Correlation analysis of 18 F-FDG PET/CT for the staging and treatment effect assessment of breast cancer

Abstract

OBJECTIVE:

Since cancer treatment and outcome differ among the patients diagnosed with breast cancer at different stages, this study aims to elucidate the factors associated with PET/CT staging, treatment effect, and maximal standardized uptake value (SUV_max) in breast cancer patients.

METHODS:

Twenty-eight patients who underwent two PET/CT examinations with the complete pathological and immunohistochemical data were retrospectively reviewed. Pearson and Spearman correlation analyses were performed to investigate the relationships of patient PET/CT staging (first round PET/CT), treatment effect (comparison between the results of two rounds of PET/CT), and tumor SUV_max, with respect to patient age, tumor location, tumor long diameter, short diameter, time of first round PET/CT examination, histological type and grade, axillary lymph node metastasis rate, interval between the two PET/CT examinations, treatment method, and the expression of the estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), P53, and Ki67.

RESULTS:

PET/CT staging (first round PET/CT) relates to HER2 and Ki67 expression with the correlation coefficients of 0.432 and 0.552, and P-values of 0.022 and 0.002, respectively. The treatment effect (comparison between the results of two rounds of PET/CT) associates with tumor site and P53 expression in which the correlation coefficients are – 0.412 and 0.845, and P-values are 0.029 and 0.000, respectively. The measured SUV_max correlates well with the tumor long diameter, short diameter, and treatment effect in which the correlation coefficients are 0.943, 0.886, and 0.878, and P-values are 0.005, 0.019, and 0.02, respectively.

CONCLUSIONS:

Study results indicate that PET/CT staging and treatment effect associate well with SUV_max and immunohistochemical results of tumor, while SUV_max of tumor associates well with tumor size.

Keywords

PET/CT FDG breast cancer

Abbreviations

PET/CT

Positron emission tomography/computed tomography

FDG

Fluorodeoxyglucose

SUV_max

Maximal standardized uptake value

Estrogen receptor

Progesterone receptor

HER2

Human epidermal growth factor receptor 2

ROI

Region of interest

H&E

Hematoxylin-eosin

IDC

Invasive ductal carcinoma

ILC

Invasive lobular cancer

IMPC

Invasive micropapillary carcinoma

MBC

Mucinous breast carcinoma

1. Introduction

Since the year 2000, the overall cancer incidence among Chinese women has increased significantly, especially for breast cancer. By 2015, the incidence of breast cancer in women accounted for 15.1% of all female cancers, and the mortality rate accounted for 6.9% of female cancer mortality [1], seriously threatening women’s physical and mental health.

The imaging methods commonly used for breast cancer detection include infrared thermography, mammography, ultrasound, computed tomography (CT or CAT), and magnetic resonance (MR) imaging. However, due to the influence of mammary glands, especially the dense breast tissue, a tumor may be hidden and is often hard to detect. Moreover, it is difficult to distinguish between surgical scars caused by surgery, radiotherapy, or chemotherapy and fibrocystic breast changes and breast glands. Positron emission tomography/computed tomography (PET/CT) is a combined imaging of anatomy and function. Not only does it show the morphological features of the lesion, but it may also report metabolic information of the lesion, bringing new opportunities for diagnosis, staging, re-staging, and treatment response assessment of breast cancer [2, 3]. It has been reported that ¹⁸F-FDG PET/CT has significant advantages in the diagnosis, staging, and re-staging of breast cancer. For some breast cancer patients, the treatment plans could be adjusted according to the PET/CT results, improving the survival rate [4].

With the advantages of PET/CT in tumor diagnosis and the augmented acknowledgement in patients, increasing amounts of breast cancer patients are choosing to have PET/CT scans prior to or following surgery. However, patients are at various stages of breast cancer when diagnosed, and the outcomes usually differ following treatment. Therefore, the present study collected data from all patients who have undergone two rounds of PET/CT examinations for breast cancer since the installation of PET/CT scanners in the First Affiliated Hospital of Xi’an Jiaotong University, and investigated the factors affecting PET/CT staging, SUV_max, and treatment effect.

