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D. Grunenwald
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MS 20 - Joint Imaging/Therapy Conference (ID 38)
- Event: WCLC 2015
- Type: Mini Symposium
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 4
- Moderators:O.T. Brustugun, D. Grunenwald
- Coordinates: 9/09/2015, 14:15 - 15:45, 601+603
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MS20.01 - Imaging for Surgical Treatment Decision and Planning (ID 1937)
14:20 - 14:40 | Author(s): H. Hoffmann, C.P. Heussel
- Abstract
- Presentation
Abstract:
When patients with early-stage non-small cell lung cancer (NSCLC) are accurately staged inappropriate surgery is avoided and on the other hand potentially curative surgical resection is not refused. The clinical algorithms using imaging studies for staging lung cancer patients with regard to surgical treatment decision and planning as recommended by current guidelines will be presented and discussed. Low-dose CT screening is now recommended for asymptomatic select patients who are at high risk for lung cancer and an increasing number of patients may come to clinical attention during screening. CT findings suggestive of malignancy in a patient with a solitary pulmonary nodule include larger lesion size, irregular or spiculated borders, upper lobe location, thick-walled cavitation, presence or development of a solid component within a ground glass lesion, and detection of growth by follow-up imaging. The general approach to patients suspected of having lung cancer begins with a thorough history and physical examination (1). Following that, essentially every patient suspected of having lung cancer should undergo a contrast-enhanced diagnostic CT scan of the chest. The diagnostic chest CT scan is an important first step, not only to help define the clinical diagnosis, but to structure the subsequent staging and diagnostic evaluation (1). In patients in whom lung cancer has been demonstrated, consideration must turn toward determining the extent of the disease to identify patients with stage IA, IB, IIA, and IIB disease who can benefit from surgical resection. **Extrathoracic (M) Staging** The purpose of extra thoracic imaging in NSCLC is to detect metastatic disease. Current literature continues to demonstrate that PET and PET-CT scans are superior to conventional staging tests (bone scan and abdominal CT scan) in terms of performance characteristics (1). Recent data confirm the superiority of the performance characteristics of PET and PET-CT scans compared with conventional scans in the evaluation of metastatic disease in key specific distant sites (1). Recommendation (1): In patients with a normal clinical evaluation and no suspicious extra thoracic abnormalities on chest CT being considered for curative-intent treatment, PET imaging (where available) is recommended to evaluate for metastases (except the brain) (Grade 1B). However, positive PET/CT scan findings for distant disease need pathologic or other radiologic confirmation (e.g., MRI of bone) (2). Brain MRI (to rule out asymptomatic brain metastases) is recommended for patients with stage II and higher (2). Patients with stage IB NSCLC are less likely to have brain metastases; therefore, brain MRI is only a category 2B recommendation in this setting (2). **Mediastinal Nodal (N) Staging** Mediastinal lymph node staging in NSCLC is particularly important, because in many cases, the nodal status actually determines whether there is surgically resectable disease. If the contrast-enhanced CT scan shows nodal mediastinal infiltration that encircles the vessels and airways, so that discrete lymph nodes can no longer be discerned or measured, non-resectable disease is evident and no further imaging studies are required to determine the exact N status (1). In patients with discrete mediastinal node enlargement further evaluation is recommended (1, 2). The NCCN Panel assessed studies that examined the sensitivity and specificity of chest CT scans for mediastinal lymph node staging. Depending on the clinical scenario, a sensitivity of 40% to 65% and a specificity of 45% to 90% were reported. PET/CT scans may be more sensitive than CT scans (2). However, in patients with discrete mediastinal node enlargement, the risks of false positive test results from either CT scanning and/or PET scanning are too high to rely on imaging alone to determine the mediastinal stage of the patient, and tissue confirmation is necessary (1). Transesophageal EUS-FNA and EBUS-TBNA have proven useful to stage patients or to diagnose mediastinal lesions; these techniques can be used instead of invasive staging procedures in select patients. When compared with CT and PET, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has a high sensitivity and specificity for staging mediastinal and hilar lymph nodes in patients with lung cancer. In patients with positive nodes on CT or PET, EBUS-TNBA can be used to clarify the results. In patients with negative findings on EBUS-TNBA, conventional mediastinoscopy can be done to confirm the results. **Thoracic Tumor (T) Staging** The size of the tumor, its location and invasion of adjacent structures as reflected in the T status determines resectablity and - in cases with given resectablity - the extent of resection. In patients with T3 tumors or centrally located tumors that may necessitate a pneumonectomy, additional functional evaluation of the patient may be required to determine operability. Contrast-enhanced CT scan is the most commonly used imaging modality for T staging and can provide all the information needed. In select cases (e.g. Pancoast-Tumors) MRI may be useful to diagnose involvement of the brachial plexus and extension into the neural foramina and the spinal canal (3). Infiltration of the mediastinal great vessels, esophagus, trachea, and vertebral body is staged as T4 and usually defines unresectability. Findings on CT scan like obliteration of fat plane between the tumor and the mediastinum, circumference of contact between the tumor and the aorta, and the length of anatomical contact between the tumor and the mediastinum are not definitive signs for invasion. Both CT scan and MRI have similar diagnostic accuracy (56-89% for CT and 50-93% for MRI) in predicting mediastinal invasion, with no modality being considered to be distinctly superior (3). References: 1. Silvestri GA, et al. Methods for Staging Non-small Cell Lung Cancer. Diagnosis and Management of Lung Cancer, 3rd ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. CHEST 2013; 143(5)(Suppl):e211S–e250S 2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Non-Small Cell Lung Cancer, Version 7.2015, NCCN.org 3. Nilendu C Purandare and Venkatesh Rangarajan.Imaging of lung cancer: Implications on staging and management. Indian J Radiol Imaging. 2015 Apr-Jun; 25(2): 109–120.
