Original Article

The role of p53 and ki67 in predicting

clinical outcome in breast cancer patients
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ABSTRACT Bhanu Prakash

Background: ki67 may be used as a proliferative index in addition to estrogen receptor (ER), progesterone receptor (PR), and human Lalkota,
epidermal growth factor receptor 2 (HER2) negative status. p53 gene expression is a well‑known biomarker in breast cancer and Srinivasa B.J1,
its role in predicting clinical outcome remains unclear. The current study aimed to determine the relationship between p53 gene Mani V. Swamy2,
mutation and ki67 expression, their clinical characteristics, and overall survival (OS), and to differentiate the significance of p53 and Diganta Hazarika,
ki67 as the prognostic value in breast cancer patients. Jeet B.M,
Jyothi K,
Methods: In this study, 135 patients were enrolled in the study from December 2015 to May 2017. Medical records for all patients
Mithua Ghosh3,
were reviewed prospectively. The inclusion criteria included age more than 18 years with histologically proven breast cancer and Suhail M. Sayeed,
willingness to be enrolled in p53 genetic study. Exclusion criteria included dual malignancy, male breast cancer, with a loss to Mohammad
follow‑up during the study. Nasiruddin3,
Results: The mean survival of patients with ki67 ≤20 index was 42.7 months (95% confidence interval [CI] 38.7–46.7) and Radheshyam Naik
129 months (95% CI 101.3–157.2) in patients with ki67 >20. The mean OS was 145 months (95% CI 105.6–185.5) in the p53
Departments of
wild‑type group and 106 months (95% CI 78.0–133.0) in the p53 mutated group, as illustrated.
Translational Medicine
Conclusion: Our results indicated that p53 mutational status and high ki67 might have an essential impact on overall survival, with and Therapeutics,
p53 mutated patients having a poorer outcome than p53 wild type patients. 1
Medical Oncology,
3
Molecular Pathology,
HCG Cancer
KEY WORDS: Breast cancer, ki67, p53 gene, prognostic marker Speciality Center,
2
Center for Academics
and Research,
HCG Foundation,
INTRODUCTION PR−, HER2+.[4,5] ki67 may be used as a proliferative Bangalore, India
index in addition to ER, PR, HER2 − status.
For correspondence:
Breast cancer is the number one frequent cancer Dr. Bhanu Prakash
in females, accounting for about 11.6% of new ki67 is a nuclear protein of molecular mass 359 kDa Lalkota,
cancer case diagnoses and 6.6% cancer mortality and is commonly used for the detection and Department of
worldwide in 2018, according to GLOBOCAN quantification of proliferating cells. An increase in Translational Medicine
and Therapeutics,
statistics.[1] Torre et al.[2] and Malvia et al.[3] in its expression is associated with cell growth. It is HCG Cancer
2012 reported 70,000 deaths in India due to commonly used as a diagnostic marker in various Speciality Center,
breast cancer, which is likely to increase up to cancers including breast cancer.[6] Sub‑grouping Bangalore, India.
1,797,900 by 2020. Breast cancer prognosis can E‑mail: bhanu.
luminal tumors based on ki67 proliferative index
lalkota@gmail.com
be predicted by histological features, tumor size, Luminal A subtype as a good prognosis and luminal
hormonal status, molecular classification (luminal B subtype as a worse Prognosis.[7] With regard to
A, luminal B, basal‑like, and human epidermal cell proliferation, ki67 is the most reliable factor Submitted: 21-Dec-2020
growth factor receptor 2 [HER2]‑enriched subtypes), for breast cancer research because of its variable Accepted in revised
and age of the patient. Luminal A differentiated expression in normal and malignant cells and the form: 29-Jul-2022
by estrogen receptor positive (ER+) and/or ease of assessing cell cycle pathways.[8] The scoring Published: 16-Mar-2023
progesterone receptor positive (PR+) or HER2 of ki67 has not been established by standard
negative (HER2−) status, low‑grade tumor, and Access this article online
valuable prognosis. Luminal B accounts for 10% of This is an open access journal, and articles are distributed under the terms of the Website: www.cancerjournal.net
all breast cancers and is identified by ER + and/ Creative Commons Attribution‑NonCommercial‑ShareAlike 4.0 License, which DOI: 10.4103/jcrt.JCRT_1830_20
allows others to remix, tweak, and build upon the work non‑commercially, as
or PR/HER2 − status. Basal‑like features ER, PR, long as appropriate credit is given and the new creations are licensed under the
Quick Response Code:

HER2 negative status, high‑grade tumor, and poor identical terms.

prognosis. HER2‑enriched subtype represents ER, For reprints contact: WKHLRPMedknow_reprints@wolterskluwer.com

Cite this article as: Lalkota BP, Srinivasa BJ, Swamy MV, Hazarika D, Jeet BM, Jyothi K, et al. The role of p53 and ki67 in
predicting clinical outcome in breast cancer patients. J Can Res Ther 2023;19:208-13.

208 © 2023 Journal of Cancer Research and Therapeutics | Published by Wolters Kluwer - Medknow
 Lalkota, et al.: p53 and Ki67 in breast cancer
operating procedures, and the inter‑laboratory and interstudy
comparability of ki67 is limited.[9] The prognostic value of ki67
scoring in breast cancer is not well established. The p53 gene
was identified in 1979 as a cellular protein complex in simian
virus 40 (SV40) in a study on the role of viruses in cancer.
Although it was initially presumed to be an oncogene, its
character as a tumor suppressor gene was revealed in 1989.
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The p53 protein is a phosphoprotein made of 393 amino acids
and it is located on the seventeenth chromosome (17p13.1). It
hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 02/21/2024
is a multifunctional tumor suppressor gene whose mutations
are responsible for the frequent genetic defects found in an
extensive range of cancers.[10,11] p53 mutation occurs in >50%
of human cancers such as colon, stomach, breast, ovary, lung,
brain, and esophagus.[12] The mutation of the p53 gene is used
as a prognostic marker in many malignancies.[13] p53 is a tumor
suppressor gene, and it plays a fundamental role in monitoring
genomic stability, reducing angiogenesis effects, restricting
tumor inflammation, immune response, and preventing
metastases.[14,15] In normal cells, the p53 protein level is low and
serves three major functions such as growth arrest, DNA repair,
and apoptosis (cell death). DNA damage and other significant
signals can trigger an increase in the levels of p53 protein. The
growth arrest stops the progression of the cell cycle, preventing
the replication of damaged DNA.[16] In cell growth inhibition,
p53 may activate the transcription of proteins involved in DNA
repair. Apoptosis is the final step to stop the proliferation of cells
containing abnormal DNA.[17] p53 mutation is present in 30% of
breast cancer patients, having its highest incidence in the basal
group and the lowest incidence in the luminal group.[18] In breast
cancer, p53 gene mutation is the most considered marker, but
anticipating the clinical outcome is still unclear.
Some studies have shown a higher incidence of p53 mutation
in carriers of mutations in BRCA1 and BRCA2.[19] The mutation
of p53 shows a new development in cancer progress because
it is noticeable at the in situ phase of cancer proliferation.[20] In
recent years, p53 and ki67 have been considered as prognostic
and predictive markers in breast cancer.[21,22]
The current study aims to determine the relationship between
p53 gene mutation and ki67 expression, their clinical
characteristics, and overall survival (OS), and to differentiate
the significance of p53 and ki67 as the prognostic value in
breast cancer patients in a tertiary care cancer specialty centre.
MATERIALS AND METHODS
This study is a single‑center experience of 135 patients who
were enrolled in the study from December 2015 to May 2017.
Medical records for all patients were reviewed prospectively.
The inclusion criteria included age more than 18 years with
histologically proven breast cancer and willingness to be
enrolled in p53 genetic study. Exclusion criteria included
dual malignancy, male breast cancer, and loss to follow‑up
during the study. Formalin‑fixed paraffin‑embedded (FFPE)
tumor samples were selected for immunohistochemistry (IHC)
Journal of Cancer Research and Therapeutics - Volume 19 - Issue 2 - January-March 2023
staining with the primary antibody against ki67. ki67 staining
was recorded as the percentage of cell staining out of all cells
and a threshold of 20% was used for estimation of high and
low ki67 expression [Figure 1]. All patient clinical data, such
as age, menopausal status, diagnosis, and patient follow‑up
data were extracted from patient files or contact by telephone.
Molecular analyses
Next generation sequencing (NGS) was performed using the
TruSight Cancer sequencing panel (Illumina, USA) and shortlisted
14 high‑risk genes (ATM, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, NBN,
NFI, PALB2, PTEN, RAD51C, RAD51D, STK11, and TP53) recommended
by the National Comprehensive Cancer Network[23] as well as
institutional guidelines. Genomic deoxyribonucleic acid (DNA)
was isolated from the patient’s blood or saliva specimen using
standardized methodology, QIAamp DNA Mini Kit (Qiagen,
Germany) or Nucleospin kit (Macherey‑Nagel, Germany). From
each patient 50 ng of input genomic DNA was used for the
preparation of NGS libraries and hybridized to a custom pool of
oligonucleotides, targeting genomic regions followed by paired
end sequencing of 150 base pairs (bp) read lengths.[24]
Statistical analysis
Data were analyzed using the Statistical Package for the Social
Sciences (SPSS) 23.0 software (Inc., Chicago, III., USA), and
descriptive statistics were used to determine the patient’s
clinical characteristics. The Chi‑squared test was used to
compare categorical tumor features in the p53‑mutated
and p53‑wild‑type groups. OS was the time from the initial
diagnosis of breast cancer to death or loss to follow‑up.
Kaplan–Meier and logrank tests were used for the analysis
of overall survival (OS). Multivariate analysis was evaluated
by stepwise forward Cox regression analysis. For all analyses,
a P value of ≤ 0.05 was considered statistically significant.
RESULTS
Patient characteristics
In this study, the total sample size was 135. The median age was
49 years, and patients aged more than 50 years were 46.7%,
followed by 53.3% of patients who were less than 50 years of
age. Eighty‑two patients (60.7%) were postmenopausal and
53 patients (39.35%) were pre‑menopausal. Histologically,
124 patients (91.9%) constituted ductal carcinoma type and
the remaining 11 patients (8.1%) were of other subtypes. p53
a b
Figure 1: Immunohistochemical analysis of ki67 of the study sample.
(a) Less than 20% (b) More than 20%
209
 Lalkota, et al.: p53 and Ki67 in breast cancer

mutations were found in 61 patients (45.2%), and 74 (54.8%)
were of the wild type. Seventy‑five patients (55.5%) had
stages I–II of the disease, 34 (25.1%) had stage III, and the
remaining 19 patients (14%) had stage IV disease. Molecular
subtyping showed that 43 patients (31.9%) belonged to the
luminal A group, 19 (14%) to the luminal B group, 25 (18.5%)
to the basal‑like group, and the remaining 48 (35.6%) to the
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P53 expression and clinical pathological characteristics
T h e c o r re l a t i o n b e t w e e n p 5 3 e x p re s s i o n a n d
clinicopathological characteristics showed, high p53
mutation was more commonly associated with a ductal
type of carcinoma (P < 0.001) and in HER2+tumors
(P < 0.001). However, the expression of p53 was not
statistically significant when associated with age, de novo

HER2 group [Table 1]. metastasis, menstrual status, stage, and ki67 proliferative
index [Table 5].
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p53 with ki‑67 index

Mann–Whitney U test was conducted for ki67 between p53
Univariate analysis showed that hormonal status (ER, PR,
mutated and wild type patients. The average ki67 index was
HER2) classification (P = 0.052; 95% CI 0.997–2.546, HR 1.593)
51.77 ± 24.53 in mutated patients and wild‑type patients
and p53 gene expression (P = 0.052; 95% CI 0.997–2.546, HR
had an average ki67 of 35.81 ± 19.54. Moreover, P value was
significant (P < 0.001) [Table 2].
Table 1: Patients and tumor characteristics