2. Materials and methods

2.1. Study population

The data of patients who have undergone two rounds of ¹⁸F-FDG PET/CT examinations for breast cancer since the installation of the PET/CT scanners in the First Affiliated Hospital of Xi’an Jiaotong University (from December 2011 to December 2018) were collected. Inclusion criteria: the patients had their first PET/CT examination prior to or following surgery; PET/CT reviews after the treatment plan continued or was adjusted; complete pathological and immunohistochemical data were present. Exclusion criteria: patients with a history of other malignant tumors or breast diseases; incomplete pathological or immunohistochemical data; no PET/CT review. A total of 28 patients were included, the 28 patients underwent a second PET/CT and were followed up using PET/CT. These 28 patients were breast cancer, had complete immunohistochemical data, and had two PET/CT examinations. Figure 1 shows the process of gradually screening out the subjects. Of the 28 patients, 6 underwent the first PET/CT before surgery, 22 underwent the first PET/CT after surgery, and all 28 patients underwent the second PET/CT after the first PET/CT and after undergoing treatment.

Fig. 1.

Flow chart of study inclusion and exclusion criteria.

2.2. Imaging protocol

All subjects underwent PET/CT examinations with a PET/CT scanner (Gemini 64TF, Philips, Cleveland, OH, USA). ¹⁸F-FDG was prepared by a MiniTrace Cyclotron (GE healthcare) and an FDG synthesis module. All patients were fasted for over 6 hours, and the fasting blood glucose levels were maintained lower than 11.1 mmol/L. The patients were administered 3.7 MBq/kg ¹⁸F-FDG via cubital vein injection. Following resting for 40–60 minutes, the patients were asked to drink 400–500 mL water to distend the stomach, and then urinate. The PET/CT scans were performed for 1.5 min in the table position. Following CT attenuation correction and iterative reconstruction, PET data was transmitted to the Extended Brilliance Workstation (EBW) for image fusion.

2.3. Imaging analysis

The images were interpreted by one chief PET/CT physician (Dr. Duan) and one attending senior physician (Dr. Li), and a consensus was reached by discussion for any difference in opinions. Decision criteria: following exclusion of physiological intake, tissue with a higher ¹⁸F-FDG uptake in the mammary gland than in the surrounding normal glandular tissue was considered a breast cancer lesion; and an increased ¹⁸F-FDG uptake in a lymph node or a distant tissue and organ than that in the same tissue of the same layer was considered lymph node or distant metastasis (Figs. 2, 3). The staging of N and M were based on the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines (2015) [5]. The regions of interest (ROIs) were marked on the axial images. The maximal standardized uptake value (SUV_max) was automatically output by computer; SUV_max= tumor activity concentration / (injected dose/body weight).

Fig. 2.

Images of a 37-year-old patient. The first PET/CT results (a–c) revealed left-sided breast cancer (red arrow) and left-sided axillary lymph node metastasis (green arrow). A modified radical mastectomy of the left breast was performed, and postoperative histology suggested IDC grade 3 (e). The PET/CT review (d and f) conducted five months after chemotherapy revealed no increased uptake of FDG in the affected or axillary regions, indicating improved conditions.

Fig. 3.

Images of a 44-year-old female. The histology (f) six years after left breast cancer surgery suggested IDC grade 3. The first PET/CT results (a–c) revealed multiple liver metastases. The PET/CT review (d and f) conducted six months after chemotherapy revealed an increased number of liver metastases, indicating progressive conditions.

2.4. Immunohistochemical analysis

All biopsy specimens were fixed in 10% neutral formaldehyde, embedded in paraffin, dewaxed, dehydrated, stained with hematoxylin-eosin (H&E) and the EnVision two-step immunohistochemical stain, and observed under an optical microscope. Regarding the expression of the estrogen (ER) and progesterone (PR) receptors, cells stained brown or with brown particles in the cell membrane and nucleus were determined positive. The expression of ER and PR was considered positive with ≥1% positive cells [6]. The detection of human epidermal growth factor receptor 2 (HER-2) expression was based on the staining of cell membranes: >10% cells with stained membranes was considered positive. The positive expression of Ki-67 was marked by brownish yellow nuclear staining: excluding the positive vascular endothelial cells, ≥14% Ki-67 positive cells was considered high expression [7]. With respect to the expression of p53, cells were considered positive with brownish yellow staining of the nucleus and/or cytoplasm: >10% positive cells were considered p53 positive.

2.5. Patient and tumor characteristics

A total of 28 female patients were included in the present study, aged 30–73 years old (median age 53) with a height of 155–166 cm (median height 162 cm) and a weight of 50–68 kg (median weight 59 kg). Among these, nine cases of breast cancer were right-sided, 18 were left-sided, and one was bilateral. There were 23 cases of invasive ductal carcinoma (IDC), two cases of invasive lobular carcinoma (ILC), two cases of IDC combined with invasive micropapillary carcinoma (IMPC), and one case of IDC combined with mucinous breast carcinoma (MBC). The axillary lymph nodes were removed intraoperatively, and the postoperative histological findings showed an axillary lymph node metastasis rate of 0–100% (median 14%). The interval between the two rounds of PET/CT scans ranged from 2 to 76 months (median interval 9 months). The details are shown in Table 1.

Table 1
Patient characteristics

Characteristic Number

Age (years) 52.55±9.26

<50 11 (39.29%)

≥50 17 (60.71%)

Gender

Male 0 (0.00%)

Female 28 (100.00%)

Height (cm) 160.96±2.83

Weight (kg) 57.68±4.64

Tumor site

Right 9 (32.14%)

Left 18 (64.29%)

Right + Left 1 (3.57%)

Axillary lymph node

Negative 10 (35.71%)

Positive 18 (64.29%)

Axillary lymph node metastasis rate (%)

Intervening time (months) 29.74±31.43

Time of first PET/CT examination 17.16±20.67

Prior to surgery 6 (21.43%)

Following surgery 22 (78.57%)

Treatment method

Surgery 10 (35.71%)

Surgery + Chemotherapy/ Radiotherapy 13 (46.43%)

Surgery + Chemotherapy + Radiotherapy 5 (17.86%)

Histology

IDC 23 (82.14%)

ILC 2 (7.14%)

IDC + IMPC 2 (7.14%)

IDC + MBC 1 (3.58)

Histological grade

2 7 (25.00%)

3 21 (75.00%)

ER

Negative 15 (53.57%)

Positive 13 (46.43%)

PR

Negative 19 (67.86%)

Positive 9 (32.14%)

HER2

Negative 9 (32.14%)

Positive 19 (67.86%)

P53

Negative 10 (35.71%)

Positive 18 (64.29%)

Ki67

Low (<14%) 5 (17.86%)

High (≥14%) 23 (82.14%)

First PET/CT results

No metastasis 10 (35.71%)

Lymph node metastasis 10 (35.71%)

Distant metastasis 8 (28.58%)

Compared with the previous results

Improved 8 (28.57%)

No significant change 7 (25.00%)

Progressive 13 (46.43%)

