Genomics and Metastatic Breast Cancer: Where Are We Today?

1. Genomics and MBC: Where are we today? Nikhil Wagle, MD 5th Annual Metastatic Breast Cancer Forum September 2016 DFCI / BWH / Broad Center for Cancer Precision Medicine

2. • What are all changes at the molecular level that can lead to metastatic breast cancer? • What explains why some patients show extraordinary responses to a particular treatment? • What explains why some tumors never respond to a particular treatment, or why some tumors initially respond but later develop resistance? • What are some factors that can lead to to developing metastatic breast cancer at a young age? • What are the genes involved in metastatic breast cancer for underrepresented and understudied groups? • How can we improve the use of genomic information in the treatment of metastatic breast cancer? • How can we develop better treatments for metastatic breast cancer? Some questions we are trying to answer in metastatic breast cancer

3. • New drugs for the estrogen receptor • Combinations with new targeted therapies (CDK4/6 inhibitors and PI3K inhibitors) Advances in Metastatic Breast Cancer Therapy ER+ HER2+ TNBC • Combining agents that target HER2 • Combinations with new targeted agents • PARP inhibitors • Immunotherapies

4. CANCER PRECISION MEDICINE “Doctors have always recognized that every patient is unique, and doctors have always tried to tailor their treatments as best they can to individuals. You can match a blood transfusion to a blood type — that was an important discovery. What if matching a cancer cure to our genetic code was just as easy, just as standard? What if figuring out the right dose of medicine was as simple as taking our temperature?” - President Obama, January 30, 2015

5. What is Cancer Precision Medicine? The use of clinical, pathological, molecular, and genomic information to direct the appropriate therapy to the appropriate patient at the appropriate time

6. Obtain tumor biopsy material Extract DNA/RNA from tumor to profile for somatic alterations The Path to Precision Cancer Medicine MacConaill and Garraway, JCO, 2010

7. Finding and Exploiting the Achilles Heel Characterizing the tumor to find vulnerabilities – and then targeting or exploiting those vulnerabilities

8. Genomic Alterations in Clinically Relevant Genes in ~1000 Early Stage Breast Cancer Samples 0% 5% 10% 15% 20% 25% 30% 35% 40% PIK3CA MYC AKT3 MCL1 FGFR1 DDR2 PTEN GNAS RARA MAP2K4 NF1 IGF1R CDKN2A RUNX1 ATM ETV6 NTRK3 CDKN1B CCND2 ESR1 KRAS FBXW7 ROS1 BCL2 ERBB4 KMT2A WT1 JAK3 FLT3 SMAD4 ATR RAF1 BRAF ASXL1 NUTM1 MSH2 ETV1 AKT1 MSH6 KDR TMPRSS2 NFKBIA PDGFRA RET ALK CDK6 TET2 CRKL EWSR1 HRAS STK11 EPHA3 EZH2 NKX2-1 BAP1 MEN1 GNA11 BRD2 MAP2K1 SMARCB1 NRAS PDGFRB MAPK1 CTNNB1 PI3 kinase inhibitors FGFR Inhibitors AKT Inhibitors HER2 kinase inhibitors Estrogen Receptor Degraders (SERDs) PARP inhibitors

9. Potential Genomic Targets in Breast Cancer Selected genes with Mutations, Amplifications/Deletions, Rearrangements in Breast Cancer ERBB2 ESR1 PIK3CA PTEN AKT1 AKT2 AKT3 PIK3R1 PIK3CB INPP4B KRAS NRAS BRAF MAP2K1 MAP3K1 NF1 FGFR1 FGFR2 FGFR3 MTOR TSC1 TSC2 CDKN2A CDKN1B CCND1 CCNE1 CDK4 RB1 BRCA1 BRCA2 ATM DNA Repair EGFR TP53 MDM2 MYC KIT NTRK3 NOTCH1 Anti-Her2 Therapies PI3k / AKT inhibitors MAPK Inhibitors FGFR Inhibitors CDK Inhibitors PARP Inhibitors Platinums Nutlins p53 Strategies Anti-MYC Strategies OthersEGFR Inhibitors Anti-ER Therapies mTOR inhibitors

10. New Models of Genomically Driven Clinical Trials

11. Metastatic tumor biopsy & blood samples PROFILE (Targeted Sequencing) Additional Molecular Studies and Banking Make Cell Line Models and Mouse Models Studies of Resistance /Discovery of New Targets Experimental Studies Pathology ER, PR, HER2 Returned to Physician for Clinical Decision Making Comprehensive Next Generation Sequencing (Whole Exome and Transcriptome Sequencing) Dana-Farber / Broad Institute Center for Cancer Precision Medicine Metastatic Breast Cancer Study Future Uses “Blood” or “Liquid” Biopsies

12. Metastatic tumor biopsy & blood sample Patients with metastatic ER+ breast cancer with resistance to endocrine therapy Clinical Trials of Novel Agents and Combinations Specific to Identified Resistance Mechanisms Trial #1 (e.g. novel SERD) Trial #2 (e.g. PI3Ki combo) Trial #3 (e.g. CDKi combo) Future Trials (to be developed) COMPREHENSIVE SYSTEMATIC TUMOR ANALYSIS Dana-Farber / Broad Institute Center for Cancer Precision Medicine Metastatic Breast Cancer Study

13. • Ultimate goal: To understand what drives breast cancer so that we eventually can interpret every patient’s cancer genome, identify the optimal treatments, and anticipate and preempt resistance before it arises • There’s been a lot of progress, but we are still far from the goal • What will it take to get there? Detailed molecular and genomic characterization of thousands of tumor and germline samples along with medical information How can we get there faster?

