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H. Kunitoh
Moderator of
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SC27 - P53 and KRAS Mutations in NSCLC (ID 351)
- Event: WCLC 2016
- Type: Science Session
- Track: Biology/Pathology
- Presentations: 4
- Moderators:F. De Marinis, H. Kunitoh
- Coordinates: 12/07/2016, 11:00 - 12:30, Strauss 3
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SC27.01 - The Role of p53 in Lung Cancer (ID 6713)
11:00 - 11:20 | Author(s): P. Hainaut
- Abstract
- Presentation
Abstract not provided
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SC27.02 - Biology of KRAS Mutations (ID 6714)
11:20 - 11:40 | Author(s): J. Tímár
- Abstract
- Presentation
Abstract:
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: Subtype-specific 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
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SC27.03 - Transforming KRAS into a Clinically Relevant Biomarker (ID 6715)
11:40 - 12:00 | Author(s): K. O’byrne
- Abstract
- Presentation
Abstract:
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 tumour-suppressor 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 tumour-infiltrating 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 mesothelin, a cell surface glycoprotein that may have a role in cell adhesion and metastases, is seen in several epithelial cancers and has recently been assessed in adenocarcinoma of the lung using immunohistochemistry. The intensity of staining and the percentage of cells expressing mesothelin in the report was blinded for molecular data and outcome. Mutations of EGFR, KRAS, BRAF, AKT1, PIK3CA and HER2 were assessed by pyrosequencing; HER2 amplification and ALK translocation were assessed by fluorescence in situ hybridization. Of the advanced lung adenocarcinomas, 53% expressed mesothelin to some degree. High mesothelin expression, defined as mesothelin positivity in more than 25% of cells, was found in 24% of patients. High mesothelin expression was associated with a worse survival (median 18.2 months vs. 32.9 months; P = 0.014) and with wild-type EGFR, and was strongly associated with mutant KRAS. The increased understanding of the tumour promoting activities of KRAS mutations, and the association with biomarkers, provides novel insights that will facilitate targeting of these tumours with novel agents in the future.
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SC27.04 - KRAS-Directed Drug Therapy in Advanced NSCLC (ID 6716)
12:00 - 12:20 | Author(s): P. Jänne
- Abstract
- Presentation
Abstract not provided
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Author of
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MA11 - Novel Approaches in SCLC and Neuroendocrine Tumors (ID 391)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:P. Lara, A. Mohn-Staudner
- Coordinates: 12/06/2016, 14:20 - 15:50, Strauss 3
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MA11.12 - Discussant for MA11.09, MA11.10, MA11.11 (ID 7084)
15:38 - 15:50 | Author(s): H. Kunitoh
- Abstract
- Presentation
Abstract not provided
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OA10 - EGFR Mutations (ID 382)
- Event: WCLC 2016
- Type: Oral Session
- Track: Biology/Pathology
- Presentations: 1
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OA10.02 - Association of Variations in HLA-Class II and Other Loci with Susceptibility to EGFR-Mutated Lung Adenocarcinoma (ID 4192)
11:10 - 11:20 | Author(s): H. Kunitoh
- Abstract
- Presentation
Background:
Lung adenocarcinoma (LADC) driven by somatic EGFR mutations is more prevalent in East Asians (30-50%) than in European/Americans (10-20%). Understanding the genetic factors underlying such LADC is required to elucidate disease etiology and to identify effective methods of prevention.
Methods:
We investigate genetic factors underlying the risk of this disease by conducting a genome-wide association study, followed by two validation studies, in 3,173 Japanese patients with EGFR mutation-positive lung adenocarcinoma and 15,158 controls.
Results:
Four loci, 5p15.33 (TERT), 6p21.3 (BTNL2, HLA-class II), 3q28 (TP63) and 17q24.2 (BPTF), previously shown to be strongly associated with overall lung adenocarcinoma risk in East Asians, were re-discovered as loci associated with a higher susceptibility to EGFR mutation-positive lung adenocarcinoma. In addition, two additional loci, HLA-class II at 6p21.32 and 6p21.1 (FOXP4) were newly identified as loci associated with EGFR mutation-positive lung adenocarcinoma (Shiraishi et al., Nature Communications, 2016, in press).
Conclusion:
This study indicates that multiple genetic factors, including an immunologic one, underlie the risk of lung adenocarcinomas with EGFR mutations.
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P1.05 - Poster Session with Presenters Present (ID 457)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Early Stage NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.05-051 - Safety and Compliance Data of the Phase III Study of Adjuvant Chemotherapy in Completely Resected P-Stage I Non Small Cell Lung Cancer: JCOG0707 (ID 3877)
14:30 - 14:30 | Author(s): H. Kunitoh
- Abstract
Background:
Post-operative UFT (tegafur/uracil) has been shown to prolong survival of Japanese patients (pts) with completely resected, pathological (p-) stage I (T1> 2 cm) non small cell lung cancer (NSCLC). This trial aimed at estimating the efficacy of S-1 (tegafur/gimeracil/oteracil) compared to UFT as adjuvant therapy in this population.
