A Way Forward: Current Research in ER+ Metastatic Breast Cancer

Moving Beyond Resistance: Current Research in ER+ Metastatic Breast Cancer Heather A. ParsonsDana-Farber Cancer InstituteHarvard Medical SchoolSeptember 24, 2016

Hormone receptorpositiveHow Do We Treat Metastatic Breast Cancer?

Some Questions to Answer in Metastatic ER+ Breast CancerWhy do some tumors never respond to a particular treatment? Why do most tumors eventually develop resistance to a particular treatment?How do we develop better treatments for metastatic ER+ breast cancer?

Demand for Precision Medicine President Obama launched the Precision Medicine Initiative (PMI) in January 2015 to accelerate biomedical discoveries and provide clinicians with new tools, knowledge, and therapies to select which treatments will work best for which patients. Precision medicine is enabling a new era of clinical care through research, technology, and policies that empower patients, researchers, and providers to work together toward development of individualized care. Advancing the science of medicine also calls for a change in the culture of medical practice and medical research to engage individuals as active collaborators not just as patients or research subjects.

Designed to obtain genomic information on all patients who come to DFCI / BWH / BCH for cancer-related care

Goals:Collect genomic information on all patients who have cancer, are presumed to have cancer, or are at risk for developing cancerReturn clinically relevant results to providersStore results in searchable databaseEnable linkage of specimen results to clinical database

PROFILE: Towards Precision Cancer MedicineSince August 2011, >30,000 patients haveconsented (75%) and >12,000 tests have been performed

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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)Center for Cancer Precision Medicine (CCPM)ER+ Metastatic 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 ANALYSISCenter for Cancer Precision Medicine (CCPM)ER+ Metastatic Breast Cancer Study

Circulating tumor DNA (ctDNA)Metastatic biopsies can be challengingCancer (and normal) cells shed ctDNA into bloodctDNA could identify markers of drug sensitivity or resistance in a cancer

ESR1 Mutations in Previously Treated ER+ Breast Cancer

ESR1 mutations in ctDNA predict benefit for Fulvestrant vs. Exemestane

Charlotte Fribbens et al. JCO doi:10.1200/JCO.2016.67.30612016 by American Society of Clinical Oncology

Progression-free survival (PFS) in SoFEA by ESR1 mutation status. (A) PFS of patients with ESR1 mutant cancers who received exemestane or a fulvestrant-containing regimen. (B) PFS of patients without detected ESR1 mutation who received exemestane or a fulvestrant-containing regimen. HR, hazard ratio.

ctDNA in EMBRACEctDNA could identify tumor alterations to direct patients to a trialctDNA may show tumor alterations that are mechanisms of treatment resistance

Selective Estrogen Receptor Degraders (SERDs)Estrogen signaling:Essential for ER+ breast cancer cell growthSERDs bind/block EROvercome ESR1 mutation mediated resistanceOral SERDs in trials

Inhibition of PI3K PI3K pathway very often altered in breast cancerResponsible for many essential cell activities: Growth promotion, energy creation, etc.Multiple PI3Ki in clinical trials currently

Selective Androgen Receptor (AR) ModulatorsAR drives cancer cell growthSARMs may be effective, have few side effectsClinical trials are available for SARMs

How Can We Do Better?Participate in Trials!Clinical trials exist for patients at any step of their breast cancer journey; trials are a part of the continuum of care

There are benefits to being on a trial!a larger treatment teampossible exposure to cutting edge new medicationshelping other patients with breast cancer

None of the advances in breast cancer could have happened without patients volunteering to be in trials!

What are clinical trial phases?Clinical trials are conducted in a series of steps (phases) - each phase is designed to answer a separate research question.

Phase I: Testing a new treatment in a small group to evaluate safety, dose, and side effects.Phase II: Evaluating within a larger group the efficacy and safety of a new treatment Phase III: A comparison study in a large group to determine if a new treatment works better than standard therapy. These trials typically involve randomization and may have a placebo; the data from a phase 3 trial can be used for FDA drug approval.

FDA approval

How Do I Enter a Trial?Your provider will discuss with you trials of interest, review rationale, as well as risks and benefits

A research RN will review a consent form with you, which describes the structure and details of the trial

After a consent is signed, there is a screening period to determine if you are eligible

When eligibility is confirmed, then you register and can begin trial therapy

Clinical Trials: FAQsIf I consent to a trial, do I have to stay on it?You can leave a trial at any time if either you or your provider thinks being on the trial is no longer in your best interest

Will I have to pay more to be on a trial?All normal procedures are billed to insurance; anything beyond normal care is paid for by the trial. There should be no upcharge for being in a trial

Is being on a trial busy?Each trial is different and has a different schedule

Will I know what medicine I am getting? I dont want a placebo.In most trials, both patient and provider know exactly what treatment is being given. Some larger trials use randomization and placebos, and in some cases neither patient nor provider know identity of study drug. But in almost every trial with placebo, at minimum a patient receives best standard of care.

ConclusionNew, exciting treatment options are on the horizon for metastatic ER+ breast cancerMetastatic biopsies and blood sampling may help direct individual patients treatment and help us move toward new, better treatmentsClinical trials allow access to new therapies and help us make progress

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