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Clemens Aigner
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MA20 - Thymic Tumors: From Molecular to Clinical Results and New Challenges in Other Rare Thoracic Tumors (ID 149)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Thymoma/Other Thoracic Malignancies
- Presentations: 1
- Now Available
- Moderators:Kazuya Kondo, Edith Michelle Marom
- Coordinates: 9/10/2019, 11:30 - 13:00, San Francisco (2009)
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MA20.07 - Thymomectomy and Total Thymectomy or Simple Thymomectomy for Early Stage Thymoma Without Myasthenia Gravis: An ESTS Thymic Working Group Study (Now Available) (ID 1683)
11:30 - 13:00 | Author(s): Clemens Aigner
- Abstract
- Presentation
Background
Resection of thymic tumors has traditionally included removal of the tumor and the thymus gland (thymothymomectomy). Nevertheless, in recent years, some authors questioned the need to remove the thymus gland in non-MG thymomas, suggesting that resection of the tumor (simple-thymomectomy) is enough from an oncological point of view in Stage I (TNM stage classification) thymoma patients. The aim of our study was to compare short- and long-term outcome of thymothymomectomy vs. simple-thymomectomy using European Society of Thoracic Surgeons (ESTS) Thymic Database.
Method
We investigated 1131 patients with thymic epithelial tumors included in the ESTS-Thymic Database. Three-hundred twenty-four clinical stage I (cT1N0M0, according to the 8th edition of the UICC/AJCC TNM stage classification) without Myasthenia Gravis (non-MG) thymoma cases were evaluated from 23 contributing centers (2000-2017), of which 300 (93%) thymothymomectomy and 24 (7%) simple-thymomectomy. Surgical upstaging was evaluated. In pathological stage I, we compared the completeness of resection, the rate of complications, the 30-day mortality, the overall survival and the disease-free survival (DFS).
Result
Overall, we observed an upstaging to stage III in 10 (3%) patients. We did not observe any significant difference between the two techniques in terms of the completeness of resection, the rate of complications and the 30-day mortality. The 5-year overall survival rate was 94% in the thymothymomectomy group and 56% in the simple-thymomectomy group (Figure 1 - P= 0.0004). The 5-year DFS was 95% in the thymothymomectomy group and 82% in the simple-thymomectomy group (Figure 1 -P= 0.013).
Conclusion
Patients affected by stage I TNM non-MG thymoma submitted to thymothymomectomy presented a significantly better DFS and overall survival than those submitted to simple-thymomectomy. Thymothymomectomy should be considered the procedure of choice in Stage I TNM non-MG thymomas, also considering the not negligible rate of pathological upstaging.
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P1.06 - Mesothelioma (ID 169)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Mesothelioma
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.06-12 - Defects in Homologous Recombination Repair Indicates Susceptibility for Olaparib Treatment in Malignant Pleural Mesothelioma (Now Available) (ID 350)
09:45 - 18:00 | Author(s): Clemens Aigner
- Abstract
Background
Malignant pleural mesothelioma (MPM) is a tumour with dismal prognosis. Chemotherapeutic treatment with pemetrexed combined with cisplatin shows unsatisfying response-rates of 40%. The reasons for the rather poor efficacy remain largely unknown. However, it is conceivable that DNA repair mechanisms lead to an impaired therapy response. We hypothesize a major role of homologous recombination (HR) for genome stability and survival of this tumour. Therefore, we analysed expression levels of genes compiled under the term “BRCAness”. An inhibition of this pathway with olaparib might abrogate this effect and induce apoptosis.
Method
We evaluated the response of three MPM cell lines and lung fibroblasts, serving as a control to treatment, with pemetrexed, cisplatin and olaparib. Furthermore, we aimed to find correlations between response and gene expression patterns associated with BRCAness phenotype. Therefore, 91 clinical MPM samples were digitally screened for gene expression patterns of HR members.
Result
We observed a BRCAness-dependent increase of apoptosis and senescence during olaparib-based treatment of BRCA-associated-protein 1 (BAP1)-mutated cell lines. The gene expression pattern identified could be found in approx. 10% of patient samples. Against this background, patients could be grouped according to their defects in the HR system. Gene expression levels of Aurora Kinase A (AURKA), RAD50 as well as DNA damage-binding protein 2 (DDB2) could be identified as prognostic markers in MPM.
Conclusion
Defects in HR compiled under the term BRCAness are a common event in MPM. The present data may improve the understanding of underlaying cellular mechanisms and open new possibilities for modern therapeutic approaches for this severe disease. Response to Poly (ADP-ribose)-Polymerase (PARP)-Inhibition could be demonstrated in the BAP1-mutated NCI-H2452 cells, especially when combined with cisplatin. This combination therapy might be effective for up to 2/3 of patients, promising to enhance patients’ clinical management and outcome.
