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Inflammatory Breast Cancer. Blakely Kute , MD Multimodality Conference January 5 th , 2012. Inflammatory Breast Cancer (IBC). General Clinical-pathological entity characterized by: Diffuse erythema and edema ( peau d’orange ) Involving ≥ 1/3 of the skin of the breast

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inflammatory breast cancer

Inflammatory Breast Cancer

Blakely Kute, MD

Multimodality Conference

January 5th, 2012

inflammatory breast cancer ibc
Inflammatory Breast Cancer (IBC)
  • General
    • Clinical-pathological entity characterized by:
      • Diffuse erythema and edema (peaud’orange)
        • Involving ≥ 1/3 of the skin of the breast
    • Caused by tumor emboli within dermal lymphatics
      • Not an infiltration of inflammatory cells
inflammatory breast cancer ibc1
Inflammatory Breast Cancer (IBC)

Robertson et al. Inflammatory Breast Cancer: The disease, the Biology, and Treatment. Cancer J Clin 2010

inflammatory breast cancer1
Inflammatory Breast Cancer
  • Secondary IBC with ulcerated nodules

Robertson et al. Inflammatory Breast Cancer: The disease, the Biology, and Treatment. Cancer J Clin 2010

inflammatory breast cancer2
Inflammatory Breast Cancer
  • General
    • Not all skin changes are designated as inflammatory breast carcinoma
    • Dimpling or nipple retraction alone does not qualify as T4 – can even see in T1 disease
inflammatory breast cancer3
Inflammatory Breast Cancer

Robertson et al. Inflammatory Breast Cancer: The disease, the Biology, and Treatment. Cancer J Clin 2010

inflammatory breast cancer4
Inflammatory Breast Cancer
  • Basic features
    • Rapidly progressive
    • Highly angiogenic and angioinvasive
inflammatory breast cancer5
Inflammatory Breast Cancer
  • Epidemiology
    • Rare
      • ≈ 2% of invasive breast cancers in US
      • Increasing incidence in US
        • Especially in Caucasian women
    • More frequent in African Americans than Caucasians
      • 50% higher incidence
    • Generally younger than non-IBC patients
inflammatory breast cancer6
Inflammatory Breast Cancer
  • Age density histograms
    • SEER 1988-2000
    • All bimodal for age at diagnosis
    • IBC predominant age peak at earlier age
      • in contrast to others - predominant peak at later age

Hance et al. Journal of National Cancer Institute 2005. 97 (13); 966-975.

inflammatory breast cancer7
Inflammatory Breast Cancer
  • MD Anderson Review of IBC registry (n=70)

Robertson et al. Inflammatory Breast Cancer: The disease, the Biology, and Treatment. Cancer J Clin 2010

inflammatory breast cancer8
Inflammatory Breast Cancer

Robertson et al. Inflammatory Breast Cancer: The disease, the Biology, and Treatment. Cancer J Clin 2010

inflammatory breast cancer9
Inflammatory Breast Cancer
  • Presentation
    • Rapid breast enlargement
    • Pain (tenderness and shooting pains)
    • Skin - firm, thick, warm
      • Color range:
        • Pink flushed  redness  purplish hue that resembles bruising
    • Often no palpable mass
inflammatory breast cancer10
Inflammatory Breast Cancer
  • Differential diagnosis
    • Mastitis Typically in lactating women
    • Breast abscess Associated with fever, leukocytosis
    • Post-radiation dermatitis – usually well demarcated
    • Congestive heart failure – can cause unilateral breast edema, but resolves with diuresis
    • Lymphoma – rare – differentiated based on pathology
inflammatory breast cancer11
Inflammatory Breast Cancer
  • Diagnosis and Staging
    • Imaging
      • Mammography
        • Calcifications in ≤ 50%
        • Global skin and trabecular thickening most common findings– nonspecific
inflammatory breast cancer12
Inflammatory Breast Cancer
  • Imaging
      • Ultrasound
        • Heterogeneous area of infiltration

