IMPORTÂNCIA DA DIFERENCIAÇÃO TERAPÊUTICA NA ABORDAGEM INDIVIDUAL A VISÃO DO ONCOLOGISTA PAULO CORTES SOCIEDADE PORTUGUESA DE ONCOLOGIA UNIDADE DE ONCOLOGIA HOSPITAL LUSÍADAS LISBOA
QUIMIOTERAPIA CLÁSSICA
DIFERENCIAÇÃO TERAPÊUTICA DE QUIMIOTERAPIA CLÁSSICA: CAPECITABINA
DIFERENCIAÇÃO TERAPÊUTICA DE QUIMIOTERAPIA CLÁSSICA: NAB-PACLITAXEL
CONVENTIONAL WISDOM IN THE NEW AGE OF MODERN DRUG DEVELOPMENT Targeted therapies are unique and distinct from classic cytotoxic chemotherapies Classical chemotherapy = poisons All new agents entering the clinical have well defined molecular targets Conventional clinical study designs are outdated, outmoded, and poorly-suited to develop targeted therapies Biomarkers rule!
DEFINITION OF BIOMARKER A measurable indicator that is used to distinguish precisely, reproducibly and objectively either a normal biological state from a pathological state, or the response to a specific therapeutic intervention.
POTENCIAL USES FOR CANCER BIOMARKERS
GENOMIC ALTERATIONS AS PUTATIVE PREDICTIVE BIOMARKERS FOR CANCER THERAPY
TERAPÊUTICA ALVO
Terapêutica alvo Anticorpos Monoclonais Inibidores Tirosina Cinase Locais/Níveis de Inibição: 1) Ligação e Neutralização ao ligando 2) Ocupação dos locais de ligação no receptor 3) Bloquear sinalização ao nível do receptor na célula tumoral 4) Interferência ao nível de moléculas intracelulares
FAMÍLIA ERBB DE RECEPTORES DE TIROSINA-QUINASES Extracellular Domain (Binds Ligand) Quatro membros: ErbB-1 (EGFR/HER1) ErbB-2 (HER2) ErbB-3 (HER3) ErbB-4 (HER4) TM Domain Cytoplasmic Domain (Kinase Activity)
Milestones in the treatment BREAST CANCER HER2 POSITIVE 1981 Murine HER2/neu gene cloned 1985 Human Her2 gene cloned 1987 HER2-positive breast cancers have a worse prognosis than HER2 negative tumors 1990 mumab 4D5 1992 phase I rhumab HER2 2001 phase III first line metastatic chemotherapy + trastuzumab 2005 phase III adjuvant ( HERA, NASBP B31, NCCTG N9831, BCIRG 006) 2005 phase III neoadjuvant
Breast cancer HER2 + Adjuvant trial Trastuzumab: Disease-free Survival AC TH* 87% 85% % AC T 75% 67% N Events AC T 1679 261 AC TH 1672 134 N: 3,351 patients HR = 0.48, 2 p = 3 x 10-12 0 1 2 3 4 5 Years * H: Herceptin (trastuzumab)
CURRENT ASSAYS OF HER2/NEU Immunohistochemistry 0 (negative) 1+ (negative) 2+ (equivocal) 3+ (positive) Fluorescence in situ hybridization (FISH) HER2 gene no amplification FISH negative HER2 gene amplification FISH positive Murthy SS, et al. Indian J Pathol Microbiol. 2011;54(3):532-538.
Please refer to slide 2 for disclaimer HER2 CAN DIMERISE WITH ANY OF THE HER FAMILY RECEPTORS TO DRIVE DOWNSTREAM SIGNALLING HER1, 3, 4 HER2 Ligand-activated HER2 heterodimer Baselga J & Swain SM. Nat Rev Cancer 2009; 9:463 475; Yarden Y & Sliwkowski MX. Nat Rev Mol Cell Biol 2001; 2:127 137; Tzahar E, et al. Mol Cell Biol 1996; 16:5276 5287.
Please refer to slide 2 for disclaimer HER2-CONTAINING DIMERS INDUCE POTENT MITOGENIC SIGNALLING RESULTING IN CELL SURVIVAL AND PROLIFERATION Homodimers Heterodimers HER1:HER1 HER2:HER2 HER3:HER3 HER4:HER4 HER1:HER2 HER1:HER3 HER1:HER4 HER2:HER3 HER2:HER4 HER3:HER4 + + + + + + + + + + + + + + + + + + Signalling activity Most common and most potent oncogenic dimer in HER2-positive breast cancer Tzahar E, et al. Mol Cell Biol 1996; 16:5276 5287; Citri A, et al. Exp Cell Res 2003; 284:54 65.
