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Locally Advanced & Inflammatory Breast Cancer

Locally Advanced & Inflammatory Breast Cancer. Suparna Bonthala Wedam, M.D. National Cancer Institute Cancer Therapeutics Branch November 17, 2003. Locally Advanced Breast Cancer. LABC. 10%-20% of newly diagnosed breast cancer Heterogeneous group of tumors Definitions vary

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Locally Advanced & Inflammatory Breast Cancer

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  1. Locally Advanced & Inflammatory Breast Cancer Suparna Bonthala Wedam, M.D. National Cancer Institute Cancer Therapeutics Branch November 17, 2003

  2. Locally Advanced Breast Cancer

  3. LABC • 10%-20% of newly diagnosed breast cancer • Heterogeneous group of tumors • Definitions vary • Stage IIB, IIIA, IIIB, and IIIC per AJCC 2002 staging guidelines (TNM staging classification) • No standard treatment regimen

  4. LABC • Large tumors (>5cm) • Extensive regional lymph node involvement • Direct involvement of the skin or underlying chest wall • No distant metastases • Inflammatory breast cancer

  5. Clinical Staging • Complete physical exam • Bilateral mammography • Blood tests • Complete blood count • Liver function tests • Radionuclide bone scan • Chest radiograph • CT scan of the abdomen and pelvis

  6. LABC Treatment • Historically considered inoperable • Distant metastases most frequent site of therapy failure with local therapy alone • 5 yr OS<20% • Adjuvant therapy-modest effect on survival • Primary chemotherapy has high response rates and increases rate of BCT • Multimodality treatment • Subsequent sequence of treatment unclear

  7. Primary ChemotherapyAdvantages • Early systemic treatment • Intact tumor vasculature • In vivo assessment of response • Decrease radical local therapy • Downstaging • Increase breast conservation • Improve resectability

  8. Primary ChemotherapyDisadvantages • Delayed local treatment • May induce drug resistance • Large tumor burden • Only have clinical staging • May increase risk of surgical/XRT complications

  9. Serial biopsies to examine Tissue architecture and histology Tumor markers/oncogenes or growth factors Matrix/stromal environment Functional studies: Dynamic imaging Metabolic testing Comparing primary to metastasis response to therapy Primary ChemotherapyResearch Rationale

  10. NSABP B-18 Operable Breast Cancer Stratification • Age • Clinical Tumor Size • Clinical Nodal Status Operation AC x 4 + TAM if >50 yrs. AC x 4 Operation + TAM if >50 yrs.

  11. B-18 Eligibility and Patient Characteristics • Palpable, operable breast cancer: • T1,2,3 N0,1 M0 • 1506 patients eligible after randomization • 51.5 % under age 49 • 74 % clinically node negative • Tumor size: • 28% <= 2 cm (T1) • 59% 2.1-5 cm (T2) • 13% >5 cm (T3)

  12. B-18Clinical and Pathologic Breast Tumor Response to Preop Chemo (685 pts) pCR (63 pts) 9% 36% 4% cCR (249 pts) pNon-Inv (26 pts) 23% pInv (160 pts) cPR (296 pts) 43% cSD + cPD (140 pts) 20%

  13. B-18Lumpectomy Rate P < 0.01 80% 60% 68% 60% 40% 20% 0 Preop Chemo Postop Chemo

  14. B-18Disease-Free and Overall Survival 100% 80% 60% P = 0.8 P = 0.5 Pts. Events Pts. Events 40% Postop 338 Postop 218 751 751 20% Preop 323 Preop 221 742 742 0 Year 2 4 6 8 2 4 6 8

  15. B-18Disease-Free and Overall SurvivalAccording to Response 100% 80% 60% pCR pCR pINV pINV P=0.0008 40% P=0.00005 cPR cPR 20% cNR cNR 0 Year 2 4 6 8 2 4 6 8

  16. B-18 Summary • Largest published trial comparing primary vs adjuvant chemo • Establishes primary and adjuvant chemo as EQUIVALENT for survival • No increased risk of local recurrence • Increased lumpectomy rate for primary chemo, esp for large tumors • Pathologic CR = better survival

  17. B-27 Schema Operable Breast Cancer Randomization AC x 4 Tam X 5 Yrs AC x 4 Tam X 5 Yrs AC x 4 Tam X 5 Yrs Surgery Docetaxel x 4 Surgery Surgery Docetaxel x 4 I II III Mamounas, Dec 2001

  18. B-27 Eligibility and Patient Characteristics • Palpable, operable breast cancer: • T1,2,3 N0,1 M0 • 2411 patients accrued • 56 % under age 49 • 70 % clinically node negative • Tumor size: • 15% <= 2 cm (T1) • 41% 2.1-4 cm • 45% >4 cm

