Customizing Therapeutic Strategies in the Management of Metastatic Breast Cancer

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1 Customizing Therapeutic Strategies in the Management of Metastatic Breast Cancer Vandana G Abramson, MD Assistant Professor of Medicine Division of Hematology/Oncology Vanderbilt University Breast Cancer Facts Breast cancer is the most commonly diagnosed cancer among women in the United States ~ 200,000 new cases/year SEER database Jemal A. CA Cancer J Clin. 2004;54:8-29; American Cancer Society. Breast Cancer Facts and Figures

2 Breast Cancer Metastatic Disease 40,000 patients die due to metastatic breast cancer each year in the U.S. Vast majority are patients relapsing after having received adjuvant treatment for early stage disease Most relapses occur in first 5 years, but can occur at any time (up to 1/5 occur after 10 years) 1 5% women with breast cancer have metastatic disease at presentation. Metastatic Breast Cancer Metastatic breast cancer is treatable, but not curable Median survival: 2 3 years 5 10% survive >5 years 2 5% may survive >10 years 2

3 The Goals of Treatment for Advanced Breast Cancer Maintain quality of life Prolong survival Maintain activity Manage pain and side effects QUALITY OF LIFE Prolong survival Breast Cancer: a Heterogeneous Disease Different cell types in the breast can give rise to a cancer. Luminal Cell Basal Cell Breast cancers have different molecular signatures that dictate tumor biology and predict outcome Luminal Basal HER2 A B 3

4 How do we choose treatment? Based on biology of the disease Hormonereceptor Positive (60% 70%) HER2 Positive (20% 25%) Triple- Negative (~15%) Anti-estrogen Therapy Anti-HER2 Therapy Chemo Therapy ER/PR+ disease Generally biologically less aggressive Can recur at any point By GEP, group to luminal A or B Mainstay of treatment: endocrine therapy 4

5 Types of Hormonal Therapy Used to Treat Advanced Breast Cancer SERMs (selective estrogen receptor modulators) Tamoxifen Estrogen Receptor Antagonist: Fulvestrant (Faslodex) Aromatase inhibitors Anastrozole (Arimidex) Letrozole (Femara) Exemestane (Aromasin) Ovarian ablation Surgery, medication, radiation Case 60 year old female with a 2.3 cm invasive mammary carcinoma, no special type, low grade, low proliferative rate, 1 out of 5 positive lymph nodes How do you decide on treatment? Risk, not stage 5

6 Adjuvant! Online Adjuvant! Online 6

7 Where Are We With Novel Targeted Therapies in ER/PR+ Hormone Resistant MBC? *AMG 479 is not approved by the FDA for the treatment of breast cancer *Everolimus (RAD 001) is not approved by the FDA for the treatment of breast cancer Strong Evidence Links Hormone Resistance to Cross Talk Between Signal Transduction Pathways and ER Signaling IGF 1R, EGFR 7

8 Crosstalk Between ER and mtor Signaling Resistance to hormonal therapy: major limitation Mechanism of endocrine resistance is aberrant signaling of the PI3K/ AKT/ mtor pathway mtor is a key regulator of cell growth and proliferation Close interaction between mtor and ER signaling; substrate of mtor, S6K1, can activate ER in a ligand independent fashion Targeting mtor is rational 1 Yamnik RL, et al. J Biol Chem. 2009; 284(10): Crowder RJ, et al. Cancer Res. 2009;69: Miller TW, et al. J Clin Invest. 2010;120(7): Everolimus (RAD001) Oral and potent inhibitor of mammalian target of rapamycin (mtor) Approved for renal cell carcinoma (multiple countries) and astrocytoma (US) 1 Boulay A, et al. Clin Cancer Res. 2005;11: Ellard SL, et al. J Clin Oncol. 2009;27: Awada A, et al. Eur J Cancer. 2008;44: Baselga J, et al. J Clin Oncol. 2009;27:

