Inflammatory Breast Cancer

1. Inflammatory Breast Cancer Blakely Kute, MD Multimodality Conference January 5th, 2012

2. 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

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

4. Inflammatory Breast Cancer • Secondary IBC with ulcerated nodules Robertson et al. Inflammatory Breast Cancer: The disease, the Biology, and Treatment. Cancer J Clin 2010

5. 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

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

7. Inflammatory Breast Cancer • Basic features • Rapidly progressive • Highly angiogenic and angioinvasive

8. 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

9. 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.

10. 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

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

12. 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

13. 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

14. Inflammatory Breast Cancer • Diagnosis and Staging • Imaging • Mammography • Calcifications in ≤ 50% • Global skin and trabecular thickening most common findings– nonspecific

15. 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

16. 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)

17. 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

18. 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

19. 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

20. 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

21. 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

22. 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.

23. 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

24. 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)

25. 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

26. 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

27. 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

28. 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.

29. 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

30. Inflammatory Breast Cancer • Trimodality therapy • Initiated in 1970s • Neoadjuvant chemo introduced in late 1970s • Followed by surgery and/or radiotherapy

31. Inflammatory Breast Cancer • Chemotherapy • Addition of anthracycline • MD Anderson 1974 to 2001 • Evaluated 4 neoadjuvant chemotherapy regimens in combination with locoregional therapies

32. 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

33. 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.

34. Inflammatory Breast Cancer • Chemotherapy • Addition of taxanes • MD Anderson retrospective study • Compared paclitaxel group to population previously discussed

35. Inflammatory Breast Cancer • Chemotherapy • Addition of taxanes

36. 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

37. 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

38. 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

39. 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

40. 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

41. 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

42. 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.

43. 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

44. Work-Home balance…