Her2. dr

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Dr. Luis M. Zetina Toache
Cancer Consultants GT

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  • ER, estrogen receptor;FISH, fluorescence in situ hybridization; MBC, metastatic breast cancer; PgR, progesterone receptor; SLNB, sentinel lymph node biopsy. Case 1 is a woman with metastatic breast cancer and no previous anti-HER2 therapy, including trastuzumab.
  • CT, computed tomography; ER, estrogen receptor; IHC, immunohistochemistry; MBC, metastatic breast cancer; PgR, progesterone receptor.
  • MBC, metastatic breast cancer.Several of the options listed here would be appropriate for the first-line metastatic breast cancer setting. However, in keeping with the case patient’s goals of therapy, which include an increased objective response rate and a prolonged survival, trastuzumab plus chemotherapy is the most appropriate answer. The data supporting this choice will be covered in the next few slides.
  • MBC, metastatic breast cancer.Several of the options listed here would be appropriate for the first-line metastatic breast cancer setting. However, in keeping with the case patient’s goals of therapy, which include an increased objective response rate and a prolonged survival, trastuzumab plus chemotherapy is the most appropriate answer. The data supporting this choice will be covered in the next few slides.
  • a similar trend. FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; MBC, metastatic breast cancer. Initial trials with trastuzumab in the phase I setting showed that it was safe, and phase II trials showed anecdotal responses. One of the first large, phase II studies evaluating single-agent trastuzumab was by Vogel and colleagues. In this study, women with HER2-positive metastatic breast cancer who refused chemotherapy were randomized to receive first-line treatment with 1 of 2 dose levels of trastuzumab. When HER2 overexpression was determined by immunohistochemistry criteria, the response rate was 26%; however, the response rate increased to 34% when amplification of the HER2 gene was confirmed in a subset of patients using fluorescence in situ hybridization. Time to progression outcomes showed
  • MBC, metastatic breast cancer; OS, overall survival; TTP, time to progression. Herceptin in combination with either chemotherapy regimen (doxorubicin and cyclophosphamide or paclitaxel) produced a large increase in the objective response rate. With the addition of Herceptin, the median time to progression increased from 4.6 months to 7.4 months, and the median overall survival rose from 20.3 months to 25.1 months. These significant outcomes were observed despite allowing crossover from chemotherapy-alone arms at the time of progression (the primary endpoint of the study).  These outcomes resulted in the first approval of a HER2-targeted agent, Herceptin, for the first-line treatment of HER2-positive breast cancer in the metastatic setting.
  • C, carboplatin; Carbo, carboplatin; E, epirubicin; G, gemcitabine; H, Herceptin; ORR, overall response rate; P, paclitaxel; T, Herceptin; TLC D-99, liposomal doxorubicin; V, vinorelbine; X, capecitabine. This is a summary of studies that have investigated Herceptin in triple-combination regimens. Recognizing the significant limitations and caveats of cross-trial comparisons, this slide provides an overview of the kinds of response rates you might expect with Herceptin in combination with chemotherapy in the first-line metastatic setting.
  • CR, complete response; ER, estrogen receptor; MBC, metastatic breast cancer; PgR, progesterone receptor; TAC, docetaxel, doxorubicin, cyclophosphamide; TCH, docetaxel, carboplatin, trastuzumab. Case 2 is a woman with HER2-positive metastatic breast cancer who has progressed on treatment with trastuzumab.
  • CR, complete response; MBC, metastatic breast cancer.
  • CR, complete response; MBC, metastatic breast cancer. Lapatinib/capecitabine would be the preferred choice for this patient. We will explore the evidence that supports this choice in the following slides.
  • MBC, metastatic breast cancer; TTP, time to progression. In patients with HER2-positive advanced or metastatic breast cancer, time to progression was significantly improved in those who continued on HER2-targeted therapy with lapatinib.
  • HR, hazard ratio; MBC, metastatic breast cancer; ORR, overall response rate; OS, overall survival; TTP, time to progression. There was a trend toward improved survival in the lapatinib-based arm, but it did not reach statistical significance. This study may not have demonstrated a survival advantage because it was prematurely ended due to the highly significant time to progression results. At that time, the study was unblinded, and patients receiving capecitabine alone were allowed to cross over to lapatinib plus capecitabine treatment.  In addition, the occurrence of brain metastases as the site of first progression appeared to be reduced in the lapatinib-based arm. Although trastuzumab does not cross the blood-brain barrier, perhaps the small-molecule oral tyrosine kinase inhibitor lapatinib does.
  • ER, estrogen receptor; MBC, metastatic breast cancer; PgR, progesterone receptor; SD, stable disease. Case 3 is a woman with HER2-positive metastatic breast cancer who relapses following dual HER2-targeting therapy with trastuzumab and lapatinib.
  • MBC, metastatic breast cancer.
  • MBC, metastatic breast cancer. Owing to the rich pipeline of promising new agents that are being developed to target HER2-positive breast cancer, enrolling in a clinical trial may be the most appropriate option. Outside of a clinical trial, dual HER2 blockade with lapatinib and trastuzumab or trastuzumab plus chemotherapy are rational approaches. We will explore the available evidence in the following slides.
  • ReferencesSlamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2, New Eng J Med 2001;344:783–792.
  • NotesTDM4450g is an ongoing phase II study in patients with HER2-positive metastatic breast cancer. Patients who have not received prior chemotherapy for MBC are being randomized to receive T-DM1 or trastuzumab + docetaxel. ReferenceA Randomized, Multicenter, Phase II Study of the Efficacy and Safety of Trastuzumab-MCC-DM1 vs. Trastuzumab (Herceptin®) and Docetaxel (Taxotere®) in Patients With Metastatic HER2-Positive Breast Cancer Who Have Not Received Prior Chemotherapy for Metastatic Disease Study TDM4450. Clinicaltrials.gov. NCT00679341.
  • ReferenceAn open-label study of trastuzumab-MCC-DM1 (T-DM1) vs. capecitabine + lapatinib in patients with HER2-positive locally advanced or metastatic breast cancer. ClinicalTrials.gov [Website]. Updated October 5, 2009. Accesed April 21, 2009.http://www.clinicaltrials.gov/ct2/show/NCT00829166? term=T-DM1&rank=2.
