Introduction to the Management of Breast Cancer

Statistics 192,370 new cases and 40,170 deaths estimated for 2009 in the US 62,280 cases in situ breast cancer Lifetime risk of developing breast cancer is 12-13%, or ~1 in 8 women Highest incidence Lifetime risk of dying is approximately 3.0% (1 in 33 women) Second cancer mortality (after lung ca) CA Cancer J Clin 2009; 59:225-249

Ten Leading Cancer Types for Estimated New Cancer Cases and Deaths, by Sex, United States, 2009 From Jemal, A. et al. CA Cancer J Clin 2009;59:225-249. Copyright ©2009 American Cancer Society

Incidence decreasing 1999-2005, -2.2% Annual Age-adjusted Cancer Incidence Rates among Males and Females for Selected Cancers, United States, 1975- 2005 Incidence decreasing 1999-2005, -2.2% Death rates decreasing 1991-2005 Absolute change of -8.7% From Jemal, A. et al. CA Cancer J Clin 2009;59:225-249. Copyright ©2009 American Cancer Society

Incidence and Mortality Increased screening (mammography) Environmental factors? 2003 7% decline in incidence (> in ER+) Decrease in use of hormone replacement therapy Mortality decreasing 2.3 percent per year from 1990 to 2002 Early detection Better adjuvant therapy Ravdin, SABCS 2006 Berry et al NEJM 2005 353:1784

Breast Cancer Risk Factors Age Prior breast biopsies with proliferative breast disease Atypical hyperplasia Lobular carcinoma in-situ Family History Thoracic radiation Endogenous hormones Early menarche Late menopause Nulliparity or older age at birth of first child Exogenous hormones Mammographic density Lifestyle Factors (alcohol, obesity, diet, exercise) Intervention – modifiable risk factors … connection is through estrogen

Most Breast Cancer is NOT Hereditary ASCO Curriculum: Cancer Genetics & Cancer Predisposition Testing Most Breast Cancer is NOT Hereditary 15%-20% 5%–10% ~10% Breast Cancer Ovarian Cancer Sporadic Family clusters Hereditary Breast and Ovarian Cancer 3

Comparing Breast Cancer Risk Estimates in BRCA Mutation Carriers ASCO Curriculum: Cancer Genetics & Cancer Predisposition Testing Comparing Breast Cancer Risk Estimates in BRCA Mutation Carriers 2% of AJ have BRCA1/2 mutation BCLC breast cancer linkage consortium Shows range of reported estimates for BRCA carriers BRCA1+ carriers (BCLC) Breast cancer risk (%) BRCA1+ carriers (Ashkenazi Jews) General population Age Easton DF et al. Am J Hum Genet 56:265, 1995 Struewing JP et al. N Engl J Med 336:1401, 1997 Breast and Ovarian Cancer 7

ACS Screening Recommendations Test or Procedure Frequency Breast Breast self-examination Monthly, starting at age 20 Clinical breast examination Every 3 years from ages 20--39 Annually, starting at age 40{a} Mammography Annually, starting at age 40 20% of breast cancers not seen on mammo When do you stop screening mammography?

ACS guidelines for Breast MRI CA Cancer J Clin 2007; 57; 75-89

Diagnosis of Breast Cancer Fine needle aspiration Cytologic diagnosis, cannot distinguish DCIS from invasive disease Negative aspiration does not rule out cancer Core-needle biopsy Preferred method for diagnosis; preserves architecture Excisional biopsy Useful to determine tumor size Precludes primary chemotherapy Needle localization Nonpalpable lesions, multiple lesions Stereotactic biopsy Image-guided FNA or core biopsy

Breast Cancer Pathology Invasive carcinoma Infiltrating ductal (75% of breast cancers) Infiltrating lobular (5-10% of breast cancers) “Indian file” histology, less distinct mass More often metastasizes to: pleura, peritoneum, meninges Medullary (5-7%) Lymphocytic and plasma cell infiltrate, well circumscribed Good prognosis Mucinous/Colloid (3%,) Papillary (1-2%) Tubular (5 %)

Breast Cancer Pathology Non-invasive tumors Ductal carcinoma in situ (DCIS) Comedo (poorly differentiated) Noncomedo (well differentiated, low-grade) Papillary, micropapillary, cribiform, solid Lobular carcinoma in situ (LCIS) Uncommon tumors Inflammatory carcinoma Paget’s disease Phyllodes tumor (cystosarcoma phyllodes)

