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18F-fluorodeoxy-glucose positron emission tomography marks MYC-overexpressing human basal-like breast cancers

ABSTRACT: Fluorine-18-fluoro-2-deoxy-D-glucose (FDG) is widely used as positron-emission-tomography (PET) radiotracer for the detection and staging of human cancer. Tumor uptake of FDG varies substantially between different cancer types and between patients with the same tumor type. The molecular basis for this heterogeneity is unknown. Using cancer cell lines and primary human tumors of distinct histologic origins, we here show that increased FDG uptake is universally associated with coordinate upregulation of genes within the glycolysis, pentose-phosphate, and other related metabolic pathways. In primary human breast cancers, this FDG signature shows significant overlap with established breast cancer signatures for the “basal-like” disease subtype and “poor prognosis”. FDG high breast cancer showed significantly more gene copy number alterations genome wide than FDG low cancers. About 50 % of primary breast cancers with high FDG uptake and FDG gene expression signature show DNA copy gain encompassing the c-myc gene locus and express gene sets regulated by the transcription factor MYC. Our data shows that FDG-PET marks a distinct subset of “basal-like” human breast cancer which is characterized by MYC and prognostically unfavorable gene expression signatures, suggesting that FDG-PET imaging may be useful to risk-stratify patients with locally advanced breast cancer. Our general strategy to identify molecular determinants of FDG-retention through a genome-wide approach consisted of FDG uptake measurements in cancer cell lines and primary human tumors, the selection of samples with particularly high versus low FDG-retention, and subsequent pathway-based analysis of RNA expression data collected from these samples. Cell line RNA was extracted from a 10 cm plate seeded simultaneously and at the same density as the wells for FDG-uptake assays. For primary human tumor samples, RNA was extracted from macrodissected frozen tumor tissue. All cell line RNA samples and the astrocytoma RNA aliquots were hybridized to Affymetrix U133 Plus 2.0 arrays. All primary breast cancer RNA samples were hybridized to Affymetrix U133A arrays.

ORGANISM(S): Homo sapiens

SUBMITTER: Palaskas N

PROVIDER: S-ECPF-GEOD-21217 | biostudies-other | 2011 Aug

REPOSITORIES: biostudies-other

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Project description:Fluorine-18-fluoro-2-deoxy-D-glucose (FDG) is widely used as positron-emission-tomography (PET) radiotracer for the detection and staging of human cancer. Tumor uptake of FDG varies substantially between different cancer types and between patients with the same tumor type. The molecular basis for this heterogeneity is unknown. Using cancer cell lines and primary human tumors of distinct histologic origins, we here show that increased FDG uptake is universally associated with coordinate upregulation of genes within the glycolysis, pentose-phosphate, and other related metabolic pathways. In primary human breast cancers, this FDG signature shows significant overlap with established breast cancer signatures for the “basal-like” disease subtype and “poor prognosis”. FDG high breast cancer showed significantly more gene copy number alterations genome wide than FDG low cancers. About 50 % of primary breast cancers with high FDG uptake and FDG gene expression signature show DNA copy gain encompassing the c-myc gene locus and express gene sets regulated by the transcription factor MYC. Our data shows that FDG-PET marks a distinct subset of “basal-like” human breast cancer which is characterized by MYC and prognostically unfavorable gene expression signatures, suggesting that FDG-PET imaging may be useful to risk-stratify patients with locally advanced breast cancer. Our general strategy to identify molecular determinants of FDG-retention through a genome-wide approach consisted of FDG uptake measurements in cancer cell lines and primary human tumors, the selection of samples with particularly high versus low FDG-retention, and subsequent pathway-based analysis of RNA expression data collected from these samples. Cell line RNA was extracted from a 10 cm plate seeded simultaneously and at the same density as the wells for FDG-uptake assays. For primary human tumor samples, RNA was extracted from macrodissected frozen tumor tissue. All cell line RNA samples and the astrocytoma RNA aliquots were hybridized to Affymetrix U133 Plus 2.0 arrays. All primary breast cancer RNA samples were hybridized to Affymetrix U133A arrays.

Project description:PurposeCervical cancer metabolic tumour volume (MTV) derived from [18F]-FDG PET/CT has a role in prognostication and therapy planning. There is no standard method of outlining MTV on [18F]-FDG PET/CT. The aim of this study was to assess the optimal method to outline primary cervical tumours on [18F]-FDG PET/CT using MRI-derived tumour volumes as the reference standard.Methods81 consecutive cervical cancer patients with pre-treatment staging MRI and [18F]-FDG PET/CT imaging were included. MRI volumes were compared with different PET segmentation methods. Method 1 measured MTVs at different SUVmax thresholds ranging from 20 to 60% (MTV20-MTV60) with bladder masking and manual adjustment when required. Method 2 created an isocontour around the tumour prior to different SUVmax thresholds being applied. Method 3 used an automated gradient method. Inter-observer agreement of MTV, following manual adjustment when required, was recorded.ResultsFor method 1, the MTV25 and MTV30 were closest to the MRI volumes for both readers (mean percentage change from MRI volume of 2.9% and 13.4% for MTV25 and - 13.1% and - 2.0% for MTV30 for readers 1 and 2). 70% of lesions required manual adjustment at MTV25 compared with 45% at MTV30. There was excellent inter-observer agreement between MTV30 to MTV60 (ICC ranged from 0.898-0.976 with narrow 95% confidence intervals (CIs)) and moderate agreement at lower thresholds (ICC estimates of 0.534 and 0.617, respectively for the MTV20 and MTV25 with wide 95% CIs). Bladder masking was performed in 86% of cases overall. For method 2, excellent correlation was demonstrated at MTV25 and MTV30 (mean % change from MRI volume of -3.9% and - 8.6% for MTV25 and - 16.9% and 19% for MTV30 for readers 1 and 2, respectively). This method also demonstrated excellent ICC across all thresholds with no manual adjustment. Method 3 demonstrated excellent ICC of 0.96 (95% CI 0.94-0.97) but had a mean percentage difference from the MRI volume of - 19.1 and - 18.2% for readers 1 and 2, respectively. 21% required manual adjustment for both readers.ConclusionMTV30 provides the optimal correlation with MRI volume taking into consideration the excellent inter-reader agreement and less requirement for manual adjustment.

Project description:ImportanceNeoadjuvant immunotherapy is a novel approach with the potential to improve outcomes for patients with oral cavity squamous cell cancer (OCSCC). Adverse events of varying severity are reported with immunotherapy, and a biomarker to predict response would be clinically useful to avoid toxic effects in those unlikely to benefit.ObjectiveTo correlate changes on fluoro-[18F]-deoxy-2-D-glucose positron emission tomography/computed tomography (FDG-PET/CT) scans with primary tumor pathologic response and immunologic biomarkers in patients with OCSCC receiving neoadjuvant immunotherapy.Design, setting, and participantsThis was a retrospective analysis of serial FDG-PET/CT scans obtained prospectively as part of a phase 2 open-label randomized clinical trial investigating neoadjuvant immunotherapy in patients with untreated OCSCC between 2016 and 2019. Included were a total of 29 patients from a single academic medical center with untreated OCSCC (≥T2, or clinically node positive) randomized 1:1 to receive neoadjuvant therapy with single agent nivolumab or combination nivolumab and ipilimumab followed by surgery and standard of care adjuvant therapy.InterventionsThe interventions in this study were FDG-PET/CT scans before (T0) and after (T1) preoperative immunotherapy.Main outcomes and measuresData collected from FDG-PET/CT scans included maximum standardized uptake value (SUVmax) of primary OCSCC and cervical lymph nodes (LNs) at T0 and T1 and new LN uptake and uptake consistent with radiologic immune-related adverse events (irAEs) at T1. Primary OCSCC pathologic response reported as percentages of viable vs nonviable tumor. The number of CD8+ cells/mm2 was determined in the primary tumor biopsy specimen and at surgery.ResultsThere was no correlation between pathologic response and change in SUVmax in the primary OCSCC between T0 and T1. Out of 27 total participants, 13 had newly FDG-avid ipsilateral LNs at T1, most negative on pathology. A total of 9 had radiologic irAEs, most commonly sarcoid-like LN (7 of 27). No correlations were found between primary OCSCC SUVmax at T0 and CD8+ T-cell number in the primary tumor biopsy, and no correlations were found between primary OCSCC SUVmax at T1 and CD8+ T-cell number in the primary tumor at surgery.Conclusions and relevanceThere were no correlations between changes in FDG uptake after neoadjuvant immunotherapy and pathologic primary tumor response. Importantly, newly FDG-avid ipsilateral LNs following neoadjuvant immunotherapy were commonly observed but did not represent progressive disease or indicate pathologically disease positive nodes in most cases. These findings argue against altering surgical plans in this setting and suggest that the role of FDG-PET/CT may be limited as an early imaging biomarker for predicting pathologic response to preoperative immunotherapy for OCSCC.Trial registrationClinicalTrials.gov Identifier: NCT02919683.

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18F-fluorodeoxy-glucose positron emission tomography marks MYC-overexpressing human basal-like breast cancers

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