Citations

Passive surveillance for disease is a public health approach that relies on documentation available within existing health records for the region or community being studied. Its two primary advantages over active case‐finding are the lower cost of research and the lower burden on the population under study. The effectiveness of passive case‐finding depends on the comprehensiveness of the healthcare coverage in a given community and the adequacy of the available medical records. The Rochester Epidemiology Project has permitted dementia case detection for Olmsted County, Minnesota, using a medical records‐linkage system. These data were compared with case ascertainment using direct assessment of individuals in an epidemiological study of the same community. At the Group Health Research Institute, investigators compared dementia and Alzheimer's disease cases detected using an electronic medical record database search with those identified by a parallel active case‐finding study. In this article, the advantages and disadvantages of passive case‐finding were discussed, and the following conclusion was drawn: the purpose of the study being conducted should determine the case‐finding approach that is to be used.

Abstract Background: Endoxifen, the active metabolite of tamoxifen (Tam), is currently being developed as a drug for the treatment of estrogen receptor (ER) + breast cancer (BC). HER2 expression in ER+ BC is associated with Tam resistance, and in vivo Tam administration to mice bearing ER+/HER2+ xenografts stimulates BC growth (Shou, JNCI 2004). In humans, endoxifen is the most important Tam metabolite responsible for inhibiting estrogen induced BC growth (Wu, Cancer Research 2009). CYP2D6 metabolism affects the concentrations (conc) of endoxifen (Stearns, JNCI, 2003) and associated with worse disease free survival (DFS) in Tam treated BC (Goetz, JCO, 2005). We sought to determine the activity of Tam and its metabolites in ER+/HER2+ BC cell lines and to evaluate the role of CYP2D6 metabolism in Tam-treated patients (pts) with ER+/HER2+ BC. Additionally, we sought to determine endoxifen conc in mice administered oral Tam.Methods: MCF7 (parental and HER2-expressing) and BT474 (ER+/HER2+) cells were used to compare the activity of Tam, 4HT, and endoxifen on estrogen- stimulated growth. Oral tam PK were characterized in mice treated with standard dose of Tam (4 mg/kg; 100 μg). Clinical data were obtained via a retrospective analysis of Tam-treated pts with ER+/ HER2+ BC randomized to receive 5 years of Tam (NCCTG 89-30-52). CYP2D6 metabolism (extensive or decreased) was based on CYP2D6 genotype (*3, 4, 6, 10, 17, 41) and co-administration of a CYP2D6 inhibitor (yes/no). HER2 was determined by immunohistochemistry (IHC) or FISH (tumors 0, 1, or 2+ by IHC). The association between CYP2D6 and DFS was assessed using the log-rank test and proportional hazards modeling.Results: Compared to Tam, endoxifen potently inhibited the growth of estrogen- stimulated BT474 cells. In MCF7 cells, expression of HER2 shifted the conc of endoxifen required for 50% inhibition of growth (IC50) from 54 nM (parental) to 131 nM (HER2 expressing). Using the range of conc of Tam and its metabolites observed in humans (Tam, 300-500 nM; 4HT, 5-10 nM; and endoxifen, 10-200 nM), only endoxifen potently inhibited estrogen- stimulated growth of MCF7HER2+ cells and only at conc achievable in CYP2D6 extensive metabolizers (>50nM). In mice, conc of 4HT and endoxifen were below 15 nM following an oral dose of 4 mg/kg. In NCCTG 89-30-52, both CYP2D6 phenotype and HER2 status was determined in 201/256 randomized pts. HER2 was expressed in 23/215 (11%) but not associated with DFS overall (p=0.62). In the HER2+ subset, pts with decreased CYP2D6 metabolism (n=10) had significantly shorter DFS compared to extensive metabolizers (n=9) (HR 9.5, p=0.03; 95% CI 1.16-76.9).Conclusions: Our in vitro and clinical data provide a simple pharmacological model for understanding HER2 resistance in Tam-treated breast cancer. Mice, which lack the CYP2D6 enzyme, may not be an appropriate model for understanding tam resistance given low conc of both 4HT and endoxifen. Given that the in vitro conc of endoxifen needed to inhibit the growth of ER+/HER-2+ BC are achievable in only a subset of humans (CYP2D6 extensive metabolizers), the primary administration of endoxifen could overcome de novo Tam resistance in ER+/HER2+ BC. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2006.

