Treatments of breast cancer in 2012: Where are we now? - Janice Walshe

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  • 1. Treatment of Breast Cancer in 2012 Where are we now? Dr Janice Walshe Consultant Medical Oncologist St Vincent‟s University Hospital, Dublin
  • 2. Outline• Overview of treatment approach• Updates in diagnostics and therapy – Oncotype Dx – Hormonal therapy advances – Chemotherapy Advances – “Targeted therapy advances”• Hereditary breast cancer• Follow-up and “what can I do”
  • 3. Projected number of Breast Cancers to 2020 5000 4500 4000 new cases per year 3500 3000 2500 2000 1500 1000 500 0 1995 2000 2005 2010 2015 2020
  • 4. risk of death from cancer before age 75 (%) 0% 1% 2% 3% 4% 1950 1954 1958 1962 1966 1970 1974 1978 1982year of death 1986 1990 1994 1998 2002 2006 2010 2014 Deaths from Breast Cancer 1950-2014
  • 5. Why?• Incidence is increasing – Mammographic screening – Environmental Factors• Mortality is decreasing – Early Detection – Better Treatment Options
  • 6. Treatment Approach
  • 7. Treatment for Breast Cancer• Local therapy – Lumpectomy + radiation – Mastectomy (+/- radiation in more advanced disease) – Goal: treat primary site of disease• Systemic therapy – Chemotherapy – Hormonal therapy – Targeted therapy
  • 8. Special Environment• Specialist Breast Cancer Unit• Multidisciplinary Approach – Histopathologist – Surgery – Medical Oncology – Radiation Oncology – Genetic Risk Assessment – Nursing Expertise – Support services (Dietician, social worker, psychologist, OT)
  • 9. What directs the sequence of the Treatment?Varies• Clinical/ pathological stage and subtype of the tumor• Biological characteristics of the tumor
  • 10. Staging Breast Cancer
  • 11. Factors that Influence Treatment Decisions• Patient Age• Histological Subtype & Grade• Tumour Size• Lymph Node Involvement• Hormone Receptor Status – Positive or Negative• Her-2 neu Expression – IHC graded 1+, 2+, 3+ – FISH amplified
  • 12. Staging Breast Cancer• Early Stage (Stage I & II)• Locally Advanced (Stage III)• Metastatic (Stage IV)
  • 13. Systemic Therapy Setting & Purpose Early Stage Locally Advanced MetastaticNo evidence of Render inoperable operable Diseasedisease control Commence systemic therapyReduce risk ofrecurrence Reduce risk metastatic disease
  • 14. Early Stage DiseaseHormones Herceptin Chemo Clinical Trial Hormone HER-2 Risk of Access to positive positive recurrence new 60% 20% therapies Tumour size / Grade / Age / Co-morbidities
  • 15. Rationale for Hormone Therapy• Prevent breast cancer cells from receiving stimulation from endogenous estrogen Beatson, 1896
  • 16. Estrogen Production in Premenopausal and Postmenopausal Patients Hypothalamus Premenopausal Premenopausal and Postmenopausal Gonadotropins Adrenocorticotropic (FSH + LH) hormone (ACTH) Pituitary gland Ovary Prolactin Adrenal gland Growth Hormone Corticosteroids Estrogens Progesterone Progesterone Androgens Estrogens Aromatase inhibitors
  • 17. Early Breast Cancer Trialists Group Overview: Tamoxifen EBCTCG, Lancet 2005,365: 1687
  • 18. Side Effects of TamoxifenCommon side effectsHot flashesRare but serious side effectsThromboembolic diseaseEndometrial cancerCataractsIssues with SSRIs
