G. Thomas Budd

Circulating Tumor Cells versus Imaging—Predicting Overall Survival in Metastatic Breast Cancer

Purpose: The presence of ≥5 circulating tumor cells (CTC) in 7.5 mL blood from patients with measurable metastatic breast cancer before and/or after initiation of therapy is associated with shorter progression-free and overall survival. In this report, we compared the use of CTCs to radiology for prediction of overall survival. Experimental Design: One hundred thirty-eight metastatic breast cancer patients had imaging studies done before and a median of 10 weeks after the initiation of therapy. All scans were centrally reviewed by two independent radiologists using WHO criteria to determine radiologic response. CTC counts were determined ∼4 weeks after initiation of therapy. Specimens were analyzed at one of seven laboratories and reviewed by a central laboratory. Results: Interreader variability for radiologic responses and CTC counts were 15.2% and 0.7%, respectively. The median overall survival of 13 (9%) patients with radiologic nonprogression and ≥5 CTCs was significantly shorter than that of the 83 (60%) patients with radiologic nonprogression and <5 CTCs (15.3 versus 26.9 months; P = 0.0389). The median overall survival of the 20 (14%) patients with radiologic progression and <5 CTCs was significantly longer than the 22 (16%) patients with ≥5 CTCs that showed progression by radiology (19.9 versus 6.4 months; P = 0.0039). Conclusions: Assessment of CTCs is an earlier, more reproducible indication of disease status than current imaging methods. CTCs may be a superior surrogate end point, as they are highly reproducible and correlate better with overall survival than do changes determined by traditional radiology.

Breast cancers with brain metastases are more likely to be estrogen receptor negative, express the basal cytokeratin CK5/6, and overexpress HER2 or EGFR

Brain metastases (BM) from breast cancer are associated with significant morbidity and mortality. In the current study, we have examined a cohort of breast cancer patients who went on to develop BM for clinical-pathologic features and predictive markers that identify this high-risk subgroup of patients at the time of diagnosis. The primary tumors from 55 patients who developed BM were used to construct a tissue microarray. The clinical and pathologic features were recorded and the tissue microarray was stained for estrogen receptor, human epidermal growth factor receptor 2, cytokeratin 5/6, and epidermal growth factor receptor by immunohistochemistry . This cohort of patients was compared against a group of 254 patients who remain free of metastases (67 mo mean follow-up), and another cohort of 40 patients who developed mixed visceral and bone metastatic disease without brain recurrence over a similar period of time. Breast cancer patients who went on to develop BM were more likely to be <50 years old (P<0.001), and the primary tumors were more likely to be estrogen receptor negative (P<0.001) and high grade (P=0.002). The primary tumors were also more likely to express cytokeratin 5/6 (P<0.001) and epidermal growth factor receptor (P=0.001), and to overexpress human epidermal growth factor receptor 2 (P=0.001). The data presented above suggest a profile for breast cancer patients at increased risk for developing BM. Predictive factors to help identify patients with metastatic breast cancer who are at an increased risk for developing central nervous system recurrence might allow for screening of this population for early detection and treatment or for the development of targeted strategies for prevention.

Novel Prognostic Immunohistochemical Biomarker Panel for Estrogen Receptor–Positive Breast Cancer

PURPOSE Patients with breast cancer experience progression and respond to treatment in diverse ways, but prognostic and predictive tools for the oncologist are limited. We have used gene expression data to guide the production of hundreds of novel antibody reagents to discover novel diagnostic tools for stratifying carcinoma patients. PATIENTS AND METHODS One hundred forty novel and 23 commercial antisera, selected on their ability to differentially stain tumor samples, were used to stain paraffin blocks from a retrospective breast cancer cohort. Cox proportional hazards and regression tree analysis identified minimal panels of reagents able to predict risk of recurrence. We tested the prognostic association of these prospectively defined algorithms in two independent cohorts. RESULTS In both validation cohorts, the Kaplan-Meier estimates of recurrence confirmed that both the Cox model using five reagents (p53, NDRG1, CEACAM5, SLC7A5, and HTF9C) and the regression tree model using six reagents (p53, PR, Ki67, NAT1, SLC7A5, and HTF9C) distinguished estrogen receptor (ER)-positive patients with poor outcomes. The Cox model was superior and distinguished patients with poor outcomes from patients with good or moderate outcomes with a hazard ratio of 2.21 (P = .0008) in validation cohort 1 and 1.88 (P = .004) in cohort 2. In multivariable analysis, the calculated risk of recurrence was independent of stage, grade, and lymph node status. A model proposed for ER-negative patients failed validation in the independent cohorts. CONCLUSION A panel of five antibodies can significantly improve on traditional prognosticators in predicting outcome for ER-positive breast cancer patients.

