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Controversias y estrategias terapéuticas prometedoras en el cáncer de mama HER2 positivo Francisco J. Esteva, MD, PhD Professor of Medicine Department of Breast Medical Oncology MD Anderson Cancer Center Houston, Texas Signal Transduction by the HER Family Promotes Proliferation, Survival, and Invasiveness Receptor specific ligands HER2 HER2 HER4 HER1, HER2, HER3*, or HER4 HER3 VEGF HER1 (EGFR) Plasma membrane P PI3K Tyrosine kinase domains Akt Nucleus SOS P RAS MAP K Cytoplasm P P RAF MEK Cell proliferation Cell survival Cell mobility and invasiveness Transcription Adapted from Hudis. N Engl J Med. 2007;357:39 HER2 Targeted Therapies • Monoclonal Antibodies – Trastuzumab* – Pertuzumab – Trastuzumab-DM1 • Small Molecule TKIs – Lapatinib* – Neratinib • Vaccines *FDA-approved for breast cancer Adapted from Esteva FJ and Hortobagyi GN. Sci Am 2008 Trastuzumab Improves Outcomes in Women with HER2+ Breast Cancer • First-line therapy as a single agent – Vogel et al. 2002 • Second-line therapy as a single agent – Cobleigh et al. 1999 • First-line therapy in combination with chemotherapy – Slamon et al. 2001, Marty et al. 2005 • Adjuvant therapy in combination or following chemotherapy – Romond et al. 2005, PiccartGebhart et al. 2005 Capecitabine + Lapatinib Locally Advanced or Metastatic Disease HER2 + stage IIIB or IIIC or metastatic disease Randomization Capecitabine 2000 mg/m2 PO BID days 1 - 14 Capecitabine 2000 mg/m2 PO BID days 1 - 14 Lapatinib 1250mg PO q day x 21 days Results: Improved Time to Progression in patients Treated with Cape/Lapatinib c/w Cape alone Geyer et al. N Engl J Med. 2006;355(26):2733-2743. Geyer et al. N Engl J Med. 2006;355:2733-2743. An Evaluation of the Safety and Efficacy of Lapatinib Plus Trastuzumab Plus Paclitaxel in First-Line HER2+ Metastatic Breast Cancer Key Inclusion Criteria • • • • • • Stage IV invasive, measurable breast cancer HER2+ by FISH or IHC (score, 3+) No prior treatment for MBC No prior HER2 inhibitor, other than adjuvant trastuzumab • >12 months since adjuvant trastuzumab If neo/adjuvant taxane given, progression must have occurred 12 mo after completion of this treatment No CNS metastases or leptomeningeal involvement Esteva FJ, et al. J Clin Oncol 28:15s, 2010 (abstr 1046) An Evaluation of the Safety and Efficacy of Lapatinib Plus Trastuzumab Plus Paclitaxel in First-Line HER2+ Metastatic Breast Cancer Esteva FJ, et al. J Clin Oncol 28:15s, 2010 (abstr 1046) Diarrhea Incidence by Maximum Severity Grade Esteva FJ, et al. J Clin Oncol 28:15s, 2010 (abstr 1046) Pharmacokinetics • The pharmacokinetic interaction between lapatinib and paclitaxel observed at higher doses also occurs at lower doses • Additional data will be required to estimate the magnitude of this interaction Esteva FJ, et al. J Clin Oncol 28:15s, 2010 (abstr 1046) Efficacy Data: Response Rate Esteva FJ, et al. J Clin Oncol 28:15s, 2010 (abstr 1046) Case Discussion • 45 y/o female diagnosed with stage II left breast cancer (IDC ER/PR+), s/p mastectomy/reconstruction, FAC x 6, adjuvant tamoxifen • After taking tamoxifen for 5 years, a routine chest x-ray showed pulmonary metastases. Biopsy: MBC, ER+, HER2+ • Treatment: letrozole -> exemestane -> trastuzumab (single agent) Response to Trastuzumab August 2001 December 2001 Progression on Trastuzumab December 2001 January 2003 Treatment Beyond Trastuzumab Progression in HER2+ MBC Lapatinib 1,500 mg PO (n=148) HER2+ MBC, Previous antrhacycline, taxane, Trastuzumab (N=296) R Lapatinib 1,000 mg PO + Trastuzumab 4mg/kg IV load, then 