBCs, including 16 6 , 2 , 1 , and 1 germline-mutated cases, was analyzed by RNA-sequencing. Differential expression and hierarchical clustering analyses were performed. Module signatures associated with central biological processes involved in breast cancer pathogenesis were also examined. Different transcriptome profiles for genes mainly involved in the cell cycle, DNA damage, and DNA repair pathways emerged between MBCs with and without germline mutations. Unsupervised clustering analysis revealed two distinct subgroups, one of which was characterized by a higher expression of immune response genes, high scores of gene-expression signatures suggestive of aggressive behavior, and worse overall survival. Our results suggest that transcriptome matched with germline profiling may be a valuable approach for the identification and characterization of MBC subtypes with possible relevance in the clinical setting.
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http://dx.doi.org/10.3390/cancers13184515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8469418PMC
September 2021

Male breast cancer: an update.

Virchows Arch 2021 Aug 30. Epub 2021 Aug 30.

Department of Cellular Pathology, Queen Elizabeth Hospital Birmingham and Cancer and Genomic Sciences, University of Birmingham, Mindelsohn Way, Edgbaston, Birmingham, B15 2GW, UK.

Male breast cancer (MBC) is rare, accounting for less than 1% of all breast cancer but the incidence has increased worldwide. Risk factors include increased longevity, obesity, testicular diseases and tumours, and germline mutations of BRCA2. BRCA2 carriers have 80 times the risk of the general population. Men generally present with breast cancer at an older age compared with women. Histologically, MBC is often of grade 2, hormone receptor positive, HER2 negative, and no special type carcinoma although in situ and invasive papillary carcinomas are common. Reporting and staging are similar to female breast cancer. Metastatic lesions to the male breast do occur and should be differentiated from primary carcinomas. Until recently, MBC was thought to be similar to the usual ER positive post-menopausal female counterpart. However, advances in MBC research and trials have highlighted significant differences between the two. This review provides an up to date overview of the biology, genetics, and histology of MBC with comparison to female breast cancers and differential diagnosis from histological mimics.
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http://dx.doi.org/10.1007/s00428-021-03190-7DOI Listing
August 2021

SP142 PD-L1 Scoring Shows High Interobserver and Intraobserver Agreement in Triple-negative Breast Carcinoma But Overall Low Percentage Agreement With Other PD-L1 Clones SP263 and 22C3.

Am J Surg Pathol 2021 08;45(8):1108-1117

Peter MacCallum Cancer Centre.

SP142 programmed cell death ligand 1 (PD-L1) status predicts response to atezolizumab in triple-negative breast carcinoma (TNBC). Prevalence of VENTANA PD-L1 (SP142) Assay positivity, concordance with the VENTANA PD-L1 (SP263) Assay and Dako PD-L1 IHC 22C3 pharmDx assay, and association with clinicopathologic features were assessed in 447 TNBCs. SP142 PD-L1 intraobserver and interobserver agreement was investigated in a subset of 60 TNBCs, with scores enriched around the 1% cutoff. The effect of a 1-hour training video on pretraining and posttraining scores was ascertained. At a 1% cutoff, 34.2% of tumors were SP142 PD-L1 positive. SP142 PD-L1 positivity was significantly associated with tumor-infiltrating lymphocytes (P <0.01), and node negativity (P=0.02), but not with tumor grade (P=0.35), tumor size (P=0.58), or BRCA mutation (P=0.53). Overall percentage agreement (OPA) for intraobserver and interobserver agreement was 95.0% and 93.7%, respectively, among 5 pathologists trained in TNBC SP142 PD-L1 scoring. In 5 TNBC SP142 PD-L1-naive pathologists, significantly higher OPA to the reference score was achieved after video training (posttraining OPA 85.7%, pretraining OPA 81.5%, P<0.05). PD-L1 status at a 1% cutoff was assessed by SP142 and SP263 in 420 cases, and by SP142 and 22C3 in 423 cases, with OPA of 88.1% and 85.8%, respectively. The VENTANA PD-L1 (SP142) Assay is reproducible for classifying TNBC PD-L1 status by trained observers; however, it is not analytically equivalent to the VENTANA PD-L1 (SP263) Assay and Dako PD-L1 IHC 22C3 pharmDx assay.
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http://dx.doi.org/10.1097/PAS.0000000000001701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277187PMC
August 2021

Interobserver variability in the assessment of stromal tumor-infiltrating lymphocytes (sTILs) in triple-negative invasive breast carcinoma influences the association with pathological complete response: the IVITA study.

Mod Pathol 2021 Jul 3. Epub 2021 Jul 3.

Department of Pathology, Onze-Lieve-Vrouwziekenhuis Aalst, Aalst, Belgium.

High stromal tumor-infiltrating lymphocytes (sTILs) in triple-negative breast cancer (TNBC) are associated with pathological complete response (pCR) after neoadjuvant chemotherapy (NAC). Histopathological assessment of sTILs in TNBC biopsies is characterized by substantial interobserver variability, but it is unknown whether this affects its association with pCR. Here, we aimed to investigate the degree of interobserver variability in an international study, and its impact on the relationship between sTILs and pCR. Forty pathologists assessed sTILs as a percentage in digitalized biopsy slides, originating from 41 TNBC patients who were treated with NAC followed by surgery. Pathological response was quantified by the MD Anderson Residual Cancer Burden (RCB) score. Intraclass correlation coefficients (ICCs) were calculated per pathologist duo and Bland-Altman plots were constructed. The relation between sTILs and pCR or RCB class was investigated. The ICCs ranged from -0.376 to 0.947 (mean: 0.659), indicating substantial interobserver variability. Nevertheless, high sTILs scores were significantly associated with pCR for 36 participants (90%), and with RCB class for eight participants (20%). Post hoc sTILs cutoffs at 20% and 40% resulted in variable associations with pCR. The sTILs in TNBC with RCB-II and RCB-III were intermediate to those of RCB-0 and RCB-I, with lowest sTILs observed in RCB-I. However, the limited number of RCB-I cases precludes any definite conclusions due to lack of power, and this observation therefore requires further investigation. In conclusion, sTILs are a robust marker for pCR at the group level. However, if sTILs are to be used to guide the NAC scheme for individual patients, the observed interobserver variability might substantially affect the chance of obtaining a pCR. Future studies should determine the 'ideal' sTILs threshold, and attempt to fine-tune the patient selection for sTILs-based de-escalation of NAC regimens. At present, there is insufficient evidence for robust and reproducible sTILs-guided therapeutic decisions.
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http://dx.doi.org/10.1038/s41379-021-00865-zDOI Listing
July 2021