Effect of statin therapy on the risk for incident heart failure in patients with breast cancer receiving anthracycline chemotherapy: an observational clinical cohort study.

OBJECTIVES The aim of this study was to evaluate the effect of continuous statin treatment on new-onset heart failure (HF) in patients with breast cancer receiving anthracycline-based chemotherapy. BACKGROUND In vitro and animal model experimental studies have reported that statins prevent doxorubicin-induced cardiotoxicity. METHODS A total of 628 women with newly diagnosed breast cancer (mean age 51.5 ± 10.8 years) treated with anthracycline were retrospectively identified and studied. The primary outcome (incident HF hospitalization) was compared in propensity-matched patients receiving uninterrupted statin therapy through the follow-up period of 2.55 ± 1.68 years and their counterparts not receiving continuous statin therapy. RESULTS After propensity matching (2:1), the 67 patients (10.7%) receiving uninterrupted statin therapy were combined with 134 controls. New-onset HF was observed in 67 of the 201 matched patients. Multivariate-matched Cox regression analysis showed a significantly lower hazard ratio [HR] of 0.3 (95% confidence interval [CI]: 0.1 to 0.9; p = 0.03) for patients taking uninterrupted statin therapy. Cardiotoxicity risk factors at the time of cancer diagnosis (HR: 5.0; 95% CI: 2.2 to 11.1; p < 0.001), baseline ejection fraction <55% (HR: 2.7; 95% CI: 1.2 to 6.3; p = 0.02), and trastuzumab use (HR: 3.0; 95% CI: 1.3 to 7.2; p = 0.01) were predictors of incident HF. CONCLUSIONS In this analysis of female patients with breast cancer treated with anthracycline chemotherapy, statin use was associated with a lower risk for incident HF. This finding is consistent with prior animal studies and warrants further investigation through prospective randomized clinical trials.

Exemestane Versus Anastrozole in Postmenopausal Women With Early Breast Cancer: NCIC CTG MA.27—A Randomized Controlled Phase III Trial

PURPOSE In patients with hormone-dependent postmenopausal breast cancer, standard adjuvant therapy involves 5 years of the nonsteroidal aromatase inhibitors anastrozole and letrozole. The steroidal inhibitor exemestane is partially non-cross-resistant with nonsteroidal aromatase inhibitors and is a mild androgen and could prove superior to anastrozole regarding efficacy and toxicity, specifically with less bone loss. PATIENTS AND METHODS We designed an open-label, randomized, phase III trial of 5 years of exemestane versus anastrozole with a two-sided test of superiority to detect a 2.4% improvement with exemestane in 5-year event-free survival (EFS). Secondary objectives included assessment of overall survival, distant disease-free survival, incidence of contralateral new primary breast cancer, and safety. RESULTS In the study, 7,576 women (median age, 64.1 years) were enrolled. At median follow-up of 4.1 years, 4-year EFS was 91% for exemestane and 91.2% for anastrozole (stratified hazard ratio, 1.02; 95% CI, 0.87 to 1.18; P = .85). Overall, distant disease-free survival and disease-specific survival were also similar. In all, 31.6% of patients discontinued treatment as a result of adverse effects, concomitant disease, or study refusal. Osteoporosis/osteopenia, hypertriglyceridemia, vaginal bleeding, and hypercholesterolemia were less frequent on exemestane, whereas mild liver function abnormalities and rare episodes of atrial fibrillation were less frequent on anastrozole. Vasomotor and musculoskeletal symptoms were similar between arms. CONCLUSION This first comparison of steroidal and nonsteroidal classes of aromatase inhibitors showed neither to be superior in terms of breast cancer outcomes as 5-year initial adjuvant therapy for postmenopausal breast cancer by two-way test. Less toxicity on bone is compatible with one hypothesis behind MA.27 but requires confirmation. Exemestane should be considered another option as up-front adjuvant therapy for postmenopausal hormone receptor-positive breast cancer.

