Tamoxifen-predictive value of gene expression signatures in premenopausal breast cancer : data from the randomized SBII:2 trial

Lundgren, Christine; Tutzauer, Julia; Church, Sarah E.; Stål, Olle; Ekholm, Maria; Forsare, Carina; Nordenskjöld, Bo; Fernö, Mårten; Bendahl, Pär Ola; Rydén, Lisa

Tamoxifen-predictive value of gene expression signatures in premenopausal breast cancer : data from the randomized SBII:2 trial

Mark

Lundgren, Christine ^LU ; Tutzauer, Julia ^LU

; Church, Sarah E. ; Stål, Olle ; Ekholm, Maria ^LU ; Forsare, Carina ^LU

; Nordenskjöld, Bo ; Fernö, Mårten ^LU ; Bendahl, Pär Ola ^LU and Rydén, Lisa ^LU

(2023) In Breast Cancer Research 25(1).

Abstract: Background: Gene expression (GEX) signatures in breast cancer provide prognostic information, but little is known about their predictive value for tamoxifen treatment. We examined the tamoxifen-predictive value and prognostic effects of different GEX signatures in premenopausal women with early breast cancer. Methods: RNA from formalin-fixed paraffin-embedded tumor tissue from premenopausal women randomized between two years of tamoxifen treatment and no systemic treatment was extracted and successfully subjected to GEX profiling (n = 437, NanoString Breast Cancer 360™ panel). The median follow-up periods for a recurrence-free interval (RFi) and overall survival (OS) were 28 and 33 years, respectively. Associations between GEX... (More); Background: Gene expression (GEX) signatures in breast cancer provide prognostic information, but little is known about their predictive value for tamoxifen treatment. We examined the tamoxifen-predictive value and prognostic effects of different GEX signatures in premenopausal women with early breast cancer. Methods: RNA from formalin-fixed paraffin-embedded tumor tissue from premenopausal women randomized between two years of tamoxifen treatment and no systemic treatment was extracted and successfully subjected to GEX profiling (n = 437, NanoString Breast Cancer 360™ panel). The median follow-up periods for a recurrence-free interval (RFi) and overall survival (OS) were 28 and 33 years, respectively. Associations between GEX signatures and tamoxifen effect were assessed in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+ /HER2−) tumors using Kaplan–Meier estimates and Cox regression. The prognostic effects of GEX signatures were studied in the entire cohort. False discovery rate adjustments (q-values) were applied to account for multiple hypothesis testing. Results: In patients with ER+/HER2− tumors, FOXA1 expression below the median was associated with an improved effect of tamoxifen after 10 years with regard to RFi (hazard ratio [HR]_FOXA1(high) = 1.04, 95% CI = 0.61–1.76, HR_FOXA1(low) = 0.30, 95% CI = 0.14–0.67, q _interaction = 0.0013), and a resembling trend was observed for AR (HR_AR(high) = 1.15, 95% CI = 0.60–2.20, HR_AR(low) = 0.42, 95% CI = 0.24–0.75, q _interaction = 0.87). Similar patterns were observed for OS. Tamoxifen was in the same subgroup most beneficial for RFi in patients with low ESR1 expression (HR_{RFi ESR1(high)} = 0.76, 95% CI = 0.43–1.35, HR_{RFi, ESR1(low)} = 0.56, 95% CI = 0.29–1.06, q _interaction = 0.37). Irrespective of molecular subtype, higher levels of ESR1, Mast cells, and PGR on a continuous scale were correlated with improved 10 years RFi (HR_ESR1 = 0.80, 95% CI = 0.69–0.92, q = 0.005; HR_{Mast cells} = 0.74, 95% CI = 0.65–0.85, q < 0.0001; and HR_PGR = 0.78, 95% CI = 0.68–0.89, q = 0.002). For BC proliferation and Hypoxia, higher scores associated with worse outcomes (HR_{BCproliferation} = 1.54, 95% CI = 1.33–1.79, q < 0.0001; HR_Hypoxia = 1.38, 95% CI = 1.20–1.58, q < 0.0001). The results were similar for OS. Conclusions: Expression of FOXA1 is a promising predictive biomarker for tamoxifen effect in ER+/HER2− premenopausal breast cancer. In addition, each of the signatures BC proliferation, Hypoxia, Mast cells, and the GEX of AR, ESR1, and PGR had prognostic value, also after adjusting for established prognostic factors. Trial registration This trial was retrospectively registered in the ISRCTN database the 6th of December 2019, trial ID: https://clinicaltrials.gov/ct2/show/ISRCTN12474687 .
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Please use this url to cite or link to this publication: https://lup.lub.lu.se/record/5523acfa-728e-4772-9825-df037c50b769

author

Lundgren, Christine ^LU ; Tutzauer, Julia ^LU

; Church, Sarah E. ; Stål, Olle ; Ekholm, Maria ^LU ; Forsare, Carina ^LU

; Nordenskjöld, Bo ; Fernö, Mårten ^LU ; Bendahl, Pär Ola ^LU and Rydén, Lisa ^LU

organization

publishing date

2023-12

type

Contribution to journal

publication status

published

subject

Cancer and Oncology

keywords

Gene expression signatures, Predictive, Premenopausal, Prognostic, Tamoxifen

in

Breast Cancer Research

volume

25

issue

1

article number

110

publisher

BioMed Central (BMC)

external identifiers

pmid:37773134
scopus:85172827812

ISSN

1465-5411

DOI

10.1186/s13058-023-01719-z

language

English

LU publication?

