scholarly journals Robust and interpretable PAM50 reclassification exhibits survival advantage for myoepithelial and immune phenotypes

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
James C. Mathews ◽  
Saad Nadeem ◽  
Arnold J. Levine ◽  
Maryam Pouryahya ◽  
Joseph O. Deasy ◽  
...  
Keyword(s):  
Survival Rates ◽  
Intrinsic Subtype ◽  
Cell Phenotype ◽  
Intrinsic Subtypes ◽  
Her2 Gene ◽  
Luminal A ◽  
Gene Group ◽  
Luminal B ◽  
Mammary Cell

Abstract We introduce a classification of breast tumors into seven classes which are more clearly defined by interpretable mRNA signatures along the PAM50 gene set than the five traditional PAM50 intrinsic subtypes. Each intrinsic subtype is partially concordant with one of our classes, and the two additional classes correspond to division of the classes concordant with the Luminal B and the Normal intrinsic subtypes along expression of the Her2 gene group. Our Normal class shows similarity with the myoepithelial mammary cell phenotype, including TP63 expression (specificity: 80.8% and sensitivity: 82.8%), and exhibits the best overall survival (89.6% at 5 years). Though Luminal A tumors are traditionally considered the least aggressive, our analysis shows that only the Luminal A tumors which are now classified as myoepithelial have this phenotype, while tumors in our luminal class (concordant with Luminal A) may be more aggressive than previously thought. We also find that patients with basal tumors surviving to 48 months exhibit favorable continued survival rates when certain markers for B lymphocytes are present and poor survival rates when they are absent, which is consistent with recent findings.

scholarly journals Robust and Interpretable PAM50 Reclassification Exhibits Survival Advantage for Myoepithelial and Immune Phenotypes

2018 ◽  
Author(s):  
James C. Mathews ◽  
Saad Nadeem ◽  
Arnold J. Levine ◽  
Maryam Pouryahya ◽  
Joseph O. Deasy ◽  
...  
Keyword(s):  
Survival Rates ◽  
Intrinsic Subtype ◽  
Cell Phenotype ◽  
Intrinsic Subtypes ◽  
Her2 Gene ◽  
Luminal A ◽  
Gene Group ◽  
Luminal B ◽  
Mammary Cell

AbstractWe introduce a classification of breast tumors into 7 classes which are more clearly defined by interpretable mRNA signatures along the PAM50 gene set than the 5 traditional PAM50 intrinsic subtypes. Each intrinsic subtype is partially concordant with one of our classes, and the 2 additional classes correspond to division of the classes concordant with the Luminal B and the Normal intrinsic subtypes along expression of the Her2 gene group. Our Normal class shows similarity with the myoepithelial mammary cell phenotype, including TP63 expression (specificity: 80.8% and sensitivity: 82.8%), and exhibits the best overall survival (89.6% at 5 years). Though Luminal A tumors are traditionally considered the least aggressive, our analysis shows that only the Luminal A tumors which are now classified as myoepithelial have this phenotype, while tumors in our luminal class (concordant with Luminal A) may be more aggressive than previously thought. We also find that patients with Basal tumors surviving to 48 months exhibit favorable survival rates when certain markers for B-lymphocytes are present and poor survival rates when they are absent, which is consistent with recent findings.

scholarly journals Heterogeneity of Breast Cancer Associations with Common Genetic Variants inFGFR2according to the Intrinsic Subtypes in Southern Han Chinese Women

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Huiying Liang ◽  
Xuexi Yang ◽  
Lujia Chen ◽  
Hong Li ◽  
Anna Zhu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Chinese Women ◽  
Intrinsic Subtype ◽  
Han Chinese ◽  
Dependent Manner ◽  
Intrinsic Subtypes ◽  
Luminal A ◽  
Luminal B ◽  
Common Genetic Variants

