BREAST CANCER: From Traditional Treatments to New Approaches

1. BREAST CANCER: From Traditional Treatments to New Approaches Diana C. Márquez-GarbánUniversity of California, Los AngelesDivision of Hematology-Oncology

2. Global Incidence • 1.3 million women diagnosed worldwide • About 555,000 will die from the disease • 77 % of cases occur in women over 50 y • Most common cancer in women

3. Risk Factors • Age • Personal history • Family history (5-10%) • Benign breast disease (atypical hyperplasia + family history) • Endocrine factors (late menopause, early menarche, OCP > 10 yrs, pm-HRT > 15 yrs, early / late pregnancy) • Environmental factors (diet, alcohol, carcinogens) • No attributable risk (70-75%)

4. Cancer : Historical Notes • An old enemy: • Anthropologists offer evidence of tumorous growths in dinosaurs dating from 100-200 million years ago • Mummies from Egypt 5000 years ago with tumors Edwin Smith Papyrus (1862): Egypt 1500-3000 B.C. : describes breast tumors Treatment: “fire drill”- non- curable

5. 1860: William Halsted Radical Mastectomy Very disfiguring, cuts breast, muscle 1960: Bernard Fisher Less surgery is as effective BO4 trial: “modified radical mastectomy” against “Halsted radical mastectomy” Fisher changes history of treatment of breast cancer

6. Anatomy of the mammary gland

7. Mammary gland development

8. Diagnosis of Breast Cancer • Physical examination • palpable mass (ductal) • diffuse thickening (lobular) • Mammogram (15% FN) • microcalcifications in clusters, spiculated lesions • architectural distortion • reduced mortality on screening age group > 50 • Biopsy -

9. Mammograms for breast cancer detection

10. Pathologic Evaluation : Breast Histology

11. Immunohistochemistry in Breast Cancer Diagnosis & Prognosis ER-positive Tumor HER-2-Overexpressing Tumor

12. Breast Cancer Staging and Tumor Size

13. Breast Cancer Stages Stage 0: carcinoma in situ Stage I: tumor < 2 centimeters; no spread outside breast. Stage IIA : cancer in axillary lymph nodes; or tu< 2 cm with spread to axillary nodes; or tumor is 2 - 5 cm and no axillary nodes. Stage IIB: 2 - 5 cm tumor, spread to axillary nodes or > 5 cm, no spread to nodes. Stage IIIA: cancer in axillary nodes attached each other; Stage IIIB: spread to tissues near the breast Stage IIIC: spread to lymph nodes under collarbone and near neck; and may have spread to lymph nodes within breast or under arm and tissues near breast. Stage IIIC breast cancer divided into operable and inoperable stage IIIC. Stage IV: spread to other organs of body, most often bones, lungs, liver, or brain. Stressful time for patients -uncertainty- Treatment decisions made- feeling of relieve

14. Prognostic Factors lymph node status negative tumor size <1cm grade nuclear grade I flow cytometry diploid, low S histology tubular, papillary ER/PR positive HER-2/neu negative Ki67 <10-15% slower Investigation: angiogenesis, p53 mutation, bone marrow micrometastasis

15. Treatment Systemic Local-Regional Surgery +/- Radiation Tamoxifen for ER+ Chemoteraphy

16. Risks of primary surgery + radiation therapy • Post-mastectomy pain syndrome • Axillary LND versus Sentinel LND • Lymphedema • Skin changes • Psychosexual effects

17. Adjuvant chemotherapy Benefits: Decreased risk recurrence 35-50% Decreased risk mortality 20-40% Risks: Acute, reversible: nausea, vomiting, fatigue, anemia, neutrocitopenia, hair loss, etc. Long-term:Acute leukemia (<1%), cardiac toxicity (1% anthracyclines), cognitive deficits “chemo brain”, psychological effects.

18. Antiestrogen therapy : TAMOXIFEN • Estrogen Receptor: first target identified 100 y ago • Used in Estrogen Receptor + breast cancer • Approx. 80% of postmenopausal women ER+ • Tamoxifen: used for the past 40 years • Standard therapy: given for 5 years • Reduces chance of late recurrence by 40% • Reduces risk of death

19. Antiestrogen therapy : TAMOXIFEN Side Effects: Common: hot flashes, menstrual changes, vaginal discharge, uterine bleeds Occasional: thromboembolism, retinopathy, cataracts leukopenia, anemia, nausea, increased risk endometrial cancer

20. Antihormonal therapy : AROMATASE INHIBITORS • Decrease estrogen production • New standard of care for ER+ cancer early and metastatic • Arimidex (anastrozole), Aromasin (exemestane) Femara (letrozole) • Taken as a pill once a day for 5 years. Continuously for metastatic disease • Only given to postmenopausal women

21. Antihormonal therapy : AROMATASE INHIBITORS • Benefits: • Reduce risk of cancer coming back or spreading • Reduce risk of a new cancer starting in the other breast • Shrink a medium-to-large breast cancer before surgery • Side Effects: • Hot flashes, vaginal dryness, decrease libido,artralgias, reduced bone mass, blood cloths