  19. B-27Treatment Regimen AC: Doxorubicin: 60 mg/m2 Cyclophosphamide: 600 mg/m2 Taxotere: 100 mg/m2 Tamoxifen: In all patients, 20 mg PO daily X 5 years starting on day 1 of chemotherapy Breast XRT: In lumpectomy patients after surgery (Groups I and II) and after Taxotere (Group III)

  20. B-27Clinical Response*P<0.001 90.7%* 85.7% 85.4%

  21. B-27Pathologic Response in BreastP<.001 26.1%* 14.5% 12.9%

  22. B-27 Pathologic Nodal StatusP<.001

  23. AC Taxotere B-27Lumpectomy Rate P = 0.33 80% 60% 63.7% 61.6% 40% 20% 0 AC Bear et al, JCO, Nov 15 2003

  24. B-27 Conclusions The addition of preoperative Taxotere to preoperative AC resulted in a significant increase in the rates of: • Clinical Complete Response:40% vs 64%(p<.001) • Pathologic Complete Response:13.7% vs 26.1% (p<.001) • Negative Axillary Nodes:50.8% vs 58.2% (p<.001) Bear et al, JCO, Nov 15th 2003

  25. B-27 Conclusions (cont.) • There was an increase in grade 4 toxicity with the addition of Taxotere to the AC regimen • (10.3% vs 23.4%) • No significant increase in lumpectomy rates Bear et al, JCO, Nov 15th 2003

  26. Chemotherapy Regimens • AC • CAF • FEC, EC-mostly in Europe • CAF • CMF • CAVP • Combination or sequential regimens with taxanes (docetaxel, paclitaxel) • Clinical trials using trastuzumab (Herceptin)

  27. LABC Conclusions • Multimodality treatment • Prognosis based on certain factors • Age • Menopausal status • Tumor stage • Histologic grade • Clinical response • LN stats following tx • HR status • Approx 50% now attain long-term survival

  28. Inflammatory Breast Cancer

  29. Inflammatory Breast Cancer • Rare, 1-5% in U.S. • Most aggressive form of breast cancer • Clinical diagnosis • diffuse erythema involving majority breast • peau d’ orange • erisypeloid edge • often no palpable mass • Significantly lower overall survival than non-IBC

  30. Inflammatory Breast Cancer • Dermal lymphatic invasion • Stage IIIB (T4d) if not metastatic • Compared to non-IBC, more frequently ER/PR negative Her2/neu positive

  31. Clinical Presentations of IBC

  32. Survival and Prognosis of IBC: Single Institution Experiences

  33. IBC Survival: NCI Experience 100 90 80 70 60 50 40 30 20 10 Non-Inflammatory Inflammatory 3 6 9 12 15 18 21 Years from On-Study Date

  34. Primary Chemotherapy Surgery RT Chemotherapy + Hormonal Therapy Inflammatory Breast CancerStandard Treatment

  35. Rationale for Primary Chemotherapy • Consideredinoperable • Tumor extension beyond visible erythema • Micrometastatic at diagnosis • Response used to guide therapy

  36. Local Therapy Issues • Surgery: Mastectomy or BCT? • Reconstruction: Immediate or delayed? • Radiation therapy

  37. Immediate vs Delayed Reconstruction Issues • Postoperative radiation interferes with cosmetic result • Probability of local recurrence • Wound closure of large mastectomy site • TRAM vs skin graft? • Psychological benefit worth risk? • Recommend: Delayed Reconstruction

  38. Radiotherapy • Post-mastectomy radiation to a dose of at least 5000 cGy • Supraclavicular nodal radiation and bolus • Bifractionated radiotherapy (MDACC, McNeese)

  39. IBC Summary • Aggressive, poor prognosis disease • Primary chemotherapy to best response • Mastectomy, chest wall radiation • Delayed reconstruction • Enrollment onto clinical trials should be encouraged, especially for: • Herceptin • High dose chemotherapy • Experimental agents

  40. Case Presentation • 43 y.o. premenopausal female presented with lump on inner quadrant of right breast • Right core biopsy-grade III infiltrating ductal carcinoma, ER-, PR-, Her-2 3+ • No other symptoms • No significant medical history • No medications

  41. Physical Examination • Right breast • Enlarged, erythematous, tender • Diffuse mass-difficult to measure • Palpable right axillary lymph node • No other abnormalities

  42. Staging Work-Up • Labs-normal except for elevation of ALT • Bone Scan-? Met focus in sternum, bilateral SI joint uptake • CT Scan-4x3.6 cm right breast mass, 1.3x0.9 supraclavicular LN, 2.7 x 1.6 cm right axillary LN; liver okay • MRI of breast-abnormalities in right breast; no sternal involvement • STAGE IIC

  43. Treatment • Primary chemotherapy with paclitaxel, carboplatin and Herceptin (TCH) for 5 cycles • Right MRM/ALND • 2 cm poorly diff IDC, negative margins, 5/28LN+ • ER-, PR-, Her-2 3+ • Adjuvant therapy with doxorubicin and cyclophosphamide (AC) for 4 cycles • XRT

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