A P53-Independent DNA Damage Response Suppresses Oncogenic Proliferation and Genome Instability

The Mre11-Rad50-Nbs1 complex is a DNA double-strand break sensor that mediates a tumor-suppressive DNA damage response (DDR) in cells undergoing oncogenic stress, yet the mechanisms underlying this effect are poorly understood. Using a genetically inducible primary mammary epithelial cell model, we demonstrate that Mre11 suppresses proliferation and DNA damage induced by diverse oncogenic drivers through a p53-independent mechanism. Breast tumorigenesis models engineered to express a hypomorphic Mre11 allele exhibit increased levels of oncogene-induced DNA damage, R-loop accumulation, and chromosomal instability with a characteristic copy number loss phenotype. Mre11 complex dysfunction is identified in a subset of human triple-negative breast cancers and is associated with increased sensitivity to DNA-damaging therapy and inhibitors of ataxia telangiectasia and Rad3 related (ATR) and poly (ADP-ribose) polymerase (PARP). Thus, deficiencies in the Mre11-dependent DDR drive proliferation and genome instability patterns in p53-deficient breast cancers and represent an opportunity for therapeutic exploitation

ESMO recommendations on the standard methods to detect NTRK fusions in daily practice and clinical research

Abstract Background NTRK1, NTRK2 and NTRK3 fusions are present in a plethora of malignancies across different histologies. These fusions represent the most frequent mechanism of oncogenic activation of these receptor tyrosine kinases, and biomarkers for the use of TRK small molecule inhibitors. Given the varying frequency of NTRK1/2/3 fusions, crucial to the administration of NTRK inhibitors is the development of optimal approaches for the detection of human cancers harbouring activating NTRK1/2/3 fusion genes. Materials and methods Experts from several Institutions were recruited by the European Society for Medical Oncology (ESMO) Translational Research and Precision Medicine Working Group (TR and PM WG) to review the available methods for the detection of NTRK gene fusions, their potential applications, and strategies for the implementation of a rational approach for the detection of NTRK1/2/3 fusion genes in human malignancies. A consensus on the most reasonable strategy to adopt when screening for NTRK fusions in oncologic patients was sought, and further reviewed and approved by the ESMO TR and PM WG and the ESMO leadership. Results The main techniques employed for NTRK fusion gene detection include immunohistochemistry, fluorescence in situ hybridization (FISH), RT-PCR, and both RNA-based and DNA-based next generation sequencing (NGS). Each technique has advantages and limitations, and the choice of assays for screening and final diagnosis should also take into account the resources and clinical context. Conclusion In tumours where NTRK fusions are highly recurrent, FISH, RT-PCR or RNA-based sequencing panels can be used as confirmatory techniques, whereas in the scenario of testing an unselected population where NTRK1/2/3 fusions are uncommon, either front-line sequencing (preferentially RNA-sequencing) or screening by immunohistochemistry followed by sequencing of positive cases should be pursued

HER2-Enriched Subtype and ERBB2 Expression in HER2-Positive Breast Cancer Treated with Dual HER2 Blockade

