P53 as a predictor for treatment strategy or disease response

Endocrine therapy, systemic chemotherapy and breast radiotherapy have been shown to significantly reduce disease relapse and prolong survival in patients with breast cancer. However, it has not been possible to confidently identify the patients in whom treatment is of benefit or those for whom such treatments ought to be avoided.

The function of a number of anticancer agents is directed towards inducing cell death or apoptosis. Loss of normal p53 function can potentially result in relative resistance of breast cancers to chemotherapeutic agents, due to loss of the apoptotic properties of p53. This has been of particular significance in the use of preoperative, neoadjuvant chemotherapy whereby poorer outcome has been observed in those tumors with higher p53 accumulation rates, as demonstrated by immunohistochem-istry,53 while patients with tumors containing wild-type p53 show a more dramatic positive response rate to the preoperative chemother-apy.54 The importance of p53 in response to chemotherapy may depend both on the chemotherapy agent(s) themselves and on the tumor subtype, since mutant p53 containing inflammatory breast cancer55 or the basal histological subtype56 may be more responsive to chemotherapy.

Several studies have suggested that p53 status is an important determinant of tumor responsiveness to antineoplastic agents in breast cancer, including Cyclophosphamide, Methotrexate and 5-fluorouracil (CMF) chemotherapy57 and anthra-cycline-based chemotherapy where specific mutations in p53 have been associated with poor response to primary systemic therapy,58,59 response to neoadjuvant therapy,60 and overall survival.61 However, a differential effect of anthra-cyclines and taxanes on breast cancers based on the p53 status of the tumor underpins the EORTC 10094 trial testing the hypothesis that taxanes may have a greater efficacy against p53 mutant breast cancer than anthracyclines.59,62

Although there have been suggestions that p53 immunohistochemistry may be a poor prognostic factor for some forms of chemotherapy but of less apparent value for others, in general, most studies suggest p53 immuno-histochemistry does not predict drug sensitivity in breast cancer.

For systemic endocrine therapy, the pro72 polymorphism appears to be associated with improved disease-free survival in patients with an ER-positive cancer given adjuvant tamoxifen.63 Node-positive patients with primary breast cancer positive for p53 mutation have a poorer response rate to adjuvant tamoxifen treatment,64 further supported by the reduced response to tamoxifen associated with p53 protein accumulation in cytosolic extracts.65 p53 protein accumulation in breast cancer is also associated with time to endocrine fail-ure,66 poor response to endocrine therapy in the metastatic setting,67 and reduced postrelapse survival.67

The relationship between radiotherapy and p53 in breast cancer also appears to be complex. There are series which have shown that tumors with wild-type p53 have a better response to radiotherapy, than for chemother-apy,54 but others suggest that tumors harboring p53 mutations should be more susceptible to postoperative radiotherapy than those with normal p53.68 One explanation of this could be that having been exposed to radiation damage, cells with mutant p53 cannot activate p53-dependent repair mechanisms.69 However, more recent microarray expression studies suggest that p53 mutation does influence gene expression patterns following radiotherapy.70

The value of p53 as an independent marker for treatment response and prognosis has also been related to the clinical stage at the time of presentation. p53 nuclear accumulation in early breast cancer (stage I), may be of significant prognostic value,71,72 whereas in locally advanced breast cancer (stage IIIA/IIIB), p53 may not have the same independent prognostic significance.73

p53 mutation alone may not be sufficient to predict response to systemic therapy in clinical settings, since both in vitro and in vivo studies74 have suggested that p53 function may be dissociated from drug resistance and other cellular factors are likely to play an important role. Whether p53 is a significant independent predictor for response to treatment remains unclear and is the subject of clinical trials; currently, there are insufficient data to support the routine assessment of p53 status as a marker of response to treatment in breast cancer. p53 has been shown to affect apoptosis by regulating the expression of Bcl-2 and Bax, which inhibit and promote apoptosis, respectively.16,75 The reduced Bcl-2 and increased Bax expression, and hence increased cell death observed in a p53-dependent manner following treatment with systemic chemotherapy, suggest that analysis of the Bcl-2:Bax ratio as well as p53 status offers more practical information on tumor response following systemic chemotherapy.

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