Characteristic	Number
Age (years)	52.55±9.26
<50	11 (39.29%)
≥50	17 (60.71%)
Gender
Male	0 (0.00%)
Female	28 (100.00%)
Height (cm)	160.96±2.83
Weight (kg)	57.68±4.64
Tumor site
Right	9 (32.14%)
Left	18 (64.29%)
Right + Left	1 (3.57%)
Axillary lymph node
Negative	10 (35.71%)
Positive	18 (64.29%)
Axillary lymph node metastasis rate (%)
Intervening time (months)	29.74±31.43
Time of first PET/CT examination	17.16±20.67
Prior to surgery	6 (21.43%)
Following surgery	22 (78.57%)
Treatment method
Surgery	10 (35.71%)
Surgery + Chemotherapy/ Radiotherapy	13 (46.43%)
Surgery + Chemotherapy + Radiotherapy	5 (17.86%)
Histology
IDC	23 (82.14%)
ILC	2 (7.14%)
IDC + IMPC	2 (7.14%)
IDC + MBC	1 (3.58)
Histological grade
2	7 (25.00%)
3	21 (75.00%)
ER
Negative	15 (53.57%)
Positive	13 (46.43%)
PR
Negative	19 (67.86%)
Positive	9 (32.14%)
HER2
Negative	9 (32.14%)
Positive	19 (67.86%)
P53
Negative	10 (35.71%)
Positive	18 (64.29%)
Ki67
Low (<14%)	5 (17.86%)
High (≥14%)	23 (82.14%)
First PET/CT results
No metastasis	10 (35.71%)
Lymph node metastasis	10 (35.71%)
Distant metastasis	8 (28.58%)
Compared with the previous results
Improved	8 (28.57%)
No significant change	7 (25.00%)
Progressive	13 (46.43%)

2.6. Statistical analysis

Data are presented as the mean±standard deviation or percentage. The correlation analyses were conducted using Pearson or Spearman analysis. P < 0.05 is considered statistically significant. PASW Statistics for Windows, Version 18.0 (SPSS Inc., Chicago, IL, USA) was used for statistical analysis.

3. Results

3.1. Analysis of factors affecting staging by first-round PET/CT

PET/CT of the 28 enrolled patients demonstrated no metastases in 10 patients, lymph node metastases in 10 patients, and distant metastases in eight patients. The staging by PET/CT was positively correlated with HER2 and Ki67 expression (Fig. 4), with correlation coefficients of 0.432 and 0.552 and P-values of 0.022 and 0.002, respectively. The details are shown in Table 2.

Fig. 4.

Relationships between staging and HER2 and Ki67 as shown by first-round PET/CT. Note: 1: no metastasis; 2: lymph node metastasis; 3: distant metastasis.

Table 2

Analysis of factors affecting staging by first-round PET/CT

	Correlation coefficient	P
Age (years)	–0.113	0.568
Tumor site	–0.050	0.801
Time of first PET/CT examination	–0.069	0.728
Histology	0.050	0.800
Histological grade	0.054	0.784
Axillary lymph node metastasis rate (%)	0.124	0.529
ER	–0.367	0.055
PR	–0.322	0.095
HER2	0.432	0.022 *
P53	–0.265	0.174
Ki67	0.552	0.002 *

p < 0.05 was considered a statistically significant difference.

3.2. Analysis of factors affecting treatment effect

All patients had their treatment plans continued or adjusted based on the first PET/CT results. The second PET/CT results were compared with the first results, demonstrating eight improved cases, seven stable cases, and 13 progressive cases. The analysis showed that the treatment outcomes were correlated with tumor location and P53 expression (Fig. 5), with correlation coefficients of – 0.412 and 0.845 and P-values of 0.029 and 0.000, respectively. The details are shown in Table 3.

Fig. 5.

Relationships between treatment outcomes and tumor location and P53. Note: 1: improved; 2: no significant change; 3: progressive.

Table 3

Analysis of factors affecting treatment effect

	Correlation coefficient	P
Age (years)	–0.111	0.575
Tumor site	–0.412	0.029 *
Time of first PET/CT examination	0.087	0.660
Histology	–0.236	0.226
Histological grade	0.027	0.890
Axillary lymph node metastasis rate (%)	0.0 80	0.686
ER	0.048	0.809
PR	0.025	0.898
HER2	–0.178	0.364
P53	0.845	0.000 *
Ki67	–0.218	0.266
Intervening time (months)	0.174	0.376
First PET/CT results	–0.128	0.515
Treatment method	0.149	0.449

p < 0.05 was considered a statistically significant difference.

3.3. Analysis of factors affecting SUV _max

In the present study, six patients underwent pre-operative PET/CT scans and the long diameters, short diameters, and SUV_max of the primary tumor lesions were measured. All the above patients had histological grade 3, positive HER2, positive Ki67, and lymph node metastasis observed in the first round of PET/CT scans. The correlations of SUV_max with patient age, tumor site, tumor long diameter, short diameter, histology, axillary lymph node metastasis rate, expression of ER, PR, and P53, second PET/CT result, and treatment effect were investigated. It was found that SUV_max was positively correlated with the tumor long diameter, short diameter, and treatment effect (Fig. 6), with correlation coefficients of 0.943, 0.886, and 0.878 and P-values of 0.005, 0.019, and 0.021, respectively. The details are shown in Table 4.

Fig. 6.

Relationships between SUV_max and tumor long diameter, short diameter, and treatment effect. Note: 1: improved; 3: progressive.

Table 4

Analysis of factors affecting SUV_max

	Correlation coefficient	P
Age (years)	0.029	0.957
Tumor site	0.098	0.854
Long diameter (mm)	0.943	0.005 *
Short diameter (mm)	0.886	0.019 *
Histology	–0.101	0.848
Axillary lymph node metastasis rate (%)	0.257	0.623
ER	–0.414	0.414
PR	–0.293	0.573
P53	0.878	0.021
Second PET/CT results	0.794	0.059
Treatment effect	0.878	0.021 *

p < 0.05 was considered a statistically significant difference.

4. Discussion

In recent years, breast cancer has gradually become a major threat to the health of Chinese women. Breast cancer is associated with female hormone levels [8]. Typically, Chinese women reach menopause at the age of roughly 50 [9]. In the present study, the 28 enrolled patients were divided into two groups according to age: 11 patients (39.29%) in the <50 years old group and 17 (60.71%) in the ≥50 years old group. It was shown that although breast cancer is beginning to occur in younger women, its presence still dominates in middle-aged and elderly women.

The survival rate of breast cancer patients with no symptoms of recurrence or metastasis after treatment reached 91.5%, while that of patients with recurrence or metastasis was only 24%, which is significantly different. The combined imaging of anatomy and function by PET/CT can improve the accuracy of the detection of recurrence and metastasis [10 –12]. The two rounds of staging results by PET/CT for all patients in the present study were clinically recognized and consistent with the pathology, follow-up results, and data reported by previous studies, highlighting the advantages of PET/CT.

ER and PR are biomarkers of breast cancer and can be used as important indicators for endocrine therapy and prognosis evaluation of breast cancer [13, 14]. Approximately 50–70% of breast cancers are hormone receptor-positive. During the tumorigenesis of mammary epithelial cells, ER and PR may be partially or completely retained, suggesting that the tumor cells are well differentiated and their growth requires hormone regulation. When ER and PR are lost, it indicates that the tumor cells are poorly differentiated and their growth does not require hormone regulation. In the present study, most patients had ER- and PR-negative breast cancer, indicating that the tumors were poorly differentiated. The staging by PET/CT showed 10 non-metastatic cases, 10 metastatic, and eight distant metastatic cases; however, neither staging by PET/CT nor treatment effect showed a significant correlation with ER or PR, which needs to be investigated further with a larger sample size.

HER2 is an important prognostic factor in breast cancer; those positive for HER2 are strongly invasive, recurrent, and metastasize relatively fast [15, 16]. The present study demonstrates that the staging by PET/CT was associated with HER2 expression. In brief, the HER2-positive patients had poor PET/CT staging, consistent with previous reports.