GWAS have identified variation in theFGFR2locus as risk factors for breast cancer. Validation studies, however, have shown inconsistent results by ethnics and pathological characteristics. To further explore this inconsistency and investigate the associations ofFGFR2variants with breast cancer according to intrinsic subtype (Luminal-A, Luminal-B, ER−&PR−&HER2+, and triple negative) among Southern Han Chinese women, we genotyped rs1078806, rs1219648, rs2420946, rs2981579, and rs2981582 polymorphisms in 609 patients and 882 controls. Significant associations with breast cancer risk were observed for rs2420946, rs2981579, and rs2981582 with OR (95% CI) per risk allele of 1.19 (1.03–1.39), 1.24 (1.07–1.43), and 1.17 (1.01–1.36), respectively. In subtype specific analysis, above three SNPs were significantly associated with increased Luminal-A risk in a dose-dependent mannerPtrend<0.01; however, only rs2981579 was associated with Luminal-B, and none were linked to ER−&PR− subtypes (ER−&PR−&HER2+ and triple negative). Haplotype analyses also identified common haplotypes significantly associated with luminal-like subtypes (Luminal-A and Luminal-B), but not with ER−&PR− subtypes. Our results suggest that associations ofFGFR2SNPs with breast cancer were heterogeneous according to intrinsic subtype. Future studies stratifying patients by their intrinsic subtypes will provide new insights into the complex genetic mechanisms underlying breast cancer.

Breast cancer intrinsic subtypes by PAM50 in older women.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 1524-1524
Author(s):  
Emily Oldham Jenkins ◽  
Allison Mary Deal ◽  
Carey K. Anders ◽  
Aleix Prat ◽  
Charles M. Perou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Biology ◽  
Continuous Variable ◽  
Intrinsic Subtype ◽  
Intrinsic Subtypes ◽  
Luminal A ◽  
Prognostic Information ◽  
Luminal B ◽  
Kaplan Meier ◽  
Treatment Data

1524 Background: Breast cancer (BC) incidence dramatically increases with age and the number of older BC patients (pts) in the U.S. is rising. Although immunohistochemical (IHC) data confirm that the incidence of luminal BC increases with age while the incidence of triple negative (TN) BC decreases, age-specific data on the frequency of BC subtypes defined by gene expression is limited. We characterized the incidence of BC intrinsic subtypes using gene microarrays according to age. Methods: Data from 2,150 pts were pooled from publicly available microarray datasets to determine the incidence of PAM50 breast cancer intrinsic subtypes (Luminal A [LumA], Luminal B [LumB], HER2-enriched [Her2E], Basal-like [Basal] and Normal-like [Norm]) by age. Adjuvant treatment data (none, chemotherapy, endocrine therapy or both) were available for 1,741 samples. Relapse-free (RFS) and overall survival (OS) differences were determined using the Kaplan-Meier method. Results: PAM50 intrinsic subtypes by age are tabulated below. The incidence of luminal (A, B, A+B) tumors increased with age (p<0.01, p<0.0001, p<0.0001, respectively), while the percentage of basal tumors decreased (p<0.0001). Basal tumors represented 13% of pts aged > 70 years (yrs); of the 70% with available IHC data, 74% were TNBC. Age as a continuous variable was not associated with RFS (p = 0.37). Subtype alone (n=2031), and after controlling for treatment (n=1645), was significantly associated with RFS (both p<0.0001). The addition of age to a multivariate analysis added no prognostic information. Conclusions: Though more favorable subtypes increase with age, older BC pts still have a substantial percentage of high-risk subtypes. Age alone was not a significant factor in outcome. Tumor biology as defined by intrinsic subtype is an important clinical predictor. [Table: see text]

scholarly journals Re-definition of claudin-low as a breast cancer phenotype

2019 ◽  
Author(s):  
Christian Fougner ◽  
Helga Bergholtz ◽  
Jens Henrik Norum ◽  
Therese Sørlie
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Subtype ◽  
Breast Tumors ◽  
Intrinsic Subtype ◽  
Intrinsic Subtypes ◽  
Luminal A ◽  
Diverse Range ◽  
Luminal B ◽  
Cancer Phenotype ◽  
Definition Of

The claudin-low breast cancer subtype is defined by gene expression characteristics and encompasses a remarkably diverse range of breast tumors. Here, we investigate genomic, transcriptomic, and clinical features of claudin-low breast tumors. We show that claudin-low is not simply a subtype analogous to the intrinsic subtypes (basal-like, HER2-enriched, luminal A, luminal B and normal-like) as previously portrayed, but is a complex additional phenotype which may permeate breast tumors of various intrinsic subtypes. Claudin-low tumors were distinguished by low genomic instability, mutational burden and proliferation levels, and high levels of immune and stromal cell infiltration. In other aspects, claudin-low tumors reflected characteristics of their intrinsic subtype. Finally, we have developed an alternative method for identifying claudin-low tumors and thereby uncovered potential weaknesses in the established claudin-low classifier. In sum, these findings elucidate the heterogeneity in claudin-low breast tumors, and substantiate a re-definition of claudin-low as a cancer phenotype.Contact informationC.F. [email protected]. [email protected]. [email protected]. [email protected]

Molecular classification of breast cancer. Treatment and prognosis implications.

