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Inflammatory Breast Cancer. Julie Lang, MD Assistant Professor of Surgery Director of Breast Surgical Oncology University of Arizona Cancer Center. Inflammatory Breast Cancer. Rare, represents <6% of all breast cancers Most aggressive form of breast cancer Clinical diagnosis

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Inflammatory Breast Cancer


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    1. Inflammatory Breast Cancer Julie Lang, MD Assistant Professor of Surgery Director of Breast Surgical Oncology University of Arizona Cancer Center

    2. Inflammatory Breast Cancer • Rare, represents <6% of all breast cancers • Most aggressive form of breast cancer • Clinical diagnosis - red skin involving more than 1/3 of the breast - peau d’orange - often no mass lesion - thickened skin - edema of breast tissue - rarely ulceration is present - Pathologic diagnosis of invasive breast cancer required International expert panel on inflammatory breast cancer: consensus statement for standardized diagnosis and treatment. Annals of Oncology 2010

    3. Inflammatory Breast Cancer • Clinical course - Onset in weeks to months rather than months to years - Often confused for an infection of the breast - Often patients see many physicians before correctly diagnosed - Usually have nodal metastasis at time of diagnosis - 30% have distant metastases at diagnosis

    4. Inflammatory breast cancer • Clinical Stage III • Tumor classified as T4D • Prognosis worse than locally advanced breast cancer • Tends to be diagnosed at a younger age than most breast cancer • May be more prevalent in African Americans than Caucasians. • More information needed on prevalence in other populations

    5. Prognostic Markers • Often triple negative • Higher frequency of HER2 amplification • Elevated Ki67

    6. Inflammatory breast cancerPresenting Symptoms Redness 100% Edema 100% Clinically positive 63% axillary nodes Enlargement 43% Warmth 33% Nipple retraction 15% Induration 13% Pain or tenderness 8% Arm Edema 3% Haagensen et al, 1951-1980. Adapted from Swain, NCI

    7. Inflammatory Breast Cancer: Differential Diagnosis • Mastitis or cellulitis • Breast abscess • Cellulitis post radiation • Radiation dermatitis • Duct ectasia

    8. Locally advanced, non-inflammatory breast cancer

    9. Yang et al, BCRT 2007

    10. Yang et al, BCRT 2007

    11. Yang et al, BCRT 2007

    12. Inflammatory breast cancer: overall survival -398 patients treated at MDACC 1974-2005 -Median follow-up 5.8 years -236 deaths -Median overall survival 4.2 years -Increasing year not associated with decreased risk of death Gonzalez-Angulo et al, The Oncologist 2007

    13. Inflammatory breast cancer: recurrence free survival -398 patients treated at MDACC 1974-2005 -Median follow-up 5.8 years -238 recurrences -Median recurrence free survival 2.3 years -Increasing year not associated with decreased risk of recurrence Gonzalez-Angulo et al, The Oncologist 2007

    14. Treatment of Inflammatory Breast Cancer • Urgent need to start chemotherapy quickly • Evaluate if surgical candidate, if so surgical treatment is modified radical mastectomy • No role for SLN dissection • No role for lumpectomy • Comprehensive radiation therapy • Consolidative chemotherapy

    15. What is the best treatment for IBC? • 256 consective patients with IBC (non-metastatic) treated at MDACC 1977-2004 • 192 completed planned course of chemotherapy, MRM, post-mastectomy radiation, 64 did not. Bristol et al, Int J. Rad Onc Biol Phys 2008

    16. Bristol et al, Int J. Rad Onc Biol Phys 2008

    17. Bristol et al, Int J. Rad Onc Biol Phys 2008

    18. Bristol et al, Int J. Rad Onc Biol Phys 2008

    19. Bristol et al, Int J. Rad Onc Biol Phys 2008

    20. What is the best treatment for IBC? • Univariate factors significant for locoregional control in the patients who completed treatment were: • Response to neoadjuvant chemotherapy • Surgical margin status • Number of involved nodes • Use of taxanes Bristol et al, Int J. Rad Onc Biol Phys 2008

    21. What is the best treatment for IBC? • Increasing the total chest-wall dose of post-mastectomy radiation from 60 to 66 Gy significantly improved locoregional control for: - patients who experienced less than a partial response to chemotherapy - patients with positive, close, or unknown margins - patients < 45 years of age Bristol et al, Int J. Rad Onc Biol Phys 2008

    22. Genes associated with IBC • “Basal-like” phenotype • High levels of p53, MUC1, RhoC, E-Cadherin • High levels of growth factor receptors such as HER2-neu and EGFR • High levels of angiogenesis and lymphangiogenesis-related factors such as VEGF-A, VEGF-C, VEGF-D, FLT-1, KDR, Tie-1, Tie-2 • Downregulation of p27kip1

    23. Chemotherapy Options • Anthracycline containing regimen followed by a taxane (AC-T, FAC-T, FEC-T) • Herceptin based regimens if indicated • Lapatinib based regimens if indicated • Hormonal based regimens if indicated • Sutent? • High dose chemotherapy with bone marrow transplant?

