Chemotherapy-induced peripheral neuropathy in breast cancer: a narrative review

Introduction

Breast cancer is the most common malignancy and leading cause of cancer-related death in women worldwide. Breast cancer mortality has decreased by 40% in the last three decades due to early detection and novel systemic therapies (1). Despite improvement in survival outcomes, drugs used in breast cancer can lead to short-term and long-term toxicities, compromising the quality of life of breast cancer survivors (2,3). Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating adverse effect of several chemotherapeutic agents used in the treatment of breast cancer. Furthermore, dose interruptions and early discontinuation of treatment due to CIPN can lead to decreased chemotherapy efficacy resulting in worse survival outcomes (4).

This review summarizes the current understanding of the mechanisms, clinical presentation, and management of CIPN in breast cancer. It also explores emerging areas of research, including racial disparities, biomarker development, and the role of the microbiome in CIPN, with the goal of guiding future strategies for risk stratification, prevention, and treatment. We present this article in accordance with the Narrative Review reporting checklist (available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-41/rc).

Methods

Design and rationale

This is a narrative review designed to synthesize clinical, mechanistic, and translational evidence on CIPN in breast cancer. A detailed methodology of our review can be found in Table 1. We searched PubMed/Medline, Embase, and the Cochrane Library from database inception through July 2025 using keywords for breast cancer, CIPN, drug classes, prevention/management, biomarkers, microbiome, and disparities, and screened reference lists. Eligible studies were English-language clinical or translational reports on CIPN in breast cancer (or mixed cohorts with extractable breast-cancer data); non-English without CIPN outcomes, purely preclinical work without translational linkage, and clinical studies unrelated to breast cancer were excluded.

The pathophysiology of CIPN with associated therapies

Taxanes

Paclitaxel, docetaxel, and albumin-bound paclitaxel (nab-paclitaxel) are common taxanes used in breast cancer treatment. The mechanism of taxane-induced peripheral neuropathy (TIPN) is multifactorial (5). Taxane-induced neurotoxicity preferentially affects sensory neurons, with sensory nerve conduction being impaired at lower cumulative doses than motor nerve conduction (6). Sensory afferent signals are transmitted by the sensory nerve fibers in the posterior gray column of the dorsal root ganglia (DRG). These sensory cell bodies are vulnerable to neurotoxic drugs, such as taxanes, because they are located exterior to the protective blood-nerve barrier (6). Taxanes cause structural changes in axonal mitochondria and destroy microtubules, restricting axonal transport and cell energy supply, and eventually causing cell death (7,8). Furthermore, reactive oxygens are generated from mitochondrial dysfunction, causing oxidative stress and subsequent neuropathic pain (9).

Nociceptive signaling is also upregulated with taxane use. Neuronal excitability occurs through complex interconnected signaling pathways. Voltage-gated Ca²⁺ channels and non-selective cation transient receptor potential (TRP) ion channels, such as the vanilloid transient receptor potential channel (TRPV4) and transient receptor potential ankyrin 1 (TRPA1), enable Ca²⁺ influx into cells and mediate nociceptive signaling (10,11). Paclitaxel has been shown to upregulate TRPA1 & TRPV4, thereby increasing intracellular Ca²⁺ release, oxidative stress, nociceptive signaling, and hyperalgesia (11-13). The interaction of paclitaxel with neuronal calcium sensor 1 (NCS1), a Ca²⁺ sensor that regulates baseline calcium levels, has a role in neuroprotective and regenerative processes. It is suspected that prolonged paclitaxel exposure induces NCS1 degradation leading to diminished intracellular calcium signaling and eventual sensory neuropathy (14,15).

Paclitaxel-induced nerve injury also recruits pro-inflammatory cytokines to sites of injury, further augmenting allodynia (16-22). Paclitaxel-induced upregulation of toll like receptor 4 (TLR4) signaling in DRG neurons leads to increased expression of C-C chemokine ligand 2 (CCL2), attracting monocytes to sites of injury and contributing to inflammation. Increased concentrations of pro-inflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-α) cause hyperalgesia to thermal and mechanical stimuli, and increase the release of bradykinin, serotonin, and histamine that further augment the pro-inflammatory process (22). TNF-α also specifically suppresses the signaling of spinal gamma-aminobutyric acid (GABA) neurons, leading to central disinhibition of pain signaling (16-20).

An observational study by Cimbro et al. found that TIPN occurred in 34.7% of patients treated with weekly paclitaxel at 4 weeks and 92.7% at 12 weeks, with a cumulative dose of 320 and 960 mg/m², respectively (23). A phase III study in patients with metastatic breast cancer reported that the mean cumulative dose to onset of grade ≥2 neurotoxicity was 371 mg/m² for docetaxel and 715 mg/m² for paclitaxel, with 13% of patients receiving docetaxel having to discontinue treatment due to neurotoxicity vs. 5% in the paclitaxel group (24).

