Accumulation of p53 Protein as a Possible Predictor of Response to Adjuvant Combination Chemotherapy With Cyclophosphamide, Methotrexate, Fluorouracil, and Prednisone for Breast Cancer

Elledge, Richard M.; Gray, Robert J.; Mansour, Edward G.; Yu, Yang; Clark, Gary M.; Ravdin, P.; Osborne, C. Kent; Gilchrist, Kennedy W.; Davidson, Nancy E.; Robert, Ngangom; Tormey, Douglass C.; Allred, D. Craig

doi:10.1093/jnci/87.16.1254

Cited by 87 publications

(42 citation statements)

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“…Unlike the in vitro study, a single in vivo study supports increased chemosensitivity in node-positive breast cancers (Allred et al, 1993). More recently, investigators have failed to detect statistically significant evidence that p53 status, as assessed by immunohistochemistry, could predict clinical response to breast cancer treatment (Elledge et al, 1995;Makris et al, 1995;Mathieu et al, 1995). Our findings are in agreement with those reports.…”

Section: Discussionmentioning

confidence: 99%

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

Niskanen

Blomqvist²,

Franssila³

et al. 1997

Br J Cancer

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Summary The value of various prognostic factors in breast cancer patients has been determined in a number of studies. Few reports have been published on the dependence of treatment outcome on histological and immunohistochemical characteristics in the primary tumour in patients with metastatic disease. We studied the incidence and prognostic value of histological and molecular abnormalities in the primary tumour of patients who had developed metastatic breast cancer. Eligible patients received a fluorouracil, epirubicin and cyclophosphamide (FEC) regimen either once a week or once every 4 weeks. Adequate specimens for various analyses were available from 127 patients. Median follow-up time of the patients ranged from 15 to 101 months. In this study, the histological grade of the malignancy best predicted response to chemotherapy (P < 0.0005). Most of the responses were observed in patients with grade 1 tumours; in this group, time to progression was delayed. C-erb B-2 gene amplification and oncoprotein expression had no predictive value. Neither p53 nor cathepsin-D predicted treatment outcome after chemotherapy. None of the factors had an effect on overall survival. Among breast cancer patients who received anthracycline-containing chemotherapy, response to treatment correlated with histological grade. In patients with histological grade 1 breast cancer, the time to progression was longest. However, overall survival was not affected by histological grade nor the other parameters tested. In addition to histological grade, other prognostic factors that are not included in this study need to be identified to determine which patients with metastatic breast cancer would benefit from cytotoxic treatment.

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Section: Discussionmentioning

confidence: 99%

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

Niskanen

Blomqvist²,

Franssila³

et al. 1997

Br J Cancer

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“…The effect of several chemotherapeutic drugs may be mediated through DNA damage and induction of apoptosis (Gewirtz, 2000), and therefore alterations to TP53 and hence p53 protein function could result in relative resistance to these agents. Studies assessing either immunohistochemically detectable p53 and/or TP53 mutations in breast cancers and response to chemotherapy differ in their findings as to their value as predictors (Bergh et al, 1995;Elledge et al, 1995;Stal et al, 1995;Aas et al, 1996;Thor et al, 1998;Berns et al, 2000;Rahko et al, 2003). However, as apoptosis plays a major role in treatment response, analysis of other apoptotic regulatory gene products, as well as p53, may give additional information.…”

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confidence: 99%

Survivin is an independent predictor of short-term survival in poor prognostic breast cancer patients

2007

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Established clinico -pathological factors can place patients with breast cancer into good and poor prognostic categories, but even within these groups behaviour and response to treatment can differ. This study examined the value of cell cycle and apoptotic regulatory proteins in predicting behaviour in a poor prognostic group. A total of 165 patients, all of whom had died of breast cancer with duration of survival 12 -127 months, median 38 months, were examined using immunohistochemistry for proliferation, apoptosis, p53, phosphorylated p53, p21, checkpoint kinase 2 (Chk2), bcl-2, bax, survivin and XIAP. All had received chemotherapy and/or hormonal therapy and were predominantly T2, node positive, grade III with only half oestrogen-receptor (ER) positive. High proliferation, phosphorylated p53, Chk2 and survivin expression correlated with grade III and lack of ER, whereas low proliferation, p21 and bcl-2 related to better grade and presence of ER. On univariate analysis grade, proliferation, phosphorylated p53, bcl-2, ER and survivin related to duration of survival. In multivariate analysis, grade (P ¼ 0.001) and survivin (P ¼ 0.005) were independent prognostic factors, grade III and presence of survivin relating to shorter survival. The latter was particularly for those patients receiving neoadjuvant therapy and adjuvant chemo-and hormonal therapy. The presence of the inhibitor of apoptosis protein survivin is a highly significant independent predictor of shorter duration of survival of patients with poor prognostic features, and merits investigation as a marker in other prognostic groups.