Breast Cancer Classification Staging (TNM) Histologic evaluation Tumor grade Hormone receptors HER2 expression Molecular subtypes

Prognostic Factors Patient age (menopausal status) Tumor size # of Lymph nodes Histologic tumor type Tumor grade (% tubule formation, nuclear pleomorphism, mitotic count) Hormone receptor status Her2/neu status Oncotype DX score/ Recurrence score

Natural History Fig 1. (A) Relapse free survival (RFS) based on size for entire cohort 1 (0.1 to 1.0 cm, top); entire cohort 2 (1.1 to 2.0 cm, middle); and entire cohort 3 (2.1 to 5.0 cm, bottom) 82% 75% 66% N=1187. No adjuvant chemo/hormones therapy. To determine natural history. Show effect of tumor size and ER status Excluded LN + and LVI+ 54%ER + Chia, S. K. et al. J Clin Oncol; 22:1630-1637 2004

Risks of Mortality by Tumor Type in Women aged 50-79 yrs SEER 1974-1998 (164,958 pts) Histology Ductal Lobular Mucinous Medullary Tubular Papillary Survival (%) 58.7 67 65.3 55.2 81.5 62.8 HR 995% CI) 1.00 (reference) 0.89 (0.86-0.91) 0.80 (0.76-0.85) 0.82 (0.78-0.87) 0.66 (0.60-0.73) 0.81 (0.73-0.90) Adjusted for age at diagnosis, year of diagnosis, SEER historic stage, registry, surgical treatment and radiation therapy No data on chemo or hormonal use available Li, et al Arch Int Med 163:2149-53, 2003

Tumor Grading Tumor grade is a system used to classify cancer cells in terms of how abnormal they look under a microscope and how quickly the tumor is likely to grow and spread

Hormone receptor status Estrogen and progesterone receptors are nuclear transcription factors Determined by immunohistochemistry Scored as a percentage of cells staining 1% or greater is considered positive

Her2/neu status Membrane-associated tyrosine kinase receptor (aka erbB2) Expressed in breast cancers, DCIS, and some other tissues such as heart Worse prognosis with HER2 gene amplification Prognosis changing with use of trastuzumab

Her2/neu status Measured by immunohistochemistry (IHC) and/or FISH FISH more accurate IHC: Graded 0, 1+, 2+, or 3+ Based on characteristics of staining 0-1 = negative 2 = in determinant, should be followed with FISH (fluorescent in situ hybridization) to determine status (amplified/not amplified) 3 = positive

Prognosis: Tumors  1 cm, HER2 gene amplification, Node-negative Press, M et al. J Clin Oncol 15:2894-904, 1997

The HER Family of Receptors Lapatinib HER3 HER1 EGFR HER2 HER4 Tumor Cell The human epidermal growth factor family of receptors consists of 4 transmembrane proteins with different properties (HER1-4), all involved in regulation of cell proliferation and survival.1-5 The prototype HER member HER1/EGFR (Erb-B1) binds a variety of growth factors, with ligand binding activating tyrosine kinase activity within the cytoplasmic domain and through various signal transduction intermediates.1 HER2 has no known ligand-binding activity, but its tyrosine-kinase activity is transactivated through HER2 interaction with other HER members (heterodimerization), usually following ligand binding to those receptors.3 The HER2 extracellular domains are fixed in an open conformation (exposed domain II loop) that resembles a ligand-activated state, and thus HER2 can constitutively interact functionally with other HER members.6 HER3 lacks inherent tyrosine kinase activity, but ligand binding promotes HER heterodimerization, resulting in complexes (eg, HER2/HER3) with highly proliferative signaling activity.2,4 The HER signaling network, mediated by these receptor interactions, stimulates and regulates not only cell proliferation, but also mobility, adhesion and survival.4,5 The activity of HER2/HER4 dimers is unclear, but may be implicated in providing survival signals to cardiomyocytes.4,5 Trastuzumab (Herceptin) Pertuzumab (Omnitarg) 1. Ritter and Arteaga. Semin Oncol. 2003;30(suppl 1):3. 2. Hung and Lau. Semin Oncol. 1999;26(suppl 12):51. 3. Tzahar and Yarden. Biochim Biophys Acta. 1998;1377:M25. 4. Pinkas-Kramarski et al. EMBO J. 1996;15:2452. 5. Zhao et al. J Biol Chem. 1998;273:10261. 6. Cho et al. Nature. 2003;421:756.

