Recent work has revealed the existence of a class of small non-coding RNA species, known as microRNAs (miRNAs), which have critical functions across various biological processes. Here we use a new, bead-based flow cytometric miRNA expression profiling method to present a systematic expression analysis of 217 mammalian miRNAs from 334 samples, including multiple human cancers. The miRNA profiles are surprisingly informative, reflecting the developmental lineage and differentiation state of the tumours. We observe a general downregulation of miRNAs in tumours compared with normal tissues. Furthermore, we were able to successfully classify poorly differentiated tumours using miRNA expression profiles, whereas messenger RNA profiles were highly inaccurate when applied to the same samples. These findings highlight the potential of miRNA profiling in cancer diagnosis.

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MicroRNA expression profiles classify human cancers

Mutations in the evolutionarily conserved codons of the p53 tumor suppressor gene are common in diverse types of human cancer. The p53 mutational spectrum differs among cancers of the colon, lung, esophagus, breast, liver, brain, reticuloendothelial tissues, and hemopoietic tissues. Analysis of these mutations can provide clues to the etiology of these diverse tumors and to the function of specific regions of p53. Transitions predominate in colon, brain, and lymphoid malignancies, whereas G:C to T:A transversions are the most frequent substitutions observed in cancers of the lung and liver. Mutations at A:T base pairs are seen more frequently in esophageal carcinomas than in other solid tumors. Most transitions in colorectal carcinomas, brain tumors, leukemias, and lymphomas are at CpG dinucleotide mutational hot spots. G to T transversions in lung, breast, and esophageal carcinomas are dispersed among numerous codons. In liver tumors in persons from geographic areas in which both aflatoxin B1 and hepatitis B virus are cancer risk factors, most mutations are at one nucleotide pair of codon 249. These differences may reflect the etiological contributions of both exogenous and endogenous factors to human carcinogenesis.

https://zenodo.org/record/1230948/files/article.pdf

p53 mutations in human cancers

The transforming growth factor beta (TGF-beta) family of growth factors control the development and homeostasis of most tissues in metazoan organisms. Work over the past few years has led to the elucidation of a TGF-beta signal transduction network. This network involves receptor serine/threonine kinases at the cell surface and their substrates, the SMAD proteins, which move into the nucleus, where they activate target gene transcription in association with DNA-binding partners. Distinct repertoires of receptors, SMAD proteins, and DNA-binding partners seemingly underlie, in a cell-specific manner, the multifunctional nature of TGF-beta and related factors. Mutations in these pathways are the cause of various forms of human cancer and developmental disorders.

TGF-beta signal transduction.

Background The aggressive and heterogeneous nature of lung cancer has thwarted efforts to reduce mortality from this cancer through the use of screening. The advent of low-dose helical computed tomography (CT) altered the landscape of lung-cancer screening, with studies indicating that low-dose CT detects many tumors at early stages. The National Lung Screening Trial (NLST) was conducted to determine whether screening with low-dose CT could reduce mortality from lung cancer. Methods From August 2002 through April 2004, we enrolled 53,454 persons at high risk for lung cancer at 33 U.S. medical centers. Participants were randomly assigned to undergo three annual screenings with either low-dose CT (26,722 participants) or single-view posteroanterior chest radiography (26,732). Data were collected on cases of lung cancer and deaths from lung cancer that occurred through December 31, 2009. Results The rate of adherence to screening was more than 90%. The rate of positive screening tests was 24.2% with low-dose CT and 6.9% with radiography over all three rounds. A total of 96.4% of the positive screening results in the low-dose CT group and 94.5% in the radiography group were false positive results. The incidence of lung cancer was 645 cases per 100,000 person-years (1060 cancers) in the low-dose CT group, as compared with 572 cases per 100,000 person-years (941 cancers) in the radiography group (rate ratio, 1.13; 95% confidence interval [CI], 1.03 to 1.23). There were 247 deaths from lung cancer per 100,000 person-years in the low-dose CT group and 309 deaths per 100,000 person-years in the radiography group, representing a relative reduction in mortality from lung cancer with low-dose CT screening of 20.0% (95% CI, 6.8 to 26.7; P=0.004). The rate of death from any cause was reduced in the low-dose CT group, as compared with the radiography group, by 6.7% (95% CI, 1.2 to 13.6; P=0.02). Conclusions Screening with the use of low-dose CT reduces mortality from lung cancer. (Funded by the National Cancer Institute; National Lung Screening Trial ClinicalTrials.gov number, NCT00047385.).

