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\/,ale CANCER J ( CENTER A Comprehensive Cancer Center Designated by the National Cancer Institute
Pathophysiology of Tobacco Induced Cancers
Roy S. Herbst, MD, PhD Ensign Professor of Medicine Professor of PharmacologyChief of Medical Oncology
Director, Thoracic Oncology Research ProgramAssociate Cancer Center Director for Translational Research
February 27, 2014
Goals of this presentation
• Pathogenesis of tobacco induced cancer – Epidemiology and mechanism – Focus on lung and head and neck cancer
• Joint AACR/NCI efforts related to tobacco control – Tobacco use in patient’s receiving treatmentfor cancer
– Clinical trials
• New Approaches to treatment of tobacco induceddisease- the lung cancer master protocol
Goals of this presentation
• Pathogenesis of tobacco induced cancer – Epidemiology and mechanism – Focus on lung and head and neck cancer
health consequences causally linked to smok ing
Cancers
Oropha
Acute myeloid leukemi
Chronic Diseases
.-------- Stroke
~ ---- Blindness , cataracts , age-related macular degeneration _,,,,,..._ .. , L- --- Congenital defects-maternal smoking: orofacial clefts
, ,,,.~--- Periodo ntitis
~ -- Aort ic aneu rysm, early abdomina l aortic ath eroscleros is in young adults
Coronary heart disease
Pneumon ia
1111---+-- Atherosclerot ic periph eral vascu lar disease
1-+---¼- -+- - Chronic obstru ctive pulmonary disease, tuberculosis, ----- asthma , and other respira tory effects
Diabetes
Reproductive effects in women (inclu ding reduced fert ility)
Ectopic pregnancy
Male sex ual functio n-e rectile dys functi on
- n heuma toid arthritis
Immun e function
Overall diminish ed healt h
Source: USDHHS 2004 , 2006 , 20 12. Note: The condit ion in red is a new disease that has been causally linked to smoking in this repor t.
The Health consequences causally linked to smoking
Tobacco is the Single Largest Cause of Cancer in the World
• Tobacco use causes cancer in no less than 18 organ sites.
• Smoking causes more than 85% of lung cancers.
• One in three cancer deaths in the U.S. is directly linked to tobacco.
• The 2014 Surgeon Generals Report added the association of tobacco with hepatocellular and colorectal cancer
Epidemiology of Tobacco-Related Cancers in the US, Estimated in 2012
Cancer type # cases # deaths Lung 226,160 160,340 Head and neck* 52,610 11,500 Esophageal 17,460 15,070 Stomach 21,320 10,540 Pancreas 43,920 37,390 Kidney 64,770 13,570 Bladder 73,510 14,880 Uterus 47,130 8,010 Cervix 12,170 4,220 Colon/rectum 143,460 51,690 Ovary 22,280 15,500 AML 13,780 10,200
* larynx, oral cavity, nasopharynx, pharynx NCI SEER
Epidemiology of Tobacco-Related Cancers Worldwide in 2008
Cancer type # cases # deaths Lung 1,606,911 1,375,919 Head and neck* 631,786 355,217 Esophageal 481,645 406,198 Stomach 987,904 736,976 Pancreas 278,470 266,543 Kidney 264,146 110,824 Bladder 382,130 150,143 Uterus 288,265 73,818 Cervix 529,601 274,668 Colon/rectum 570,795 288,323 Ovary 222,613 139,472
* larynx, oral cavity, nasopharynx, pharynx WHO GLOBOCAN 2008
How Smoking Causes Cancer • Cigarette smoke contains more than 7,000 compounds of which >60 are known carcinogens (600 added to enhance flavor/nicotine absorption)
• Inhaling this mix of chemicals induces tissue injury and changes in the cellular environment fostering the proferation and transformation into cancer
• Mutations result in loss of normal growth control, silencing of tumor progression genes, and promotion of cancer
• Field effects, second (or more) primary cancers are common
9
Effects of stopping smoking at various ages on the cumulative risk (%) of death from lung cancer by age 75
for men CUMULATIVE RISK (%) 18
15
12
9
6
3
0
Current cigarette smoker Stopped smoking at 60 Stopped smoking at 50 Stopped smoking at 40 Stopped smoking at 30 Lifelong non-smoker
45 50 55 60 65 70 75
Age AGE
Peto, R., BMJ 2000, 321(7257):323-
eliited-
·~ Common
P,.,._orn'llOI o..,.r, · -,....,..1o::a,1~.,,. r
wtltn<ltut:aJfJLN'affi -"'=PY
Cana,r k
Molecular Carcinogenesis of Lung Cancer
RS Herbst, et al, N Engl J Med 2008.