Loss of Breast Cancer Metastasis Suppressor 1 Protein Expression Predicts Reduced Disease-Free Survival in Subsets of Breast Cancer Patients

Purpose: This study aims to determine the effect of loss of breast cancer metastasis suppressor 1 (BRMS1) protein expression on disease-free survival in breast cancer patients stratified by estrogen receptor (ER), progesterone receptor (PR), or HER2 status, and to determine whether loss of BRMS1 protein expression correlated with genomic copy number changes. Experimental Design: A tissue microarray immunohistochemical analysis was done on tumors of 238 newly diagnosed breast cancer patients who underwent surgery at the Cleveland Clinic between January 1, 1995 and December 31, 1996, and a comparison was made with 5-year clinical follow-up data. Genomic copy number changes were determined by array-based comparative genomic hybridization in 47 breast cancer cases from this population and compared with BRMS1 staining. Results: BRMS1 protein expression was lost in nearly 25% of cases. Patients with tumors that were PR negative (P = 0.006) or HER2 positive (P = 0.039) and <50 years old at diagnosis (P = 0.02) were more likely to be BRMS1 negative. No overall correlation between BRMS1 staining and disease-free survival was observed. A significant correlation, however, was seen between loss of BRMS1 protein expression and reduced disease-free survival when stratified by either loss of ER (P = 0.008) or PR (P = 0.029) or HER2 overexpression (P = 0.026). Overall, there was poor correlation between BRMS1 protein staining and copy number status. Conclusions: These data suggest a mechanistic relationship between BRMS1 expression, hormone receptor status, and HER2 growth factor. BRMS1 staining could potentially be used in patient stratification in conjunction with other prognostic markers. Further, mechanisms other than genomic deletion account for loss of BRMS1 gene expression in breast tumors.

Delivering adjuvant chemotherapy to women with early-stage breast carcinoma: Current patterns of care

Variations in practice patterns are markers for the quality of patient care in general medicine, but little is known about variation in care delivered to cancer patients. This studys purpose was to describe chemotherapy use, variations in chemotherapy delivery, and the incidence of complications in community practice settings.

A Phase I Study of Sunitinib plus Bevacizumab in Advanced Solid Tumors

Purpose: Bevacizumab is an antibody against vascular endothelial growth factor; sunitinib is an inhibitor of vascular endothelial growth factor and related receptors. The safety and maximum tolerated dose of sunitinib plus bevacizumab was assessed in this phase I trial. Experimental Design: Patients with advanced solid tumors were treated on a 3+3 trial design. Patients received sunitinib daily (starting dose level, 25 mg) for 4 weeks on followed by 2 weeks off and bevacizumab (starting dose level, 5 mg/kg) on days 1, 15, and 29 of a 42-day cycle. Dose-limiting toxicities during the first 6-week cycle were used to determine the maximum tolerated dose. Results: Thirty-eight patients were enrolled. Patients received a median of 3 cycles of treatment (range, 1-17+). There was one dose-limiting toxicity (grade 4 hypertension) at 37.5 mg sunitinib and 5 mg/kg bevacizumab. Grade 3 or greater toxicity was observed in 87% of patients including hypertension (47%), fatigue (24%), thrombocytopenia (18%), proteinuria (13%), and hand-foot syndrome (13%). Dose modifications and delays were common at higher dose levels. No clinical or laboratory evidence of microangiopathic hemolytic anemia was observed. Seven patients had a confirmed Response Evaluation Criteria in Solid Tumors–defined partial response (18%; 95% confidence interval, 8-34%). Nineteen of the 32 patients with a postbaseline scan (59%) had at least some reduction in overall tumor burden (median, 32%; range, 3-73%). Conclusions: The combination of sunitinib and bevacizumab in patients with advanced solid tumors is feasible, albeit with toxicity at higher dose levels and requiring dose modification with continued therapy. Antitumor activity was observed across multiple solid tumors. (Clin Cancer Res 2009;15(19):6277–83)

