Robert L. DeWitty

Enrollment of African Americans Onto Clinical Treatment Trials: Study Design Barriers

PURPOSE African Americans have the highest cancer mortality rates and poorest survival and are more often uninsured and underinsured compared with other ethnic groups. Minority participation in clinical trials has traditionally been low, with reports ranging from 3% to 20%. The present study systematically assesses 235 consecutively diagnosed African American cancer patients regarding recruitment onto cancer treatment clinical trials at Howard University Cancer Center between January 1, 2001, and December 31, 2002. Our intent is to determine the rate-limiting factors associated with enrolling African Americans onto clinical trials at a historically black medical institution. PATIENTS AND METHODS Two hundred thirty-five consecutively diagnosed African American cancer patients were assessed for participation in clinical trials at Howard University Hospital and Cancer Center. The study population comprised 165 women and 70 men. RESULTS The overall eligibility rate was 8.5% (20 of 235 patients); however, among those eligible, the enrollment rate (ie, enrollment among the eligible population) was 60.0% (12 of 20 patients). Comorbidities rendered 17.1% of the patient population ineligible for the trials. Advanced disease stage, associated with poor performance status, premature death, and short life expectancy, made an additional 10% of the patient population ineligible. Respiratory failure, HIV positivity, and anemia accounted for 37.8% of the comorbidities in this population. Cardiovascular diseases and renal insufficiency represented 16.2% of the comorbidities. CONCLUSION It was evident that study design exclusion and inclusion criteria rendered the majority of the study population ineligible. Among African Americans, comorbidity is a major issue that warrants considerable attention.

Identification of MMP-1 as a putative breast cancer predictive marker by global gene expression analysis

Breast cancer is the second leading cause of cancer death for women in the United States. In 2005, about 215,000 cases of invasive breast cancer (IBC) and 50,000 cases of ductal carcinoma in situ will be diagnosed and 40,000 women will die of IBC in the US. Yet there is presently no molecular marker that can be used to detect a precancerous state or identify which premalignant lesions will develop into invasive breast cancer. Here we report the gene expression analysis of atypical ductal hyperplastic tissues from patients with and without a history of breast cancer. We identify MMP-1 as a candidate marker that may be useful for identification of breast lesions that can develop into cancer.

Molecular detection of micrometastatic breast cancer in histopathology-negative axillary lymph nodes correlates with traditional predictors of prognosis: An interim analysis of a prospective multi-institutional cohort study

Objective:We sought to establish the clinical relevance of micrometastatic disease detected by reverse transcription polymerase chain reaction (RT-PCR) in axillary lymph nodes (ALN) of breast cancer patients. Background:The presence of ALN metastases remains one of the most valuable prognostic indicators in women with breast cancer. However, the clinical relevance of molecular detection of micrometastatic breast cancer in sentinel lymph nodes (SLN) and nonsentinel ALN has not been established. Methods:Four hundred eighty-nine patients with T1–T3 primary breast cancers were analyzed in a prospective, multi-institutional cohort study. ALN were analyzed by standard histopathology (H&E staining) and by multimarker, real-time RT-PCR analysis (mam, mamB, muc1, CEA, PSE, CK19, and PIP) designed to detect breast cancer micrometastases. Results:A positive marker signal was observed in 126 (87%) of 145 subjects with pathology-positive ALN, and in 112 (33%) of 344 subjects with pathology-negative ALN. In subjects with pathology-negative ALN, a positive marker signal was significantly associated with traditional indicators of prognosis, such as histologic grade (P = 0.0255) and St. Gallen risk category (P = 0.022). Mammaglobin was the most informative marker in the panel. Conclusion:This is the first report to show that overexpression of breast cancer–associated genes in breast cancer subjects with pathology-negative ALN correlates with traditional indicators of disease prognosis. These interim results provide strong evidence that molecular markers could serve as valid surrogates for the detection of occult micrometastases in ALN. Correlation of real-time RT-PCR analyses with disease-free survival in this patient cohort will help to define the clinical relevance of micrometastatic disease in this patient population.

Molecular Breast Cancer Subtypes in Premenopausal African-American Women, Tumor Biologic Factors and Clinical Outcome

