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P1.02-068 The Impact of TP53 Overexpression on EMT and the Prognosis in Lung Adenocarcinoma Harboring Driver Mutations
January 2017
P1.02-067 Repeated Biopsy for Immunohistochemical and Mutational Analysis of Non-Small Cell Lung Cancer: Feasibility and Safety Topic: Other Mutations in Thoracic Malignancies Mariona Riudavets, Georgia Anguera, Alfons Torrego, Virginia Pajares, Ana Gimenez, Laura López Vilaró, Elisabeth Martínez Tellez, Joan Carles Trujillo, Núria Farré, Enrique Lerma, Josep Belda, Valle Camacho, Alejandro Fernandez, Ana Muñoz, Margarita Majem Hospital de La Santa Creu I Sant Pau, Barcelona/Spain Background: Repeated biopsy in lung cancer may be necessary at diagnosis or after cancer progression on initial therapy to properly target treatments. The objective of this study is to evaluate the feasibility and safety of repeated biopsy for immunohistochemical and/or mutational analysis in patients with non-small cell lung cancer. Methods: We have retrospectively analyzed repeated biopsies performed in patients with advanced non-small cell lung cancer during the last 4 years. The technical success rates for the repeated biopsy and the adequacy rates of specimens were evaluated. Biopsy-related complications were recorded. Clinical details were collected, specially focusing in EGFR mutation data. Results: 110 repeated biopsies were performed in 74 patients (34 women, 40 men, mean age 63 [36-84]), the histology was: 74% adenocarcinoma, 12% squamous cell carcinoma, 11% NOS, 3% other. The mean number of repeated biopsies per patient was 1 (1-4). The main reasons for repeated biopsy were immunohistochemical +/- mutational analysis (34/110, 31%), mutational analysis (16/110, 14.6%) and EGFR at progression (28/ 110, 24.4%). The technical success rate for biopsy was 98/110 (89.1%), and post-procedural complications occurred in 3/110 cases: 2 pneumothorax and 1 wound infection. Biopsy specimens came mostly from primary tumor (56/110, 51%), lymph nodes (26/110, 23.6%) and pleura (9/110, 8.2%), the most used technique was bronchoscopy +/- EBUS (45/110, 40%), followed by percutaneous transthoracic lung biopsy (28/110, 26%) and thoracoscopy and/or mediastinoscopy: (19/110, 17%). Results from repeated biopsy were used to select the next line of treatment in 86/110 procedures (78%), and 40/86 of them (46.5%) allowed to include the patient in a clinical trial. 28 repeated biopsies were performed in 21 EGFR mutant lung cancer patients with acquired resistance at disease progression, T790M was
Abstracts
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detected in 13/28 (46%) of samples, corresponding to 10/21 (47.6%) EGFR mutant lung cancer patients. Conclusion: Our data demonstrate that repeated biopsy in non-small cell lung cancer is safe and clinically feasible. Findings from repeated biopsy were used to direct subsequent treatment in 78% of patients. Keywords: repeated biopsy, Acquired resistance in EGFR mutant lung cancer
P1.02-068 The Impact of TP53 Overexpression on EMT and the Prognosis in Lung Adenocarcinoma Harboring Driver Mutations Topic: Other Mutations in Thoracic Malignancies Shigeto Nishikawa, Toshi Menju, Terumasa Soawa, Koji Takahashi, Ryo Miyata, Hiroyuki Cho, Shinya Neri, Takao Nakanishi, Masatsugu Hamaji, Hideki Motoyama, Kyoko Hijiya, Akihiro Aoyama, Toshihiko Sato, Fengshi Chen, Makoto Sonobe, Hiroshi Date Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto/Japan Background: Epithelial-mesenchymal transition (EMT) and p53 mutations are known to be pivotal for driving metastasis and recurrence in lung cancer, but the nature of these factors is not completely understood. Some papers have previously described the relationship between EMT and TP53 in other carcinomas, however there have been few reports about the impact of TP53 on EMT and prognosis in lung adenocarcinoma harboring driver mutations such as EGFR or K-ras. Methods: The aim of the present study is to clarify the impact of TP53 overexpression in lung adenocarcinoma with driver mutations. A total of 282 lung adenocarcinoma specimens were collected from patients who had undergone surgery in our institute from January 2001 to December 2007. Both EMT markers (E-cadherin, vimentin) and TP53 were analyzed through immunostaining of tumor specimens. The association between EMT and TP53 as well as the patients’ clinical information was integrated and statistically analyzed. EGFR and K-ras mutation were determined by single stranded conformational polymorphism and direct sequencing. Correlations were compared using Pearson’s chi-square test and overall survival were compared using the logrank test. Results: Both mesenchymal type (E-cadherin negative, vimentin positive) and TP53 overexpression were significantly correlated with poor prognosis (P¼0.0001,
