Personalizing Treatment Strategies in the Management of Metastatic Breast Cancer

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1 Personalizing Treatment Strategies in the Management of Metastatic Breast Cancer Vandana G Abramson, MD Assistant Professor of Medicine Division of Hematology/Oncology Vanderbilt University Breast cancer incidence/mortality: U.S., Incidence Mortality 1

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 What does it mean to personalize treatment for breast cancer? 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 Kadcyla Brief history First breast cancer cases documented in the Edwin Smith Papyrus, ~ BC Etiology: The Gods Treatment: There is none Described by the Greeks (Hippocrates and Galen) in ~ BC Etiology: Humoral theory (excess of black bile in the blood liver and spleen dysfunction cancer) Treatment: Purging, bleeding, diet, topical solutions 3

4 Brief history Renaissance: Autopsies led to an understanding of the lymphatic system and circulation Ramazzini, 1713: Lack of sexual activity organ decay cancer Hoffman, 1730s: Vigorous intercourse lymphatic blockage cancer Morgagni, 1730s: Curdled milk cancer Le Cat, 1750s: Depression constriction of blood vessels trapping of coagulated milk cancer Brief history Treatment in the 16 th 18 th century: Various forms and extents of surgery 4

5 Case 1 Year 1982 Patient Imaging Biopsy Surgery Pathology 54yo F with first screening mammogram Mammogram 2.1 cm mass Excisional bx 2.3 cm IMC, high grade Modified radical mastectomy (MRM) 1 cm residual disease, 5/24 positive LNs Case 1: Systemic treatment Adjuvant chemotherapy: CMF x 12 months Cyclophosphamide 100 mg/m2 PO X 14 days, MTX 40 mg/m2 IV D1 and D8, 5 FU 600mg/m2 IV D1, D8, 28 day cycle Adjuvant radiation Risk of relapse: 70% (83% prior to CMF) Would not have been tested for ER. Today, if ER+, would have gotten tamoxifen for 10 years. 5

6 Estrogen and breast cancer 1882: Relationship of ovarian function to breast cancer first noted (BC receded in women going into menopause) 1880 s: Observation that breasts of rabbits stopped producing milk after removal of their ovaries 1895: First oophorectomy for a patient with breast cancer Patient experienced a remission and lived for 4 years Next 75 years: Oophorectomy for BC falls out of favor (high mortality, benefit unclear) 1920s: Estrogen isolated as the female hormone 1930s: Observation that estrogen enhanced BC development in mice Lacassagne (1936): A therapeutic antagonist should be found to prevent the congestion of oesterone in the breast 1958: Estrogen receptor identified by using radioactively labeled estrogen 1968: ER assay for breast cancer developed 2/3 of BC express ER! Tamoxifen 1966: Tamoxifen first synthesized as a morning after oral contraceptive Found to have estrogen antagonist properties Activity against breast cancer noted in vitro 1969: Tamoxifen first tested in 46 women with metastatic BC, 27 had visible responses (not ER selected) 1974: VC Jordan recognizes that tamoxifen responders express the estrogen receptor Tamoxifen becomes the first targeted therapy for cancer 1977: Approved for stage IV disease in the U.S. 1986: Tamoxifen approved for early breast cancer in node positive women 1990: Approved for node negative disease 6

7 Impact of adjuvant endocrine therapy Average reduction in recurrences by 50% at 15 years for women taking tamoxifen for 5 years Estimated 90,000 lives saved worldwide in the next 15 years Assuming 1 million women taking tamoxifen for 5 years Case 1: Would have received tamoxifen upon relapse. Case 2 Year 2002 Patient Imaging Biopsy Surgery Pathology 54yo F, yearly screening mammogram Mammogram 1.8 cm mass Core bx IMC, ER+/PR+, HER 2+ by FISH Lumpectomy + sentinel LN bx 1.5 cm IMC, high grade, high proliferative rate, 1 of 1 positive SLNs, 2 of 24 positive remaining axillary LNs 7

8 Case 2 : Systemic treatment May have been enrolled in study examining trastuzumab + standard chemo v. chemo alone Trastuzumab approved in 2005 for adjuvant treatment of HER2+ disease Chemotherapy: AC x 4 Adjuvant tamoxifen x 5 years Adjuvant radiation Risk of recurrence: >28% (without trastuzumab) 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 8

