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Overview of Breast Cancer TRACO Lecture Series - 2009

Overview of Breast Cancer TRACO Lecture Series - 2009. Farah Zia, MD Medical Officer, DCTD, NCI November 9, 2009. Definition of Breast Cancer Cancer that forms in tissues of the breast: Ducts: Tubes that carry milk to the nipple Lobules: Glands that make milk. Breast Cancer Progression. A.

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Overview of Breast Cancer TRACO Lecture Series - 2009

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  1. Overview of Breast CancerTRACO Lecture Series - 2009 Farah Zia, MD Medical Officer, DCTD, NCI November 9, 2009

  2. Definition of Breast CancerCancer that forms in tissues of the breast:Ducts: Tubes that carry milk to the nippleLobules: Glands that make milk

  3. Breast Cancer Progression A B C D Time Normal In situ Atypical Hyperplasia Local Invasion Primary Tumor Time Points: Overt non invasive carcinoma Onset of local invasion Onset of metastatic dissemination

  4. Types of Breast Cancer

  5. Ductal Carcinoma in situ(DCIS) Most common type of non-invasive breast cancer.The cancer is only in the ducts and has not spread through the wall of the ducts into the tissue of the breast.Nearly all women with cancer at this stage can be cured.Best form of early detection is with a mammogram (non-palpable, asymptomatic)

  6. Lobular Carcinoma in situ(LCIS)This condition begins in the milk glands, but does not go through the walls of the lobules into the breast tissue.Although not a true cancer, it does increase a woman’s risk of developing cancer later in life.It is important that women with LCIS have regular mammograms.

  7. Invasive Ductal Carcinoma(IDC)This is the most common type of breast ca, accounting for 8 out of 10 invasive breast cancersDuct  breaks thru duct wall  invades tissueFrom there, it may enter the lymphatics and spread to other parts of the body.

  8. Invasive Lobular Carcinoma(ILC)Lobules  breaks thru wall  breast tissueIt can then enter the lymphatics and spread to other parts of the bodyAccounts for only 1/10 invasive cancers

  9. Inflammatory Breast Cancer (IBC) • Rare, 1-5% in U.S. • Most aggressive form of breast cancer • Clinical diagnosis • diffuse erythema involving majority breast • peau d’ orange • erisypeloid edge • often no palpable mass • Significantly lower overall survival than non-IBC

  10. IBC-patient

  11. Clinical Presentations of IBC

  12. Inflammatory Breast Cancer • Dermal lymphatic invasion • Stage IIIB (T4d) if not metastatic • Compared to non-IBC, more frequently ER/PR negative Her2/neu positive

  13. Key Statistics For Breast Cancer, 2009 • Chance of developing invasive breast cancer at some point in a woman’s life: 1 in 8 (12%) • In 2009, 192,370 new cases of invasive breast cancer will be diagnosed among women in the US. • Also, there will be about 62,280 new cases of carcinoma in situ in 2009. • It is the most common cancer diagnosed among American women • 2nd leading cause of cancer death, exceeded only by lung cancer. • In 2009, about 40,170 women will die from breast cancer in the US

  14. Female breast cancer by race

  15. Relative Survival* (%)By Cancer SiteSite 1974-6 1983-5 1995-9All sites 50 53 64Breast (female) 75 78 88Colon 50 58 63Leukemia 34 41 46Lung and bronchus 13 14 15Melanoma of the skin 80 85 91Non-Hodgkin lymphoma 47 54 59Ovary 37 41 44†Pancreas 3 3 4Prostate 67 75 99

  16. Breast Cancer Risk Factors • Age • Prior breast cancer • High risk pre-malignant lesion LCIS, ADH • Excess endogenous or exogenous hormones • Early menarche • Late menopause • HRT • Nulliparity or age >35 at birth of first child • History of breast biopsies • Family History, e.g. BRCA 1/2 • Radiation exposure before age 40 • Mammographic density • Energy balance, lifestyle factors (alcohol)

  17. Breast CancerScreening MammographyReduces mortality by 26% in women aged 50-74,17% in women 40-49ACS recommends20 or older, BSE20-39 breast exam by physician every three years, 40 or older every yearMammography at age 40 and annually thereafter

  18. Two Major Limitations:Mammography • Fails to detect 20% of cancer that become palpable within 1 year • Sensitivity less in denser (younger) breasts

  19. Digital Mammography Overall accuracy=to film mammograms Better accuracy in <50 yrs Increased mammographic density Pre/peri menopause MRI 2-6% of cancers seen only on MRI alone Sensitivity for MRI higher than mammo Specificity for MRI lower than mammo More false + , more biopsies Promising technique, need longer follow up and survival data Other modalities of screening in high risk women

