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

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”

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

• 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

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

“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%

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

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

≠

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%

Finding Therapeutic Targets in IBC

•HER-2

•Angiogenesis

• JAK2-STAT3

Finding Therapeutic Targets in IBC

• Targeting HER-2

•Angiogenesis

• JAK2-STAT3

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

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)

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 TherapyEndocrine 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 ?

Finding Therapeutic Targets in IBC

• Targeting HER-2

•Angiogenesis

• JAK2-STAT3

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

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

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

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

Finding Therapeutic Targets in IBC

• Targeting HER-2

•Angiogenesis

• JAK2-STAT3

Slides curtesy of Kornelia Polyak MD, PhD

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 #2Primary:

Pharmacodynamic

Secondary:Clinical

TBCRC 039 - SCHEME

Sponsored by Incyte, and Inflammatory Breast Cancer Research Foundation

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.