Genetics in Cancer Therapy Raju Kucherlapati, Ph.D. Harvard Medical School
RK Financial interests I do not intend to discuss an off-label use of a product during this activity AVEO Pharmaceuticals KEW Group Metamark Genetics Puretech 2
A lung cancer case - 60 year old woman with lung cancer metastatic to the kidney - Previous testing showed wild-type EGFR and no ALK translocation - Tumor had progressed on standard chemotherapy - Core needle biopsy of kidney metastasis sent for sequencing of a large panel of genes - Next-Gen sequencing results identified an uncommon BRAF mutation (p.g469v) that would not have been detected by conventional methods that only detect V600E/K - Oncologist was able place patient in a treatment protocol that included in the use of a MEK inhibitor and BRAF inhibitor Ten years ago the only option for this patient would have been the use of another chemotherapy regimen 3
Cancer is a genetic disease Germline mutations cause predisposition to cancer BRCA 1 and 2 Breast and Ovarian cancer APC, MLH1, MSH2, MSH6 Colorectal cancer RB1, TP53, MEN1 and many other genes Cancer predisposition syndromes and cancers Somatic mutations in the same genes are seen in sporadic cancers. Example, APC in colorectal cancer Mutations in known oncogenes and tumor suppressor genes are seen in virtually all cancers Other types of genetic changes (CNV, DNA methylation) also play an important role A comprehensive understanding of all genetic changes would help in developing therapeutic approaches to cancer
2001 The knowledge about the human genome and the explosion of new tools and technologies are bringing unprecedented knowledge about genes involved in human health and disease 5
NGS can replace different assays FISH assay IHC or FISH Sequencing Microarray Roychowdhury et al 2011 6
Mutations in Endometrial cancer
NSCLC - Adenocarcinoma 8
Chronic Myelogenous Leukemia (CML)
BCR-ABL translocation Gleevec approved 2001 2013 Revenues = 4.8 B Philadelphia chromosome 1960
Mrs. Baker s response to Iressa Before
Mrs. Baker s response to Iressa Before Two months later
EGFR Mutations Iressa approved in the EU with genetic test. Tarceva approved in EU for first line therapy with test
Crizotinib approved with companion Dx test - 2011 EML-ALK4 TX by FISH CT before and after crizotinib
Genetic changes in non-small cell lung cancer Targeted therapies for all of these genetic alterations are approved or in development 15
Lung-MAP Launches: First Precision Medicine Trial From National Clinical Trials Network SWOG's Lung-MAP partners National Cancer Institute's National Clinical Trials Network Foundation for the National Institutes of Health Friends of Cancer Research Amgen Genentech Pfizer AstraZeneca MedImmune Foundation Medicine multiple lung cancer advocacy organizations 16
New NCCN guidelines, clinical studies and FDA approvals Date Type Outcome 11/13 Guideline NCCN: New guideline Non-Small Cell Lung Carcinoma: adenocarcinoma, large cell, NSCLC NOS; -EGFR ± ALK testing should be conducted as part of a multiplex/next-generation sequencing. For patients with metastatic disease, the histologic subtype should be evaluated with adequate tissue for molecular testing (consider re-biopsy if appropriate). 01/14 Guideline NCCN: New guidelines for the Workup of Colon Cancer; Determination of tumor RAS (KRAS/NRAS) genes status (if RAS non-mutated, consider BRAF testing) 03/14 Guideline NCCN: Recommending that newly diagnosed colorectal cancer patients be screened for Lynch syndrome, previously called HNPCC. (Lynch syndrome genes: MLH1, PMS2, MLH3, MSH2, MSH6) 09/13 Trial Douillard et al 2013. Panitumumab FOLFOX4 Treatment and RAS Mutations in Colorectal Cancer NEJM 369: 1023-104 (Need complete KRAS and NRAS sequence) 09/13 Trial Liao et al 2012 Aspirin Use, Tumor PIK3CA Mutation, and Colorectal-Cancer Survival NEJM 367:1596 1606; Domingo et al 2013 Evaluation of PIK3CA mutation as a predictor of benefit from nonsteroidal anti-inflammatory drug therapy in colorectal cancer. J Clin Oncol. 31:4297-305. (Clinical trial getting underway) 04/14 FDA Ceritinib approved for ALK-positive NSCLC based on Phase I clinical trials 05/14 FDA Panitumumab combined with FOLFOX approved (5/14) for KRAS-WT CRC
Cancer susceptibility genes Breast Cancer BRCA1 BRCA2 ATM BLM CDH1 CDKN2A MUTYH MLH1 NBN PRSS1 and SLX4 Colon Cancer/Lynch syndrome MLH1 MLH3 PMS2 MSH2 MSH3 MSH6 MUTY NCCN: All CRC patients should be tested for Lynch syndrome NCCN: All CRC patients should be tested for KRAS, NRAS and BRAF 1
KRAS mutations Lung All 19
BRAF alterations on lung and other cancers Lung All 20
Genetic changes in tumors Lawrence et al (2014) Nature 505:495-501.
