oracic Oncology Advances

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1 Winter 2011 oracic Oncology Advances Page 2 Page 4 Page 6 Page 7 Innovative Clinical Trials and Research Expand Targeted Medical Therapies and Personalized Approaches to Lung Cancer Care Medical oncologists and researchers are introducing new clinical trials of targeted therapies based on discoveries in the genomic characterization of lung cancer tumors. Minimally Invasive Thoracic Surgery Delivers Significant Patient Benefits Thoracic surgeons perform complex, minimally invasive approaches for the treatment of thoracic malignancies that offer faster recovery, less pain, and better outcomes than conventional techniques. Improved Outcomes and Reduced Side Effects with Highly-Targeted Radiation Techniques Radiation oncologists are employing state-of-the-art radiation techniques that provide more precise targeting of the tumor, preservation of normal surrounding tissue, and higher dosing with less toxicity. Groundbreaking Discoveries in Mesothelioma New discoveries in genomics, staging, and prognostic indicators in mesothelioma are advancing the understanding of the disease.

2 2 Thoracic Oncology Advances Thoracic Oncology Center Highlights From left: Elizabeth H. Baldini, MD, MPH, Radiation Oncology Director, Thoracic Oncology Center; Bruce E. Johnson, MD, Medical Oncology Director, Thoracic Oncology Center; Scott J. Swanson, MD, Chief Surgical Officer, Dana-Farber/Brigham and Women s Cancer Center and Director, Thoracic Oncology Center Comprised of subspecialty experts in thoracic surgery, medical oncology, radiation oncology, pathology, and radiology, our multidisciplinary team: Provides advanced care for more than 4,000 patients each year from nearly every state in the nation and more than 14 countries; Delivers a comprehensive array of minimally invasive surgical treatments and diagnostic techniques and performs more than 3,500 surgical procedures each year; Leads an average of 15 clinical trials at a time, including trials that are rapidly expanding the availability of targeted therapies and changing the standard of care for many patients with thoracic cancers; Offers a wide range of cutting-edge radiation therapies and planning techniques that maximize outcomes and minimize side effects; Pioneers basic science research that is advancing the understanding of the development, prognosis, and screening benefits for lung cancer. Innovative Clinical Trials and Research Expand Targeted Medical Therapies and Personalized Approaches to Lung Cancer Care Making groundbreaking discoveries in the genomic characterization of lung cancer tumors and clinical response to targeted treatments, medical oncologists and researchers in the Thoracic Oncology Center are introducing new clinical trials based on recent findings. By genotyping all of our patients with lung cancer, we currently deliver highly targeted therapies based on specific genetic mutations to approximately 30 percent of patients, said Bruce E. Johnson, MD, Medical Oncology Director of the Thoracic Oncology Center. Within the next five years, we expect to increase the availability of targeted therapies to more than half of all lung cancer patients. Changing the Standard of Care Among the first to discover epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer, medical oncologists and researchers in the Center demonstrated clinical response to the EGFR kinase inhibitors gefitinib (Science 2004; 304 (5676): ) and erlotinib (Clin Cancer Res Jul 1;12(13):3908.) in patients with tumors characterized by EGFR mutations. Researchers in the Center also have shown that cytologic samples obtained through minimally invasive methods, including fine needle aspirations, bronchial washings, and bronchoalveolar lavages, are suitable for EGFR mutation analysis (Cancer Cytopathol Feb 25;117(1):67-72.). In October 2010, specialists in the Center published results from a recent Phase I study of crizotinib (PF ), a small-molecule inhibitor of anaplastic lymphoma kinase (ALK), among patients with non-small cell lung cancer with ALK rearrangements, currently found in two to three percent of all lung cancer patients. The study concluded that most patients responded to treatment with either tumor shrinkage or stable disease (N Engl J Med 2010; 363: ). Phase II and Phase III trials of this therapy are ongoing (see Page 3 for more information).