  • ReferenceAn open-label study of trastuzumab-MCC-DM1 (T-DM1) vs. capecitabine + lapatinib in patients with HER2-positive locally advanced or metastatic breast cancer. ClinicalTrials.gov [Website]. Updated October 5, 2009. Accesed April 21, 2009.http://www.clinicaltrials.gov/ct2/show/NCT00829166? term=T-DM1&rank=2.
  • Her2. dr

    1. 1. CANCER DE MAMA HER 2+ Dr. Luis Miguel Zetina Toache Cancer Consultants GT
    2. 2. Trastuzumab:Copyright © 2005 Massachusetts Medical Society. All rights reserved. Burstein HJ, et al. N Engl J Med. 2005;353:1652-1654.
    3. 3. Novel anti-HER2 therapies: Baselga J Ann Oncol 2010;21:vii36-vii40
    4. 4. HER pathways are of critical importance in cancer“Beginning with benign hyperplasia and extending through invasive metastasis, a number of studies demonstrate that [HER family] receptor activation can play a major role in all aspects of cancer development.” — Sliwkowski MX, ―Alterations in the ErbB Signaling Network in Breast Cancer‖1 1. Sliwkowski MX. In: Harris JR, Lippman ME, Morrow M, Osborne CK, eds. Diseases of the Breast. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:415-426.
    5. 5. Structure of a HER family receptor1 HER family receptors exist on the surface of cells and contain extracellular, transmembrane, and tyrosine kinase domains. Each of these domains isresponsible for a different aspect of HER signaling pathways1 1. Burgess AW, Cho HS, Eigenbrot C, et al. Mol Cell. 2003;12:541-542.
    6. 6. Components of HER family receptors
    7. 7. Activation of HER receptors has numerous cellular effects and is a complex process Receptor activation is a complex, multistep process Role of HER2 gene expression in breast carcinoma. Ménard S, Tagliabue E, Campiglio M, Pupa SM. Copyright © 2000 J Cell Phys; Reprinted with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.1. Ménard S, Tagliabue E, Campiglio M, Pupa SM. J Cell Phys. 2000;182:150-162. 2. Sliwkowski MX. In: Harris JR, Lippman ME, Morrow M, Osborne CK,eds. Diseases of the Breast. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:415-426. 3. Olayioye MA, Neve RM, Lane HA, Hynes NE. EMBOJ. 2000;19:3159-3167.
    8. 8. Signal Transduction by the HER Family PromotesProliferation, Survival, and Invasiveness Receptor specific ligands HER2 HER1, HER2, HER3 HER3*, or HER4 HER4 HER2 VEGF HER1 (EGFR)Plasma PI3K P SOS Pmembrane Tyrosine kinase domains P RAS Akt RAF MAP K P MEKCytoplasm Cell proliferation Cell survival Cell mobility and invasivenessNucleus Transcription Adapted from Hudis. N Engl J Med. 2007;357:39
    9. 9. Receptor regulation through internalization Receptor internalization is animportant regulator of HER family signaling in normal cells, and is retained in cancerous cells1: 1. Sliwkowski MX. In: Harris JR, Lippman ME, MorrowM, Osborne CK, eds. Diseases of the Breast. 3rd ed. Adapted with permission from Lippincott Williams & Wilkins. Sliwkowski MX. In: Harris JR,Philadelphia, PA: Lippincott Williams & Wilkins; Lippman ME, Morrow M, Osborne CK, eds. Diseases of the Breast. 3rd ed. Philadelphia, PA:2004:415-426. Lippincott Williams & Wilkins; 2004:415-426.
    10. 10. HER2 Overexpression in Breast Cancer HER2 is overexpressed in ~ 25% of breast cancers Normal (1x) ~ 25,000-50,000 HER2 receptors Overexpressed HER2 (10-100x) up to ~ 2,000,000 HER2 receptorsPegram MD, et al. Cancer Treat Res. 2000;103:57-75. Excessive cellular divisionRoss JS, et al. Am J Clin Pathol. 1999;112(suppl 1):S53-S71.Slamon DJ, et al. Science. 1987;235:177-182.
    11. 11. HER2 Overexpression Shortens Survival HER2 oncogene amplification HER2 oncoprotein overexpression Shortened survival Median Survival From First Diagnosis HER2 overexpressing 3 years HER2 normal 6-7 yearsSlamon DJ, et al. Science. 1987;235:177-182.Slamon DJ, et al. Science. 1989;244:707-712.
