Early Detection of Breast Cancer and it Recurrence
| Institution: | Huntington Medical Research Institute | ||
| Investigator(s): |
Syed Ashraf Imam , M.S., Ph.D. -
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| Award Cycle: | 2001 (Cycle VII) | Grant #: 7WB-0023 | Award: $365,446 |
| Award Type: | STEP Award | ||
| Research Priorities | |||
| Imaging, Biomarkers, & Molecular Pathology>Biomarkers and novel screening approaches: unmasking the hidden signs | |||
Initial Award Abstract (2001)
One of the most important aspects of the management of breast cancer is early identification of low- vs. high-risk patients with localized non-invasive breast ductal carcinoma in stiu (DCIS) for subsequently developing invasive breast cancer. Utilizing currently available prognostic markers, low- vs. high-risk patients with breast DCIS are difficult to be reliably identified prior to the development of invasive breast cancer which are often fatal. In addition, many patients with primary invasive breast cancer, with the exception of those with steroid hormone receptors positive or Her2/neu positive, are given adjuvant therapy without pre-screening for prognosis and effectiveness of therapy. Therefore, the current lack of an effective selection strategy, with the exceptions as stated above, means that many women are subjected to adjuvant therapy unnecessarily with side effects and significant costs. For these reasons, we have developed a potential prognostic biomarker (LEA.135), a cell surface marker with potential for pre-screening patients for an appropriate therapy. In a preliminary study funded by the CBCRP, LEA.135 expression has been shown to be independently and significantly associated with a decreased risk of developing recurrence (log rank p<0.001) and an increase in overall survival (logrank p<0.001) of patients with primary invasive breast cancer. Now, we wish to extend the preliminary study to evaluate the usefulness of the presence of LEA.135 on cancer cells to identify the low-risk patients as described below. We wish to test the following hypotheses: 1) LEA.135expression can independently and significantly identify patients with breast DCIS at a decreased risk of developing invasive breast cancer; and 2) LEA.135 expression can identify a particular adjuvant therapy which is most effective in either LEA.135-positive or LEA.135-negative patients with primary invasive breast cancer. To test the first hypothesis, LEA.135 expression will be determined using monoclonal anti-LEA.135 antibody by immuno-staining tissue sections from patients with breast DCIS (n=310). In order to perform multivariate analyses, the following information for each patient are available: age at diagnosis, follow-up after surgery (medium follow-up of 8 years), clinical outcome of the disease, tumor type, margin of the excised lesion and adjuvant therapy. To test the second hypothesis, LEA.135 expression will be determined in tissue sections from well-documented patients with primary invasive breast cancer (n=480). We will then evaluate the association of LEA.135 expression with three separate adjuvant therapies in terms of clinical outcome of the disease, measured as recurrence and overall survival of the patients with primary invasive breast cancer. What is innovative about this Innovative elements of the project is to establish LEA.135 expression as an independent and reliable marker for an early identification of low- vs. high-risk DCIS patients before the development of invasive breast cancer. Furthermore, the development of strategies, based on LEA.135 status, for pre-screening of patients with primary invasive breast cancer for choosing an effective adjuvant therapy would be an Movement over the current practice.
