Presenter: Dr. Suman Rao May 13, 2016

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1 Presenter: Dr. Suman Rao May 13,

2010 Breast Cancer Estimates 207,090 NEW CASES 4% Melanoma of Skin 2% Thyroid 31% Breast 13% Lung & Bronchus 2% Pancreas 11% Colon & Rectum 4% Ovary 6% Uterus 3% Urinary 4% Non-Hodgkin s Lymphoma 21%

2 2010 Breast Cancer Estimates 207,090 NEW CASES 4% Melanoma of Skin 2% Thyroid 31% Breast 13% Lung & Bronchus 2% Pancreas 11% Colon & Rectum 4% Ovary 6% Uterus 3% Urinary 4% Non-Hodgkin s Lymphoma 21% All Other Sites 39,840 DEATHS 2% Brain 15% Breast 25% Lung & Bronchus 6% Pancreas 11% Colon & Rectum 5% Ovary 2% Uterus 2% Urinary 2% Stomach 5% Non-Hodgkin s Lymphoma 4% Leukaemia 23% All Other Sites 2

3 Breast Cancer Incidence and Mortality in 2010 Invasive breast cancer Women: 207,090 (1 in 8, 12%) Men: 1,970 In-situ cancer 54,010 Breast cancer deaths Women: 39,840 Men: million survivors! 3

4 Mortality Trends 4

5 TNM Staging Stage 0 in situ (noninvasive) cancer Stage I T 2 cm or smaller, node negative Stage II T > 2 cm OR positive lymph nodes Stage III involves skin OR 4+ axillary lymph nodes OR supraclavicular/internal mammary nodes Stage IV distant metastasis (brain, lung, liver, bone) 5

6 Staging 10 yr. survival by stage: Stage 0 - no metastatic potential, local therapies are curative Stage I 70-90% Stage II 50-70% Stage III 20-40% Stage IV - < 10% 6

7 Targeted Biologic Therapy 1. Need to have a target unique to the cancer cells (not on normal cells). 2. The Magic Bullet that attacks ONLY the target on the cancer cells. 7

8 Overview of Biomarkers: What is a Biomarker? Biomarker: A biological molecule found in blood, other body fluids, or tissues that is a sign of a normal or abnormal process, or of a condition or disease 8

RAS RAF MAPK MEK P Trastuzumab P Cytoplasm P P P P ER ER p160 CBP Basal transcription

9 Anastrozole Therapeutic Modification of Different Signalling Pathways Growth factor Estrogen Plasma membrane ER Cell survival P P P IGFR P Akt PI3-K P p90 RSK P HER2 P P SOS RAS RAF MAPK MEK P Trastuzumab P Cytoplasm P P P P ER ER p160 CBP Basal transcription machinery Cell growth Nucleus Mackey JR, et al. SABCS Abstract 3. ERE ER-mediated gene transcription 9

10 Case I 56 year old woman 2.2 cm infiltrating ductal carcinoma All lymph nodes negative ER Positive (90%), PR positive (60%), Her 2 negative, Grade II 10

11 Gene Profiling ( Health Oncotype DX assay (Genomic used fixed, paraffin-embedded tissue samples from NSABP 14 and 20 trials (ER +, node negative, tamoxifen, long term ( follow-up multi-gene RT-PCR screen of 200 genes identified 21-gene panel assay that strongly predicted for recurrence risk SABCS 2003 #16 11

12 PROLIFERATION Ki-67 STK15 Survivin Cyclin B1 MYBL2 INVASION Stromelysin 3 Cathepsin L2 Oncotype DX Technology: Final Gene Set HER2 GRB7 HER2 GSTM1 CD68 BAG1 ESTROGEN ER PGR Bcl2 SCUBE2 REFERENCE Beta-actin GAPDH RPLPO GUS TFRC 12

6% Intermediate (RS 18-30) 22% 14.3% 8.3%, 20.3% High (RS 31) 27% 30.5% 23.6%, 37.

