KR20160134072A - Method for providing information of prediction for recurrence of breast cancer - Google Patents

Abstract

The present invention relates to a method for providing information for predicting recurrence of a breast cancer including a step of comparing axillary lymph node to primary tumor maximum standard uptake value ratio (ALN/T SUV) ratio with 0.43 in fluorodeoxyglucose positron emission tomography (FDG PET) data. The present invention provides the method for providing information for predicting recurrence of the breast cancer by checking ALN/T SUV ratio in FDG PET data of a breast cancer patient. The present invention can reduce death rate by determining a proper treatment method according to a predicted prognosis.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for providing information for prediction of recurrence of breast cancer,

The present invention relates to a method for providing information for predicting recurrence of breast cancer.

Breast cancer is a rapidly growing disease worldwide. According to the 2014 International Cancer Report, the incidence of breast cancer increased by 20% in 2012 compared to 2008. Korea is classified as a country with high cancer incidence along with North America and Western Europe. Breast cancer is the second most common cancer among women in Korea, following thyroid cancer. According to the Ministry of Health and Welfare's Central Cancer Registration Report, breast cancer accounts for 14.8% of total female cancer in 2011.

As interest in breast cancer has increased, the survival rate of breast cancer has been increasing due to early diagnosis by active health screening, newly developed imaging technology, and chemotherapy. However, breast cancer patients still die with a probability of close to 30%.

Therefore, it is very important to determine the optimal treatment method by selectively identifying patients who are suspected or suspected of having recurrence.

Hormonal status including HER2 (human epidermal growth factor receptor 2), MIB-1 (Mindbomb E3), histologic grade, histologic grade, axillary lymph node involvement, estrogen receptor and progesterone receptor status, ubiquitin protein ligase 1), and p53 are known to be prognostic factors of breast cancer. In addition, some of the study, the ¹⁸ F-FDG uptake of the original cancer reported as prognostic factors on FDG PET / CT bar.

However, these factors are still insufficient as a meaningful parameter for accurately predicting the recurrence of breast cancer.

The purpose of the present invention is to determine the maximum standard uptake ratio of axillary lymph nodes for primary carcinomas (FDG PET, [ ¹⁸ F] fluorodeoxyglucose positron emission tomography) data for breast cancer patients (ALN / T SUV ratio, axillary lymph node to primary tumor maximum standard uptake value ratio of the breast cancer to 0.43. The present invention also provides a method for providing information for predicting the recurrence of breast cancer.

In order to achieve the above object, the present invention provides a method for measuring the maximum standard absorption coefficient (ALN / T SUV ratio) of axillary lymph nodes for primary cancer in FDG PET ([ ¹⁸ F] fluorodeoxyglucose positron emission tomography) and a first step of comparing the maximum standard uptake value ratio of the axillary lymph node to the primary tumor to 0.43, to provide an information providing method for predicting the recurrence of breast cancer.

In the present invention, breast cancer refers to a clinical diagnosis of breast cancer and includes all specific sub-phenotypes of breast cancer. For example, the breast cancer may be selected from the group consisting of Ductal Carcinoma In Situ (DCIS), microinvasive ductal carcinoma, invasive ductal carcinoma (IDC), aqueous carcinoma, invasive lobular carcinoma, ductal carcinoma, , Breast epithelial carcinoma, male breast cancer, follicular tumors of the breast, recurrent and metastatic breast cancer, or a combination thereof.

Breast cancer is divided into stages 0, 1, 2, 3 and 4 according to the progression. The stage of breast cancer is determined by tumor size, axillary lymph node metastasis, and systemic metastasis including bone and lung involvement including neck lymph node metastasis. These three factors are important factors in determining prognosis. Breast cancer is a non-invasive breast cancer (cancer of the epithelium). Cancer cells are localized within the epithelium. The first stage of breast cancer is a tumor with a size of less than 2 cm and no lymph node metastasis. For example. Breast cancer stage 1 is an early stage of cancer progression, so there is less recurrence and metastasis, very high survival rate. Breast cancer stage 2 refers to the case when the tumor size is 2 ~ 5cm but not the lymph node metastasis or the lymph node metastasis but the tumor size is more than 5cm. The stage 3 breast tumor is less than 5cm in size but the lymph node metastasis is severe or the tumor size A case of large lymph node metastasis greater than 5 cm. The fourth stage of breast cancer, also called terminal stage, refers to cases of systemic metastasis such as lungs, bones, and liver.

Preferably, the breast cancer patient of the present invention may be a patient with invasive ductal carcinoma (IDC). More preferably, the breast cancer patient of the present invention may be an invasive breast cancer patient having axillary lymph node metastasis.

In the present invention, recurrence means that the cancer recurs after the curative treatment for breast cancer, and includes locoregional recurrence and systemic metastasis recurrence. The local recurrence refers to the occurrence of cancer in the ipsilateral breast, pectoral muscle, and skin after the initial treatment, and recurrence refers to the development of cancer in the ipsilateral axillary lymph node, the upper clavicle, the subclavian lymph node, and the internal mammary lymph node. In addition, systemic recurrence refers to the transfer of cancer to the lungs, bones, and liver.

Since breast cancer has a high risk of recurrence after surgery, it is important to predict the recurrence prognosis accurately and determine the appropriate treatment direction according to the predicted prognosis, thereby reducing the recurrence rate and decreasing the mortality rate.

In the present invention, prediction refers to predicting medical consequences in advance, and means for estimating the recurrence of breast cancer patients for the purpose of the present invention in advance, that is, predicting the recurrence of breast cancer.

In the present invention, the prognosis includes the progression or mortality of a disease such as recurrence, metastasis, etc. of a breast cancer patient for the purpose of the present invention in anticipation of a medical cause (for example, recurrence, long-term survival possibility, disease-free survival rate etc.) do.

Meanwhile, in the present invention, positron emission tomography (PET) is one of the nuclear medicine testing methods using positron emission, in which a drug containing a radioactive isotope releasing a positron is injected into the body, followed by a positron emission tomography It refers to the method of knowing the body distribution. Specifically, PET is a non-invasive diagnostic technique that uses biomolecules such as glucose, amino acid, fatty acid and nucleic acid labeled with radioactive isotopes such as 18F, 11C, 13N, and 15O as tracers to image biochemical changes in the body to be. [ ¹⁸ F] fluorodeoxyglucose (FDG) PET (FDG PET) is the most widely used PET test, allowing direct assessment of glucose metabolism in cells. Most of the tumor cells have hyperglycemia due to overexpression of enzymes involved in glycolysis or glucose transporter proteins such as hexokinase and phosphofructokinase. In addition, the expression of glucose-6-phosphatase is decreased in most cancer cells, and FDG accumulates in the cells, thus showing more FDG accumulation than normal cells. It is known that FDG-PET imaging can differentiate between malignant and benign tumors by measuring the difference in the degree of glucose metabolism in various tumors.

Such PET is mainly used for evaluating cancer test, heart disease, brain disease, etc., and is used in the present invention to provide information for predicting the recurrence of breast cancer.

The PET is also used as a PET / CT scanner combined with a computerized tomography (CT) scanner. The PET / CT can provide more accurate image correction along with anatomical information, have.

Thus, the method of providing information of the present invention can utilize data obtained by PET, preferably PET / CT, for patients with breast cancer, such as invasive breast cancer.

Preferably, the FDG PET data of the present invention may be obtained prior to surgery for surgical resection of breast cancer patients.

In the present invention, a primary tumor is an anatomic site where a mass is formed, and refers to a site where tumor metastasis begins. In breast cancer, primary carcinoma is present in the breast.

In the present invention, the Standardized Uptake Value (SUV) is a software calculated value of the metabolic hypertension detected on a PET (or FDG PET) image. The radioactivity released per gram of tissue is measured by radioactivity administered per kilogram of body weight Of the total amount. Also, in the present invention, the maximum standard intake coefficient (SUV _max ) refers to the maximum value of the standard intake coefficient.

According to the present invention, the maximum standard uptake ratio (ALN / T SUV ratio) of axillary lymph nodes to primary cancer is a parameter that can predict the recurrence of breast cancer in advance. Among patients suffering from breast cancer, The higher the patient's score, the higher the patient's score.

In a specific embodiment, pre-operative FDG PET / CT data were analyzed by univariate and multivariate analysis for patients with invasive breast cancer, and it was found that the ALN / T SUV ratio was the only independent factor in predicting relapse (Tables 1 and 2) .

In a preferred embodiment of the present invention, the above-described information providing method of the present invention determines that the possibility of recurrence of breast cancer is high when the ALN / T SUV ratio is greater than 0.43 and that the probability of recurrence of breast cancer is low when the ALN / T SUV ratio is less than 0.43 And may further include a second step.

More specifically, according to a graph of a survival free survival (RFS) over time in FIG. 2, when the ALN / T SUV ratio is 0.43 or less, the RFS is kept high, while the ALN / T SUV ratio is 0.43 , RFS was significantly reduced and the possibility of recurrence of breast cancer was very high.

As described above, the ALN / T SUV ratio of the present invention can be an independent index for predicting the recurrence of breast cancer and can be used as a method of providing information necessary for predicting recurrence as a predictive marker of recurrence of breast cancer.

Since the ALN / T SUV ratio among the FDG PET data of breast cancer patients according to the present invention can be used as an independent predictor of breast cancer recurrence, it is possible to accurately predict the recurrence prognosis of breast cancer patients and determine the appropriate treatment direction according to the predicted prognosis So that the information can be provided.

Figure 1 shows an image of a 47-year-old woman with primary breast cancer and axillary lymph node metastasis. Increased FDG uptake (SUV _max 3.2) was observed in the upper part of the right breast in AC, and FDG uptake SUV _max 1.5). SUV _max ratio of axillary lymph node to primary cancer was 0.47 on FDG PET / CT and the RFS period was 190 days.
Figure 2 shows the results of survival analysis using the Kaplan-Meier method for invasive breast cancer with axillary lymph node metastasis. The significant statistical difference is between high primary carcinoma SUV _max and low primary carcinoma SUV _max (A), high ALN SUV _max And low ALN SUV _max (B), and between high ALN / T SUV ratio and low ALN / T SUV ratio (C).

Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the examples.

<Experimental Method>

1. Selection of patients

A medical chart of 153 IDC (invasive breast cancer) female patients with ALN (axillary lymph node) metastases enrolled from November 2010 to December 2012 was reviewed retrospectively. The Reward Chart Study (2014-04-27) was conducted with the approval of the Institutional Review Board.

Based on histologic evaluation, primary tumor size was determined as 1 cm or more on pathologic size based on pre-operative FDG PET / CT, and full-width at half maximum (FWHM) Respectively. Patients with both breast cancer and patients with neoadjuvant chemotherapy or radiotherapy were excluded from the patient group. The mean age of the patients was 50.5 ± 10.5 years (range: 30-76 years).

All patients underwent surveillance lymph node biopsy and / or breast conserving surgery with axillary lymph node dissection or modified radiation mastectomy. Post-operative systemic chemotherapy included a taxane-based therapy consisting of doxorubicin and cyclophosphamide leading to docetaxel. Radiation therapy was performed postoperatively. Hormone therapy or trastuzumab was given to hormone receptor positive or HER2-positive primary carcinoma patients. Patients returned to the clinic every six months for at least three years after initial treatment and underwent physical examination, mammography, breast ultrasound, and whole body bone scan tests. FDG PET / CT and breast MRI were performed at 1 year and 3 years after initial treatment. Patients suspected of having recurrence were subjected to further examination in addition to conventional imaging. Survival time was calculated from the first diagnosis day to the recurrence or last follow-up date. Recurrence-free survival (RFS) is defined as ipsilateral breast or locally invasive recurrence; Remote recurrence; Or breast cancer, the cause of non-breast cancer, or death due to unknown causes mentioned in previous studies. Breast cancer was determined to be recurrent or metastatic based on the evaluation of the primary care physician as reported on the medical chart.

2. ¹⁸ F- FDG  PET / CT protocol

FDG PET / CT images were obtained using a Siemens Biograph mCT / 128 PET / CT scanner (Siemens Medical Solutions, Knoxville, USA). Prior to administration of 3-5 MBq / kg of ¹⁸ F-FDG, patients were fasted for at least 6 hours to achieve plasma glucose levels below 150 mg / dL. After 60 minutes of ¹⁸ F-FDG administration, CT scans were performed in two axes directions and parameters were set at 120 kVp and 50 mAs using CAUSE Dose (Siemens Medical Solutions, Knoxville, USA). FDG PET / CT images were obtained for 2 minutes per bed position from the middle to the thigh. CT images were used as transmission for attenuation correction and PET images were reconstructed into a 200 × 200 image matrix using an ordered subset expectation maximum iterative reconstruction algorithm.

3. ¹⁸ F- FDG  PET / CT image analysis

Preoperative FDG PET / CT image ALN and to measure the SUV _max of the original cancer, equipment software program (syngo via;. Siemens Medical Solutions , Knoxville, USA) to the hoengmyeon (transaxial) side portions, and primary to the fused image using We have drawn a spherical volume of interest (diameter ≥ 1) that is semi-automatically delineated against breast tumors. The ALN / T SUV ratio was calculated (Figure 1) after recalibration with reference to the anatomical image to avoid overlap with the background ingestion region where the relatively high intake of the sphere of interest in the axilla was avoided. ALN size was defined as the longest ALN diameter measured on pre-operative FDG PET / CT CT.

4. Immunohistochemistry

The immunohistochemical characteristics of breast cancer were confirmed by skilled breast pathologists. Briefly, pathologic tumors and ALN staging were interpreted according to guidelines recommended by the American Joint Committee on Cancer. Histologic or nuclear grade was also determined according to the modified Bloom-Richardson Grading system, in which grade 3 was positive. Allred scores of> 2 were used to define ER or PR positivity as described previously. Positive for p53 was defined as the presence of tumor cells with moderate or high scores of at least 5% staining. MIB-1 positive was defined as ≥20% staining of invasive tumor cells and HER2 positive was defined as high intensity or gene amplification stained with a receptor antibody using fluorescent in situ hybridization Was defined as the presence of at least 10% tumor cells. For the original carcinoma size, the longest primary carcinoma diameter was measured from post-operative permanent tissue.

