Association between molecular subtype of local advanced breast cancer with Ca 15-3 level

1. Introduction

Breast cancer is a malignancy in breast tissue that can originate from the ductal epithelium or lobule [1]. The incidence of breast cancer in the world is 14.9 million new cases in 2012 [2]. Indonesia, the estimated incidence of breast cancer is 40.3 per 100,000 women or 48,998 new cases per year [3]. In East Kalimantan breast cancer ranked first with a total of 1879 cases [1]. Based on data obtained from the medical record of Abdul Wahab Sjahranie Hospital in Samarinda, the incidence of breast cancer from 2014 to September 2016 was 883 cases and the incidence of breast cancer in 2015 was 324 cases.

The molecular subtype of breast cancer cells is being developed as an initial step for selecting therapy and predicting the prognosis of breast cancer patients [4]. At the 2013 St. Gallen consensus breast cancer subtypes were grouped into types Luminal A, Luminal B, HER-2 positive, and triple-negative [5]. Luminal molecular subtypes, HER-2 overexpression, and Basal Like/TNBC are closely related to luminal maturation, luminal progenitors, and cell progenitors from normal breast tissue. Based on these findings, it was concluded that the less differentiated subtype lacked circulating antigens. Luminal subtypes are characterized by gene expression associated with high hormone receptors (HR), whereas the HER-2 or Basal Like/TNBC Overexpression subtype shows a low association of gene expression with HR [6].

Tumor markers play an important role in the early diagnosis and management of treatment plans [7]. Some tumor markers that can detect the presence of breast cancer, namely estrogen receptors, progesterone receptors, DNA ploidy, epidermal growth factor, HER2, p53 tumor gene suppressor, cathepsin D, a proliferation marker, CEA and Carbohydrate Antigen - (CA 15-3) [8].

CA 15-3 is an antigens protein called mucins, mucins is a transmembrane glycoprotein. MUC1 can be found in various organs, but what makes it different is the level of glycosylation, namely carbohydrate content in the tissue, the breast carbohydrate content is quite high compared to other organs, which reaches 50%. The exact function of MUC1 is not yet fully known, but some clear things are inhibiting cell-cell interaction and inhibiting cytolysis of tumor cells [8]. CA 15-3 is produced by epithelial secretions from the breast, lung, digestive tract, and ovaries. Increased levels of serum CA-15-3 concentrations of more than 30 U/ml are predominant in breast cancer patients [9]. CA 15-3 is a tumor marker specific to breast cancer [10]. Increased levels of CA 15-3 levels are more often found in molecular subtypes luminal compared to HER-2 or triple-negative overexpression. This is because the luminal type is affected by hormonal receptors [6]. In the case of metastases, elevated levels of CA 15-3 levels are found in breast cancer metastases of the liver and accompanied by pleural effusion [11]. In a recent review, the application of CA 15-3 most important is in monitoring therapy in patients with advanced breast cancer [12]. CA 15-3 in addition to being used to determine the prognosis can also be used as a diagnostic marker [10].

2. Methods

This study is a cross-sectional study to determine the association between molecular subtypes of locally advanced breast cancer with CA 15-3 level at Abdul Wahab Sjahranie Samarinda Hospital. The population in this study were all breast cancer patients that were confirmed by histopathological examination. The exclusion criteria were breast cancer patients with locally advanced stage who did not undergo IHC examination, breast cancer patients with locally advanced stage who did not undergo the CA-15-3 examination. Inclusion criteria were breast cancer patients who had not received previous therapy, breast cancer patients with locally advanced stage (Stage IIIB-IIIC). Locally advanced stage in this study based on AJCC criteria, luminal B and overexpression HER2 conforms to St. Gallen’s criteria,

Patients diagnosed with breast cancer who came to the Abdul Wahab Sjahranie Hospital, Samarinda had a breast cancer biopsy and a CA 15-3 level examination. After a biopsy, the biopsy tissue is examined to determine the immunohistochemicals present in the tissue. From immunohistochemistry, molecular subtypes will be obtained according to the criteria previously described. The known levels of CA 15-3 and immunohistochemicals were used by researchers to analyze the relationship between the two.

Tests for bivariate statistical analysis using Anova to see the association between molecular subtypes of locally advanced breast cancer with Ca 15-3 level. The results are statistically significant if the value isp < 0.05.

3. Results

A total of 75 patients were included for this study, 29 patients (38.7%) known as Overexpression HER2, 18 patients (24.0%) were Luminal B with HER2 (+), 11 patients (14.7%) were Luminal B with HER2 (−), 11 patients (14.7%) were Basal-like/TNBC, and 6 patients (8,0%) were Luminal A. From the ANOVA test, the value of p = 0.045 (p < 0.05) means there was an association between Ca 15-3 level and molecular subtypes in patients with locally advanced breast cancer at the Abdul Wahab Sjahranie Hospital in Samarinda 2017. In this study Ca 15-3 levels were obtained on average for Luminal A 16.98 U/mL, Luminal B with HER2 (−) 42.41 U/mL, Luminal B with HER2 (+) 73.75 U/mL, Overexpression HER2 47.73 U/mL, and Basal Like/TNBC 63.50 U/mL (Table 1).