Platinums

Platinum agents include first generation (cisplatin), second generation (carboplatin), and third generation (oxaliplatin) (25). Carboplatin is the most incorporated platinum in breast cancer treatment (26,27). Platinum agents exert their cytotoxic effects via cellular uptake into the nucleus, where they bind to G-C rich sites to form DNA strand cross-links that inhibit transcription, translation, and programmed cell death (28,29). This cytotoxic mechanism optimizes the anti-tumor effects of platinum agents but comes at a cost of off-target nerve damage. In the DRG and peripheral nerves, platinum complexes cause cellular apoptosis through the formation of DNA-adducts and direct DNA damage, which cellular machinery is unable to repair (25). In vitro studies show that platinums increase intracellular mitochondrial reactive oxygen species and induce demyelination of Schwann cells (30). Carboplatin is less neurotoxic than cisplatin and oxaliplatin; however, neurotoxicity can still occur with high doses (31). In vitro, carboplatin required a ten-fold higher drug concentration than cisplatin to induce equivalent cytotoxicity in rat sensory neurons (32). A post-mortem study of human sural nerves from cisplatin and carboplatin treated patients additionally demonstrated that cisplatin accumulates evenly in both peripheral nerves and ganglia, but carboplatin, even when given at a much higher dose, accumulates less in the ganglia than cisplatin (33). Ganglia are key sites of nerve damage in CIPN, which could explain why neurotoxicity is less severe with carboplatin use. Estimates vary widely, but chronic neurotoxicity rates are ~4–6%, 28–36%, and 15–20% for patients receiving carboplatin, cisplatin, and oxaliplatin, respectively (34,35).

Eribulin

Eribulin, a synthetic analogue of halichondrin B, belongs in the class of epothilones and inhibits the polymerization of tubulin and microtubules (36). The disruption of microtubules interferes with axonal transport and cytoplasmic flow in affected neurons, leading to peripheral neuropathy. CIPN attributed to eribulin is generally reversible but can last beyond 1-year in 5% of patients (37). The phase 3, open-label EMBRACE trial in patients with advanced breast cancer reported that CIPN occurred in 35% of all patients (grade 3/4 =9%) and was the most common adverse event leading to treatment discontinuation (36). More recently, the combination of eribulin with dual human epidermal growth factor receptor 2 (HER2) blockade was compared to the standard CLEOPATRA-based regimen of trastuzumab, pertuzumab and a taxane in the phase III EMERALD trial (38). Eribulin-based treatment resulted in higher any grade (61.2% vs. 52.8%) and grade ≥3 neuropathy (9.8% vs. 4.1%) (38).

Vinorelbine

Vinorelbine is a semisynthetic vinca alkaloid, a group of plant-derived cytotoxic agents that interfere with the polymerization of tubulin and inhibit microtubule assembly. It chemically differs from vinblastine, which is the most neurotoxic of the vinca alkaloids, by a substitution affecting the catharatine moiety (39). This change provides for its anti-tumor activity by allowing for the selectivity of mitotic microtubules and minimizes its neurotoxic potential by sparing axonal microtubules (40). Vinorelbine causes mild distal neuropathy that is dose-dependent and reversible with treatment discontinuation (39,41). Severe neuropathy is rare and occurs most often in patients with prior paclitaxel exposure (40).

Antibody drug conjugates (ADCs)

ADCs are a new therapeutic class that consist of a monoclonal antibody, a linker, and cytotoxic payload to allow for more targeted delivery of chemotherapy to tumor cells (42). Trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), sacituzumab govitecan, and datopotamab deruxtecan (Dato-DXd) are four ADCs that are approved for the treatment of breast cancer. T-DM1 and T-DXd consist of a humanized anti-HER2 monoclonal antibody which is linked to DM1, a potent maytansinoid microtubule inhibitor, or DXd, a topoisomerase I inhibitor (43). Sacituzumab govitecan and Dato-DXd are composed of an antitrophoblast cell-surface antigen 2 (Trop-2) IgG1 kappa antibody which is coupled to SN-38, an active metabolite of irinotecan and a topoisomerase I inhibitor, or DXd, respectively (44).