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MS20.02 - Imaging for Radiation Therapy Planning (ID 1938)
14:40 - 15:00 | Author(s): J. Bogart
- Abstract
- Presentation
Abstract:
This session reviews considerations of imaging for radiotherapy planning and delivery with particular focus on available completed and active prospective clinical research. State - of - the - art (intensive) treatment approaches, including definitive concurrent radiotherapy and chemotherapy for locally advanced lung cancer, and stereotactic body radiotherapy for treating early stage lung cancer, depend on the ability to precisely identify sites of gross tumor and surrounding critical normal structures. As such, the incorporation of optimal anatomic and functional imaging studies, both three-dimensional (3D) and four-dimensional (4D), in the radiation planning process has become increasing critical. Prospective trials initiated in the late 1990's were the first studies assessing three-dimensional conformal radiotherapy based on computed tomography simulation. These trials directly assessed the ability to adequately dose 3D targets and permitted implementation of tissue heterogeneity dose correction. The routine inclusion of mediastinal lymph node stations that were not pathologically enlarged was also questioned in the design of these studies, and while the initial prospective study from the University of North Carolina mandated elective nodal irradiation (ENI), subsequent studies performed by the RTOG and NCCTG did not include ENI. These single arm prospective studies suggested improved survival in stage III disease with delivery of high dose conventionally fractionated radiotherapy. Somewhat surprisingly, the landmark RTOG 0617 phase III trial did not confirm these results, but perhaps refinement of target volumes through improved imaging (and treatment planning/delivery) would lead to a different result. Functional imaging with FDG-PET (/CT) has had a profound overall impact on the staging and ultimate therapy for patients with lung cancer, and radiotherapy plans are frequently altered by including FDG-PET imaging data in addition to cross sectional imaging. Moreover, while the treatment volume may be increased, such as inclusion of PET avid mediastinal lymph nodes not enlarged on CT, the radiation target volume may also be reduced particularly in instances with atelectasis or tumor obstruction. Prospective studies in the US and Europe have prospectively assessed the impact of PET on radiotherapy planning. For example, RTOG 0515 reported that PET/CT-derived tumor volumes were smaller than those derived by CT alone and that PET/CT changed nodal GTV contours in most patients. Techniques to determine the gross target volume using PET images vary and include simple visualization and a variety of software / hardware based methods including automated solutions. This remains an area of active investigtion and an understanding of potential pitfalls of PET fusion with CT simulation is necessary in defining target volumes. Retrospective series suggest a correlation between the pre-treatment standardized uptake value (SUV) and survival in patients with non-small cell lung cancer. Though the primary objective of ACRIN 6668 / RTOG 0235 was to assess post-treatment SUV for patients receiving radiotherapy as part of their treatment for stage III NSCLC, pre-treatment FDG-PET SUV (mean and max) were also assessed. While pre-treatment FDG-PET SUV did not predict outcomes, active research is assessing the delivery of differential dosing (via IMRT dose painting) based on variation in PET activity. Understanding the impact of tumor and organ motion during respiration is essential when utilizing highly conformal techniques in treating lung cancer. This is a key component of the simulation process and AAPM Task Group 76 describes various options for tumor motion management in detail. Four-dimensional CT-simulation 4D CT is accomplished by correlating the motion of an external surrogate device to the time signature of CT scans. Multiple scans are acquired during each phase of respiration and should provide sufficient motion detail to properly define the internal target volume (ITV). These phase calibrated images can then be processed into average or maximal intensity projections (MIP), or used directly as a cinema image of the tumor motion. In order to incorporate the extent of tumor motion from breathing during SBRT, contouring on the MIP, as opposed to helical or average intensity images, may be optimal. Tumor motion seen on the 4D CT is only representative of the motion at the time of simulation, so further assessment is needed to ensure this will be representative of tumor motion during the actual treatment. Real-time confirmation of tumor location during treatment, whether using the ITV method, respiratory gating, or tumor tracking may be provided by use of “cine” mode or fluoroscopy. Routine real-time imaging should be performed given the potential for variability in breathing and tumor motion over the treatment course. Image guided radiotherapy (IGRT), particularly KV cone-beam CT (CBCT) or MV – CT, is essential for ensuring accurate tumor targeting during radiotherapy. For example, image guidance capable of confirming the position of the target with each treatment was required for the RTOG 0236 trial.While the majority of clinical experience is based on 3D CBCT, 4D (respiration correlated) CBCT is now commercially available and reduces motion artifact and may have additional advantages over 3D CBCT in the treatment of lung tumors. IGRT also allows for routine assessment of tumor response and anatomic changes over time and facilitates implementation of adaptive radiotherapy approaches. Several experiences have detailed changes in tumor volume during the radiotherapy course and the (potential) impact of revising the radiotherapy plan during therapy. An ongoing prospective randomized phase II trial, RTOG 1106, is studying adaptive radiotherapy in stage III non-small cell lung cancer by incorporating changes in both functional and anatomic imaging. Repeat PET/CT and CT simulation in the midst of RT is performed for all patients on study with the “boost” volume in the experimental arm defined by the repeat PET/CT. The total dose for each patient in the experimental arm is dictated by the boost volume and predicted NTCP toxicity. The RTOG 1106 trial includes evaluation of [18]F-fluoromisonidazole (FMiso) PET imaging, which may help identify areas of hypoxia, in a subset of patients. Magnetic resonance imaging (MRI) traditionally has been reserved for assessment of select lung tumors (potentially) invading soft tissue structures such as chest wall, mediastinum, lung apex in proximity to the brachial plexus (pancoast tumors), and lesions in proximity to the spinal cord. The recent development of a commercial hybrid radiotherapy /MRI unit may expand the role of MRI and permits IGRT (without the need for additional patient exposure to ionizing radiation) while also facilitating soft tisse tracking and adaptive radiotherapy.