    24. Anti-angiogenesis Inhibitors Bevacizumab – monoclonal Ab VEGF Pilot neoadjuvant study in IBC clinical response rate 67% after single dose combined with doxorubicin/docetaxel Further studies necessary to determine if anti-angiogenesis inhibitors are clinically relevant approach in IBC Nature Reviews Clinical Oncology 2009

    25. Nature Reviews Clinical Oncology 2009

    26. Lapatinib • Neoadjuvant Lapatinib + Paclitaxel in IBC • 42 patients HER2 positive +/- EGFR positive • 7 patients HER2 negative, EGFR positive • Lack of efficacy in HER2 negative patients • pCR rate 18%, clinical response rate 78% in HER2 positive patients Boussen et al, JCO 2010

    27. Radiation Therapy • Accelerated hyperfractionated radiation to 66 Gy • Local control 70-80% • 70% of patients have localized disease at presentation Bristol et al, Breast Dis 2005

    28. IM nodes identified on US and CT pre-chemo post-chemo Courtesy of Dr Welela Tereffe, MD

    29. Locally advanced disease:Lateral Tangents + Medial Electrons Lateral Tangents Medial Electrons IMN Courtesy of Dr Welela Tereffe, MD

    30. Initially positive IM nodes receive additional boost radiation Courtesy of Dr Welela Tereffe, MD

    31. Heart and lung exposure can actually be reduced by the use of an IMN field Courtesy of Dr Welela Tereffe, MD

    32. IBC Research • Clinical trials help determine which treatments are most effective for breast cancer patients • Rare form of cancer, many biological and treatment questions still unanswered • An important area of disparities research

    33. Drug Development – Current Model • One FDA-Approved Drug from Start to Finish • 10 - 15 Years • 1,000 - 6,000 Volunteers • $1 billion

    34. It Is Time to Implement a More Efficient Clinical Trial Process Inefficient clinical trials account for a majority of the time and cost associated with the failures of the current system. We need to: • Reduce time to conclusive results & accelerate learning • Reduce patients/volunteers required • Reduce cost of conducting trials • Increase collaboration & data sharing

    35. Design Trials with the Future in Mind

    36. Drug Development – I-SPY 2 Model 40 20 5 FIVE FDA- APPROVED DRUGS 0.5 – 1 YEAR 2 – 3 YEARS 3 – 5 YEARS • Five FDA-Approved Drugs from Start to Finish • 5.5 - 9 Years • 1,000 - 3,000 Volunteers • $200 Million • One FDA-Approved Drug from Start to Finish • 10 - 15 Years • 1,000 - 6,000 Volunteers • $1 billion • 5 times more products for 1/5 of the cost (25 x improvement) • ½ of the time with ½ the volunteers (4 x improvement)

    37. Paclitaxel* + Investigational Agent A (12 weekly cycles) Paclitaxel* + Investigational Agent B (12 weekly cycles) RANDOMIZE Screening ON STUDY MRI Biopsy Blood Draw MUGA/ECHO CT/PET Consent #2 Treatment Consent Paclitaxel * (12 weekly cycles) Tissue I-SPY 2 TRIAL Schema AC (4 cycles) SURGER Y >= 2.5 cm Mammaprint high risk AC (4 cycles) AC (4 cycles) MRI Blood Draw MRI Blood Draw MRI Biopsy Blood Draw * HER2 positive participants will also receive Trastuzumab. An investigational agent may be used instead of Trastuzumab.

    38. I-SPY 2 Participating SitesAs of December 4, 2009 I-SPY 2 Participating & Candidate Sites

    39. I-SPY 2 Adaptive Trial: Learn, Drop, Graduate, and Replace Agents Over Time Taxol + Trastuzumab Key Taxol + Trastuzumab* + New Agent A Randomize MRI HER 2 (+) AC Taxol + Trastuzumab* + New Agent B Surgery Residual Disease (Pathology) Learn and adapt from each patient as we go along Taxol + Trastuzumab* + New Agent C Taxol + Trastuzumab* + New Agent F Patient is on Study Taxol Randomize Taxol + New Agent C Taxol + New Agent F HER 2 (–) Surgery AC Taxol + New Agent D Taxol + New Agent GH *Or equivalent Taxol + New Agent E

    40. I-SPY 2 Biospecimen Collection:Biospecimen Availability Tissue (Core Bx, Section Frozen in OCT) Blood (Serum, Plasma, Buffy Coat) Ship to I-SPY Lab H&E for % tumor Section Sample Process 1 core into FFPE Aliquot Sample Process & Distribute Samples to Labs Approved Biomarkers Per Protocol Qualifying Biomarkers Per Protocol Exploratory Biomarkers Per Protocol caTISSUE Shipping/Receiving, Quality information of Sample and Processed Sample caINTEGRATOR Assay Results

    41. Residual Cancer Burden

    42. ∆S1 S0 ∆S1 ∆S2 PE = SER = S1 S2 ∆S1 S injection ∆S2 S0 t0 t1 t2 Primary Imaging Measurement:Tumor volume based on the Signal Enhancement Ratio (SER) ENHANCEMENT KINETICS: S0 S1 S2 1.3 Washout SER>1.1 1.0 Plateau 0.9≤SER≤1.1 0 Gradual SER<0.9 SER map

    43. Partial Response MRI before chemotherapy MRI after 1 cycle of chemotherapy MRI after full course of chemotherapy

    44. Complete Response MRI before chemotherapy MRI after 1 cycle of chemotherapy MRI after full course of chemotherapy

    45. Conclusions • IBC has unique tumor biology from non-IBC • Consensus exists on minimal diagnostic criteria • HER2 targeted therapy effective in HER2 positive disease • Given aggressive biology, these patients would benefit from clinical trial participation