Breast Cancer

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  • Breast Cancer

    1. 1. BREAST CANCER Lawrence E. Flaherty M.D. Professor of Medicine and Oncology Karmanos Cancer Institute Wayne State University
    2. 2. Breast Cancer Incidence <ul><li>U.S Incidence </li></ul><ul><li>Affects 1 in 8 women living to age 85 </li></ul><ul><li>Total Cases – 2008 = 211,000 </li></ul><ul><li>Total Deaths – 2008 = 40,500 (1/6 female deaths) </li></ul><ul><li>Ethnic incidence </li></ul><ul><li>Caucasians Hispanic Asian African Amer </li></ul><ul><li>African Americans – higher stage and mortality </li></ul><ul><li>Stage at presentation – localized 58% (node -) </li></ul><ul><li> - regional 32% (node +/ stage III) </li></ul>
    3. 3. Breast Cancer Risk Factors
    4. 4. Breast Cancer Risk Factors <ul><li>Personal History </li></ul><ul><ul><li> Biopsy Pathology Relative Risk (RR) </li></ul></ul><ul><ul><ul><li>Lobular Carcinoma in situ 8-10 </li></ul></ul></ul><ul><ul><ul><li>Ductal Carcinoma in situ 8-10 </li></ul></ul></ul><ul><ul><ul><li>Atypical Ductal Hyperplasia 4-5 </li></ul></ul></ul><ul><ul><ul><li>Atypical Lobular Hyperplasia 4-5 </li></ul></ul></ul><ul><ul><ul><li>Hyperplasia 1.5-2.0 </li></ul></ul></ul><ul><ul><li> Prior Biopsy - Any 1.3-1.6 </li></ul></ul>
    5. 5. Breast Cancer Risk Factors <ul><li>Age </li></ul><ul><li>Age Incidence </li></ul><ul><li>by age 30 1 in 2,525 </li></ul><ul><li>by age 40 1 in 217 </li></ul><ul><li>by age 50 1 in 50 </li></ul><ul><li>by age 60 1 in 24 </li></ul><ul><li>by age 70 1 in 14 </li></ul><ul><li>by age 80 1 in 10 </li></ul>
    6. 6. Breast Cancer Risk Factors <ul><li>Family History </li></ul><ul><li># Affected Relationship RR Percentage </li></ul><ul><li>1 1st degree* 2.45 9-21%** </li></ul><ul><li>2 1st degree 11-48% </li></ul><ul><li>1 2nd degree 1.82 8-14% </li></ul><ul><li>2 2nd degree 9-26% </li></ul><ul><li>*1st degree = sisters, mother, daughters </li></ul><ul><li>2nd degree = cousins, grandparents </li></ul><ul><li>**Range affected by the age of diagnosis of affected family individual – younger = higher </li></ul>
    7. 14. Breast Cancer Risk Factors <ul><li>Reproductive/Other </li></ul><ul><ul><li>Feature RR </li></ul></ul><ul><ul><li>Menarche < age 12 1.2 </li></ul></ul><ul><ul><li>1st Live Birth > age 30 1.9 </li></ul></ul><ul><ul><li>Menopause after age 55 1.5 </li></ul></ul><ul><ul><li>HRT Long Term exposure 1.1-1.4 </li></ul></ul><ul><ul><li>Radiation Exposure - Hodgkin's/Mantle RT </li></ul></ul>
    8. 15. Monthly Incidence 1998 thru 2002 (for women 50 and older) Stable Incidence Year of Diagnosis Incidence Per 100,000 Women / Month
    9. 16. Updated with an Additional Year of Data Monthly Incidence 1998 thru 2003 Decrease In 2003 Year of Diagnosis Incidence Per 100,000 Women / Month
    10. 17. Effect Seen in All SEER 9 Registries Relative Reduction (2003 vs 2000/2001) Relative reduction in incidence (%) San Franscisco Connecticut Detroit Hawaii Iowa New Mexico Seattle Utah Atlanta All Registries
    11. 18. Effect Only Evident In Subsets Of Patients 50 and Older Relative reduction in incidence (%) < 40 40 – 49 50 – 64 65 – 74 75 – 84 Any Age
    12. 19. Influence of ER Status Relative reduction in incidence (%) ER + ER – Any ER
    13. 20. Usage of Hormonal Agents in the US www.drugtopics.com/drugtopics/
    14. 21. % Of Population Treated Buist et al. Obstet Gynecol 2004;104:1042–50. Use and Decrease Mainly in Women 50 and Older 0 5 10 15 20 25 30 35 40 40-44 45 50 45-49 50-54 55-59 60-64 65-69 70-74 75-79 Pre-WHI Dec-02 Change In Use The Prevalence Of Use Of HT Pre/Post WHI (Estimates Derived From HMO Data)
    15. 22. Mammography <ul><li>Established Guidelines </li></ul><ul><ul><ul><li>Annual 2 view study in women 50 years of age and older </li></ul></ul></ul><ul><ul><ul><li>Meta - analysis </li></ul></ul></ul><ul><ul><ul><ul><li>13 randomized trials </li></ul></ul></ul></ul><ul><ul><ul><ul><li>26% reduction in breast cancer </li></ul></ul></ul></ul>
    16. 23. Mammography <ul><li>Controversy in Age 40-49 </li></ul><ul><ul><ul><li>Recommended by American Cancer Society (ACS), the National Cancer Institute (NCI), the American Medical Association (AMA) and the American College of Surgeons (ACS) - CoC </li></ul></ul></ul><ul><ul><ul><li>Earlier detection and mortality benefits smaller </li></ul></ul></ul><ul><ul><ul><li>Less “cost effective” </li></ul></ul></ul><ul><ul><ul><li>Leave decision to the individual “well informed women” </li></ul></ul></ul><ul><ul><ul><li>Identify higher risk populations within your practice </li></ul></ul></ul>
    17. 24. Mammography <ul><li>Earlier Routine Mammograms </li></ul><ul><ul><li>High Risk Groups </li></ul></ul><ul><ul><ul><li>strong family history </li></ul></ul></ul><ul><ul><ul><ul><li>multiple family members with breast and or ovarian cancer, particularly when occurring at an early age </li></ul></ul></ul></ul><ul><ul><ul><li>personal history of thoracic radiation therapy </li></ul></ul></ul><ul><ul><ul><ul><li>Hodgkin’s disease </li></ul></ul></ul></ul><ul><ul><ul><li>screening beginning 10 years earlier than the age of the youngest affected family member, but not before age 25 </li></ul></ul></ul>
    18. 25. Mammography - Ordering <ul><li>Screening </li></ul><ul><ul><li>Patient without physical finding or symptoms </li></ul></ul><ul><ul><ul><li>MLO - mediolateral oblique (side) </li></ul></ul></ul><ul><ul><ul><li>CC - craniocaudal (above) </li></ul></ul></ul><ul><li>Diagnostic </li></ul><ul><ul><li>new symptoms - lump, thickening, skin change </li></ul></ul><ul><ul><li>additional imaging including magnification </li></ul></ul><ul><ul><li>additional evaluation including US </li></ul></ul>
    19. 26. Mammography - Reporting <ul><li>BIRADS - Breast Imaging Reporting and Data System </li></ul><ul><li>Category Assessment Recommendations </li></ul><ul><li>0 Incomplete Additional views </li></ul><ul><li>1 Negative Routine - 12 months </li></ul><ul><li>2 Benign Routine - 12 months </li></ul><ul><li>3 Probable Benign F/U short term - 6 mos. </li></ul><ul><li>4 Suspicious Biopsy considered </li></ul><ul><li>5 Cancer suggested Appropriate action </li></ul>
    20. 27. Breast Cancer Diagnosis <ul><li>Fine Needle Aspiration </li></ul><ul><li>Ultrasound Guided Core Biopsy </li></ul><ul><li>Excisional or Incisional Biopsy </li></ul>
    21. 28. Breast Cancer Diagnosis <ul><li>FNA - Fine Needle Aspiration </li></ul><ul><ul><li>simple - 21-23 gauge needle - 5-10 cc syringe </li></ul></ul><ul><ul><li>relatively atraumatic </li></ul></ul><ul><ul><li>sensitivity of 73-99% </li></ul></ul><ul><ul><li>ideal for simple cyst aspiration </li></ul></ul><ul><ul><li>can’t distinguish in-situ vs invasive cancer </li></ul></ul>
    22. 29. Breast Cancer Diagnosis <ul><li>CNB - Core Needle Biopsy </li></ul><ul><ul><li>14 - 20 gauge cutting needle </li></ul></ul><ul><ul><li>greater trauma </li></ul></ul><ul><ul><li>high sensitivity - 100% </li></ul></ul><ul><ul><li>distinguishes between invasive and in-situ </li></ul></ul><ul><ul><li>stereotactic with mammography and US </li></ul></ul><ul><ul><li>may completely remove small areas </li></ul></ul>