3 Dana-Farber/Brigham and Women s Cancer Center 3 Female patient with adenocarcinoma with exon 19 EGFR deletion mutation treated with gefitinib. Before Female patient with EML4-ALK non-small cell lung cancer treated with crizotinib. Before After After New Clinical Trials Offering an average of 15 open trials at a time, medical oncologists in the Center are currently evaluating additional targeted therapies and combinations of treatments for lung cancer, including: Phase II study of crizotinib (PF ) in patients with advanced non-small cell lung cancer with ALK gene mutation Study is evaluating the safety and efficacy of PF and will allow patients from a Phase III trial who received standard of care chemotherapy (Study A ) to receive PF , led by Principal Investigator Pasi A. Jänne, MD, PhD; Prospective evaluation of first line erlotinib therapy and the subsequent development of mechanisms of secondary resistance in patients with non-small cell lung cancer and known sensitizing EGFR mutations, led by Principal Investigator David M. Jackman, MD. Upcoming trials include evaluation of BRAF inhibitors for lung cancer patients with BRAF mutations and MEK inhibitors for lung cancer patients with KRAS mutations. For more information regarding these and other trials in the Thoracic Oncology Center, please contact Joan Lucca, RN, at Visit Us Online Visit us online at dfbwcc.org to access our physician directory and learn more about our specialists and researchers. (617) or jlucca@partners.org or Linda Morse, RN, at (617) or lmorse2@partners.org. Overcoming Resistance to Therapy Led by Pasi A. Jänne, MD, PhD, Director of the Translational Research Laboratory, researchers in the Center also are striving to uncover the mechanisms of cancer resistance to treatment in order to develop the next generation of therapies. Our efforts will keep us ahead of the curve, so that we have the next set of treatments to offer when resistance begins to occur, said Dr. Jänne. Researchers in the Center recently demonstrated that EGFR kinase inhibitor resistance can be successfully treated with combined EGFR and MET inhibition, highlighting the potential to prospectively identify treatment naive patients with EGFR-mutant lung cancer who will benefit from initial combination therapy (Cancer Cell Jan 19;17(1):77-88.). The combination of EGFR and MET inhibitors is currently being evaluated in two clinical trials: Phase Ib/II study of Xl184 with or without erlotinib in subjects with non-small cell lung cancer, led by Principal Investigator Pasi A. Jänne, MD, PhD; Phase I trial of PF and PF299804, led by Principal Investigator Pasi A. Jänne, MD, PhD. For more information regarding these and other trials in the Thoracic Oncology Center, please contact Joan Lucca, RN, at (617) or jlucca@partners.org or Linda Morse, RN, at (617) or lmorse2@partners.org. In late 2009, researchers in the Center identified a new type of EGFR inhibitor (covalent pyrimidine) by screening against the gatekeeper EGFR T790M mutation, commonly attributed to resistance to EGFR therapy. Findings from the study demonstrate that functional pharmacological screens against clinically important mutant kinases are key to identifying new classes of mutant-selective kinase inhibitors (Nature Dec 24;462(7276): ). Bruce E. Johnson, MD Medical Oncology Director, Thoracic Oncology Center Pasi A. Jänne, MD, PhD Director, Translational Research Laboratory, Thoracic Oncology Center Michael S. Rabin, MD Clinical Director, Thoracic Oncology Center

4 4 Thoracic Oncology Advances Minimally Invasive Thoracic Surgery Delivers Significant Patient Benefits Brigham and Women s Hospital is home to one of the largest Divisions of Thoracic Surgery worldwide. The team of 13 attending thoracic surgeons actively participates in the Thoracic Oncology Center and performs more than 3,500 procedures each year. Many of these procedures, including some of the most complex techniques, are completed using minimally invasive, image-guided approaches. Compared with conventional procedures, newer minimally invasive and image-guided techniques in thoracic surgery not only provide a much faster recovery with less pain and risk of complications but also improved outcomes, said Scott J. Swanson, MD, Center Director of the Thoracic Oncology Center and Chief Surgical Officer at Dana-Farber/ Brigham and Women s Cancer Center. Video-assisted Thoracoscopic Surgery Thoracic surgeons in the Center have vast experience in video-assisted thoracoscopic surgery (VATS) lobectomies, thymectomies, esophagectomies, and metastasectomies, as well as innovative endoscopic and