IntroductionBreast cancer is currently viewed as a heterogeneous disease made up of various subtypes, with distinct differences in prognosis. Our goal was to study the distribution and to characterize the clinical and biological factors that influence the behavior and clinical management of the different molecular breast cancer subtypes in premenopausal African-American women.MethodsA retrospective analysis of Howard University Hospital tumor registry, for all premenopausal African-American women aged less than 50 years, diagnosed with breast cancer from 1998–2005, was performed.ResultsThe luminal A subtype was the most prevalent (50.0%), vs basal-cell-like (23.2%), luminal B (14.1%), and HER-2/neu (12.7%). However when stratified by age groups, results showed that in the age group <35 years the basal-cell-like subtype was the most prevalent (55.6%), vs 25.9%, 14.8%, and 5.6% for luminal A, luminal B, and HER-2/neu subtypes, respectively (P < .000). P53 mutation was more prevalent in the basal-cell-like subtype compared to luminal A (48.0% vs 18.6%, P < .01).The expression of the Bcl-2 gene differed by subtype, with the luminal A and luminal B subtypes more likely to overexpress the Bcl-2 gene (89.1% luminal A, 80.0% luminal B vs 47.6% basal-cell-like and 40.0% HER-2/neu, P < .000). Though not statistically significant, HER-2/neu and basal-cell-like subtypes had the shortest survival time (P < .31).ConclusionThe high prevalence of the basal-cell-like subtype in young premenopausal African-American women aged <35 years may contribute to the poorer prognosis observed in this cohort of African-American women.

Expression of Carcinoembryonic Antigen Cell Adhesion Molecule 6 Oncoprotein in Atypical Ductal Hyperplastic Tissues Is Associated with the Development of Invasive Breast Cancer

Background: Epidemiologic studies have established that women with prior atypical ductal hyperplastic (ADH) lesions have a 5-fold increased risk of developing invasive breast cancer (IBC). However, there is currently no means of identifying a subclass of ADH from women who will most likely develop cancer. The purpose of this study is to investigate whether elevated expression of carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) in ADH tissues is associated with the development of IBC. Methods: A retrospective study was conducted with archival ADH tissues and clinical information on the development/nondevelopment of IBC. The control group was ADH from patients who had no prior history of IBC and did not develop cancer within 5 years after the diagnosis of ADH (n = 44). The test group was ADH from patients who either developed cancer concurrently or subsequently after diagnosis (ADHC; n = 44). The expression of CEACAM6 was studied by immunohistochemistry and the results were statistically analyzed for significant association to develop cancer (P value), specificity, sensitivity, positive predictive value, and negative predictive value. Results: Of the 44 control ADH tissues from patients with no history of cancer, 9 were positive for CEACAM6. Among the ADHC tissues, 40 of 44 samples were positive. Statistical analysis of CEACAM6 expression data showed a significant association between its expression and cancer development, high sensitivity, specificity, positive predictive value, and negative predictive value. Conclusions: The expression of CEACAM6 in ADH lesions is strongly associated with the development of IBC, therefore, it can be applied as a diagnostic marker either singly or in combination with other marker(s) to predict IBC development in women with ADH lesions. It could also be a potential molecular therapeutic target for preventing IBC.

Intraoperative Radiotherapy for Patients with Carcinoma of the Pancreas: The Howard University Hospital Experience, 1978–1986

During the period from 1978 to 1986, 106 patients were diagnosed with carcinoma of the pancreas; 30 of these patients were excluded from this study. Of the remaining 76 patients, 40 did not receive intraoperative radiotherapy (IORT) and were used as the nonrandomized control group for the 36 patients who did receive IORT after histologie confirmation of carcinoma of the pancreas. The records of 35 patients were available for review. The group receiving IORT ranged in ages from 43 to 89 years (20 males and 15 females). Seventeen patients had distant metastatic disease. The primary was located in the head of the pancreas in 32 and the body in three. No patient in this group had a curative resection. All patients were treated by a combination of biliary and gastric bypass prior to or concurrent with IORT. IORT was begun only after obtaining a histologie diagnosis and prior to the completion of any anastomosis. Necrotizing pancreatitis occurred in the treated group. There was no statistically significant difference in the survival of the nonrandomized control and treated groups.

Treatment and Survival Outcome for Molecular Breast Cancer Subtypes in Black Women

Objective:To analyze whether the local-regional surgical treatments (breast-conserving therapy, mastectomy) resulted in different overall survival, distant metastasis-free survival, and locoregional recurrence-free survival rates for the various molecular breast cancer subtypes. Summary Background Data:Molecular gene expression profiling has been proposed as a new classification and prognostication system for breast cancer. Current recommendation for local-regional treatment of breast cancer is based on traditional clinicopathologic variables. Methods:Retrospective analysis of 372 breast cancer cases with assessable immunohistochemical data for ER, PR, and Her-2/neu receptor status, diagnosed from 1998 to 2005. Molecular subtypes analyzed were luminal A, luminal B, basal like, and Her-2/neu. Results:No substantial difference was noted in overall survival, and locoregional recurrence rate between the local-regional treatment modalities as a function of the molecular breast cancer subtypes. The basal cell-like subtype was an independent predictor of a poorer overall survival (hazard ratio [HR] = 2.52, 95% confidence interval [CI] 1.28–4.97, P < 0.01) and a shorter distant metastasis-free survival time (HR = 3.61, 95% CI 1.27–10.2, P < 0.01), and showed a tendency toward statistical significance as an independent predictor of locoregional recurrence (HR = 3.57, 95% CI 0.93–13.6, P = 0.06). Conclusions:The basal cell-like subtype is associated with a worse prognosis, a higher incidence of distant metastasis, and may be more prone to local recurrence when managed with breast-conserving therapy.

