Thymic Carcinoma Patients Research Articles

Checkpoint inhibitor-induced myocarditis and myasthenia gravis in a recurrent/metastatic thymic carcinoma patient: a case report.

BackgroundPembrolizumab, an immune checkpoint inhibitor (ICI), is an IgG4 antibody that blocks interaction between programmed cell death protein 1 and programmed death-ligand 1. Myocarditis, an immune-related adverse event, has been reported in thymic epithelial tumours. Pembrolizumab has also been associated with development/exacerbation of myasthenia gravis (MG).Case summaryA 70-year-old woman with metastatic thymic cancer presented to the hospital with shortness of breath, 21 days after initiation of pembrolizumab. She was diagnosed with ICI-related myocarditis and was subsequently intubated due to respiratory failure. A dual-chamber pacemaker was placed due to complete heart block with asystole. Her troponin levels were elevated, an electrocardiogram was suspicious for myocardial infarction, but coronary angiogram revealed normal coronary arteries and endomyocardial biopsy confirmed the presence of myocarditis. Treatment was started with high-dose intravenous methylprednisolone and cardiovascular status improved. However, the patient was unable to be weaned from mechanical ventilation and tested positive for acetylcholine receptor binding/blocking antibodies due to de novo MG. After 50 days of hospitalization, she was discharged home in stable condition. A computed tomography scan was performed 6 weeks after pembrolizumab; results showed significant decrease/resolution of all measurable sites of metastatic disease in the lungs.DiscussionThis is the first reported case of a patient developing single-agent pembrolizumab-induced myocarditis concomitant with new-onset MG after treatment for advanced thymic malignancy. Additional studies are needed to explore the association between myocarditis, MG, and ICI therapy.

A mutation analysis of the EGFR pathway genes, RAS, EGFR, PIK3CA, AKT1 and BRAF, and TP53 gene in thymic carcinoma and thymoma type A/B3.

Thymic carcinoma is rare and usually has a fatal outcome. Gene mutations in the epidermal growth factor receptor (EGFR) signalling pathway and TP53 have not been well analysed in thymic carcinoma. We examined a large cohort of thymic carcinoma and thymoma type A/B3 and looked for gene mutations in the RAS family, EGFR, PIK3CA, AKT1, BRAF and TP53. Among 54 thymic carcinoma cases, RAS family mutations were detected in 10 cases, EGFR in two, PIK3CA in one, AKT1 in one, BRAF in none and TP53 in five. Among 33 thymoma type A/B3 cases, HRAS gene mutation were found in one, PIK3CA in two and AKT1 in one. All these mutations were those of missense type activating mutations. RAS family mutations were significantly more frequent in thymic carcinoma than in thymoma type A/B3 (P=0.0461). A prognostic analysis focusing on thymic squamous cell carcinoma cases (n=44) showed that the overall survival was significantly shorter in patients with EGFR pathway mutations (n=9) than in those without in a univariate analysis (P=0.0173). Subsequently, EGFR pathway mutations were selected as an independent factor for a poor overall survival in a multivariate analysis (P=0.0389). Mutations in the EGFR pathway and TP53 in thymic carcinoma may be frequent, and the EGFR pathway mutations may be associated with a poor prognosis in thymic squamous cell carcinoma patients. The therapeutic significance of gene mutations in thymic carcinoma should be further clarified.

P2.15-06 Pretreatment Neutrophil to Lymphocyte Ratio Predicts Survival in Thymic Carcinoma Patients

P2.15-06 Pretreatment Neutrophil to Lymphocyte Ratio Predicts Survival in Thymic Carcinoma Patients

