Taxane-induced Peripheral Neuropathy Research Articles

Acupuncture for the Treatment of Taxane-Induced Peripheral Neuropathy in Breast Cancer Patients: A Pilot Trial.

Objectives Some chemotherapy drugs can damage the nerves and cause peripheral neuropathy which is accompanied by severe neuropathic pain or gait impairment. The purpose of this study was to assess the feasibility and the safety of acupuncture for the treatment of peripheral neuropathy following chemotherapy in Korean breast cancer patients. Design This study was a prospective single-arm observational study using before and after measurements in breast cancer patients presenting with taxane-induced peripheral neuropathy. Settings/Location This study was performed at East-West Medical Center at Daegu Catholic University Hospital, Daegu, South Korea. Interventions Acupuncture was administered 3 times a week for 4 consecutive weeks, for 25 ± 5 minutes at each session. Outcome Measures The primary outcome measure was severity of CIPN using the Neuropathic Pain Symptom Inventory (NPSI) assessed by a self-administered questionnaire and Nerve Conduction Study (NCS) of extremities. The secondary outcome measure was quality of life (QoL) assessed by a self-administered questionnaire using the 36-Item Short From Health Survey (SF-36). Results Acupuncture significantly reduced the severity of CIPN assessed by NPSI score. Four weeks after the last treatment, the symptoms were not aggravated. According to NCS, 42.9% of participants showed improvement of sensory neuropathy. At the end of the treatment, SF-36 scores were significantly increased for variables including physical functioning, role limitations due to physical health problems, social functioning, and general health perceptions compared to those of baseline measurement. Conclusions Acupuncture improved symptoms of CIPN and QoL in Korean women suffering from peripheral neuropathy after chemotherapy using taxane for breast cancer. The effects of acupuncture lasted for at least 1 month after the treatment.

Impact of Genetic Ancestry on Outcomes in ECOG-ACRIN-E5103.

Racial disparity in breast cancer outcomes exists between African American and Caucasian women in the United States. We have evaluated the impact of genetically determined ancestry on disparity in efficacy and therapy-induced toxicity for breast cancer patients in the context of a randomized, phase III adjuvant trial. This study compared outcomes between 386 patients of African ancestry (AA) and 2473 patients of European ancestry (EA) in a randomized, phase III breast cancer trial; ECOG-ACRIN-E5103. The primary efficacy endpoint, invasive disease free survival (DFS) and clinically significant toxicities were compared including: anthracycline-induced congestive heart failure (CHF), taxane-induced peripheral neuropathy (TIPN), and bevacizumab-induced hypertension. Overall, AAs had significantly inferior DFS (p=0.002; HR=1.5) compared with EAs. This was significant in the estrogen receptor-positive subgroup (p=0.03); with a similar, non-significant trend for those who had triple negative breast cancer (TNBC; p=0.12). AAs also had significantly more grade 3-4 TIPN (OR=2.9; p=2.4 ×10-11) and grade 3-4 bevacizumab-induced hypertension (OR=1.6; p=0.02), with a trend for more CHF (OR=1.8; p=0.08). AAs had significantly more dose reductions for paclitaxel (p=6.6 ×10-6). In AAs, dose reductions in paclitaxel had a significant negative impact on DFS (p=0.03); whereas in EAs, dose reductions did not impact outcome (p=0.35). AAs had inferior DFS with more clinically important toxicities in ECOG-ACRIN-E5103. The altered risk to benefit ratio for adjuvant breast cancer chemotherapy should lead to additional research with the focus centered on the impact of genetic ancestry on both efficacy and toxicity. Strategies to minimize dose reductions for paclitaxel, especially due to TIPN, are warranted for this population.

Incidence of taxane-induced peripheral neuropathy receiving treatment and prescription patterns in patients with breast cancer.

