Subtypes Of Breast Cancer Patients Research Articles

Functional characterization of selective exosite-binding inhibitors of matrix metalloproteinase-13 (MMP-13) - experimental validation in human breast and colon cancer.

Considering the pathological significance of MMP-13 in breast and colon cancers, exosite-based inhibition of the C-terminal hemopexin (Hpx) domain could serve as an alternative strategy to develop selective inhibitors for MMP-13.Two of six lead compounds, compound 5 (2,3-dihydro-1,4-benzodioxine-5-carboxylic acid) and compound 6 (1-acetyl-4-hydroxypyrrolidine-2-carboxylic acid) exhibited considerable inhibitory activity against MMP-13. Complementing to this study, we have also shown the gene expression levels of MMP-13 within the subtypes of colon and breast cancers classified from patients' tissue samples to provide a better understanding on which subtype of breast cancer patients would get benefited by MMP-13 inhibitors.Our current results show that compounds 5 and 6 could effectively inhibit MMP-13 and provide specific therapeutic possibilities in the treatment of inflammatory disorders and cancers. The characterization of these lead compounds would provide a better mechanistic understanding of exosite-based inhibition of MMP-13, which could overcome the challenges in the identification of other MMP catalytic domain-specific inhibitors.

Quantitative proteomics revealed novel proteins associated with molecular subtypes of breast cancer

The early diagnosis and successful treatment of breast cancer (BC) is still a challenging task due to the diverse origin and functional heterogeneity of cancer cells. The heterogeneity of BC may likely to explained by molecular BC subtypes, comprises Luminal-A (LA), Luminal-B (LB), Triple-negative (TN) and HER2-positive (HP), which are governed by a variety of cancer associated pathways. To identify protein signatures in different BC subtypes, we performed isobaric tag for absolute and relative quantitation (iTRAQ) of enriched blood plasma samples of BC subtypes (N=32) and healthy subjects (N=8). After analyses of data, 58 proteins were found to be modulated in BC subtypes from healthy subjects (p<0.05) and among these; Fibronectin (FN1), Alpha-2-macroglobulin (A2M), and Complement component-4-binding protein-alpha (C4BPA) and Complement factor-B (CFB) were selected for validation in BC subtypes and healthy subjects in the independent set of blood plasma (N=100) and tissue samples (N=25). Statistical analysis showed the significant modulation of FN1 and C4BPA in LB, and A2M in TN patients in both plasma as well as tissues comparatively control (p<0.05). Further, FN1 and C4BPA in LB subtype revealed a good diagnostic accuracy in plasma level validation. The receiver operating characteristic (ROC) curve and regression analysis demonstrated that these proteins with associated criterion of expression could act as discriminating signatures among BC subtypes with diagnostic and prognostic relevance. SignificanceThe heterogeneity of breast cancer (BC) has gained many challenges for successful management of BC, thus, the delineating proteomic alterations BC subtypes may provide great clinical values in diagnostic, prognostic and therapeutics of BC. The findings from the present quantitative proteomic study have deciphered the altered proteomic patterns and their possible molecular interactions in each BC subtype. The study showed a strong association of FN1, A2M, C4BPA and CFB in molecular subtypes of BC, in which, C4BPA and A2M demonstrated a potent signature in blood plasma and tissue samples of LB and TN subtypes in BC patients, respectively. The findings also revealed the altered level expressions of these selected proteins could classify BC subtypes through plasma and tissue based expression analysis in patients and control samples. Hence, these proteins could have clinical importance for the diagnosis and prognosis purposes among molecular BC subtypes.

