Joel Okoli

High prevalence of triple-negative tumors in an urban cancer center†

A disparate proportion of breast cancer deaths occur among young women, those of African‐American (AA) ancestry, and particularly young AA women. Estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor‐2 (HER‐2) are key clinically informative biomarkers. The triple‐negative (ER‐/PR‐/HER‐2‐) tumor subgroup is intrinsically resistant to treatment and portends a poor prognosis. Age, race, and socioeconomic status have been associated with triple‐negative tumors (TNT). In the current study, the authors investigated breast cancer subgroups among patients in an urban cancer center serving a multiracial, low socioeconomic population.

Effects of an outreach and internal navigation program on breast cancer diagnosis in an urban cancer center with a large African-American population

Compared with white women, African‐American (AA) women who are diagnosed with breast cancer experience an excess in mortality. To improve outcomes, the authors implemented community education and outreach initiatives in their cancer center, at affiliated primary care sites, and in the surrounding communities. They then assessed the effectiveness of these outreach initiatives and internal patient navigation on stage of diagnosis.

BRCA1a has antitumor activity in TN breast, ovarian and prostate cancers.

Breast cancer gene 1 (BRCA1) mutations predispose women to breast and ovarian cancers and men to increased risks for prostate cancer. We have previously showed BRCA1 splice variant BRCA1a/p110 to induce apoptosis of human breast cancer cells. In the current study, stable expression of BRCA1a/p110 resulted in inhibition of growth of estrogen receptor (ER)-positive and triple-negative (TN) human breast, ovarian, prostate and colon cancer cells and mouse fibroblast cells. Similar to wild-type BRCA1, only those cells with wild-type Rb were sensitive to BRCA1a-induced growth suppression and the status of p53 did not affect the ability of BRCA1a to suppress growth of tumor cells. BRCA1a also significantly inhibited tumor mass in nude mice bearing human CAL-51 TN breast cancer, ES-2 ovarian cancer and PC-3 prostate cancer xenografts. These results suggest that the majority of exon 11 sequences (residues 263–1365) are not required for the tumor suppressor function of BRCA1 proteins. This is the first report demonstrating antitumor activity of BRCA1a in human ER-positive and TN breast, hormone-independent ovarian and prostate cancer cells. Currently, there are no effective treatments against TN breast cancers and results from these studies will provide new treatments for one of the biggest needs in breast cancer research.

Is cumulative frequency of mitochondrial DNA variants a biomarker for colorectal tumor progression

To examine the relationship between mitochondrial DNA (mtDNA) alterations and colorectal tumorigenesis, we used high-resolution restriction endonucleases and sequencing to assess the mitochondrial genome from three histologic subtypes of colorectal adenomas (tubular = 8; tubulovillous = 9; and villous = 8), colorectal cancer (CRC) tissues = 27, and their matched surrounding normal tissue (MSNT) = 52. The mitochondrial genomes were amplified using 9 pairs of overlapping primers and systematically analyzed by means of high-resolution analysis. DNA fragments showing a shift in banding patterns between the three adenomas, CRC, in comparison to the MSNT were sequenced to identify the mtDNA alterations. A total of thirty-eight germ-line mtDNA variants were observed in this study. Twenty-two of the thirty-eight were identified as mutations and 59% (13 of 22) were silent mutations and one was a 1-bp insertion. Sixteen of thirty-eight were distinct SNPs in flanking regions of the restriction sites and, 6 of the 16 (37%) SNPs were not previously reported. Most of these mutations/SNPs were homoplasmic and distributed in various regions of mitochondrial genes including the 16S and 12S rRNA. Based on our results, mtDNA germline variants increased in prevalence with adenoma CRC progression. To the best of our knowledge, this is the first report to show an increased prevalence of mitochondrial gene variants in CRC tumorigenesis.

Abnormal Mammogram Follow-Up: Do Community Lay Health Advocates Make a Difference?

This pilot study evaluates a community lay health advocate (CLHA) intervention in promoting follow-up for abnormal mammograms among African American women. A controlled trial was implemented at an urban hospital in Atlanta, with 48 women in a CLHA intervention group and 35 in a usual care group. Participants were 25 or older and had an abnormal mammogram between March 25, 2002, and May 2, 2003. Intervention group women received CLHA support including encouragement of timely abnormal mammogram follow-up, reminders of follow-up appointments, identification and removal of barriers to follow-up, and accompaniment to follow-up appointments. Women in the intervention group were significantly more likely to keep their first abnormal mammogram follow-up appointment, all of their scheduled follow-up appointments, and their biopsy or fine needle aspiration appointment. CLHAs are effective in promoting abnormal mammogram followup among African American women and may be an important resource in reducing racial disparities in breast cancer mortality.

Triple Negative Breast Cancer – An Overview

Triple Negative Breast Cancer (TNBC) is a heterogeneous disease that based on immunohistochemistry (IHC) is estrogen receptor (ER) negative, progesterone receptor (PR) negative and human epidermal growth factor receptor 2 (HER2) negative. TNBC is typically observed in young AA women and Hispanic women who carry a mutation in the BRCA1 gene. TNBC is characterized by a distinct molecular profile, aggressive nature and lack of targeted therapies. The purpose of this article is to review the current and future novel signalling pathways as therapeutic approaches to TNBC. Recent Identification of a new BRCA1 trafficking pathway holds promise in the future for the development of targeted therapies for TNBC.

Using National Quality Forum breast cancer indicators to measure quality of care for patients in an AVON comprehensive breast center.

