Triple-negative breast cancer (TNBC) lacks estrogen, progesterone, and HER2 receptors. It represents 15% of breast cancers and has a higher sensitivity to chemotherapy than other subtypes. New targeted therapies are being developed and tested in clinical trials based on TNBC's defective DNA repair pathways. These include PARP inhibitors, platinum chemotherapy, and angiogenesis inhibitors. TNBC is a heterogeneous disease with multiple molecular subtypes, each with different treatment responses. Participation in clinical trials is important to advance new targeted therapies for TNBC.

1. Targeting Advanced
Triple-Negative Breast Cancer
Erica L. Mayer, MD, MPH
Dana-Farber Cancer Institute
June 2013

2. Outline
• Definitions: What is TNBC? What makes TNBC
different?
• Treatment: Optimizing therapy for TNBC
– Chemotherapy
– Biologic targeted therapy
• Everything you need to know about Clinical Trials

3. Clinical Breast Cancer Subsets
Defined by IHC
All Breast Cancers
Triple
negative
15%
Burstein, Goldhirsch. St Gallen 2007.
ER+
65%-75%
HER2+
15%-20%
3

4. “Triple Negative” Breast Cancer (TNBC)
• Defined as negative for estrogen, progesterone, and HER2
receptors
• Represents about 15% of all breast cancer
• More likely to present in younger women (<40 years old) or in
women of African American or Hispanic background
• May be associated with having an inherited mutation in the
BRCA1/2 genes

5. How to Target Advanced TNBC?
• High growth rate
• Impaired repair of DNA
• Blood vessel growth
Increased sensitivity
to chemotherapy?
Increased sensitivity
to platinum chemotherapy?
PARP inhibitors?
Role of angiogenesis
inhibitors?

6. TNBC Can be Chemotherapy Sensitive!
• Although endocrine and HER2-directed therapies not used,
chemotherapy works the best against TNBC
• Trials of chemotherapy suggest recent advances (addition of
taxane, use of “dose dense” schedules) provide greatest benefits to
TNBC vs HR+ breast cancer
• A significant percentage of TNBC treated with chemotherapy before
surgery completely disappear, demonstrating sensitivity to therapy
• Therefore, although therapy selection for TNBC focuses on
chemotherapy, this class of medicines may work best in TNBC

7. Chemotherapy for Metastatic Breast Cancer
Many active and tolerable chemotherapy choices

8. Cisplatin is of Special Interest for TNBC
• Cisplatin: commonly used chemotherapy for many cancers (lung,
esophageal, sarcoma, testicular)
• Studies in metastatic breast cancer in 1980s showed it to be
active, but development in breast cancer lagged
• Recent interest in patients with TNBC
– DNA damaging mechanism of action may be especially active against TNBC
• Data from recent series of preoperative studies support
significant activity in TNBC
• Activity may be greater in BRCA1/2 breast cancers
Sledge et al, JCO 2008; Silver et al JCO 2010; Gronwold et al, ASCO 2009

9. Preoperative Cisplatin As Preoperative Therapy in
Patients With BRCA1 Mutations
• 25 patients with BRCA1 mutations
• Stage I-III disease
• Treatment:
– Preoperative Cisplatin every 3 weeks x 4 doses
– Mastectomy
• Path CR = No invasive tumor in breast or nodes
Path CR rate = 18/25 = 72%
Gronwold et al, ASCO 2009

10. Are Platinums Preferred for the
Treatment of TNBC?
• TNBC is sensitive to a wide variety of chemotherapeutic agents.
• Are the tumors responding to platinum therapy the same that
would have responded to other agents?
• Perhaps there is selective advantage for BRCA1/2 mutation
carriers as a result of impaired DNA repair?
• Platinum chemotherapy is a reasonable treatment selection for
metastatic TNBC

11. Eribulin for TNBC
• Eribulin:
– New chemotherapy, approved in 2010 for metastatic breast cancer
– Similar to paclitaxel or vinorelbine in mechanism
– Toxicities: numbness, low blood counts, some hair loss
• Recent trial of eribulin vs capecitabine for metastatic breast
cancer
– In all patients, both drugs performed equally well, with expected
toxicities for each
– Patients reported improved quality of life with eribulin
– Analysis of TNBC subset suggested greatest improvement in activity
with eribulin in TNBC, more than in HR+
Kaufman et al, SABCS 2012; Cortes et al ASCO 2013

12. Novel biologic agents for TNBC

13. PARP Inhibitors: Mechanism
• If BRCA1/2 is damaged or not
working, the cell is dependent 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 normally
function to repair daily DNA
damage
• Allows cells to grow in a
healthy way
• Too much DNA damage-> cell
death
Ellisen, Cancer Cell 2011; Tutt et al, Lancet 2010

14. 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

15. 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!

16. Can we make a cancer cell more sensitive to
PARP inhibition?
• Reseachers at BIDMC discovered that PI3
kinase (PI3K) helps DNA repair using BRCA1
• Inhibiting PI3K decreases DNA repair;
creates a unstable DNA environment similar
to having a BRCA1 mutation
• Experiments showed treatment with a PI3K
inhibitor BKM120 increased DNA damage in
cells
Ibrahim et al, Cancer Discovery 2012
Exposure to BKM120 increases
markers of DNA damage (pink)

17. Can we combine a PI3K inhibitor and PARP inhibitor?
• These data suggest exposure to
a PI3K inhibitor might make a
cancer cell with normal
BRCA1/2 more sensitive to
PARP inhibition
• Ongoing trial at Dana-
Farber/Harvard Cancer Center
is combining PI3K inhibitor
BKM120 and PARP inhibitor
olaparib in TNBC
Juvekar et al, Cancer Discovery 2012
PARP inhibitor alone
PARP inhibitor +
PI3K inhibitor