The risk of developing ADC-induced peripheral neuropathy is dependent on the cytotoxic payload and is the highest with payloads that are microtubule inhibitors. Nonspecific uptake of ADCs by peripheral nerves can cause destruction of microtubules that are involved in the maintenance of axonal transport and subsequent neurodegeneration (42,43). Therefore, patients treated with T-DM1 are more likely to develop peripheral neuropathy than those treated with T-DXd, sacituzumab govitecan, or Dato-DXd (42-44). A metanalysis by Jahan et al. of the GATSBY, KRISTINE and MARIANNE trials showed a 12.1% incidence of any grade peripheral neuropathy with T-DM1 (45). The relative risk (RR) of any grade peripheral neuropathy was still lower with T-DM1 than with systemic taxane therapy (RR 0.59; P=0.01) (45). The incidence of peripheral neuropathy for T-DXd, sacituzumab govitecan, and Dato-DXd is relatively low (any grade neuropathy: 13% with T-DXd, 12% with sacituzumab govitecan, 3.6% with Dato-DXd) with no grade 3 or 4 events seen in prior clinical trials (43,44,46,47).

The pathophysiologic mechanisms of the therapies discussed in this review are summarized in Figure 1.

Figure 1 Physiological mechanisms of chemotherapy-induced peripheral neuropathy. Created in BioRender.com. Dato-DXd, datopotumab deruxtecan; T-DXd, trastuzumab deruxtecan.

Clinical presentation of CIPN

The clinical presentation of CIPN ranges from numbness and tingling to severe neuropathic pain and functional impairment. These symptoms can lead to dose reduction, dose delay, and early discontinuation of chemotherapy disrupting timely delivery of chemotherapy, which results in decreased treatment efficacy and worse survival outcomes (4).

Furthermore, CIPN can persist after chemotherapy is completed, contributing to chronic morbidity among survivors. A study of 646 breast cancer survivors showed that 59.4–93.3% of patients with moderate-severe TIPN reported clinically relevant impairments in physical functioning (48). Another study found that after 3.6 years post-treatment at least one sensory or motor neuropathy symptom remained persistent in 57.5% and 61.0% of patients, respectively (49).

Risk factors for CIPN

Many different clinical factors have been associated with increased CIPN risk. In this review we will highlight a few common risk factors found in our literature search.

Age

The association of older age with CIPN risk has been demonstrated repeatedly (50,51). A prospective study of 350 breast cancer patients receiving taxanes found increased neuropathy risk with older age [age 45–59 years, odds ratio (OR) =5.12; age ≥60 years, OR =9.37] (52). Rattanakrong et al. showed increased sensory and motor TIPN risk with age ≥60 years in breast cancer patients as well [hazard ratio (HR) =1.02; 95% confidence interval (CI): 1.01–1.05, P=0.02 and HR =1.05; 95% CI: 1.01–1.08, P=0.01] (53). The mechanism of CIPN susceptibility with age is likely multifactorial, including, but not limited to, reduced nerve regenerative capacity (54), chronic inflammation preventing neuron repair (55), comorbidities (51), alterations in metabolism (56) and nutritional deficiencies (57).

Body mass index (BMI)

A recent meta-analysis on the dose-response relationship between BMI and CIPN found that among 10 studies, and 6,481 patients, the relative risk of CIPN increased by 15% for every additional 5 kg/m² BMI. Higher BMI was associated with CIPN risk (OR =1.55, 95% CI: 1.20–1.99) (58). Conversely, lower fat mass may be a protective factor against CIPN (59). The pathophysiology of CIPN susceptibility and BMI is complex, but obesity associated chronic inflammation, altered pharmacokinetics, altered microbiome composition, changes in immune response, and comorbidities are possible contributors (51,60-62).

Vitamin D deficiency

Lixian et al. reported a strong association between CIPN risk and vitamin D deficiency (OR =6.214) (52). Vitamin D deficiency has been reported as a CIPN risk factor in other studies well (63,64), but prospective data on vitamin D supplementation to prevent CIPN is lacking. Activated vitamin D plays a role in neuroprotection, neuroregeneration, and nociceptive signaling (65,66), which may elucidate higher rates of CIPN with low vitamin D levels.

Race & genetics

Notably, the rate of development of TIPN is not homogenous across the breast cancer population. Blacks develop TIPN at higher rates even when controlling for co-morbidities and environmental factors (67). A retrospective review of the ECOG 5103 trial illustrated that patients of genetically African ancestry were more likely than other races to experience grade 2–4 (HR =2.1; P=5.6×10⁻¹⁶) and grade 3–4 (HR =2.6; P=1.1×10⁻¹¹) TIPN (67). The mechanism for this difference is uncertain. There have been several studies investigating the intersection of genetic polymorphisms and CIPN, but high-quality evidence demonstrating an association is lacking (68). A study reported the association of grade 2–4 TIPN in Black patients with the single nucleotide polymorphism (SNP) rs1856746 (P=1.6×10⁻⁷; OR =5.5) (67) near the FCAMR gene, which mediates immunoglobulin A and M (IgA/IgM) binding activity and transmembrane signaling receptor activity upstream of immune responses (69). A follow-up study highlighted the association between grade 3–4 TIPN and the gene set binding factor 2 (SBF2) (P=4.35×10⁻⁶) (70). Based on these results, the ECOG-ACRIN EAZ171 trial prospectively tested whether a predefined high risk (SBF2) versus low-risk (FCAMR) neuropathy genotype panel could discriminate TIPN risk in Black women. However, this study found no association between genotype and TIPN risk (71). Instead, the study found that schedule/agent selection exerts a larger effect on neuropathy risk than known germline variants, with grade ≥3 TIPN and dose reductions being more common with weekly paclitaxel vs. every-3-week docetaxel (9.4% vs. 1.7%; P=0.01 & 28.1% vs. 8.5%; P<0.001, respectively) (71). These results tempered enthusiasm for employing genetic panels in the clinical care of Black patients.