    23. 30. Breast Cancer Diagnosis <ul><li>Open Biopsy (incisional or excisional) </li></ul><ul><ul><li>any suspicious finding </li></ul></ul><ul><ul><li>clinical or radiologic finding with negative FNA or CNB </li></ul></ul><ul><ul><li>atypia on FNA or CNB </li></ul></ul><ul><ul><ul><li>20-50% associated with malignancy on open biopsy </li></ul></ul></ul><ul><ul><li>recurring cyst </li></ul></ul>
    24. 31. Breast Cancer Non-Invasive
    25. 32. Breast Cancer Pathology <ul><li>Non – Invasive </li></ul><ul><li>Lobular (LCIS) Ductal (DCIS) </li></ul><ul><li>Invasive </li></ul><ul><li>Low Risk * Standard (high) Risk </li></ul><ul><li>Pure Tubular Ductal </li></ul><ul><li>Pure Mucinous/Colloid Lobular </li></ul><ul><li>Pure Papillary Medullary ** </li></ul><ul><li>Pure Medullary ? Mixed </li></ul><ul><li>Squamous </li></ul>* Requires careful pathology review ** atypical and mixed
    26. 33. Breast Cancer Non-Invasive – Lobular (LCIS) <ul><li>Features </li></ul><ul><ul><li>Increased risk of subsequent invasive cancer (~ 1%/yr) </li></ul></ul><ul><ul><li>Likely to be bilateral </li></ul></ul><ul><li>Management Options </li></ul><ul><li>Observation ( negative surgical margins NOT required) </li></ul><ul><li>No SLNBx or ALND is necessary </li></ul><ul><li>Bilateral mastectomies can be considered </li></ul><ul><li>Potential candidates for Tamoxifen or chemoprevention trials </li></ul><ul><li>Work-Up/Follow-Up </li></ul><ul><li>Bilateral mammogram, then yearly </li></ul><ul><li>Exam every 6-12 months </li></ul>
    27. 34. Breast Cancer Non-Invasive – Ductal (DCIS) <ul><li>Incidence </li></ul><ul><li>Incidence 4,800 50,000 in past 20 years </li></ul><ul><li>Represents 20% of new cancer diagnosis in U.S. </li></ul><ul><li>Risk </li></ul><ul><li>Pre-invasive to invasive ductal cancer (IDC) </li></ul><ul><li> Increased risk of subsequent invasive cancer (~ 1%/yr) </li></ul><ul><li>Features </li></ul><ul><ul><li>90 % found on mammogram – 76% as micro Ca++ </li></ul></ul><ul><ul><li>Likely to be unilateral </li></ul></ul><ul><ul><li>ER + in 70% (lower in high grade) </li></ul></ul><ul><ul><li>Her 2 neu + in 50% (higher in high grade) </li></ul></ul>Note: if diagnosed by core biopsy – 10-15% will have invasive component at excision
    28. 35. Breast Cancer Non-Invasive – Ductal (DCIS) <ul><li>Management Options – Surgery - Breast </li></ul><ul><li>1). Complete Excision Alone </li></ul><ul><li>2). Complete Excision + RT </li></ul><ul><li>3). Mastectomy </li></ul>Possible for low risk lesion, but “low risk” difficult to define Relative Contraindications 1 – in 2 or more quadrants 2 – diffuse or malignant appearing Ca++ 3 – persistent + margins 4 – not RT candidates prior RT pregnancy CTD – lupus/scleroderma Margins need to be negative, >1mm, less than 10 mm. 2-3 mm usually recommended Post excision Imaging - specimen mammogram and/or - post lump mammogram
    29. 36. Breast Cancer Non-Invasive – Ductal (DCIS) <ul><li>Management Options – Radiation Therapy </li></ul><ul><li>Excision Alone – recommended </li></ul><ul><li>Post Mastectomy – unnecessary </li></ul><ul><li>No effect on mortality </li></ul><ul><li>Decreases Breast Recurrence Risk by 50% (1% ½%/yr) </li></ul><ul><li>Treatment is to Breast Only </li></ul><ul><li>Contraindications: </li></ul><ul><li>Omitted in low risk? </li></ul><ul><li> controversial </li></ul><ul><li> < 5mm, low grade, unicentric </li></ul>Relative Contraindications 1 – in 2 or more quadrants 2 – diffuse or malignant appearing Ca++ 3 – persistent + margins 4 – not RT candidates prior RT pregnancy CTD – lupus/scleroderma
    30. 37. Breast Cancer Non-Invasive – Ductal (DCIS) <ul><li>Management Options – Systemic Therapy </li></ul><ul><li>NSABP – B-24 (BCS +/- RT) Tamoxifen No Tamoxifen </li></ul><ul><li>Invasive 4.1% 7.2% </li></ul><ul><li> Non-Invasive 4.2% 6.2% </li></ul><ul><li> 8.2% 13.4% </li></ul><ul><li>5% absolute difference at 6 yrs </li></ul><ul><li>No survival advantage (97-98%) </li></ul><ul><li>Tamoxifen indicated if there are no contraindications </li></ul><ul><li>ER analysis – necessary? </li></ul><ul><li>Follow-Up - Visits every 6-12 months </li></ul><ul><li>Yearly mammograms </li></ul><ul><li>Yearly pelvic if intact uterus on Tamoxifen ) </li></ul>
    31. 38. Breast Cancer Non Invasive - Ductal (DCIS) <ul><li>Excision </li></ul><ul><li>ALND – unnecessary </li></ul><ul><li>SLNBx – optional but recommended if: </li></ul><ul><li>1). Palpable </li></ul><ul><li>2). In the tail </li></ul><ul><li>Mastectomy </li></ul><ul><li>SLNBx – recommended </li></ul><ul><li>ALND – unnecessary unless palpable and SLNBx unavailable </li></ul>Surgical Management – Lymph Nodes
    32. 39. Breast Cancer - Invasive
    33. 40. Breast Cancer - Invasive Lumpectomy + RT Mastectomy == Lymph Nodes Micrometastasis Risk Size Lymph node/# Grade ER/PR Her 2-neu Adjuvant Therapy Surgery Medical Oncology
    34. 41. Breast Cancer - Invasive Micrometastasis Risk (1-99%) Size Lymph node/# Grade ER/PR Her 2-neu Adjuvant Therapy Medical Oncology Hormonal Rx Chemotherapy >1.0 cm or node + or Her 2-neu + IV – 2-6 months 25-75% RRR ER or PR + Oral x 5yrs (+ ?) 33-50% RRR Pre – Tamoxifen Post - AIs
    35. 42. Breast Cancer - Invasive <ul><li>Stages I – IIB + IIIA (T3 > 5 cm, N1 only) </li></ul><ul><li>Management Priorities </li></ul><ul><li>Surgery </li></ul><ul><li>Adjuvant Chemotherapy </li></ul><ul><li>Hormonal Rx* Radiation Rx* </li></ul>*can be given together or sequentially with RT first
    36. 43. Breast Cancer - Invasive <ul><li>Stages I – IIB + IIIA (T3 > 5 cm, N1 only) </li></ul><ul><li>Breast Surgery – Breast </li></ul><ul><li>Mastectomy = Breast Conservation Surgery (BCS)+ RT </li></ul><ul><li>Margins – 2mm minimum </li></ul><ul><li>BCS contraindications: </li></ul><ul><li>Absolute – 1) Prior RT </li></ul><ul><li> 2) RT during pregnancy </li></ul><ul><li> 3) multicentric disease </li></ul><ul><li> 4) diffuse/susp/malignant micro Ca </li></ul><ul><li>Relative - 1) large tumor (>5cm) – cosmesis </li></ul><ul><li> 2) periareolar </li></ul><ul><li> 3) CTD (lupus/scleroderma) </li></ul>
    37. 44. Breast Cancer - Invasive <ul><li>Stages I – IIB + IIIA (T3 > 5 cm, N1 only) </li></ul><ul><li>Breast Surgery – Axilla </li></ul><ul><li>ALND (axillary lymph node dissection) </li></ul><ul><li>- indicated in clin/path node + at time of initial dx </li></ul><ul><li>- largely prognostic </li></ul><ul><li>- level I/II – if gross disease level III </li></ul><ul><li>- optional ? In clinically negative with : </li></ul><ul><li>serious co-morbidity </li></ul><ul><li>elderly (age undefined) </li></ul><ul><li>if no influence on adjuvant therapy choices </li></ul><ul><li>favorable tumors </li></ul>
    38. 45. Breast Cancer - Invasive <ul><li>Stages I – IIB + IIIA (T3 > 5 cm, N1 only) </li></ul><ul><li>Breast Surgery – Axilla </li></ul><ul><li>SLNBx (Sentinel Lymph Node Biopsy) </li></ul><ul><li>- largely replacing ALND as initial management </li></ul><ul><li>- requires experienced team (path and imaging) </li></ul><ul><li>- serial sectioning H & E (cytokeratin IHC controversial) </li></ul><ul><li>- if + recommend ALND level I/II (ACOSOG trial) </li></ul><ul><li>- relative contraindications – multicentric disease, >5cm, prior chemo/hormonal therapy </li></ul>
    39. 46. Breast Cancer - Invasive <ul><li>Adjuvant Therapy for Breast Cancer </li></ul><ul><li>What features identify risk ? </li></ul><ul><li>How are they used to predict risk? </li></ul><ul><li>Who is a Candidate? </li></ul><ul><li>What is the benefit? </li></ul>