Abstract Abstract #6037 Background: Tamoxifen (Tam) is biotransformed to the potent antiestrogen, endoxifen, by the CYP2D6 enzyme. We previously demonstrated that patients (pts) receiving adjuvant TAM with impaired CYP2D6 metabolism due to CYP2D6 (*4) and/or concurrent administration of a CYP2D6 inhibitor had a higher risk of recurrence. Other studies suggest CYP2C19*17 (Schroth JCO 2007) and SULT1A1*2 (Nowell JNCI 2002) may be associated with treatment outcome. With extended follow-up, we sought to evaluate the importance of comprehensive CYP2D6 genotyping as well as the potential association between CYP2C19*17 and SULT1A1 copy number with clinical outcome in pts randomized to TAM in NCCTG 89-30-52.
 Methods: Using DNA derived from paraffin embedded sections, CYP2D6 and SULT1A1 genotype were determined using quantitative multiplex PCR and CYP2C19 by sequencing. Pts administered the following CYP2D6 inhibitors (fluoxetine, paroxetine, sertraline, cimetidine, amiodarone, doxepin, ticlopidine and haloperidol) were considered as intermediate (IM) or poor metabolizers (PM) based on the potency of CYP2D6 inhibition. CYP2D6 phenotype was defined as follows: extensive metabolizers (EM) were pts not administered an inhibitor who did not carry a null allele (*3, *4, *6) and who were not homozygous for an IM allele (*10, *17, *41). CYP2D6 IM were either heterozygous for a null allele or homozygous for an IM allele but not administered an inhibitor or CYP2D6 EM administered a weak inhibitor. PM were pts homozygous for a null allele, or any patient administered a potent inhibitor. The association between genotype or CYP2D6 phenotype and clinical outcome was determined using the log-rank test. Multivariate Cox modeling was performed using traditional prognostic factors.
 Results: The median follow-up of living pts is now 14.5 years. Of 256 pts. randomized to TAM, genotype was determined for CYP2D6 (n=210), CYP2C19*17 (n=170), and SULT1A1 (n=169) with the following allele frequencies: CYP2D6 *3 (.02), *4(.20), *6 (.01), *10 (.03), *17 (.00), *41(.08), and CYP2C19*17 (.22). The frequency of SULT1A1 copy number alleles (CNA) was 1 (4%), 2 (67%), 3 (20%), and 4+ (9%). 14/227 patients (6%) were administered an inhibitor. A multivariate analysis accounting for nodal status and tumor size demonstrated that compared to CYP2D6 EM, CYP2D6 PM had significantly shorter time to recurrence (TTR) (HR 4.0, p=0.001) and DFS (HR 2.0, p=0.02) and CYP2D6 IM tended to have shorter TTR (HR 1.8, p=0.08) and DFS (HR 1.4, p=0.10). DFS did not differ by SULT1A1 copy number (p=0.62) or CYP2C19 *17 (p=0.47)
 Conclusion: Long term follow-up of pts in NCCTG 89-30-52 confirms the importance of CYP2D6 metabolism and further demonstrates the importance of comprehensive genotyping and phenotyping with CYP2D6 inhibitors. We could not identify an association between CYP2C19*17 or SULT1A1 copy number with recurrence but further evaluation is needed in larger cohorts. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6037.

