Abstract
Cumulative toxicity from weekly paclitaxel (myalgia, peripheral neuropathy, fatigue) compromises long-term administration. Preclinical data suggest that the burden of critically short telomeres (< 3 kilobases, CSTs), but not average telomere length by itself, accounts for limited tissue renewal and turnover capacity. The impact of this parameter (which can be modified with different therapies) in chemotherapy-derived toxicity has not been studied.Blood from 115 treatment-naive patients from a clinical trial in early HER2-negative breast cancer that received weekly paclitaxel (80 mg/m2 for 12 weeks) either alone or in combination with nintedanib and from 85 healthy controls was prospectively obtained and individual CSTs and average telomere lenght were determined by HT Q-FISH (high-throughput quantitative FISH). Toxicity was graded according to NCI common toxicity criteria for adverse events (NCI CTCAE V.4.0). The variable under study was “number of toxic episodes” during the 12 weeks of therapy.The percentage of CSTs ranged from 6.5%–49.4% and was directly associated with the number of toxic events (R2 = 0.333; P < 0.001). According to a linear regression model, each 18% increase in the percentage of CSTs was associated to one additional toxic episode during the paclitaxel cycles; this effect was independent of the age or treatment arm. Patients in the upper quartile (> 21.9% CSTs) had 2-fold higher number of neuropathy (P = 0.04) or fatigue (P = 0.019) episodes and >3-fold higher number of myalgia episodes (P = 0.005). The average telomere length was unrelated to the incidence of side effects.The percentage of CSTs, but not the average telomere size, is associated with weekly paclitaxel-derived toxicity.
Highlights
Paclitaxel is a commonly administered cancer chemotherapy regimen in breast cancer and other malignancies due to its efficacy and tolerability both in early and advanced disease [1, 2]
Blood from 115 treatment-naive patients from a clinical trial in early HER2negative breast cancer that received weekly paclitaxel (80 mg/m2 for 12 weeks) either alone or in combination with nintedanib and from 85 healthy controls was prospectively obtained and individual critically short telomeres (CSTs) and average telomere lenght were determined by HT highthroughput quantitative telomere FISH (Q-FISH)
There were not significant clinical or demographic differences between the patients that were valid for analysis and the patients that did not participate in the telomere substudy (13 because of not signing informed consent or having an inadequate sample and 2 because of screening failure and lack of toxicity data availability) (Table 1)
Summary
Paclitaxel is a commonly administered cancer chemotherapy regimen in breast cancer and other malignancies due to its efficacy and tolerability both in early and advanced disease [1, 2]. It is not unusual to withold or interrupt paclitaxel because of non-tolerable neuropathy, fatigue or myalgia while patients are still experiencing clinical benefit, due to cumulative dose and interaction with previously administered neurotoxic drugs, which may affect the overall efficacy of the drug. Detection of those patients at high risk of developing toxic complications, as well as understanding the physiopathology behind the toxicity, may help to perform personalized treatment decisions and develop supportive care alternatives. This feature is in contrast with the genetic polymorphisms associated with paclitaxel toxicity in previous studies [reviewed elsewhere [19], that would complicate potential interventions
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