Taxane-induced peripheral neuropathy (TIPN) can affect quality of life and treatment outcomes in breast cancer patients. Despite the high incidence, treatment of PN has not been established. This study aimed to evaluate the incidence, risk factors, and prescribing pattern of TIPN receiving pharmacologic treatment in real-world practice. We conducted a retrospective chart review of 1629 breast cancer patients who received taxanes at the Seoul National University Hospital from July 2012 to June 2014. We determined the incidence and predictors for TIPN treated with anti-neuropathic pain medications during taxane treatment and the 1-year follow-up period after discontinuation of taxanes. The prescribing pattern of anti-neuropathic drugs was also analyzed. A total of 1516 patients with breast cancer were included, and the incidence of TIPN receiving treatment was 21.9% overall, with 42.2% of patients using paclitaxel and 15.8% using docetaxel. The median time to the first anti-neuropathic pain medication prescribed from the start of taxane treatment was 64days and was significantly earlier in the paclitaxel group. In 21% of patients, TIPN treatment was started after the end of taxane treatment. Identified risk factors for TIPN were paclitaxel use (vs. docetaxel), old age, overweight, metastatic (vs. non-metastatic) breast cancer, and possibly a 3-weekly taxane schedule (vs. weekly). Gabapentin and pregabalin accounted for 71.7 and 24.3% of total use of anti-neuropathic agents, respectively. One-fifth of breast cancer patients who were treated with taxane-based chemotherapy experienced TIPN receiving treatment, and its risk factors were paclitaxel use, old age, overweight, and metastatic cancer.

Abstract OT1-01-10: Multi-center phase IB trial of ACY-1215 (Ricolinostat) combined with nab-paclitaxel in unresectable or metastatic breast cancer

Abstract BACKGROUND: HDAC6, a cytoplasmic histone deacetylase, targets non-chromatin substrates including tubulin, HSP90, and cortactin, playing an important role in cell-cell interactions, motility, chaperone function, and protein degradation. ACY-1215 (Ricolinostat) is an orally active, selective HDAC6 inhibitor. Preclinical studies have demonstrated ACY-1215 to have activity in breast cancer, synergistic cytotoxicity with taxanes, possibly due to combined effects on microtubule stabilization, and protective effects against neurodegeneration and potentially peripheral neuropathy. Analysis of human primary breast cancer gene expression data has identified a set of 162 genes corresponding to a HDAC6 master regulator (MR) score that correlates with IC50 or sensitivity to ACY-1215, and may serve as a potential biomarker. TRIAL DESIGN: This is an open-label, multicenter Phase 1b trial (NCT01323751) of ACY-1215 combined with nab-paclitaxel in unresectable or metastatic breast cancer. Patients will receive ACY-1215 daily for 21 days of each 28-day cycle in combination with nab-paclitaxel 100 mg/m2 on days 1, 8, and 15 until progression of disease or unacceptable toxicity. KEY ELIGIBILITY CRITERIA: Patients aged ≥ 18 years with unresectable or metastatic breast adenocarcinoma, measurable or non-measurable disease, an ECOG performance status of 0 to 1, baseline toxicities and symptoms grade ≤1, and at least 2 weeks since prior treatment. STATISTICAL METHODS: Dose escalations will be performed according to the time to event continual reassessment method (TITE-CRM), starting at 120 mg to a maximum dose of 240 mg. The maximum tolerated dose (MTD) will be identified as the dose level associated with a target probability of dose limiting toxicity (DLT) of 0.25. The TITE-CRM will use an empirical dose-toxicity model, with a sample size of 24. The dose-toxicity model is calibrated to select a dose that yields between 17 and 33% DLT, which will be the recommended phase II dose (RP2D). OBJECTIVES: The primary objective of this trial is to determine the MTD of ACY-1215 in combination with weekly nab-paclitaxel. Secondary objectives include the evaluation of safety and tolerability, progression free survival, overall response rate (measured by RECIST 1.1), and clinical benefit rate. Exploratory analyses will assess pharmacokinetics and pharmacodynamics, correlation of biomarkers including the HDAC6 score with response, and the effect of ACY-1215 on taxane-induced peripheral neuropathy. ACCRUAL: Target Accrual is 24 patients. CONTACT INFORMATION: Kevin Kalinsky, MD, MS 212-305-1945 kk2693@cumc.columbia.edu. Citation Format: Onishi M, Chiuzan C, Fasano J, Crew K, Accordino M, Tiersten A, Shapiro C, Jarpe M, Qualye S, Trede N, Wheeler C, Hershman D, Silva J, Maurer M, Kalinksy K. Multi-center phase IB trial of ACY-1215 (Ricolinostat) combined with nab-paclitaxel in unresectable or metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT1-01-10.