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“…In order to follow and further expand these early experiments, and put them into perspective with recent insights into the regulation of proliferation inhibition and generation of apoptosis on the molecular level, we have investigated the induction of these phenomena by a series of retinoids (9-cis-retinoic acid (9cRA), 13-cis-retinoic acid (13cRA), all-trans retinoic acid (tRA)) and IFN-α in various human STS cell lines including HTB-82 (rhabdomyosarcoma), HTB-91 (fibrosarcoma), HTB-92 (liposarcoma), HTB-93 (synovial sarcoma) and HTB-94 (chondrosarcoma) in vitro and put them into context with p53 genotype as well as p53 protein expression. This was of particular interest, as growth arrest and induction of apoptosis resulting from appropiate chemo-and/or radiotherapeutic measures have been demonstrated to be dependent upon the intact function of the p53 gene in various models (Bergh et al, 1995;Elledge et al, 1995;Sarkis et al, 1995). Thus, patients with testicular tumours with regular p53 function have been shown to respond particularly well to chemotherapy (Lutzker and Levine, 1996), whereas patients with malignancies exhibiting high frequency of p53 mutations are known to present often with resistance to chemotherapeutic agents (Aas et al, 1996).…”

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confidence: 99%

Inhibition of proliferation and induction of apoptosis in soft tissue sarcoma cells by interferon-α and retinoids

Brodowicz¹,

Wiltschke²,

Kandioler-Eckersberger³

et al. 1999

Br J Cancer

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Summary Uncontrolled proliferation and a defect of apoptosis constitute crucial elements in the development and progression of tumours. Among many other biological response modifiers known to influence these mechanisms, the efficacy of retinoids and interferons in the treatment of various malignant entities is currently matter of discussion. In the present study, we have investigated the effects of 9-cis-retinoic acid (9cRA), 13-cis-retinoic acid (13cRA), all-trans-retinoic acid (tRA) and interferon-α on proliferation and apoptosis of human soft tissue sarcoma (STS) cell lines HTB-82 (rhabdomyosarcoma), HTB-91 (fibrosarcoma), HTB-92 (liposarcoma), HTB-93 (synovial sarcoma) and HTB-94 (chondrosarcoma) in relation to p53 genotype as well as p53 expression. HTB-91, HTB-92 and HTB-94 STS cells exhibited mutant p53, whereas wild-type p53 was found in HTB-93 STS cells, and a normal p53 status in HTB-82 STS cells, carrying a silent point mutation only. Interferon-α, irrespective of p53 status, inhibited the proliferation of all five cell lines dose-and time-dependently. Similarly, 9cRA, 13cRA and tRA decreased the proliferation of HTB-82 and HTB-93 STS cells, whereas the proliferation of p53-mutated HTB-91, HTB-92 and HTB-94 STS cells remained unchanged. Furthermore, only 9cRA and tRA were capable of inducing apoptosis in HTB-82 and HTB-93 STS cells, whereas HTB-91, HTB-92 and HTB-94 STS cells did not undergo apoptosis under the influence of 9cRA or tRA. Retinoic acid receptor (RAR)-α and RAR-β mRNA were not detectable by Northern blot analysis in the five STS cell lines, whereas mRNA for the universal retinoic acid receptor, RAR-γ, was expressed in all STS cell lines indicating that retinoid resistance was not associated with a lack of RAR expression. Apoptosis was not induced by interferon-α or 13cRA in any of the five STS cell lines tested. Our results indicate that within the panel of tested STS cell lines, inhibition of proliferation and induction of apoptosis result from different mechanisms which differ in their dependence upon the presence of intact p53.

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Accumulation of p53 Protein as a Possible Predictor of Response to Adjuvant Combination Chemotherapy With Cyclophosphamide, Methotrexate, Fluorouracil, and Prednisone for Breast Cancer

Cited by 87 publications

References 0 publications

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

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

Survivin is an independent predictor of short-term survival in poor prognostic breast cancer patients

Inhibition of proliferation and induction of apoptosis in soft tissue sarcoma cells by interferon-α and retinoids

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