BREAST CANCER UPDATE C H R I S S Z Y A R T O, D O G E N E S E E H E M A T O L O G Y O N C O L O G Y F L I N T, M I

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1 BREAST CANCER UPDATE C H R I S S Z Y A R T O, D O G E N E S E E H E M A T O L O G Y O N C O L O G Y F L I N T, M I

2 Overview Why is it important to understand breast cancer? Choosing wisely Appropriateness for treatment Staging for early breast cancer Surveillance for breast cancer Treatment of metastatic breast cancer Review of prognostic factors New drugs for HER2 positive disease Perjeta (Pertuzumab) Kadcyla (Ado-trastuzumab emtansine)

3 Breast Cancer Statistics 1 Most common neoplasm in women 2 nd leading cause of cancer death overall Leading cause of cancer death in women < 65 years old Influence on all of us Professional Personal

4 Choosing Wisely 2 An initiative of ABIM foundation Originally conceived/piloted by NPA Lists were developed by health care organizations Providers identified tests, procedures, treatments to discuss Topics of discussion are being disseminated

5 Choosing Wisely 2 Goal is to promote conversations between providers and patients Patients should choose care that is: Supported by evidence Not redundant Truly necessary Guidelines to help determine an appropriate treatment plan together

6 Treatment 2 Don t use cancer directed therapy for solid tumor patients with the following characteristics: Low performance status (ECOG 3 or 4) No benefit from prior evidence based interventions Not eligible for a clinical trial No strong evidence supporting the clinical value of further anti-cancer treatments

7 Treatment 2 Studies show cancer treatment likely ineffective for those solid tumor patients Use palliative and supportive care in these patients Exceptions exist: Functional limitations from other conditions Disease characteristics suggesting high likelihood of response

8 Performance Status 3 ECOG scale 0: Fully active (Karnofsky ) 1: Able to do light work (Karnofsky 70-80) 2: All self care, up > 50% of waking hours (Karnofsky 50-60) 3: Limited self care, at rest >50% of waking hours (Karnofsky 30-40) 4: Bed bound (Karnofsky 10-20) 5: Dead (Karnofsky 0)

9 Treatment 4 Patient s that are bedridden prior to treatment do worse than fully active patients Physiologic reserve helps determine how a patient copes with stresses of cancer and its treatment

10 Treatment 5 NCCN Breast Cancer guidelines Recurrent or stage 4 disease with ECOG 3 or 4 Consider no further cytotoxic therapy Transition to palliative care

11 Breast Cancer Staging 2 Don t perform PET, CT, and radionuclide bone scans in staging of early breast cancer at low risk of metastasis.

12 Breast Cancer Staging 2 Lack of evidence demonstrating benefit in asymptomatic patients with: DCIS Stage I or II invasive cancer Unnecessary imaging is harmful Unnecessary procedures Over treatment Radiation exposure Misdiagnosis

13 Breast Cancer Staging 5 NCCN Breast Cancer guidelines Staging studies (PET, CTs, bone scans) Stage IIIA or greater If signs/symptoms in patient with earlier stage

14 Cancer and Radiation 6 We Are Giving Ourselves Cancer New York Times article on 1/30/14 CT radiological dose is 100 to 1000 times that of conventional Xray Single CT can expose a patient to amount of radiation that epidemiologic evidence shows can be cancer causing

15 Breast Cancer Surveillance 2 Don t perform surveillance testing (biomarkers) or imaging (PET, CT, radionuclide bone scans) for asymptomatic individuals who have been treated for breast cancer with curative intent.

16 Breast Cancer Surveillance 2 No benefit from routine imaging or serial measurement of tumor markers in asymptomatic patients Differs from some other cancers (ex: colon cancer) Decision to image based on patient symptoms and physical exam Unnecessary imaging is harmful Unnecessary procedures Over treatment Radiation exposure Misdiagnosis

17 Breast Cancer Surveillance 5 NCCN Breast Cancer guidelines History and physical exam every 4-6 months for 5 years then every year Mammogram every year

18 Metastatic Breast Cancer 2 Don t use combination chemotherapy (multiple drugs) instead of chemotherapy with one drug when treating an individual for metastatic breast cancer unless the patient needs a rapid response to relieve tumor related symptoms.