13 B-14 RESULTS Low, Intermediate & High Risk Groups Risk Group % of 10-yr Rate 95% CI Patients Recurrence Low (RS<18) 51% 6.8% 4.0%, 9.6% Intermediate (RS 18-30) 22% 14.3% 8.3%, 20.3% High (RS 31) 27% 30.5% 23.6%, 37.4% Test for the 10-year DRFS comparison between the Low and High risk groups: p< Paik et al, SABCS

14 Predictive Value NSABP B-20 BENEFIT OF CHEMO Low Risk Int Risk Tam Tam + Chemo High Risk DRFS at 10 Years (%) 14

15 Recurrence Score as a Continuous Predictor Paik et al, SABCS

16 Oncotype DX Oncotype Recurrence score isa better predictor of recurrence than standard factors such as age, tumor size and grade, both in prognostic power and reproducibility How might this be applied? 16

17 CASE 1: 2.2 cm 17

18 MammaPrint Assay Retrospective studies in both ER+/ ER- breast cancers 70 gene assay, originally on fresh tissue, now on frozen tissue 3 different studies with Stage 1-3 cancers 18

19 MINDACT Trial Participants divided into four groups based on risk assessment by both MammaPrint And Adjuvant! Online : 2,745 low risk of recurrence G-low/C-low 1,806 High risk of recurrence G-high/C-high 592 high risk by MammaPrint and low risk by Adjuvant! Online G-high/C-low 1,550 were low risk by MammaPrint and high risk by Adjuvant! Online G-low/C-high. Patients G-low/C-low,no adjuvant chemotherapy G-high/C-high adjuvant chemotherapy. Patients G-high/C-low or G-low/C-high were randomly assigned adjuvant chemotherapy or no adjuvant chemotherapy. 19

20 MINDACT TRIAL Overall chemotherapy use was reduced by 14% In patients with High risk by Adjuvant/ Low risk by Mammaprint, DF was over 94% 20

21 Old is still SEXY! Hormonal manipulation is the oldest targeted therapy! (oophorectomy 1896, tamoxifen 1977) 21

22 Premenopausal Gonadotropins (FSH + LH) Estrogen Production: Pre vs. postmenopausal Hypothalamus Pituitary Gland Premenopausal and Postmenopausal Adrenocorticotropic Hormone (ACTH) Ovary Prolactin Growth Hormone Corticosteroids Adrenal Gland aromatase Estrogens Progesterone Androgens Estrogens Progesterone 22

23 Hormonal Therapy: Treatment Options Summary Premenopausal patients Ovarian ablation - Oophorectomy - Chemical castration (LHRH agonists: Trelstar, Zoladex, Lupron) tamoxifen (Faslodex) Postmenopausal patients tamoxifen aromatase inhibitors (Faslodex) 23

24 X Ovarian Ablation GROWTH Breast cancer cell = Estrogen Receptor = Estrogen 24

25 Tamoxifen Benefits ( 25% ) increased overall survival decreased contralateral breast ( 50% ) cancer increased bone mineral density with decreased incidence of hip fracture lower cholesterol levels (total and ( HDL Toxicities increased risk of thromboembolic events ( 1-2/100 ) increased risk of uterine cancer (2- ( 4/1000 cataracts hot flashes,vaginal dryness and discharge ( gain (depression, weight 25

26 Aromatase Inhibitors - Inhibit conversion of androgens from the adrenal glands to estrogens via the :( muscle aromatase enzyme (in fat and ( anastrozole ) - Arimidex ( letrozole ) - Femara ( exemestane ) - Aromasin Effective in POSTMENAPAUSAL women only! 26

27 100 ATAC TRIAL Disease-free Survival in ITT Population Proportion event free (%) Anastrozole Tamoxifen Combination HR 95.2% CI p-value AN vs. TAM Comb vs. TAM Lancet 2002; 359: Time to event (months) 27

28 Significant Difference in Pre-defined Adverse Events In favor of anastrozole In favor of tamoxifen Hot flushes Weight gain* Vag. bleeding Vag. discharge Endo Ca ICVA VTE DVT (-8.6%) (-5.4%) (-3.6%) (-1.8%) (-0.4%) (-1.1%) (-1.4%) (-0.7%) (2.1%) (0.8%) (6.6%) MSK disorders Fractures Fractures of hip, spine, wrist * proportion with 10% gain in body weight from baseline to year Difference between anastrozole and tamoxifen AEs (%) 28