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MS20.03 - Optimal Monitoring After Combined Modality Treatment (Imaging and Markers) (ID 1939)
15:00 - 15:20 | Author(s): M. Macmanus
- Abstract
- Presentation
Abstract:
When response assessment is carried out after definitive high-dose radiation therapy (RT) or chemoRT for patients with locally-advanced non-small cell lung cancer (NSCLC), it should give an early indication of the likely prognosis of the patient. Ideally it should identify those patients most likely to experience long term freedom from progression, who require no further therapy, and it should further identify patients with persistent or progressive disease who could benefit from additional therapy or who may be candidates for clinical trials of investigational treatments designed to improve their poor prognosis. In usual clinical practice, response assessment in NSCLC involves the use of structural imaging with computed tomography (CT), to assess the effect of treatment on tumor volumes. The initial dimensions of tumor sites are compared with their dimensions after treatment, either on a single occasion or with serial images acquired over time. Potential sites of distant disease progression are also sought within the field of view of the restaging CT scan although this is a relatively insensitive test for small volume metastatic tumour. Another possible approach to response assessment is to employ a global measure of the success of therapy, typically by analysing serial blood samples for a tumor-specific biomarker. A sensitive blood-based assay could potentially detect the presence of very small amounts of persistent tumor, beyond the resolution of currently available imaging modalities. A disadvantage of a blood test compared to imaging in a locoregionally confined rather than a metastatic cancer is the absence of any indication of the likely location of persistent or recurrent disease, making it impossible to implement any local salvage therapies without additional information. However, a combination of a sensitive biomarker and state of the art imaging could potentially provide detailed and clinically useful prognostic information after therapy. The use of both local and global approaches to response assessment will be discussed.Using Imaging to assess local Treatment Response in NSCLCStructural Imaging Traditionally, serial imaging with CT has been used to assess treatment response in NSCLC. Serial tumor measurements are compared with specific response assessment criteria, enshrined in systems such as the Response Evaluation Criteria In Solid Tumors (RECIST) [1]. Patients are categorized by RECIST as having either; Complete Response (CR): Disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started, or Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions Although these categories have prognostic significance, they can be an unreliable predictor of ultimate survival in individual cases. Tumor masses are often slow to resolve after RT and their margins may be obscured by fibrotic or consolidated lung, making accurate measurements impossible. The very concept of remission is hard to define after RT in NSCLC because of the changes in the thorax that occur due to a combination of invasion and destruction of parenchyma by tumor and of the morphological changes that result from atelectasis, radiation pneumonitis and radaition induced pulmonary fibrosis. Fibrotic masses may persist indefinitely even in cured cases. Regions of dense fibrosis can harbor persistent tumor that only becomes apparent when regrowth occurs months or years after treatment is complete. The CR category, with disappearance of all lesions, may be especially hard to define on CT imaging. CT scanning, although it is the standard response assessment modality in clinical trials, has very significant limitations when used for this purpose.Functional Imaging with PET Some of the limitations of CT can be transcended by the use of molecular imaging. The advent of positron emission tomography (PET), using [18]F-fluoro-deoxyglucose (FDG) as the tracer, has provided a means of “seeing inside” areas of fibrosis and persistent mass lesions and identifying focal areas of persistent tumor. Furthermore PET imaging compensates for another major limitation of CT, that of its poor sensitivity and specificity for assessing the true status of mediastinal nodes. Unlike CT, PET can detect tumor in small (<1cm short axis) mediastinal nodes and correctly defines enlarged reactive nodes as non-malignant in the great majority of cases. Several meta-analyses have confirmed the superiority of PET-based mediastinal staging in this regard, making it a logical choice for re-staging the mediastinum after therapy. Prospective data have shown the superiority of PET-based response assessment compared to CT-based response assessment after RT in NSCLC. Our group developed FDG-PET response criteria based on visual assessment and used them prospectively in patients treated with RT/chemoRT [2]. Patients were classified into four metabolic response categories groups, namely; 1) Complete Metabolic Response (CMR): tumor FDG uptake absent or less than mediastinal blood pool. 2) Partial Metabolic Response (PMR): appreciable reduction in the intensity of tumor FDG uptake or tumor volume. 3) Stable Metabolic Disease (SMD): no appreciable change in intensity of tumor FDG uptake or volume. 4) Progressive Metabolic Disease (SMD); any new sites of disease, and/or an appreciable increase in intensity of tumour FDG uptake or volume in known tumor sites. In 73 patients, PET response was evaluated at a median of 70 days post-treatment. PET and CT responses were the same in only 40% of cases and PET response predicted survival much better than CT response. There were many more complete responders on FDG criteria (n=34) compared to CT (N=10), and no patients were inevaluable by PET on compared to 6 on CT. In this study, PET was clearly far superior to CT and in an expanded cohort it was clear that a poor PET response was strongly associated with distant metastasis [3]. Without standardization, the use of visual response criteria may be limited by interobserver variability. The Deauville criteria were developed specifically for use in lymphoma in an effort to standardise visual response assessment by comparing residual tumor FDG uptake with uptake in the liver and mediastinum [4]. Another way to reduce interobserver variability is to use a semi-quantitative method of response