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Primary Systemic Therapy for Inflammatory Breast Cancer

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Part of the 2017 Metastatic Breast Cancer Forum, held by Dana-Farber Cancer Institute.

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Primary Systemic Therapy for Inflammatory Breast Cancer

  1. 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. 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. 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. 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. 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. 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. 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. 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. 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. 10. Finding Therapeutic Targets in IBC •HER-2 •Angiogenesis •JAK2-STAT3
  11. 11. Finding Therapeutic Targets in IBC •Targeting HER-2 •Angiogenesis •JAK2-STAT3
  12. 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. 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. 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. 15. Finding Therapeutic Targets in IBC •Targeting HER-2 •Angiogenesis •JAK2-STAT3
  16. 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. 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. 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. 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. 20. Finding Therapeutic Targets in IBC •Targeting HER-2 •Angiogenesis •JAK2-STAT3
  21. 21. Slides curtesy of Kornelia Polyak MD, PhD
  22. 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. 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.

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