  20. BREAST CANCER: Early Stage Metastasis to ipsilateral axillary lymph node(s) N1 = movable N2 = fixed to one another or to other structures M0 = no distant metastasis

  21. BREAST CANCERSpread to lymph nodes Supraclavicular Subclavicular Distal (upper) axillary Central (middle) axillary Proximal (lower) axillary Mediastinal Internal mammary Interpectoral (Rotter’s)

  22. Systemic Therapy • Endocrine Directed (Hormone) Therapy • Chemotherapy • Biologic agents • Trastuzumab (Herceptin) • Bevacizumab (Avastin)

  23. Hormone Therapy

  24. Targeting the Estrogen PathwayBlock receptorSERM (selective estrogen receptor modulators)Tamoxifen treatmentRaloxifene preventionDecrease ligandAromatase inhibitorsOopherectomyGnRH analogs

  25. EBCTCG: Tamoxifen

  26. Tamoxifen Pharmacogenetics …. A Developing Area…. JAMA, Oct. 7, 2009 The growth inhibitory effect of tamoxifen is mediated by its metabolites:4-hydroxytamoxifenEndoxifenThe formation of these active metabolites is catalyzed by the polymorphic cytochrome P450 2D6 (CYP2D6) enzyme

  27. CYP 2DG VariantsApproximately 100 CYP 2D6 genetic variants have been identified.These manifest in the population as 4 distinct phenotypes:Extensive (normal activity)Intermediate (reduced activity)Poor (no activity)Ultra-rapid (high activity)Thus, it can be speculated that genotype related differences in the formation of active metabolites influence therapeutic response to tamoxifen.

  28. CYP 2DG VARIANTSTo investigate this relationship:Genotyped tumor tissue DNA for CYP2D6 variations in 1,325 breast cancer patients taking adjuvant tamoxifen.Women were classified as having either: 1. Extensive Metabolism (609 pts) 2. Heterozygous extensive/intermediate (637 pts) 3. Poor metabolism (79)Researchers found clear evidence that breast cancer was more likely to return in pts with reduced or absent CYP 2D6 function

  29. CYP 2DG ACTIVITYExtensive metabolizers have a 14.9% recurrence at 9 yr FU Heterozygotes have a 20.9% recurrence at 9 yr FU Poor metabolizers have a 29% recurrence at 9 yr FU

  30. Aromatase Inhibitors (AI):AI’s are drugs that reduce the level of estrogen in postmenopausal women.

  31. Aromatase Inhibitors:Currently, 3 AI’s are approved by U.S. FDAAnastrozole (Arimidex)Letrozole (Femara)Exemestane (Aromasin)

  32. Trials of AIs in the early adjuvant setting. In the ATAC trail patients received tamoxifen x5, anastrozole x 5 or tamoxifen + anastrozole x 5 resulting in a 22% improvement in DFS on anastrozole.In the BIG I-98 trial patients received tamoxifen x 5, letrosole x 5, tamoxifen x 2 + letrozole x 3 or tamoxifen x 3 + letroxole x 2.In the IES trial pateients received tamoxifen x 2-3 + tamoxifen x 2-3 or exemestane x 2-3 resulting in a 32% improvement in DFS with exemestane.In the ABCSGi ARNO 95 Ita trial pateints receive tamofen x 2-3 plus tamoxifen x 2-3 or anastozole x 2-3 resulting in a 43% improvement in DFS on letrozole.

  33. Breast cancerShould aromatase inhibitors be used in place of tamoxifen?Is there a role for sequential therapy with an AI and Tam?

  34. SABCS 2008: Meta-analysis: Adjuvant Aromatase Inhibitors vs Tamoxifen in Postmenopausal WomenData was pooled from all trials started by 2000, prospectively comparing an AI and tamoxifen.The large number of events properly powered the subgroup analysis.

  35. In the meta-analysis 9,856 breast cancer patients received: TAM x 5 yrs vs AI x 5 yrs.The 5 year recurrence with TAM or AI was 12.6% and 9.6% respectively. The 8 year recurrence with TAX or SI was 19.2 and 15.3% respectively.

  36. AI’s reduced breast cancer recurrence.AI’s were associated with an absolute 2.9% lower recurrence rate at 5 years, that improved to a 3.9% gain at 8 years (15.3% vs 19.2%, P < 0.00001).Mortality Analysis, although still early at 3.9 years fu, showed a small, non-significant advantage to 5 years of AI mono-therapy. Gains of 1.1 % and 0.5% for 5 and 8 year breast cancer mortality.