9 Everolimus in combination with exemestane for postmenopausal women with advanced breast cancer who are refractory to letrozole or anastrozole: results of the BOLERO 2 phase III trial J. Baselga, M. Campone, T. Sahmoud, M. Piccart, H. Burris, H. Rugo, S. Noguchi, M. Gnant, P. Mukhopadhyay, G. Hortobagyi On behalf of the BOLERO 2 Investigators December 7, 2011 ( /NEJMoa ) BOLERO 2: Trial Design N = Postmenopausal ER+ /HER2 Met BC 1 refractory to letrozole or anastrozole Everolimus 10 mg/day + Exemestane 25 mg/day (N = 485) Placebo + Exemestane 25 mg/day (N = 239) PFS OS ORR Bone Markers Safety PK Stratification: Sensitivity to prior hormonal therapy Presence of visceral disease No cross over Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, Abstract: 9LBA. 9

10 BOLERO 2: Baseline Characteristics Characteristic Everolimus + Exemestane (N=485), % Placebo + Exemestane (N=239), % Median age (range), years 62 (34, 93) 61 (28, 90) Race Caucasian Asian Performance status Liver involvement Lung involvement Measurable disease a a All other patients had 1 bone lesion. Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, Abstract: 9LBA. BOLERO 2 Primary Endpoint: PFS Central Assessment 100 HR = 0.36 (95% CI: ) Log rank P value = 3.3 x Probability of Event (%) Everolimus + Exemestane: 10.6 Months Placebo + Exemestane: 4.1 Months 0 Everolimus + Exemestane (E/N=114/485) Placebo + Exemestane (E/N=104/239) No. of Patients Still at Risk: Time (weeks) Everolimus Placebo Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, Abstract: 9LBA. 10

11 BOLERO 2: Overall Survival As of PFS interim analysis: 83 deaths 10.6% in everolimus arm 13.0% in placebo arm OS interim analysis after 173 events OS final analysis at 392 events 80% power to detect 26% reduction in hazard ratio (0.74) Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, Abstract: 9LBA. BOLERO 2: Summary Addition of everolimus to exemestane prolongs PFS in patients with ER+ HER2 breast cancer refractory to initial non steroidal aromatase inhibitors Local: median 7.4 vs. 3.2 months, HR = 0.44, P<1X10 16 Central: median 11 vs. 4.1 months, HR = 0.36, P<1X10 16 Benefit is observed in all subgroups Adverse events are consistent with previous experience with everolimus including stomatitis, fatigue, non infectious pneumonitis and hyperglycemia Everolimus is the first agent to enhance the clinical benefit of hormonal therapy in refractory ER+ patients These results represent a paradigm shift in the management of patients with hormone receptor positive breast cancer Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, Abstract: 9LBA. 11

12 How to choose treatment? Anastrazole + Fulvestrant Fulvestrant (500 mg) Exemestane + Everolimus Tamoxifen GNRH agonist Other AIs Metastatic at presentation 1st Line, better than anastrazole alone Fine in 2 nd, 3 rd line 2 nd line or early relapse More toxic than other endocrine options Tamoxifen 1 st line for premenopausal Add GNRH agonist POD: all other options to left QUALITY OF LIFE TOXICITY EFFICACY 12

13 ER/PR/HER2 negative disease or triple negative BC TNBC 15% of new cases of breast cancer will be triple negative (ER/PR/HER2 negative) TNBC: more aggressive higher proliferative rates, higher histologic grades, present with larger tumors, higher recurrence rates, and lower survival (stage for stage than ER+) More common in younger, Hispanic, and AA women 13

14 Triple negative Breast Cancer Time to recurrence Dent R et al. Clin Cancer Res 2007;13: Recurrences tend to occur more often in visceral organs (compared to ER/PR+ BC) : higher rate of brain, lung, distal nodal, and liver mets Not all TNBC are the same: - Good TNBC vs. bad TNBC 14

15 Definitions: TNBC v. Basal like TNBC (triple negative breast cancer): defined based on immunohistochemistry Lack of expression of ER/PR/HER2 Basal like: defined based on gene expression profiling GEP shares characteristics with basal epithelial cells High EGFR, proliferation genes, and basal cluster (CK 5, 14, and 17) Most basal likes are TN 25% of basal like BCs will express ER/PR/HER2 by IHC On GEP, 25% of TNBC do not have basal like pattern Claudin low: found in non basal TNBC: express epithelialmesenchymal transition genes and stem cell like patterns TNBC v. basal like Poor prognosis associated with TNBC is likely driven by the majority with basal like biology Basal like cancers have a worse prognosis than the overall BC population or TN subgroup. Prognostic value strong in LN negative patients Molecular profiling not widely available, so TN phenotype is a clinical surrogate 15