18. • New strategies (PARP inhibitors, platinum chemotherapy) target
defective DNA repair, always found in BRCA1/2 tumors
• Can we identify non-BRCA1/2 tumors which also have defective
DNA repair, and can be treated with PARP inhibitors? Of special
interest for TNBC
• HRD assay designed to find cancers which are “BRCA1/2-like”
and may benefit from DNA-targeting strategies
• HRD assay is performed on tumor tissue already removed from
the body
Can We Identify Other TNBC Sensitive to PARP inhibitors?
Homologous Recombination Deficiency (HRD) Assay:

19. Trial of Platinum Chemotherapy before Surgery:
Rate of Favorable Response by HRD Score in non-
BRCA1/2 mutation carriers
p = 0.0001
Telli ML, Timms K, Hartmann A-R, Ford JM, et al. SABCS 2012; abstract PD09-04
HRD negative HRD positive
70% response rate in non BRCA1/2 mutation carriers
with HRD positive tumors

20. PARP Inhibitors in Advanced Breast Cancer:
Key Questions
• Is target treatment population only BRCA1/2 carriers, or can
they be useful for other breast cancer populations, ie TNBC?
• Should PARP inhibitors be used alone as monotherapy, or work
best in combination with chemotherapy and/or radiation
therapy?
• Are all of the PARP inhibitors the same, or are there differences
in efficacy and safety?
• Need further study in trial in advanced breast cancer

21. Is There a Role for Angiogenesis Inhibition in Triple
Negative Breast Cancer?
• Triple negative breast cancer frequently displays
blood vessel tufts
• Anti-angiogenic medications prevent growth of the
blood vessels that cancer cells need to thrive
• Does vascularity of triple negative breast cancer
predict sensitivity to targeted vascular disruption?
Foulkes et al, Cancer Res 2004; Nalwoga et al, BCRT 2011

22. Is There a Role for Angiogenesis Inhibition
in Triple Negative Breast Cancer?
• Trials including all breast cancer subtypes have not shown
consistent activity
• Analysis of TNBC subset of recent studies of bevacizumab
(Avastin) has suggested possible special benefit for TNBC,
more than that seen with ER+ breast cancer
• Ongoing studies continue to evaluate this question
Brufsky ASCO 2011; Von Minckwitz et al, NEJM 2012; Von Minckwitz et al, ASCO 2013

23. BATON BC: Randomized Phase II Study of Tivozanib, a VEGF
Receptor Inhibitor, in Metastatic TNBC
•TNBC
•No prior systemic
therapy for
metastatic breast
cancer treatment
Tivozanib +Paclitaxel
Paclitaxel + Placebo
• Tivozanib: oral angiogenesis inhibitor (VEGFR
antagonist)
• Can be combined with weekly paclitaxel chemotherapy,
toxicities include high blood pressure, mild diarrhea
• BATON BC trial designed to see if adding tivozanib to
standard paclitaxel improves efficacy of treatment
• Trial also includes scientific analysis to test a tumor
signature which may identify best tumors to treat with
tivozanib

24. What’s New in TNBC?
Tumor Heterogeneity
• Gene expression
profile analysis from
over 500 TNBC
samples
• 6 TNBC subgroups
were identified with
unique profiles
Lehmann et al, JCI 2011

25. Heterogeneity of TNBC
• Different subtypes
displayed differential
response to therapies
in preclinical mouse
models
Lehmann et al, JCI 2011

26. Heterogeneity of TNBC
TNBC

27. Heterogeneity of TNBC
“A disease defined by negatives is not one disease!”
Andrew Tutt, MD
VEGF
EGFR
SrcBRCA1-
PARP
AR

28. Many Agents Under Evaluation for TNBC in Clinical Trials!
Targeted Agent Target
PARP inhibitors DNA repair pathways
Tivozanib VEGFR, angiogenesis
dasatinib Src
CDK inhibitors Cell cycle control
MetMab, ARQ197 Met
Tigatuzumab Death receptor
PI3K inhibitors PI3K
mTOR inhibitors mTOR
FGF inhibitors FGF
Ruxolitinib JAK-1
Bicalutamide AR, androgen receptor

29. 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)

30. 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!

31. 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

32. Active Protocols for mTNBC at DFCI
Protocol ID Phase Regimen Target Key Eligibility
12-398 II Paclitaxel +/- Tivozanib VEGFR -1, -2, -3 1st line TNBC
12-024* II Ruxolitinib JAK 1/2 TNBC, pStat3+
12-438 II BKM120 PI3K TNBC, > 2 priors
11-031 I XL765 + MSC1936369B PI3K/mTOR + MEK TNBC
11-010* I GDC-0032 PI3K TNBC > 1 prior
11-129 II MK-2206 Akt MBC any subtype with
PIKCA/Akt mutation or
PTEN loss
12-017 II ARQ-197 c-MET TNBC, 1-3 priors
12-430 II Cabozantinib c-MET TNBC, 0-3 priors
11-063* I LCL161 + paclitaxel IAP MBC any subtype,
“signature positive”
12-084 II Veliparib/TMZ vs
veliparib/carbo/taxol vs
veliparib/placebo
PARP MBC with BRCA 1/2
mutation; 0-1 priors

33. 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

34. 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.

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

36. Advanced TNBC: Conclusions
• TNBC is a special breast cancer subgroup that requires personalized
therapy
• Chemotherapy works for TNBC, and has gotten better
• No single best target has been identified; novel biologic agents may have
activity for some subgroups
• TNBC is an area of very active research; many exciting new agents in the
pipeline
• In the past year, 4 new metastatic TNBC trials opened at DFCI. Speak to
you provider about entering a trial!
• Future progress depends on.....Making every woman count!