The prognostic relevance of p53 and Ki-67 to chemotherapy sensitivity and prognosis in triple-negative breast cancer
Introduction
Triple-negative breast cancer (TNBC), which was first described by Brenton et al. in 2005 (1), refers to breast cancer that is negative for hormone receptors and human epidermal growth factor receptor 2 (HER2). TNBC is a complex subtype that represents approximately 12% to 17% of all breast cancers (2), and most frequently occurs in premenopausal and young (<40 years old) women (3). TNBC displays especial biological behavior, pathological characteristics, and clinical manifestations. TNBC is not sensitive to endocrine therapy or targeted therapy, and is highly malignant with a high rate of distant metastasis.
Chemotherapy is the only systemic treatment available for TNBC at present (4). The expression of p53 is a potential predictor of sensitivity to chemotherapy in breast cancer, especially for patients with luminal breast cancer, but its prognostic function in TNBC is poor (5). Lee et al. reported that the chemotherapeutic effect on TNBCs with high p53 expression was greater than that on TNBCs with low p53 expression (6), but a later study found the opposite (7). Ki-67 is one of the most widely used tumor proliferation-related biomarkers, and it can predict the chemosensitivity of TNBC (8). Although chemotherapy has been shown to be effective in the treatment of TNBC under the guidance of some predictive markers, it has a high recurrence rate and short overall survival (9).
Recurrence is an independent prognostic factor for survival of TNBC; thus, illuminating the relationship between tumor markers and recurrence would assist in improving the prognosis of TNBC. In this study, we aimed to investigate the prognostic function of p53 and Ki-67 protein expression in chemosensitivity and prognosis in patients with TNBC.
We present the following article in accordance with the REMARK reporting checklist (available at http://dx.doi.org/10.21037/tcr-21-180).
Methods
General information
Patients who were confirmed with TNBC by pathological examination between January 2006 and February 2018 in Wenzhou Geriatric Hospital and Wenzhou Hospital of Traditional Chinese Medicine (including the Oncology Department, Tumor Surgery Department, and Gynecology Department) were enrolled in this study. The patients were followed up to August, 2020, and the median follow-up time was 9 years and 4 months.
All procedures performed in this study involving human participants were in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by ethics board of Wenzhou Geriatric Hospital (NO.: WLNY2020-005). Because of the retrospective nature of the research, the requirement for informed consent was waived.
Inclusion criteria
Immunohistochemical (IHC) detection of estrogen receptor (ER), progesterone receptor (PR), HER2, Ki-67, and p53 was performed as standard, using the following definitions: ER positivity: ≥1% ER-positive cells; PR positivity: ≥1% PR-positive cells; HER2 positivity: 10% of tumor cell membranes uniform and strong staining; p53 positivity: positive p53 protein expression with brown-yellow nuclear staining, and >10% tissue cells stained positive; and Ki-67 positivity: positive Ki-67 protein expression with brown-yellow nuclear staining, and >14% tissue cells stained positive.
Only breast cancers confirmed as being triple negative for ER, PR, and HER2 were included in the study. All patients were female, and none of the patients had distant metastasis or other primary malignant tumors. All patients received surgical treatment and had a pathological diagnosis. None of the patients received radiotherapy or chemotherapy preoperatively. All patients received standardized adjuvant treatment postoperatively and had complete clinical follow-up data.
Data
All patients were classified according to age, tumor size, menopausal status, lymph node status, tumor-node-metastasis (TNM) stage, histological grading, p53 and Ki-67 expression, whether or not relapse occurred, chemosensitivity.
Criteria for treatment sensitivity
After multiple courses of treatment, tumor cells may undergo heterogeneous changes and subsequently develop insensitivity to chemotherapy. Therefore, we selected the effectiveness of first-line rescue chemotherapy as the reference for treatment sensitivity. After the completion of first-line chemotherapy, the objective curative effect was evaluated according to the American Cancer Society’s Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as follows: complete remission (CR): the disappearance of all target lesions; partial remission (PR): total diameter of target lesions reduced by ≥30% from baseline; progressive disease (PD): total diameter of target lesions increased by ≥20% from baseline or the appearance of new lesions; stable disease (SD): a decrease or increase in the total long diameters of the target lesions from baseline without reaching PR or PD. Tumors evaluated as CR or PR were regarded as being sensitive to chemotherapy, while those evaluated as SD or PD were regarded as being insensitive.