    12. 12. TRATAMIENTO DECÁNCER DE MAMA HER 2 POSITIVO
    13. 13. Estimación de las recurrencias prevenidas por el uso de trastuzumab en EBC en USA (M Danese; SABCS 08 poster 2107)• Los datos del SEER estiman que Trastuzumab adyuvante previene 2,800 recurrencias en 1 año en USA• Extrapolado en un período de 25 años podría prevenir más de 50,000 recurrencias• Estos resultados son consistentes con los europeos de Weisgerber-Kriegl presentados en ASCO 2008 PILAR DE TRATAMIENTO PARA PTES HER 2 POSITIVAS
    14. 14. New Directions in the Treatment of Patients With HER2-Positive Breast Cancerclinicaloptions.com/oncology Trastuzumab: Mecanismo de accion Copyright © 2005 Massachusetts Medical Society. All rights reserved. Burstein HJ, et al. N Engl J Med. 2005;353:1652-1654
    15. 15. Estudios de Herceptin en Adyuvancia: >13,000 pacientes tratados HERA (ex-USA) BCIRG 006 (global) Observación IHC / FISH FISH 1 año (n=5090) (n=3222) 1 año 2 años 1 año NCCTG N9831 (USA) NSABP B-31 (USA)IHC / FISH IHC / FISH 1 año (n=3505) (n=2030) 1 año 1 año Quimioterapia Doxorubicina + Docetaxel + ciclofosfamida Docetaxel carboplatino Herceptin Paclitaxel estándar Piccart-Gebhart et al 2005;FISH, hibridización fluorescente in situ Romond et al 2005; Slamon et al 2006
    16. 16. Análisis combinado de NCCTG N9831 actualizado / NSABP B-31: Beneficio de DFS*Pacientes (%) 100 92.3% 87.9% 85.9% 80 86.4% 52% 77.6% 73.1% 60 Seguimiento medio: 2.9 años 40 n Eventos ACPH 1989 222 20 ACP 1979 397 HR=0.48; p 0.00001 Años desde la 0 randomización 0 1 2 3 4 5 6 7 No. 1854 1347 868 522 202 4 at risk 1800 1235 753 460 168 8 *Eventos intención de tratamiento: enfermedad recurrente, cáncer de mama contralateral, muerte por 2ndo primario. Perez et al 2007 DFS: sobrevida libre de enfermedad
    17. 17. Actualización de NCCTG N9831 / NSABP B-31 – análisis combinado: beneficio de OS*Pacientes (%) 100 97.5% 94.6% 92.6% 95.9% 92.7% 89.4% 80 35% 60 40 n ACPH 1989 20 ACP 1979 HR=0.65; p=0.0007 Años desde la 0 randomización 0 1 2 3 4 5 No. 1886 1419 938 570 217 at risk 1863 1376 898 562 211 *Eventos intención de tratamiento: enfermedad recurrente, cáncer de mama contralateral, 2ndo primario, muerte Perez et al 2007
    18. 18. Estudios de Herceptin adyuvante: beneficio en DFS probado Seguimiento medio a 2 años HERA H 1 año 2 B-31 / N9831 ACPH 4 BCIRG 006 ACDH 3 BCIRG 006 DCarboH 3 FinHer VH / DHa 3 0 1 2 Favorece a No favorece Herceptin a Herceptin HRV, vinorelbina Joensuu et al 2006; Perez et al 2007;aSobrevida libre de recaída Slamon et al 2006; Smith et al 2007
    19. 19. Estudios de Herceptin adyuvante:beneficio de OS probado Seguimiento medio en años HERA H 1 año 2 B-31 / N9831 ACPH 4 BCIRG 006 ACDH 3 BCIRG 006 DCarboH 3 FinHer VH / DHa 3 0 1 2 Favorece a No favorece a Herceptin Herceptin HR Joensuu et al 2006; Perez et al 2007; Slamon et al 2006; Smith et al 2007
    20. 20. Conclusions:The addition of 1 year of adjuvant trastuzumab significantly improved disease-free and overall survival among women with HER2-positive breast cancer. Therisk–benefit ratio favored the nonanthracycline TCH regimen over AC-T plustrastuzumab, given its similar efficacy, fewer acute toxic effects, and lower risks ofcardiotoxicity and leukemia. (Funded by Sanofi-Aventis and Genentech; BCIRG-006 ClinicalTrials .gov number, NCT00021255.)Table 2. Therapeutic Index for Critical Clinical Events.* AC-T plusClinical Event AC-T Trastuzumab TCH number of eventsTotal events 201 146 149Distant breast-cancer recurrence 188 124 144Grade 3 or 4 congestive heart failure 7 21 4Acute leukemia 6 1 1† D. Slamon New England Journal of Medicine october 6, 2011 vol. 365 no. 14
    21. 21. Estudio internacional, fase III, randomizado en CMLA: NOAH CMLA HER2-positivo CMLA HER2-negativo (IHC 3+ or FISH+) (IHC 0/1+) n=115 n=113 n=99 H + AP AP AP c3s x 3 ciclos c3s x 3 ciclos c3s x 3 ciclos H+P P P c3s x 4 ciclos c3s x 4 ciclos c3s x 4 ciclos H c3s x 4 ciclos CMF CMF + CMF c4s x 3 ciclos c4s x 3 ciclos c4s x 3 ciclos Cirugía seguida de Cirugía seguida de Cirugía seguida de radioterapiaa radioterapiaa radioterapiaa H continuada c3s hasta la semana 52AP, doxorubicina (60 mg/m2), paclitaxel (150 mg/m2); CMF, ciclofosfamida, metotrexate, fluorouracilo; H, Herceptin (8 mg/kg dosisde carga, luego 6 mg/kg);CMLA: cáncer de mama localmente avanzadolocally; P, paclitaxel (175 mg/m2); Gianni et al 2007aPacientes positivos por receptor hormonal recibirán tamoxifeno adyuvante
    22. 22. Herceptin neoadyuvante duplica la tasa de respuesta patológica Pacientes 50 p=0.002 (%) p=0.003 40 43 38 p=0.29 30 p=0.43 20 23 20 17 16 10 0 Con H Sin H HER2 Con H Sin H HER2 negativo negativo HER2 positivo HER2 positivo pCR tpCRtpCR: total pCR en mama y ganglios Gianni et al 2007
    23. 23. Y los tumores menores de 2 cms, ganglios (-) ?High Risk of Recurrence for Breast Cancer Patients with HER2-Positive Node NegativeTumors 1 cm or Smaller HER2-positive (%) HER2-negative (%) P value 5-yr RFS 77 94 <0.001 Gonzalez-Angulo AM, et al. J Clin Oncol 2009;27(34):5700-6
    24. 24. New Directions in the Treatment of Patients With HER2-Positive Breast Cancerclinicaloptions.com/oncology Case 1: Woman With MBC and No Previous Trastuzumab  Presentation: 58-yr-old woman was found to have architectural distortion in the right breast, upper outer quadrant, on routine screening mammography – Core needle biopsy confirmed invasive ductal carcinoma, estimated by imaging to be a T1 lesion  Treatment: She underwent lumpectomy/SLNB that revealed a 0.9-cm intermediate-grade invasive ductal carcinoma that was ER+/PgR+/HER2+ by FISH, with a Ki-67 value of 30% – 2 sentinel nodes were removed and found to be uninvolved by cancer T1 NO MO G2 ER/PR+ HER2+