Correlation of ki67 with survival Characteristic No. of patients %

The mean survival of patients with ki67 ≤20 index was Age
≤50 years 72 53.3
42.7 months (95% confidence interval [CI] 38.7–46.7)
>50 years 63 46.7
and 129 months (95% CI 101.3–157.2) in patients with Menstrual Status
ki67 >20 [Table 3]. The average OS with ki67 in all patients Pre-menopause 53 39.3
was 130 months (95% CI 102.2–157.8) [Figure 2]. In the Post-menopause 82 60.7
Histological Type
ki67 ≤20 group, 13 out of 14 patients (92.9%) were on Ductal carcinoma 124 91.9
follow‑up whereas the ki67 >20 group comprised of Others 11 8.1
108 patients out of 121 (89.3%) who were on follow‑up and p53
13 events occurred. Mutated 61 45.2
Wildtype 74 54.8
Stage
Correlation of p53 status with survival 1-2 75 55.5
The mean survival was 145.5 months (95% CI 105.6–185.5) in 3 26 19.3
the p53 wild‑type group and 105.5 months (95% CI 78.0–133.0) 4 34 25.1
Hormone Receptor Classification
in the p53 mutated group [Table 3]. The average mean overall Luminal A 43 31.9
survival (OS) among all patients with p53 was 130 months (95% HER2+ 48 35.6
CI 102.3–157.8) [Figure 2]. From the above statistical evidence, Basal‑like 25 18.5
p53 mutational status may have a very significant bearing on Luminal B 19 14.0
the OS of the patients, as demonstrated by our subgroup analysis
that showed that 74 patients (95.9%) with p53 wild‑type in Table 2: Mann-Whitney U test for ki67 between p53 wild type
current follow‑up had far fewer events (3 patients) than the p53 and p53 mutated
mutated group with 61 patients (82%) who had 11 events. At the ki67 Score Mean±SD STD error P
end of the study, 121 patients (89.6%) were alive on follow‑up p53
and 14 events occurred [Table 4]. Logrank comparison of ki67 Wildtype (n=74) 35.81±19.54 2.272 <0.001
and p53 did not show any significance in this study. Mutated (n=61) 51.77±24.53 3.141

a b
Figure 2: Overall survival of breast cancer patients. (a) ki67 proliferative index with ≤20% and >20% (b) p53 mutation and p53 wildtype

210 Journal of Cancer Research and Therapeutics - Volume 19 - Issue 2 - January-March 2023
 Lalkota, et al.: p53 and Ki67 in breast cancer

Table 3: Mean and median survival time with ki67 and p53
ki67/p53 Mean Median
Estimate Std. Error 95% Confidence Interval Estimate Std. Error 95% Confidence Interval
Lower Bound Upper Bound Lower Bound Upper Bound
ki67
ki67≤20 42.758 2.020 38.798 46.718 . . . .
ki67>20 129.327 14.271 101.356 157.297 130.751 . . .
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Overall 130.119 14.172 102.342 157.896 130.751 . . .

p53
p53 wildtype 145.595 20.400 105.612 185.579 . . . .
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p53 mutated 105.518 14.032 78.016 133.021 130.751 69.725 0.000 267.412
Overall 130.119 14.172 102.342 157.896 130.751 . . .