assessment, such as by comparing pre- and post treatment standardized uptake values (SUV). Although this is an attractive approach, accuracy may be affected by differences technique on different scanning occasions and by the fact that after treatment, uptake of FDG in radiation penumonitis is often within the range associated with the presence of tumor. This is especially so after high dose hypofractionated stereotactic body radiotherapy (SBRT). It is inappropriate therefore to consider a particular SUV cut-off as being diagnostic of persistent disease. Uptake in lung affected by radiation pneumonitis can also hamper visual response assessment but on a qualitative reading of the scan, pattern recognition can take this into account and still provide valuable prognostic information [5]. Despite the apparent superiority of PET for response assessment, no large prospective studies have yet helped refine how this information might be used. The ideal time for imaging is undecided. A longer interval between treatment and imaging is likely to be associated with greater accuracy but less clinical utility. The use of PET imaging during RT is being actively explored by several groups but remains investigational. In anecdotal cases, patients with resectable PET-detected residual disease have undergone successful salvage surgery after RT but large prospective trials are required to validate this approach.Use of circulating biomarkers to measure global treatment response in NSCLC In some cancers, the use of biomarkers in the blood to monitor disease status is a well established part of standard management. Commonly used circulating biomarkers include paraproteins in multiple myeloma, prostate specific antigen in prostate cancer and alpha-fetoprotein and human chorionic gonadotrophin in germ cell tumors. These markers can be highly specific and sensitive and can be used to guide therapy. However, in NSCLC, the search for a practical circulating biomarker with wide application has been hampered by the extreme heterogeneity of this group of diseases. Two of the most intensely investigated tumor biomarkers in NSCLC have been carcinoemryonic antigen (CEA), which is commonly detected in adenocarcinoma and CYFRA21-1 which can be detected in squamous carcinoma. In a review of the literature in 2012, Grunnet and Sorensen analysed the level of CEA as a prognostic marker in NSCLC in 23 studies of serum and two of plasma [6]. In 18 studies CEA was found to be a prognostic marker for either overall survival OS, recurrence after surgery and/or progression free survival (PFS) in NSCLC patients. The remaining 7 studies contained an excess of patients with squamous carcinoma. One study found that a tumor marker index (TMI), based on preoperative CEA and CYFRA21-1 serum levels was useful as a prognostic marker for OS. Six studies evaluated the use of CEA as a predictive marker. Four of these studies found, that serial CEA measurement had some potential as a predictive marker for recurrence and death. Although a combination of CEA and CYFRA21-1 markers have some value in a proportion of patients with NSCLC the heterogeneity of their expression limits their role in response assessment after RT [7]. Measurement of circulating tumor (ct)DNA has shown promise as a "liquid biopsy" for assessing cancer burden but ctDNA detection methods have to date been insensitive or lacked the broad coverage needed to permit clinical application in NSCLC where genetic variation is extreme. Because background circulating DNA is present in healthy individuals, tumour derived ctDNA can be detected and quantified only if it contains a tumour specific sequence. Diehn and colleagues at Stanford reported a breakthrough in ctDNA in NSCLC, which they called “Cancer Personalized Profiling by Deep Sequencing” (CAPP-Seq) [8]. This is an ultrasensitive method for quantifying ctDNA with clinical applicability. CAPP-Seq was implemented in NSCLC patients with a design covering multiple classes of somatic alterations that identified mutations in >95% of tumours. The method detected ctDNA in 100% of patients with stage II–IV NSCLC and in 50% of patients with stage I disease, with 96% specificity for mutant allele fractions down to ~0.02%. At least one, and on average 4, mutations were covered in >95% of patients. Levels of ctDNA detected by CAPP-Seq were highly correlated with tumour volume and helped distinguish between residual disease and treatment-related imaging changes in several cases. A large clinical trial is being planned to establish the utility of ctDNA for monitoring disease status after RT in NSCLC.Conclusions Structural imaging with CT gives useful prognostic information after RT in NSCLC but is inferior to FDG-PET. Of all of the blood based methods for estimating global tumour burden, ctDNA analysis seems the most promising at present. A combination of PET and ctDNA could potentially provide prognostic information of previously unattainable accuracy and utility.References1. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205-216.2. Mac Manus MP, Hicks RJ, Matthews JP, et al. Positron emission tomography is superior to computed tomography scanning for response-assessment after radical radiotherapy or chemoradiotherapy in patients with non-small-cell lung cancer. J Clin Oncol 2003;21:1285-1292.3. Mac Manus MP, Hicks RJ, Matthews JP, Wirth A, Rischin D, Ball DL. Metabolic (FDG-PET) response after radical radiotherapy/chemoradiotherapy for non-small cell lung cancer correlates with patterns of failure. Lung Cancer 2005;49:95-108.4. Gallamini A, Barrington SF, Biggi A, et al. The predictive role of interim positron emission tomography for Hodgkin lymphoma treatment outcome is confirmed using the interpretation criteria of the Deauville five-point scale. Haematologica 2014;99:1107-1113.5. Hicks RJ, Mac Manus MP, Matthews JP, et al. Early FDG-PET imaging after radical radiotherapy for non-small-cell lung cancer: inflammatory changes in normal tissues correlate with tumor response and do not confound therapeutic response evaluation. Int J Radiat Oncol Biol Phys 2004;60:412-418.6. Grunnet M, Sorensen JB. Carcinoembryonic antigen (CEA) as tumor marker in lung cancer. Lung Cancer 2012;76:138-143.7. Okamura K, Takayama K, Izumi M, Harada T, Furuyama K, Nakanishi Y. Diagnostic value of CEA and CYFRA 21-1 tumor markers in primary lung cancer. Lung Cancer 2013;80:45-49.8. Newman AM, Bratman SV, To J, et al. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med 2014;20:548-554.