    25. 25. New Directions in the Treatment of Patients With HER2-Positive Breast Cancerclinicaloptions.com/oncology Case 1: Woman With MBC and No Previous Trastuzumab  Follow-up: She received adjuvant radiation therapy followed by letrozole for 1 yr, at which time she was seen by her oncologist for new cough and mild shortness of breath – CT scan of the chest revealed a mild right pleural effusion and several nodules up to 1 cm in size in the right, middle, and lower lobes – Biopsy revealed adenocarcinoma that was ER+/PgR-/HER2 3+ by IHC, consistent with breast primary – No other metastases were detected by CT or bone scan  There are no clinical trials available at your center for which she is eligible. You review multiple treatment options with her and she tells you she would like to take the treatment that has the highest chance of leading to a response and to a prolonged survival, as she recently found out her daughter is pregnant with her first grandchild
    26. 26. New Directions in the Treatment of Patients With HER2-Positive Breast Cancerclinicaloptions.com/oncology Case 1: Woman With MBC and No Previous Trastuzumab What treatment option would you recommend at this time? A. Trastuzumab plus chemotherapy B. Trastuzumab plus aromatase inhibitor C. Lapatinib plus capecitabine D. Single-agent aromatase inhibitor E. Trastuzumab single agent
    27. 27. New Directions in the Treatment of Patients With HER2-Positive Breast Cancerclinicaloptions.com/oncology
    28. 28. New Directions in the Treatment of Patients With HER2-Positive Breast Cancerclinicaloptions.com/oncology Case 1: Woman With MBC and No Previous Trastuzumab What treatment option would you recommend at this time? A. Trastuzumab plus chemotherapy (preferred choice) B. Trastuzumab plus aromatase inhibitor C. Lapatinib plus capecitabine D. Single-agent aromatase inhibitor E. Trastuzumab single agent
    29. 29. Single-Agent Trastuzumab in First-line Treatment of HER2+ MBCPatients Response Rate, % Median Time to Progression, MosHER2+ by IHC 26 3.5(N = 111)HER2+ by FISH 34 4.9(n = 79) Vogel CL, et al. J Clin Oncol. 2002; 20:719-726.
    30. 30. Herceptin Combinations as First-line Therapy for MBC: Pivotal Phase III Trial Paclitaxel Previous (n = 96) Patients with adjuvant HER2+ (IHC 2+/3+) AC Herceptin MBC, no previous + Paclitaxel chemotherapy, (n = 92) measurable disease, KPS ≥ 60% AC No previous (n = 138) (N = 469) adjuvant AC Herceptin + AC (n = 143)Slamon DJ, et al. N Engl J Med. 2001;344:783-792.
    31. 31. Herceptin in MBC: The Pivotal Trial Treatment Objective Median TTP, Mos Median OS, Mos Response Rate, % Chemo 32 4.6 20.3 Chemo + 50 7.4 25.1 Herceptin P < .001 for all 3 comparisons. Despite crossover at TTPSlamon DJ, et al. N Engl J Med. 2001;344:783-792.
    32. 32. Herceptin in Triple-Combination Regimens: Response Rates Yardley et al, 2004 (N = 24) H+V+T Untch et al, 2004 (N = 25) H + E90 + C Untch et al, 2004 (N = 26) H + E60 + C Dirix et al, 2006 (N = 34) H + Carbo + T Chan et al, 2007 (N = 34) H+V+XFountzilas et al, 2004 (N = 40) H+G+P Yardley et al, 2006 (N = 41) H + G + Carbo Miller et al, 2002 (N = 45) H+G+P Venturini et al, 2006 (N = 45) H+E+T Perez et al, 2005 (N = 43) H + Carbo + P every 3 wks Perez et al, 2005 (N = 48) H + Carbo + P every wk Cortes et al, 2004 (N = 54) H + TLC D-99 + P Yardley et al, 2002 (N = 61) H + Carbo + T Pegram et al, 2004 (N = 59) H + Carbo + T Pegram et al, 2004 (N = 62) H + Cisplatin + T Robert et al, 2006 (N = 92) H + Carbo + P Wardley et al, 2006 (N = 111) H+X+T Forbes et al, 2006 (N = 130) H + Carbo + T 0 10 20 30 40 50 60 70 80 90 100 ORR (%)
    33. 33. Herceptin in Recommended First-line Combinations for HER2+ MBCHER2+ disease without previous Herceptin: Herceptin plus• Paclitaxel ± carboplatin• Docetaxel• Vinorelbine• CapecitabineHER2+ disease with previous Herceptin: Herceptin plus• Other first-line agents• Capecitabine• Lapatinib (without cytotoxic therapy) NCCN. Clinical practice guidelines in oncology: breast cancer. v2.2011.
    34. 34. Cross-talk Between Signal Transduction and Endocrine Pathways Growth Factor IGFR Estrogen EGFR/HER2 MoAb Plasma P P Membrane P P P SOS P P13-K RAS RAFAI Cell Survival P Akt MEK P ER p90RSK MAPK P P Cytoplasm Cell P P P Basal P Transcription Growth ER p160 CBP Machinery ER Nucleus ERE ER Target Gene Transcription Adapted from Johnston SRD. Clin Cancer Res. 2005;11:889s-899s.
    35. 35. Cross-talk between signal transduction pathways and ER signaling in endocrine-resistant breast cancer, with opportunities for targeted intervention. Johnston S R Clin Cancer Res 2010;16:1979-1987©2010 by American Association for Cancer Research
    36. 36. Hormonal Therapy in HER2+ MBC Regimen ORR, % PFS, Mos Trastuzumab (N = 79)[1] 26 3.5-3.8 Anastrozole + trastuzumab (N = 103)[2] 20 4.8 Anastrozole (N = 104)[2] 7 2.4 Lapatinib + letrozole (N = 642)[3] 28 8.2 Letrozole (N = 644)[3] 15 3.0 Lapatinib (N = 138)[4] 24 NA1. Vogel C, et al. J Clin Oncol. 2002;20:719-726.2. Mackey JR, et al. SABCS 2006. Abstract 3.3. Johnston S, et al. J Clin Oncol. 2009;27:5538-5546.4. Gomez HL, et al. J Clin Oncol. 2008;26:2999-3005.