image-guided procedures. Between 80 and 90 percent of all lobectomies are performed using VATS. Dr. Swanson was the Principal Investigator of the first prospective multi-institution study (CALGB 39802) supporting the technical feasibility and safety of VATS lobectomy for the treatment of early non-small cell lung cancer (Journal of Clinical Oncology, Vol 25, No 31 (November 1), 2007: ). In a comparative review of 39 studies with an aggregate of 3,256 thoracotomy patients and 3,114 VATS patients, thoracic surgeons in the Center determined that, compared with thoracotomy, VATS lobectomy appears to favor lower morbidity and improved survival rates for early-stage nonsmall cell lung cancer. VATS lobectomy was associated with shorter chest tube duration, shorter length-of-hospital stay, and improved survival at four years post resection compared with thoracotomy (Ann Thorac Surg Dec;86(6): ; discussion ). In addition to a faster rate of recovery, VATS also offers: More rapid delivery of adjuvant therapy Full doses of postoperative chemotherapy often can be provided sooner; Access with One Call For more information or to schedule a consultation with a member of our team, please call to speak with one of our experienced referral coordinators. Options for patients considered ineligible for traditional surgery, including patients with limited pulmonary and cardiac reserves; Fewer complications and shorter length-of-stay; Improved lung function. Image-guided Diagnostic and Therapeutic Techniques Thoracic surgeons in the Center are among few in the country to offer a comprehensive range of image-guided diagnostic and therapeutic techniques. In addition to VATS, techniques include: Navigational bronchoscopy uses real-time electromagnetic guidance to improve navigation within the lung parenchyma and offers diagnostic benefits over standard flexible bronchoscopy. This technique is valuable in performing biopsies of peripheral lung lesions and mediastinal lymph nodes for the staging of lung cancer, as well as in placing fiducial catheters to aid stereotactic radiotherapy; Endobronchial ultrasound (EBUS) enables visualization of the tissue beyond the bronchial wall, including lymph nodes and lesions outside of the bronchial airways. This technique also enables simultaneous diagnosis and lung cancer staging; Radiofrequency ablation is performed percutaneously under CT guidance and offers treatment for patients who are not surgical candidates or patients with unresectable tumors, as well as palliative care for patients with lung metastasis. Evaluating Outcomes of Surgery and Chemoradiation Thoracic surgeons together with radiation and medical oncologists in the Center have conducted studies evaluating outcomes of patients undergoing surgery and chemoradiation for lung cancer. Findings include: Outcomes of pneumonectomy after induction chemoradiotherapy in patients with locally advanced non-small cell lung cancer (Cancer, March 1, 2008;Vol 112: No 5: ) showed benefits of trimodality therapy and a low associated mortality compared to that observed in other centers; Brain metastases constitute the most common site of recurrence in stage IIIA non-small cell lung cancer patients downstaged to N0 disease (J Clin Oncol, 2005;23: ). Aggressive therapies to control brain metastases can lead to long-term survival, and future studies focusing on prophylaxis of brain metastases or more aggressive treatment may improve the outcome of these patients;

5 Dana-Farber/Brigham and Women s Cancer Center 5 Minimally Invasive Esophagectomy: A Revolutionary Advance in Esophageal Cancer Treatment Thoracic surgeons in the Center perform among the highest volume of resections for esophageal cancer in the nation, and the vast majority of these procedures are completed using complex minimally invasive approaches, including minimally invasive esophagectomy (MIE). MIE offers patients a much faster rate of recovery with less pain and long-term complications, including pneumonia, and is associated with a very low mortality rate. Neo-adjuvant treatment with chemotherapy and radiation are provided to patients with locally advanced esophageal cancers to improve outcomes. In a retrospective analysis of 116 consecutive esophagectomies utilizing a completely thoracoscopic mobilization of the esophagus, thoracic surgeons in the Center determined that this effective, minimally invasive alternative to dissecting the esophagus was associated with a low mortality of less than one percent. Thirtyday and in-hospital mortality was 0.9 percent compared with national mortality rates among the largest esophageal centers