Abstract IA09: Impact of genetically determined race on outcomes in E5103

Abstract Background: African Americans (AAs) have inferior breast cancer outcomes. AAs have a higher percentage of the poor prognosis triple negative breast cancer subtype and also have inferior relative benefit from chemotherapy when compared to other races. While some of the disparity may be due to socio-economic factors, the underlying biology of the tumor may also play a pivotal role. Using ancestry informative markers, we have evaluated race-specific outcomes and various therapy-induced side effects in the adjuvant breast cancer trial, E5103. We have further explored the roles of germline genetic biomarkers to predict the increased risk for the most common chemotherapy induced toxicity; taxane-induced peripheral neuropathy (TIPN) in AAs. Methods: E5103 was a phase III adjuvant breast cancer trial that randomized 4,994 patients with node-positive or high risk node-negative breast cancer to intravenous doxorubicin and cyclophosphamide every 2 or 3 weeks for four cycles followed by 12 weeks of weekly paclitaxel alone (Arm A) or to the same chemotherapy with either concurrent bevacizumab (Arm B) or concurrent plus sequential bevacizumab (Arm C). Germline (blood) DNA and clinical data were available from 3394 patients across all arms. Genome-wide analyses were performed in these patients and race was determined by principle components analysis (PCA). Clinical outcome and the occurrence of therapy-induced toxicities were compared in genetically defined AAs against other races. Germline biomarkers were evaluated to predict the risk of TIPN in AAs through a genome wide association study (for common variants) and through whole exome sequencing (for rare variants). Results: PCA determined 386 AAs among 3394 available patients from E5103. Compared to other races, AA patients had an inferior disease free survival. AAs were also more likely to experience the most common, severe side effects from each of the agents used in E5103, including: CTCAE v 4.0 grade 3-4 TIPN (p=2.4 × 10-11; OR=2.9) and grade 3-4 bevacizumab induced hypertension (p=0.002; OR=1.6). Despite a small number of events, the same trend was observed for anthracycline induced congestive heart failure (p=0.08, OR=1.8). The genome wide study identified several germline biomarkers that impacted the risk of TIPN specific to AAs. Specifically, a SNP in FCAMR demonstrated a trend toward decreased risk of grade 2-4 TIPN in AAs (p-value=2.8 × 10-7). Whole exome sequencing revealed an association between deleterious rare variants in SET binding factor 2 (SBF2) with a marked increased risk of grade 3-4 TIPN in AAs (p-value=4.35 × 10-6). Conclusion: AA breast cancer patients had an inferior DFS and were more likely to experience bevacizumab-induced hypertension, TIPN, and anthracycline-induced congestive heart failure compared with other races in E5103. Germline biomarkers for predicting the risk of TIPN, pending validation in independent trials, can drastically impact counseling patients for the likelihood of this toxicity. Citation Format: Bryan Paul Schneider. Impact of genetically determined race on outcomes in E5103. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr IA09.

Association of Charcot-Marie-Tooth gene, SBF2, with taxane-induced peripheral neuropathy in African Americans.

1026Background: Taxane-induced peripheral neuropathy (TIPN) is one of the most important survivorship issues for cancer patients. African Americans (AA) have previously been shown to have an increa...

Randomized sham-controlled pilot trial of weekly electro-acupuncture for the prevention of taxane-induced peripheral neuropathy in women with early stage breast cancer.