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P¼0.0019). A positive correlation was found between EMT activation level and TP53 overexpression (P¼0.017). TP53 overexpression was significantly correlated with poor prognosis in the subgroup of lung adenocarcinoma with driver mutation (EGFR or K-ras) (P¼0.011, P¼0.026), whereas there was no significant correlation between TP53 overexpression and the prognosis in adenocarcinoma without driver mutations (P¼0.359). Conclusion: TP53 overexpression is supposed to be the key factor that affects EMT and the prognosis, and also might be an additional therapeutic target for lung adenocarcinoma with driver mutations. Keywords: Driver mutation, TP53, epithelial-mesenchymal transition, lung adenocarcinoma
P1.02-069 Genomic Alterations and Survival in Young Patients under 40 Years with Completely Resected Non-Small Cell Lung Cancer Topic: Other Mutations in Thoracic Malignancies Xinmin Yu,1 Zhengbo Song,2 Yiping Zhang1 1Zhejiang Cancer Hospital, Hangzhou/China, 2Medical Oncology, Zhejiang Cancer Hospital, Hangzhou/China Background: Young patients diagnosed as non-small cell lung cancer (NSCLC) is rare. Little is known for its genomic alterations and survival. This study retrospectively evaluated the genomic alterations, treatment and prognosis with NSCLC in our institution between January 2009 and July 2014. Methods: All patients were examined for EGFR, KRAS, NRAS, PIK3CA, BRAF, HER2 mutations and ALK, ROS1, RET fusion genes based on reverse transcription PCR. The Kaplan-Meier method was used to estimate survival and comparison using the log-rank test. Results: Totally, 54 were with age under 40 years old among 640 patients. Among the 640 patients, three hundred and fifty eight patients were with identified genomic alterations with frequency of 55.9 %. The frequencies of genomic alterations in younger and older were 68.5% and 54.8%, respectively (P¼0.05). The frequencies difference between younger and older existed in fusions genes (22.2% vs.4.1%, P<0.001), but not mutations genes (46.3% vs.45.6%, P¼0.92). There was a trend of shorter recurrence free survival in younger than older (35.2 vs.43.8 months, P¼0.050), while no survival difference was found between younger and older (50.2 vs 51.4 months, P¼0.112).
Journal of Thoracic Oncology
Vol. 12 No. 1S
Conclusion: We concluded that younger age of NSCLC is associated with a trend of increased of harboring targeted genes and mainly with difference of fusion genes. An inferior overall survival existed in younger than older. Keywords: non-small cell lung cancer, age, survival, genomic alterations
P1.02-070 Gene Spectrum and Survival Analyses of Pathologic Subtypes in Resected Lung Squamous Cell Carcinoma Topic: Other Mutations in Thoracic Malignancies Zhengbo Song,1 Yiping Zhang,2 Xinmin Yu2 1Medical Oncology, Zhejiang Cancer Hospital, Hangzhou/China, 2 Zhejiang Cancer Hospital, Hangzhou/China Background: Based upon the 2015 Lung Cancer Pathologic Classification, squamous cell carcinoma of lung (SQCC) has been classified as three types of keratinized, non-keratinized and basaloid squamous cell carcinoma (BSCC). The spectrum of common driver genes and clinical prognosis were examined for different subtypes in SQCC in present study. Methods: From 2009 to 2013, a total of 201 patients with completely resected stages I-IIIA SQCC were recruited. Reverse transcription-polymerase chain reaction (RT-PCR) was utilized for detecting the mutations of EGFR, KRAS, NRAS, PIK3CA, BRAF, DDR2, HER2 and the fusion genes of ALK, ROS1 and RET. Survival curves were plotted with Kaplan-Meier method. Cox’s proportional hazard model was used for multivariate analysis. Results: The pathological types were BSCC (n¼16), nonkeratinizing (n¼83) and keratinizing (n¼102). The overall frequency of gene abnormality was 18.4%. The most common driver genes in a decreasing frequency were PIK3CA mutation (n¼14), EGFR mutation (n¼8), DDR2 mutation (n¼8), KRAS mutation (n¼3), HER2 mutation (n¼2), ALK rearrangement (n¼1) and ROS1 rearrangement (n¼1). No mutations of NRAS, BRAF or RET were observed . The frequency of gene abnormality was greater in keratinized (19.6%), followed with nonkeratinized (19.2%) and BSCC types (6.3%). Targeted therapy was offered for 35 patients, including 32 on EGFR-TKIs (EGFR mutation, n¼5; EGFR wild-type, n¼27), ALK-positive on crizotinib (n¼1) and HER2 mutation on afatinib (n¼1). The median progressionfree survival (PFS) of EGFR-TKIs were 6.0 and 1.87 months in EGFR mutant and wild types respectively (P¼0.004). And the PFS for those two with crizotinib and