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MS20.04 - Prevention, Diagnosis and Treatment of Radiation Pneumonitis (ID 1940)
15:20 - 15:40 | Author(s): L. Gaspar
- Abstract
- Presentation
Abstract not provided
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ORAL 13 - Immunotherapy Biomarkers (ID 104)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 8
- Moderators:D. Kim, D. Grunenwald
- Coordinates: 9/07/2015, 16:45 - 18:15, Four Seasons Ballroom F3+F4
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ORAL13.01 - PD-L1 Expression in Lung Adenocarcinomas Correlates with KRAS Mutations and Th1/Cytotoxic T Lymphocyte Microenvironment (ID 2496)
16:45 - 16:56 | Author(s): T. Huynh, V. Morales-Oyarvide, H. Uruga, E. Bozkurtlar, J.F. Gainor, A. Hata, E. Mark, M. Lanuti, J.A. Engelman, M. Mino-Kenudson
- Abstract
- Presentation
Background:
The interaction of PD-1, with its ligand, PD-L1 induces apoptosis of T cells and inhibits cytokine production, allowing tumor cells to bypass immune surveillance. PD-L1 expression on tumor cells can be upregulated via interferon gamma that is secreted by CD8+ cytotoxic T lymphocytes (CTLs) and/or Th1 pathway activation, counterbalancing the Th1/CTL microenvironment. Blockade of the PD-1/PD-L1 immune checkpoint in solid tumors has resulted in durable responses in early phase clinical trials. Moreover, protein expression of PD-L1 by immunohistochemistry (IHC) reportedly predicts patient response to anti-PD-1/PD-L1 therapies. Multiple studies have reported associations of PD-L1 expression with clinicopathological variables in lung adenocarcinomas (ADC), but such studies have produced conflicting results, possibly due to use of different antibody clones and cutoffs and possibly different ethnicities of the cohort. Thus, we correlated PD-L1 expression with clinicopathological and molecular profiles including subtypes of tumor infiltrating lymphocytes (TILs) in a large lung ADC cohort using a cut-off commonly used in clinical trials.
Methods:
PD-L1 (E1L3N, 1:200, CST), CD8 (4B11, RTU, Leica Bond), T-bet (Th1 transcription factor, D6N8B, 1:100, CST), and GATA3 (Th2 transcription factor, L50-823, 1:250, Biocare) IHC were performed on tissue microarrays constructed of 242 resected lung ADC. All cases underwent detailed histological analysis and a subset (n=128) of cases underwent clinical molecular testing. Membranous expression (regardless of intensity) in 5% or more tumor cells was deemed positive for PD-L1 expression. CD8+, T-bet+ and GATA3+ tumor infiltrating lymphocytes (TILs) were evaluated using a 4-tier grading system (0-3).
Results:
Our study cohort consisted of 242 patients with a pathologic stage of 0 in 1 case, I in 188, II in 37, III in 9, and IV in 7. Among those, 38 (15.7%) exhibited PD-L1 expression which was significantly associated with smoking history (p=0.008), large tumor size (p=0.007), solid predominant pattern (p<0.001), high nuclear grade (grade 3, p<0.001), vascular invasion (p=0.012), increased T-bet+ TILs (grade 2, p<0.001) and CD8+ TILs (grade 2, p<0.001), and KRAS mutations (p=0.001). High nuclear grade (p=0.011), KRAS mutations (p=0.004), and increased CD8+ TILs (p=0.005) remained significant predictors of PD-L1 expression in multivariate analysis, while advanced stage (II or higher vs. I, p=0.056) showed a trend towards PD-L1 expression. There was no difference in the 5-year progression free survival (PFS) between the PD-L1 positive and negative patients. In contrast, increased CD8+ TILs showed a borderline significance with favorable outcome (p=0.082), with the 5-year PFS being 87% for the CD8 positive group and 68% for the CD8 negative group, but neither PD-L1 nor CD8+ TILs was a significant predictor of survival by the cox proportional-hazards regression model.
Conclusion:
PD-L1 expression in ADC significantly correlates with KRAS mutations and several clinicopathological signatures of KRAS-mutants, including significant smoking history. The latter may have resulted in development of multiple passenger mutations that serve as neoantigens promoting the Th1/CTL microenvironment. These results suggest that blockade of the PD-1/PD-L1 axis may be a promising treatment strategy to reinstitute the Th1/CTL microenvironment for patients with KRAS-mutated ADC, in which there are currently no available treatment options.
