Exploring the two-gene ratio in breast cancer—independent roles for HOXB13 and IL17BR in prediction of clinical outcome

Jerevall, Piiha-Lotta; Brommesson, Sara; Strand, Carina; Gruvberger-Saal, Sofia K.; Malmström, Per; Nordenskjöld, Bo; Wingren, Sten; Söderkvist, Peter; Fernö, Mårten; Stål, Olle

doi:10.1007/s10549-007-9541-8

Cited by 62 publications

(47 citation statements)

References 28 publications

(36 reference statements)

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“…Because high HOXB13 and low IL17BR expression levels are associated with recurrence, we proposed that a simple HOXB13:IL17BR two-gene ratio could serve as a novel biomarker for predicting recurrence in breast cancer patients receiving adjuvant tamoxifen therapy. Subsequent studies by us (9, 10) and others (11,12) have shown that HOXB13:IL17BR is both prognostic (i.e., predicts the risk of breast cancer recurrence) and predictive of tamoxifen benefit (i.e., tamoxifen response/resistance).Given the well-established prognostic importance of histologic tumor grade (13) and tumor grade -associated genes (7) in breast cancer, a simple robust gene expression assay for tumor grade would be a valuable clinical tool. Herein, we developed a simple 5-gene tumor grade signature (MGI for molecular grade index) that recapitulates tumor grade and show that it predicts clinical outcome with comparable performance to the wellcharacterized 97-gene tumor grade index.…”

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confidence: 84%

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confidence: 99%

“…HOXB13:IL17BR has been shown to predict tamoxifen response in the metastatic setting (12) and benefit from prolonged tamoxifen monotherapy in the adjuvant setting (11). Thus, beyond risk stratification, MGI and HOX-B13:IL17BR may prove to be important predictors of benefit from endocrine and chemotherapy agents.…”

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confidence: 99%

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A Five-Gene Molecular Grade Index and HOXB13:IL17BR Are Complementary Prognostic Factors in Early Stage Breast Cancer

Ma¹,

Salunga²,

Dahiya

et al. 2008

Clinical Cancer Research

296

205

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Purpose: Histologic tumor grade is a well-established prognostic factor for breast cancer, and tumor grade^associated genes are the common denominator of many prognostic gene signatures. The objectives of this study are as follows: (a) to develop a simple gene expression index for tumor grade (molecular grade index or MGI), and (b) to determine whether MGI and our previously described HOXB13:IL17BR index together provide improved prognostic information. Experimental Design: From our previously published list of genes whose expression correlates with both tumor grade and tumor stage progression, we selected five cell cycle^related genes to build MGI and evaluated MGI in two publicly available microarray data sets totaling 410 patients. Using two additional cohorts (n = 323), we developed a real-time reverse transcription PCR assay for MGI, validated its prognostic utility, and examined its interaction with HOXB13:IL17BR. Results: MGI performed consistently as a strong prognostic factor and was comparable with a more complex 97-gene genomic grade index in multiple data sets. In patients treated with endocrine therapy, MGI and HOXB13:IL17BR modified each other's prognostic performance. High MGI was associated with significantly worse outcome only in combination with high HOXB13:IL17BR, and likewise, high HOXB13:IL17BR was significantly associated with poor outcome only in combination with high MGI. Conclusions: We developed and validated a five-gene reverse transcription PCR assay for MGI suitable for analyzing routine formalin-fixed paraffin-embedded clinical samples. The combination of MGI and HOXB13:IL17BR outperforms either alone and identifies a subgroup (f30%) of early stage estrogen receptor^positive breast cancer patients with very poor outcome despite endocrine therapy.The most recent (2005) St. Gallen consensus guidelines for treatment selection for early stage breast cancer consider both risk of recurrence and endocrine responsiveness to better balance risk and benefit of systemic adjuvant therapies (1). To better define risk stratification, genome-wide expression profiling studies have created multiple prognostic gene signatures for breast cancer (2, 3). An important issue is whether these signatures overlap in their prognostic information and whether combining several of these signatures would provide more accurate prognosis. In one comparative study, four signatures (the intrinsic subtypes, 70-gene signature, wound response signature, and Recurrence Score) were found to be highly concordant in classifying patients into low and high-risk groups (4). Notably, combining these signatures did not yield significant improvement in predictive accuracy, suggesting that the prognostic information provided by these signatures is largely overlapping (4). Sotiriou et al. (5) showed that a 97-gene tumor grade signature was comparable with the 70-gene signature and the Recurrence Score algorithm (6) in independent cohorts, and they hypothesized that most of the prognostic power of these signatures comes f...

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A Five-Gene Molecular Grade Index and HOXB13:IL17BR Are Complementary Prognostic Factors in Early Stage Breast Cancer

Ma¹,

Salunga²,

Dahiya

et al. 2008

Clinical Cancer Research

296

205

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“…In addition to prostate cancer, HOXB13 has also been shown to have a role as a tumor suppressor in primary colorectal cancers (CRC; ref. 16), and it predicts breast cancer recurrence (17) and tamoxifen response (18).…”

Section: Introductionmentioning

confidence: 99%

HOXB13 G84E Mutation in Finland: Population-Based Analysis of Prostate, Breast, and Colorectal Cancer Risk

Laitinen

Wahlfors

Saaristo

et al. 2013

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background: A recently identified germline mutation G84E in HOXB13 was shown to increase the risk of prostate cancer. In a family-based analysis by The International Consortium for Prostate Cancer Genetics (ICPCG), the G84E mutation was most prevalent in families from the Nordic countries of Finland (22.4%) and Sweden (8.2%).Methods: To further investigate the importance of G84E in the Finns, we determined its frequency in more than 4,000 prostate cancer cases and 5,000 controls. In addition, 986 breast cancer and 442 colorectal cancer (CRC) cases were studied. Genotyping was conducted using TaqMan, MassARRAY iPLEX, and sequencing. Statistical analyses were conducted using Fisher exact test, and overall survival was analyzed using Cox modeling.Results: The frequency of the G84E mutation was significantly higher among patients with prostate cancer and highest among patients with a family history of the disease, hereditary prostate cancer [8.4% vs. 1.0% in controls; OR 8.8; 95% confidence interval (CI), 4.9-15.7]. The mutation contributed significantly to younger age ( 55 years) at onset and high prostate-specific antigen (PSA; !20 ng/mL) at diagnosis. An association with increased prostate cancer risk in patients with prior benign prostate hyperplasia (BPH) diagnosis was also revealed. No statistically significant evidence for a contribution in CRC risk was detected, but a suggestive role for the mutation was observed in familial BRCA1/2-negative breast cancer.Conclusions: These findings confirm an increased cancer risk associated with the G84E mutation in the Finnish population, particularly for early-onset prostate cancer and cases with substantially elevated PSA.Impact: This study confirms the overall importance of the HOXB13 G84E mutation in prostate cancer susceptibility. Cancer Epidemiol Biomarkers Prev; 22(3); 452-60. Ó2012 AACR.

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“…The interleukin 17 receptor B (IL17RB or IL17BR) is an estrogen-regulated gene (Wang et al, 2007) and found to be a prognostic marker, together with homeobox 13 expression, for breast cancer (Jerevall et al, 2008;Ma et al, 2008). In general, interleukins, chemokines, cytokines and other immunological molecules are known to play a major role during implantation.…”

Section: Discussionmentioning

confidence: 99%

Gene Expression and Premature Progesterone Rise

Vaerenbergh¹,

Blockeel²

2012

In Vitro Fertilization - Innovative Clinical and Laboratory Aspects

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Exploring the two-gene ratio in breast cancer—independent roles for HOXB13 and IL17BR in prediction of clinical outcome

Abstract: Background: The two-gene expression ratio HOXB13:IL17BR has been proposed to predict

Cited by 62 publications

References 28 publications

A Five-Gene Molecular Grade Index and HOXB13:IL17BR Are Complementary Prognostic Factors in Early Stage Breast Cancer

A Five-Gene Molecular Grade Index and HOXB13:IL17BR Are Complementary Prognostic Factors in Early Stage Breast Cancer

HOXB13 G84E Mutation in Finland: Population-Based Analysis of Prostate, Breast, and Colorectal Cancer Risk

Gene Expression and Premature Progesterone Rise

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