Abstract
Background:
Breast cancer is the most common cancer in Myanmar women. Revealing the hormonal receptor status, human epidermal growth factor receptor 2 (HER2) and Ki-67 expression is useful for estimating patient prognosis as well as determination of treatment strategy. However, immunohistochemical features and classification of molecular subtypes in breast cancers from Myanmar remain unknown.
Methods:
The clinicopathological features of 91 breast cancers from Myanmar women were examined. Immunohistochemistry was performed on tissue specimens with antibodies to estrogen receptor (ER), progesterone receptor (PgR), HER2, Ki-67, cytokeratin (CK)5/6 and CK14. Immunohistochemistry-based molecular subtyping was conducted.
Results:
Breast cancers in Myanmar women were relatively large, high grade with frequent metastatic lymph nodes. Of the 91 patients, tumors with ER positive, PgR positive, and HER2 positive were 57.1%, 37.4%, and 28.6%, respectively. The most prevalent subtype was luminal B (HER2-) (39.6%), followed by HER2 (22.0%), triple negative (TN)-basal-like (12.1%), luminal A (11.0%), TN-null (8.8%) and luminal B (HER2+) (6.6%). The mean Ki-67 expression of 91 cases was 33.9% (33.9% ± 19.2%) and the median was 28% (range; 4%-90%). The mean Ki-67 expression of luminal A, luminal B, HER2 and TN-basal-like/null was 7%, 30%, 40%, and 57%/43%, respectively. A higher Ki-67 expression significantly correlated with a higher grade, larger size and higher stage of malignancy.
Conclusions:
We, for the first time, investigated the histopathological features of breast cancers from Myanmar women. Myanmar breast cancers appeared to be aggressive in nature, as evidenced by high frequency of poor-prognosis subtypes with high level of Ki-67 expression.
Keywords: Breast cancer, molecular subtypes, Ki-67 expression, Myanmar
Introduction
Breast cancer is a heterogeneous disease, composed of many morphological and molecular entities. The heterogeneity reflects different clinical outcomes (Polyak, 2007). By gene expression profiling, breast cancer is classified into 5 intrinsic subtypes (Perou et al., 2000; Sølie et al., 2001). For clinicopathological practice, 5 molecular subtypes, luminal A, luminal B (HER2-), luminal B (HER2+), HER2 and triple negative (TN), are defined based on the expression of estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), and Ki-67 (Goldhirsch et al., 2011). TN was subdivided into two subtypes, basal-like and null (Nielsen et al., 2004; Chuangsuwanich et al., 2014). It is well known that molecular subtypes are important biological markers not only for predicting prognosis but for decisions of effective treatment (Blows et al., 2010; Engstrø et al., 2013; Sung et al., 2016). Luminal types are cancers with a better prognosis in comparison to non-luminal types. Luminal breast cancer subtypes were found to predominate across racial/ethnic groups, while frequency of TN breast cancer progressively increases among white American, African-American, and Ghanaian/Africans (Amirikia et al., 2011; Huo et al., 2009; Kurian et al., 2010; Stark et al., 2010).
As with other countries, breast cancer is a leading cause of morbidity and mortality in Myanmar women (Moore, 2014). The aim of this study was to unveil the histopathological features and molecular subtypes in Myanmar breast cancer patients. We analyzed the clinicopathological characteristics and expression patterns of ER/PgR/HER2/Ki-67 using 91 female patients with breast cancer.
Materials and Methods
Study subjects
A total of 91 female patients diagnosed with breast cancer in the year 2015 were retrieved from pathology records at Myeik General Hospital (Myeik City, Myanmar) and Sakura Specialist Hospital (Yangon City, Myanmar). Clinicopathological data such as age, tumor size, lymph node and distant metastasis status were retrieved from the clinical and pathology records. All hematoxylin and eosin-stained sections were reviewed by two independent pathologists. Criteria defined by the World Health Organization (2012) were used for the histopathological diagnosis and classification of breast carcinoma. Nottingham combined histological grading system (Elston and Ellis, 1991) was used for tumor grading. American Joint Committee on Cancer staging system 8th edition was applied for tumor staging. The experimental protocol employed in this study was approved by the Ethics Committee of Okayama University (Japan) and the Ethics Review Committee of Department of Medical Research of Yangon City (Myanmar).
Immunohistochemical analysis
Immunohistochemistry was performed by using standardized automated techniques according to the manufacturer’s protocol. Tissue sections were stained with antibodies ER (SP1), PgR (1E2), HER2 (4B5), Ki-67 (MIB-1), cytokeratin (CK) 5/6 (D5/16B4) and CK14 (LL002) using a Discovery XT autostainer with iVIEW DAB detection kit (Ventana Medical Systems, Tucson, Arizona). In case of ER/PgR, a staining > 1% of tumor cell nuclei was considered positive (Hammond et al., 2010). HER2 was analyzed according to the American Society of Clinical Oncology and College of American Pathologists (Wolff et al., 2013). A score of 0 to 1+ was considered as negative and 3+ as positive. Specimens with score of 2+ were analyzed by HER2 dual-color in situ hybridization at Hyogo Clinical Laboratory Cooperation (Himeji City, Japan). Ki-67 labeling index was defined as the percentage of positive nuclei, in which over 500 tumor cells were counted in each case. CK5/6 and CK14 were scored positive if any (weak or strong) cytoplasmic and/or membranous staining was observed. Breast cancers were classified into 5 molecular subtypes according to the St. Gallen International Expert Consensus 2011 (Goldhirsch et al., 2011): luminal A; ER/PgR+/HER2-/Ki-67<14%, luminal B (HER2-); ER/PgR+/HER2-/Ki-67≥14%, luminal B (HER2+); ER/PgR+/HER2+/any Ki-67 percentage, HER2; ER/PgR-/HER2+, and TN; ER/PgR-/HER2-. TN subtype was further subdivided into basal-like type (ER/PgR-/HER2- with CK5/6+ and/or CK14+) and null type (ER/PgR-/HER2-/ CK5/6-/CK14-).
Statistical analysis
Statistical analyses were performed using SPSS software version 16.0. Fisher’s exact test was used for data categorized into 2 × 2 contingency tables. The age, mitosis count and Ki-67 expression were reported using descriptive statistics and Mann Whitney U test to compare the mean of the variables. Two-sided tests were used for all analyses and p value <0.05 was considered as significant.
Results
Patient characteristics
Clinical data for the enrolled 91 female patients with breast cancer were shown in Table 1. Ages ranged from 30 to 81 years with mean age of 51.3. Tumor sizes ranged from 1.5 cm to 7.2 cm with average size of 4.0 cm. Most of the cancers (94.5%) were invasive carcinoma of no special type (NST) with high histological grade (grade II; 46.2%, grade III; 53.8%). No grade I tumor was found. There were lymph node metastases in 57.1% of patients. The numbers of patients with stage I, II, III and IV were 6 (6.6%), 50 (54.9%), 31 (34.1%) and 4 (4.4%), respectively.
Table 1.
Clinical Data for the Enrolled Breast Cancer Patients
| Categories | Number of Cases (%) |
|---|---|
| Age (years) | |
| <35 | 4 (4.4) |
| 35-50 | 39 (42.9) |
| >50 | 48 (52.7) |
| Tumor size (cm) | |
| ≤2.0 | 6 (6.6) |
| 2.1-5.0 | 61 (67.0) |
| >5.0 | 24 (26.4) |
| Histological type | |
| Invasive carcinoma of no special type (NST) | 86 (94.5) |
| Mucinous carcinoma | 2 (2.2) |
| Carcinoma with neuroendocrine differentiation | 2 (2.2) |
| Pleomorphic lobular carcinoma | 1 (1.1) |
| Histological grade | |
| Grade I | 0 (0.0) |
| Grade II | 42 (46.2) |
| Grade III | 49 (53.8) |
| Metastatic lymph node | |
| Absent | 39 (42.9) |
| Present | 52 (57.1) |
| Staging | |
| Stage I | 6 (6.6) |
| Stage II | 50 (54.9) |
| Stage III | 31 (34.1) |
| Stage IV | 4 (4.4) |
Molecular subtypes and immunophenotypic analyses
ER positive, PgR positive and HER2 positive cases were 57.1%, 37.4% and 28.6%, respectively. Molecular subtypes and clinicopathological features of 91 breast cancers were shown in Table 2. The frequency of luminal A, a good prognostic subtype, was 11.0%. The most common subtype (39.6%) was luminal B (HER2-). Poor-prognosis subtypes, HER2 and TN subtypes, were 22.0 and 20.9%, respectively. Among TN subtypes, 11 cases (12.1%) were basal-like type (7 cases; CK5/6+ and CK14+, 4 cases; CK5/6- and CK14+) and 8 cases (8.8%) were null type. Compared to luminal A as the reference, tumors larger than 2 cm were more in HER2 subtype. TN-basal-like also tended to be larger than 2 cm although it was not statistically significant. Histological grade III (poorly differentiated) was more frequently found in non-luminal A subtypes, particularly in TN-basal-like and HER2, with more advanced stages at diagnosis (stage II, III and IV). As compared to luminal A, HER2 subtype tended to metastasize to lymph nodes, although it was not statistically significant (Table 2). The mean Ki-67 index of all 91 cases was 33.9% (mean ± SD, 33.9 ± 19.2) and the median score was 28% (range; 4%-90%). In the subtype analyses, the mean Ki-67 expression was increased in the following order; luminal A < luminal B < HER2 < TN (null<basal-like), which corresponded well to the increased number of mitoses (Table 2).
Table 2.
Molecular Subtypes and Clinicopathological Features of Breast Cancers
| Luminal A | Luminal B | HER2 | Triple Negative | Total | |||
|---|---|---|---|---|---|---|---|
| HER2- | HER2+ | basal-like | null | ||||
| Number (%) | 10 (11.0) | 36 (39.6) | 6 (6.6) | 20 (22.0) | 11 (12.1) | 8 (8.8) | 91 |
| Age (years) | |||||||
| Mean (range) | 58 (42-81) | 52 (32-75) | 47 (30-60) | 51 (30-74) | 49 (35-62) | 50 (37-67) | |
| p value | reference | 0.158 | 0.103 | 0.134 | 0.121 | 0.142 | |
| Tumor Size | |||||||
| ≤2cm | 3 | 2 | 1 | 0 | 0 | 0 | 6 |
| >2cm | 7 | 34 | 5 | 20 | 11 | 8 | 85 |
| p value | reference | 0.061 | 1 | 0.030* | 0.09 | 0.216 | |
| Histological grade | |||||||
| Grade II | 10 | 25 | 1 | 2 | 1 | 3 | 42 |
| Grade III | 0 | 11 | 5 | 18 | 10 | 5 | 49 |
| p value | reference | 0.088 | 0.001* | <0.001* | <0.001* | 0.007* | |
| Nodal status | |||||||
| negative | 7 | 15 | 2 | 6 | 7 | 2 | 39 |
| positive | 3 | 21 | 4 | 14 | 4 | 6 | 52 |
| p value | reference | 0.159 | 0.302 | 0.056 | 1 | 0.153 | |
| Stage | |||||||
| Stage I | 3 | 2 | 1 | 0 | 0 | 0 | 6 |
| Stage II to IV | 7 | 34 | 5 | 20 | 11 | 8 | 85 |
| p value | reference | 0.061 | 1 | 0.030* | 0.09 | 0.216 | |
| Ki-67 expression | |||||||
| Mean (range) | 7 (4-13) | 30 (17-80) | 30 (9-54) | 40 (18-77) | 57 (26-90) | 43 (20-75) | |
| p value | reference | <0.001* | 0.003* | <0.001* | <0.001* | <0.001* | |
| Mitoses/10HPF | |||||||
| Mean (range) | 12 (6-20) | 27 (6-86) | 39 (21-72) | 40 (18-93) | 77 (38-118) | 49 (18-110) | |
| p value | reference | 0.002* | 0.001* | <0.001* | <0.001* | 0.001* | |
statistically significant
Association between Ki-67 expression and clinicopathological features
The Ki-67 expression was divided into 3 levels (<14; 12.1%, 14-30; 40.7%, >30; 47.2%) and the associations between Ki-67 expression and clinicopathological features were investigated (Table 3). Compared to Ki-67<14 as the reference, tumors with increased Ki-67 expression were associated with unfavorable features such as more mitoses and higher grade. Furthermore, younger patients, larger size (>2 cm), and higher stage were related to tumors with >30% Ki-67 expression. Interestingly, no difference was found in nodal status. ER/PgR negative tumors showed higher Ki-67 expression, whereas Ki-67 expression was not associated with HER2 overexpression. Overall, these data indicated that Ki-67 expression was significantly accompanied by advanced and aggressive cancer.
Table 3.
Association between Ki-67 Expression and Clinicopathological Features
| Ki-67 index Categories (%) | Total | |||
|---|---|---|---|---|
| Index | <14 | 14-30 | >30 | |
| Number (%) | 11 (12.1) | 37 (40.7) | 43 (47.2) | 91 |
| Age (years) | ||||
| Mean (range) | 57 (42-81) | 54 (32-75) | 48 (30-75) | |
| p value | reference | 0.589 | 0.037* | |
| Tumor size | ||||
| ≤2cm | 3 | 2 | 1 | 6 |
| >2cm | 8 | 35 | 42 | 85 |
| p value | reference | 0.072 | 0.023* | |
| Histological grade | ||||
| Grade II | 10 | 20 | 12 | 42 |
| Grade III | 1 | 17 | 31 | 49 |
| p value | reference | 0.035* | <0.001* | |
| Nodal Status | ||||
| positive | 4 | 22 | 26 | 52 |
| negative | 7 | 15 | 17 | 39 |
| p value | reference | 0.302 | 0.186 | |
| Stage | ||||
| Stage I | 3 | 2 | 1 | 6 |
| Stage II to IV | 8 | 35 | 42 | 85 |
| p value | reference | 0.072 | 0.023* | |
| ER | ||||
| positive | 11 | 26 | 15 | 52 |
| negative | 0 | 11 | 28 | 39 |
| p value | reference | 0.048* | <0.001* | |
| PgR | ||||
| positive | 11 | 15 | 8 | 34 |
| negative | 0 | 22 | 35 | 57 |
| p value | reference | <0.001* | <0.001* | |
| HER2 | ||||
| positive | 1 | 9 | 16 | 26 |
| negative | 10 | 28 | 27 | 65 |
| p value | reference | 0.416 | 0.143 | |
| Mitoses/10HPF | ||||
| Mean (range) | 14 (6-36) | 31 (6-108) | 48 (6-118) | |
| p value | reference | 0.001* | <0.001* | |
Discussion
The present study reported the histopathological characteristics of Myanmar breast cancer patients. We analyzed 91 cases, in which 93% of the breast cancers were larger than 2 cm. There was no histological grade I and 53.8% of the cancers were grade III. Over half of the patients (57.1%) had lymph node involvement at the time of diagnosis. These findings may result from the lack of early detection system in Myanmar. It is also possible that Myanmar breast cancers are aggressive in nature.
Revealing the hormonal receptor status and HER2 and Ki-67 expression is useful not only for treatment strategy but for estimating the patient prognosis (malignant potential) (Goldhirsch et al., 2011). Generally, overall survival of breast cancers by subtypes from good- to poor-prognosis is: luminal A, luminal B, HER2 and TN (Hennigs et al., 2016). ER positive breast cancers are most frequent in western countries. In the United States, most (73%) breast cancers are luminal A and luminal B (HER2-) subtypes. About 10% of breast cancers are luminal B (HER2+), 4% are HER2 and 12% are TN (Howlader et al., 2014). Table 4 shows the summary of the percent composition of molecular subtypes of breast cancers in western countries, South Asia, South-east Asia and East Asia. In Asian countries except China, HER2 and TN subtypes are prevailing compared to those in western countries. In the present Myanmar study, unfavorable molecular subtypes, HER2 and TN, were responsible for 42.9% of all cancers, suggesting that most breast cancers in Myanmar are aggressive in nature. Interestingly, the composition of molecular subtypes in Myanmar (this study) is comparable to that in a Vietnamese study (Thang et al., 2015), with low luminal A and B and in contrast high HER2 and TN. These similarities may be related to some genetic or biological connections, as well as comparable environmental factors.
Table 4.
Percent Composition of Molecular Subtypes of Breast Cancer in Different Countries
| Luminal A | Luminal B (%) | HER2 | TN | Number of cases | reference | ||
|---|---|---|---|---|---|---|---|
| (%) | HER2- | HER2+ | (%) | (%) | |||
| United States | (72.7 | ) | 10.3 | 4.6 | 12.2 | 50,571 | Howlader et al., 2014 |
| Italy | 34.0 | 25.0 | 11.0 | 10.2 | 19.0 | 1,487 | Caldarella et al., 2013 |
| Germany | 44.7 | 31.8 | 6.2 | 5.0 | 12.3 | 3,454 | Hennigs et al., 2016 |
| Australia | 29.0 | 37.0 | 14.0 | 4.6 | 16.0 | 285 | Mandaliya et al., 2016 |
| India | (53.3 | ) | 10.1 | 13.0 | 23.8 | 1,284 | Doval et al., 2015 |
| China | (65.3 | ) | 19.0 | 6.5 | 9.2 | 3,198 | Zhu et al., 2014 |
| Japan | 30.6 | 26.2 | 19.0 | 11.3 | 12.9 | 363 | Yanagawa et al., 2012 |
| Indonesia | 38.1 | (16.7 | ) | 20.2 | 25.0 | 84 | Widodo et al., 2014 |
| Malaysia | (48.0 | ) | 12.0 | 11.0 | 29.0 | 1,034 | Devi et al., 2012 |
| Thailand | 39.0 | 8.0 | 10.0 | 18.0 | 25.0 | 100 | Chuangsuwanich et al., 2014 |
| Vietnam | 10.6 | 33.5 | 23.0 | 19.3 | 13.6 | 237 | Thang et al., 2015 |
| Myanmar | 11.0 | 39.6 | 6.6 | 22.0 | 20.9 | 91 | Present study |
In conclusion, the present study for the first time highlights the clinicopathological features of breast cancers from Myanmar women, which provide valuable information for the breast cancer control. Approximately 80% of the breast cancers were positive for either hormone receptor or HER2. Hormone therapy and anti-HER2 therapy may offer significant benefits to the Myanmar breast cancer patients, when used properly. Moreover, it is essential to establish early detection of breast cancer: education to promote early diagnosis and screening. Early detection alleviates the advanced breast cancer and increases the opportunities for successful treatment.
Conflict of Interest
Authors have no conflict of interest to declare.
Acknowledgements
The authors would like to thank Mr Yasuharu Arashima and Mr Haruyuki Watanabe for their kind help in histopathology work.
References
- Amirikia KC, Mills P, Bush J, Newman LA. Higher population-based incidence rates of triple-negative breast cancer among young African-American women: implications for breast cancer screening recommendations. Cancer. 2011;117:2747–53. doi: 10.1002/cncr.25862. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Blows FM, Driver KE, Schmidt MK, et al. Subtyping of breast cancer by immunohistochemistry to investigate a relationship between subtype and short and long term survival: a collaborative analysis of data for 10,159 cases from 12 studies. PLoS Med. 2010;7:e1000279. doi: 10.1371/journal.pmed.1000279. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Caldarella A, Buzzoni C, Crocetti E, et al. Invasive breast cancer: a significant correlation between histological types and molecular subgroups. J Cancer Res Clin. 2013;139:617–23. doi: 10.1007/s00432-012-1365-1. [DOI] [PubMed] [Google Scholar]
- Chuangsuwanich T, Pongpruttipan T, O-charoenrat P, et al. Clinicopathologic features of breast carcinomas classified by biomarkers and correlation with microvessel density and VEGF expression: a study from Thailand. Asian Pac J Cancer Prev. 2014;15:1187–92. doi: 10.7314/apjcp.2014.15.3.1187. [DOI] [PubMed] [Google Scholar]
- Devi CRB, Tang TS, Corbex M. Incidence and risk factors for breast cancer subtypes in three distinct South-East Asian ethnic groups: Chinese, Malay and natives of Sarawak, Malaysia. Int J Cancer. 2012;131:2869–77. doi: 10.1002/ijc.27527. [DOI] [PubMed] [Google Scholar]
- Doval DC, Sharma A, Sinha R, et al. Immunohistochemical profile of breast cancer patients at a tertiary care hospital in New Delhi, India. Asian Pac J Cancer Prev. 2015;16:4959–64. doi: 10.7314/apjcp.2015.16.12.4959. [DOI] [PubMed] [Google Scholar]
- Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology. 1991;19:403–10. doi: 10.1111/j.1365-2559.1991.tb00229.x. [DOI] [PubMed] [Google Scholar]
