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Location of triple-negative breast cancers: comparison with estrogen receptor-positive breast cancers on MR imaging.

ABSTRACT: There has been a major need to better understand the biological characteristics of triple-negative breast cancers. Compared with estrogen receptor (ER)-positive cancers, several magnetic resonance (MR) imaging findings have been reported as characteristic findings. However, information regarding their location has not been described. Our study was to compare the location of triple-negative breast cancers with that of ER-positive breast cancers using magnetic resonance (MR) imaging. The locations of 1102 primary breast cancers (256 triple-negative and 846 ER-positive) in 1090 women (mean, 52.1 years) were reviewed using three-dimensional (3D) coordinates. The x-axis measurement was recorded as the transverse distance from the posterior nipple line; y-axis measurement as the anteroposterior distance from the chest wall; z-axis measurement as the superoinferior distance from the posterior nipple line. The association between breast cancer subtype and tumor location was evaluated using multiple linear regression analysis. Triple-negative breast cancers were significantly closer to the chest wall than ER-positive breast cancers in absolute (1.8 cm vs. 2.3 cm, P < .0001) and normalized (0.21 vs. 0.25, P < .0001) y-axis distances. The x- and z-axes distances were not significantly different between triple-negative and ER-positive breast cancers. Multiple linear regression analysis revealed that age, mammographic density, axillary nodal status, and triple-negative subtype were significantly associated with absolute and normalized distances from the chest wall (all P < .05). Our results show that triple-negative breast cancers have a tendency toward a posterior or prepectoral location compared with ER-positive breast cancers.

SUBMITTER: Kim WH

PROVIDER: S-EPMC4301951 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PURPOSE:A subset of estrogen receptor-positive (ER-positive) breast cancer (BC) contains high levels of tumor-infiltrating lymphocytes (TILs), similar to triple-negative BC (TNBC). The majority of immuno-oncology trials target TNBCs because of the greater proportion of TIL-rich TNBCs. The extent to which the immune microenvironments of immune-rich ER-positive BC and TNBC differ is unknown. PATIENTS AND METHODS:RNA sequencing data from The Cancer Genome Atlas (TCGA; n = 697 ER-positive BCs; n = 191 TNBCs) were used for discovery; microarray expression data from Molecular Taxonomy of Breast Cancer International Consortium (METABRIC; n = 1,186 ER-positive BCs; n = 297 TNBCs) was used for validation. Patients in the top 25th percentile of a previously published total TIL metagene score distribution were considered immune rich. We compared expression of immune cell markers, immune function metagenes, and immuno-oncology therapeutic targets among immune-rich subtypes. RESULTS:Relative fractions of resting mast cells (TCGA P adj = .009; METABRIC P adj = 4.09E-15), CD8+ T cells (TCGA P adj = .015; METABRIC P adj = 0.390), and M2-like macrophages (TCGA P adj= 4.68E-05; METABRIC P adj = .435) were higher in immune-rich ER-positive BCs, but M0-like macrophages (TCGA P adj = 0.015; METABRIC P adj = .004) and M1-like macrophages (TCGA P adj = 9.39E-08; METABRIC P adj = 6.24E-11) were higher in immune-rich TNBCs. Ninety-one immune-related genes (eg, CXCL14, CSF3R, TGF-B3, LRRC32/GARP, TGFB-R2) and a transforming growth factor ? (TGF-?) response metagene were significantly overexpressed in immune-rich ER-positive BCs, whereas 41 immune-related genes (eg, IFNG, PD-L1, CTLA4, MAGEA4) were overexpressed in immune-rich TNBCs in both discovery and validation data sets. TGF-? pathway member genes correlated negatively with expression of immune activation markers (IFNG, granzyme-B, perforin) and positively with M2-like macrophages (IL4, IL10, and MMP9) and regulatory T-cell (FOXP3) markers in both subtypes. CONCLUSION:Different immunotherapy strategies may be optimal in immune-rich ER-positive BC and TNBC. Drugs targeting the TGF-? pathway and M2-like macrophages are promising strategies in immune-rich ER-positive BCs to augment antitumor immunity.