2021 ◽  
Vol 32 (2) ◽  
pp. 155-159
Author(s):  
M Alcaide Lucena ◽  
CJ Rodríguez González ◽  
S de Reyes Lartategui ◽  
R Gallart Aragón ◽  
MT Sánchez Barrón ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Treatment ◽  
Molecular Classification ◽  
Breast Cancer Treatment ◽  
Cáncer De Mama ◽  
Luminal A ◽  
Luminal B ◽  
Her 2

Resumen Los avances recientes en el campo de la biología molecular y la secuenciación del genoma se han traducido en una nueva clasificación del cáncer de mama, que busca mayor precisión y se correlaciona mejor con el riesgo de recaída de la enfermedad y la respuesta al tratamiento. Establece cuatro subtipos de cáncer de mama: luminal A, luminal B, HER 2 positivo y triple negativo, siendo el subtipo luminal A el de mejor pronóstico, y el triple negativo, el de peor pronóstico. Si combinamos la clasificación clásica histológica con la nueva molecular, nos permite encuadrar a estas pacientes de una forma más precisa en función del riesgo, definiendo así un manejo terapéutico adaptado.

Correlations Between Ultrasonographic Findings of Invasive Lobular Carcinoma of the Breast and Intrinsic Subtypes

2018 ◽  
Vol 40 (06) ◽  
pp. 764-770
Author(s):  
Xin Wen ◽  
Yingjiao Yu ◽  
Xiwen Yu ◽  
Wen Cheng ◽  
Zhuozhong Wang ◽  
...  
Keyword(s):  
Invasive Lobular Carcinoma ◽  
Breast Imaging ◽  
Lobular Carcinoma ◽  
Her2 Overexpression ◽  
Intrinsic Subtypes ◽  
Luminal A ◽  
Luminal B ◽  
The Masses ◽  
Accurate Imaging ◽  
Acoustic Shadowing

Abstract Purpose To analyze the ultrasonographic findings of invasive lobular carcinoma (ILC) of the breast in 360 women and the correlations between the characteristics and the intrinsic subtypes. Materials and Methods We evaluated the imaging findings according to the lexicon of the American College of Radiology Breast Imaging Reporting and Data System (BI-RADS). The included ultrasonographic features were shape, orientation, margin, echo pattern, posterior features, calcifications, the vascularity of the masses and the presence of architectural distortions. The associations between those features and the intrinsic ILC subtypes were investigated. Results The most common manifestations of ILC on ultrasound (US) were hypoechoic masses with irregular shape, parallel orientation, spiculated margin, posterior acoustic shadowing, no calcification and blood vessels in the rim. The patients in the luminal A subtype were the youngest, and the patients in the HER2 overexpression subtype were the oldest (p = 0.01). On US, the HER2 overexpression subtype was characterized by microlobulated margins (p = 0.002), while the luminal A subtype and the luminal B subtype mostly had spiculated margins. The basal-like subtype was distinctive in that it had no posterior features (p = 0.041), rather than acoustic shadowing, and the masses in the HER2 and basal-like subtypes were larger than in the other two groups (p = 0.03). Conclusion There were significant differences and several trends in the ultrasonographic characteristics of different intrinsic subtypes, which may supply accurate imaging diagnostic criteria to assist in the management of individuals with ILC.

scholarly journals Data Perturbation Independent Diagnosis and Validation of Breast Cancer Subtypes Using Clustering and Patterns

2006 ◽  
Vol 2 ◽  
pp. 117693510600200 ◽  
Author(s):  
G. Alexe ◽  
G.S. Dalgin ◽  
R. Ramaswamy ◽  
C. Delisi ◽  
G. Bhanot
Keyword(s):  
Breast Cancer ◽  
Data Perturbation ◽  
Luminal A ◽  
Cancer Subtypes ◽  
Luminal B ◽  
Molecular Stratification ◽  
Core Cluster ◽  
Therapeutic Decisions ◽  
Disease Subtypes

