Tumor proliferative activity and response to first-line chemotherapy in advanced breast carcinoma

Abstract

The relationship between tumor proliferative activity and response to first-line chemotherapy and survival was investigated in 76 advanced breast cancer patients. Proliferative activity was determined by means of Ki-67 immunohistologic staining on primary tumors (55 patients) or at the relapse site (21 patients), and was classified as low ( < or = 25% of stained cells) or high ( > 25% of stained cells). The usual WHO response criteria were used. The median duration of follow-up was 18 months (range 3-58). Forty-seven patients (62%) had tumors with low, and 29 (38%) had tumors with a high rate of proliferative activity. The two groups were well balanced in terms of important variables such as disease-free survival, performance status, age, menopausal status, and the type of first-line chemotherapy (anthracycline-based regimens versus cyclophosphamide-methotrexate-5-fluorouracil). The estrogen receptor (ER) content, measured by means of immunohistochemical assay, was markedly different in the two groups, with 27/47 tumors with low proliferative activity (57%) and 6/29 with high-proliferative activity (21%) being ER positive ( > or = 45% of stained cells) (p = 0.003). Moreover, a significant difference in the metastatic pattern was also evident, with a higher incidence of bone and a lower incidence of soft tissue metastases in the group of patients with tumors with low proliferative activity (p = 0.004). Overall, 10/47 responses (21%: PR = 7, and CR = 3) were observed in the group with a low rate of proliferative activity, versus 14/29 (48%: PR = 9, and CR = 5) in the group with highly proliferative tumors, the difference being statistically significant (p = 0.03). When a multivariate analysis was performed, the only factor that retained independent prognostic significance was the predominant site of disease, particularly soft tissues (p = 0.003). Despite the difference in response rate, when survival analysis was performed according to the Kaplan-Meier method, no significant difference was observed in the two groups, but when the analysis was limited to responsive patients, the median survival observed in those with a low and those with a high rate of proliferation was 35 and 19 months respectively (p = 0.02). The same results were obtained when multivariate survival analysis was carried out using Cox's regression model. These data suggest that there is a link between tumor proliferative activity and response to chemotherapy in advanced breast cancer, and may indicate the need to use more intensive treatments in selected patients with highly proliferative tumors.

Early changes in apoptosis and proliferation following primary chemotherapy for breast cancer

“…Pretreatment levels of proliferation positively correlated with clinical response. This is consistent with other studies, either using the MIB1 antibody or S-phase fraction (Bonetti et al, 1996;Chevillard et al, 1996;MacGrogan et al, 1996). Ki67 is an antigen that binds to a protein expresssed in late G1-, S-, G2-, and M-phase of the cell cycle, and although most cytotoxic drugs have maximum effect in S-phase, some also act in other phases of the cell cycle, and therefore this finding would be compatable with the biology (Boyer and Tannock, 1998).…”

Cytotoxic and antiproliferative activity of the single agent epirubicin versus epirubicin plus tamoxifen as primary chemotherapy in human breast cancer: a single-institution phase III trial

“…The distribution of clinical and pathological response was more frequently observed in patients with ERprimary breast cancer as well as in those with elevated Ki67 expression at baseline. This is a subgroup analysis and by definition underpowered; these data anyway confirm the results of a number of published studies showing that steroid receptor negativity (Bonadonna et al 1990, MacGrogan et al 1996, Colleoni et al 1999 and elevated proliferation activity (Bonetti et al 1996, Amadori et al 1997, Daidone et al 1999 are both predictors for chemo-sensitivity. The relationship between proliferation activity and chemotherapy response is expected since the cellular growth rate is traditionally thought to be important in determining the sensitivity of human cancer to chemotherapy.…”

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

“…Both primary endocrine (Clarke et al, 1993) and cytotoxic treatments (Daidone et al, 1991;Gardin et al, 1994) inhibit tumour growth. 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.…”