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Molecular features and survival outcomes of the intrinsic subtypes within HER2-positive breast cancer.

ABSTRACT: The clinical impact of the biological heterogeneity within HER2-positive (HER2+) breast cancer is not fully understood. Here, we evaluated the molecular features and survival outcomes of the intrinsic subtypes within HER2+ breast cancer. We interrogated The Cancer Genome Atlas (n = 495) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) datasets (n = 1730) of primary breast cancers for molecular data derived from DNA, RNA and protein, and determined intrinsic subtype. Clinical HER2 status was defined according to American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines or DNA copy-number aberration by single nucleotide polymorphism arrays. Cox models tested the prognostic significance of each variable in patients not treated with trastuzumab (n = 1711). Compared with clinically HER2 (cHER2)-negative breast cancer, cHER2+ breast cancer had a higher frequency of the HER2-enriched (HER2E) subtype (47.0% vs 7.1%) and a lower frequency of Luminal A (10.7% vs 39.0%) and Basal-like (14.1% vs 23.4%) subtypes. The likelihood of cHER2-positivity in HER2E, Luminal B, Basal-like and Luminal A subtypes was 64.6%, 20.0%, 14.4% and 7.3%, respectively. Within each subtype, only 0.3% to 3.9% of genes were found differentially expressed between cHER2+ and cHER2-negative tumors. Within cHER2+ tumors, HER2 gene and protein expression was statistically significantly higher in the HER2E and Basal-like subtypes than either luminal subtype. Neither cHER2 status nor the new 10-subtype copy number-based classification system (IntClust) added independent prognostic value to intrinsic subtype. When the intrinsic subtypes are taken into account, cHER2-positivity does not translate into large changes in the expression of downstream signaling pathways, nor does it affect patient survival in the absence of HER2 targeting.

SUBMITTER: Prat A

PROVIDER: S-EPMC4151853 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe introduction of pertuzumab has greatly improved pathological complete response (pCR) rates in HER2-positive breast cancer, yet effects on long-term survival have been limited and it is uncertain which patients derive most benefit. In this study, we determine the prognostic value of BluePrint subtyping in HER2-positive breast cancer. Additionally, we evaluate its use as a biomarker for predicting response to trastuzumab-containing neoadjuvant chemotherapy with or without pertuzumab.MethodsFrom a cohort of patients with stage II-III HER2-positive breast cancer who were treated with neoadjuvant chemotherapy and trastuzumab with or without pertuzumab, 836 patients were selected for microarray gene expression analysis, followed by readout of BluePrint standard (HER2, Basal and Luminal) and dual subtypes (HER2-single, Basal-single, Luminal-single, HER2-Basal, Luminal-HER2, Luminal-HER2-Basal). The associations between subtypes and pathological complete response (pCR), overall survival (OS) and breast cancer-specific survival (BCSS) were assessed, and pertuzumab benefit was evaluated within the BluePrint subgroups.ResultsBluePrint results were available for 719 patients. In patients with HER2-type tumors, the pCR rate was 71.9% in patients who received pertuzumab versus 43.5% in patients who did not (adjusted Odds Ratio 3.43, 95% CI 2.36-4.96). Additionally, a significantly decreased hazard was observed for both OS (adjusted hazard ratio [aHR] 0.45, 95% CI 0.25-0.80) and BCSS (aHR 0.46, 95% CI 0.24-0.86) with pertuzumab treatment. Findings were similar in the HER2-single subgroup. No significant benefit of pertuzumab was seen in other subtypes.ConclusionsIn patients with HER2-type or HER2-single-type tumors, pertuzumab significantly improved the pCR rate and decreased the risk of breast cancer mortality, which was not observed in other subtypes. BluePrint subtyping may be valuable in future studies to identify patients that are likely to be highly sensitive to HER2-targeting agents.

Project description:BackgroundFeatures in preoperative ultrasound could predict the prognosis of triple-negative breast cancer (TNBC), while its prognostic value in other molecular subtypes of breast cancer (BC) was unknown. The study aimed to assess the prognostic value of preoperative sonographic features, including orientations, on long-term outcomes in BC and its association with different molecular subtypes.MethodsWomen diagnosed with invasive BC > 5 mm who underwent surgery were retrospectively reviewed. Clinical, pathological, and sonographic profiles were collected and recurrence-free survival (RFS) and breast cancer-specific survival (BCSS) were reported. Interactions between clinicopathological features and tumor orientations in predicting RFS and BCSS were analyzed. Competing risk model was performed to estimate prognostic values of sonographic features for RFS and BCSS.ResultsA total of 2812 patients were included. With a median follow-up of 60.0 months, 268 (9.5%) patients suffered from recurrences and 104 (3.7%) died of BC. The prognostic values of vertical orientation in predicting RFS (P = .001) and BCSS (P = .001) were strongly associated with molecular subtypes. Non-TNBC tumors with vertical orientation had less recurrence events compared with parallel orientation (6.3% vs 8.7%, P = .035), whereas failed to predict disease outcomes in multivariate analysis (P > .05). Oppositely, in TNBC, vertical orientation was associated with worse RFS (HR = 3.50; 95% confidence interval [CI] 1.69-7.24; P < .001) and BCSS (HR = 6.36; 95% CI 2.86-14.14; P < .001) in multivariate analysis with a 5-year RFS and BCSS of 73.4% and 74.6%. Meanwhile, vertical orientation was related with smaller tumor size (P < .001), human epidermal growth factor receptor 2 nonamplification (P < .001), and lower Ki-67 expression (P = .001) among non-TNBC population, whereas TNBC tumors with vertical orientation had a higher burden of axillary lymph node metastases (2.8 ± 1.0 vs 1.4 ± 0.2, P = .001).ConclusionsPrognostic values of sonographic orientation in predicting BC disease outcomes were associated with molecular subtypes. Vertical orientation in preoperative sonogram may serve as a prognostic biomarker for TNBC patients.

Project description:BackgroundBasal-like constitutes an important molecular subtype of breast cancer characterised by an aggressive behaviour and a limited therapy response. The outcome of patients within this subtype is, however, divergent. Some individuals show an increased risk of dying in the first five years, and others a long-term survival of over ten years after the diagnosis. In this study, we aim at identifying markers associated with basal-like patients' survival and characterising subgroups with distinct disease outcome.MethodsWe explored the genomic and transcriptomic profiles of 351 basal-like samples from the METABRIC and ROCK data sets. Two selection methods, labelled Differential and Survival filters, were employed to determine genes/probes that are differentially expressed in tumour and control samples, and are associated with overall survival. These probes were further used to define molecular subgroups, which vary at the microRNA level and in DNA copy number.ResultsWe identified the expression signature of 80 probes that distinguishes between two basal-like subgroups with distinct clinical features and survival outcomes. Genes included in this list have been mainly linked to cancer immune response, epithelial-mesenchymal transition and cell cycle. In particular, high levels of CXCR6, HCST, C3AR1 and FPR3 were found in Basal I; whereas HJURP, RRP12 and DNMT3B appeared over-expressed in Basal II. These genes exhibited the highest betweenness centrality and node degree values and play a key role in the basal-like breast cancer differentiation. Further molecular analysis revealed 17 miRNAs correlated to the subgroups, including hsa-miR-342-5p, -150, -155, -200c and -17. Additionally, increased percentages of gains/amplifications were detected on chromosomes 1q, 3q, 8q, 10p and 17q, and losses/deletions on 4q, 5q, 8p and X, associated with reduced survival.ConclusionsThe proposed signature supports the existence of at least two subgroups of basal-like breast cancers with distinct disease outcome. The identification of patients at a low risk may impact the clinical decisions-making by reducing the prescription of high-dose chemotherapy and, consequently, avoiding adverse effects. The recognition of other aggressive features within this subtype may be also critical for improving individual care and for delineating more effective therapies for patients at high risk.

Project description:BackgroundDifferent estrogen receptor (ER) and progesterone receptor (PR) expression patterns have important biological and therapeutic implications in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, little is known about hormone receptor (HR)-positive and triple-positive subtypes, making therapy selection and survival prognosis difficult. This study investigated the clinical characteristics and nomogram-predicted survival of patients with HER2-positive breast cancer.Materials and methodsData on patients with HER2-positive breast cancer were retrieved from the Surveillance, Epidemiology, and End Results database. Comparisons were carried out between single HR-positive and double HR-positive/double HR-negative subtypes. A nomogram-based model of predicted outcomes was developed.ResultsThis cohort study included 34 819 patients with breast cancer (34 606 women and 213 men). Single HR-positive and double HR-positive/double HR-negative subtypes showed distinct clinicopathological characteristics. Multivariable Cox regression analysis showed that patients with ER-positive/PR-negative/HER2-positive [hazard ratio (HR) = 1.24; 95% confidence interval (CI): 1.14-1.39], ER-negative/PR-positive/HER2-positive (HR = 1.56; 95% CI: 1.23-1.97), and ER-negative/PR-negative/HER2-positive (HR = 1.56; 95% CI: 1.43-1.70) subtypes had worse breast cancer-specific survival than patients with the triple-positive subtype. Thirteen clinical parameters were included as prognostic factors in the nomogram: age, sex, race, grade, histology type, bone, brain, liver, and lung metastasis, TNM (tumor-node-metastasis) staging, and molecular subtype. The C-index was 0.853 (95% CI: 0.845-0.861). Calibration plots indicated that the nomogram-predicted survival was consistent with the recorded 3-year and 5-year prognoses.ConclusionsSignificant differences in survival rates were observed between single HR-positive and double HR-positive/double HR-negative subtypes. A nomogram accurately predicted survival. Different treatment strategies may be required for HER2-positive patients with single HR-positive and double HR-positive tumors to ensure optimal treatment and benefits.

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Molecular features and survival outcomes of the intrinsic subtypes within HER2-positive breast cancer.

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