OP-14 - Single institution experience of thymoma and thymic carcinoma patients

OP-14 - Single institution experience of thymoma and thymic carcinoma patients

1858P - Transcriptomic difference of thymoma and thymic carcinoma

BackgroundThymoma and thymic carcinoma (TC) are rare diseases of thymus with relatively good prognosis. Different pathological sub-types of thymoma and TC show clear differences on clinical characteristics, morphology, molecular markers, and prognosis. MethodsIn this study, 26 thymoma and thymic carcinoma patients with most common thymic epithelial tumor subtypes were enrolled, including 2 type A, 6 type AB, 3 type B1, 1 type B1/B2, 5 type B2, 2 type B2/B3, 4 type B3, and 3 type TC patients in total. The frozen tissues of all patients were processed for RNA-seq sequencing. ResultsWe used unsupervised clustering to divide all samples into 5 clusters. Four clusters showed clear concordance with pathological subtypes, i.e. cluster AB (5 AB, 1 B1, and 2 B2), cluster B1/B2 (2 B1, 1 B1/B2, and 2B2), cluster B2/B3 (1 B2, 1 B2/B3, and 2B3), and cluster TC (3TC and 1 A). Only one cluster (1 A, 1 AB, and 2 B3) was labeled as cluster A/AB according to the result of joint clustering analysis with TCGA THYM RNA-seq data. We performed gene function enrichment analysis on highly expressed genes in each cluster. Cluster A showed gene function enrichment on two development related pathways (nervous system development and epithelium development) and cell differentiation. Cluster AB had enriched function of cell proliferation and regulation of cell development. Cluster B1/B2 did not show any enriched functions. Cluster B2/B3 showed gene function enrichment of cell adhesion and regulation of developmental process. CD274 (PD-L1) was also highly expressed in this cluster. Cluster TC had enriched function of several pathways, including cell adhesion, cell migration, cell differentiation, immune system process, immune response, and nervous system development. Moreover, PI3K-Akt signaling pathway, pathway in cancer, and transcriptional misregulation in cancer were also enriched in cluster TC’s highly expressed genes. ConclusionsThymic epithelial tumor subtypes show clearly different expression profiles. The highly expressed genes of each subtype relate to development, immune, and cancer related functions. PD-L1 is highly expressed in B2/B3 samples which suggests potential immunotherapy for the subtypes. Legal entity responsible for the studyPeking Union Medical College Hospital. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

MS08.01 Adjuvant Radiotherapy for Resected Thymic Carcinoma

Thymic carcinoma is a rare malignancy with peak incidence in the 4th-6th decade. In contrast to thymoma, it is commonly associated with higher rates of both lymph node and distant metastatic spread and also with shorter disease free survival. For localized or locally advanced disease, surgical resection, with the intention of complete disease extirpation, remains the standard of care. Due to its rarity however, definitive clinical trial data regarding optimal and appropriate addition of adjuvant therapy is lacking. Thus, decision making for post-operative patients is guided by data from large institutional, national or international retrospective series or databases (evidence level IV or V). Recommendations for adjuvant therapy for thymic carcinoma are influenced principally by stage and adequacy of resection (R0 vs R1 vs R2). Thymic carcinoma is classically staged us the Masaoka-Koga (MK) system but, based on recommendation to the AJCC by the IASLC Staging Prognostic Factors Committee and the International Thymic Malignancy Interest Group (ITMIG), using a database of more than 10 000 patients (Detterbeck et al 2014), a TNM-based system has now been incorporated into the 8th Edition of the AJCC/UICC TNM Classification of Malignant Tumours. However, since much of the published data regarding thymic malignancies is based on the Masaoka-Koga system, at present this remains commonly used for clinical decision-making but, as data continues to accumulate, will likely be superseded by the TNM system over time. Post-operative radiotherapy is routinely recommended for patients with MK stage III (TNM Stage I – T1bN0, Stage II, IIIA/B) thymic carcinoma following R0 resection. Similarly, adjuvant radiation is recommended following R1 resection, regardless of stage, with adjuvant chemoradiation recommended following R2 resection. Adjuvant radiotherapy is not recommended for MK I or IIA (TNM Stage 1 T1aN0 with no extension to mediastinal fat) disease. Controversy exists regarding the utility of adjuvant radiotherapy in the management of MK IIB (TNM Stage I – T1aN0 with extension to mediastinal fat) disease but can be considered for this group of patients. The optimal adjuvant radiotherapy dose remains undefined for thymic carcinoma patients but typical doses reported in the literature for patients in the above recommended groups range from 45-50 Gy in 1.8-2 Gy per fraction daily. Following R1 resection, 50-54 Gy in 1.8-2 Gy per fraction is typically recommended. Following R2 resection, 60-70 Gy (with or without concurrent chemotherapy) is considered standard. Nodal involvement is much more frequent in patients with thymic carcinoma compared with thymoma. Resected, unexpectedly N+ patients are typically recommended to receive adjuvant RT to 45-60 Gy if complete resection was obtained or 60-70 Gy (with or without concurrent chemotherapy) if residual nodal disease is suspected/documented. Under the TNM staging system, N1 nodes are defined as those in the anterior mediastinal compartment (IASLC levels 1, 3a, 6 and/or supradiaphragmatic/inferior phrenics/pericardial) and N2 nodes are defined as deep intrathoracic or cervical nodes (IASLC levels 2, 4, 5, 7, 10 and/or internal mammary nodes). Whether inclusion of N1 or N2 nodal compartments in adjuvant RT target volumes is of benefit for N0 or completely resected N1 or N2 patients remains unknown but may be prudent to consider during radiotherapy planning based on clinical factors. Radiotherapy should conform to modern standards with CT-based simulation with photon-based 3D conformal or beam-modulated treatment delivery, motion management and image guidance to reduce margins and dose to organs at risk. The utility of adjuvant proton-based RT for patients with resected thymic malignancy remains the focus of ongoing study but may offer some dosimetric advantages with respect to OAR dose (e.g. lung or heart). Selected