Molecular stratification of disease based on expression levels of sets of genes can help guide therapeutic decisions if such classifications can be shown to be stable against variations in sample source and data perturbation. Classifications inferred from one set of samples in one lab should be able to consistently stratify a different set of samples in another lab. We present a method for assessing such stability and apply it to the breast cancer (BCA) datasets of Sorlie et al. 2003 and Ma et al. 2003. We find that within the now commonly accepted BCA categories identified by Sorlie et al. Luminal A and Basal are robust, but Luminal B and ERBB2+ are not. In particular, 36% of the samples identified as Luminal B and 55% identified as ERBB2+ cannot be assigned an accurate category because the classification is sensitive to data perturbation. We identify a “core cluster” of samples for each category, and from these we determine “patterns” of gene expression that distinguish the core clusters from each other. We find that the best markers for Luminal A and Basal are (ESR1, LIV1, GATA-3) and (CCNE1, LAD1, KRT5), respectively. Pathways enriched in the patterns regulate apoptosis, tissue remodeling and the immune response. We use a different dataset (Ma et al. 2003) to test the accuracy with which samples can be allocated to the four disease subtypes. We find, as expected, that the classification of samples identified as Luminal A and Basal is robust but classification into the other two subtypes is not.

Stage, biology, and age.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e11512-e11512
Author(s):  
Hee Jeong Kim ◽  
Beom Seok Ko ◽  
Jong Han Yu ◽  
jong Won Lee ◽  
Byung Ho Sohn ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lymph Node ◽  
Triple Negative ◽  
Medical Center ◽  
Intrinsic Subtype ◽  
Young Age ◽  
Tnm Stage ◽  
Intrinsic Subtypes ◽  
Luminal A ◽  
Survival Difference

e11512 Background: Breast cancer subtypes are prognostic and predictive for patients. In this study, prognostic value of TNM stage, intrinsic subtype, and age were compared. Methods: We analyzed results from 7,626 breast cancer patients registered on the Asan medical center database between 1999 and 2009. We compared survival according to the TNM stage, intrinsic subtype using ER, PR, Her2- immunohistochemical staining, and age. Results: Luminal A subtype showed the best survival rates while triple negative subtype showed the worst survival rate amongst intrinsic subtypes. Survival analysis showed that Stage I triple negative breast cancer showed better survival compared to Stage III Luminal A subtype breast cancer (89.0% vs 76.6% P<0.001). Survival differences between intrinsic subtypes were more significant in lymph node positive breast cancer compared to lymph node negative breast cancer. Age did not affect survival between stages and intrinsic subtypes except for the young age subgroup (≤35), for whom there was no survival difference amongst intrinsic subtypes. Conclusions: Staging of breast cancer showed a more direct correlation to survival than known prognosis for intrinsic subtypes, as advanced, good prognostic intrinsic subtype breast cancer had worse survival than early, worse prognostic intrinsic subtype breast cancer. However for the young age group (≤35), the survival of all intrinsic subtypes were similar.

scholarly journals BIOM-07. EXPRESSION OF ANDROGEN RECEPTOR AND PROGRAMMED DEATH-LIGAND 1 IN BREAST-TO-BRAIN-METASTASES.

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii2-ii3
Author(s):  
Maleeha Qazi ◽  
Katarzyna Jerzak ◽  
Sharon Nofech-Mozes
Keyword(s):  
Breast Cancer ◽  
Brain Metastases ◽  
Triple Negative ◽  
Chromosome 17 ◽  
Medical Systems ◽  
Her2 Gene ◽  
Luminal A ◽  
Programmed Death Ligand 1 ◽  
Luminal B ◽  
Programmed Death

