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Lisa A. Carey, MD, Medical Oncology

UNC Internal Medicine Resident Lecture January, 2010. Breast Cancer: Contemporary Issues, Survivorship, and the Primary Physician. Lisa A. Carey, MD, Medical Oncology.

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Lisa A. Carey, MD, Medical Oncology

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  1. UNC Internal Medicine Resident Lecture January, 2010 Breast Cancer: Contemporary Issues, Survivorship, and the Primary Physician Lisa A. Carey, MD, Medical Oncology There’s a guy at the door from the Parks department. He wants to know if there are any poor swimmers here in need of swimming lessons Tell him no. We know how to swim. No. He seemed disappointed.

  2. Objectives • Describe the biologic heterogeneity of breast cancer • Discuss how this heterogeneity translates into the clinic

  3. Cancer Incidence Rates* for Women, 1975-2003 Rate Per 100,000 250 200 Breast 150 100 Colon and rectum Lung & bronchus 50 Uterine Corpus Ovary Non-Hodgkin lymphoma 0 1975 1978 1981 1984 1987 1990 1993 1996 1999 2002 From SEER, NCI

  4. 100 80 60 40 20 0 1990 1995 2000 1950 1955 1960 1965 1970 1975 1930 1935 1940 1945 1980 1985 Cancer Death Rates*, for Women, US,1930-2003 Rate Per 100,000 Lung & bronchus Uterus Breast Colon & rectum Stomach Ovary Pancreas *Age-adjusted to the 2000 US standard population. Source: US Mortality Public Use Data Tapes 1960-2003, US Mortality Volumes 1930-1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 2006.

  5. Adjuvant Choices

  6. Prognostic relevance of LN

  7. AJCC TNM Staging • T – tumor size • T1 = < 2cm • T2 = 2-5 • T3 = >5 cm • T4 = chest wall or skin involvement. • N - ipsilateral lymph nodes • N1 = 1-3 • N2 = 4-9 • N3 = 10+, infraclavicular, supraclavicular • M – distant metastases • 0 : Tis • I : T1N0 • IIA: T0-1N1; T2N0 • IIB: T2N1; T3N0 • IIIA: T0-3 N2; T3N1 • IIIB: any T4 • IIIC: any N3 • IV: M1

  8. Online Modeling Programs Several prognosticators available, most commonly used: Adjuvantonline • Lets you calculate recurrence risk and benefit of known interventions • http://www.adjuvantonline.com • Validated in large British Columbia registry (Olivotti et al, JCO 2005) • Doesn’t include trastuzumab (yet) • Doesn’t include HER2 • Doesn’t include Oncotype Dx results

  9. www.Adjuvantonline.com

  10. 50 year old otherwise healthy woman has surgery for a breast mass. She is found to have a 3cm, high grade, node-positive, hormone receptor-positive, HER2-negative breast cancer.

  11. How do I counsel her? Risk of relapse untreated: 80% With optimal endocrine therapy: 50% Endocrine and chemotherapy: 30%

  12. A More Pessimistic View of My Counsel Over- Treatment (50%) Under- Treatment (30%) Optimal Treatment (20%) Patients whowould have been fine with no therapy or endocrine therapy only Chemotherapy made the difference Cancer recurred despite “optimal” treatment

  13. Issues in Adjuvant Therapy: Side Effects of Long Term Therapy • Herceptin for HER2+ (infusional x1 year) • LVEF decline ~ 10%, symptomatic in <5% • Unlike anthracyclines, probably partly reversible • Implications later (aging, other cardiac RF) unknown • Tamoxifen for ER+ (5 years) • Hot flashes, uterine Ca (1/2000 overall, ~0.5-1% in selected pts), DVT/PE (4x baseline risk) • BUT improved bone health • Aromatase inhibitors for ER+ postmenopausal (5 years) • Myalgia/arthralgias (most common reason to discontinue) • Osteoporosis acceleration • Bisphosphonates – on trial (for now) 3-5 years • ONJ 0.7% maximum. May be ameliorated by oral Abx and washes.

  14. Issues in Adjuvant Therapy: Long Term Effects of Prior Therapy • Anthracyclines • Cardiotoxicity – clinical ~1%. May increase long term risk of cardiomyopathy • Leukemia ~ 0.5%. Onset usually 2-3 years after therapy. • Alkylating agents (CMF-type) • Leukemia ~0.5%. Onset usually 5+ years after therapy. • Taxanes • Peripheral neuropathy ~ 5% persistent • Stocking/glove numbness/paresthesias • Begins with therapy. Onset post Rx is something else. • Herceptin ?