2 mg/kg IV weekly (n=148) Lapatinib Lapatinib + Trastuzumab Odds Ratio P Value Response Rate 6.9 10.3 1.5 0.46 Clinical Benefit Rate 12.4 24.7 2.2 0.01 O’Shaughnessy J, et al. J Clin Oncol 26: 2008 (May 20 suppl; abstr 1015) Patient Characteristics ITT Population Lapatinib n = 148 Lapatinib + Trastuzumab n = 148 Median Age (Years) 51 52 % ECOG 0/1/2 47/49/4 54/41/5 Median Prior Chemotherapy Regimens 4 5 Median Prior Trastuzumab Regimens for MBC 3 3 > 6 Prior Treatment Regimens 28% 34% HER2(+) 98.6% 99.3% % HR(-) 51 51 O’Shaugnessy J, et al. J Clin Oncol. 2008;26(15S): Abstract 1015. Progression-Free Survival Cumulative % Alive without Progression Lapatinib + trastuzumab vs. Lapatinib in HER2+ MBC progressing on or after trastuzumab 100 80 60 L N = 145 L+T N = 146 Progressed or Died, n 128 127 Median, wks 8.1 12.0 Hazard ratio (95% CI) 0.73 (0.57, 0.93) P value 40 0.008 28% 6 Mo PFS 20 13% 0 0 10 Subjects At Risk L L+T 148 148 53 73 20 30 40 21 42 13 27 5 8 Time from Randomization (wks) 50 60 0 2 O’Shaughnessy J, et al. J Clin Oncol 26: 2008 (May 20 suppl; abstr 1015) Trastuzumab and Lapatinib Resistance in Breast Cancer: Clinical Considerations • Less than a third of patients with HER2+ MBC respond to single-agent trastuzumab or lapatinib • Most responding patients develop progressive disease within one year. • Approximately 15% of patients with early-stage breast cancer develop metastatic disease regardless of trastuzumab adjuvant therapy Esteva FJ, et al. Nat Rev Clin Oncol. 2010;7(2):98-107 Potential Molecular Mechanisms of Trastuzumab Resistance Disrupted antibodyreceptor interaction HER-2 MAPK PI3K Increased receptor signaling: HER members, IGF-IR p27-cdk2 cyclin D1 Alterations in downstream molecules: PTEN downregulation, increased Akt signaling, reduced p27kip1 Esteva FJ, et al. Nat Rev Clin Oncol. 2010;7(2):98-107 p p p p p p p p p p p p p p p PI3-kinase p p p p p85 p110 PKB(AKT) mTOR/FRAP p70S6K Proliferation Survival Differentiation Cell metabolism Patients with PTEN deficient breast tumors have a poor response rate to Trastuzumab-based therapy 80 CR+PR SD+PD n=30 100 * n=17 60 40 20 0 Response rate (%) Response rate (%) 100 80 * CR+PR SD+PD * n=9 n=38 60 40 20 0 12-9 6-0 PTEN IRS 12-4 3-0 PTEN IRS Nagata Y et al. Cancer Cell 2004;6:117-127 Combined treatment with PI3K inhibitors and Trastuzumab Significantly Inhibits the Growth of PTEN AS- treated, BT 474 Xenografts Agents tested in vivo: Perifosine, Edelfosine, Triciribine, KP-372-1, A838, RAD001 TCN+HCP TCN HCP DMSO (N=7) 500 250 * * 750 tumor size (mm 3) tumor size (mm 3) 750 RAD+HCP RAD HCP DMSO (N=7) 500 250 * p<0.05 0 0 0 1 2 3 4 5 6 weeks Trastuzumab + Triciribine 0 1 2 3 4 weeks Trastuzumab + RAD001 Lu CH, et al. Clin Cancer Res 2007 Simultaneous Targeting of Her2 signaling at two levels: Rationale for combining Rad001 and Trastuzumab Her2/neu P P P P P src P PI3K Akt PTEN P Rapamycin TOR P Phase I / II: Everolimus + Trastuzumab in HER2+ Patients With Resistance to Trastuzumab Everolimus 10 mg qday and Trastuzumab 6 mg/kg q3wk • Pts had ≤ 2 prior trastuzumab regimens and 1 prior lapatinibbased regimen for MBC Best Response N (%) N = 47 Complete response (CR) - Partial response (PR) 7 (15%) Stable disease ≥ 24 weeks (SD) 9 (19%) Overall response rate 7 (15%) Clinical benefit rate 16 (34%) Median time to progression 3.4 months (Range 1-14) Most frequent grade 3 / 4 adverse events (> 10%) Lymphopenia, hyperglycemia, mucositis Morrow PK, et al. J Clin Oncol 28:7s, 2010 (abstr 1014) Trastuzumab/RAD001 Protocol 2005-0471 (Pt#10) CT at Baseline (7/30/07) Baseline PET scan (8/1/07) SUV=9.1 CT after Cycle 2 (9/20/07) PET scan after C2 (8/29/07) SUV=5.5 CT after C12 (4/16/08) PD after x 12 cycles (best response: SD) Molecular targets and therapeutic approaches to overcome trastuzumab and lapatinib resistance mTOR Adapted from Esteva FJ, et al. Nat Rev Clin Oncol. 