yes

additional info

id

5523acfa-728e-4772-9825-df037c50b769

date added to LUP

2023-12-04 14:09:09

date last changed

2024-04-17 10:17:45

@article{5523acfa-728e-4772-9825-df037c50b769,
  abstract     = {{<p>Background: Gene expression (GEX) signatures in breast cancer provide prognostic information, but little is known about their predictive value for tamoxifen treatment. We examined the tamoxifen-predictive value and prognostic effects of different GEX signatures in premenopausal women with early breast cancer. Methods: RNA from formalin-fixed paraffin-embedded tumor tissue from premenopausal women randomized between two years of tamoxifen treatment and no systemic treatment was extracted and successfully subjected to GEX profiling (n = 437, NanoString Breast Cancer 360™ panel). The median follow-up periods for a recurrence-free interval (RFi) and overall survival (OS) were 28 and 33 years, respectively. Associations between GEX signatures and tamoxifen effect were assessed in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+ /HER2−) tumors using Kaplan–Meier estimates and Cox regression. The prognostic effects of GEX signatures were studied in the entire cohort. False discovery rate adjustments (q-values) were applied to account for multiple hypothesis testing. Results: In patients with ER+/HER2− tumors, FOXA1 expression below the median was associated with an improved effect of tamoxifen after 10 years with regard to RFi (hazard ratio [HR]<sub> FOXA1(high)</sub> = 1.04, 95% CI = 0.61–1.76, HR<sub> FOXA1(low)</sub> = 0.30, 95% CI = 0.14–0.67, q <sub>interaction</sub> = 0.0013), and a resembling trend was observed for AR (HR<sub> AR(high)</sub> = 1.15, 95% CI = 0.60–2.20, HR<sub> AR(low)</sub> = 0.42, 95% CI = 0.24–0.75, q <sub>interaction</sub> = 0.87). Similar patterns were observed for OS. Tamoxifen was in the same subgroup most beneficial for RFi in patients with low ESR1 expression (HR<sub>RFi ESR1(high)</sub> = 0.76, 95% CI = 0.43–1.35, HR<sub>RFi, ESR1(low)</sub> = 0.56, 95% CI = 0.29–1.06, q <sub>interaction</sub> = 0.37). Irrespective of molecular subtype, higher levels of ESR1, Mast cells, and PGR on a continuous scale were correlated with improved 10 years RFi (HR<sub> ESR1</sub> = 0.80, 95% CI = 0.69–0.92, q = 0.005; HR<sub>Mast cells</sub> = 0.74, 95% CI = 0.65–0.85, q &lt; 0.0001; and HR<sub> PGR</sub> = 0.78, 95% CI = 0.68–0.89, q = 0.002). For BC proliferation and Hypoxia, higher scores associated with worse outcomes (HR<sub>BCproliferation</sub> = 1.54, 95% CI = 1.33–1.79, q &lt; 0.0001; HR<sub>Hypoxia</sub> = 1.38, 95% CI = 1.20–1.58, q &lt; 0.0001). The results were similar for OS. Conclusions: Expression of FOXA1 is a promising predictive biomarker for tamoxifen effect in ER+/HER2− premenopausal breast cancer. In addition, each of the signatures BC proliferation, Hypoxia, Mast cells, and the GEX of AR, ESR1, and PGR had prognostic value, also after adjusting for established prognostic factors. Trial registration This trial was retrospectively registered in the ISRCTN database the 6th of December 2019, trial ID: https://clinicaltrials.gov/ct2/show/ISRCTN12474687 .</p>}},
  author       = {{Lundgren, Christine and Tutzauer, Julia and Church, Sarah E. and Stål, Olle and Ekholm, Maria and Forsare, Carina and Nordenskjöld, Bo and Fernö, Mårten and Bendahl, Pär Ola and Rydén, Lisa}},
  issn         = {{1465-5411}},
  keywords     = {{Gene expression signatures; Predictive; Premenopausal; Prognostic; Tamoxifen}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Breast Cancer Research}},
  title        = {{Tamoxifen-predictive value of gene expression signatures in premenopausal breast cancer : data from the randomized SBII:2 trial}},
  url          = {{http://dx.doi.org/10.1186/s13058-023-01719-z}},
  doi          = {{10.1186/s13058-023-01719-z}},
  volume       = {{25}},
  year         = {{2023}},
}

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Tamoxifen-predictive value of gene expression signatures in premenopausal breast cancer : data from the randomized SBII:2 trial