SUMMARY: Taxane-induced peripheral neuropathy (TIPN) is a notable side effect associated with taxane chemotherapy agents, particularly Paclitaxel, and has significant implications for patient quality of life and treatment outcomes. Notably, Black women with early-stage breast cancer exhibit a disproportionately higher incidence of TIPN compared to their White counterparts. This disparity is critical, as TIPN can lead to increased dose reductions, which in turn may adversely affect treatment efficacy and long-term cure rates.
Historically, retrospective analyses, such as those from the ECOG-ACRIN-E5103 trial, revealed that Black patients experience more severe TIPN and subsequent dose reductions when treated with weekly Paclitaxel. This pattern was less pronounced in patients treated with every 3 week Docetaxel. Additionally, genetic studies identified specific germline variants associated with a heightened risk of severe TIPN in individuals of African ancestry. These findings prompted the need for a prospective trial to validate these genetic markers and to evaluate the comparative tolerability of Paclitaxel versus Docetaxel specifically in Black women.
The EAZ171 study was designed with several key objectives. It aimed to prospectively validate whether specific germline genetic variants are associated with a higher risk of TIPN in Black women. The focus was on genetic variants in the SBF2 and FCAMR genes. The Secondary objective of this study was to compare the incidence of TIPN and the frequency of dose reductions between two taxanes—weekly Paclitaxel and every 3 week Docetaxel, in a cohort of Black women with early-stage breast cancer.
This study included 249 Black women who self-identified as such and were scheduled to receive either Paclitaxel 80 mg/m² IV weekly for 12 doses (N=121) or Docetaxel 75 mg/m² IV every 3 weeks for 4-6 cycles (N=128). The study utilized a pragmatic design where the choice of taxane was based on physician discretion and patient-specific disease characteristics, rather than a randomized design. Patients could also receive Cyclophosphamide, Doxorubicin, Trastuzumab, and/or Pertuzumab per institution routine care, per treating physician discretion. After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.
Participants were genotyped to identify genetic variants associated with neuropathy risk. Those with FCAMR homozygous wild type or SBF2 mutations were categorized as high risk, while those with variant alleles in FCAMR and wild type SBF2 were categorized as low risk. The incidence of Grade 2-4 TIPN was evaluated using physician-reported CTCAE v.5, while patient-reported outcomes were assessed through PRO-CTCAE, FACT/GOG-NTx, and EORTC CIPN20 questionnaires.
The key findings were:
Genetic Predictors: Germline variations did not significantly influence the risk of TIPN for either treatment group. The anticipated differences in TIPN based on genetic risk did not reach statistical significance.
TIPN Incidence: Grade 2-4 TIPN was notably higher in the Paclitaxel group compared to the Docetaxel group. Physician-reported TIPN was 45% in the Paclitaxel arm versus 29% in the Docetaxel arm (P=0.02). Similarly, patient-reported TIPN symptoms were 40% with Paclitaxel versus 24% with Docetaxel (P=0.03).
Dose Reductions: Patients receiving Paclitaxel experienced more frequent dose reductions due to TIPN (28% vs. 9%, p<0.001) and for any cause (39% vs. 25%, p=0.02) compared to those receiving Docetaxel.
Patient-Reported Outcomes: The trends in worsening neuropathy scores over time were similar between the two arms, but significant differences were not observed at the one-year mark.
In summary, the EAZ171 study provided crucial insights into the management of TIPN in Black women with early-stage breast cancer. Despite the lack of significant impact from genetic markers, the clear advantage of Docetaxel over Paclitaxel in terms of lower incidence of severe TIPN and fewer dose reductions underscores its potential as a preferable taxane for this patient population. This trial results advocate for considering Docetaxel in treatment regimens for Black women to mitigate TIPN-related complications and possibly enhance treatment outcomes. The findings emphasize the need for tailored treatment strategies to improve health equity and therapeutic efficacy in breast cancer care.
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. Ballinger TJ, Zhao F, Sparano JA, et al. J Clin Oncol 42, 2024 (suppl 17; abstr LBA503). DOI: 10.1200/JCO.2024.42.17_suppl.LBA503
