Patient-centered Strategies for Breast Cancer Screening and Prevention Dean A. Seehusen, MD, MPH, FAAFP Department of Family and Community Medicine Eisenhower Army Medical Center Fort Gordon, GA 30905 Overview Introduction Case based scenarios – Risk calculation – BRCA testing – Screening strategies for high risk women – Chemoprophylaxis Question and answer session Incidence and Prevalence About 1 in 8 women will develop Almost 180,000 cases annually in US 1 in 4 of all female cancers Over 40,000 deaths annually in US 2.5 million American women with a history of breast cancer Breast Cancer Facts and Figures 2007-8. ACS Trends Increasing incidence from 1980 to 2001 Decreasing incidence since 2001 Mortality decreasing since 1990 Breast Cancer Facts and Figures 2007-8. ACS Risk Factors RR > 4.0 – Age 65+ – BRCA gene mutations – 2+ first degree relatives – Personal history of breast cancer – Increased breast tissue density – Atypical hyperplasia on breast biopsy Breast Cancer Facts and Figures 2007-8. ACS Risk Factors continued RR = 2.1 – 4.0 – One first degree relative – High dose radiation to chest – High bone density if postmenopausal Breast Cancer Facts and Figures 2007-8. ACS Risk Factors continued RR = 1.1- 2.0 – First full-term pregnancy after age 30 – Menarche before age 12 – Menopause after age 55 – No full-term pregnancies – Never breastfed a child – Recent OCP use (within 10 years) – Recent and long term HRT – Obesity (postmenopausal only) Breast Cancer Facts and Figures 2007-8. ACS Risk Factors continued Other risk factors – Personal history of endometrial, ovarian or colon cancer – Alcohol consumption – Height – High socioeconomic status – Jewish Breast Cancer Facts and Figures 2007-8. ACS Mrs. Lee A 39-year-old white woman, comes in for her annual well woman visit. She tells you that since her last visit, her 44-year-old sister has been diagnosed with breast cancer. She would like to know what her risk is. Further History No significant past medical history Never smoked, social alcohol Menarche at age 12 Term deliveries at ages 21 and 23 One benign breast biopsy Mother with breast cancer at age 62 BMI = 28 Normal mammogram last year Clinical Question How can you estimate Mrs. Lee’s risk for breast cancer? Risk Modeling Many models available The Gail Model the most widely used – Never been validated for population based screening – Would dramatically underestimate risk in women with BRCA 1 or 2 NCI website very user friendly and based on the Gail Model Breast Tissue Density Recent area in interest Women with dense tissue in 50% or greater total breast area are at 3-5 fold greater risk than those with <25% Several newer risk models incorporate Tice et al. Ann Int Med 2008 Mrs. Lee continued At the end of the well woman visit, you enter an order for a mammogram. Mrs. Lee wants to know if there is any other screening that she should have done given her risk. Clinical Question What additional screening options exist for women with a high risk of breast cancer? Mammography Utility varies depending upon age, risk factors, breast density, frequency Conflicting results from meta-analyses Quality has changed considerably Mortality rate has dropped about 25% during since widespread screening Current Guidelines USPSTF recommendations a mammogram every 1-2 years for average risk women beginning at 40 Evidence for benefit is greatest for women aged 50-69 No clear upper age limit can be given USPSTF Ann Int Med 2002 Additional Considerations Women with a first degree relative should begin 10 years prior to age of diagnosis Mammograms should never begin prior to age 25 Additional Screening Tools Breast self-examination Clinical breast examination Digital mammography US MRI Breast Self-Examination No proven benefit 2003 Cochrane Review found a possible increase in biopsy rate USPSTF found insufficient evidence to recommend for or against AAFP, ACOG, AMA, ACS all support BSE Knutson and Steiner AFP 2007 USPSTF Ann Int Med 2002 Clinical Breast Examination Has mostly been studied in conjunction with mammography Highly dependent upon technique and time spent performing exam USPSTF found insufficient evidence to recommend for or against Knutson and Steiner AFP 2007 USPSTF Ann Int Med 2002 Digital Mammography Overall accuracy similar to film More accurate in women under 50 More accurate for dense breasts Recent cost-effectiveness model – Exclusive use = $331,000 per QALY gained – Targeted use = $26,500 per QALY gained Pisano et al. NEJM 2005 Tosteson et al. Ann Intern Med 2008 Breast Ultrasound In theory would be most useful for younger women and in dense breasts Berg et al. in 2008 showed a 55% increase in sensitivity when added to mammography in high risk women Found mostly small, node (-) tumors No mortality benefit proven to date Berg et al. JAMA 2008 Breast MRI Gadolinium contrast study Fat subtraction images Used as an adjunct to mammography in high risk patients High sensitivity, low specificity Higher rates of recall and biopsy Expensive Saslow et al. CA 2007 2007 ACS Guidelines Annual MRI Adjunct to Mammogram Based on evidence – Known BRCA mutation – Untested 1 degree relative of BRCA carrier – Lifetime risk of 20-25% or greater Based on consensus opinion – Chest radiation between ages 10 and 30 – Li-Fraumeni, Cowden, Bannayan-Riley- Ruvalcaba syndromes and first degree relatives Saslow et al. CA 2007 2007 ACS Guidelines Annual MRI adjunct to mammogram Insufficient Evidence – Lifetime