  15. Breast cancers can look like this… ....or like this High grade, aggressive appearing Low grade, more benign appearing Courtesy A. Harden, L. Dressler

  16. Looks Can Be Deceiving… Bono: International humanitarian Bernie Madoff: Estate planner and philanthropist Like people, we can’t tell how cancers will behave based upon appearance

  17. Time and selective pressure by drugs Early cancer Advanced cancer Acquisition of mutations Increasing genomic instability Increasing metastatic potential • Arguments in favor: • Screening, e.g. mammography, works • Demonstrated, e.g. Vogelstein colon cancer progression model Traditional Progressive Model of Cancer Development

  18. The Biologic Model Calvinist model: Biologic predeterminism Behavioral heterogeneity Cancer subtypes Initial differences Biologic variability • Arguments in favor: • Screening doesn’t work that well • Demonstrated, e.g. intrinsic subtypes of breast cancer

  19. Understanding Biology:Gene Expression Microarray Approach Green Red Spot 1 Normal Cells Tumor Cells Spot 2 Spot 3

  20. Thank god for computers

  21. Gene Expression Patterns Before the computer gets to it… …and after Genome-wide picture of what genes are up, what are down, and how they relate Courtesy Chuck Perou

  22. Breast Cancer Molecular Subtypes Normal breast-like Luminal B2 Luminal B Luminal A HER2+/ER- Basal-like Breast cancer is not one disease. But a group of biologically distinct diseases. What does this mean? It means that it does not make sense to ask “what causes breast cancer?” It also means that individualized medicine is not just desirable, it is crucial. Courtesy Chuck Perou

  23. Subtype Example: Basal-like Breast Cancer: • Low HER2 cluster expression • High basal cluster • EGFR • basal cytokeratins • others… • Low ER (and related genes) cluster expression • Very proliferative • High degree of genomic instability HER2 Basal Luminal Proliferation Insensitive to conventional targeted therapies

  24. Subtypes and Prognosis Sorlie T et al, PNAS 2001

  25. Clinical Characteristics of Breast Cancer Subtypes: Carolina Breast Cancer Study (CBCS) Courtesy of R. Millikan Population-based case-control study of breast cancer risk. Phase I 1993-96, 40% African-American, 50% < 50yo

  26. Carolina Breast Cancer Study: Subtype Incidence

  27. Basal-like Breast Cancer Clinicopathologic Characteristics Basal-like (n=100) Luminal A (n=255) P-value HER2+/ER- (n=33) Luminal B (n=77) AA Premenopausal Postmenopausal White Premenop. Postmenopausal 39% 14% 16% 16% 9% 7% 6% 6% 36% 59% 51% 58% 9% 16% 18% 16% <0.001 Stage I II III-IV 44% 47% 9% 24% 62% 13% 28% 53% 19% 39% 54% 6% 0.06 34% Lymph node + 41% 56% 47% 0.04 70% 12% 9% 3% Invasive ductal Invasive lobular Mixed “Poor” histologies 84% 0 6% 10% 94% 0 6% 0 79% 7% 12% 1% <0.001 31% Grade III 84% 75% 31% < 0.001 < 0.001 P53 mutated 44% 43% 15% 23% Carey LA et al, JAMA 2006

  28. Risk Factors by Subtype May Differ,Potentially Modifiable Adjusted OR cases v. controls N=1424, population-based Varying magnitude of effect Varying direction of effect Millikan et al, Breast Cancer Res Treat, 2008 If confirmed 68% of basal-like in young African-American women could be prevented by weight control and breast feeding!

  29. 1980s Mitoxantrone 1990s: AIs (metastatic) Zoladex Zoledronate Taxanes (metastatic) Epirubicin Vinorelbine Gemcitabine Liposomal doxorubicin Capecitabine Dexrazoxane (cardiac toxicity) New drugs for breast cancer • 2000s: • Anastrozole • Letrozole • Exemestane • Fulvestrant • Docetaxel • Paclitaxel • Epirubicin • N-abpaclitaxel • Ixabepilone • Trastuzumab • Lapatinib • Bevacizumab Mostly chemotherapy Mostly stage IV Adjuvant (early) treatment Chemo, endocrine, targeted Rx

  30. More Drugs, Smarter Drugs… Fewer effects on the normal tissues of the body More specific effects upon the “Achilles’ heel” of the tumor Synergistic drugs: A+B+C… The law of unintended consequences = unexpected toxicities (for example trastuzumab (Herceptin) cardiotoxicity)

  31. What About Smarter Doctors? Volume 351:2817-2826December 30, 2004Number 27 A Multigene Assay to Predict Recurrence of Tamoxifen-Treated, Node-Negative Breast Cancer Soonmyung Paik, M.D., Steven Shak, M.D., Gong Tang, Ph.D., Chungyeul Kim, M.D., Joffre Baker, Ph.D., Maureen Cronin, Ph.D., Frederick L. Baehner, M.D., Michael G. Walker, Ph.D., Drew Watson, Ph.D., Taesung Park, Ph.D., William Hiller, H.T., Edwin R. Fisher, M.D., D. Lawrence Wickerham, M.D., John Bryant, Ph.D., and Norman Wolmark, M.D.

