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J. Tímár
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MA17 - Genetic Drivers (ID 409)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Biology/Pathology
- Presentations: 1
- Moderators:M. Satouchi, G.R. Simon
- Coordinates: 12/07/2016, 14:20 - 15:50, Lehar 1-2
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MA17.04 - Discussant for MA17.01, MA17.02, MA17.03 (ID 6980)
14:38 - 14:50 | Author(s): J. Tímár
- Abstract
- Presentation
Abstract not provided
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P1.06 - Poster Session with Presenters Present (ID 458)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.06-012 - Central and Peripheral Lung Adenocarcinomas Exhibit Different Timing and Predilection for Distant Metastasis (ID 5649)
14:30 - 14:30 | Author(s): J. Tímár
- Abstract
Background:
Although distant metastases are major factors for unfavorable prognosis in lung adenocarcinoma (ADC), metastatic patterns have not been widely analyzed in this malignancy.
Methods:
Clinicopathological data of 1126 ADC patients (541 men, 585 women, mean age: 62.1 ± 9.4 years, 32-88 years) were studied retrospectively, focusing on the localization of primary tumor and distant metastases. Metastases diagnosed at the time of primary tumor diagnosis were defined as early metastases. For statistical analyses, Fisher's exact test and a chi-squared independence test were performed.
Results:
At time of diagnosis, 621 patients had stage IV disease. 435 of them had a solitary organ metastasis, mainly in the contralateral lung (n=187), in the brain (n=66), or in the bone (n=59). During the follow up period another 242 patients developed distant metastasis. 39% of all patients had central (i.e. endobronchially visible) tumor. In cases with early-, late-, and non-metastatic disease, the proportions of central tumors were 43%, 35% and 31%, respectively. Central primary tumors were significantly more likely to give rise to early metastases than peripheral ones (p=0.021). When comparing central and peripheral lung cancers according to their metastatic sites, in central tumors lung metastases appeared significantly earlier (p=0.017), while in peripheral ones bone metastases appeared significantly later (p=0.015). There were significant differences in the metastatic organ distributions of central vs. peripheral primary tumors for early (p=0.025) and late (p=0.009) metastases. There was no significant difference in the metastatic organ distributions of right vs. left lung primaries both for early and late metastases. In right lung tumors brain metastases appeared later (p=0.047). No significant difference was observed in the metastatic organ distributions of primary tumors of the upper vs. lower lobes for early (p=0.051), and late (p=0.528) metastases. Early appearance was characteristic for lung, pleural, and adrenal involvement (p<0.001 in all comparisons), while late development was typical for brain metastasis (p=0.002). Bone, liver, subcutaneous, and pericardial metastases showed no such tendencies.
Conclusion:
There are significant differences in metastatic organ distributions of central vs. peripheral lung cancers both for early and late metastases. Central primary tumors are more likely to give rise to early metastases than peripheral ones. Results of molecular subgroup analyses will be presented during the Conference.
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P2.01 - Poster Session with Presenters Present (ID 461)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.01-088 - Prenylation Inhibitors in Lung Adenocarcinoma: Comparison of Zoledronic Acid and a Novel Lipophilic Bisphosphonate (ID 5640)
14:30 - 14:30 | Author(s): J. Tímár
- Abstract
Background:
The prenylation inhibitor zoledronic acid is a standard-of-care therapeutic option in bone metastasis. Recent studies suggest that prenylation inhibition using novel lipophilic bisphosphonates might be active against various malignancies outside the bone metastatic setting. Since prenylation is an important posttranslational modification in RAS protein function we explored the sensitivity of a panel of lung adenocarcinoma cells representing various oncogenic driver mutations.
Methods:
8 human lung adenocarcinoma cell lines were investigated in vitro to assess the short-term viability and long-term clonogenic potential following zoledronic acid and BPH-1222 treatments. The eight lung cancer cell lines represented wild type (HCC78, CALU3), EGFR- (H1650, H1975) KRAS- (A549, H358), BRAF- (CRL5885) and BRAF + NRAS double mutant (CRL5922) molecular subtypes. Effect on short and long term proliferation were measured with a SRB based photometric assay.
Results:
Neither short-term nor long-term treatment showed significant differences between the proliferation inhibitory effect of the hydrophilic zoledronic acid and novel lipophilic bisphosphonate BPH-1222. Interestingly, we found that the two KRAS mutant lung adenocarcinoma cell lines were more sensitive in the long-term bisphosphonate treatment assays than non-KRAS mutant cell lines. BRAF or EGFR mutations did not show a differential response against these inhibitors.
Conclusion:
In vitro proliferation inhibitory efficacies of hydrophilic and lipophilic bisphosphonates were not different in lung adenocarcinoma cells. Nevertheless, due to the different bone accumulation properties of zoledronic acid and lipophilic bisphosphonates further in vivo preclinical studies are warranted to evaluate the inhibitory effect in a more physiological setting.
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P2.03b - Poster Session with Presenters Present (ID 465)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03b-005 - Correlation between Primary Tumor Location and Brain Metastasis Development or Peritumoral Brain Edema in Lung Cancer (ID 5913)
14:30 - 14:30 | Author(s): J. Tímár
- Abstract
Background:
In lung cancer overall survival and quality of life are affected adversely by brain metastases, while peritumoral brain edema is responsible for life-threatening complications.
Methods:
The clinicopathological and cerebral radiological data of 575 consecutive lung cancer patients with brain metastases were analyzed retrospectively.
Results:
In squamous cell carcinoma (SCC) and adenocarcinoma (ADC) peritumoral brain edema was more pronounced as compared with small cell lung cancer (SCLC) (p<0.001, p˂0.001, respectively). There was positive correlation between size of metastasis and thickness of peritumoral brain edema (p<0.001). It was thicker in supratentorial tumors (p=0.019), in younger patients (≤50 years) (p=0.042), and in females (p=0.016). The interval time to brain metastasis was shorter in case of central as compared with peripheral lung cancer (5.3 vs. 9.0 months, p=0.035). Early brain metastasis was characteristic for ADCs. A total of 135 patients had brain only metastases (N0 disease) characterized by peripheral lung cancer predominance (p<0.001), and longer time-to-metastasis interval (9.2 vs. 4.4 months, p<0.001). Overall survival was longer in the brain only subgroup than in patients with N1-3 diseases (p˂0.001).
Conclusion:
According to our results, clinicopathological characteristics of lung cancer are related to the development and radiographic features of brain metastases, and these findings might be helpful in selecting patients who could benefit from prophylactic cranial irradiation.
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SC27 - P53 and KRAS Mutations in NSCLC (ID 351)
- Event: WCLC 2016
- Type: Science Session
- Track: Biology/Pathology
- Presentations: 1
- Moderators:F. De Marinis, H. Kunitoh
- Coordinates: 12/07/2016, 11:00 - 12:30, Strauss 3
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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
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
