HER2-overexpressing Subtypes Research Articles

12IN - Modulation of Immune Response in Breast Cancer and Clinical Implications

ABSTRACT Recently, the emergence of effective immunotherapies has become a reality for cancer patients. Immunity has two seemingly paradoxical effects on cancer. On the one hand, immunity prevents against the development of potential tumours, a concept is known as immunosurveillance. On the other hand, immunity can shape the nature of developing tumour through immunological pressure, by selecting out the non-immunological variants. This combination is termed “cancer immunoediting” and describes the ability of some tumours to grow whilst actively avoiding destruction by the immune system. Recent newly-developed therapies that serve to release tumour-mediated immunosuppression, through inhibition of T effector cell negative regulators such as cytotoxic T-lymphocyte antigen-4 (CTLA4) and programmed death 1 (PD-1), have been reported to be effective in metastatic melanoma and lung cancer. Whilst immunotherapies have been traditionally for solid tumour types considered “immunogenic” such as melanoma and renal cell carcinoma, our evidence suggests that certain subtypes of breast cancer may also be amendable to immune approaches. In the triple negative (TNBC) and HER2-overexpressing (HER2+) subtypes, immune surrogates have been correlated with prognosis now in a number of large clinical trial datasets. As clinical trials have carefully collected prospective data on survival, correlations between biomarkers and outcome are considered more robust using these samples. In particular, there is a strong correlation between lymphocytic infiltration and a good outcome in TNBC. In HER2+ disease, innate and adaptive immune responses seem to be important for mediating responses to anti-HER2 therapy. Oncogenic signalling seems to have a role in potentiating immunosuppression in tumours. At present it is unknown if inhibition of T effector cell negative regulators such as anti- CTLA4 and anti-PD 1 will be effective in the treatment of TNBC and HER2+ disease. These phase II trials are about to start. If these compounds are shown to be effective, a new paradigm in the treatment of breast cancer will begin. Disclosure: The author has declared no conflicts of interest.

Relationship between chemotherapy and prognosis in different subtypes of node-negative breast cancer.

Knowledge is limited about the relationship between chemotherapy and prognosis among the subtypes of axillary node-negative breast cancer (ANNBC). In this study, a population including 2,236 primary and operable ANNBC patients, with a median age of 53, were included. All breast tumors were classified into five immunohistochemically defined subtypes-luminal A, luminal B, luminal human epidermal growth factor receptor 2 (HER2), HER2 overexpression, and triple negative. With a median follow-up of 73.6 months, the rate of relapse was lowest in luminal A (6.5 %) and highest in HER2 overexpression subtype (16.4 %). Multivariate analysis indicated that the risks of relapse and death were enhanced in HER2 overexpression and triple-negative (TN) subtypes, and these two subtypes were independent predictors of relapse and death. Luminal A patients with risk factors could benefit from chemotherapy in terms of relapse-free survival (RFS). The relapse rate of TN patients after chemotherapy with taxanes was lower compared with that after chemotherapy without taxanes. In conclusion, women with ANNBC were at higher risks of relapse and death if suffering from HER2 overexpression or TN diseases. Chemotherapy could reduce the recurrence rate of luminal A patients with risk factors. TN patients may benefit from adjuvant chemotherapy containing taxanes.

Association of race/ethnicity, socioeconomic status, and breast cancer subtypes in the National Cancer Data Base (2010-2011).

To estimate the odds of breast cancer subtypes in minority populations versus non-Hispanic (NH) whites stratified by socioeconomic status (SES) [a composite of individual-level SES (insurance status) and area-level SES (median household income quartile from 2000 U.S. Census data)] using a large nationwide cancer database. We used the National Cancer Data Base to identify breast cancer cases diagnosed in 2010 and 2011, the only 2 years since U.S. cancer registries uniformly began collecting HER2 results. Breast cancer cases were classified into five subtypes based on hormone receptor (HR) and HER2 status: HR+/HER2-, HR+/HER2+, HR-/HER2+ (HER2-overexpressing), HR-/HER2- (TN), and unknown. A polytomous logistic regression was used to estimate odds ratios (ORs) comparing the odds of non-HR+/HER2-subtypes to HR+/HER2- for racial/ethnic groups controlling for and stratifying by SES, using a composite of insurance status and area-level income. Compared with NH whites, NH blacks and Hispanics were 84 % (OR = 1.84; 95 % CI 1.77-1.92) and 17 % (OR = 1.17; 95 % CI 1.11-1.24) more likely to have TN subtype versus HR+/HER2-, respectively. Asian/Pacific Islanders (API) had 1.45 times greater odds of being diagnosed with HER2-overexpressing subtype versus HR+/HER2- compared with NH whites (OR = 1.45; 95 % CI 1.31-1.61). We found similar ORs for race in high and low strata of SES. In a large nationwide hospital-based dataset, we found higher odds of having TN breast cancer in black women and of HER2-overexpressing in API compared with white women in every level of SES.

