Citations

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 #4018 Background: Preoperative breast magnetic resonance imaging (MRI) has been shown to identify occult breast disease in women with newly diagnosed breast cancer. We sought to determine the accuracy of MRI in predicting the actual pathologic tumor size in women with newly diagnosed breast cancer.
 Methods: Preoperative breast MRI was reviewed in 460 women with newly diagnosed breast cancer. The size in terms of maximum tumor dimension, of 476 incident breast cancers on MRI were recorded and correlated with the actual pathologic size upon surgical resection. The correlation of size from MRI to pathology was determined. The size discrepancy was analyzed in relation to tumor size and histology.
 Results: MRI demonstrated 476 breast cancers (460 in the ipsilateral breast and 16 with concurrent contralateral breast cancer). Median age was 62 with a range of 25 to 91. The T stages of the population included T0 in 19% of the women, 60% had T1 lesions, 18% had T2 lesions and 3% were T3 or T4. The histology consisted of DCIS alone in 20%, infiltrating ductal in 74% and infiltrating lobular in 6%. Pre-operative MRI was unable to define an enhancing lesion usually due to hematoma following core needle biopsy in 9.8% (47/476). MRI described the size of the incident lesion in 90% (429/476). The mean difference in size between the preoperative MRI and the actual pathologic size for the entire group was 2.4 mm. MRI underestimated tumor size in only 3% of cases. The mean difference according to T stage and histology between MRI and actual pathologic size is listed in Table 1. The percentage of difference between MRI size and pathologic size for the entire group is presented in Table 2.
 
 
 
 Discussion: The mean difference in tumor size estimated by preoperative MRI in women with newly diagnosed breast cancer was within 5 mm of the actual pathologic size in 68% of patients. MRI was accurate in predicting T stage with no significant difference in relation to histology or T stage. This analysis further clarifies the role of preoperative MRI in surgical and treatment planning. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4018.

Abstract Abstract #1005 Background: Several models for the prediction of non-sentinel lymph node metastasis (+NSLN) in sentinel lymph node positive (+SLN) breast cancer patients have been published. Multiple variables have been shown to be important in prediction of +NSLN. To this date, models that utilize 7-8 variables have been significantly more discriminatory than models using only 2-3 variables. In this study, we evaluate the performance of the newly created Stanford online calculator (SOC) to predict the likelihood of +NSLN. The SOC uses 3 variables: primary tumor size, sentinel lymph node metastasis size, and presence/absence of lymphovascular invasion.
 Methods: From 1997-2004, 465 breast cancer patients with clinically negative axillae were found to have a +SLN and underwent completion axillary lymph node dissection (ALND) at the Mayo Clinic. Using the SOC the probability of having +NSLN was determined for each patient. Complete variable data was available for 464 patients which make up the cohort reported here. A receiver-operating characteristic (ROC) curve was created and the area-under-the-curve (AUC) was calculated. Mean probabilities of patients with and without +NSLN were compared. Additionally, patients with a low Stanford probability were examined to determine the model's accuracy in discriminating patients who could potentially be spared ALND. These results were compared to the results of the Mayo Clinic and Memorial Sloan Kettering Cancer Center (MSKCC) nomograms which have been previously applied to this same cohort of patients.
 Results: The AUC of the Stanford model was 0.72 (95% CI 0.67-0.77). The mean Stanford probabilities for patients with and without NSLN disease were 0.75 (range 0.06 to 1.0) and 0.50 (range 0.05 to 1.0), respectively (p < 0.0001). Examining patients with a Stanford probability <= 10%, we found that 47 patients met this criterion; 6 had +NSLN and 41 did not, for a false negative (FN) prediction rate of 13%. There was only 1 patient with Stanford probability <= 5%, and this patient did not have +NSLN. The AUC of the MSKCC and Mayo nomograms in this same patient population was 0.74 and 0.77, respectively. The AUCs did not differ significantly (p = 0.13) among the 3 models.
 
 Conclusion: Despite using only three variables, the Stanford nomogram appears to perform as well as, but not better than the MSKCC and Mayo nomograms in our patient cohort. Further validation in other patient populations is needed prior to widespread utilization of this nomogram. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1005.

