Predictive value of c-erbB-2, p53, cathepsin-D and histology of the primary tumour in metastatic breast cancer

Niskanen, Eero; Blomqvist, Carl; Franssila, Kaarle; Hietanen, Päivi; Wasenius, Veli-Matti

doi:10.1038/bjc.1997.484

Cited by 70 publications

(29 citation statements)

References 37 publications

(40 reference statements)

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“…16,17 The value of these prognostic markers in women after they develop their first recurrence is uncertain. In one study that involved 127 patients with metastatic disease who were treated with chemotherapy, histologic grade, c-erbB-2, p53, and cathepsin D were not significant prognostic markers of outcome or survival, 18 in agreement with our own results showing that c-erbB-2 and p53 are not independent predictors of outcome at the time of first disease recurrence. In addition, future studies should address the utility of newer techniques, in particular, gene amplification of c-erbB-2 by fluorescent in situ hybridization, as prognostic factors in the metastatic setting.…”

Section: Discussionsupporting

confidence: 84%

Survival of patients with metastatic breast carcinoma

Chang‐Claude

Clark

Allred

et al. 2003

Cancer

229

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BACKGROUNDWomen with metastatic breast carcinoma have a highly variable clinical course and outcome. Intrinsic genetic heterogeneity of the primary breast tumor may play a role in this variability and may explain it in part. Therefore, the authors tested the hypothesis that the characteristics of primary breast tumors are important determinants of prognosis and survival in patients with metastatic breast carcinoma.METHODSThe prognostic significance of the biology of the primary tumor for outcome in patients with metastatic breast disease was assessed in 346 patients with lymph node positive breast carcinoma who developed distant, recurrent disease. Traditional prognostic indicators (age, tumor size, number of involved lymph nodes, sites of recurrence, disease free interval [DFI], adjuvant treatments, estrogen receptor [ER] expression, progesterone receptor [PgR] expression, S‐phase fraction [SPF], and DNA ploidy), together with three newer biologic markers (c‐erbB‐2, p53, and bcl‐2) were assessed. Sites of recurrence were defined as nonvisceral (bone and locoregional lymph nodes) or visceral (lung, liver, brain, and other organs).RESULTSThe median duration of survival was 17.8 months (95% confidence interval, 15.2–21.5 months). Univariate analysis showed that age > 50 years, visceral disease, and shorter DFI were associated significantly with poor outcome (P < 0.05). In addition, the molecular phenotype of the primary breast tumor was significant, with primary tumors that showed ER negativity and PgR negativity, high SPF, aneuploidy, accumulation of p53 protein, and lower bcl‐2 expression, together with c‐erbB‐2 overexpression, all associated with a poorer clinical outcome (P < 0.05). In a multivariate analysis, older age, visceral disease, shorter DFI, PgR negativity, high SPF, and lower bcl‐2 expression were significant predictors of worse survival (P < 0.05).CONCLUSIONSIn addition to traditional risk factors, bcl‐2 negativity was associated significantly with a worse clinical outcome. Biologic features of primary tumors were correlated independently with outcome after first recurrence in patients with metastatic breast carcinoma and may be used as indicators of prognosis in the metastatic setting. Cancer 2003;97:545–53. © 2003 American Cancer Society.DOI 10.1002/cncr.11083

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Section: Discussionsupporting

confidence: 84%

Survival of patients with metastatic breast carcinoma

Chang‐Claude

Clark

Allred

et al. 2003

Cancer

229

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“…Our results also reject HER2 status as a predictive marker of response to epirubicin treatment. Studies comparable to ours -comprising a total of 429 patients, in whom the response of the primary tumour to treatment with anthracyclines was measured -have reached the same conclusions (MacGrogan et al, 1996;Niskanen et al, 1997;Vargas-Roig et al, 1999;VincentSalomon et al, 2000). In contrast, Colleoni et al (1999) report that, in 40 patients, HER2-positive tumours (n ¼ 5) had a significantly increased response rate to neoadjuvant treatment with doxorubicin.…”

