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EARLY STAGE BREAST CANCER Operable local-regional inv cancer (Stage I, II, some IIIA)

EARLY STAGE BREAST CANCER Operable local-regional inv cancer (Stage I, II, some IIIA). Elshami M. Elamin, MD Medical Oncologist Central care Cancer Center www.cccancer.com Wichita, KS - USA. TNM Staging. Stage IA: T1 ( < 2 cm) Stage IB: T0-1, N1mi Stage IIA: T0-1, N1 or

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EARLY STAGE BREAST CANCER Operable local-regional inv cancer (Stage I, II, some IIIA)

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  1. EARLY STAGE BREAST CANCEROperable local-regional inv cancer(Stage I, II, some IIIA) Elshami M. Elamin, MD Medical Oncologist Central care Cancer Center www.cccancer.com Wichita, KS - USA

  2. TNM Staging • Stage IA: T1 (< 2 cm) • Stage IB: T0-1, N1mi • Stage IIA: T0-1, N1 or T2 (>2 - 5cm) • Stage IIB: T2 + N1 T3 (>5cm) • Stage IIIA: T0-2 + N2 T3 +N1-2 (N2 = adv IIIA)

  3. Work-up • H/P • CBC, LFT, Alk • Mammo +/- US • Path review • Bone scan detects mets • Stage I = 5.1% • Stage II = 5.6% • T3N1 = 14% • Liver US, C-x-ray detect mets: • Stage I,II = None • CT abd+/-pelvis, Chest imaging, Bone scan; • Should be considered for T3N1 • Staging PET not recommended

  4. PROGNOSTIC FACTORS

  5. Lymph Nodes • Node +ve: • 50-70% Risk of relapse • 10 LN+ve: 80% Risk of relapse/mets • Node –ve: • Up to 20-30% Risk of relapse • Negativity is reliable only if 6-10 LN were removed and examined

  6. Axillary LN 5 Yr Survival (%) N - 1-3 + 4 + Moon et al 89 68 48 Carter et al 92 81 57 Valagussa et al 88 69 42 Ariel et al 81 66 48 Fisher et al 78 62 32

  7. Tumor size 5 Yr Survival (%) <2cm 2-5cm >5cm Carter et al (24,740 pts) 91 80 63 Schottenfeld (304 pts) 92 71 55 Nemoto et al (13,384 pts) 62 49 34

  8. Estrogen Receptor DFS (%)* OS (%)# ER+ ER- ER+ ER- NSABP 74 66 92 82 San Antonio 76 67 84 75 * P value <0.001 # P value <0.0001

  9. STEROID RECEPTORS The best use of ER/PR is not in determination of prognosis but in the selection of optimal adjuvant systemic therapy

  10. Age • Young age is a significant predictor of local recurrence after breast conserving therapy

  11. Histology • Invasive ductal and lobular have similar prognosis • Pure tubular, mucinous or colloid, and papillary: • usually small, N-ve • favorable prognosis (ER+, Her2 –ve) • treat with breast conservation • May omit systemic adj therapy (if T <3cm) • Pure or typical medullary has better prognosis than ductal but favorable as tubular or colloid. • However, because pure/typical medullary is uncommon and difficult to diagnose pathologically it is recommended to treat medullary same as inv ductal carcinoma.

  12. Pathologic Factors • Histologic subtypes • Histologic grade • Nuclear grade • Mitotic indix • Vascular/lymphatic invasion • Inflammatory response • Tumor necrosis • Mononuclear cell infiltration

  13. Biologic Factors • S-phase • Ki 67 • Her-2/neu • Tumor supressor genes P53

  14. Principle of Her-2 neutesting • IHC assay (Lab meets quality assurance standards for IHC methodology) • IHC 0, 1+ (negative) • IHC 2+ (borderline) • FISH • IHC 3+ (positive) • FISH assay (Lab meets quality assurance standards for Her-2 neu methodology • FISH non-amplified (negative) • FISH borderline • IHC or Retest or Count additional cells • FISH amplified (positive) • HERmark (quantitative test) • Her-2 Dual ISH assay detect both Her2 and chromos. 17

  15. Molecular Subtypes of Breast Cancer • Luminal A: ER+ and or PR+ Her2 -ve • Luminal B: ER+ and or PR + Her2+ • Her2: Her2+ ER-ve PR-ve • Basal-like: ER-ve PR-ve Her2-ve, cytokeratin 5/6+, and or Her1+ • Normal-like: negative for all markers

