Recent Advances in Treatment of Breast Cancer

Transcription

1 2013 년혈액종양내과분과춘계연수강좌 Recent Advances in Treatment of Breast Cancer 성균관의대 삼성서울병원혈액종양내과 박연희

2 Contents Breast Cancer Overview Hormone Receptor (HR)-positive Bolero-2 (everolimus) HER2-positive CLEOPATRA (pertuzumab) EMILIA (T-DM1) Triple Negative Breast Cancer Future Perspectives

3 Breast Cancer is not a single disease Basal-like HER2 +++ Luminal A Luminal B Perou CM, et al. 2000, Nature Carey et al, 2006, JAMA

4 Breast Cancer Phenotypes Present Near Future Early recurrence ER+ 65% 75% late recurrence. All Breast Cancer HER2+ 15% 20% Triple Neg 15% PI3K mutation PTEN loss. BL1, 2 IM M MSL Phenotypes of interest for having clear therapeutic implication LAR Array-based genomics NGS

5 [TITLE]

6 Massively Parallel Sequencing in Cancer [TITLE] Presented By Levi A. Garraway, MD, PhD at 2013 ASCO Annual Meeting

7 Nature 406, , 2000 Tumors & germ line DNA samples from 825 patients DNA copy number arrays, DNA methylation, Exome sequencing, Messenger RNA arrays, microrna sequencing and reverse-phase protein arrays (RPPA) Nature 490, 61-70, 2012

8 TCGA: Significantly Mutated Genes & Correlations with Genomic and Clinical Features 30,262 somatic mutations 28,319 point mutations, 4 dinucleotide mutations, 2,302 indels Point mutations 6,486 silent, 19,045 missense, 1,437nonsense, 28 read through 605 splice and 819 in RNA genes Nature 490, 61-70, 2012

9 Hormone Receptor-Positive Overcoming Endocrine Resistance

10 Management of HR+ve BC Presented By Todd W. Miller, PhD at 2013 ASCO Annual Meeting

11 Mechanisms of Hormone Resistance VEGFR P P P P IGF1R PI3-K EGFR/HER2 P P SOS RAS RAF Increased signaling through EGFR and/or IGF1-R AI SERD T E2 ER Cytoplasm Plasma membrane Akt P P P P ER ER p160 ERE p90 RSK Basal transcription CBP machinery MAPK MEK ER target gene transcription Nucleus Increased signaling through PI3-K pathway Reprinted by permission from the American Association for Cancer Research: Johnston SR. Clin Cancer Res. 2005;11:889 s-899s.

12 Combined targeting PI3K & ER MCF-7 tumor Miller et al. J Clin Invest 120:2406, 2010 Miller et al. Cancer Discovery 1:338, 2011

13 13

14 14

15 Results 15

16 Final Progression-Free Survival Analysis of BOLERO-2: A Phase III Trial of Everolimus for Postmenopausal Women With Advanced Breast Cancer Martine Piccart, 1 Jose Baselga, 2 Shinzaburo Noguchi, 3 Howard Burris, 4 Michael Gnant, 5 Gabriel Hortobagyi, 6 Pabak Mukhopadhyay, 7 Tetiana Taran, 7 Tarek Sahmoud, 7 Hope Rugo 8 1 Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium; 2 Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA; 3 Department of Breast and Endocrine Surgery, Osaka University, Osaka, Japan; 4 Sarah Cannon Research Institute, Nashville, TN, USA; 5 Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; 6 The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 7 Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 8 University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, CA, USA San Antonio Breast Cancer Symposium December 4-8,

17 BOLERO-2 Trial Design N=724 Postmenopausal ER + HER2 Unresectable locally advanced or metastatic BC Recurrence or progression after letrozole or anastrozole R 2:1 Everolimus 10 mg/d + Exemestane 25 mg/d (n=485) Placebo + Exemestane 25 mg/d (n=239) Stratification: 1. Sensitivity to prior hormonal therapy 2. Presence of visceral disease Endpoints No crossover Primary: PFS (local assessment) Secondary: OS, ORR, CBR, QOL, safety, bone markers, PK Abbreviations: BC, breast cancer; CBR, clinical benefit rate; ER +, estrogen-receptor positive; HER2, human epidermal growth factor receptor 2-negative; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PK, pharmacokinetics; QOL, quality of life. 17