To investigate the effect of electro-acupuncture (EA) as a non-pharmacological intervention to prevent or reduce chemotherapy-induced peripheral neuropathy (CIPN) in breast cancer patients undergoing chemotherapy of taxane. Women with stage I-III breast cancer scheduled to receive taxane therapy were randomized to receive a standardized protocol of 12 true or sham EA (SEA) weekly treatments concurrent with taxane treatment. Subjects completed the Brief Pain Inventory-Short Form (BPI-SF), Functional Assessment of Cancer Therapy-Taxane neurotoxicity subscale (FACT-NTX), and other assessments at baseline and weeks 6, 12, and 16. A total of 180 subjects were screened, 63 enrolled and 48 completed week 16 assessments. Mean age was 50 with 25 % white, 25 % black, and 43 % Hispanic; 52 % had no prior chemotherapy. At week 12, both groups reported an increase in mean BPI-SF worst pain score, but no mean differences were found between groups (SEA 2.8 vs. EA 2.6, P = .86). By week 16, the SEA group returned to baseline, while the EA group continued to worsen (SEA 1.7 vs. EA 3.4, P = .03). The increase in BPI-SF worst pain score was 1.62 points higher in the EA group than in the SEA group at week 16 (P = .04). In a randomized, sham-controlled trial of EA for prevention of taxane-induced CIPN, there were no differences in pain or neuropathy between groups at week 12. Of concern, subjects on EA had a slower recovery than SEA subjects. Future studies should focus on EA for treatment as opposed to prevention of CIPN.

Identifying Predictors of Taxane-Induced Peripheral Neuropathy Using Mass Spectrometry-Based Proteomics Technology.

Major advances in early detection and therapy have significantly increased the survival of breast cancer patients. Unfortunately, most cancer therapies are known to carry a substantial risk of adverse long-term treatment-related effects. Little is known about patient susceptibility to severe side effects after chemotherapy. Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of taxanes. Recent advances in genome-wide genotyping and sequencing technologies have supported the discoveries of a number of pharmacogenetic markers that predict response to chemotherapy. However, effectively implementing these pharmacogenetic markers in the clinic remains a major challenge. On the other hand, recent advances in proteomic technologies incorporating mass spectrometry (MS) for biomarker discovery show great promise to provide clinically relevant protein biomarkers. In this study, we evaluated the association between protein content in serum exosomes and severity of CIPN. Women with early stage breast cancer receiving adjuvant taxane chemotherapy were assessed with the FACT-Ntx score and serum was collected before and after the taxane treatment. Based on the change in FACT-Ntx score from baseline to 12 month follow-up, we separated patients into two groups: those who had no change (Group 1, N = 9) and those who had a ≥20% worsening (Group 1, N = 8). MS-based proteomics technology was used to identify proteins present in serum exosomes to determine potential biomarkers. Mann–Whitney–Wilcoxon analysis was applied and maximum FDR was controlled at 20%. From the serum exosomes derived from this cohort, we identified over 700 proteins known to be in different subcellular locations and have different functions. Statistical analysis revealed a 12-protein signature that resulted in a distinct separation between baseline serum samples of both groups (q<0.2) suggesting that the baseline samples can predict subsequent neurotoxicity. These toxicity-associated biomarkers can be further validated in larger retrospective cohorts for their utility in identifying patients at high risk for CIPN.

Genome-Wide Association Studies for Taxane-Induced Peripheral Neuropathy in ECOG-5103 and ECOG-1199.

