1. BREAST CANCER DR. R. RAJKUMAR M.D. D.M. Dr. R. RAJKUMAR M.

2. Breast Cancer Incidence: – Invasive breast cancer 1 1.4 million new cases in 2008 – Past 25 years Breast cancer incidence rates have risen globally Highest rates occurring in the westernized countries – Change in reproductive patterns – Increased screening – Dietary changes – Decreased activity Mortality – Mortality has been decreasing – Especially in industrialized countries. 1 American Cancer Society

3. BREAST CANCER IN INDIA Around 1 lakh cases /yr Peak incidence - 55-59/yr Age shift Rising numbers Late presentation Lack of awareness and screening Aggressive cancers in young

4. Age shift – cases in seen 30’s& 40’s

5. Young onset breast cancerYoung onset breast cancer High grade (aggressive) tumorsHigh grade (aggressive) tumors High proliferative tumorsHigh proliferative tumors ER negative tumorsER negative tumors “Triple negative” (ER-/PR-/HER2-) tumors“Triple negative” (ER-/PR-/HER2-) tumors INDIAN Women More Likely to Have:

6. Importance of Pathology: Not all Breast Cancers Are the Same!! Estrogen Receptor (ER) + 75% of Breast Cancer HER-2 + 20-25% of Breast Cancer Tumor ER and HER2 status critical in selecting therapy in both early stage and metastatic breast cancer

7. Treatment of Early Stage Breast Cancer Breast cancer most curable when detected earlyBreast cancer most curable when detected early –Micrometastases (undetectable) can exist at time of diagnosis in many patients, leading to eventual recurrence Multidisciplinary care critical for best outcomesMultidisciplinary care critical for best outcomes –Surgery –Radiation therapy –Adjuvant systemic (drug) therapy reduces risk of recurrence and death »Should be tailored to the patient and tumor

8. No surgery mastectomy chemotherapy + endocrine therapy chemotherapy + endocrine therapy + HER2 targeted therapy Incremental Benefit of Adjuvant Treatments in Early Stage Breast Cancer in USA Survival

9. Adjuvant (Early Stage) Endocrine Therapy in Breast Cancer Tamoxifen has substantial clinical efficacy, less cost, and several decades of use throughout worldTamoxifen has substantial clinical efficacy, less cost, and several decades of use throughout world –Still the standard for premenopausal –Reasonable for many postmenopausal –Longer duration (> 5 years) may benefit many patients Adjuvant aromatase inhibitors: small differences in recurrences (and in some trials deaths)Adjuvant aromatase inhibitors: small differences in recurrences (and in some trials deaths) –Side effects different Ovarian suppression effective as a sole treatmentOvarian suppression effective as a sole treatment –Still unclear whether it adds to chemo/tamoxifen

10. Early Breast Cancer Trialists’ Collaborative Group Clinical Trials of Tamoxifen in Early Stage Breast Cancer: Disease-free Survival ER Negative ER Positive Adjuvant tamoxifen significantly reduces recurrence in ER positive breast cancer tamoxifen control Tamoxifen effective in both pre- and postmenopausal women Adjuvant tamoxifen doesn’t impact recurrence in ER negative breast cancer

11. Adjuvant (Early stage) Chemotherapy in Breast Cancer Adjuvant chemotherapy reduces recurrences and deathsAdjuvant chemotherapy reduces recurrences and deaths –Reducing dose from that proven to be effective in clinical trials reduces benefit –Chemotherapy drugs have significant side effects For unselected patients/tumors:For unselected patients/tumors: – anthracyclines better than CMF regimens – taxanes add to anthracyclines – expensive Not all patients/tumors benefit from chemotherapy!Not all patients/tumors benefit from chemotherapy! ER-negative, high grade, HER-2+ tumors get most benefit from chemotherapyER-negative, high grade, HER-2+ tumors get most benefit from chemotherapy

12. Chemotherapy Dose Matters Adjuvant Chemotherapy - 20 Year Follow-up Milan Study Bonadonna G et al, N Engl J Med 332: 901-6,1995 0.9 1.0 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 5101520 Years after Mastectomy Disease-free survival Probability of Relapse-free Survival 5101520 Years after Mastectomy 0.9 1.0 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Overall survival Probability of Overall Survival >85% of dose <65% of dose Control 65-84% of dose If chemotherapy is given, it should be given at full dose