- Engstrø MJ, Opdahl S, Hagen AI, et al. Molecular subtypes, histopathological grade and survival in a historic cohort of breast cancer patients. Breast Cancer Res Tr. 2013;140:463–73. doi: 10.1007/s10549-013-2647-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Goldhirsch A, Wood WC, Coates AS, et al. Strategies for subtypes--dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol. 2011;22:1736–47. doi: 10.1093/annonc/mdr304. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hammond ME, Hayes DF, Wolff AC, Mangu PB, Temin S. American society of clinical oncology/college of American pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Oncol Pract. 2010;6:195–7. doi: 10.1200/JOP.777003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hennigs A, Riedel F, Gondos A, et al. Prognosis of breast cancer molecular subtypes in routine clinical care: a large prospective cohort study. BMC Cancer. 2016;16:734. doi: 10.1186/s12885-016-2766-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Howlader N, Altekruse SF, Li CI, et al. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J Natl Cancer Inst. 2014;106:dju055. doi: 10.1093/jnci/dju055. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Huo D, Ikpatt F, Khramtsov A, et al. Population differences in breast cancer: survey in indigenous African women reveals over-representation of triple-negative breast cancer. J Clin Oncol. 2009;27:4515–21. doi: 10.1200/JCO.2008.19.6873. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kurian AW, Fish K, Shema SJ, Clarke CA. Lifetime risks of specific breast cancer subtypes among women in four racial/ethnic groups. Breast Cancer Res. 2010;12:R99. doi: 10.1186/bcr2780. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mandaliya HA, Oldmeadow C, Evans T, Troke P, George M. Breast cancer demographics, screening and survival outcome at a regional Australian cancer centre: a retrospective study. Ann Oncol. 2016;27:1385P. [Google Scholar]
- Moore MA. Cancer control programs in East Asia: evidence from the international literature. J Prev Med Public Health. 2014;47:183–200. doi: 10.3961/jpmph.2014.47.4.183. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nielsen TO, Hsu FD, Jensen K, et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res. 2004;10:5367–74. doi: 10.1158/1078-0432.CCR-04-0220. [DOI] [PubMed] [Google Scholar]
- Perou CM, Sølie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature. 2000;406:747–52. doi: 10.1038/35021093. [DOI] [PubMed] [Google Scholar]
- Polyak K. Breast cancer: origins and evolution. J Clin Invest. 2007;117:3155–63. doi: 10.1172/JCI33295. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sølie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A. 2001;98:10869–74. doi: 10.1073/pnas.191367098. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Stark A, Kleer CG, Martin I, et al. African ancestry and higher prevalence of triple-negative breast cancer: findings from an international study. Cancer. 2010;116:4926–32. doi: 10.1002/cncr.25276. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sung H, Garcia-Closas M, Chang-Claude J, et al. Heterogeneity of luminal breast cancer characterised by immunohistochemical expression of basal markers. Br J Cancer. 2016;114:298–304. doi: 10.1038/bjc.2015.437. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Thang VH, Skoog L, Duc NB, Van TT, Tani E. Cell proliferation measured by Ki67 staining and correlation to clinicopathological parameters in operable breast carcinomas from Vietnamese and Swedish Patients. J Anal Oncol. 2015;4:58–68. [Google Scholar]
- Widodo I, Hartmann B, Marton E, et al. Clinicopathological features of Indonesian breast cancers with different molecular subtypes. Asian Pac J Cancer Prev. 2014;15:6109–13. doi: 10.7314/apjcp.2014.15.15.6109. [DOI] [PubMed] [Google Scholar]
- Wolff AC, Hammond ME, Hicks DG, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 2013;31:3997–4013. doi: 10.1200/JCO.2013.50.9984. [DOI] [PubMed] [Google Scholar]
- Yanagawa M, Ikemot K, Kawauchi S, et al. Luminal A and luminal B (HER2 negative) subtypes of breast cancer consist of a mixture of tumors with different genotype. BMC Res Notes. 2012;5:376. doi: 10.1186/1756-0500-5-376. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zhu X, Ying J, Wang F, Wang J, Yang H. Estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 status in invasive breast cancer: a 3,198 cases study at National Cancer Center, China. Breast Cancer Res Tr. 2014;147:551–5. doi: 10.1007/s10549-014-3136-y. [DOI] [PubMed] [Google Scholar]