Radiographic Assessment of Objective Responses Using the ITMIG-Modified Criteria in Thymic Carcinoma

Introduction: Pleural metastases are common among patients with thymic carcinoma. Accurate and consistent measurement of pleural lesions is often difficult because of their unique locations and growth patterns. To minimize intraobserver variability, the International Thymic Malignancies Interest Group (ITMIG) proposed modified criteria for measurement of tumor response for thymic epithelial tumors. Methods: We conducted a retrospective review of the medical records of advanced or recurrent thymic carcinoma patients treated with chemotherapy between 1980 and 2016 in our institution. The best objective responses were assessed using the Response Evaluation Criteria in Solid Tumor version 1.1 (RECIST 1.1) and the ITMIG-modified criteria. Results: A total of 26 patients were included in the present study. According to the RECIST criteria, 1 (3.8%) patient showed complete response (CR), and 13 (50.0%), 10 (38.5%), and 2 (7.7%) showed partial response (PR), stable disease (SD), and progressive disease (PD), respectively. All 26 patients had the same best overall response using the ITMIG criteria. The median time to progression (TTP) according to the RECIST criteria and the ITMIG-modified criteria was 5.5 months (95% confidence interval [CI] 3.8–8.6) and 7.0 months (95% CI 3.8–9.3), respectively (p = 0.993). Conclusion: The ITMIG-modified criteria showed a high concordance rate with RECIST 1.1 criteria in response assessment of thymic carcinoma.

Abstract CT171: Phase I/II study to evaluate the safety and preliminary activity of nivolumab in combination with vorolanib in patients with refractory thoracic tumors