Background: Identification of HER2-positive breast cancers with high anti-HER2 sensitivity could help de-escalate chemotherapy. Here, we tested a clinically applicable RNA-based assay that combines ERBB2 and the HER2-enriched (HER2-E) intrinsic subtype in HER2-positive disease treated with dual HER2-blockade without chemotherapy. Methods: A research-based PAM50 assay was applied in 422 HER2-positive tumors from five II-III clinical trials (SOLTI-PAMELA, TBCRC023, TBCRC006, PER-ELISA, EGF104090). In SOLTI-PAMELA, TBCRC023, TBCRC006, and PER-ELISA, all patients had early disease and were treated with neoadjuvant lapatinib or pertuzumab plus trastuzumab for 12-24 weeks. Primary outcome was pathological complete response (pCR). In EGF104900, 296 women with advanced disease were randomized to receive either lapatinib alone or lapatinib plus trastuzumab. Progression-free survival (PFS), overall response rate (ORR), and overall survival (OS) were evaluated. Results: A total of 305 patients with early and 117 patients with advanced HER2-positive disease were analyzed. In early disease, HER2-E represented 83.8% and 44.7% of ERBB2-high and ERBB2-low tumors, respectively. Following lapatinib and trastuzumab, the HER2-E and ERBB2 (HER2-E/ERBB2)-high group showed a higher pCR rate compared to the rest (44.5%, 95% confidence interval [CI] = 35.4% to 53.9% vs 11.6%, 95% CI = 6.9% to 18.0%; adjusted odds ratio [OR] = 6.05, 95% CI = 3.10 to 11.80, P <. 001). Similar findings were observed with neoadjuvant trastuzumab and pertuzumab (pCR rate of 66.7% in HER2-E/ERBB2-high, 95% CI = 22.3% to 95.7% vs 14.7% in others, 95% CI = 4.9% to 31.1%; adjusted OR = 11.60, 95% CI = 1.66 to 81.10, P =. 01). In the advanced setting, the HER2-E/ERBB2-high group was independently associated with longer PFS (hazard ratio [HR] = 0.52, 95% CI = 0.35 to 0.79, P <. 001); higher ORR (16.3%, 95% CI = 8.9% to 26.2% vs 3.7%, 95% CI = 0.8% to 10.3%, P =. 02); and longer OS (HR = 0.66, 95% CI = 0.44 to 0.97, P =. 01). Conclusions: Combining HER2-E subtype and ERBB2 mRNA into a single assay identifies tumors with high responsiveness to HER2-targeted therapy. This biomarker could help de-escalate chemotherapy in approximately 40% of patients with HER2-positive breast cancer

Recommendations for the use of next-generation sequencing (NGS) for patients with metastatic cancers: a report from the ESMO Precision Medicine Working Group

Next-generation sequencing (NGS) allows sequencing of a high number of nucleotides in a short time frame at an affordable cost. While this technology has been widely implemented, there are no recommendations from scientific societies about its use in oncology practice. The European Society for Medical Oncology (ESMO) is proposing three levels of recommendations for the use of NGS. Based on the current evidence, ESMO recommends routine use of NGS on tumour samples in advanced non-squamous non-small-cell lung cancer (NSCLC), prostate cancers, ovarian cancers and cholangiocarcinoma. In these tumours, large multigene panels could be used if they add acceptable extra cost compared with small panels. In colon cancers, NGS could be an alternative to PCR. In addition, based on the KN158 trial and considering that patients with endometrial and small-cell lung cancers should have broad access to anti-programmed cell death 1 (anti-PD1) antibodies, it is recommended to test tumour mutational burden (TMB) in cervical cancers, well- and moderately-differentiated neuroendocrine tumours, salivary cancers, thyroid cancers and vulvar cancers, as TMB-high predicted response to pembrolizumab in these cancers. Outside the indications of multigene panels, and considering that the use of large panels of genes could lead to few clinically meaningful responders, ESMO acknowledges that a patient and a doctor could decide together to order a large panel of genes, pending no extra cost for the public health care system and if the patient is informed about the low likelihood of benefit. ESMO recommends that the use of off-label drugs matched to genomics is done only if an access programme and a procedure of decision has been developed at the national or regional level. Finally, ESMO recommends that clinical research centres develop multigene sequencing as a tool to screen patients eligible for clinical trials and to accelerate drug development, and prospectively capture the data that could further inform how to optimise the use of this technology

Processed pseudogenes acquired somatically during cancer development.

Cancer evolves by mutation, with somatic reactivation of retrotransposons being one such mutational process. Germline retrotransposition can cause processed pseudogenes, but whether this occurs somatically has not been evaluated. Here we screen sequencing data from 660 cancer samples for somatically acquired pseudogenes. We find 42 events in 17 samples, especially non-small cell lung cancer (5/27) and colorectal cancer (2/11). Genomic features mirror those of germline LINE element retrotranspositions, with frequent target-site duplications (67%), consensus TTTTAA sites at insertion points, inverted rearrangements (21%), 5' truncation (74%) and polyA tails (88%). Transcriptional consequences include expression of pseudogenes from UTRs or introns of target genes. In addition, a somatic pseudogene that integrated into the promoter and first exon of the tumour suppressor gene, MGA, abrogated expression from that allele. Thus, formation of processed pseudogenes represents a new class of mutation occurring during cancer development, with potentially diverse functional consequences depending on genomic context

