Lack of Vitamin D May Increase Chemo-Induced Neuropathy Risk in Breast Cancer

CancerNetwork^® originally published this article. This version is lightly edited.

Breast cancer with lymphatic involvement | Image Credit: Axel Kock - stock.adobe.com

Patients with breast cancer who have a vitamin D deficiency prior to receiving paclitaxel treatment are more likely to experience chemotherapy-induced peripheral neuropathy (CIPN), according to data from a biomarker analysis of the phase 3 SWOG S0221 study (NCT00070564) that was published in Journal of the National Comprehensive Cancer Network.¹

In a population of 1191 patients with early-stage breast cancer, 20.7% who had a vitamin D deficiency experienced grade 3 or higher sensory CIPN compared with 14.2% of patients with sufficient vitamin D levels (OR, 1.57; 95% CI, 1.14-2.15; P = .005), according to findings from the primary univariate analysis. The association was maintained after adjusting for age and chemotherapy treatment schedule, the investigators reported (adjusted OR [aOR], 1.65; 95% CI, 1.18-2.30; P = .003). However, significance was lost after adjusting for self-reported race (aOR, 1.39; 95% CI, 0.98-1.97; P = .066).

Older patients (OR, 1.02; 95% CI, 1.01-1.04; P = .005), those who self-reported being Black (OR, 2.48; 95% CI, 1.57-3.86; P < .001), those of other races (OR, 1.84; 95% CI, 1.06-3.07; P = .025), and those randomized to receive paclitaxel twice weekly (OR, 2.37; 95% CI, 1.73-3.29; P < .001) had more CIPN events.

“These results suggest that vitamin D supplementation in patients with lower levels of vitamin D may reduce peripheral neuropathy, and particularly high-grade peripheral neuropathy, which would improve these patients’ long-term quality of life,” said senior researcher Daniel L. Hertz, PharmD, PhD, University of Michigan College of Pharmacy, in a press release on the analysis’ findings.² “There are barely any negative consequences that come from taking steps to increase vitamin D levels. Patients can easily take safe, inexpensive, and widely available over-the-counter supplements.”

Investigators analyzed data from the randomized phase 3 SWOG S0221 trial in which different chemotherapy dosing schedules were examined in 2849 eligible patients with early-stage breast cancer. Of that population, 1620 had a minimum of 2 available serum samples, and 1191 patients were selected for the biomarker analysis.

The results were adjusted based on age, body mass index, and race. The researchers found that vitamin D deficiency (OR, 8.56; 95% CI, 5.44-13.92; P < .001) and CIPN incidence (OR, 2.48; 95% CI, 1.57-3.86; P < .001) were more prevalent in Black patients (77.1% and 29.4%, respectively) than White patients (28.2% and 14.3%).

When investigators assessed mechanical hypersensitivity based on vitamin D deficiency in mice, they reported that a vitamin D–deficient diet resulted in neurotoxicity-like symptoms.

CIPN affects up to 70% of patients who receive paclitaxel. Despite this, there are no established treatments that prevent or treat CIPN or alleviate its sensory or motor symptoms. Pretreatment with vitamin D is the first validated and potentially modifiable biomarker that may reduce the chances of experiencing CIPN from paclitaxel.

Investigators reported several limitations of the analysis. Firstly, although there was evidence that vitamin D deficiency was more prevalent in Black patients, the researchers acknowledged there was a limited number of non-White participants in their analysis. Larger populations are needed to continue to understand the link between race, vitamin D, and CIPN. Further analysis may come from the phase 2 EAZ171 trial (NCT04001829), which will be examining options to reduce CIPN following docetaxel or paclitaxel in African American patients with stage I to III breast cancer.

In addition, because data were received from another study and S0221 did not include patients who experienced grade 2 CIPN or document detailed paclitaxel dosing information, misclassification of CIPN grades could have occurred.

Secondly, even though Common Terminology Criteria for Adverse Events (CTCAE) is considered less sensitive for detecting subjective toxicities, the researchers chose to use CTCAE data rather than patient-reported outcomes as the primary CIPN end point because CTCAE were available in all patients in the study. Additionally, there was no data collection of other CIPN risk factors, such as preexisting peripheral neuropathy and diabetes.

Therefore, additional trials are needed to determine whether sufficient vitamin D levels prevent CIPN and improve treatment outcomes in patients with breast and other cancer types.

References

1. Chen CS, Zirpoli G, Barlow WE, et al. Vitamin D insufficiency as a risk factor for paclitaxel-induced peripheral neuropathy in SWOG S0221. J Natl Compr Canc Netw. 2023;21(11):1172-1180. doi:10.6004/jnccn.2023.7062

2. New research in JNCCN suggests a simple and inexpensive option for reducing a major chemotherapy side-effect. News release. PR Newswire. November 7, 2023. Accessed November 8, 2023. https://bit.ly/49stLS0