Rates of Taxane-Induced Peripheral Neuropathy Underscore Need to Tailor Treatment for Black Patients With Early Breast Cancer

Treatment with docetaxel once every 3 weeks was associated with significantly less grade 2 or higher taxane-induced peripheral neuropathy (TIPN) and required fewer dose reductions compared with once-weekly paclitaxel in Black patients with early-stage breast cancer, according to data from the phase 2 ECOG-ACRIN EAZ171 study (NCT04001829) presented at the 2024 ASCO Annual Meeting and simultaneously published in the Journal of Clinical Oncology.^1,2

Notably, the study did not meet its primary end point, which was to prospectively validate germline predictors of TIPN. In patients treated with paclitaxel, those with high-risk genotypes (n = 91) experienced a grade 2 or higher TIPN rate of 47% compared with 35% for those with low-risk genotypes (n = 26; P = .27). In the docetaxel arm, these rates were 28% for high-risk patients (n = 87) and 19% for low-risk patients (n = 31; P = .47).

However, when comparing rates of physician-adjudicated grade 2 or higher TIPN by treatment groups, 25% of patients treated with docetaxel (n = 118) experienced grade 2 or higher TIPN compared with 44% of patients in the paclitaxel arm (n = 121; P = .004). Moreover, 1.7% of patients in the docetaxel arm had grade 3 or higher TIPN vs 9.4% of patients in the paclitaxel arm (P = .011). Importantly, fewer dose reductions due to TIPN were observed in the docetaxel arm (8.5%) vs the paclitaxel arm (28.1%; P < .001). A total of 24.6% of patients in the docetaxel arm experienced dose reductions due to any cause vs 38.8% in the paclitaxel arm (P = .019).

“Importantly, the trial did demonstrate significantly less neuropathy and less dose reductions with every-3-week docetaxel compared [with] weekly paclitaxel, suggesting this may be the preferred taxane specifically for Black women with early-stage breast cancer,” lead study author Tarah J. Ballinger, MD, of the Indiana University Melvin and Bren Simon Comprehensive Cancer Center in Bloomington, reported in a presentation of the data.

Understanding Breast Cancer Disparities in Black Patients

Despite treatment advancements across the breast cancer therapeutic landscape, Black patients do not reap the same benefits as their White counterparts due to multifactorial gaps in care, ranging from social determinants of health to the actual disease histology, biology, and genetics. Worse survival and higher rates of toxicities have also been observed in Black patients compared with White patients.¹

“One theme that we have in breast cancer is trying to minimize the toxic effects of some of the treatments. We know that in Black women especially, the risk of developing peripheral neuropathy is increased with taxane[-based therapy],” Sunil Adige, MD, explained in an interview with OncLive® during Breast Cancer Awareness Month.

Adige serves as an assistant professor at the George Washington (GW) Cancer Center, George Washington University, in Washington, DC.

“[The ECOG-ACRIN EAZ171 study showed] that using the 3-week dosing of [docetaxel] is [was associated with] less neuropathy in Black women compared with weekly paclitaxel dosing. This is exciting because it allows us to better [identify] patients who would benefit from this specific regimen when there are 2 regimens we had thought to be mostly equivalent [in toxicity]. This is pushing us in one direction or the other to minimize toxicity and make life more tolerable for patients on treatment,” he continued.

Furthermore, these disparate outcomes can be seen with taxane-based therapy, the backbone of curative treatment in early-stage breast cancer. This treatment can be limited or altered in patients who experience TIPN, and previous research has shown that women of African ancestry had significantly higher rates of TIPN compared with patients from other races. Notably, dose reductions have been associated with worse survival in patients of African ancestry, whereas patients of European ancestry did not experience worse survival outcomes with dose reductions.³

“The other thing that's been recognized now is some of the complications related to treatment with chemotherapy can be worse for African American women. One particular complication is neuropathy from a [taxane]-based chemotherapy, which is a dreaded complication,” said Sheldon M. Feldman, MD, chief of the Division of Breast Surgery and Breast Surgical Oncology, the director of Breast Cancer Services, and a professor in the Department of Surgery at Montefiore Einstein, in New York, New York. He shared these insights with OncLive in another interview during Breast Cancer Awareness Month.

“There are several different types of taxanes, including paclitaxel and docetaxel, which are commonly used. Recent studies have shown that docetaxel may have a lower incidence of neuropathy for African American women than the other drug,” he emphasized.

Although weekly paclitaxel is considered a standard of care, the data for the regimen have largely been driven by outcomes in White patients due to lower enrollment rates of Black patients across trials. This prompted investigators to prospectively validate germline predictors of neuropathy in a Black patient population and evaluate optimal taxane use with regard to TIPN for Black patients.^1,2

A Deeper Dive into EAZ171

Enrollment for the trial was conducted between 2019 and 2022, and the study included 249 patients with stage I to III breast cancer who self-identified as African American or Black and planned to receive a taxane in the curative setting. Patients were not allowed to have pre-existing neuropathy.