Abstract Background: Nivolumab monotherapy results in limited responses (19-25%) in thoracic tumors, therefore the potential exists to design combination strategies to improve tumor response. Evidence exists to suggest that antiangiogenic agents have the potential to stimulate the immune system. Several pilot trials combined inhibitors of PD-1/PD-L1 and VEGFR in renal cell carcinoma, and the combinations outperformed either single agent. However, none of the combinations were well tolerated at full doses of the drugs. Therefore, it is desirable to explore immunotherapy and antiangiogenic agent combinations that have lower toxicity. Vorolanib is structurally similar to the antiangiogenic agent sunitinib but was designed to improve the safety profile without compromising efficacy. Preclinically, vorolanib had comparable anti-tumor activity to sunitinib, and toxicokinetic analyses suggested a very high safety window. Methods: NCT03583086 is a multi-institutional, phase I/II study of nivolumab and vorolanib in patients with thoracic tumors who failed at least one prior line of chemotherapy. The primary objective of phase I is to determine the maximum tolerated dose. Dose escalation uses a standard 3+3 design with three dose levels of vorolanib (200, 300, and 400 mg once-daily) and 240 mg nivolumab every two weeks. Phase II evaluates efficacy of the combination among five cohorts: immunotherapy naïve non-small cell lung cancer (NSCLC), NSCLC patients that have progressed (primary refractory and acquired resistance) on immunotherapy, thymic carcinoma, and small cell lung cancer (SCLC) patients with progression on prior platinum-based chemotherapy. Primary refractory is defined as radiographic progression of disease within 12 weeks after initiation of checkpoint therapy; acquired resistance includes achieving radiographic partial or complete response, or stable disease for at least 12 weeks followed by radiographic disease progression. Enrollment to phase II will use a Simon two-stage design for each cohort. Exploratory objectives will be performed to quantify changes in the innate and adaptive immune responses after treatment. Mass cytometry will be used to monitor serial changes in multiple immune markers on individual circulating cells in the blood. Changes in each marker will be correlated with response using the Lasso-based elastic net method. Single cell gene expression analysis from peripheral blood samples collected prior to and at the end of treatment will be performed and correlated with response to combination therapy in order to improve our understanding of the biology behind systemic changes to this treatment. Enrollment to phase I is ongoing; 7 patients have been enrolled, including 3 in dose cohort 1 and 4 in dose cohort 2. Thus far, a dose-limiting toxicity of elevated liver function tests possibly related to nivolumab and vorolanib was observed in one patient enrolled in dose cohort 2. Citation Format: Jennifer G. Whisenant, Katy Beckerman, Hossein Borghaei, Taofeek Owonikoko, Jyoti Patel, Yu Shyr, Kimberly Harrow, Chris Liang, Allison Holzhausen, Heather Wakelee, Leora Horn. Phase I/II study to evaluate the safety and preliminary activity of nivolumab in combination with vorolanib in patients with refractory thoracic tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT171.

Effect of clinicopathologic features on survival of patients with thymic carcinomas and thymic neuroendocrine tumors: A population-based analysis

Background: Thymic carcinomas (TCs) and thymic neuroendocrine tumors (TNETs) are aggressive cancers with poor survival outcome and limited investigation. This study is to investigate clinicopathologic features on TC and TNET patients’ prognosis of a large cohort. Materials and Methods: The Surveillance, Epidemiology, and End Results database were used to identify a total of 362 TC and TNET patients with documented clinicopathologic features we investigated. The characteristics and overall survival of the TC and TNET patients were studied. Results: Two hundred and forty TC and 122 TNET patients were identified. For the entire cohort of TC and TNET, histologic type (P < 0.001), tumor size (P = 0.015), Masaoka-Koga stage (P = 0.008), regional node positive (P = 0.004), surgery of primary site (P < 0.001), lymph node surgery (P = 0.013), and chemotherapy (P = 0.001) were considered as significant clinicopathologic features that could affect prognosis of TC and TNET patients in univariate analysis. More importantly, histologic type (P < 0.001), regional nodes positive (P = 0.03) and surgery of primary site (P < 0.001) were able to independently predict overall survival of those patients. In addition, for the cohort of TC, we found that regional nodes positive (P = 0.034) and surgery of primary site (P = 0.001) could be independent predictors of TC patients’ survival. Conclusion: Regional nodes detection is essential for TC and TNET patients. Surgery of primary site is the preferred primary treatment for those patients.

Proton therapy for thymic malignancies: multi-institutional patterns-of-care and early clinical outcomes from the proton collaborative group and the university of Florida prospective registries

Objective: Thymic malignancies (TM) are rare tumors with long-term survivorship, causing concerns for radiotherapy-related late side effects. Proton therapy (PT) reduces the radiation dose to organs at risk, potentially decreasing long-term toxicities while preserving disease control. We report patterns-of-care and early clinical outcomes after PT for thymoma and thymic carcinoma.Methods: Between January 2008 and March 2017, 30 patients with TMs enrolled on one of two IRB-approved prospective protocols and received postoperative or definitive PT. Clinical outcomes, pathology, treatment dose, toxicities, and follow-up information were analyzed.Results: Twenty-two thymoma patients with a median age of 52.1 years (range, 23–72) received a median RT dose of 54 Gy (RBE) (range, 45–70) either postoperatively (91%) or definitively (9%); 23% received adjuvant chemotherapy. Among eight thymic carcinoma patients, the median age was 65.5 years (range, 38-88) and median RT dose was 60 Gy (RBE) (range, 42–70) delivered postoperatively (75%) or definitively (25%); 50% received chemotherapy.Median follow-up for all patients was 13 months (range, 2–59 months). Five patients relapsed, one locally (3%). Three patients died of disease progression, including two thymomas and one thymic carcinoma patient; a fourth died of intercurrent disease. One patient with thymic carcinoma and 1 with thymoma are alive with disease. No patients treated with PT for their initial disease (de novo) experienced grade ≥3 toxicities. The most common grade 2 toxicities were dermatitis (37%), cough (13%), and esophagitis (10%).Conclusion: Adjuvant and definitive PT are being used in the treatment of TMs. Early results of the largest such cohort reported to date demonstrates an acceptable rate of recurrence with a favorable toxicity profile. Longer follow-up and a larger patient cohort are needed to confirm these findings.