    40. 47. Breast Cancer - Invasive <ul><li>Risk Prediction for Adjuvant Therapy </li></ul><ul><li>Invasive Component Features </li></ul><ul><li>1) Lymph Node Status (extent & #) </li></ul><ul><li>2) Tumor Histology </li></ul><ul><li>3) Tumor Size </li></ul><ul><li>4) Grade </li></ul><ul><li>5) ER/PR Status </li></ul><ul><li>6) Her 2 neu status </li></ul>
    41. 48. Breast Cancer - Invasive <ul><li>Risk Prediction for Adjuvant Therapy </li></ul><ul><li>Invasive Component Features </li></ul><ul><li>1) Lymph Node Status (extent & #) </li></ul><ul><li>- most powerful prognostic feature </li></ul><ul><li>- # strongly predictive 0, 1-3, 4-9, >10 </li></ul><ul><li>- extent an issue in the era of SLNBx </li></ul><ul><li>N1 if 0.2mm or > </li></ul><ul><li>N0 if true negative or </li></ul><ul><li> < 0.2mm or clusters by IHC, RT-PCR, </li></ul><ul><li>- Extra nodal extension doesn’t change risk </li></ul><ul><li>- Risk Range 30 – 90% </li></ul>
    42. 49. Breast Cancer Pathology <ul><li>Non – Invasive </li></ul><ul><li>Lobular (LCIS) Ductal (DCIS) </li></ul><ul><li>Invasive </li></ul><ul><li>Low Risk * Standard (high) Risk </li></ul><ul><li>Pure Tubular Ductal </li></ul><ul><li>Pure Mucinous/Colloid Lobular </li></ul><ul><li>Pure Papillary Medullary ** </li></ul><ul><li>Pure Medullary ? Mixed </li></ul><ul><li>Squamous </li></ul>* Requires careful pathology review, with same treatment recommendations when they reach 3.0cm ** atypical and mixed
    43. 50. Molecular profiling Sorlie et al. PNAS 98:10869, 2001 Individual Genes 78 Individual Tumors & 4 Normal Breast
    44. 51. Molecular profiling Sorlie et al. PNAS 98:10869, 2001
    45. 52. Note: Does not include lobular CA (5-10% frequency) 85% 18% Basal-like (triple negative) 62% 14% Her-2+ 49% 20% Luminal B (weak ER/+/-PR and Her-2) 21% 52% Luminal A(ER/PR+/Her-2-) % High grade Frequency
    46. 53. Breast Cancer - Invasive <ul><li>Risk Prediction for Adjuvant Therapy </li></ul><ul><li>Invasive Component Features </li></ul><ul><li>3) Tumor Size </li></ul><ul><li>- based on the largest diameter of the invasive component </li></ul><ul><li>- if multiple tumors, based on the size of the largest </li></ul><ul><li>- most important prognostic factor after LN # </li></ul>
    47. 54. Breast Cancer - Invasive <ul><li>Risk Prediction for Adjuvant Therapy </li></ul><ul><li>Invasive Component Features </li></ul><ul><li>4) Tumor Grade </li></ul><ul><li>Grade Prognosis </li></ul><ul><li> I well/low better </li></ul><ul><li> II moderate standard </li></ul><ul><li> III high/poor standard </li></ul><ul><li>- subjective - interobserver variability problematic </li></ul><ul><li>- moderate initially better but = poor long term </li></ul><ul><li>- Nottingham (1-3) </li></ul><ul><li>% tubular formation </li></ul><ul><li>Degree of nuclear pleomorphism </li></ul><ul><li>Mitotic index </li></ul>
    48. 55. Breast Cancer - Invasive <ul><li>Risk Prediction for Adjuvant Therapy </li></ul><ul><li>Invasive Component Features </li></ul><ul><li>5) ER/PR Status </li></ul><ul><li>Prognostic – modest </li></ul><ul><li>Predictive – strong (for hormonal rx benefit) </li></ul><ul><li>Assay by IHC and reported as </li></ul><ul><li>negative (0-1%) </li></ul><ul><li>weakly pos (1-10%) </li></ul><ul><li>strongly pos (10-100%) </li></ul>
    49. 56. Breast Cancer - Invasive <ul><li>Risk Prediction for Adjuvant Therapy </li></ul><ul><li>Invasive Component Features </li></ul><ul><li>5) ER/PR Status </li></ul><ul><li>Prognostic – modest </li></ul><ul><li>Predictive – strong (for hormonal rx benefit) </li></ul><ul><li>Allred’s Score </li></ul><ul><li>Percentage + Intensity = Score </li></ul><ul><li>1 <1% 0 = none 0-2 = neg </li></ul><ul><li>2 1-10% 1 = weak 3-8 = pos </li></ul><ul><li>3 10-33% 2 = intermed </li></ul><ul><li>4 33-66% 3 = strong </li></ul><ul><li>5 >66% </li></ul>
    50. 57. Breast Cancer - Invasive <ul><li>Risk Prediction for Adjuvant Therapy </li></ul><ul><li>Invasive Component Features </li></ul><ul><li>6) Her -2 neu status </li></ul><ul><li>- oncogene, overexpressed protein </li></ul><ul><li>- EGFR family of growth receptor tyrosine kinase </li></ul><ul><li>- both prognostic and predictive </li></ul><ul><li>- over expressed in 20-30% of breast tumors, but rarely in lobular </li></ul><ul><li>- assessed by IHC (herceptest 0, 1, 2, 3+) or </li></ul><ul><li> by FISH (gene amp – pos or neg) </li></ul><ul><li>- FISH = gold standard </li></ul>
    51. 58. Breast Cancer - Invasive <ul><li>Risk Prediction for Adjuvant Therapy </li></ul><ul><li>Invasive Component Features </li></ul><ul><li>6) Her -2 neu status </li></ul><ul><li>- shorter time to relapse and survival </li></ul><ul><li>- greater benefit with Adria based adjuv regimens </li></ul><ul><li>- in pts also ER + possible less benefit from tamoxifen favors use of AIs </li></ul><ul><li>- ongoing trials in adjuvant setting </li></ul>
    52. 59. Breast Cancer - Invasive <ul><li>Adjuvant Therapy for Breast Cancer </li></ul><ul><li>What features identify risk ? </li></ul><ul><li>How are they used to predict risk? </li></ul><ul><li>Who is a Candidate? </li></ul><ul><li>What is the benefit? </li></ul>
    53. 60. Breast Cancer – Invasive Adjuvant Therapy <ul><li>Assessing Risk – Mortality at 10 years </li></ul><ul><li>Node negative (overall – 1-30+%) </li></ul><ul><li>Typical 60 y.o with grade 2 and ER pos </li></ul><ul><li>Risk approx - 8% / 1 .0 cm of tumor size </li></ul><ul><li>increase by 20% for ER neg </li></ul><ul><li>increase by 20% for grade III </li></ul><ul><li>Node positive (overall – 30+ - 90+%) </li></ul><ul><li>Use risk for node negative features </li></ul><ul><li>add 10-15% for 1 st node then 5% for each additional node </li></ul>
    54. 61. Adjuvant! A program for aiding health professionals in making estimates of outcome of patients with invasive cancer who have undergone definitive local therapy (without prior radiation or systemic therapy) and who are now deciding on whether to get systemic adjuvant therapy.
    55. 62. Information Input Natural Mortality Br Ca Mortality Tx Efficacy
    56. 65. Breast Cancer – Invasive Adjuvant Therapy <ul><li>Assessing Risk – Mortality at 10 years </li></ul><ul><li>www.adjuvantonline.com </li></ul><ul><li>- breast cancer relapse and mortality </li></ul><ul><li>- tumor size, grade, node groupings, ER </li></ul><ul><li>- assesses benefit from hormonal and chemorx </li></ul><ul><li>- limitations </li></ul><ul><li>size 1.1 – 2.0, 2.1 – 3.0, etc </li></ul><ul><li>LNs 1-3, 4-9, >9 </li></ul><ul><li>ER - positive, negative </li></ul><ul><li>no her-2 neu </li></ul><ul><li>mortality at 10 yrs - ? Sufficient </li></ul><ul><li>relapse rate >>> OS , includes ?local </li></ul>
    57. 66. Breast Cancer - Invasive <ul><li>Adjuvant Therapy for Breast Cancer </li></ul><ul><li>What features identify risk ? </li></ul><ul><li>How are they used to predict risk? </li></ul><ul><li>Who is a Candidate? </li></ul><ul><li>What is the benefit? </li></ul>
    58. 67. Integrating / Presenting Information The Biology Of The Patient Decision Treatment Efficacy / Toxicity The Biology Of The Tumor Doctor’s Opinions Patient’s Opinions
    59. 68. Adjuvant Guidelines (Never A Mention Of Numbers) A Relic Of The Empire !