Psychomotor Predictive Processing.

Authors:
Stephen Fox

Entropy (Basel) 2021 Jun 24;23(7). Epub 2021 Jun 24.

VTT Technical Research Centre of Finland, FI-02150 Espoo, Finland.

Psychomotor experience can be based on what people predict they will experience, rather than on sensory inputs. It has been argued that disconnects between human experience and sensory inputs can be addressed better through further development of predictive processing theory. In this paper, the scope of predictive processing theory is extended through three developments. First, by going beyond previous studies that have encompassed embodied cognition but have not addressed some fundamental aspects of psychomotor functioning. Second, by proposing a scientific basis for explaining predictive processing that spans objective neuroscience and subjective experience. Third, by providing an explanation of predictive processing that can be incorporated into the planning and operation of systems involving robots and other new technologies. This is necessary because such systems are becoming increasingly common and move us farther away from the hunter-gatherer lifestyles within which our psychomotor functioning evolved. For example, beliefs that workplace robots are threatening can generate anxiety, while wearing hardware, such as augmented reality headsets and exoskeletons, can impede the natural functioning of psychomotor systems. The primary contribution of the paper is the introduction of a new formulation of hierarchical predictive processing that is focused on psychomotor functioning.
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http://dx.doi.org/10.3390/e23070806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303599PMC
June 2021

Computational Methods and Tools in Antimicrobial Peptide Research.

J Chem Inf Model 2021 07 24;61(7):3172-3196. Epub 2021 Jun 24.

Bioinformatics Institute at A*STAR (Agency for Science, Technology and Research), 30 Biopolis Street, #07-01 Matrix, Singapore 138671.

The evolution of antibiotic-resistant bacteria is an ongoing and troubling development that has increased the number of diseases and infections that risk going untreated. There is an urgent need to develop alternative strategies and treatments to address this issue. One class of molecules that is attracting significant interest is that of antimicrobial peptides (AMPs). Their design and development has been aided considerably by the applications of molecular models, and we review these here. These methods include the use of tools to explore the relationships between their structures, dynamics, and functions and the increasing application of machine learning and molecular dynamics simulations. This review compiles resources such as AMP databases, AMP-related web servers, and commonly used techniques, together aimed at aiding researchers in the area toward complementing experimental studies with computational approaches.
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http://dx.doi.org/10.1021/acs.jcim.1c00175DOI Listing
July 2021

Remodelin Is a Cryptic Assay Interference Chemotype That Does Not Inhibit NAT10-Dependent Cytidine Acetylation.

ACS Med Chem Lett 2021 Jun 27;12(6):887-892. Epub 2020 Jul 27.

Chemical Biology Laboratory, National Cancer Institute, Frederick, Maryland 21702, United States.

Remodelin is a putative small molecule inhibitor of the RNA acetyltransferase NAT10 which has shown preclinical efficacy in models of the premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS). Here we evaluate remodelin's assay interference characteristics and effects on NAT10-catalyzed RNA cytidine acetylation. We find the remodelin chemotype constitutes a cryptic assay interference compound, which does not react with small molecule thiols but demonstrates protein reactivity in ALARM NMR and proteome-wide affinity profiling assays. Biophysical analyses find no direct evidence for interaction of remodelin with the NAT10 acetyltransferase active site. Cellular studies verify that N4-acetylcytidine (ac4C) is a nonredundant target of NAT10 activity in human cell lines and find that this RNA modification is not affected by remodelin treatment in several orthogonal assays. These studies display the potential for remodelin's chemotype to interact with multiple protein targets in cells and indicate remodelin should not be applied as a specific chemical inhibitor of NAT10-catalyzed RNA acetylation.
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http://dx.doi.org/10.1021/acsmedchemlett.0c00193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201477PMC
June 2021

Evaluation of Crizotinib Treatment in a Patient With Unresectable GOPC-ROS1 Fusion Agminated Spitz Nevi.

JAMA Dermatol 2021 Jul;157(7):836-841

Peter MacCallum Cancer Centre, Melbourne, Australia.

Importance: Spitz nevi are benign melanocytic neoplasms that classically present in childhood. Isolated Spitz nevi have been associated with oncogenic gene fusions in approximately 50% of cases. The rare agminated variant of Spitz nevi, thought to arise from cutaneous genetic mosaicism, is characterized by development of clusters of multiple lesions in a segmental distribution, which can complicate surgical removal. Somatic single-nucleotide variants in the HRAS oncogene have been described in agminated Spitz nevi, most of which were associated with an underlying nevus spilus. The use of targeted medical therapy for agminated Spitz nevi is not well understood.