Capecitabine and Celecoxib as a Promising Therapy for Thymic Neoplasms.

For patients with unresectable or metastatic thymic epithelial neoplasms, few therapy options are available and outcomes are poor. This case series demonstrates that the combination of capecitabine and celecoxib may be a promising therapeutic option for these patients. The current report describes the outcomes of 5 patients with thymic neoplasms treated on a drug-drug interaction study of capecitabine and celecoxib in patients with advanced solid malignancies (NCT01705106) conducted at the University of Chicago, plus a sixth patient treated with the same regimen outside of the protocol. Six patients with thymic neoplasms were treated with capecitabine 1000 mg/m twice daily and celecoxib 200 mg twice daily, day 1 to day 14 on a 21-day cycle. This included 3 patients with thymic carcinoma, 1 with thymic neuroendocrine tumor, and 2 with thymomas. Objective response rates were noted in 3 of 6 patients. Two of the 3 thymic carcinoma patients had complete responses, and the third had a partial response. Best response for the other patients included stable disease for both thymoma patients and progressive disease for the thymic neuroendocrine patient. Other than grade 3 palmar-plantar erythrodysesthesia, which developed in 4 of 6 patients and required dose reductions, the regimen was well tolerated. This case series suggests that capecitabine plus celecoxib may be an effective and well-tolerated treatment option for patients with thymic carcinoma. Further studies should be carried out to establish the efficacy of capecitabine plus celecoxib in thymic carcinoma, and to determine whether monotherapy with capecitabine would be similarly effective.

MTE07.02 From Surgical Perspective

MTE07.02 From Surgical Perspective

Impact of PD-L1, transforming growth factor-β expression and tumor-infiltrating CD8+ T cells on clinical outcome of patients with advanced thymic epithelial tumors.

BackgroundAdvanced thymic epithelial tumors (TETs) are indolent and poorly responsive to chemotherapy. PD‐1/PD‐L1 inhibitors have shown remarkable clinical benefit in several cancers; however, many immunomodulatory molecules have been identified that affect the immune response. This study examined the progonostic roles of PD‐L1, transforming growth factor‐β (TGF‐β), and CD8+ tumor‐infiltrating lymphocytes (CD8+ TILs) in patients with TETs.MethodsRetrospective analysis was performed on the data of 20 patients with stage IV thymic carcinoma and 13 with stage III/IV invasive thymoma. Tissue biopsies were obtained before first‐line chemotherapy was administered. Protein levels were assessed by immunohistochemistry. Objective response rate, overall survival (OS), and progression‐free survival (PFS) were analyzed.ResultsPatients with advanced thymic carcinoma exhibited higher levels of PD‐L1 and TGF‐β than patients with advanced invasive thymic carcinoma (PD‐L1: 65.0% vs. 46.2%, P = 0.472; TGF‐β: 65.0% vs. 15.4%, P = 0.011). Five advanced thymic carcinoma patients with low levels of PD‐L1 and TGF‐β exhibited high levels of CD8 staining. The median OS was 29.5 months patients with high TGF‐β expression versus 62.9 in patients with low TGF‐β (P = 0.052). In patients with advanced thymic carcinoma, the median PFS in the high PD‐L1 expression group was 13.3 months versus 23.5 (P = 0.043) in the low PD‐L1, and the median OS was 50.7 months in the high CD8 expression versus 15.1 in the CD8 low group (P = 0.154).ConclusionsOur results showed the prognostic roles of PD‐L1, TGF‐β, and CD8+ TILs in patients with advanced TETs, and the potential for development of anti‐PD‐1/PD‐L1 therapies.

