Journal Thoracic Oncology

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Abstracts Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017 Martin Reck Lungen Clinic Grosshansdorf, Großhansdorf/Germany The concept of tumor-induced neoangiogenesis has been shown to be a relevant factor for tumor proliferation and metastasis already a couple of years ago (1). Therefore interaction with proangiogenic pathways appears to be a promising therapeutic target across several solide tumors. In eligible patients with advanced non-squamous NSCLC the addition of the anti vascular endothelial growth factor (anti VEGF) antibody bevacizumab to platinum based chemotherapy has shown consistent improvement of response, progression free survival (PFS) and overall survival. However also the combination did increase the incidence of characteristic adverse events like hypertension, arterial and venous vascular events, bleeding events, proteinuria and other (2). Recently two large randomised phase III trials revealed a significant increase in efficacy by the combination of antiangiogenic agents and chemotherapy in pretreated patients with advanced NSCLC. In the LUME 1 trial the combination of the oral angiokinase inhibitor nintedanib and docetaxel revealed a significant improvement of PFS (median PFS 3.4 vs 2.7 months, HR 0.79, 95% CI 0.68-0.92) and OS in patients with adenocarcinoma histology (median OS 12.6 vs 10.3 months, HR 0.82, 95% CI 0.7-0.99) compared to docetaxel (3). The combination of the anti VEGF receptor 2 antibody ramucirumab and docetaxel did show a significant improvement of response (response rate: 23% versus 14%, p
Abstracts Journal of Thoracic Oncology • Volume 12 Issue S1 January 2017 2 nd Department of Pathology, Semmelweis University (SE), Budapest/Hungary Molecular classification of lung cancer revealed that the most frequently mutated oncogene in lung cancer is the KRAS due to smoking and this molecular subclass is exclusively occur in the adenocarcinoma histologic variant and rarely in large cell variant. It also can be detected in the mixed histological variants like the adenosquamous subtype. The incidence of KRAS mutation in lung adenocarcinoma is 30% based on exon2 testing. (1) However, it is expected that similar to colorectal cancer, a complex RAS panel mutational analysis involving rare KRAS exon3 and 4 and NRAS exon2-4 could increase this figure significantly (probaly by 5-10%). Since RAS mutations are exclusive and do not occur together with other oncogenic driver mutations the complett RAS panel mutation determination could help to clearly define a large set of adenocarcinoma patents where further molecular analysis is not necessary. Analysis of two large patient cohort of lung adenocarcinoma and colorectal cancer (500 pt each) revealed that the alleic variations are highly similar in mutant KRAS exon2 in this two cancer types. The TGT (G-C) transversion in codon 12 was proved to be lung cancer specific while the GAC (G-D) codon 13 alteration was colorectal cancer specific. Since the RAS mutation in lung cancer is considered to be smoking-related, this highly similar allelic profile in colorectal cancer can be the molecular signature of smoking in this cancer type. Analysis of KRAS exon 2 aminoacid conversions by smoking status revealed that in non-smokers mutation is rare and if it occurs it is most frequently G12V unlike in smokers where G12C is the predominant. G12V-type patients may respond better to conventional chemoterapy (2). RAS mutant lung cancer patients are resistant to EGFR TKI inhibitors (1). EGFR protein expression is highly similar in KRAS mutant and wt lung adenocarcinoma but interestingly phosphorylated-EGFR is overexpressed in KRAS mutant tumors even overcoming EGFR mutated ones suggesting an aberrant RAS-driven signaling. (3) KRAS mutation in lung cancer is a poor prognostic factor. Analysis of the organ metastatic pattern of KRAS mutant lung adenocarcinoma revealed that brain and bone metastatic potential of these tumors are similar to KRASwt ones while these tumors tend to prefer pleural dissemination and liver. On the other hand, KRAS mutant lung adenocarcinoma is less likely give rise adrenal- or lung metastasis, a clearly indication a different biology as compared to KRASwt cancers. It is an important issue today the maintenance of the molecular profiles in metastases as compared to the primary tumor. This issue may be less sensitive in case of patients