Taxane-induced peripheral neuropathy (TIPN) is an important survivorship issue for many cancer patients. Currently, there are no clinically implemented biomarkers to predict which patients might be at increased risk for TIPN. We present a comprehensive approach to identification of genetic variants to predict TIPN. We performed a genome-wide association study (GWAS) in 3,431 patients from the phase III adjuvant breast cancer trial, ECOG-5103 to compare genotypes with TIPN. We performed candidate validation of top SNPs for TIPN in another phase III adjuvant breast cancer trial, ECOG-1199. When evaluating for grade 3-4 TIPN, 120 SNPs had a P value of <10(-4) from patients of European descent (EA) in ECOG-5103. Thirty candidate SNPs were subsequently tested in ECOG-1199 and SNP rs3125923 was found to be significantly associated with grade 3-4 TIPN (P = 1.7 × 10(-3); OR, 1.8). Race was also a major predictor of TIPN, with patients of African descent (AA) experiencing increased risk of grade 2-4 TIPN (HR, 2.1; P = 5.6 × 10(-16)) and grade 3-4 TIPN (HR, 2.6; P = 1.1 × 10(-11)) compared with others. An SNP in FCAMR, rs1856746, had a trend toward an association with grade 2-4 TIPN in AA patients from the GWAS in ECOG-5103 (OR, 5.5; P = 1.6 × 10(-7)). rs3125923 represents a validated SNP to predict grade 3-4 TIPN. Genetically determined AA race represents the most significant predictor of TIPN.

Taxane-induced peripheral sensorial neuropathy in cancer patients is associated with duration of diabetes mellitus: a single-center retrospective study.

The purpose of this study was to determine whether the presence of diabetes mellitus (DM) influences the incidence and severity of peripheral sensory neuropathy (PSN) in patients using taxane therapy. A retrospective single-center analysis was conducted: Patients with PSN at baseline were excluded. The incidence of PSN was evaluated retrospectively in patient subgroups who received taxane arm and taxane-plus-platinum-agents combination arm with or without known DM at baseline. Three hundred seventy-four patients were enrolled in this study, 81 (21.6%) of patients had DM at baseline. The incidence of grade 1 PSN (non-DM/DM) in patients receiving taxane-based chemotherapy was 33.4/25.9% and more than grade 2 PSN (non-DM/DM) was 15/34.6%. The rate of neuropathy of non-diabetic patients was 48.8%, while the rate of diabetic patients was 52.8 and 75% in DM duration below 5 years and above 5 years group, respectively. This retrospective analysis indicates that taxane-based therapy in DM patients whose disease duration is above 5 years appears to affect the incidence and severity of PSN without known baseline neuropathy. The probability of PSN with taxane-based therapy was similar in DM duration below 5 years and non-DM patients.

Identifying predictors of taxane-induced peripheral neuropathy using shotgun proteomics technology.

9607 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of taxanes. Advances in proteomic technologies incorporating mass spectrometry (MS) for biomarker discover...

Randomized sham controlled pilot trial of weekly electro-acupuncture for the prevention of taxane-induced peripheral neuropathy.

e20738 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common and potentially disabling effect of taxanes. There are no effective preventive therapies. Electro-acupuncture (EA) u...

Current Methods for the Assessment and Management of Taxane-Related Neuropathy

Taxane-induced peripheral neuropathy (TIPN) affects a number of patients with breast cancer. To properly manage these patients, nurses must be able to identify and assess TIPN, as well as educate patients on TIPN as a side effect of taxane therapy. This article provides practical suggestions regarding how nurses can incorporate clinically feasible measurement approaches into practice and includes examples of grading TIPN that illustrate the limitations of the current tools and techniques for assessment. For example, a shortened and revised version of the Total Neuropathy Score and the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity subscale should be considered for future use. In addition, neuropathy-related results from numerous phase III trials in breast cancer are discussed, and the latest evidence regarding pharmacologic interventions for TIPN is briefly summarized.