Efficacy of milciclib (PHA-848125AC), a pan-cyclin d-dependent kinase inhibitor, in two phase II studies with thymic carcinoma (TC) and B3 thymoma (B3T) patients.

8519Background: Thymic carcinoma (TC) and B3 thymoma (B3T) are rare malignant tumors of the thymus. While TC, a highly aggressive and easily metastasizing cancer, has a very poor prognosis, B3T is ...

Expression Patterns, Prognostic Value, and Intratumoral Heterogeneity of PD-L1 and PD-1 in Thymoma and Thymic Carcinoma.

Thymic epithelial tumors (TETs) including thymoma and thymic carcinoma are rare tumors with little data available to guide treatment. Immunotherapy with checkpoint blockade has shown promising activity, but data regarding the expression patterns and prognostic implications of programmed death 1 (PD-1) and its ligand (PD-L1) in TETs have yielded conflicting results. Intratumoral heterogeneity of PD-1/L1 expression has been shown in other cancers, but has not been described in the TET literature. We performed a retrospective single-center review of 35 patients with resected TET. PD-1/L1 expression was assessed by immunohistochemistry using PD-1 clone: NAT105 and PD-L1 clone: 22C3. Tumor samples from 35 patients were evaluated including 32 patients with thymoma and 3 patients with thymic carcinoma. PD-L1 expression was detected in 83% (29 of 35) tumor samples, including 100% (3 of 3) of thymic carcinoma patients and 81% (26 of 32) of thymoma patients. PD-1 expression was detected in 77% (27 of 35), including 33% (1 of 3) of thymic carcinoma patients and 81% (26 of 32) thymoma patients. High PD-1 expression was associated with lower grade tumors. Unlike prior studies, PD-L1 expression was not associated with higher grade tumors or higher stage. Neither PD-L1 nor PD-1 expression was significantly associated with survival. Three patients with thymoma had multiple tumor sections evaluated for expression of PD-1/L1, with differing expression patterns of both PD-L1 and PD-1 observed in two patients. This study confirms high expression of PD-L1 and PD-1 in TET and shows for the first time intratumoral heterogeneity of PD-L1 and PD-1 in thymoma patients.

WT1 peptide-based immunotherapy for advanced thymic epithelial malignancies.

Thymic epithelial tumors are rare malignancies, and no optimal therapeutic regimen has been defined for patients with advanced disease. Patients with advanced thymic epithelial tumors, which were resistant or intolerable to prior therapies, were eligible for this study. Patients received 9 mer-WT1-derived peptide emulsified with Montanide ISA51 adjuvant via intradermal administration once a week as a monotherapy. After the 3-month-protocol treatment, the treatment was continued mostly at intervals of 2-4 weeks until disease progression or intolerable adverse events occurred. Of the 15 patients enrolled, 11 had thymic carcinoma (TC) and 4 had invasive thymoma (IT). Median period from diagnosis to the start of treatment was 13.3 and 65.5 months for TC and IT, respectively. No patients achieved a complete or partial response. Of the 8 evaluable TC patients, 6 (75.0%) had stable disease (SD) and 2 had progressive disease (PD). Of the 4 evaluable IT patients, 3 (75.0%) had SD and 1 (25.0%) had PD. Median period of monotherapy treatment was 133 and 683 days in TC and IT patients, respectively. No severe adverse events occurred during the 3-month-protocol treatment. As adverse events in long responders, thymoma-related autoimmune complications, pure red cell aplasia and myasthenia gravis occurred in two IT patients. Cerebellar hemorrhage developed in a TC patient complicated with Von Willebrand disease. Induction of WT1-specific immune responses was observed in the majority of the patients. WT1 peptide vaccine immunotherapy may have antitumor potential against thymic malignancies.

