OA06.04 Constructing a Global Molecular Database for Thoracic Malignancies: The IASLC Molecular Subcommittee Lung Cancer Dataset

The importance of haplotype association and gene-environment interactions (GxE) in the context of rare variants has been underlined in voluminous literature. Recently, a software based on logistic Bayesian LASSO (LBL) was proposed for detecting GxE, where G is a rare (or common) haplotype variant (rHTV)-it is called LBL-GxE. However, it required relatively long computation time and could handle only one environmental covariate with two levels. Here we propose an improved version of LBL-GxE, which is not only computationally faster but can also handle multiple covariates, each with multiple levels. We also discuss details of the software, including input, output, and some options. We apply LBL-GxE to a lung cancer dataset and find a rare haplotype with protective effect for current smokers. Our results indicate that LBL-GxE, especially with the improvements proposed here, is a useful and computationally viable tool for investigating rare haplotype interactions.

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Pump operations in locally advanced thoracic malignancies

Acta medica Lituanica ◽

10.6001/actamedica.v19i4.2551 ◽

2013 ◽

Vol 19 (4) ◽

pp. 417-420 ◽

Cited By ~ 1

Author(s):

Saulius Cicėnas ◽

Vytautas Jonas Sirvydis ◽

Giedrius Uždavinys ◽

Gintaras Kalinauskas ◽

Renatas Aškinis ◽

...

Keyword(s):

Lung Cancer ◽

Left Atrium ◽

Median Survival ◽

Adjuvant Treatment ◽

Locally Advanced ◽

University Hospital ◽

Study Objective ◽

Lung Cancer Patients ◽

Thoracic Malignancies ◽

Left Pneumonectomy

Background. The study objective is to evaluate the efficacy of pump operations in locally advanced IIIB (T4N0-1M0) lung cancer and other thoracic malignancies and the results of treatment. Materials and methods. In the period 2003–2011, 6 patients (pts) with locally advanced thoracic malignancies underwent surgery in the Center of Cardiac Surgery of Vilnius University Hospital Santariskiu Clinics (VUH SC). Patients’ characteristics and stage: lung cancer – 3 pts (50.0%), stage IIIB (T4N0-1M0), sarcoma of mediastinum – 2 pts (33.3%), fibrous tumour of mediastinum – 1 pt (16.7%). Patients according to morphology: squamous cell carcinoma – 3 pts (50.0%), neuroangiosarcoma – 1 pt (16.7%), neurosarcoma – 1 pt (16.7%), solitary fibrous tumour – 1 pt (16.7%). After surgery patients received adjuvant treatment: 3 pts with lung cancer received 4 cycles of chemotherapy Gemcitabine with cisplatinum, 2 pts with angiosarcoma received radiation therapy 66 Gy and 6 cycles of chemotherapy Ifosfamide. Results. We performed pneumonectomy with left atrium resection – 2 pts (33.3%), left pneumonectomy with aorta resection – 1 pt (16.7%), left atrium resection with left upper lobectomy – 1 pt (16.7%), mediastinum resection with chest wall reconstruction – 1 pt (16.7%), left pneumonectomy – 1 pt (16.7%). We had no complications after pump operations. Median survival of patients with lung cancer was 2.5 ± 0.5 years, with angiosarcoma 3.5 ± 1.0 years. Five-year survival was 25%. Conclusions. 1. Pump operations are safe and possible in locally advanced thoracic malignancies. 2. Pump operations and adjuvant treatment may prolong median survival in IIIB (T4N0-1M0) lung cancer patients by 2.5 ± 0.5 years and in angiosarcoma patients by 3.5 ± 1.0 years.

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Barriers for accrual to clinical trials in adult patients (pts) with thoracic malignancies

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.6058 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 6058-6058

Author(s):

M. Q. Baggstrom ◽

E. Gilstrap ◽

A. Skelton ◽

A. Viswanathan ◽

D. Morgensztern ◽

...

Keyword(s):