A novel morphologic-molecular recurrence predictive model refines traditional prognostic tools for invasive breast carcinoma.

Histologic grade, TNM stage, and Nottingham Prognostic Index are traditional prognostic tools for breast cancer. "IHC-molecular" classification of breast cancer can also identify patients at different recurrence risks and provides insight into cancer therapy. However, cancers in each group are heterogeneous. A model based on the comprehensive analysis of morphologic features and molecular subtype was constructed to predict recurrence and refine these traditional prognostic tools. Morphologic features including histologic grade, fibrotic focus, extensive intraductal component, lymphocytic infiltrate, lymphovascular invasion, tumor necrosis, tumor margin and TNM stage, and molecular subtypes approximated by immunohistochemistry were analyzed in 633 patients with invasive breast carcinoma (excluding those with HER2 targeted therapy). Significant independent predictors for recurrence included: high histologic grade (p = 0.004), presence of lymphovascular invasion (p = 0.004), fibrotic focus (p = 0.020), mild lymphocytic infiltrate (p = 0.013), high TNM stage (p < 0.001), and HER2-overexpressing (p = 0.004) and basal-like (p < 0.001) molecular subtypes. A morphologic-molecular recurrence predictive model based on these features was useful in recurrence prediction, independent of treatment modalities, and was able to refine the traditional prognostic tools of histologic grade, TNM stage, and Nottingham prognostic index, particularly for intermediate-risk groups, and to refine the luminal group molecular subtypes. Such findings were reproducible with a validation cohort. TNM stage, histologic grade, lymphovascular invasion, fibrotic focus, mild lymphocytic infiltrate, HER2-overexpressing and basal-like molecular subtypes were important independent recurrence risk factors for breast cancer. This morphologic-molecular model was robust in recurrence prediction and refined recurrence risk stratified by the traditional prognostic parameters, independent of treatment modalities.

MRI and pathological features of different molecular subtypes of breast cancers

Objective To investigate the MRI and pathological features of different molecular subtypes of breast cancer.Methods The data of 202 patients who underwent primary breast cancer resection were retrospectively reviewed.All of the patients had MRI preoperatively.The molecular subtypes of breast cancer defined by immunohistochemistry were classified as basal-like,luminal and HER-2 overexpression.Morphology (including mass or non-mass like enhancement,shape and margin of masses,unifocal or multifocal masses) and enhancement characteristics on MRI,histologic types and grades of tumors were analyzed with Chi-square test,exact test,Fisher exact test,Kruskal-Wallis H test,and Wilcoxon test.Results Among the 202 patients,34 were basal-like,144 were luminal and 24 were HER-2 overexpression.The number of mass cases in each subtype was 29,133 and 19 respectively,making no significant difference (x2 =4.136,P =0.126).As for the shape of basal-like lesions,8 were round,19 were lobular and 2 were irregular,while this distribution was 23,58,52 in luminal subtype and 1,11,7 in HER-2 overexpression subtype (x2 =13.391,P ＜ 0.05).The margin was also strikingly different among three groups (smooth,spiculated,irregular):20,5,4 respectively in basal-like,27,53,53 respectively in luminal,and 4,7,8 respectively in HER-2 overexpression (x2 =28.515,P ＜ 0.01).52.6％ (10/19) of HER-2 overexpression cases were multifocal,while only 6.9％ (2/29) of luminal and 8.0％ (24/133) of basal-like ones were multifocal (x2 =16.140,P ＜ 0.01).Characteristics in dynamic contrast-enhanced MRI were statistically different,with homogeneous,heterogeneous,and rim enhancement 0,13,16 respectively in basal-like cases,28,93,11 respectively in luminal cases and 2,11,6 respectively in HER-2 overexpression cases (P ＜ 0.01).However,the difference for enhancement curve did not reach significance (P =0.457).Histologic types were significantly different among molecular subtypes (P ＜ 0.01).Luminal breast cancer consisted of various histologic types,32.6％ (47/144) of which were mixed type.The majority of the other two molecular subtypes were invasive ductal carcinoma.Furthermore,invasive ductal carcinomas with different molecular subtypes showed different histologic grades (Hc =30.014,P ＜ 0.01).Basal-like breast cancer was more likely associated with a higher grade of malignancy.Conclusions Different molecular subtypes of breast showed distinct MRI features and pathologic characteristics.MRI might be a useful tool for preoperative prediction of molecular subtypes of breast cancer. Key words: Breast neoplasms ; Magnetic resonance imaging; Pathology

Subtype is a predictive factor of nonsentinel lymph node involvement in sentinel node-positive breast cancer patients.