ranging from four to ten percent for open esophagectomy. At four weeks after MIE, patients are back to full activity and have scars that are barely visible. Above image illustrates the division of the stomach to form the gastric conduit. The left portion of the stomach shows the distal esophagus and GE junction with the tumor, as well as the proximal stomach. The right portion of the staple line designates the part of the stomach that will be used to recreate the esophagus. Staplers will be used to complete the division and separate the specimens. Above diagram shows the completed reconstruction. The esophagus has been resected, and the stomach has been tubularized, brought up into the chest, and attached to the remaining cervical esophagus. (Wee JO, Bizekis C, Luketich JD, Minimally Invasive Esophagectomy in Adult Chest Surgery text by Sugarbaker et al., McGraw-Hill Medical publisher, 2009, page 127.) Above image shows the completed reconstruction. Patients with stage IIIA N2-positive non-small cell lung cancer whose nodal disease is eradicated after neoadjuvant therapy and surgery have significantly improved cancer-free survival. Based on our results, we tailor the therapy of individual patients based on their response to various agents. Additional studies and current endeavors include: Comparison of lobectomy and segmentectomy The Center is one of few in New England to participate in a national, Phase III trial evaluating outcomes in patients undergoing either lobectomy or segmentectomy for the treatment of stage IA non-small cell lung cancer. The trial aims to determine the amount of lung tissue needed to be removed in order to cure patients with early lung cancer. While participating centers may choose to perform each procedure using a minimally invasive or open technique, surgeons in the Center perform the vast majority of these procedures using a minimally invasive approach. A retrospective review of patients who underwent thoracoscopic segmentectomy or lobectomy for clinical stage I non small cell lung cancer determined that thoracoscopic segmentectomy was a safe option for experienced thoracoscopic surgeons treating patients with small stage I lung cancers. No significant difference in oncologic outcome was seen between thoracoscopic segmentectomy and thoracoscopic lobectomy, and lymph node dissection could be performed as effectively during segmentectomy as lobectomy (The Journal of Thoracic and Cardiovascular Surgery, Volume 137, Issue 6, June 2009, Pages ). Computed tomography benefits in lung cancer screening The Thoracic Oncology Center also is establishing a screening clinic for lung cancer in an effort to promote earlier diagnosis and improved outcomes. Specialists in the Center were part of the National Lung Cancer Screening Trial (NLST), a randomized trial comparing the continued on back cover

6 6 Thoracic Oncology Advances Improved Outcomes and Reduced Side Effects with Highly-Targeted Radiation Techniques Radiation oncologists in the Thoracic Oncology Center are employing state-of-the-art radiation techniques that offer more precise targeting of the tumor, preservation of normal surrounding tissue, and higher dosing with less toxicity. With the advent of newer technologies, we are able to offer patients with lung cancer a broader range of treatment options that deliver better results with less side effects compared with older techniques, said Elizabeth H. Baldini, MD, MPH, Radiation Oncology Director for the Thoracic Oncology Center. Radiation therapy techniques provided by specialists in the Center include: Stereotactic body radiation therapy (SBRT) is a cuttingedge technique delivering three-to-five high-dose treatments to peripheral lung tumors with excellent results. This approach combines advanced radiation-delivery equipment with complex imaging technology to map precise tumor dimensions and location. Center specialists are among few to offer this technique, which is suitable for patients with early stage lung cancers who are not candidates for surgery, for patients with inoperable tumors, or for patients with metastases to the lung from other sites. A novel clinical trial, which combines a course of 3D conformal or IMRT treatment followed by an extra boost dose to the tumor given with SBRT, will soon be available; Advanced radiation planning methods, such as 4D CT, which tracks the movement of the tumor during breathing, and fusion of diagnostic PET/CT imaging with the planning CT scan software to ensure accurate delineation of the primary tumor and lymph node targets; 3D conformal radiation therapy and intensity-modulated