  16. BREAST CA SUBTYPES • Hormone responsive; • ER/PR positive • Luminal A and B disease by microarray • Her-2neu overexpression; • Herceptin responsive • Her-2 neu overexpression by microarray • Non hormone responsive, non-Her-2 neu overexpressive; • poor prognosis TRIPLE NEGATIVE • basal-like by microarray

  17. Risk Categories Low Intermed High (All) (> 1) • LN -ve -ve +ve • Tumor size < 1cm > 1-2cm > 2cm • ER/PR +ve +ve -ve • Grade 1 1-2 2-3 • Age > 35 <35

  18. St Gallen's risk categories for Node negative • Low risk: • ER/PR+ve and all of following: • pT < 2cm (inv component) • G1 • > 35Y • High risk: • ER/PR -ve or • ER/PR +ve + one of following: • pT> 2cm (inv component) • G 2-3 • <35Y

  19. Management ofEarly STAGE invasiveDisease

  20. SURGERY

  21. Surgical Options • Breast conservation • Lumpectomy + ALN staging • MRM + reconstruction

  22. Breast ConservationCONTRAINDICATIONS Absolute • Multicentricity • Diffuse microcalcifications • Early pregnancy • Previous RT • Positive margins Relative • Tumor size vs breast size • Tumor location, or >5 cm • Collagen vascular disease (excluding RA) • Focally positive margin

  23. Re-excision of Primary • Indications: • Extensive Intraductal Component (EIC) especially with close margins (<2cm) • Positive/uncertain margins • Residual microcalcifications

  24. Margin status • Breast conserving surgery is predicted on achieving a negative margin • What if margins remain positive?! • Mastectomy • In selected cases may accept microscopically focally positive margin, but with conditions: • Absence of extensive intraductal component • Use of higher R.T. boost to tumor bed

  25. ROLE OF LN DISSECTION • Diagnostic and/or Therapeutic? • LN –ve: • 70-90% 5YS • 10% chance of death in 10Y • LN+ve: • 50-70% risk of relapse • 35% chance of death in 10Y • 1-3 LN+ve: 60-80% 5YS • >4 LN+ve: 30-50% 5YS

  26. Sentinel L. Node Dissection • Candidates: • Clinically -ve nodes • Solitary T1 or T2 • ?? High grade/extensive DCIS • No large hematoma or seroma • No neoadjuvant chemo • SLN can’t be identified or +ve: • Formal axillary dissection

  27. RADIATION THERAPY

  28. Breast conservation(Lumpectomy + RT) MRM: S% Lump/RT: S% NSABP 60 62 EORTC 73 71 Danish 82 79 NCI 75 77

  29. Lumpectompy + RT Local recurrence Pts L% L+RT% NSABP 1262 35 10 Milan 567 12 2 Ontario 837 35 11 Sweden 381 18 2 Scottish 585 25 6 British 418 35 13

  30. Post-MRM R.T. • > 4 positive LN: • RT to chest wall + ICV LN + SCV LN +/- IM LN: • 1-3 positive LN: • Strongly consider RT to chest wall + ICV LN + SCV LN +/- IM LN: • T > 5 cm or positive margins: • Consider RT to chest wall +/- ICV LN/SCV LN/IM LN • T < 5 cm and margin <1mm: • RT to chest wall • T < 5 cm, N negative, margins > 1mm: • No RT

  31. Is R.T. required for elderly? • Age > 70, Stage I, ER +ve treated with lumpectomy +/- RT  Tam: • Median f/u of 8.2Y • Local-regional recurrence rate: 1% vs 4% • No diff in OS, DFS or need for mastectomy

  32. PREOPERATIVE THERAPY

  33. Why Neoadjuvant Therapy? • Downstages the primary tumor in most women. • Allows a higher rate of breast preservation. • Provides an in vivo assessment of tumor response to the particular drug regimen and, hence, an opportunity to optimize therapy. • Pathologic complete response (pCR) after preoperative therapy is a powerful surrogate of long-term disease free survival. • It is hypothesized that a regimen that produces higher rates of pCR in the neoadjuvant treatment setting will also result in higher rates of long-term cure.