Methods:
Eligible pts had undergone complete resection with lymph node dissection for p-stage I (T1-2N0M0, T1> 2 cm, by 5[th] Edition UICC TNM) NSCLC, within 56 days of enrollment. Pts were randomized to receive either oral UFT 250mg/M2/d for 2 years (Arm A), or oral S-1 80mg/M2/d for 2 weeks followed by 1 week of rest, for 1 year (Arm B). The initial primary endpoint was overall survival (OS). Based upon the results of monitoring in Jun. 2013, which showed the combined OS of the 2 arms better than expected (4-year OS of 91.6% vs. presumed 5-year OS of 70-76.5%), the study was judged to be underpowered. The study protocol was amended so that the primary endpoint was relapse-free survival (RFS). With a calculated sample size of 960, this study would detect the superiority of Arm B over Arm A with power 79% and a one-sided type I error of 0.05, assuming the 5-year RFS of 75% in Arm A and the hazard ratio of 0.75.
Results:
From Nov. 2008 to Dec. 2013, 963 pts were enrolled: median age 66 (range: 33 to 80), male 58%, adenocarcinoma 80%, p-T1/T2 46%/54%. Only 2 pts received pneumonectomy. All pts had completed protocol therapy. >Grade 3 toxicities (hematologic/nonhematologic) were observed in 15.9 (1.5/14.7) % in Arm A, and in 14.6 (3.6/11.9) % in Arm B, respectively. In Arm A, 59.5% of the pts completed protocol therapy, and 70.7% received UFT for >1 year, which was comparable to prior studies. In Arm B, 54.7% completed protocol therapy, and 69.9% received S-1 for > 6 months. There were 4 cases of on-protocol deaths, probably of cardio-vascular origin: 1 in Arm A and 3 in Arm B. Based on the 2[nd] interim analysis in Sep. 2015, the data and safety monitoring committee recommended the follow-up of pts without unmasking of treatment arms. Estimated combined 2-year OS and RFS were 97.3% and 89.6%, respectively.
Conclusion:
Both post-operative adjuvant therapies were feasible, with similar compliances. Main results will be available in 2019.
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P1.05-063 - Multicenter Observational Study of Patients with Resected Early-Staged NSCLC, Who Were Excluded from an Adjuvant Chemotherapy Trial (ID 4713)
14:30 - 14:30 | Author(s): H. Kunitoh
- Abstract
Background:
From Nov. 2008 to Dec. 2013, the Japan Clinical Oncology Group (JCOG) conducted a randomized phase III trial (JCOG0707), which compared the survival benefit of UFT and S-1 for completely resected pathological (p-) stage I (T1>2 cm and T2 in the 6th TNM classification) NSCLC and a total of 963 patients were enrolled. Recently, there is a growing concern that those who participated in clinical trials are highly selected and do not represent the “real-world” population. Hereby, we conducted a multicenter observational study of patients excluded from JCOG0707 trial during the study period.
Methods:
We retrospectively collected and analyzed the patients’ backgrounds, tumor profiles, post-surgical treatment of the patients who underwent R0 resection of p-stage I (T1>2cm and T2 in TNM 6th) NSCLC by lobectomy or larger lung resection but were excluded from JCOG0707 from Japanese multi-centers.
Results:
Of the 48 institutions which took part in JCOG0707, 34 (enrolling 917 or 95.2% of all JCOG0707 patients) participated in this multicenter study, and 5006 patients were enrolled. Among them, 2617 (52.3%) patients fulfilled the eligibility criteria, but were not enrolled to JCOG0707 mainly due to patients’ decline (69.2%), or physicians’ discretion (20.5%). The accrual rate to JCOG0707 was various by institutions (4.1 to 46.1%), but was 25.9% (917 / [917+2617]) as a whole. Total number of p-stage I and eligible patients at each institution did not correlate the accrual rate (R2=0.003 and 0.046). In the remaining 2389 (47.7%) patients, main ineligible reasons included the existence of active multiple cancer (29.1%), physicians’ decision based on the patients’ comorbidities (19.4%), delayed recovery from surgery (14.1%), and high age ≥81 years (10.7%). Majority of patients received no adjuvant chemotherapy (n = 3338, 66.7%). This proportion differed according to p-T factor (T1: 75.3% vs. T2 : 57.8%, p<0.001) and the JCOG0707 eligibility (ineligible population: 77.6% vs. eligible population: 56.7%, p<0.001). Standard UFT and experimental S-1 were given in 1550 (31.0%) and 21 (0.4%) patients, respectively. Among those who received adjuvant UFT, 971 (62.6%) took UFT for one year or longer.
Conclusion:
Only selected population of candidate patients, even if they met the eligibility criteria, were enrolled to JCOG0707 adjuvant chemotherapy trial for early-stage NSCLC. The “excluded” patients were mainly treated with observation alone or standard UFT treatment. Further analysis of this “excluded” population, including long-term survival, should be necessary for external validation of the randomized trial results.
