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. 2016 Jun 28;7(26):39809-39822.
doi: 10.18632/oncotarget.9489.

Pharmacometabolomics study identifies circulating spermidine and tryptophan as potential biomarkers associated with the complete pathological response to trastuzumab-paclitaxel neoadjuvant therapy in HER-2 positive breast cancer

Gianmaria Miolo  1 , Elena Muraro  2 , Donatella Caruso  3 , Diana Crivellari  1 , Anthony Ash  4 , Simona Scalone  1 , Davide Lombardi  1 , Flavio Rizzolio  2 , Antonio Giordano  5 , Giuseppe Corona  2
Affiliations

Pharmacometabolomics study identifies circulating spermidine and tryptophan as potential biomarkers associated with the complete pathological response to trastuzumab-paclitaxel neoadjuvant therapy in HER-2 positive breast cancer

Gianmaria Miolo et al. Oncotarget. .

Abstract

Defining biomarkers that predict therapeutic effects and adverse events is a crucial mandate to guide patient selection for personalized cancer treatments. In the present study, we applied a pharmacometabolomics approach to identify biomarkers potentially associated with pathological complete response to trastuzumab-paclitaxel neoadjuvant therapy in HER-2 positive breast cancer patients. Based on histological response the 34 patients enrolled in the study were subdivided into two groups: good responders (n = 15) and poor responders (n = 19). The pre-treatment serum targeted metabolomics profile of all patients were analyzed by liquid chromatography tandem mass spectrometry and the differences in the metabolomics profile between the two groups was investigated by multivariate partial least squares discrimination analysis. The most relevant metabolites that differentiate the two groups of patients were spermidine and tryptophan. The Good responders showed higher levels of spermidine and lower amounts of tryptophan compared with the poor responders (p < 0.001, q < 0.05). The serum level of these two metabolites identified patients who achieved a pathological complete response with a sensitivity of 90% [0.79-1.00] and a specificity of 0.87% [0.67-1.00]. These preliminary results support the role played by the individual patients' metabolism in determining the response to cancer treatments and may be a useful tool to select patients that are more likely to benefit from the trastuzumab-paclitaxel treatment.

Keywords: breast; cancer; metabolomics; pharmacometabolomics; pharmacometabonomics.

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Conflict of interest statement

There are no conflicts of interests to declare.

Figures

Figure 1
Figure 1. Partial least squares discrimination analysis (PLS-DA) graph used to distinguish the metabolomics profile of the two groups GR (n = 15) and PR (n = 19)
Each point corresponds to the metabolomics profile of a patient.
Figure 2
Figure 2. Metabolites that produce the largest contribution in discriminating between GR and PR groups in the PLS-DA model, relative to the VIP score
Figure 3
Figure 3. Heatmap of the relative concentration of five metabolites with VIP > 1 in the serum of the GR and PR groups of patients according to the response to trastuzumab-paclitaxel treatment
Figure 4
Figure 4. Significance analysis of microarray plot sheet output (SAM) under the four sets of criteria: cutup = 3.916, cutlow = 3.914; false=0.07; FDR = 0.032; which are indicated at the upper right corner
The red, green, and black dots represent upregulated, downregulated, and insignificant metabolites.
Figure 5
Figure 5. Polyamine biosyntethic pathway and the mean concentration [μM] of metabolites among the GR and PR groups of patients
A p value of *p < 0.05 and **p < 0.001 was considered statistically significant. AdoMet: S-Adenosyl-Methionine, DC-AdoMet: Decarboxylated S-Adenosyl-Methionine, AdoT: S-AdenosylTransferase, AdoMDC: S-Adenosyl-Methionine Decarboxylase, ODC: Ornitine Decarboxylase, PAT(I and II): PropylAminoTransferase-1 and 2, ATP: AdenosylTriphosphate. SMA: S-MethylAdenosyl. PLP: Pyridoxal-5′-Phosphate, (*) Spermine and Spermidine can be inter converted to Putrescine in two steps catalized by the (1) Spermine/Spermidine-N-1-AcetylTransferase (SSAT); (2) Polyamine Oxidase (PO).
Figure 6
Figure 6. Tryptophan catabolic pathway and the mean concentration [μM] of metabolites among the GR and PR groups of patients
A p value of *p < 0.05 and **p < 0.001 was considered statistically significant. TH: Tryptophan Hydroxylase, AADC: Aromatic Amino Acid Decarboxylase, NAT: N-Acetyl Transferase, HMT: 5-Hydroxylindole-O-MethylTransferase, Indoleamine-2, 3 dioxygenase, F: Formamidase.
Figure 7
Figure 7. Receiving operating and scatter plots curve for (a) Spd, (b) Trp and (c) Trp/Spd ratio
Area under curve plots (95% confidence interval in brackets).
See this image and copyright information in PMC

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