  • 19. Hormonal Therapy inPostmenopausal Women
  • 20. Aromatase Inhibitors- Mechanism of Action Smith et al., N Engl J Med 348(24):2431-42 2003
  • 21. Recurrence Rate for HR+ Patients 25 A T HR 95% CI P-value 20 HR+ 424 497 0.83 (0.73–0.94) 0.005 ITT 575 651 0.87 (0.78-0.97) 0.01 Patients (%) 15 Anastrozole (A) Tamoxifen (T) 10 5 Absolute 0 difference: 1.7% 2.4% 2.8% 3.7% 0 1 2 3 4 5 6 At risk: Follow-up time (years) A 2618 2540 2448 2355 2268 2014 830 T 2598 2516 2398 2304 2189 1932 774DFS includes all deaths as a first event Howell A, et al. Lancet 2005
  • 22. Aromatase Inhibitors• Anastrazole (Arimidex), Femara (Letrozole), Aromasin (Exemestane)• Improve outcome in postmenopausal women• Side Effects – Osteopenia, Osteoporosis, Increased risk of fractures – Possible increase in cholesterol – Arthralgias
  • 23. AdjuvantChemotherapy
  • 24. Progress in Chemotherapy for Early Stage Breast Cancer 1970s Combination chemotherapy (CMF) Use of anthracyclines Addition of taxanes Superior taxane containing regimens 2000s Addition of trastuzumabBUT: ALL chemotherapy is associated with toxicities andrisks… need better ways to identify which patients will benefitfrom treatment
  • 25. Adjuvant Chemotherapy• Degree of benefit varies according to nodal status and patient age• Degree of benefit varies according to sensitivity of tumor to hormones (ER+ vs. ER-)
  • 26. Side effects• Cardiac toxicity – Anthracyclines increase risk of congestive heart failure – Arrhythmias increased with taxanes – Radiation• Neuropathy – Taxanes• Hypersensitivity – Taxanes, require steroids• Ovarian ablation – Premature menopause » Infertility, Impaired quality of life, bone effects• Second malignancies
  • 27. SO…How can we do better?• Better selection of patients for treatment with chemotherapy• Treat only those patients who are most likely to recur AND who will therefore benefit most from the addition of chemotherapy• Take advantage of genomics
  • 28. Oncotype DX or Recurrence Score (RS) Assay for patients with ER + LN- disease16 Cancer and 5 Reference Genes From 3 StudiesPROLIFERATION ESTROGEN RS = + 0.47 x HER2 Group Score Ki-67 ER - 0.34 x ER Group Score STK15 PR + 1.04 x Proliferation Group Score + 0.10 x Invasion Group Score Survivin Bcl2 + 0.05 x CD68 Cyclin B1 SCUBE2 - 0.08 x GSTM1 MYBL2 - 0.07 x BAG1 GSTM1 BAG1 INVASION Stromelysin 3 CD68 Category RS (0 – 100) Cathepsin L2 REFERENCE Low risk RS < 18 HER2 Beta-actin Int risk RS ≥ 18 and < 31 GAPDH GRB7 RPLPO High risk RS ≥ 31 HER2 GUS TFRC
  • 29. Recurrence Score as a Continuous Predictor 40% Intermediate Low Risk Group High Risk Group Risk Group 35% Distant Recurrence at 10 Years My RS is 30, What is the chance of 30% recurrence within 10 yrs? 25% 20% 15% 10% 5% 95% CI 0% 0 5 10 15 20 25 30 35 40 45 50 Recurrence Score
  • 30. Oncotype DX™ Clinical Validation: B-14 Results – DRFS DRFS for the three distinct cohorts identified 100% 90% 80% 70% 60% DRFS 50% P <0.00001 40% 30% Low Risk (RS <18) n = 338 20% Intermediate Risk (RS 18-30) n = 149 10% High Risk (RS 31) n = 181 0% 0 2 4 6 8 10 12 14 16 Years Paik et al. N Engl J Med. 2004;351:2817-2826.