22. Antiestrogen therapy : Faslodex (fulvestrant) • Estrogen Receptor down regulator • Approved for metastatic breast cancer after hormonal treatments failed • No risk of endometrial cancer • Works as well or better than AI • Given as an injection once a month • Similar side effects as AI and tamoxifen

23. Molecular alterations in breast cancer progression - p 5 3 - p 5 3 - B R C A 1 , 2 - B R C A 1 , 2 p 5 3 G r o w t h f a c t o r , + H E R - 2 + H E R - 2 B R C A 1 h o r m o n e , E R + C y c l i n - D + C y c l i n - D B R C A 2 d e r e g u l a t i o n ? + m y c + m y c N o r m a l H y p e r p l a s i a I n S i t u I n v a s i v e D y s p l a s i a C a r c i n o m a C a r c i n o m a

24. Src Estrogen signaling interacts with EGFR/HER pathways EGFR/HER estrogen shc ER MNAR ER ARO cytoplasm MAPK/AKT ER ER Ligand-independent Ligand-dependent P ER SRC-3 Growth Survival Angiogenesis TF ER ER nucleus

25. Targeted Therapies • • Monoclonal antibodies- Herceptin • • Protein kinase inhibitors (Lapatinib, Gleevec, Iressa,Tarceva) • • Anti-angiogenic agents ( Squalamine, Avastin, SU5418, Thalidomide) • •Retinoids • Antihormone agents- Endocrine Therapy

26. Herceptin (Trastuzumab) • • Humanized antibody to HER-2 receptor • • For use in treatment of HER-2-expressing breast cancer • Approved for metastatic disease and early as adjuvant therapy • • Increases survival and time to progression • Infusion-related symptom complex • • Risk of cardiomyopathy

27. Targeted Therapies • Monoclonal antibodies (Rituximab, Herceptin) • Protein kinase inhibitors (Lapatinib, Gleevec, Iressa,Tarceva) • Anti-angiogenic agents ( Squalamine, Avastin, SU5418, Thalidomide) •Retinoids

28. Lapatinib • • TKI-targets EGFR and HER-2 • • Oral drug • Useful fro patients resistant to trastuzumab • May be effective for brain metastasis • Used with Capecitabine for advanced disease • • Increases survival and time to progression • Used in inflammatory breast cancer

29. Targeted Therapies • Monoclonal antibodies (Rituximab, Herceptin) • Protein kinase inhibitors (Lapatinib, Gleevec, Iressa,Tarceva) • Anti-angiogenic agents ( Squalamine, Avastin, SU5418, Thalidomide) •Retinoids

30. Tumor-Associated Angiogenesis

31. Bevacizumab- Avastin • • Humanized antibody to VEGF • • Approved for metastatic disease in combination with Taxol (HER-2 neg) • High blood pressure, nose bleeds, protein in urine • Trials combined with Paclitaxel produce overall response of 50%

32. Diet Exercise Life quality Targeted Therapies Herceptin, Avastin, Dasatinib, Lapatinib Treatment Systemic Local-Regional Tamoxifen for ER+ Surgery Chemoteraphy +/- Radiation No-antracyclins Aromatase Inhibitors Fulvestrant

33. Life Style Changes First • Body Weight • Diet • Exercise • Stess managemenet • Complementary therapy • Supplements

34. Body Weight and Diet • Healthy weight reduces first time breast cancer and recurrence • Low fat diet • Plenty of vegetables and fruits (5 servings) • Avoid trans fats, red meats and smoked foods • Extra protein: • Non-fat dairy • Fish, beans, tofu • Nuts

35. The 3 As Antinflamatories Omega 3 Fatty Acids: fish, flaxseed • Anticarcinogens • Black raspberries • Curry • Citrus fruits • Green Tea • Pomegranate • Nuts • Tomatoes • Saffron • Antioxidants • Pomegranate • Red grapes and red wine • Berries • Beans • Green and black tea • Onions, chives, garlic • Cabbage family

36. Life Style Changes First • Body Weight • Diet • Exercise: weights and resistance exercise- bone health and muscle preservation • Stress management: yoga, tai chi, meditation, journalism, joyful activities, NO INTERNET • Complementary therapy • Supplements • Spirituality

37. Complementary and Alternative Therapies • 50-70 % of breast cancer patients use some form of complementary therapy: • Diet: megavitamins, supplements • Acupuncture, massages • Spiritual healing • Most patients do not tell their doctor about alternative therapies they are using Evidence-based methods : • meditation to reduce stress • acupuncture for relief of pain and nausea

38. Quality of Life After cancer: renewal, rebirth, recovery, reasonable goals • Focus on wellness: • Nutrition • Exercise • Alternative therapies • Stress management • Spirituality-Journalism • Peer support, art

39. Acknowledgments National Program Excellent University EU/Slovakia UCLA Richard J. Pietras Hermes J. Garbán Hsiao-Wang Chen Olga Weinberg Edward Garon Eugene Tsai Jeison Recinos

40. Angel's Fall or Churun Meru (Canaima-Venezuela) The highest waterfall on earth with 3,212 feet (979 m) of free fall. Photo by Fernando Santos