– or –

        • Conglomerate of masses
        • Skin and subcutaneous edema
        • Enables adequate evaluation of axillary nodes
        • Helpful in assessing response to chemotherapy
inflammatory breast cancer13
Inflammatory Breast Cancer
  • Imaging
    • MRI
      • Dynamic contrast enhanced – exploits presence of angiogenesis
      • Most accurate test for detecting a primary breast lesion in IBC
      • Findings:
        • Diffuse skin thickening, edema (normal ≈3 mm; IBC up to 13mm)
        • Breast mass (A) or non mass-like parenchymal enhancement (B)
inflammatory breast cancer14
Inflammatory Breast Cancer
  • Imaging
    • MRI
      • Role in accessing tumor response to chemotherapy and surgical planning not clearly defined in IBC
    • PET/CT
      • May be beneficial given the frequent lack of clinically identifiable mass in IBC
        • Observes functional changes
    • Basic photographs may be helpful in assessing disease response to therapy
inflammatory breast cancer15
Inflammatory Breast Cancer
  • Diagnosis and Staging
    • Biopsy
      • Core biopsy to confirm invasive breast carcinoma
      • Ideally, 2 skin punch biopsies
        • Not always seen due to sampling error
        • Not necessary for diagnosis of IBC

Robertson et al. Inflammatory Breast Cancer: The disease, the Biology, and Treatment. Cancer J Clin 2010

inflammatory breast cancer16
Inflammatory Breast Cancer
  • Pathology
    • Invasive ductal carcinoma usually
    • High nuclear grade
    • High mitotic rate
    • Sentinal node biopsy NOT recommended
      • Sentinal node only identified in 70-85% with high false positive rate
        • Secondary to architectural distortion of lymphatic channels
    • Can perform FNA of clinically detectable nodes
inflammatory breast cancer17
Inflammatory Breast Cancer
  • Biomarkers
    • Estrogen and progesterone receptor expression
      • More likely than non-IBC to lack HR expression
        • Varying reports, but between 50 – 80% lack ER expression

Robertson et al. Inflammatory Breast Cancer: The disease, the Biology, and Treatment. Cancer J Clin 2010

inflammatory breast cancer18
Inflammatory Breast Cancer
  • Biomarkers
    • Her2
      • Higher Her2 overexpression than in non-IBC
      • Generally amplified in 40-50% of tumors
    • “Triple-negative”
      • Approximately 1/3 of patients
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Inflammatory Breast Cancer
  • Age-density diagrams
    • SEER data
    • Comparing ER negative group to ER positive group

Hance et al. Journal of National Cancer Institute 2005. 97 (13); 966-975.

