Steering Committee. Waiting on photo. Paul A. Bunn, Jr., MD Kavita Garg, MD Kim Geisinger, MD Fred R. Hirsch, Gregory Riely, MD, PhD.

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1 Steering Committee Paul A. Bunn, Jr., MD Kavita Garg, MD Kim Geisinger, MD Fred R. Hirsch, Gregory Riely, MD, PhD MD, PhD Waiting on photo Paul Van Schil, MD, PhD William D. Travis, MD Ming-Sound Tsao, MD, FRCPC Ignacio I. Wistuba, MD

2 Modules and Participating Faculty 1. Introducing The New IASLC/ATS/ERS Lung Adenocarcinoma Classification William D. Travis, MD Memorial Sloan Kettering Cancer Center New York, NY Fred R. Hirsch, MD, PhD University of Colorado Aurora, CO Gregory Riely, MD, PhD Memorial Sloan Kettering Cancer Center New York, NY 2. Implications of the New IASLC/ATS/ERS Classification Fred R. Hirsch, MD, PhD University of Colorado Aurora, CO Paul E. Van Schil, MD, PhD University Hospital of Antwerp Edegem (Antwerp), Belgium William D. Travis, MD Memorial Sloan Kettering Cancer Center New York, NY Kavita Garg, MD University of Colorado Aurora, CO 3. Highlights for the Pathologist Ming S. Tsao, MD, FRCPC Princess Margaret Hospital Toronto, Ontario, Canada Ignacio I. Wistuba, MD The University of Texas M.D. Anderson Cancer Center Houston, TX Kim R. Geisinger, MD Piedmont Pathology Associates Hickory, NC 4. Highlights for the Radiologist Kavita Garg, MD University of Colorado Aurora, CO The faculty wish to acknowledge Drs Yasushi Yatabe (Aichi Cancer Center; Nagoya, Japan) and Andrew Nicholson (Royal Brompton Hospital; London, UK) as external reviewers for this module Gregory Riely, MD, PhD Memorial Sloan Kettering Cancer Center New York, NY The faculty wish to acknowledge Drs Ryutaro Kakinuma(National Cancer Center Hospital; Tokyo, Japan) and Mathias Prokop (University Medical Center; Utrecht, Netherlands) as external reviewers for this module 5. Case Studies for the Practicing Clinician Gregory Riely, MD, PhD Memorial Sloan Kettering Cancer Center New York, NY William D. Travis, MD Memorial Sloan Kettering Cancer Center New York, NY Fred R. Hirsch, MD, PhD University of Colorado Aurora, CO Paul A. Bunn, Jr., MD University of Colorado Aurora, CO Paul E. Van Schil, MD, PhD University Hospital of Antwerp Edegem (Antwerp), Belgium

3 Introducing The New IASLC/ATS/ERS Lung Adenocarcinoma Classification Module 2 Implications of the New IASLC/ATS/ERS Classification

4 Rationale for New Adenocarcinoma Classification Lung cancer has the highest incidence and mortality rates of any major cancer worldwide Adenocarcinoma is the most common histologic subtype of NSCLC Widely divergent clinical, radiologic, molecular and pathologic spectrum Bronchioloalveolar carcinoma (BAC) terminology is confusing Used many different ways despite 99/04 WHO; mucinous/nonmucinous Rapid evolving molecular advances (EGFR, ALK) Different Treatment for squamous and non-squamous ADC=Adenocarcinoma; ALK=Anaplastic Lymphoma Kinase; BAC=Bronchioloalveolar Carcinoma; EGFR=Epidermal Growth Factor Receptor; WHO=World Health Organization

improve outcomes even in earliest-stage disease 5-Year

5 Lung Cancer Survival By Pathologic Stage: IASLC New Classification OS depends on pathologic stage Need to improve outcomes even in earliest-stage disease 5-Year OS rate Goldstraw P, et al. J Thorac Oncol 2007;2:

Biomarker Selection: Purpose Prognostic Marker: Associates with outcome independent of therapy Predictive Marker: Associates with outcome for specific