Cardioprotective Effect of β-Adrenoceptor Blockade in Patients With Breast Cancer Undergoing Chemotherapy Follow-Up Study of Heart Failure

Background—Chemotherapy with trastuzumab and anthracycline is associated with incident heart failure (HF) in patients with breast cancer. We hypothesized that continuous incidental use of &bgr;-blocker agents (BB) was protective against HF in patients without established structural heart disease who were receiving trastuzumab and anthracycline. Methods and Results—We identified 920 consecutive patients with breast cancer (age 52.3±11.0 years) with normal ejection fraction before receiving trastuzumab and anthracycline therapy at our institution between 2005 and 2010. Using a propensity score and a greedy 5 to 1 digit-matching algorithm, 106 of these patients on continuous BB during cancer treatment were matched with 212 patients from the same pool with similar characteristics but not on continuous BB. During a median follow-up of 3.2±2.0 years, 32 incident HF admissions were identified in these 318 patients with breast cancer, whereas 28 cancer-related (noncardiac) deaths occurred before any incident HF. Cumulative incidence regression models and cause-specific hazards of new HF events were estimated from competing risk Cox models of time-dependent covariates. Although trastuzumab therapy showed significant association with incident HF, independent of anthracycline-related cardiotoxicity (hazard ratio, 9.0; 95% confidence interval, 3.0–27.0; P<0.0001), continuous use of BB was associated with lower risk of new HF events (hazard ratio, 0.2; 95% confidence interval, 0.1–0.5; P=0.003). Conclusions—Coincidental, continuous use of BB is associated with lower incidence of HF in patients with breast cancer and normal baseline ejection fraction in a competing risk framework, and after matching for demographics, clinical, and cancer-related treatment characteristics. Prospective randomized clinical trials to validate these findings are warranted.

Cardioprotective Effect of β-Adrenoceptor Blockade in Patients With Breast Cancer Undergoing ChemotherapyClinical Perspective

Background—Chemotherapy with trastuzumab and anthracycline is associated with incident heart failure (HF) in patients with breast cancer. We hypothesized that continuous incidental use of &bgr;-blocker agents (BB) was protective against HF in patients without established structural heart disease who were receiving trastuzumab and anthracycline. Methods and Results—We identified 920 consecutive patients with breast cancer (age 52.3±11.0 years) with normal ejection fraction before receiving trastuzumab and anthracycline therapy at our institution between 2005 and 2010. Using a propensity score and a greedy 5 to 1 digit-matching algorithm, 106 of these patients on continuous BB during cancer treatment were matched with 212 patients from the same pool with similar characteristics but not on continuous BB. During a median follow-up of 3.2±2.0 years, 32 incident HF admissions were identified in these 318 patients with breast cancer, whereas 28 cancer-related (noncardiac) deaths occurred before any incident HF. Cumulative incidence regression models and cause-specific hazards of new HF events were estimated from competing risk Cox models of time-dependent covariates. Although trastuzumab therapy showed significant association with incident HF, independent of anthracycline-related cardiotoxicity (hazard ratio, 9.0; 95% confidence interval, 3.0–27.0; P<0.0001), continuous use of BB was associated with lower risk of new HF events (hazard ratio, 0.2; 95% confidence interval, 0.1–0.5; P=0.003). Conclusions—Coincidental, continuous use of BB is associated with lower incidence of HF in patients with breast cancer and normal baseline ejection fraction in a competing risk framework, and after matching for demographics, clinical, and cancer-related treatment characteristics. Prospective randomized clinical trials to validate these findings are warranted.