Patients with ER+ breast cancer have many treatment options, and a better understanding of mechanisms of resistance to therapy is leading to new treatments.
Local Housewife and effective ☎️ 8250192130 🍉🍓 Sexy Girls VIP Call Girls Chan...
Making Progress in the Treatment of Estrogen Receptor Positive Metastatic Breast Cancer
1. Ian Krop
Dana-Farber Cancer Institute
Harvard Medical School
September 2016
Making progress in the treatment
of estrogen receptor positive
metastatic breast cancer
3. Invasive Breast Cancer Subsets
Defined by IHC
All Breast Cancers
Triple
negative
15%
Burstein, Goldhirsch. St Gallen 2007.
ER+
65%-75%
HER2+
15%-20%
3
5. “Targeted” therapy
• Drug which inhibits a protein or molecule
that is only expressed in cancer or which
only the cancer is dependent
• Offer the promise of reduced side effects
compared to less targeted drugs
10. Hormonal therapy
• The original targeted therapy
• Several types:
– Tamoxifen
• Blocks estrogen from binding to ER
– Aromatase inhibitors (anastrozole, letrozole, exemestane)
• Blocks production of estrogen
– Fulvestrant (Faslodex)
• Blocks estrogen from binding to ER and helps degrade ER
11. Endocrine Therapy Side Effects
Good (tam)
• Bone Strengthening
Bad
• More common
– Hot Flashes
– Vaginal discharge/dryness
– Arthralgias (AIs)
– Osteopenia/Osteoporosis (AI)
• Rare
– Blood Clots (tam)
– Endometrial cancer (tam)
– Cataracts (tam)
– ?stroke (tam)
12. Blocking cancer cell growth: 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
13. CDK 4/6 inhibition blocks cancer cell division
• CDK 4/6 Inhibition:
– puts the brakes on cell growth
– pushes cancer cells towards cell death
14. 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
15. 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
17. 17
PALOMA-1: Progression-Free Survival
(ITT Population)
Finn RS et al. Presented at AACR 2014; San Diego, California, USA
PAL + LET
(N=84)
LET
(N=81)
Number of Events (%) 41 (49) 59 (73)
Median PFS, months
(95% CI)
20.2
(13.8, 27.5)
10.2
(5.7, 12.6)
Hazard Ratio
(95% CI)
0.488
(0.319, 0.748)
p-value 0.0004
90
80
70
60
50
40
30
20
10
0
Progressionfreesurvivalprobability(%)
0 4 8 12 16 20 24 28 32 36 40
Time (months)
84 67 60 47 36 28 21 13 8 5 1
81 48 36 28 19 14 6 3 3 1
PAL + LET
LET
Number of patients at risk
100
18. 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
19. 0 2 4 6 8 10 12
Time (Month)
0
10
20
30
40
50
60
70
80
90
100
ProgressionFreeSurvivalProbability(%)
347 279 132 59 16 6PAL+FUL
174 109 42 16 6 1FUL
Number of patients at risk
PALOMA 3: Palbociclib delays cancer progression
when added to fulvestrant
CI=confidence interval; ITT=intent-to-treat; NE=not estimable;
PFS=progression-free survival.
Placebo +
Fulvestrant
n=174
Palbociclib
+
Fulvestran
t
n=347
# Events
(%) 93 (53.4) 102 (29.4)
Median
PFS
3.8
(3.5, 5.5)
9.2
(7.5, NE)
Hazard
Ratio
0.422 (0.318, 0.560)
<0.000001
Similar benefit seen in all
subgroups examined
20. HOW CAN WE OVERCOME RESISTANCE
TO ENDOCRINE THERAPY?
21. Dual Targeting
An endocrine sensitive cell depends on the estrogen receptor
nucleus
Cancer cell
Estrogen
receptor
22. Dual Targeting
In setting of endocrine resistance, other pathways are activated
nucleus
Cancer cell
Estrogen
receptor
Growth factor
receptor
PI3K
mTOR
23.
24. Dual Targeting
In setting of endocrine resistance, other pathways are activated
nucleus
Cancer cell
Estrogen
receptor
Growth factor
receptor
PI3K
mTOR
25. Dual Targeting
In setting of endocrine resistance, dual targeting may be important
nucleus
Cancer cell
Estrogen
receptor
Growth factor
receptor
mTOR
PI3K
26. 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
27. Everolimus delays cancer progression
4 month improvement in PFS over AI alone
Baselga et al, NEJM 2012
28. Hormonal
therapy
Hormonal
therapy
Chemotherapy Chemotherapy
Chemotherapy Chemotherapy Chemotherapy
Herceptin +
perjeta +
chemotherapy
TDM1
Lapatinib +
Capecitabine
Herceptin +
chemotherapy
Herceptin +
chemotherapy
Hormone receptor
positive
Triple-negative
HER2-Positive
*Note, these are just examples. Each patient is different and treatment is tailored accordingly.
How Do We Treat
Metastatic Breast Cancer?
37. Antibodies to PD-1 or PD-L1 prevent
tumor cells from inactivating T-cells
38.
39. Antibodies to PD-1 shrinks cancers in the
majority of patients with metastatic melanoma
40. Why such durable responses in very
advanced cancers?
• Immune system targets many parts of the
cancer (antigens)
– Harder for cancer to escape recognition
• Advanced cancers’ frequent mutations make
them more “foreign” to immune system
42. Immune therapy in triple negative
cancers
• Highest rate of PD-L1 expression
• Highest rate of mutations
• High level of immune cells in the tumor
(TILS)
43. This presentation is the intellectual property of the presenter, Rita Nanda. Contact rnanda@medicine.bsd.uchicago.edu for permission to reprint and/or distribute.
December 9-13, 2014
Change From Baseline in Target Lesions Over Time
(Central Review)
-100
-80
-60
-40
-20
0
20
40
60
80
100
0 8 16 24 32 40 48 56
ChangeFromBaseline,%
Time, weeks
Analysis cut-off date: November 10, 2014.
On treatment
Discontinued treatment
44. What do these trials tell us?
• Provides proof that immunotherapy can work
in breast cancer
• Important to note that:
– Only patients with PD-L1 positive TNBC were
included
– Only a minority of these patients benefited
45. Immunotherapy in ER+ breast cancer
– Low PD-L1 expression
– Fewer mutations
– Likely will need something to increase recognition
by immune system
46. Other immunotherapy targets in development
Activating Inhibiting
Mellman et al. Nature, 2011
Ipilimumab
Pembrolizumab
Nivolumab
47. Conclusion
• Patients with ER+ breast cancer have many treatment
options
– Hormonal therapies (tamoxifen, AI’s, fulvestrant)
– Palbociclib + hormonal therapy
– Everolimus + hormonal therapy
– Chemotherapy
• A better understanding of mechanisms of resistance to
therapy is leading to new treatments
• Clinical trials allow access to new therapies and help us
make progress
48. 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!
49. 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
50. 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
51. 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.