/pdf/reduced-lung-cancer-mortality-with-low-dose-computed-315bk0rtxu.pdf

Reduced lung-cancer mortality with low-dose computed tomographic screening.

METHODS In this phase 3, open-label study, we randomly assigned previously untreated patients in East Asia who had advanced pulmonary adenocarcinoma and who were nonsmokers or former light smokers to receive gefitinib (250 mg per day) (609 patients) or carboplatin (at a dose calculated to produce an area under the curve of 5 or 6 mg per milliliter per minute) plus paclitaxel (200 mg per square meter of body-surface area) (608 patients). The primary end point was progression-free survival. RESULTS The 12-month rates of progression-free survival were 24.9% with gefitinib and 6.7% with carboplatin–paclitaxel. The study met its primary objective of showing the noninferiority of gefitinib and also showed its superiority, as compared with carboplatin– paclitaxel, with respect to progression-free survival in the intention-to-treat population (hazard ratio for progression or death, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). In the subgroup of 261 patients who were positive for the epidermal growth factor receptor gene (EGFR) mutation, progression-free survival was significantly longer among those who received gefitinib than among those who received carboplatin–paclitaxel (hazard ratio for progression or death, 0.48; 95% CI, 0.36 to 0.64; P<0.001), whereas in the subgroup of 176 patients who were negative for the mutation, progression-free survival was significantly longer among those who received carboplatin–paclitaxel (hazard ratio for progression or death with gefitinib, 2.85; 95% CI, 2.05 to 3.98; P<0.001). The most common adverse events were rash or acne (in 66.2% of patients) and diarrhea (46.6%) in the gefitinib group and neurotoxic effects (69.9%), neutropenia (67.1%), and alopecia (58.4%) in the carboplatin–paclitaxel group. CONCLUSIONS Gefitinib is superior to carboplatin–paclitaxel as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia. The presence in the tumor of a mutation of the EGFR gene is a strong predictor of a better outcome with gefitinib. (ClinicalTrials.gov number, NCT00322452.)

https://www.nejm.org/doi/pdf/10.1056/NEJMoa0810699

Gefitinib or Carboplatin–Paclitaxel in Pulmonary Adenocarcinoma

The authors regret the Author Affiliations of Dr. Jianming Ying and Dr. Ying Cheng were listed incorrectly in the published paper. The correct affiliations are as follows: Jianming Ying, Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Ying Cheng, Department of Thoracic Oncology, Jilin Cancer Hospital, Changchun, China. All other author affiliations are correct. The authors would like to apologise for any inconvenience caused. Consensus for HER2 alterations testing in non-small-cell lung cancerESMO OpenVol. 7Issue 1PreviewHuman epidermal growth factor receptor 2 (HER2) is a transmembrane glycoprotein receptor with intracellular tyrosine kinase activity. Its alterations, including mutation, amplification and overexpression, could result in oncogenic potential and have been detected in many cancers such as non-small-cell lung cancer (NSCLC). Such alterations are, in general, considered markers of poor prognosis. Anti-HER2 antibody-drug conjugates, e.g. trastuzumab deruxtecan (T-DXd, DS-8201) and disitamab vedotin (RC48), were recently approved for HER2-positive breast and gastric cancers. Full-Text PDF Open Access 

Corrigendum to 'Consensus for HER2 Alterations Testing in Non-small Cell Lung Cancer': [ESMO Open Volume 7 Issue 1 (2022) 100395].

clinical significance Expression of human telomerase subunit genes in primary lung cancer and its

Propensity score analysis for the efficacy of preoperative antibiotics in patients with resected primary lung cancer: Levofloxacin versus cefazolin

L'invention concerne un procede pour predire la recurrence d'un adenocarcinome pulmonaire apres l'elimination chirurgicale du cancer du poumon chez un patient atteint d'un adenocarcinome pulmonaire en utilisant un jeu de genes specifiques. L'invention concerne egalement une composition a utiliser dans le procede.

