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Detection at precancerous stage to reduce deaths in Afro-American patients
Breast Cancer Disparities
Race is emerging as a poor prognostic factor for poorer survival among African American (AA) patients based on recent studies that adjusted for age, risk factors, socio-demographic variables, menopausal status, treatment variables, ER, grade, histology and stage. It is also recognized that AA patients develop fast growing highly aggressive tumors with high frequency of nuclear atypia, higher S-phase fraction, higher mitotic activity, higher tumor necrosis, lower ER and PR expression, high grade and higher proliferation rates. Mortality rate could continue to be the highest in this population unless alternate measures are developed for early detection and treatment before aggressive tumors are formed. Detection at the precancerous stage and treatment before aggressive cancer will be developed is the logical strategy to reduce/eliminate death rate of women in all races particularly ethnically at risk AA population. Our objective is to develop molecular approaches to identify very high risk AA patients with or without precancerous lesions so that they could be treated before invasive cancer develops. We have recently identified about 300 putative cancer promoting molecules that could potentially be applied to identify very high risk patients. We will apply those molecules and test a hypothesis that ?expression of the putative cancer promoting molecules in the precancerous tissues (Benign and ADH) predicts subsequent development of breast cancer?. We will pursue two specific aims to test the hypothesis: 1. Screen archival precancerous breast tissues from AA patients for the expression of about ten putative cancer promoting molecular markers by immunohistochemistry (IHC) and establish in a retrospective study that elevated expression of at least three markers in AA precancerous tissues is associated with subsequent development of invasive breast cancer. 2. Establish that expression of cancer promoting molecular markers in Aim 1 could be detected at their mRNA levels in ductal cells by RT QPCR. We will use archival UDH and ADH tissues from AA patients who 1) developed cancer in 1-5 or more years (test) and 2) had no cancer previous to precancerous diagnosis and did not develop cancer in 5 or more years after precancerous diagnosis (control) and screen for about ten markers by IHC and establish that the expression of at least three markers is associated with subsequent development of cancer. We will also establish the feasibility of detecting the three markers in ductal cells obtained by procedures such as ductal lavage by RTQ PCR. If successful, we will establish that expression of certain cancer promoting molecules in UDH/ADH tissues will predict subsequent development of IBC, and those markers could be used as diagnostic tools to screen UDH/ADH lesions or ductal cells and identify AA patients who are at very high risk of developing IBC. In addition, established markers could be targeted to design therapeutics/vaccines to prevent development of IBC.
It is now well established that African American (AA) patients experience highest death rate with breast cancer although the incidence is lower than in other population. It was originally thought that the highest death rate was due to late of stage of diagnosis, socio-economic status and limited access to heath care. However, based on recent studies, race is emerging as a poor prognostic factor for poorer survival among AA patients after adjusting for age, risk factors, socio-demographic variables, menopausal status, treatment variables, ER status, tumor grade, histology and stage at diagnosis. In addition, it is now well recognized that AA patients develop fast growing highly aggressive tumors that are difficult to control. Death rate could continue to be the highest in this population unless alternate measures are developed for early detection and treatment before aggressive cancers are formed. Detection at the precancerous stage and treatment before aggressive cancer will be developed is the logical strategy to reduce the death rate among ethnically at risk AA population. The current proposal is aimed at developing strategies in predicting cancer development in patients who have benign (precancerous) mass/tumors so that they could be treated before aggressive tumors are formed and prevented from developing cancer. We will conduct a retrospective study using benign tissues from AA patients who subsequently developed cancer as test group and benign tissues from patients who did not develop cancer in 5 or more years after benign diagnosis as control group. We will look for the presence of certain markers in the benign tissues. We expect that the patients who showed the presence of markers developed cancer subsequently but not patients whose benign tumors did not have the markers. If we are successful in establishing a correlation between the presence of markers and subsequent development of cancer, then those markers could be used to screen benign tissues and identify patients who are at very high risk of developing cancer. Identification and treatment before aggressive cancer is formed could significantly decrease death rate in a sub-set of AA patients who develop benign lesions prior to invasive cancer. In addition, we will also test the feasibility of detecting those markers in cells obtained from milk ducts. If successful, then cells from milk ducts could be used to screen for the markers in women who have no mammographically detectable masses and identify those who are at very high risk of developing cancer so that they could be treated and prevented from developing cancer. Detection and prediction of cancer development before the tumors are formed and treatment could significantly decrease mortality rate in at risk AA population.