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HERA

Trastuzumab after Adjuvant Chemotherapy in HER2-Positive Breast Cancer. HERA. Breast Cancer Review. In situ breast cancer breast cancer in which the cells have remained within their place of origin — they haven't spread to breast tissue around the duct or lobule.

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HERA

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  1. Trastuzumab after Adjuvant Chemotherapy in HER2-Positive Breast Cancer HERA

  2. Breast Cancer Review • In situ breast cancer • breast cancer in which the cells have remained within their place of origin — they haven't spread to breast tissue around the duct or lobule. • most common type of noninvasive breast cancer is ductal carcinoma in situ (DCIS), which is confined to the lining of the milk ducts, with appropriate treatment- DCIS has an excellent prognosis. • Invasive breast cancer • Invasive (infiltrating) breast cancers spread outside the membrane that lines a duct or lobule, invading the surrounding tissues • Invasive ductal carcinoma (IDC) • IDC accounts for about 70 percent of all breast cancers • the cancer cells break through the ductal wall invading nearby breast tissue and may have lymphatic or hematogenous metastases • Invasive lobular carcinoma (ILC) • starting in the milk-producing lobules and then breaking into the surrounding breast tissue • Unusual types of breast cancer include: • inflammatory breast cancer, phyllodes tumor, angiosarcoma, osteosarcoma, metaplastic breast cancer, adenoid cystic carcinoma and Paget's disease of the breast. There are also rare subtypes of invasive ductal carcinoma — tubular, mucinous, medullary and papillary.

  3. Cellular Classification • Carcinoma, NOS (not otherwise specified). • Ductal • Intraductal (in situ) • Invasive with predominant intraductal component • Invasive, NOS • Comedo • Inflammatory • Medullary with lymphocytic infiltrate • Mucinous (colloid) • Papillary • Scirrhous • Tubular • Other • Lobular • In situ • Invasive with predominant in situ component • Invasive • Nipple • Paget disease, NOS • Paget disease with intraductal carcinoma • Paget disease with invasive ductal carcinoma • Other. Undifferentiated carcinoma

  4. Histologic Grading • Breast cancers are graded on a 1 to 3 scale for 3 variables: • Acinar/tubule formation is assessed over the whole tumor • Nuclear evaluation is of the worst area • Mitotic count is also in the most mitotic area • Scores are combined to create a low (3-5), intermediate (6-7), and high grade (8-9)

  5. Staging • Stage 0—Carcinoma in situ • atypical cells have not spread outside of the ducts or lobules, it is classified in two types: • DCIS— very early cancer that is highly treatable and survivable • Lobular Carcinoma In Situ (LCIS)—not a cancer but an indicator that identifies a woman as having an increased risk of developing breast cancer • Stage I- Early stage invasive breast cancer • the cancer is no larger than two centimeters and has not spread to surrounding lymph nodes or outside the breast. • Stage II- divided into two categories according to the size of the tumor and whether or not it has spread to the lymph nodes: • Stage II A Breast Cancer—the tumor is less than two centimeters and has spread up to three auxiliary underarm lymph nodes. Or, the tumor has grown bigger than two centimeters, but no larger than five centimeters and has not spread to surrounding lymph nodes. • Stage II B Breast Cancer— the tumor has grown to between two and five centimeters and has spread to up to three auxiliary underarm lymph nodes. Or, the tumor is larger than five centimeters, but has not spread to the surrounding lymph nodes. • Stage III • Stage III A Breast Cancer—the tumor is larger than two centimeters but smaller than five centimeters and has spread to up to nine auxiliary underarm lymph nodes. • Stage III B Breast Cancer— the cancer has spread to tissues near the breast including the skin, chest wall, ribs, muscles, or lymph nodes in the chest wall or above the collarbone. • Stage IV- spread to other organs or tissues: liver, lungs, brain, skeletal system, or lymph nodes near the collarbone

  6. Molecular Classification • Hormone receptor status • estrogen receptor positive (ER positive) or progesterone receptor positive (PR positive) • hormone receptor positive cancers typically grow more slowly than do HR negative cancers • hormone-blocking medications, such as tamoxifen, slow the cancer's growth • HER-2 status • drives production of the growth-promoting HER-2 protein • 20-30% of breast cancers are HER-2 positive • tend to grow and spread more aggressively than do other breast cancers • Two tests can detect HER-2 in cancer cells: • Immunohistochemistry. Special antibodies that attach to HER-2 protein are applied to the tissue sample, and cells change color if too many HER-2 protein receptors are present. • Fluorescent in situ hybridization (FISH). Fluorescent pieces of DNA find extra copies of the HER-2 gene. Chromogenic in situ hybridization (CISH) is a similar technique. • Treated with drugs that specifically target the HER-2 protein such as trastuzumab (Herceptin- humanized monoclonal antibody) and lapatinib (Tykerb- HER-2 specific protein kinase inhibitor)