29 Case 2 45 year old woman 2.6 cm infiltrating ductal cancer, 2 lymph nodes positive ER +(30%), PR -, Her 2 positive ( 3+), Grade III 29

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32 The HER Family Ligand binding domain erb-b1 EGFR HER1 neu Erb-b2 HER2 Erb-b3 HER3 Erb-b4 HER4 Transmembrane Tyrosine kinase domain 32

33 Targeted Therapy Herceptin. Kadcyla (TDM-1), Pertuzumab Lapatinib (neratinib, dovitinib) * 33

34 Adjuvant Herceptin Results THE MOST POSITIVE ADJUVANT BREAST CANCER TRIAL EVER Herceptin now standard for her 2 + patients with tumor size of 6. 0 cm Only about 25% of patients overexpress Her 2 34

35 Disease-Free Survival % AC T AC TH 87% 75% 85% 67% N Events AC T AC TH HR=0.48, 2P=3x10-12 Romond EH, et al. N Engl J Med 2005;353: Years From Randomization 35

36 Pertuzumab Her2 receptor must form a pair (dimerize) to activate TK pathways Pertuzumab binds to Her2 dimerization domain to block this Her2 forms heterodimers with Her1,3,4 so potentially more patients can respond (not just Her2 amplified patients) 36

37 Addition of Pertuzumab NeoSphere Trial THP x 4 cycles or TH or TP or DT All received 3 cycles of FEC chemo + 1 year of Herceptin pcr rates of 46,29,17 and 24% Tryphaena Trial 223 women Combination of FEC/ Docetaxel /Trastuzumab with or without Pertuzumab, did not show any difference in PCR rates ( all over 50%) Lapatinib has also shown some increase in PCR, however, side effects are worse 37

38 Case 3 40 year old African American woman. Felt lump in November, pea sized. Saw her Gyn in January, by then was 3 cm Surgery showed a 3 cm Invasive ductal carcinoma, 4 LN positive ER-/PR-/Her2 Family H/o a paternal aunt with breast cancer. Paternal GM with ovarian cancer 38

39 Triple-negative Breast Cancer ER/PR/Her 2 negative lacks all targets younger and African American woman aggressive, high 3 yr mortality rate prevalent in BRCA mutation carriers 39

40 Triple-negative Breast Cancer No identifiable targets yet that can be used to make treatment decisions Usually treated with adjuvant chemotherapy with Adriamycin, cytoxan and taxanes Carboplatin may be beneficial in these patients PARP inhibitors are being tested in clinical trials in patients with BRCA mutations 40

41 Case 4 62 year old patient Has not been getting routine mammogram Found lump Mammogram/ ultrasound shows a 4 cm tumor with 3 suspicious lymph nodes. Biopsy of the tumor as well as lymph nodes confirms an infiltrating ductal carcinoma PET scan negative for any metastases ER/PR/Her 2 41

42 Stage III: Locally advanced Main approach is neoadjuvant therapy Defintion: chemotherapy, hormonal therapy or radiation before surgery primary chemotherapy 42

43 Case 4-1 ER 70 + positive, PR 40+ positive Anthracycline based regimens, AC-T or TAC. RR of 90% clinically, pcr of 25 % Addition of other drugs such as Capecitabine does not seem to make a difference Endocrine therapy Not standard In a phase II trial- 239 patients postmenopausal patients, randomized to Exemestane or 4 cycles of Adriamycin/Taxol. No difference in Response rates. cpr 3 versus 6% GEICAM Trial, 95 patients 4 cycles of Epirubicin/ Cytoxan followed by Taxotere or 24 weeks of Exemestane. Clinical response was 66 vs. 48%, 3 patients with pcr vs. none 43

44 Case 4-2 ER+ 40%/PR+ 10%,Her2+ 3 by FISH Pooled analysis of 2 Trials combining chemotherapy with Trastuzumab pcr 43% vs. 20%.Reduction in relapse rate- 26%vs 39% and a trend toward improved OS. NOAH trial Improved DFS and OS at 5 years Trastuzumab is then continued for a duration of 1 year 44

