Intracellular hypoxia measured by  18 F-fluoromisonidazole positron emission tomography has prognostic impact in patients with estrogen receptor-positive breast cancer

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Abstract

Background

Hypoxia is a key driver of cancer progression. We evaluated the prognostic impact of ¹⁸F-fluoromisonidazole (FMISO) prior to treatment in patients with breast cancer.

Methods

Forty-four patients with stage II/III primary breast cancer underwent positron emission tomography/computed with ¹⁸F-fluorodeoxyglucose (FDG-PET/CT) and FMISO. After measurement by FDG-PET/CT, the tissue-to-blood ratio (TBR) was obtained using FMISO-PET/CT. FMISO-TBR was compared for correlation with clinicopathological factors, disease-free survival (DFS), and overall survival (OS). Multiplex cytokines were analyzed for the correlation of FMISO-TBR.

Results

Tumors with higher nuclear grade and negativities of estrogen receptor (ER) and progesterone receptor had significantly higher FMISO-TBR than other tumors. Kaplan-Meier survival curves showed that patients with a higher FMISO-TBR (cutoff, 1.48) had a poorer prognosis of DFS ( p = 0.0007) and OS ( p = 0.04) than those with a lower FMISO-TBR. Multivariate analysis indicated that higher FMISO-TBR and ER negativity were independent predictors of shorter DFS ( p = 0.01 and 0.03). Higher FMISO-TBR was associated with higher plasma levels of angiogenic hypoxic markers such as vascular endothelial growth factor, transforming growth factor-α, and interleukin 8.

Conclusions

FMISO-PET/CT is useful for assessing the prognosis of patients with breast cancer, but it should be stratified by ER status.

Trial registration

UMIN Clinical Trials Registry, UMIN000006802. Registered on 1 December 2011.

Electronic supplementary material

The online version of this article (10.1186/s13058-018-0970-6) contains supplementary material, which is available to authorized users.

Related collections

Most cited references 25

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Ki67 Index, HER2 Status, and Prognosis of Patients With Luminal B Breast Cancer

Maggie C. U. Cheang, Stephen Chia, David Voduc … (2009)

Background Gene expression profiling of breast cancer has identified two biologically distinct estrogen receptor (ER)-positive subtypes of breast cancer: luminal A and luminal B. Luminal B tumors have higher proliferation and poorer prognosis than luminal A tumors. In this study, we developed a clinically practical immunohistochemistry assay to distinguish luminal B from luminal A tumors and investigated its ability to separate tumors according to breast cancer recurrence-free and disease-specific survival. Methods Tumors from a cohort of 357 patients with invasive breast carcinomas were subtyped by gene expression profile. Hormone receptor status, HER2 status, and the Ki67 index (percentage of Ki67-positive cancer nuclei) were determined immunohistochemically. Receiver operating characteristic curves were used to determine the Ki67 cut point to distinguish luminal B from luminal A tumors. The prognostic value of the immunohistochemical assignment for breast cancer recurrence-free and disease-specific survival was investigated with an independent tissue microarray series of 4046 breast cancers by use of Kaplan–Meier curves and multivariable Cox regression. Results Gene expression profiling classified 101 (28%) of the 357 tumors as luminal A and 69 (19%) as luminal B. The best Ki67 index cut point to distinguish luminal B from luminal A tumors was 13.25%. In an independent cohort of 4046 patients with breast cancer, 2847 had hormone receptor–positive tumors. When HER2 immunohistochemistry and the Ki67 index were used to subtype these 2847 tumors, we classified 1530 (59%, 95% confidence interval [CI] = 57% to 61%) as luminal A, 846 (33%, 95% CI = 31% to 34%) as luminal B, and 222 (9%, 95% CI = 7% to 10%) as luminal–HER2 positive. Luminal B and luminal–HER2-positive breast cancers were statistically significantly associated with poor breast cancer recurrence-free and disease-specific survival in all adjuvant systemic treatment categories. Of particular relevance are women who received tamoxifen as their sole adjuvant systemic therapy, among whom the 10-year breast cancer–specific survival was 79% (95% CI = 76% to 83%) for luminal A, 64% (95% CI = 59% to 70%) for luminal B, and 57% (95% CI = 47% to 69%) for luminal–HER2 subtypes. Conclusion Expression of ER, progesterone receptor, and HER2 proteins and the Ki67 index appear to distinguish luminal A from luminal B breast cancer subtypes.

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Prognostic significance of [18F]-misonidazole positron emission tomography-detected tumor hypoxia in patients with advanced head and neck cancer randomly assigned to chemoradiation with or without tirapazamine: a substudy of Trans-Tasman Radiation Oncology Group Study 98.02.

June Corry, David Binns, Sandro Porceddu … (2006)