Final Report (2004)
A retrospective study was undertaken to determine and compare the prognostic significance of LEA-135 protein expression by immunohistochemistry with other prognostic pathologic parameters, with respect to recurrence and overall survival. This study was conducted in freshly frozen tissue sections from a cohort of 367 patients having primary invasive breast cancer, with axillary lymph node metastasis. The association of LEA-135 expression was compared with estrogen and progesterone receptor status, segmentectomy or radical mastectomy and hormonal or chemotherapy in terms of recurrence or disease-free survival. Pathologic parameters including tumor size, histologic tumor type and histologic grade, as well as age of patients at the time of initial diagnosis, and the treatments, together with a median follow-up of 8.8 years were contemplated for the study. Among these parameters, tumor size and histologic grade were individually and significantly associated with an increased probability of recurrence (logrank p<0.001 in both cases) and short survival (logranks p<0.001 and p= 0.002 respectively), whereas age was only significantly associated with an increased probability of recurrence (logrank p=0.002) by univariate analysis. By multivariate analysis, both tumor size and histologic grade remained statistically significant for recurrence (logrank p<0.001 and p= 0.013 respectively) and overall survival (logranks p<0.001 and p= 0.016 respectively). Among the prognostic biomarkers, both ER and PR expression was associated with a decreased rate of recurrence (logranks p<0.001 and p=0.008 respectively) and overall survival (logranks p<0.001 and p=0.002 respectively) by univariate analysis. By multivariate analysis only the ER expression remained significantly associated with a decreased recurrence and increased overall survival (logranks p=0.023 and p=0.002 respectively). Patients with high (>50% positive cells) or moderate (5-50% positive cells) number of LEA-135-positive cells had a lower probability (46%) of recurrence at 10 years after surgery compared to 76% in LEA-135-negative patients (log rank p<0.001) by univariate analysis. Moreover, the probability of overall survival was higher in patients with high or moderate expression of LEA-135 (46% and 47% respectively) compared to LEA-135-negative patients (24%) by univariate analysis (logrank p=0.009). By multivariate analysis, the association remained statistically significant for recurrence (logrank p<0.001) and survival (logrank p=0.002). However, there was no significant association between LEA-135 and any of the pathologic parameters, age, hormone receptor status, the mode of surgery or the form of therapy (chemo- and/or hormonal) received by this cohort of patients. These results show that an improved prognosis was directly associated with the density of LEA-135-positive cancer cells, while loss of LEA-135 expression was associated with an aggressive phenotype of cancer cells during breast cancer progression. Thus, LEA-135 expression can be implicated as a significant and independent biomarker to identify and distinguish high from low-risk patients with lymph node-positive invasive breast cancer for an aggressive treatment. Moreover, according to the present results, LEA-135 expression appears to be associated with the tumor cells that have retained certain normal biological characteristics, leading to their lack of aggressiveness and hence a better prognosis.
Symposium Abstract (2003)
Aims: A retrospective study was undertaken to evaluate LEA.135 expression with chemotherapy or anti-hormone (tamoxifen) therapy, as well as to compare the prognostic significance of LEA.135 expression with other recognized pathologic prognostic parameters in freshly frozen tissue specimens from 367 patients with primary invasive breast cancer. Patients: Pathologic prognostic parameters included tumor size, histologic tumor type, histologic grade, as well as age of patients at initial diagnosis, treatments (chemotherapy, anti-hormone therapy) together with median follow-up of 8.8 years. Methods and Results: Among these parameters, tumor size and histologic grade were individually and significantly associated with increased probability of recurrence and short survival by univariate analysis, whereas age was significantly associated only with an increased probability of recurrence. By multivariate analysis, both tumor size and histologic grade remained statistically significant for recurrence and overall survival. With regard to treatments, patients who received chemotherapy exhibited a significantly decreased probability of recurrence (log rank p=0.003), but showed no association with increased overall survival. LEA.135 protein expression was localized by mono-clonal anti-LEA.135 antibody in the above tissue specimens by immunohistochemical (IHC) staining method. The patients with high (>50% positive cells) or low (<50% positive cells) number of LEA.135-positive cancer cells showed a significantly decreased probability of recurrence (log rank p<0.001) and an increased overall survival (log rank p=0.009) compared with those with LEA.135-negative cancer cells. Furthermore, the association remained significant by multivariate analysis for recurrence (log rank p<0.001) and overall survival (log rank p=0.007) when assessed with other pathologic prognostic parameters. Finally, no significant association was observed between treatments and LEA.135 expression with respect to recurrence or overall survival. Conclusion: The results showed LEA.135 expression is a significant and independent favorable prognostic biomarker for patients with primary invasive breast cancer, that the favorable prognosis is density-dependent LEA.135-positive cancer cells, that the loss of LEA.135 expression is associated with aggressive phenotype of cancer cells during the breast cancer progression, and that LEA.135 expression is not associated with either chemotherapy or anti-hormone (tamoxifen) therapy with respect to recurrence or overall survival. Acknowledgements: Supported by California Breast Cancer Research Program (grant no. 7WB-0023)
LEA.135 expression: identifies low-risk patients with breast ductal carcinoma in situ.
Periodical:Anticancer Research
Index Medicus: Anticancer Res
Authors: Baltayan A, Naritoku WY, Chaiwun B, Tsao-Wei DD, Groshen S, Hern RA, Gusterson BA, et al.
| Yr: 2002 | Vol: 22 | Nbr: 5 | Abs: | Pg:2933-7 |