45 Case 4-3 ER-/PR-/Her 2- Triple negative breast cancer Standard is a combination of Adriamycin/ Cytoxan every 2 weeks followed by Taxol weekly x 12 weeks or a 3 drug combination of Docetal,Adriamycin and Cytoxan every 3 weeks x 6 cycles. Addition of Carboplatin in a recent study improved cpr, no significant difference in DFS/OS so far PARP inhibitors being investigated 45

46 Case 5 68 year old woman. Never had mammogram Lump in right breast forsom e months.l ymph nodesfelt in axilla on exam Scans show multiple lytic lesions in bone as well 2 lesions in liver, suspicious Biopsy, infiltrating lobular carcinoma, ER 90%,PR 70%, Her 2-46

47 Treatment Strategy in Advanced (metastatic) Disease Hormones, hormones and more hormones Use one hormonal manipulation after another, milking each one for all you can, then moving onto the next. Use chemotherapy only when hormones fail, or one needs a quick response, or hormone independent disease 47

48 Hormonal Therapy: Treatment Options Summary Premenopausal patients Ovarian ablation - Oophorectomy - Chemical castration (LHRH agonists: Trelstar, Zoladex, Lupron) tamoxifen (Faslodex) Postmenopausal patients tamoxifen aromatase inhibitors (Faslodex) 48

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51 Palbociclib Inhibitors of CD4 and CD6 kinases Phase 2 study in combination with Letrozole. 165 patients randomized PFS 20 months vs. 10 months in favor of Palbociclib OS 37 vs. 33 months Increased side effects of fatigue, neutropenia Combination with Fulvestrant also improved PFS 51

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53 Everolimus plus Exemestane (BOLERO TRIAL). 724 women who progressed on Anastrozole Exemestane plus Everolimus or placebo Improvement in PFS, 7 vs. 3 months Higher ORR No improvement in OS 53

54 Pertuzumab Phase III CLEOPATRA trial presented 12/11 1 st line metastatic Her2 amplified Taxotere/Herceptin +/- pertuzumab prolonged PFS from 12 to 18 months 54

55 T-DM1: Her 2 antibody-drug conjugate Approved last year Response rates 40-50% Minimal toxicity (thrombocytopenia) 55

56 T-DM1:Her 2 antibody-drug conjugate First in class Cytotoxic agent (microtubule inhibitor) tightly bound to Herceptin Delivered intracellulary, released once antibody binds to Her 2 receptor 56

57 Systemic Chemotherapy Choices: Juggling Toxicities Adriamycin - cardiomyopathy Cytoxan - leukemia Taxol/Taxotere - neuropathy 5FU/xeloda (oral) hand-foot syndrome Carboplatin thrombocytopenia Navelbine neuropathy Gemcitabine 57

58 DRIVER Mutations DRIVER mutations- useful biomarkers for predicting efficacy of targeted therapy somatic genome alterations occur in the genome of cancer cells within genes that encode for proteins critical to cell growth and survival. impart an oncogene-addicted biology to the transformed cell, meaning that the mutated protein causes reliance within the cancer cell to receive a signal from the driver in order to survive 58

59 Gene Profiling Improving our prognostic and predictive powers: Who is most likely to recur? Who is most likely to benefit from a particular hormonal manipulation? Who is most likely to benefit from a particular chemotherapy drug? Define genetic marker profiles to determine what is the best therapy for the individual patient. 59

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62 THEN NOW 62

63 In conclusion we are seeing: Less invasive local therapies More discriminating use of chemotherapy incorporating tumor biology, not just anatomic information More elegant targeted therapies with less normal cell toxicity Rapidly accelerating rate of new drug development MORE SURVIVORS 63

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BREAST CANCER. Dawn Hershman, MD MS. Medicine and Epidemiology Co-Director, Breast Program HICCC Columbia University Medical Center.

BREAST CANCER. Dawn Hershman, MD MS. Medicine and Epidemiology Co-Director, Breast Program HICCC Columbia University Medical Center. BREAST CANCER Dawn Hershman, MD MS Florence Irving Assistant Professor of Medicine and Epidemiology Co-Director, Breast Program HICCC Columbia University Medical Center Background Breast cancer is the