Data processing
Data on Ki-67 and p53 expression, chemosensitivity, and recurrence were extracted for all cases. Microsoft Office Excel software was used to establish a database. SPSS 20.0 software was used to process the data statistically. The number of cases in each group was tested for normal distribution.
Results
General clinical data
A total of 285 patients with TNBC were enrolled in the study. The patients ranged in age between 19 and 76 years old, with a median age of 53 years old. Pathologic stage I accounted for 68.07% of cases. The positive expression rates of Ki-67 and p53 were 53.33% and 56.84%, respectively. The overall recurrence rate was 31.58%. The clinical pathological characteristics of all the TNBC patients are shown in Table 1.
Table 1
| Clinicopathological characteristics | No. of cases | % |
|---|---|---|
| Age (years) | ||
| <50 | 161 | 56.49 |
| ≥50 | 124 | 43.51 |
| Menopausal status | ||
| Premenopausal | 166 | 58.25 |
| Postmenopausal | 119 | 41.75 |
| Tumor size (pT) | ||
| ≤2 cm | 143 | 50.18 |
| >2 cm | 142 | 49.82 |
| Lymph node status (pN) | ||
| Yes | 141 | 49.47 |
| No | 144 | 50.53 |
| Pathological stage (pTNM) | ||
| I | 194 | 68.07 |
| II–III | 91 | 31.93 |
| Histological grading | ||
| I–II | 204 | 71.58 |
| III | 81 | 28.42 |
| p53 | ||
| Negative | 123 | 43.16 |
| Positive | 162 | 56.84 |
| Ki-67 | ||
| Negative | 133 | 46.67 |
| Positive | 152 | 53.33 |
| Relapse | ||
| Yes | 90 | 31.58 |
| No | 195 | 68.42 |
TNBC, triple-negative breast cancer; pT, pathology tumor; pN, pathology node; pTNM, pathology tumor node metastasis.
The prognostic function of Ki-67 in chemosensitivity and recurrence in TNBC
The positive expression rate of Ki-67 in chemosensitive and non-chemosensitive cases was 92.11% and 21.43%, respectively, and the difference was statistically significant. Among the patients who experienced relapse, the positive expression rate of Ki-67 was 82.22%, compared with a rate of 40.00% in patients without recurrence, constituting a statistically significant difference (Table 2).
Table 2
| Ki-67 | χ2 | P | ||
|---|---|---|---|---|
| Negative <14% | Positive >14% | |||
| Chemosensitivity | 38.545 | <0.001 | ||
| Sensitive | 6 (7.89%) | 70 (92.11%) | ||
| Not sensitive | 11 (78.57%) | 3 (21.43%) | ||
| Recurrence | 44.107 | <0.001 | ||
| Relapse | 16 (17.78%) | 74 (82.22%) | ||
| No recurrence | 117 (60.00%) | 78 (40.00%) | ||
The prognostic function of p53 in chemosensitivity and recurrence in TNBC
The positive expression rate of p53 was 96.05% in chemosensitive patients and 35.71% in non-chemosensitive patients, and the difference was statistically significant. In patients who suffered recurrence, the positive expression rate of p53 was 71.11%, which was statistically significantly higher than the rate of 56.41% observed in patients without recurrence (Table 3).
Table 3
| P53 | χ2 | P | ||
|---|---|---|---|---|
| Negative <14% | Positive >14% | |||
| Chemosensitivity | 37.247 | <0.001 | ||
| Sensitive | 3 (3.95%) | 73 (96.05%) | ||
| Not sensitive | 9 (64.29%) | 5 (35.71%) | ||
| Recurrence | 47.695 | <0.001 | ||
| Relapse | 12 (28.89%) | 78 (71.11%) | ||
| No recurrence | 111 (43.59%) | 84 (56.41%) | ||
The prognostic function of simultaneous expression of Ki-67 and p53 in chemosensitivity and recurrence in TNBC
The rate of chemosensitivity in TNBC patients with positive expression of both Ki-67 and p53 protein reached 98.53%, while the chemosensitivity rate of TNBC patients with negative expression of both Ki-67 and p53 protein was 0.00% (Table 4), showing a statistically significant difference. Among TNBC patients with positive expression of both Ki-67 and p53 protein, the recurrence rate was 53.13%, which was statistically significantly higher than the recurrence rate in patients with negative expression of both Ki-67 and p53 protein (6.93%) (Table 5).