Section: Discussionsupporting

confidence: 80%

Breast cancer response to neoadjuvant chemotherapy: predictive markers and relation with outcome

et al. 2003

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The aim of this study was to provide a better insight into breast cancer response to chemotherapy. Chemotherapy improves outcome in breast cancer patients. The effect of cytotoxic treatment cannot be predicted for individual patients. Therefore, the identification of tumour characteristics associated with tumour response and outcome is of great clinical interest. We studied 97 patients, who received anthracycline-based neoadjuvant chemotherapy. Tumour samples were taken prior to and after chemotherapy. We quantified the response to chemotherapy clinically and pathologically and determined histological and molecular tumour characteristics. We assessed changes in the expression of Bcl-2, ER, P53 HER2 and Ki-67. Association with response and outcome was tested for all parameters. The experimental results showed 15 clinical (17%) and three (3%) pathological complete remissions. There were 18 (20%) clinical vs 29 (33%) pathological nonresponders. The expression of most markers was similar before and after chemotherapy. Only Ki-67 was significantly decreased after chemotherapy. Factors correlated with response were: large tumour size, ER negativity, high Ki-67 count and positive P53 status. Tumour response and marker expression did not predict disease-free or overall survival. In conclusion, clinical and pathological response assessments are poorly associated. Proliferation decreases significantly after chemotherapy. ER negativity and a high proliferation index are associated with better response. HER2 status does not predict response, and outcome is not related to tumour response.

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“…It also appears that Topo IIa expression is often correlated to Her-2/neu overexpression in breast carcinoma. This complex relationship between the two genes may explain the altered sensitivity to anthracyclines of Her-2/neu-amplified breast carcinomas (Bitran et al, 1996;MacGrogan et al, 1996a;Niskanen et al, 1997;Clahsen et al, 1998;Jarvinen et al, 1998;Paik et al, 1998;Thor et al, 1998;Vincent-Salomon et al, 2000). Most previous studies regarding the effect of Topo IIa poisons in relation to the cellular level of Topo IIa expression were either performed in vitro or on breast tumour fragments without analysis of the direct in vivo effect (Gudkov et al, 1993;Asano et al, 1996a, b;Vassetzky et al, 1996;Withoff et al, 1996a, b;Zhou et al, 1999;Stacey et al, 2000).…”

mentioning

confidence: 99%

DNA topoisomerase IIα expression and the response to primary chemotherapy in breast cancer

MacGrogan

Rudolph²,

Mascarel

et al. 2003

Br J Cancer

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The a isoform of Topoisomerase IIa (Topo IIa) is a proliferation marker as well as a target for several chemotherapeutic agents such as anthracyclines. In vitro studies have demonstrated the relationship between the Topo IIa expression level and chemosensitivity of target cancer cells. To verify this effect in vivo, we selected 125 patients presenting with T 2 43 cm and T 3 N 0 -1 M 0 breast tumours who were treated by six cycles of primary chemotherapy, including epirubicin before any surgery. Therapy response was assessed by clinical and X-ray mammogram measurements of tumour shrinkage. The pretherapeutic core biopsies were immunostained with a monoclonal antibody (Ki-S7) against Topo IIa. Ki-S7 positivity ranged from 0 to 50% (median, 15%). A high percentage of Ki-S7-positive cells (415%) was associated with tumour regression under chemotherapy (OR ¼ 2.88, CI: 1.3 -6.4, P ¼ 0.004). Ki-S7 further emerged as an independent predictor of tumour regression (OR ¼ 3.34, CI: 1.41 -7.93, P ¼ 0.006), together with tumour size of less than 40 mm (OR ¼ 3.82, CI: 1.58 -9.25, P ¼ 0.002) and negative oestrogen receptor (ER) status (OR ¼ 3.35, CI: 1.43 -7.86, P ¼ 0.005), in a multivariate analysis including tumour size, SBR grade, ER and PR status, Ki-67, p53 and Her-2/neu. Our clinical results confirm in vitro data on the relationship between Topo IIa expression and tumour chemosensitivity and thus may have important practical implications.

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Predictive value of c-erbB-2, p53, cathepsin-D and histology of the primary tumour in metastatic breast cancer

Cited by 70 publications

References 37 publications

Survival of patients with metastatic breast carcinoma

Survival of patients with metastatic breast carcinoma

Breast cancer response to neoadjuvant chemotherapy: predictive markers and relation with outcome

DNA topoisomerase IIα expression and the response to primary chemotherapy in breast cancer

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