Bridging the Causeway:A Center for Healthcare Policy and Research Symposium

In cooperation with:The Clinical and Translational Science Center

The Center for Reducing Health Disparities

Cancer Breakout Group

University of California, DavisMemorial UnionMarch 25, 2008

Therapeutic Resistance in Her2(+) Breast Cancer

Colleen Sweeney, Ph.D.

Associate Professor

Biochemistry & Molecular Medicine

UC Davis School of Medicine

Therapeutic Resistance in Her2(+) Breast Cancer

Her2 is amplified in ~ 25% of human breast cancers &

predicts reduced disease free and overall survival.

Herceptin is a humanized monoclonal antibody used

in combination with chemotherapy for the management

of Her2 (+) breast cancer.

Primary & acquired resistance to Herceptin combination

therapy is a vexing clinical problem: 20 – 50% of patients

display primary resistance; most patients show evidence

of disease progression within one year.

Her2 signaling in tumor cell growth

Proposed Mechanisms of Action of Herceptin

Resistance Mechanisms

Sawyers CL Nature 449, 993-996.

IB: Her2

IB: Met

IB: Actin

Met in Her2 (+) breast cancer

0

50

100

150

200

therapy responsive non-responsive

% e

xpre

ssio

n

HGFMet Receptor

0

10

20

30

40

50

60

SU11274 Trastuzumab Trastuzumab+ SU11274

Perc

ent I

nhib

ition

BT474

05

1015202530354045

SU11274 Trastuzumab Trastuzumab + SU11274

Perc

ent I

nhib

ition

SKBR3IB: pMet

IB: MetIB: Actin

IB: pMet

IB: MetIB: Actin

Con SU

Con SU

Inhibition of Met improves response to Herceptin

Multiple RTKs are activated in Her2 (+) Breast Cancer

Tumor #1

Tumor #2

Phospho-RTK array analysis of Her2 (+) breast tumors

“Simultaneous inhibition of multiple RTK pathways holds the promise of a more complete approach to anti-cancer therapy”

Targeted agents Personalized therapy

Inadequate access to patient specimens limits translation of

results from bench to bedside; partnering with physicians

will address this problem.

“Oncogene addiction” predicts that single molecule targeting should be effective.

Kinase switching allows tumors to escape growth inhibition by targeted agents such as Herceptin.

Therapeutic Resistance in Her2(+) Breast Cancer

Tailored Interactive Multimedia to Improve Colorectal Cancer Screening in Primary Care

Anthony Jerant, MDDepartment of Family & Community Medicine

UC Davis School of Medicine

Peter Franks, MD; Richard Kravitz, MD, MSPH; Matthew Kreuter, PhD, MPH; Mairin Rooney; Scott Amerson

Funded by UC Davis Health System and UC Davis Department of Family & Community Medicine Research Grants

Goals

Discuss the initial results and follow-up plans from a study of a new approach to increasing colorectal cancer (CRC) screening uptake

Provide an example of fundable, cross-disciplinary “T2” translational research

CRC Screening Uptake is Low

Uptake: Proportion of those eligible for screening in a population invited for and completing screening in a given time period

2004 BRFSS data: Uptake of 57 % in adults aged > 50 years, much lower than for other evidence-based cancer screening tests!

Personally Tailored (PT) Interventions

Individualized education and feedback, provided in direct response to a patient’s answers to questions

Growing body of research: may more powerfully influence health behaviors than traditional patient education approaches

Most successful when tailoring is to mediators of health behavior

Interactive multimedia computer programs (IMCPs) – attractive potential method of delivery

Personally Tailored (PT) Interventions

Research question:

Can a PT IMCP be successfully deployed in primary care offices, linked with doctor visits, to increase colorectal cancer screening uptake?

Jerant AF et al. Patient Education & Counseling 2006; 66:67-74

Hypotheses

Compared with a non-tailored IMCP (attention control), the PT IMCP will result in:

Significantly more favorable CRC screening readiness and self- efficacy, significantly fewer perceived barriers to screening – core variables from the Transtheoretical Model (TTM) of behavior

Trend toward greater CRC screening uptake

Subjects and Recruitment

English speaking patients aged > 50 in the UC Davis Primary Care Network lacking up to date CRC screening per USPSTF recommendations

Asked to arrive 60 minutes before appointment to do informed consent, use study software in primary care office on a laptop we provided

Random assignment by computer program to experiment or attention control (“electronic leaflet”) at each patient’s log in

Patient answered series of questions

Demographics, health statusCRC screening knowledgeCRC screening preferences, prior experiencesCRC screening determinants from the TTM

Tailored Information

First feedback message: tailored CRC screening recommendation (22 message variants)

Generated by an algorithm that considered (in priority order) subject’s responses to the following questions:

CRC screening preferenceReadinessSelf-efficacyPerceived barriersPrior experiences