Observations: A girl aged 30 months presented with facial agminated Spitz nevi that recurred rapidly and extensively after surgery. Owing to the morbidity of further surgery, referral was made to a molecular tumor board. The patient's archival nevus tissue was submitted for extended immunohistochemical analysis and genetic sequencing. Strong ROS1 protein expression was identified by immunohistochemistry. Consistent with this, analysis of whole-genome sequencing data revealed GOPC-ROS1 fusions. These results indicated likely benefit from the oral tyrosine kinase inhibitor crizotinib, which was administered at a dosage of 280 mg/m2 twice daily. An excellent response was observed in all lesions within 5 weeks, with complete flattening after 20 weeks.

Conclusions And Relevance: Given the response following crizotinib treatment observed in this case, the kinase fusion was believed to be functionally consequential in the patient's agminated Spitz nevi and likely the driver mutational event for growth of her nevi. The repurposing of crizotinib for GOPC-ROS1 Spitz nevi defines a new treatment option for these lesions, particularly in cases for which surgery is relatively contraindicated.
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http://dx.doi.org/10.1001/jamadermatol.2021.0025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173474PMC
July 2021

EGFR mutation profile in Australian patients with non-small cell lung cancer.

Pathology 2021 May 6. Epub 2021 May 6.

Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Vic, Australia; Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Vic, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.pathol.2021.01.017DOI Listing
May 2021

Multiscale Free Energy Analysis of Human Ecosystem Engineering.

Authors:
Stephen Fox

Entropy (Basel) 2021 Mar 26;23(4). Epub 2021 Mar 26.

VTT Technical Research Centre of Finland, FI-02150 Espoo, Finland.

Unlike ecosystem engineering by other living things, which brings a relatively limited range of sensations that are connected to a few enduring survival preferences, human ecosystem engineering brings an increasing variety and frequency of novel sensations. Many of these novel sensations can quickly become preferences as they indicate that human life will be less strenuous and more stimulating. Furthermore, they can soon become addictive. By contrast, unwanted surprise from these novel sensations may become apparent decades later. This recognition can come after the survival of millions of humans and other species has been undermined. In this paper, it is explained that, while multiscale free energy provides a useful hypothesis for framing human ecosystem engineering, disconnects between preferences and survival from human ecosystem engineering limit the application of current assumptions that underlie continuous state-space and discrete state-space modelling of active inference.
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http://dx.doi.org/10.3390/e23040396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066531PMC
March 2021

Overcoming Challenges to Surrogate Decision Making for Young Adults at the End of Life.

Am J Hosp Palliat Care 2021 Jun 10;38(6):596-600. Epub 2021 Mar 10.

Department of Medicine, 12231Georgetown University Hospital, Washington, DC, USA.

Surrogate decision makers (SDMs) are challenged by difficult decisions at the end of life. This becomes more complex in young adult patients when parents are frequently the SDMs. This age group (18 to 39 years old) commonly lacks advanced directives to provide guidance which results in increased moral distress during end of life decisions. Multiple factors help guide medical decision making throughout a patient's disease course and at the end of life. These include personal patient factors and SDM factors. It has been identified that spiritual and community group support is a powerful, but inadequately used resource for these discussions. It can improve patient-SDM-provider communications, decrease psycho-social distress, and avoid unnecessary interventions at the end of life.
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http://dx.doi.org/10.1177/10499091211001007DOI Listing
June 2021

SSSPTA is essential for serine palmitoyltransferase function during development and hematopoiesis.

J Biol Chem 2021 Jan-Jun;296:100491. Epub 2021 Mar 1.

Cancer and Developmental Biology Laboratory, National Cancer Institute, Frederick, Maryland, USA. Electronic address:

Serine palmitoyltransferase complex (SPT) mediates the first and rate-limiting step in the de novo sphingolipid biosynthetic pathway. The larger subunits SPTLC1 and SPTLC2/SPTLC3 together form the catalytic core while a smaller third subunit either SSSPTA or SSSPTB has been shown to increase the catalytic efficiency and provide substrate specificity for the fatty acyl-CoA substrates. The in vivo biological significance of these smaller subunits in mammals is still unknown. Here, using two null mutants, a conditional null for ssSPTa and a null mutant for ssSPTb, we show that SSSPTA is essential for embryogenesis and mediates much of the known functions of the SPT complex in mammalian hematopoiesis. The ssSPTa null mutants are embryonic lethal at E6.5 much like the Sptlc1 and Sptlc2 null alleles. Mx1-Cre induced deletion of ssSPTa leads to lethality and myelopoietic defect. Chimeric and competitive bone marrow transplantation experiments show that the defect in myelopoiesis is accompanied by an expansion of the LinSca1c-Kit stem and progenitor compartment. Progenitor cells that fail to differentiate along the myeloid lineage display evidence of endoplasmic reticulum stress. On the other hand, ssSPTb null mice are homozygous viable, and analyses of the bone marrow cells show no significant difference in the proliferation and differentiation of the adult hematopoietic compartment. SPTLC1 is an obligatory subunit for the SPT function, and because Sptlc1 and ssSPTa mice display similar defects during development and hematopoiesis, we conclude that an SPT complex that includes SSSPTA mediates much of its developmental and hematopoietic functions in a mammalian model.
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http://dx.doi.org/10.1016/j.jbc.2021.100491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047174PMC
September 2021

Active Inference: Applicability to Different Types of Social Organization Explained through Reference to Industrial Engineering and Quality Management.

Authors:
Stephen Fox

Entropy (Basel) 2021 Feb 5;23(2). Epub 2021 Feb 5.

VTT Technical Research Centre of Finland, VTT, FI-02044 Espoo, Finland.