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ORAL13.02 - Characterization of PD-L1 Expression Related to Unique Genes in NSCLC Tissue Samples (ID 2173)
16:56 - 17:07 | Author(s): E.B. Garon, R. McKenna, J. Dering, B. Wolf, S. Pitts, N. Kamranpour, H. Chen, A. Lisberg, R.B. Cameron, J.M. Lee, S.M. Dubinett, D.J. Slamon
- Abstract
- Presentation
Background:
Programmed cell death protein 1 (PD-1) receptors are members of the B7:CD28 family that interact with PD-1 ligands PD-L1 and PD-L2 to regulate cytotoxic T cell (CTL) tolerance (Freeman, J Exp Med. 2000; Latchman, Nat Immunol. 2001). Successful evasion of transformed cells from host defense is a feature of cancer (Hanahan, Cell 2011). Immune evasion can occur via the engagement of PD-1 with PD-L1 or PD-L2 (Dong, Nature Med 2002). In metastatic non-small cell lung cancer (NSCLC), PD-L1 expression has been associated with increased response to inhibitors of PD-1 (Garon, NEJM 2015). Current adjuvant cytotoxic approaches are associated with a real but small survival increases and significant toxicity. Characterization of PD-L1 expression in resected tumors could guide development of immune checkpoint based adjuvant trials.
Methods:
Microarray analyses were performed to assess gene expression for 320 NSCLC and 15 normal lung resection specimens profiled on the Agilent Whole Human Genome 4x44K 2-color platform. The reference sample used in the experiments was an equal mixture of 258 of the 320 NSCLC samples included in the study. Microarray data was imported into Rosetta Resolver for analysis. The Rosetta Similarity Tool (ROAST) was utilized to find genes correlated to PD-L1 expression. Both PD-L1 and the target gene had to be differentially expressed for sample to be included in computation of correlation. Cosine correlation was used as the similarity metric. Functional genomic analysis on the list of PD-L1 correlated genes was performed using tools available with the DAVID Bioinformatics resources (david.abcc.ncifcrf.gov) Survival analyses based on PD-L1 expression were performed using the Kaplan-Meier method and compared using the log-rank test. Samples with PD-L1 log(ratio) > 0 and p-value < 0.01 were classified as upregulated, samples with p-value>0.01 were classified as unchanged, and sample with log(ratio) < 0 and p-value <0.01 were classified as downregulated.
Results:
The reference level of PD-L1 expression among the subset of normal lung and NSCLC tissue samples was higher compared to levels seen in 503 breast cancer and 149 endometrial cancer tissue samples. Within the 320 NSCLC tissue samples, 174 unique genes are highly correlated with PD-L1 expression (r range= 0.692-0.904). 80 tissue samples (25%) had a PD-L1 log ratio > 0, and 63 tissue samples had large sets of highly correlated genes, a similar prevalence to membranous staining in half the cells in metastatic NSCLC (Garon, NEJM 2015). Functional analyses revealed that the genes significantly correlated with PD-L1 expression were involved in immune and inflammatory response. No significant difference in overall survival was noted (p=.661), but increased PD-L1 expression was clearly not associated with better outcomes.
Conclusion:
Within the NSCLC cohort, there is a group of patients with high expression for PD-L1 and related genes. This group does not have a better prognosis in comparison to those with typical or decreased PD-L1 expression. Due to the relationship between PD-L1 expression and response to anti-PD-1 therapy in metastatic NSCLC, this data and its correlation with other clinical characteristics of the patients can guide the design of adjuvant approaches based on immune checkpoint inhibitors.
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ORAL13.03 - Spatiotemporal Effects on Programmed Death Ligand 1 (PD-L1) Expression and Immunophenotype of Non-Small Cell Lung Cancer (NSCLC) (ID 1609)
17:07 - 17:18 | Author(s): M. Kowanetz, H. Koeppen, M. Boe, J.E. Chaft, C.M. Rudin, W. Zou, D. Nickles, R. Desai, R. Nakamura, A. Sandler, L. Amler, P. Hegde, N.A. Rizvi, M.D. Hellmann
- Abstract
Background:
PD-L1 is one of the immune-checkpoint molecules that regulates Th1 immune responses and mediates cancer immune evasion. PD-L1 can be expressed on tumor cells (TC) or tumor-infiltrating immune cells (IC) and expression in both cell types can negatively regulate T-cell function in the tumor microenvironment. The goal of this study was to evaluate the intra-patient heterogeneity and temporal changes in PD-L1 expression and overall immune phenotype in NSCLC using paired synchronous and metachronous tumor specimens.
Methods:
Thirty-nine patients (pts) with NSCLC treated at Memorial Sloan Kettering Cancer Center were evaluated as part of an IRB approved project. Most were former/current smokers (n=30, 77%) and had adenocarcinoma histology (n=36, 92%). 17 pts were KRAS mutant (45%), and 5 were EGFR mutant (13%). Paired synchronous samples were collected from 17 pts with stage IIIA-N2 resected primary lung and metastatic lymph node (met LN) tissue. Paired metachronous samples were collected from 23 pts (including one patient also with synchronous tissue) with at least two metachronous primary/metastatic (n=14) or metastatic/metastatic tissues (n=9). In pts with metachronous samples, 14 (61%) had systemic intercurrent anti-cancer therapy and 9 (39%) had none. PD-L1 expression was assessed by IHC (clone SP142) on TC and IC. CD8 expression was evaluated by IHC using the C8/144 clone. In addition, expression of ~600 immune genes was analyzed by iChip.