    37. 37. New Directions in the Treatment of Patients With HER2-Positive Breast Cancerclinicaloptions.com/oncology Lapatinib Blocks Signaling Through Multiple Receptor Combinations  Blocks signaling through 1+1 2+2 1+2 ErbB1 and ErbB2 homodimers and heterodimers  Might also prevent signaling through heterodimers between these receptors and other ErbB family members  Potentially blocks multiple ErbB signaling pathways Downstream signaling cascade Lapatinib is indicated in MBC only for patients with progression after trastuzumab, anthracycline, and taxane treatment
    38. 38. New Directions in the Treatment of Patients With HER2-Positive Breast Cancerclinicaloptions.com/oncology Lapatinib as First-line Treatment for HER2- Amplified LABC or MBC  Patients (N = 138) randomized to 2 schedules of lapatinib monotherapy Endpoint Lapatinib Lapatinib All Patients 1500 mg/day 500 mg BID (N = 138) (n = 69) (n = 69) Response rate, n (%) 15 (22) 18 (26) 33 (24) Clinical benefit rate, n (%) 20 (29) 23 (33) 43 (31) 6-mo PFS, % 41 45 43  Median time to response (all patients): 7.9 wks; median duration of response (all patients): 28.4 wks  Safety: only grade 1/2 asymptomatic cardiac adverse events (4 patients)Gomez HL, et al. J Clin Oncol. 2008;26:2999-3005.
    39. 39. Current therapeutic cascade in HER2+ MBC HER2+ /ER + MBCGood performance status Poor performance status Visceral disease Non visceral disease Rapidly progressing Slow progression Prior A.I.? YES NO Herceptin + Herceptin Herceptin + Chemotherapy monotherapy Aromatase Inhibitor
    40. 40. Tratamiento mas allá de progresión
    41. 41. New Directions in the Treatment of Patients With HER2-Positive Breast Cancerclinicaloptions.com/oncology Case 2: Woman With HER2+ MBC and Progression Following Trastuzumab  Background: 39-yr-old woman diagnosed with stage IIA, breast cancer in 2004. T2 N0 MO – 2.6-cm tumor – ER+/PgR-/HER2+  Treatment: TAC for 6 cycles plus radiation therapy and tamoxifen  Follow-up: 1 yr after end of chemotherapy, she is found to have bone and lymph node metastases – Lymph node biopsy reveals the tumor is negative for hormone receptors (ER/PgR) and continues to overexpress HER2  Treatment: she receives 6 cycles of TCH and achieves CR – She continues on maintenance single-agent trastuzumab without progression for almost 2 yrs
    42. 42. New Directions in the Treatment of Patients With HER2-Positive Breast Cancerclinicaloptions.com/oncology Case 2: Woman With HER2+ MBC and Progression Following Trastuzumab Scans reveal new liver metastases, and vinorelbine is added to trastuzumab. She has another CR that lasts 9 mos, at which time scans reveal progressive disease in the liver and bones. What treatment option would you recommend at this time? A. Switch to lapatinib/capecitabine B. Switch to lapatinib/trastuzumab C. Switch to trastuzumab and new chemotherapy D. Start chemotherapy without HER2-targeted therapy E. Switch to lapatinib alone
    43. 43. New Directions in the Treatment of Patients With HER2-Positive Breast Cancerclinicaloptions.com/oncology Case 2: Woman With HER2+ MBC and Progression Following Trastuzumab Scans reveal new liver metastases, and vinorelbine is added to trastuzumab. She has another CR that lasts 9 mos, at which time scans reveal progressive disease in the liver and bones. What treatment option would you recommend at this time? A. Switch to lapatinib/capecitabine (preferred choice) B. Switch to lapatinib/trastuzumab (reasonable) C. Switch to trastuzumab and new chemotherapy D. Start chemotherapy without HER2-targeted therapy E. Switch to lapatinib alone
    44. 44. New Directions in the Treatment of Patients With HER2-Positive Breast Cancerclinicaloptions.com/oncology Mechanism of Action of Lapatinib Compared to Trastuzumab Trastuzumab T 1 1 2 2 1 2 Erb receptors L L L L L L Lapatinib Downstream signaling pathways Cell proliferation Cell survival
    45. 45. New Directions in the Treatment of Patients With HER2-Positive Breast Cancerclinicaloptions.com/oncology EGF100151 Phase III Study: Lapatinib + Capecitabine in Advanced Breast Cancer Lapatinib 1250 mg/day PO + Capecitabine Patients with HER2+ 2000 mg/m2/day on progressive MBC or Days 1-14 every 21 days stage IIIB/IIIC LABC with T4 lesion and unlimited Capecitabine previous therapies* 2500 mg/m2/day on Days 1-14 every 21 days  Primary endpoint: TTP  Secondary endpoints: OS, PFS, ORR *No previous capecitabine and must have included trastuzumab (MBC) or anthracycline/taxane (MBC or adjuvant).Geyer C, et al. N Engl J Med. 2006;355:2733-2743.
    46. 46. New Directions in the Treatment of Patients With HER2-Positive Breast Cancer clinicaloptions.com/oncology Lapatinib + Capecitabine in HER2+ MBC: TTP TTP With 1 Previous Trastuzumab Regimen TTP With > 1 Previous TrastuzumabCumulative Progression Free (%) Cumulative Progression Free (%) 100 100 Regimen 80 80 Capecitabine Capecitabine Lapatinib + capecitabine Lapatinib + capecitabine 60 60 40 40 20 20 0 0 0 20 40 60 80 0 20 40 60 80 Wks Wks Reproduced with permission of The Oncologist, from Lapatinib plus capecitabine in women with HER-2–positive advanced breast cancer: Final survival analysis of a phase III randomized trial, Cameron D, et al., Vol 15, 2010; permission conveyed through Copyright Clearance Center, Inc. Cameron D, et al. Oncologist. 2010;15:924-934.
