PL2-02: Molecular staging of lung cancer

Journal of Thoracic Oncology • Volume 2, Number 8, Supplement 4, August 2007

• Reclassify T2aN1 tumours (≤5 cm) as stage IIA (from IIB). • Reclassify T2bN0 tumours (>5-7 cm) as stage IIA (from IB). • Reclassify T4N0 and T4N1 tumours as stage IIIA (from IIIB).

descriptors in the forthcoming (7th) edition of the TNM classification for Lung Cancer. J Thorac Oncol 2007;X:XXX-XXX.

4. Postmus PE, Brambilla E, Chansky K, Crowley JJ, Patz EF, Yokomise H, Goldstraw P, et al The IASLC Lung Cancer Staging Project: Proposals for revision of the M descriptors in the forthcoming (7th) edition of the TNM classification for Lung Cancer. J Thorac Oncol 2007;X:XXX-XXX.

The resultant TNM stage groupings are summarised as: Occult carcinoma

TX

N0

M0

Stage 0

Tis

N0

M0

Stage IA

T1a, b

N0

M0

Stage IB

T2a

N0

M0

Stage IIA

T1a, b

N1

M0

T2a

N1

M0

T2b

N0

M0

T2b

N1

M0

T3

N0

M0

T1, T2

N2

M0

T3

N1, N2

M0

Stage IIB Stage IIIA

5. Groome PA, Bolejack V, Crowley JJ, Kennedy C, Krasnik M, Sobin LH, Goldstraw P, et al. The IASLC Lung Cancer Staging Project: Validation of the proposals for revision of the T, N, and M descriptors and consequent stage groupings in the forthcoming (7th) edition of the TNM classification for Lung Cancer. J Thorac Oncol 2007;X:XXX-XXX. 6. Goldstraw P, Crowley JJ, Chansky K, Giroux DJ, Groome PA, Rami-Porta R, Postmus PE, Rusch V, Sobin LH, et al. The IASLC Lung Cancer Staging Project: Proposals for revision of the TNM stage groupings in the forthcoming (7th) edition of the TNM classification for Lung Cancer. J Thorac Oncol 2007;X:XXX-XXX.

PL2-02

T4

N0, N1

M0

T4

N2

M0

Any T

N3

M0

Stage IV

Any T

Any N

M1a,b

The table below summarises the descriptors, proposed T and M categories, and proposed stage groupings. Shaded cells indicate a proposed change from the 6th Edition of the TNM Classification for lung cancer for a particular TNM category. Proposed T/M

N0

N1

N2

N3

T1 (<=2cm)

T1a

IA

IIA

IIIA

IIIB

T1 (>2 – 3 cm)

T1b

IA

IIA

IIIA

IIIB

T2(<=5cm)

T2a

IB

IIA

IIIA

IIIB

T2 (>5-7cm)

T2b

IIA

IIB

IIIA

IIIB

T2 (>7cm)

T3

IIB

IIIA

IIIA

IIIB

IIB

IIIA

IIIA

IIIB

T3 invasion T4 (same lobe nodules) T4 (extension)

T4

M1 (ipsilateral lung) T4 (pleural effusion)

M1a

M1 (contralateral lung) M1 (distant)

M1b

Advances in Staging, Tue, Sept 4, 08:15 - 10:00

Molecular staging of lung cancer

Stage IIIB

UICC6 T/M and Descriptor

12th World Conference on Lung Cancer

IIB

IIIA

IIIA

IIIB

IIIA

IIIA

IIIB

IIIB

IIIA

IIIA

IIIB

IIIB

IV

IV

IV

IV

IV

IV

IV

IV

IV

IV

IV

IV

References

1. Goldstraw P, Crowley JJ. The International Association for the Study of Lung Cancer International Staging Project on Lung Cancer. J Thorac Oncol 2006;1:281-286.

2. Rami-Porta R, Ball D, Crowley JJ, Giroux DJ, Jett J, Travis WD, Tsuboi M, Vallieres E, Goldstraw P et al. The IASLC Lung Cancer Staging Project: Proposals for revision of the T descriptors in the forthcoming (7th) edition of the TNM classification for Lung Cancer. J Thorac Oncol 2007;X:XXX-XXX.