  7. Molecular Classification • Luminal A and luminal B- estrogen receptor (ER)-positive, usually low grade, and tend to grow fairly slowly. • The gene expression patterns of these cancers are similar to normal cells that line the breast ducts and glands • Luminal A cancers have the best prognosis. Luminal B cancers generally grow somewhat faster than the luminal A cancers and their prognosis is not as good. • HER-2- positve cancers have extra amounts of HER-2 protein (overexpression) and/or extra copies of the gene (amplification) and carry a poor prognosis • Basal- normal amounts of HER-2 and lack estrogen and progesterone receptors (triple negative), poor prognosis

  8. Basic Prognostic Factors • The age and menopausal status of the patient. • The stage of the disease • The histologic and nuclear grade of the primary tumor • The ER and PR status of the tumor • HER2/neu gene amplification or epidermal growth factor receptor • The measures of proliferative capacity of the tumor: mitotic index, thymidine labelling index, S-phase fraction, Ki-67 staining • Measures of invasiveness: cathepsin D, plasminogen activators and inhibitors, laminin receptors • Angiogenesis

  9. Trastuzumab after Adjuvant Chemotherapy in HER2-Positive Breast Cancer Martine J. Piccart-Gebhart, M.D., Ph.D., Marion Procter, M.Sci., Brian Leyland-Jones, M.D., Ph.D., AronGoldhirsch, M.D., Michael Untch, M.D., Ian Smith, M.D., Luca Gianni, M.D., Jose Baselga, M.D., Richard Bell, M.D., Christian Jackisch, M.D., David Cameron, M.D., Mitch Dowsett, Ph.D., Carlos H. Barrios, M.D., Günther Steger, M.D., Chiun-Shen Huang, M.D., Ph.D., M.P.H., Michael Andersson, M.D., Dr.Med.Sci., Moshe Inbar, M.D., Mikhail Lichinitser, M.D., IstvánLáng, M.D., Ulrike Nitz, M.D., Hiroji Iwata, M.D., ChristophThomssen, M.D., Caroline Lohrisch, M.D., Thomas M. Suter, M.D., Josef Rüschoff, M.D., TamásSütő, M.D., Ph.D., Victoria Greatorex, M.Sc., Carol Ward, M.Sc., Carolyn Straehle, Ph.D., Eleanor McFadden, M.A., M. Stella Dolci, and Richard D. Gelber, Ph.D. N Engl J Med Volume 353;16:1659-1672 October 20, 2005

  10. Design Overview • A three-arm multi-center comparison of womenwith HER-2 positive primarybreast cancer who have completed adjuvant chemotherapy and randomized to: • 1 yeartrastuzumab • 2 yearstrastuzumab • or no trastuzumab • Primaryendpoint: disease free survival • Recurrance of breast cancer, ipsilateral/contralateralbreast cancer, secondary non-breastmalignancy, deathfromany cause s/o documentation of a cancer relatedevent • SecondaryEndpoints: cardiacsafety, overallsurvival, site of 1st disease free survivalevent, time to recurrance

  11. Consolidated Standards of Reporting Trials (CONSORT) Chart of the Herceptin Adjuvant (HERA) Trial Piccart-Gebhart, M. et al. N Engl J Med 2005;353:1659-1672

  12. Design Overview Womenwith HER2 POSITIVE invasive breast cancer IHC3+ or FISH+ centrallyconfirmed Surgery + (neo)adjuvant chemotherapy (CT)  radiotherapy Stratification Nodal status, adjuvant CT regimen, hormone receptorstatus and endocrine therapy, age, region Randomization Trastuzumab 8 mg/kg  6 mg/kg 3 weekly x 2 years n= 1694 Trastuzumab 8 mg/kg  6 mg/kg 3 weekly x 1 year n= 1694 Observation N= 1693

  13. ACCRUAL: 5090 WOMEN 478 centersfrom39 countries (2002-2005) NORDIC COUNTRIES EASTERN EUROPE:  11% CANADA 71.5% EU JAPAN  12% ASIA PACIFIC CENTRAL & SOUTH AMERICA 5.5% AUSTRALIA – NEW ZEALAND SOUTH AFRICA

