1 / 35

Importance of phenotyping (and genotyping) breast and lung cancer Modena, march 1 st 2011 PierFranco Conte

Grazie per aver scelto di utilizzare a scopo didattico questo materiale delle Guidelines 2011 libra. Le ricordiamo che questo materiale è di proprietà dell’autore e fornito come supporto didattico per uso personale. Importance of phenotyping (and genotyping) breast and lung cancer

uzuri
Download Presentation

Importance of phenotyping (and genotyping) breast and lung cancer Modena, march 1 st 2011 PierFranco Conte

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Grazie per aver scelto di utilizzare a scopo didattico questo materiale delle Guidelines 2011 libra.Le ricordiamo che questo materiale è di proprietà dell’autore e fornito come supporto didattico per uso personale.

  2. Importance of phenotyping (and genotyping) breast and lung cancer Modena, march 1st 2011 PierFranco Conte Department of Oncology, Hematology and Respiratory Diseases - University of Modena and Reggio Emilia

  3. Dec 1971, National Cancer Act by Richard Nixon • Conquest of Cancer is a National Crusade • 1971 to 2008: 200 billion $ (US budget for cancer research) • 1971 to 2005: overall cancer mortality from has fallen 7.5% • 1971 to 2005: mortality for cardiovascular disease has fallen 70% One tumor is smarter than 100 brilliant cancer scientists O. Brawley, American Cancer Society We fought cancer ....and cancer won (Newsweek, september 6, 2008)

  4. Molecular characterization of human tumors:the dawn of a new beginning A successful story from the past…. Lessonsfrom a successfulstory…. Fromsizetobiology: - achievements - opportunities - challenges

  5. Prognostic factors Predictive Factors Risk assessment Proportional benefit Absolute benefit Toxicities (short & long term) Patient Characteristics and preference Adjuvant medical treatments Adjuvant Rx of EBC - Decision-making Algorithm

  6. Cancer Mortality in women - Italy Breast Stomach Uterus Lung ITALY1951–2001 70 60 50 40 30 20 10 0 70 60 50 40 30 20 10 0 Screening Adj HT Adj ChemoRx Annual cancer mortality / 100,000 women, ages 35–69* 1950 1960 1970 1980 1990 2000 2010 *Mean of annual rates in the component 6-year age groups Source: WHO mortality and UN population estimates

  7. Molecular characterization of human tumors:the dawn of a new beginning A successful story from the past…. Lessonsfrom a successfulstory…. Fromsizetobiology: - achievements - opportunities - challenges

  8. M.R. 62y old - May 2005 Left radical mastectomy + ALND ILC, pT2 (2.3cm), N2 (14/44 N+), ER 90%, PgR 80%, HER2 1+, Ki 67 10% A nicestory…. A sadstory…. C.B. 44 y old - April 2009 SE quadrantectomy + SN IDC, pT1c (1.7cm), N0, ER <1%, PgR 0%, HER2 0, Ki 67 60% May-September 2005 • dd chemoRx AC x 4 -> Paclitaxel x 4 • RT on chest wall and axylla • anastrozole for 5y May-September 2009 ChemoRx TAC x 6 RT on the breast December 2009: lungmets December 2010: NED Thistumoris big and lazy Thistumorissmall and busy

  9. Molecular characterization of human tumors:the dawn of a new beginning A successful story from the past…. Lessons from a successful story: lesson # 1: biology can be more important than size From size to biology: - achievements - opportunities - challenges

  10. Number of patients with EBC needed to treat with Adjuvant Therapy to prevent ONE recurrence

  11. Molecular characterization of human tumors:the dawn of a new beginning A successful story from the past…. Lessons from a successful story: lesson # 1: biology can be more important than size lesson # 2: we treat many patients to benefit one From size to biology: - achievements - opportunities - challenges

  12. non cancer death (4%) 20% 12% Anthracyclines 6% 6% 9% IIIrd generation regimens Trastuzumab relapses CMF 60 yrs, pT1cN+, ER-, HER2+ cured by locoregional therapy (43%) ChemoRx + Trastuzumab is recommended based on level 1 scientific evidence; however, this treatment is applied to 4% of the patients who will die for other reasons, 43% who will never relapse, 9% cured by CMF, 6% cured by anthra, 6% cured by taxanes. Eventually, 12% of the patients will actually benefit from trastuzumab

  13. Molecular characterization of human tumors:the dawn of a new beginning A successful story from the past…. Lessons from a successful story: lesson # 1: biology can be more important than size lesson # 2: many patients are treated to benefit one lesson # 3: the “best” Rx is applied to all the patients as we are unable to predict individual treatment sensitivity From size to biology: - achievements - opportunities - challenges

  14. Molecular characterization of human tumors:the dawn of the new beginning A successful story from the past…. Lessons from a successful story…. From size to biology: - achievements - opportunities - challenges

  15. Hallmarks of Malignancy Independence from growthsignaling Insensitivity to growth inhibitorysignals No limit on proliferation Cancer cell Evasion ofapoptosis Invasionand metastasis Development of angiogenic ability Hanahan D, et al. Cell. 2000;100:57-70.