Abstract Abstract #57 Background: ABCSG 8 is the only prospective trial examining the value of switching patients (pts) to an aromatase inhibitor after tamoxifen (Tam) in which randomization occurred prior to therapy. This trial demonstrated that 2 years (yrs) of Tam followed by 3 yrs of anastrozole (TAM to A) was superior to 5 yrs of Tam (Jakesz SABC 2005). Tam is metabolically activated by CYP2D6 to endoxifen and pts with impaired CYP2D6 metabolism have a higher risk of recurrence (Goetz JCO 2005). The HOXB13/IL17BR (H/I) index (Ma Cancer Cell 2004) is associated with Tam resistance while a 5-gene molecular grade index (MGI) distinguishes outcome in grade II tumors. H/I and MGI are complementary prognostic factors that define low (low MGI), intermediate (low H/I, high MGI) and high risk groups (high H/I and MGI) (Ma Clin Cancer Res 2008). We sought to validate these biomarkers in ABCSG Trial 8, and hypothesized that they may predict the benefit of sequencing TAM to A versus Tam alone.
 Methods: From 1996-2004, ABCSG 8 randomized 3,901 pts with ER positive breast cancer. The primary endpoint was event-free survival. Assuming 40% of pts had reduced CYP2D6 metabolism, we designed a nested case control study in which 110 Tam treated cases matched to 2 controls would yield 80% power to detect a relative risk of 2.3 for pts with reduced CYP2D6 metabolism. Additionally, we sought to perform an exploratory analysis of the benefit of switching from Tam to A in pts with impaired vs non-impaired CYP2D6 metabolism. DNA and RNA derived from paraffin embedded sections were used to genotype for CYP2D6 and to obtain H/I and MGI RT-PCR profiles.
 Findings: Thus far, CYP2D6 genotyping is complete in 345 pts corresponding to 53 cases/106 controls (Tam) and 62 cases/124 controls (Tam to A). DNA and RNA yields were excellent with a CYP2D6 genotype call rate of >95%. CYP2D6 allele frequencies were as expected: *3 (.01), *4, (.23), *6 (.01), *10 (.02), *17 (.00), and *41 (.10). 44% of pts had reduced CYP2D6 metabolism (at least one CYP2D6 null allele or intermediate metabolizer) and 8% were CYP2D6 poor metabolizers. For H/I and MGI, 340 pts were profiled with 64%, 20% and 16% in the low, intermediate, and high risk groups, respectively. Tissue sectioning/genotyping for additional cases/controls is ongoing.
 Discussion: This is the first retrospective analysis of a large Tam versus Tam to A trial to evaluate the association between 1) CYP2D6, HOXB13/IL17BR, and MGI with TAM treatment outcome and 2) the predictive benefit of these biomarkers in pts randomized to switch from Tam to AI versus Tam alone. Final results will be presented at the meeting. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 57.

Abstract Background: African Americans are underrepresented in cancer research trials. We propose that a collaborative effort with African American churches that brings cancer education events and a translational research project to the community with a mobile research unit will facilitate cancer awareness education and increase participation in translational research protocols among African Americans. Methods: From February 2010 through April 2010, Mayo Clinic partnered with predominantly African American Jacksonville churches, with the Volunteers in Medicine Clinic for the working uninsured, and with the local chapter of the Leukemia and Lymphoma Society, to provide 12 education programs focused on five behaviors that reduce cancer risk: proper nutrition, adequate fitness, tobacco cessation, breastfeeding, and limited alcohol consumption. Also offered during these programs was on site access to a translational cancer research pilot project evaluating the prevalence of t(14,18) and monoclonal proteins in African Americans and other racial/ethnic minorities. Translational research participation was facilitated by a mobile research unit (MRU), a converted RV that has sample collection, processing, and storage capabilities. Participants were surveyed on health knowledge and their willingness to participate in research. Results: A total of 236 of 318 participants (74%) returned written questionnaires provided during the education events. Forty-three percent resided in a health zone of Jacksonville that has worse health outcomes compared with any other sections of the city. Eighty-three percent responded that they had some type of health insurance and 88% had a primary care provider. Sixty-seven percent had never received any information on multiple myeloma, and 57% had never received information about clinical research studies. Sixty percent responded that they would participate in research studies and 61 % indicated that they would participate if the research focused on health issues that impacted African Americans. A total of 175 of 318 participants (55%) were enrolled in the translational research feasibility study. Seventy-two percent of the research study participants were female and 77% were African American, 19% Caucasians, and 4% Hispanic or of other racial/ethnic group. Ninety-three percent agreed to have their samples used for research of other health conditions and 85% agreed to have their samples shared with other research institutions. Conclusions: A high rate of participation in a blood collection translational research project was observed among this predominantly African American population. Most participants expressed a positive attitude towards research participation. Partnerships with African American churches in projects that provide community education and bring research to church venues with a mobile research unit are effective in improving health literacy related to a targeted topic, and in increasing translational research participation among African Americans. Funded by Mayo Clinic Comprehensive Cancer Center (NCI grant number P50-CA01508), Mayo Clinic CTSA (NCRR/NIH Grant Number 1 UL1 RR024150) and Active SPORE CA 90297052. Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):A38.