  • 31. B-14 Benefit of Tamoxifen By Recurrence Score Risk Category 1.0 1.0 0.8 0.8DRFS DRFS 0.6 0.6 0.4 0.4 Low Risk (RS<18) Int Risk (RS 18-30) 0.2 N N 0.2 Placebo 171 Placebo 85 Tamoxifen 142 Tamoxifen 69 0.0 0.0 0 2 4 6 8 10 12 14 16 0 2 4 6 8 10 12 14 16 Years Years 1.0 0.8 Interaction P = 0.06 DRFS 0.6 0.4 High Risk (RS≥31)1 1 The results should not be used 0.2 N to indicate that tamoxifen should 99 Placebo Tamoxifen 79 not be given to the high-risk 0.0 group 0 2 4 6 8 10 12 14 16 Years
  • 32. Oncotype Dx: Chemotherapy benefit RS < 18 RS 18-30 RS ≥ 31 1.0 1.0 1.0 0.9 0.9 0.9 0.8 0.8 0.8 0.7 0.7 0.7 0.6 0.6 DRFS 0.6DRFS DRFS 0.5 0.5 0.5 0.4 0.4 0.4 0.3 0.3 0.3 0.2 0.2 0.2 Low Risk Patients (RS < 18) Int Risk (RS 18 - 30) High Risk Patients (RS 31) 0.1 Tam + Chemo 0.1 Tam + Chemo 0.1 Tam + Chemo Tam Tam Tam 0.0 0.0 0.0 0 2 4 6 8 10 12 0 2 4 6 8 10 12 0 2 4 6 8 10 12 Years Years Years • 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
  • 33. Early Stage Breast Cancer – Overtreatment & Inadequate Treatment Clinical features are not sufficiently predictive of relapse after primary therapy, resulting in… – Overtreatment, because… – most patients with early stage disease will not have a future recurrence – Inadequate treatment, because either… • treatment is not given because of favorable clinical features, or • relapse occurs despite treatment
  • 34. Biological or Targeted Therapy
  • 35. Targeted therapies for Early Stage Breast Cancer• Treatments that „target‟ specific proteins or receptors expressed by tumor – Hormonal therapy was the first targeted therapy for breast cancer• Monoclonal antibodies – Trastuzumab (Herceptin)
  • 36. HER-2 Positivity in Breast Cancer • OVEREXPRESSION: marked increase in number of HER2 receptors on the cell surface • AMPLIFICATION: increase in number of HER2/neu gene copies in the nucleus HER2-normal (HER2-) breast HER2-positive breast cancer cell epithelium cell (~20,000 receptors) (up to 1-2 million receptors)Courtesy of Jeffrey Ross, Albany Medical College, Albany, NY.
  • 37. Anti-HER2 Antibodies: Mechanism of Action P P P P P P P P Excessive cell proliferation, Potentiation of Inhibition of tumor cell Facilitation of survival, and angiogenesis chemotherapy proliferation immune functionBaselga and Albanell. Ann Oncol. 2001;12(suppl 1):S35.Noonberg and Benz. Drugs. 2000;59:753.
  • 38. NSABP B-31/N9831 Joint Analysis: Impact of Adding Trastuzumab to AC Paclitaxel on Disease-Free Survival* % Surviving disease-free 100 Trastuzumab 87.1% (133 events) 90 85.3% 80 Median FU 2.0 y Control 70 (261 events) 75.4% 67.1% 60 P<0.0001 HR=0.48 50 0 0 1 2 3 4 5 Years after randomization No. at risk 3351 2379 1455 801 133 0 Control 1679 1162 689 374 59 0 Trastuzumab 1672 1217 766 427 74 0* N9831 arm B (sequential trastuzumab Romond et al. N Engl J Med., after AC P) not included in joint analysis. 2005;353:1673.
