CHICAGO – A clinical trial evaluating the use of germline variants to predict vulnerability to taxane-induced peripheral neuropathy (TIPN) in Black women with early-stage breast cancer missed its primary endpoint but demonstrated that such a study could be tailored to assess healthcare issues affecting underserved populations.
In the study presented at the American Society of Clinical Oncology's annual meeting, researchers saw a numerically higher rate of TIPN in patients with a high-risk genotype, but the trend did not reach statistical significance.
Historically, Black women have worse outcomes and experience higher rates of toxicity from breast cancer treatment than their White counterparts. These disparities are attributed to factors including genetics, access to care, and implicit bias. Taxane-based chemotherapy is a standard, curative treatment in early-stage breast cancer. However, the taxane dose a patient can receive is limited by TIPN, a common side effect of widely prescribed chemotherapies such as paclitaxel and docetaxel in which the hands and feet become weak, cold, numb, and tingly. Patients with chronic TIPN experience pain and can lose sensation in their extremities.
In Black patients, but not patients of European ancestry, taxane dose reductions are associated with reductions in cure rates. "Here we have a disparity in a toxicity that may be contributing to inequitable outcomes in breast cancer," said Tarah Ballinger, an oncologist at Indiana University Health and the lead investigator of the study.
Ballinger and her group performed whole-exome sequencing on samples from a prior study, ECOG-ACRIN 5103, and identified rare, deleterious germline variants in the SBF2 gene associated with an increased risk of TIPN. And in genome-wide association studies, they found common variants in FKMR associated with reduced risk of TIPN specific to patients of African ancestry.
In the current trial, ECOG-ACRIN EAZ171, they sought to validate those germline variants as predictors of TIPN and explore the optimal type of taxane for Black patients. They enrolled more than 240 self-identified Black patients with early-stage breast cancer and assigned them to receive docetaxel or paclitaxel as neoadjuvant or adjuvant therapy. The trial was not randomized. Rather, physicians prescribed one of the two taxanes to patients based on their disease characteristics.
Investigators were primarily interested in whether there was an association between the presence of germline variants and TIPN occurrence a year after registration. They also measured safety, quality of life, and financial toxicity. Out of 178 patients with the high-risk genotype, 67 patients, or 38 percent, had TIPN. In comparison, 15 out of 57 patients, or 26 percent, with the low-risk genotype experienced TIPN. The researchers considered patients high risk if they were FCAMR homozygous wild type or had a deleterious SBF2 mutation. Patients with a variant in FCAMR or wild-type SBF2 were low risk.
Although there was a numerical association between TIPN and the high-risk genotype, it did not reach statistical significance. However, patients in the docetaxel arm had significantly less TIPN than those in the paclitaxel arm.
At the 12-month mark, the rate of TIPN was 34.7 percent in the overall study. The only variable significantly associated with TIPN was patients' body mass index. In the paclitaxel arm, 44 percent of patients had grade 2 or higher TIPN compared to just 25 percent in the docetaxel arm. As a result, there were fewer dose reductions due to TIPN or any other cause in the docetaxel arm compared to the paclitaxel arm. Ballinger said that suggests docetaxel may be a better taxane option for Black breast cancer patients.
Although the trial missed its primary endpoint, Ballinger felt the trial still had value by demonstrating that a study focusing on a population typically underrepresented in healthcare research could be successfully designed and executed. Researchers often bemoan the lack of diversity in clinical trials and their inability to enroll more non-White participants.
Ballinger attributed her team's ability to enroll enough patients in the trial to strong involvement from Black patients and patient advocates and a social media campaign. "This trial was successful because of a partnership with the patients it was meant to serve," Ballinger said.
Lisa Carey, an oncologist at the University of North Carolina's Lineberger Comprehensive Cancer Center, who wasn't involved in Ballinger's study, called the trial a "tour de force" for achieving its enrollment goal for Black patients. "They engaged social media [and] lay health advisers. … They figured out novel ways of getting it done," said Carey, reflecting on the study at the meeting. "They accrued [more than] 240 Black patients receiving taxanes in two years in spite of a pandemic."