Project description:ObjectiveDifferent molecular subtypes of triple-negative breast cancer (TNBC) have previously been identified through analysis of gene expression profiles. The luminal androgen receptor (LAR) subtype has been shown to have a lower rate of pathologic complete response to neoadjuvant chemotherapy than other TNBC subtypes. The purpose of this study was to determine if the imaging features of TNBCs differ by AR (androgen receptor) status, which is a surrogate immunohistochemical (IHC) marker for the chemoresistant LAR subtype of TNBC.Materials and methodsThis sub-study was part of a clinical trial in patients with stage I-III TNBC who were prospectively monitored for response while receiving neoadjuvant systemic therapy (NAST) at a single comprehensive cancer center. This interim imaging analysis included 144 patients with known AR status measured by IHC. AR-positive (AR+) tumors were defined as those in which at least 10% of tumor cells had positive nuclear AR staining. Two experienced, fellowship-trained breast radiologists who were blinded to the IHC results retrospectively reviewed and reached consensus on all imaging studies for the index lesion (i.e., mammogram, ultrasound, and breast magnetic resonance imaging). The index lesion for each patient was reviewed and described according to the fifth edition of the Breast Imaging Reporting and Data System lexicon. Logistic regression modeling was used to identify imaging features predictive of AR status. p ≤ 0.05 was considered statistically significant.ResultsUnivariate logistic regression models for AR status showed that AR+ TNBC was significantly associated with heterogeneously dense breast composition on mammography (p = 0.02), mass with calcifications (p = 0.05), irregular mass shape on mammography (p = 0.03), and irregular mass shape on sonography (p = 0.003). Multivariate logistic regression models for AR status showed that AR+ TNBC was significantly associated with heterogeneously dense breast composition on mammography (p = 0.01), high mass density on mammography (p = 0.003), and irregular mass shape on sonography (p = 0.0004).ConclusionThe imaging features of TNBCs differ by AR status. Multimodality breast imaging may help identify the LAR subtype of TNBC, which has been shown to be a subtype that is relatively resistant to neoadjuvant chemotherapy.

Project description:BackgroundDirectly comparing gene expression profiles of estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) breast cancers cannot determine whether differentially expressed genes between these two subtypes result from dysregulated expression in ER+ cancer or ER- cancer versus normal controls, and thus would miss critical information for elucidating the transcriptomic difference between the two subtypes.Principal findingsUsing microarray datasets from TCGA, we classified the genes dysregulated in both ER+ and ER- cancers versus normal controls into two classes: (i) genes dysregulated in the same direction but to a different extent, and (ii) genes dysregulated to opposite directions, and then validated the two classes in RNA-sequencing datasets of independent cohorts. We showed that the genes dysregulated to a larger extent in ER+ cancers than in ER- cancers enriched in glycerophospholipid and polysaccharide metabolic processes, while the genes dysregulated to a larger extent in ER- cancers than in ER+ cancers enriched in cell proliferation. Phosphorylase kinase and enzymes of glycosylphosphatidylinositol (GPI) anchor biosynthesis were upregulated to a larger extent in ER+ cancers than in ER- cancers, whereas glycogen synthase and phospholipase A2 were downregulated to a larger extent in ER+ cancers than in ER- cancers. We also found that the genes oppositely dysregulated in the two subtypes significantly enriched with known cancer genes and tended to closely collaborate with the cancer genes. Furthermore, we showed the possibility that these oppositely dysregulated genes could contribute to carcinogenesis of ER+ and ER- cancers through rewiring different subpathways.ConclusionsGPI-anchor biosynthesis and glycogenolysis were elevated and hydrolysis of phospholipids was depleted to a larger extent in ER+ cancers than in ER- cancers. Our findings indicate that the genes oppositely dysregulated in the two subtypes are potential cancer genes which could contribute to carcinogenesis of both ER+ and ER- cancers through rewiring different subpathways.

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Location of triple-negative breast cancers: comparison with estrogen receptor-positive breast cancers on MR imaging.

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