PurposeThis study aimed to identify the effect of breast cancer subtype on nonsentinel lymph node (NSLN) metastasis in patients with a positive sentinel lymph node (SLN).MethodsThe records of 104 early breast cancer patients with a positive SLN between April 2009 and September 2013 were retrospectively evaluated. All patients underwent axillary lymph node dissection. The effects of the tumor subtype (luminal A, luminal/HER2+, human epidermal growth factor receptor 2 [HER2] overexpression, and triple-negative) and other clinicopathological factors on NSLN metastasis were examined by univariate and multivariate statistical analyses.ResultsFifty of 104 patients (48%) exhibited NSLN metastasis. Univariate and multivariate analyses revealed that tumor size and the ratio of positive SLNs were significant risk factors of NSLN metastasis in patients with a positive SLN. The rate of NSLN metastasis was higher in patients with luminal/HER2+ and HER2 overexpression subtypes than that in patients with other subtypes in the univariate analysis (p<0.001). In the multivariate analysis, both patients with luminal/HER2+ (p<0.006) and patients with HER2 overexpression (p<0.031) subtypes had a higher risk of NSLN metastasis than patients with the luminal A subtype.ConclusionSubtype classification should be considered as an independent factor when evaluating the risk of NSLN metastasis in patients with a positive SLN. This result supports the development of new nomograms including breast cancer subtype to increase predictive accuracy.

Prognostic Significance of Deregulated Dicer Expression in Breast Cancer

BackgroundDicer, an RNase III-type endonuclease, is the key enzyme involved in RNA interference and microRNA pathways. Aberrant expression of Dicer is reported in several human cancers. Our aim was to assess the prognostic role of Dicer in breast cancer.MethodsThe entire series comprised 666 invasive breast cancers (IBCs), 480 DCIS cases (397 associated with IBC and 83 pure DCIS) and 305 lymph node metastases. Cytoplasmic Dicer expression by immunohistochemistry was scored as negative (no staining) and positive (weak, moderate or strong staining).ResultsDicer staining was assessable in 446 IBC, 128 DCIS and 101 lymph node metastases. Expression of Dicer was observed in 33% (145/446) of IBCs, 34% (44/128) of DCIS and 57% (58/101) of lymph node metastases. Dicer expression was increased in nodal metastases compared to primary tumours (p<0.001); and was associated with ER negativity (p<0.001), HER2 positivity (p<0.001), high Ki67 labeling index (p<0.001) and expression of basal-like biomarkers (p = 0.002). Dicer positivity was more frequent in the HER2 overexpressing (p<0.001) and basal-like (p = 0.002) subtypes compared to luminal A subtype. Dicer expression was associated with reduced overall survival (OS) on univariate analysis (p = 0.058) and remained an independent predictor of OS on multivariate analysis (HR 2.84, 95% CI 1.43–5.62, p = 0.003), with nodal status (HR 2.61, 95% CI 1.18–5.80, p = 0.018) and PR (HR 0.28, 95% CI 0.13–0.59, p = 0.001). Further, moderate or strong expression of Dicer was associated with improved disease-free survival in the HER2-overexpressing subtype compared to negative or weak expression (p = 0.038).ConclusionDeregulated Dicer expression is associated with aggressive tumour characteristics and is an independent prognostic factor for OS. Our findings suggest that Dicer is an important prognostic marker in breast cancer and that its prognostic role may be subtype specific.

Abstract P2-11-14: Does the Nottingham prognostic index further refine survival within the breast cancer subtypes?

Abstract Background The Nottingham Prognostic Index (NPI), based on tumor size, lymph node status, and histologic grade, is a well established method of predicting survival of operable breast cancer. Breast cancer survival of the luminal, triple negative, and HER2 overexpressing subtypes has been previously described. The purpose of this study is to determine if the NPI can further refine survival of these subtypes within the AJCC stages of breast cancer. Method We identified 118,923 cases of stages 1-3 first primary female invasive breast cancer from the California Cancer Registry diagnosed between January 1, 2000 and December 31, 2010 with known ER/PR/HER2 status. The subtypes were classified as Luminal A (ER and/or PR-positive, HER2-negative), Luminal B (ER and/or PR-positive, HER2-positive), triple negative (ER-/PR-/HER2-), or HER2-overexpressing (ER-/PR-/HER2+). The NPI was computed and cases were stratified as having good (NPI &amp;lt;3.4), moderate (3.4-5.4) or poor (&amp;gt;5.4) prognosis. Kaplan Meier survival analysis (95% CIs) was used to compare survival among the NPI categories within each subtype and stage. Results The table shows that in stage 1, there was a statistically significant difference in survival between the good versus the moderate and poor NPI categories for luminal A, luminal B, and the triple negative subtypes. For the HER2-overexpressing subtype, the only difference was between the good and poor NPI category. For stage 2, the only difference in survival was for Luminal A where both the moderate (94.6%; 93.4%, 95.8%) and poor (84.3%; 83.6%, 85.0%) NPI categories had worse survival than the good category (99.9%; 97.1%, 100.0%). For stage 3, there were no differences among the NPI categories for any of the subtypes. Eight year survival of stage 1 breast cancer subtypes within the NPI categories 8-Year Survival95% LCL*95% UCL*Luminal A Good95.695.196.2Moderate94.493.994.9Poor90.389.191.5Luminal B Good95.894.097.5Moderate94.393.195.5Poor88.686.291.0Triple Negative Good93.690.197.0Moderate88.186.090.1Poor86.084.287.8HER2-overexpressing Good92.387.697.1Moderate89.786.992.4Poor86.483.389.5*CL = Confidence Limit For stage 2, the only difference in survival was for Luminal A where both the moderate (94.6%; 93.4%, 95.8%) and poor (84.3%; 83.6%,85.0%) NPI categories had worse survival than the good category (99.9%; 97.1%, 100.0%). For stage 3, there were no differences among the NPI categories for any of the subtypes. Conclusion The NPI is a valuable addition to AJCC stage 1 for all breast cancer subtypes. The NPI and AJCC staging systems both incorporate lymph node status and tumor size. However, histologic grade, found only in the NPI, may improve the accuracy of survival, especially in stage 1. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-11-14.

