Management of Inflammatory Breast Cancer: Collaboration is the path forward

Transcription

1 Management of Inflammatory Breast Cancer: Collaboration is the path forward Massimo Cristofanilli, M.D., F.A.C.P. Professor of Medicine Associate Director of Translational Research and Precision Medicine Robert H Comprehensive Lurie Cancer Center, Northwestern University Chicago, USA

2 Introduction IBC is the most deadly malignancy of the breast IBC is a distinct clinical and biological entity - Lymphangiogenesis - Immune dysfunctions - early micrometastases - Genomic instability The use of breast-cancer directed therapies is unable to significantly improve the outcome in this disease Need novel approaches and strategies

3 What is IBC? IBC is simply a locally advanced breast cancer

4 Locally Advanced Breast Cancer Non-IBC IBC

5 Clinical Features Inflammatory Breast Cancer (IBC) is characterized by the rapid onset of aggressive locally advanced disease; There is no report of an early stage IBC. Approximately 35% of patients have de-novo metastatic disease; Multimodality approach contributes to improved survival but still worse outcome compared to non-ibc; The predictable pattern of disease recurrence suggest micrometastatic disease also in localized IBC

6 NCCN Retrospective Analysis Disease outcome and stage at presentation

7 NCCN Retrospective Analysis Disease Recurrence in IBC Site N % Bone/Bone marrow Brain/CNS/Meninges Lung/Pleural Effusion Liver Chest Wall Regional Lymph Nodes Contralateral locoregional Lymph Nodes Skin Ipsilateral Breast Other %

8 Initial Recurrence of IBC 8

9 Treatment-refractory IBC 9

10 Molecular Features Distinct biological features

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12 Genomic abnormalities in IBC

13 mtor pathway activation in IBC

14 IBC harbor frequent genomic alterations in ERBB (HER) and PI3K pathways ERBB Family Receptors P P P P P P RAS p85 PIK3CA PIP3 PDK1 AKT P P P PTEN GPCRs Gene Variant Freq (% cases) p85 PIK3CG P TSC1 TSC2 RICTOR mtor P mtorc2 ERBB2 Amp 52% ERBB3 Mut 26% RHEB TSC1 Mut 26% PIK3CA Mut / Amp 21% TSC2 Mut 16% AKT3 Mut 16% EGFR Mut 16% FKBP12 RAPTOR mtor P mtorc1 Phospho-S6 positive (3+): 95% cases PIK3CG Mut 11% AKT2 Mut 11% 4E-BP1 P S6K P RICTOR Mut 11% RAPTOR Mut 11% eif-4e S6 P P85α Mut 11% P85β Mut 5%

15 Hyperactivated mtor and JAK2/STAT3 Pathways Jhaveri K, et al. Clin Breast Cancer 2016

16 Novel Therapeutics Improving Neoadjuvant and Adjuvant Therapies

17 Neoadjuvant CT and multimodality treatment Improve neoct Combo Adjuvant therapy

18 Preoperative Treatment with Standard CT + JAK2 Inhibitor (ruxolitinib) in TN IBC Phase 1: Metastatic BC - N = up to 12 Weekly paclitaxel + ruxolitinib Phase 2: Untreated Triple Negative IBC N = up to 32 Biopsy 1 ruxolitinib Biopsy 2 (1 week) ruxolitinib Cycle 1-4 Weekly paclitaxel x 12 + ruxolitinib Biopsy 3 Cycle 5-8 ddac ELIGIBILITY: Phase II Clinical diagnosis of IBC Triple negative breast cancer Extensive nodal involvement is allowed No prior treatment for breast cancer Biopsy 4 MRM DFCI Inflammatory Breast Cancer Program

19 I-TARGET IBC: A prospective, single arm, Phase 2 study of nab-paclitaxel combined with alpelisib BYL719 following anthracycline-based regimen in patients with primary HER2- IBC End of Study AC x 4 Clinical Response Nabpaclitaxel Alpelisib Surgery XRT Adjuvant* Tissue biopsy RPPA Pathological Response AC: Doxorubicin 60 mg/m2/cyclophosphamide, 600 mg/m2, iv q 3 weeks FEC: Fluorouracile, 500mg/m2/Epirubicin, 100mg/m2/ mg/m2/cyclophosphamide, 500 mg/m2, iv q 3 weeks

20 IBC Clinical trials in Primary IBC at MD Anderson Newly diagnosed primary IBC NEOADJUVANT ER+ HER2- Phase 2 Neratinib+paclitaxel followed by AC HER2+ Phase 2 Neratinib, Pertuzumab, Trastuzumab + Taxol followed by AC TNBC Phase 2 Randomized Carboplatin + paclitaxel +/- Panitumumab followed by AC ADJUVANT Phase 2 Pembrolizumab and hormonal therapy for patients with residual disease following standard of care chemotherapy

21 Window of opportunity trial of Ipilimumab and Nivolumab in metastatic inflammatory breast cancer (IBC): THE WIN TRIAL

22 Metastatic IBC Clinical trials at MD Anderson Metastatic IBC ER+ HER2- Phase 2 Denosumab (bone predominant disease) Phase 2 Pembrolizumab (maintenance) Phase 2 BIBF 1120 (Nintedanib) HER2+ Phase 1b Neratinib, Pertuzumab, Trastuzumab and Taxol TNBC Phase 2 Pembrolizumab (maintenance) Phase 2 BIBF 1120 (Nintedanib) Phase 2 Atezolizumab, cobimetinib, eribulin (ACE) Phase 2 T-VEC (skin metastasis) Phase 1 OTS167 PO (Oral MELK inhibitor)

23 IBC is not a priority for..many

24 IBC is not a priority for..all

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26 Website

27 IBC advocacy to work with(in) IBC-IC

28 What are the really issues to address together? Treatment: - No argument on the multimodality treatment (no lumpectomy) - How to improve response in neoadjuvant non-metastatic setting? - Use of novel adjuvant treatments - When to use aggressive modalities in limited metastatic IBC? Diagnostics: - New functional staging for IBC? - Should we use NGS in all metastatic IBC cases? - How to monitor IBC patients after completion of primary treatment? - Should we monitor CNS disease? Etiology - What causes IBC?

29 Locally Advanced Breast Cancer Non-IBC Tumor IBC Tumor Non-IBC Patient IBC Patient

30 Conclusions IBC is a deadly and unique form of breast cancer requiring combined dedicated resources and research efforts (IBC-IC) The disease is associated with treatment resistance and early dissemination and metastasis requiring IBC-dedicated trials including adjuvant combinations treatments IBC is unique and not common, misdiagnosed but not a rare disease MBC mortality is significantly associated with metastatic IBC We need to study the IBC patient to completely understand and hopefully prevent the disease

31 IBC Conferences: Collaboration is the path forward 1 st IBC Clinic Research Program Houston st International IBC Conference Houston st International IBC Conference Marseille rd International IBC Conference Philadelphia th International IBC Conference Antwerp h International IBC Conference Boston th International IBC Madrid 2018 IBC Consensus Statement

32 The Future of IBC Rests In Our Hands Researchers, Clinicians, Patients, Advocates Inflammatory Breast Cancer International Consortium (IBC-IC)