  • 39. Adjuvant Trastuzumab: Room to Improve• Generally well tolerated• Some patients will still recur• Intravenous infusion q1-3 wks for one year• Serious side effect: cardiotoxicity Study Regimen Symptomatic CHF B31/NCCTG AC TH 3.5 – 4.1% NCCTG AC T  H 2.5% HERA Chemo  H 0.6% BCIRG 006 TCH 0.4% FinHER H  chemo 0% Piccart-Gephardt, ASCO 2006
  • 40. Early Stage DiseaseHormones Herceptin Chemo Multiple regimensPremenopausal Postmenopausal IV 4-6 months 3wkly for 1 year Alopecia / Mucositis /Tamoxifen Tamoxifen Cardiac monitoring Sepsis Aromatase Inhibitors
  • 41. Locally Advanced Breast Cancer• Same Treatment but Different Sequence• Systemic therapy first (CT/HT)• Definitive surgery later
  • 42. Metastatic disease: Principles of Treatment• Hormonal therapy for indolent disease• Single agent chemotherapy for aggressive/symptomatic disease or disease not responding to hormonal therapy• Polyagent chemotherapy for visceral crisis or disease requiring rapid response• Iv bisphosphonates for bone secondaries
  • 43. Trastuzumab emtansine (T-DM1): A unique ADC- KADLYCA DM1 Thioether Trastuzumab linker• The mAb, trastuzumab, is conjugated by a thioether linker to the highly potent antimicrotubule agent DM1 – Targets HER2-positive tumor cells Junttila et al. Br Cancer Res 2011
  • 44. T-DM1 MoA: Binding of T-DM1• The trastuzumab component of T-DM1 binds to HER2 receptors on the tumor cell surface – Leads to downstream signaling inhibition/blockade Lewis Phillips et al. Cancer Res 2008
  • 45. T-DM1 MoA: Endocytosis• HER2 receptor–T-DM1 complex is internalized into the tumor cell via endocytosis Erickson et al. Cancer Res 2006
  • 46. T-DM1 MoA: Lysosomal degradation • Once endocytosis is complete, trastuzumab and the HER2 receptor are degraded and a cytotoxic metabolite* is released*Lysine-bound emtansine plus linker Erickson et al. Cancer Res 2006 Lewis Phillips et al. Cancer Res 2008
  • 47. How Much Breast and Ovarian Cancer Is Hereditary? 15% 20% 5%–10% ~10% Breast Cancer Ovarian Cancer Sporadic Family clusters Hereditary47
  • 48. Features Consistent with Hereditary Breast/Ovarian Cancer Multiple cases of early onset breast cancer Ovarian cancer (with family history of breast or ovarian cancer) Breast and ovarian cancer in the same woman Bilateral breast cancer Ashkenazi Jewish heritage Male breast cancer48
  • 49. Treatment is finished- what now?• Purpose of follow up: – Deal with complications of therapy – Detect recurrence / metastatic disease – Encourage adherence to anti-hormonal therapy• How? – History, Examination & Annual Mammogram – In asymptomatic women: » Tumour markers / routine scanning are not associated with a survival benefit and are not recommended
  • 50. Metastatic Disease is slightly different…• Tumour markers may be helpful in making clinical decisions• Restaging studies every 3-6 months to determine progression, sooner if symptomatic, clinically warranted
  • 51. Lifestyle Modifications• Obesity increases risk of postmenopausal breast cancer-Maintain a normal Body mass index• Evidence suggests that physical activity decreases risk of breast cancer and risk of recurrence- Get Active• Low fat diet decreases risk of breast cancer recurrence – Balanced Healthy Diet• Moderate alcohol intake-
  • 52. Breast Cancer Treatment: Progress and Promise• Chemotherapy – Better treatments – Progress toward targeting only those who will benefit• Hormonal therapy – AIs improve outcome in postmenopausal women – Premenopausal women – optimal hormonal treatment still unknown• Targeted therapy – Trastuzumab decreases risk of recurrence and improves survival – Promising new agents being studied• Access and participation in well designed clinical trials holds the key to further improvements