2010;7(2):98-107 Pertuzumab: a HER dimerization inhibitor Prevents pairing with other HER family members, including HER3, HER1, and HER4 Combination of Trastuzumab and Pertuzumab: Increased Apoptosis in vitro % Annexin V + 7-AAD Cells 30 25 20 15 10 5 0 0 0.1 1 10 100 Trastuzumab + 2C4 (ug/mL) Trastuzumab 0 0.1 1 10 0.1 2C4 1 Trastuzumab + 2C4 10 0.1 1 10 PARP Full length 116kD 89 kD 24 kD Nahta. Nahta R, Hung MC, Esteva FJ. Cancer Res 2004;64:2343-6 Antitumor activity of trastuzumab and/or pertuzumab in NSCLC (Calu-3) and breast cancer (KPL-4) xenograft tumor models. Scheuer W et al. Cancer Res 2009;69:9330-9336 ©2009 by American Association for Cancer Research HER2 A Good ADC Target • • • Tumor expression >>> Normal-tissue expression Absolute Expression levels very high Internalized without down regulation Austin et al. (2004) Mol Biol Cell 15, 5268-82. Trastuzumab-DM1 – Binds to HER2 with affinity similar to trastuzumab – Provides intracellular delivery of anti-microtubule agent DM1 • Binds to tubulin competitively with vinca alkaloids, 20-100 times more potently than vincristine2-4 – Combines trastuzumab mediated inhibition of HER2 signaling with selective delivery of potent cytotoxic Phase II study of trastuzumab-DM1 for the treatment of HER2+ breast cancer after prior HER2-directed therapy Burris H A et al. J Clin Oncol 2011;29:398-405 Phase II study of trastuzumab-DM1 for the treatment of HER2-positive breast cancer after prior HER2-directed therapy Efficacy based on centrally assessed HER2 status and quantitative reverse transcriptase polymerase chain reaction (qRTPCR) expression levels of HER2 Burris H A et al. J Clin Oncol 2011;29:398-405 Ongoing and Planned Randomized Trials of Trastuzumab, Pertuzumab and T-DM1 in HER2+ Metastatic Breast Cancer Combination Trial Trastuzumab/Docetaxel +/- Pertuzumab CLEOPATRA (phase III)* Trastuzumab/Docetaxel vs. T-DM1 Randomized phase II* Trastuzumab/taxane vs. T-DM1 vs. T-DM1 + Pertuzumab MARIANNE (phase III)* T-DM1 vs. Capecitabine/Lapatinib EMILIA (phase III)** *first-line **second-line after trastuzumab Trastuzumab & Erythropoietin Liang, et al. Cancer Cell 18:423-435, 2010 Trastuzumab & Epo = Resistance Liang, et al. Cancer Cell 18:423-435, 2010 Trastuzumab & Epo = Resistance Liang, et al. Cancer Cell 18:423-435, 2010 SRC is a Key Modulator of Trastuzumab Response Zhang S., et al. Nat Med 2011 SRC Trastuzumab treatment plus SRC inhibition overcomes multiple resistance mechanisms in vitro Zhang S., et al. Nat Med 2011 Trastuzumab plus SRC inhibition overcomes trastuzumab resistance in vivo Zhang S., et al. Nat Med 2011 Trastuzumab plus saracatinib combinatorial treatment overcomes trastuzumab resistance in vivo Zhang S., et al. Nat Med 2011 Zhang S., et al. Nat Med 2011 Future Directions • Incorporate prospective tissue collection in clinical trials to assess molecular changes in breast cancer tissue – Characterize mechanisms of action and resistance – Identify patients most likely to benefit • Preclinical and clinical development of novel combination targeting receptors and pathways • Integrate non-invasive methods to monitor response to treatment • Characterize the potential toxicity of long-term pathway blockade (especially important in adjuvant setting) Thank you for your attention!