• Communications for Statistical Applications and Methods
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• v.26 no.4
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• pp.411-430
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• 2019

Tumor development is driven by complex combinations of biological elements. Recent advances suggest that molecularly distinct subtypes of breast cancers may respond differently to pathway-targeted therapies. Thus, it is important to dissect pathway disturbances by integrating multiple molecular profiles, such as genetic, genomic and epigenomic data. However, missing data are often present in the -omic profiles of interest. Motivated by genomic data integration and imputation, we present a new statistical framework for pathway significance analysis. Specifically, we develop a new strategy for imputation of missing data in large-scale genomic studies, which adapts low-rank, structured matrix completion. Our iterative strategy enables us to impute missing data in complex configurations across multiple data platforms. In turn, we perform large-scale pathway analysis integrating gene expression, copy number, and methylation data. The advantages of the proposed statistical framework are demonstrated through simulations and real applications to breast cancer subtypes. We demonstrate superior power to identify pathway disturbances, compared with other imputation strategies. We also identify differential pathway activity across different breast tumor subtypes.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.17
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• pp.7819-7824
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• 2015

Purpose: To subtype breast cancer (BC) in Saudi women according to the recent molecular classification and to correlate these subtypes with available clinicopathological parameters. Materials and Methods: Estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (Her2/neu) immunostaining was semi-quantitatively assessed to define molecular subtypes of luminal A and B, HER-2 and triple negative (basal-like) in BC paraffin embedded sections from 115 Saudi female patients diagnosed between 2005 to 2015 at the Department of Pathology, King Fahd Hospital, Almadinah, Saudi Arabia. Results: The most common subtypes were luminal A (47%), followed by luminal B (27.8%) and basal like subtypes (18.3%), whereas HER-2 was the least common subtype (6.9%). Luminal A was predominantly found in the old age group, with low tumor grade (p<0.001) and small tumor size, whereas HER-2 and basal-like subtypes were significantly associated with young age, high tumor grade, lymph node metastasis and lymphovascular invasion (p<0.03, 0.004, 0.05 and 0.04 respectively). All subtypes showed advanced clinical stage at the time of presentation. Conclusions: Molecular subtypes of Saudi BC patients in Almadinah region are consistent with most of the worldwide subtyping. The biological behaviour of each molecular subtype could be expected based on its characteristic clinicopathological features. Along with other prognostic indicators, molecular subtyping would be helpful in predicting prognosis and management of our BC patients. We recommend screening and early diagnosis of BC in our population.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.4
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• pp.1973-1978
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• 2016

Background: Breast cancer is a heterogeneous disease that represents a major public health problem. The immunohistochemical determination of breast cancer subtypes with regard to estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2) status can contribute to improved selection of therapy and patientcare. The purpose of this study was to determine the prevalence of the molecular breast cancer subtypes and to assess their associations with classical clinicopathologic parameters for better therapeutic decisions in women with breast cancer in the Ivory Coast. Materials and Methods: Formalin-fixed and paraffin-embedded blocks of patients diagnosed with primary breast carcinoma were subjected to immunohistochemical assay for the assessment of ER/RP and HER2 expression. The one-way analysis of variance evaluated the difference between breast cancer subtypes and mean age of patients. The Chi-square Test was used to compare standard clinicopathologic prognostic parameters with tumor subtypes. Results. Among 302 patients, 57% were premenopausal and 43% were postmenopausal. The invasive ductal carcinoma not otherwise specified (IDC NOS) (82.8%) was the most frequent histological type, and the tumor grade 2 (56%) was predominant followed by grade 3 (20.9%). The proportion of positivity of ER, PR, and HER2 was 56%, 49%, and 15.6%, respectively. Half of patients of this study (51.6%) had luminal A breast tumor type followed by TN (32.1%). Other subtypes were luminal B (10.1% ) and non-luminal HER2+ (6.3%). Conclusions. The findings of the present study are in line with the literature and should assist in management of breast cancer in our country.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.2
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• pp.459-462
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• 2012

Expression of estrogen-receptor (ER), progesterone-receptor (PR) and HER-2 has recently been linked with various breast cancer subtypes identified by gene microarray. This study aimed to document breast cancer subtypes based on ER, PR and HER-2 status in Thai women, where expression of these subtypes may not be similar to those evident in Western women. During 2009 to 2010, histological findings from 324 invasive ductal carcinomas (IDC) at Siriraj Hospital were studied. Various subtypes of IDC were identified according to expression of ER, PR and HER-2: luminal-A (ER+;PR+/-;HER-2-), luminal-B (ER+;PR+/-;HER-2 +), HER-2 (ER-;PR- ;HER-2+) and basal-like (ER-;PR-;HER-2-). As well, associations of tumor size, tumor grade, nodal status, angiolymphatic invasion (ALI), multicentricity and multifocality with different breast cancer subtypes were studied. Of 324 IDCs, 143 (44.1%), 147 (45.4%), 15 (4.6%) and 12 (3.7%) were T1, T2, T3 and T4, respectively. Most tumors were grade 2 (54.9%) and had no nodal involvement (53.4%). According to ER, PR and HER-2 status, 192 (59.3%), 40 (12.3%), 43 (13.3%) and 49 (15.1%) tumors were luminal-A, luminal-B, HER-2 and basal-like subtypes. HER-2 subtype presented with large tumor (p=0.04, ANOVA). Luminal-A IDC was associated with single foci (p<0.01, ${\chi}^2$). HER-2 and basal-like subtypes were likely to have high tumor grade (p<0.01, ${\chi}^2$). In addition, HER-2 subtype had higher number of nodal involvement (p=0.048, ${\chi}^2$). In conclusion, the luminal-A subtype accounted for the majority of IDCs in Thai women. Percentages of HER-2 and basal-like IDCs were high, compared with a recent study from the USA. The HER-2 subtype was related with high nodal invasion. The findings may highlight biological differences between IDCs occurring in Asian and Western women.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.5
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• pp.1881-1886
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• 2012

Breast cancer is a heterogeneous disease that is affected by ethnicity of patients. According to hormone receptor status and gene expression profiling, breast cancers are classified into four molecular subtypes, each showing distinct clinical behavior. Lack of sufficient data on molecular subtypes of breast cancer in Iran, prompted us to investigate the prevalence and the clinicopathological features of each subtype among Iranian women. A total of 428 women diagnosed with breast cancer from 2002 to 2011 were included and categorized into four molecular subtypes using immunohistochemistry. Prevalence of each subtype and its association with patients' demographics and tumor characteristics, such as size, grade, lymph-node involvement and vascular invasion, were investigated using Chi-square, analysis of variance and multivariate logistic regression. Luminal A was the most common molecular subtype (63.8%) followed by Luminal B (8.4%), basal-like (15.9%) and HER-2 (11.9%). Basal-like and HER-2 subtypes were mostly of higher grades while luminal A tumors were more of grade 1 (P<0.001). Vascular invasion was more prevalent in HER-2 subtype, and HER-2 positive tumors were significantly associated with vascular invasion (P=0.013). Using muti-variate analysis, tumor size greater than 5 cm and vascular invasion were significant predictors of 3 or more nodal metastases. Breast cancer was most commonly diagnosed in women around 50 years of age and the majority of patients had lymph node metastasis at the time of diagnosis. This points to the necessity for devising an efficient screening program for breast cancer in Iran. Further, prospective surveys are suggested to evaluate prognosis of different subtypes in Iranian patients.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.5
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• pp.3197-3203
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• 2013

Background: microRNAs (miRNAs) that regulate proliferation, invasion and metastasis are considered to be the principal molecular basis of tumor heterogeneity. Breast cancer is not a homogeneous tissue. Thus, it is very important to perform microarray-based miRNA screening of tumors at different sites. Methods: Breast tissue samples from the centers and edges of tumors of 30 patients were classified into 5 clinicopathological subtypes. In each group, 6 specimens were examined by microRNA array. All differential miRNAs were analyzed between the edges and centers of the tumors. Results: Seventeen kinds of miRNAs were heterogeneously distributed in the tumors from different clinicopathological subtypes that included 1 kind of miRNA in Luminal A and Luminal B Her2+ subtypes, 4 kinds in Luminal A and Her2 overexpression subtypes, 6 kinds in Luminal B Ki67+ and Luminal B Her2+ subtypes, 2 kinds between Luminal B Ki67+ and triple-negative breast cancer (TNBC) subtypes, 2 kinds between Luminal B Her2+ and TNBC subtypes, and 2 kinds between Luminal B Ki67+, Luminal B Her2+, and TNBC subtypes. Twenty kinds of miRNAs were homogenously distributed in the tumors from different clinicopathological subtypes that included 6 kinds of miRNAs in Luminal B Ki67+ and Luminal B Her2+ subtypes, 1 kind in Luminal B Ki67+ and Her2 overexpression subtypes, 10 kinds between Luminal B Ki67+ and TNBC subtypes, 2 kinds in Luminal B Her2+ and TNBC subtypes, and 1 kind between Luminal B Ki67+, Luminal B Her2+, and TNBC subtypes. Conclusions: A total of 37 miRNAs were significantly distributed in tumors from the centers to edges, and in all clinicopathological subtypes.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.14
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• pp.5539-5544
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• 2014

