Conceived and designed the experiments: M-BC Y-QZ P-HL. Performed the experiments: M-BC J-YX L-QW C-YL. Analyzed the data: M-BC Y-QZ P-HL. Contributed reagents/materials/analysis tools: Y-QZ J-YX L-QW. Wrote the paper: M-BC Y-Q Z. Helped edit the manuscript C-YL Z-YJ.
The authors have declared that no competing interests exist.
Numerous studies have yielded inconclusive results regarding the relationship between tumor suppressor protein TP53 overexpression and/or
A total of 26 previously published eligible studies including 3,476 cases were identified and included in this meta-analysis. TP53 status (over expression of TP53 protein and/or
The results of the present meta-analysis suggest that TP53 status is a predictive factor for response in breast cancer patients undergoing neoadjuvant chemotherapy. Further larger and well-designed prospective studies are required to evaluate the predictive role of TP53 status in clinical practice.
Neoadjuvant chemotherapy, also known as primary or induction chemotherapy, refers to chemotherapy administered before locoregional treatment, such as surgery and/or irradiation. Neoadjuvant chemotherapy has become the standard treatment for the management of locally advanced breast cancer, primarily because of its ability to downsize large tumors. Neoadjuvant chemotherapy is increasingly used for the treatment of early-stage breast cancer. However, despite generally high response rates, a small proportion of patients fail to respond to neoadjuvant chemotherapy, or even progress during therapy. Recent evidence suggests that biological markers may be useful for identifying those patients who would benefit from neoadjuvant chemotherapy
The
The use of TP53 status as a biological marker to predict the response of breast cancer to neoadjuvant chemotherapy, however, is disappointing, and the findings to date have shown conficting results
PubMed, Embase, and Web of Science databases were searched (up to December 20, 2011) using the search terms: ‘TP53’, ‘p53’, ‘p53 protein’, ‘p53 mutation’, ‘17p13 gene’, ‘chemotherapy’ and ‘breast cancer’. All potentially eligible studies were retrieved and their bibliographies were carefully scanned to identify other eligible studies. Additional studies were identified by a hand search of the references cited in the original studies. When multiple studies of the same patient population were identified, we included the published report with the largest sample size. Only studies published in English were included in this meta-analysis.
Studies included in this meta-analysis had to meet all of the following criteria: (a) evaluation of TP53 status for predicting the response to neoadjuvant chemotherapy in early-stage breast cancer, locally-advanced breast cancer, (b) described therapeutic response, (c) retrospective or prospective cohort study, (d) inclusion of sufficient data to allow the estimation of a risk ratio (RR) with 95% confidence intervals (95% CI), and (e) studies published in English. Letters to the editor, reviews, and articles published in books, or papers published in a language other than English were excluded.
According to the inclusion criteria listed above, the following data were extracted for each study: the first author’s surname, publication year, country of origin, number of patients analyzed, types of measurement, and treatment. Data on the main outcomes were entered in tables showing the clinical and pathological responses to chemotherapy with respect to TP53 status. Information was carefully and independently extracted from all eligible publications by two of the authors (Chen and Zhu). Any disagreement between the researchers was resolved by discussions until a consensus was reached. If they failed to reach a consensus, a third investigator (Lu) was consulted to resolve the dispute.
We used the definitions and standardizations for ‘TP53’ and ‘response to chemotherapy’ as reported by Pakos et al.