Background: Although a gradual increase in heart rate (HR) during dobutamine stress testing (DST) is desired, few data exists regarding whether this is similarly achieved in patients of widely varying body mass index (BMI). Whether difference in BMI contributes to variation in the hemodynamic and symptomatic response to dobutamine is also unknown. Methods: From prospectively acquired data of 2776 consecutive patients who underwent DST according to standard weight-based clinical protocol, we classified patients into 4 groups of BMI (kg/m 2 ): <25 (normal), 25 to 29.9 (overweight), 30 to 39.9 (obese), and ≥40 (severely obese) and compared the rate of increase of HR, mean blood pressure, and development of symptoms for the groups. Results: Age was 68 + 12 years, 52% were men, BMI was 29.8 + 6.6 kg/m 2 (range 14.5-81.4), 198 (7%) had BMI ≥40, and target HR was achieved in 2433 (88%). The rate of increase in HR was similar for each group of BMI after adjustment for age, gender, baseline HR, negative chronotropic use, and atropine administration. The percentage of patients in each group who achieved target HR was similar and the percentage of target HR achieved at each stage of dobutamine was essentially equivalent. Blood pressure responses and development of symptoms were similar in the 4 groups of BMI. Independent predictors of failure to achieve target HR included age, diabetes mellitus, treatment with negative chronotropic medications, and baseline HR; BMI was not a predictor (odds ratio [OR] 0.98, P = .086). Conclusion: The current weight-based protocol of dobutamine dosing for DST results in similar increases in HR and blood pressure for patients of widely varying BMI.

Abstract Background: Genetic susceptibility for cancer can differ substantially among families. We use trait-related covariates to identify a genetically homogeneous subset of families with the best evidence for linkage in the presence of heterogeneity. Methods: We performed a genome-wide linkage screen in 93 families. Samples and data were collected by the familial lung cancer recruitment sites of the Genetic Epidemiology of Lung Cancer Consortium. We estimated linkage scores for each family by the Markov chain Monte Carlo procedure using SimWalk2 software. We used ordered subset analysis (OSA) to identify genetically homogenous families by ordering families based on a disease-associated covariate. We performed permutation tests to determine the relationship between the trait-related covariate and the evidence for linkage. Results: A genome-wide screen for lung cancer loci identified strong evidence for linkage to 6q23–25 and suggestive evidence for linkage to 12q24 using OSA, with peak logarithm of odds (LOD) scores of 4.19 and 2.79, respectively. We found other chromosomes also suggestive for linkages, including 5q31–q33, 14q11, and 16q24. Conclusions: Our OSA results support 6q as a lung cancer susceptibility locus and provide evidence for disease linkage on 12q24. This study further increased our understanding of the inheritability for lung cancer. Validation studies using larger sample size are needed to verify the presence of several other chromosomal regions suggestive of an increased risk for lung cancer and/or other cancers. Impact: OSA can reduce genetic heterogeneity in linkage study and may assist in revealing novel susceptibility loci. Cancer Epidemiol Biomarkers Prev; 19(12); 3157–66. ©2010 AACR.

PurposeTo determine whether increased duration of radiation therapy (RT) and overall treatment (RX) time has a detrimental effect in anal cancer.Patients and MethodsData from Radiation Therapy Oncology Group (RTOG) 87-04 and RTOG 98-11 trials were combined to form three treatment groups: RT/fluorouracil (FU)/mitomycin (n = 472), RT/FU/cisplatin (n = 320), and RT/FU (n = 145). Cox proportional hazards models were used with the following variables: RT duration, RT intensity, RX duration, treatment group, age, sex, Karnofsky performance score (KPS), T stage, N stage, and RT dose.ResultsIn the univariate analysis, there was a significant association between RX duration and colostomy failure (CF; hazard ratio [HR] = 1.51; 95% CI, 1.07 to 2.14; P = .02), local failure (HR = 1.52; 95% CI, 1.14 to 2.03; P = .005), locoregional failure (HR = 1.51; 95% CI, 1.15 to 1.98; P = .003), and time to failure (HR = 1.40; 95% CI, 1.10 to 1.79; P = .007). The significance of RX duration was maintained after adjusting for treatment group. In multivariate modeling there was a trend toward an association between RX duration and CF (HR = 1.57; 95% CI, 0.98 to 2.50; P = .06) and a statistically significant association with local failure (HR = 1.96; 95% CI, 1.34 to 2.87; P = .0006). Age, sex, KPS, T stage, N stage, and RT dose, but not RT duration, RT intensity, or RX duration, were found to be statistically significant predictors of OS and colostomy-free survival.ConclusionTotal treatment time, but not duration of radiation therapy, seems to have a detrimental effect on local failure and colostomy rate in anal cancer. Induction chemotherapy may contribute to local failure by increasing total treatment time.