Enrolled patients were assigned to either weekly paclitaxel at 80 mg/mg2 for 12 weeks in arm A or docetaxel at 75 mg/mg2 every 3 weeks for 4 to 6 cycles in arm B. The trial was not randomized; patients were assigned to treatment based on disease characteristics and physician’s choice of therapy.

The primary objective of the trial was to prospectively validate germline predictors of TIPN. Secondary objectives include comparing grade 2 to 4 TIPN between treatment arms at 12 months and comparing dose reductions between arms at 12 months. Patient-reported outcome objectives included validation of germline predictors and comparison of TIPN between arms. Exploratory objectives encompassed the comparison of other adverse effects, disease-free survival, and overall survival.

The median age of patients receiving paclitaxel was 53 years (range, 23-72) vs 56 years (range, 27-80) in the docetaxel arm. The paclitaxel group consisted predominantly of Black patients (99.2%), with 1 participant identifying as multiracial. In the docetaxel cohort, all 123 participants were Black. Additionally, the majority of patients across both groups (paclitaxel, 71.4%; docetaxel, 68.3%) had a body mass index (BMI) of at least 30 kg/m2.

A majority of patients had an ECOG performance status of 0 (paclitaxel, 70.6%; docetaxel, 76.4%) and stage II disease (51.6%; 43.9%). Moreover, 40.8% of patients in the paclitaxel group and 56.9% in the docetaxel group had estrogen receptor–positive/HER2-negative disease; triple-negative breast cancer represented 44.8% of the paclitaxel group and 29.3% of the docetaxel group; and HER2-positive disease accounted for 14.4% and 13.8% of patients, respectively. Additionally, 68.3% of patients in the paclitaxel arm and 80.4% of patients in the docetaxel arm had hemoglobin A1c levels below 6.5%.

Investigators also looked at socioeconomic insights such as education, marital status, income, household size, and insurance coverage. The majority of patients completed high school or a higher level of education. Fifty-four percent of patients in the paclitaxel arm and 65% of those in the docetaxel arm reported earnings less than $90,000 per year. Ninety-five percent of patients in the paclitaxel arm and 97% of patients in the docetaxel arm had health insurance.

At 12 months, grade 2 or higher TIPN occurred in 34.7% of patients receiving at least 1 dose of a taxane. Key continuous variables associated with this incidence included age (odds ratio [OR], 1.00; 95% CI, 0.97-1.03; P = .89) and BMI (OR, 1.04; 95% CI, 1.00-1.08; P = .02).

Notably, patients with a BMI of at least 30 kg/m2 had a higher incidence of TIPN (37.5%) compared with those with a BMI lower than 30 kg/m2 (28.2%; P = .18).

"[In the study,] 235 patients had successful genotyping. Of these, the percent with high-risk genotype of FCAMR wild-type and SBF or SBF2-mutated [disease] matched what we had expected from our retrospective analysis. However, while rates of TIPN were higher in this high-risk genotype group, this did not reach statistical significance in the overall population or either of the study arms," Ballinger explained in the presentation.

Implications of Data

Although the trial did not demonstrate a statistically significant difference in rates of grade 2 or higher TIPN in the high-risk vs low-risk genotype groups, there were implications for Black patients with early-stage breast cancer regarding the rates of TIPN for docetaxel vs paclitaxel. This suggests that docetaxel may be the preferred taxane option in Black patients, according to Ballinger.

Additionally, these findings show that it is possible to tailor research and trials to meet the needs of underserved populations.

“The biology of the cancer, the genetics of the individual, and the particular characteristics of different racial subgroups is very important [in breast cancer]. We're beginning to understand that [more],” Feldman explained.

References

1. Ballinger TJ, Zhao F, Sparano JA, et al. ECOG-ACRIN EAZ171: prospective validation trial of germline variants and taxane type in association with taxane-induced peripheral neuropathy (TIPN) in Black women with early-stage breast cancer. J Clin Oncol. 2024;42(17):LBA503. doi:10.1200/JCO.2024.42.17_suppl.LBA503
2. Schneider BP, Zhao F, Ballinger TJ, et al. ECOG-ACRIN EAZ171: prospective validation trial of germline predictors of taxane-induced peripheral neuropathy in Black women with early-stage breast cancer. J Clin Oncol. 2024;42(24):2899-2907. doi:10.1200/JCO.24.00526
3. Schneider BP, Shen F, Jiang G, et al. Impact of Genetic Ancestry on Outcomes in ECOG-ACRIN-E5103. JCO Precis Oncol. 2017;2017:PO.17.00059. doi:10.1200/PO.17.00059