16 No validated targets identified: chemo is the standard of care Anthracyclines Doxorubicin (Adriamycin) Liposomal doxorubicin (Doxil) Taxanes Docetaxel (Taxotere) Paclitaxel (Taxol) Nab paclitaxel (Abraxane) Platinum containing compounds Cisplatin Carboplatin Others Gemcitabine (Gemzar) Capecitabine (Xeloda) Vinorelbine (Navelbine) Ixabepilone (Ixempra) Eribulin Mesylate (Halaven) Can we target TNBC? Stem cell inhibitors Angiogenesis inhibitors JAK2 inhibitors EGFR inhibitors Src inhibitors MET Inhibitors Histone Deacetylase inhibitors Platinum agents PARP (Polyadenosine Diphosphate Ribose Polymerase) inhibitors PI3K inhibitors 16

17 PARP inhibitors: targeted therapy for BRCA+ and triple negative breast cancer Background: Mechanism of PARP inhibitors DNA damage Environmental causes/carcinogens (unwanted) Chemotherapy (wanted) Repair Two major mechanisms: Homologous recombination (BRCA) Base excision repair (PARP) 17

18 Mechanism of Cell Death from Inhibition of Polyadenosine Diphosphate Ribose Polymerase 1 (PARP 1) Iglehart et al., N Engl J Med. 2009;361: Olaparib and Veliparib in BRCA mutated breast cancer PARP inhibitors which have shown activity in BRCA mutated breast cancers Single agent oral olaparib 400 mg BID has substantial activity in heavily pretreated BRCA1/BRCA2 carriers with advanced breast/ovarian cancer Olaparib: First report of a targeted therapy trial designed for BRCA1/BRCA2 carriers with breast or ovarian cancer Veliparib alone, Veliparib + carboplatin, Veliparib + carboplatin + paclitaxel, Veliparib + temozolamide: promising early results 18

19 Why PARP inhibition in TNBC? TNBC shares clinical and pathologic features with BRCA-1 related BC Characteristics Hereditary BRCA1 Triple Negative/Basal Like [1-3] ER/PR/HER2 status Negative Negative TP53 status Mutant Mutant BRCA1 status Mutational inactivation* Diminished expression* Gene-expression pattern Basal like Basal like Tumor histology Poorly differentiated (high grade) Poorly differentiated (high grade) Chemosensitivity to DNA-damaging agents Highly sensitive Highly sensitive *BRCA1 dysfunction due to germline mutations, promoter methylation, or overexpression of HMG or ID4. [4] PARP is upregulated in most TNBC Dual blockade of DNA repair mechanisms may be important 1. Perou C, et al. Nature. 2000;408: Cleator S, et al. Lancet Oncology. 2007;8: Sorlie T, et al. Proc Natl Acad Sci U S A. 2001;98: Miyoshi Y, et al. Int J Clin Oncol. 2008;13: PARP Inhibitors in TNBC 1. PLATINUM CHEMOTHERAPY Inflicts DNA damage via adducts and DNA crosslinking CG CG AT T TA CG GC A PARP1 2. PARP1 UPREGULATION Base-excision repair of DNA damage CG CG AT T TA C G A PARP1 BSI INHIBITION OF PARP1 PARP1 Disables DNA base-excision repair 4. REPLICATION FORK COLLAPSE Double-strand DNA break BRCA1 BRCA2 Cell Survival Cell Death O Shaughnessy J, et al. ASCO Abstract 3. 19

20 Multicenter, randomized, open label phase III study of Gemcitabine/Carboplatin +/ Iniparib Iniparib: small molecule PARP inhibitor Patients Metastatic breast cancer, ER/PR/HER2 negative (TNBC) < 2 prior chemotherapy regimens for metastatic disease Measurable disease ECOG PS 0-1 Stable brain mets allowed Arm A (n=62) Gemcitabine 1000 mg/m2 d1, d8 + Carboplatin AUC 2 d1, d8 21 day cycle Arm B (n=61) 1:1 randomization Gemcitabine 1000 mg/m2 d1, d8 + Carboplatin AUC 2 d1, d mg/kg IV d 1,4,8,11 q 3 wks 21 day cycle BSI 201 *Patients randomized to gem/carbo alone could crossover to receive gem/carbo + Iniparib at disease progression. Randomization stratified by prior chemo in the metastatic setting: -1 st -line (no prior therapy -2 nd /3 rd -line (1-2 prior therapies) Studies of PARP inhibitors Phase II study of iniparib: improvement in OS Phase III study: benefit in PFS, not OS Why? Multifactorial Is iniparib a PARP inhibitor? Wrong population tested? Target patients with defects in homologous recombination or BRCA 1/2 mutations Target basal subtype? 20