Her2 therapy Trastuzumab (Herceptin) Lapatinib (Tykerb) Monoclonal antibody directed towards Her2/neu receptor cardotoxicty Lapatinib (Tykerb) Small molecule tyrosine kinase inhibitor blocking HER2 and EGFR1 (HER1) Diarrhea, rash Cardiotoxicity?

Molecular Portrait of Breast Cancers “Normal” Luminal B HER-2 Basal-like Luminal A This is seminal working from Torres Sorlie, Chuck Perou, and the Brown bostein lab to look at molecular profiles in breast cancer. In this figure, genes that are upregulated are expressed in red, those down regulated are expressed as green. When Sorlie and Perou performed statistical analysis on the gene expression profiles of breast cancers, they found that the cancers segregated into 5 clusters. Two luminal clusters, luminal A and B, that most closely resembled luminal epithelium. A Normal group who’s profile most closely resembled normal breast tissue, the basal like group I’ll discuss here, and the her-2 group, which had previously been identified immunohistochemically… Sorlie T et al, PNAS 2001 Slide courtesy of L. Carey

Proxies for Gene Signature “Subtypes” Triple Negative ER/PR+ HER2+ ER/PR- Basal-like 75% 9% 0% Luminal 12% 76% 14% “HER2” 5% 85% Unfortunately, it is not yet practical to perform gene expression profiling on all tumors; however, we have reasonable “proixes” for the relevant subtypes; the worst, “basal-like” is associated with ER-/PR-/Her-2 negative cancers. “luminal” are predominantly ER/PR+, and the Her-2 subtype is Her-2 positive. Note that these are prognostic… and so are modifiable by therapy. Courtesy of L Carey

Subtypes and Prognosis It turns out that these clusters described cancers with different prognoses. We are paying special attention now to the basal-like subtype in red because of this poor prognosis Sorlie T et al, PNAS 2001

2003 AJCC: Primary Tumor (T) T1:  2 cm T1mic microinvasion  0.1 cm T1a >0.1 - 0.5 cm T1b 0.6 – 1 cm T1c 1.1 – 2 cm T2: 2.1- 5 cm T3: > 5 cm T4a: Extension to chest wall, not including pectoralis T4b: Edema, ulceration, satellite skin nodules T4c: both T4a and T4b T4d: inflammatory ca

AJCC 2003: Stage Grouping Stage 0 Tis N0 M0 Stage I T1 Stage IIA T0 N1 Stage IIB T3 Stage IIIA T0-3 N2 Stage IIIB T4 N0-2 Stage IIIC Any T N3 Stage IV Any N M1

Staging Classification of Breast Tumour

Therapy of Breast Cancer Local: Surgery Mastectomy Breast Conserving Therapy SLND/ALND Radiation therapy Systemic: Endocrine/hormonal therapy Chemotherapy Biologic therapy

Breast Cancer Local Treatment Modified radical mastectomy with axillary lymph node dissection Breast-conserving therapy – lumpectomy with axillary lymph node dissection followed by radiation Equivalence established by NSABP B-06 Original report (Fisher, et al., NEJM 1985) 12 year follow up (Fisher, et al., NEJM 1995) NCI audit (Christian, et al., NEJM 1995)

Surgical Treatment for early stage localized breast cancer Lumpectomy (partial mastectomy/ breast conserving therapy) Mastectomy Total (simple) Subcutaneous Modified Radical Radical Breast reconstruction is a part of treating a woman with a mastectomy -Lumpectomy- aka. Partial mastectomy, aka. Breast conserving therapy; most common form of breast cancer surgery today. Remove the “tumor” plus margins and give radiation -total (simple) mastectomy = removal of both breasts and overlaying skin without axillary dissections -subcutaneous mastectomy = removal of both breasts with preservation of the overlying skin and nipple-areolar complexes -modified radical mastectomy = removal of both breasts (not the pectoralis muscles) with overlaying skin and axillary contents -radical mastectomy = removal of both breasts with overlaying skin, pectoralis muscles, and axillary contents. 33

Contraindications to BCT Pregnancy Previous breast or mantle RT Diffuse malignant microcalcifications Collagen vascular disease (SLE, scleroderma) Multicentric disease

Indications for Post-Mastectomy Radiation 4 or more positive axillary lymph nodes Tumor 5 cm or greater Tumor invading the skin or adjacent musculature Positive surgical margins Note: Role in patients with 1 – 3 positive nodes is controversial (balanced discussion) ASCO guidelines for postmastectomy XRT Recht, et al., JCO 19:1539, 2001.