6 Biomarker Selection: Purpose Prognostic Marker: Associates with outcome independent of therapy Predictive Marker: Associates with outcome for specific therapy Adjuvant Therapy Prognosis Prediction of benefit from specific therapies Advanced Disease Prediction of response/outcome after CT or targeted therapy

8 IASLC/ATS/ERS Adenocarcinoma Classification Preinvasive lesions Atypical Adenomatous Hyperplasia (AAH) Adenocarcinoma in situ (AIS, 3 cm) Non-mucinous Mucinous Minimally Invasive Adenocarcinoma (MIA, 3 cm) Lepidic predominant tumor with 5 mm invasion Invasive adenocarcinoma Lepidic pattern predominant Acinar pattern predominant Papillary pattern predominant Micropapillary pattern predominant Solid pattern predominant

Recurrence-Free Survival by IASLC Histologic Type in Stage I Adenocarcinoma RFS N=514 Histologic Type (n) 5-Yr RFS (%) AIS (1) and MIA (8) 100 Lepidic NM (29) 90 Papillary (143) 83 Acinar

9 Recurrence-Free Survival by IASLC Histologic Type in Stage I Adenocarcinoma RFS N=514 Histologic Type (n) 5-Yr RFS (%) AIS (1) and MIA (8) 100 Lepidic NM (29) 90 Papillary (143) 83 Acinar (232) 85 Mucinous ADC (13) 76 Colloid (9) 71 Solid (67) 71 Micropapillary (12) 64 P = RFS=Recurrence-Free Survival Yoshizawa A. Modern Pathology 2011;24: Time to Recurrence (Years)

10 Why Optimal Classification Matters Growth Pattern: Efficient Prognostic Factor Single institution study of patients with completely resected invasive ADC, N=487, stages IA through IV Patients with lepidic-predominant ADC have better survival than the other subtypes OS DFS Warth A. J Clin Oncol 2012; epub March 5

11 Adenocarcinoma in Situ (Previous BAC): Implications for TNM Staging AIS would be classified as Tis Tis (squamous CIS) Tis (AIS) Similar to breast cancer Tis (DCIS) Tis (LCIS) MIA would be classified as Tmi

12 Stage I Adenocarcinomas (N=514): Multivariate Analysis Factor HR P-value IASLC/ATS/ERS classification (High vs Intermediate/Low Grade) Gender (Male vs Female) Stage (IB vs IA) Invasive Tumor Size* WHO Histologic Grade (Poor vs Moderate/Well) Necrosis (Yes vs No) Vascular invasion (Yes vs No) * Tumor size adjusted by subtracting percentage of lepidic growth ATS=American Thoracic Society; ERS=European Respiratory Society; IASLC=International Association for the Study of Lung Cancer Yoshizawa, A. Mod Path 2011;24:

13 BAC RIP March 31, 2008 BAC Bronchioloalveolar Carcinoma RIP Rest In Peace

14 IASLC/ATS/ERS Adenocarcinoma Classification: Surgical Implications Preinvasive lesions Atypical Adenomatous Hyperplasia (AAH) Adenocarcinoma in situ (AIS, 3 cm) Non-mucinous Mucinous Minimally Invasive Adenocarcinoma (MIA, 3 cm) Lepidic predominant tumor with 5 mm invasion Invasive adenocarcinoma Lepidic pattern predominant Acinar pattern predominant Papillary pattern predominant Micropapillary pattern predominant Solid pattern predominant

15 LCSG 821 Trial Is Lobectomy Standard Therapy for AIS? Lobectomy vs limited resection Prospective, randomized study N=495 registered, N=276 randomized N=247 ultimately eligible Peripheral ct1n0 < 3 cm 50% of registered patients not eligible Not T1 (size, pleura) Not N0 (25% mediastinal LN involvement) Equal postoperative morbidity and mortality LN=Lymph Node Ginsberg RJ. Ann Thorac Surg 1995; 60: Lederle FA. Ann Thorac Surg 1996; 62: Overall Survival p= Recurrence-Free Survival p= 0.042