Active inference is a physics of life process theory of perception, action and learning that is applicable to natural and artificial agents. In this paper, active inference theory is related to different types of practice in social organization. Here, the term social organization is used to clarify that this paper does not encompass organization in biological systems. Rather, the paper addresses active inference in social organization that utilizes industrial engineering, quality management, and artificial intelligence alongside human intelligence. Social organization referred to in this paper can be in private companies, public institutions, other for-profit or not-for-profit organizations, and any combination of them. The relevance of active inference theory is explained in terms of variational free energy, prediction errors, generative models, and Markov blankets. Active inference theory is most relevant to the social organization of work that is highly repetitive. By contrast, there are more challenges involved in applying active inference theory for social organization of less repetitive endeavors such as one-of-a-kind projects. These challenges need to be addressed in order for active inference to provide a unifying framework for different types of social organization employing human and artificial intelligence.
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http://dx.doi.org/10.3390/e23020198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916013PMC
February 2021

The Ubiquitin-Specific Peptidase USP18 Promotes Lipolysis, Fatty Acid Oxidation, and Lung Cancer Growth.

Mol Cancer Res 2021 04 30;19(4):667-677. Epub 2020 Dec 30.

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Ubiquitin specific peptidase 18 (USP18), previously known as UBP43, is the IFN-stimulated gene 15 (ISG15) deconjugase. USP18 removes ISG15 from substrate proteins. This study reports that USP18-null mice (vs. wild-type mice) exhibited lower lipolysis rates, altered fat to body weight ratios, and cold sensitivity. USP18 is a regulator of lipid and fatty acid metabolism. Prior work established that USP18 promotes lung tumorigenesis. We sought to learn whether this occurs through altered lipid and fatty acid metabolism. Loss of USP18 repressed adipose triglyceride lipase (ATGL) expression; gain of USP18 expression upregulated ATGL in lung cancer cells. The E1-like ubiquitin activating enzyme promoted ISG15 conjugation of ATGL and destabilization. Immunoprecipitation assays confirmed that ISG15 covalently conjugates to ATGL. Protein expression of thermogenic regulators was examined in brown fat of USP18-null versus wild-type mice. Uncoupling protein 1 (UCP1) was repressed in USP18-null fat. Gain of USP18 expression augmented UCP1 protein via reduced ubiquitination. Gain of UCP1 expression in lung cancer cell lines enhanced cellular proliferation. UCP1 knockdown inhibited proliferation. Beta-hydroxybutyrate colorimetric assays performed after gain of UCP1 expression revealed increased cellular fatty acid beta-oxidation, augmenting fatty acid beta-oxidation in Seahorse assays. Combined USP18, ATGL, and UCP1 profiles were interrogated in The Cancer Genome Atlas. Intriguingly, lung cancers with increased USP18, ATGL, and UCP1 expression had an unfavorable survival. These findings reveal that USP18 is a pharmacologic target that controls fatty acid metabolism. IMPLICATIONS: USP18 is an antineoplastic target that affects lung cancer fatty acid metabolism.
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http://dx.doi.org/10.1158/1541-7786.MCR-20-0579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026529PMC
April 2021

An Information-Theoretic Analysis of Flexible Efficient Cognition for Persistent Sustainable Production.

Entropy (Basel) 2020 Apr 14;22(4). Epub 2020 Apr 14.

VTT Technical Research Centre of Finland, VTT, FI-02044 Espoo, Finland.

Amidst certainty, efficiency can improve sustainability by reducing resource consumption. However, flexibility is needed to be able to survive when uncertainty increases. Apropos, sustainable production cannot persist in the long-term without having both flexibility and efficiency. Referring to cognitive science to inform the development of production systems is well established. However, recent research in cognitive science encompassing flexibility and efficiency in brain functioning have not been considered previously. In particular, research by others that encompasses information (), information entropy (), relative entropy (), transfer entropy (), and brain entropy. By contrast, in this paper, flexibility and efficiency for persistent sustainable production is analyzed in relation to these information theory applications in cognitive science and is quantified in terms of information. Thus, this paper is consistent with the established practice of referring to cognitive science to inform the development of production systems. However, it is novel in addressing the need to combine flexibility and efficiency for persistent sustainability in terms of cognitive functioning as modelled with information theory.
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http://dx.doi.org/10.3390/e22040444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516917PMC
April 2020

Genetic analysis of oviposition deterrence to orange wheat blossom midge in spring wheat.

Theor Appl Genet 2021 Feb 16;134(2):647-660. Epub 2020 Nov 16.

Morden Research and Development Centre, Agriculture and Agri-Food Canada, Morden, MB, Canada.

Key Message: A major QTL for oviposition deterrence to orange wheat blossom midge was detected on chromosome 1A in the Canadian breeding line BW278 that was inherited from the Chinese variety Sumai-3. Orange wheat blossom midge (OWBM, Sitodiplosis mosellana Géhin, Diptera: Cecidomyiidae) is an important insect pest of wheat (Triticum aestivum L.) that reduces both grain yield and quality. Oviposition deterrence results in a reduction of eggs deposited on spikes relative to that observed on a wheat line preferred by OWBM. Quantification of oviposition deterrence is labor-intensive, so wheat breeders require efficient DNA markers for the selection of this trait. The objective of this study was to identify quantitative trait loci (QTL) for oviposition deterrence in a doubled haploid (DH) population developed from the spring wheat cross Superb/BW278. The DH population and check varieties were evaluated for OWBM kernel damage from five field nurseries over three growing seasons. QTL analysis identified major effect loci on chromosomes 1A (QSm.mrc-1A) and 5A (QSm.mrc-5A). Reduced kernel damage was contributed by BW278 at QSm.mrc-1A and Superb at QSm.mrc-5A. QSm.mrc-1A mapped to the approximate location of the oviposition deterrence QTL previously found in the American variety Reeder. However, haplotype analysis revealed that BW278 inherited this oviposition deterrence allele from the Chinese spring wheat variety Sumai-3. QSm.mrc-5A mapped to the location of awn inhibitor gene B1, suggesting that awns hinder OWBM oviposition. Single-nucleotide polymorphisms (SNPs) were identified for predicting the presence or absence of QSm.mrc-1A based upon haplotype. Functional annotation of candidate genes in 1A QTL intervals revealed eleven potential candidate genes, including a gene involved in terpenoid biosynthesis. SNPs for QSm.mrc-1A and fully awned spikes provide a basis for the selection of oviposition deterrence to OWBM.
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http://dx.doi.org/10.1007/s00122-020-03720-yDOI Listing
February 2021