Racial differences in levels of baseline inflammation could also contribute to deferential development of TIPN in Blacks. Studies have documented that Blacks can have significantly higher baseline levels of inflammatory markers. Baseline IL-6 (pg/mL) in Blacks was 2.7±0.4 compared to 1.7±0.2 in Whites (P<0.05). CRP (mg/L) was 17.2±1.3 in Blacks vs. 13.2±0.7 and 13.4±0.7 in Hispanics and Whites, respectively (72,73). Another systematic review of population-based studies found a positive association between non-European ethnic background and higher baseline CRP levels, independent of socioeconomic and lifestyle factors (74). Given the inflammatory mediated pathophysiology of CIPN, it is plausible that these racial differences in baseline inflammation contribute to TIPN racial disparities.

Treatment and prevention of CIPN

Data on therapies evaluated for the treatment and prevention of CIPN is limited by the small sample sizes of patients, inconsistent scales used to measure neuropathy, and the heterogeneity of therapy dosing and follow-up time. The 2020 American Society of Clinical Oncology (ASCO) consensus guidelines on the prevention and management of CIPN reported moderate evidence to support the use of duloxetine for the treatment of CIPN. No recommendations could be made on non-pharmacologic approaches (i.e., exercise, acupuncture, cryotherapy) for the treatment of CIPN. There was additionally no sufficient evidence to recommend the use of a preventative treatment for neuropathy (75). Data for the pharmacologic approaches to managing CIPN are summarized in Table 2.

Pharmacologic approaches for the treatment and prevention of CIPN

Neurotransmitter-based therapy

Duloxetine is currently the only medication that is recommended by ASCO for the treatment of CIPN (75). This recommendation is based on three clinical trials comparing the use of duloxetine to placebo, venlafaxine, and vitamin B12, respectively (76-78). Duloxetine is a serotonin-norepinephrine reuptake inhibitor (SNRI), a class of medications that are traditionally used to treat major depressive disorder but also approved for the treatment of diabetic peripheral neuropathy. SNRIs are thought to decrease pain transmission by increasing the synaptic concentrations of serotonin and norepinephrine, thereby decreasing the input to the descending inhibitory nociceptive pathway (88,89). In a trial enrolling 231 patients across 8 National Cancer Institute-funded research networks (78), Smith et al. demonstrated that five weeks of duloxetine significantly improved Brief Pain Inventory-Short Form (BPI-SF) mean pain scores in comparison to placebo (mean difference in average pain score 0.73, 95% CI: 0.26–1.20). Duloxetine was compared against venlafaxine (another SNRI) and placebo in a single-center randomized trial including 156 patients. Decreased neuropathy was seen in both the venlafaxine and duloxetine groups, with a more pronounced decrease in the duloxetine group (P<0.05) (76). Duloxetine is relatively well tolerated with mild side effects that can include fatigue, nausea, constipation, and changes in sleeping patterns (88).

Venlafaxine has also been evaluated in the prevention of CIPN. A phase II randomized, placebo-controlled trial of 50 patients undergoing oxaliplatin-based chemotherapy showed no significant benefit with venlafaxine in preventing CIPN (P=0.55) (90).

Tricyclic antidepressants (TCAs) such as amitriptyline and nortriptyline also work by blocking the reuptake of serotonin and norepinephrine. TCAs are used for the treatment of a variety of neuropathic pain states (91), but unfortunately, the benefits of TCAs have not translated in the management of CIPN. Two randomized trials showed no significant improvement in paresthesia or pain with the TCAs amitriptyline and nortriptyline (79,80). TCAs also carry a significant side-effect profile because of their anti-cholinergic, antihistaminic, and peripheral anti-alpha-1-adrenergic effects (92).