16 Selection Criteria for Sublobar Resection: Prospective Trials Ongoing JCOG 0804 Ph II, single-arm trial (N = 334) Adenocarcinoma 2 cm GGO with < 25% solid component JCOG 0802 Ph III, randomized trial (N = 1,100) Adenocarcinoma 2 cm GGO with % solid component CALGB Ph III, non-inferiority trial (N = 1,300) Peripheral carcinoma 2 cm with negative hilar nodes Stratification: smoking, histology, tumor size Wedge resection Lobectomy Limited, sublobar resection + LN drop out lobectomy Lobectomy Sublobar resection (segmentectomy/ wedge) Endpoint: RFS Endpoints: OS Pulmonary function Endpoints Primary: OS Secondary: DFS, pulmonary function GGO=Ground-Glass Opacity Asamura H. Workshop Classification Adenocarcinoma, NY, 03/09.Tsuboi M. 12th Annual Lung Cancer Congress, 2011.

17 T1a Peripheral Lung Lesions Prospective, single-center study Goal: to establish an algorithm for the type of resection of small peripheral lesions using new indicators N=179 (10/97-09/02) T1a 2 cm on HRCT Hilar, mediastinal LN 1 cm (cn0) No organ dysfunction (cardiopulmonary or other) No active malignant lesions in other organs CLASSIFICATION 10 mm, any opacity type Any size, pure GGO mm, GGO type mm, solid type mm, GGO type mm, solid type Observation WWR, segmentectomy, VATS lobectomy Segmentectomy and LN sampling Segmentectomy and LN dissection Lobectomy and LN dissection size or density Resection margin + LN frozen section + VATS=video-assisted thoracic surgery; WWR: wide angle resection. Kodama K. Eur J Cardiothorac Surg 2008;34:

18 T1a Peripheral Lung Lesions Disease-Free Survival Overall Survival 5-year limited resection 98% lobectomy 74% 5-year limited resection 97% lobectomy 80% Kodama K. Eur J Cardiothorac Surg 2008;34:

19 Screening-Detected Lung Cancers: Is Systematic Nodal Dissection Always Essential? Screening (N = 97) Non-screening (N = 193) p size nodule SUV max pn0 pn+ pn0 pn+ 10 mm < mm > 10 mm < > 10 mm Systematic nodal dissection can be avoided in early stage cn0 if: SUV max < 2.0 Pathological (not radiological) nodule size 10 mm Pathological diagnosis is AIS Veronesi G, et al. J Thorac Oncol 2011;6:

20 Surgical Key Issues Small (5-10 mm) 100 % GGO nodules suspected to be AIS or MIA: CT follow-up Lobectomy standard treatment for early stage NSCLC Limited resection may be appropriate for AIS-MIA (prospective trials) At least lobe-specific systematic nodal dissection advised ct1-2n0 or non-hilar N1: sampling appropriate Small AIS or MIA: lymph node sampling or dissection may not be required (no randomized trials!) Multiple lung adenocarcinoma considered for resection when multiple synchronous or metachronous, early stage primary tumors intrapulmonary metastases

21 Surgical Areas of Uncertainty Role of limited resection (lack of randomized trials)? Extent of lymph node dissection controversial Accuracy of frozen section (invasive lesions)? Role of focused radiation and radiofrequency ablation for NSCLC 3 cm? How to differentiate multiple primary tumors from synchronous metastases? Role of VATS diagnosis, staging and treatment of early-stage lung cancer? Van Schil P. Eur Resp J 2012;39:

22 Surgical Implications of the New Classification: Conclusions Small nodules: ct1an0 Heterogenous group Different behavior Limited resection: AIS < 2 cm (especially < 1 cm)? Minimally Invasive Adenocarcinoma (MIA)? > 50% GGO component on chest CT Peripheral tumor location No LN involvement Many unresolved issues and questions

23 Kris MG, et al. J Clin Oncol 2011;29: abstr CRA7506. Molecular Profiling of Advanced Adenocarcinoma

24 First-Line EGFR TKI Therapy in EGFR-Mutated Advanced NSCLC EGFR TKIs are superior to chemotherapy in patients with EGFR-mutant tumors: Evidence from randomized trials Trial N Treatment Comparison PFS Median OS WJTOG Gefitinib vs. Cis/Docet NEJ Gefitinib vs. Carbo/Paclit OPTIMAL 165 Erlotinib vs. Carbo/Gem EURTAC 153 Erlotinib vs. Plat-based CT All PFS differences were statistically significant (P < ) OS differences were not statistically significant Mitsudomi T, et al. Lancet Oncol 2010;11: Maemondo M, et al. N Engl J Med 2010;362: Zhou C, et al. Lancet Oncol 2011;12: Rosell R, et al. Lancet Oncol. 2012; epub Jan vs 6 mo HR= vs 5 mo HR= vs 5 mo HR= vs 5 mo HR=0.42 N/A 31 vs 24 mo N/A 23 vs 19 mo