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P1.14 - Targeted Therapy (ID 182)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.14-43 - A Novel Patient Derived Synchronous Cell Pair with Different Mutations in an ALK-Rearranged Lung Adenocarcinoma Underlines Tumor Heterogeneity (ID 2162)
09:45 - 18:00 | Author(s): Clemens Aigner
- Abstract
Background
ALK targeted therapy can provide prolonged clinical response rates in ALK-rearranged lung adenocarcinoma (ADC) patients. However, most tumors relapse within a few years of treatment pressure due to a variety of resistance mechanisms, including intratumoral heterogeneity. Understanding these mechanisms is of utmost importance to more precisely tailor future targeted therapies.
Method
We established a novel synchronous ALK-translocated lung ADC cell pair from the malignant pleural effusion (PF240-PE) and the pleural carcinosis (PF240-PC) of a 38-year-old female patient following sequential ALK targeted therapy. Immunohistochemistry and mutational analyses were executed in pleural carcinosis tissue specimens and in the tumor cell lines. SRB assays were performed for viability testings following different generations ALK inhibitor treatment alone and combined with SAHA, a pan-HDAC inhibitor. As positive control for all treatment lines we used PF521, another newly established ALK-rearranged but treatment naïve lung ADC cell line. In vivo tumorigenicity was evaluated by performing subcutaneous xenografts.
Result
We identified two distinct resistance mutations in both tissue specimens: a so far non-characterized E1161K and the already described L1152R. Strikingly, PF240-PC harbored E1161K and PF240-PE carried L1152R. Immunohistochemistry showed changes from epithelial/carcinomatous to mesenchymal/sarcomatous differentiation following resistance acquisition. In vitro testing revealed that both cell lines were significantly different in morphology and sensitivity to different generation ALK inhibitors including crizotinib, alectinib and lorlatinib. However, the novel tyrosine kinase inhibitor entrectinib was effective in both E1161K and L1152R mutant cells. Importantly, combination treatment of crizotinib or alectinib plus pan-HDAC inhibitor SAHA yielded strong synergism. Of note, both novel cell lines were highly tumorigenic in vivo. In vivo treatment response profiles are currently under evaluation.
Conclusion
This is the first evidence of the synchronous establishment of two highly distinct patient-derived ALK translocated lung ADC cell lines carrying different resistant mutations. This concept supports the paramount significance of spatiotemporal intratumoral heterogeneity under targeted therapy. Furthermore, our findings showed that HDAC inhibition could enhance sensitivity of resistant tumor cells to ALK targeted therapy in vitro. Altogether, our findings provide strong evidence for the synchronous emergence of multiple resistance mechanisms and emphasize the importance of multiple site re-biopsies to better identify acquired resistance mechanisms under targeted therapy.
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P2.01 - Advanced NSCLC (ID 159)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.01-94 - Advanced Age and High Modified Glasgow Prognostic Score Are Associated with Increased Complications After Pneumonectomy (ID 2964)
10:15 - 18:15 | Author(s): Clemens Aigner
- Abstract
Background
Pneumonectomy is associated with increased morbidity and mortality compared to parenchyma sparing anatomic lung resections. The aim of this study was to identify risk factors in lung cancer patients undergoing curative intent pneumonectomy.
Method
All newly diagnosed non-small cell lung cancer patients undergoing pneumonectomy in curative intent as the primary surgical procedure between 1/2013 and 12/2018 were retrospectively analyzed. We reviewed demographic, clinical, functional and surgical variables. Postoperative complications and 30‐ as well as 90‐ day mortality were analyzed to identify risk factors for postoperative morbidity and mortality .
Result
103 lung cancer patients (67% male; mean age 62.3 ± 8.5) who underwent pneumonectomy with a curative intent have been identified. 62 patients (60%) received neoadjuvant treatment with chemotherapy (n=20) chemoradiation (n=42). Postoperative complications were registered in 35 (34%) patients (34%), with a major complication rate of 12%. Patients older than 65 years had a significantly higher risk for complications (p=0.0039). There was a strong trend in patients with modified Glasgow Prognostic Score >1 for higher postoperative complications (p=0.0715). There was no increase in postoperative morbidity in patients who underwent neoadjuvant treatment. 30‐ and 90‐day mortality was 2.9% and 2.9%, respectively.
Conclusion
Pneumonectomy for lung cancer can be done with low postoperative morbidity and mortality. Elderly patients should receive a careful preoperative evaluation. Modified Glasgow Prognostic Score can be considered for risk stratification for this procedure.