3. Rusch V, Crowley JJ, Giroux DJ, Im J-G, Tsuboi M, Tsuchiya R, Vansteenkiste J, Goldstraw P, et al. The IASLC Lung Cancer Staging Project: Proposals for revision of the N

Copyright © 2007 by the International Association for the Study of Lung Cancer

Hirsch, Fred R.; Dziadziuszko, Rafal University of Colorado Cancer Center, Aurora, CO, USA Current staging methods are inadequate for predicting outcome of treatment of lung cancer. Although, the need for better staging systems seems more relevant for early stage disease, improvements in treatment results also for advanced disease calls for a better staging/prognostic system. The ability to define cancer subtypes, recurrence of disease and response to specific therapies using DNA microarray-based gene expression signatures has been demonstrated in multiple studies (1) 1. Early Stage NSCLC; Within the last years emerging data has justified adjuvant therapy for subsets of early stage disease. Clinical studies have not yet justified the role of adjuvant therapy for stage IA. However, still about 25% of the NSCLC patients in stage IA will later have disease recurrence, which emphasize the importance of a better staging system. More recently several studies based on molecular markers have been published indicating the possibility of a more refined classification of NSCLC patients with different outcome after surgery. In a study high risk stage I lung adenocarcinomas of Beer et al (2), it was possible to make a gene-risk profiling based on oligonucleotide array defining clusters of genes with good and poor outcome. A kind of similar approach was taken by Potti et al. (3) in the lung metagene model. The lung metagene model predictited recurrence for individual patients significantly better than did clinical prognostic factors and was consistent across all early stages of NSCLC.The predictor also identified a subgroup of patients with stage IA disease who were at high risk for recurrence and who might be best treated with adjuvant chemotherapy. The metagene predictor is currently validated in a prospective CALGB study. Bild et al.(4) demonstrated that by identifying patterns of several pathway deregulation by using hierarchical clustering, it is possible to identify populations of patients with different prognosis. Independent of tumor histopathology concerted deregulation of Ras with β-catenin, Src and myc identified a group of lung cancer patients with poor survival with a median survival of 19.7 months versus 51.3 months for all other clusters (4). This analysis demonstrated the ability of integrated pathway analysis, based on multiple signatures of component pathway deregulation, to define improved categorization of lung cancer patients. Other studies have used PCR based analysis in order to find a better molecular prognostic signature. In a study from Taiwan a five-gene signature identified from 125 randomly selected patients who had undergone surgical resection of NSCLC, and the model were validated

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Journal of Thoracic Oncology • Volume 2, Number 8, Supplement 4, August 2007

in an independent cohort demonstrating close association with relapsefree and overall survival (5). Future comparative studies need to define “common” signatures from the different studies, which might optimize the gene prognostic models for early stage NSCLC. DNA Synthesis and Repair genes (i. e RRM1 and ERCC1) have been associated with sensitivity to certain chemotherapeutica (gemcitabine/ cisplatinum). The prognostic value of these markers have also been studied by a new immunohistochemistry/fluorescence technique (the AQUA-system), which demonstrated a strong association to survival after surgery for patients between high expression of RRM1 and ERCC1, especially for the 30% of the patients with tumors expressing both markers. As a single marker patients with high expression of RRM1 had an overall survival of 120 months versus 60 months for the patients with low expression (HR for death was 0.61, p=0.02). (6). 2. Advanced Disease: In the advanced disease situation the prognostic information is more related to prediction of sensitivity to any give systemic therapy. Within the last years much progress has been done in this area, both with regard to new targeted therapies as well as conventional chemotherapy. Epidermal Growth Factor Tyrosine Kinase Inhibitors (EGFR TKIs) have demonstrated significant effect in a subset of patients with advanced NSCLC. The identification of certain EGFR mutations role for sensitivity to these agents was a significant discovery and focused the future research in this field (8). EGFR mutations in the tyrosine kinase domain, especially in exons 19 and 21 play a role for response to EGFR TKIs and several reports points to the fact that EGFR mutations in exon 19 are more related to sensitivity than exon 21 mutations, which also seems to have a prognostic association (9). While the EGFR mutations in Asian populations seems to be clearly associated to survival as well, more clinical data seems to be needed to verify the same for the western populations. More consistent association to response and survival has been published for increased EGFR gene copy number detected by FISH (10, 11). While the routine use of tissue based predictive markers could have some limitations in terms of tissue acquisition and tumor heterogeneity, the identification of blood- based predictive markers could be advantageous. Most recently, a serum proteomic profiling was identified, which could distinguish NSCLC patients with good and poor outcome after EGFR TKIs (12). While other targeted therapies have emerged promising in the treatment of advanced NSCLC, no validated predictive molecular signatures have so far been identified, which could immediately be ready for routine clinical management. References: 1. Ramaswamy S and Golub TR: DNA microarrays in clinical oncology. J Clin Oncol 20: 1932-1941, 2002. 2. Beer DG, Kardia SLR, Chiang-Ching H et al: gene-expression profiles predict survival of patients with lung adenocarcinoma. Nature Medicine 8: 816-824.2002 3. Potti A, Mukherjee S, Petersen R et al: A genomic strategy to refine prognosis in earlystage non-small cell lung cancer. N Engl J Med 355: 570-80.2006 4. Bild AH, Yao G, Chang JT et al: Oncogenic pathway signatures in human cancers as guide to targeted therapies. Nature Med 439: 353-357, 2006. 5. Chen H-y, Yu S-L, Chen C-H et al: A five-gene signature and clinical outcome in nonsmall cell lung cancer. N Engl J Med 356: 11-20. 2007 6. Olaussen KA, Dunant A, Fouret P et al: DNA repair by ERCC1 in non-small cell lung cancer and cis-platin based adjuvant chemotherapy. N Engl J Med 335: 983-91. 2006. 7. Zheng Z, Chen T, Li X et al: DNA synthesis and repair genes RRM1 and ERCC1 in lung cancer. N Engl J Med 356:800-8. 2007