Gabapentinoids

Gabapentinoids, such as gabapentin and pregabalin, bind to the alpha2-delta protein on presynaptic voltage-gated calcium channels on neurons and prevent the release of excitatory neurotransmitters (93). Gabapentin and pregabalin are often used off-label in the management of neuropathic pain (94). No guidelines for the use of gabapentinoids in the prevention and treatment of CIPN have been provided in prior ASCO guidelines given heterogeneous data and conflicting results from past trials (75). Two placebo-controlled, randomized crossover trials including 141 patients did not identify any benefit with gabapentin or pregabalin as compared with placebo (81,82). These findings contradict a randomized study by Manjushree et al. comparing gabapentin to pregabalin in 70 patients that showed equivalent efficacy (P<0.001) of both medications with significant improvement in intensity and quality of neuropathic pain (83). Avan et al. and Salehifar et al. also demonstrated that pregabalin offered a similar quality of life benefit to duloxetine and provides superior control of neuropathic pain (pain improvement of 92.5% with pregabalin, 38.1% with duloxetine, P<0.001) in breast cancer patients treated with taxane-based chemotherapy (84,85). The discrepancy in the efficacy results for gabapentinoids from prior trials may be explained by variation in the type and dose of chemotherapy received by patients, the dose of gabapentinoids and duloxetine given to patients, the timing of starting treatment, and the duration of follow-up (95). Somnolence and dizziness are the main side effects that have been associated with gabapentinoids. These were generally mild and did not lead to treatment discontinuation (81,82,84,85,95).

The use of pregabalin in the prevention of CIPN has been evaluated in two placebo-controlled trials. One trial showed that pregabalin was not superior to placebo in preventing TIPN in 46 breast cancer patients (average pain score 2.6 vs. 2.2, P=0.48) (96).

Topical anesthetics

Topical anesthetic combinations have been explored to optimize neuropathic pain control without encountering the risk of cumulative side effects with oral administration (97). A phase III placebo-controlled trial of 462 patients reported no improvement in CIPN when comparing topical 4% amitriptyline plus 2% ketamine, a NMDA receptor antagonist, versus placebo (adjusted mean difference in pain scores =−0.17, P=0.36) (86). Similarly, another study evaluating the combination of topical baclofen (a GABA receptor agonist) 10 mg, amitriptyline HCL 40 mg, and ketamine 20 mg in 203 patients did not show significant improvement in CIPN control with topical treatment as compared to placebo (P=0.195) (87). Topical high-dose 8% capsaicin, a TRPV1 agonist, has shown some efficacy in small single-center studies. One study evaluating 8% capsaicin in 18 patients receiving oxaliplatin-based chemotherapy showed pain reduction of 84% in patients taking lower doses of oxaliplatin and 97% in patients taking larger doses of oxaliplatin (98). Another study involving 16 patients with a chronic history of CIPN similarly found a significant reduction in spontaneous pain (mean pain reduction −1.27; 95% CI: 0.2409 to 2.301; P=0.02) (99). These results have not been validated in larger clinical trials.

Other medications

Ganglioside-monosialic acid (GM-1) is a glycolipid that plays a role in the process of neurogenesis, nerve development and differentiation and signal transduction (100). Preclinical studies have shown that exogenous GM1 can promote the recovery of neurotic processes in injured nerve cells (101). A placebo-controlled, double-blind study in 183 patients treated with taxane-based chemotherapy for early-stage breast cancer also showed a significant reduction in the severity and incidence of CIPN (P<0.001) (100). The placebo group in this trial did not suffer from long-term CIPN, making the results difficult to interpret without confirmatory trials (75).

Nonpharmacologic treatment of CIPN

Exercise, acupuncture, cryotherapy and scrambler therapy are all nonpharmacologic treatments that have been evaluated for the management of CIPN. The variability in individual programs and the difficulty in conducting rigorous, placebo-controlled trials have precluded consensus guidelines on these interventions (75). Given the low potential for harm, these interventions may be reasonable to suggest to patients until further trials are completed to evaluate their efficacy.

Physical exercise

Exercise has been shown to influence neurologic factors implicated in the development of CIPN by enhancing the expression of neurotrophic factors, reducing inflammation, and regulating mitochondrial dysfunction (102). Randomized controlled trials (RCTs) evaluating exercise-based interventions vary in the type of exercise program used, the frequency and duration of the program, and the timing of program initiation relative to chemotherapy. A large retrospective cross-sectional study including 5,444 breast cancer survivors post-chemotherapy showed that exercise, defined as ≥5 days of moderate or ≥3 days of strenuous exercise per week, decreased the prevalence of CIPN (28% among exercisers vs. 38% among non-exercisers, P<0.001) and that this reduction in CIPN prevalence was dose-dependent (42% for <6 MET-hours/week, 33% for 6–20.24 MET-hours/week, 29% >20.25 MET-hours/week; P<0.001) (103). A recent systematic review and meta-analysis of four RCTs comprising 171 patients additionally illustrated that exercise before and/or during taxane-containing chemotherapy reduced CIPN symptoms compared to usual care (standardized mean difference =−0.71; P=0.012) (102).