19 Metastatic Breast Cancer 2 Multiple drugs/combination treatments May slow tumor growth for a longer time No overall survival difference compared to single agents More frequent and severe side effects Dose reductions may be needed May worsen quality of life

20 Metastatic Breast Cancer 2 Single drugs No overall survival difference compared to combination treatments Lower risk of side effects May improve quality of life

21 Metastatic Breast Cancer 2 Exceptions exist Significant symptoms from tumor burden Life threatening symptoms HER2 positive breast cancer

22 Metastatic Breast Cancer 5 NCCN Breast Cancer guidelines No compelling evidence that combination regimens are superior to sequential single agents Preferred single agents include: Anthracyclines Taxanes Antimetabolites Other microtubule inhibitors

23 Prognostic Factors 1 Age?? Tumor size Tumor grade Lymph node status Distant mets Estrogen/Progesterone receptor HER2 status Oncotype or Mammaprint score

24 HER2 Status 1 Human epidermal growth factor receptor 2 gene Found on all normal cells HER2 gene amplification results in increased expression of a transmembrane tyrosine kinase Increased proliferation of tumor Increased survival of tumor Increased metastasis Metastasize earlier Worse prognosis

25 HER2 Status 5 Immunohistochemical (IHC) staining 0+ = negative 1+ = negative 2+ = equivocal 3+ = positive FISH testing Number on HER2 gene copies per nucleus 6 or greater signals per cell is positive FISH ratio (HER2/CEP 17) HER2/CEP 17 ratio 2 or greater is positive If ratio < 2 then positive if 6 or greater signals per cell

26 HER2 Drugs Herceptin (Trastuzumab) Tykerb (Lapatinib) Perjeta (Pertuzumab) Kadcyla (Ado-trastuzumab emtansine)

27 Perjeta (Pertuzumab) 5 Recombinant humanized monoclonal antibody Inhibits the ligand dependent dimerization of HER2 and its downstream signaling Binds to different epitopes of HER2 receptor than Trastuzumab (Herceptin)

28 Perjeta (Pertuzumab) 5 Pertuzumab and Trastuzumab have complementary mechansims of action Provide a greater overall anti-tumor effect than either alone Evaluated in metastatic and neoadjuvant setting

29 NeoSphere 7 Lancet Oncology (January 2012) NeoSphere study Efficacy and Safety of Neoadjuvant Pertuzumab and Trastuzumab in Women With Locally Advanced, Inflammatory, or Early HER2 Positive Breast Cancer Multicenter, open label, phase 2 study

30 NeoSphere patients with locally advanced or inflammatory breast cancer Primary end point was pathological complete response Randomly assigned equally to four groups Each group received four neoadjuvant cycles of chemotherapy

31 NeoSphere 7 Trastuzumab and Docetaxel Pertuzumab, Trastuzumab, and Docetaxel Pertuzuzmab and Trastuzumab Pertuzumab and Docetaxel

32 NeoSphere 7 Pathologic complete response rates 31 of 107 (29%) 49 of 107 (45.8%) 18 of 107 (16.8%) 23 of 96 (24%)

33 NeoSphere 7 Most common adverse events of grade 3 or 4 Neutropenia (48 patients) Leukopenia (5 patients) Febrile neutropenia (9 patients) Serious adverse events similar in all groups except the Pertuzumab and Trastuzumab group Lower events in this group because no Docetaxel

34 NeoSphere 7 Patients given Pertuzumab, Trastuzumab, and Docetaxel had significantly improved pathological complete response No substantial differences in tolerability This study supports the neoadjuvant approach with Pertuzumab

35 TRYPHAENA 8 Annals of Oncology (September 2013) TRYPHAENA study Pertuzumab Plus Trastuzumab In Combination With Standard Neoadjuvant Anthracycline-containing And Anthracycline-free Chemotherapy Regimens In Patients With HER2 Positive Early Breast Cancer Multicenter, open label, phase 2 study

36 TRYPHAENA patients with locally advanced or inflammatory breast cancer Study focused on tolerabilty Cardiac safety Symptomatic left ventricular systolic dysfunction (LVSD) Pathological complete response also assessed Randomly assigned equally to three groups Each group received six neoadjuvant cycles of chemotherapy

37 TRYPHAENA 8 FEC = 5 Fluorouracil, Epirubicin, Cyclophosphamide FEC plus Trastuzumab and Pertuzumab x 3 then Docetaxel plus Trastuzumab and Pertuzumab x 3 FEC x 3 then Docetaxel, Trastuzumab, and Pertuzumab x 3 Docetaxel, Carboplatin, Trastuzumab, and Pertuzumab x 6

38 TRYPHAENA 8 Left ventricular ejection fraction Declines of 10% or greater from baseline to <50% 11 total patients Arm A: 4 (5.6%) Arm B: 4 (5.3%) Arm C: 3 (3.9%) Symptomatic LVSD 2 patients (2.7%) Both from Arm B

39 TRYPHAENA 8 Most common side effect was diarrhea Pathological complete response Arm A: 61.6% Arm B: 57.3% Arm C: 66.2%

40 TRYPHAENA 8 Combination of Pertuzumab with Trastuzumab and standard chemotherapy resulted in low rates of symptomatic LVSD

41 Perjeta (Pertuzumab) 5 NeoSphere and TRYPHAENA trials FDA granted accelerated approval for Pertuzumab in combination with Trastuzumab and Docetaxel Neoadjuvant setting Early stage breast cancers T2 or greater (2 cm tumors) N1 or greater

42 CLEOPATRA 9 About 20% of all breast cancers are HER2 positive More aggressive cancer Poor prognosis Most cases of advanced disease eventually progress