Table 4
| Ki-67 and P53 | Chemosensitivity | χ2 | P | |
|---|---|---|---|---|
| Sensitive | Not sensitive | |||
| Negative | 0 (0.00%) | 7 (100.00%) | 64.66 | <0.001 |
| Positive | 67 (98.53%) | 1 (1.47%) | ||
Table 5
| Ki-67 and P53 | Recurrence | χ2 | P | |
|---|---|---|---|---|
| Relapse | No recurrence | |||
| Negative | 7 (6.93%) | 94 (93.07%) | 54.697 | <0.001 |
| Positive | 68 (53.13%) | 60 (46.88%) | ||
Correlation analysis between p53 and Ki-67 protein expression in TNBC
Among the TNBC patients, 128 patients had positive expression of both p53 and Ki-67, while 101 patients had negative expression of both p53 and Ki-67(Table 6). There was a positive correlation between the expression of p53 and Ki-67 in TNBC (P=0.000).
Table 6
| Ki-67 (−) | Ki-67 (+) | χ2 | P | |
|---|---|---|---|---|
| P53 (−) | 101 (35.44%) | 22 (7.72%) | 104.784 | <0.001 |
| P53 (+) | 34 (11.93%) | 128 (44.91%) |
Discussion
TNBC is a systemic disease that can easily metastasize through the blood tract to the central nervous system and lungs during the early stage (10). Although chemotherapy is a highly effective treatment for TNBC, it is associated with a high rate of recurrence, which is attributable to the special biological behavior of this malignancy. Patients with TNBC who have poor sensitivity to chemotherapy have unfavorable outcomes, with short overall survival, disease-free survival, and relapse-free survival (11). To further improve the treatment efficacy for TNBC patients, it is necessary to study the molecular mechanism of the occurrence and development of TNBC.
Ki-67 and p53 are 2 widely studied indicators, which serve as IHC markers in almost all hospitals. Investigation of the relationships between Ki-67, p53, chemosensitivity, and recurrence of TNBC can help to guide clinical practice. This study showed that Ki-67 and p53 were both independent indicators of chemosensitivity and recurrence in patients with TNBC. TNBC patients with high Ki-67 or p53 expression were more sensitive to chemotherapy and displayed a higher recurrence rate. Among the TNBC patients, 128 patients had positive expression of both p53 and Ki-67, and 101 patients had negative expression of both p53 and Ki-67. We found a positive correlation between p53 and Ki-67 protein expression in TNBC tissue, suggesting that p53 and Ki-67 play synergistic roles in the growth of TNBC. The predictive function of Ki-67 and p53 was more obvious in TNBC patients with a positive expression of both markers.
In 2013, the definition of HER2-positive tumors in IHC was changed to include those with 10% uniformity of tumor cell membranes (reduced from 30%) and strong staining (12). Some IHC reports show only positive or negative results, and do not describe the uniformity rate of tumor cell membranes or the strength of staining. In the present study, we eliminated cases that were not fully described by IHC, which might have led to a decrease in the number of enrolled cases.
Some previous studies have reported the recurrence rate of TNBC to be approximately 40% (13,14), which was slightly higher than the rate in this study. Zeng et al. found that a younger age at onset might indicate a higher degree of malignancy in TNBC (15), and the age of onset has also been identified as a factor related to recurrence (16). More than half of the cases in our study were under the age of 50 years old, which should have, on the basis of previous reports, led to an increase in the recurrence rate; however, our result was inconsistent with this. Further statistical analysis showed that 56 cases were operated on after 2015, and the follow-up time was less than 5 years. The shorter follow-up time might be the main reason for the low recurrence rate in our study. In the future, more accurate results will be obtained by extending the follow-up time and calculating the 2-, 5-, and 10-year recurrence rates.
Acknowledgments
Funding: This study was supported by
Footnote
Reporting Checklist: The authors have completed the REMARK reporting checklist. Available at http://dx.doi.org/10.21037/tcr-21-180
Data Sharing Statement: Available at http://dx.doi.org/10.21037/tcr-21-180
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr-21-180). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study involving human participants were in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by ethics board of Wenzhou Geriatric Hospital (NO.: WLNY2020-005). Because of the retrospective nature of the research, the requirement for informed consent was waived.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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(English Language Editor: J. Reynolds)