radiation therapy (IMRT) are both used to provide precise, high-dose radiation treatment. IMRT is particularly useful when treatment geometry is challenging because it uses steep dose gradients to preserve normal surrounding tissues and enable precise pinpointing of the treatment site; Image-guided radiation therapy (IGRT) employs frequent 2D and 3D imaging studies that are acquired in the treatment room immediately prior to treatment to confirm Visit Us Online Visit us online at dfbwcc.org to access our physician directory and learn more about our specialists and researchers. optimal patient position for each treatment; Adaptive treatment planning is performed in appropriate cases. If significant changes occur in tumor position or tumor size due to response during treatment, patients are re-planned to ensure accurate tumor coverage throughout treatment; Chemoradiation Many radiation treatment courses are delivered with simultaneous chemotherapy, requiring close coordination between radiation and medical oncologists. In addition, the Center is interested in exploring new combinations of radiation therapy with novel chemotherapy agents. Stereotactic body radiation therapy (SBRT) treatment plan used to treat a medically inoperable stage I non-small cell lung cancer Radiation oncologists and physicists in the Center also use other advanced techniques to maximize radiation dose to a smaller target area, including: Dose painting to enable different target volumes to receive different cumulative doses of radiation; Cone beam CT and cinematic data acquisition during the treatment course; Respiratory gating, which times the delivery of treatment with the tumor movement during breathing; Improved patient immobilization. continued on back cover

7 Dana-Farber/Brigham and Women s Cancer Center 7 Groundbreaking Discoveries in Mesothelioma Thoracic Oncology Center investigators in conjunction with the International Mesothelioma Program at Brigham and Women s Hospital have pioneered new discoveries in genomics, staging, and prognostic indicators in mesothelioma. Genomic Sequencing Researchers in the Center were the first to report a comprehensive, unbiased analysis of all genes expressed in a cancerous tumor based on findings from a two-year genomic study of mesothelioma tumors. Tumor samples taken from four patients with malignant pleural mesothelioma (MPM) revealed that each had unique genetic mutations. Researchers employed transcriptome sequencing to uncover a specific set of three to four genetic mutations in the coding regions of genes in each tumor and developed a mutational profile for each patient with MPM. The study was conducted by David J. Sugarbaker, MD, Chief of Thoracic Surgery and Director of the International Mesothelioma Program, Raphael Bueno, MD, Associate Chief of Thoracic Surgery, pathologist Lucian R. Chirieac, MD, and their colleagues. Genetic studies of tumors have typically focused only on genes already known to be involved in cancer, said Dr. Bueno. This approach is limited, as it does not account for the individual mutations specific to each tumor and does not allow for the discovery of previously uncharacterized human cancer mutations. Our study demonstrated that each cancer had multiple types of mutations in genes not previously implicated in cancer or mesothelioma. In a subsequent study of second-generation sequencing of the mesothelioma tumor genome (PLoS One May 13;5(5):e10612.), researchers in the Center found many more tumor-specific rearrangements than point mutations in MPM, and nearly all identified candidate point mutations appeared to be previously unknown single nucleotide polymorphisms (SNPs). The finding provides a possible explanation for the lack of specific oncogenes or tumor suppressors for MPM and supports the use of deeper sequencing, functional analysis, and genotyping to identify true driver mutations in MPM to better define specific targets for therapy. Refining MPM Staging A recent study by pathologists and surgeons in the Center examined pathologic characteristics and explored correlations with outcomes among 354 patients with epithelioid MPM who underwent extrapleural pneumonectomy (Cancer May 15;116(10):2503.). Comparisons of survival among patients with and without each tumor or lymph node feature guided adjustments to the American Joint Commission on Cancer (AJCC)/International Union Against Cancer (UICC) classification criteria. By AJCC/UICC criteria, 233 patients (66 percent) in the study were stage III, whereas by study criteria, 194 patients (55 percent) were stage III. Overall median survival was 18 months