risk of 15-20% – Lobular carcinoma in situ or atypical lobular hyperplasia – Atypical ductal hyperplasia – Mammographically dense breast tissue Recommend against MRI – Less than 15% lifetime risk Saslow et al. CA 2007 Mrs. Lee continued A month later, Mrs. Lee calls you and says that her other sister has been diagnosed with ovarian cancer. She wants to know if perhaps she should be tested for “those genes” that cause breast cancer. Clinical Question Who should be tested for genetic mutations that put them at increased risk for breast cancer? BRCA1 and BRCA2 Autosomal dominant mutations 1/500 to 1/1000 in general population 1/50 in Jewish populations Responsible for 1-2% of breast cancers Lifetime breast cancer risk 50 – 85% More aggressive tumors at younger ages Other increased cancer risks Saslow et al. CA 2007 Family History Know BRCA mutations Multiple close relatives with breast or ovarian cancer Breast cancer before the age of 50 Both breast and ovarian cancer Close relatives with multiple cancers Male breast cancer Saslow et al. CA 2007 Genetic Testing Many risk alleles have been identified Tests for most of these genes are not widely available Individual genetic risk determination may be possible in the future Pharoah et al. NEJM 2008 BRCA Testing BRCA risk models – BRCAPRO, BOADICEA, MYRIAD II, others – All with unique characteristics Using multiple models has advantages Threshold of ~10% suggested American Society of Clinical Oncology in 2003 recommended using clinical judgment instead of numerical cutoff Berliner and Fay J Genet Counsel 2007 BRCA and USPSTF Grade D for general public Grade B for women with increased risk of breast or ovarian cancer associated with BRCA1 or BRCA2 – Threshold risk cannot be determined – Testing should be preceded by genetic counseling done by a trained provider USPSTF Ann Intern Med 2005 Genetics Counseling Done prior to testing Should be done be trained individual Guidelines available from the NSGC 2007 Cochrane review of counseling: – short term improvement in psychological wellbeing – decreased level of worry – improved accuracy of risk perception – increased knowledge Sivell et al. Cochrane Database 2007 Mrs. Lee continued After counseling, Mrs. Lee decides she does not want to be tested for BRCA but does wants to know if there any medications she can take to reduce her risk of breast cancer. Clinical Question How can Mrs. Lee reduce her risk of breast cancer? Is chemoprophylaxis an option? Lifestyle Modification Regular exercise Decreasing alcohol intake Maintaining a healthy BMI Eating a low fat diet showed a 9%, statistically non-significant, reduction Afonso JABFM 2009 Tamoxifen Studies National Surgical Adjunct Breast and Bowel Project (NSABP) P-1 Study – 13,338 women – Randomized controlled trial – 20 mg/d tamoxifen vs. placebo – 5 years of therapy Fisher et al. J Natl Caner Inst 1998 P-1 Eligibility Criteria > 60 years of age History of LCIS 5 year risk ≥ 1.66% by Gail Model Excluded if history of DVT or PE Fisher et al. J Natl Caner Inst 1998 P-1 Results About 20% drop out rate in both arms 49% reduction in breast cancer rate 50% reduction in invasive disease Estrogen receptor positive only No survival difference at 4 years Fisher et al. J Natl Caner Inst 1998 P-1 Adverse Reactions Tamoxifen group had higher rates of: – Endometrial cancer – PE – Newly diagnosed cataracts Women over age 50 at greatest risk of vascular events Fisher et al. J Natl Caner Inst 1998 Other Tamoxifen Studies Italian Tamoxifen Prevention Study – 5,408 subjects – RR = 0.92 (95% CI not available) Royal Marsden Hospital Tamoxifen Randomised Chemoprevention Trial – 2,471 subjects – RR = 0.94 (95% CI = 0.7 – 1.7) Levine et al. CMAJ 2001 Raloxifen Studies Multiple Outcomes of Raloxifen (MORE) 7,705 subjects Randomized controlled trial 60 mg/d vs. 120 mg/d vs. placebo 90% reduction in ER+ breast cancer Increased DVT/PE risk (RR = 3.1) Levine et al. CMAJ 2001 Aromatase Inhibitors Last enzyme in estrogen synthesis 3rd generation: anastrozole (arimidex), letrozole (Femara), vorozole Often used in breast cancer therapy Early evidence suggests effects better than SERMs with less side effects Large trials underway Smith and Dowsett NEJM 2003 Cuzick Recent Results Cancer Res 2003 Individualized Approach Must weigh several factors – Individualized risk – Age less than or greater than 50 – Risk of VTE disease USPSTF recommends discussing chemoprophylaxis with high risk women CTFPHC supports consideration if 5 year risk ≥ 1.66% American Society of Clinical Oncology and ACOG have similar positions USPSTF Ann Intern Med 2002 Levine et al. CMAJ 2001 Prophylaxis Mastectomy Decreases breast cancer risk by 95% Consider only after significant counseling ASSO guidelines: – BRCA or other genetic mutations – Strong family history – ADH, ALH, LCIS on biopsy – Difficult surveillance such as excessively dense breasts Afonso JABFM 2009 Salpingo-oophorectomy Considered in known BRCA 1 or 2 80-95% reduction in ovarian cancer 50% reduction in breast cancer Negative effects – Menopausal symptoms – Increase cardiovascular risk – Accelerated bone loss – Decreased quality of life measures Afonso JABFM 2009 Conclusion Determining individual risk is the key to patient-centered care Women at highest risk should undergo additional screening examinations Genetic testing can be offered to selected women after counseling Chemoprophylaxis decisions need to be based on a risk-benefit analysis Questions ?