where surgical removal of the primary is impossible (a significant proportion of lung cancers) while can be more significant where only metastases are present in the patients. Analysis of the literature data indicates that the discrepancy rate of RAS mutation status in lymphatic metastases is low (below 10%), in case of visceral metastases increases to 14-24% range while is was reported to be the highest in bone metastasis (1). Lung cancer is reported to be a clonally heterogenous cancer and these alterations are most probably due to clonal variations during metastatic dissemination. With the advent of liquid biopsy technology monitorization of this process is now feasible using circulating DNA. A major issue clinically today is the development of resistance to target therapies. Both lung adenocarcinoma and colorectal cancer is treated by EGFR-targeted therapies where the molecular mechnisms of acquired resistance are now reported. It is interesting that in colorectal cancer patients the main cause of resistance to anti-EGFR antibody therapy is the emergence of RAS mutated clones in progressing tumors which were in minority in the primary. Although RAS mutation is equally frequent in lung adenocarcinoma, EGFR-TKI resistance is most frequently due to EGFR T790M mutation or HER2 amplification but no report on the emergence of RAS mutated clones.(4) In case of ALK mutated lung adenocarcinoma resistance to ALK inhibitors is mainly due to novel mutations in ALK. In a small proportion of cases KRAS amplification or NRAS mutation can be detected which suggest that in ALK-translocated lung cancer no minor RAS mutant clones are present in the tumors. (5) Check point inhibitor therapy is a new modality of lung cancer management targeting CTLA4, PD1 or PDL1 as targets on immune cells or cancer cells (PDL1). Although two drugs are registered in NSCLC, the significance of RAS mutations in this new modality is not known yet. In case of Nivolumab it is known that smokers are responding better to anti-PD1 therapy than nonsmokers suggesting that KRAS mutant tumors might be a better target but direct subgroup analysis is lacking. In case of Pembrolizumab even such an indirect data are missing therefore the question cannot be answered yet. The fact that EGFR mutant tumors are tend to respond less to anti-PD1 therapy suggest that beside PDL1 status molecular classification can also be a predictive factor for selecting patients for immunotherapy. (6)References 1.Tímár J: The clinical relevance of KRAS gene mutation in non-small-cell lung cancer. Curr Opin Oncol 26: 138-144, 2014 2. Cserepes M, Ostoros Gy, Lohinai Z, Rásó E, Barbai T, Tímár J, Rozsás A, Moldvay J, Kovalszky I, Fabián K, Gyulai M, Ghanim B, László V, Klikovits T, Hoda MA, Grusch M, Berger W, Klepetko W, Hegedűs B, Döme B: Subtypespecific KRAS mutations in advanced lung adenocarcinoma: A retrospective study of patients treated with platinum-based chemotherapy. Eur J Cancer 50: 1819-1828, 2014 3.Moldvay J, Barbai T, Bogos K, Piurko V, Fillinger J, Popper HH, Tímár J: EGFR autophosphorylation but not protein score correlates with histologic and molecular subtypes in lung adenocarcinoma. Diagn Mol Pathol 22: 204-209, 2013 4. Belchis DA, Tseng LH, Gmiadek T et. al. Heterogeneity of resistance mutations detectable by next-generation sequencing in TKI-treated lung adenocarcinoma. Oncotarget 2016 (in ress) 5. Dagogo-Jack I, Show AT. Crizotinib resistance: implications for therapeutic strategies. Ann Oncol 273:iii42-iii50,2016 6. El-Osta H, Shahid K, Mills GM, Peddi P. Immune checkpoint inhibitors: the new frontier in non-small-cell lung cancer. Oncotarget 9:5101-5016,2016 Keywords: KRAS, lung adenocarcinoma, Prognosis, mutational profile SC27: P53 AND KRAS MUTATIONS IN NSCLC WEDNESDAY, DECEMBER 7, 2016 - 11:00-12:30 SC27.03 TRANSFORMING KRAS INTO A CLINICALLY RELEVANT BIOMARKER Kenneth O’Byrne Cancer Services, Princess Alexandra Hospital, Brisbane/Australia TP53 mutations represent the commonest mutation seen in NSCLC. Over 50% of NSCLC tumours harbour a TP53 mutations. TP53 mutations in tobacco smokers are predominantly G-to-T transversions and deletions. In non-smokers, however, these alterations are rare. p53 is a stress response protein/transcription factor and is involved in cellular response to DNA damage induced by oxidative stress and external factors such as sunlight and radiation. Expression of p53 protein is largely controlled through degradation of the