Acupuncture

Acupuncture is an intervention in which fine metallic needles are inserted into anatomic locations of the body to stimulate the central and peripheral nervous system (104). Two RCTs have been performed investigating the use of acupuncture in breast cancer patients treated with taxane-based chemotherapy. One study randomized 180 patients to receive 12 electro-acupuncture or sham weekly treatments concurrent to taxane treatment and found no difference in pain or neuropathy between both groups at week 12 (BPI-SF pain severity score 2.6 vs. 2.8, respectively, P=0.86) (105). The acupuncture group additionally had higher pain scores than the sham group at week 16 (BPI-SF pain severity score 3.4 vs. 1.7, respectively, P=0.03), suggesting against the use of acupuncture for CIPN prevention given slower recovery times (105). However, another RCT of 40 patients who underwent an 8-week acupuncture treatment regimen showed a significant improvement in neuropathic pain and sensory symptoms (BPI-SF pain severity score −1.1±1.7 vs. 0.3±1.5, respectively; P=0.03) (104). A systematic review and metanalysis by Chien et al. including 386 patients from six randomized clinical trials showed that acupuncture improved pain scores (BPI-SF mean worst pain score reduction −1.21, P<0.001) and nervous system symptoms (Functional Assessment of Cancer Therapy/Neurotoxicity score reduction: −2.02, P<0.00001) (106).

Cryotherapy

Cryotherapy involves cooling the skin surface (with cooling gloves or socks) to limit the local toxicity of chemotherapy (107). One prospective trial including 36 women being treated with weekly paclitaxel for breast cancer evaluated the use of cryotherapy with patients wearing frozen gloves and socks on their dominant side before, during and after each infusion. Cryotherapy in the dominant side decreased the incidence of objective and subjective CIPN in comparison to the control nondominant side (change in tactile sensitivity hand: 27.8% vs. 80.6%, P<0.001; foot: 25% vs. 63.9%, respectively, P<0.001) (108). Data from subsequent trials have been mixed, in part due to the various methods of administering cryotherapy across trials.

Compression therapy

Compression therapy has been evaluated independently and as an addition to cryotherapy in the prevention of CIPN. The combination of cryotherapy and compression study was evaluated in a single-arm trial of 13 patients that showed that combined therapy was more efficacious than either treatment alone (decrease in sensory nerve amplitude −28.1%±21.9%) (109). A phase IIb trial that randomized 63 patients to receive cryotherapy, compression therapy or placebo during taxane-based treatment showed that compression therapy was superior to cryotherapy and placebo in CIPN prevention (<5-point decrease in the Functional Assessment of Cancer Therapy Neurotoxicity 64.7% with compression vs. 41.1% cryotherapy vs. 41.1% placebo) (110). The POLAR trial, another RCT, randomized 101 patients to cooling or compression of the dominant hand and showed a significant reduction in high-grade CIPN with both modalities (grade ≥2 CIPN: 29% with cooling vs. 50% with placebo, P=0.002; and 24% with compression vs. 38% with placebo, P=0.008) (111). The European Society of Medical Oncology (ESMO) guidelines state that both cryotherapy and compression therapy can be considered as preventive strategies for CIPN (112).

Future directions

Microbiome

To better elucidate the pathophysiology of inflammation in CIPN, there is a burgeoning area of research investigating the role of the gut microbiome in mediating inflammation and the contribution of microbiota dysbiosis to chemotherapy-related adverse events. The gut microbiome has been shown to be an important mediator of inflammatory cytokine release, intestinal epithelial integrity, and neural messaging via the gut-brain axis. The involvement of the gut microbiome in systemic inflammation has relevance given the role pro-inflammatory cytokines play in the development of CIPN.

Mucosal tissue in the gastrointestinal (GI) tract contains a vast neural network, the enteric nervous system (ENS), that interacts with immune mediators that are integrated into the mucosal barrier to maintain host defense and mucosal homeostasis. The ENS communicates with the gut microenvironment and is sensitive to changes in microbial composition and direct GI mucosal toxicity (113). Enteric glial dysfunction from chemotherapy can result in compromised mucosal defense and propagation of systemic inflammatory responses. Direct gut toxicity from chemotherapy can additionally reduce microbial diversity and disrupt the natural balance of the microbiome in favor of pro-inflammatory species (114). A study evaluating gut microbiome response to chemotherapy in breast cancer patients reported significant changes in beta diversity and taxa abundance with chemotherapy use (P<0.05, P<0.0001, respectively). Furthermore, greater change in microbial taxa positively correlated with TNF-α (β=0.16, P<0.05), suggesting an association between taxa shifts and increased inflammation (115).

The interplay between microbiota dysbiosis and TIPN has been described in mice. B6 and 129SvEv mice, which are phenotypically more sensitive and resistant to paclitaxel-induced pain, respectively, were injected with 4 mg/kg paclitaxel. Gut microbiotas were collected from each species of mouse prior to antibiotic depletion of the gut microbiome. The authors transplanted the fecal microbiome of one mouse species into the other and discovered that the B6 mice became more resistant to paclitaxel-induced pain and the 129SvEv mice became more sensitive (116). There have been studies using probiotics to prevent or reduce the effects of TIPN. Mice given probiotic SLAB51 evidenced decreases in TNF-α, IL-1β, and IL-6 concentrations (P<0.005, P<0.0001, P<0.005 vs. paclitaxel respectively) in conjunction with improved allodynia (P<0.005) (117).

Data on TIPN and the microbiome in humans is less robust, but one study of 45 patients who received taxane-based therapy found β-diversity post treatment and differential abundance of Clostridiaceae family were associated with TIPN (P=0.013) (118). Insights into the relationship between the microbiome and TIPN are relevant, because they could guide targeted interventions to improve gut health and enhance supportive care options. Evidence also shows racial variations in microbiome composition. A study which examined microbiomes from Blacks and Whites found that at the family level, beta diversity was different by race (P=0.033) (119). A separate study comparing Blacks, Whites, Hispanics, and Asians found distinct relative abundance of dominant microbial families for each ethnicity (P<0.047) (120).

Biomarkers

Researchers have devoted significant effort to identifying ways to predict the onset of CIPN through biomarker testing. Because inflammation plays a role in the pathophysiology of CIPN, cytokines have been studied extensively in preclinical models (121). A study of 50 rats treated with 4 mg/kg paclitaxel found that compared to control rats, treated rats demonstrated allodynia at 31 days and significant increases in plasma levels of IL-1α, IL-1β, IL-6, TNF-α, INF-γ. A single dose of 6 mg/kg etanercept, a TNF-α blocking agent, attenuated allodynia at 24- and 48-hour post-drug treatment (P<0.01, P<0.001 respectively). In a separate study, gene expression of complement component 5a receptor 1 (C5aR1), a protein which binds paclitaxel and induces the pro-inflammatory NFkB/p38 pathway, was shown to be upregulated in mice 15 days post-paclitaxel treatment. Inhibition of C5aR1 improved TIPN compared to controls and resulted in significantly decreased expression of TNF-α, IL-1β, and IL-6 (122).

There have been a limited number of human studies investigating the efficacy of anti-inflammatory drugs in mitigating CIPN. One study evaluated loratadine in patients receiving vinca alkaloids based on preclinical trials showing that loratadine downregulates pro-inflammatory gene expression and antihistamines have anti-neuropathic effects (123,124). Investigators found that after 3 cycles of chemotherapy there was worse neuropathy (P<0.002) and increased concentrations of IL-1β and TNF-α (D20.05 pg/mL, D122.63 pg/mL, P<0.001, respectively) in controls, but attenuated change in IL-1β (D5.33 pg/mL, P<0.05) and improved neuropathy in the intervention group (125). These results suggest that modulating inflammation could improve neuropathy outcomes; however, more studies are required to confirm these results. Furthermore, a study in breast cancer patients of 55 patients receiving taxanes for at least 6 weeks found an association between increased baseline concentration of IFN-γ and worse neuropathy symptoms at completion of treatment (β=1.16; 95% CI: 0.23–2.09; P=0.016) (126). However, whether cytokines can be monitored to predict CIPN onset remains an open question.

Predictive biomarkers that correlate with severity of CIPN are lacking. Nerve growth factor (NGF), among the more well-defined biomarkers, promotes the survival and differentiation of sensory and sympathetic neurons and also has protective, regenerative, and nociceptive functions (127). A study by Cavaletti et al. found that decreased NGF levels negatively associated with CIPN severity (r=−0.579; P<0.001; 95% CI: −0.702 to −0.423) but did not find baseline NGF to be predictive for the development of CIPN (128,129).