    47. 47. New Directions in the Treatment of Patients With HER2-Positive Breast Cancerclinicaloptions.com/oncology Lapatinib + Capecitabine in HER2+ MBC: Efficacy Result Capecitabine Capecitabine + HR P Value (n = 201) Lapatinib (n = 207†) Median TTP, wks[1] 18.6 31.3 0.50 < .001 OS, wks[1] 56.6 71.4 0.79 .077 ORR, %[2] 13.9 23.7 -- .017 Brain mets as site of first 13 (6) 4 (2) -- .045 progression,* n (%)[2] † n=198 in 2008 study. *Exploratory analysis.1. Cameron D, et al. Oncologist. 2010;15:924-9342. Cameron D, et al. Breast Cancer Res Treat. 2008;112:533-543.
    48. 48. New Directions in the Treatment of Patients With HER2-Positive Breast Cancerclinicaloptions.com/oncology Combining Lapatinib and Trastuzumab Increases Antitumor Activity 1600  Treatment with lapatinib plusTumor Volume (mm3) 1400 trastuzumab resulted in complete 1200 Control Trastuzumab tumor remission in mouse model 1000 800 Lapatinib * Trastuzumab + lapatinib – Effect was durable: no tumor relapse 600 † observed at 8 mos after treatment * 400 †‡ † 200  Lapatinib induced accumulation of 0 13 16 19 21 23 inactive HER2 at plasma membrane Days After Injection *P < .05; †P < .01 vs control; ‡P < .05 vs trastuzumab; – Trastuzumab-mediated cytotoxicity P < .01 vs both lapatinib and trastuzumab. was higher with the addition of lapatinib in MCF7/HER2 cells  In vivo activity was consistent with in vitro data demonstrating the combination as synergistic Scaltriti M, et al. Oncogene. 2009;28:803-814. Reprinted by permission from Macmillan Publishers Ltd: Konecny GE, et al. Cancer Res. 2006;66:1630- Oncogene; Scaltriti, et al. 28:803-814, copyright 2009. 1639. Xia W, et al. Oncogene. 2004;23:646-653.
    49. 49. EGF104900 Estudio fase III: Bloqueo dualde Her2 en CMM Lapatinib 1500 mg/day PO Patients with HER2+ (n = 148) (FISH/IHC3+) MBC and progression on anthracycline, taxane, and Lapatinib 1000 mg/day PO + Herceptin Herceptin 4 mg/kg → 2 mg/kg IV weekly (n = 148)  Objetivo primario: supervivencia libre de progresión  Objetivos secundarios: Supervivencia global, respuesta, beneficio clínicoBlackwell KL, et al. J ClinOncol. 2010;28:1124-1130.
    50. 50. EGF104900 Estudiofase III:Bloqueo dual de Her2 en CMM 100 L L+T Supervivencia (n = 145) (n = 146) 80% Muertes, n (%) 113 (78) 105 (72) 80 Mediana (m) 9.5 14 Supervivencia global HR (95% CI) 0.74 (0.57-0.97) 56% 60 70% Log-rank P value .026 6 meses SG 40 41% L 12 meses SG 20 L+T 0 0 5 10 15 20 25 30 35 Pacientes en riesgo, n Meses desde la aleatorización L 148 121 88 64 43 25 1 L + T 148 102 65 47 28 13 Blackwell KL, et al. SABCS 2009. Abstract 61.
    51. 51. Nuevas terapias anti Her2
    52. 52. New Directions in the Treatment of Patients With HER2-Positive Breast Cancerclinicaloptions.com/oncology Case 3: Woman With HER2+ MBC and Relapse Following Trastuzumab/Lapatinib  Presentation: 56-yr-old woman was diagnosed with stage III ER+/ PgR-/HER2+ breast cancer – Treatment: doxorubicin/cyclophosphamide and docetaxel/trastuzumab  Follow-up: 3 yrs after completing maintenance trastuzumab, she was diagnosed with bone and lung metastases – Treatment: docetaxel/trastuzumab  Follow-up: after achieving PR that lasted for 9 mos, she developed liver metastases – Treatment: lapatinib/capecitabine  Follow-up: she achieved SD for 6 mos, after which she developed lung and lymph node metastases
    53. 53. New Directions in the Treatment of Patients With HER2-Positive Breast Cancerclinicaloptions.com/oncology Case 3: Woman With HER2+ MBC and Relapse Following Trastuzumab/Lapatinib What treatment options do you feel are appropriate to consider for this patient at this time? A. Lapatinib/trastuzumab B. Enrollment in a trial evaluating a new agent for HER2+ breast cancer C. Trastuzumab plus bevacizumab D. Lapatinib/trastuzumab/chemotherapy E. Trastuzumab plus chemotherapy
    54. 54. New Directions in the Treatment of Patients With HER2-Positive Breast Cancerclinicaloptions.com/oncology Case 3: Woman With HER2+ MBC and Relapse Following Trastuzumab/Lapatinib What treatment options do you feel are appropriate to consider for this patient at this time? A. Lapatinib/trastuzumab (reasonable) B. Enrollment in a trial evaluating a new agent for HER2+ breast cancer (preferred choice) C. Trastuzumab plus bevacizumab D. Lapatinib/trastuzumab/chemotherapy E. Trastuzumab plus chemotherapy (reasonable)
    55. 55. Can we further optimise the treatment of HER2-positive MBC in the future? Despite the proven efficacy of the standard of care, Herceptin plus chemotherapy, a proportion of patients with HER2-positive breast cancer will not respond, while the majority of patients with MBC will progress within 1 year1 1. Slamon et al. New Eng J Med 2001; 344:783–792MBC = metastatic breast cancer
    56. 56. Pertuzumab Mechanism of action
    57. 57. There are four receptors in the HER family HER1/EGFR HER2 HER3 HER4 • Receptors are able to homo- and heterodimerise • HER2 does not appear to have a direct ligand and HER3 lacks kinase activity • However, HER2 and HER3 are highly complementary to each otherEGFR = epidermal growth factor receptor Yarden & Sliwkowski. Nat Rev Mol Cell Biol 2001;2:127–137
    58. 58. HER2:HER3 dimers initiate the strongestmitogenic signalling Homodimers Heterodimer s HER1:HER2 HER1:HER3 HER4:HER4 HER1:HER4 HER3:HER3 HER2:HER3 HER2:HER2 HER2:HER4HER1:HER1 HER3:HER4 + + + + + + + + + + + + + + + + Signalling activity +Tzahar et al. Mol Cell Biol 1996;16:5276–5287; Citri et al. Exp Cell Res 2003;284:54–65; Huang et al. Cancer Res 2010;70:1204–1214.