18 Probability of Event, % Probability of Event, % Final PFS at 18 month follow-up A Local assessment B Central assessment HR=0.45 (95% CI, ) Log-rank p< Kaplan-Meier medians EVE+EXE: 7.8 mo PBO+EXE: 3.2 mo HR=0.38 (95% CI, ) Log-rank p< Kaplan-Meier medians EVE+EXE: 11.0 mo PBO+EXE: 4.1 mo Censoring times 20 Censoring times 0 EVE+EXE (n/n=310/485) PBO+EXE (n/n=200/239) 0 EVE+EXE (n/n=188/485) PBO+EXE (n/n=132/239) Patients at risk EVE+EXE PBO+EXE Time, wk Patients at risk EVE+EXE PBO+EXE Time, wk Abbreviations: CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; PBO, placebo. 18

19 PFS - Subgroup Analyses The effect of EVE+EXE treatment was consistent among prospectively defined subgroups by local investigator and central review All Local Age group < Region Asia Europe North America Other Japanese patients Japan Non-Japan Central N Hazard Ratio and 95% CI Favors EVE+EXE Median PFS, mo HR EVE+EXE PBO+EXE Favors PBO+EXE Race Asian Caucasian Other Baseline ECOG performance status 0 1, 2 PgR status Negative Positive Presence of visceral metastasis No Yes Bone only lesions at baseline No Yes N Hazard Ratio and 95% CI Favors EVE+EXE Median PFS, mo HR EVE+EXE PBO+EXE NA Favors PBO+EXE 19

20 Safety: Most Common Adverse Events (Reported in 25% of Patients) AE (Preferred Term) EVE+EXE (n=482), % PBO+EXE (n=238), % Grade Grade All All Any AE Stomatitis <1 0 Rash Fatigue < Diarrhea < <1 0 Nausea <1 < Decreased appetite Weight decreased Cough Pneumonitis* Hyperglycemia* < <1 0 *Incidence <25%, but AE of special interest. Abbreviations: AE, adverse event; EVE, everolimus; EXE, exemestane; PBO, placebo. 20

21 BOLERO-2: Conclusions In patients with HR+ HER2 advanced BC progressing after initial NSAIs The combination of EVE+EXE resulted in a clinically significant improvement of PFS compared to EXE alone This effect was consistent among all prospectively defined subgroups There are fewer deaths in the EVE+EXE arm compared with PBO+EXE The adverse event profile was consistent with the known mtor class safety events Careful monitoring from initiation of therapy and timely management of EVE associated adverse events including prevention strategies are important!

22

23

24 HORIZON: letrozole + temsirolimus Wolff AC. J Clin Oncol 2013;2:197

25 [TITLE]

26 Combining Targeted and Antiestrogen Therapies in HR-Positive Breast Cancer PI3K inhibitors BMK120 BYL790 GDC0980 mtor Inhibitors Everolimus Sirolimus Temsirolimus CDK 4/6 Inhibitor PD HDAC Inhibitor Entinostat P RAS RAF Cell Cycle EGFR HER2 MEK P PI3K MAPK Transcription Silencing AKT TKI mtor PTEN E E ER ER E E E ER Aromatase Inhibitor Nonsteroidal AIs Anastrozole Letrozole Steroidal AIs Exemestane ER Downregulator Fulvestrant Selective Estrogen Receptor Modulators Tamoxifen Toremifene ER target gene transcription

27 Targeting the Cell Cycle: Cyclin D1/CDK 4-6 In AI resistance models ER drives a CDK 4/E2F dependent transcriptional program CDK 4-6 inhibition reduces cell proliferation in both ER-dependent and ER-independent, AI resistance breast cancer models Miller TW, et al. Cancer Discovery. 2011;1(4): Lange CA, et al. Endocr Relat Cancer. 2011;18:C19-C24.

28 Study Design: Phase II Trial (2 parts)

29 [TITLE]

30 attom (adjuvant Tamoxifen Treatment offers more) 20,187 women with ER-positive or ER-unknown diseased randomized in 5 trials of 10 vs 5 years of tamoxifen: ECOG, Scottish & NSABP B-14 1,588 ATLAS 11,646 attom 6,953 ASCO 2013 #5 plenary session

31 HER2-Positive A Great Oncogenic Addiction A Wealth of Riches

32 HER2/neu B a proto-oncogene involved in the dysregulation of cell proliferation Gene amplification or receptor overexpression occurs in 20-25% of breast cancers Are associated with poor prognosis and shortened diseasefree/overall survival be predictive of response to therapy Ross JS et al. The Oncologist 2009;14:

33 Dual HER2 Targeting? Trastuzumab HER2/HER3 Lapatinib PI3K Ras PTEN PIP 3 Raf TORC2 Akt PDK1 MEK Tuberin Rheb TORC1 Erk Rsk

34 Dual HER-2 Targeted Approaches Can we improve clinical outcomes of upfront therapy?

35 Pertuzumab and Trastuzumab Bind to Distinct Extracellular HER2 Epitopes Pertuzumab-HER2 Complex Trastuzumab-HER2 Complex I II Pertuzumab I II Dimerization domain III III Trastuzumab IV IV Inhibits HER2 dimerization with other HER family receptors (particularly HER3) Activates ADCC Inhibits multiple HER-mediated signaling pathways Activates ADCC Inhibits HER-mediated signaling pathways Prevents HER2 domain cleavage Hubbard SR. Cancer Cell. 2005;7:

36 Inhibition of HER2-HER3 Dimerization Ferguson et al. Mol Cell. 2003;11: Olayioye et al. EMBO J. 2000;19: Hynes et al. Nat Rev Cancer. 2005;5: Rowinsky. Annu Rev Med. 2004;55:

37 San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 A Phase III, Randomized, Double-Blind, Placebo-Controlled Registration Trial to Evaluate the Efficacy and Safety of Placebo + Trastuzumab + Docetaxel vs. Pertuzumab + Trastuzumab + Docetaxel in Patients with Previously Untreated HER2-Positive Metastatic Breast Cancer (CLEOPATRA) J Baselga, 1 S-B Kim, 2 S-A Im, 3 R Hegg, 4 Y-H Im, 5 L Roman, 6 J L Pedrini, 7 J Cortés, 8 A Knott, 9 E Clark, 9 G Ross 9 and S M Swain 10 1 Massachusetts General Hospital Cancer Center, Boston, MA, USA; 2 Department of Oncology, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea; 3 Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea; 4 Hospital Pérola Byington, São Paulo, Brazil; 5 Division of Hematology and Medical Oncology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; 6 Leningrad Regional Oncology Dispensary, St Petersburg, Russian Federation; 7 CPMEC-Mastology Unit of Conceição Hospital, Porto Alegre, Brazil; 8 Department of Oncology, Vall d Hebron University Hospital, Barcelona, Spain; 9 Roche Products Limited, Welwyn, UK; 10 Washington Cancer Institute, Washington Hospital Center, Washington D.C., USA Copyrights for this presentation are held by the author/presenter. Contact them at JBASELGA@PARTNERS.ORG for permission to reprint and/or distribute.

38 Study design San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 n=406 Placebo + trastuzumab PD Patients with HER2-positive MBC centrally confirmed (N = 808) 1:1 Docetaxel* 6 cycles recommended Pertuzumab + trastuzumab PD n=402 Docetaxel* 6 cycles recommended Randomization was stratified by geographic region and prior treatment s tatus (neo/adjuvant chemotherapy received or not) Study dosing q3w: Pertuzumab/Placebo: Trastuzumab: Docetaxel: 840 mg loading dose, 420 mg maintenance 8 mg/kg loading dose, 6 mg/kg maintenance 75 mg/m 2, escalating to 100 mg/m 2 if tolerated *<6 cycles allowed for unacceptable toxicity or PD; >6 cycles allowed at investigator discretion MBC, metastatic breast cancer; PD, progressive disease Copyrights for this presentation are held by the author/presenter. Contact them at JBASELGA@PARTNERS.ORG for permission to reprint and/or distribute. 38

39 Progression-free survival (%) San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 Primary endpoint: Independently assessed PFS Median follow-up: 19.3 months, n = 433 PFS events n at risk Ptz + T + D 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 Time (months) = 6.1 months HR = % CI p< Stratified by prior treatment status and region Copyrights for this presentation are held by the author/presenter. Contact them at JBASELGA@PARTNERS.ORG for permission to reprint and/or distribute. 39

40 Overall survival (%) San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 Overall survival: Predefined interim analysis Median follow-up: 19.3 months, n = 165 OS events HR = 0.64* 95% CI p = * Ptz + T + D: 69 events Pla + T + D: 96 events n at risk Time (months) 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 Copyrights for this presentation are held by the author/presenter. Contact them at JBASELGA@PARTNERS.ORG for permission to reprint and/or distribute. 40