Outcomes According to Breast Cancer Subtype in Patients Treated With Accelerated Partial Breast Irradiation

BackgroundThe purpose of the study was to determine outcomes for patients treated with accelerated partial breast irradiation (APBI) on the basis of breast cancer subtype (BCST). Patients and MethodsOur single-institution, institutional review board-approved APBI database was queried for patients who had complete testing results for the estrogen (ER), progesterone (PR), and HER2/neu receptors to determine outcomes for each BCST. Women were assigned as luminal A (LA), luminal B (LB), HER2, and basal BCST using their ER, PR, and HER2/neu receptor status. Degree of ER expression supplemented the receptor-based luminal BCST assignment. Two hundred seventy-eight patients had results for all 3 receptors (LA = 164 [59%], LB = 81 [29%], HER2 = 5 [2%], basal = 28 [10%]), which were submitted for analysis (ipsilateral breast tumor recurrence [IBTR], regional nodal failure, distant metastasis [DM], disease-free survival [DFS], cause-specific survival [CSS], and overall survival [OS]). ResultsMedian follow-up was 5.4 years (range, 0.1-12.4 years). Basal and HER2 subtype patients had higher histologic grades (Grade 3 = 75% vs. 10% LA/LB; P < .001), larger tumors (13.0 mm basal vs. 10.7 mm LA/LB; P = .059), and were more likely to receive chemotherapy (68% vs. 15% LA/LB; P < .001). Margin and nodal status were similar among BCSTs. At 5 years, IBTR rates were similar (1.8%, 2.9%, 0%, and 4.8%) for LA, LB, HER2, and basal subtypes, respectively (P = .62). DM was only seen in LA (2.9%) and LB (1.3%) (P = .83). DFS (95%-100%), CSS (97%-100%), and OS (80%-100%) were not statistically different (P = .97, .87, .46, respectively). ConclusionFive-year local control rates after breast-conserving surgery, APBI, and appropriate systemic therapy are excellent for luminal, HER2, and basal phenotypes of early-stage breast cancer; however, further study of receptor subtype effect on risk stratification in early-stage breast cancer is needed.

TXR1 and TSP1 expression varies by the molecular subtypes of breast cancer patients who received previous docetaxel-based first-line chemotherapy.

The expression of taxol resistance gene 1 and thrombospondin 1 remains unknown in human breast cancer tissues. In the current study, we sought to measure the mRNA expression levels of taxol resistance gene 1 and thrombospondin 1 in breast cancer tissue and adjacent normal tissue specimens and further analyzed their expression according to the molecular subtypes and age of breast cancer patients who had received taxane-containing regimens. Archived breast cancer and adjacent non-tumor tissue specimens were obtained at Beijing Friendship Hospital, Beijing, China. The mRNA transcript levels of taxol resistance gene 1, thrombospondin 1 and multi-drug resistance 1 were determined by quantitative RT-PCR. Taxol resistance gene 1 and multi-drug resistance 1 protein levels were measured by immunoblotting assays. Forty-nine archived breast cancer tissue specimens were included. The majority of the specimens (65.3%) were of the molecular subtype A followed by triple negative breast cancer (14.3%). The mRNA transcript levels of taxol resistance gene 1 , thrombospondin 1 and multi-drug resistance 1 in breast cancer tissues were higher than those of adjacent normal tissues. The mRNA expression of TXR1 in the HER2 subtype (4.513 ± 0.810) was the highest and in the Luminal B subtype was the lowest (3.103 ± 0.417) among the four molecular subtypes. The HER2 subtype also had the highest mRNA expression of thrombospondin 1(4.827 ± 0.927) and the Luminal B subtype had the lowest TSP1 mRNA level (3.197 ± 0.565) among the four molecular subtypes. Our study represents the first attempt in delineating taxol resistance gene 1 and thrombospondin 1 expression in breast cancer and we demonstrate that taxol resistance gene 1 and thrombospondin 1 expression may vary according to the molecular subtypes of breast cancer.

Ultraconserved long non-coding RNA uc.63 in breast cancer.

Transcribed-ultraconserved regions (T-UCRs) are long non-coding RNAs (lncRNA) encoded by a subset of long ultraconserved stretches in the human genome. Recent studies revealed that the expression of several T-UCRs is altered in cancer and growing evidences underline the importance of T-UCRs in oncogenesis, offering also potential new strategies for diagnosis and prognosis. We found that overexpression of one specific T-UCRs named uc.63 is associated with bad outcome in luminal A subtype of breast cancer patients. uc.63 is localized in the third intron of exportin-1 gene (XPO1) and is transcribed in the same orientation of its host gene. Interestingly, silencing of uc.63 induces apoptosis in vitro. However, silencing of host gene XPO1 does not cause the same effect suggesting that the transcription of uc.63 is independent of XPO1. Our results reveal an important role of uc.63 in promoting breast cancer cells survival and offer the prospect to identify a signature associated with poor prognosis.