43 CLEOPATRA 9 New England Journal of Medicine (1/20/2012) CLEOPATRA study Pertuzumab Plus Trastuzumab Plus Docetaxel For Metastatic Cancer Randomized, double blind, placebo controlled phase 3 trial

44 CLEOPATRA patients with HER2 positive metastatic breast cancer Primary end point was progression free survival (independently assessed) Secondary endpoints Overall survival Progression free survival (investigator assessed) Objective response rate Safety

45 CLEOPATRA 9 Two groups Placebo, Trastuzumab, and Docetaxel Pertuzumab, Trastuzumab, and Docetaxel First line treatment in metastatic setting Continued until disease progression or toxic effects

46 CLEOPATRA 9 Median progression free survival 12.4 months in placebo group 18.5 months in Pertuzumab group P value < Overall survival Strong trend in favor of Pertuzumab group Data not mature yet

47 CLEOPATRA 9 Safety Generally similar in the two groups No increase in LVSD Side effects greater in Pertuzumab group Febrile neutropenia Diarrhea

48 CLEOPATRA 9 Pertuzumab plus Trastuzumab and Docetaxel First line metastatic treatment for HER2 positive breast cancer Significantly prolongs progression free survival Possible overall survival benefit

49 Perjeta (Pertuzumab) 5 NCCN Breast Cancer guidelines Pertuzumab plus Trastuzumab in combination with a taxane is preferred option for first line treatment of HER2 positive metastatic breast cancer Docetaxel is NCCN category 1 recommendation Pacliataxel is NCCN category 2A recommendation

50 EMILIA 10 Trastuzumab emtansine (TDM-1) Antibody-drug conjugate HER2 targeted antitumor properties of Trastuzumab Cytotoxic activity of microtubule inhibitor DM1 Conjugated by a stable linker Allows intracellular drug delivery Specific to HER2 positive cells Minimizes exposure of normal tissue

51 EMILIA 10 New England Journal of Medicine (11/8/2012) EMILIA study Trastuzumab Emtansine For HER2 Positive Advanced Breast Cancer Randomized, open-label, international phase 3 trial

52 EMILIA patients with HER2 positive advanced breast cancer Previously treated with Trastuzumab and a taxane Primary end points Progression free survival (independent review) Overall survival Safety

53 EMILIA 10 Two arms T-DM1 Lapatinib and Capecitabine

54 EMILIA 10 Median progression free survival 9.6 months versus 6.4 months P value < Median overall survival 30.9 months versus 25.1 months P value < Safety Rates of grade 3 or greater adverse events higher in Lapatinib with Capecitabine group (57% vs 41%) Thrombocytopenia and increased serum aminotransferase levels higher in T-DM1 group

55 EMILIA 10 T-DM1 significantly prolongs progression free survival and overall survival Less toxicity compared to Lapatinib with Capecitabine

56 Kadcyla (T-DM1) 5 NCCN Breast Cancer guidelines T-DM1 is a preferred treatment option with HER2 positive metastatic breast in patients previously exposed to a Trastuzumab based regimen

57 Metastatic Breast Cancer 5 Perjeta (Pertuzumab) First line treatment for metastatic HER2 positive breast cancer Use with Trastuzumab and a taxane Kadcyla (T-DM1) Preferred treatment for metastatic HER2 positive breast cancer in patients who have previously received a Trastuzumab based regimen

58 Summary Why important to understand breast cancer Choosing Wisely Appropriateness for treatment Staging for early breast cancer Surveillance for breast cancer Treatment of metastatic breast cancer Review of prognostic factors

59 Summary New drugs for HER2 positive disease Perjeta (Pertuzumab) NeoSphere trial TRYPHAENA trial CLEOPATRA trial Kadcyla (T-DM1) EMILIA trial

60 THANK YOU!!

61 References 1. Casciato D, Territo M. Manual of Clinical Oncology. 6 th ed. Philadelphia: LWW; Choosing Wisely. American Society of Clinical Oncology. 10 Things Physicians and Patients Should Question American Joint Committee on Cancer. AJCC Cancer Staging Handbook. 7 th ed. New York: Springer; Longo D. Harrison s Hematology and Oncology. 17 th ed. New York: McGraw Hill; 2010.

62 References (cont.) 5. NCCN Practice Guidelines In Oncology. Breast Cancer. V Redberg R, Smith-Bindman R. We Are Giving Ourselves Cancer. New York Times. January 30, Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 2012; 13(1):

63 References (cont.) 8. Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol 2013; 24(9): Baselga J, Cortes J, Kim SB, et al. Pertuzumab plus Traastuzumab plus Docetaxel for Metastatic Breast Cancer. N Engl J Med 2012; 366:

64 References (cont.) 10. Verma S, Miles D, Gianni L, et al. Trastuzumab Emtansine for HER2-Positive Advanced Breast Cancer. New Engl J Med 2012; 367: