Reshma Jagsi, MD, DPhil, and Tarah J. Ballinger, MD, on Early-Stage Breast Cancer in Black Women: Docetaxel and Peripheral Neuropathy

Reshma: Tarah, thank you so much for joining me. We are so excited to have you to speak a little bit about the incredibly exciting work that you presented at the recent ASCO annual meeting. And I wanted to start by asking you to talk a little bit about where this idea came from, what we knew at baseline about the incidence of taxane-induced peripheral neuropathy in patients overall, and how those rates might vary by race and ethnicity and how that led you to the work that you presented more recently. Tarah: Yeah, thank you so much for having me here. So we know from looking back retrospectively at some prior trials, namely ECOG-ACRIN-E5103, all patients got weekly paclitaxel in that trial. And we know that in that study, as in others, black patients have significantly higher rates of moderate or severe neuropathy compared to white patients or patients of other races. And that matters beyond just the fact that neuropathy affects quality of life and physical functioning. But we also see more dose reductions in black patients because of that. And then in black patients, we see those things go on to impact their cure rates. We did not see that same relationship between dose reductions and reduced cure rates in white patients. We also looked at that through genetic ancestry and saw the same thing looking at African ancestry versus European ancestry. So we then went on to try to look at individual variability in the germline and found a couple of germline biomarkers that may be able to modify risk of TIPN specifically in black patients who are at higher risk for it. Reshma: Thank you. And so then how did you come to the design of your current study? And can you describe that for us? Tarah: Yeah. So based on some of the retrospective data that I was just discussing, EAZ171 was designed to prospectively validate high-risk versus low-risk genotypes, specifically in black patients. That was using two genetic variants in SBF2 and FKMR. So the primary goal was to validate those findings. We also wanted to compare rates of neuropathy between docetaxel and paclitaxel, and look at dose reductions between those two taxanes. So we enrolled only black women or African American women. This was self-identified race, and patients were planned to receive a taxane in the curative setting. It wasn't a randomized trial, it was pragmatic physician's choice based on the patient's disease characteristics. They either received weekly paclitaxel times 12 or docetaxel every three weeks for four to six. Reshma: And what did you find? Tarah: The trial didn't meet its primary endpoint. We were not able to validate the germline biomarkers for neuropathy risk. We did see numerically more neuropathy in the high-risk genotype, but that didn't reach statistical significance. I think it's still important though, because we saw significantly more neuropathy in patients who received paclitaxel compared to docetaxel, both by physician reporting and patient-reported toxicity, which we tried really hard to capture well in this trial. We also saw significantly more dose reductions in the patients who received paclitaxel, and that was either dose reductions due to neuropathy, but importantly also dose reductions due to any cause. So ultimately, I think still very important findings for this specific high-risk underserved population. Reshma: Very, very important. And I think there's two reasons to find your results particularly exciting. One is that you robustly accrued to a trial that is exclusively recruiting black women, and we hear a lot in this country about under-representation of various groups in clinical research, and the very sad fact that that means the science doesn't generalize to all populations equitably. Tarah: Exactly. Reshma: What have you learned about recruitment, enrollment? Can you talk a little bit about the characteristics, the diversity of the patients that were enrolled in terms of their socioeconomic status and other characteristics and what you learned? Tarah: Yeah, that's a great question. I think historically we have put the onus on the patients for the reasons why we're not seeing more under-represented populations in trials. But we know it's very multifactorial and a lot of it is on us to design our trials well and to ask patients to participate. So for EAZ171, we had a lot of early involvement from black patient advocates who helped us with the design, helped us with the education materials. We had a very specific and well-designed recruitment plan. A lot of it was done via social media. Again, specifically designed to recruit this population to our trial. We also had a lot of involvement from community sites. About 40% of the patients enrolled from an NCORP community site, which is important in terms of representation of the patients. We also did allow diabetes in this trial. About a quarter of the patients had a hemoglobin A1C over six and a half, which again is important for eligibility criteria. In terms of socioeconomic status, about a quarter of the patients had a household income under $20,000 a year. So I think we were capturing a broader spectrum of patients that's more representative. Almost all the patients in the trial were covered by health insurance. So I think there are some gaps in the patients that we're seeing, but I think overall, this trial really does show us that we can do this if we try to do it. And I think it's on us to design trials in the future that really enroll these high-risk populations and try to actually intervene on these disparities. Reshma: I can't thank you enough for doing this work. We talk a lot about trust and sometimes we forget that the onus is on us to make our institutions and our organizations trustworthy. So I think this is a real testament to that. Can I ask one last question? As a radiation oncologist looking at this, why are black women getting weekly paclitaxel if we know that three weekly docetaxel will have fewer dose reductions and lower incidence of neuropathy? Tarah: Yeah. So the only data we had for that prior to EAZ171 came from retrospective unplanned analyses of trials with very few black patients in them that weren't well phenotyped in terms of the physician-reported neuropathy. So I think this is the first time we have prospective data on a group specifically designed to answer this. It's not a randomized trial, but I think this is the best data we have, and I think it really does support, thinking about this and paying attention to whether your patient should be receiving docetaxel based on their race to reduce their risk of toxicity and dose reductions. Reshma: Thank you so much again for joining me and for sharing your wisdom. Thanks again. Tarah: Thank you so much.