Results:
Twenty-five out of 39 tissue pairs were evaluable by PD-L1 IHC (14/17 synchronous, 11/23 metachronous). Among pts with synchronous samples, in the primary tumor, PD-L1 was expressed in <1% of TC or IC in 6 pts, in 1-4% of cells in 5 pts, and in ≥5% of cells in 3 pts. Among those with metachronous samples, in the first collected sample, the PD-L1 expression in <1% of TC or IC was detected in 6 pts, in 1-4% of cells in 2 pts, and in ≥5% of cells in 3 pts. PD-L1 expression was similar across all paired tissues. PD-L1 status at the TC or IC 5% cut-off remained unchanged in all evaluable paired specimens and at the TC or IC 1% cut-off remained unchanged in 80% (11/14 synchronous and 9/11 metachronous) pairs. In both synchronous and metachronous samples, CD8 expression was also similar across paired specimens. The median inter-sample difference in CD8+ T-cell infiltration was 0.5% (95% CI: -0.6% - 3.4%) in synchronous pairs; three pts had a difference >5%. In metachronous pairs, the median difference was -0.4% (95% CI: -1.4% - 0.1%); one pt had a >5% change in CD8+ T-cell infiltration.
Conclusion:
In this study, there was a high agreement in PD-L1 expression and CD8+ T-cell infiltration in both paired synchronous and metachronous NSCLC specimens. The low intra-patient heterogeneity of PD-L1 and CD8 expression in this study suggests any available tissue (e.g. primary or met) may be reliable to assess these markers in NSCLC. Overall immune characterization by gene expression analysis in paired tumor specimens will be presented.
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ORAL13.04 - Discussant for ORAL13.01, ORAL13.02, ORAL13.03 (ID 3403)
17:18 - 17:28 | Author(s): S.N. Gettinger
- Abstract
- Presentation
Abstract not provided
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ORAL13.05 - Predictive Biomarker Testing for Programmed Cell Death 1 Inhibition in Non-Small Cell Lung Cancer (ID 1081)
17:28 - 17:39 | Author(s): B.S. Sheffield, G. Geller, E. Pleasance, S. Zachara-Szczakowski, K. Milne, S.E. Kalloger, E. Zhao, S. Bidnur, M. Jones, B.H. Nelson, S. Yip, M.A. Marra, J. Laskin, C. Ho, D. Ionescu
- Abstract
- Presentation
Background:
Lung cancer is the largest cause of cancer-related mortality in the developed world. Advances in molecular targeted therapies have led to improved survival in a subset of non-small cell lung cancer (NSCLC) patients. Recently, inhibitors of the programmed cell death receptor 1 (PD1) have proven clinical efficacy in NSCLC. Only a subset of patients respond to PD1 inhibitors, likely reflecting variation in tumor-expression of the PD1 ligand (PD-L1). Many clinical trials have evaluated PD-L1 as a possible predictive biomarker for immune therapy; however several parallel and uncoordinated efforts have led to a high amount of heterogeneity, uncertainty, and ambiguity in the literature around PD-L1 and its use as a biomarker. We aim to investigate the feasibility of PD-L1 biomarker testing in NSCLC using immunohistochemistry (IHC).
Methods:
Cases of stage II, surgically resected NSCLC, adenocarcinoma were identified retrospectively from the archives of the British Columbia Cancer Agency. A tissue microarray (TMA) was constructed with matched primary and metastatic lung tumors. IHC directed towards PD-L1 was performed with 3 different primary antibody clones: E1L3N (Cell Signaling Technology), SP142 (Spring Bioscience), and 28-8 (Dako), each stain was prepared using a unique protocol. Additional cases of NSCLC with available whole-genome sequence were also stained. Staining results were reviewed and scored by intensity of staining and the percentage of positive tumor cells. Cases with positive staining of any intensity in greater than 1% of tumor cells were considered positive (H score > 1). Clinical, pathological, and genomic features of PD-L1 positive cases were reviewed.
Results:
Eighty cases of NSCLC were identified and used in TMA construction. 78 cases had matched lymph node metastases included in the TMA. 29 cases (36%) were positive by the SP142 clone, 19 (24%) by E1L3N, and 27 (34%) by the 28-8 clone. The 3 clones showed concordant results in 61 (76%) of cases, 15 (19%) discordant cases showed low level staining with SP142/28-8 and no staining with E1L3N, 2 (2.5%) cases showed no staining by 28-8 with moderate staining by SP142/E1L3N. Lymph node metastases showed a concordant PD-L1 score in 65 (83%) cases, with no detectable trend in the discordance. Comparison of primary antibodies showed a high rate of concordance (κ=0.68). Exploratory analysis of 6 additional cases with whole-genome and transcriptome data showed no statistical correlation between PD-L1 IHC and tobacco-induced hypermutation signature (p=0.22), or PD-L1 mRNA expression (R[2] = 0.35) by linear regression.
Conclusion:
PD-L1 IHC is reproducible in the setting of an academic reference laboratory. There are small, but potentially clinically relevant, differences between commercially available PD-L1 diagnostic antibodies. Primary tumor PD-L1 status is generally reflective of metastatic tumor PD-L1 status. Molecular correlates of PD-L1 positive cases remain to be elucidated and warrant further investigation.
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ORAL13.06 - Programmed Death Ligand-1 (PDL-1) Expression in Non-Small Cell Lung Cancer (NSCLC): Analysis of a Large Early Stage Cohort; and Concordance of Expression in Paired Primary-Nodal and Primary-Metastasis Tumour Samples (ID 3226)
17:39 - 17:50 | Author(s): P. Mitchell, C. Murone, K. Asadi, C. Harbison, S. Knight, T. John
- Abstract
- Presentation
Background:
PDL-1 expression in NSCLC is frequently associated with response to PD-1 pathway inhibitor therapy. However, it is unclear whether PDL-1 expression status is maintained in nodes and distant metastases and further information is needed on the relationship between expression and patient and tumour characteristics and prognosis
Methods:
TMAs were constructed using 1mm cores (triplicate) of FFPE primary tumour from patients undergoing surgery with curative intent, from N2 nodal tumour (triplicate) and from metastatic NSCLC tumour (duplicate cores or single small sections). PDL-1 protein expression was measured using a validated, automated immuno-histochemical assay using the 28-8 monoclonal antibody (Dako, Carpinteria, CA), with samples categorised as positive when tumour cell membranes were stained to any intensity in 5% of assessable tumour in any core.