21 Triple Negative Subtype GE Patterns are Reproducible UNS Unclassified BL1 Basal like 1 BL2 Basal like 2 Characterized by cell cycle and DNA damage response genes IM Immunomodulatory Defined by immune cell surface antigens, receptors, and signal transduction genes M Mesenchymal MSL Mesenchymal/Stem like Enriched in cell differentiation, epithelialmesenchymal transition and growth factor pathways Cell cycle/dna replication TGF /growth factors mesencymal p63/cell communication Immune Signaling Focal Adhesion/growth factors stem cell LAR Luminal/Androgen receptor Driven by androgen receptor signaling Androgen Signaling 21

22 How to choose treatment for mtnbc? Questions to consider Adjuvant tx? Visceral disease? Performance status? Comorbidities Taxanes Paclitaxel (nabpaclitaxel) Docetaxel Most efficacious Often used adjuvantly Neuropathy Well tolerated Platinums cisplatin carboplatin Efficacious, esp for basal-like Well tolerated Eribulin Anthracyclines Combinations Gemcitabine/Carbo Docetaxel/Xeloda Combinations for visceral disease QUALITY OF LIFE TOXICITY EFFICACY TNBC: Conclusions Triple negative breast cancer is composed of a number of subtypes Challenge: recognizing which subtypes are targetable Clinical trials underway to target TNBC, but it is important to select patients rationally, not just TNBC patients 22

23 HER 2+ Breast Cancer HER2 positive MBC 20 25% of breast cancers overexpress HER 2 Normal breast epithelium (~20,000 receptor molecules) HER2-positive tumor cell (Up to 1-2 million receptor molecules) Courtesy of Jeffrey Ross, Albany Medical College, Albany, NY. 23

24 HER2/neu proto oncogene: poor prognosis in breast cancer 1.0 HER2 gene amplification (FISH) HER2 protein overexpression (IHC) Surviving HER-2/neu signal per chr17cen 2 (711) > 2 (189) Log-Rank p= Wilcoxon p= Time (months) HER2 overexpression Poorly differentiated tumors Markers of high proliferation Worse DFS and OS Median Survival: HER2 overexpression HER2 normal 6 7 yrs 3 yrs Slamon Science 1987 Targeting HER2+ Tumors Inhibit Dimerization Inhibit Kinase Activity Moderate Receptor Expression Refine Antibodies Potentiate Downstream Effects Burstein HJ. N Engl J Med. 2005;353:

25 4/16/2013 Trastuzumab prolongs survival of patients with MBC FISH (+) 1.0 Herceptin+Chemotherapy (n=125) Chemotherapy Alone (n=116) Probability 0.8 IHC 2+/3+ Herceptin+Chemotherapy (n=235) Chemotherapy Alone (n=234) 0.6 Median (months) Relative Risk * ( ) 25* ( ) *p< Survival (months) Slamon NEJM 2001 HER2 treatment options beyond trastuzumab 25

26 Lapatinib Mechanism of Action Binds to intracellular ATP binding site of EGFR (ErbB 1) and HER2 (ErbB 2) preventing phosphorylation and activation Lapatinib Blocks downstream signaling through homodimers and heterodimers of EGFR (ErbB 1) and HER2 (ErbB 2) Dual blockade of signaling may be more effective than the single target inhibition provided by agents such as trastuzumab Downstream signaling cascade Rusnak et al. Mol Cancer Ther 2001;1:85-94; Xia et al. Oncogene 2002;21: ; Konecny et al. Cancer Res. 2006;66: EGF100151: Phase III study of capecitabine +/ lapatinib Stage III/IV refractory or MBC HER2+ (FISH+) Prior anthracycline, taxane, and/or trastuzumab therapy ECOG PS 0 1 R A N D O M I Z E n=161 n=160 Capecitabine 1250 mg/m 2 bid d1 14 q3w Capecitabine 1000 mg/m 2 bid d Lapatinib 1250 mg qd d1 21 q3w Primary end point: TTP Secondary end points: ORR, clinical benefit, DOR, PFS, OS, safety, QOL, ErbB2 serum concentration Geyer NEJM,