41 San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6-10, 2011 Summary and conclusions CLEOPATRA met its primary endpoint and demonstrated a statistically significant and clinically meaningful improvement in PFS (HR = 0.62) in patients with HER2-positive MBC Median PFS increased by 6.1 months from 12.4 to 18.5 months The PFS improvement was consistent across subgroups and supported by the secondary endpoints of ORR and OS (immature) The combination of pertuzumab and trastuzumab plus docetaxel increased rates of diarrhea, rash, mucosal inflammation, and febrile neutropenia These adverse events were primarily grades 1 2, manageable, and occurred during docetaxel therapy There was no increase in cardiac adverse events or LVSD This new regimen may be practice-changing in HER2-positive first-line MBC Copyrights for this presentation are held by the author/presenter. Contact them at JBASELGA@PARTNERS.ORG for permission to reprint and/or distribute. 41

42

43

44 T-DM1: Trastuzumab-MCC-DM1 DM1(derivative of maytansine) Inhibitor of tubulin polymerization Up to 100 times more potent than vincristine Significant clinical toxicity as free drug HER2 antibody-drug conjugate Preserve specificity: target to cancer cells Improve therapeutic index of DM1 Enhance cytotoxicity

45 T-DM1 Mechanism of Action (MoA) T-DM1 binds to the HER2 protein on cell Receptor-T-DM1 complex is internalized into HER2+ cell Antimicrotubule agent is released inside HER2+ cell

46 EMILIA Study Design HER2-positive (centrally confirmed) locally advanced or metastatic breast cancer (N = 991) T-DM1 q3wk (n = 495) Lapatinib + Capecitabine q3wk (n = 496) Treatment continues until disease progression or unmanageable toxicity No provision for cross-over Primary endpoints: PFS by IRF, OS, safety Secondary endpoints: OS, QOL: FACT-B Key inclusion criteria Previous treatment to include a taxane and trastuzumab in adjuvant, locally advanced or metastatic setting Documented progression of disease during or after treatment for advanced/metastatic disease, or within 6 mos of completing adjuvant therapy Verma S, et al. N Engl J Med. 2012;367:

47 PFS (%) PFS by Independent (IRF) Review Lapatinib-capecitabine T-DM1 Median No. of Mos No. of Events Stratified HR: 0.65 (95% CI: ; P <.001) T-DM1 Pts at Risk, n Lapatinibcapecitabine T-DM Lapatinib-capecitabine Mos Verma S, et al. N Engl J Med. 2012;367:

48 OS (%) OS: Second Interim Analysis % (95% CI: ) 78.4% (95% CI: ) 64.7% (95% CI: ) Median No. of Mos Lapatinib-capecitabine 25.1 T-DM T-DM1 51.8% (95% CI: ) Lapatinib-capecitabine No. of Events Stratified HR: 0.68 (95% CI: ; P <.001) Efficacy stopping boundary P =.0037 or HR: Mos Pts at Risk, n Lapatinib- agent 496 for 471 the 453 treatment of patients with HER2-positive MBC 7 4 who capecitabine T-DM1 previously received trastuzumab and a 136 taxane On February 22, 2013, the FDA approved T-DM1 for use as a single Data cutoff July 31, 2012; median follow-up: 18.6 mos. Verma S, et al. N Engl J Med. 2012;367:

49

50 Triple Negative Breast Cancer Marked Improved Biologic Understanding But, No Clinical Implication

51 Slide 51 TNBC, BLBC and BRCA By Default! BRCAness TNBC BRCA1 BLBC DNA repair defect Treatment strategies for BRCA1-deficient cancers may be relevant for sporadic triple negative disease, X chromosome inactivation TP53 mutation Genomic instability TNBC classification significantly enriches for BLBC (~75%), however, it misses ~25% of BLBC and includes ~25% of tumors that are non- BLBC. A Free sample background from

52 Mammary development meets cancer genomics Prat A et al. 2009:15: Nat Med

53 Somatic Rearrangements in Breast Cancer: TNBC s are Smart Cancers Nature 2009;462:

54 (N=386) (N=201) BL1 BL2 IM M MSL LAR Cisplatin PI3K, mtor, abl/src inhibitors AR antagonist IM: medullary M & MSL: metaplastic (claudin-low ; high EMT) LAR: apocrine

55 TNBC: Low clonality vs. high clonality primary tumors The genomes and transcriptomes of 104 TNBCs Primary TNBCs are still treated as if they were a single disease entity, yet it is clear they do not behave as a single entity in response to current therapies. Treatment-naïve TNBCs display a complete spectrum of mutational and clonal evolution. The clonal heterogeneity of these cancers is also continuum, with some patients presenting with low-clonality cancers and other cases exhibiting more extensive clonal evolution at diagnosis. Nature 486, 395-9, 2012

