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

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)

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

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

Cancer Mortality in women - Italy Adj HT Screening Annual cancer mortality / 100,000 women, ages 35–69* *Mean of annual rates in the component 6-year age groups Source: WHO mortality and UN population estimates ITALY 1951–2001 Breast Stomach Uterus Lung Adj ChemoRx

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

This tumor is big and lazy 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% May-September 2005 dd chemoRx AC x 4 -> Paclitaxel x 4 RT on chest wall and axylla anastrozole for 5y December 2010: NED A nice story…. 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 2009 May-September 2009 ChemoRx TAC x 6 RT on the breast RT on the breast December 2009: lung mets A sad story…. This tumor is small and busy

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

Number of patients with EBC needed to treat with Adjuvant Therapy to prevent ONE recurrence ComparisonAbsolute Risk Reduction % NNT Tamoxifen vs. Nil ^11.88 Aromatase Inhibitors vs TAM* Aromatase Inhibitors vs Nil°  16  6 Polychemo vs. Nil ( < 50)^12.38 Polychemo vs. Nil ( 50+)^4.223 Anthra vs CMF^4.025 Taxanes vs. Anthra §  rd gen taxane regimen vs Nil°  23  4 ChemoRx + Trastuzumab vs ChemoRx ChemoRx + Trastuzumab vs Nil

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

9% 6% 12% 20% non cancer death (4%) relapses CMF Anthracyclines III rd generation regimens Trastuzumab 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 60 yrs, pT1cN+, ER-, HER2+

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

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

Hallmarks of Malignancy Independence from growth signaling Development of angiogenic ability Invasion and metastasis No limit on proliferation Evasion of apoptosis Insensitivity to growth inhibitory signals Cancer cell Hanahan D, et al. Cell. 2000;100:57-70.

Shortened median survival HER2 overexpressing3 years HER2 normal6–7 years Slamon et al. Science 1987 HER2/neu in breast cancer Abnormal high amplification

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

N Events AC  T AC  TH HR=0.48, 2P=3x % 87% 67 % 85% B31/N9831- Disease-Free Survival

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

Survival time (months) Proportion event free At risk Gefitinib 500 mg/day Gefitinib 250 mg/day Placebo WE DIDN’T KNOW ABOUT EGFR MUTATION Median survival, months 1-year survival rate, % Log rank vs placebo (p=0.4377) (p=0.3034) INTACT 1: Gefitinib in combination with chemotherapy

EGFR mutations in NSCLC EGFR mutations are over- represented in responders to EGFR inhibitors Mutations that confer sensitivity to EGFR-TKIs include: –exon 19 small in-frame deletions (50%) –exon 21 point mutations (40%) e.g. 40% EGFR L858R Mutations known to cause resistance to first-generation EGFR-TKIs include: –exon 20 in-frame insertions –exon 20 point mutations (e.g. T790M) –Role of cMET amplification 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 TM Exon Extracellular ligand-binding domain Tyrosine kinase domain Deletions (vIII) ~ 1% TM 22

K Kobayashi et al, P ASCO 2009

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

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

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

Accelerated Clinical Translation BRAF-mutated melanoma EML-ALK4 lung cancer

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.

The Erb-B signalling network

30 LCC 15 %ADENO 40% SCC 30% SCLC 15% Lung Cancers Breast Cancer ER % HER % Triple negative 15% Breast Cancers HER3+ IGFR1+ P53 mut 30-40% FGFR1 Ampl 8% PTEN loss 30-50% PI3K mut 10% BRCA Mut 8% p95 4-8% Somatic Mutations in Adenocarcinoma EML-ALK4 3-5% EGFR 10-15% Lung and Breast Cancer Diseases – 201…

High throughput technologies Shifting paradigms Prognostic and predictive factors are identified at molecular level

32 CHERLOB – Gene expression and pCR pCR

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

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

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 has an only answer…. molecular characterization of human tumors