1) Primary systemic therapy with chemotherapy is used to begin treatment for inflammatory breast cancer (IBC) since it is inoperable at diagnosis. 2) IBC has been shown to be relatively chemoresistant, so identifying targeted therapeutic approaches is important. 3) Clinical trials specifically designed for IBC are needed, as including IBC patients in locally advanced breast cancer trials makes it difficult to interpret outcomes for IBC. Such trials should incorporate translational components to further understand IBC biology.

1. Primary Systemic Therapy:
Beginning the Journey
Beth Overmoyer MD, FACP
Director, Inflammatory Breast Cancer Program
1st Annual IBC Patient Forum
Dana Farber Cancer Institute
May 13, 2017

2. Historical Perspective of IBC
• The historical identification of IBC is important as a reminder of the
acceptance of classic clinical criteria that differentiates the disease
from other forms of locally advanced breast cancer
• 1814 – Sir Charles Bell described a grave prognosis associated with
breast cancer when the following characteristics are present:
• “when a purple color is on the skin over the tumor accompanied
by shooting pains it is a very unpropitious beginning”
• Lee and Tannenbaum (1924) – “inflammatory breast cancer”

3. IBC – A Distinct Subtype of Breast Cancer
Distinct subtype of breast cancer
• Definitive or pathologic
diagnostic criteria do not
exist
• “Clinical diagnosis” fraught
with potential problems,
both underestimating and
overestimating the
diagnosis
• Seer 2004-7: 2-yr BCS
• IBC = 84%
• LABC = 91%
• 43% higher risk of breast cancer death in
IBC vs. LABC
• German study: 4.5x greater risk of
dying within 5 years
Diessner Arch Gyn Obs 2015;292:655; Anderson WF, JCO 21:2254, 2003
IBC
LABC

4. • 1-5% incidence in US
• Difficulty in tracking the disease due to variation in diagnostic criteria
over time
• Underestimate incidence
Clinical definition with confirmed breast cancer: Rapid onset – 3 – 6 mo
• Erythema > 1/3 breast
• Edema (peau d’orange)
• Often warm breast, pain
• Breast enlargement – often without a mass
• Highly metastatic:
35% metastasis at presentation
Clinical Presentation - IBC

5. Clinical Diagnosis of IBC
• Tumor emboli in dermal lymphatics without classical signs is not
considered IBC
• The presence of dermal lymphatic invasion is not necessary for
the diagnosis of IBC

6. “Trimodality” Therapy: Importance of pCR
Primary
Systemic Therapy
Mastectomy +
Axillary LN Dissection
Radiation to Chest Wall
and Regional LN
Adjuvant Endocrine Rx (HR+)
+/or Trastuzumab (HER2+)
Nakhlis 2016
Overall survival
86%
51%
Time to tumor recurrence
79%
33%

7. Retrospective Studies of Preoperative
Chemotherapy for IBC
No.
IBC
Chemotherapy RR Median
Survival
Italy 68 CAF or CEF / CMF pCR: 3% 4 yr.
U Penn 52 CMF +/- CAF pCR: 12% NR
France 120 FEC-HD pCR: 15% 5 yr.
British Columbia 308 CT v intensive CT (+ T) pCR:
28% v 33%
3.2 yr.
MD Anderson 240 FAC v FAC + T pCR:
10% v 25%
3.4 v 4.3 yr
Primary chemotherapy backbone = anthracycline and taxane

8. Dose-Dense versus Conventional Preoperative
Chemotherapy (AGO-1) – Overall ≠ IBC
• 668 patients with locally advanced breast cancer
• Overall group benefitted from intensive
chemotherapy:
• Improved pCR – 18% vs 10%
• Improved time to disease recurrence
• Improved overall survival
Untch M JCO 2009; 27:2938
• 100 IBC
• No difference with intensity of chemotherapy:
• No difference in pCR – 12% vs 10%
• No difference in time to disease recurrence
• No difference in overall survival
≠

9. pCR Rates in SWOG 0012: Standard AC versus
“Continuous” AC
Georgiana K. Ellis et al. JCO 2011;29:1014-1021
• 356 Overall vs 111 IBC (31%)
• Overall: no difference in outcome
• Higher pCR in IBC with continuous dosing of chemotherapy – 27% vs 13%