Breast Cancer Subtypes in Patients Aged 70 Years and Older

ABSTRACTRecurrence and survival pattern in breast cancer (bc) patients (pts) ≥ 70 years subcategorized according to subtype and age are still an area of uncertainty. Tumor characteristics, patient demographics, therapies applied, and recurrence pattern were compared between luminal A (LA), luminal B (LB), Her2/neu overexpressing (Her+) and triple-negative (TN) bc subtypes and the age subcategories 70–74, 75–79, ≥80 years. Based on univariate Cox-regression-analyses distant-disease-free-survival (DDFS) differed significantly for bc subtypes (p = 0.0002), notably for Her+ vs. LA (p = 0.0014), TN vs. LA (p < 0.001), and TN vs. LB (p = 0.0086). Not age, but Her+ and TN represented prognostic factors for DDFS.

Clinical significance of molecular subtypes of breast cancer in patients aged over 60 years

Objective To retrospectively analyze the distribution percentage points of molecular subtypes of breast cancer and investigate its guiding significance in the prognosis and personalized therapy in patients with breast cancer aged over 60 years. Methods A retrospective analysis of all patients with invasive breast cancer aged over 60 years from January 2009 to June 2014 in Breast Center of Beijing Hospital was performed.Based on the immunohistochemical methods recommended in the St.Gallen International Expert Consensus Report 2013, the molecular subtypes of breast cancer in these patients were identified.All patients were followed up every 6 months after operation until December 2014.Clinical pathological characteristics and prognosis indexes in different molecular subtypes of breast cancer were evaluated. Results Totally 770 patients aged over 60 years with invasive breast cancer met the criterion.The luminal A, luminal B, human epidermal growth factor receptor 2(HER2)over-expression, triple- negative subtypes accounted for 29.1%(224 cases), 47.5%(366 cases), 6.5%(50 cases)and 16.9%(130 cases)of patients, respectively.The luminal A subtype of breast cancer had larger tumor size, more lymph node metastasis and more late TNM stage as compared with other subtypes(all P<0.01). Univariate and multivariate analysis showed that aged ≥80 years and the triple- negative molecular subtype were the independent poor prognostic factors for breast cancer(both P<0.05). The luminal A subtype of breast cancer had relatively good prognosis, while the triple- negative subtype had relatively poor prognosis. Conclusions Molecular subtypes have a significant prognostic effect on breast cancer in patients aged over 60 years, which suggests molecular subtype can be considered as a reference indicator in personalized therapy.Patients aged over 80 years has poor prognosis due to less rational treatment.The reasonable and target treatment based on the molecular subtype of breast cancer should be provided for patients aged over 80 years in clinical medicine. Key words: Breast neoplasms; Molecular subtype; Prognosis

Association between efficacy and molecular subtypes in breast cancer patients receiving neoadjuvant chemotherapy

To investigate the association between pathological complete response (pCR), clinicopathological characteristics and clinical outcomes in breast cancer patients receiving neoadjuvant chemotherapy. Medical records of 221 patients who underwent neoadjuvant chemotherapy for breast cancer between January 2006 and December 2008 were retrospectively reviewed. Their clinicopathological features, response to neoadjuvant chemotherapy, survivals and prognostic factors were then analyzed. The total pCR rate was 11.3% (25/221). The rate of pCR was 0%(0/12), 5.7%(6/106), 7.4%(2/27) and 16.9%(11/65) in the luminal A, luminal B, HER-2, and Basal-like subtypes, respectively. Statistically significant association was found between the pCR rate and the molecular substypes of breast cancer(P<0.05). The median 5-year disease free survival and the 5-year overall survival were 72 months and 79 months. The 5-year disease free survival rate and 5-year overall survival rate were 61.1% and 71.9% in all the 221 patients. The 5-year disease free survival rates of pCR and non-pCR patients were 84.0% and 58.2%, and the 5-year overall survival rates of pCR and non-pCR patients were 96.0% and 68.9%, respectively(P<0.05 for all). The multivariate survival analysis showed that clinical and pathological node stage and pCR are independent prognostic factors for the 5-year disease-free survival and 5-year total survival in patients with neoadjuvant chemotherapy (P<0.05 for both). pCR is more frequently observed in HER-2 and basal-like breast cancer subtypes compared with the luminal breast cancer subtype. The status of clinical and pathological node status and pCR are independent prognostic factors in patients treated with neoadjuvant chemotherapy.