Abstract A182: Apobec-mutagenesis drives mutational heterogeneity while copy number alterations drive transcriptomic and proteogenomic heterogeneity in metastatic lung adenocarcinoma and thymic carcinoma

Abstract Background: Molecular characterization of metastatic tumors to investigate intra- and intertumor heterogeneity has proven more difficult than early stage disease as opportunities for surgical removal are limited. Rapid/warm autopsy programs that are conducted soon after death minimize tissue ischemia, thereby enabling procurement of high-quality viable tissue. To our knowledge, integrated proteo-genomics studies to characterize tumor heterogeneity of metastatic lung adenocarcinoma and thymic carcinoma are lacking. Methods: We sought to characterize and decipher mechanisms of intra- and intertumor heterogeneity of Stage IV lung adenocarcinoma and thymic carcinoma through whole exome sequencing, RNA sequencing, copy number estimation, and mass spectrometry-based proteomics of 38 tumors from five rapid/warm autopsy patients. The autopsy procedure was initiated between 2-4 hours of death. Results: One lung adenocarcinoma (RA003) and one thymic carcinoma (RA006) patient had high mutation burden and extreme mutational (SNV) heterogeneity. This was likely driven by APOBEC-mutagenesis. We constructed phylogenetic trees showing truncal, shared, and private SNVs and copy number alterations (CNAs). Interestingly, we discovered a pattern of recurrent, parallel but opposite arm level CNAs in different metastatic branches within a subset of patients (RA000, RA004, and RA006). In contrast, RA003 had only truncal CNAs and the least heterogeneity at the CNA level. Assessment of intra- and intertumor heterogeneity at the transcriptomic and proteomic levels revealed high concordance in gene expression and protein abundance within tumors from patient RA003 compared to patient RA004, potentially reflecting the downstream effect of CNA vs. APOBEC-induced mutations. Further analysis of cis vs. trans effects of CNA on gene expression and protein abundance in all the metastatic tumors revealed many trans-acting hot spots and limited cis effects, which is contrary to copy number effects on gene expression in primary lung adenocarcinoma tumors. Trans-acting hot spots differed between two major metastatic lineage of patient RA004, suggesting copy number changes may be responsible for high intermetastatic proteomic heterogeneity in this patient. Conclusions: Our results demonstrate ongoing mutational and chromosomal instability throughout the metastatic process of lung adenocarcinoma and thymic carcinoma. APOBEC mutagenesis was likely the primary driver of SNV heterogeneity. However, intertumor heterogeneity of metastatic disease at the level of the transcriptome and proteome occurred in association with CNA rather than mutational heterogeneity. APOBEC mutagenesis and CNA are complementary mechanisms of tumor evolution and heterogeneity affecting tumor metastasis. Citation Format: Nitin Roper, James Gao, Rouf Banday, Tapan Maity, Xu Zhang, Abhilash Venugopalan, Rajesh Patidar, Sivasish Sindiri, Constance Cultraro, Alexandr Goncearenco, Anna Panchenko, Romi Biswas, Jing Wang, Stephen Hewitt, David Kleiner, Bing Zhang, Javed Khan, Ludmila Prokunina-Olsson, Udayan Guha. Apobec-mutagenesis drives mutational heterogeneity while copy number alterations drive transcriptomic and proteogenomic heterogeneity in metastatic lung adenocarcinoma and thymic carcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A182.

Rapid/warm autopsy to reveal APOBEC-mutagenesis as driver of heterogeneity of metastatic thoracic tumors.

9023 Background: Intratumor heterogeneity has been characterized among multiple cancer types. In lung adenocarcinoma, APOBEC-mutagenesis has been shown to be a source of heterogeneity. However, these data are largely limited to early stage primary tumors. There is limited information about the role of APOBEC-mutagenesis and somatic variants, copy number changes, transcript and protein expression in influencing tumor heterogeneity in metastatic lung adenocarcinoma and other thoracic tumors. Methods: We applied whole exome sequencing, RNA-seq, OncoScan CNV and mass spectrometry-based proteomic analyses on 46 tumor regions from metastatic sites including lung, liver and kidney, obtained by rapid/warm autopsy from 4 patients (pts) with stage IV lung adenocarcinoma, 1 pt each with pleural mesothelioma and thymic carcinoma. The autopsy procedure was initiated between 2-4 hours of death. Results: All tumors displayed organ-specific, branched evolution that was consistent across exome, transcriptome and proteomic analyses. The degree of heterogeneity at the genomic and proteomic level was patient-specific. There was extensive heterogeneity within the tumors of one of four patients with lung adenocarcinoma and in the thymic carcinoma patient (both non-smokers) with multiple driver mutations and copy number changes occurring in only some of the tumors suggesting ongoing late tumor evolution. Further examination of the heterogenous thymic and lung adenocarcinoma tumors showed strong enrichment with the APOBEC-mutagenesis pattern and high associated levels of APOBEC3B mRNA. Conclusions: Metastatic lung adenocarcinoma, thymic carcinoma and mesothelioma evolve through a branched, organ-specific process with marked differences in the acquisition of significant driver mutations and copy number changes. APOBEC3B is a potential driver of heterogeneity in pts with advanced, heterogeneous metastatic lung adenocarcinoma and thymic carcinoma and needs to be evaluated further.