56 Lessons from NGS of TNBCs Having identified candidate driver genes and significantly overrepresented pathways (p53, PTEN, and PIK3CA) The abundance of implicated pathways can be seen in some portion of TNBCs Some 12% of cases did not contain somatic aberrations in any of the frequent drivers or cytoskeletal genes. suggests that primary TNBCs are mutationally heterogeneous Nature 486, 395-9, 2012

57 Abstract ES2-3

58 Future Perspectives Genomics-Driven Oncology

59 # 2011 Presidential Address The Genomic Era 2001: First human genome sequenced Data Points per Patients 2009: First cancer genomes sequenced Now: Large-scale sequencing Soon: Population-based sequencing

60 Genome alteration affecting actionable signaling pathways Garraway L. J Clin Oncol 2013; 24:

61 Enabling Components for Genomicsdriven Cancer Medicine Levi A, Garraway. J Clin Oncol 31: , 2013.

62 [TITLE] Presented By Joseph A. Sparano, MD at 2013 ASCO Annual Meeting

63 Awarded Breakthrough Prize in Life Sciences 2013 Cancer is, in essence, a genetic disease Driver genes can be classified into 12 signaling pathways that regulate core cellular processes. A better understanding of these pathways is one of the most pressing needs in basic cancer research. Even now, however, our knowledge of cancer genomes is sufficient to guide the development of more effective approaches for reducing cancer morbidity and mortality.

64 Thank You!

65 유방암 voting 박연희

66 Case 1 A 68-yr-old woman presents with a T4N2 left breast mass with associated contraction and fibrosis that had been developing over 3-4 yrs Breast biopsy shows ER+/PgR+, HER2- IDC, grade 2 Staging evaluation shows bone metastases and multiple pulmonary nodules The patient has mild DOE but no bone pain

67 문제 1 An IV bisphosphonate or SC denosumab is recommended for this patient, next treatment? 1. Fulvestrant 500 mg 2. Letrozole 3. Exemestane + Everolimus 4. Fulvestrant + A nonsteroidal AI

68

69

70 문제 2 Which of the following endocrine therapies is NOT recommended as first-line? 1. Fulvestrant 500 mg 2. Letrozole 3. Exemestane + Everolimus 4. Fulvestrant + A nonsteroidal AI

71 Endocrine Therapy Sequencing in MBC: Which Order Is Best? AI or fulvestrant are most effective first-line single agents Fulvestrant ± AI reasonable option for endocrine therapy naive patients with MBC. Continue endocrine therapies until resistance. mtor inhibition with everolimus + exemestane is best second-line therapy after progression on nonsteroidal AI. After everolimus, back to anti-er therapy alone or enhanced blockade of PI3K pathway. Addition of CDK4/6 inhibitor to first-line letrozole may have potential to become a new standard; phase III trial under way.

72 Case 2 A 30-yr-old woman presents with a T4N3 left breast mass (11 10 cm) with tenderness. Breast biopsy shows ER-/PgR-, HER2+ IDC, grade 3 Staging evaluation shows bone metastases and multiple mediastinal LN metastases The patient has progressing breast pain

73

74 문제 3 Which of the following is a category 1 recommendation for this patient in the NCCN guidelines? 1. Docetaxel + trastuzumab 2. Paclitaxel + carboplatin + trastuzumab 3. Docetaxel + pertuzumab + trastuzumab 4. Trastuzumab + lapatinib 5. T-DM1

75 Case 2 The patient was enrolled to CLEOPATRA clinical trial. Pertuzumab/Placebo (420mg) + Trastuzumab (340mg) + Docetaxel (87mg) #6 (#45) from to with stable PR breast mass increased

76 문제 4 Which of the following is your next recommendation for this patient? 1. Lapatinib + Capecitabine 2. Trastuzumab + Capecitabine 3. Trastuzumab + Vinorelbine 4. Trastuzumab + Lapatinib 5. T-DM1

77 Case 2 The patient was enrolled to EMILIA clinical trial. The patients was randomized to T-DM1 T-DM1 3.6 mg ivs #15 from to with stable PR breast mass increased The patient was received palliative AC #6 chemotherapy from

78 The patient received salvage MRM. ypt1n OPD f/u

79