Lung Cancer ◽

Clinical Trials ◽

Esophageal Cancer ◽

Early Stage ◽

Small Cell ◽

Advanced Esophageal Cancer ◽

Small Cell Lung ◽

Early Stage Nsclc ◽

Thoracic Malignancies ◽

Morbid Conditions

6058 Background: Despite recent advances in the treatment of pts with thoracic malignancies, the outcome continues to be poor. Only about 3% of all adult oncology pts enroll in clinical trials compared to approximately 50% of pediatric pts. The proportion of adult pts enrolled in clinical trials is low, even in tertiary cancer centers. It is critical to understand the barriers for accrual to clinical trials. Methods: We reviewed the outpatient charts of all pts with thoracic malignancies (non-small cell lung cancer [NSCLC], small cell lung cancer, and esophageal cancer) referred to the thoracic medical oncology group at our institution from 11/1/2004 to 10/31/2005. Available and appropriate clinical trials are presented to the pts routinely and reasons for non-enrollment are documented. We collected information on histology, stage, performance status (PS) and co-morbid conditions. Appropriate studies at the time of initial consultation were noted from database. Results: Of 284 consecutive patient charts reviewed, 13 pts (4.6%) did not require therapy, 6 pts (2.1%) were deemed to have a non-thoracic primary on review, and 15 pts (5.3%) had already initiated therapy at the time of consultation. Of the remaining 250 evaluable pts, 88 pts (35.2%) were not enrolled because of lack of available appropriate clinical trials at the time of initial consultation. The most common categories were adjuvant therapy for early stage NSCLC and advanced esophageal cancer. Twenty-one pts (8.4%) enrolled onto a clinical trial. The most common reasons for not participating in a clinical trial include: ineligibility due to PS (28 pts, 11.2%), geographic issues (23 pts, 9.2%), patient refusal (16 pts, 6.4%) and co-morbid conditions (9 pts, 3.6%). Ten pts (4.0%) were lost to follow up. Conclusions: 1. Lack of appropriate and available clinical trials and poor PS are the two most common reasons for lack of patient enrollment in clinical trials at our institution. 2. It is critical to develop innovative clinical trials for pts with advanced esophageal cancer, adjuvant therapy in early stage NSCLC, and poor PS. 3. More work is needed to understand patient perception about clinical trials. [Table: see text]

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Phase I trial of escalating doses of ABI-007 (nanoparticle albumin-bound paclitaxel) and gemcitabine in patients (pts) with thoracic malignancies

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.18094 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 18094-18094

Author(s):

C. B. Lee ◽

T. E. Stinchcombe ◽

M. A. Socinski ◽

D. N. Hayes ◽

R. M. Goldberg ◽

...

Keyword(s):

Lung Cancer ◽

Febrile Neutropenia ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Severe Neutropenia ◽

Hematologic Toxicity ◽

Small Cell Lung ◽

Grade 3 ◽

Thoracic Malignancies

18094 Background: ABI-007, nanoparticle albumin-bound paclitaxel, has a different toxicity profile than solvent-based paclitaxel including a lower rate of severe neutropenia. This trial was designed to determine the maximum tolerated dose (MTD) of ABI-007 in combination with gemcitabine (G) in patients with thoracic malignancies. Methods: Patients were required to have a performance status of 0–1, =3 cytotoxic chemotherapy regimens, and preserved renal, hepatic, and bone marrow function. Patients received G 1,000 mg/m2 on days 1, 8 in all cohorts and ABI-007 on day 1 at doses of 260, 300, 340 mg/m2 depending on the treatment cohort every 21 days (1 cycle = 21 days). Day 8 G dose modifications were: G held for ANC < 500 x 109/L or platelets (plts) < 50,000 x 109/L, and 75% of the G dose was given if the ANC 500–999 x 109/L or plts 50,000–99,000 x 109/L. Dose limiting toxicities (DLT) were assessed after the first cycle and were defined as: grade 3 non-hematologic toxicity, febrile neutropenia, grade 4 anemia or thrombocytopenia, ANC = 500 for = 7 days, 2-week delay in initiating the second cycle, or omission of the day 8 G. Doses were escalated in cohorts of 3–6 pts. Results: Thirteen patients were consented and 12 pts were treated (median age 62.5 years (range 35–75); median number of prior treatments 2.5 (range 1–4); tumor types: 6 non-small cell lung cancer (NSCLC), 5 small cell lung cancer (SCLC), and 1 esophageal. At an ABI-007 dose of 300 mg/m2, 1 of 6 pts experienced a DLT (omission of day 8 G due to ANC < 500), and at an ABI-007 dose of 340 mg/m2 2 of 3 patients experienced a DLT (1 pt grade 3 rash and pruritus; 1 pt grade 3 fatigue and anorexia). Additional grade 3 or 4 toxicities observed over all cycles were: neutropenia (n=2), sensory neuropathy (n=1), febrile neutropenia (n=1). G was given at full dose in 38 of the 39 cycles. Eight pts were evaluable for response by RECIST: 4 partial responses (SCLC, n=2; NSCLC, n=2), 4 stable disease (NSCLC, n=3; esophageal, n=1). Conclusions: The MTD of ABI-007 is 300 mg/m2 day 1 in combination with G 1,000 mg/m2 on days 1, 8 every 21 days. This combination was well tolerated and demonstrated activity in previously treated NSCLC and SCLC patients. No significant financial relationships to disclose.

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Clinical and molecular characteristics of TSC1/2 mutant lung cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e21647 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e21647-e21647

Author(s):

Yanye Wang ◽

Song Xu ◽

Shikang Zhao ◽

Shuai Zhu ◽

Xiongfei Li ◽

...