Comparison of clinical features and survival between thymic carcinoma and thymic carcinoid patients.

Thymic carcinoma (TC) and thymic carcinoid (TCD) are aggressive thymic epithelial neoplasms with a poor prognosis. Due to rarity, little is known about their comparative clinical characteristics, treatment outcomes and patterns of relapse. A retrospective cohort study was performed on 287 patients with TC and 56 patients with TCD who were treated at the Shanghai Chest Hospital between February 2003 and April 2014. Patient demographics, tumour stage, treatment, pathologic findings and postoperative outcomes were compared between the two tumour types using both multivariable Cox regression analysis and propensity-matched analysis. Compared to patients with TC, significantly more patients with TCD were male, had larger tumours, and displayed a greater proportion of lymph node metastases. However, overall survival was similar (60.7% 5-year survival for TC, 80.7% for TCD, P = 0.159), as was disease-free survival (41.1% 5-year survival for TC, 37.6% for TCD, P = 0.696) and patterns of relapse. Multiple Cox regression analysis identified younger patients [hazard ratio (HR) 1.018; 95% confidence interval (CI) 1.000-1.035; P = 0.047], more completeness of resection (HR 1.424; 95% CI 1.105-1.836; P = 0.006), adjuvant radiotherapy (HR 0.455; 95% CI 0.276-0.751; P = 0.002), and no adjuvant chemotherapy (HR 1.799; 95% CI 1.017-3.183; P = 0.044) as independent factors predicting better overall survival. Completeness of resection (HR 1.258; 95% CI 1.022-1.548; P = 0.031) and TNM stage (HR 1.479; 95% CI 1.107-1.977; P = 0.008) were independent predictors of disease-free survival. Propensity matching produced 46 patients in each group and no significant difference on overall survival or disease-free survival was found. Patients with TCD have discrete features but share a similar clinical course to those with TC. The importance of complete resection in both of these thymic malignancies is emphasized. Further investigation at multiple centers with the longer follow-up data is required to substantiate our conclusion.

Expression of excision repair cross-complementation group 1 and class III β-tubulin in thymic carcinoma.

Thymic carcinoma is a rare mediastinum malignant tumor derived from thymic epithelial cells. With the exception of complete resection, an effective therapy has not been established to date for advanced or relapsed thymic carcinoma. The present study examined the protein expression of excision repair cross-complementation group 1 (ERCC1) and class III β-tubulin (TUBB3), which are consider to be indicators of the anticancer activity of platinum-based and taxane-based chemotherapy, respectively. The expression of ERCC1 and TUBB3 proteins was examined in 40 thymic carcinoma patients who underwent either surgical resection or core-needle biopsy. The present study investigated whether the expression of ERCC1 and TUBB3 proteins was associated with the overall survival and clinicopathological factors of thymic carcinoma patients. The expression of ERCC1 and TUBB3 proteins was also evaluated in 50 patients who underwent curative resection for non-small cell lung cancer (NSCLC). The expression of ERCC1 and TUBB3 proteins was positive in 8 cases (20%) among the thymic carcinoma patients. ERCC1 was expressed in 21 cases (42%), while TUBB3 was expressed in 27 cases (54%), among the 50 NSCLC patients evaluated in the present study. Only complete resection was observed to be associated with a better prognosis than incomplete resection (P=0.0341). Other clinicopathological factors, including expression of ERCC1 and TUBB3 proteins, exhibited no effect on overall survival. The expression of ERCC1 and TUBB3 proteins in the thymic carcinoma cases was lower than that in the NSCLC cases. The present results suggest a possibility for better antitumor effects of platinum-based and taxane-based chemotherapy on thymic carcinoma patients.