inflammatory breast cancer20
Inflammatory Breast Cancer
  • New Biomarkers
    • p53 mutations and nuclear overexpression
      • Detected in ≈ 40% of IBC
        • Associated with larger tumor size and disseminated disease at presentation
        • Non-significant trend towards p53 mutation, ER negativity, and lower response to therapy
      • 2 mechanisms can impair normal tumor suppression in IBC
        • Direct mutation (typically found in nuclear p53)
        • Cytoplasmic sequestration of wild-type protein
      • Prognostic
        • p53 nuclear overexpression – poorer prognosis
inflammatory breast cancer21
Inflammatory Breast Cancer
  • New Biomarkers
    • Loss of heterozygosity
      • Detected in ≈ 50% of IBC
      • Frequently loss alleles: 3p, 6p, 11p, 11q, 13q, 17q
      • Poor prognosis (retrospectively)
inflammatory breast cancer22
Inflammatory Breast Cancer
  • Newer biomarkers
    • Rho C GTPase
      • Oncogene (member of ras superfamily)
        • involved in cytoskeleton reorganization during invasion
        • regulation of angiogenic growth factors
        • production of inflammatory cytokines
      • Overexpressed in 90% of IBC tumors examined
      • Requires post-translational modifications via farnyeslation for activation
        • Potential targeted therapy Zarnestra (farnesyl transferase inhibitor) in clinical trial
inflammatory breast cancer23
Inflammatory Breast Cancer
  • Newer biomarkers
    • E-cadherin
      • Overexpression in IBC
      • Calcium-dependent transmembrane glycoprotein
        • Mediated aggregation of cells comprising tumor emboli
      • Associated with loss of sialyl-Lewis (sLex/a)
        • Usually mediated binding of the tumor emboli to endothelium
      • Gain of E-cadherin and loss of sLex/a = tight aggregation of cells within tumor emboli while preventing emboli binding to endothelium.
      • Preclinical studies with anti-E-cadherin antibodies promising
inflammatory breast cancer24
Inflammatory Breast Cancer
  • Newer biomarkers
    • Loss of WISP3
      • Tumor suppressor gene
      • Cross talk with IGFR (insulin-like growth factor receptor)
      • Lost in 80% of IBC tumors examined
    • EGFR- current studies evaluated targeted therapies with panitumumab and erlotinib
    • Cytokines
      • VEGF-D, IL-6, IL-8, basic fibroblast growth factor
        • VEGF-D is a ligand for VEGFR-3 – important in tumor lymphangiogenesis and subsequent mets
inflammatory breast cancer25
Inflammatory Breast Cancer
  • Prognosis
    • IBC more aggressive than non-IBC
  • SEER data 1988 to 2000
    • Tri-modality era with neoadjuvant chemo
    • Pre-taxane era
  • Hance et al. Journal of National Cancer Institute 2005. 97 (13); 966-975.
inflammatory breast cancer26
Inflammatory Breast Cancer
  • Treatment history
    • Pre-1970s
      • Local control with surgery and/or radiation therapy
      • 5 year survival <5%
      • Median survival < 15 months
      • Local recurrence rates >50%
    • Efforts to improve local control
      • MD Anderson noted repopulation of tumor cells in between radiation treatments
      • Initiated accelerated hyperfractionated radiation therapy (1.5Gy bid for 51-54 Gy followed by boost of 15-20 Gy)
      • Improved locoregional control but most patients still died from distant metastatic disease
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Inflammatory Breast Cancer
  • Trimodality therapy
    • Initiated in 1970s
      • Neoadjuvant chemo introduced in late 1970s
      • Followed by surgery and/or radiotherapy
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Inflammatory Breast Cancer
  • Chemotherapy
    • Addition of anthracycline
      • MD Anderson 1974 to 2001
        • Evaluated 4 neoadjuvant chemotherapy regimens in combination with locoregional therapies
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Inflammatory Breast Cancer
  • Chemotherapy
    • MD Anderson experience
      • Improved DFS and OS compared to locoregional therapy alone
        • DFS
          • 5 yrs – 32%
          • 10 and 15 yrs – 28%
        • OS
          • 5 yrs – 40%
          • 10 yrs – 33%
      • No significant difference in DFS or OS among protocols
inflammatory breast cancer30
Inflammatory Breast Cancer
  • Chemotherapy
    • MD Anderson experience
      • Best prognostic factor:
        • Response to induction chemotherapy
          • 15 yr DFS rates with chemo response:
            • CR (12% of pts): 44%
            • PR (60%): 31%
            • < PR (23%): 7%
      • Other prognostic factors such as age, race, estrogen receptor status did not affect overall outcome.
inflammatory breast cancer31
Inflammatory Breast Cancer
  • Chemotherapy
    • Addition of taxanes
      • MD Anderson retrospective study
        • Compared paclitaxel group to population previously discussed
inflammatory breast cancer32
Inflammatory Breast Cancer
  • Chemotherapy
    • Addition of taxanes
inflammatory breast cancer33
Inflammatory Breast Cancer
  • Chemotherapy
    • Addition of paclitaxel shows trend to improved DFS and OS in all IBC patients
      • Statistically significant in the ER negative group
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Inflammatory Breast Cancer
  • Chemotherapy
    • Addition of trastuzumab
      • Similar improvements in survival in IBC and non-IBC
      • Vital to incorporate into regimen if Her2 overamplified
    • If no response to first therapy chemotherapy
      •  2nd line chemo with response  surgery and adjuvant radiation
      •  radiation with response  surgery
      •  palliative resection for severe wounds
inflammatory breast cancer35
Inflammatory Breast Cancer
  • Surgery
    • Mastectomy alone without chemotherapy with poor survival
    • Retrospectively, surgery improves:
      • Local control in patients that responded
      • Survival duration to chemotherapy
        • Fleming et al (1974-1993, 178 patients, pre-taxane error)
          • Chemo + RT + Surgery: Local recurrence 16.3%
          • Chemo + RT: Local recurrence 35.7% (p = 0.015)
          • Mortality rate after local recurrence 98%
    • Response to chemotherapy good predictor for clinical outcome
      • Hennessey et al, 61 patients with IBC
        • CR after chemotherapy 5 yr DFS: 78.6%, 5 yr OS: 82.5%
        • Residual disease after chemo: 5 yr DFS: 25.4%, 5 yr OS: 37.1%