    60. 69. Breast Cancer – Invasive Adjuvant Therapy <ul><li>Chemotherapy – Hormonal Therapy – Both </li></ul><ul><li>Guiding Principles </li></ul><ul><li>Not Recommended: </li></ul><ul><li>node neg </= 5mm </li></ul><ul><li>May be considered in: </li></ul><ul><li>node neg, 6-10 mm with unfavorable features: </li></ul><ul><li>angiolymphatic invasion </li></ul><ul><li>high nuclear/histo grade (PD/III) </li></ul><ul><li>her-2neu + (FISH) </li></ul><ul><li>ER/PR - </li></ul>
    61. 70. How Much Of A Reduction In Breast Cancer Would Make The Adjuvant Worthwhile ? % Reduction Breast Cancer Mortality Minimally Acceptable Bimodal Distribution Of Answers North American Study Australian Study % Of Patients Responding
    62. 71. Breast Cancer – Invasive Adjuvant Therapy <ul><li>Chemotherapy – Hormonal Therapy – Both </li></ul><ul><li>Guiding Principles </li></ul><ul><li>Discussion! </li></ul><ul><li>Candidates – invasive tumors >/= 1.0 cm or node + Risk benefit ratio needs to be individualized - benefit </li></ul><ul><li>- toxicity </li></ul><ul><li>- co-morbidities </li></ul><ul><li>Chemotherapy </li></ul><ul><li>- benefit in all under 70 years old </li></ul><ul><li>- polychemotherapy should be used </li></ul><ul><li>- relative risk reduction is 25-33% </li></ul>
    63. 72. Breast Cancer - Invasive <ul><li>Adjuvant Therapy for Breast Cancer </li></ul><ul><li>What features identify risk ? </li></ul><ul><li>How are they used to predict risk? </li></ul><ul><li>Who is a Candidate? </li></ul><ul><li>What is the benefit? </li></ul>
    64. 73. Adjuvant Regimens and their Benefit <ul><li>Generation Regimens Relative DFS/OS </li></ul><ul><li>1 st CMF (6) or AC (4) 20-25% </li></ul><ul><li>2 nd CA(E)F (6) 20-25% </li></ul><ul><li>AC (4)-> T (4) q3wk </li></ul><ul><li>TC (4) q 3wk </li></ul><ul><li>3 rd TAC (6) 20-25% </li></ul><ul><li>AC (4) -> T (4) q2wk </li></ul><ul><li>AC (4) q 3 -> T x 12 wk </li></ul>
    65. 74. Breast Cancer - Invasive <ul><li>Adjuvant Therapy for Breast Cancer </li></ul><ul><li>What features identify risk ? </li></ul><ul><li>How are they used to predict risk? </li></ul><ul><li>Who is a Candidate? </li></ul><ul><li>What is the benefit? </li></ul>
    66. 75. Breast Cancer – Invasive Adjuvant Therapy <ul><li>Chemotherapy – Hormonal Therapy – Both </li></ul><ul><li>Guiding Principles </li></ul><ul><li>Hormonal Therapy </li></ul><ul><li>- ER and/or PR positive patients should be considered regardless of age </li></ul><ul><li>- ER / PR negative patients should not be rxed </li></ul><ul><li>If patient is a candidate for both chemo and hormonal therapy – chemo is given 1 st . </li></ul>
    67. 76. Breast Cancer – Invasive Adjuvant Therapy <ul><li>Adjuvant Hormonal Options: </li></ul><ul><li>Premenopausal </li></ul><ul><li>Tamoxifen x 5 years </li></ul><ul><li>Oophorectomy (surgical or RT) </li></ul><ul><li>LHRH alone x 5 years </li></ul><ul><li>LHRH + Tamoxifen or AI (subject of ongoing trials) </li></ul><ul><li>Postmenopausal </li></ul><ul><li>Aromatase Inhibitor (AI) x 5 years ? Tamoxifen x 5 years </li></ul>
    68. 77. Breast Cancer – Hormonal Therapy <ul><li>Background </li></ul><ul><li> Up to 75% of breast cancer will be ER and or PR positive </li></ul><ul><li> Estrogen remains their main stimulant to growth and development </li></ul><ul><li> Estrogen deprivation has been the major treatment approach </li></ul><ul><li> Surgery – historically – 1 st </li></ul><ul><li>Pre-menopausal - oophorectomy </li></ul><ul><li>Post-menopausal - adrenalectomy </li></ul><ul><li> hypophysectomy </li></ul>
    69. 78. Breast Cancer – Hormonal Therapy <ul><li>Medical Management </li></ul><ul><li>- largely replaced surgical management </li></ul><ul><li>- major therapeutic option has been Tamoxifen </li></ul><ul><li>- SERM ( s elective e strogen r eceptor m odulator) </li></ul><ul><li>others – Raloxifene (Evista), Toremifene </li></ul><ul><li>- mixed agonist and antagonist effects </li></ul><ul><li>- agonist effects may be partially responsible for loss of effect in breast cancer </li></ul>
    70. 79. Breast Cancer – Hormonal Therapy <ul><li>Medical Management </li></ul><ul><li>- largely replaced surgical management </li></ul><ul><li>- major therapeutic option has been Tamoxifen </li></ul><ul><li>- associated with: </li></ul><ul><li>- 2 fold increase in thromboembolism </li></ul><ul><li>- 2.5 fold increase in endometrial cancer - prevents bone demineralization - adjuvant therapeutic effect </li></ul><ul><li>= 28% reduction in mortality </li></ul><ul><li>(’98 overview) </li></ul>
    71. 80. Breast Cancer – Hormonal Therapy <ul><li>Medical Management </li></ul><ul><li>- can better strategies be developed to block estrogen effect by blocking estrogen production? </li></ul><ul><li>Aromatase Inhibitors </li></ul>testosterone androstenedione estradiol estrone aromatase
    72. 81. Inhibition of Estrogen-Dependent Growth Estrogen biosynthesis Tumor cell Nucleus Inhibition of cell proliferation Estrogen biosynthesis Antiestrogens Aromatase inhibitors
    73. 82. Breast Cancer – Hormonal Therapy <ul><li>Medical Management </li></ul><ul><li>- can better strategies be developed to block estrogen effect by blocking estrogen production? </li></ul><ul><li>Aromatase Inhibitors </li></ul><ul><li>- at menopause – 95% of estrogen production is lost </li></ul><ul><li>- the source of remaining estrogen production is: </li></ul><ul><li>breast cells </li></ul><ul><li>breast cancer cells </li></ul><ul><li>adipose tissue – mesenchymal cells </li></ul><ul><li>bone, liver, and muscle </li></ul>
    74. 83. Breast Cancer – Invasive Adjuvant Therapy <ul><li>Adjuvant Hormonal Options – Aromatase Inhibitors </li></ul><ul><li>- mechanism of action makes them only of value in patients that are postmenopausal </li></ul><ul><li>- nonsteroidal (inhibitor – reversible) </li></ul><ul><li>anastrozole = Arimidex (1mg/d) </li></ul><ul><li>letrozole = Femara (2.5 mg/d) </li></ul><ul><li>- steroidal (inactivator – irreversible) </li></ul><ul><li>exemestane = Aromasin (25mg/d) </li></ul><ul><li>- clinical results – metastatic disease </li></ul><ul><li>- more effective than tamoxifen (RR/RFS/OS) </li></ul><ul><li>- considered 1 st line hormoal rx in MBC </li></ul>
    75. 84. Aromatase Inhibitor (AIs) in the Adjuvant Setting <ul><li>Background – Hormonal Therapy </li></ul><ul><li>AIs as Initial Adjuvant Therapy </li></ul><ul><li>ATAC Trial </li></ul><ul><li>BIG 1-98 Trial </li></ul><ul><li>Switching to AIs from Tamoxifen (2-3 yrs) </li></ul><ul><li>IES Trial </li></ul><ul><li>Meta Analysis (ARNO/ABCSG-8/ITA) </li></ul><ul><li>AIs after Tamoxifen </li></ul><ul><li>Updated MA-17 data </li></ul><ul><li>Open Trials and Conclusions </li></ul>