Brain specific progression free survival (bsPFS) according to breast cancer subtypes in patients with brain metastases.

e13040 Background: Whole brain external radiotherapy (WBRT) of 30Gy is the most frequently used palliative treatment for brain metastases (BM). Disease control in brain with palliative RT might alt...

Abstract P4-11-43: Ki-67 and p53 are useful factors to predict long term survival in low-risk luminal A breast cancer patients

Abstract Overexpression of p53 is the most frequent genetic alteration in breast cancer. Recently, many studies have shown that the expression of mutant p53 differs for each subtype of breast cancer and is associated with different prognoses. In this study, we aimed to determine the suitable cut-off value to predict the clinical outcome of p53 overexpression and its usefulness as a prognostic factor in each subtype of breast cancer, especially in luminal A breast cancer. Approval was granted by the Institutional Review Board of Samsung Medical Center. We analyzed a total of 7739 patients who were surgically treated for invasive breast cancer at Samsung Medical Center between Dec 1995 and Apr 2013. Luminal A subtype was defined as ER&amp;amp;PR + and HER2- and was further subclassified according to Ki-67 and p53 expression as follows: luminal A (Ki-67-,p53-), luminal A (Ki-67+, p53-), luminal A (Ki-67 -, p53+) and luminal A (Ki-67+, p53+). Low-risk luminal A subtype was defined as negative for both Ki-67 and p53 (luminal A (ki-67-, p53-)), and others subtypes were considered to be high-risk luminal A breast cancer. A cut-off value of 10% for p53 was a good predictor of clinical outcome in all patients and luminal A breast cancer patients. The prognostic role of p53 overexpression for OS and DFS was only significant in luminal A subtype. The combination of p53 and Ki-67 has been shown to have the best predictive power as calculated by the area under curve (AUC), especially for long-term overall survival. Table 1. Factors associated with overall survival in luminal A subtype breast cancer patients (N=3918). Univariable Multivariable* Factors HRP-value95% CI for HRHRP-value95% CI for HRBreast surgery TM- (ref.)- (ref.)- (ref.) BCS0.4430.03180.211-0.932 Presence of LVI No- (ref.)- (ref.)- (ref.) Yes4.783&amp;lt;0.00012.163-10.578 RM Positive2.7260.32690.367-20.244 Negative- (ref.)- (ref.)- (ref.) NG 1&amp;2- (ref.)- (ref.)- (ref.) 33.7930.00041.806-7.969 AJCC Stage 1- (ref.)- (ref.)- (ref.)- (ref.)- (ref.)- (ref.) 22.2830.16970.703-7.4161.7840.33800.546-5.833 312.967&amp;lt;0.00014.303-39.0839.912&amp;lt;0.00013.265-30.096Ki-67 Positive4.2940.00321.631-11.3032.5870.06030.960-6.971 Negative- (ref.)- (ref.)- (ref.)- (ref.)- (ref.)- (ref.)p53 Positive6.107&amp;lt;0.00012.905-12.8374.494&amp;lt;0.00012.105-9.594 Negative- (ref.)- (ref.)- (ref.)- (ref.)- (ref.)- (ref.)BCS, breast-conserving surgery; LVI, lymphovascular invasion; NG, nuclear grade; RM, resection margin; TM, total mastectomy; NG, LVI and total mastectomy were not significant in multivariable Cox analysis;* Cox-proportional hazard regression model. In this study, we have shown that overexpression of p53 and Ki-67 could be used to discriminate low-risk luminal A subtype in breast cancer. Therefore, using the combination of p53 and Ki-67 expression in discriminating low-risk luminal A breast cancer may improve the prognostic power and provide the greatest clinical utility. Citation Format: Ha Woo Yi, Se Kyung Lee, Soo Youn Bae, Jun Ho Lee, Hyun-Chul Lee, Won Ho Kil, Jeong Eon Lee, Seok Won Kim, Seok Jin Nam. Ki-67 and p53 are useful factors to predict long term survival in low-risk luminal A breast cancer patients [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-11-43.

FOXA1 Expression Significantly Predict Response to Chemotherapy in Estrogen Receptor-Positive Breast Cancer Patients.

Most estrogen receptor (ER)-positive breast cancer responds poorly to chemotherapy and no single cost-effective biomarker capable of selecting chemosensitive ones has been found yet. We investigated FOXA1 for its role in predicting chemosensitivity of this subgroup in neoadjuvant chemotherapy settings. We reviewed pathologic slides of 123 patients who were diagnosed with ER-positive breast cancer on core needle biopsy and underwent neoadjuvant chemotherapy at our institution between 2002 and 2012. FOXA1 expression and pathologic response were evaluated. We then statistically analyzed FOXA1 expression and its relationship with chemosensitivity. FOXA1 expression before NAC was correlated with poor chemoresponse in ER-positive as well as luminal A and luminal B breast cancer patients (p = 0.002, 0.001, and 0.049 respectively). Significant association between change of FOXA1 staining position after NAC and chemosensitivity also was observed (p = 0.024). Multivariate analysis identified FOXA1 expression before NAC as an independent predictor of chemosensitivity in ER-positive and luminal A breast cancer patients [p = 0.002; relative risk (RR) 0.163; 95 % confidence interval (CI) 0.053-0.500, and p = 0.002; RR 0.055; 95 % CI 0.008-0.353, respectively]. Additionally, change of FOXA1 staining position after NAC was shown to be an independent predictor of chemoresponse in luminal B subtype breast cancer patients (p = 0.012; RR 0.153; 95 % CI 0.035-0.665). FOXA1 expression can independently predict chemosensitivity of ER-positive breast cancer patients.

Impact of body mass index on neoadjuvant treatment outcome: a pooled analysis of eight prospective neoadjuvant breast cancer trials.

Obesity is associated with an increased risk of breast cancer (BC) and poorer outcome. We assessed the impact of body mass index (BMI) on pathological complete response (pCR), disease-free (DFS), and overall survival (OS), according to BC subtypes in patients with primary BC treated with neoadjuvant chemotherapy. 8,872 patients with primary BC from eight neoadjuvant trials were categorized according to BMI: underweight (<18.5kg/m(2)), normal weight (18.5 to <25kg/m(2)), overweight (25 to <30kg/m(2)), obese (30 to <40kg/m(2)), and very obese (≥40kg/m(2)). BC subtypes were defined as luminal-like (ER/PgR-positive and HER2-negative), HER2/luminal (ER/PgR-positive and HER2-positive), HER2-like (ER/PgR-negative and HER2-positive), and triple-negative (TNBC; ER/PgR- and HER2-negative). pCR rate was higher in normal weight patients compared with all other BMI groups (P=0.003). Mean DFS and OS were shorter in obese (87.3months, P=0.014 and 94.9months, P=0.001, respectively) and very obese (66.6months, P<0.001 and 75.3months, P<0.001, respectively) compared with normal weight patients (91.5 and 98.8months, respectively) which was confirmed by subpopulation treatment effect pattern plot analyses and was consistent in luminal-like and TNBC. No interaction was observed between BMI and pCR. Normal weight patients experienced less non-hematological adverse events (P=0.002) and were more likely to receive full taxane doses (P<0.001) compared with all other BMI groups. In multivariable analysis, the dose of taxanes was predictive for pCR (P<0.001). Higher BMI was associated with lower pCR and a detrimental impact on survival. Normal weight patients had the best compliance to chemotherapy and received the highest taxane doses, which seems to be related with treatment outcomes.

