Anders G. Fallenius

Prognostic significance of DNA measurements in 409 consecutive breast cancer patients

Four hundred nine consecutive breast cancer patients were studied retrospectively. Microspectrophotometric DNA measurements were performed using archival, fine‐needle slide preparations upon which the primary diagnoses had been based 8 to 13 years earlier. The DNA distribution patterns of the tumor cell populations were analyzed according to various criteria and the cytochemical data were correlated to the clinical course, defined as distant recurrence‐free survival. The results demonstrated a strong relationship between nuclear DNA content of the breast cancer cells and prognosis. Tumors exhibiting DNA values within the limits of normal tissues (DNA euploidy) were found to be correlated with a favorable prognosis. In contrast, tumors with increased and scattered DNA values (DNA aneuploidy) were found indicative of poor prognosis. This was found to be the case regardless whether the percentage of cells above 2.5c or 5c, DNA index/modal value, or the histogram typing according to Auer et al were utilized to discriminate low‐grade from high‐grade malignant cases. All of these DNA variables were also shown to be significantly correlated. With the aid of the Cox regression method, the additional prognostic value of any given variable was tested against the others. The statistical analyses showed that the histogram typing gives significant prognostic information in addition to that provided by any other variable. In conclusion, the current study demonstrates that tumor nuclear DNA content is a strong indicator of prognosis in patients suffering from invasive breast adenocarcinoma. However, the results also show that simple determination of the stemline position is not the optimal DNA measure of intrinsic tumor malignancy potential. The fraction of cells scattered outside the modal peaks of the histograms are of utmost importance for adequate cytochemical malignancy grading in breast carcinomas.

Predictive value of nuclear DNA content in breast cancer in relation to clinical and morphologic factors. A retrospective study of 227 consecutive cases

The predictive value of nuclear DNA content in breast cancer in relation to clinical and morphologic factors was studied in 227 consecutive cases of invasive breast adenocarcinomas with follow‐up periods of 8 to 13 years. The results show that, with the use of Cox multivariate analysis, nuclear DNA content provided significant prognostic information additional to that given by all other clinical and histomorphologic variables taken together. This fact indicates that the DNA content of breast cancer cells reflects biological properties, associated with the malignant behavior of the tumor, other than those determining the stage of the disease. Nuclear DNA content was strongly correlated to histopathologic grading of the ductal carcinomas, with poorly differentiated tumors more likely to be aneuploid. On the other hand, no clear correlation was found to exist between nuclear DNA content and axillary node status, indicating that these two factors are independent prognostic parameters. It is noteworthy that DNA content provided additional prognostic information within both the node‐negative and node‐positive patient groups. In summary, the results shown here indicate that nuclear DNA content, as an objective biological marker of tumor aggressiveness, can significantly improve our prognostic capabilities within the currently designated stages.

Prognostic value of nuclear DNA content in breast cancer in relation to tumor size, nodal status, and estrogen receptor content

SummaryThe prognostic value of nuclear DNA distribution pattern in relation to tumor size, axillary lymph node status, and estrogen receptor (ER) content was studied in 464 patients with primary, operable mammary adenocarcinoma. The median follow-up time was 3 1/2 years. Slide cytophotometric DNA analysis was performed on morphologically identified Feulgen-stained tumor cells. The tumors were classified into four subgroups according to their DNA histogram type. DNA content was significantly related to tumor size and ER level but not to nodal status. When all variables were stimultaneously introduced into Coxs proportional hazards model, tumor size, nodal status, and DNA profile remained as significant predictors of recurrence. Restricting the analysis to node-negative patients, both DNA profile and tumor size showed a significant prognostic value. DNA did not contribute significant prognostic information in node-positive patients. However, the trends in recurrence-free survival were similar to those in the node-negative subgroup: patients with aneuploid tumors tended to fare worse than those with euploid carcinomas.

Cytochemical changes in the nucleus during tumour development

SummaryThe general background to tumour analytic work using quantitative optical cytochemical methods is first presented. An instrument complex, constructed especially for multiparameter work in cytopathological material has been developed. Nuclear changes have been followed in cell populations during their development through different grades of atypia to cancer and conspicuous cytochemical changes were observed.In a comprehensive series of clinically verified mammary carcinomas, a large percentage of cases was found in which the DNA values were within the normal range, while the others showed pronounced aneuploidy. A clear correlation was found between DNA profile-type and patient survival, the latter of which reflects the degree of malignancy in the individual case.The shift from resting state (G0) to growth activated G1-stage is initiated by a large increase of the nuclear proteins. Mammary tumours of a high malignancy grade, as judged by their DNA profile type, showed an especially great accumulation of nuclear protein and thus a high degree of activation.DNA-profile measurements, preferably combined with determinations of nuclear proteins can thus be used for judging malignancy grades in mammary tumours, which is also of considerable clinical interest. An as yet limited observational material also indicates similar situations in some other types of tumour.

Prognostic significance of nuclear DNA analysis in histological sections in mammary carcinoma.

The nuclear DNA content in tumor cells from invasive ductal breast carcinomas was analyzed in 26 patients who survived more than 10 years and in 23 patients who died within 2 years after operation. The DNA content of individual tumor cells was measured in sections from the originally paraffin-embedded specimens. In short-term survivors, a large proportion of cells with very high DNA values was found in all tumors except one. Only two patients of the long-term survivors had tumors that exhibited such high DNA values. Prognostic information obtained by DNA analysis compared with histologic malignancy grading showed that the specificity using DNA analysis was distinctly higher. The data thus suggest that analysis of DNA content of tumor cells in breast adenocarcinomas can be a useful supplement to histologic malignancy grading to obtain prognostic guidance in individual patients.

Nuclear DNA content, histological grade, and clinical course in patients with nonpalpable mammographically detected breast adenocarcinomas.

Sixty-five consecutive female patients, age 35–83, with non- palpable breast carcinomas detected by mammography were classified with both morphological and cytochemical malignancy grading. Cytochemically, the tumors were divided into euploid and aneuploid types indicating low and high malignancy potential, respectively. The mean follow-up time in the euploid group was 6.7 years and in the aneuploid group 8.0 years. No significant difference in mortality was observed in the two groups comprising 65% euploid and 35% aneuploid tumors. Our results here indicate that an early detection of breast cancer at a clinically occult and nonpalpable level leads to better prognosis even in patients with aneuploid tumors whose tumors otherwise are considered to be highly malignant.

Nuclear DNA content in mammary carcinomas in women aged 35 or younger

Nuclear DNA content was studied in cytologic preparations obtained from 50 patients aged 35 or less with primary mammary carcinoma. As many as 90% of the tumors were aneuploid, i.e., exhibited DNA profile types III and IV. The cytologic diagnosis was confirmed by histologic examination in 46 patients. The majority of these tumors, 83%, were invasive ductal carcinomas, while medullary carcinomas constituted 13% of the surgical material. As judged from their DNA profiles, most mammary carcinomas in this age group would be tumors of high malignancy potential. This does not seem, however, to influence the prognosis of young women with breast cancer as much as would be expected, possibly because of a better-functioning immune surveillance system in this age group.