  16. Abnormal high amplification HER2/neu in breast cancer Shortened median survival HER2 overexpressing 3 yearsHER2 normal 6–7 years Slamon et al. Science 1987

  17. Trastuzumab: humanised anti-HER2 monoclonal antibody • Targets HER2 oncoprotein • High affinity (Kd=0.1nM) and specificity • 95% human, 5% murine • decreased potential for immunogenicity • increased potential for recruiting immune-effector mechanisms

  18. B31/N9831- Disease-Free Survival 87% 85% 75 % 67 % N Events ACT 1679 261 ACTH 1672 134 HR=0.48, 2P=3x10-12

  19. 12-02 BAC EGFR mut+: Response to TKI 12-00

  20. INTACT 1: Gefitinib in combination with chemotherapy Median survival, months 1-year survival rate, % Log rank vs placebo 9.92 43 0.7759 (p=0.4377) 9.86 41 1.0290 (p=0.3034) 11.07 45 Proportioneventfree 1.0 0.8 WE DIDN’T KNOW ABOUT EGFR MUTATION Gefitinib 500 mg/day Gefitinib 250 mg/day Placebo 0.6 0.4 0.2 0.0 0 4 8 12 16 20 24 Survival time (months) At risk 1093 898 641 463 152 11

  21. EGFR mutations in NSCLC EGFR mutations are over-represented in responders to EGFR inhibitors Mutations that confer sensitivityto EGFR-TKIs include: exon 19 small in-frame deletions (50%) exon 21 point mutations (40%)e.g. 40% EGFR L858R Mutations known to cause resistanceto first-generation EGFR-TKIs include: exon 20 in-frame insertions exon 20 point mutations (e.g. T790M) Role of cMET amplification Extracellular ligand-binding domain Deletions (vIII) ~ 1% TM TM Exon 18 19 20 Tyrosine kinasedomain 21 22 23 24 Sharma et al. Nature Rev Cancer 2007;7;169 Ji et al. Proc Natl Acad Sci USA 2006;103;7817 Stephens et al. Nature 2004;431:525

  22. K Kobayashi et al, P ASCO 2009

  23. Activity of Crizotinib in EML-ALK4 Fusion Non-Small Cell Lung Cancer 60 40 20 0 –20 –40 –60 –80 –100 Progressive disease Stable disease Confirmed partial response Confirmed complete response Maximum change in tumor size (%) –30% Bang et al ASCO 2010

  24. Molecular characterization of human tumors: opportunities and challenges Accelerated clinical translation Biological complexity Cancers as rare diseases High through-put technologies Costs of cancer treatments

  25. Rate of success in drug development Cost of bringing a new cancer drug to clinical practice is >€1 Billion! Likelihood of success 11% 5% CNS Arthritis Oncology Metabolic disease Women’s health All Cardio- vascular Infectious diseases Opthal- mology Urology Kola Nat Rev Drug Discovery 2004

  26. Accelerated Clinical Translation BRAF-mutated melanoma 2002 2004 2006 2009 2010 2011 EML-ALK4 lung cancer 2007 2008 2012 2009 2010

  27. Different Models Emerge • Tumors with real “oncogene addiction”[1] • HER2+ BC • EGFR-mutated NSCLC • EML-ALK4 NSCLC • GIST • CML • BRAF mut+ MM • HIF/VEGF RCC • Tumors with a more complex genetic make-up • Deciphering relative importance of one pathway vs others • Importance of drug combinations 1. Weinstein IB. Science. 2002;297:63-64.

  28. The Erb-B signalling network

  29. Breast Cancers PI3Kmut 10% HER3+ Breast Cancer ER+ 65-75% IGFR1+ p95 4-8% HER2+ 15-20% P53mut 30-40% FGFR1 Ampl 8% Triple negative 15% Somatic Mutations in Adenocarcinoma PTENloss 30-50% BRCAMut 8% EML-ALK4 3-5% EGFR 10-15% Lung and Breast Cancer Diseases – 201… Lung Cancers SCLC 15% SCC 30% ADENO 40% LCC 15 % 30

  30. High throughput technologiesShifting paradigms Prognostic and predictive factors are identified at molecular level

  31. CHERLOB – Gene expression and pCR pCR

  32. The Challenge of Personalized Oncology “If it were not for the great variability among individuals, medicine might have well been a science and not an art” ― Sir William Osler, 1892

  33. Challenging the “classic” paradigms • Reinforce the “no tumor no drug” policy (BioBanks) • Establish a new Pharma-Academia partnership • Allow for joint development of NMEs from different Pharma companies • Project Zero Delay: A Process for Accelerating the Activation of Cancer Clinical Trials (R. Kurzrock, JCO, e-pub august 3, 2009) • Improve the scientific advice process with regulatory authorities • Implement and govern post-launch studies

  34. has an only answer…. molecular characterization of human tumors The quest for personalized cancer medicine.. The Right Dose of The Right Drug for The Right Indication for The Right Patient at The Right Time

More Related