Prognostic implication of intratumoral metabolic heterogeneity in invasive ductal carcinoma of the breast

BackgroundThe purpose of this study was to evaluate the prognostic implication of findings of intratumoral metabolic heterogeneity on pretreatment 18F-FDG PET/CT scans in patients with invasive ductal carcinoma (IDC) of the breast.MethodsOne hundred and twenty-three female IDC patients who underwent pretreatment 18F-fluorodeoxyglucose positron-emission tomography/computed tomography (18F-FDG PET/CT) scans were retrospectively evaluated in this study. The heterogeneity factor (HF) defined as the derivative (dV/dT) of a volume threshold function from 40% to 80%, was computed for each primary tumor. Other metabolic PET parameters (maximum standardized uptake value [SUVmax], metabolic tumor volume [MTV], and total lesion glycolysis [TLG]) were measured. The HF was compared with clinicopathologic factors and other PET parameters. Univariate and multivariate analyses for the overall survival (OS) were performed.ResultsThe HF ranged from 0.02 to 6.72 (mean, 0.35 ± 0.82) and significantly correlated with MTV (r = 0.955; p < 0.0001) and TLG (r = 0.354; p = 0.0001). The HF was significantly higher (implying more heterogeneity) in tumors with higher T and N stages. The optimal cut-off values for the OS determined using a receiver operating characteristic (ROC) curve were 0.34 for the HF, 5.6 for SUVmax, 8.55 cm3 for MTV, and 14.43 for TLG. The OS rate among the 123 patients was 86.2%. T stage (1, 2 vs. 3, 4), N stage (0, 1 vs. 2, 3), M stage (0 vs. 1), ER status (+ vs. –), SUVmax (≤ 5.6 vs. > 5.6), MTV (≤ 8.55 cm3 vs. > 8.55 cm3), TLG (≤ 14.43 vs. > 14.43), and HF (< 0.34 vs. ≥ 0.34) affected the OS on univariate analysis. After adjustment for the effects of TNM stage and ER status, the HF and MTV were significant predictors of OS. Among the PET parameters, the best prognostic factor for OS was the HF.ConclusionsIntratumoral metabolic heterogeneity correlated closely with the MTV and significantly affected the OS in IDC patients. The HF may act as a robust surrogate marker for the prediction of OS in IDC patients.

[1]  I. Fidler,et al.  Biological diversity in metastatic neoplasms: origins and implications. , 1982, Science.

[2]  G. Heppner.  Tumor heterogeneity. , 1984, Cancer research.

[3]  G. Heppner,et al.  Mutagenic activity of tumor-associated macrophages in Salmonella typhimurium strains TA98 and TA 100. , 1984, Cancer research.

[4]  G. Heppner,et al.  Therapeutic implications of tumor heterogeneity. , 1989, Seminars in oncology.

[5]  Heppner Gh,et al.  Therapeutic implications of tumor heterogeneity. , 1989 .

[6]  T Ido,et al.  Intratumoral distribution of fluorine-18-fluorodeoxyglucose in vivo: high accumulation in macrophages and granulation tissues studied by microautoradiography. , 1992, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[7]  T. Ido,et al.  Microautoradiographic study for the differentiation of intratumoral macrophages, granulation tissues and cancer cells by the dynamics of fluorine-18-fluorodeoxyglucose uptake. , 1994, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[8]  R. Wahl,et al.  Intratumoral distribution of tritiated fluorodeoxyglucose in breast carcinoma: I. Are inflammatory cells important? , 1995, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[9]  H. Yagata,et al.  Predicting the prognoses of breast carcinoma patients with positron emission tomography using 2‐deoxy‐2‐fluoro[18F]‐D‐glucose , 1998, Cancer.

[10]  R. Gillies,et al.  Causes and effects of heterogeneous perfusion in tumors. , 1999, Neoplasia.

[11]  S. Ramón y. Cajal,et al.  Tumor heterogeneity: morphological, molecular and clinical implications. , 2000, Histology and histopathology.

[12]  F. Chapon,et al.  Non-invasive grading of oligodendrogliomas: correlations between in vivo metabolic pattern and histopathology , 2000, European Journal of Nuclear Medicine.

[13]  Leila Mohammadi,et al.  BMC Cancer , 2001 .

[14]  P. Grigsby,et al.  Measurement of tumor volume by PET to evaluate prognosis in patients with advanced cervical cancer treated by radiation therapy. , 2002, International journal of radiation oncology, biology, physics.

[15]  C. Compton,et al.  AJCC Cancer Staging Manual , 2002, Springer New York.

[16]  G. Semenza,et al.  HIF-1 and tumor progression: pathophysiology and therapeutics. , 2002, Trends in molecular medicine.

[17]  E. Berg,et al.  World Health Organization Classification of Tumours , 2002 .

[18]  T. Taguchi,et al.  Preoperative evaluation of prognosis in breast cancer patients by [18F]2-Deoxy-2-fluoro-D-glucose-positron emission tomography , 2004, Journal of Cancer Research and Clinical Oncology.