Molecular Carcinogenesis of Head and Neck Cancer
Mild Moderate Severe Carcinoma Invasive Normal Hyperplasia Dysplasia Dysplasia Dysplasia in situ Carcinoma Metastasis
E-cadherin CXCR4/SDF-1 VEGF(R)s, PDGF(R) FGF(R), TGFα/β(R) ILK-8(R)
LOH: 3p14, 9p21, 17p13
LOH: 8p, 11q, 13q,14q
EGFR, Rb, p53, p65, Cox-2, p16, Cyclin D1, PTEN
MMPs
LOH: 6p, 4q27, 10q23
Chemoprevention Therapy
Haddad RI and Shin DM. NEJM 2008;359:1143-1154.
Complexity of Tobacco-Related Carcinogenesis
Early Intermediate Late
Normal Hyperplasia Dysplasia CIS Invasive Epithelium Carcinoma 3p LOH/Small Telomeric Deletions 3p LOH/Contiguous Deletions
Microsatellite Alterations 9p21 LOH
Telomerase Dysregulation Telomerase Upregulation MYC Overexpression
8p21-23 LOH Loss of Fhit immunostaining
p53 LOH TP53 Mutations
Aneuploidy
Methylation 5q21 APC-MCC LOH
Wistuba, et al. Oncogene 2008
HrtO
. oo-7 !)
&l) l I
~o i I
O.· ·I
;J()
~l!i
10
o r i
- in, ' I
,o
I ·HiO .a. ,w,
Cigairelt ei pack · 1e"a.~ ;5mr;Jked
40
~ 30 O• i 25
.e 20 ,o
j 115
:;i! 10
5
o ln.(,~I. ~ ~ i ,- r-- ~
273
248
157
Cigarette Smoke Carcinogen Adducts at Lung Cancer Mutational Hotspots in P53 • Identification of p53 • Cigarette smoke carcinogen BPDE
G:C to T:A mutations in adducts in p53 mapped to guanines in lung cancer smokers codons 157, 248, and 273 - major
mutational hotspots in human lung cancer
Frequency of G:C to T:A transversions (%)
Takeshima et al. Lancet 1993; 342:1520-21 Dennisenko et al. Science 1996;274:430-432.
•
Widespread Dispersed p53 Mutation in Respiratory Epithelium of a Smoker
66-yr-old Smoker – Male TP53 Mutation Codon 245 (G:C to T:A)
Right Left
Mutant Wild-Type
Franklin WA et al. J Clin Invest. 1997;100:2133-2137.
itiation of cigarette smoking,' nicotine addiction
Regular cigarette smoking
Receptor binding
Uptake of Metabolic carcinogens activat ion
Metabolic detoxification
Excretion
Uptake of cocarcinogens and tumor promoters
Protein kinase A and B activation and other changes
DNA Persistence adducts miscoding
Repa~
Apoptosis
Normal DNA
Mutations in oncogenes and tumorsuppressor
genes
Gene promoter hypermethylation
Tumor-suppressor gene inactivation
and other changes
Loss of normal growth
control mechanisms
Cancer
Link between Cigarette Smoking and Cancer through Carcinogens in Tobacco Smoke
Genetic Profiles by Histologic Subtype Oncogenic drivers differ between adenocarcinomas and squamous cell carcinomas
Adenocarcinoma
• KRAS.
