DNA flow cytometric analysis of primary operable breast cancer. Relation of ploidy and S-Phase fraction to outcome of patients in NSABP B-04

Abstract

Between 1971 and 1974, 1665 women with primary operable breast cancer were randomized into a National Surgical Adjuvant Breast and Bowel Project (NSABP) trial (B‐04) conducted to evaluate the effectiveness of several different regimens of surgical and radiation therapy. No systemic therapy was given. Cells from archival paraffin‐embedded tumor tissue taken from 398 patients were analyzed for ploidy and S‐phase fraction (SPF) using flow cytometry. Characteristics and outcome of patients with satisfactory DNA histograms were comparable to those from whom no satisfactory cytometric studies were available. In patients with diploid tumors (43%), the mean SPF was 3.4% ± 2.3%; in the aneuploid population (57%), the SPF was 7.9% ± 6.3%. Only 29.9% ± 17.3% of cells in aneuploid tumors were aneuploid. Diploid tumors were more likely than aneuploid tumors to be of good nuclear grade (P less than 0.001) and smaller size (P equals 0.03). More tumors with high SPF were of poor nuclear grade than were tumors with low SPF (P equals 0.002). No significant difference in 10‐year disease‐free survival (P equals 0.3) or survival (P equals 0.1) was found between women with diploid or aneuploid tumors. Patients with low SPF tumors had a 13% better disease‐free survival (P equals 0.006) than those with a high SPF and a 14% better survival (P equals 0.007) at 10 years than patients with high SPF tumors. After adjustment for clinical tumor size, the difference in both disease‐free survival and survival between patients with high and low SPF tumors was only 10% (P equals 0.04 and 0.08, respectively). Although SPF was found to be of independent prognostic significance for disease‐free survival and marginal significance for survival, it did not detect patients with such a good prognosis as to preclude their receiving chemotherapy. The overall survival of patients with low SPF was only 53% at 10 years. These findings and those of others indicate that additional studies are necessary before tumor ploidy and SPF can be used to select patients who should or should not receive systemic therapy.

Lack of prognostic significance of DNA ploidy and S phase fraction in breast cancer

“…Seven large series (> 300 patients) with long follow up () 5 years median) have used multivariate analysis to assess the independence of observed effects, but with variable results (Cornelisse et al, 1987;Hedley et al, 1987;Kallionemi et al, 1988;Clark et al, 1989;Toikkanen et al, 1989;Stal et al, 1989;Fisher et al, 1991). We have studied these variables in a large cohort of homogeneously treated patients with breast cancer who have been followed up for a median period of over 10 years, paying particular attention to technical factors which may be responsible for the varying results obtained by previous workers, and report here upon this experience.…”

“…Ploidy and SPF could be combined to create three prognostic groups which were independent predictors of survival, although once again this relied upon cutoffs determined by examination of the data. Finally, Fisher et al (1991) have reported upon results from the NSABP-04 trial in 398 patients. This represented only 54% of available tumour blocks, the remainder failing to provide adequate histograms.…”

Evaluation of ER, PgR, HER-2 and Ki-67 as predictors of response to neoadjuvant anthracycline chemotherapy for operable breast cancer

“…Tumour cell proliferation has been shown to be a prognostic marker in some reports (Remvikos et al, 1989;Bonetti et al, 1996;Chevillard et al, 1996), but data on its predictive value are conflicting. S-phase fraction, proliferating cell nuclear antigen and thymidine labelling index predict overall survival (Clayton, 1991;Fisher et al, 1991;Merkel et al, 1993) and response (Collecchi et al, 1996;Bottini et al, 1998;Nishimura et al, 2002), but not diseasefree survival (Bianchi et al, 1993;Pisansky et al, 1993;Tahan et al, 1993) in patients treated with primary surgery or chemotherapy.…”

Peculiarities of hemoglobin interaction with serum proteins of mice with Ehrlich carcinoma

“…However, the attempts to isolate and identify specific protein failed [1,3]. It can be hypothesized that not individual protein, but a complex of proteins exhibits biological activity.…”