Evaluation of the process of reabilitation of a stretch of Riparian forest in Itapemirim river watershed - ES

Este estudo foi realizado em uma área de floresta ciliar em processo de recuperação mediante reabilitação.A área de estudo está localizada na sub-bacia hidrográfica do rio Itapemirim, no Município de Alegre, ES, Brasil.A ocupação e uso do solo antes da revegetação eram de pastagem com Brachiaria sp. A revegetação da áreafoi feita em 1997, com espécies autóctones e alóctones arbóreas, em arranjo de distribuição aleatório, em umaárea de 1,2 ha. Para a realização dos estudos foram feitos inventários florestais nos períodos de 2004/2005e 2005/2006, sendo medidos os indivíduos de hábito arbustivo e arbóreo com circunferência à altura do peito(CAP) > 5 cm e suas alturas totais. As espécies encontradas na área foram identificadas e classificadas de acordocom seus grupos ecológicos, síndromes de dispersão e presença silvestre, sendo calculados os parâmetros florísticos,a estrutura vertical e a dinâmica estrutural desse povoamento. O objetivo do trabalho foi avaliar o desenvolvimentodo povoamento implantado para subsidiar práticas silviculturais quanto à seleção e implantação de espécies pararevegetação de áreas de floresta ciliar degradadas, em condições semelhantes. Os resultados demonstraram quefoi implantado um povoamento florestal com grande diversidade de espécies e a estratificação em classes dealtura foi à semelhança de povoamentos heterogêneos naturais. As espécies identificadas como edificadoras darevegetação da área estudada foram: Anadenanthera colubrina, Caesalpinia leyostachia, Acacia auriculiformis,Acacia mangium, Handroanthus serratifolius, Inga edulis, Joannesia princeps, Pterogyne nitens, Enterelobiumcontortisiliquum, Tabernaemontana hystrix e Anthocephalus indicus. A distribuição em classes de tamanho dacomunidade implantada ocorre em forma de "J" reverso, havendo a predominância de indivíduos pioneiros emtodas as classes de CAP. A dinâmica da estrutura horizontal apontou que, para o sucesso, continuidade e desenvolvimentoda recuperação da área, seja monitorada a regeneração natural em relação à sua presença e à eficiência dos fatoresbióticos e abióticos que nela interferem. A não observância de indivíduos arbustivos e arbóreos regenerados naturalmente,na classe de inclusão do estudo, indica a fragilidade inicial da área rumo à sustentabilidade do sistema.The study was realized in an area of riparian forest in process by means of rehabilitation. Thestudy area is located in Rio Itapemirim, in Alegre city, Brazil. The occupation and use of the soil beforethe recovery were of pasture with Brachiaria sp. The recovery of this area was in 1997, with autochthonousand allochthonous species, in casually distribution arrangement, in an area of 1,2 ha. For this studies wasrealized forest inventories in the periods of 2004/2005 and 2005/2006, being measured the arboreal individualswith circumference at breast height (CBH) and total heights. The species found in the area were identifiedand classified in this ecological groups, dispersion syndromes and wild presence, it forms calculated thefloristic parameters, the vertical structure and the structural dynamics of this plantation. The objective ofthis work went evaluate the development of the plantation implanted to subsidize practical silviculture withrelationship to the selection and plantation of species for the revegetation of degraded areas of riparianforest, in similar conditions. The results of the studies demonstrated that a forest plantation was implantedwith great diversity of species and the bedding in height classes it went to the likeness of natural heterogeneous.The species identified as builders of the plantation of the studied area were: Anadenanthera colubrina, Caesalpinia leyostachia, Acacia auriculiformis, Acacia mangium, Handroanthus serratifolius, Inga edulis, Joannesia princeps,Pterogyne nitens, Enterelobium contortisiliquum, Tabernaemontana hystrix, and Anthocephalus indicus . Theimplanted community's distribution diametric happens in reverse J shape having the pioneer individuals'predominance in all the classes of CBH. The dynamics of the horizontal structure points that for the success,continuity and development of the recovery of the area, the natural regeneration be monitored in relationto its presence and efficiency of the biotic factors and abiotic those interfere in the same. The not tree individualsobservance in natural regeneration, in the class of inclusion of the study, indicate the initial fragility of thearea heading for sustentabilidade of the system