No specific method recommendation for controls

Tailored Information

Subsequent feedback messages: tailored to enhance self-efficacy and readiness for and reduce perceived barriers to screening

Up beat, “can do,” gently persuasive framingTap into prior preventive habits or “successes”Vicarious experiences (testimonials)Direct ties to patient’s answers to key tailoring variable questions (microtailoring)

Control subjects: non-tailored information

Results

54 subjects enrolled

Data for 5 excluded - software glitches

49 subjects with analyzable data

25 control, 24 experimental

Results

Versus control, the tailored intervention group had:

A significant increase in CRC screening self-efficacy. Adjusted improvement of 0.23 on a 5-point scale, 95% CI (0.00, 0.46), p = 0.049

Effect size = 0.51, compares favorably with those observed in prior studies of personalized behavioral interventions that improved outcomes

A significantly greater likelihood of moving to higher stage of readiness for screening. Adjusted OR = 5.01, 95% CI (1.13, 23.23), p = 0.034

Results

At 1 year, CRC screening uptake was:

Higher in experimental vs. control subjects: 48% vs. 39%

Higher among experimental vs. control group Hispanics: 50% vs. 25%

Sample was small, effects not statistically significant

Results

Subjects required an average of 55 minutes to use the software

Study RA provided assistance to about 1/3 of subjects

1/3 of intervention subjects had to finish the pre-visit part of the program post-visit

No difference in satisfaction with software, good in both groups

Summary

Personally tailored interactive multimedia computer program (PT IMCP) was more effective in bolstering several key determinants of CRC screening than a non-tailored attention control IMCP

The PT IMCP was successfully deployed prior to doctor visits in busy primary care offices

Limitations

Small study sample size

Powered only to look at screening determinants, not actual screening outcomes

Beta software - further iterations must:

Require less time to complete (reduce content)

Have a simpler user interface (touch screen)

Be more reliable (1000s of lines of code to debug!)

Future Translational Research

Follow-up NCI R01 proposal - Tailored Interactive Multimedia to Reduce Colorectal Cancer Screening Disparities

Powered to examine CRC screening uptake and explore ability of PT IMCP to lessen or eliminate the glaring Hispanic/non-Hispanic White CRC screening disparity

Develop similar personally tailored IMCPs to influence other health behaviors and outcomes

Kravitz RL et al NIMH R01 - Depression care seeking and initial treatment adherence

Cross-Disciplinary Collaboration

Such work requires a talented team with expertise in many areas:

Health educationModels and mediators of health behaviorTailoring - algorithm development, implementationComputer programming and interface designCross-cultural issues in health careHealth disparitiesDevelopment and evaluation of health care interventions

Digital vs. Film Mammography: Does Evidence Drive Technology

Transfer?Neal D. Kohatsu, MD, MPH

Kirsten Knutson, MPHCalifornia Department of Public Health

Digital vs. Film Mammography: Overview

• Radiation dose is comparable• In general, digital is as accurate as film

for screening• Digital is more accurate than film in:

– Pre- and peri-menopausal women– Women under 50– Women with dense breast tissue

• Interpretation more important than technology for quality

Digital vs. Film Mammography: Advantages

• Electronic image acquisition, transmission, and storage– Image can be seen just after capturing – Contrast, brightness and magnification can be changed– Easy to send or retrieve– No lost images– Potential for lower radiation dose than film

• Potential to integrate with facility’s existing technology– Improved workflow– Side-by-side exam comparison– Less training for radiologists – Long-term cost savings

Digital vs. Film Mammography: Disadvantages

• Greater cost– Expense of technology and equipment– Cost of integrating with facility’s existing technology– Initial loss in efficiency

• Not cost-effective (except for one subgroup of women)• Potential for quality breakdowns

– Lack of radiologist experience in using technology– Lack of compatibility of digital technology across systems and

over time– Lack of compatibility of digital technology with facility’s other

technology

• Mortality benefit not proven

Prevalence of Digital Mammography

• Mammography is one of last radiology tests to be digitized

• Many facilities are replacing film with digital

Number %U.S. Digital (March 2008) 2,847 32

California (Nov 2007) Digital Only 146 20 Film and Digital 37 5 Film Only 533 74

Mammography Facilities Providing Digital Mammography

Why are Providers Adopting Digital Mammography?

• Scientific evidence that digital is at least as accurate as film

• Marketing– Patient demand– Concern for market competitiveness

• Possibility for increased profit for facilities

• Film obsolescence; digital future

• Liability fears

Research Implications• Can (should) research address adoption of

new medical technology?• How can economic analyses be better

integrated with outcomes research?• How can research optimize population

benefit in a PH mammography program?

Bridging the Causeway:A Center for Healthcare Policy and Research Symposium

In cooperation with:The Clinical and Translational Science Center

The Center for Reducing Health Disparities

Cancer Breakout Group

University of California, DavisMemorial UnionMarch 25, 2008