Machine-Learning Analysis of Serum Proteomics in Neuropathic Pain after Nerve Injury in Breast Cancer Surgery Points at Chemokine Signaling via SIRT2 Regulation

Abstract

Background: Persistent postsurgical neuropathic pain (PPSNP) can occur after intraoperative damage to somatosensory nerves, with a prevalence of 29–57% in breast cancer surgery. Proteomics is an active research field in neuropathic pain and the first results support its utility for establishing diagnoses or finding therapy strategies. Methods: 57 women (30 non-PPSNP/27 PPSNP) who had experienced a surgeon-verified intercostobrachial nerve injury during breast cancer surgery, were examined for patterns in 74 serum proteomic markers that allowed discrimination between subgroups with or without PPSNP. Serum samples were obtained both before and after surgery. Results: Unsupervised data analyses, including principal component analysis and self-organizing maps of artificial neurons, revealed patterns that supported a data structure consistent with pain-related subgroup (non-PPSPN vs. PPSNP) separation. Subsequent supervised machine learning-based analyses revealed 19 proteins (CD244, SIRT2, CCL28, CXCL9, CCL20, CCL3, IL.10RA, MCP.1, TRAIL, CCL25, IL10, uPA, CCL4, DNER, STAMPB, CCL23, CST5, CCL11, FGF.23) that were informative for subgroup separation. In cross-validated training and testing of six different machine-learned algorithms, subgroup assignment was significantly better than chance, whereas this was not possible when training the algorithms with randomly permuted data or with the protein markers not selected. In particular, sirtuin 2 emerged as a key protein, presenting both before and after breast cancer treatments in the PPSNP compared with the non-PPSNP subgroup. Conclusions: The identified proteins play important roles in immune processes such as cell migration, chemotaxis, and cytokine-signaling. They also have considerable overlap with currently known targets of approved or investigational drugs. Taken together, several lines of unsupervised and supervised analyses pointed to structures in serum proteomics data, obtained before and after breast cancer surgery, that relate to neuroinflammatory processes associated with the development of neuropathic pain after an intraoperative nerve lesion.

Targeting Members of the Chemokine Family as a Novel Approach to Treating Neuropathic Pain

“…This chemokine is expressed by the endothelium, macrophages, and Th17 lymphocytes [135]. In 2022, it was reported that in patients who developed persistent postoperative neuropathic pain (PPSNP) after breast cancer surgery, the level of CCL20 was increased [136]. Moreover, other recently published data have shown that a high level of CCL20 is strongly associated with thermal allodynia in patients after traumatic nerve injuries [137].…”

“…CCR9 is a selective target for CCL25. The role of the CCL25/CCR9 axis in the development of neuropathy requires research; however, in 2022, it was shown that in the CSF of patients who developed postoperative neuropathic pain after breast cancer surgery, an enhanced level of CCL25 was observed [136].…”

Artificial Intelligence and Machine Learning in Cancer Related Pain: A Systematic Review

“…Neural Networks (NN) [33], [25], [34], [26], [27], [28], [51], [52], [16], [10], [46], [38], [53], [54], [55], [56], [31] Composed of node layers, containing an input layer, one or multiple hidden layers and an output layer. Could be supervised, unsupervised or semi-supervised.…”

“…Their study highlighted that global DNA methylation held a comparable diagnostic accuracy for persistent pain, compared to established non-genetic predictors. Finaly, Lotsch et al (2022) [53] explore the potential of ML techniques such as (PCA, NN, RF) to identify proteins that distinguish patients with persistent postsurgical neuropathic pain (PPSNP). The study revealed 19 proteins that showed significant differences between the groups, marking a key finding.…”

Contribution of immune cells to cancer-related neuropathic pain: An updated review

“… 11 , 12 , 13 Taking breast cancer for example, the causes of pain include surgical outcome, tumor spread, bony metastasis to the spine, and chemotherapy. 14 , 15 It is worthy to mention that cancer-related neuropathic pain is generally associated with poor outcomes. 16 , 17 Of interest, Rayment et al have reported that cancer patients with neuropathic pain have worse physical, cognitive, and social functioning.…”