P1.02-067 Repeated Biopsy for Immunohistochemical and Mutational Analysis of Non-Small Cell Lung Cancer: Feasibility and Safety Topic: Other Mutations in Thoracic Malignancies Mariona Riudavets, Georgia Anguera, Alfons Torrego, Virginia Pajares, Ana Gimenez, Laura López Vilaró, Elisabeth Martínez Tellez, Joan Carles Trujillo, Núria Farré, Enrique Lerma, Josep Belda, Valle Camacho, Alejandro Fernandez, Ana Muñoz, Margarita Majem Hospital de La Santa Creu I Sant Pau, Barcelona/Spain Background: Repeated biopsy in lung cancer may be necessary at diagnosis or after cancer progression on initial therapy to properly target treatments. The objective of this study is to evaluate the feasibility and safety of repeated biopsy for immunohistochemical and/or mutational analysis in patients with non-small cell lung cancer. Methods: We have retrospectively analyzed repeated biopsies performed in patients with advanced non-small cell lung cancer during the last 4 years. The technical success rates for the repeated biopsy and the adequacy rates of specimens were evaluated. Biopsy-related complications were recorded. Clinical details were collected, specially focusing in EGFR mutation data. Results: 110 repeated biopsies were performed in 74 patients (34 women, 40 men, mean age 63 [36-84]), the histology was: 74% adenocarcinoma, 12% squamous cell carcinoma, 11% NOS, 3% other. The mean number of repeated biopsies per patient was 1 (1-4). The main reasons for repeated biopsy were immunohistochemical +/- mutational analysis (34/110, 31%), mutational analysis (16/110, 14.6%) and EGFR at progression (28/ 110, 24.4%). The technical success rate for biopsy was 98/110 (89.1%), and post-procedural complications occurred in 3/110 cases: 2 pneumothorax and 1 wound infection. Biopsy specimens came mostly from primary tumor (56/110, 51%), lymph nodes (26/110, 23.6%) and pleura (9/110, 8.2%), the most used technique was bronchoscopy +/- EBUS (45/110, 40%), followed by percutaneous transthoracic lung biopsy (28/110, 26%) and thoracoscopy and/or mediastinoscopy: (19/110, 17%). Results from repeated biopsy were used to select the next line of treatment in 86/110 procedures (78%), and 40/86 of them (46.5%) allowed to include the patient in a clinical trial. 28 repeated biopsies were performed in 21 EGFR mutant lung cancer patients with acquired resistance at disease progression, T790M was
Abstracts
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detected in 13/28 (46%) of samples, corresponding to 10/21 (47.6%) EGFR mutant lung cancer patients. Conclusion: Our data demonstrate that repeated biopsy in non-small cell lung cancer is safe and clinically feasible. Findings from repeated biopsy were used to direct subsequent treatment in 78% of patients. Keywords: repeated biopsy, Acquired resistance in EGFR mutant lung cancer
P1.02-068 The Impact of TP53 Overexpression on EMT and the Prognosis in Lung Adenocarcinoma Harboring Driver Mutations Topic: Other Mutations in Thoracic Malignancies Shigeto Nishikawa, Toshi Menju, Terumasa Soawa, Koji Takahashi, Ryo Miyata, Hiroyuki Cho, Shinya Neri, Takao Nakanishi, Masatsugu Hamaji, Hideki Motoyama, Kyoko Hijiya, Akihiro Aoyama, Toshihiko Sato, Fengshi Chen, Makoto Sonobe, Hiroshi Date Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto/Japan Background: Epithelial-mesenchymal transition (EMT) and p53 mutations are known to be pivotal for driving metastasis and recurrence in lung cancer, but the nature of these factors is not completely understood. Some papers have previously described the relationship between EMT and TP53 in other carcinomas, however there have been few reports about the impact of TP53 on EMT and prognosis in lung adenocarcinoma harboring driver mutations such as EGFR or K-ras. Methods: The aim of the present study is to clarify the impact of TP53 overexpression in lung adenocarcinoma with driver mutations. A total of 282 lung adenocarcinoma specimens were collected from patients who had undergone surgery in our institute from January 2001 to December 2007. Both EMT markers (E-cadherin, vimentin) and TP53 were analyzed through immunostaining of tumor specimens. The association between EMT and TP53 as well as the patients’ clinical information was integrated and statistically analyzed. EGFR and K-ras mutation were determined by single stranded conformational polymorphism and direct sequencing. Correlations were compared using Pearson’s chi-square test and overall survival were compared using the logrank test. Results: Both mesenchymal type (E-cadherin negative, vimentin positive) and TP53 overexpression were significantly correlated with poor prognosis (P¼0.0001,