RR with 95% CIs was used to estimate the association between TP53 status and response to neoadjuvant chemotherapy in breast cancer patients. Subgroup analyses were performed to evaluate the effects of treatment regimens (anthracycline-based) and different methods of
A total of 1,223 articles were retrieved by a literature search of the PubMed, Embase, and Web of Science databases, using different combinations of key terms. As indicated in the search flow diagram (
Author | Year | Country | Cases | TreatmentSubgroup of treatment | Detection | Response | ||
Makris et al. |
1997 | UK | 80 | mitoxantrone, methotrexate (± mitomycin C) and tamoxifen | N | IHC | clinical response | CR + PR |
Kandioler-Eckersberger et al. |
2000 | Austria | 67 | FEC or paclitaxel | N | PCR amplification sequencing and IHC | clinical response | CR + PR |
Geisler et al. |
2001 | Norway | 90 | weekly doxorubicin scheduled for 16 weeks | A-b | IHC, TTGE and sequencing | clinical response | PR |
Schneider et al. |
2001 | Spain | 52 | FAC or CMF | N | IHC | clinical response | CR + PR |
Aas et al. |
2003 | Norway | 90 | doxorubicin | A-b | IHC | clinical response | PR+SD |
Anelli et al. |
2003 | Brazil | 73 | AT | A-b | IHC | clinical response | CR + PR |
Bonnefoi et al. |
2003 | Switzerland | 179 | FEC,EC + G-CSF | A-b | IHC | clinical response | CR |
Martin-RIHCard et al.[] | 2003 | Spain | 38 | FAC or FEC | A-b | IHC | clinical response | CR + PR |
Geisler et al. |
2003 | Norway | 35 | FUMI regimen | N | IHC | clinical response | PR |
Mathieu et al. |
2004 | France | 129 | AVCMF or FAC/FEC | A-b | IHC | Pathologic response | CR |
Deissler et al. |
2004 | Germany | 50 | anthracycline/taxane | A-b | FASAY | clinical response | CR |
Kim et al. |
2005 | Japan | 63 | docetaxel | N | IHC | Pathologic response | RR |
Learn et al. |
2005 | USA | 121 | AC vs. AC+D | A-b | IHC | Pathologic response | CR |
Bertheau et al. |
2007 | France | 80 | EC | A-b | FASAY | Pathologic response | CR |
Tiezzi et al. |
2007 | Brazil | 60 | CMF or FEC | N | IHC | clinical response | CR + PR |
Keam et al. |
2007 | Korea | 145 | docetaxel and doxorubicin | A-b | IHC | Pathologic response | CR + PR |
Lee et al. |
2008 | Korea | 61 | AT | A-b | IHC | clinical response | RR |
Pathologic response | CR | |||||||
Zhou et al. |
2008 | China | 135 | taxanes and anthracycline | A-b | IHC | Pathologic response | CR |
Yonemori et al. |
2009 | Japan | 44 | trastuzumab-containing neoadjuvant | N | IHC | Pathologic response | CR |
Shekhar et al. |
2009 | USA | 20 | AC, AT, FAC, FAT | A-b | IHC | clinical and pathologic response | CR + PR |
Silver et al. |
2010 | USA | 22 | DDP | N | IHC | clinical and pathologic response | CR + PR |
Masuda et al. |
2010 | Japan | 33 | FEC100 and taxanes | A-b | IHC | Pathologic response | CR |
Sanchez-Munoz et al. |
2010 | Spain | 73 | EC followed by GP (+ trastuzumab in Her2 patients) | A-b | IHC | Pathologic response | CR |
Bonnefoi et al. |
2011 | Europe | 1469 | FEC VS. T-ET | A-b | FASAY | clinical and pathologic response | CR |
Ono et al. |
2011 | Japan | 179 | anthracycline-based regimens | A-b | IHC | Pathologic response | CR |
Oshima et al. |
2011 | Japan | 88 | P-FEC | A-b | genomic sequencing, DNA microarray and IHC | Pathologic response | CR |
IHC, immunohistochemistry; FEC, 5-fluorouracil, epirubicin, and cyclophosphamide; FAC, 5-fluorouracil, doxorubicin, and cyclophosphamide; CMF, cyclophosphamide, mitomycin C and 5-fluorouracil; AVCMF, doxorubicin, vincristine, cyclophosphamide, methotrexate and 5-fluorouracil; P-FEC, sequential paclitaxel and 5-FU/epirubicin/cyclophosphamide; FUMI regimen, 5-fluorouracil (1,000 mg/m2 on days 1 and 2) and mitomycin; EC, epirubicin and cyclophosphamide; A, doxorubicin; E, epirubicin; T, docetaxel; P, paclitaxel; G, gemcitabine; FASAY, RNA-based functional assay in yeast; TTGE, temporal temperature gradient gel electrophoresis. N, can not be grouped; A-b, anthracycline-based neoadjuvant chemotherapy.