    76. 85. ATAC Trial: Probability of Recurrence in Receptor-Positive Population *Censoring non-BC deaths before recurrence No. of patients at risk AN TAM 2617 2598 2533 2516 2436 2386 2243 2180 1258 1210 602 574 Patients with recurrence* (%) 0 6 12 18 24 30 36 42 48 54 HR 95% CI p -value AN vs TAM 0.78 0.65-0.93 0.007 Time to event (months) Absolute difference 1.8% Absolute difference 2.6% Anastrozole (AN) Tamoxifen (TAM) Source: With permission from Buzdar A. Presentation. SABCS, 2002; Abstract 13 . 0 5 10 15 20
    77. 86. Significant Difference in Pre-defined Adverse Events * proportion with  10% gain in body weight from baseline to year 2 -10 -5 0 5 10 Difference between anastrozole and tamoxifen AEs (%) (-5.4%) (-1.8%) (-3.6%) (-8.6%) (-1.1%) (-1.4%) (-0.7%) Fractures of hip, spine, wrist Fractures MSK disorders (-0.4%) In favour of anastrozole Hot flushes Weight gain* Vag. bleeding (6.6%) (2.1%) (0.8%) Endo Ca ICVA VTE DVT Vag. discharge In favour of tamoxifen
    78. 87. Aromatase Inhibitor (AIs) in the Adjuvant Setting <ul><li>Background – Hormonal Therapy </li></ul><ul><li>AIs as Initial Adjuvant Therapy </li></ul><ul><li>ATAC Trial </li></ul><ul><li>BIG 1-98 Trial </li></ul><ul><li>Switching to AIs from Tamoxifen (2-3 yrs) </li></ul><ul><li>IES Trial </li></ul><ul><li>Meta Analysis (ARNO/ABCSG-8/ITA) </li></ul><ul><li>AIs after Tamoxifen </li></ul><ul><li>Updated MA-17 data </li></ul><ul><li>Open Trials and Conclusions </li></ul>
    79. 89. Aromatase Inhibitor (AIs) in the Adjuvant Setting <ul><li>Background – Hormonal Therapy </li></ul><ul><li>AIs as Initial Adjuvant Therapy </li></ul><ul><li>ATAC Trial </li></ul><ul><li>BIG 1-98 Trial </li></ul><ul><li>Switching to AIs from Tamoxifen (2-3 yrs) </li></ul><ul><li>IES Trial </li></ul><ul><li>Meta Analysis (ARNO/ABCSG-8/ITA) </li></ul><ul><li>AIs after Tamoxifen </li></ul><ul><li>Updated MA-17 data </li></ul><ul><li>Open Trials and Conclusions </li></ul>
    80. 90. Annual Risk of Recurrence by Hormone Receptor Status <ul><li>A large proportion of breast cancer recurrences occur >5 y postsurgery </li></ul><ul><li>The annual risk of late recurrence is higher in ER+ tumors </li></ul>Years 0 0.1 0.2 0.3 0 1 2 3 4 5 6 7 8 9 10 11 12 ER – (n=1305) ER+ (n=2257) Saphner et al. J Clin Oncol . 1996;14:2738. Recurrence hazard rate
    81. 91. Relapse-Free Survival Decreases Consistently Regardless of ER/PgR Status ER/PgR – (n=430) ER+ and/or PgR+ (n=778) P <0.001 20 15 10 5 1.0 0.9 0.8 0.7 0.6 0.5 0.4 Hortobagyi et al. Proc Am Soc Clin Oncol. 2004;23:23. Abstract 585. Courtesy of G. Hortobagyi. All Patients <ul><li>Late recurrences (>5 y) more frequent in ER+ and/or PgR+ tumors </li></ul>Years postdiagnosis Proportion disease-free
    82. 92. 7 Years Follow-Up of NSABP-B-14: 5 versus > 5 Years of Adjuvant Tamoxifen: Node-Negative, ER-Positive Disease-free survival Relapse-free survival Survival Years p = 0.03 p = 0.13 p = 0.07 100 90 80 70 60 50 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7 No. No. of of pts events 5 y 569 106 >5 y 583 137 No. of events 34 47 No. of deaths 39 57 Source: Fisher B et al. Five versus more than five years of Tamoxifen… J Natl Cancer Inst 2001;93:684-90, by permission of Oxford University Press. Abstract Percent Placebo Tamoxifen
    83. 93. Letrozole versus Placebo in Women Completing at Least 5 Years of Adjuvant Tamoxifen Source: Goss P et al. N Engl J Med 2003;349(19):1793-802. Abstract Protocol ID: CAN-NCIC-MA17 Accrual: 5,187 (Closed) Eligibility Postmenopausal ER- and/or PR-positive or unknown Previously treated with adjuvant tamoxifen for 4.5 to 6 years Letrozole x 5 y Placebo x 5 y R
    84. 94. MA.17 Results: Disease-Free Survival by Treatment Duration (cont’d) Goss et al. N Engl J Med . 2003;349:TBD. 87% 93% <ul><li>Increasing benefit in estimated DFS with treatment duration </li></ul>
    85. 95. Hormonal Therapy - Conclusions <ul><li>Aromatase Inhibitors </li></ul><ul><li>Post Menopausal Women ER and/or PR + </li></ul><ul><li>Drug of Choice – 1 st Line Metastatic Breast Cancer </li></ul><ul><li>Initial Consideration in the Adjuvant Setting </li></ul><ul><li>Anastrozole (Arimidex) or Letrozole (Femara) </li></ul><ul><li>Considered for any pt. presently receiving Tamoxifen </li></ul><ul><li>Exemestane (Aromasin) or Anastrozole (Arimidex) </li></ul><ul><li>Considered for any pt completing 5 yrs of Tamoxifen* </li></ul><ul><li>Letrozole (Femara) or Exemestane (Aromasin) </li></ul>* Within 1-5 years from the completion of Tamoxifen
    86. 96. Breast Cancer – Invasive Adjuvant Therapy <ul><li>Adjuvant Hormonal Options – Aromatase Inhibitors </li></ul><ul><li>- Optimal Treatment duration – unclear </li></ul><ul><li>- Possibly better for prevention ~ 75% v 49% (tam) </li></ul><ul><li>- Side effects more favorable than Tam </li></ul><ul><li>no increased endometrial cancer </li></ul><ul><li>no increased vascular events </li></ul><ul><li>fewer hot flashes (5%) </li></ul><ul><li>less vaginal bleeding/ discharge (10%) </li></ul><ul><li>- Side effects less favorable than Tam </li></ul><ul><li>greater osteopenia/porosis and fxstures (1-3%) </li></ul><ul><li>greater musculoskeletal disorders - arthralgias </li></ul>
    87. 97. Breast Cancer – Invasive Prognostic and Predictive Gene Assays
    88. 98. Oncotype DX 21 Gene Recurrence Score (RS) Assay RS = + 0.47 x HER2 Group Score - 0.34 x ER Group Score + 1.04 x Proliferation Group Score + 0.10 x Invasion Group Score + 0.05 x CD68 - 0.08 x GSTM1 - 0.07 x BAG1 PROLIFERATION Ki-67 STK15 Survivin Cyclin B1 MYBL2 ESTROGEN ER PR Bcl2 SCUBE2 INVASION Stromolysin 3 Cathepsin L2 HER2 GRB7 HER2 BAG1 GSTM1 REFERENCE Beta-actin GAPDH RPLPO GUS TFRC CD68 16 Cancer and 5 Reference Genes From 3 Studies Paik S, et al. NEJM 2004 RS ≥ 31 High risk RS ≥ 18 and < 31 Intermediate risk RS < 18 Low risk RS (0 – 100) Category
    89. 99. <ul><li>668 NSABP B-14 tamoxifen treated patients </li></ul><ul><li>Performance exceeded standard measures of patient age and tumor size </li></ul>NSABP B-14 Clinical Validation Study of Oncotype DX Habel et al (SABCS 2004) in Kaiser Permanente Study reinforces the NSABP findings in a community-based patient population Paik S, et al. NEJM 2004 338 pts 149 pts 181 pts
    90. 100. Onco type DX ™ Clinical Validation: B-14 Results – DRFS (cont) Risk Group % of 10-yr Rate of 95% CI Patients Recurrence Low (RS <18) 51% 6.8% 4.0%, 9.6% Intermediate (RS 18-30) 22% 14.3% 8.3%, 20.3% High (RS ≥ 31) 27% 30.5% 23.6%, 37.4% Test for the 10-year DRFS comparison between the low-and high-risk groups: p <0.00001
    91. 101. All Patients (N = 645) B-14 Overall Benefit of Tamoxifen 0 2 4 6 8 14 16 Years 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 DRFS Placebo Tamoxifen 12 10
    92. 102. B-14 Benefit of Tamoxifen By Recurrence Score Risk Category Low Risk (RS<18) N 171 142 Int Risk (RS 18-30) N 85 69 High Risk (RS ≥ 31) N 99 79 Interaction p=0.06 0 2 4 6 8 14 16 Years 0.0 0.2 0.4 0.6 0.8 1.0 DRFS Placebo Tamoxifen 12 10 0 2 4 6 8 14 16 Years 0.0 0.2 0.4 0.6 0.8 1.0 DRFS Placebo Tamoxifen 12 10 0 2 4 6 8 14 16 Years 0.0 0.2 0.4 0.6 0.8 1.0 DRFS Placebo Tamoxifen 12 10