• EGFR
• ALK
PIK3CA
HER2
• BRAF
ROS
• RET
NRAS
• MET
Other/unknown
Squamous cell carcinoma
• FGFR
PIK3CA
• KRAS
• PDGFR
• DDR2
• EGFR
NRAS
Other/unknown
Sequist et al., Ann Oncol 22:2616, 2011; Bergethon et al., JCO Jan 3, 2012; Weiss et al., Sci Transl Med 2:62ra93. 2010; Kris et al., WCLC 2011; Hammerman et al., Cancer Discovery 1 :78, 2011; AJ Iafrate, personal communication
Lung Cancer Mutation Consortium: Squamous Cell Cancers also have driver mutations
Goals of this presentation
• Pathogenesis of tobacco induced cancer – Epidemiology and mechanism – Focus on lung and head and neck cancer
• Joint AACR/NCI efforts related to tobacco control – Tobacco use in patient’s receiving treatmentfor cancer
– Clinical trials
• New Approaches to treatment of tobacco induceddisease- the lung cancer master protocol
Pubi<..h<d ~F"" April 13, 2010 . OOl· 10 11581!nl8 ,5472 CAN,11).11)87
M,( ·""l American Association .i7n "-. forCa11cerR esenrch
Tobacco and Cancer: An American Association for Cancer Research Policy Statement l<asiso mayaJula Vlswanath , Roy S. Her'blS.t, St&J)h.3nle R, Land , Soolt J . U isehOw , 3nd Ptl at" G . Shield $; Writin g COnvnitl:ee f or the AACR T3$k Foree on TOb.;"\C(Xl Md c.-mc:t r
E"xll!!'C-ulive Summary
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a..,,. It• m'"f.l .U1'.Jtl IJJDIO .UC.It
Tobacco and Cancer: An AACR Policy Statement
• Includes research and policy recommendations for:
– Preventing tobacco use
– Treating tobacco addiction and fostering cessation
– Reducing exposure to second hand smoke
– Addressing tobacco-related cancer Cancer Research, April 15, 2010 3419-3430
ASSESSING ANO TREATING TOBACCO USE BY
CANCER PATIENTS: RECOMMENDATIONS FROM THE
ltsiaMrblilltf a '*' • ae13gi..o llllheaa,pderaQQ~-•me,.waqt1p.JS81tMl'*1 • hl r~ trfstwal91N1'1DtO>-.Th!'....., • .., .. 1DCQCa•IJJJar!l8 .. C111CSO!lmaallfemd,,.. ll'ldS:-, UClfa'11eme;a,~~oeoe..qua 11r,«•roe.sn~lld::fft31'1JIIOe*9!S•utaml' ~ an:IM.CIIOP-.llla'Jtancl:l.
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lb!l'-.,Cbi!Medt:8rlAn:ldlttllllrc::.ie r~wp901be...-rg
RECOMMENDATIONS
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Assessing Tobacco Use by Cancer Patients and Facilitating Cessation: An AACR Policy Statement
• Primary recommendations: • Provide patients in all clinical cancer
settings, including clinical trials, with evidence-based tobacco cessation assistance
• Evaluate the confounding effects of tobacco on cancer treatment, disease progression, comorbid events, and survival in all oncology clinical trials from registration to survival endpoints.
Clinical Cancer Research, April 15, 2013 19; 1941
Problem (Clinical) Cancer patients and survivors who smoke
cigarettes have worse health outcomes (including higher all-cause and cancer-specific mortality, and risk of tobacco-related second primary cancer).
Smokers may have higher risk of recurrence, poorer response to treatment, and increased toxicity.
* Phipps, 2011 (colorectal cancer)** Kenfield, 2011 (prostate cancer)
Clinical significance of smoking by cancer patients
• Relative risk of all-cause mortality* – Current smokers 1.5 (relative to never smokers) – Former smokers 1.3
• Relative risk of cancer-specific mortality** – Current smokers 1.6 (relative to never smokers) – Former smokers 1.05
Problem
There are many scientific questions related to tobacco use in the cancer patient population.
Current approaches to data collection: - Not widely assessed in trials or practice - Inconsistent tobacco use assessment methods - Little follow-up during/after treatment
Current practice
• NCI-Designated Cancer Centers – < 50% include tobacco use as a vital sign in the
medical record
• NCI-funded phase III Cooperative Group trials – 22% record cigarette smoking status at
enrollment, and – 4% during follow-up.
Goldstein, NTR, 2012; Warren, IJC, 2012
NCI-AACR Cancer Patient Tobacco Use Assessment Task Force
• History – Formed March, 2013 – Conference calls, writing groups, and in-person meeting September 2013
(Bethesda) • Goal
– Develop recommendations for assessing and documenting tobacco use in clinical trials
– Identify research priorities • Progress
– Drafted two tiers of measurement items and protocol for the timing and conduct of the assessment in cancer clinical trials. • Tier 1: minimum set of baseline and follow-up items recommended for
clinical trials in any cancer patient or survivor study. • Tier 2: longer menu of curated items for use when more comprehensive
assessment is feasible. • Items focus on tobacco use history, status, and intensity
– Recommended assessment items for specific NCTN trials in development
Draft recommended measures Tier 1 (minimal) paraphrased
Baseline: • Ever smoked 100+ cigarettes in lifetime? • How long since smoked? • How many years smoked? • Average number of cigarettes per day?