Please refer to slide 2 for disclaimer PERTUZUMAB AND TRASTUZUMAB BIND TO DIFFERENT DOMAINS ON HER2 AND HAVE COMPLEMENTARY MECHANISMS OF ACTION Pertuzumab HER1, 3, 4 HER2 Trastuzumab 1. Franklin MC, et al. Cancer Cell 2004; 5:317 328; 2. Junttila TT, et al. Cancer Cell 2010; 15:429 440; 3. Nahta R, et al. Cancer Res 2004; 64:2343 2346; 4. Scheuer W, et al. Cancer Res 2009; 69:9330 9336; 5. Fields C, et al. AACR 2010. Abstract 5607.
Trastuzumab emtansine (T-DM1): DM1 Trastuzumab Thioether linker The mab, trastuzumab, is conjugated by a thioether linker to the highly potent antimicrotubule agent DM1 ADC, antibody drug conjugate; DM1, derivative of maytansine, a microtubule polymerisation inhibitor; mab, monoclonal antibody. Breast Cancer Res Treat 2011; 128:347 356.
Activação do EGFR: Activação da via RAS-RAF-MAPK (via principal de sinalização) Via da PI3K-Akt Controla: Divisão e multiplicação celular Diferenciação Sobrevivência
A via do EGFR e a importância do estado do KRAS O gene KRAS pode ser normal (wild-type) ou mutado A proteína wild-type KRAS é activada por um curto período quando o EGFR é estimulado Os efeitos do KRAS são muito controlados Quando o KRAS está mutado a proteína está sempre activada, mesmo sem ser estimulada pela via de sinalização do EGFR Os efeitos do KRAS estão desregulados (crescimento do tumor e disseminação) 1 DiFiore F, et al. Br J Cancer 2007;96:1166-9.
Cetuximab anticorpo monoclonal quimérico. Panitumab anticorpo monoclonal humanizado. Estes anticorpos são específicos para EGFR. A ligação ao receptor bloqueia a passagem (transdução) do sinal.
Anticorpos anti-egfr e KRAS Quando o KRAS está mutado e permanentemente ligado o bloqueio do EGFR não vai controlar os eventos para jusante do KRAS Neste caso, o tratamento anti-egfr não vai evitar o crescimento e disseminação tumoral Logo, o bloqueio do EGFR com um anticorpo monoclonal só vai ser eficaz nos tumores KRAS wild-type 1 No CCRm, cerca de 60% dos doentes apresentam tumores wild-type 2 1 Ramos FJ, et al. Clin Colorectal Cancer 2008;7(S2):S52-7 2 Lang CH, et al.. ECCO-15 ESMO-34 2009, Abstract No. 6,078
As mutações do KRAS são muito específicas para os que não respondem: 95%-100% dos doentes com mutação não respondem à terapêutica anti-egfr. Mas não é sensível: 40 60% dos doentes KRAS wild-type não respondem ao tratamento. Indica a presença de outros determinantes da terapêutica.
A identificação de alterações genéticas determinantes para a resistência das terapêuticas anti-egfr é fundamental: Identificar os doentes que não respondem à terapêutica. Evitar a exposição a uma terapêutica ineficaz e dispendiosa e evitar toxicidade. Permitir o desenvolvimento racional de estratégias de tratamento alternativas.