    93. 103. Chemotherapy Benefit and Onco type DX <ul><li>Design </li></ul><ul><li>Objective: Determine the magnitude of the chemotherapy benefit as a function of 21- gene Recurrence Score assay </li></ul>Randomized Tam + MF Tam + CMF Tam NSABP B-20 Chemo Benefit Study in N – , ER+ Pts
    94. 104. B-20 Results 0 2 4 6 8 10 12 Years 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 All Patients Tam + Chemo Tam p = 0.02 N Events 424 33 227 31 DRFS Tam vs Tam + Chemo – All 651 Pts
    95. 105. B-20 Results <ul><li>Tam vs Tam + Chemo – Low Risk (RS < 18) </li></ul>p = 0.76 N Events 218 11 135 5 10 yr 96 % 95% Paik, et al. PSABCS, 2004
    96. 106. B-20 Results <ul><li>Tam vs Tam + Chemo – Int Risk (RS 18–30) </li></ul>10 yr 89% 90% Paik, et al. PSABCS, 2004 p = 0.71 N Events 89 9 45 8
    97. 107. B-20 Results <ul><li>Tam vs Tam + Chemo – High Risk (RS ≥ 31) </li></ul>60% 88% 10yr Paik, et al. PSABCS, 2004 p = 0.001 N Events 117 13 47 18
    98. 108. Low RS<18 Int RS18-30 High RS ≥31 0 10% 20% 30% 40% B-20: Absolute % Increase in DRFS at 10 Years n = 353 n = 134 n = 164 % Increase in DRFS at 10 Yrs (mean ± SE)
    99. 109. 0 10 20 30 40 50 Recurrence Score 0.0 0.1 0.2 0.3 0.4 Distant Recurrence at 10 Years Recurrence Score Oncotype Dx 21 Gene Recurrence Score Assay: Predictive in NSABP B-20 and Informs TAILORx Benefit from CMF TAILORx Intergroup Trial Chemoendo vs endo Minimal, if any, Chemo Benefit Clear Chemo Benefit Sparano, TBCI San Antonio, 2005; Paik JCO 2006 Tam Tam + Chemo
    100. 110. Overall Conclusions: Onco type DX TM <ul><li>Data reflects evaluation in postmenopausal, node negative, hormone receptor positive patients. There is no data to date on other subsets, (premenopausal, node positive, etc) </li></ul><ul><li>Prognostic </li></ul><ul><li>Predicts tamoxifen benefit </li></ul><ul><li>Predicts chemotherapy (CMF) benefit </li></ul><ul><ul><li>Low RS associated with minimal chemotherapy benefit </li></ul></ul><ul><ul><li>High RS associated with large chemotherapy benefit </li></ul></ul>
    101. 111. Breast Cancer – Invasive The Role of Targeted Therapy -Herceptin
    102. 112. Joint Analysis of HER2+ Adjuvant Trials 2 Arms of Intergroup N9831 + NSABP-31 Control Group (n=1,979) : AC  T N9831 Group A B-31 Group 1 Trastuzumab Group (n= 1,989 ) : AC  T+H N9831 Group C B-31 Group 2 = AC (doxorubicin/cyclophosphamide 60/600 mg/m 2 q3w × 4) = T (paclitaxel 80 mg/m 2 /wk × 12) = T (paclitaxel 175 mg/m 2 q3w × 4 or 80 mg/m 2 /wk × 12) = H (trastuzumab 4 mg/kg loading dose + 2 mg/kg/wk × 51) AC T H AC T AC T H AC T
    103. 113. Joint Analysis Disease-Free Survival 87% 85% 67% 75% N Events AC  T 1679 261 AC  TH 1672 134 % HR=0.48, 2P=3x10 -12 AC  TH AC  T Years From Randomization B31/N9831 ASCO 2005
    104. 114. Cardiac Toxicity Summary in 3 Adjuvant Trastuzumab Studies ASCO 2005 Special Session Percent Congestive Heart Failure 0.5 0 HERA 2.2-3.3 0 N9831 4.1 0.7 B-31 Trastuzumab arm Control Study
    105. 115. B-31: Post-AC LVEF and Age Are Independent Predictors of Trastuzumab-Associated CHF LVEF (%) Age P(Age)=0.04 P(LVEF)<0.0001 1.3% 0.6% 65+ 5.2% 2.2% 55-64 19.1% 6.3% 50-54  50 <50
    106. 116. Breast Cancer Adjuvant Herceptin <ul><li>Points to remember: </li></ul><ul><li>1). Trials included patients with normal LVEF, excluded pts with cardiomyopathy, CHF, prior MI, and arrhythmias </li></ul><ul><li>2). No data on q 2week taxanes with GF support – </li></ul><ul><li>3). 7% of patients didn’t start Herceptin </li></ul><ul><li> 30% required at least one dose delay </li></ul><ul><li> 19% discontinued herceptin prior to one year </li></ul><ul><li>(14.3% asymptomatic decrease, 4.3% symptomatic) </li></ul><ul><li>4). No difference among subsets – age, # nodes, size, ER status </li></ul><ul><li>5). Only ~ 10% of patients were node negative (not significant) </li></ul>
    107. 117. Breast Cancer - Invasive <ul><li>Stages I – IIB + IIIA (T3 > 5 cm, N1 only) </li></ul><ul><li>Work-Up – H and P </li></ul><ul><li> CBC/SMA </li></ul><ul><li> Chest X-Ray </li></ul><ul><li> Bilateral mammograms/US </li></ul><ul><li> Path Review </li></ul><ul><li>Histology Size </li></ul><ul><li>Margins Histology </li></ul><ul><li>Node Status Her 2 neu </li></ul><ul><li>ER/PR </li></ul>
    108. 118. Breast Cancer - Invasive <ul><li>Stages I – IIB + IIIA (T3 > 5 cm, N1 only) </li></ul><ul><li>Work-Up – Optional </li></ul><ul><li>Bone Scan </li></ul><ul><li>Abdominal imaging </li></ul><ul><li>Breast MRI </li></ul><ul><li> - If ChemoRx – Adria candidates </li></ul><ul><li>MUGA or ECHO </li></ul><ul><li>Port Placement </li></ul>Recommended if: 1) Abnormal labs 2) Symptoms 3) High Risk T3 or N1
    109. 119. Breast Cancer – Invasive Adjuvant Therapy <ul><li>Radiation Therapy </li></ul><ul><li>Post lumpectomy </li></ul><ul><li>- indicated in all </li></ul><ul><li>Post mastectomy – recmded (chest wall + supraclav) </li></ul><ul><li>- > 5 cm (T3) tumors </li></ul><ul><li>- > 3 + lymph nodes </li></ul><ul><li>- + surgical margins (close < 1mm) </li></ul><ul><li>Post mastectomy – consider and controversial </li></ul><ul><li>- 1-3 + nodes </li></ul><ul><li>- benefit may require rx of IM nodes (controversial – IM nodes in non-US trials demonstrating benefit) </li></ul>
    110. 120. Breast Cancer – Invasive Pre-operative Rx - Neoadjuvant
    111. 121. ASCO - Breast Cancer Surveillance Guidelines <ul><li>Postoperative, Post adjuvant chemotherapy </li></ul><ul><li>Evidence based </li></ul><ul><li>Recommended Frequency </li></ul><ul><li>History and Physical every 3- 6 mos x 3yrs </li></ul><ul><li>every 6-12 mos x 2yrs </li></ul><ul><li>Breast Self-exam monthly </li></ul><ul><li>Mammography yearly </li></ul><ul><li>Pelvic exam* yearly </li></ul><ul><li>Patient Symptom Education </li></ul><ul><li>with appropriate eval of any new sxs </li></ul>* If on tamoxifen with an intact uterus
    112. 122. ASCO - Breast Cancer Surveillance Guidelines <ul><li>Postoperative, Post adjuvant chemotherapy </li></ul><ul><li>Evidence based </li></ul><ul><li>Not Recommended </li></ul><ul><li>Complete Blood Count (CBC) </li></ul><ul><li>Automated Chemistry (SMA) </li></ul><ul><li>Routine Chest x-ray </li></ul><ul><li>Bone Scan </li></ul><ul><li>Liver imaging (US or CT) </li></ul><ul><li>Tumor markers (CA 15-3, CA 27.29, CEA) </li></ul><ul><li>Endometrial bx or US if no sxs on Tamoxifen </li></ul>
    113. 123. Systemic Recurrence – Stage IV Metastatic Breast Cancer (MBC) <ul><li>Principles of Management </li></ul><ul><li>1) Tissue confirmation is important </li></ul><ul><li>ER, her-2 (esp if unavailable from original) </li></ul><ul><li>2) Complete re-staging is appropriate </li></ul><ul><li>3) Therapy is palliative </li></ul><ul><li>4) Therapy requires re-evaluation every 3-6 mos. </li></ul><ul><li>5) Treatment should be individualized based on: </li></ul><ul><li>- local regional urgencies </li></ul><ul><li>- hormonal sensitivity </li></ul><ul><li>- candidacy for chemotherapy </li></ul><ul><li>- candidacy for herceptin </li></ul>