13. Adjuvant (Early Stage) HER-2 Targeted Therapy Anti-HER2 monoclonal antibody trastuzumab (Herceptin) for 1 year is standardAnti-HER2 monoclonal antibody trastuzumab (Herceptin) for 1 year is standard –Reduces recurrence by 1/2 & deaths by 1/3 when added to chemo in early stage breast cancer –Trastuzumab going off patent soon, and prices will drop All regimens include chemotherapy in addition to HER2 targeting therapyAll regimens include chemotherapy in addition to HER2 targeting therapy

14. Molecular classification & Prognosis: Luminal A= Best prognosisLuminal A= Best prognosis Luminal BLuminal B Luminal CLuminal C Normal breast likeNormal breast like Her 2+Her 2+ Basal like= Worst= Triple NegativeBasal like= Worst= Triple Negative 14

15. SUBTYPE TypeImportance Luminal A ER +, Best overall survival, Best DFS Luminal BER,Her2+,Intermediate Her 2 +veER-, Intermediate Basal likeER-,PR-, Her2 - Worst 15

16. BREAST CANCER Stage IV Any T any N M1 Examples of distant mestastatic disease

17. BREAST CANCER Sites of distant metastases SkinLiverBone PleuraLung Lymph nodes Brain

18. Treatment of Metastatic Breast Cancer Metastatic breast cancer is not curable, but can be very treatableMetastatic breast cancer is not curable, but can be very treatable Goals:Goals: –Control and regression of disease –Prolongation of life –Improvement in symptoms and quality of life

19. Choices in the Treatment of Metastatic Breast Cancer Choice of treatment is based on many factors:Choice of treatment is based on many factors: –Patient age, menopausal status, general health and functional status –Tumor ER status, HER-2 status –Previous treatments –Extent and sites of disease –Available therapies in the patient’s country

20. Breast Cancer Systemic Therapies Drug treatments that can attack cancer cells throughout the bodyDrug treatments that can attack cancer cells throughout the body –Endocrine therapy –Chemotherapy –Biologically-targeted therapy

21. Endocrine Therapy in Breast Cancer Estrogen Cell Growth and Division Estrogen Receptor SERMS (tamoxifen), SERDS Aromatase inhibitors, ovarian suppression Endocrine therapy effective only in ER-positive breast cancer ER/PR staining: CRITICAL IN SELECTING THERAPY!

22. Endocrine Therapy for Metastatic Breast Cancer Endocrine therapy is the preferred choice for ER+ metastatic breast cancerEndocrine therapy is the preferred choice for ER+ metastatic breast cancer –Less side effects than chemotherapy Exceptions:Exceptions: –Concern or proof of endocrine resistance –Need for fast response (location, symptoms)

23. Hormonal Therapies (FDA indications) 1 st line therapy:1 st line therapy: –Tamoxifen, anastrozole (Arimidex), letrozole (Femara) 2 nd line therapy:2 nd line therapy: –Fulvestrant (Faslodex), toremifene (Fareston), exemestane (Aromasin) “Palliative”“Palliative” –Goserelin (LHRH analog, Zoladex)

24. Chemotherapy

25. Treatment of Metastatic Breast Cancer: Cytotoxic Agents Anthracyclines (doxorubicin, liposomal doxorubicin)Anthracyclines (doxorubicin, liposomal doxorubicin) CyclophosphamideCyclophosphamide Taxanes (paclitaxel, docetaxel)Taxanes (paclitaxel, docetaxel) Antimetabolites (5-FU, capecitabine)Antimetabolites (5-FU, capecitabine) GemcitabineGemcitabine VinorelbineVinorelbine Carboplatin/cisplatinCarboplatin/cisplatin

26. European School of Oncology Guideline: Chemotherapy for Metastatic Breast Cancer Cardosa F et al, J Natl Cancer Inst 101:1174-1181, 2009 Sequential single agent chemotherapy generally preferred choiceSequential single agent chemotherapy generally preferred choice –Less toxicity than combination chemo –No data to support optimal sequence Combination chemotherapy reserved for patients with:Combination chemotherapy reserved for patients with: –rapid clinical progression –life-threatening visceral metastases –need for rapid symptom/disease control Chosen regimen should be evidence-based, with proven efficacy and acceptable toxicityChosen regimen should be evidence-based, with proven efficacy and acceptable toxicity

27. Biologically-Targeted Therapy

28. Her2/neu status Membrane-associated tyrosine kinase receptor (aka erbB2) related to EGFMembrane-associated tyrosine kinase receptor (aka erbB2) related to EGF –Expressed in breast cancers, DCIS, and some other tissues such as heart –Overexpressed in 25-30% of breast cancers –Associated with more aggressive disease and worse prognosis