9 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 9

10 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 3 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 10

11 Adjuvant! Online Adjuvant! Online 11

12 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 12

13 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:

14 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. 14

15 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. 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. 15

16 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 16

17 Frequency of mutations in the PIK3CA and PTEN genes in 1,261 human breast cancers 17

18 PI3K pathway inhibitors Personalization goals Find what is driving what the tumor in addition to ER/PR Androgen receptor signaling CDK signaling 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:

19 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 19

20 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 20

21 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 21

22 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 22

23 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) 23

24 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 24

25 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. 25

26 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 26

27 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 27

28 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. 28

29 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 Trastuzumab 29

30 Trastuzumab prolongs survival of patients with HER2+ MBC 1.0 FISH (+) Herceptin+Chemotherapy (n=125) Chemotherapy Alone (n=116) Probability IHC 2+/3+ Herceptin+Chemotherapy (n=235) Chemotherapy Alone (n=234) Median OS (months) 27* 18 Relative Risk 0.6 ( ) Survival (months) 25* 0.8 ( ) *p<0.05 Slamon NEJM 2001 HER2 Treatment Options beyond trastuzumab Trastuzumab TDM-1 Pertuzumab HER2 - HER2 PTEN Lapatinib PI3K SOS Akt RAS RAF MAPK MEK Cell proliferation Cell survival Cell mobility and invasiveness Transcription 30

31 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,

32 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. Pertuzumab Trastuzumab HER2 Pertuzumab HER3 Subdomain IV of HER2 Dimerization domain of HER2 32

33 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 2012 CLEOPATRA: Progression free Survival Progression-free survival (%) n at risk Time (months) Ptz + T + D 402 Pla + T + D D, docetaxel; PFS, progression free survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab Ptz + T + D: median 18.5 months Pla + T + D: median 12.4 months = 6.1 months HR = % CI p< Stratified by prior treatment status and region 33

34 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 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 34

35 TDM 1 (Kadcyla) Novel antibody drugconjugate linked to a potent cytotoxic agent (maytansine derivative; a microtubule inhibitor): selectively delivers DM1 to HER2+ cells 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 Verma, NEJM

36 EMILIA: Progression free survival NEJM 2012 EMILIA: Response rate and Treatment Duration 36

37 EMILIA: Overall Survival 2 nd Interim Analysis Adverse Events 37

38 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 Phase II trial of TDM1 vs. trastuzumab/ docetaxel in 1 st line treatment of HER2+ MBC :PFS Perez et al. JCO

39 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 MARIANNE: Phase III study of TMD1 +/ pertuzumab vs. trastuzumab + taxane combination, in 1 st line treatment for HER2+ MBC 39

40 Other ongoing trials with T DM1 in HER2+ Breast Cancer Trial (NCT Identifier) Phas e Setting Treatment Primary Endpoint Secondary Endpoints NCT I Trastuzumab pretreated T-DM1 + pertuzumab + paclitaxel AEs, DLTs, PK ORR, PFS, CBR, duration of response NCT II Trastuzumab naive T-DM1 versus trastuzumab + docetaxel PFS OS, ORR, CBR, duration of OR, TTSP NCT II Neoadjuvant T-DM1 versus T-DM1 + hormonotherapy versus trastuzumab + hormonotherapy pcr OS, cardiac safety, toxicity, HRQL NCT II Neoadjuvant T-DM1 versus T-DM1 + pcr HT versus trastuzumab + HT OS, toxicity, safety, HRQL NCT III Adjuvant T-DM1 versus trastuzumab IDFS DFS, OS, DRFI, safety, PRO 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? 40

41 Suggestions Chemo + Trastuzumab + Pertuzumab T DM1 Upon progression: Biopsy residual disease HER2+ HER2 Lapatinib + Capecitabine Lapatinib + Trastuzumab Chemo + Trastuzumab +/ everolimus Chemo (not HER2 based) PI3K pathway and and resistance to trastuzuamab Vanderbilt-Ingram Cancer Center 41