Follow-up: • How long since smoked?
Task Force Roster Jeffrey S. Abrams, MD Thomas H. Brandon, PhD Jan C. Buckner, MD Paul M. Cinciripini, PhD K. Michael Cummings, PhD, MPH Carolyn Dresler, MD, MPA, Sonia A. Duffy, PhD, RN, FAAN Michael C. Fiore, MD, MPH, MBA Ellen R. Gritz, PhD Dorothy K. Hatsukami, PhD Roy S. Herbst, MD, PhD Jennifer A. Hobin, PhD Fadlo R. Khuri, MD, FACP Stephanie R. Land, PhD Scott J. Leischow, PhD Sandra Mitchell, CRNP, PhD, AOCN Carol Moinpour, PhD
Jamie S. Ostroff, PhD Sheila Prindiville, MD, MPH Nancy Rigotti, MD Linda Sarna, PhD, RN, FAAN, AOCN Robert A. Schnoll, PhD Peter Shields, MD Benjamin Toll, PhD K. (Vish) Viswanath, PhD
Graham Warren, MD, PhD
,•\ •. •
• -;. ! ... ..~· .. ~·· ,, ._ . .,..,
E":- Molecular Cancer
Therapeutics - ~-=:=
• Research and review articles published in AACR journals • Editorial Overview: AACR Celebrates 50 Years of Tobacco
Research and Policy • Commentary from Howard Koh • Q&As with Howard Koh and Mitchell Zeller
MEmNG
SAN DIEGO
Tobacco Science and Policy at AACR Annual Meeting 2014
• Honoring the 50th Anniversary Surgeon General’s Report—The Health Consequences of Smoking: 50 Years of Progress Speakers: Roy S. Herbst, Jonathan Samet, Graham Warren, Robert Croyle, Mitchell Zeller
• Advancing Tobacco Regulatory Science: Meet Experts in FDA CTP Speakers: Carolyn M. Dresler, Cathy L. Backinger, Dana M. van Bemmel, Nicolette Borek
AACR-ASCO Policy Statement on Electronic Cigarettes
• Subcommittee of AACR and ASCO members
• Statement will include recommendations for – Research – Clinical practice – Regulation
Goals of this presentation
• Pathogenesis of tobacco induced cancer – Epidemiology and mechanism – Focus on lung and head and neck cancer
• Joint AACR/NCI efforts related to tobacco control – Tobacco use in patient’s receiving treatment for
cancer – Clinical trials
• New Approaches to treatment of tobacco induced disease- the lung cancer master protocol
0 JI.PC or
lumor cell
.. PO-ti
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, ... .,.;., , t-- ,i 14-.... ,. .... ...... ~ ...
'-
r,. ... -... ··-·---" ··-
........... _ M,._,,. ••••
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Targeting microRNA
Targeting EGFR Targeting Resistance PD-1/B7-H1(PD-
L1)
Targeting lung cancer risk characteristics for personalized prevention by smoking cessation
iI I
I
BATTLE-2 – Targeting Kras
EML4-ALK Fusion or EGFR Μut exclusion
Protocol enrollment Biopsy performed
Stage 1: (n=200) Adaptive Randomization by KRAS mut status
Primary endpoint: 8-week disease control (N = 400)
Sorafenib E+MK-2206 (AKTi)
MK-2206+ AZD6244 (MEKi)
Stage 2: (n=200) Refined Adaptive Randomization
“Best” discovery markers/signatures
Erlotinib
Statistical modeling and biomarker selection
Discovery Markers:
• Protein expression (IHC): p-AKT (Ser473), PTEN, HIF-1α, LKB1
• Mutation analysis (Sequenom): PI3KCA, BRAF, AKT1, HRAS, NRAS, MAP2K1 (MEK1), MET, CTNNB1, STK11 (LKB1)
• mRNA pathways activation signatures: Affymetrix® - BATTLE-1: WT-EGFR-
Erlotinib, EMT, and Sorafenib - BATTLE-2: new “discovery”
signatures
• Protein profiling – RPPA (n=174) • NGS-Foundation Medicine • RNA sequencing
NCI RO1 funded, Yale, MDACC
~ FNIH ; Foundation for the National Institutes of Health
• • National
Clinical TrialsNetwork
S1400 Master Protocol Unique Private-Public Partnerships with the NCTN
Alliance
ECOG-Acrin
NRG NCI-C
SWOG S1400 Master
Protocol
Rationale for Master Protocol Design • Multi-arm Master Protocol • Homogeneous patient populations & consistent eligibility
from arm to arm • Each arm independent of the others • Infrastructure facilitates opening new arms faster • Phase II-III design allows rapid drug/biomarker testing for
detection of “large effects” • Screening large numbers of patients for multiple targets by a
broad-based NGS platform reduces the screen failure rate • Provides a sufficient “hit rate” to engage patients & physicians • Bring safe & effective drugs to patients faster • Designed to faciliate FDA approval of new drugs
-f/) C .0 80
a Syn. 2 ~ 60 - nl 1... 40
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mutation
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RB1
0.5 2.0 3.5 -log10
(Q value)
nature
Significantly mutated genes in lung SQCC.