protein by the mouse double minute 2 (MDM2) E3 ligase and MDM4. Post-translational modification by various kinases/phosphatases and acetylases/deacetylases also regulates p53 activity. Amongst the various type of TP53 mutation that can occur, conformational TP53 mutations may contribute to the emergence of new functions leading to genomic instability, inhibition of apoptosis, cell migration, and drug resistance. These mutations may result in the binding and inactivation of p53-related proteins such as p63 and p73, or with other transcriptional factors resulting in modification of their activity and, hence, altered gene expression. Apart from the loss of tumoursuppressor functions, TP53 mutations may result in gain of function favouring cellular proliferation, inhibition of apoptosis, and genomic instability. As a result not all P53 mutations are the same with some more likely to affect the pathogenesis of NSCLC than others. Broadly speaking TP53 mutations may be divided into disruptive and non-disruptive cohorts. Many non-disruptive p53 mutations result in gain of function. In a recent series of 318 patients that included 125 with EGFR-mutations, non-disruptive TP53 mutations were associated with a poor prognosis. A recent study using an ELISA demonstrated p53 antibodies in 20.4% of lung cancer patients. A significant correlation between serum p53 antibodies and high levels of p53 expression in the corresponding tumour samples was seen. In NSCLC, the presence of p53 antibodies were significantly associated with poorly differentiated. High levels of p53 antibodies were also associated with high grade tumours, with squamous cell histology and with a poor prognosis in squamous cell carcinoma. Oncogenic KRAS mutations have been reported in up to 40% of adenocarcinomas and 5% of squamous cell carcinomas of the lung. These mutations are found largely in lung adenocarcinomas with solid growth patterns. While KRAS mutations are classically associated with a significant smoking history, they are also identified in a substantial proportion of never-smokers. KRAS mutations are relatively mutually exclusive from EGFR, BRAF and ALK mutations/rearrangements but have considerable overlap with both P53 and PIK3CA mutations. The commonest mutation is in codon 12 but mutations in codon 13 and 61 are also been described. Substitutions in these residues result in constitutively elevated levels of Ras-GTP due to reduced intrinsic GTP hydrolysis and resistance to GTPase-activating proteins and hence activation of the Raf and phosphatidylinositol 3-kinase. Although controversy on the prognostic and predictive value of the presence of a KRAS mutation in a tumour exists, recent studies indicate that patients with KRAS mutations are resistant re chemotherapy and radiotherapy, with a lower objective response rate and worse progression free and overall survival rates. A number of recent studies have allowed us to gain novel insights into the role of KRAS in the pathogenesis of lung cancer, in particular adenocarcinoma of the lung. Increasing evidence indicates a role for chronic inflammation in the pathogenesis of lung cancer, an observation being exploited clinically through the use of immune checkpoint inhibitors such as pembrolizumab. A proportion of KRAS mutation positive tumours have been found to have a high tumour mutation burden that may indicate sensitivity to such agents. KRAS mutations have also been associated with tumourinfiltrating lymphocytes. Recent work has demonstrated that KRAS mutation in lung epithelial cells preferentially leads to recruitment of Th17 positive immune cells that produce IL-17, a cytokine that promotes inflammation. IL-17 induces tumorigenesis by recruiting GR1C CD11bC immune cells. Recent work has demonstrated that miRs may play a role in the regulation of KRAS. For example miR-31 has recently been reported to be over-expressed in lung adenocarcinoma and to correlate with worse survival. Using a transgenic mouse model that allows for lung-specific expression, induction of miR-31 results in lung hyperplasia, followed by adenoma formation and later the development of adenocarcinoma. Induced expression of miR-31 acts with mutant KRAS to accelerate lung tumourigenesis by down-regulating a number of negative regulators of RAS/MAPK signaling. The expression of Copyright © 2016 by the International Association for the Study of Lung Cancer S71
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