Abstract:  In April 2007, the National Quality Forum (NQF) endorsed the first nationally recognized hospital‐based performance measures for quality of care for breast cancer. The aim of this study was to measure quality of care at our AVON Center for Breast Care (AVONCBC) using these indicators. We retrospectively reviewed tumor registry and medical records of females under age 70 diagnosed with breast cancer in years 2005–2006. For patients diagnosed with hormone receptor negative breast cancer, 22 of 29 (75.9%) and 28 of 32 (87.5%) were considered for or received chemotherapy in 2005 and 2006, respectively. Of those patients, 21 of 29 (72.4%) and 24 of 32 (75.0%) were considered for or received chemotherapy within the NQF 4‐month period. For patients undergoing breast conserving surgery (BCS), 20 of 23 (86.9%) in 2005 and 37 of 39 (94.9%) in 2006 were referred for adjuvant radiation therapy. The proportion of patients who received radiation therapy within 1 year of diagnosis was 18 of 23 (78.2%) and 29 of 39 (74.4%) for diagnosis years 2005 and 2006, respectively. The vast majority of patients in our AVONCBC are referred to medical and/or radiation oncology for adjunctive therapy and about three‐fourths receive treatment compliant with the NQF QI. To increase our compliance rate, we are developing methods to improve access to the multiple disciplines in our AVONCBC. Using the NQF indicators serves to assess hospital performance at a systems‐level and as a useful method for tracking cancer quality of care.

Effects of HIV-1 nef, a cytotoxic viral protein, on the growth of primary colorectal cancer

Colorectal cancer is the third leading cause of cancer deaths in American men and women. We describe the cytotoxic use of HIV-1 Nef protein and a cytotoxic peptide identified within the HIV-1 Nef structure in targeting human cancer cells in vitro and in vivo in a human xenograft model. A human colorectal tumor was implanted and propagated in the subcutaneous tissue of SCID mice. The mice were injected biweekly with the Nef apoptotic peptide. The tumor treated with Nef peptide underwent significant growth inhibition by as much as 300 percent when compared to the control (untreated) tumors. The Nef peptides were found to have an apoptotic effect on the human colon tumor similar to the effect seen on CD4 cells when the viral protein is secreted by the HIV-1 virus infected cells. The evidence from the xenograft mouse model suggests that the Nef peptides can be used to inhibit human colorectal cancer growth.

Improving on National Quality Indicators of Breast Cancer Care in a Large Public Hospital as a Means to Decrease Disparities for African American Women

BackgroundIn April 2007, the National Quality Forum (NQF) endorsed the first nationally recognized hospital-based performance measures for stage I, II, and III breast cancer. The purpose of this study was to document compliance with the 3 NQF breast quality indicators during 2 time intervals in a metropolitan public hospital.Materials and MethodsTumor registry and medical records were used to identify patient demographics and treatments before (2005–2006) and after (2008) implementations in 2007 as a result of the NQF audit. Program changes included: hiring a dedicated medical oncology nurse practitioner, requiring the radiation oncology case manager to attend weekly multidisciplinary conferences, educating Patient Navigators of the importance of multimodal care, and providing support groups for patients addressing importance of completion of all treatment options.ResultsA total of 213 female patients were diagnosed with and treated for stage I, II, or III breast cancer in 2005–2006 and 2008. Of these, 189 (89%) were African American (AA) women. Also, 70 patients of 86 (81.3%) received radiation therapy, 60 of 77 (77.9%) received or were considered for adjuvant chemotherapy, and 124 of 144 (86.1%) for hormonal therapy according to NQF indicators. After 2007, patients receiving radiation therapy increased from 75.8 to 95.8%. Patients receiving or considered for adjuvant chemotherapy or hormonal therapy increased from 73.7 to 93.7% and from 84.1 to 90.0%, respectively.ConclusionsNQF breast cancer indicators provided a mechanism to improve compliance of multimodal treatment in our center. Raising awareness of these indicators in the multidisciplinary conference, hiring dedicated personnel, and educating patients has led to major improvements in breast cancer care.

Molecular Mechanism Linking BRCA1 Dysfunction to High Grade Serous Epithelial Ovarian Cancers with Peritoneal Permeability and Ascites

Ovarian cancer constitutes the second most common gynecological cancer with a five-year survival rate of 40%. Among the various histotypes associated with hereditary ovarian cancer, high-grade serous epithelial ovarian carcinoma (HGSEOC) is the most predominant and women with inherited mutations in BRCA1 have a lifetime risk of 40-60%. HGSEOC is a challenge for clinical oncologists, due to late presentation of patient, diagnosis and high rate of relapse. Ovarian tumors have a wide range of clinical presentations including development of ascites as a result of deregulated endothelial function thereby causing increased vascular permeability of peritoneal vessels. The molecular mechanisms remain elusive. Studies have shown that fallopian tube cancers develop in women with BRCA1 gene mutations more often than previously suspected. Recent studies suggest that many primary peritoneal cancers and some high-grade serous epithelial ovarian carcinomas actually start in the fallopian tubes. In this article we have addressed the molecular pathway of a recently identified potential biomarker Ubc9 whose deregulated expression due to BRCA1 dysfunction can result in HGSEOC with peritoneal permeability and formation of ascites. We also discuss the role of downstream targets Caveolin-1 and Vascular Endothelial Growth Factor (VEGF) in the pathogenesis of ascites in ovarian carcinomas. Finally we hypothesize a signaling axis between Ubc9 over expression, loss of Caveolin-1 and induction of VEGF in BRCA1 mutant HGSEOC cells. We suggest that Ubc9-mediated stimulation of VEGF as a novel mechanism underlying ovarian cancer aggressiveness and ascites formation. Agents that target Ubc9 and VEGF signaling may represent a novel therapeutic strategy to impede peritoneal growth and spread of HGSEOC.