1.
What’s New in Treatment of ER+
Breast Cancer?
Erica L. Mayer MD MPH
Dana-Farber Cancer Institute

2.
Invasive Breast Cancer Subsets
Defined by IHC
All Breast Cancers
Triple
negative
15%
Burstein, Goldhirsch. St Gallen 2007.
ER+
65%-75%
HER2+
15%-20%
2

3.
Therapy for Advanced ER+ Breast Cancer
• Strong preference to begin treatment using endocrine
(hormone) therapy, unless cancer is causing significant
symptoms/problems
• At least 4+ choices (“lines”) of therapy; generally can be very
effective at controlling the cancer with minimal side effects
• New approaches are needed to improve efficacy of endocrine
therapy and delay onset of resistance

4.
HOW CAN WE ENHANCE EFFICACY
OF ENDOCRINE THERAPY?

5.
Cyclin Dependent Kinase (CDK 4/6) inhibition
• A classic feature of breast cancer is
uncontrolled growth
• In ER+ breast cancer, out-of-control
growth may be due to a failure in the
braking system: overactive CDK4/6

6.
What’s Hot for ER+ Breast Cancer?
CDK 4/6 inhibition
• CDK 4/6 Inhibition:
– puts the brakes on cell growth
– pushes cancer cells towards cell death

7.
Palbociclib (Ibrance)
• Palbociclib: oral inhibitor of CDK 4/6
• Taken daily, 3 weeks on, 1 week off
• Most common toxicities: low white
blood cell count (but no infections),
fatigue, mild hair thinning

8.
PALOMA-1 Trial: Schema
• First randomized trial of palbociclib in breast cancer (phase II)
• Women with newly diagnosed metastatic breast cancer were
randomized to first-line therapy with letrozole alone, or
letrozole + palbociclib
Letrozole
Palbociclib
+
Letrozole
• Metastatic breast cancer
• ER+/HER2-
• First line

9.
PALOMA-1 Trial: Results
• Women taking the 2 medications had substantially better
disease control that those taking the 1 medication
• The combination arm was well tolerated

10.
PALOMA-3 Study Design
• Larger trial in women whose cancer previously
showed resistance to endocrine therapy (Phase III)
Placebo
+
Fulvestrant
Palbociclib
+
Fulvestrant• Metastatic breast cancer
• ER+/HER2-
• Tumor has shown
resistance to endocrine
therapy

11.
PALOMA-3 Results
• Combination arm again did substantially better
than fulvestrant and placebo
• Toxicity profile very similar to PALOMA-1
• Validates activity of palbociclib seen in PALOMA-1
• No new toxicity signals with the drug
• Await results of PALOMA-2: similar to PALOMA-1
but a larger trial

12.
IF IT WORKS IN ADVANCED DISEASE,
WILL IN WORK EARLIER ON TO PREVENT
METASTATIC BREAST CANCER?

13.
PALLAS: Phase III Randomized Trial of Adjuvant
Endocrine Therapy +/- Palbociclib
Patient Population
•N = 4600
•HR+ and HER2-
• Stage II or III
Arm A
Palbociclib (2 yrs)
+
Endocrine Treatment
(5+ yrs)
Arm B
Endocrine treatment
(5+ yrs)
R
A
N
D
O
M
I
Z
E
1:1 Survival/Disease Follow-up
Arm A: palbociclib at a dose of 125 mg once daily, Day 1-21 in a 28-day cycle for total
duration of 2 years, in addition to standard adjuvant endocrine therapy
Arm B: standard adjuvant endocrine therapy (AI, tamoxifen)
Opening 11/2015….

14.
HOW CAN WE OVERCOME RESISTANCE
TO ENDOCRINE THERAPY?

15.
Dual Targeting
An endocrine sensitive cell depends on the estrogen receptor
nucleus
Cancer cell
Estrogen
receptor

16.
Dual Targeting
In setting of endocrine resistance, other pathways are activated
nucleus
Cancer cell
Estrogen
receptor
Growth factor
receptor
mTOR
PI3K

17.
Dual Targeting
In setting of endocrine resistance, dual targeting may be important
nucleus
Cancer cell
Estrogen
receptor
Growth factor
receptor
mTOR
PI3K

18.
BOLERO-2 Study Design
• Trial of mTOR inhibitor added to exemestane (AI) in
endocrine resistant ER+ advanced breast cancer
Placebo
+
Exemestane
Everolimus
+
Exemestane• Metastatic breast cancer
• ER+/HER2-
• Tumor has shown
resistance to endocrine
therapy

19.
BOLERO-2 Results
• Combination arm had better cancer control than exemestane
and placebo
• Toxicity profile: mouthsores, fatigue diarrhea, can be
controlled with dose reduction
• Enhancement of activity in setting of resistance validates
laboratory model
• Results of BOLERO-2 led to FDA approval of everolimus for
breast cancer in July 2012
• Currently under study in the adjuvant setting

20.
What About Targeting PI3K?
• Laboratory work suggests PI3K
inhibitor + endocrine therapy is
synergistic
• Almost 40-45% of ER+ breast cancer
has a PIK3CA mutation – does this
predict a cancer will be sensitive?
• Trials of 1st generation PI3K
inhibitors did not show enough signal
to move forward.
• 2nd generation agents are more
selective (“alpha specific”) and may
show greater activity
21
MCF-7 (E545K)
1. Miller et al. JCO 2010
2. Baselga et al. NEJM 2012; Bachelot et al. JCO 2012
3. Raynaud et al., MCT 2009

21.
Alpha Specific PI3K Inhibitors are Now
in Phase III Trials!
SANDPIPER trial
Normal
Assignment of treatment by presence of mutation: an
example of “precision medicine”

22.
How Can We Do Better?
Participate in Trials!
• “One reason I chose to participate in a clinical trial
was to help women with triple-negative breast
cancer. It is thanks to women who have enrolled in
clinical trials that we have the treatments that give
us hope.”
– Natalia (LBBC, Guide to Understanding TNBC)

23.
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!

24.
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

25.
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

26.
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.

27.
How to learn about trials?
Or ask your provider…

28.
Current Trials at DFCI for Advanced ER+ Breast Cancer
(as of 10/15/15)
Protocol # Short Title
15-060 Palbociclib + Bazedoxifene
15-058
Abemaciclib in Patients with Brain Metastases secondary to
HR+ Breast Cancer
14-569 Ph I SRN-927 in Postmenopausal ER+ MBC
14-565
Ph III Rand. DB LEE011 or Placebo in comb. w/TAM + Goserlin or NSAI + Goserlin
for Premenopausal BC
(MONALEESA-7)
14-518 Fulvestrant +/- Abemaciclib
14-098
LEE011/Fulvestrant/BYL719/
BKM120 for BC
14-070 LY2835219 + Endocrine for HR+ MBC
13-157 BYL719+Letrozole in HR+ BC
11-477 Faslodex +/- Ganetespib for HR+ MBC
11-010 GDC0032 + Endocrine
11-208 Cabozantinib + Fulvestrant for MBC

29.
Conclusions
• Incredibly exciting work going on in breast
cancer research for ER+ breast cancer
– New targets
– Moving away from chemotherapy
– Learning a tremendous amount from each biopsy
• Future progress depends on.....Making every
woman count!