Adjuvant systemic therapy Can eliminate hidden, microscopic metastases Decreases local recurrence in patients treated with breast conservation Includes: Hormone therapy Chemotherapy Target therapy (ie Herceptin) 36 36

Who should receive adjuvant therapy? Consensus statements: Early Breast Cancer Trialists’ Collaborative Group (EBCTCG, aka Oxford Overview) last published 2005 7th International Conference on Adjuvant Therapy of Primary Breast Cancer (St. Gallen, 2009) NCI Consensus Conference (Nov 2000) NCCN guidelines Oxford overview 2005 publication was from the 2000 meeting

Indications for Adjuvant Chemotherapy All lymph node-positive Her2/neu positive tumors Triple negative tumors Invasive, lymph node-negative - invasive ductal/lobular, > 1 cm (NIH) - invasive ductal/lobular, > 2 cm (St. Gallen’s) - invasive, favorable histology, > 3 cm

Case#1 68 y.o. postmenopausal female noted to have abnormality in left breast on screening mammogram approx 1 cm abnormality noted in upper outer quadrant No sig PMH or FH Negative ROS

Left core biopsy-infiltrating ductal carcinoma, grade 1, ER 90%, PR 95%, Her2/neu negative

Left lumpectomy and SLNB-1.1cm IDC, 0/2LN+ What adjuvant therapy should she receive?

Hormonal treatment first choice Could consider chemotherapy Oncotype DX

Indications for Adjuvant Hormonal Therapy Indicated for almost all patients with ER or PR expression > 1% Sequential preferred over concurrent chemo-hormonal therapy Tamoxifen and/or AI No AI in premenopausal women Need references for sequential/concurrent Albain, K. St Gallen Conf 2003

Hormonal (Endocrine) Therapies: Mechanisms of Action Decrease ligand Aromatase inhibitors Oophorectomy Goserelin, Leuprolide Block receptor SERM (selective estrogen receptor modulators) SERD (selective estrogen receptor downregulator)

Diff hormonal agents Tamoxifen Blood clots, uterine cancer, increased LFTs, cataracts, hot flashes Improves BMD in postmenopausal, improves lipid profile Aromatase Inhibitors (anastrozole, letrozole, exemestane) Myalgias/arthralgias, decrease in BMD Elevate BP, elevate lipids, CV risk?

Adjuvant Therapy Guiding Principles: Hormones EBCTCG Lancet. 365(9472):1687-717 2005

EBCTCG tamoxifen in subgroups Tamoxifen benefits all groups: Older and younger Chemo or not Lymph node + or not EBCTCG Lancet 2005 365: 1687 - 1717

Trials of AIs in the adjuvant setting TAMOXIFEN x 5 ATAC ANASTROZOLE x 5 TAM + ANAST x 5 TAMOXIFEN x 5 LETROZOLE x 5 BIG I-98 TAM x 2 LET x 3 LET x 2 TAM x 3 TAM x 2-3 IES TAM x 2-3 EXEMESTANE x 2-3 ABCSG 8 TAM x 2-3 ARNO 95 TAM x 2-3 ITA Anastozole x 2-3 LETROZOLE x 5 MA-17 TAMOXIFEN x 5 PLACEBO x 5

Summary of Results from Large Adjuvant Aromatase Inhibitor Trials 0.4 0.6 0.8 1.0 1.2 BIG I-98 0.81 (0.70, 0.93) ABSCG/ ARNO 0.60 (0.44, 0.81) ATAC 0.83 (0.73, 0.94) MA.17 0.58 (0.45, 0.76) IES 0.76 (0.66, 0.88)

Length of Hormonal Tx Atleast 5 years Up to 10 years Maybe more?

Endocrine Rx: What you need to know Use in anyone with ER+ and/or PR+ Sequence after chemotherapy Tamoxifen reduces the risk of recurrence and improves overall survival across the board AIs reduce risk of recurrence compared with tamoxifen. NO increased OS yet. Try to use AIs in all postmenopausal women SERM and AI side effect profiles differ, keep in mind when assessing individual patients Ovarian suppression is an option for premenopausal women (added benefit with hormonal tx?)