42 Phase III trials of trastuzumab with mtor inhibitors in HER2+ MBC BOLERO - 3 HER2+ LABC or MBC Resistant to trastuzumab and taxane pretreated (N = 569) 1:1 Vinorelbine, trastuzumab + Everolimus 5 mg/d Vinorelbine, trastuzumab + Placebo O Regan et al. ASCO 2013 BOLERO-3: Progression Free Survival O Regan et al. ASCO

43 Personalizing Treatment: Foundation One testing Foundation One CURRENT GENE LIST ABL1 BTK CTNNB1 FGF23 IL7R MLH1 PDGFRA SMO AKT1 CARD11 DAXX FGF3 INHBA MLL PDGFRB SOCS1 AKT2 CBFB DDR2 FGF4 IRF4 MLL2 PDK1 SOX10 AKT3 CBL DNMT3A FGF6 IRS2 MPL PIK3CA SOX2 ALK CCND1 DOT1L FGFR1 JAK1 MRE11A PIK3CG SPEN APC CCND2 EGFR FGFR2 JAK2 MSH2 PIK3R1 SPOP AR CCND3 EMSY FGFR3 (C11orf30) JAK3 MSH6 PIK3R2 SRC ARAF CCNE1 EP300 FGFR4 JUN MTOR PPP2R1A STAG2 ARFRP1 CD79A EPHA3 FLT1 KAT6A (MYST3) MUTYH PRDM1 STAT4 ARID1A CD79B EPHA5 FLT3 KDM5A MYC PRKAR1A STK11 ARID2 CDC73 EPHB1 FLT4 KDM5C MYCL1 PRKDC SUFU ASXL1 CDH1 ERBB2 FOXL2 KDM6A MYCN PTCH1 TET2 ATM CDK12 ERBB3 GATA1 KDR MYD88 PTEN TGFBR2 ATR CDK4 ERBB4 GATA2 KEAP1 NF1 PTPN11 TNFAIP3 ATRX CDK6 ERG GATA3 KIT NF2 RAD50 TNFRSF14 AURKA CDK8 ESR1 GID4 KLHL6 (C17orf39) NFE2L2 RAD51 TOP1 AURKB CDKN1B EZH2 GNA11 KRAS NFKBIA RAF1 TP53 AXL CDKN2A FAM123B GNA13 (WTX) LRP1B NKX2 1 RARA TSC1 BAP1 CDKN2B FAM46C GNAQ MAP2K1 NOTCH1 RB1 TSC2 BARD1 CDKN2C FANCA GNAS MAP2K2 NOTCH2 RET TSHR BCL2 CEBPA FANCC GPR124 MAP2K4 NPM1 RICTOR VHL BCL2L2 CHEK1 FANCD2 GRIN2A MAP3K1 NRAS RNF43 WISP3 BCL6 CHEK2 FANCE GSK3B MCL1 NTRK1 RPTOR WT1 BCOR CIC FANCF HGF MDM2 NTRK2 RUNX1 XPO1 BCORL1 CREBBP FANCG HRAS MDM4 NTRK3 SETD2 ZNF217 BLM CRKL FANCL IDH1 MED12 NUP93 SF3B1 ZNF703 BRAF CRLF2 FBXW7 IDH2 MEF2B PAK3 SMAD2 BRCA1 CSF1R FGF10 IGF1R MEN1 PALB2 SMAD4 BRCA2 CTCF FGF14 IKBKE MET PAX5 SMARCA4 BRIP1 CTNNA1 FGF19 IKZF1 MITF PBRM1 SMARCB1 Breast Cancer DNA Panel Testing at Vanderbilt Vanderbilt-Ingram Cancer Center 43

44 Breast Cancer DNA Panel Testing at Vanderbilt Vanderbilt-Ingram Cancer Center Breast Cancer DNA Panel Testing at Vanderbilt Vanderbilt-Ingram Cancer Center 44

45 Breast Cancer DNA Panel Testing at Vanderbilt Vanderbilt-Ingram Cancer Center Breast Cancer DNA Panel Testing at Vanderbilt Vanderbilt-Ingram Cancer Center 45

46 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 History Future Mortality 46

47 THANK YOU 47