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12th World Conference on Lung Cancer

8. Lynch TJ, bell DW, Sordella R et al: activating mutations in the epidermal growth factor receptor underlying responsivness of non-small cell lung cancer to gefitinib. N Engl J Med 350: 2129-2139, 2004. 9. Hirsch FR, Varella-Garcia M, Cappuzzo F et al: combination of EGFR gene copy number and protein expression predicyts outcome for advanced non-small cell lung cancer patients treated with gefitinib. Ann Oncol: 18; 752-760. 2007. 10. Cappuzzo F, Hirsch FR, Rossi E et al: Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small cell lung cancer. J Natl Cancer Inst 97: 643-655 2005 11. Hirsch FR, Varella-Garcia M, McCoy J et al: Increased epidermal growth factor receptor gene copy number detected by FISH is associated with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma subtypes. A Southwest Oncology Group study J Clin Oncol 23: 6838- 6845. 2005 12. Taguchi F, Solomon B, Gregorc V et al: Mass spectrometry to classify non-small cell lung cancer patients for clinical outcome after treatment with epidermal growth factor receptor tyrosine kinase inhibitors: a multicohort cross-institutional study . J Natl Cancer Inst, in press (June) 2007.

PL2-03

Advances in Staging, Tue, Sept 4, 08:15 - 10:00

New imaging techniques (PET, PET/CT, MRI, E(B)US.) for lung cancer staging and response assessment

Smit, Egbert F.1 Hoekstra, Otto S.2 1 Department of Pulmonary Diseases, Vrije Universiteit Medical Centre, Amsterdam, The Netherlands; 2 Department of Nuclear Medicine & PET Research, Vrije Universiteit Medical Centre, Amsterdam, The Netherlands; Appropriate management of (N)SCLC depends on precise disease staging and accurate response assessment. Currently, the tumor-nodemetastases (TMN) staging is used in most parts of the world. The 1997 staging system adopted by the AJCC and UICC is currently undergoing revision as a result of the IASLC staging effort. In the recent years, common imaging modalities used for staging lung cancer patients include chest radiography, CT, magnetic resonance imaging, (FDG)PET and fused modality imaging (PET-CT). Whereas chest CT is useful in identifying tumor location and the presence of mediastinal lymph node involvement, its limitation is the ability to differentiate between benign and malignant pulmonary nodules and lymph nodes. FDG-PET as a single imaging modality has shown to be superior to conventional imaging in direct comparisons with respect to differentiate between benign and malignant pulmonary nodules, mediastinal lymph node metastases and distant metastatic disease (with the noteworthy exception of brain metastases). Although recent reports indicate that the accuracy of staging of integrated PET-CT is superior to either CT alone and dedicated PET that was visually correlated with a CT scan, the true cost-effectiveness of this staging modality is unknown. One drawback of FDG-PET is that it still lacks absolute specificity for differentiating benign (eg inflammation) from malignant disease. For this reason, tissue sampling of “decisive” lesions (eg those that will determine stage) is still mandatory. For suspect mediastinal deposits the procedure of choice has long been invasive surgical staging: depending on their localization either mediastinoscopy, mediastinotomy anterior or less frequently VATS. The advent of ultra sound (US) -guided endoscopes, through which fine needle aspiration is possible, is now changing the diagnostic algorithm. Endobronchial US-guided fine needle aspiration (EBUS) can be performed during fiberoptic bronchoscopy, and a prior (PET-)CT allows nodes to be targeted and sampled, mainly in the same areas accessible to cervical mediastinoscopy, with the addition of some hilar nodes. Esophageal endoscopic ultrasound (EUS) allows examination of the posterior and inferior mediastinum and far more-the liver, the celiac axis, and the left adrenal gland. In Copyright © 2007 by the International Association for the Study of Lung Cancer