Case #2 48 y.o. perimenopausal female notes a 1.5 cm mass in her right breast on self exam Mammogram shows no abnormalities

Biopsy-IDC, grade 3, ER 30%, PR 10%, Her2/neu negative

Lumpectomy and SLNB-2cm IDC, grade 3, 1/2 LN+ What should she receive as adjuvant therapy?

Lymph Node Positive Breast Cancer ER negative chemotherapy (pre-menopausal or post-menopausal) ER positive premenopausal: chemotherapy + tamoxifen** postmenopausal: tamoxifen/AI + - age > 70: tamoxifen (+ chemotherapy?) ** ovarian ablation/GnRH analog may be considered

Adjuvant! Computer program to determine breast cancer prognosis by adjuvant therapy http://www.adjuvantonline.com Recurrence rates based on Oxford Overview data Overall survival based on SEER data

Adjuvant Online

Adjuvant Online Printout

Genomic Health 21 Gene Panel Predicts Benefit from Chemotherapy - Results from NSABP B-14 and B-20 Soonmyung Paik1, Steven Shak2, Gong Tang1, Chungyeul Kim1, Joffre Baker2, Maureen Cronin2, Rick Baehner2, Drew Watson2, John Bryant1, Joseph Costantino1, William Hiller1, and Norman Wolmark1 From 1. Division of Pathology, Operation Center, and Biostatistics Center, NSABP, Pittsburgh, PA 2. Genomic Health, Inc., Redwood City, CA

Oncotype DX 21 Gene Recurrence Score (RS) Assay 16 Cancer and 5 Reference Genes From 3 Studies PROLIFERATION Ki-67 STK15 Survivin Cyclin B1 MYBL2 ESTROGEN ER PR Bcl2 SCUBE2 GSTM1 BAG1 INVASION Stromolysin 3 Cathepsin L2 CD68 Category RS (0 – 100) Low risk RS < 18 Int risk RS ≥ 18 and < 31 High risk RS ≥ 31 REFERENCE Beta-actin GAPDH RPLPO GUS TFRC HER2 GRB7

Validation Study of Oncotype DX Tamoxifen treated patients from NSABP B-14 (N=668) Performance exceeded standard measures of patient age, tumor size 338 pts 149 pts 181 pts

OncotypeDX Results I would then refer back again to the patient KL, whose Adjuvant! Predictions we saw earlier. She underwent Oncotype Dx testing and, perhaps surprisingly, her risk turne out to be in the “low risk” category. What should be recommended for her? According to Adjuvant, she would expect an 8% absolute risk reduction with chemotherapy. According to Oncotype Dx, with only a 9% rate of distant recurrence, chemotherapy could only benefit her by 3%-4%.

Oncotype Dx: Chemotherapy benefit RS < 18 RS 18-30 RS ≥ 31 Patients with tumors that have high Recurrence Scores have a large absolute benefit of chemotherapy (similar results with CMF and MF) Patients with tumors that have low Recurrence Scores derive minimal, if any, benefit from chemotherapy Paik et al, J Clin Oncol. 2006;Epub May 23.

EBCTCG: Chemotherapy reduces risk of recurrence <50 years 50- 69 years The most important information regarding the benefit of chemotherapy comes from the EBCTCG which meet every 5 years to go thru data from global cancer trials. This analysis the benefit of chemotherapy in women who received chemotherapy compared to those that did not. On the left here, you can see the benefit of chemotherapy in women <50 years who did and did not receive chemotherapy. On the right, the benefit of chemotherapy is divided for women between the age of 50-69. The gains are more marked in premenopausal women. These benefits are twice as great at 15 For women under 50, women randomized to a combination of chemotherapy agents compared with no treatment reduced the risk of disease relapse by 37% and death by 30% and a 15 year that translated into a 10% absolute survival benefit. For women aged 50-69years, the risk of relapse was reduced by 19% and the risk of death 12% which translated into a 3% absolute gain in 15yr survival. Important to remember these are the benefits seen without the addition of taxanes, dose dense scheduling and herceptin based treatment…so could be more EBCTCG Lancet. 365(9472):1687-717 2005