Results:
57 paired primary–metastasis cases were analysed: median age 64 years (33-56); 30 male (53%); adenocarcinoma 27 (47%) and squamous cell 15 (26%). Metastatic sites were: brain 27; trachea/bronchus/lung/pleura 17; chest wall/skin 5; lymph nodes 6. Seven cases were synchronous (6 brain) while the median interval between primary and metastasis for other cases was 1.3 years (range 0.2-8.5). Primary and metastatic tumour samples were PDL1 positive for 13 (23%) and 14 (25%) cases respectively and for 44 cases (77%) expression was concordant. Discordance with negative primary and positive metastasis was seen in 7 cases (12%), while 6 cases (11%) were positive in primary and negative in metastasis. Using assay cut offs of 1% and 50%, concordance was 63% and 89% respectively. Eight cases had more than one metastasis analysed and the primary and all metastases were concordant for 6 cases while 2 cases were positive in primary but negative in one of the metastases. TMAs from 518 primary cases were also analysed and data on 123 cases are currently available. Histology was adenocarcinoma 58 (47%) and squamous 38 (31%). Thirty seven cases (30%) were PDL1+. Of the 13 never or light (≤10 PY) smokers, only 2 (9%) were positive. Further data on all cases and matched primary-nodes will be presented.
Conclusion:
PDL1 expression in ≥5% tumour cell was seen in 30% of cases. Concordance of expression in matched primary and metastasis was seen in 77% of cases. These data suggest that if PDL-1 expression status is critical in the decision to treat metastatic NSCLC with a PD-1 pathway inhibitor, then re-biopsy of a metastasis may be warranted.
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ORAL13.07 - EMT Is Associated with an Inflammatory Tumor Microenvironment with Elevation of Immune Checkpoints and Suppressive Cytokines in Lung Cancer (ID 2134)
17:50 - 18:01 | Author(s): Y. Lou, L. Diao, E.R.P. Cuentas, W. Denning, L. Chen, Y. Fan, J. Rodriguez, L. Byers, J. Wang, V. Papadimitrakopoulou, C. Behrens, I.I. Wistuba, P. Hwu, J.V. Heymach, D.L. Gibbons
- Abstract
- Presentation
Background:
Promising results in the treatment of NSCLC have been seen with immunomodulatory agents targeting immune checkpoints, such as programmed cell death 1 (PD-1) or programmed cell death 1 ligand (PD-L1). However, only a select group of patients respond to these interventions. The identification of biomarkers that predict clinical benefit to immune checkpoint blockade is critical to successful clinical translation of these agents. Epithelial-mesenchymal transition (EMT) is a key process driving metastasis and drug resistance. Previously we have developed a robust EMT gene signature, highlighting differential patterns of drug responsiveness for epithelial and mesenchymal tumor cells.
Methods:
We conducted an integrated analysis of gene expression profiling from three independent large datasets, including The Cancer Genome Atlas (TCGA) of lung and two large datasets from MD Anderson Cancer Center, Profiling of Resistance patterns and Oncogenic Signaling Pathways in Evaluation of Cancers of the Thorax (named PROSPECT) and the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (named BATTLE-1). Comprehensive analysis of mRNA gene expression, reverse phase protein array (RPPA), immunohistochemistry, in vivo mouse models and correlation with clinical data were performed.
Results:
EMT is highly associated with an inflammatory tumor microenvironment in lung adenocarcinoma, independent of tumor mutational burden. We found immune activation co-existent with elevation of immune checkpoint molecules, including PD-L1, PD-L2, PD-1, TIM-3, BTLA and CTLA-4, along with increases in tumor infiltration by CD4+Foxp3+ regulatory T cells in lung adenocarcinomas that displayed an EMT phenotype. Similarly, IL-6 and indoleamine 2, 3-dioxygenase (IDO) were elevated in these tumors. We demonstrate that in murine models of lung adenocarcinoma, many of these changes are recapitulated by modulation of the miR-200/ZEB1 axis, a known regulator of EMT. Furthermore, B7-H3 is found to negatively correlate with overall survival and recurrence free survival, indicating a potential new therapeutic target in lung adenocarcinoma in the future.
Conclusion:
EMT, commonly related to cancer metastasis and drug resistance, is highly associated with an inflammatory tumor microenvironment with elevation of multiple targetable immune checkpoints and that is regulated at least in part by the miR-200/ZEB1 axis. These findings suggest that EMT may have potential utility as a biomarker selecting patients more likely to benefit from immune checkpoint blockade agents and other immunotherapies in NSCLC and possibly a broad range of other cancers.
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ORAL13.08 - Discussant for ORAL13.05, ORAL13.06, ORAL13.07 (ID 3404)
18:01 - 18:11 | Author(s): D. Rimm
- Abstract
- Presentation
Abstract not provided
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MINI 36 - Imaging and Diagnostic Workup (ID 163)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Screening and Early Detection
- Presentations: 1
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MINI36.10 - Discussant for MINI36.07, MINI36.08, MINI36.09 (ID 3556)
19:20 - 19:30 | Author(s): D. Grunenwald
- Abstract
- Presentation
Abstract not provided
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