    59. 59. HER2 dimerises preferentially with HER3 to drivedownstream signalling HER2 HER3 Ligand-activated HER2:HER3 dimer P P P P Phosphorylation of the HER3 intracellular domain by HER2 initiates a signalling cascade Baselga, Swain. Nat Rev Cancer 2009;9:463–475; Yarden, Sliwkowski. Nat Rev Mol Cell Biol 2001;2:127–137; Graus-Porta et al. EMBO J 1997;1647–1655; Tzahar et al. Mol Cell Biol 1996;16:5276–5287; Lee-Hoeflich et al. Cancer Res 2008;68:5878–5887.
    60. 60. HER2:HER3 dimerisation initiates multiple signallingpathways, including increased tumour cell proliferation HER2 HER3 RAS Sos GRb 2 Shc PI3K P PP P P P Akt PDK RAF P 1 Downstream PI3K/Akt signalling is GSK36 mainly mediated by HER3 after MEK mTOR NF B Cyclin 01 BAD transphosphorylation by HER2 p27 Apoptosis MAPK P P Cell cycle Survival control Angiogenesis Proliferation Yarden, Sliwokowski. Nat Rev Mol Cell Biol 2001;2:127–137; Olayioye et al. EMBO J 2000;19:3159–3167; Kim et al. J Biol Chem 1994;269:24747–24755; Soltoff et al. Mol Cell Biol 1994;14:3550–3558; Baselga, Swain. Nat Rev Cancer 2009;9:463–475; Rowinsky. Annu Rev Med 2004;55:433–457;
    61. 61. Pertuzumab is the first in a new class of targetedanticancer therapeutic agents called HER2 DimerisationInhibitors• By blocking HER2 dimerisation, pertuzumab inhibits key HER signalling pathways that mediate cancer cell proliferation and survival1–4• Pertuzumab prevents the formation of HER2:HER3 receptor pairs1,5 HER2 HER3 Pertuzumab Dimerisation domain 1. Agus et al. Cancer Cell 2002;2:127–137; 2. Baselga. Cancer Cell 2002;2:93–95; 3. Citri et al. Exp Cell Res 2003;284:54–65. 4. Franklin et al. Cancer Cell 2004;5:317–328; 5. Hughes et al. Mol Cancer Ther 2009;8:1885–1892
    62. 62. Herceptin and pertuzumab bind to different epitopes onHER2 and show complementary mechanism of actions PertuzumabHerceptin HER2 HER3 Dimerisation domain Subdomain IV • Herceptin does not inhibit ligand- • Pertuzumab inhibits ligand-activated activated HER2 dimerisation HER2 dimerisation • Herceptin prevents HER2 activation by • Pertuzumab flags cells for destruction extracellular domain shedding by the immune system • Pertuzumab suppresses multiple HER • Herceptin inhibits ligand-independent signalling pathways, leading to a more HER2 signalling and flags cells for comprehensive blockade of HER2-driven destruction by the immune system signalling Cho et al. Nature 2003;421:756–760; Fendly et al. Cancer Res 1990;50:1550–1558; Franklin et al. Cancer Cell 2004;5:317–328; Nahta et al. Cancer Res 2004;64:2343–2346; Scheuer et al. Cancer Res 2009;69:9330–9336
    63. 63. Pertuzumab HER2-positive MBC combination studies
    64. 64. Summary of pertuzumab combinationtrials in HER2-positive breast cancer EBC First-line MBC Second-line MBC Third-line MBC (Neo-adjuvant) NEOSPHERE CLEOPATRA PHEREXA (n=400) (n=800) (n=450) D+T vs D+T+P vs D+T±P Capecitabine+T±P T+P vs D+P TRYPHAENA (n=225) BO17929 cohorts 1+2 (n=66) D+FEC+T+P vs P+Tcarboplatin+D+T+P BO17929 cohort 3 (n=29) P mono then P+T NCI study (n=11) Enrolment complete P+T EnrollingD = docetaxel; EBC = early-stage breast cancer;FEC = 5-fluorouracil, epirubicin, cyclophosphamide; MBC = metastaticbreast cancer; Data on file. Genentech USA, Inc., CA, USA andP = pertuzumab; T = Herceptin F Hoffmann-La Roche Ltd., Basel, Switzerland
    65. 65. Trastuzumab-DM1 (T-DM1)is a first-in-class antibody drug-conjugate (ADC) Aim for paradigm shift in treatment of breast cancer Providing greater efficacy and better tolerability than Herceptin plus chemotherapy as single agent or in combination with a biologic “… replacing Herceptin plus chemotherapy” 74
    66. 66. Anatomy of T-DM1 75
    67. 67. T-DM1 selectively delivers a highly toxic payload to HER2-positive tumor cells • Trastuzumab-like activity by binding to HER2 to the HER2 protein T-DM1 binds on cancer cells • Targeted intracellular delivery of a potent antimicrotubule agent, DM1Receptor-T-DM1 complex is Potent antimicrotubuleinternalized into HER2-positive agent is released once insidecancer cell the HER2-positive tumor cell
    68. 68. TDM4450g: ongoing Phase II study of T-DM1 vstrastuzumab + docetaxel in first-line HER2-positiveMBCPrimary endpoints HER2-positive MBC• PFS (independent No prior chemotherapy for MBC assessment) (n=137)• SafetySecondary endpoints• OS• ORR• DoR Trastuzumab + T-DM1• CBR docetaxel• Pharmacokinetic properties Fully recruited, results to be• Time to symptom presented later this year progressionPI: Edith Perez Clinicaltrials.gov