5. Statistical Analysis

Numerical data were expressed as mean ± SD. The optimal cutoff values for the original carcinogenic SUV _max , ALN SUV _max , and ALN / T SUV ratios were confirmed using the reciever operating characteristic (ROC) curve for recurrence prediction. Survival analysis was performed using the Kaplan-Meier method. Univariate and multivariate analyzes were performed using the Cox proportional-hazards model. Statistical significance was defined as p <0.05. All statistical analyzes were performed using MedCalc software (version 11.4.4; MedCalc Software, Mariakerke, Belgium).

<Experimental Results>

1. Evaluation of patient characteristics

The characteristics of 119 patients are summarized in Table 1 below. The mean preoperative FDG PET / CT interval was 6.7 ± 9.4 days and the average follow-up period was 28.4 ± 9.0 months. Ten of 119 breast cancer patients underwent pre-FDG PET / CT preoperative ALN biopsy. Of the 119 patients, 118 (99.2%) received adjuvant chemotherapy and 101 (84.9%) received postoperative radiation therapy. 82 patients (68.9%) had breast cancer stage II and 37 patients (31.1%) had stage III disease. During follow-up, 102 patients (85.7%) remained disease free, and 17 patients (14.3%) recurred. Of the 17 recurred patients, 6 had local recurrence lesions and 11 had distant metastatic lesions. The mean RFS of 17 recurred IDC patients was 16.3 ± 8.6 months.

[Table 1]

2. RFS  For prediction Parameter  evaluation

Recurrent IDC patients had significantly higher primary carcinoma SUV _max and ALN SUV _max than patients who did not recur. The primary carcinoma SUV _max of recurrent patients was 11.3 ± 6.7 and the primary carcinoma SUV _max of 7.9 ± 4.6 (95% confidence interval [CI] difference, -6.00 to -0.83, p = 0.010). The ALN SUV _max of the two groups were 6.9 ± 6.5 and 3.4 ± 4.2, respectively (95% CI, -5.86 to -1.15, p = 0.04). The ALN / T SUV ratio in the recurrent group was 0.97 ± 1.60 and the ALN / T SUV ratio in the non-relapse group was 0.45 ± 0.40 (95% CI, -0.88 to -0.16, p = 0.005). The primary tumor size and ALN size of recurrent IDC patients were not significantly different from those of original IDC patients without recurrence ( p = 0.698 and 0.068, respectively).

Using the ROC curve to predict recurrence, the optimal cutoff values for ALN and primary carcinoma SUV _max were 2.2 (sensitivity, 88.2%; specificity, 56.9%; AUC, 0.738%; standard error [SE], 0.0575 ) And 11.1 (sensitivity, 52.9%, specificity, 81.4%; AUC, 0.660; SE, 0.0815). Comparisons of AUCs from ROC curves showed no significant difference between primary carcinoma SUV _max , tumor SUV _max , ALN SUV _max and ALN / T SUV (all p > 0.05). Survival analysis using the Kaplan-Meier analysis showed a significant predisposing factor for the RFS of IDC: primary carcinoma SUV _max (> 11.1), ALN SUV _max (> 2.2) and ALN / T SUV ratio (Fig. 2).

Univariate analysis also showed that primary carcinoma SUV _max , ALN SUV _max , and ALN / T SUV ratio were significant contributors to RFS in IDC (Table 2). Clinical pathological findings, including ALN status (pN1 vs. pN2, pN3), nuclear and histological grades (I, II vs. III), ER (positive vs. negative) and MIB- Were significant sig- nificant factors for RFS. Multivariate analysis, however, showed that the ALN / T SUV ratio (4.20; 95% CI, 1.74-10.13; p = 0.002) was a significant independent predictor of RFS.

[Table 2]

Claims (5)

Recurrence of breast cancer including the first stage comparing the ALN / T SUV ratio (primary tumor maximum standard uptake value ratio) to 0.43 in FDG PET ([ ¹⁸ F] fluorodeoxyglucose positron emission tomography) data of breast cancer patients / RTI &gt; The method according to claim 1, further comprising a second step of determining that the likelihood of recurrence of breast cancer is high if the ALN / T SUV ratio is greater than 0.43 and that the probability of recurrence of breast cancer is low if the ALN / T SUV ratio is less than 0.43. 3. The method of claim 1 or 2, wherein the FDG PET data is obtained prior to surgical resection surgery. The method according to claim 1 or 2, wherein the breast cancer patient is an invasive ductal carcinoma patient. 5. The method of claim 4 wherein the patient with invasive breast cancer is a patient with axillary lymph node metastasis.

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