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18FDG-PET/CT and molecular markers to predict response to neoadjuvant chemotherapy and outcome in HER2-negative advanced luminal breast cancers patients.

ABSTRACT: The efficacy of neoadjuvant chemotherapy regimens in advanced luminal breast cancer patients is difficult to predict. Intrinsic properties of breast tumors, including altered gene expression profile and dynamic evaluation of metabolic properties of tumor cells using positron emission tomography/computed tomography (PET/CT) of tumor cells, have been identified to guide patient's prognosis. The aim of this study is to determine if both analyses may improve the prediction of response to neoadjuvant chemotherapy in ER-positive / HER2-negative breast cancers (BCs) patients.We used metabolic PET parameters, at diagnosis and after two cycles of chemotherapy and proliferation gene expression profile on biopsy at diagnosis, in particular, the genomic grade index (GGI) analyzed by reverse transcription and quantitative polymerase chain reaction (RT-qPCR). The pathological response was the surrogate endpoint.The change of FDG uptake between baseline PET and interim PET after 2 cycles of neoadjuvant chemotherapy (?SUVmax) was highly associated with pCR (p=0.008). We also observed an ability of P53 mutated status (p=0.042), in addition to histological grade (p=0. 0004), and PR expression (p=0.01) to predict pCR in ER-positive BCs, whereas no proliferation marker predicted pCR (P=0.39 for GGI). Finally, only ?SUVmax was significantly associated with event free survival (p=0.047).Our results confirm the predictive and prognostic value of tumor ?SUVmax in ER-positive /HER2-negative advanced BCs patients. These findings can be helpful to select high-risk patients within trials investigating novel treatment strategies.

SUBMITTER: de Cremoux P

PROVIDER: S-EPMC5893244 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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<sup>18</sup>FDG-PET/CT and molecular markers to predict response to neoadjuvant chemotherapy and outcome in HER2-negative advanced luminal breast cancers patients.

de Cremoux Patricia P Biard Lucie L Poirot Brigitte B Bertheau Philippe P Teixeira Luis L Lehmann-Che Jacqueline J Bouhidel Fatiha A FA Merlet Pascal P Espié Marc M Resche-Rigon Matthieu M Sotiriou Christos C Groheux David D

Oncotarget 20180327 23

<h4>Background</h4>The efficacy of neoadjuvant chemotherapy regimens in advanced luminal breast cancer patients is difficult to predict. Intrinsic properties of breast tumors, including altered gene expression profile and dynamic evaluation of metabolic properties of tumor cells using positron emission tomography/computed tomography (PET/CT) of tumor cells, have been identified to guide patient's prognosis. The aim of this study is to determine if both analyses may improve the prediction of resp ...[more]

PMID: 29662649

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Project description:BACKGROUND:Pompe disease (PD) is an autosomal recessive, lysosomal storage disease due to a mutation of the acid ?-glucosidase (GAA) gene. In adult patients, PD is characterized by slowly progressive limb-girdle and trunk myopathy and restrictive respiratory insufficiency. Enzyme replacement therapy (ERT) is available, improving or stabilizing muscle-function in some and slowing deterioration in other patients. Unfortunately, there is no biomarker available to indicate therapeutic efficacy and/or disease activity. Whole body MRI depicts all skeletal muscles demonstrating foci of atrophic muscles, i.e., late and irreversible pathological changes. Any method indicating the localizations of increased muscle glycogen storage, muscle inflammation and/or degradation could possibly help identifying newly afflicted tissue and may be of prognostic value. We therefore investigated 2-deoxy-2-[18]fluoro-D-glucose (FDG) PET, a biomarker for glucose-metabolism, as a tool to evaluate disease activity and prognosis in PD. METHODS:In a pilot study, we investigated four patients by FDG dynamic PET/CT while on ERT. One patient had FDG-PET/CT twice, before and after 12 months on ERT. Dynamic FDG-PET/CT quantifies the metabolic rate of glucose utilisation in mg/ml/min. MRI was performed in parallel with pelvic and thigh muscles semi-quantitatively scored for atrophy and disease-activity. RESULTS:None of the muscles analysed showed a focally increased FDG-uptake. Thus, quantification of muscle glucose metabolism could not be calculated. However, increased FDG-uptake, i.e., increased glucose utilisation, was observed in the respiratory muscles of one patient with severe, restrictive respiratory failure. In contrast, specific MRI sequences showed oedematous as well as atrophic muscle areas in PD. CONCLUSIONS:Our pilot study demonstrates that FDG-uptake does not correlate with glycogen storage in vivo. In contrast, MRI is an excellent tool to demonstrate the extent of muscle involvement. Specific MRI sequences may even demonstrate early changes possibly allowing prognostic predictions or localization of early stages of PD.