1.Fleming et al. Ann Surg Oncol, Vol 4, No. 6, 1997 2. Hennessey et al. 2006

inflammatory breast cancer36
Inflammatory Breast Cancer
  • Surgery
    • Based on chemotherapy response
      • Non-responders: Mastectomy does NOT improve disease outcomes
        • May need palliative resection for wound and pain control
      • Partial responders: Mastectomy decreases rate of distant mets from 69% without mastectomy to 47% (Fleming et al)
      • Complete responders: Mastectomy improves survival
inflammatory breast cancer37
Inflammatory Breast Cancer
  • Surgery
    • Mastectomy vs breast conservation
      • Breast conservation in patients with CR being studied, but NOT recommended at this time
      • Skin sparing mastectomy NOT recommended
      • Modified radical mastectomy is standard
        • Op field wide enough to encompass all skin changes
        • Current imaging and physical exam can underestimate involved field– newer imaging improving this (MRI with gating for angiogenesis)
    • Special considerations
      • No sentinal node biopsy
      • No immediate reconstruction because radiation therapy required
inflammatory breast cancer38
Inflammatory Breast Cancer
  • Radiation therapy
    • Adjuvant RT directed to chest wall and lymph nodes within the axillary, infraclavicular, supraclavicular, and internal mammary regions
    • Varying schedules of radiation therapy
      • Standard fractionation: 50 Gy in 1.8 – 2 Gy fractions with 10 Gy boost to chest wall
        • Dose escalation to 66 Gy considered in women:
          • <45 years of age
          • Close or positive surgical margins
          • ≥ 4 positive nodes following neoadjuvant chemo
          • Poor response to neoadjuvant chemo
inflammatory breast cancer39
Inflammatory Breast Cancer
  • Radiation therapy
    • Varying schedules
      • Accelerated fractionation
        • Bid to 66 Gyvs bid to 60 Gy
          • improved 5 yrlocoregional control (84% vs 58% at 5 yr) – benefit highest in high risk of relapse group (above)
          • trend towards improved DFS
          • Higher rate of grade ¾ late complications
    • Neoadjuvant RT
      • Currently not recommended due to high complication rates including wound necrosis.

Liao et al. Int J Radiat Oncol Biol Phys 2000; 47: 1191 – 1200.

ibc therapy
IBC: Therapy
  • Current standards for IBC
    • Neoadjuvant chemo
      • Taxane / anthracyclin regimen ± trastuzumab
    • Modified radical mastectomy for responders
    • Adjuvant radiation therapy of 60 – 66 Gy to chest wall and regional nodes
    • Adjuvant trastuzumab to complete 1 yr if indicated
    • Adjuvant hormonal therapy if indicated