Keyword(s):

Lung Cancer ◽

Smoking History ◽

Rank Test ◽

Molecular Characteristics ◽

Fisher Exact Test ◽

Continuous Variables ◽

Cancer Dataset ◽

Kaplan Meier ◽

Oncogenic Gene ◽

Gene Alterations

e21647 Background: Tumor suppressor genes TSC1 and TSC2 inhibit cell growth through inactivation the function of mTORC1. Previous studies have demonstrated that loss of function mutation of either TSC1 or TSC2 gene result in formation of neoplasm in multiple tissues. However, the clinical significance of TSC1 and TSC2 in non-small-cell lung cancer (NSCLC) remains unknown. This study aimed to investigate the clinical and molecular characteristics of TSC1 and TSC2 mutation in NSCLC patients. Methods: We retrieved the clinical and genomic information of 1144 NSCLC from the Pan-Lung cancer dataset through the cBioportal ( www.cbioportal.org) . The cohorts of TSC1 and TSC2 mutant patients were identified. We compared baseline characteristics of patients with the Fisher exact test for categorical data and the Mann-Whitney U test for continuous variables. Overall survival (OS) was estimated with Kaplan-Meier curves, and differences were compared with the log-rank test. Results: Among 1144 patients, 27(2.36%) of them had TSC1 mutation and 40 (3.50%) had TSC2 mutation. Most patients with TSC1 and TSC2 mutations coexisted with other oncogenic gene alterations. TP53 was the most frequent concurrent gene (n = 53), followed with ERBB family genes (n = 24) and KRAS (n = 15). Compared to squamous cell carcinoma, TSC1/2 mutation was slightly more common in adenocarcinoma (53.7% vs 46.3%). 61.2% TSC1/2 mutant patients were male and 88.1% patients had former/current smoking history. Kaplan–Meier analysis showed that the patients harboring TSC1 mutation had a median OS of 14.1 months, whereas patients with TSC2 mutation had a median OS 110.6 months. However, there was not a statistically difference (P = 0.201). Conclusions: TSC1/2 mutation may define a unique population of NSCLC, which often coexists with other oncogenic gene alterations such as TP53 mutation. The function of TSC1/2 mutation and the value of TSC1/2 as therapeutic target in NSCLC are under investigation.

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Application of Genetic Algorithm for Discovery of Core Effective Formulae in TCM Clinical Data

Computational and Mathematical Methods in Medicine ◽

10.1155/2013/971272 ◽

2013 ◽

Vol 2013 ◽

pp. 1-16 ◽

Cited By ~ 5

Author(s):

Ming Yang ◽

Josiah Poon ◽

Shaomo Wang ◽

Lijing Jiao ◽

Simon Poon ◽

...

Keyword(s):

Lung Cancer ◽

Genetic Algorithm ◽

Chinese Medicine ◽

Traditional Chinese Medicine ◽

Clinical Data ◽

Cancer Dataset ◽

Synergy Index ◽

Average Confidence ◽

Group A ◽

Tcm Theory

Research on core and effective formulae (CEF) does not only summarize traditional Chinese medicine (TCM) treatment experience, it also helps to reveal the underlying knowledge in the formulation of a TCM prescription. In this paper, CEF discovery from tumor clinical data is discussed. The concepts of confidence, support, and effectiveness of the CEF are defined. Genetic algorithm (GA) is applied to find the CEF from a lung cancer dataset with 595 records from 161 patients. The results had 9 CEF with positive fitness values with 15 distinct herbs. The CEF have all had relative high average confidence and support. A herb-herb network was constructed and it shows that all the herbs in CEF are core herbs. The dataset was divided into CEF group and non-CEF group. The effective proportions of former group are significantly greater than those of latter group. A Synergy index (SI) was defined to evaluate the interaction between two herbs. There were 4 pairs of herbs with high SI values to indicate the synergy between the herbs. All the results agreed with the TCM theory, which demonstrates the feasibility of our approach.

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Objective improvement in lung cancer patient care by the development of a multidisciplinary clinic (MDC) in the community

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.17086 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 17086-17086

Author(s):

W. Mayfield ◽

R. Bordoni ◽

R. Holder ◽

M. Waldman ◽

A. Muster ◽

...