Targets for Drugs Available or in Development Garraway JCO 31: 1806-1814 2013 22
Approved Targeted Therapies Adenocarcinoma of the stomach or gastroesophageal junction: Trastuzumab (Herceptin ) Basal cell carcinoma: Vismodegib (Erivedge ) Brain cancer: Bevacizumab (Avastin ), Everolimus (Afinitor ) Breast cancer: Everolimus (Afinitor ), tamoxifen, toremifene (Fareston ), Trastuzumab (Herceptin ), fulvestrant (Faslodex ), anastrozole (Arimidex ), exemestane (Aromasin ),lapatinib (Tykerb ), letrozole (Femara ), pertuzumab (Perjeta ), ado-trastuzumab emtansine (Kadcyla ) Colorectal cancer: Cetuximab (Erbitux ), Panitumumab (Vectibix ), Bevacizumab (Avastin ),Ziv-aflibercept (Zaltrap ), Regorafenib (Stivarga ) Dermatofibrosarcoma protuberans: Imatinib mesylate (Gleevec ) Head and neck cancer: Cetuximab (Erbitux ) Gastrointestinal stromal tumor: Imatinib mesylate (Gleevec ), Sunitinib (Sutent ),Regorafenib (Stivarga ) Giant cell tumor of the bone: Denosumab (Xgeva ) Kaposi sarcoma: Alitretinoin (Panretin ) Kidney cancer: Bevacizumab (Avastin ), Sorafenib (Nexavar ), Sunitinib (Sutent ), Pazopanib (Votrient ), Temsirolimus (Torisel ), Everolimus (Afinitor ), Axitinib (Inlyta ) Leukemia: Tretinoin (Vesanoid ), Imatinib mesylate (Gleevec ), Dasatinib (Sprycel ), Nilotinib (Tasigna ), Bosutinib (Bosulif ), Rituximab (Rituxan ), Alemtuzumab (Campath ), Ofatumumab (Arzerra ), Obinutuzumab (Gazyva ) Liver cancer: Sorafenib (Nexavar ) Lymphoma: Tositumomab and 131I-tositumomab (Bexxar ), Ibritumomab tiuxetan (Zevalin ),Denileukin diftitox (Ontak ), Brentuximab vedotin (Adcetris ), Rituximab (Rituxan ), Vorinostat (Zolinza ), Romidepsin (Istodax ), Bexarotene (Targretin ), Bortezomib (Velcade ),Pralatrexate (Folotyn ), Lenalidomide (Revlimid ), Ibrutinib (Imbruvica ), Siltuximab (Sylvant ) Melanoma: Ipilimumab (Yervoy ), Vemurafenib (Zelboraf ), Trametinib (Mekinist ), Dabrafenib (Tafinlar ) Multiple myeloma: Bortezomib (Velcade ), Carfilzomib (Kyprolis ), Lenalidomide (Revlimid ),Pomalidomide (Pomalyst ) Myelodysplastic/myeloproliferative disorders: Imatinib mesylate (Gleevec ) Non-small cell lung cancer: Bevacizumab (Avastin ), Crizotinib (Xalkori ), Erlotinib (Tarceva ), Gefitinib (Iressa ), Afatinib dimaleate (Gilotrif ), Ceritinib (LDK378/Zykadia) Pancreatic cancer: Erlotinib (Tarceva ), Everolimus (Afinitor ), Sunitinib (Sutent ) Prostate cancer: Cabazitaxel (Jevtana ), Enzalutamide (Xtandi ), Abiraterone acetate (Zytiga ), Radium 223 chloride (Xofigo ) Soft tissue sarcoma: Pazopanib (Votrient ) Stomach cancer: Ramucirumab (Cyramza ) Systemic mastocytosis: Imatinib mesylate (Gleevec ) Thyroid cancer: Cabozantinib (Cometriq ), Vandetanib (Caprelsa ), Sorafenib (Nexavar ) National Cancer Institute Website. Bethesda, MD. Available at: http://www.cancer.gov/. Accessed August 28, 2014. 23
Ipilumumab in Melanoma patients Hodi FS et al. N Engl J Med 2010;363:711-723.
Summary Our knowledge of the genetic and genomic changes that are critical for cancer initiation and progression is increasing at a rapid pace In addition to gene mutations, CNV, mutation frequency, gene expression, DNA methylation, mitochondrial DNA mutations and pathogens play critical roles Specific biochemical pathways can be altered by many different mechanisms Many of these changes are either associated with approved or emerging therapies 25