Procédé et composition pour prédire la récurrence postchirurgicale chez un patient atteint d'un adénocarcinome pulmonaire


 The recent accelerated approval of the KRASG12C mutant-selective inhibitor sotorasib (AMG 510) for the treatment of 2nd line KRASG12C mutation-positive NSCLC patients marks the first approved targeted therapy for tumors with any KRAS mutation. While KRASG12C inhibitors deliver clinical benefit, most patients who achieved an objective response ultimately progressed. Recent insights into clinical KRASG12C inhibitor resistance identified reactivation of the RAS/MAPK pathway as a common putative driver mechanism of resistance. Multiple ongoing trials seek to augment responses to KRASG12C inhibitors through rational combination strategies, including the pan-KRAS SOS1 inhibitor BI 1701963. Here we use different preclinical experimental approaches to interrogate KRASG12C inhibitor resistance mechanisms with the aim to identify strategies to overcome resistance. To predict on-target resistance, Ba/F3 cells were transduced with KRASG12C, ENU-mutagenized and chronically exposed to KRASG12C inhibitors. Resistant clones were screened for secondary KRAS mutations, highlighting that KRAS G12C/Y96D and Y96S cis mutations did confer resistance to KRASG12C inhibition but could be overcome by MEK inhibitor combination with a SOS1 inhibitor. As second strategy a high-complexity single site variant library of KRASG12C encompassing all possible secondary KRAS mutations was employed to establish Ba/F3 transgenic cell pools. The response of this KRASG12C Ba/F3 clone library harboring a comprehensive set of secondary mutations was tested following treatment with KRASG12C inhibitors alone and in combination with a pan-KRAS SOS1 inhibitor. In parallel, acquired KRASG12C inhibitor resistance was generated in solid cancer cells following long-term MRTX849 treatment. Clones were characterized and their response to KRASG12C inhibition and combination therapy was analyzed. Both in the Ba/F3 cell pool as well as in KRASG12C inhibitor resistant clones combining SOS1 inhibition to KRASG12C inhibition proved to be beneficial. Finally, bringing these findings in vivo, SW837(CRC) tumor-bearing mice were long-term treated with adagrasib until tumors relapsed after initial regression and resistant tumors were randomized for second line treatments. In this KRASG12C inhibitor resistant context, treatment with adagrasib plus cetuximab resulted in tumor stasis and adagrasib plus SOS1i resulted in tumor regression. While more work is currently being undertaken to map the resistance mechanisms in both our in vitro and in vivo settings, all results highlight the benefit of combining a SOS1 inhibitor with a KRASG12C inhibitor to prevent and/or overcome acquired resistance. The pan-KRAS SOS1 inhibitor BI 1701963 is the first direct RAS signaling modifier in phase I clinical trials both as a monotherapy as well as in combination with KRASG12C inhibitors, MEK inhibitors and liposomal irinotecan.
 Citation Format: Marco H. Hofmann, Sabine Jurado, Daniel Gerlach, Takamasa Koga, Francesca Trapani, Michael Gmachl, Donat Alpar, Simone Lieb, Astrid Jeschko, Tetsuya Mitsudomi, Norbert Kraut, Mark P. Petronczki. Probing and overcoming KRASG12C inhibitor resistance by combination with a pan-KRAS SOS1 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3255.

Tetsuya Mitsudomi

Papers

Corrigendum to 'Consensus for HER2 Alterations Testing in Non-small Cell Lung Cancer': [ESMO Open Volume 7 Issue 1 (2022) 100395].

clinical significance Expression of human telomerase subunit genes in primary lung cancer and its

Propensity score analysis for the efficacy of preoperative antibiotics in patients with resected primary lung cancer: Levofloxacin versus cefazolin

Procédé et composition pour prédire la récurrence postchirurgicale chez un patient atteint d'un adénocarcinome pulmonaire

Abstract 3255: Probing and overcoming KRASG12C inhibitor resistance by combination with a pan-KRAS SOS1 inhibitor