[19]  Peter Devilee,et al.  Pathology and Genetics of Tumours of the Breast and Female Genital Organs , 2003 .

[20]  L. Murphy,et al.  Intermittent Hypoxia Induces Proteasome-Dependent Down-Regulation of Estrogen Receptor α in Human Breast Carcinoma , 2004, Clinical Cancer Research.

[21]  G. Nicolson.  Generation of phenotypic diversity and progression in metastatic tumor cells , 2004, Cancer and Metastasis Reviews.

[22]  G. Heppner,et al.  Tumor heterogeneity: biological implications and therapeutic consequences , 2004, Cancer and Metastasis Reviews.

[23]  Nagara Tamaki,et al.  Biologic correlates of intratumoral heterogeneity in 18F-FDG distribution with regional expression of glucose transporters and hexokinase-II in experimental tumor. , 2005, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[24]  R. Walker,et al.  World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Breast and Female Genital Organs , 2005 .

[25]  Manuela Milani,et al.  Hypoxia-inducible factor-1alpha expression predicts a poor response to primary chemoendocrine therapy and disease-free survival in primary human breast cancer. , 2006, Clinical cancer research : an official journal of the American Association for Cancer Research.

[26]  Manuela Milani,et al.  Hypoxia-Inducible Factor-1α Expression Predicts a Poor Response to Primary Chemoendocrine Therapy and Disease-Free Survival in Primary Human Breast Cancer , 2006, Clinical Cancer Research.

[27]  Cai Grau,et al.  Dose painting: art or science? , 2006, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[28]  J. Kaanders,et al.  Mini Symposium: Pet—the Future from Anatomical to Biological Target Volumes: the Role of Pet in Radiation Treatment Planning , 2022 .

[29]  Carissa A. Sanchez,et al.  Genetic clonal diversity predicts progression to esophageal adenocarcinoma , 2006, Nature Genetics.

[30]  Anthony Rhodes,et al.  American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. , 2006, Archives of pathology & laboratory medicine.

[31]  I. Buvat,et al.  Partial-Volume Effect in PET Tumor Imaging* , 2007, Journal of Nuclear Medicine.

[32]  Johan Wennerberg,et al.  2-Deoxy-2-[18F] fluoro-D-glucose uptake and correlation to intratumoral heterogeneity. , 2007, Anticancer research.

[33]  J. Steinbach,et al.  Effect of increase of radiation dose on local control relates to pre-treatment FDG uptake in FaDu tumours in nude mice. , 2007, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[34]  Philippe Lambin,et al.  Correlation of intra-tumour heterogeneity on 18F-FDG PET with pathologic features in non-small cell lung cancer: a feasibility study. , 2008, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[35]  H. Tsuda,et al.  Clinicopathological and prognostic relevance of uptake level using 18F-fluorodeoxyglucose positron emission tomography/computed tomography fusion imaging (18F-FDG PET/CT) in primary breast cancer. , 2008, Japanese journal of clinical oncology.

[36]  J. Dick,et al.  Stem cell concepts renew cancer research. , 2008, Blood.

[37]  F. O’Sullivan,et al.  Spatial Heterogeneity in Sarcoma 18F-FDG Uptake as a Predictor of Patient Outcome , 2008, Journal of Nuclear Medicine.

[38]  Mike Partridge,et al.  Evaluation of the role of 18FDG-PET/CT in radiotherapy target definition in patients with head and neck cancer , 2008, Acta oncologica.

[39]  P. Grigsby,et al.  Intratumoral Metabolic Heterogeneity of Cervical Cancer , 2008, Clinical Cancer Research.

[40]  S. Fox,et al.  Phosphorylated ERalpha, HIF-1alpha, and MAPK signaling as predictors of primary endocrine treatment response and resistance in patients with breast cancer. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[41]  T. Hoey.  Drug Resistance, Epigenetics, and Tumor Cell Heterogeneity , 2010, Science Translational Medicine.

[42]  B. Manaster.  Spatial Heterogeneity in Sarcoma 18F-FDG Uptake as a Predictor of Patient Outcome , 2010 .

[43]  M. Hatt,et al.  Intratumor Heterogeneity Characterized by Textural Features on Baseline 18F-FDG PET Images Predicts Response to Concomitant Radiochemotherapy in Esophageal Cancer , 2011, The Journal of Nuclear Medicine.

[44]  M. Sim,et al.  AJCC Cancer Staging Manual 7th edition criteria for colon cancer: do the complex modifications improve prognostic assessment? , 2013, Journal of the American College of Surgeons.

[45]  Guangyu Liu,et al.  18F-Fluoromisonidazole PET/CT: A Potential Tool for Predicting Primary Endocrine Therapy Resistance in Breast Cancer , 2013, The Journal of Nuclear Medicine.

[46]  He N. Xu,et al.  Characterizing the metabolic heterogeneity in human breast cancer xenografts by 3D high resolution fluorescence imaging , 2013, SpringerPlus.