ALK Inhibition in NSCLC: Crizotinib Study A8081001 Best Response (N*=106) Retrospective

25 ALK Inhibition in NSCLC: Crizotinib Study A Best Response (N*=106) Retrospective comparison in ALK-positive patients Treated: from 1001 study Naïve: patient series from study sites OS PFS OS Median PFS = 10.0 mo Median OS: NR (79% pts still in f/u) Survival probability 6 months: 90.0% 12 months: 80.5% Kwak EL. N Engl J Med 2010;363: Shaw AT. Lancet Oncol. 2011;12:

Proposed Methods to Detect ALK-Positive Tumors

Fluorescent in-situ hybridization (FISH) Also

transcriptase polymerase chain reaction (RT-PCR)

26 Proposed Methods to Detect ALK-Positive Tumors Proposed methods of testing Recommended standard: Fluorescent in-situ hybridization (FISH) Also possible Immunohistochemistry (IHC) Reverse transcriptase polymerase chain reaction (RT-PCR) Hirsch F et al. Clin Cancer Res. 2010;16: FISH IHC RT-PCR

27 Pemetrexed is More Effective in ADC and LCC Than in SQCC Pemetrexed is not recommended for patients with SQCC (any treatment line): Evidence from randomized trials Treatment Population N Median OS (Pem vs control) Treatment-by-Histology Interaction Pem/Cis vs Gem/Cis (first-line JMDB trial) Pem vs Docet (second-line) Pem vs Plbo (maintenance JMEN trial) Squamous vs 11 mo Non-squam vs 10 mo Squamous vs 7 mo Non-squam vs 8 mo Squamous vs 11 mo (NS) Non-squam vs 10 mo P = P = P = All OS differences were significantly different between treatment arms, except where noted (NS) Treatment-by-histology interactions were also significant for PFS in all three trials (not shown) LCC=Large-Cell Carcinoma; SQCC=Squamous-Cell Carcinoma Scagliotti G, et al. J Clin Oncol 2008;26: Scagliotti G, et al. Oncologist 2009;14: Ciuleanu T, et al. Lancet 2009; 374:

28 Key Clinical Messages Good Clinical Practice If molecular testing is planned, biopsies should provide sufficient tissue for Pathologic diagnosis Molecular analyses Make cell block whenever possible from cytology specimens (i.e. pleural fluid) Multidisciplinary coordination necessary for rapid diagnosis and molecular testing

29 Conclusions BAC is no longer used. Such tumors are characterized as AIS, MIA, or invasive ADC Histology (ADC subtypes) is a prognostic factor Management of small lung lesions (including AIS, MIA, and invasive ADC) is evolving and studies are ongoing Molecular and histologic analyses of NSCLC (i.e. ADC or SQCC) play an important role in choice of therapy

30 Benefits of IASLC Membership Not a member of IASLC? Join today and enjoy the benefits of membership Check for upcoming program and event registration dates, and IASLC membership information

Steering Committee. Waiting on photo. Paul A. Bunn, Jr., MD Kavita Garg, MD Kim Geisinger, MD Fred R. Hirsch, Gregory Riely, MD, PhD.

Steering Committee. Waiting on photo. Paul A. Bunn, Jr., MD Kavita Garg, MD Kim Geisinger, MD Fred R. Hirsch, Gregory Riely, MD, PhD. Steering Committee Paul A. Bunn, Jr., MD Kavita Garg, MD Kim Geisinger, MD Fred R. Hirsch, Gregory Riely, MD, PhD MD, PhD Waiting on photo Paul Van Schil, MD, PhD William D. Travis, MD Ming-Sound Tsao,