  34. Why pre-Chemo SLND? • Pathologic LN CR following preop chemo • Guide local and systemic treatment

  35. NSABP B-18 • Preop AC: • Breast conservation is more likely • Improves DFS/OS in pt with Pathologic CR • No disease specific survival advantage over adj chemo in stage II

  36. NSABP B-27 • Three arms: • Preop AC  local therapy • Preop AC/Doce  local therapy • Preop AC  local therapy  Doce

  37. NSABP B-27 • ACx4  surg • 40% clinical CR • 14% partial CR • ACx4  Taxotere100 x4  surg • 65% cCR • 26% pCR • AC-->surg-->Taxotere • No improvement in lumpectomy • Higher rate of pathologic CR with AC/Doce • No DFS and OS diff • DFS favors preop Doce vs postop Doce in subset of pts with partial response to AC

  38. MD Anderson regimen(Her2-neu +ve) • NeoAdj: Taxol X4 + Trastuzumzb  CEF x4 + Trastuzumab (Total of 24 wks) • Trastuzumab increases path CR from 26 to 65.2%

  39. Significantly Higher Pathologic Complete Remission Rate After Neoadjuvant Therapy With Trastuzumab, Paclitaxel, and Epirubicin Chemotherapy: Results of a Randomized Trial in Human Epidermal Growth Factor Receptor 2–Positive Operable Breast CancerAman U. Buzdar, Nuhad K. Ibrahim, Deborah Francis, Daniel J. Booser, Eva S. Thomas,Richard L. Theriault, LajosPusztai, Marjorie C. Green, Banu K. Arun, Sharon H. Giordano,Massimo Cristofanilli, Debra K. Frye, Terry L. Smith, Kelly K. Hunt, Sonja E. Singletary,Aysegul A. Sahin, Michael S. Ewer, Thomas A. Buchholz, Donald Berry, and Gabriel N. Hortobagyi • MD Anderson protocol: • prospective randomized phase III study were the goal of the study was to demonstrate that the addition of trastuzumab to a complete 6-month preoperative chemotherapy regimen will increase pCR rate two-fold compared with chemotherapy alone. • The study was powered to detect a 20% improvement in the pCR rate (ie, from 21% to 41%)

  40. Ongoing Anti-Her2 Neoajuvant • NeoALTTO – BIG 01-06 (phase III): • Adj Lap/Traz/Taxol vs LT vs H/T • Then adj ECF and Anti-Her2 • LHT: pCR 51.3% in Breast and 47% in breast and LN (higher in ER neg) • GeparQuinto: • Neoad EC/Doce + Herc or Tykerb followed by adj Herc • 50% pCR (more with Herceptin) • NeoSphere: • Neoadj Doce +/- Pertuzumab +/- Traztuzumab • 3 drugs is better with 46% pCR; sig

  41. Stage II-IIIA (T3N1)(Pt desires breast preservation) 1- Core biopsy of breast tumor + mark tumor bed 2- Axillary LN: • Clinically –ve • Consider SLD • Clinically +ve • Consider core Bx or FNA; if -ve • Consider SLD 3- Then preop chemo/hormone: • Any adj regimen or • A.I. for postpenopausal or • Trastuzumab-bsed therapy for her2-neu +ve

  42. Stage II-IIIA (T3N1)(Pt desires breast preservation) 4- According to preop chemo response: • Lumpectomy + LND (may omit if preop SLN –ve) • Mastectomy + LND (may omit if preop SLN –ve) 5- Additional chemo in clinical trial 6- Adj therapy may include: • RT • Trastuzumab • Hormonal therapy (could be given with herceptin) • Xeloda as radiosensitizer for high risk of local recurrence (may give with herceptin)

  43. Adjuvant Therapy

  44. Who is a candidate for adj. Systemic therapy? • Healthy • Positive LN • T >1 cm • (IDC or ILC) • T >3 cm • (tubular, papillary, mucinous) • Data is limited for chemo in elderly (>70 yrs)

  45. chemotherapy

  46. Chemotherapy • Chemo reduce mortality by 25% • N+ =8% benefit • N-ve.=2% benefit • Chemo reduce risk of recurrence by: • 30% in pre menopausal • 20% in post menopausal • Chemo reduce risk of death by: • 25% in pre menopausal • 15% in post menopausal

  47. ANTHRACYCLINEs

  48. Anthracyclines • Anthracycline vs non-Anthracycline: • 12% proportional odd risk reduction of recurrence • 11% odd risk reduction of death • Absolute gain in survival; • 4% in N+ve • 1.7% in N-ve • Anthracycline benefits the most: • Her2-neu +ve • Topoisomerase lla +ve

  49. CEF vs CMF • CEF-120 vs CMF: • DFS; 62% vs 53% • OS; 77% vs 70% • CEF: • 29% risk reduction in recurrence • 19% risk reduction in mortality

  50. TAXANES

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