To determine the association between tumor hypoxia, treatment regimen, and locoregional failure (LRF) in patients with stage III or IV squamous cell carcinoma of the head and neck randomly assigned to radiotherapy (70 Gy in 35 fractions over 7 weeks) plus either tirapazamine and cisplatin in weeks 1, 4, and 7 and tirapazamine alone in weeks 2 and 3 (TPZ/CIS) or cisplatin and infusional fluorouracil during weeks 6 and 7 (chemoboost). Forty-five patients were enrolled onto a hypoxic imaging substudy of a larger randomized trial. Pretreatment and midtreatment [18F]-fluoromisonidazole positron emission tomography scans (FMISO-PET) were performed 2 hours after tracer administration, with qualitative scoring of uptake in both primary tumors and nodes. Thirty-two patients (71%) had detectable hypoxia in either or both primary and nodal disease. In patients who received chemoboost, one of 10 patients without hypoxia had LRF compared with eight of 13 patients with hypoxia; the risk of LRF was significantly higher in hypoxic patients (exact log-rank, P = .038; hazard ratio [HR] = 7.1). By contrast, in patients who received the TPZ/CIS regimen, only one of 19 patients with hypoxic tumors had LRF; risk of LRF was significantly higher in chemoboost patients (P = .001; HR = 15). Similarly, looking at the primary site alone, in patients with hypoxic primaries, zero of eight patients treated with TPZ/CIS experienced failure locally compared with six of nine patients treated with chemoboost (P = .011; HR = 0). Hypoxia on FMISO-PET imaging, in patients receiving a nontirapazamine-containing chemoradiotherapy regimen, is associated with a high risk of LRF. Our data provide the first clinical evidence to support the experimental observation that tirapazamine acts by specifically targeting hypoxic tumor cells.

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A compact VEGF signature associated with distant metastases and poor outcomes

Zhiyuan Hu, Cheng Fan, Chad Livasy … (2009)

Background Tumor metastases pose the greatest threat to a patient's survival, and thus, understanding the biology of disseminated cancer cells is critical for developing effective therapies. Methods Microarrays and immunohistochemistry were used to analyze primary breast tumors, regional (lymph node) metastases, and distant metastases in order to identify biological features associated with distant metastases. Results When compared with each other, primary tumors and regional metastases showed statistically indistinguishable gene expression patterns. Supervised analyses comparing patients with distant metastases versus primary tumors or regional metastases showed that the distant metastases were distinct and distinguished by the lack of expression of fibroblast/mesenchymal genes, and by the high expression of a 13-gene profile (that is, the 'vascular endothelial growth factor (VEGF) profile') that included VEGF, ANGPTL4, ADM and the monocarboxylic acid transporter SLC16A3. At least 8 out of 13 of these genes contained HIF1α binding sites, many are known to be HIF1α-regulated, and expression of the VEGF profile correlated with HIF1α IHC positivity. The VEGF profile also showed prognostic significance on tests of sets of patients with breast and lung cancer and glioblastomas, and was an independent predictor of outcomes in primary breast cancers when tested in models that contained other prognostic gene expression profiles and clinical variables. Conclusion These data identify a compact in vivo hypoxia signature that tends to be present in distant metastasis samples, and which portends a poor outcome in multiple tumor types. This signature suggests that the response to hypoxia includes the ability to promote new blood and lymphatic vessel formation, and that the dual targeting of multiple cell types and pathways will be needed to prevent metastatic spread.

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Author and article information

Contributors

Aya Asano: asanoa16@saitama-med.ac.jp

Shigeto Ueda: syueda2000@yahoo.co.jp

Ichiei Kuji:

ORCID: http://orcid.org/0000-0003-4700-4781

kuji@saitama-med.ac.jp

Tomohiko Yamane: yamane_t@saitama-med.ac.jp

Hideki Takeuchi: htake@saitama-med.ac.jp

Eiko Hirokawa: eiko1126@saitama-med.ac.jp

Ikuko Sugitani: iku0215@saitama-med.ac.jp

Hiroko Shimada: h0113@saitama-med.ac.jp

Takahiro Hasebe: thasebe@saitama-med.ac.jp

Akihiko Osaki: aosaki@saitama-med.ac.jp

Toshiaki Saeki: tsaeki@saitama-med.ac.jp

Journal

Journal ID (nlm-ta): Breast Cancer Res

Journal ID (iso-abbrev): Breast Cancer Res

Title: Breast Cancer Research : BCR

Publisher: BioMed Central (London )

ISSN (Print): 1465-5411

ISSN (Electronic): 1465-542X

Publication date (Electronic): 27 July 2018

Publication date PMC-release: 27 July 2018

Publication date (Print): 2018

Volume: 20

Electronic Location Identifier: 78

Affiliations

[1 ]ISNI 0000 0001 2216 2631, GRID grid.410802.f, Department of Breast Oncology, , Saitama Medical University, ; 38 Morohongo, Moroyama-machi, Irumagun, Saitama, 350-0451, Japan

[2 ]GRID grid.412377.4, Department of Breast Oncology, , Saitama Medical University International Medical Center, ; 1397-1 Yamane, Hidaka, Saitama, 350-1241, Japan

[3 ]GRID grid.412377.4, Department of Nuclear Medicine, , Saitama Medical University International Medical Center, ; 1397-1 Yamane, Hidaka, Saitama, 350-1241, Japan

[4 ]GRID grid.412377.4, Department of Pathology, , Saitama Medical University International Medical Center, ; 1397-1 Yamane, Hidaka, Saitama, 350-1241, Japan

Author information

Ichiei Kuji http://orcid.org/0000-0003-4700-4781

Article

Publisher ID: 970

DOI: 10.1186/s13058-018-0970-6

PMC ID: 6063018

PubMed ID: 30053906

SO-VID: 0b09dd9b-59fb-4540-a5de-8985bd89147e

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 11 December 2017

Date accepted : 20 April 2018

Funding

Funded by: JSPS KAKEN

Award ID: 16K10361

Award ID: 16K10293

Award Recipient : Shigeto Ueda Ichiei Kuji

Funded by: JSPS KAKEN

Award ID: 17H03591

Award Recipient : Toshiaki Saeki

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: breast cancer,hypoxia,prognosis,18f-fluoromisonidazole,positron emission tomography

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: breast cancer, hypoxia, prognosis, 18f-fluoromisonidazole, positron emission tomography