Management of Inflammatory Breast Cancer: Collaboration is the path
forwardMassimo Cristofanilli, M.D., F.A.C.P.
Professor of MedicineAssociate Director of Translational Research and Precision Medicine
Robert H Comprehensive Lurie Cancer Center, Northwestern UniversityChicago, USA
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
What is IBC?
IBC is simply a locally advanced breast cancer
Locally Advanced Breast Cancer
Non-IBC IBC
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
NCCN Retrospective AnalysisDisease outcome and stage at presentation
NCCN Retrospective AnalysisDisease Recurrence in IBC
Site N % Bone/Bone marrow 57 28.1 Brain/CNS/Meninges 43 21.2 Lung/Pleural Effusion 43 21.2 Liver 42 20.7 Chest Wall 32 15.8 Regional Lymph Nodes 16 7.9 Contralateral locoregional Lymph Nodes 10 4.9 Skin 9 4.4 Ipsilateral Breast 7 3.4 Other 40 19.7
36.4%
8
Initial Recurrence of IBC
9
Treatment-refractory IBC
Molecular Features
Distinct biological features
Genomic abnormalities in IBC
mTOR pathway activation in IBC
RAS PIK3CAp85 PTENPIP3PDK1
AKT PPP
PIK3CGp85GPCRs
PPP
PPP
TSC1TSC2 mTOR
RICTORP
RHEB
P
mTORRAPTOR P mTORC1
mTORC2
S6K
S6 P
P4E-BP1
eIF-4E
P
FKBP12Phospho-S6 positive (3+):
95% cases
ERBB FamilyReceptors
Gene Variant Freq (% cases)
ERBB2 Amp 52%
ERBB3 Mut 26%
TSC1 Mut 26%
PIK3CA Mut / Amp 21%
TSC2 Mut 16%
AKT3 Mut 16%
EGFR Mut 16%
PIK3CG Mut 11%
AKT2 Mut 11%
RICTOR Mut 11%
RAPTOR Mut 11%
P85α Mut 11%
P85β Mut 5%
IBC harbor frequent genomic alterations in ERBB (HER) and PI3K pathways
Hyperactivated mTOR and JAK2/STAT3 Pathways
Jhaveri K, et al. Clin Breast Cancer 2016
Novel TherapeuticsImproving Neoadjuvant and Adjuvant Therapies
Neoadjuvant CT and multimodality treatment
Improve neoCT
Combo Adjuvant therapy
Weekly paclitaxel
+ ruxolitinib
Cycle 1-4Weekly
paclitaxel x 12 +
ruxolitinib
Biopsy 3
Cycle 5-8
ddAC
Biopsy 4
MRM
Phase 1: Metastatic BC -N = up to 12
Biopsy 1
ruxolitinib
Biopsy 2
(1 week)
ruxolitinib
Phase 2: Untreated Triple Negative IBC – N = up to 32
Preoperative Treatment with Standard CT + JAK2 Inhibitor (ruxolitinib) in TN IBC
DFCI Inflammatory Breast Cancer Program
ELIGIBILITY: Phase II• Clinical diagnosis of IBC• Triple negative breast cancer• Extensive nodal involvement is allowed• No prior treatment for breast cancer
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
AC x 4 Clinical Response
Nab-paclitaxelAlpelisib
Surgery
Pathological Response
XRTAdjuvant*
End of Study
AC: Doxorubicin 60 mg/m2/Cyclophosphamide, 600 mg/m2, iv q 3 weeksFEC: Fluorouracile, 500mg/m2/Epirubicin, 100mg/m2/ mg/m2/Cyclophosphamide, 500 mg/m2, iv q 3 weeks
Tissue biopsyRPPA
IBC Clinical trials in Primary IBC at MD Anderson
Phase 2Neratinib+paclitaxel
followed byAC
ER+ HER2- HER2+
Phase 2Neratinib, Pertuzumab, Trastuzumab + Taxol
followed by AC
Phase 2Randomized
Carboplatin + paclitaxel +/- Panitumumabfollowed by AC
TNBC
Newly diagnosed primary IBC
NEOADJUVANT
ADJUVANT Phase 2Pembrolizumab and hormonal therapy for patients with residual
disease following standard of care chemotherapy
Window of opportunity trial of Ipilimumab and Nivolumab in metastatic inflammatory breast cancer (IBC): THE WIN TRIAL
Metastatic IBC Clinical trials at MD Anderson
Phase 2Denosumab (bone predominant
disease)
ER+ HER2- HER2+Phase 1b
Neratinib, Pertuzumab, Trastuzumab and Taxol
TNBC
Metastatic IBC
Phase 2Pembrolizumab (maintenance)
Phase 2Pembrolizumab (maintenance)
Phase 2Atezolizumab, cobimetinib, eribulin (ACE)
Phase 2T-VEC (skin metastasis)
Phase 2BIBF 1120 (Nintedanib)
Phase 2BIBF 1120 (Nintedanib)
Phase 1OTS167 PO (Oral MELK inhibitor)
IBC is not a priority for..many
IBC is not a priority for..all
Website – www.IBCIC.org
IBC advocacy to work with(in) IBC-IC
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?
Locally Advanced Breast Cancer
Non-IBC Tumor IBC Tumor
Non-IBC Patient IBC Patient
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
IBC Conferences: Collaboration is the path forward
1st IBC ClinicResearch Program
Houston 2006
1st
International IBC
ConferenceHouston 2008
2st
International IBC
ConferenceMarseille 2010
3rd
International IBC Conference
Philadelphia2012
4th
International IBC
ConferenceAntwerp 2014
5h
International IBC
ConferenceBoston 2016
IBC Consensus Statement
6th
International IBC
Madrid 2018
The Future of IBC Rests In Our Hands
Researchers, Clinicians, Patients, AdvocatesInflammatory Breast Cancer International Consortium (IBC-IC)
