Jyotsna M. Bhatavdekar

DNA repair proficiency in breast cancer patients and their first-degree relatives

Defective DNA repair capacity as measured by enumerating chromatid aberrations induced in G2 phase by X‐irradiation may explain increased risk of breast cancer among relatives of patients. In the present study, chromatid damage was determined in peripheral blood lymphocytes (PBL) following in vitro exposure to 50R X‐irradiation in G2 phase from 14 breast cancer (BrCa) patients, 19 first‐degree relatives (FDR) of BrCa patients and 17 control women who had no family history of cancer for the last 3 generations. Controls, BrCa patients and their FDR had comparable frequency of gaps and breaks when cells were arrested with Colcemid (30 min) after X‐irradiation. A steep decline in chromatid damage was observed in cells of controls when arrested after 30, 90 and 120 min of X‐irradiation. BrCa patients and their FDR showed higher frequencies of lymphocytic chromatid damage as compared to controls. Chromatid damage (95 gaps + breaks per 100 cells) observed among controls at 90 min post X‐irradiation was considered as the optimal level of efficient DNA repair. Thirty‐five percent of controls, 93% of BrCa patients and 79% of FDR showed sub‐optimal DNA repair. Amongst the FDR, the likelihood of having suboptimal DNA repair was 7 times higher and the risk of developing breast cancer was 2.7 times higher as compared to controls. Moreover, in the BrCa patients, there was frequent involvement of chromosomes 1 and 2, and chromosomes of B, D and E groups, while in FDR, involvement of chromosome 2 and chromosomes of B, D and E groups was more frequent. Int. J. Cancer 73:20–24, 1997.

Coexpression of Bcl-2, c-Myc, and p53 oncoproteins as prognostic discriminants in patients with colorectal carcinoma

PURPOSE: This study was undertaken to evaluate the clinical use of Bcl-2, c-Myc, and p53 oncoproteins, either singly or in combination, as prognostic discriminants relative to recurrence and overall survival in patients with Dukes B or C colorectal carcinoma. METHODS: Analyses were made on archival pathology tissues of 48 patients with colorectal cancer. The oncoproteins were localized using commercially available monoclonal antibodies: clone 124 for Bcl-2, 9E11 for c-Myc, and DO-7 for p53. The avidin-biotin peroxidase complex method was used. Patients were followed up for a period of 2 to 36 months. RESULTS: Expression of Bcl-2 and c-Myc was cytoplasmic, whereas nuclear p53 immunoreactivity was localized in the tumor cells. Sixty percent (29/48), 65 percent (31/48), and 37 percent (18/ 48) of the tumors showed overexpression of Bcl-2, c-Myc, and p53 oncoproteins, respectively. Fifty-four percent (18/ 33) and 100 percent (9/9) of moderately and poorly differentiated tumors, respectively, were positive for Bcl-2 (P<0.01). No such correlation was noted for c-Myc and p53 oncoproteins. Univariate analysis showed that patients with Bcl-2 and c-Myc overexpression were associated with poorer overall survival than patients with Bcl-2-negative (P<0.0124) and c-Myc-negative (P<0.036) tumors. In addition, when patients were subgrouped according to Dukes stage, a statistically significant poorer overall survival was observed in Dukes C patients with Bcl-2-positive tumors (P<0.017). Furthermore, multivariate analysis revealed that coexpression of three oncoproteins was predictive of a worse prognosis than for those individuals expressing none of the oncoproteins (P<0.031) and only one positive oncoprotein (P<0.014). CONCLUSION: These findings suggest that oncoprotein coexpression possesses significant prognostic and potential therapeutic value; incorporation of molecular markers into future prospective randomized trials is advisable.

Molecular markers are predictors of recurrence and survival in patients with Dukes B and Dukes C colorectal adenocarcinoma

PURPOSE: The goal was to investigate the prognostic value of various molecular markers like CEA, Cyclin D1, Bcl-2, c-Myc, p53, p21ras, Ki-67, CD44, Factor VIII-related antigen, cytokeratin-19, adenoma antigen, and prolactin in patients with Dukes B and Dukes C colorectal adenocarcinoma. METHODS: These molecular markers were localized immunohistochemically in nonmalignant (n=36) and malignant (n=98) diseases of the colorectum. Data were analyzed statistically using the SPSS software program. The patients with colorectal cancer were followed for a period of five years or their death within that period. RESULTS: The expression of carcinoembryonic antigen, Cyclin D1, Bcl-2, CD44, cytokeratin-19 and prolactin was significantly higher in malignant diseases (P<0.05), whereas, p21ras was found to be significantly higher in nonmalignant diseases (P=0.002) as compared with their respective counterparts. Besides Dukes stage, multivariate analysis indicated a significantly reduced relapse-free survival in patients expressing CD44 and cytokeratin-19 (P<0.005). Similarly, besides Dukes stage, multivariate analysis indicated a significantly poor overall survival in patients expressing CD44, cytokeratin-19 and prolactin (P<0.01). In patients with Dukes B disease, only cytokeratin-19 and CD44 expression attained statistical significance (P<0.05), whereas in patients with Dukes C disease, CD44, p21ras and c-Myc expression attained statistical significance (P<0.018). Also, a multivariate analysis in relation to treatment given was performed using CD44 and cytokeratin-19. CONCLUSION: Besides Dukes stage, multivariate analysis of all the studied molecular markers showed that patients expressing CD44 and cytokeratin-19 had a significantly reduced relapse-free and poor overall survival. Moreover, patients expressing both these markers (CD44 and cytokeratin-19) had the lowest significant relative risk for developing recurrence than patients with both markers negative when treated with surgery followed by adjuvant chemotherapy as compared with patients treated with surgery alone. Thus, in patients with colorectal cancer, immunohistochemical localization of CD44 and cytokeratin-19 may be included as a part of routine pathologic evaluation along with conventional prognostic factors.