    114. 124. Systemic Recurrence – Stage IV Metastatic Breast Cancer (MBC) <ul><li>Local Regional Urgencies </li></ul><ul><li>- may require regional RT or surgery or interventional proceedures prior to or along with systemic rx </li></ul><ul><li>1) Brain mets 8) Obtructions of: </li></ul><ul><li>2) Cord compression - biliary tree </li></ul><ul><li>3) Choroid disease - ureteral / trachea </li></ul><ul><li>4) Pleural effusion - bowel / esophageal </li></ul><ul><li>5) Pericardial effusion 9) Localized disease </li></ul><ul><li>6) Pathologic fracture - intractable pain </li></ul><ul><li>7) Impending fracture - skin integrity / ulcer </li></ul><ul><li> </li></ul>
    115. 125. Systemic Recurrence – Stage IV Metastatic Breast Cancer (MBC) <ul><li> </li></ul>Tissue confirmation - restaging Local regional urgencies Systemic therapies Hormonal therapy Chemotherapy 1 st line 2 nd line 3 rd line 4 th line 1 st line 2 nd line H + Taxane + H + Navelbeine ER + ER - Her - Her + At PD
    116. 126. Systemic Recurrence – Stage IV Metastatic Breast Cancer (MBC) <ul><li> </li></ul>Tissue confirmation - restaging Local regional urgencies Systemic therapies Hormonal therapy Chemotherapy 1 st line 2 nd line 3 rd line 4 th line 1 st line 2 nd line H + Taxane + H + Navelbeine ER + ER - Her - Her + At PD
    117. 127. Systemic Recurrence – Stage IV Metastatic Breast Cancer (MBC) <ul><li>Hormonal Therapy </li></ul><ul><li>- palliation is the goal along with minimal toxicity </li></ul><ul><li>- whenever possible hormonal better than chemo </li></ul><ul><li>Candidates </li></ul><ul><li>- those pts with ER and/or PR positive disease </li></ul><ul><li>- with bone, soft tissue, or lung disease </li></ul><ul><li>- asymptomatic visceral disease </li></ul><ul><li>- selected ER/PR negative </li></ul><ul><li>- findings above with long disease free interval (5-10 yrs) </li></ul>
    118. 128. Systemic Recurrence – Stage IV Metastatic Breast Cancer (MBC) <ul><li>Hormonal Therapy </li></ul><ul><li>Benefit </li></ul><ul><li>- 50-80% (Responses + SD) </li></ul><ul><li>- response duration 6-12 months (some 2-10+ years </li></ul><ul><li>- > benefit associated with > ER/PR positivity </li></ul><ul><li>- 10% of ER/PR neg pts respond to hormones </li></ul><ul><li>Treatment Change </li></ul><ul><li>- only for disease progression (sypmtomatic ?) </li></ul><ul><li>- serial hormonal rx if response or prolonged SD to prior hormonal rx </li></ul><ul><li>- subsequent hormonal benefit likely shorter </li></ul>
    119. 129. Systemic Recurrence – Stage IV Metastatic Breast Cancer (MBC) <ul><li>Hormonal Therapy </li></ul><ul><li>Post Menopausal </li></ul><ul><li>- AIs superior to Tamoxifen </li></ul><ul><li>- Prior Tamoxifen  AI (Letrozole, Anastrozole) </li></ul><ul><li> AI steroidal inhibitor (Exemestane) </li></ul><ul><li> Fulvesterant (Faslodex) </li></ul><ul><li> Tamoxifen (if not previously used) </li></ul><ul><li> Megesterol Acetate (Megace) </li></ul><ul><li> Fluoxymesterone (Halotestin) </li></ul><ul><li> Ethinylestradiol </li></ul>
    120. 130. Systemic Recurrence – Stage IV Metastatic Breast Cancer (MBC) <ul><li>Hormonal Therapy </li></ul><ul><li>Pre Menopausal </li></ul><ul><li> Tamoxifen </li></ul><ul><li> LHRH agonist or oophorectomy </li></ul><ul><li>+/- Tamoxifen or AI ? (as in post menopausal) </li></ul><ul><li> Megesterol Acetate (Megace) </li></ul><ul><li> Fluoxymesterone (Halotestin) </li></ul><ul><li> Ethinylestradiol </li></ul>
    121. 131. Systemic Recurrence – Stage IV Metastatic Breast Cancer (MBC) <ul><li> </li></ul>Tissue confirmation - restaging Local regional urgencies Systemic therapies Hormonal therapy Chemotherapy 1 st line 2 nd line 3 rd line 4 th line 1 st line 2 nd line H + Taxane + H + Navelbeine ER + ER - Her - Her + At PD
    122. 132. Systemic Recurrence – Stage IV Metastatic Breast Cancer (MBC) <ul><li>Chemotherapy </li></ul><ul><li>Her 2 neu + disease (20-30% of patients) </li></ul><ul><li> - associated with increased risk of CNS metastasis </li></ul><ul><li> - Herceptin therapy considered standard and 1 st line </li></ul><ul><li>- associated with survival advantage </li></ul><ul><li>- Hercetin alone ~ 20-25% response rate </li></ul><ul><li>- combined with chemo = survival advantage </li></ul><ul><li>- benefit of continuing once progression occurs ??? </li></ul><ul><li>- RR of H+CRx ~ 50-80% - some prolonged </li></ul><ul><li> </li></ul>
    123. 133. Systemic Recurrence – Stage IV Metastatic Breast Cancer (MBC) <ul><li>Chemotherapy </li></ul><ul><li>Her 2 neu + disease </li></ul>“ synergy” Taxanes Navelebine Cisplatin Carboplatin “ non-synergistic” Xeloda Gemcitabine “ avoid” anthracyclines “ Standard” - Hercetin + Taxane alone or Taxane + Carboplatin
    124. 134. Systemic Recurrence – Stage IV Metastatic Breast Cancer (MBC) <ul><li>Chemotherapy </li></ul><ul><li>Her- 2 neu neg (70-80% of patients) </li></ul><ul><li>- treatment is palliative </li></ul><ul><li>- use the least toxic therapy whenever possible </li></ul><ul><li>- weekly taxanes better than q 3 week </li></ul><ul><li>- some evidence to support doublet over single agent therapy (TxX and TG) </li></ul><ul><li>- response should be assessed every 2-4 months </li></ul><ul><li>- active drugs include: anthracyclines, taxanes, platinum compds, 5-FU (xeloda), methotrexate, gemcitabine, navelbeine </li></ul><ul><li>- RR ~ 50-80% of 6-12 mos., some longer </li></ul>
    125. 135. ECOG 2100 Phase III Trial Progression-Free Survival HR = 0.51 (0.43-0.62) Log Rank Test P < 0.0001 Pac. + Bev. 11.4 mos Paclitaxel 6.11 mos 484 events reported Miller et al. Breast Cancer Res Treat. 2005;94(Suppl 1):S6. Abstract 3. 0.0 0.2 0.4 0.6 0.8 1.0 Months PFS Probability 0 6 12 18 24 30
    126. 136. Systemic Recurrence – Stage IV Metastatic Breast Cancer (MBC) <ul><li>Is There a Role for the Surgical Resection of a Primary Breast Cancer in the Presence of Metastatic Disease ? </li></ul>
    127. 137. Breast Surgery for Women Presenting with Stage IV Breast Cancer <ul><li>Goals: Compared survival between women who received therapeutic surgery (S) to the breast versus those who did not receive surgical therapy (NS) </li></ul><ul><li>Design: Retrospective </li></ul><ul><li>170 patients with Stage IV breast cancer 1998-2005 </li></ul><ul><li>44% underwent therapeutic resection </li></ul>Barkley CR et al SABCS 2007 poster #5085
    128. 138. Breast Surgery for Women Presenting with Stage IV Breast Cancer <ul><li>Overall unadjusted median survival </li></ul><ul><ul><li>Therapeutic resection 4.05 years </li></ul></ul><ul><ul><li>No therapeutic resection 2.36 years (p=0.02) </li></ul></ul><ul><li>Overall survival with adjustments (age, number of sites of metastasis, chemotherapy, endocrine therapy, trastuzumab, ER status) </li></ul><ul><ul><li>Therapeutic resection 5.34 years </li></ul></ul><ul><ul><li>No therapeutic resection 2.36 years (p=0.0004) </li></ul></ul>