Keyword(s):

Lung Cancer ◽

Stage Iv ◽

Cost Effective ◽

Pulmonary Medicine ◽

Optimal Care ◽

Cancer Management ◽

Cancer Registry Data ◽

Secondary Endpoints ◽

Definitive Surgery ◽

Thoracic Malignancies

17086 Background: Medical resources allocated to lung cancer management are limited, scattered and uncoordinated, resulting in sub-optimal care. The MDC offers patients access to multi-disciplinary care (Pulmonary Medicine, Thoracic Surgery, Medical and Radiation Oncology) to operate in an efficient, cost effective way. Methods: 2004 Cancer Registry data on time to treatment (TTT) for lung cancer was 53 days. A project with the primary endpoint of reducing the TTT from 53 to 30 days was designed. Secondary endpoints were improvement in treatment planning; enhancement in clinical trials referral, and patient satisfaction. On 9/15/05 the MDC open its doors. The project was assigned to this clinic including patients with solitary lung nodules, lung, esophageal, and mediastinal cancers, mesothelioma, and other thoracic malignancies. Results: 54 pts were seen in the first 90 days; median age 60 (range 41–82), 29 males; 32 (59%) lung cancer (94% NSCLC), 8 (15%) esophageal cancer, 6 other diagnosis, and 6 abnormal radiological findings without diagnosis. The TTT of 30 evaluable patients is 26.36 days. Of the 30 NSCLC the TNM stage was: 4 IA, 5 IB, 2 each IIA/IIB, 8 (27%) IIIA, 3 (10%) IIIB, and 6 (20%) IV. Fifteen of the cases had pathologic staging. Out of 9 pts with cstage I, 7 (78%) had definitive surgery; 4 pts confirmed to have pstage IB, were evaluated for adjuvant chemo. Four pts with cstage II had surgery, 2 of them adjuvant chemo. Of the 11 pts with cstage III, 5 (46%) received concurrent CHRT, 1 (stage IIIA) underwent surgery f/b chemo, 2 received chemo alone and 2 refused therapy. Out of 6 pts with stage IV, 5 (83%) received systemic therapy. Conclusions: The TTT of 26.36 days represents a 50.26% improvement from our institutional benchmark of 53 days. Updated and expanded data on our project primary and secondary endpoints will be presented at the meeting. No significant financial relationships to disclose.

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RASA1 and NF1 co-mutated non-small cell lung carcinomas: Cancer genomic data and evaluation of sensitivity to MEK inhibition.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.11600 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 11600-11600

Author(s):

Takuo Hayashi ◽

Patrice Desmeules ◽

Roger Smith ◽

Alexander E. Drilon ◽

Romel Somwar ◽

...

Keyword(s):

Lung Cancer ◽

Mapk Pathway ◽

Negative Control ◽

Small Cell ◽

Molecular Characteristics ◽

Loss Of Function ◽

Small Cell Lung ◽

Cancer Dataset ◽

Lung Carcinomas ◽

Mek Inhibition

11600 Background: Ras-GTPase activating proteins (RasGAPs), notably NF1 and RASA1, mediate negative control of the RAS/MAPK pathway. While NF1 mutations are enriched in non-small cell lung carcinomas (NSCLC) lacking KRAS alterations, they are not completely mutually exclusive. We evaluated clinical and molecular characteristics of NSCLC with RASA1 mutations in comparison with NF1-mutated cases. Methods: Large genomic datasets of NSCLC [MSK-IMPACT™ dataset at MSKCC (n = 2004), TCGA combined lung cancer dataset (n = 1144)] were analyzed to define concurrent mutations and clinical features of RASA1-mutated NSCLCs. Functional studies were performed using immortalized human bronchial epithelial cells (HBECs) and NSCLC lines with RasGAP truncating mutations, in RASA1 (RERFLCKJ), NF1 (LCLC103H and H1838), or both (EPLC272H). Results: Overall, approximately 2% of NSCLCs had RASA1 truncating mutations, and this alteration was statistically, but not completely, mutually exclusive with known activating EGFR (p = .02) and KRAS (p = .02) mutations. Unexpectedly, RASA1 truncating mutations had a strong tendency to co-occur with NF1 truncating mutations (p < .001), suggesting selection for loss of more than one RasGAP. Furthermore, all patients (16/16) with concurrent RASA1/NF1 truncating mutations lacked other known lung cancer drivers, including KRAS. Knockdown of RASA1 in HBECs activated signaling downstream of RAS and promoted cell growth. Conversely, restoration of RASA1 expression in RERFLCKJ cells reduced MAPK and PI3K signaling. While growth of cell lines with inactivation of only one of these two RasGAPs showed moderate and variable sensitivity to inhibitors of MEK (trametinib) or PI3K (GDC0941, PI103), EPLC272H cells (with concurrent RASA1/NF1 mutations) showed notably more profound sensitivity (IC50: 0.040µM trametinib). Finally, simultaneous silencing of RASA1 and NF1 sensitized both HBECs and NSCLC cells to MEK inhibition. Conclusions: Cancer genomic and functional data nominate concurrent RASA1/NF1 loss of function mutations as a strong mitogenic driver in NSCLC. Patients whose tumors show this distinctive genotype should be considered for trials of MEK inhibitors.

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