PS Hammerman et al. Nature 000, 1-7 (2012) doi:10.1038/nature11404
Common Broad Platform CLIA Biomarker Profiling*
I Biomarker A I I Biomarker B I I Biomarker C I
• I • • I • • I •
Non-mate
I Biomarker D I
• I •
Nonmatch drug
.............,,= =-----'
CT*
MASTER PROTOCOL
Biomarker C
TT C+CT CT*
Biomarker Β
TT B CT*
Biomarker A
TT A CT*
Common Broad Platform CLIA Biomarker Profiling*
Biomarker D
TT D+E E*
Non-match drug
Non-match S1400
Endpoint PFS/OS
Endpoint PFS/OS
Endpoint PFS/OS
Endpoint PFS/OS
Phase II/III Biomarker-Driven Master Protocol for Second Line Therapy of Squamous Cell Lung
Cancer
Non-mate -----i
Common Broad Platform CLIA Biomarker Profiling*
13K CDK4/6 FGFR GF M:PIK3CA mut M: CCNDl, CCND2, M: FGFR ampl,
mut, fusion M :c-Met Expr
CCND3, cdk4 ampl
I\ DC-003... I ~~ D-033299
• I • • I • • • I • I
TT=Targeted therapy, CT=chemotherapy (docetaxel), E=erlotinib *Archival FFPE tumor, fresh CNB if needed
Target/M: Drug target and biomarker
•
CT* MASTER PROTOCOL
AZD4547 CT*
Common Broad Platform CLIA Biomarker Profiling*
AMG102 +E
E*
Non-match S1400
Endpoint PFS/OS
Endpoint PFS/OS
Endpoint PFS/OS
Endpoint PFS/OS
PI3K CDK4/6 FGFR M:PIK3CA mut M: CCND1, CCND2, M: FGFR ampl,
CCND3, cdk4 ampl mut, fusion
Anti-PD-L1:
MEDI4736 HGF M:c-Met Expr
GDC-0032 CT* PD-0332991 CT*
TT=Targeted therapy, CT=chemotherapy (docetaxel), E=erlotinib *Archival FFPE tumor, fresh CNB if needed
Target/M: Drug target and biomarker
of CANCER RESEARCH
~ FiNIH ; Foundation for llhe National In titute ofH alth
I I
Sites 1,2,3…10Sites 1,2,3…10Sites 1,2,3…10
The Lung Master Protocol trial will be managed with multiple partners
Oversight Committee NCI, ex-Industry, Advocates, PI’s (ex-officio), FNIH
[supported by FNIH]
Executive Operations Group Roy Herbst, Vali Papadimitrakopoulou, co-
chairs
Partner Science Focus Group
Contracts, Fundraising, Data Sharing, IP
Drug and Biomarker Selection Committee
Assay Company RFP, selection
Project Management Office FNIH, SWOG, FOCR
NCTN, CTSU, CTEP, oversight
Project Management
DSMB
Working Groups
IND management
Clinical Project Management
Sites 1,2,3…n
Conclusions
• Association of tobacco with cancer is well documented
• Unique concerns in patient’s getting therapy for cancer- issues being addressed
• While primary and secondary prevention is of course critical- better therapeutic options/trial designs for smoking related cancers are underway
THANK YOU!