S530
P¼0.0019). A positive correlation was found between EMT activation level and TP53 overexpression (P¼0.017). TP53 overexpression was significantly correlated with poor prognosis in the subgroup of lung adenocarcinoma with driver mutation (EGFR or K-ras) (P¼0.011, P¼0.026), whereas there was no significant correlation between TP53 overexpression and the prognosis in adenocarcinoma without driver mutations (P¼0.359). Conclusion: TP53 overexpression is supposed to be the key factor that affects EMT and the prognosis, and also might be an additional therapeutic target for lung adenocarcinoma with driver mutations. Keywords: Driver mutation, TP53, epithelial-mesenchymal transition, lung adenocarcinoma
P1.02-069 Genomic Alterations and Survival in Young Patients under 40 Years with Completely Resected Non-Small Cell Lung Cancer Topic: Other Mutations in Thoracic Malignancies Xinmin Yu,1 Zhengbo Song,2 Yiping Zhang1 1Zhejiang Cancer Hospital, Hangzhou/China, 2Medical Oncology, Zhejiang Cancer Hospital, Hangzhou/China Background: Young patients diagnosed as non-small cell lung cancer (NSCLC) is rare. Little is known for its genomic alterations and survival. This study retrospectively evaluated the genomic alterations, treatment and prognosis with NSCLC in our institution between January 2009 and July 2014. Methods: All patients were examined for EGFR, KRAS, NRAS, PIK3CA, BRAF, HER2 mutations and ALK, ROS1, RET fusion genes based on reverse transcription PCR. The Kaplan-Meier method was used to estimate survival and comparison using the log-rank test. Results: Totally, 54 were with age under 40 years old among 640 patients. Among the 640 patients, three hundred and fifty eight patients were with identified genomic alterations with frequency of 55.9 %. The frequencies of genomic alterations in younger and older were 68.5% and 54.8%, respectively (P¼0.05). The frequencies difference between younger and older existed in fusions genes (22.2% vs.4.1%, P<0.001), but not mutations genes (46.3% vs.45.6%, P¼0.92). There was a trend of shorter recurrence free survival in younger than older (35.2 vs.43.8 months, P¼0.050), while no survival difference was found between younger and older (50.2 vs 51.4 months, P¼0.112).
Journal of Thoracic Oncology
Vol. 12 No. 1S
Conclusion: We concluded that younger age of NSCLC is associated with a trend of increased of harboring targeted genes and mainly with difference of fusion genes. An inferior overall survival existed in younger than older. Keywords: non-small cell lung cancer, age, survival, genomic alterations
P1.02-070 Gene Spectrum and Survival Analyses of Pathologic Subtypes in Resected Lung Squamous Cell Carcinoma Topic: Other Mutations in Thoracic Malignancies Zhengbo Song,1 Yiping Zhang,2 Xinmin Yu2 1Medical Oncology, Zhejiang Cancer Hospital, Hangzhou/China, 2 Zhejiang Cancer Hospital, Hangzhou/China Background: Based upon the 2015 Lung Cancer Pathologic Classification, squamous cell carcinoma of lung (SQCC) has been classified as three types of keratinized, non-keratinized and basaloid squamous cell carcinoma (BSCC). The spectrum of common driver genes and clinical prognosis were examined for different subtypes in SQCC in present study. Methods: From 2009 to 2013, a total of 201 patients with completely resected stages I-IIIA SQCC were recruited. Reverse transcription-polymerase chain reaction (RT-PCR) was utilized for detecting the mutations of EGFR, KRAS, NRAS, PIK3CA, BRAF, DDR2, HER2 and the fusion genes of ALK, ROS1 and RET. Survival curves were plotted with Kaplan-Meier method. Cox’s proportional hazard model was used for multivariate analysis. Results: The pathological types were BSCC (n¼16), nonkeratinizing (n¼83) and keratinizing (n¼102). The overall frequency of gene abnormality was 18.4%. The most common driver genes in a decreasing frequency were PIK3CA mutation (n¼14), EGFR mutation (n¼8), DDR2 mutation (n¼8), KRAS mutation (n¼3), HER2 mutation (n¼2), ALK rearrangement (n¼1) and ROS1 rearrangement (n¼1). No mutations of NRAS, BRAF or RET were observed . The frequency of gene abnormality was greater in keratinized (19.6%), followed with nonkeratinized (19.2%) and BSCC types (6.3%). Targeted therapy was offered for 35 patients, including 32 on EGFR-TKIs (EGFR mutation, n¼5; EGFR wild-type, n¼27), ALK-positive on crizotinib (n¼1) and HER2 mutation on afatinib (n¼1). The median progressionfree survival (PFS) of EGFR-TKIs were 6.0 and 1.87 months in EGFR mutant and wild types respectively (P¼0.004). And the PFS for those two with crizotinib and