É um dos constituintes da via de sinalização EGFR - KRAS - BRAF... Tem um papel importante na regulação desta via de sinalização que controla a divisão celular, proliferação e diferenciação. Mutações no gene BRAF: 5-10 % dos CCR. A mutação mais frequente (90%) é a V600E. Di Fiore et al; BJC 2010
As mutações de KRAS/NRAS e BRAF são mutuamente exclusivas. Um tumor BRAF mutado é KRAS wild-type As mutações de BRAF têm um impacto negativo nas respostas dos tumores KRAS wildtype. As mutações de KRAS e NRAS também são mutuamente exclusivas. Teste RAS alargado : detectar mutações exons 2, 3, 4
Colon cancer: biomarkers and response Responder (15%) KRAS-NRAS mutated (35-45%) BRAF mutated (8%) PIK3CA mutated and/or PTEN loss (15-20%) KRAS/PIK3CA mutated BRAF/PIK3CA mutated 20-25%??? Bardelli and Siena, J Clin Oncol 2010 De Roock et al., Lancet Oncology 2010
MELANOMA: MAPK PATHWAY BRAF AND MEK INHIBITORS
CORE QUESTIONS TO IDENTIFY TARGETS F. Andre et al Annals of Oncology 25; 2014
TCGA: THE CANCER GENOME ATLAS Launched in 2006 by NCI & NHGRI Complete characterization of 35 adult cancers 20 common cancers 15 rare cancers Copy Number, Gene Expression, Methylation, DNA Sequencing (WGS/WXS) Clinical data 11,000 cases Future projects to use the TCGA infrastructure: Exceptional Responders, ALChEMIST, Clinical Trial Sequencing Program (CTSP), Cancer Driver Discovery Program (CDDP)
THE CANCER GENOME ATLAS PAN-CANCER ANALYSIS PROJECT
MULTIPLATFORM ANALYSIS OF 12 CANCER TYPES REVEALS MOLECULAR CLASSIFICATION WITHIN AND ACROSS TISSUES OF ORIGIN Cell August 2014
DR. WILLIAM B. COLEY THE FATHER OF CANCER IMMUNOTHERAPY In 1891, William B. Coley injected streptococcal organisms into a patient with inoperable cancer. He thought that the infection he produced would have the side effect of shrinking the malignant tumor. He was successful, and this was one of the first examples of immunotherapy. Over the next forty years, as head of the Bone Tumor Service at Memorial Hospital in New York, Coley injected more than 1000 cancer patients with bacteria or bacterial products. These products became known as Coley s Toxins. He and other doctors who used them reported excellent results, especially in bone and soft-tissue sarcomas.
CANCER IMMUNOTHERAPY KEY MILESTONES Discovery of the dendritic cell Tumour specific mabs Adoptive T cell immunotherapy IFN-α as adjuvant therapy for melanoma BCG approved for bladder cancer Discovery of checkpoint inhibitor First immunotherapy approved for prostate cancer (sipuleucel-t) First-line approval of ipilimumab 1970s 1980s 1990s 2000s 2010s Immune component to spontaneous regressions in melanoma First tumourassociated antigen cloned (MAGE-1) IL-2 approved for RCC and melanoma (US) First checkpoint inhibitor (ipilimumab) approved for advanced melanoma Figure adapted from Kirkwood JM. Ca J Clin 2012;62:309 35, Copyright 2012 American Cancer Society; George S, et al. JNCCN 2011;9:1011 8; Garbe C, et al. The Oncologist 2011;16:2 24; Rosenberg SA. Sci Transl Med 2012;4:127ps8; Cheever MA, et al. Clin Cancer Res 2011;17:3520 6; Kantoff PW, et al. N Engl J Med 2010;363; Mansh M. Yale J Biol Med 2011;84:381 9; Hodi FS, et al. N Engl J Med 2010;363:711 23
ANTI-CTLA4 IPILIMUMAB Pooled Analysis of Long-term Survival Data From Phase II and Phase III Trials of Ipilimumab in Metastatic or Locally Advanced, Unresectable Melanoma Pooled OS Analysis Including EAP Data: 4846 Patients Hodi S, ESMO 2013 Maio M, 10th EADO Congress
Immune-biomarkers are indicators of immune activity Immune-biomarkers are measures of activity within the tumor microenvironment, differing from established gene mutation biomarkers, such as BRAF and EGFR. 84-87 As components and regulators of the immune response, immune-biomarkers include: 84 Tumor-infiltrating immune cells Secreted peptides Cell surface proteins Immunosuppressive cells Evaluating multiple immune-biomarkers may provide a more realistic representation of the tumor microenvironment, as well as a more accurate and comprehensive assessment of clinical relevance. EXPLORING PREDICTORS OF RESPONSE: IMMUNE BIOMARKERS
PD-L1 AS A BIOMARKER: RATIONALE T cell PD-1 PD-L2 Lung: 53% 98% Colorectal: 64% PD-L1 Kidney/renal pelvis: 24% Melanoma: 38% 100% chl: 46% 100% Tumor cell SCCHN: 99% HCC: 27% Urothelial carcinoma: 28% 67% Gastric/Esophageal: 40% 43.9% TNBC: 18% 44
MULTIFACTORIAL BIOMARKERS OF CLINICAL RESPONSE TO PD1 PATHWAY BLOCKADE NATURE REVIEWS CANCER - 2016
GENE EXPRESSION ESSAY ( IMMUNOCHIP)
IMUNOTHERAPY MISMATCH REPAIR Whole-exome sequencing revealed a mean of 1782 somatic mutations per tumor in mismatch repair deficient tumors, as compared with 73 in mismatch repair proficient tumors (P=0.007) High somatic mutation loads were associated with prolonged progression-free survival (P=0.02) NEJM372;26, 2015