From pathology research to stratified medicine trials

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1 From pathology research to stratified medicine trials Dr. John Bartlett Program Director Transformative Pathology C CCTG Breast Group Steering Committee ASCO-CAP HER2 Panel As is your Pathology, so is your Medicine. Sir William Osler

2 San Antonio Breast Cancer Symposium, December 9-13, 2014 Cancer = the big C? s Cancer as 1 disease DNA structure discovered s Cancer as site specific one size fits all s Cancer subtypes Herceptin targeted treatments 2010s: Molecular complexity and Heterogeneity Genomic data overload 4.1Million mutations in 1000 cancers..

3 Cancer Treatment: 20 th century ONTARIO INSTITUTE FOR CANCER RESEARCH Radiotherapy Surgery

4 Pan Cancer projects: Unlocking cancer genomic data

5 Information at the pathway level Version: 26Apr2012

6 Insights into global cancer processes Mutation vs CNAs a fork in the cancer genome road map? M vs C class cancers? Mutations and CNAs represent fundamentally different aspects of cancer. Most cancers are mixed with low numbers of alterations Ciriello G, et al, Nat Genetics :

7 M-Class Cancers Nature Genetics 45, (2013) 7

8 C-Class Cancers Nature Genetics 45, (2013) 8

10 The challenge posed by ICGC: ONTARIO INSTITUTE FOR CANCER RESEARCH Cancers are heterogeneous: Between patient heterogeneity requires stratified treatment approaches; Within tumour heterogeneity target multiple clones requires combination/multi-agent targeted therapy; Selection of resistant clones during treatment requires adaptive therapies. NB Cancer has not changed our understanding has improved current treatments are effective in the context of molecular heterogeneity. ICGC puts widely recognized and existing therapeutic and treatment challenges in a molecular context enabling a rational targeted therapeutic approach. 10

11 Cancer Paradoxes or cancer successes? TCGA colorectal cancer 4 molecular subgroups ULTRA mutated cancers Genetically unstable, multiple driver mutations

12 Cancer Paradoxes or cancer successes? Version: 26Apr2012

13 PIK3CA mutations: One gene two results Probability of Progression-Free Survival In early breast cancer PIK3CA mutation is linked to good outcome, in metastatic breast cancer PIK3CA is linked to poor outcome what changed? EVE.PIK3CA.WT EVE.PIK3CA.Alt PBO.PIK3CA.WT PBO.PIK3CA.Alt Time, days 13

14 The challenge of Context: It is not enough to model gene function in isolation. Treatment of different cancers, even with similar molecular drivers, varies. Molecular drivers, viewed in isolation, may have different impacts at different stages of disease. The relationship between the molecular make up of a cancer and outcome for a patient reflects a complex integration of multiple treatment and response variables.

15 Cancer is highly complex. 10,048 cancers An average of 400 mutations per cancer Over 100 different druggable mutations 9.3x permutations! If only 10% are present = 3.6x10 6 permutations

16 To summarize. 16

17 Personalised medicine progress to date 17

18 HER2 the test that came in from the cold:

19 HER2 selective for Herceptin Benefit (2005!) % AC TH 87% 85% AC T 75% HR=0.48,2P=3x10-12 Herceptin/Trastuzumab: Humanised mouse antibody Targets BRCA driver gene HER2 Reverses poor outcome in some HER2 positive BRCA (15%) 67% Years From Randomisation

Successful personalised drug development Rapid identification of potential targets For druggable targets Interval from target to clinical candidate is

20 Successful personalised drug development Rapid identification of potential targets For druggable targets Interval from target to clinical candidate is shorter FDA Approval 2011 For clinically important targets Interval from FIH to drug approval is short Chin L et al. Nature Medicine 17: , 2011

21 Personalized medicine? In 2015 the FDA Approved 15 new therapeutic agents Approved 11 new applications of existing therapeutic agents Approved one new diagnostic test for existing EGFr mutation detection As is your Pathology, so is your Medicine. Sir William Osler As is your molecular pathology so is your molecular medicine - David Huntsman 21

