Christina Laukaitis, MD, PhD, FACP

22 June 2012

*Cancer Prevention: Clinical Trials

*NACP Specific Aims

* To continue to increase the competitive stance of cancer research and training at Northern Arizona University by adding new cancer researchers and by continuing strong faculty development programs for all junior faculty.  

* To develop programs that facilitate the successful transition of Native American students into the universities and that enhance the retention and graduation of Native Americans undergraduates in biomedical sciences.

* To develop sustainable community education programs and research for cancer prevention that meet the unique needs of the Hopi Tribe and the Navajo and Tohono O’odham Nations.

*Research program

*Analysis of the roles of genes and chromosome rearrangements in genomic instability

*Uranium as environmental risk factor for cancer among the Navajo

*Allostery, protein complexes and cellular distribution for the Nitric Oxide Receptor & soluble Guanylyl Cyclase 

*Training program

*Focused on transitioning Native American students into undergraduate work at Partnership institutions and preparing them to enter graduate programs in biomedical sciences through a research-based training program

*Summer research program

*NAU or UA

*Stipend & mentoring provided

153 Participating

students

106 American

Indian

13 Science & healthcare

10 Grad

school

*Community outreach program

*Developing a continuing education curriculum for community healthcare workers

*Identifying resource and educational needs of healthcare providers, and partnering to fill those needs

*In collaboration with IHS, a ‘virtual’ colon cancer screening program has been created in remote areas of the Navajo Nation

Cancer

Risk

Exam & Test Results

Symptoms

Family History

Medical History

Habits

At-risk person Person with cancer

Family history/geneticsBehaviors (e.g. smoking)Exposures (e.g. uranium, HPV)Medical issues (e.g. diabetes, obesity, previous cancer)

Intervention

*Keys to a successful prevention trial

*Choose an appropriate group to study

*Elevated baseline risk

*Develop an appropriate intervention

*Likely to change physiology of disease

*Side effect minimal/tolerable

*Intervene at the right time

*Before pre-cancerous changes are irreversible

*Follow up for an appropriate time-period

*Breast cancer prevention

*16,000 women at high-risk of breast cancer

*½ treated with placebo, ½ with tamoxifen

*After 5 years, breast cancer rates were ½ for those treated with tamoxifen versus placebo

Cumulative number of cases (per 1000 women)

Placebo

Tamoxifen

0 1 2 3 4 5 6

40

30

20

10

0

Invasive breast cancer rates in women at high risk

Years

Tamoxifen (BCPT) Raloxifene (STAR)

Invasive breast cancer risk reduction

~45% Similar to tamoxifen

LCIS/DCIS risk reduction

~50% None

Thrombotic events 3x increase 29% less than tamoxifen

Uterine cancer risk 2-3x increase Slightly less than tamoxifen

* Raloxifene has similar benefits to tamoxifen

Fisher et al., JNCI 2005Vogel et al., JAMA 2006

Bad effects•Increases uterine cancer

risk•Increases blood clot risk

Tamoxifen

Good effects•Reduces breast cancer

risk•Lowers LDL cholesterol•Strengthens bones

*Benefits and risks of tamoxifen

Kleinsmith et al. NCI 2002

Raloxifene

Bad effects• No relief for hot flashesNo reduction of LCISNo reduction of DCIS

Good effectsLowers LDL

cholesterolReduces risk for

invasive breast cancer

Strengthens bonesFewer uterine

cancers than tamoxifen

Fewer blood clots than tamoxifen

*Raloxifene has different risks

Kleinsmith et al. NCI 2002

*Interventions

*Behavioral interventions for risk factors

*Nutritional supplements

*Vaccinations against infectious cancer causes

*Medications for people at high-risk

*Eliminating pre-cancerous cells

*Intensive screening to identify cancer early

*Prevention Trials

*Test whether intervention reduces cancer rates

*Inherently difficult

*Measuring something that DOESN’T happen

*May be many years before see effects

*Difficult to determine cause v. chance

*Choose appropriate subjects

*I didn’t have an accident today ;)

*June in Tucson v. January in Flagstaff

*Gail Model

1. Does the woman have a medical history of any breast cancer or of ductal carcinoma in situ (DCIS) or lobular carcinoma in situ (LCIS)?

2. What is the woman's age?

3. What was the woman's age at the time of her first menstrual

period?

4. What was the woman's age at the time of her first live birth of a

child?

5. How many of the woman's first-degree relatives - mother, sisters,

daughters - have had breast cancer?

6. Has the woman ever had a breast biopsy?

  6a.How many breast biopsies (positive or negative) has the woman

had?

  6b

.

Has the woman had at least one breast biopsy with atypical

hyperplasia?

7. What is the woman's race/ethnicity?

Gail et al., JNCI 1989

*Average risk

*~12% lifetime risk

*1/8 women will develop breast cancer in her life

*Moderate risk

*<5x average risk

*15-25% lifetime

*1 first-degree relative >60, obese, alcohol use, etc.

*High risk

*5-10x average risk

*Lifetime risk >25% by Claus & >50% by Gail models

*LCIS, ADH, ALH; 2 first-degree relatives, or 1 <60

*Very high risk

*>10x average risk

*>50% lifetime risk

*BRCA1 or BRCA2 mutation or other syndrome

*Risk categories

Schwartz et al., The Breast J 2007Schwartz et al., Cancer 2007Zakhireh et al., Eur J Cancer 2008

*Ongoing trials at UACC

*Breast cancer prevention

*Vitamin D

*Deficient pre-menopausal women with elevated baseline risk

*Outcome: breast density

*Broccoli extract

*Post-menopausal women with elevated risk on tamoxifen

*Outcomes: breast density & tamoxifen tolerability

*Letrozole (dose-finding Phase I trial)

*Post-menopausal women with elevated breast cancer risk

*Outcomes: side effects & pathology on random fine needle aspirate

*Risk reduction strategies

*Lifestyle modification

*Intensive screening

*Chemoprevention

*Prophylactic surgery

Risk Benefit

Potential Risk

Potential Benefit