Immunohistochemistry-based subtyping of breast carcinoma in Egyptian women

Breast carcinoma is a heterogeneous disease affected by patients' ethnicity. Gene expression analysis identified several molecular subtypes, and similar subtyping has now been found to be feasible using immunohistochemistry. This study estimated the distribution of intrinsic breast cancer subtypes using estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 (Her2/neu), and cytokeratin 5/6 immunostaining in a cohort of 125 Egyptian women diagnosed as having invasive breast carcinoma. Associations with clinicopathologic variables and the prognostic markers Bcl-2 and Cyclin D1 were investigated and statistically analyzed. Population difference in breast cancer subtypes was detected, suggesting etiologic and genetic heterogeneity among demographic groups. As reported worldwide, most tumors were luminal A (39.2%), but basal-like and unclassified subtypes had higher proportions among our cohort (16.8% and 16%, respectively), particularly in premenopausal patients (P = .0001), in contrast to postmenopausal African Americans, premenopausal European Americans, and other populations. Her2-overexpressing subtype was the least common subtype (13.65%) among our patients, although it is more common in Asians. Basal-like and unclassified carcinomas were more frequently grade 3 neoplasms (P = .035). Lobular histology was distributed among luminal A, B and unclassified subtypes (P = .006). The highest frequency of nodal positivity was associated with Her2 overexpressing carcinomas (94.1%, P = .0001). Luminal and unclassified carcinomas more likely expressed Bcl-2 (P = .011) and Cyclin D1 (P = .0001), whereas basal and Her2 subtypes had the lowest expression levels. Immunohistochemistry-based subtyping can be helpful in separating breast carcinoma into subtypes that vary in distribution among different populations. These subtypes have distinct clinicopathologic features and diverse prognostication, which may imply different therapeutic options for each subtype.

Clinical Significance of Lymph Node Ratio in Locally Advanced Breast Cancer Molecular Subtypes

Background: The ratio of metastatic to dissected lymph nodes (lymph node ratio; LNR) is a sensitive and superior prognostic factor for lymph node evaluation, but its relationship to cancer subtypes is unclear. Patients and Methods: Data from 469 patients with axillary lymph node metastasis out of 640 early breast cancer cases were retrospectively analyzed. They were classified into 4 molecular subtypes; luminal A, luminal B HER2(+), HER2 overexpression, basal-like. LNRs were compared between groups and with other prognostic factors. Results: The distribution of LNRs was 35.2% in luminal A, 43.2% in luminal B HER2(+), 46.9% in HER2 over-expression, and 39.1% in basal-like. A significant difference was found between luminal A and HER2 over-expression subtypes (p = 0.023). LNR was significantly correlated with tumor size and lymphovascular invasion, but not with other prognostic factors including menopausal status, laterality, grade, and perineural invasion. An LNR of 29.8% was defined as the cut-off value, and significant differences in survival rates were identified accordingly between basal-like and both luminal A (p = 0.003) and luminal B HER2(+) (p = 0.04). Conclusion: The LNR differs between some molecular subtypes of breast cancer, and it correlates with certain prognostic factors and survival. These data support using the LNR to assess breast cancer patients.

Abstract A124: Characterization of claudin-low breast cancers

Abstract Molecular profiling of human breast cancers has defined 5 molecular subtypes: luminal A, luminal B, HER2 over-expressing, basal-like and claudin-low. The claudin-low subtype was identified in 2007 and is characterized by low expression of claudin proteins, E-cadherin and markers of luminal differentiation, and is reported to be associated with expression of mesenchymal and cancer stem cell (CSC) markers. The prevalence of this subtype is reported to be between 7-14% and there are an excess of tumors with metaplastic and medullary-like features, an association with poor prognosis and evidence that they may be resistant to conventional chemotherapies. Using information from publicly available gene expression microarray data, we sought to identify immunohistochemical markers of the claudin-low subtype and to further describe the morphological features of claudin-low breast tumors and the overall survival characteristics of patients with these tumors, along with any associations between these tumors and CSC markers. Using the gene expression microarray datasets, we performed hierarchical clustering to assign a molecular subtype to the tumors. Differential gene expression analysis was used to identify genes that were significantly upregulated and downregulated between claudin-low tumors and other tumor subtypes as candidates for immunohistochemical markers for our formalin fixed paraffin embedded (FFPE) tumor cohort. We utilized 943 stage I or stage II, lymph node negative primary invasive breast cancers treated with breast conserving surgery and adjuvant radiation, which had FFPE tumor blocks available for tissue microarray construction. On the basis of IHC expression of ER, PR, HER2, Ki67, EGFR, CK5/6, Claudin proteins and E-cadherin, tumors were classified as luminal A, luminal B, HER2 over-expressing, basal-like or claudin-low. Kaplan-Meier methods were used to estimate overall survival, and Fisher's exact tests were used to compare tumor characteristics and expression of CSC markers (ALDH1, CD44hi/CD24low) between claudin-low and luminal A tumors. Claudin-low tumors comprised 8% of our cohort with an overall survival of 73.6% at a median follow up of 12 years, similar to that of basal-like and HER2 over-expressing subtypes. Compared to luminal A type tumors, the claudin-low tumors were statistically more likely to have circumscribed tumor margins. However, there was no statistically significant association between claudin-low subtype and the expression of CSC markers. The claudin-low subtype represents a minority of invasive breast cancers, however this group is characterized by poor prognosis, and as such the identification of these tumors is useful to determine treatment options in the clinical setting. Citation Format: Kay Dias, Anna Dvorkin-Gheva, Greg Pond, Mark Levine, Timothy Whelan, Anita Bane. Characterization of claudin-low breast cancers. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A124.

Association of osteopontin and cyclooxygenase-2 expression with breast cancer subtypes and their use as potential biomarkers

Breast cancer is one of the most common malignant tumors among females worldwide and remains a leading cause of cancer-related mortality. Due to the heterogeneous clinical nature of breast cancer, it is necessary to identify new biomarkers that are associated with tumor growth, angiogenesis and metastasis. Osteopontin (OPN) and cyclooxygenase-2 (COX-2) are known to be overexpressed in invasive breast cancer and their overexpression is associated with aggressive histological and clinical features. The present study assessed OPN and COX-2 expression in various subtypes of breast cancer. The expression of OPN and COX-2 was analyzed using immunohistochemistry (IHC) in a cohort of 67 invasive ductal breast carcinoma patients. The statistical analysis was performed using standard statistical software SPSS version 18.0. The associations between OPN and COX-2 and the human epidermal growth factor receptor type 2 (HER2)-overexpressing and non-HER2-overexpressing subtypes were evaluated using the Mann-Whitney U test. The mean OPN level was significantly higher in the HER2-overexpressing subtype compared with the non-HER2-overexpressing subtype. Furthermore, the mean COX-2 expression levels were higher in the HER2-overexpressing subtype compared with the luminal A, luminal B or triple-negative groups. It is well known that carcinomas overexpressing HER2/neu have a worse prognosis than luminal tumors. Hence, it may be hypothesized that an elevated expression of OPN and COX-2 in a HER2-overexpressing subtype may contribute to a more aggressive behavior and be used as diagnostic and prognostic markers in breast cancer.

Differential Distribution of microRNAs in Breast Cancer Grouped by Clinicopathological Subtypes

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. 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. 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. A total of 37 miRNAs were significantly distributed in tumors from the centers to edges, and in all clinicopathological subtypes.

Correlation between Tau expression and clinicopathological characteristics of breast invasive ductal carcinomas

To explore the expression of Tau protein in breast invasive ductal carcinomas and examine the correlation between its expression and clinicopathological characteristics of breast cancer. The clinicopathological data of 150 breast cancer patients at Third Municipal Hospital from October 2007 to June 2011 were collected and analyzed. Immunohistochemical method was used to detect the expressions of estrogen receptor (ER), progesterone receptor (PR), HER-2 and Tau protein. No correlations existed between the expression of Tau protein and age, tumor size or node metastasis of breast cancer patients (χ(2) = 0.02, P = 0.88; χ(2) = 0.55, P = 0.46; χ(2) = 1.02, P = 0.31). The expressions of Tau in ER positive patients were significantly higher than ER negative patients. And this trend extended to PR positive and HER-2 negative patients (χ(2) = 15.77, P = 0.00; χ(2) = 5.03, P = 0.03; χ(2) = 8.00, P = 0.01). The expression of Tau protein in Luminal A subtype was significantly higher than in Luminal B subtype, HER-2 over-expression subtype and basal like subtype (χ(2) = 7.26, P = 0.01). Over-expressed in breast cancer, Tau protein is associated with ER, PR and HER-2. However, the relation between Tau protein and prognosis of breast cancer requires further researches.

Prognostic and Predictive Significance of MYC and KRAS Alterations in Breast Cancer from Women Treated with Neoadjuvant Chemotherapy

Breast cancer is a complex disease, with heterogeneous clinical evolution. Several analyses have been performed to identify the risk factors for breast cancer progression and the patients who respond best to a specific treatment. We aimed to evaluate whether the hormone receptor expression, HER2 and MYC genes and their protein status, and KRAS codon 12 mutations may be prognostic or predictive biomarkers of breast cancer. Protein, gene and mutation status were concomitantly evaluated in 116 breast tumors from women who underwent neoadjuvant chemotherapy with doxorubicin plus cyclophosphamide. We observed that MYC expression was associated with luminal B and HER2 overexpression phenotypes compared to luminal A (p<0.05). The presence of MYC duplication or polysomy 8, as well as KRAS mutation, were also associated with the HER2 overexpression subtype (p<0.05). MYC expression and MYC gain were more frequently observed in early-onset compared to late-onset tumors (p<0.05). KRAS mutation was a risk factor of grade 3 tumors (p<0.05). A multivariate logistic regression demonstrated that MYC amplification defined as MYC/nucleus ratio of ≥2.5 was a protective factor for chemotherapy resistance. On the other hand, age and grade 2 tumors were a risk factor. Additionally, luminal B, HER2 overexpression, and triple-negative tumors presented increased odds of being resistant to chemotherapy relative to luminal A tumors. Thus, breast tumors with KRAS codon 12 mutations seem to present a worse prognosis. Additionally, MYC amplification may help in the identification of tumors that are sensitive to doxorubicin plus cyclophosphamide treatment. If confirmed in a large set of samples, these markers may be useful for clinical stratification and prognosis.

Abstract P3-09-02: The HER2 –positive subtypes by stage and race/ethnicity

Abstract HER2-positivity is often associated with poor survival. The purpose of this study is to determine if there are differences in mortality among the HER-positive subtypes when stratified by stage and race/ethnicity. Methods: Using the California Cancer Registry for years 2000–2010, we examined 99,897 cases of stages 1–3 ER+/PR+/HER2− and all HER2-positive first primary female invasive breast cancers. Race/ethnicity was defined as white, black, Hispanic, and Asian/Pacific Islander (API). Kaplan-Meier (KM) and the Log-Rank test were used to compute 6-year survival. Cox proportional hazards was used to assess the risk of mortality of each of the HER2-positive subtypes when compared with the ER+/PR+/HER2− subtype (the most common subtype). All analyses were adjusted for age, grade, year of diagnosis (&amp;lt;2007, 2007+), and socioeconomic status and run separately by race for stages 1, 2, and 3. Results: For all stages combined, of the subtypes comprising the luminal B-HER2 positive category, the ER+/PR+/HER2+ had the best survival (85%), only 2% less than the ER+/PR+/HER2−. When compared with the ER+/PR+/HER2− subtype, no difference in KM survival was noted for stage 1 luminal B (ER+/PR+/HER2+;ER+/PR−/HER2+; ER−/PR+/HER2+). Both had 90% 72-month survival. The ER−/PR−/HER2+ had 88% survival (p &amp;lt; 0.02). For stage 2, luminal B had 83% survival and ER−/PR−/HER2+ had 76% survival. Both were significantly different (p &amp;lt; 0.001) from the ER+/PR+/HER2− subtype (86%). The luminal B had 68% survival and the ER−/PR−/HER2+ had 55% survival for stage 3. Both were statistically significantly worse (p &amp;lt;.006) than the ER+/PR+/HER2− (72%). Adjusted mortality for the ER+/PR+/HER2+ was only increased for blacks in stage 1 (HR = 1.59; 95%CI=1.09–2.33). Mortality for the ER−/PR−/HER2+ was increased for whites in all stages; for blacks in stages 1 (HR = 1.82; 95%CI=1.11–3.00) and 3 (HR = 1.90; 95%CI=1.36–2.66); for Hispanics in stages 2 (HR = 1.58; 95%CI=1.28–1.95) and 3 (HR = 2.19; 95%CI=1.73–2.78); and APIs only in stage 2 (HR = 1.70; 95%CI=1.31–2.19) Year of diagnosis made no difference in risk of mortality in stage 1 for any race. For stage 2, blacks had slightly reduced mortality if diagnosed in 2007 or later, and for stage 3, all races except blacks had reduced risk of mortality when diagnosed in 2007 or later. Conclusions: 1. There is variation in survival among the luminal B-HER2 positive subtypes.2. The driving force behind the increased mortality of the HER2 positive subtype is the ER−/PR−/HER2+ subtype, the molecularly defined HER2 overexpressing subtype.3. Year of diagnosis does not influence survival in stage 1 for any race.4. There are differences in mortality among the HER2 positive subtypes when stratifying by stage and race and adjusting for age, grade, year of diagnosis, and SES. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-09-02.

Cancer stem cell markers are associated with adverse biomarker profiles and molecular subtypes of breast cancer

Cumulative evidence has demonstrated the presence of cancer stem cells (CSC) in breast cancer and its putative role in cancer progression. Nonetheless, the clinical significance of CSC in breast cancer remains elusive. The underlying reasons could be due to the heterogeneity of breast cancer subtypes as well as different markers used to define breast CSC. In this study, three widely used markers (aldehyde dehydrogenase (ALDH)1+ and CD24-CD44+) were used to define two populations of CSC in a large cohort of breast cancers. The expressions of these markers were correlated with different clinicopathological features and the molecular subtypes. ALDH1+ breast cancers were associated with basal-like and HER2-overexpressing subtypes and the characteristics histologic features were related to these two subtypes. On the other hand, CD24-CD44+ breast cancers were associated positively with the presence of extensive in situ component, the absence of lymph node involvement, and basal markers, but negatively with HER2. CD24-CD44+ breast cancers were also positively associated with luminal B cancers. As the expression of CSC markers varied among different molecular subtypes and different clinicopathological features, it appeared that each CSC population could have distinct clinical values in different subgroups of breast cancers. For improved prognostication with CSC, combining the analysis of CSC markers would be required. Within the luminal cancers, CSC appeared to identify cancers with poor outcome. The presence of CSC populations was associated with ER-PR+ cancers and tumors expressing basal markers. Basal marker expression can complement with CSC for improved indicator for poor prognosis in luminal breast cancers. For the first time, the possible contribution of CSC to these aggressive luminal cancers was demonstrated. The association of basal features and CSC in luminal cancers also raised the possibility that luminal cancer cells may acquire basal phenotype and CSC properties together during their progression.

Association between common risk factors and molecular subtypes in breast cancer patients

BackgroundBreast cancer is the most commonly diagnosed cancer in women worldwide and characterized its by molecular and clinical heterogeneity. Gene expression profiling studies have classified breast cancers into five subtypes: luminal A, luminal B, HER-2 overexpressing, basal-like, and normal breast-like. Although clinical differences between subtypes have been well described in the literature, etiologic heterogeneity have not been fully studied. The aim of this study was to assess the associations between several hormonal and nonhormonal risk factors and molecular subtypes of breast cancer. MethodsThis cross-sectional study consisted of 1884 invasive breast cancer cases. Variables studied included family history, age at first full-term pregnancy, number of children, duration of lactation, menstruation history, menopausal status, blood type, smoking, obesity, oral contraceptive use, hormone replacement therapy and in vitro fertilization. The odds ratios (OR) and 95% confidence intervals (CI) were estimated using multivariate logistic regression analysis. ResultsThousand two-hundred and forty nine patients had luminal A, 234 had luminal B, 169 had HER-2 overexpressing and 232 had triple negative breast cancer. The age of ≥40 years was found to be a risk factor for luminal A (OR 1.41 95% CI 1.15–1.74; p=0.001) and HER-2 overexpressing subtype (OR: 1.51, 95% CI: 1.01–2.25; p=0.04). Women who were nulliparous (OR 1.48, 95% CI 1.03–2.13; p=0.03) or who had their first full-term pregnancy at age 30 years or older (OR 1.25 95% CI 0.83–1.88; p=0.04) were at increased risk of luminal breast cancer, whereas women with more than two children had a decreased risk (OR 0.68, 95% CI 0.47–0.97; p=0.03). Breast-feeding was also a protective factor for luminal subtype (OR 0.74, 95% CI 0.53–1.04; p=0.04) when compared to non-luminal breast cancer. We found increased risks for postmenopausal women with HER-2 overexpressing (OR 2.20, 95% CI 0.93–5.17; p=0.04) and luminal A (OR 1.87, 95% CI 0.93–3.90, p=0.02) breast cancers, who used hormone replacement therapy for 5 years or more. Overweight and obesity significantly increased the risk of triple negative subtype (OR 1.89 95% CI 1.06–3.37; p=0.04 and OR 1.90 95% CI 1.00–3.61; p=0.03), on the contrary, decreased the risk of luminal breast cancer (OR 0.63 95% CI 0.43–0.95; p=0.02 and OR 0.50 95% CI 0.32–0.76; p=0.002, respectively) in premenopausal women. There were no significant differences between risk of breast cancer subtypes and early menarche, late menopause, family history, postmenopausal obesity, oral contraseptive use, smoking, in vitro fertilization, blood groups and use of hands. ConclusionsReproductive and hormonal characteristics (breastfeeding, parity, age at first full-term birth, hormone replacement therapy) were associated with luminal subtype, compared to non-luminal breast cancer, as consistent with previous studies. Obesity and overweight increased the risk of triple negative subtype, particularly in premenopausal women. Older age and use of hormone replacement therapy were related to the risk of HER-2 overexpressing breast cancer. Our data suggest a significant heterogeneity in association of traditional breast cancer risk factors and tumor subtypes.

