A look at the new and exciting treatment options that are on the horizon for metastatic ER+ breast cancer.

1. Moving Beyond Resistance:
Current Research in ER+
Metastatic Breast Cancer
Heather A. Parsons
Dana-Farber Cancer Institute
Harvard Medical School
September 24, 2016

2. Hormonal
therapy
Hormonal
therapy
Chemotherapy ChemotherapyHormone receptor
positive
How Do We Treat
Metastatic Breast Cancer?

3. Some Questions to Answer in
Metastatic ER+ Breast Cancer
• Why 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?

4. 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.

5. 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 cancer
• Return clinically relevant results to providers
• Store results in searchable database
• Enable linkage of specimen results to clinical database
PROFILE: Towards Precision Cancer Medicine
Since August 2011, >30,000 patients have
consented (75%) and >12,000 tests have been performed

6. 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)
Center for Cancer Precision Medicine (CCPM)
ER+ Metastatic Breast Cancer Study
Future Uses
“Blood” or “Liquid” Biopsies

7. 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
Center for Cancer Precision Medicine (CCPM)
ER+ Metastatic Breast Cancer Study

8. Circulating tumor DNA
(ctDNA)
• Metastatic biopsies can
be challenging
• Cancer (and normal) cells
shed ctDNA into blood
• ctDNA could identify
markers of drug sensitivity
or resistance in a cancer

9. ESR1 Mutations in Previously
Treated ER+ Breast Cancer

10. ESR1 mutations in ctDNA predict
benefit for Fulvestrant vs. Exemestane
Charlotte Fribbens et al. JCO doi:10.1200/JCO.2016.67.3061
©2016 by American Society of Clinical Oncology

11. ctDNA in EMBRACE
• ctDNA could identify
tumor alterations to
direct patients to a
trial
• ctDNA may show
tumor alterations
that are
mechanisms of
treatment resistance

12. Selective Estrogen Receptor
Degraders (SERDs)
• Estrogen signaling:
– Essential for ER+
breast cancer cell
growth
• SERDs bind/block
ER
• Overcome ESR1
mutation mediated
resistance
• Oral SERDs in trials

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

14. Selective Androgen Receptor
(AR) Modulators
• AR drives cancer cell growth
• SARMs may be effective, have few side
effects
• Clinical trials are available for SARMs

15. 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 team
– possible exposure to cutting edge new medications
– helping other patients with breast cancer
• None of the advances in breast cancer could have happened
without patients volunteering to be in trials!

16. 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

17. 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

18. Clinical Trials: FAQs
• If 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 don’t 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.

19. Conclusion
• New, exciting treatment options are on the horizon for
metastatic ER+ breast cancer
• Metastatic biopsies and blood sampling may help direct
individual patients’ treatment and help us move toward
new, better treatments
• Clinical trials allow access to new therapies and help us
make progress