Distribution and prognostic significance of molecular subtypes of breast cancer patients in three institutions: a retrospective analysis

Distribution and prognostic significance of molecular subtypes of breast cancer patients in three institutions: a retrospective analysis

Breast cancer brain metastases: clinical and prognostic characteristics of different biological subtypes

To analyze the clinical characteristics and survival depending on biological subtypes in breast cancer patients with brain metastases (BM). A retrospective analysis was performed on 152 breast cancer patients with BM admitted to the Cancer Institute & Hospital, Chinese Academy of Medical Sciences from January 2003 to December 2012. Depending on the biological characteristics, these patients were divided into three subtypes: Luminal, human epidermal growth factor receptor 2 (HER-2)-overexpressing, and triple-negative subtypes. The clinicopathological characteristics, recurrence status, and prognostic factors were analyzed at the initial diagnosis. The systemic therapy after BM was further studied. Among the 152 patients, the number of Luminal, HER-2-overexpressing, and triple-negative breast cancer (TNBC) subtypes were 60, 53, and 39 cases, respectively. The median time from first recurrence to BM of all patients was 7.3 months, the median time of Luminal, HER-2-overexpressing, and TNBC subtypes was 11.0 months, 9.6 months, and 5.5 months, respectively (P < 0.001). Compared with the TNBC subtype, BM occurred later in the HER-2-overexpressing subtype (P < 0.001). In the HER-2-overexpressing subtype, trastuzumab could delay the occurrence of BM in advanced breast cancer patients (17.1 vs. 1.7 months, P < 0.001, 95%CI 5.21-13.98). The median time of overall survival (OS) in the whole group was 56.5 months (7.5-240.2 months, 95%CI 52.6-60.4). The median survival time of Luminal, HER-2-overexpressing and TNBC subtypes was 70.9 months, 53.9 months, and 40.9 months, respectively (P = 0.013). The median survival time of after BM was 11.5 months in the whole group, and the median survival time of Luminal, HER-2-overexpressing and TNBC subtypes was 11.2 months, 12.7 months, and 11.6 months, respectively, with a difference of no statistical significance. Compared with non-BM as the first site, the patients with BM as the first site had a longer survival (14.8 months vs. 8.0 months, P = 0.001). Systemic therapy could prolong the survival after BM. The median survival of chemotherapy, chemotherapy in combination with trastuzumab, and without systemic therapy was 13.6 months, 19.0 months, and 6.5 months, respectively (P = 0.043). The survival after BM is influenced by biological subtypes. Compared with the Luminal subtype, brain meatastases occurr earlier in HER-2-overexpressing and TNBC subtypes. Trastuzumab can delay the occurrence of BM from advanced breast cancer, and systemic therapy can improve the survival of patients after brain metastasis.

Survival analysis of breast cancer subtypes in patients with spinal metastases.

We conducted a retrospective cohort study of 151 patients with breast cancer spinal metastases. To investigate the influence of breast cancer subtypes on survival duration of patients with breast cancer spinal metastases, and to aid spine surgeons in selecting treatments on a more precise basis. There is lack of knowledge about specific prognosis of patients with spinal metastases in various breast cancer subtypes. Estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (Her-2) status are the key factors in determining breast cancer subtypes and predicting patients' response to adjuvant treatments. Until August 2013, we retrieved 151 surgically treated patients with breast cancer spinal metastases and followed up all the patients for at least 2 years. Survival duration analysis and Cox proportional hazards regression model unadjusted and adjusted by age were used. Patients with ER-negative (-) breast cancer had 11 months shorter median survival duration (10.6 vs. 21.5 mo) and 48% higher mortality risk (P=0.03) than those with ER-positive (+) breast cancer. Patients with PgR (-) status had 59% higher mortality risk than those with PgR (+) status (P=0.02). Hormone receptor (HR) status is a combination of ER and PgR status. Patients with HR (-) status had an 11-month shorter median survival duration and 52% higher mortality risk (P=0.01) than patients with HR (+) status. Human epidermal growth factor receptor 2 subtypes had similar median survival duration and mortality risk. Patients with triple-negative breast cancer had a median survival duration of only 9.9 months. Patients with spinal metastases with ER/HR (-) status and triple-negative breast cancer could be downgraded from score "5" to "3" in Tokuhashi scoring system and from "slow growth" to "moderate growth" in Tomita scoring system. Spine surgeons should be critical before performing high-risk extensive surgery in patients with ER/HR (-) status, and especially, in those with triple-negative status. 3.

Treatment and prognosis of breast cancer patients with brain metastases according to intrinsic subtype.

How breast cancer subtypes should affect treatment decisions for breast cancer patients with brain metastases is unclear. We analyzed local brain metastases treatments and their outcomes according to subtype in patients with breast cancer and brain metastases. We reviewed records and database information for women treated at the National Kyushu Cancer Center between 2001 and 2010. Patients were divided into three breast cancer subtype groups: Luminal (estrogen receptor positive and/or progesterone receptor positive, but human epidermal growth factor receptor 2 negative); human epidermal growth factor receptor 2 positive and triple negative (estrogen receptor negative, progesterone receptor negative and human epidermal growth factor receptor 2 negative). Of 524 advanced breast cancer patients, we reviewed 65 (12%) with brain metastases and records showing estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status, as well as outcome data; there were 26 (40%) Luminal, 26 (40%) had human epidermal growth factor receptor 2 and 13 (20%) had triple negative subtypes. There was no statistical difference in the number of brain metastases among subtypes; however, rates of stereotactic radiosurgery or surgery for brain metastases differed significantly by subtype (human epidermal growth factor receptor 2: 81%, Luminal: 42% and triple negative: 47%; P = 0.03). Patients having the human epidermal growth factor receptor 2 subtype, a performance status of ≤1 and ≤4 brain metastases, who underwent systemic therapy after brain metastases and underwent stereotactic radiosurgery or surgery, were predicted to have longer overall survival after brain metastases. Multivariate analysis demonstrated that not having systemic therapy and not having the human epidermal growth factor receptor 2 subtype were independent factors associated with an increased risk of death (hazard ratio 2.4, 95% confidence interval 1.01-5.6; P = 0.05 and hazard ratio 2.9, 95% confidence interval 1.5-5.8; P = 0.003, respectively). Our study showed that local brain treatments and prognosis differed by subtype in breast cancer patients with brain metastases.

Circulating miR-19a and miR-205 in serum may predict the sensitivity of luminal A subtype of breast cancer patients to neoadjuvant chemotherapy with epirubicin plus paclitaxel.

BackgroundThe luminal A subtype of breast cancer has a good prognosis and is sensitive to endocrine therapy but is less sensitive to chemotherapy. It is necessary to identify biomarkers to predict chemosensitivity and avoid over-treatment. We hypothesized that miRNAs in the serum might be associated with chemosensitivity.MethodsSixty-eight breast cancer patients received neoadjuvant chemotherapy with epirubicin plus paclitaxel. The serum of the patients was collected before chemotherapy and stored at −80°C. The samples were classified into two groups in term of the chemosensitivity. We identified the differential expression patterns of miRNAs between the chemotherapy sensitive and resistant groups using microRNA profiling. Four miRNAs that were differentially expressed between the two groups were further validated in another 56 samples. We created a model fitting formula and a receiver operating characteristics (ROC) curve using logistic regression analysis to evaluate the prediction potency.ResultsWe identified 8 miRNAs differentially expressed between the two groups: 6 miRNAs were up-regulated, and 2 miRNAs were down-regulated in the resistant group compared with the sensitive group. The expression of miR-19a and miR-205 were determined to have significant differences between the two groups (P<0.05). A predictive model of these two miRNAs was created by the logistic regression analysis. The probability of this model was 89.71%. Based on the ROC curve, the specificity was 75.00%, and the sensitivity was 81.25%.ConclusionsThe combination of miR-19a and miR-205 in the serum may predict the chemosensitivity of luminal A subtype of breast cancer to epirubicin plus paclitaxel neoadjuvant chemotherapy.