Multi-center real-world comparison of the fully automated Idylla™ microsatellite instability assay with routine molecular methods and immunohistochemistry on formalin-fixed paraffin-embedded tissue of colorectal cancer.

Virchows Arch 2021 May 10;478(5):851-863. Epub 2020 Nov 10.

Institute of Pathology, University Hospital Cologne, Cologne, Germany.

Microsatellite instability (MSI) is present in 15-20% of primary colorectal cancers. MSI status is assessed to detect Lynch syndrome, guide adjuvant chemotherapy, determine prognosis, and use as a companion test for checkpoint blockade inhibitors. Traditionally, MSI status is determined by immunohistochemistry or molecular methods. The Idylla™ MSI Assay is a fully automated molecular method (including automated result interpretation), using seven novel MSI biomarkers (ACVR2A, BTBD7, DIDO1, MRE11, RYR3, SEC31A, SULF2) and not requiring matched normal tissue. In this real-world global study, 44 clinical centers performed Idylla™ testing on a total of 1301 archived colorectal cancer formalin-fixed, paraffin-embedded (FFPE) tissue sections and compared Idylla™ results against available results from routine diagnostic testing in those sites. MSI mutations detected with the Idylla™ MSI Assay were equally distributed over the seven biomarkers, and 84.48% of the MSI-high samples had ≥ 5 mutated biomarkers, while 98.25% of the microsatellite-stable samples had zero mutated biomarkers. The concordance level between the Idylla™ MSI Assay and immunohistochemistry was 96.39% (988/1025); 17/37 discordant samples were found to be concordant when a third method was used. Compared with routine molecular methods, the concordance level was 98.01% (789/805); third-method analysis found concordance for 8/16 discordant samples. The failure rate of the Idylla™ MSI Assay (0.23%; 3/1301) was lower than that of referenced immunohistochemistry (4.37%; 47/1075) or molecular assays (0.86%; 7/812). In conclusion, lower failure rates and high concordance levels were found between the Idylla™ MSI Assay and routine tests.
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http://dx.doi.org/10.1007/s00428-020-02962-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099763PMC
May 2021

Recurrent fusions in pediatric sarcoma and brain tumors.

Cold Spring Harb Mol Case Stud 2020 12 17;6(6). Epub 2020 Dec 17.

Children's Cancer Institute, University of New South Wales, Randwick, 2031, Australia.

The identification of rearrangements driving expression of neurotrophic receptor tyrosine kinase () family kinases in tumors has become critically important because of the availability of effective, specific inhibitor drugs. Whole-genome sequencing (WGS) combined with RNA sequencing (RNA-seq) can identify novel and recurrent expressed fusions. Here we describe three fusions identified in two pediatric central nervous system cancers and an extracranial solid tumor using WGS and RNA-seq. These fusions arose either through a simple balanced rearrangement or in the context of a complex chromoplexy event. We cloned the fusion directly from a patient sample and showed that enforced expression of this fusion is sufficient to promote cytokine-independent survival and proliferation. Cells transformed by expression are sensitive to a TRK inhibitor drug. We report here that fusions can arise in a range of pediatric cancers. Although WGS and RNA-seq are not required to detect fusions, these techniques may be of benefit when fusions are not suspected on clinical grounds or not identified by other methods.
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http://dx.doi.org/10.1101/mcs.a005710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784491PMC
December 2020

Immune molecular profiling of a multiresistant primary prostate cancer with a neuroendocrine-like phenotype: a case report.

BMC Urol 2020 Oct 28;20(1):171. Epub 2020 Oct 28.

Tumor Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Australia.

Background: Understanding the drivers of recurrence in aggressive prostate cancer requires detailed molecular and genomic understanding in order to aid therapeutic interventions. We provide here a case report of histological, transcriptional, proteomic, immunological, and genomic features in a longitudinal study of multiple biopsies from diagnosis, through treatment, and subsequent recurrence.

Case Presentation: Here we present a case study of a male in 70 s with high-grade clinically-localised acinar adenocarcinoma treated with definitive hormone therapy and radiotherapy. The patient progressed rapidly with rising PSA and succumbed without metastasis 52 months after diagnosis. We identified the expression of canonical histological markers of neuroendocrine PC (NEPC) including synaptophysin, neuron-specific enolase and thyroid transcription factor 1, as well as intact AR expression, in the recurrent disease only. The resistant disease was also marked by an extremely low immune infiltrate, extensive genomic chromosomal aberrations, and overactivity in molecular hallmarks of NEPC disease including Aurora kinase and E2F, as well as novel alterations in the cMYB pathway. We also observed that responses to both primary treatments (high dose-rate brachytherapy and androgen deprivation therapies) were consistent with known optimal responses-ruling out treatment inefficacy as a factor in relapse.

Conclusions: These data provide novel insights into a case of locally recurrent aggressive prostate cancer harbouring NEPC pathology, in the absence of detected metastasis.
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http://dx.doi.org/10.1186/s12894-020-00738-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592533PMC
October 2020

Metaplastic carcinomas of the breast without evidence of epithelial differentiation: a diagnostic approach for management.