10. Finding Therapeutic Targets in IBC
•HER-2
•Angiogenesis
•JAK2-STAT3

11. Finding Therapeutic Targets in IBC
•Targeting HER-2
•Angiogenesis
•JAK2-STAT3

12. NOAH – IBC Experience
64% v 24%
74% v 44%
5-YR EFS
5-YR OS
Doxorubicin
60mg/m2 →
Paclitaxel
150mg/m2 q21d x 3
Paclitaxel
175mg/m2 q21d x 4
CMF x 3
Subset Analysis
• 61 / 228 pts with IBC,
HER2+
• pCR = 48 % with
trastuzumab
•13% without trastuzumab
Gianni L. Lancet Oncol 2014 15:640

13. Anti-HER2 Therapy
Trypheana (13/225
= 6% IBC)
FEC+HP x 3 →T+HP x 3
(N=73)
FEC x 3 → T+HP x 3
(N=75)
TCH+P x 6
(N=77)
IBC 5(7%) 4(5%) 4(5%)
tpCR 41(56%) 41(55%) 48(64%)
NeoSphere
(29/417 = 7% IBC)
T+D (N=107) T+D+P (N=107) T+P (N=107) P+D (N=96)
IBC* 7 (7%) 10 (9%) 7 (7%) 5 (5%)
tpCR (all) 23 (22%) 42 (40%) 12 (11%) 17 (18%)
5y –DFS 81% 84% 80% 75%
Gianni Lancet Oncol 2012;13:25-32; Schneeweiss Ann Oncol 2013;2278-84; Gianni Lancet Oncol 2016; Gianni Lancet Oncol 2012;
Boussen, JCO 2010; Untch Lancet Onc 2012.
Investigating lapatinib Regimen Number enrolled pCR
MDACC Lapatinib +
paclitaxel
32 3/17 (18%)
GeparQuinto EC→D
(L v H)
82/620 =13% IBC 23% v 30% (p=0.04)
Odds ratio IBC = 0.72 (NS)

14. Run In Phase – Day 1 week 1 (breast biopsy #1)
Pertuzumab IV 840 mg loading dose Trastuzumab IV 4 mg/kg loading
dose
Treatment Phase – Day 8 week 2 (breast biopsy #2)
Trastuzumab IV 2mg/kg weekly and paclitaxel 80 mg/m2 IV weekly x 16 weeks.
Day 21 week 4
Continue trastuzumab and paclitaxel as above and begin pertuzumab 420 mg IV
every 21 days for 5 doses
Modified radical mastectomy
(assess residual disease)
Post-operative Treatment:
Doxorubicin 60 mg/m2 IV and cyclophosphamide 600 mg/m2 IV every 3 weeks x 4 cycles*
Followed by trastuzumab 6 mg/kg and pertuzumab 420 mg every 21 days x 8 months**
(loading dose given first after AC completed)
Radiation Therapy
Endocrine therapy if HR+
*Optional
**Metastatic disease (nodal disease only):
continue on pertuzumab + trastuzumab
until disease progression
Primary Objective: pCR
• Accept benefit if > 8/ 27
pts have pCR
NCI-2013-01110, NCT0179619712-497; Genentech, IBC Network - sponsor
Hypothesis:
Can we limit the amount
of chemotherapy and
maximize the HER2-
directed therapy in the
treatment of HER2+ IBC ?

15. Finding Therapeutic Targets in IBC
•Targeting HER-2
•Angiogenesis
•JAK2-STAT3

16. Angiogenesis and Lymphangiogenesis in IBC
• IBC makes its own blood supply and
lymphatic supply throughout the
breast
• Increased expression of
angiogenesis related genes
• Increased expression of
lymphangiogenesis related genes
• Is this “encircling
lymphovasculogenesis” or
lymphovascular invasion ?
Colpaert CG, Br J Ca 2003;88:718; Van der Auwera Clin Can Res 2005;11:7637