P53 is a tumor suppressor gene. The absence of this gene is why approximately 50% of human malignancies progress [17]. In the present study, the treatment effect was related to the tumor site; treatment outcomes of left-sided breast cancer were poor. This finding would possibly be supported by a larger sample size. However, it may also be biased by the excessive amount left-sided breast cancer patients included in the present study. P53-positive patients had worse treatment outcomes, matching the biological characteristics of the tumor-promoting factor p53.

Ki67 is expressed during all stages of cell proliferation, and its index is closely related to the differentiation, invasion, metastasis, and prognosis of various tumors [7]. In the present study, PET/CT staging was associated with Ki67 expression. Briefly, patients with high Ki67 expression had poor staging, which is consistent with previous reports.

The SUV_max of breast cancer lesions was positively correlated with tumor invasion, ER expression, karyotype, tumor stage, and tumor size [18, 19]. Our study demonstrates that the SUV_max was positively correlated with tumor long diameter and short diameter, with correlation coefficients of 0.943 and 0.886, respectively, consistent with previous reports. It has been reported that the larger the SUV_max, the higher the degree of malignancy and the higher the metastatic risk [20]. The six patients with the primary tumor SUV_max measured in the present study had the same staging from their first PET/CT examination. Furthermore, the SUV_max was not significantly correlated with the second PET/CT staging results, likely due to limited case numbers enrolled in the present study. Nevertheless, the results demonstrate that SUV_max was significantly associated with treatment effect (P = 0.021), and indirectly support the notion that the larger the SUV_max, the higher the malignancy of the tumor, and the worse the treatment outcome.

The advantages of the present study are that data has been collected from all breast cancer patients since the installation of PET/CT scanners in an upper first-class hospital that can accommodate 2,560 beds for patients and is directly under the Ministry of Education, giving typical numbers and characteristics. In addition, all patients enrolled in the present study underwent two rounds of PET/CT examinations, and had complete pathological and immunohistochemical data, in addition to treatment plan information. Thus, the PET/CT staging and treatment effect assessment performed in this study objectively represent the treatment process of breast cancer patients. In summary, results of this study indicate that PET/CT staging and treatment effect associate well with the computed SUV_max and immunohistochemical results. In addition, the SUV_max associates well with the tumor size.

The present study has several limitations. PET/CT was a good technical method for tumor staging, but its application was rather confusing in our hospital. Firstly, the number of enrolled cases was small. Due to the high cost and lack of insurance coverage, most breast cancer patients only had one round of PET/CT examination, and only a few patients had a PET/CT review. This issue requires effort from the government, the hospital, and the patient’s family. Our research team will continue to collect cases to augment the sample size. Secondly, among the enrolled patients, only a few had preoperative PET/CT results, which is related to the current lack of understanding of PET/CT by many Chinese surgeons. When breast cancer is highly suspected or has been confirmed by histology, PET/CT should be performed for preoperative staging instead of postoperatively. Lastly, the present study may have data bias due to the small sample size.

Availability of data and materials

The datasets generated and/or analyzed during the current study are not publicly available due [the protecting provision about the patients’ privacy included in informed consent] but are available from the corresponding author on reasonable request.

Authors’ contributions

YL and Y-lD made substantial contributions to conception and design, acquisition of data, analysis and interpretation of data; YL, Y-lD, J-sW and X-yD were involved in drafting the manuscript. X-yD and Y-mG gave final approval of the version to be published. X-yD agreed to be 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 authors read and approved the final manuscript.

Ethics approval and consent to participate

The work was carried out at the First Affiliated Hospital of Xi’an Jiaotong University. The ethics committee of the First Affiliated Hospital of Xi’an Jiaotong University approved this study, and all study participants provided informed consent.

Consent for publication

The current study contained PET/CT images of two patients. These patients had signed the consent form for agreement of publishing.

Competing interests

The authors declare that they have no competing interests.

Footnotes

Acknowledgment

This study was supported by National Natural Science Foundation of China (no. 81471710).

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