1698P - Do the Well-Known Risk Factors of Breast Cancer Have the Same Impact on Development of Molecular Subtypes?

ABSTRACT Background Altough clinical differences between breast cancer (BC) subtypes have been well-described, etiologic heterogeneity have not been fully studied. The aim of this study was to assess the associations between risk factors and molecular subtypes of BC. Methods 1884 invasive BC cases were retrospectively analyzed. The odds ratios (OR) and 95% confidence intervals (CI) were estimated using multiple logistic regression analysis. Results 1249 patients had luminal A, 234 had luminal B, 169 had HER-2 overexpressing and 232 had triple negative BC. The age of ≥40 years was found to be a risk factor for luminal A (OR 1.41 95% CI 1.15-1.74; p = 0.001) and HER-2 overexpressing subtype (OR:1.51, 95% CI:1.01-2.25; p = 0.04). Women who were nulliparous (OR 1.48, 95% CI 1,03-2,13; p = 0.03) or who had their first full-term pregnancy ≥30 years (OR 1.25 95% CI 0.83-1.88; p = 0.04) were at increased risk of luminal BC, whereas women with >2 children had a decreased risk (OR 0.68, 95% CI 0.47-0.97; p = 0.03). Breast-feeding was a protective factor for luminal BC (OR 0.74, 95% CI 0.53-1.04; p = 0.04). We found increased risks for postmenopausal women with HER-2 overexpressing (OR 2.20, 95% CI 0.93-5.17; p = 0.04) and luminal A (OR 1.87, 95% CI 0.93-3.90, p = 0.02) BC, who used hormone replacement therapy for ≥5 years. Overweight and obesity increased the risk of triple negative BC (OR 1.89 95% CI 1.06-3.37; p = 0.04 and OR 1.90 95% CI 1.00-3.61; p = 0.03), on the contrary, decreased the risk of luminal BC (OR 0.63 95% CI 0.43-0.95; p = 0.02 and OR 0.50 95% CI 0.32-0.76; p = 0.002, respectively) in premenopausal women. There were no significant differences between risk of BC subtypes and early menarche, late menopause, family history, postmenopausal obesity, oral contraseptive use, smoking, in vitro fertilization and blood groups. Conclusions Reproductive and hormonal characteristics were associated with luminal BC. Obesity and overweight increased the risk of triple negative subtype, particularly in premenopausal women. Older age and use of hormone replacement therapy were related to the risk of HER-2 overexpressing BC. Our data suggest a significant heterogeneity in association of traditional BC risk factors and tumor subtypes. Disclosure All authors have declared no conflicts of interest.

Prevalence of molecular subtypes and prognosis of invasive breast cancer in north-east of Morocco: retrospective study

BackgroundBreast carcinoma is known as a heterogeneous disease because gene expression analyses identify several subtypes and the molecular profiles are prognostic and predictive for patients. Our aim, in this study, is to estimate the prevalence of breast cancer subtypes and to determine the relationship between clinico-pathological characteristics, overall survival (OS) and disease free survival (DFS) for patients coming from north-east of Morocco.MethodsWe reviewed 366 cases of breast cancer diagnosed between January 2007 to June 2010 at the Department of pathology. Age, size tumor, metastatic profile, node involvement profile, OS and DFS were analyzed on 181 patients. These last parameters were estimated by Kaplan-Meier analysis and log-rank test to estimate outcome differences among subgroups.ResultsThe average age was 45 years, our patients were diagnosed late (57% stage III, 17.5% stage IV) with a high average tumor size. Luminal A subtype was more prevalent (53.6%) associated with favorable clinic-pathological characteristics, followed by luminal B (16.4%), Her2-overexpressing (12.6%), basal-like (12.6%) and unclassified subtype (4.9%).Survival analysis showed a significant difference between subtypes. The triple negative tumors were associated with poor prognosis (49% OS, 39% DFS), whereas the luminal A were associated with a better prognosis (88% OS, 59% DFS). The luminal B and the Her2-overexpressing subtypes were associated with an intermediate prognosis (77% and 75% OS, and 41% and 38% DFS respectively).ConclusionThis study showed that molecular classification by immunohistochemistry was necessary for therapeutic decision and prognosis of breast carcinoma. The luminal A subtype was associated with favorable biological characteristics and a better prognosis than triple negative tumors that were associated with a poor prognosis and unfavorable clinic-pathological characteristics.