  32. Genes Selected to Predict Behavior In Spite of Anti-Hormone Treatment PROLIFERATION Ki-67 STK15 Survivin Cyclin B1 MYBL2 HER2 GRB7 HER2 ESTROGEN ER PGR Bcl2 SCUBE2 GSTM1 CD68 INVASION Stromolysin 3 Cathepsin L2 BAG1

  33. No screening or treatment Screening Treatment Both screening and treatment Breast Cancer U.S. Numbers Despite similar incidence (150-200k/yr) > 30% decrease in mortality (~35 k/yr) ½ from improved screening ½ from improved treatment An increasing proportion of breast cancer patients (by far the majority) are “cured” Berry DA et al, NEJM 2005

  34. 100% 90% 80% 70% 60% 50% DRFS 40% Low Risk Genes 30% Intermediate Risk Genes 20% 10% High Risk Genes 0% 0 2 4 6 8 10 12 14 16 Years Relapse after Anti-Hormone Therapy (Tamoxifen) According to Genetic Profile No further treatment (<7% risk of relapse) DRFS for the Three RS Groups Needs chemotherapy in addition to antihormone (>30% risk, most of benefit) These assays allow us to only give chemotherapy to those that need it

  35. Commercial Prognostic Profiles Sotiriou and Pusztai, NEJM 2009 37

  36. Molecular Profiles Are Concordant Adding them together doesn’t prognosticate any better than each alone – they are not measuring independent processes Fan C et al. NEJM 2006 38

  37. Genomic Profile-Driven Decision-making and False Dichotomies Numbers the tests provide are misleading. HighRecurence Score risk by tumor size: • < 1cm ~ 20% • 1-4 cm ~ 30% • 4+ cm ~ 65% Risk assessment must take into account biology and anatomy

  38. Tailored TherapyTamoxifen and CYP2D6 Tamoxifen as “prodrug” TTP RFS OS DFS Goetz BCRT 06 Shorter time to recurrence, worse DFS in 2D6 “poor metabolizers” Can 2D6 help choose tamoxifen versus aromatase inhibitors?

  39. LCCC 0801: Genotype-Driven Tamoxifen DosingW. Irvin • Can we use 2D6 to choose not only use of tamoxifen but dose of tamoxifen e.g. compensate for inherited variability in metabolism by dose? Extensive metabolizers (EM) Same tam dose Tamoxifen treated patients Intermediate metabolizers (IM) Double tam dose Poor metabolizers (PM) Double tam dose 2D6 genotyping Endoxifen levels Repeat endoxifen levels • Hypotheses: • Endoxifen will increase in IM • Endoxifen change IM > PM • Treatment is tolerable

  40. Genotype-Driven Tamoxifen Dose Study: Pilot Intermediate metabolizers (only) In spite of impaired tamoxifen metabolism, endoxifen levels were significantly increased. 40mg 20mg

  41. Projected supply of and demand for oncologist visits Ganz, P. A. et al. J ClinOncol; 26:759-767 2008

  42. What Happens Next?Survivorship Issues in Breast Cancer “period following first diagnosis and treatment before recurrence or death” Well, on no Rx YOU / ME (when?) 200,000 New dx/yr “Active Rx” 6m-1.5y • Well, on Rx • Endocrine (5-10y) • Bisphosphonates ME • Relapsed • 40,000 / year • 75% within 5 y ME

  43. Screening: relapse and new cancer Hot flashes Bone Issues Osteoporosis Arthralgias/myalgias Lymphedema (10% AND) Cardiotoxicity 1% after anthracycline VTE Peripheral neuropathy Taxanes (5% any degree) Platinum agents Weight gain Fatigue / Depression Sexual Health / Infertility Second cancers MDS/AML 0.2-1% after standard adjuvant therapy Endometrial Cancer 0.5-1% women on tam for 5 years Survivorship Issues

  44. Example:Bone loss at 12 mos in Lumbar Spine % ∆ 1) Warming et al Osteoporosis Int 13:105-12, 2002; 2) Eastell et al J Bone Min Res 21:1215-23, 2006; 3) Shapiro et al J Clin Oncol 14:3306-11, 2001; 4) Fogelman et al Osteoporosis Int 14:1001-6, 2003 Shapiro CL, et al. ASCO 2008

  45. Fractures with Aromatase Inhibitors Courtesy of Charles Shapiro, MD

  46. Treatment of Bone Loss in Breast Cancer Survivors • Assess and Modify Risk Factors • Increase Physical Activity • 30 min 3x/week also helps fatigue and weight gain • Calcium (1500 mg) and Vitamin D (800-1000 IU) • Stop smoking; reduce alcohol • DEXA screening every 2 years • Bisphosphonate treatment if indicated by T-score • <-2.5 or <-2.0 with risk factors • Risk Factors: smoking; alcohol; sedentary; family history; chronic corticosteroids; being on AI; ovarian suppression

  47. ZolendronicAcid andTherapy-induced Bone Loss • Zoledronic acid reduced bone loss • Premenopausal popn • All ovarian suppressed • Fractures were rare • (but premenopausal) • ONJ not seen • 35% decrease in breast cancer relapse • If confirmed, we oncologists will be putting it in the water… + Zoledronic acid - Zoledronic acid + Zoledronic acid - Zoledronic acid GnantM et al. J ClinOncol2007 Gnant, M. F.X. et al. J Clin Oncol; 25:820-828 2007

  48. The Future Might Include More Bisphosphonates 2 large trials (AZURE, B-34) to be reported SWOG S0307 (randomized b/w 3 different bisphosphonates) ongoing

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