genomics and metastatic breast cancer: where are we today?
TRANSCRIPT
Tumor Genomic Profiling of FFPE Samples by Massively Parallel Sequencing
Genomics and MBC:Where are we today?Nikhil Wagle, MD5th Annual Metastatic Breast Cancer ForumSeptember 2016
DFCI / BWH / BroadCenter for Cancer Precision Medicine
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
New drugs for the estrogen receptorCombinations with new targeted therapies (CDK4/6 inhibitors and PI3K inhibitors)Advances in Metastatic Breast Cancer Therapy
ER+
HER2+
TNBCCombining agents that target HER2Combinations with new targeted agentsPARP inhibitorsImmunotherapies
CANCER PRECISION MEDICINEDoctors 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
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
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
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Finding and Exploiting the Achilles Heel
Characterizing the tumor to find vulnerabilities and then targeting or exploiting those vulnerabilities
Genomic Alterations in Clinically Relevant Genes in ~1000 Early Stage Breast Cancer SamplesPI3 kinase inhibitorsFGFR InhibitorsAKT InhibitorsHER2 kinase inhibitorsEstrogen Receptor Degraders (SERDs)PARP inhibitors
PIK3CA H1047 and E545 in breast cancerBRAF V600 in breastMEK1 EGFRERBB2 mutations in breast
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Potential Genomic Targets in Breast CancerSelected genes with Mutations, Amplifications/Deletions, Rearrangements in Breast CancerERBB2
ESR1
PIK3CAPTENAKT1AKT2AKT3PIK3R1PIK3CBINPP4BKRASNRASBRAFMAP2K1MAP3K1NF1
FGFR1FGFR2FGFR3
MTORTSC1TSC2CDKN2ACDKN1BCCND1CCNE1CDK4RB1
BRCA1BRCA2ATMDNA RepairEGFR
TP53MDM2
MYC
KITNTRK3NOTCH1
Anti-Her2 TherapiesPI3k / AKT inhibitorsMAPK InhibitorsFGFR InhibitorsCDK InhibitorsPARP InhibitorsPlatinumsNutlinsp53 StrategiesAnti-MYC StrategiesOthersEGFR Inhibitors
Anti-ER TherapiesmTOR inhibitors
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New Models of Genomically Driven Clinical Trials
Metastatic tumor biopsy & blood samples
PROFILE(Targeted Sequencing)Additional Molecular Studies and BankingMake Cell Line Models and Mouse Models
Studies of Resistance /Discovery of New Targets
ExperimentalStudiesPathologyER, 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 MedicineMetastatic Breast Cancer StudyFuture UsesBlood or Liquid Biopsies
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 MechanismsTrial #1 (e.g. novel SERD)Trial #2 (e.g. PI3Ki combo)Trial #3 (e.g. CDKi combo)Future Trials (to be developed) COMPREHENSIVESYSTEMATICTUMOR ANALYSISDana-Farber / Broad Institute Center for Cancer Precision MedicineMetastatic Breast Cancer Study
Ultimate goal: To understand what drives breast cancer so that we eventually can interpret every patients cancer genome, identify the optimal treatments, and anticipate and preempt resistance before it arises
Theres 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?
Most tumor samples have not been readily available for studyChallenges of Studying Patient Tumor SamplesTechnology, 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
Only ~ 5% of patients in the U.S. are enrolled in clinical trials.85% of cancer patients are treated in community settings rather than at Comprehensive Cancer Centers.Even for patients on trials, tumor tissue is not collected for study.Even for collected samples, the cost of genome sequencing has historically been too high to do systematic analysis.Direct outreach to patients on a national or international scale has historically been considered impractical.Most tumor samples have not been readily available for study
THE SITUATION IS NOW CHANGING:Most patients and/or their families are internet- and technology-savvySocial media now make it possible to communicate with patients in new, powerful waysThe cost of genome sequencing has plummeted nearly one million-fold over the past decade making it possible to take on projects at a scale never before imaginableIt has become acceptable for patients to directly participate in genetic researchThere is a new opportunity to engage cancer patients and directly partner with them in this research
The Metastatic Breast Cancer Project MBCproject.org
The Metastatic Breast Cancer ProjectMBCproject.orgOver 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
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Patient-Reported Data
95% submitted the 16-question survey
98% response rate to each question (all are optional)
6 minutes to completeDisease Characteristics:Dates of initial diagnosisDate of diagnosis with metastatic diseaseER+, PR+, and HER2+ status
Treatment Response:Questions about extraordinary responsesFree text about treatmentsDate of most recent biopsy
Demograpgics:Year of birthRace and ethnicity
Free text about anything additionalDetailed patient reported data from >2500 patients
Keep, but make less wordy, for example: Overall response rate: 95% (Use three words, not a paragraph)19
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 abstractedTumor blocks requested from local pathology departments by the MBCproject teamMolecular 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 patientsDe-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
DETAILS ARE IN ADDITIONAL SLIDES
Will also discuss IRB issues here.
In January, we started sending online consents to all registered patientsIn March, we started sending saliva kits to consenting patients>1500>900>2600Soft launch Official LaunchWith Advocacy PartnersSan Antonio Breast Cancer SymposiumFacebook and Twitter posts by patients/advocatesFacebook post by a metastatic breast cancer patient/advocateASCO
Steady state of 200 registrants/month, 140 consents/month, 140 saliva samples/month
Over past 2 months: 200 registrants/month, 150 consents/month, 125 salivas/month
4 months: 200 registrants/month, 150 consents/month, 150 salivas/month
Nearly 100 medical records have been received and reviewed to date
Dozens of tumor samples have been received and examined
Whole exome and transcriptome sequencing of initial pilot group of tumor and saliva samples is now complete 21
The Metastatic Breast Cancer ProjectPatient 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 diseasePatients diagnosed with MBC at a young ageUnderrepresented Populations
Each of these groups is readily identifiable based on the screening questions on the MBCProject.org website
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99% of those who responded Yes provided the drug names98% of those who responded Yes provided drug names and additional free text details Studying patients with Exceptional ResponsesHundreds of patients with self-reported long-term and/or exceptional responses identified. For example:Capecitabine (Xeloda): 117Platinums (Carboplatin, Cisplatin) and PARP inhibitors: 63Everolimus: 36
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
Patients and advocates have been involved from the beginning in conceiving, designing, implementing, testing, and refining this project.
A Collaboration with Patients and Advocates
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#MBCproject on Facebook and Twitter
#BCSM twitter chat: > 2 million impressions; 1 Facebook post: 300 enrollments in 12 hours
Count Me In
I want to live and watch my children grow up, but if I cant, then I want to leave a legacy and a cure.Houston, TXAs 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, CAAmazing 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
SummaryCancer 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
Thank you!
DFCI / BWH / BroadCenter for Cancer Precision Medicinembcproject.orgQuestions? Email [email protected]
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