Histopathology 2021 Apr 16;78(5):759-771. Epub 2020 Dec 16.

Department of Histopathology, The University of Nottingham and the Nottingham University Hospitals NHS Trust, Nottingham City Hospital, Nottingham, UK.

Aims: Although rare, malignant sarcomatoid breast tumours without evidence of epithelial differentiation comprise a diagnostic challenge with management implications. Earlier studies have generally considered these to be primary breast sarcomas; however, supporting evidence is lacking and management remains variable. This study aimed to provide an evidence-based approach to improve the consistency of diagnosis and management for such cases.

Methods And Results: A large series (n = 140) of metaplastic breast carcinoma (MBC) diagnosed in Nottingham over 18 years was analysed. Only cases with available data on immunohistochemical expression of cytokeratins (CKs) were included. The prevalence and pattern of expression for various CKs were assessed and details of tumours negative for CKs were collected. A diagnostic approach based on our experience is provided. Forty-seven cases (34%) showed foci of conventional type invasive breast carcinoma or ductal carcinoma in situ (DCIS), while 93 cases (66%) were diagnosed as MBC based on morphology and/or CK expression. Ninety-seven cases (69%) were negative for one or more CKs, with 18 cases (13%) negative for five or more CKs. Eight cases (6%) lacked expression of all CKs tested. Further examination showed evidence of carcinomatous nature in five cases, and three were diagnosed as MBC following extensive diagnostic work-up and based on our experience.

Conclusion: This study suggests that MBC represents a spectrum of neoplasms, with some lacking CK expression. Sarcomatoid neoplasms of the breast lacking evidence of carcinomatous morphology and CK expression may represent an extreme end of differentiation that can be considered as carcinomas rather than sarcomas for management purposes (following extensive work-up).
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http://dx.doi.org/10.1111/his.14290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492009PMC
April 2021

CUP-AI-Dx: A tool for inferring cancer tissue of origin and molecular subtype using RNA gene-expression data and artificial intelligence.

EBioMedicine 2020 Nov 9;61:103030. Epub 2020 Oct 9.

The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT, USA; The Jackson Laboratory Cancer Center, Bar Harbor, ME, USA. Electronic address:

Background: Cancer of unknown primary (CUP), representing approximately 3-5% of all malignancies, is defined as metastatic cancer where a primary site of origin cannot be found despite a standard diagnostic workup. Because knowledge of a patient's primary cancer remains fundamental to their treatment, CUP patients are significantly disadvantaged and most have a poor survival outcome. Developing robust and accessible diagnostic methods for resolving cancer tissue of origin, therefore, has significant value for CUP patients.

Methods: We developed an RNA-based classifier called CUP-AI-Dx that utilizes a 1D Inception convolutional neural network (1D-Inception) model to infer a tumor's primary tissue of origin. CUP-AI-Dx was trained using the transcriptional profiles of 18,217 primary tumours representing 32 cancer types from The Cancer Genome Atlas project (TCGA) and International Cancer Genome Consortium (ICGC). Gene expression data was ordered by gene chromosomal coordinates as input to the 1D-CNN model, and the model utilizes multiple convolutional kernels with different configurations simultaneously to improve generality. The model was optimized through extensive hyperparameter tuning, including different max-pooling layers and dropout settings. For 11 tumour types, we also developed a random forest model that can classify the tumour's molecular subtype according to prior TCGA studies. The optimised CUP-AI-Dx tissue of origin classifier was tested on 394 metastatic samples from 11 tumour types from TCGA and 92 formalin-fixed paraffin-embedded (FFPE) samples representing 18 cancer types from two clinical laboratories. The CUP-AI-Dx molecular subtype was also independently tested on independent ovarian and breast cancer microarray datasets FINDINGS: CUP-AI-Dx identifies the primary site with an overall top-1-accuracy of 98.54% in cross-validation and 96.70% on a test dataset. When applied to two independent clinical-grade RNA-seq datasets generated from two different institutes from the US and Australia, our model predicted the primary site with a top-1-accuracy of 86.96% and 72.46% respectively.

Interpretation: The CUP-AI-Dx predicts tumour primary site and molecular subtype with high accuracy and therefore can be used to assist the diagnostic work-up of cancers of unknown primary or uncertain origin using a common and accessible genomics platform.

Funding: NIH R35 GM133562, NCI P30 CA034196, Victorian Cancer Agency Australia.
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http://dx.doi.org/10.1016/j.ebiom.2020.103030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553237PMC
November 2020

CD8 tumor-infiltrating lymphocytes within the primary tumor of patients with synchronous metastatic colorectal carcinoma do not track with survival.

Clin Transl Immunology 2020 17;9(7):e1155. Epub 2020 Jul 17.

Peter MacCallum Cancer Centre Melbourne VIC Australia.

Objectives: Tumor-infiltrating lymphocytes (TIL), particularly CD8 TILs in patients with colorectal cancer (CRC), are highly prognostic in the early-disease stages (I-II). In metastatic disease (stage IV; mCRC), their influence is less well defined. It has presumably failed to contain tumor cells to the primary site; however, is this evident? We explored the prognostic impact of TILs at the primary site in patients who presented with mCRC.

Methods: Treatment-naïve patients (109) with mCRC were assessed for CD8 TILs and PD-L1 expression. Microsatellite instability (MSI) was evaluated by IHC for PMS2 and MSH6 proteins and/or by PCR using the Bethesda panel.

Results: Microsatellite instability-high tumors had significantly more CD8 TILs, with no significant survival advantage observed between MSI-H and microsatellite stable (MSS) tumors (12 vs 19 months,  = 0.304). TIL density for all cases had no impact on OS (low: 20 vs high: 13 months,  = 0.426), while PD-L1 of 1% or higher was associated with reduced mean survival (9.6 vs 18.9 months;  = 0.038). MSI-H tumors and associated immune cells had higher PD-L1 expression than in MSS cases. A positive correlation between PD-L1 on immune cells and CD8+ve TILs was found. A subset of MSS tumors had relatively high TILs approximating that of MSI-H tumors.

Conclusion: In contrast to early-stage CRC, the immune response in primary tumors of patients with mCRC does not appear to influence survival. A subgroup of MSS tumors was identified with increased TILs/PD-L1 comparable to MSI-H tumors, traditionally not be considered for immune checkpoint blockade and perhaps should be.
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http://dx.doi.org/10.1002/cti2.1155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484874PMC
July 2020

Metaplastic breast cancers frequently express immune checkpoint markers FOXP3 and PD-L1.

Br J Cancer 2020 11 17;123(11):1665-1672. Epub 2020 Sep 17.

Faculty of Medicine, UQ Centre for Clinical Research, The University of Queensland, Herston, Brisbane, QLD, Australia.

Background: Metaplastic breast carcinoma encompasses a heterogeneous group of tumours with differentiation into squamous and/or spindle, chondroid, osseous or rhabdoid mesenchymal-looking elements. Emerging immunotherapies targeting Programmed Death Ligand 1 (PD-L1) and immune-suppressing T cells (Tregs) may benefit metaplastic breast cancer patients, which are typically chemo-resistant and do not express hormone therapy targets.

Methods: We evaluated the immunohistochemical expression of PD-L1 and FOXP3, and the extent of tumour infiltrating lymphocytes (TILs) in a large cohort of metaplastic breast cancers, with survival data.

Results: Metaplastic breast cancers were significantly enriched for PD-L1 positive tumour cells, compared to triple-negative ductal breast cancers (P < 0.0001), while there was no significant difference in PD-L1 positive TILs. Metaplastic breast cancers were also significantly enriched for TILs expressing FOXP3, with FOXP3 positive intra-tumoural TILs (iTILs) associated with an adverse prognostic outcome (P = 0.0226). Multivariate analysis identified FOXP3 iTILs expression status as an important independent prognostic factor for patient survival.

Conclusions: Our findings indicate the clinical significance and prognostic value of FOXP3, PD-1/PD-L1 checkpoint and TILs in metaplastic breast cancer and confirm that a subset of metaplastics may benefit from immune-based therapies.
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http://dx.doi.org/10.1038/s41416-020-01065-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686342PMC
November 2020

A MXI1-NUTM1 fusion protein with MYC-like activity suggests a novel oncogenic mechanism in a subset of NUTM1-rearranged tumors.

Lab Invest 2021 01 1;101(1):26-37. Epub 2020 Sep 1.

Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia.

Most NUTM1-rearranged neoplasms (NRNs) have fusions between NUTM1 and BRD (bromodomain-containing) family members and are termed NUT carcinomas (NCs) because they show some squamous differentiation. However, some NRNs are associated with fusions between NUTM1 and members of the MAD (MAX dimerization) gene family of MYC antagonists. Here we describe a small round cell malignancy from the gastro-esophageal junction with a previously unreported fusion between NUTM1 and the MAD family member MXI1. In contrast to NCs, the MXI1-NUTM1 tumor did not show squamous differentiation and did not express MYC, TP63 or SOX2, genes known to be targets of BRD-NUTM1 proteins and critical for NC oncogenesis. Transcriptome analysis showed paradoxical enrichment of MYC target genes in the MXI1-NUTM1 tumor despite the lack of MYC expression. When expressed in vitro MXI1-NUTM1 partially phenocopied MYC, enhancing cell proliferation and cooperating with oncogenic HRAS to produce anchorage-independent cell growth. These data provide evidence that MAD family members, which are normally repressors of MYC activity, can be converted into MYC-like mimics by fusion to NUTM1. The pathological features and novel oncogenic mechanism of the MXI1-NUTM1 tumor show that identification of NUTM1 fusion partners can be important for accurate diagnostic classification of some NRN subtypes, and potentially may guide therapeutic options.
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http://dx.doi.org/10.1038/s41374-020-00484-3DOI Listing
January 2021

Degradation of 5hmC-marked stalled replication forks by APE1 causes genomic instability.

Sci Signal 2020 08 18;13(645). Epub 2020 Aug 18.

Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.

Synthetic lethality between poly(ADP-ribose) polymerase (PARP) inhibition and deficiency is exploited to treat breast and ovarian tumors. However, resistance to PARP inhibitors (PARPis) is common. To identify potential resistance mechanisms, we performed a genome-wide RNAi screen in BRCA2-deficient mouse embryonic stem cells and validation in KB2P1.21 mouse mammary tumor cells. We found that resistance to multiple PARPi emerged with reduced expression of TET2 (ten-eleven translocation), which promotes DNA demethylation by oxidizing 5-methylcytosine (5mC) to 5-hydroxymethycytosine (5hmC) and other products. TET2 knockdown in BRCA2-deficient cells protected stalled replication forks (RFs). Increasing 5hmC abundance induced the degradation of stalled RFs in KB2P1.21 and human cancer cells by recruiting the base excision repair-associated apurinic/apyrimidinic endonuclease APE1, independent of the status. TET2 loss did not affect the recruitment of the repair protein RAD51 to sites of double-strand breaks (DSBs) or the abundance of proteins associated with RF integrity. The loss of TET2, of its product 5hmC, and of APE1 recruitment to stalled RFs promoted resistance to the chemotherapeutic cisplatin. Our findings reveal a previously unknown role for the epigenetic mark 5hmC in maintaining the integrity of stalled RFs and a potential resistance mechanism to PARPi and cisplatin.
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http://dx.doi.org/10.1126/scisignal.aba8091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575062PMC
August 2020

Clinical implications of prospective genomic profiling of metastatic breast cancer patients.