  37. AI’s reduced breast cancer recurrence.In 9015 patients treated with Tam x 2-3 years then aldosterone x 2-3 years, the 3 years recurrence for Tax or AI was 8.1% and 5% respectively.Patients treated with TAX or AI, the 6 year recurrence was 16.1% and 12.6% respectively.

  38. Switch to an AI (after 2-3 years on TAM): absolute gain of 3.1% lower recurrence rate at 3 yrs after the switch and 3.5% at 6 years after the switch (P<0.00001) 0.7% lower breast cancer mortality at 3 years and 1.6% at 6 years (P=0.02)

  39. How Long Should You Take AI’s? Studies are ongoingNo current absolute guidelinesAdjuvant options per the oncologists discretion include:Primary Rx  AI x 5 yrsPrimary Rx  TAM x 2 or 3 yrs  AI x 2 or 3 yrsPrimary Rx  TAM x 5 yrs  AI x 5 yrs * Note: current standard of care = AI, Max 5 years Rx

  40. SystemicAdjuvant Chemotherapy

  41. Absolute Risk Reductions of Relapse with Polychemotherapy Age<50 Age 50-69 Recurrence Mortality

  42. EBCTCG: Systemic therapy28,000 women in 56 trials: Meta-analysisImpact of Polychemotherapy On Absolute Risk Reduction at 5 years (in % )Subgroup age < 50, Node- had a Recurrenceof 9.9% (SE 1.3).Subgroup Age < 50, Node+ had a recurrence of 14.6% (SE 2.3).Subgroup Age 50-69, Node- had a recurrence of 5.3 (SE 1.0).Subgroup Age 50-69, Node + had a recurrence of 5.9 (SE 1.0).

  43. Adjuvant Systemic Polychemotherapy • Polychemotherapy is more effective than single agent • Proportional benefits not affected by nodes, ER, menopausal status, or use of tamoxifen • Compared with CMF, anthracyclines produced an absolute benefit of 4% in recurrence and survival

  44. Low risk/ lymph node negative AC x 4 CMF x 6 CAF x 6 FEC-100 Lymph node positive/high risk Dose dense AC x 4  Paclitaxel x 4 (q2wk) AC x 4  Docetaxel x 4 (q3wk) TAC x 6 (q3wk) Trastuzumab if HER2 positive Adjuvant Chemotherapy Options

  45. Biologic Agents

  46. ErbB2/HER2 Action in Breast CA Member of the membrane-spanning type I receptor tyrosine kinase family, comprising 4 closely related family members.They dimerize upon ligand stimulation and transduce their signals by subsequent autophosphorylation, catalyzed by the receptor tyrosine kinase activity.This results in recruitment of an array of downstream signaling cascades (survival and mitogenic ) The incidence of ErbB2 amplification is ≈ 30% in breast cancer …Identifying it as a therapeutic target

  47. The EGFR/HER Family HRG (NRG1) HB-EGF -cel Epi EGF HB-GF Amp TGF NRG1 NRG2 Epi NRG3 Ligand binding domain NRG4 Transmembrane Tyrosine kinase domain neu Erb-b2 HER2 Erb-b3 HER3 Erb-b4 HER4 erb-b1 EGFR HER1

  48. HER-2: TrastuzumabBench to BedsideTargets HER2 proteinHigh affinity (Kd = 0.1 nM) and specificity95% human, 5% murineDecreases potential for immunogenicityIncreases potential for recruiting immune effector mechanisms Early-stage breast ca: 2005 - Herceptin + Chemo ↑OS ↑DFS HER2 epitopes recognized by hypervariable murine antibody fragment Human IgG-1

  49. NSABP B-31Control: ACTThe patient receives4 treatments of doxorubicin/cyclophosphamide (AC) 60/600 mg/m2 q 3 wk x 4 followed by 4 treatments of paclitaxel (T) 175 mg/m2 q 3 wk x 4. Alternatively the patient receives 4 treatments of doxorubicin/cyclophosphamide (AC) 60/600 mg/m2 q 3 wk x 4 followed by 4 treatments of paclitaxel (T) 175 mg/m2 q 3 wk x 4followed by 4.5 treatments of trastuzumab (H) 4mg/kg LD + 2 mg/kg/wk x 51

  50. N9831 and B-31:Disease-Free Survival ACTH 87% 85% ACT 75% % 67% N Events ACT 1679 261 ACTH 1672 134 HR=0.48, 2P=3x10-12 ASCO 2005 B31/N9831 Years From Randomization

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