Prognostic Significance of Immunohistochemically Localized Biomarkers in Stage II and Stage III Breast Cancer: A Multivariate Analysis

Background: The aim was to investigate the expression of a panel of biomarkers such as prolactin (PRL), p53, Bcl-2, c-erb B2, Ki-67, CD44, and factor VIII-related antigen (FVIII-RA) in primary tumors of stage II and stage III breast cancer and its correlation with disease prognostication.Methods: The streptavidin-biotin peroxidase complex technique was used for the detection of these antigens. Cytoplasmic staining pattern was observed for PRL, Bcl-2, and Ki-67. Staining pattern for p53 was nuclear. Membranous and/or cytoplasmic staining was noted for c-erb B2 and CD44. Microvessel staining was noted for FVIII-RA.Results: Of the 93 primary breast tumors analyzed, positivity for PRL was noted in 82%, for p53 in 56%, for Bcl-2 in 73%, for c-erb B2 in 68%, and for Ki-67 and CD44 in 78% each. The microvessel count (MVC) for FVIII-RA ranged from 0.0 to 29.0, with a median of 6.0, which was used as a cutoff. MVC

Node negative breast carcinoma: Hyperprolactinemia and/or overexpression of p53 as an independent predictor of poor prognosis compared to newer and established prognosticators

6.0 was noted in 51% of breast tumors. With increasing tumor size, the higher frequency of positivity of MVC

Clinical significance of p53, nm23, and bcl‐2 in T3–4N1M0 oesophageal carcinoma: An immunohistochemical approach

6.0 (P 5 .0001), CD44 (P 5 .001), PRL (P 5 .002), and c-erb B2 (P 5 .008), and higher frequency of Bcl-2 negativity (P 5 .033), was noted. In stage III patients, a higher positivity of the following biomarkers was noted, compared with stage II patients: MVC

Spontaneous Chromosomal Instability in Breast Cancer Families

6.0 (P 5 .0004), PRL (P 5 .0002), c-erb B2 (P 5 .001), and CD44 (P 5 .005). Further, Bcl-2 positivity was significantly lower in patients with stage III disease compared with those with stage II disease (P 5 .024). In patients with nodal involvement, the frequency of c-erb B2 (P 5 .006), MVC

Ectopic production of prolactin by colorectal adenocarcinoma

6.0 (P 5 .011), and PRL (P 5 .032) was higher than in those without nodal involvement. Moreover, in these patients, with the increase in the number of involved lymph nodes, there was a significant increase in frequency of CD441 (P 5 .0004) and PRL1 (P 5 .013) tumors. Abnormal expression of one biomarker was seen in 7% of tumors, of two biomarkers in 4%, of three in 15%, of four in 19%, of five in 28%, of six in 20%, and of all seven biomarkers in 7% of tumors. The frequency of an increasing number of biomarkers coexpressed was higher in stage III patients compared with stage II patients (P 5 .00003). In the total number of patients (n 5 93), tumors with Bcl-2 negativity (P 5 .00001), MVC

Overexpression of CD44: A useful independent predictor of prognosis in patients with colorectal carcinomas

6.0 (P 5 .001), PRL positivity (P 5 .02), and CD44 positivity (P 5 .034) had a significantly poorer overall survival (OS) compared with their respective counterparts. In stage II patients (n 5 40), only p53 expression was significantly associated with reduced relapse-free survival (P 5 .009) and OS (P 5 .040). In multivariate analysis, p53 expression was an independent prognostic factor that influenced relapse-free survival (P 5 .034) of stage II breast cancer patients. However, it failed to attain statistical significance for OS. In stage III patients (n 5 53), tumors with Bcl-2 negativity (P 5 .0005) and MVC

Tumor markers in patients with advanced breast cancer as prognosticators : a preliminary study

6.0 (P 5 .039) had a significantly poorer OS compared with their respective counterparts. In multivariate analysis of stage III patients, Bcl-2 was the only independent prognostic factor (P 5 .001) for predicting OS. There was a significant association between coexpression of the biomarkers and OS (P 5 .001). The OS rates decreased with the increase in number of abnormally expressed biomarkers.Conclusions: p53 expression in primary tumors was an independent prognostic factor that influenced relapse-free survival in patients with stage II disease. In stage III patients, lack of Bcl-2 expression was independently associated with a poor prognosis and, thus, may be an indicator of aggressive phenotype.