  14. Key Inclusion Criteria • Histologicallyconfirmed, completelyexcisedbreast cancer • Centrallyconfirmed HER-2 overexpression or amplification • Node-positive or (sentinel) node-negativewith T1c • Completed  4 cycles of approved (neo)adjuvant chemotherapyregimen • Baseline LVEF  55% (Echo or MUGA) • Known hormone receptorstatus

  15. Exclusion Criteria • Distant metastases • Previous invasive breast carcinoma • Neoplasm not involving the breast • T4 tumors or supraclavicular involvement • Suspicious internal mammary nodes • High dose XRT, chemotherapy, or stem cell support • Cardiac: CHF, CAD with Q-wave MI, angina, uncontrolled HTN, valvular disease, and unstable arryrthmias

  16. Design Caveats • Anyaccepted adjuvant chemotherapyregimen • Tamoxifenwas the primary adjuvant endocrine therapy, aromataseinhibitorswereallowed to beusedduring the trial • Trastuzumab not initiateduntilafter the completion of all chemo and radiation therapy • Trastuzumabadministered on a q3 weeklyschedule • Large proportion of nodenegative and Stage 2/3 patients

  17. LHRH ± TAM LHRH ± TAM 16% 17% TAMAI TAMAI 11% 8% TAM TAM 8% 9% AI 66% AI 64% Adjuvant Endocrine Therapy 1 yeartrastuzumab Observation

  18. Baseline characteristics of the Patients, Tumors, and Primary Treatments (Intention-to-Treat Groups) Piccart-Gebhart, M. et al. N Engl J Med 2005;353:1659-1672

  19. < 35 y 35- 49 y 50 - 59 y  60 y missing No anthracyclines, no taxane Anthracyclines missing Patient/Tumor Characteristics Age (%) Observation (n = 1693) 1 yeartrastuzumab (n = 1694) 7.3 7.6 43.7 44.3 32.7 31.8 16.2 16.2 0.2 0.2 Adjuvant chemotherapy (%) 6.1 6.2 68.3 67.9 25.5 26.0 0.1 0.2 Anthracyclines + taxanes

  20. Patient/Tumor Characteristics Menopausalstatusatrandomization (%) Observation (N=1693) 1 yeartrastuzumab (N=1694) Prem 15.4 16.1 37.2 37.9 Uncertain 47.1 50.0 Postmenopausal

  21. Patient/Tumor Characteristics Observation (N=1693) 1 yeartrastuzumab (N=1694) Nodal Status (%) Any (neoadjuvant) 10.2 11.1 Node neg. 32.9 32.1 1-3 + nodes 28.9 28.5  4 + nodes 27.9 28.3 missing 0.1 0.2 Hormone Receptor (%) HR negative 49.9 49.0 49.0 HR positive 50.0 50.9

  22. Adverse Events, with a Special Focus on Cardiotoxicity, among Patients Included in the Safety Analysis Piccart-Gebhart, M. et al. N Engl J Med 2005;353:1659-1672

  23. Efficacy End-Point Events (Intention-to-Treat Groups) Piccart-Gebhart, M. et al. N Engl J Med 2005;353:1659-1672

  24. Kaplan-Meier Curves Showing Disease-free Survival (Panel A), Time to Distant Recurrence (Panel B), and Overall Survival (Panel C) Piccart-Gebhart, M. et al. N Engl J Med 2005;353:1659-1672

  25. Kaplan-Meier Curves Showing Disease-free Survival (Panel A), Time to Distant Recurrence (Panel B), and Overall Survival (Panel C) Piccart-Gebhart, M. et al. N Engl J Med 2005;353:1659-1672

  26. Kaplan-Meier Curves Showing Disease-free Survival (Panel A), Time to Distant Recurrence (Panel B), and Overall Survival (Panel C) Piccart-Gebhart, M. et al. N Engl J Med 2005;353:1659-1672

  27. Analyses of Disease-free Survival According to Subgroup Piccart-Gebhart, M. et al. N Engl J Med 2005;353:1659-1672

  28. Conclusions • At one yearmedianfollow-up: • One year of treatment with trastuzumab after adjuvant chemotherapy significantly improves disease-free survival among women with HER2-positive breast cancer • Trastuzumabsignificantlyreduces the risk of distant metastases • Trastuzumab’sclinicalbenefits are independent of patients’ baselinecharacteristics (nodal status, hormone receptorstatus, etc.) and of type of adjuvant chemotherapyreceived

  29. Questions Raised • Dosing: when to start, how long to give, and what to give with- chemotherapy, hormone therapy, additional anti-HER-2 agents • Cardiac and long-term safety • Benefit after disease progression

  30. Trials of Adjuvant Trastuzumab in HER2-Positive Early-Stage Breast Cancer Hudis C. N Engl J Med 2007;357:39-51

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