22 CDK/CCND pathway CDK4/CCND1 amplified 15-20% breast cancer Luminal ER+ BC cells sensitive to CDK4/6 inhibitor palbociclib Palbociclib + letrozole approved for ER+/HER2- breast cancer No biomarkers to select patients for treatment 22

23 PI3K/AKT/mTOR pathway Most commonly altered pathway in BC PIK3CA mutated in 35-40% ER+ BC AKT1 2-4% ER+ BC PTEN 29-44% ER+ BC Resistance to endocrine therapy Everolimus + exemestane approved for ER+/HER2- breast cancer 23

24 Current paradigm Treat Test benefit from therapy 5-15% benefit from therapy Don t Treat do not benefit try alternate therapy Identify new target response to therapy no response to therapy F4LBC Dream Team 24

25 Current reality Treat benefit from therapy Test 5-15% benefit from therapy Treat do not benefit response to therapy no response to therapy F4LBC Dream Team 25

26 Multiple targets - multiple opportunities F4LBC Dream Team Zardavas D, et al. Nat Rev Clin Oncol. 2013;10(4):

27 How do we treat breast cancer NPI Adjuvant! Stage Biology Biology Risk Grade + receptors Chemotherapy benefit estimate from proportional hazards Assumes that breast cancer is a single disease (One size fits all) Assumes that chemotherapy benefit is present in ALL cancer subtypes. Endocrine therapy HER2-targeted therapy

28 How should we treat cancer? Don t treat TEST Less therapy 5-15% benefit from therapy Treat Current therapy Alternate therapies

29 Breast Cancer Mortality (%) Lack of Personalised Medicine: One Size Fits All ONTARIO INSTITUTE FOR CANCER RESEARCH % 7.9% 25% exhibit or acquire Tamoxifen/endocrine resistance NEW TREATMENT For each treatment success 3 patients experience resistance 7 patients are treated unnecessarily <10% of patients gain benefit ALL risk side effects None Tamoxifen (5yrs) 9.2% Benefit from Tamoxifen Treat 11 benefit 1. 65% cured by surgery/rx REDUCE TREATMENT Years

30 Reducing treatment: Integrate risk and reduce treatment for low risk patients

31 Distant Recurrence at 10 Years ONTARIO INSTITUTE FOR CANCER RESEARCH Oncotype DX: RS as Continuous Predictor in tam treated patients 40% 35% Low-Risk Group Intermediate- Risk Group High-Risk Group 30% 25% 20% 15% 10% 5% 0% Recurrence Score Data from NSABP B14: Paik NEJM 2004, 351:2817

32 B-20 Results: Relative benefit of chemo on 10 Year DDFS 32 Paik et al. J Clin Oncol

33 Optimal Personalised Treatment of early breast cancer using Multi-parameter Analysis Objectives 1. To establish a method of selecting patients with hormone sensitive primary breast cancer who are likely to benefit or not benefit from postoperative chemotherapy. 2. To establish the cost-effectiveness of alternative test-guided treatment strategies compared to standard practise

34 OPTIMA Design Adequate surgery Age 40 ER +ve, HER2 ve N+/ N0 & T>30mm Central confirmation of ER & HER2 Exclusion: advanced stage = 10 N+/ IM+ R Sample size to demonstrate non-inferiority (-3%) = 1860 per arm 1 1 Test Patients receiving chemotherapy blind to randomisation chemo. chemo. endocrine endocrine endocrine Endocrine therapy continued to 5+ yrs Radiotherapy given according to local practise Permitted chemotherapy: pre-specified by patient before randomization FEC x 6 cycles TC x 4 cycles FEC100-T E-CMF Permitted endocrine therapy: postmenopausal - any AI premenopausal - GnRH agonist (3 yrs) + tamoxifen 34

35 Stratified medicine and diagnostics ONTARIO INSTITUTE FOR CANCER RESEARCH Don t treat TEST Less therapy 5-15% benefit from therapy Treat Current therapy Alternate therapies