Background: To evaluate the location of tumor relapse and imaging modality for detection according to the breast cancer subtype: luminal A, luminal B, HER2 positive luminal B, nonluminal HER2 positive, and triple negative. Materials and Methods: A total of 1244 patients with breast cancer with known estrogen receptor (ER), progesterone receptor (PR), Ki-67 and human epidermal growth factor receptor 2 (HER2), who underwent breast surgery from 2009 to 2012 were analyzed. Patients were classified into the following categories: luminal A (n=458), luminal B (n=241), HER2 positive luminal B (n=227), nonluminal HER2 positive (n=145) and triple negative (n=173). A total of 105 cases of relapse were detected in 102 patients: locoregional recurrence (n=46), recurrence in the contralateral breast (n=28) and distant metastasis (n=31). Comparison of proportions was used to determine the difference between subtypes. Results: Relapse rates by subtypes are as follows: luminal A 23 of 458 (5.02%), luminal B 19 of 241(7.88%), HER2 positive luminal B 15 of 227 (6.61%), nonluminal HER2 postive 19 of 145 (13.10%) and triple negative 29 of 173(16.76%). Luminal A tumors had the lowest rate of recurrence and had significantly lower recurrence rate in comparison with nonluminal HER2 postive (p=0.0017) and triple negative subtypes (p<0.0001). Compared with all other subtypes except nonluminal HER2 positive, triple negative tumors had the highest rate of tumor recurrence (p<0.01). Triple negatives were most likely to develop contralateral recurrence against all subtypes (p<0.05). Detection rate of locoregional and contralateral tumor recurrence were 28.3% on mammography (n=17/60). Conclusions: Luminal A tumors are associated with a low risk of recurrence while triple negative lesions have a high risk. In case of triple negative tumors, the contralateral breast has much more recurrence as compared with all other subtype. In terms of detection rates, breast USG was the best modality for detecting tumor recurrence, compared with other modalities (p<0.05). Subtyping of breast tumors using a molecular gene expression panel can identify patients who have increased risk of recurrence and allow prediction of locations of tumor recurrence for each subtype.

• Laboraroty Animal Research
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• v.34 no.4
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• pp.160-165
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• 2018

Breast cancer remains the second leading cause of cancer death among woman, worldwide, despite advances in identifying novel targeted therapies and the development of treating strategies. Classification of clinical subtypes (ER+, PR+, HER2+, and TNBC (Triple-negative)) increases the complexity of breast cancers, which thus necessitates further investigation. Mouse models used in breast cancer research provide an essential approach to examine the mechanisms and genetic pathway in cancer progression and metastasis and to develop and evaluate clinical therapeutics. In this review, we summarize tumor transplantation models and genetically engineered mouse models (GEMMs) of breast cancer and their applications in the field of human breast cancer research and anti-cancer drug development. These models may help to improve the knowledge of underlying mechanisms and genetic pathways, as well as creating approaches for modeling clinical tumor subtypes, and developing innovative cancer therapy.

• Archives of Plastic Surgery
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• v.41 no.4
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• pp.374-378
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• 2014

Background Angioleiomyoma, a vascular leiomyoma, is a rare, benign smooth-muscle tumor that originates in the tunica media of vessels. It occurs anywhere in the body, most frequently in the lower extremities. Methods We reviewed the medical records of 16 patients who were treated for angioleiomyoma between 2000 and 2012. The clinical features of angioleiomyoma and the correlation between symptoms and pathological subtypes were investigated. Results There were 9 males and 6 females. Ages of the patients ranged from 21 to 61. Pain was the primary symptom in 44% of the patients. Tumors were smaller than 2.0 cm in all dimensions and were located in the face in 4 patients, whereas 5 lesions occurred in the upper extremities and the remaining 7 in the lower extremities. Three histologic subtypes were identified: solid, venous, and cavernous. The subtypes did not correlate with the clinical symptoms. Conclusions Angioleiomyoma appears to be a rare tumor that occurs in the face and the extremities. The tumor usually occurs in middle age. A differential diagnosis of this tumor is difficult, but the tumor should be considered in the diagnosis of painful subcutaneous masses. Ultrasonography and magnetic resonance imaging can be helpful in the diagnosis of angioleiomyoma. These tumors can be successfully treated with simple excision, with a low recurrence rate.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.2
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• pp.1003-1007
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• 2013

Objective: This work aimed to investigate the correlations of tumor-associated macrophages (TAMs) and their subtypes M1 and M2 with liver metastasis of colorectal cancer, and provide useful references for seeking predictors of liver metastasis and studying mechanisms. Methods: 120 patients with colorectal cancer from 2000 to 2009 were divided into low, middle and high liver metastasis groups (group A, B and C, respectively). S-P immunohistochemical staining and microscopic observation were conducted to compare expression in CD68-positive cells (TAMs), CD80-positive cells (M1) and CD163-positive cells (M2) in three groups. Correlations of TAMs, M1, M2, and M2/M1 ratio with clinical and pathological parameters were analyzed. Results: With increase of liver metastatic ability, the number of TAMs decreased gradually, with no significant difference between any two of the three groups (P > 0.05), while the numbers of M1 and M2 were significantly decreased and increased, respectively, with significant difference between any two of three groups (P < 0.05 or P < 0.01). In addition, the M2/M1 ratio increased with increase of liver metastatic ability (P < 0.01). There was no statistical significance of correlation of TAMs with each clinical and pathological parameter. M1 was negatively related with lymphatic metastasis and liver metastatic ability. M2 was positively correlated with preoperative CEA level, lymphatic metastasis, tumor differentiation degree and liver metastatic ability. The same was the case for the M2/M1 ratio. Conclusions: Effects of TAMs on liver metastasis of colorectal cancer do not depend on the total number of TAMs, but on the number and proportion of functional subtypes M1 and M2. M2 number and M2/M1 ratio are more accurate predictors for liver metastasis of colorectal cancer.