27 EGF100151: Progression free Survival % of patients progression-free* Lapatinib + Capecitabine (n=160) Capecitabine (n=161) Progressed or 49 (28%) 72 (43%) died* Median TTP, mo HR (95% CI) 0.49 ( ) P value < Weeks *Censors 4 patients who died from causes other than breast cancer. EGF104900: Phase III study of lapatinib +/ trastuzumab Key Inclusion HER2+(FISH+/ IHC3+) MBC Progression on Anthracycline Taxane Trastuzumab Stratification Factors Visceral Disease Hormone Receptor R A N D O M I Z E Lapatinib 1500 mg/day PO N=148 Crossover if PD after 4wk therapy (N=73) Lapatinib 1000 mg/day PO Trastuzumab 2 mg/kg IV weekly N=148 Blackwell JCO

28 EGF104900: Progression free Survival Cumulative % Alive without Progression % 28% 6 Mo PFS L N = 145 L+T N = 146 Progressed or Died, n Median, mos 2 3 Hazard ratio (95% CI) 0.73 (0.57, 0.93) P value Subjects At Risk Time from Randomization (wks) L L+T EGF104900: Overall Survival 28

29 Pertuzumab Trastuzumab HER2 Pertuzumab HER3 Subdomain IV of HER2 Dimerization domain of HER2 CLEOPATRA: Phase III Study of Docetaxel/ Trastuzumab +/ Pertuzumab 1:1 randomization Trastuzumab + docetaxel + placebo HER2+ MBC First line n = 808 Trastuzumab + docetaxel + pertuzumab Endpoints: Progression-free survival Overall survival Quality of life Biomarker analysis Baselga NEJM

30 CLEOPATRA: Progression free Survival Progression-free survival (%) n at risk Ptz + T + D: median 18.5 months Pla + T + D: median 12.4 months HR = % CI p< Time (months) = 6.1 months Ptz + T + D 402 Pla + T + D Stratified by prior treatment status and region D, docetaxel; PFS, progression free survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab CLEOPATRA: Preliminary Overall Survival Overall survival (%) Ptz + T + D: 69 events Pla + T + D: 96 events Time (months) HR = 0.64* 95% CI p = * n at risk Pertuzumab + T + D Placebo + T + D * The interim OS analysis did not cross the pre-specified O Brien-Fleming stopping boundary (HR 0.603; p ) D, docetaxel; OS, overall survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab 30

31 Pertuzumab: Practical Questions Previous treatment with trastuzumab or AI? Probably fine Other taxanes (paclitaxel?) Probably fine, phase II studies were fine. Other chemo combination? (Vinorelbine?) Absence of toxicity data T DM1 (Kadcyla) 31

32 EMILIA: Phase III Study of T DM1 vs. capecitabine + lapatinib HER2+ (central) LABC or MBC (N=991) Prior taxane and trastuzumab Progression of metastatic tx or within 6 months of adjuvant tx T DM1 3.6 mg/kg q3w IV 1:1 randomization Capecitabine 1000 mg/m2 orally BID, days 1 14, q3w + Lapatinib 1250 mg/day orally QD Stratification: world region, # prior chemo, visceral disease Primary endpoints: PFS, OS and safety Secondary endpoints: PFS by investigator, ORR, duration of response, time to symptom progression Blackwell, ASCO 2012 EMILIA: Progression free survival NEJM

33 EMILIA: Response rate and Treatment Duration EMILIA: Overall Survival 2 nd Interim Analysis 33

34 Adverse Events 1 st line MBC: TDM1 HER2+ MBC or recurrent locally advanced breast cancer First-line (N=137) T DM1 3.6 mg/kg q3w IV 1:1 randomization Docetaxel 75 or 100 mg/m2 q 3 weeks + Trastuzumab 6 mg/kg q 3 weeks 34

35 Progression Free Survival 1 st line HER2+ MBC Ph II study Lower rates of neutropenia and alopecia, T DM1 better tolerated (less gr 3/4 events) Preliminary OS: no difference 2011 European Multidisciplinary Cancer Congress 35