Progress in Adjuvant Chemotherapy of Breast Cancer 1970s Before Anthracyclines CMF, CMFVP With Anthracyclines Combination: AC, FAC, FEC, CEF Sequence and Alternating Dose intensity, dose density, HDCT Taxanes (Paclitaxel/Docetaxel) Sequential: A → T → C or AC → T Combination: TA, TAC Biologic Modifiers 1980s The bottom line is that the regimens are getting more sophisticated, using very active drugs and combining with biologic agents with the idea of tailoring the therapy to the patient--- here is an example of that. 1990s 2000s Vogel CL, ASCO 2003

Adjuvant Chemotherapy Regimens Low risk/lymph node negative ACx4 CMFx6 CAFx6 TCx4 High risk/lymph node positive dd ACx4paclitaxel x4 (q2 week) TACx6 FEC-100 or CAFx6 if taxane not tolerated TC 4-6 cycles if anthracycline not tolerated Her2+ Herceptin based regimen

Neoadjuvant Therapy Indications Inoperable tumors Inflammatory breast cancer May consider to increase chance for BCS In operable breast cancer where chemotherapy is recommended, neoadjuvant therapy can be considered No difference in DFS or OS between neoadjuvant and adjuvant Rx Patients with pCR after neoadjuvant Rx have > 90% OS (reported rates range of pCR 4-65%) The optimal approach to staging the axilla in patients getting neoadjuvant Rx is not known This impacts surgery and radiation therapy

Surveillance History and physical every 4-6 months for 5 years, then annually Mammogram annually (and at 6 months after treatment with XRT and breast conserving surgery) Pelvic exam annually for women with intact uterus on tamoxifen Other imaging only as indicated by history and physical exam

Case #3 56 y.o. female with newly diagnosed stage III right breast cancer (IDC, gr 2, ER+, PR-, Her2/neu-) On staging studies found to have multiple bony lesions on bone scan and suspicious liver lesions on CT

Liver bx-consistent with metastatic breast cancer What do you do?

Disease Recurrence ER+ ER- Biopsy ER, PR, HER2/neu status ER+ Hormonal therapy ER+ ER- Up to 20% of discordance can exist between the primary and the metastatic lesions in ER/PR status, either as a function of technical assay variability or biologic heterogeneity. Furthermore, tumors can acquire Her-2/neu positivity either due to clonal selection et cetera. Chemotherapy + Trastuzumab Hormonal Therapy +/- Trastuzumab Chemotherapy 2nd line/3rd line hormonal therapy Chemotherapy Chemotherapy + Trastuzumab

Metastatic disease: General principles Hormonal therapy for indolent disease Trastuzumab-based therapy for HER2/neu positive disease Single agent chemotherapy for aggressive/symptomatic disease or disease not responsive to hormonal therapy Consider tx with bevacizumab Polyagent chemotherapy for visceral crisis or disease requiring rapid response

History of Drug Approvals for Breast Cancer General approvals Methotrexate Dec 1953 Cyclophosphamide Nov 1959 Doxorubicin Aug 1974 1st Breast Cancer Approval Paclitaxel Apr 1994 Docetaxel July 1994 Capecitabine Mar 1998 Pamidronate Sept 1998 Trastuzumab Sept 1998 Epirubicin Sept 1999 Abraxane Jan 2005 Bevacizumab Feb 2008 Hormonal Tamoxifen Dec 1977 Anastrozole Dec 1995 Goserelin Dec 1995 Toremifene May 1997 Letrozole July 1997 Exemestane Oct 1999 Fulvestrant Apr 2002

Metastatic Breast Cancer Not curable 1st recurrence should be biopsied!! 1st goal is to maintain good QOL – consider it a chronic disease Bisphosphonates for bone metastases

Metastatic disease Tumor markers not shown to be helpful in making clinical decisions Restaging studies every 3 to 6 months to determine progression, sooner if symptomatic, clinically warranted Clinical trials!

High Dose Chemotherapy with Stem Cell Rescue Toxicities are substantial, including a 5-8% mortality in past, 1-2% at present Overall survival benefit has not been demonstrated; relapse-free benefit is controversial in high risk patients No proven benefit in metastatic disease Should be done only on clinical trials

Conclusions Many effective treatment regimens Efforts now focused on defining subtypes to individualize treatment and avoid overtreatment

Questions???