What's the latest in breast cancer treatment and research? Erica Mayer, MD, MPH, a medical oncologist in the Susan F. Smith Center for Women's Cancers, shares the latest breast cancer news.
This presentation was originally given on Oct. 16, 2015, at the annual Young Women with Breast Cancer Forum, hosted by the Program for Young Women with Breast Cancer in the Susan F. Smith Center for Women's Cancers at Dana-Farber Cancer Institute, in Boston, Mass.
Learn more: http://www.susanfsmith.org
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What's Hot in Breast Cancer Treatment
1. What’s Hot in Breast Cancer
Treatment
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. Breast Cancer is Not Just One Disease
At least 4 major subtypes:
Luminal A
Luminal B
HER2-positive
Basal
ER+
HER2-
ER-
PR-
HER2-
4. What does all this complexity mean?
•There is likely not going
to be a single “cure for cancer”
•Different cancers may have
different strengths & weaknesses
•Figuring this out won’t be easy!
“half empty”
5. What does all this complexity mean?
•There is likely not going
to be a single “cure for cancer”
•Different cancers may have
different strengths & weaknesses
•Figuring this out won’t be easy!
“half empty” “half full”
•The opportunity to individualize
therapy—one size doesn’t fill all
•We may be able take advantage
of specific weaknesses and
knock out specific strengths
•It should be possible!
6. What’s Hot for ER+ Breast Cancer?
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
7. 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
8. 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
9. 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
10. 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
11. PALOMA-3 Study Design
• Larger trial in women whose cancer previously
showed resistance to endocrine therapy
(Phase III)
• Placebo controlled
Placebo
+
Fulvestrant
Palbociclib
+
Fulvestrant• Metastatic breast cancer
• ER+/HER2-
• Tumor has shown
resistance to endocrine
therapy
12. 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
14. IF IT WORKS IN ADVANCED DISEASE,
WILL IN WORK EARLIER ON TO PREVENT
METASTATIC BREAST CANCER?
15. 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….
17. The HER2 Timeline
1981 neu described as a transforming oncogene in rat brain tumor
carcinogenesis model
1985 a) neu is homologous to the v-erb B viral oncogene
b) “EGFR-like” gene amplified in a human breast cancer cell line – named
“HER2”
1986 HER2 found to have tyrosine kinase activity similar to EGFR
1987 HER2 amplification correlated with poor OS in human breast cancer
1989 Discovery of HER3
1993 Discovery of HER4
1998 FDA approval of trastuzumab
2007 FDA approval of lapatinib
2012 FDA approval of pertuzumab
2013 FDA approval of trastuzumab emtansine (T-DM1)
18. Pertuzumab (Perjeta)
• Dual targeting of the HER2 receptor
– prevents growth stimulation of cancer cell
– promotes cancer cell destruction
Herceptin
Pertuzumab
HER2 receptor
19. CLEOPATRA:
Phase III Trial of Docetaxel + Trastuzumab vs Docetaxel +
Trastuzumab + Pertuzumab
1:1HER2-positive
Advanced
Breast Cancer
Docetaxel + trastuzumab
+ placebo
Docetaxel + trastuzumab
+ pertuzumab
N=808
20. Results from CLEOPATRA
• Women receiving chemotherapy with both
herceptin and pertuzumab had
– Longer period of disease control
– Longer survival
• Overall very well tolerated
• Quickly “THP” has become a new standard of
care for advanced HER2+ breast cancer
21. Can we Offer Pertuzumab Before
Cancer is Advanced?
• “NeoSPHERE” study added pertuzumab to
chemotherapy and herceptin before breast
surgery
• Patients receiving the 3 drugs had a doubling in
“pathologic complete response” – complete
eradication of cancer from breast and nodes at
time of surgery
• FDA approved “THP” in 9/2013 in preoperative
setting
23. T-DM1 selectively delivers DM1 to
HER2-positive tumor cells
Receptor-T-DM1 complex is
internalized into HER2-positive
cancer cell
Potent antimicrotubule
agent is released once inside
the HER2-positive
tumor cell
T-DM1 binds to the HER2 protein
on cancer cells
HER2
24. EMILIA Study Design
HER2+ Advanced
breast cancer
Prior treatment with
chemotherapy and
herceptin
T-DM1
Capecitabine (Xeloda)
+
Lapatinib (Tyberk, oral HER2)
25. Results of EMILIA
• Patients receiving TDM1 had better cancer
control and lived longer than those receiving the
other arm
• TDM1 contributed SIGNIFICANTLY fewer side
effects than the chemotherapy containing arm.