14. Most tumor samples have not been readily available for study Challenges of Studying Patient Tumor Samples Technology, social media, and cultural changes now provide a new opportunity to engage cancer patients and directly partner with them in this research Only 5% of U.S. cancer patients are enrolled in clinical trials 85% of U.S. cancer patients are treated in community settings

15. The Metastatic Breast Cancer Project MBCproject.org

16. The Metastatic Breast Cancer Project MBCproject.org Over 2600 women and men with metastatic breast cancer from all 50 states have joined the MBCproject in the 11 months since our launch in October 2015

17. Patient-Reported Data 95% submitted the 16- question survey 98% response rate to each question (all are optional) 6 minutes to complete Disease Characteristics: • Dates of initial diagnosis • Date of diagnosis with metastatic disease • ER+, PR+, and HER2+ status Treatment Response: • Questions about extraordinary responses • Free text about treatments • Date of most recent biopsy Demograpgics: • Year of birth • Race and ethnicity Free text about anything additional Detailed patient reported data from >2500 patients

18. ONLINE CONSENT MEDICAL HISTORY TISSUE COLLECTION GENOMIC ANALYSIS INTERPRETATION REPORTING / DATA SHARING Electronic consent form asks patients for permission to obtain a saliva sample, tumor tissue and medical records. Medical records are obtained by the MBCproject team and centrally reviewed and abstracted Tumor blocks requested from local pathology departments by the MBCproject team Molecular characterization of tumor and saliva includes whole exome sequencing (WES) and transcriptome sequencing (RNASeq) Genomic data is interpreted in the context of clinical data (extraordinary response, de novo disease, age, etc) at the individual level and in aggregate across similar patients De-identified genomic & clinical data shared widely with research community. Overall progress, findings, and discoveries regularly communicated directly to patients Metastatic Breast Cancer Project: Approach SALIVA COLLECTION Consenting patients are sent a saliva kit and asked to mail back their saliva sample

19. 0 500 1000 1500 2000 2500 3000 8/31/11 10/20/11 12/9/11 1/28/12 3/18/12 5/7/12 6/26/12 8/15/12 MBCProject: Patients Enrolled, Consented, and Saliva Samples Received Registered Consented Saliva Received In January, we started sending online consents to all registered patients In March, we started sending saliva kits to consenting patients >1500 >900 >2600 Soft launch Official Launch With Advocacy Partners San Antonio Breast Cancer Symposium Facebook and Twitter posts by patients/advocates Facebook post by a metastatic breast cancer patient/advocate ASCO

20. The Metastatic Breast Cancer Project Patient Groups to Study Identified groups of rare patients who have been challenging to study with traditional approaches: • Patients with extraordinary responses to therapies • Patients who present with advanced disease • Patients diagnosed with MBC at a young age • Underrepresented Populations Each of these groups is readily identifiable based on the screening questions on the MBCProject.org website

21. 99% of those who responded “Yes” provided the drug names 98% of those who responded “Yes” provided drug names and additional “free text” details Studying patients with Exceptional Responses Hundreds of patients with self-reported long-term and/or exceptional responses identified. For example: • Capecitabine (Xeloda): 117 • Platinums (Carboplatin, Cisplatin) and PARP inhibitors: 63 • Everolimus: 36 632 1107 12 7 Any therapy >2yrs? Yes No Don't Know No Response 946 569 195 48 Any Extraordinary Response? Yes No Don't Know No Response

22. 0 50 100 150 200 250 300 350 400 450 0 1 2 3 4 5 6 7 8 9 10 >10 Years Since Diagnosis of Metastasis As of April 2016, Based on 1730 responses (98.4% response rate) 100 respondents report living with metastatic disease for more than 10 years. Studying patients with Exceptional Responses

23. Patients and advocates have been involved from the beginning in conceiving, designing, implementing, testing, and refining this project. A Collaboration with Patients and Advocates

24. #MBCproject on Facebook and Twitter #BCSM twitter chat: > 2 million impressions; 1 Facebook post: 300 enrollments in 12 hours

25. “Count Me In” “I want to live and watch my children grow up, but if I can’t, then I want to leave a legacy and a cure.” —Houston, TX “As someone who does not live near a research center and therefore cannot easily participate in trials, I finally feel like I can contribute.” —Lake Tahoe, CA “Amazing how happy that little box makes you feel! I felt like a 2 year old. Let me help! I feel a sense of pride and belonging because of this.” —Minneapolis, MN “Giving us HOPE for the future and if not for some of us, for our families.” —Scottsdale, AZ

26. Summary • Cancer precision medicine is the use of clinical, pathological, molecular, and genomic information to direct the appropriate therapy to the appropriate patient at the appropriate time • The identification of numerous potentially clinically relevant alterations plus the development of genomically-driven clinical trials now allows us to apply/test precision medicine in breast cancer • This is particularly true in metastatic disease, where there are important genomic and molecular differences relevant for targeted therapies and immunotherapies • Large, open databases of clinical, genomic, and molecular information are needed to advance precision medicine. • Patient-driven research movements can enable rapid identification of thousands of patients willing to share tumors, saliva, and medical records to accelerate this research

27. Thank you! DFCI / BWH / Broad Center for Cancer Precision Medicine mbcproject.org Questions? Email info@mbcproject.org

Genomics and Metastatic Breast Cancer: Where Are We Today?

Dana-Farber Cancer Institute

Genomics and Metastatic Breast Cancer: Where Are We Today?