Quality-of-Life Considerations With Taxane-Based Therapy in Metastatic Breast Cancer

As with many other types of chemotherapy, taxanes are associated with side effects that can affect patients' quality of life. One of the major side effects of taxane therapy is taxane-induced peripheral neuropathy (TIPN). The development of TIPN is accompanied by troublesome burning, tingling, and numbness; TIPN also can affect patient safety because of the decreased ability to perceive sensations (e.g., pain, heat). Pain and fatigue are common side effects of taxane therapy. These particular symptoms may hinder patients from working or performing daily activities, thus affecting quality of life. This case vignette provides an example of the symptoms that can accompany taxane therapy, including TIPN. The case vignette also demonstrates the long-lasting effects that TIPN can have on patients receiving taxane-based therapy, as well as the hindrance to the ability to work and perform daily activities because of numbness, pain, and fatigue. In addition, identification and management of taxane-related side effects are explored from the nursing perspective, and important aspects of patient education are discussed.

Efficacy of lafutidine, a histamine H2-receptor antagonist, for taxane-induced peripheral neuropathy in patients with gynecological malignancies

ObjectiveLafutidine, an antagonist of histamine H2-receptor, has gastroprotective activity associated with activation of capsaicin-mediated sensory nerves. The objective of this study was to investigate the efficacy of lafutidine for the treatment of taxane-induced peripheral neuropathy in patients with gynecological malignancies. MethodsTwenty patients with taxane-induced peripheral neuropathy during the treatment of gynecological malignancy were enrolled in this study. After obtaining their informed consent, lafutidine (20mg per day) was administered orally, the efficacy of which was assessed according to the Patient Neurotoxicity Questionnaire item 1. ResultsSignificant, moderate, slight, and no effects were observed in four, five, five, and six patients, respectively. The efficacy including significant and moderate effect was observed in nine (45%) of the 20 patients (95% confidence interval, 25.8%–65.8%). No adverse effects due to lafutidine were observed. ConclusionThis pilot study supports the relatively high efficacy of lafutidine for the treatment of taxane-induced peripheral neuropathy. Further prospective studies are warranted.

Taxane-induced peripheral neuropathy and health-related quality of life in postoperative breast cancer patients undergoing adjuvant chemotherapy: N-SAS BC 02, a randomized clinical trial

To elucidate whether adjuvant taxane monotherapy is a feasible and tolerable for postoperative breast cancer patients, we evaluated the severity of chemotherapy-induced peripheral neuropathy (CIPN) and the relative tolerability of regimens by health-related quality of life (HRQOL) assessment in node-positive breast cancer patients treated with taxane-containing regimens. We evaluated CIPN and HRQOL in the first 300 patients enrolled in a larger (1,060 total) multicenter phase III trial randomized to one of four adjuvant regimens: (1) anthracycline-cyclophosphamide followed by paclitaxel (ACP), (2) AC followed by docetaxel (ACD), (3) paclitaxel alone (PTX), or (4) docetaxel alone (DTX). CIPN was assessed by the Patient Neurotoxicity Questionnaire (PNQ) and the National Cancer Institute Common Toxicity Criteria, and HRQOL by Functional Assessment of Cancer Therapy-General (FACT-G). CIPN and HRQOL scores were compared between ACP and ACD vs. PTX and DTX, and ACP and PTX vs. ACD and DTX. PNQ sensory scores were significantly higher in patients treated with taxane monotherapy compared to treatment with AC followed by taxane (P = .003). No significant differences in PNQ sensory scores were observed between the ACP and PTX vs. ACD and DTX regimens (P = .669). Regardless of taxane regimen, PNQ severity scores for CIPN appear to be largely reversible within 1 year of adjuvant treatment. No significant difference in FACT-G scores was observed between any regimens during the study treatments. Patient-reported CIPN was significantly more severe with single-agent adjuvant taxane compared to AC followed by taxane treatment; however, the HRQOL findings support that single-agent taxane treatment is tolerable.