After ANOVA test, followed by a Posthoc test using the Scheffe method to determine association Ca 15-3 levels with two molecular subtypes. Results are significant if p < 0.05. So in this study, the sub-types that have relationships are Luminal A with Luminal B with HER2 (−), luminal A with Luminal B with HER2 (+), Luminal A with Overexpression HER2, Luminal A with Basal Like/TNBC, Luminal B with HER2 (−) with Luminal B with HER2 (+), Luminal B with HER2 (−) with Basal Like/TNBC, Luminal B with HER2 (+) with HER2 Overexpression, and HER2 Overexpression with Basal Like/TNBC (Table 2).

The results showed that there was a relationship between luminal A and Ca 15-3 level with p = 0.045. The average Ca 15-3 level in luminal A is 16.98 U/mL. This is in accordance with Mudduwa, et al., which states that there is a relationship between luminal A and Ca 15-3 level. However, the study stated that there was an increase in Ca 15-3 levels of 30.4% in luminal A [13]. Another study by Shao Y, et al., stated that there was a relationship between luminal A and Ca 15-3 level with a p-value of 0.012. The study also stated that there was a slight increase in Ca 15-3 level in luminal A by 8.8% [7]. The luminal subtype A has a low Ki67 expression, with a value of less than 14% [5]. The Ki-67 expression is closely related to the proliferation and growth of tumor cells, widely used to identify pathological processes as markers of proliferation [14]. Ki67 expression is also important to know to determine therapy, based on Prihantono’s research in 2017, positive Ki67 will respond with neoadjuvant chemotherapy, while negative Ki67 does not respond with neoadjuvant chemotherapy [15].

The results showed that there was a relationship between luminal B HER + with Ca 15-3 level and luminal B HER - with Ca 15-3 level with p = 0.045. The average Ca 15-3 level in Luminal B with HER2 (+) is 73.75 U/mL, while in Luminal B with HER2 (−) is 42.41 U/mL. This is consistent with the study of Mudduwa, et al., which states that there is a relationship between luminal B and Ca 15-3 level. In this study, it was found that Ca 15-3 level in luminal B HER + increased by 30.4%. where the Ca 15-3 level in luminal B HER - increased by 24.2% [13]. Another study by Shao Y, et al., stated that there was a relationship between luminal B and Ca 15-3 level, an increase in Ca 15-3 level in luminal B obtained at 11.4% [7].

The results showed that there was a relationship between overexpression HER-2 and Ca 15-3 level with p = 0.045. The average Ca 15-3 level in overexpression HER-2 is 47.73 U/mL. This is in accordance with the research of Shao Y, et al., which states that there is a relationship between overexpression HER-2 with Ca 15-3 level, with a p-value of 0.012. However, this study found an increase in the Ca level of 15-3 by 27.3% in the molecular subtype of overexpression HER-2 [7]. In contrast study by Mudduwa’s, et al., which states that there is no relationship between overexpression HER-2 and Ca 15-3 level [13].

The results showed that there was a relationship between basal-like/TNBC and Ca 15-3 level with p = 0.045. The average Ca 15-3 level at basal-like/TNBC is 63.50 U/mL. This is consistent with the study of Mudduwa, et al., which states that there is a relationship between basal-like/TNBC with Ca 15-3 level. In this study Ca 15-3 level increased significantly in basal-like/TNBC molecular subtypes with a percentage of 48.0%. In addition, another study by Yang, et al., stated that there was a relationship between basal likes/TNBC and Ca 15-3 level with a p-value of 0.001 [16]. Another study by Shao Y, et al., stated that there was a relationship between basal likes/TNBC with Ca 15-3 level, where there was an increase in Ca 15-3 level by 18.9% at basal likes/TNBC [7]. In contrast to the above research, another research by Chanana, et al., stated that Ca 15-3 level at basal-like/TNBC was lower than non-basal likes/TNBC [17]. Poor prognosis is found in basal-like/TNBC with increased expression of B-Cell Lymphoma 2 (BCL-2) [18]. Other studies suggest that BCL-2 expression is not significantly related to pathological responses in patients with basal-like/TNBC and patients with BCL-2 negative is more sensitive to chemotherapy compared to positive BCL-2 [19]. This study is also supported by Prihantono’s study which states that BCL-2 cannot predict the neoadjuvant chemotherapy response [20].

5. Conclusion

In this study Ca 15-3 levels were obtained on average for Luminal A 16.98 U/mL, Luminal B with HER2 (−) 42.41 U/mL, Luminal B with HER2 (+) 73.75 U/mL, Overexpression HER2 47.73 U/mL, and Basal Like/TNBC 63.50 U/mL. Statistically, it was found that there was an association between Ca 15-3 levels and molecular subtypes in patients with locally advanced breast cancer at the Abdul Wahab Sjahranie Hospital in Samarinda 2017.