29. Measurement of Her2/neu Measured by immunohistochemistry (IHC)Measured by immunohistochemistry (IHC) –Graded 0, 1+, 2+, or 3+ –Based on characteristics of staining –0-1 = negative –2 = indeterminant, should be followed with FISH (fluorescent in situ hybridization) to determine status (amplified/not amplified) –3 = positive Fluorescence In Situ Hybridization (FISH) correlates with response to Herceptin, but more expensive than IHCFluorescence In Situ Hybridization (FISH) correlates with response to Herceptin, but more expensive than IHC

30. Four US FDA-Approved Drugs with HER-2 as a Target cell division HER-2 nucleus cancer cell Trastuzumab (Herceptin) Anti-HER-2 Antibody Lapatinib (Tykerb) Dual HER-1/HER-2 Tyrosine Kinase Inhibitor Pertuzumab Anti-HER-2 Antibody T-DM1 Antibody-Drug Conjugate 20-25% of breast cancers overexpress HER2 Only effective for HER2+ breast cancer

31. Trastuzumab (Herceptin) Humanized monoclonal antibody against her2/neuHumanized monoclonal antibody against her2/neu FDA approved for metastatic breast cancer in 1998FDA approved for metastatic breast cancer in 1998 Responses in patients with her2/neu positive breast cancerResponses in patients with her2/neu positive breast cancer –IHC 3+ –FISH positive Single agent therapy has 26% response rate as 1 st line therapySingle agent therapy has 26% response rate as 1 st line therapy May be given as an IV infusion weekly or every 3 weeksMay be given as an IV infusion weekly or every 3 weeks

32. European School of Oncology Guideline: HER2 Targeted Therapy for Metastatic Breast Cancer Cardosa F et al, J Natl Cancer Inst 101:1174-1181, 2009 Anti-HER2 therapy should be offered early to all HER2+ metastatic breast cancer patients unless contraindicated (or unavailable)Anti-HER2 therapy should be offered early to all HER2+ metastatic breast cancer patients unless contraindicated (or unavailable) Optimal duration of anti-HER2 therapy for metastatic breast cancer (when to stop) unknownOptimal duration of anti-HER2 therapy for metastatic breast cancer (when to stop) unknown

33. Complications of Breast Cancer Bone Metastases Pain Spinal cord compression Radiation therapy Orthopedic surgery Hypercalcemia Fractures The bone is the initial site of recurrence in 35-40% of breast cancer patients

34. European School of Oncology Guideline: Bone Metastases in Breast Cancer Cardosa F et al, J Natl Cancer Inst 101:1174-1181, 2009 Bone modifying agents should be routinely used in combination with other systemic therapy in patients with bone metastasesBone modifying agents should be routinely used in combination with other systemic therapy in patients with bone metastases –Bisphosphonates (pamidronate, zoledronic acid) –RANK ligand inhibitor (denosumab) Agents should be started early, if possible before onset of bone symptomsAgents should be started early, if possible before onset of bone symptoms Should be continued even in presence of disease progressionShould be continued even in presence of disease progression

35. Zoledronic Acid (Zometa) Bisphosphonic acid – inhibitor of osteoclastic bone resorptionBisphosphonic acid – inhibitor of osteoclastic bone resorption Indicated for solid tumor patients with bone metastasesIndicated for solid tumor patients with bone metastases 4 mg IV over 15-30 minutes4 mg IV over 15-30 minutes Check serum creatinine before each administrationCheck serum creatinine before each administration Comparable in efficacy to pamidronateComparable in efficacy to pamidronate Rosen LS, Cancer J 7:377, 2001Rosen LS, Cancer J 7:377, 2001Rosen LS, Cancer J 7:377, 2001Rosen LS, Cancer J 7:377, 2001

36. Systemic Treatment of Breast Cancer: Summary Main principles of modern oncologyMain principles of modern oncology –Multidisciplinary treatment –Evidence-based medicine –Individualized (tailored) therapy Keep in mind goals of therapyKeep in mind goals of therapy –Adjuvant: curative intent –Metastatic: incurable but treatable Include psychosocial and supportive care and symptom- related interventionsInclude psychosocial and supportive care and symptom- related interventions Include patient preferences and active participationInclude patient preferences and active participation –Patients, families and caregivers should be invited to participate in decision-making