Relationship between detection of circulating tumor cells and molecular subtypes in breast cancer patients

Objective To investigate the correlation between circulating tumor cells (CTCs) and the predefined molecular classification of patients with breast cancer.Methods We used real-time quanti-tative reverse transcription-polymerase chain reaction (RT-qPCR) to detect cytokeratin 19 (CK19),human mammaglobin (hMAM),and small breast epithelial mucin (SBEM) mRNA expression levels in 285 cases of breast cancer and 123 controls.Statistical analyses were additionally performed to examine the correlation between the mRNA expression levels of these markers with the clinicopathological features of breast cancer patients.Results The sensitivity of these three mRNA markers of the patients with breast cancer was 33.3％,17.9％,and 18.2％ respectively,which was significantly higher than the control group (P ＜ 0.05).The sensitivity of these three markers combined was 47％,which was significantly higher than that of single marker detection (P ＜ 0.05).However,no significant difference in CTC detection was noted among the predefined molecular classifications.Statistical analysis demonstrated that high expression levels of CTC were correlated with the age and menopause status (P ＜ 0.05).In addition,overexpression of these three mRNA markers was positively correlated with tumor size (P ＜ 0.05).Conclusion Combined detection of three markers (CK19,hMAM and SBEM) based on a RT-qPCR platform has higher sensitivity to detect CTC in peripheral blood of breast cancer patients.Although CTC have no clear correla-tion with breast cancer molecular subgroups,but close correlation with age,postmenopausal status and tumor size of patients with breast cancer. Key words: Breast cancer; Circulating tumor cells; Molecular classification

S-Score: A Scoring System for the Identification and Prioritization of Predicted Cancer Genes

A new method, which allows for the identification and prioritization of predicted cancer genes for future analysis, is presented. This method generates a gene-specific score called the “S-Score” by incorporating data from different types of analysis including mutation screening, methylation status, copy-number variation and expression profiling. The method was applied to the data from The Cancer Genome Atlas and allowed the identification of known and potentially new oncogenes and tumor suppressors associated with different clinical features including shortest term of survival in ovarian cancer patients and hormonal subtypes in breast cancer patients. Furthermore, for the first time a genome-wide search for genes that behave as oncogenes and tumor suppressors in different tumor types was performed. We envisage that the S-score can be used as a standard method for the identification and prioritization of cancer genes for follow-up studies.

Expression of enhancer of zeste homologue 2, correlated with HIF-1α, to refine relapse risk and predict poor outcome for breast cancer.

538 Background: Overexpression of enhancer of zeste homologue 2 (EZH2), a key component of polycomb proteins, has been linked to aggressive tumor behavior for breast cancer. In vitro, hypoxia-inducible factor 1 alpha (HIF-1α) transcriptionally activates EZH2 and promotes breast tumor initiating cells progression. Here, we characterized the clinicopathological effect of HIF-1α and EZH2 in breast cancer patients. Methods: Tumor specimens from 410 luminal subtype breast cancer patients were used to construct tissue microarray. EZH2 and HIF-1α level were examined by immunohistochemistry staining and Western blot analysis. With the 5-year follow up, the prognostic effect of EZH2 was subjected to multivariate analysis. Results: EZH2 and HIF-1α were highly expressed in 99 (24.1%) and 272 (70.6%) patients, respectively. EZH2 overexpression was associated with high histological grade (P=0.030), lymphatic invasion (P=0.025), HER2 overexpression (P=0.005) and hypoxic condition (P&lt;0.001). Forced expression of EZH2 predicted a poor 5-year overall survival (OS, 74.8% vs. 93.4%, P=0.001), disease-free survival (DFS, 72.2% vs. 88.6%, P=0.031), local failure-free survival (LFFS, 95.7% vs. 97.9%, P=0.045) and distant metastasis-free survival (DMFS, 75.4% vs. 90.5%, P=0.039). However, the prognostic effect of HIF-1α was not detected for breast cancer. Cox multivariate analysis confirmed that EZH2 was an independent prognostic factor for OS, DFS and LFFS. Moreover, a positive correlation was detected between EZH2 and HIF-1α (r=0.299, P&lt;0.001). Importantly, tumors with HIF-1α and EZH2 co-overexpression were correlated with a worsened OS (P=0.007). Conclusions: EZH2 was an independent negative prognostic biomarker for luminal subtype breast cancer. Targeting HIF-1α transcriptionally regulated EZH2 pathway might be of benefit in the treatment of luminal subtype of breast cancer.