Project description:PURPOSE:The histological response to neoadjuvant chemotherapy is an important prognostic factor in patients with osteosarcoma (OS) and Ewing sarcoma (EWS). The aim of this study was to assess baseline primary tumour FDG uptake on PET/CT, and serum values of alkaline phosphatase (ALP) and lactate dehydrogenase (LDH), to establish whether these factors are correlated with tumour necrosis and prognosis. METHODS:Patients treated between 2009 and 2014 for localized EWS and OS, who underwent FDG PET/CT as part of their staging work-up, were included. The relationships between primary tumour SUVmax at baseline (SUV1), SUVmax after induction chemotherapy (SUV2), metabolic response calculated as [(SUV1?-?SUV2)/SUV1)]?×?100, LDH and ALP and tumour response/survival were analysed. A good response (GR) was defined as tumour necrosis >90 % in patients with OS, and grade II-III Picci necrosis (persitence of microscopic foci only or no viable tumor) in patients with Ewing sarcoma. RESULTS:The study included 77 patients, 45 with EWS and 32 with OS. A good histological response was achieved in 53 % of EWS patients, and 41 % of OS patients. The 3-year event-free survival (EFS) was 57 % in EWS patients and 48 % OS patients. The median SUV1 was 5.6 (range 0?-?17) in EWS patients and 7.9 (range 0?-?24) in OS patients (p?=?0.006). In EWS patients the GR rate was 30 % in those with a high SUV1 (?6) and 72 % in those with a lower SUV1 (p?=?0.0004), and in OS patients the GR rate was 29 % in those with SUV1 ?6 and 64 % in those with a lower SUV1 (p?=?0.05). In the univariate analysis the 3-year EFS was significantly better in patients with a low ALP level (59 %) than in those with a high ALP level (22 %, p?=?0.02) and in patients with a low LDH level (62 %) than in those with a high LDH level (37 %, p?=?0.004). In EWS patients the 3-year EFS was 37 % in those with a high SUV1 and 75 % in those with a low SUV1 (p?=?0.004), and in OS patients the 3-year EFS was 32 % in those with a high SUV1 and 66 % in those with a low SUV1 (p?=?0.1). Histology, age and gender were not associated with survival. In the multivariate analysis, SUV1 was the only independent pretreatment prognostic factor to retain statistical significance (p?=?0.017). SUV2 was assessed in 25 EWS patients: the median SUV2 was 1.9 (range 1?-?8). The GR rate was 20 % in patients with a high SUV2, and 67 % in those with a low SUV2 (p?=?0.02). A good metabolic response (SUV reduction of ?55 %) was associated with a 3-year EFS of 80 % and a poor metabolic response with a 3-year EFS of 20 % (p?=?0.05). In the OS patients the median SUV2 was 2.7 (range 0?-?4.5). Neither SUV2 nor the metabolic response was associated with outcome in OS patients. CONCLUSION:FDG PET/CT is a useful and noninvasive tool for identifying patients who are more likely to be resistant to chemotherapy. If this finding is confirmed in a larger series, SUV1, SUV2 and metabolic response could be proposed as factors for stratifying EWS patients to identify those with high-grade localized bone EWS who would benefit from risk-adapted induction chemotherapy.

Project description:Abstract Introduction Response rates to chemotherapy remain highly variable in breast cancer patients. We set out to identify genes associated with chemotherapy resistance. We analyzed what is currently the largest single-institute set of gene expression profiles derived from breast cancers prior to a single neoadjuvant chemotherapy regimen (dose-dense doxorubicine and cyclophophamide). Methods We collected, gene expression-profiled and analyzed 178 HER2-negative breast tumor biopsies (M-bM-^@M-^XNKI datasetM-bM-^@M-^Y). We employed a recently developed approach for detecting imbalanced differential signal (DIDS) in order to identify markers of resistance to treatment. In contrast to traditional methods, DIDS is able to identify markers that show aberrant expression in only a small subgroup of the non-responder samples. Results We found a number of markers of resistance to anthracycline-based chemotherapy. We validated our findings by the analysis of three external datasets, which contained 456 HER2-negative samples in total. Since these external sets included patients who received differing treatment regimens we could only validate markers of general chemotherapy resistance. There was a highly significant overlap in the markers identified in the NKI dataset and the other three datasets. Five resistance markers, SERPINA6, BEX1, AGTR1, SLC26A3, and LAPTM4B, were identified in three of the four datasets (p-value overlap <1e-6). These five genes identified resistant tumors that could not have been identified by merely taking ER-status or proliferation into account. Conclusion The identification of these genes might lead to a better understanding of the mechanisms involved in (clinically) observed chemotherapy resistance and could possibly assist in the recognition of breast cancers in which chemotherapy does not contribute to response or survival. We collected, gene expression profiled and analyzed 178 HER2-negative breast tumor biopsies, obtained from patients scheduled to undergo neoadjuvant therapy.

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18FDG-PET/CT and molecular markers to predict response to neoadjuvant chemotherapy and outcome in HER2-negative advanced luminal breast cancers patients.

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<sup>18</sup>FDG-PET/CT and molecular markers to predict response to neoadjuvant chemotherapy and outcome in HER2-negative advanced luminal breast cancers patients.

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