36 T DM1 Ongoing Phase III study Ongoing Phase III study: MARIANNE: T DM1 v. T DM1 + pertuzumab v. paclitaxel + trastuzumab How to choose treatment? Lapatinib + Capecitabine Lapatinib + Trastuzumab Chemo + Trastuzumab + Pertuzumab T DM1 2 nd Line Relatively toxic (diarrhea, rash) Possible benefit in CNS disease > 2 nd Line Less toxic, no chemo Possible benefit in CNS disease QUALITY OF LIFE TOXICITY 1 st Line Very efficacious Little additional toxicity from pertuzumab EFFICACY 2 nd Line Very efficacious Well tolerated Is residual disease posttreatment still HER2 positive? 36

37 Suggestions Chemo + Trastuzumab + Pertuzumab T DM1 Upon progression: Biopsy residual disease HER2+ HER2 Lapatinib + Capecitabine Lapatinib + Trastuzumab Chemo + Trastuzumab Chemo (not HER2 based) Advances in the Treatment of MBC 1980 Tamoxifen CMF Doxorubicin Mitoxantrone Epirubicin Paclitaxel Vinorelbine Aromatase Inhibitors Docetaxel Gemcitabine MBC Trastuzumab ER or PR+ MBC Capecitabine HER2+ MBC Fulvestrant Albumin-Bound Paclitaxel Lapatinib Everolimus Ixabepilone Pertuzumab Eribulin TDM-1 37

38 Conclusions Breast Cancer is a heterogeneous disease; its different subsets (ER+, HER2+, TN) are associated with markedly distinct outcomes Recent advances in breast CA screening/ diagnosis and treatment have clearly improved survival; new targeted therapies are likely to improve outcomes even more TUMOR BIOLOGY is the most important factor in treatment and survival Future: identifying more relevant targets, understanding mechanisms of resistance THANK YOU 38

39 PD (CDK4/6 inhibitor) + Letrozole vs Letrozole: Study Design 2 part, randomized phase II study Stratified by disease site (visceral, bone only, or other); Disease-Free Interval (>12 vs 12 mo from end of adjuvant to recurrence or de novo advanced disease) Part 1 Part 2 Stratified by disease site (visceral, bone only, or other); Disease-Free Interval (>12 vs 12 mo from end of adjuvant to recurrence or de novo advanced disease) Postmenopausal women with ER positive, HER2 negative advanced breast cancer (N = 66) PD mg QD + Letrozole 2.5 mg QD Letrozole 2.5 mg QD Postmenopausal women with ER positive, HER2 negative advanced breast cancer, CCND1 amp, and/or p16 loss (N = 99) PD mg QD + Letrozole 2.5 mg QD Letrozole 2.5 mg QD All patients continued assigned treatment until disease progression, withdrawal of consent, or unacceptable toxicity with follow-up tumor assessment every 2 mos Finn RS, et al. SABCS Abstract S1-6. PD Plus Letrozole vs Letrozole: PFS Significant improvement with PD plus letrozole vs letrozole PFS PD Letrozole (n = 84) Letrozole (n = 81) Events, n (%) 21 (25) 40 (49) Median PFS, mos (95% CI) 26.1 ( ) 7.5 ( ) HR (95% CI) 0.37 ( ) P Value <.001 Finn RS, et al. SABCS Abstract S1-6. Reproduced with permission. 39

40 PD Plus Letrozole vs Letrozole: PFS Clinical benefit evident with combination of PD plus letrozole Best Overall Response (ITT), % PD Letrozole (n = 84) Letrozole (n = 81) All randomized patients, n ORR, % (95% CI) 34 (24 46) 26 (17 37) CR 0 1 PR Patients with measurable disease, n (%) 64 (76) 65 (80) ORR, % (95% CI) 45 (33 58) 31 (20 43) CR 0 0 PR SD 24 wks Clinical benefit rate SD < 24 wks PD 4 21 Indeterminate 10 7 Finn RS, et al. SABCS Abstract S1-6. Reproduced with permission. PD Plus Letrozole vs Letrozole: Adverse Events Most common and concerning PD associated adverse event was 51% grade 3/4 neutropenia Finn RS, et al. SABCS Abstract S