17. Angiogenesis in IBC: Is it a Useful Target ?
Addition of Anti-angiogenic Agents to Pre-operative Chemotherapy
Treatment Number Stage pCR Median
DFS (III)
Correlatives
SU5416, doxorubicin 17 III or IV 0 32 mo DCE/MRI –
(Kep) – 58%
(p=0.033)
Bevacizumab,
docetaxel,
doxorubicin
21 (1 LABC) III or IV 1 (5%) 25.3 mo DCE-MRI –
(Ktrans) – 34%
(p=.003)
BEVERLY-1 (FEC(B) x
4 → D(B) x 4)
100 III 19 (19%) 53 mo CTC not
associated with
pCR
BEVERLY-2 (FEC(B) x
4 → D(B+H) x 4)
52 III 33 (64%) NA CTC not
associated with
pCR
Overmoyer CCR 2007; Wedam JCO 2006; Bertucci 2016; Pierga 2012

18. Eribulin and Normalization of Vasculature
Region of Interest (ROI) Ktrans (1/min/1000)
Pre-Eribulin Post-Eribulin (d 8)
#1 ROI 78.1 115.2
#2 ROI 47.5 71.4
• Eribulin effects on mice:
• Improves blood flow to inside of tumor
• Increased overall tumor blood flow
• Changes in expression of genes for blood
vessel formation and cancer survival
• In IBC – investigate eribulin’s effect on tumor
blood flow
• Also investigate expression on genes for
blood vessel formation and cancer survival
2
1
Agoulnik Vasc Cell 2014.; Funahashi Cancer Sci 2014; Yoshida Br J Cancer 2014.; Dezso PLoS One 2014.; Overmoyer SABCS 2016.
2
1

19. Pre-treatment breast biopsy #1
Eribulin x 1 (cycle 1 day 1)
Breast biopsy #2: 1 wk after eribulin
(cycle 1 day 8)
Eribulin q 3 wks x 3 cycles
dd AC q 2 wks x 4 cycles
Mastectomy (harvest residual tumor)
Radiation therapy + endocrine therapy
Imaging subset study
Pre-treatment
breast DCE-MRI
1 wk after eribulin
(c1,d8) breast DCE-
MRI
Eribulin
1.4mg/m2 IV
d1,d8 q21d x 4
cycles
Doxorubicin 60
mg/m2 +
cyclophosphamide
600 mg/m2 IV q2w x
4 cycles
Overview
• Primary Objective: pCR rate
• Two-stage design:
• Reject if pCR is < 15%
• Accept if pCR > 30%
• > 2/16 pCR – go forward
• Accept benefit if > 5/ 25 pts
have pCR
NCI-2016-00329, NCT0262397215-292; Eisai-sponsor

20. Finding Therapeutic Targets in IBC
•Targeting HER-2
•Angiogenesis
•JAK2-STAT3

21. Slides curtesy of Kornelia Polyak MD, PhD

22. N=64
(50 +)
Ruxolitinib x 7
days
(N=32)
Ruxolitinib x 7d +
Paclitaxel x 1 wk
(N=32)
Paclitaxel x 12
weeks (N=16)
Ruxolitinib +
Paclitaxel x 12
weeks (N=16)
Ruxolitinib +
Paclitaxel x 11
weeks (N=32)
dd doxorubicin/cyclophosphamide x
4 cycles (N=64)
Modified radical mastectomy
Radiation therapy
Pre-treatment biopsy #1
Post-run-in biopsy #2
Primary:
Pharmacodynamic
Secondary:
Clinical
TBCRC 039 - SCHEME
Sponsored by Incyte, and
Inflammatory Breast Cancer Research Foundation

23. Primary Systemic Therapy for IBC:
Beginning the Journey
• IBC is inoperable at the time of diagnosis, therefore initial therapy with
“systemic treatment” is indicated.
• IBC is relatively chemo-resistant, therefore identifying therapeutic targets is
critical.
• We must focus our efforts on designing clinical trials specifically for IBC
• Inclusion of IBC patients into LABC trials will dilute the interpretation of
outcome
• Incorporate translational components
• Identify biologic markers that confirm the diagnosis, not just rely on “clinical
features” that are not consistent.