Oncotarget

Research Papers:

Inborn-like errors of metabolism are determinants of breast cancer risk, clinical response and survival: a study of human biochemical individuality

Ismael da Silva, Rene da Costa Vieira, Carolina Stella, Edson Loturco, André Lopes Carvalho, Carlos Veo, Cristovam Neto, Sandra M. Silva, Paulo D'Amora, Marcia Salzgeber, Delcio Matos, Celso R. Silva, Jose R. Oliveira, Iara Rabelo, Patricia Yamakawa, Rui Maciel, Rosa Biscolla, Maria Chiamolera, Renato Fraietta, Felipe Reis, Marcelo Mori, Dirce Marchioni, Antonio Carioca, Gustavo Maciel, Renato Tomioka, Edmund Baracat, Clovis Silva, Celso Granato, Ricardo Diaz, Bruno Scarpellini, Daniel Egle, Heidi Fiegl, Irmgard Himmel, Christina Troi and Robert Nagourney _

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Oncotarget. 2018; 9:31664-31681. https://doi.org/10.18632/oncotarget.25839

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Abstract

Ismael da Silva1,2,8, Rene da Costa Vieira8, Carolina Stella1, Edson Loturco6, André Lopes Carvalho8, Carlos Veo8, Cristovam Neto8, Sandra M. Silva8, Paulo D'Amora1, Marcia Salzgeber1, Delcio Matos3, Celso R. Silva4, Jose R. Oliveira4, Iara Rabelo4, Patricia Yamakawa4, Rui Maciel2,5, Rosa Biscolla5, Maria Chiamolera5, Renato Fraietta6, Felipe Reis7, Marcelo Mori9, Dirce Marchioni10, Antonio Carioca10, Gustavo Maciel2,11, Renato Tomioka11, Edmund Baracat11, Clovis Silva12, Celso Granato2,13, Ricardo Diaz13, Bruno Scarpellini2,13, Daniel Egle14, Heidi Fiegl15, Irmgard Himmel15, Christina Troi16 and Robert Nagourney17

1Gynecology Department, College of Medicine of the Federal University of São Paulo (EPM-UNIFESP), São Paulo, Brazil

2Fleury Laboratories, São Paulo, Brazil

3Department of Surgery, Surgical Gastroenterology Division, College of Medicine of the Federal University of São Paulo (EPM-UNIFESP), São Paulo, Brazil

4Clinical and Experimental Oncology Department, Hematology and Hemotherapy Division, College of Medicine of the Federal University of São Paulo (EPM-UNIFESP), São Paulo, Brazil

5Department of Medicine, Endocrinology Division, College of Medicine of the Federal University of São Paulo (EPM-UNIFESP), São Paulo, Brazil

6Department of Surgery, Urology Unit, Human Reproduction Division, College of Medicine of the Federal University of São Paulo (EPM-UNIFESP), São Paulo, Brazil

7Biophysics Department, College of Medicine of the Federal University of São Paulo (EPM-UNIFESP), São Paulo, Brazil

8Barretos Cancer Hospital (HCB), Barretos, Brazil

9Department of Biochemistry and Tissue Biology, State University of Campinas (UNICAMP), Campinas, Brazil

10Nutrition Department, School of Public Health, University of São Paulo School of Medicine (FMUSP), São Paulo, Brazil

11Department of Obstetrics and Gynecology, University of São Paulo School of Medicine (HCFMUSP), São Paulo, Brazil

12Department of Pediatrics, Children’s Hospital, University of São Paulo School of Medicine (HCFMUSP), São Paulo, Brazil

13Retrovirology Laboratory, Infectious Diseases Unit, Medicine Department, College of Medicine of the Federal University of São Paulo (EPM-UNIFESP), São Paulo, Brazil

14Department of Obstetrics and Gynecology, Medical University of Innsbruck, Innsbruck, Austria

15Department of Gynecology, Meran Hospital, Meran, Italy

16Department of Gynecology, Brixen Hospital, Brixen, Italy

17Department of Obstetrics and Gynecology, Gynecological Oncology Unit, University of California Irvine (UCI), California, USA

Correspondence to:

Robert Nagourney, email: rnagourney@nagourneyci.com

Keywords: breast cancer; metabolism; prognosis; response; survival

Received: May 31, 2018     Accepted: July 12, 2018     Published: August 03, 2018

ABSTRACT

Breast cancer remains a leading cause of morbidity and mortality worldwide yet methods for early detection remain elusive. We describe the discovery and validation of biochemical signatures measured by mass spectrometry, performed upon blood samples from patients and controls that accurately identify (>95%) the presence of clinical breast cancer. Targeted quantitative MS/MS conducted upon 1225 individuals, including patients with breast and other cancers, normal controls as well as individuals with a variety of metabolic disorders provide a biochemical phenotype that accurately identifies the presence of breast cancer and predicts response and survival following the administration of neoadjuvant chemotherapy. The metabolic changes identified are consistent with inborn-like errors of metabolism and define a continuum from normal controls to elevated risk to invasive breast cancer. Similar results were observed in other adenocarcinomas but were not found in squamous cell cancers or hematologic neoplasms. The findings describe a new early detection platform for breast cancer and support a role for pre-existing, inborn-like errors of metabolism in the process of breast carcinogenesis that may also extend to other glandular malignancies.

Statement of Significance: Findings provide a powerful tool for early detection and the assessment of prognosis in breast cancer and define a novel concept of breast carcinogenesis that characterizes malignant transformation as the clinical manifestation of underlying metabolic insufficiencies.


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