Molecular subtype and tumor characteristics of breast cancer metastases as assessed by gene expression significantly influence patient post-relapse survival

Tobin, Nicholas P.; Harrell, J. Chuck; Lövrot, John; Brage, Suzanne Egyházi; Stolt, Marianne Frostvik; Carlsson, Lena; Einbeigi, Zakaria; Linderholm, Barbro; Loman, Niklas; Malmberg, Martin; Walz, Thomas; Fernö, Mårten; Perou, Charles M.; Bergh, Jonas; Hatschek, Thomas; Lindström, Linda S.; Hedenfalk, Ingrid; Brandberg, Yvonne; Carstensen, John; Egyhazy, Suzanne; Skoog, Lambert; Hellström, Mats; Maliniemi, Maarit; Svensson, Harry; Åström, Gunnar; Bjöhle, Judith; Lidbrink, Elisabet; Rotstein, Samuel; Wallberg, Birgitta; Carlsson, Per; Malmström, Per Uno; Söderberg, Martin; Lindh, Birgitta; Sundqvist, Marie; Malmberg, Lena

doi:10.1093/annonc/mdu498

Cited by 88 publications

(95 citation statements)

References 17 publications

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“…2D), there was an overlap between the two groups with a subset of tumors with high ITGB6 expression with no lymph node metastasis and conversely, a few tumors with low ITGB6 expression had metastasized to the lymph node. Further, analysis of the TEX trial data 36 showed that HER2+ metastatic lesions possessed the highest mean expression of ITGB6 mRNA level ( P < 0.0001, Fig. S3) compared to other PAM50 subtypes, further lending support to integrin β 6‐mediated metastasis in HER2+ tumors.…”

Section: Discussionmentioning

confidence: 82%

High expression of integrin β6 in association with the Rho–Rac pathway identifies a poor prognostic subgroup within HER2 amplified breast cancers

et al. 2016

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Integrin αvβ6 is involved in the transition from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) of the breast. In addition, integrin β6 (ITGB6) is of prognostic value in invasive breast cancers, particularly in HER2+ subtype. However, pathways mediating the activity of integrin αvβ6 in clinical progression of invasive breast cancers need further elucidation. We have examined human breast cancer specimens (N = 460) for the expression of integrin β6 (ITGB6) mRNA by qPCR. In addition, we have examined a subset (N = 147) for the expression of αvβ6 integrin by immunohistochemistry (IHC). The expression levels of members of Rho–Rac pathway including downstream genes (ACTR2,ACTR3) and effector proteinases (MMP9,MMP15) were estimated by qPCR in the HER2+ subset (N = 59). There is a significant increase in the mean expression of ITGB6 in HER2+ tumors compared to HR+HER2‐ and triple negative (TNBC) subtypes (P = 0.00). HER2+ tumors with the highest levels (top quartile) of ITGB6 have significantly elevated levels of all the genes of the Rho–Rac pathway (P‐values from 0.01 to 0.0001). Patients in this group have a significantly shorter disease‐free survival compared to the group with lower ITGB6 levels (HR = 2.9 (0.9–8.9), P = 0.05). The mean level of ITGB6 expression is increased further in lymph node‐positive tumors. The increased regional and distant metastasis observed in HER2+ tumors with high levels of ITGB6 might be mediated by the canonical Rho–Rac pathway through increased expression of MMP9 and MMP15.

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Section: Discussionmentioning

confidence: 82%

High expression of integrin β6 in association with the Rho–Rac pathway identifies a poor prognostic subgroup within HER2 amplified breast cancers

et al. 2016

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“…Of note, this short-term cutoff was defined retrospectively to capture the visually apparent distribution in postrelapse BCSS (41% of patients died within 1.5 years) and was determined by applying a model of two normal distributions to the survival time variable. A comprehensive description of this cutoff and associated methods has been previously published (17). To assess differences between primary tumor clinicopathologic variables and metastatic tumor gene-expression subtypes statistical tests were chosen based on the class of variables being compared: ordinal versus nominal (e.g., RS vs. ER)—Wilcoxon/Mann–Whitney test; categorical versus nominal (e.g., PAM50 vs. ER)—χ 2 or Fisher exact tests; categorical versus ordinal—Kruskal–Wallis test; ordinal versus ordinal—Spearman rank correlation test.…”

Section: Methodsmentioning

confidence: 99%

“…We have previously demonstrated that transcriptional pathway activity and the molecular subtypes (PAM50) of breast cancer metastases significantly influence patient postrelapse survival (17). Here, we aim to extend these findings through Kaplan–Meier and Cox regression analysis of five routinely employed gene expression signatures, along with a simple cell-cycle classifier, with specific focus on site of metastatic relapse.…”

Section: Introductionmentioning

confidence: 99%

PAM50 Provides Prognostic Information When Applied to the Lymph Node Metastases of Advanced Breast Cancer Patients

Tobin

Lundberg

Lindström

et al. 2017

Clinical Cancer Research

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Purpose Transcriptional pathway activity and the molecular subtypes of breast cancer metastases have been shown to significantly influence patient postrelapse survival. Here, we further determine the relevance of clinically employed gene signatures in the advanced breast cancer (ABC) setting. Experimental Design Sufficient RNA for expression profiling was obtained from distant metastatic or inoperable locoregional relapse tissue by fine-needle aspiration from 109 patients of the Swedish TEX clinical trial. Gene signatures (GGI, 70 gene, recurrence score, cell-cycle score, risk of recurrence score, and PAM50) were applied to all metastases, and their relationship to long- (5-year) and short-term (1.5-year) postrelapse survival at all and locoregional lymph nodes (n = 40) versus other metastatic sites (n = 69) combined was assessed using Kaplan-Meier and/or multivariate Cox regression analyses. Results The majority of metastases were classified into intermediate or high-risk groups by all signatures, and a significant association was found between metastatic signature subgroups and primary tumor estrogen receptor status and histologic grade (P < 0.05). When considering all sites of metastasis, only PAM50 was statistically significant in Kaplan–Meier analysis (Log-rank P = 0.008 and 0.008 for long- and short-term postrelapse breast cancer–specific survival, respectively). This significance remained in both uni- and multivariate models when restricting analyses to lymph node metastases only, and a similar trend was observed in other metastatic sites combined, but did not reach formal significance. Conclusions Our findings are the first to demonstrate that the PAM50 signature can provide prognostic information from the lymph node metastases of ABC patients.

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“…Overall, 32% of the metastases were HER2-enriched, 25% basal-like, 10% luminal A and 28% luminal B. (61) Oakman C et al and Rubovszky G et al also reported that Triple negative breast cancer (TNBC) accounts for approximately 15% of breast cancer cases. TNBC occurs in younger women and is marked by high rates of visceral and CNS metastases, relapse and early death.…”

Section: Figure (2)mentioning

confidence: 98%

The Prognostic Value of Luminal Subtypes of Breast Cancer and their Impact on the Patient's Outcome

Kader¹

2017

JMSCR

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Background: Breast cancer is the major cause of death by cancer among females in developing countries. Although the overall breast cancer incidence rate in the developed countries is double that seen in developing countries (6) and human epidermal growth factor receptor 2 (HER2) (7) status are all major risk factors for relapse. The response of breast cancer patients to hormonal therapy is currently guided by the expression of two steroid hormonal receptors (HR): estrogen receptor-α (ER-α), progesterone receptor (PR) and proliferation marker

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Molecular subtype and tumor characteristics of breast cancer metastases as assessed by gene expression significantly influence patient post-relapse survival

Cited by 88 publications

References 17 publications

High expression of integrin β6 in association with the Rho–Rac pathway identifies a poor prognostic subgroup within HER2 amplified breast cancers

High expression of integrin β6 in association with the Rho–Rac pathway identifies a poor prognostic subgroup within HER2 amplified breast cancers

PAM50 Provides Prognostic Information When Applied to the Lymph Node Metastases of Advanced Breast Cancer Patients

The Prognostic Value of Luminal Subtypes of Breast Cancer and their Impact on the Patient's Outcome

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