36 Use existing Phase III trial of current SOC to develop stratified medicine approaches to breast cancer We rarely know why patients respond to treatment; We more often know why they do not and it is usually different for different patients. 36

57 USH2A 2.16 1.22-3.83 11.35 TP53 1.93 0.96-3.91 8.01 AKT1 0.77 0.18-3.15 3.78 MET 0.69 0.28-1.72 9.

37 adjusted HR TEAM trial: integrating genomics CGH/CNV targeted sequencing Gene Hazard Ratio 95% CI Freq(%) UPF3B CBLB ERBB BRCA USH2A TP AKT MET PIK3CA GATA EPHA mrna profiles F4LBC Dream Team 37

38 PIK3CA pathway: mutation, CNV, mrna PIK3CA AKT1 CNV PIK3CA/AKT gain, PTEN loss

39 A Functional Focus: Pathways are paramount: Molecular alterations rarely exist in isolation mutations/cnas in each cancer. Intracellular regulatory pathways have key mutational nodes Evaluation of multiple events/nodes is essential Mutation Copy number change Expression Proteins etc etc.

40 Developing novel stratified diagnostics: Pathway and target oriented. 40

41 Umbrella or basket? ONTARIO INSTITUTE FOR CANCER RESEARCH Biankin et al, Nature 2015

42 HIGH RISK BREAST CANCER ONTARIO INSTITUTE FOR CANCER RESEARCH Stratified clinical trials Molecular diagnostic screen Randomise Arm 1: Conventional treatment Arm 2: Experimental treatment A Arm 3: Experimental treatment B Arm 4: Experimental treatment C Low risk conventional or reduced treatment 42 Pre-operative Neo-adjuvant Adjuvant 2-3 weeks 3-4 months 3-5 years

43 Stratified medicine and diagnostics ONTARIO INSTITUTE FOR CANCER RESEARCH Don t treat TEST Less therapy 5-15% benefit from therapy Treat Current therapy Alternate therapies

right time, to the right patient Stratified medicine requires stratified diagnostics Failure to improve diagnostic

44 To Dream the impossible dream? RNA CNA CpG Mut mrna mirna Mutation CNA CpG Ptn a new era of medicine one that delivers the right treatment at the right time, to the right patient Stratified medicine requires stratified diagnostics Failure to improve diagnostic pathology, both in the quantity and the quality of information derived will continue to restrict the development of personalised medicine. As is your Pathology, so is your Medicine. William Osler

45 I want the country that eliminated polio and mapped the human genome to lead a new era of medicine one that delivers the right treatment at the right time, President Obama 21 st Jan 2015.

46 OICR Diagnostic Development: mi casa es su casa ONTARIO INSTITUTE FOR CANCER RESEARCH IHC and FISH: Ventana, Dako autostainer, FISH Light and fluorescence microscopy Bioview (FISH), Ariol, Definiens mrna: Multiplex PCR/Nanostring q-mi/mrna RNAseq DNA targeted seq/cnv MLPA etc Preclinical cell culture, high throughput drug screening, in vitro, invivo. Tissue:- Laser capture micro/manual macro 10,000s samples ONTARIO TUMOUR BANK 15,000 samples Breast/Prostate tissues (20-30,000) TMAs, frozen section, etc etc

47 Funding for the Ontario Institute for Cancer Research is provided by the Government of Ontario

48 The Tumor Ecosystem: Joan Brugge Hypothesis: there is a limit to the number of insults that the ecosystem can withstand. Need to identify critical set of perturbants that push the ecosystem to point beyond its ability to adapt. Susan Komen Lecture The facts expressed here belong to everybody, the opinions to me. The distinction is yours to draw.

Assessment of Risk Recurrence: Adjuvant Online, OncotypeDx & Mammaprint

Assessment of Risk Recurrence: Adjuvant Online, OncotypeDx & Mammaprint William J. Gradishar, MD Professor of Medicine Robert H. Lurie Comprehensive Cancer Center of Northwestern University Classical