• FDA approved for treatment of advanced breast
cancer in February 2013
26. Will there be a role for TDM1 earlier in therapy?
ATEMPT Trial
Stage I
HER2+
500 patients
Trastuzumab-DM1 q3weeks X17
Paclitaxel + Trastuzumab x12
Trastuzumab q3weeks x13
N=375
N=125
R
3
1
PI: Sara Tolaney, MD, MPH
28. PARP Inhibitors: Mechanism
• If BRCA1/2 is not working, the cell
depends on PARP for all DNA repair
• PARP inhibitors prevent DNA repair
in cancer cells
– May increase cancer cell death
– May help chemo and radiation work
better
• PARP and BRCA1/2 function
to repair daily DNA damage
• Too much DNA damage-> cell
death
Ellisen, Cancer Cell 2011; Tutt et al, Lancet 2010
29. Phase II trial of the PARP inhibitor olaparib in BRCA-
deficient advanced breast cancer
Study design:
- To assess efficacy/tolerability of olaparib in BRCA 1/2 mutation carriers
- Phase II single arm sequential cohort multicenter trial
Confirmed BRCA1 or BRCA2 mutation
Advanced refractory breast cancer
(stage IIIB/IIIC/IV) after failure of ≥1 prior chemotherapy for
advanced disease (med prior regimens = 3)
Olaparib 400 mg po bid
28-day cycles; 27 patients
Cohort 1 (enrolled first)
Olaparib 100 mg po bid
28-day cycles; 27 patients
Cohort 2
Tutt et al, ASCO 2009
30. Objective tumor response rate (RECIST)
Overall Response Rate, n (%)
Complete Response, n (%)
Partial Response, n (%)
11 (41)*
1 (4)
10 (37)
Olaparib
400 mg bid
(n=27)ITT cohort
Adverse Events:
Fatigue grade 1 or 2, 56% grade 3, 15%
Nausea grade 1 or 2, 26%, grade 3 11%
ASCO 2009; #suppl. CRA501
• Median of 3 prior lines of chemotherapy.
Substantial activity with
biologic monotherapy in a
heavily pretreated
BRCA1/2 population!
31. Single Agent PARP Inhibition:
Ongoing Trials evaluating Chemotherapy vs PARPi in Patients
with BRCA Mutations
gBRCA1/BRCA2
Carriers
Advanced
anthracycline+taxane
resistant breast cancer
PARP inhibitor
Physician Choice
chemotherapy
R
Olaparib – OLYMPIAD – NCT02000622
Niraparib – BRAVO – NCT01905592
BMN673 – EMBRACA – NCT01945775
32.
33.
34.
35.
36. Immunotherapy in Cancer
• First generation (anti-CTLA4)
– Ipilumumab: approved for melanoma
• Second generation (anti-PD1 or PDL1)
– Nivolumab: approved for melanoma, lung cancer
– Pembrolizumab: approved for melanoma
What about breast cancer?
37. Early PD1/PDL1 Experience in Breast Cancer
• Immune cells often found infiltrating triple negative breast cancer –
potentially indicates candidacy for immune therapy!
• Two Phase 1 trials completed in patients with advanced triple
negative breast cancer
– More response seen than expected with chemotherapy
– Will tolerated
• Phase 2 and 3 trials opening now
• Many questions need to be figured out:
– Is immunotherapy for everyone or can we find tumor markers that predict
who will get more benefit?
– Do we need to test tumor for PDL1
– Will immunotherapy have benefit in other types of breast cancer, ie HR+,
HER2+?
39. THE PRECISION MEDICINE INITIATIVE
“Doctors 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
40.
41. 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
42. 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 >8,000 tests have been performed
45. Clinical Breast Cancer Cancer Genomics
• To date, genomic studies in breast cancer have
highlighted the landscape of genomic alterations in
breast cancer overall
• Now, we have developed clinically-focused studies to
help us understand:
– The genetics of specific types of breast cancer
– Why breast cancers behave in different ways
– How breast cancers develop resistance to therapies
– Why some breast cancers are exquisitely sensitive to some
therapies
46. 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)
47. 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!
48. 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 of people 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
49. 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
50. 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.
51. How to learn about trials?
Or ask your provider…
52. Conclusions
• Incredibly exciting work going on in breast
cancer research
– New targets
– Advances for all subtypes
– Moving away from chemotherapy
– Learning a tremendous amount from each biopsy
• Future progress depends on.....Making every
woman count!