Breast Cancer Res 2020 08 18;22(1):91. Epub 2020 Aug 18.

Division of Research, Peter MacCallum Cancer Centre, Melbourne, Australia.

Background: Metastatic breast cancer remains incurable. Next-generation sequencing (NGS) offers the ability to identify actionable genomic alterations in tumours which may then be matched with targeted therapies, but the implementation and utility of this approach is not well defined for patients with metastatic breast cancer.

Methods: We recruited patients with advanced breast cancer of any subtype for prospective targeted NGS of their most recent tumour samples, using a panel of 108 breast cancer-specific genes. Genes were classified as actionable or non-actionable using the European Society of Medical Oncology Scale for Clinical Actionability of Molecular Targets (ESCAT) guidelines.

Results: Between February 2014 and May 2019, 322 patients were enrolled onto the study, with 72% (n = 234) of patients successfully sequenced (n = 357 samples). The majority (74%, n = 171) of sequenced patients were found to carry a potentially actionable alteration, the most common being a PIK3CA mutation. Forty-three percent (n = 74) of patients with actionable alterations were referred for a clinical trial or referred for confirmatory germline testing or had a change in therapy outside of clinical trials. We found alterations in AKT1, BRCA2, CHEK2, ESR1, FGFR1, KMT2C, NCOR1, PIK3CA and TSC2 to be significantly enriched in our metastatic population compared with primary breast cancers. Concordance between primary and metastatic samples for key driver genes (TP53, ERBB2 amplification) was > 75%. Additionally, we found that patients with a higher number of mutations had a significantly worse overall survival.

Conclusion: Genomic profiling of patients with metastatic breast cancer can have clinical implications and should be considered in all suitable patients.
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http://dx.doi.org/10.1186/s13058-020-01328-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436992PMC
August 2020

The TP53 mutation rate differs in breast cancers that arise in women with high or low mammographic density.

NPJ Breast Cancer 2020 7;6:34. Epub 2020 Aug 7.

Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC Australia.

Mammographic density (MD) influences breast cancer risk, but how this is mediated is unknown. Molecular differences between breast cancers arising in the context of the lowest and highest quintiles of mammographic density may identify the mechanism through which MD drives breast cancer development. Women diagnosed with invasive or in situ breast cancer where MD measurement was also available ( = 842) were identified from the Lifepool cohort of >54,000 women participating in population-based mammographic screening. This group included 142 carcinomas in the lowest quintile of MD and 119 carcinomas in the highest quintile. Clinico-pathological and family history information were recorded. Tumor DNA was collected where available ( = 56) and sequenced for breast cancer predisposition and driver gene mutations, including copy number alterations. Compared to carcinomas from low-MD breasts, those from high-MD breasts were significantly associated with a younger age at diagnosis and features associated with poor prognosis. Low- and high-MD carcinomas matched for grade, histological subtype, and hormone receptor status were compared for somatic genetic features. Low-MD carcinomas had a significantly increased frequency of mutations, higher homologous recombination deficiency, higher fraction of the genome altered, and more copy number gains on chromosome 1q and losses on 17p. While high-MD carcinomas showed enrichment of tumor-infiltrating lymphocytes in the stroma. The data demonstrate that when tumors were matched for confounding clinico-pathological features, a proportion in the lowest quintile of MD appear biologically distinct, reflective of microenvironment differences between the lowest and highest quintiles of MD.
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http://dx.doi.org/10.1038/s41523-020-00176-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414106PMC
August 2020

Immune system and angiogenesis-related potential surrogate biomarkers of response to everolimus-based treatment in hormone receptor-positive breast cancer: an exploratory study.

Breast Cancer Res Treat 2020 Nov 7;184(2):421-431. Epub 2020 Aug 7.

Department of Medical, Surgery & Health Sciences, University of Trieste, Piazza Ospitale 1, 34129, Trieste, Italy.

Purpose: mTOR inhibitor everolimus is used for hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer (mBC). No reliable predictive biomarker of response is available. Following evidences from other solid tumors, we aimed to assess the association between treatment-associated immune system features and everolimus activity.

Methods: We retrospectively explored a correlation with the therapeutic activity of everolimus and tumor-associated immune pathways with ingenuity pathway analysis (IPA), neutrophil-to-lymphocyte ratio (NLR), circulating lymphocytes, and endothelial cells (CECs) in 3 different HR+ mBC studies, including the BALLET phase IIIb study.

Results: The circulating levels of CD3/CD8, CD3/CD4, and overall T lymphocytes were higher in responders versus non-responders at baseline (p = 0.017, p < 0.001, p = 0.034) and after treatment (p = 0.01, p = 0.003, p = 0.023). Reduced CECs, a tumor neoangiogenesis marker, were observed in responders after treatment (p < 0.001). Patients with low NLR (≤ 4.4) showed a better progression-free survival compared to patients with high NLR (> 4.4) (p = 0.01). IPA showed that the majority of immunity-related genes were found upregulated in responders compared to non-responders before treatment, but not after.

Conclusions: Lymphocytes subpopulations, CECs and NLR could be interesting biomarkers predictive of response to everolimus-based regimens, potentially useful in daily clinical practice to select/monitor everolimus-based treatment in mBC. Further studies to confirm such hypotheses are warranted.
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http://dx.doi.org/10.1007/s10549-020-05856-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599144PMC
November 2020
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