    69. 69. • Se observó una mejora significativa de la SSP en las pacientes del grupo de trastuzumab emtansina (n= 67) en comparación con el grupo de Herceptin + quimioterapia (n = 70), (mediana de SSP: 14,2meses frente a 9,2; HR: 0,59; p: 0,035).• La TRO fue mayor en el grupo de trastuzumab emtansina que en el de Herceptin + quimioterapia(64,2% frente al 58,0%).• Los eventos adversos (EA) frecuentes y graves (grado 3 o superior) disminuyeron significativamenteen el grupo de trastuzumab emtansina en comparación con el grupo de Herceptin + quimioterapia:Los EA más frecuentes en el grupo de trastuzumab emtansina fueron fatiga (49,3%), náuseas (47,8%),un aumento de las cifras de una enzima específica secretada por el hígado y otros órganos (aspartatoaminotransferasa o AST, 39,1%) y fiebre (39,1%). Los EA más frecuentes en el grupo de Herceptin +quimioterapia fueron pérdida de cabello (66,7%), una cifra reducida de un tipo específico deleucocitos (neutropenia, 63,6%), diarrea (45,5%) y fatiga (45,5%). Coincidiendo con resultados yapublicados, EA graves (grado 3 o superior) se notificaron con menor frecuencia en el grupo detrastuzumab emtansina que en el de Herceptin + quimioterapia (46,4% frente a 89,4%), al igual quesuspensiones del tratamiento por EA (7,2% frente a 28,8%). Los EA graves más frecuentes en el grupode trastuzumab emtansina consistieron en una cifra aumentada de dos enzimas hepáticas diferentes(ALT y AST) y una cifra baja de plaquetas (8,7%). Los EA graves más frecuentes en el grupo de3/5Herceptin + quimioterapia consistieron en una cifra reducida de un tipo específico de leucocitos(neutropenia, 60,6%), una cifra total reducida de leucocitos (leucocitopenia, 25,8%) y fiebre asociadacon una cifra reducida de un tipo específico de leucocitos (neutropenia febril, 13,6%).• Los datos de la supervivencia global no están maduros en este momento. El número de fallecimientosen cada grupo del estudio fue idéntico. Según los investigadores, ninguna muerte estaba relacionadacon el tratamiento (trastuzumab emtansina o Herceptin + quimioterapia).
    70. 70. TDM4370g (EMILIA): ongoing Phase III study of T-DM1 vs capecitabine + lapatinib in the second-line settingPrimary endpoints HER2-positive incurable locally advanced● PFS (independent assessment) breast cancer or MBC● Safety Prior trastuzumab and / or taxaneSecondary endpoints (n=580)● OS● PFS (investigator assessment)● ORR● CBR● DoR Capecitabine + T-DM1 lapatinib● Quality of life● TTF n=319 as of June 4, 2010 200 sites FPI: February 27 2009TTF, time to treatment failureFPI, first patient in Clinicaltrials.gov
    71. 71. TDM4788g/BO22589 (MARIANNE): first-line T-DM1 + pertuzumab vs trastuzumab + docetaxelPrimary endpoints● PFS (independent assessment) HER2-positive MBC No prior chemotherapy● Safety (n=1092)Secondary endpoints● ORR (independent assessment)● OS● 1-year survival● PFS Trastuzumab T-DM1 + T-DM1 +● ORR (investigator assessment) + taxane pertuzumab placebo● CBR● TTF Global study starts summer 2010● DoR 332 centers in 40 countries● Safety and tolerability Clinicaltrials.gov
    72. 72. T-DM1 and Pertuzumab: Binding to HER2 Pertuzumab-HER2 Complex Herceptin/T-DM1-HER2 Complex Pertuzumab I I Dimerization domain II II Herceptin/T-DM1 III III IV IVDiéras V, et al. SABCS 2010. Abstract P3-14-01.
    73. 73. T-DM1 and Pertuzumab: Mechanism of Action Pertuzumab HER2 Dimer T-DM1 HER2 Lysosome DM1 NucleusDiéras V, et al. SABCS 2010. Abstract P3-14-01.
    74. 74. New Directions in the Treatment of Patients With HER2-Positive Breast Cancerclinicaloptions.com/oncology mTOR Inhibition May Overcome Trastuzumab Resistance IGF-1R Increased signaling through IGF-1R EGFR/HER2 Nutrients Truncated HER2 PI3K PTEN Constitutive PI3K/AKT activation LKB1 AKT Absent or low PTEN AMPK TSC1 TSC2 Elevated AKT or pAKT RHEB Growth & mTOR mTOR inhibitor proliferation  Downstream inhibition with mTOR inhibitor counters these resistance mechanisms  Synergy of mTOR inhibition and trastuzumab in vitro and in vivo Angiogenesis Cell metabolismWidakowich C, et al. Anticancer Agents Med Chem. 2008;8:488-496.Miller TW, et al. Clin Cancer Res. 2009;15:7266-7276.
    75. 75. New Directions in the Treatment of Patients With HER2-Positive Breast Cancerclinicaloptions.com/oncology Angiogenesis in MCF-7 Spheroids: Day 14 MCF-7 Neo: 3.5 x mag.  Mature vasculature  No vessel buds  Development stopped MCF-7 HER-2/neu: 10 x mag.  High number mature vessels  Vessel buds in center of tumor  Vasculature still growing
    76. 76. New Directions in the Treatment of Patients With HER2-Positive Breast Cancerclinicaloptions.com/oncology Targeted Agents for HER2+ Breast Cancer Trastuzumab Bevacizumab phase III VEGF T-DM1 phase III Sunitinib EGFR Pertuzumab phase II VEGFR HER2 phase III P P P P P P PI3-K P P Akt/PKB Lapatinib PTEN phase III Everolimus phase III mTOR Neratinib phase III 4E-BP1 S6K1 Gefitinib elF-4E phase II Protein synthesis Cell growth, proliferation, survival, metastasis, angiogenesis
    77. 77. Muchisimas GraciasDr. Luis Miguel Zetina Toache Cancer Consultants GT

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