Table 4: Case summary with ki67 and p53 DISCUSSION

ki67/p53 Total No. No of Events Censored
n Percentage Cancer is the most common genetic disease that results from
ki67 acquired genetic alterations. These genetic alterations form
ki67≤20 14 1 13 92.9% the basis for early detection, monitoring, and prognosis
ki67>20 121 13 108 89.3% of cancer. Cancer may result either due to a single gene
Overall 135 14 121 89.6%
mutation or defects in multiple genes. This study explores
p53
p53 wildtype 74 3 71 95.9% the expression of the p53 gene in its wild type and mutated
p53 mutated 61 11 50 82.0% forms, where it predicts disease prognosis and overall survival.
Overall 135 14 121 89.6% We examined p53 and ki‑67 expression in 135 cases of breast
cancer and found that p53 gene mutation was mutated in
Table 5: Relationship between p53 and clinicopathological 82.0%. Almost 90% of cases had a ki67 value greater than
characteristics of breast cancer 20%. Although the association between p53 and disease
Characteristic p53 mutated (%) p53 wildtype (%) P characteristics are inconsistent among various studies, we
Age found that the hormonal receptor (ER, PR, HER2) classification
≤50 years 33 (54.1) 39 (52.7) 0.871 of breast cancer had a significant correlation (P < 0.001).
>50 years 28 (45.9) 35 (47.3)
Our series contained 35.6% of HER2+overexpression, and
De novo metastasis
Metastasis 38 (62.3) 43 (58.1) 0.621 coexistence of p53 gene mutation along with ki67 expression
No metastasis 23 (37.7) 31 (41.9) is a strong prognostic biomarker in breast cancer according
Menstrual status to recently published studies.[25–27] ki67 proliferative index is
Premenopausal 23 (37.7) 30 (40.5) 0.737
Postmenopausal 38 (62.3) 44 (59.5)
the most practiced marker in breast cancer, where elevated
Histological type ki67 expression has been correlated with enlarged tumor
Ductal carcinoma 50 (82.0) 74 (100) <0.001 size, high grade, shorter DFS and OS, and poor prognosis.[5,6]
Others 11 (18.0) 0 Delpech et al.[7] described that low ki67 expression in the
Stage
1 1 (1.6) 7 (9.6) 0.180 tumor is associated with good clinical benefit and longer
2 34 (55.7) 33 (45.2) survival. It was reported that increased ki67 expression was
3 10 (16.4) 16 (21.9) highly correlated with poor relapse‑free survival and OS in
4 16 (26.2) 17 (23.3)
breast cancer patients.[6] Although different methodological
Hormonal Receptor
Classification and clinical parameters have been applied to explore the
Luminal A 10 (16.4) 33 (45.8) <0.001 role of p53 gene and ki67 proliferative index in predicting
HER2+ 30 (49.2) 18 (25) therapy response and patient outcomes, most of the decisions
Basal‑like 9 (14.8) 15 (20.8)
Luminal B 12 (19.7) 6 (8.3)
are questionable.[20] In our study, ki67 score had an impact
ki67 on p53 gene expression types (wild type and mutated) and
≤20 3 (4.9) 11 (14.9) 0.059 it was statistically significant with P < 0.001. However, our
>20 58 (95.1) 63 (85.1) study showed that ki67 >20% patients had a better survival
of 129.3 months (95% CI 101.356–157.297) compared to
1.593) were predictors for overall survival. Multivariate Cox ki67 ≤20% of 42.75 months (95% CI 38.798–46.718). As the
regression analysis indicated that p53 gene expression alone sample size of the low ki67 group (14 subjects) is much lower
when compared to the high ki67 group (121 subjects), our data
had the significant P = 0.029 (95% CI 1.197–26.54, HR 5.636)
may have overestimated the OS in the study groups.
and other parameters such as age, stage, menstrual status,
histological type, chemotherapy regimen, and ki67 did not Recent data explored that p53 gene expression is correlated
shown any significance [Table 6]. with the bad prognosis in breast cancer patients (12, 18).

Journal of Cancer Research and Therapeutics - Volume 19 - Issue 2 - January-March 2023 211
 Lalkota, et al.: p53 and Ki67 in breast cancer

Table 6: Univariate and multivariate overall Cox analysis in breast cancer patients with overall survival
Covariate Univariate analysis Multivariate analysis
HR P 95% CI HR P 95% CI
Age 0.972 0.222 0.929-1.017 1.023 0.591 0.943-1.109
Stage 1.159 0.608 0.660-2.034 0.620 0.264 0.268-1.434
De novo metastasis 0.345 0.169 0.076-1.569 0.278 0.146 0.049-1.561
Menstrual status 0.531 0.267 0.174-1.623 0.142 0.083 0.016-1.292
Histological type 3.415 0.249 0.423-27.580 1.707 0.633 0.191-15.295
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Hormone receptor classification 1.593 0.052 0.997-2.546 1.671 0.099 0.907-3.079

Chemotherapy regimen 1.008 0.989 0.338-3.001 1.671 0.475 0.409-6.831
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ki67 1.486 0.707 0.188-11.745 0.696 0.751 0.075-6.499

p53 1.593 0.052 0.997-2.546 5.636 0.029 1.197-26.542

Survival analysis of p53 gene expression showed that wild REFERENCES

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prognostic significance in breast cancer patients.[18,24]
Univariate analysis identified two‑factor hormonal receptor
classification (ER, PR, HER2) and p53 gene expression (P = 0.052),
On the other hand, multivariate overall Cox analysis found p53
to be significant (P = 0.029; 95% CI 1.197–26.542, HR 5.636).
ki67 was not shown to have significant impact in this series.
Even though our study found an association between
hormonal receptor status, high ki67 and p53 gene expression
status, a lack of sufficient sample size made it difficult to
confirm the same.
CONCLUSION
Our results indicate that p53 mutational status has an
important impact on overall survival, with p53 mutated
patients having a poorer outcome than p53 wild type patients.
Pathological subgroups and molecular subtypes are also other
parameters that play an important role in determining overall
survival along with p53 mutational status. Hormonal receptor
status, ki67 index, and p53 might be prognostic biomarkers
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Ethics approval
Considering that the subjects in the trial were not being given
any additional intervention apart from the standard of care,
the study was exempted from review by the ethics committee.
Informed consent
Informed consent was obtained from all participants included
in the study.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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