from surgery. The study demonstrated that the proposed adjustments to staging criteria improved outcome stratification of patients with epithelial tumor histology who received extrapleural pneumonectomy and complete pathologic assessment. Predicting Prognosis Researchers in the Center recently investigated the value of a previously developed gene ratio test in predicting the outcome of 120 MPM patients undergoing debulking surgery (J Natl Cancer Inst 2009;101: ). Gene expression data was obtained for four genes from tumor specimens, and the gene ratio test was used to assign patients to good or poor prognosis groups. Patient survival was analyzed, and robustness was determined by using many specimens, two biopsy techniques, and two performance sites. The gene ratio test was determined to have robust predictive value and technical assay performance. Pathologists in the Center are among few to perform asbestos body counts on all patients with MPM and have found that higher asbestos counts are associated with poorer survival rates (Environ Health Perspect. 2008;116:723-6.). Recent retrospective studies assessing only epithelial mesothelioma have confirmed this finding in a larger cohort. Based on insights gleaned from genomic, staging, and prognostic studies, researchers in the Center are striving to develop more effective treatments, including targeted therapies, for patients with mesothelioma. David J. Sugarbaker, MD Chief, Thoracic Surgery Raphael Bueno, MD Associate Chief, Thoracic Surgery John Godleski, MD Director, Pulmonary Pathology Edmund Cibas, MD Director, Cytology and Fine Needle Aspiration Center

8 Minimally Invasive Thoracic Surgery Delivers Significant Patient Benefits continued from page 5 effects of lung cancer screening using low-dose computed tomography (CT) imaging and chest X-ray on lung cancer mortality among current and former heavy smokers. Initial results of the study found that lung cancer screening using CT imaging resulted in more than a 20 percent decrease in lung cancer mortality compared with chest X-ray. Real-time Image-guided Lymphatic Mapping and Nodal Targeting in Lung Cancer While accurate nodal staging is a key factor in treatment planning in non-small cell lung cancer, a reliable method of sentinel lymph node mapping for lung cancer has not been identified to date. Preclinical research conducted through the Thoracic Oncology Center has demonstrated the feasibility of an intraoperative optical imaging technology that uses safe, invisible, near-infrared (NIR) fluorescent light for thoracic nodal mapping (Seminars in Thoracic and Cardiovascular Surgery. 2009; 21(4): ). Led by Principal Investigator Yolonda Colson, MD, PhD, Director of the Women s Lung Cancer Program, the Thoracic Oncology Center is now enrolling eligible patients in an NCI-sponsored Phase I/II clinical trial evaluating the efficacy of this imaging platform in sentinel lymph node identification during surgery for early-stage lung cancer. For more information regarding study participation, please contact Principal Investigator Yolonda Colson, MD, PhD, at (617) or ycolson@partners.org. David J. Sugarbaker, MD Chief, Thoracic Surgery Scott J. Swanson, MD Chief Surgical Officer, Dana-Farber/Brigham and Women s Cancer Center; Center Director, Thoracic Oncology Center; Director, Minimally Invasive Thoracic Surgery Raphael Bueno, MD Associate Chief, Thoracic Surgery Yolonda Colson, MD, PhD Director, Women s Lung Cancer Center Jon O. Wee, MD Co-Director, Minimally Invasive Thoracic Surgery Improved Outcomes and Reduced Side Effects with Highly-Targeted Radiation Techniques continued from page 6 Genomic Identification of Lung Cancer Radiosensitizers Radiation oncologist David Kozono, MD, PhD, and his colleagues are using RNA interference to determine which genes are directly required for lung cancer proliferation. He is currently performing a whole genome screen with lung cancer cells treated with daily fractionated radiation to establish which genes may be targeted to improve cancer cell killing by radiation, in a manner mimicking clinical therapy. Call Our Physician Liaison For direct assistance with patient referrals and consultations with our specialists, contact Physician Liaison Ellen Steward at (617) or esteward@partners.org. Elizabeth H. Baldini, MD, MPH Radiation Oncology Director, Thoracic Oncology Center Aileen Chen, MD Associate Radiation Oncology Director David J. Sher, MD, MPH Director of Stereotactic Body Radiation Therapy Dana-Farber Cancer Institute Brigham and Women s Hospital 450 Brookline Avenue 75 Francis Street Boston, MA Boston, MA DFCI-BWH