Among the studies of breast cancer patients who received neoadjuvant therapy, 26 studies involving 3,476 patients contributed data on total OR (clinical OR + pathological OR). TP53 status-positivity was significantly associated with improved total OR among patients treated with neoadjuvant therapy (RR = 1.20; 95% CI = 1.09–1.33; p<0.001,
Among the 26 studies in the neoadjuvant subgroup, 18 used anthracycline-based neoadjuvant chemotherapy,while the remaining studies can not be grouped (
Different measurements of TP53 status (either by protein or gene detection) have been used to evaluate associations with favorable responses to neoadjuvant chemotherapy. We therefore calculated the associations using both protein and gene statuses of TP53. The results of subgroup analysis are presented in
Comparison | Total OR |
Pathological OR | Total CR |
Pathological CR | ||||||||||||
N | RR (95%CI) | p value | Ph | N | RR (95%CI) | p value | Ph | N | RR (95%CI) | p value | Ph | N | RR (95%CI) | p value | Ph | |
All studies | 26 | 1.20 (1.09–1.33) | <0.001 | 0.292 | 15 | 1.37 (1.20–1.57) | <0.001 | 0.329 | 15 | 1.33 (1.15–1.53) | <0.001 | 0.095 | 12 | 1.45 (1.25–1.68) | <0.001 | 0.391 |
Treatment | ||||||||||||||||
Anthracycline-based | 17 | 1.18 (1.04–1.33) | 0.010 | 0.298 | 10 | 1.33 (1.19–1.62) | 0.005 | 0.109 | 12 | 1.33 (1.15–1.54) | <0.001 | 0.031 | 9 | 1.45 (1.24–1.69) | <0.001 | 0.175 |
Type of measurement | ||||||||||||||||
Protein | 21 | 1.06 (0.94–1.20) | 0.310 | 0.796 | 12 | 1.22 (1.01–1.48) | 0.041 | 0.637 | 12 | 1.15 (0.92–1.43) | 0.235 | 0.209 | 9 | 1.32 (1.02–1.69) | 0.032 | 0.659 |
Gene | 8 | 1.41 (1.20–1.65) | <0.001 | 0.207 | 4 | 1.49 (1.24–1.79) | <0.001 | 0.089 | 5 | 1.46 (1.22–1.75) | <0.001 | 0.076 | 4 | 1.49 (1.24–1.79) | <0.001 | 0.089 |
Subgroup analysis was performed when there were at least two studies in each subgroup.
N, number of studies; Ph, p value of Q-test for heterogeneity.
For studies using both clinical and pathological responses, we used the pathological response data, but also examined the clinical response data, and found similar results (data not shown).
#One study (Oshima et al.
Begg’s funnel plot and Egger’s test were used to estimate the publication bias of the included literature. The shapes of the funnel plots showed no evidence of obvious asymmetry(
TP53 status had been shown to play a pivotal role in the response to a large panel of anticancer drugs. Previous studies suggested that breast cancers with
The current meta-analysis of 26 studies systematically evaluated the association between TP53 status and response to neoadjuvant chemotherapy in a large population. The results indicate that altered TP53 status may predict good response rates to neoadjuvant chemotherapy in patients with breast cancer. TP53 status was associated with total and pathologically relevant increases in OR and CR. Stratification according to different treatments showed that altered TP53 status was significantly associated with increased OR and CR in patients who received anthracycline-based neoadjuvant chemotherapy. Further stratification by gene detection revealed imprecise results, but amplification of the
Despite our attempts to perform a comprehensive analysis, there were some limitations associated with this meta-analysis. First, the meta-analysis may have been influenced by publication bias, we limited the search to studies performed in English, and we did not search conference proceedings and abstract books, which may have introduced publication bias to meta-analysis. We tried to identify all relevant data and retrieve additional unpublished information, some missing data were unavoidable. Second, the studies used different measurements of TP53 status (either protein or gene detection), and the cut-off values for TP53 for overexpression by IHC and for gene amplification differed between studies. Standardization is therefore of great importance for obtaining an accurate assessment of the clinical significance of TP53 status. Although we made considerable efforts to standardize definitions, some variability in definitions of methods, measurements, and outcomes among studies was inevitable. Third, our analysis was observational in nature, and we therefore cannot exclude confounding as a potential explanation of the observed results. Despite these limitations, this meta-analysis had several strengths. First, a substantial number of cases were pooled from different studies, and 3,476 subjects represent a sizeable number, significantly increasing the statistical power of the analysis. Secondly, no publication biases were detected, indicating that the pooled results may be unbiased.
This study is the first meta-analysis to assess the usefulness of TP53 status for predicting the response of breast cancer patients to neoadjuvant chemotherapy. Our data support TP53 status as a useful predictive factor for assessing treatment response to neoadjuvant chemotherapy in breast cancer patients. However, future prospective studies with large sample sizes and better study designs are required to confirm our findings. Moreover, the interactions of this marker with other molecular markers such as HER-2
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