Neurofilament light chain (NFL), another well described biomarker in CIPN, is a component of neurofilament, a protein involved in neuronal cytoskeleton integrity and function. Increased NFL levels have been associated with neurodegenerative diseases (130,131). Consequently, studies have assessed the role of NFL as a biomarker for CIPN, with some longitudinal studies showing a positive correlation between NFL levels and severity of CIPN. A study of 59 breast cancer patients receiving paclitaxel found serum NFL >85 pg/mL at week 3 of treatment independently predicted the development of grade 2–3 TIPN at week 12 (132). An analysis of two studies of breast cancer patients receiving taxanes found NFL concentrations were strongly associated with the cumulative dose of chemotherapy (r=0.869, P=4.5×10⁻¹⁹ & r=0.932, P=2.0×10⁻¹³), but weak to moderately associated with EORTC CIPN20 motor subscores (r=0.30 and 0.40) and sensory subscores (r=0.67 and 0.34) (133). One study demonstrated paclitaxel to be associated with an early mid-treatment increase in NFL levels, which remained significantly elevated at completion of chemotherapy (134). These studies show a potential role for NFL as a predictive biomarker for CIPN, but larger trials are needed to confirm an association between NFL and objective CIPN assessments.

Strengths & weaknesses

This review provides an up-to-date analysis on the pathophysiology, epidemiology, and available treatments for CIPN in contemporary breast cancer therapies. Notably, we have highlighted underrepresented aspects of CIPN research, including the roles of racial disparities, biomarkers, and the microbiome in modulating neuropathy risk—areas that may provide valuable data to develop new preventive and therapeutic strategies. We have also drawn attention to the CIPN risks associated with ADCs that may be overlooked compared to well-known traditional chemotherapy. The scope of the review, while intentionally broad to reflect the multifactorial nature of CIPN, does not allow for deep analysis of any single mechanistic pathway or therapeutic approach, and there is by necessity some omissions. This review was conducted as a narrative synthesis rather than a systematic or scoping review. Selection and confirmation biases in studies chosen are possible. Additionally, limiting the review to English-language studies may omit relevant findings published in other languages.

Discussion

CIPN continues to pose a major challenge to oncologic care and the therapeutic landscape remains sparse despite decades of research. Duloxetine remains the only guideline-directed pharmacologic intervention to treat CIPN, but its therapeutic benefit is limited to partial relief in some patients. While several nonpharmacologic modalities—particularly cryotherapy and compression therapy—have shown promising results, their generalization is limited by the absence of uniform cooling or compression parameters. Furthermore, the lack of interventions that prevent CIPN is an unmet need for our patients with breast cancer. Clinicians and patients could benefit from standardized protocols that can be easily integrated into the workflow of infusion units. A multimodal approach to treatment may be preferable in the absence of an effective targeted therapy.

Novel approaches to treating CIPN are necessary given the paucity of benefit from existing therapies. Translating emerging data on inflammation into large biomarker-driven trials that longitudinally track inflammatory markers during treatment could be one approach to evaluate anti-inflammatory agents against standard care. Such studies could determine whether modulating inflammation prevents CIPN and, in parallel, establish a cost-effective framework for monitoring neuropathy onset and adapting treatment in real time. The incorporation of serial biomarker assessments into clinical trials would allow investigators to delineate patterns of inflammation during treatment and identify high-risk patients enabling early, personalized intervention before irreversible CIPN occurs.

With increasing recognition of the gut microbiome as a modulator of neurotoxicity risk, another approach to CIPN mitigation could be to examine whether the prevention of chemotherapy-induced dysbiosis (using prebiotics or probiotics) can mitigate CIPN. Future microbiome-focused CIPN trials should include comprehensive microbial profiling before, during, and after chemotherapy to identify shifts associated with inflammation and symptom development. Moreover, combining microbiome modulation with dietary interventions or anti-inflammatory agents could offer a multifaceted, low-toxicity approach to CIPN prevention.

Emerging evidence also suggests that racial differences may influence susceptibility to CIPN through genetic polymorphisms affecting drug metabolism and inflammatory responses. However, high-quality data on this topic is limited. Future CIPN trials would benefit from greater inclusion of racial minorities, particularly Black patients, who face disproportionate breast cancer morbidity and mortality yet comprised only 1–3% of participants in breast cancer trials as of 2019 (135,136).

Conclusions

CIPN remains a common, dose-limiting toxicity in breast cancer care with persistent effects on function, quality of life, and treatment delivery. Risk increases with cumulative dose and is modified by host factors. Preventive strategies with consistent clinical benefit are lacking. For symptomatic management, duloxetine has the most reliable evidence for pain reduction; trials for other non-pharmacologic approaches such as exercise, acupuncture, and cryotherapy have shown heterogeneous results and should be framed as adjunctive.

Clinically, best practice centers on proactive risk communication, baseline assessment, and routine surveillance using patient-reported outcome measures. Early recognition should trigger shared decision-making around dose modification, schedule adjustment, or alternative therapies.

Further research based on biomarker-informed designs that test anti-inflammatory or neuroprotective strategies, as well as microbiome-targeted interventions, may accelerate clinical breakthroughs. For trials, priority recruitment of patients from high-risk racial groups is critical to reduce disparities in CIPN burden.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-41/rc

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Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-41/coif). The authors have no conflicts of interest to declare.

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