    129. 139. Breast Surgery for Women Presenting with Stage IV Breast Cancer <ul><li>Conclusions : </li></ul><ul><ul><li>Therapeutic surgery significantly improves survival in patients with Stage IV breast cancer </li></ul></ul><ul><ul><li>Optimal timing to integrate surgery remains unclear </li></ul></ul><ul><ul><li>Prospective trial is warranted to confirm these results </li></ul></ul>
    130. 140. Optimal loco-regional treatment of the primary tumor in metastatic breast cancer patients is associated with a significant survival advantage <ul><li>SEER 9-Registries Database </li></ul><ul><li>Determine overall survival (OS) and the breast cancer specific survival (BCSS) </li></ul><ul><li>8761 women, </li></ul><ul><ul><li>3905 no surgery, median BCSS 17 mo </li></ul></ul><ul><ul><li>2070 lumpectomy, median BCSS 28 mo </li></ul></ul><ul><ul><li>2786 mastectomy, median BCSS 31 mo </li></ul></ul><ul><li>46.6% BCS patients received XRT </li></ul><ul><ul><li>BCSS 24 mo without XRT vs 31mo with XRT (p <0.0001) </li></ul></ul><ul><li>39.6% mastectomy patients received XRT </li></ul><ul><ul><li>32 without XRT vs 31 months with XRT (p= 0.330) </li></ul></ul>Vlastos G et al SABCS 2007 Poster # 5077
    131. 141. Optimal loco-regional treatment of the primary tumor in metastatic breast cancer patients is associated with a significant survival advantage <ul><li>Conclusions: confirms previous results on benefit of complete surgical treatment of primary tumor in metastatic breast cancer patients. </li></ul><ul><li>Strongly suggests that adjuvant local radiation therapy improve patients survival. </li></ul>Vlastos G et al SABCS 2007 Poster # 5077
    132. 142. Breast Cancer Prevention Trial Results: P1 and STAR
    133. 143. BCPT Design: Schema Fisher et al. J Natl Cancer Inst 1998;90:1371-1388. Eligible Women at High Risk (5-yr risk  1.66%) Randomization n = 13,388 Tamoxifen 5 Years n = 6681 Placebo 5 Years n = 6707
    134. 144. BCPT Results: Overview <ul><li>Median follow-up 54.6 months (25% of women received 5 years of therapy) </li></ul><ul><li>Tamoxifen group </li></ul><ul><ul><li>49% reduction in invasive breast cancer </li></ul></ul><ul><ul><li>50% reduction in noninvasive breast cancer* </li></ul></ul><ul><ul><li>45% reduction in incidence of hip fractures </li></ul></ul><ul><ul><li>No effect on ischemic heart disease </li></ul></ul><ul><ul><li>Increased number of vascular events and endometrial cancer in women over 50 </li></ul></ul>*Analysis included women who had LCIS at baseline. Fisher et al. J Natl Cancer Inst 1998;90:1371-1388.
    135. 145. BCPT Results: Cumulative Rate of Invasive Breast Cancer Placebo Tamoxifen 0 1 2 3 5 4 Placebo 175 43.4 Tamoxifen 89 22.0 Events Rate per 1000 Rate/1000 P < 0.00001 0 1 0 2 0 3 0 4 0 Years Fisher et al. J Natl Cancer Inst 1998;90:1371-1388.
    136. 146. BCPT Results: Invasive Breast Cancer Cases in All Age Groups 0 2 0 4 0 6 0 8 0 1 0 0 1 2 0 1 4 0 1 6 0 1 8 0 T o t a l 3 5 - 4 9 5 0 - 5 9 6 0 + P l a c e b o Fisher et al. J Natl Cancer Inst 1998;90:1371-1388. Age Group Number of Invasive Breast Cancers 175 89 68 38 50 25 57 26 Tamoxifen
    137. 147. BCPT Results: Cumulative Rate of Noninvasive Breast Cancer* Placebo Tamoxifen 0 1 2 3 5 4 Placebo 69 15.9 Tamoxifen 35 7.7 Events Rate per 1000 Rate/1000 0 1 0 2 0 3 0 4 0 *Analysis included women who had LCIS at baseline. Fisher et al. J Natl Cancer Inst 1998;90:1371-1388. Years
    138. 148. Endometrial Cancer Perspective <ul><li>Breast and endometrial cancer share common risk factors </li></ul><ul><li>Annual endometrial cancer rate in BCPT* </li></ul><ul><ul><li>Placebo group: 0.9 per 1000 </li></ul></ul><ul><ul><li>Tamoxifen group: 2.3 per 1000 </li></ul></ul><ul><li>Early stage endometrial cancer is highly curable (>96% survival) </li></ul><ul><li>Consequences of endometrial cancer are not equivalent to consequences of breast cancer </li></ul>*Fisher et al. J Natl Cancer Inst 1998;90:1371-1388.
    139. 149. BCPT Results: Vascular Events PE TIA DVT CVA 25 19 0 1 0 2 0 3 0 4 0 PE = pulmonary embolism; DVT = deep vein thrombosis; CVA = cerebral vascular accident (stroke); TIA = transient ischemic attack P l a c e b o Number of Events 18 22 35 38 24 6 Fisher et al. J Natl Cancer Inst 1998;90:1371-1388. Tamoxifen
    140. 150. <ul><li>Risk-Eligible </li></ul><ul><li>Post-Menopausal Women </li></ul>NSABP STAR Schema RALOXIFENE 60 mg/day x 5 years <ul><li>STRATIFICATION </li></ul><ul><li>Age </li></ul><ul><li>Relative Risk </li></ul><ul><li>Race </li></ul><ul><li>History of LCIS </li></ul>TAMOXIFEN 20 mg/day x 5 years <ul><li>Age 35 + </li></ul><ul><li>No history of: </li></ul><ul><ul><li>cancer </li></ul></ul><ul><ul><li>A-fib </li></ul></ul><ul><ul><li>Clotting </li></ul></ul><ul><ul><li>DM & HTN </li></ul></ul>
    141. 151. STAR Average Annual Rate & Number of Invasive Breast Cancers 163 168 * # of events 312* 0 2 4 6 8 10 Gail Model Projection TAM Raloxifene Av Ann Rate per 1000
    142. 152. STAR: Cumulative Incidence of IBC Cumulative Incidence (per 1000) Time Since Randomization (months) At Risk by Year # of Rate/1000 Treatment 0 3 6 Events at 6 yrs. P-value Tamoxifen 9726 6653 809 163 25.1 0.83 Raloxifene 9745 6703 833 168 24.8 0 5 10 15 20 25 30 35 40 0 6 12 18 24 30 36 42 48 54 60 66 72
    143. 153. STAR: Average Annual Rate and # of Uterine Cancers 36* 23 * # of events RR = 0.62, 95% CI: 0.35 to 1.08 0 1 2 3 TAM Raloxifene Av Ann Rate per 1000
    144. 154. STAR: Endometrial Hyperplasia # Hysterectomies 244 111 13 72 w/o Atypia 1 12 with Atypia 14 84 Hyperplasia RAL TAM
    145. 155. STAR: Average Annual Rates of Cataracts 394* 313 RR = 0.79; 95% CI(0.68 – 0.92) * # of events 0 2 4 6 8 10 12 14 TAM Raloxifene Av ann rate per 1000
    146. 156. STAR: # of Osteoporotic Fractures 0.46-1.53 0.85 23 27 Radius 0.65-1.46 0.98 52 53 Spine 0.48-1.60 0.88 23 26 Hip RR 95% Confidence Interval Risk Ratio (RR) Raloxifene # Tamoxifen # Type of event
    147. 157. STAR: Thromboembolic Events Cumulative Incidence (per 1000) Time Since Randomization (months) At Risk by Year # of Rate/1000 Treatment 0 3 6 Events at 6 yrs. RR Tamoxifen 9726 6682 814 141 21.0 0.70 Raloxifene 9745 6764 836 100 16.0 P-value= 0.01 0 5 10 15 20 25 30 35 40 0 6 12 18 24 30 36 42 48 54 60 66 72
    148. 158. STAR: A verage Annual Rate and # of In Situ (DCIS & LCIS) Cancers 57* 80 * # of events RR = 1.40 95% CI: 0.98 to 2.00 0 1 2 3 TAM Raloxifene Av Ann Rate per 1000
    149. 159. STAR: Summary <ul><li>R is as effective as T in the prevention of primary IBC. </li></ul><ul><li>R is less effective than T in the prevention of LCIS & DCIS – (not statistically different). </li></ul><ul><li>Compared to T, R use results in: </li></ul><ul><ul><li>Fewer thromboembolic events </li></ul></ul><ul><ul><li>Fewer endometrial cancers and </li></ul></ul><ul><ul><li>Fewer cataracts </li></ul></ul>

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