Abstract INTRODUCTION Therapies targeting androgen receptors (AR) and programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) have demonstrated intracranial activity. In this study, we analyzed the expression of AR and PD-L1 in breast cancer brain metastases (BrM) to identify patients who may benefit from anti-androgenic or anti-PD-1/PD-L1 therapies. METHODS Consecutive BrM resected in our institution (July 1999-June 2013) that were signed out as breast origin were identified and included from the Anatomic Pathology departmental database. A tissue microarray of BrMs was studied by immunohistochemistry for AR, PD-L1, ER, PR and HER2 (SP107, SP142, SP1, IE2, 4B5; Ventana Medical Systems). HER2 gene amplification was determined by INFORM HER2 DNA and Chromosome 17 (Ventana Medical Systems). Immunohistochemistry was used as a surrogate to determine intrinsic subtypes. RESULTS Among 61 breast cancer BrM with available tissue blocks, AR was expressed in 38 (62%) cases and PD-L1 was expressed in 9 (15%) cases. Among BrMs of luminal A subtype (ER+PR+/-HER2-Ki67&lt; 16%; n=2), 50% expressed AR and none expressed PD-L1. Within the luminal B subtype (ER+/PR+/-), all 15 HER2+ BrM expressed AR (100%), while only 1 expressed PD-L1 (7%). Among HER2- luminal B subtype BrMs (n=16), 50% and 12.5% of cases expressed AR and PD-L1, respectively. In BrM of HER2+ subtype (ER-/PR-; n=14), 71% expressed AR and 14% expressed PD-L1. The frequency of AR+ (30%) and PD-L1+ (30%) cases was equivalent in triple negative BrM (ER-/PR-/HER2-; n=14). CONCLUSION Almost two-thirds of breast cancer BrM expressed AR, while only 15% expressed PD-L1. HER2+ luminal B and HER2+ subtypes were most likely to be AR+. Meanwhile, PD-L1 expression was predominant in the triple negative subgroup. Our data suggests that certain subtypes of breast cancer BrM are more likely to be AR+ or PD-L1+; intracranial efficacy of AR-antagonists and immunotherapy warrants investigation for breast cancer BrM, particularly in biomarker-positive subtypes.

scholarly journals 61. EXPRESSION OF ANDROGEN RECEPTOR IN BREAST CANCER BRAIN METASTASIS

2020 ◽  
Vol 2 (Supplement_2) ◽  
pp. ii13-ii13
Author(s):  
Maleeha Qazi ◽  
Katarzyna Jerzak ◽  
Sharon Nofech-Mozes
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Treatment Options ◽  
Clinical History ◽  
Chromosome 17 ◽  
Medical Systems ◽  
Her2 Gene ◽  
Luminal A ◽  
Luminal B ◽  
Breast Cancer Brain Metastasis

Abstract INTRODUCTION Treatment options for women with breast cancer brain metastases (BrM) are generally limited to surgery and/or radiotherapy because most systemic therapies do not cross the blood-brain barrier. Androgen receptors (ARs) are frequently expressed in breast cancer and anti-androgenic therapies have been shown to penetrate the central nervous system. In this study, we analyzed the expression of AR in breast cancer BrM to identify patients who may benefit from anti-androgenic therapies. METHODS Consecutive BrM resected in our institution (July 1999-June 2013) were identified from the Anatomic Pathology departmental database. Cases that were signed out as breast origin given the available immunohistochemical profile and clinical history were included. A tissue microarray was constructed using 1 mm cores in triplicates and studied by immunohistochemistry for AR, ER, PR and HER2 (SP107, SP1, IE2, 4B5; Ventana Medical Systems, Tucson AZ, USA). HER2 gene amplification was determined by INFORM HER2 DNA and Chromosome 17 (both by Ventana Medical Systems, Tucson AZ, USA). Immunohistochemistry was used as a surrogate to determine intrinsic subtypes. RESULTS Among 61 breast cancer BrM with available tissue blocks, AR was expressed in 38 (62%) cases. Among BrMs of luminal A subtype (ER+, PR+/-, HER2-, Ki67&lt;16%), 50% expressed AR (n=1/2). Within the luminal B subtype (ER+, PR+/-), all 15 HER2+ BrM expressed AR (100%), while only 50% of HER2- BrM expressed AR (n=8/16). Among 14 BrM of HER2+ subtype (ER-, PR-), 71% expressed AR (n=10/14). Only 30% of triple negative BrM (ER-, PR-, HER2-) were AR+ (n=4/14). CONCLUSION Almost two-thirds of breast cancer BrM expressed AR. HER2+ luminal B and HER2+ subtypes were most likely to be AR+, while only 30% of triple negative BrM were AR+. Our data suggests that certain subtypes of breast cancer BrM are more likely to be AR+ and could serve as a potential therapeutic target.

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