Molecular Risk Assessment for Breast Cancer Development in Patients with Ductal Hyperplasias

Purpose: It has been reported that approximately a million women are diagnosed with benign breast lesions that include ductal hyperplasias per year in the United States. Recent studies that followed women with benign lesions have established that about 8% to 9% of them will subsequently develop invasive breast cancer (IBC). However, currently, there are no means of identifying a subclass of “true precancerous tissues” in women with ductal hyperplasias who will subsequently develop cancer. The purpose of this study is to investigate whether expression of hyaluronoglucosaminidase 1 (HYAL1), a known tumor promoter, in hyperplastic tissues identifies a “true precancerous stage” and predicts subsequent IBC development. Experimental Design: A retrospective study was conducted with archival benign tissues of various histologic types and clinical information on development/nondevelopment of IBC. The control group was hyperplastic tissues from women who had no prior history of IBC and did not develop cancer in 5 to 7 years after diagnosis (n = 81). The test group was hyperplastic tissues from patients who developed cancer (n = 82). HYAL1 expression was studied by immunohistochemistry, and the results were statistically analyzed for significant association to develop cancer (P value), specificity, sensitivity, positive predictive value, and negative predictive value. Results: Statistical analysis of HYAL1 expression data showed very highly significant association between its expression and subsequent cancer development (P = 0) and very high sensitivity (0.83), specificity (0.84), positive predictive value (0.84), and negative predictive value (0.83). Conclusions: The expression of HYAL1 in ductal hyperplastic tissues is a strong predictor of subsequent development of IBC; therefore, it can be applied as a diagnostic marker either singly or in combination with other marker(s) to screen benign tissues to predict subsequent development of IBC. Detection at the precancerous stage and treatment could drastically cut down breast cancer incidence and deaths from it.

Breast Cancer Risk Assessments Comparing Gail and CARE Models in African‐American Women

Abstract:  The Gail model has been used to predict invasive breast cancer risk in women using risk factors of age, age at menarche, age at first live birth, number of first‐degree relatives with breast cancer, and number of previous benign breast biopsies. However, this model underestimates breast cancer risk in African‐American women. The Contraceptive and Reproductive Experience (CARE) model has been developed to replace the Gail model in predicting breast cancer risk in African‐American women. In a sample of 883 women who participated in the breast cancer screening program at Howard University Cancer Center, we compared the breast cancer risk estimates from the Gail model and the CARE model. The mean 5‐year breast cancer risk was 0.88% (Range: 0.18–6.60%) for the Gail model and 1.29% (Range: 0.20–4.50%) for the CARE model. Using the usual cutoff‐point of 1.67% or above for elevated risk, there is a significant difference in the proportion of women with elevated breast cancer risk between the Gail and the CARE models (McNemar’s test, p < 0.0001). For both models, there was a significant mean risk difference between those with and without a family history of breast cancer (Wilcoxon rank‐sum test, p < 0.0001). Our results confirm the need for validation of the Gail model in African‐Americans and diversity in research. Although these findings are not perfect and perhaps not definitive, they are additive in the discussions during counseling and risk assessment in African‐Americans. Furthermore, these findings will be complemented by new technologies such as genomics in refining our ability to assess risk.

Strong association of fascin expression with triple negative breast cancer and basal-like phenotype in African-American women

Background Fascin, an actin bundling protein, plays a critical role in cell motility due to formation of actin rich protrusions called filopodia, important in cell migration, invasion and metastatic spread. Fascin overexpression has been associated with epithelial to mesenchymal transition and correlates with progression and unfavourable prognosis in breast carcinoma. Objective To evaluate fascin expression by immunohistochemistry and correlate the expression pattern with clinicopathological parameters in breast cancer in African-American (AA) women, in whom triple negative breast cancer (TNBC), an aggressive subtype, is more prevalent. Methods Tissue microarrays were constructed from formalin-fixed, paraffin-embedded blocks of tumour tissue from primary breast carcinomas in 202 AA women. Immunohistochemical detection of fascin was correlated with four major subtypes of breast carcinoma (luminal A, luminal B, human epidermal growth factor receptor 2 and triple negative (TN)) and other clinicopathological factors, including age, grade, tumour size, stage, regional lymph node status and survival. Results We observed a significant association between fascin expression and TN subtype, oestrogen receptor (ER) negativity, progesterone receptor (PR) negativity, Elston–Nottingham (EN) grade 3 and decreased overall survival. There was also a significant association between expression of CK 5/6, a marker of basal-like phenotype, and fascin expression. Conclusion These results suggest that fascin is a marker for TN subtype having a basal-like phenotype and decreased overall survival. Fascin may represent a target for therapy in TNBC in AA women.