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ALDH1 Cancer Stem Cell Marker as a Prognostic Factor in Triple-Negative Breast Cancer

ALDH1 Cancer Stem Cell Marker as a Prognostic Factor in Triple-Negative Breast Cancer Hindawi International Journal of Surgical Oncology Volume 2020, Article ID 7863243, 7 pages https://doi.org/10.1155/2020/7863243 Research Article ALDH1 Cancer Stem Cell Marker as a Prognostic Factor in Triple-Negative Breast Cancer 1 1 1 2 Sonar Soni Panigoro, Dian Kurnia , Ahmad Kurnia , Samuel Johny Haryono, and Zafiral Azdi Albar Oncology Division Department of Surgery Cipto Mangunkusumo National Hospital, Faculty of Medicine Universitas Indonesia, Jakarta 10430, Indonesia Department of Surgical Oncology, Dharmais Hospital, National Cancer Hospital, Jakarta 11420, Indonesia Correspondence should be addressed to Dian Kurnia; diansurgeonjr@gmail.com Received 7 March 2020; Accepted 1 June 2020; Published 3 July 2020 Academic Editor: C. H. Yip Copyright © 2020 Sonar Soni Panigoro et al. *is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Breast cancer is the most common cancer with an increasing incidence in Asia. About 20% of all breast cancers are triple-negative breast cancers (TNBCs). BCSC is a subset of tumor cells that has stem cell-like characteristics, such as a high capacity for self- renewal and tumor initiation, which implies that BCSC may cause aggressiveness of TNBC. ALDH1 has a role in early stem cell differentiation through its function in the oxidation of retinol to retinoic acid, proposed to be a strong candidate for breast cancer stem cells. Various studies have shown that ALDH1 is one of the markers of CSC that can be used as a prognosis indicator because it can be a biological marker for poor prognostic factors in TNBC. *is study assessed the prognostic survival rate with a retrospective cohort method in TNBC patients. A total of 54 of 55 patients treated at RSCM were tested for the expression of ALDH1 through an immunohistochemistry assay of breast cancer tissue using ALDH1 staining. Survival analysis was done to obtain the prognostic data of ALDH1. Positive ALDH1 expression was obtained at 38.89% in TNBC patients. One-year survival and three years of survival in TNBC patients with positive ALDH1 expression were 42.9% and 33.3%, respectively. In this study, ALDH1 can be used as a poor survival prognostic factor with HR 2.636 and p value 0.013. *e conclusion of this study is that ALDH1 can be used as a poor prognostic factor in TNBC patients although it cannot be an independent prognostic factor. course including high metastasis to the visceral organs and 1. Background central nervous system [2]. TNBC has a higher prevalence in Breast cancer is the most common cancer with an increasing African Americans, more frequently affects younger patients incidence in Asia. According to GLOBOCAN 2012, the (average age <50 years), and is associated with a greater risk incidence of breast cancer in Indonesia was 40.31 per of mortality [3]. 100,000 women, with a death rate of 16.58 per 100,000 A study in Brazil shows that the overall survival was 62% women. *e five-year survival rate of patients with a di- for TNBC and 81% for non-TNBC and disease-free survival agnosis of localized, regionally metastasized, and remotely was 57% for TNBC and 75% for non-TNBC. *is tumor metastasized breast cancers were 98.5%, 84.6%, and 25%, subtype tended to show a worse clinical course, with earlier respectively [1]. and more frequent recurrence and worse 5-year survival, *ere are various types of tumors in breast cancers, compared with non-TNBC [4]. Aside from having a poor which also possess different characteristics, clinical out- prognosis, triple-negative breast cancers also pose a chal- comes, and therapeutic responses. About 20% of all breast lenge in terms of therapy. *erefore, new biologic markers cancers are triple-negative breast cancers (TNBCs) because for prognosis, including prediction of therapeutic resistance, they contain little estrogen and progesterone receptors and are needed. Among others are the breast cancer stem cells lack the HER2 gene. TNBC also has an aggressive clinical (BCSCs), which are believed to have a contribution to 2 International Journal of Surgical Oncology tumorigenesis, metastasis, and resistance against chemo- 2.3. Variable and Data Measurements. Data from medical therapy. Breast cancer stem cell is a subset of tumor cells that records of patients with triple-negative breast cancers from January 2010 to December 2016 were determined at a follow- has a characteristic of stem cells, having a high capacity of self-renewal and tumor initiations, which imply that BCSC up of three years since the diagnosis and were treated until may cause aggressiveness of TNBC [5]. the completion of the study. From the medical records, data *e majority of the biologic markers that are proven to regarding identities, epidemiological data, clinical data and have an association with TNBC resistance against therapy anamnesis, physical examinations, tumor size, clinical are found in the cytoplasm of TNBC cells. Identification of staging, and supporting examinations on the patients’ first cytoplasmic biologic markers in breast cancers, which are visit were obtained. *e anatomical pathology registration proteins that run in the PUKCA/AKT/mTOR pathways, number was recorded. From the registration number, data such as PIK3CA, PTEN, pAKT/pS6, metabolites, and al- about histopathological diagnosis, grading, and Ki67 were dehyde dehydrogenase 1 (ALDH1), is being widely devel- obtained. *ereafter, immunohistochemistry staining for oped [3]. ALDH1 was done on paraffin blocks from the specimens of tumor tissue biopsy. ALDH1, which has a role in the early differentiation of stem cells through its function in the oxidation of retinol to From the results of the staining specimens and ALDH1 retinoic acid, is suggested to be a strong candidate for cancer levels, which are independent variables, a sample group was stem cells in the breast. Various studies showed that ALDH1 divided into positive ALDH1 groups who had died, positive is one of the CSC markers that can be used as an inde- ALDH1 who had survived, negative ADLH1 who had died, pendent prognostic indicator in node-positive breast cancer and negative ADLH1 who had survived. After group divi- [6]. *ere has been no study of ALDH1 as a prognostic sion, survival analysis is carried out to determine the survival indicator for TNBC in Indonesia; therefore, this research is rate, as a dependent variable, with the hope of determining essential to be made. From this study, it is hoped that we can the survival rate for one year and three years. determine whether ALDH1 cancer stem cell markers are a In this study, sampling was not determined by age limits poor prognostic factor in triple-negative breast cancer pa- or specific criteria. Instead, we determined several variables that could influence the determination of prognostic factors tients. *erefore, we can determine survival rates for triple- negative breast cancer patients with ALDH1. in triple-negative patients, such as age (>50 years or <50 years), tumor size (T1, T2, T3, or T4), lymph node metas- tases (N0, N1, N2, or N3), distant metastases (present or 2. Methods not), histological grading (based on the Bloom and Richardson criteria), Ki67 (<20% or> 20%), local recurrence 2.1. Study Design. *is study was a retrospective cohort with (whether or not there is), and chemotherapy therapy that has a unique design of survival analysis. Data were obtained been given until before the study is conducted (NO and retrospectively from the medical records of the Oncology CEF/CAF) for analysis between variables with survival rates. Surgery and Anatomical Pathology departments at Cipto Mangunkusumo National General Hospital (RSCM), and then the history of recurrence and mortality were recorded. 2.4. Statistical Methods. After data were collected, we con- ducted a descriptive analysis to determine the characteristics of research subjects. *en, survival analysis using the 2.2. Sample. *e accessible population was patients who Kaplan–Meier method is performed to show the overall were firstly diagnosed with triple-negative breast cancers survival rate. Bivariate analysis was also performed between from January 2010 to December 2016 who came to RSCM, ALDH1 expression and survival rate (p< 0.05), as well as with an observation period until December 2017. *e analyzing the survival of the negative ALDH1 and positive sampling method is done by performing consecutive sam- ALDH1 groups using the Kaplan–Meier method. In the pling, using the sample size formula, and the sample size presence of confounding variables, an analysis of the rela- (n � 55) was obtained. *e sample that is used is all patients tionship between these variables and survival rate was who came to the oncology surgical clinic, who met the performed. From these results (p< 0.05), a multivariate inclusion criteria. *e sampling method was carried out by analysis was performed. obtaining the data of paraffin blocks from the anatomical pathology laboratory. All subjects who met the inclusion criteria were included in the study until the sample size was 2.5.EthicsStudy. *is study did not involve patients directly, fulfilled. and the sample that we used was a paraffin block. *is study Inclusion criteria were specimens of triple-negative was approved by the Faculty of Medicine, Universitas breast cancer paraffin blocks after immunochemistry ex- Indonesia Ethics Committee, with number 1072/UN2.F1/ amination was made, the specimens able to be adequately ETIK/2017. stained with ALDH1 immunochemistry staining, well- recorded medical records, and patients with triple-negative 3. Results breast cancers who already had therapy, whereas exclusion criteria included paraffin blocks that were considered broken *ere were 367 patients with TNBC who were admitted to or missing, broken specimens upon staining, and incomplete the oncology surgery department at RSCM from 2010 to medical records. 2016. Based on the inclusion and exclusion criteria, fifty five International Journal of Surgical Oncology 3 Table 1: Subject characteristics. samples were obtained. One sample was excluded due to damage to the paraffin block. *erefore, a total of 54 samples Variables Total Percentage participated in this study. Twenty four subjects (44.44%) Age experienced an event of interest, which was death due to any ≥50 years 25 46.30 reasons, and thirty subjects (55.56%) were alive until the end <50 years 29 53.70 of the observation period. *e observation period had a Tumor size (T) median of 21 months with an interval of 1 to 79 months. 1 2 3.70 Most of the subjects in this study were under the cate- 2 14 25.93 gories of younger than 50 years (53.70%), T4 tumor size 3 14 25.93 (44.44%), involvement of the N1 lymph node (57.41%), no 4 24 44.44 metastasis (72.22%), grade 2 histological grading (51.84%), Involvement of lymph nodes (N) Ki67≥ 20% (83.33%), stages 2 and 3 (35.19%), chemotherapy 0 15 27.78 TC (48.15%), no recurrence (77.78%), radiotherapy (57.41%), 1 31 57.41 2 4 7.41 and negatively expressed ALDH1 (61.11%) (Table 1). 3 4 7.41 *e survival analysis with the Kaplan–Meier method showed an overall survival rate in 12, 36, and 60 months as in Remote metastasis (M) Negative 39 72.22 Figure 1. From the bivariate analysis, there was an associ- Positive 15 27.78 ation between the expression of ALDH1 with the survival Histological grading rate, with HR 2.636 (95% CI 1.168–5.950), p � 0.013 (Ta- 1 2 3.70 ble 2). Besides, there was also a significantly different sur- 2 28 51.85 vival rate between negatively and positively expressed 3 24 44.44 ALDH1 against the survival rate of TNBC (log-rank Ki67 p � 0.013), where the negative ALDH1 group had a longer <20% 9 16.67 survival rate compared to those with positive ALDH1. ≥20% 45 83.33 Negative ALDH1 had a lifespan of 43 months, where pos- Staging itive ALDH1 had a lifespan of 24 months (Table 2). 1 1 1.85 From the Kaplan–Meier survival analysis, it can be seen 2 19 35.19 that at the beginning of the follow-up, the proportion be- 3 19 35.19 tween positive ALDH1 expressions occurred significantly in 4 15 27.78 the first year, whereas there were 12 deaths in the first year Chemotherapy on positive ALDH (Figure 2). TC 26 48.15 *e observation on the relationship between variables CAF/CEF 25 46.30 with the increase in the hazard ratio showed that the factors Others 3 5.56 which had a significant proportion of the hazard ratio were Recurrence T4 tumor size (HR 6.94 [95% CI 2.02–6.86] with p � 0.002), Negative 46 85.19 remote metastasis (HR 14.89 [95% CI 5.91–37.5] with Positive 8 14.81 p< 0.001), advanced stage (HR 38.31 [95% CI 8.25–177.95] Radiotherapy with p< 0.001), and other types of chemotherapy (HR 3.42 Negative 23 42.59 [95% CI 1.190–10.61] with p � 0.033). *e Ki67≥ 20% group Positive 31 57.41 had HR 1.24 (95% CI 0.422–3.630); however, it was not ALDH1 statistically significant (p � 0.697) (Table 3). Positive 21 38.89 Variables that have p value <0.05 in the bivariate analysis Negative 33 61.11 are included in multivariate analysis. Variables included in multivariate analysis were tumor size, distant metastases, staging, and chemotherapy. Nevertheless, based on the concept years, with a percentage of 25.9%. *e risk of patients aged of collinearity, where tumor size and metastasis are part of the ≥50 years was found to be 0.7 times less than those aged<50 stadium, only stadium and chemotherapy are included in years. However, the result was not considered to be sig- multivariate analysis. From the multivariate results, it was nificant since the p value was 0.535. found that HR reduced from ALDH 1 to 0.982. Changes in the Regarding tumor size, a significant result was found in adjusted hazard ratio for positive ALDH1 expression at each T4 tumor size compared to T1-T2 tumor size (p � 0.002). addition of confounding variables can be seen in Table 4. *e group with T4 size of the tumor appeared to have 6.94 times greater risk than the group with T1-T2 size of the tumor. However, the group with T3 size of tumor possessed 4. Discussion 0.859 hazard ratio. However, the result was not significant *e age range of patients in this study was 25 to 75 years, (p � 0.868). It was consistent with the study by Ma et al., with an average age of 50.9 years. According to the patient which showed that the result of overall survival was 1.253 characteristic data, twenty nine patients (53.70%) aged <50 times higher risk in tumor >2 cm than tumor <2 cm; years and 25 patients (46.30%) aged ≥50 years. *e highest however, it was not significant (p � 0.647). *e difference in number of mortality was found in the age group of <50 this study was that the grouping of tumor size was based on 4 International Journal of Surgical Oncology Survival function 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0 12 24 36 48 60 Time Figure 1: Kaplan–Meier curve for overall survival. Table 2: Relationship between ALDH1 and survival rate. Status Variables Alive Dead Mean survival rate (months) HR (95% CI) p value n % n % Negative 14 66.67 7 33.33 43 2.636 ALDH1 Positive 10 30.60 23 69.70 24 (1.168–5.950) 0.013 Total 24 44.44 30 55.56 the TNM criteria [7]. A significant result was also found in Survival functions the group with remote metastases than those without me- 1.0 tastases, with a risk of 14.98 times (p< 0.001). A significant result was found in terms of staging, which showed that the advanced stage group possessed 38.309 0.8 times higher risk compared to the early-stage group (p< 0.001). *e result of a locally advanced stage group revealed to have 4.544 times greater risk compared to the 0.6 early-stage group; however, it was not statistically significant (p � 0.059). *is finding was consistent with the study by Ma et al., which showed 5.511 times greater risk at stage III 0.4 compared to stage I-II with a p value of 0.033 [7]. In terms of chemotherapy, the group that received other types of chemotherapy had 3.422 times higher risk than 0.2 those with TC chemotherapy. *is result was statistically significant (p � 0.033). Besides, the group which acquired CAF/CEF chemotherapy was found to have 1.741 times greater risk compared to the group with TC chemotherapy. 0.0 However, this result was not statistically significant, with the 04 12 24 368 60 72 p value of 0.235. Time *e expression of positive ALDH1 was 38.89% from a ALDH1 total patient with TNBC in this study. *is finding did not Negative Negative-censored differ much from the study by Perou et al. (31.6%), Yoshioka Positive Positive-censored et al. (26%), and Zhou et al. (35%) [6, 8–10]. Figure 2: Kaplan–Meier curve which shows the survival rate of *e expression of ALDH1 was found to be statistically ALDH1. significant concerning survival rate and HR with a result of Cum survival Cum survival International Journal of Surgical Oncology 5 Table 3: Relationship between all variables and survival rate. Table 4: Crude HR and adjusted HR with 95% IK for ALDH1 expression for mortality in the gradual addition of confounding Status variables. Characteristics Died Live HR (IK 95%) p Variable expression ALDH HR (IK 95%) HR change (%) n % n % Crude HR 2.636 (1.168–5.950) Ages Adjusted HR ≥50 years 10 40.00 15 60.00 Reff + Stadium 0.969 (0.373–2.157) 63.24 1.294 <50 years 14 48.28 15 51.72 0.535 + Chemotherapy 0.982 (0.373–2.157) 1.3 (0.574–2.916) Tumor size T1-T2 3 20.00 12 80.00 Reff ALDH1 expression. It was consistent with the study by Ma 0.859 T3 2 14.29 12 85.71 0.868 et al. who found that TNBC with positive ALDH had a 2.368 (0.142–5.143) times risk compared to negative ALDH [7]. *e result was 6.935 T4 19 76.00 6 24.00 0.002 (2.019–23.819) statistically significant with a p value of 0.039. Similar results were also suggested by Zhou et al. (HR 19.186), Yoshioka Lymph node metastasis N0-N1 19 42.22 26 57.78 Reff et al. (HR 1.1930), Zhong et al. (HR 11.932), and Dewi, who 0.966 stated that positive ALDH1 expression suggested poor N2 2 50.00 2 50.00 0.963 (0.223–4.175) prognosis in patients with TNBC [6, 9–12]. 2.020 Ohi et al. stated that several studies had reported N3 3 60.00 2 40.00 0.260 (0.595–6.858) identifying aldehyde dehydrogenase 1 (ALDH1) as the Distant metastasis marker of the cancer stem cell, which was clinically sig- Negative 9 23.08 30 76.92 Reff nificant in indicating the prognosis of patients with breast 14.894 Positive 15 100.00 0 0.00 <0.001 cancer. *ey also found the prognosis of TNBC with positive (5.909–37.54) ALDH1 to be reduced. Besides, patients who experienced Histological grading nodal metastases with positive ALDH1 expression were also 1 1 50.00 1 50.00 Reff suggested to have poor prognosis. *ey also found that 0.603 2 12 42.86 16 57.14 0,628 (0.078–4.669) TNBC expresses ALDH1 more often than the other types of 0.631 breast cancer [13]. 3 11 45.83 13 54.17 0.661 (0,081–4,936) Research by Zhou et al. which studied the level of Ki67 ALDH1 and other factors measured with immunohisto- <20% 4 40.00 6 60.00 Reff chemistry staining, also supported those results. Zhou et al. 1.238 ≥20% 20 46.51 23 53.49 0.697 revealed that ALDH1 was higher in cases with TNBC (0.422–3.630) compared to non-TNBC cases (p � 0.015). CC3 staining and Stadium positive ALDH1 were significantly correlated with poor Early 2 10.00 18 90.00 Reff prognosis of breast cancer with the TNBC subtype. Besides, 4.544 Advance local 7 36.84 12 63.16 0.059 positive ALDH1 was also related to reduced overall survival (0.942–21.921) rate (RR � 2.83; 95% CI 2.16–3.67; p � 0.001). Stem cell 38.309 Advance 15 100.00 0 0.00 <0.001 (8.247–177.950) marker was a prognostic factor in breast cancer [9]. Chemotherapy Poor prognosis influenced by ALDH1 was described in TC 12 44.44 15 55.56 Reff the metabolic pathway of PIK3CA/AKT/mTOR of breast 1.741 cancer concerning grading and metastases. ALDH1 might CAF/CEF 8 38.10 13 61.90 0.235 (0.698–4.342) be suggested as the specific biomarker for TNBC in the 3.422 Others 4 80.00 1 20.00 0.033 future direction. Studies also identified a lower survival rate (1.103–10.610) with positive ALDH1 expression. ALDH1 catalyzes en- Recurrence dogenous and exogenous aldehyde oxidation into an in- Negative 21 45.65 25 54.35 Reff active carboxylic acid. ALDH1 is known to be a cytoplasmic Positive 3 37.50 5 62.50 1.493(0.444–5.024) 0.517 stem cell-related marker that was found in breast cancer, Radiotherapy and it was associated with tumor initiating cells. ALDH1 Negative 9 40.91 13 59.09 Reff expression is significantly correlated with tumor grade 0.811 Positive 15 48.39 16 51.61 0.620 (0.354–1.856) metastasis, and it may be associated with the enhancement of taxane- and epirubicin-based chemotherapy resistance [3]. 2.636 (p � 0.013). *is result showed that TNBC samples According to the other study by Zhong, positive with positive ALDH1 possessed 2.636 times higher risk ALDH1A1 cells were detected in 93 out of a total of 147 compared to those with negative ALDH1. *e survival time tumors (63.3%). Besides, eighty percent (32 of 40) tumors of patients with positive ALDH1 and negative ALDH1 was with strong ALDH1A1 staining showed early recurrence 24 months and 43 months, respectively. As described in the compared to 20.0% (8 of 40) tumors with negative Kaplan–Meier graph (Figure 2), the significant number of ALDH1A1 expression (p � 0.027). *e ALDH1A1 corre- mortality happened in the first year of those with positive lated significantly with malignant proliferations based on 6 International Journal of Surgical Oncology Ki67 staining (p � 0.001), indicating an association of the 5. Conclusion ALDH1A1 phenotype with malignant proliferation in in- In this study, we can conclude that the one-year survival rate vasive ductal carcinoma [11]. for triple-negative breast cancer patients with positive Moreover, Yoshioka et al. mentioned ALDH1 as the ALDH1 expression was 42.9% and the one-year survival rate detoxification agent, which oxidized intracellular aldehyde for triple-negative breast cancer patients with negative and caused the resistance of the alkylating agent. *e fact ALDH1 expression was 78.8%, also the three-year survival that ALDH1 possessed the ability to carry out detoxifica- rate for triple-negative breast cancer patients with positive tion by protecting the stem cell from the influence of ALDH1 expression was 33.3%, and the three-year survival oxidation explained the low response of therapy. Besides, rate for triple-negative breast cancer patients with negative ALDH1 also played a role in the conversion of retinol to ALDH1 expression was 72.7%. From the statistical analysis retinoic acid, which acted as the stimulus of stem cell of the data, ALDH1 can be used as a prognostic factor of proliferation. *us, it resulted in the low survival rate of poor survival in triple-negative breast cancer patients with a TNBC with positive ALDH1 expression [6]. Zhou et al. hazard ratio of 2.636 with a p value of 0.013 although it supported those findings by stating that positive ALDH1 cannot be an independent prognostic factor. expression was correlated with the resistance of chemo- therapy and poor prognosis [9]. *rough the chi-square test and multivariate analysis, this Data Availability study found that the clinicopathological factors, which influ- enced the statistical analysis of ALDH1 and survival rate, were *e data used and analyzed during the study are available the size of the tumor, advanced metastasis, advanced stage, and from the corresponding author upon request. chemotherapy. Yoshioka et al. found that large size tumors and high grades were associated with ALDH1 expression [6]. Also, Conflicts of Interest Ginister et al. mentioned the relationship of ALDH1 expression with high grade and poor OS, and Ohi et al. stated the as- *e researchers declare that there are no conflicts of interest sociation of high grade with ALDH1 expression [13]. Overall, in this study. almost all references in this study proposed that ALDH1 ex- pression was correlated with high grade. Acknowledgments ALDH1 is one of the ethanol metabolism principal enzymes which equip the human breast epithelium, so a role *e authors would like to thank Dr. Anggindita Diah comparison review with the other enzymes is needed. ADH, Widihidayati who assisted in the publication process of this ALDH, and ADH isoenzyme expressions are lower in tumor research. cells than in the normal cells [14]. *us, these enzymes are considered have important roles in carcinogenesis process. 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ALDH1 Cancer Stem Cell Marker as a Prognostic Factor in Triple-Negative Breast Cancer

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Copyright © 2020 Sonar Soni Panigoro et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Abstract

Hindawi International Journal of Surgical Oncology Volume 2020, Article ID 7863243, 7 pages https://doi.org/10.1155/2020/7863243 Research Article ALDH1 Cancer Stem Cell Marker as a Prognostic Factor in Triple-Negative Breast Cancer 1 1 1 2 Sonar Soni Panigoro, Dian Kurnia , Ahmad Kurnia , Samuel Johny Haryono, and Zafiral Azdi Albar Oncology Division Department of Surgery Cipto Mangunkusumo National Hospital, Faculty of Medicine Universitas Indonesia, Jakarta 10430, Indonesia Department of Surgical Oncology, Dharmais Hospital, National Cancer Hospital, Jakarta 11420, Indonesia Correspondence should be addressed to Dian Kurnia; diansurgeonjr@gmail.com Received 7 March 2020; Accepted 1 June 2020; Published 3 July 2020 Academic Editor: C. H. Yip Copyright © 2020 Sonar Soni Panigoro et al. *is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Breast cancer is the most common cancer with an increasing incidence in Asia. About 20% of all breast cancers are triple-negative breast cancers (TNBCs). BCSC is a subset of tumor cells that has stem cell-like characteristics, such as a high capacity for self- renewal and tumor initiation, which implies that BCSC may cause aggressiveness of TNBC. ALDH1 has a role in early stem cell differentiation through its function in the oxidation of retinol to retinoic acid, proposed to be a strong candidate for breast cancer stem cells. Various studies have shown that ALDH1 is one of the markers of CSC that can be used as a prognosis indicator because it can be a biological marker for poor prognostic factors in TNBC. *is study assessed the prognostic survival rate with a retrospective cohort method in TNBC patients. A total of 54 of 55 patients treated at RSCM were tested for the expression of ALDH1 through an immunohistochemistry assay of breast cancer tissue using ALDH1 staining. Survival analysis was done to obtain the prognostic data of ALDH1. Positive ALDH1 expression was obtained at 38.89% in TNBC patients. One-year survival and three years of survival in TNBC patients with positive ALDH1 expression were 42.9% and 33.3%, respectively. In this study, ALDH1 can be used as a poor survival prognostic factor with HR 2.636 and p value 0.013. *e conclusion of this study is that ALDH1 can be used as a poor prognostic factor in TNBC patients although it cannot be an independent prognostic factor. course including high metastasis to the visceral organs and 1. Background central nervous system [2]. TNBC has a higher prevalence in Breast cancer is the most common cancer with an increasing African Americans, more frequently affects younger patients incidence in Asia. According to GLOBOCAN 2012, the (average age <50 years), and is associated with a greater risk incidence of breast cancer in Indonesia was 40.31 per of mortality [3]. 100,000 women, with a death rate of 16.58 per 100,000 A study in Brazil shows that the overall survival was 62% women. *e five-year survival rate of patients with a di- for TNBC and 81% for non-TNBC and disease-free survival agnosis of localized, regionally metastasized, and remotely was 57% for TNBC and 75% for non-TNBC. *is tumor metastasized breast cancers were 98.5%, 84.6%, and 25%, subtype tended to show a worse clinical course, with earlier respectively [1]. and more frequent recurrence and worse 5-year survival, *ere are various types of tumors in breast cancers, compared with non-TNBC [4]. Aside from having a poor which also possess different characteristics, clinical out- prognosis, triple-negative breast cancers also pose a chal- comes, and therapeutic responses. About 20% of all breast lenge in terms of therapy. *erefore, new biologic markers cancers are triple-negative breast cancers (TNBCs) because for prognosis, including prediction of therapeutic resistance, they contain little estrogen and progesterone receptors and are needed. Among others are the breast cancer stem cells lack the HER2 gene. TNBC also has an aggressive clinical (BCSCs), which are believed to have a contribution to 2 International Journal of Surgical Oncology tumorigenesis, metastasis, and resistance against chemo- 2.3. Variable and Data Measurements. Data from medical therapy. Breast cancer stem cell is a subset of tumor cells that records of patients with triple-negative breast cancers from January 2010 to December 2016 were determined at a follow- has a characteristic of stem cells, having a high capacity of self-renewal and tumor initiations, which imply that BCSC up of three years since the diagnosis and were treated until may cause aggressiveness of TNBC [5]. the completion of the study. From the medical records, data *e majority of the biologic markers that are proven to regarding identities, epidemiological data, clinical data and have an association with TNBC resistance against therapy anamnesis, physical examinations, tumor size, clinical are found in the cytoplasm of TNBC cells. Identification of staging, and supporting examinations on the patients’ first cytoplasmic biologic markers in breast cancers, which are visit were obtained. *e anatomical pathology registration proteins that run in the PUKCA/AKT/mTOR pathways, number was recorded. From the registration number, data such as PIK3CA, PTEN, pAKT/pS6, metabolites, and al- about histopathological diagnosis, grading, and Ki67 were dehyde dehydrogenase 1 (ALDH1), is being widely devel- obtained. *ereafter, immunohistochemistry staining for oped [3]. ALDH1 was done on paraffin blocks from the specimens of tumor tissue biopsy. ALDH1, which has a role in the early differentiation of stem cells through its function in the oxidation of retinol to From the results of the staining specimens and ALDH1 retinoic acid, is suggested to be a strong candidate for cancer levels, which are independent variables, a sample group was stem cells in the breast. Various studies showed that ALDH1 divided into positive ALDH1 groups who had died, positive is one of the CSC markers that can be used as an inde- ALDH1 who had survived, negative ADLH1 who had died, pendent prognostic indicator in node-positive breast cancer and negative ADLH1 who had survived. After group divi- [6]. *ere has been no study of ALDH1 as a prognostic sion, survival analysis is carried out to determine the survival indicator for TNBC in Indonesia; therefore, this research is rate, as a dependent variable, with the hope of determining essential to be made. From this study, it is hoped that we can the survival rate for one year and three years. determine whether ALDH1 cancer stem cell markers are a In this study, sampling was not determined by age limits poor prognostic factor in triple-negative breast cancer pa- or specific criteria. Instead, we determined several variables that could influence the determination of prognostic factors tients. *erefore, we can determine survival rates for triple- negative breast cancer patients with ALDH1. in triple-negative patients, such as age (>50 years or <50 years), tumor size (T1, T2, T3, or T4), lymph node metas- tases (N0, N1, N2, or N3), distant metastases (present or 2. Methods not), histological grading (based on the Bloom and Richardson criteria), Ki67 (<20% or> 20%), local recurrence 2.1. Study Design. *is study was a retrospective cohort with (whether or not there is), and chemotherapy therapy that has a unique design of survival analysis. Data were obtained been given until before the study is conducted (NO and retrospectively from the medical records of the Oncology CEF/CAF) for analysis between variables with survival rates. Surgery and Anatomical Pathology departments at Cipto Mangunkusumo National General Hospital (RSCM), and then the history of recurrence and mortality were recorded. 2.4. Statistical Methods. After data were collected, we con- ducted a descriptive analysis to determine the characteristics of research subjects. *en, survival analysis using the 2.2. Sample. *e accessible population was patients who Kaplan–Meier method is performed to show the overall were firstly diagnosed with triple-negative breast cancers survival rate. Bivariate analysis was also performed between from January 2010 to December 2016 who came to RSCM, ALDH1 expression and survival rate (p< 0.05), as well as with an observation period until December 2017. *e analyzing the survival of the negative ALDH1 and positive sampling method is done by performing consecutive sam- ALDH1 groups using the Kaplan–Meier method. In the pling, using the sample size formula, and the sample size presence of confounding variables, an analysis of the rela- (n � 55) was obtained. *e sample that is used is all patients tionship between these variables and survival rate was who came to the oncology surgical clinic, who met the performed. From these results (p< 0.05), a multivariate inclusion criteria. *e sampling method was carried out by analysis was performed. obtaining the data of paraffin blocks from the anatomical pathology laboratory. All subjects who met the inclusion criteria were included in the study until the sample size was 2.5.EthicsStudy. *is study did not involve patients directly, fulfilled. and the sample that we used was a paraffin block. *is study Inclusion criteria were specimens of triple-negative was approved by the Faculty of Medicine, Universitas breast cancer paraffin blocks after immunochemistry ex- Indonesia Ethics Committee, with number 1072/UN2.F1/ amination was made, the specimens able to be adequately ETIK/2017. stained with ALDH1 immunochemistry staining, well- recorded medical records, and patients with triple-negative 3. Results breast cancers who already had therapy, whereas exclusion criteria included paraffin blocks that were considered broken *ere were 367 patients with TNBC who were admitted to or missing, broken specimens upon staining, and incomplete the oncology surgery department at RSCM from 2010 to medical records. 2016. Based on the inclusion and exclusion criteria, fifty five International Journal of Surgical Oncology 3 Table 1: Subject characteristics. samples were obtained. One sample was excluded due to damage to the paraffin block. *erefore, a total of 54 samples Variables Total Percentage participated in this study. Twenty four subjects (44.44%) Age experienced an event of interest, which was death due to any ≥50 years 25 46.30 reasons, and thirty subjects (55.56%) were alive until the end <50 years 29 53.70 of the observation period. *e observation period had a Tumor size (T) median of 21 months with an interval of 1 to 79 months. 1 2 3.70 Most of the subjects in this study were under the cate- 2 14 25.93 gories of younger than 50 years (53.70%), T4 tumor size 3 14 25.93 (44.44%), involvement of the N1 lymph node (57.41%), no 4 24 44.44 metastasis (72.22%), grade 2 histological grading (51.84%), Involvement of lymph nodes (N) Ki67≥ 20% (83.33%), stages 2 and 3 (35.19%), chemotherapy 0 15 27.78 TC (48.15%), no recurrence (77.78%), radiotherapy (57.41%), 1 31 57.41 2 4 7.41 and negatively expressed ALDH1 (61.11%) (Table 1). 3 4 7.41 *e survival analysis with the Kaplan–Meier method showed an overall survival rate in 12, 36, and 60 months as in Remote metastasis (M) Negative 39 72.22 Figure 1. From the bivariate analysis, there was an associ- Positive 15 27.78 ation between the expression of ALDH1 with the survival Histological grading rate, with HR 2.636 (95% CI 1.168–5.950), p � 0.013 (Ta- 1 2 3.70 ble 2). Besides, there was also a significantly different sur- 2 28 51.85 vival rate between negatively and positively expressed 3 24 44.44 ALDH1 against the survival rate of TNBC (log-rank Ki67 p � 0.013), where the negative ALDH1 group had a longer <20% 9 16.67 survival rate compared to those with positive ALDH1. ≥20% 45 83.33 Negative ALDH1 had a lifespan of 43 months, where pos- Staging itive ALDH1 had a lifespan of 24 months (Table 2). 1 1 1.85 From the Kaplan–Meier survival analysis, it can be seen 2 19 35.19 that at the beginning of the follow-up, the proportion be- 3 19 35.19 tween positive ALDH1 expressions occurred significantly in 4 15 27.78 the first year, whereas there were 12 deaths in the first year Chemotherapy on positive ALDH (Figure 2). TC 26 48.15 *e observation on the relationship between variables CAF/CEF 25 46.30 with the increase in the hazard ratio showed that the factors Others 3 5.56 which had a significant proportion of the hazard ratio were Recurrence T4 tumor size (HR 6.94 [95% CI 2.02–6.86] with p � 0.002), Negative 46 85.19 remote metastasis (HR 14.89 [95% CI 5.91–37.5] with Positive 8 14.81 p< 0.001), advanced stage (HR 38.31 [95% CI 8.25–177.95] Radiotherapy with p< 0.001), and other types of chemotherapy (HR 3.42 Negative 23 42.59 [95% CI 1.190–10.61] with p � 0.033). *e Ki67≥ 20% group Positive 31 57.41 had HR 1.24 (95% CI 0.422–3.630); however, it was not ALDH1 statistically significant (p � 0.697) (Table 3). Positive 21 38.89 Variables that have p value <0.05 in the bivariate analysis Negative 33 61.11 are included in multivariate analysis. Variables included in multivariate analysis were tumor size, distant metastases, staging, and chemotherapy. Nevertheless, based on the concept years, with a percentage of 25.9%. *e risk of patients aged of collinearity, where tumor size and metastasis are part of the ≥50 years was found to be 0.7 times less than those aged<50 stadium, only stadium and chemotherapy are included in years. However, the result was not considered to be sig- multivariate analysis. From the multivariate results, it was nificant since the p value was 0.535. found that HR reduced from ALDH 1 to 0.982. Changes in the Regarding tumor size, a significant result was found in adjusted hazard ratio for positive ALDH1 expression at each T4 tumor size compared to T1-T2 tumor size (p � 0.002). addition of confounding variables can be seen in Table 4. *e group with T4 size of the tumor appeared to have 6.94 times greater risk than the group with T1-T2 size of the tumor. However, the group with T3 size of tumor possessed 4. Discussion 0.859 hazard ratio. However, the result was not significant *e age range of patients in this study was 25 to 75 years, (p � 0.868). It was consistent with the study by Ma et al., with an average age of 50.9 years. According to the patient which showed that the result of overall survival was 1.253 characteristic data, twenty nine patients (53.70%) aged <50 times higher risk in tumor >2 cm than tumor <2 cm; years and 25 patients (46.30%) aged ≥50 years. *e highest however, it was not significant (p � 0.647). *e difference in number of mortality was found in the age group of <50 this study was that the grouping of tumor size was based on 4 International Journal of Surgical Oncology Survival function 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0 12 24 36 48 60 Time Figure 1: Kaplan–Meier curve for overall survival. Table 2: Relationship between ALDH1 and survival rate. Status Variables Alive Dead Mean survival rate (months) HR (95% CI) p value n % n % Negative 14 66.67 7 33.33 43 2.636 ALDH1 Positive 10 30.60 23 69.70 24 (1.168–5.950) 0.013 Total 24 44.44 30 55.56 the TNM criteria [7]. A significant result was also found in Survival functions the group with remote metastases than those without me- 1.0 tastases, with a risk of 14.98 times (p< 0.001). A significant result was found in terms of staging, which showed that the advanced stage group possessed 38.309 0.8 times higher risk compared to the early-stage group (p< 0.001). *e result of a locally advanced stage group revealed to have 4.544 times greater risk compared to the 0.6 early-stage group; however, it was not statistically significant (p � 0.059). *is finding was consistent with the study by Ma et al., which showed 5.511 times greater risk at stage III 0.4 compared to stage I-II with a p value of 0.033 [7]. In terms of chemotherapy, the group that received other types of chemotherapy had 3.422 times higher risk than 0.2 those with TC chemotherapy. *is result was statistically significant (p � 0.033). Besides, the group which acquired CAF/CEF chemotherapy was found to have 1.741 times greater risk compared to the group with TC chemotherapy. 0.0 However, this result was not statistically significant, with the 04 12 24 368 60 72 p value of 0.235. Time *e expression of positive ALDH1 was 38.89% from a ALDH1 total patient with TNBC in this study. *is finding did not Negative Negative-censored differ much from the study by Perou et al. (31.6%), Yoshioka Positive Positive-censored et al. (26%), and Zhou et al. (35%) [6, 8–10]. Figure 2: Kaplan–Meier curve which shows the survival rate of *e expression of ALDH1 was found to be statistically ALDH1. significant concerning survival rate and HR with a result of Cum survival Cum survival International Journal of Surgical Oncology 5 Table 3: Relationship between all variables and survival rate. Table 4: Crude HR and adjusted HR with 95% IK for ALDH1 expression for mortality in the gradual addition of confounding Status variables. Characteristics Died Live HR (IK 95%) p Variable expression ALDH HR (IK 95%) HR change (%) n % n % Crude HR 2.636 (1.168–5.950) Ages Adjusted HR ≥50 years 10 40.00 15 60.00 Reff + Stadium 0.969 (0.373–2.157) 63.24 1.294 <50 years 14 48.28 15 51.72 0.535 + Chemotherapy 0.982 (0.373–2.157) 1.3 (0.574–2.916) Tumor size T1-T2 3 20.00 12 80.00 Reff ALDH1 expression. It was consistent with the study by Ma 0.859 T3 2 14.29 12 85.71 0.868 et al. who found that TNBC with positive ALDH had a 2.368 (0.142–5.143) times risk compared to negative ALDH [7]. *e result was 6.935 T4 19 76.00 6 24.00 0.002 (2.019–23.819) statistically significant with a p value of 0.039. Similar results were also suggested by Zhou et al. (HR 19.186), Yoshioka Lymph node metastasis N0-N1 19 42.22 26 57.78 Reff et al. (HR 1.1930), Zhong et al. (HR 11.932), and Dewi, who 0.966 stated that positive ALDH1 expression suggested poor N2 2 50.00 2 50.00 0.963 (0.223–4.175) prognosis in patients with TNBC [6, 9–12]. 2.020 Ohi et al. stated that several studies had reported N3 3 60.00 2 40.00 0.260 (0.595–6.858) identifying aldehyde dehydrogenase 1 (ALDH1) as the Distant metastasis marker of the cancer stem cell, which was clinically sig- Negative 9 23.08 30 76.92 Reff nificant in indicating the prognosis of patients with breast 14.894 Positive 15 100.00 0 0.00 <0.001 cancer. *ey also found the prognosis of TNBC with positive (5.909–37.54) ALDH1 to be reduced. Besides, patients who experienced Histological grading nodal metastases with positive ALDH1 expression were also 1 1 50.00 1 50.00 Reff suggested to have poor prognosis. *ey also found that 0.603 2 12 42.86 16 57.14 0,628 (0.078–4.669) TNBC expresses ALDH1 more often than the other types of 0.631 breast cancer [13]. 3 11 45.83 13 54.17 0.661 (0,081–4,936) Research by Zhou et al. which studied the level of Ki67 ALDH1 and other factors measured with immunohisto- <20% 4 40.00 6 60.00 Reff chemistry staining, also supported those results. Zhou et al. 1.238 ≥20% 20 46.51 23 53.49 0.697 revealed that ALDH1 was higher in cases with TNBC (0.422–3.630) compared to non-TNBC cases (p � 0.015). CC3 staining and Stadium positive ALDH1 were significantly correlated with poor Early 2 10.00 18 90.00 Reff prognosis of breast cancer with the TNBC subtype. Besides, 4.544 Advance local 7 36.84 12 63.16 0.059 positive ALDH1 was also related to reduced overall survival (0.942–21.921) rate (RR � 2.83; 95% CI 2.16–3.67; p � 0.001). Stem cell 38.309 Advance 15 100.00 0 0.00 <0.001 (8.247–177.950) marker was a prognostic factor in breast cancer [9]. Chemotherapy Poor prognosis influenced by ALDH1 was described in TC 12 44.44 15 55.56 Reff the metabolic pathway of PIK3CA/AKT/mTOR of breast 1.741 cancer concerning grading and metastases. ALDH1 might CAF/CEF 8 38.10 13 61.90 0.235 (0.698–4.342) be suggested as the specific biomarker for TNBC in the 3.422 Others 4 80.00 1 20.00 0.033 future direction. Studies also identified a lower survival rate (1.103–10.610) with positive ALDH1 expression. ALDH1 catalyzes en- Recurrence dogenous and exogenous aldehyde oxidation into an in- Negative 21 45.65 25 54.35 Reff active carboxylic acid. ALDH1 is known to be a cytoplasmic Positive 3 37.50 5 62.50 1.493(0.444–5.024) 0.517 stem cell-related marker that was found in breast cancer, Radiotherapy and it was associated with tumor initiating cells. ALDH1 Negative 9 40.91 13 59.09 Reff expression is significantly correlated with tumor grade 0.811 Positive 15 48.39 16 51.61 0.620 (0.354–1.856) metastasis, and it may be associated with the enhancement of taxane- and epirubicin-based chemotherapy resistance [3]. 2.636 (p � 0.013). *is result showed that TNBC samples According to the other study by Zhong, positive with positive ALDH1 possessed 2.636 times higher risk ALDH1A1 cells were detected in 93 out of a total of 147 compared to those with negative ALDH1. *e survival time tumors (63.3%). Besides, eighty percent (32 of 40) tumors of patients with positive ALDH1 and negative ALDH1 was with strong ALDH1A1 staining showed early recurrence 24 months and 43 months, respectively. As described in the compared to 20.0% (8 of 40) tumors with negative Kaplan–Meier graph (Figure 2), the significant number of ALDH1A1 expression (p � 0.027). *e ALDH1A1 corre- mortality happened in the first year of those with positive lated significantly with malignant proliferations based on 6 International Journal of Surgical Oncology Ki67 staining (p � 0.001), indicating an association of the 5. Conclusion ALDH1A1 phenotype with malignant proliferation in in- In this study, we can conclude that the one-year survival rate vasive ductal carcinoma [11]. for triple-negative breast cancer patients with positive Moreover, Yoshioka et al. mentioned ALDH1 as the ALDH1 expression was 42.9% and the one-year survival rate detoxification agent, which oxidized intracellular aldehyde for triple-negative breast cancer patients with negative and caused the resistance of the alkylating agent. *e fact ALDH1 expression was 78.8%, also the three-year survival that ALDH1 possessed the ability to carry out detoxifica- rate for triple-negative breast cancer patients with positive tion by protecting the stem cell from the influence of ALDH1 expression was 33.3%, and the three-year survival oxidation explained the low response of therapy. Besides, rate for triple-negative breast cancer patients with negative ALDH1 also played a role in the conversion of retinol to ALDH1 expression was 72.7%. From the statistical analysis retinoic acid, which acted as the stimulus of stem cell of the data, ALDH1 can be used as a prognostic factor of proliferation. *us, it resulted in the low survival rate of poor survival in triple-negative breast cancer patients with a TNBC with positive ALDH1 expression [6]. Zhou et al. hazard ratio of 2.636 with a p value of 0.013 although it supported those findings by stating that positive ALDH1 cannot be an independent prognostic factor. expression was correlated with the resistance of chemo- therapy and poor prognosis [9]. *rough the chi-square test and multivariate analysis, this Data Availability study found that the clinicopathological factors, which influ- enced the statistical analysis of ALDH1 and survival rate, were *e data used and analyzed during the study are available the size of the tumor, advanced metastasis, advanced stage, and from the corresponding author upon request. chemotherapy. Yoshioka et al. found that large size tumors and high grades were associated with ALDH1 expression [6]. Also, Conflicts of Interest Ginister et al. mentioned the relationship of ALDH1 expression with high grade and poor OS, and Ohi et al. stated the as- *e researchers declare that there are no conflicts of interest sociation of high grade with ALDH1 expression [13]. Overall, in this study. almost all references in this study proposed that ALDH1 ex- pression was correlated with high grade. Acknowledgments ALDH1 is one of the ethanol metabolism principal enzymes which equip the human breast epithelium, so a role *e authors would like to thank Dr. Anggindita Diah comparison review with the other enzymes is needed. ADH, Widihidayati who assisted in the publication process of this ALDH, and ADH isoenzyme expressions are lower in tumor research. cells than in the normal cells [14]. *us, these enzymes are considered have important roles in carcinogenesis process. 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International Journal of Surgical Oncology – Hindawi Publishing Corporation

Published: Jul 3, 2020

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