Taxane-induced peripheral neuropathy has good long-term prognosis: a 1- to 13-year evaluation

Taxane-induced neuropathy is a frequent complication, in particular in women with breast cancer. The incidence can be variable and ranges from 11 to 87%, depending on the taxane used and identified risk factors, such as cumulative dose, additional neurotoxic chemotherapy agents and previous nerve fragility. However, little is known about long-term outcome and interference with daily life activities. The objective of this study was to assess clinical and electrophysiological neurological evaluation (ENMG) in a cohort of patients, 1-13 years (median 3 years) after the end of the last cure. Sixty-nine women were enrolled in the lymphology unit of Cognacq-Jay's Hospital. They were 58 ± 9 years old (mean age ± SD) and had been treated by docetexel (n = 56), paclitaxel (n = 10) or both (n = 3), 1-13 years before. Sensory neuropathy occurred in 64% and totally disappeared within months for only 14% after cessation of treatment. However, if symptoms were still present at the time of examination, they were considered as minor by almost all patients, with no interference with daily life activities (grade 2 CTCAE v.3.0). ENMG was accepted by 14 patients; it was normal in 7, and showed sensory axonal neuropathy in 5 and sensory-motor neuropathy in 2. The incidence of taxane-induced neuropathy is high, more frequent with paclitaxel than docetaxel, and is characterized by minor or moderate axonal sensory polyneuropathy. When persistent, it is extremely well tolerated by the patient. When clinical motor signs occur, the patient should be referred to a neurologist.

Variants in the BRCA1/Fanconi-Anemia Repair Pathway and Taxane-Induced Neuropathy in SWOG S0221.

Abstract Background: Taxane-induced peripheral neuropathy is a dose-limiting side effect that leads to suboptimal cancer treatment and diminished quality of life. The mode of taxane neurotoxicity is unclear, but may be through stabilization of microtubules and induction of spindle checkpoint, leading to cell cycle arrest at G2/M. Fanconi Anemia (FA) genes, including FANCD2, and FANCA, appear to be involved in G2/M phase checkpoint maintenance as well as spindle checkpoint in response to internal and external signals, such as taxane treatment. Thus, we hypothesized that variants in FA genes could impact severity of taxane-induced neuropathies.Methods: Using DNA extracted from blood collected from 893 breast cancer patients participating in a trial evaluating metronomic dosing of cyclophosphamide, doxorubicin and paclitaxel (S0221), we genotyped for single nucleotide polymorphisms (SNPs) that represent all of the variability across FANCA (44 SNPs) and FANCD2 (24 SNPs) in all race/ethnicity groups, as well as a panel of ancestry informative markers to control for potential population stratification, using Illumina GoldenGate platform. SNPs with minor allele frequency (MAF) less than 0.10 and those out of Hardy Weinberg Equilibrium (HWE) proportions (p&amp;lt;0.001) were removed from analyses. Ordinal regression was used to test for allelic and haplotypic association with grade 3 or 4 toxicities relative to 0, 1, and 2 toxicities, adjusting for age, genetic admixture index and treatment arm. To adjust for multiple testing, permutation analyses were performed on both single SNP and haplotype models.Results: Eighteen SNPs in FANCD2 and 38 SNPs in FANCA passed MAF and HWE proportion requirements. For FANCD2, 4 SNPs spanning 67.5 Kb (rs7648104, rs2272125 [coding SNP], rs6786638 and rs644215), were significantly associated with taxane-induced neuropathy (p&amp;lt;0.001) after controlling for multiple testing, with each SNP resulting in approximately a twofold increase in odds of severe taxane-induced neuropathy. Haplotype estimation showed that all 18 SNPs comprise a single haplotype. Two major (&amp;gt;1% frequency) haplotypes were found. The frequencies of the risk haplotype in cases (patients with grade 3 or 4 neuropathy) and controls (patients with ≤ grade 2 neuropathy) were 0.25 and 0.15, respectively. Ordinal regression analyses were highly significant (p&amp;lt;0.0005); patients with at least one copy of the risk haplotype had more than a twofold increased risk of grade 3 or 4 taxane-induced neuropathy (OR=2.2, 95% CI 1.44, 3.44). For FANCA, no SNPs or haplotypes were significantly associated with grade 3 or 4 neurotoxicity, either prior to or after correction for multiple testing.Conclusions: These results indicate that the Fanconi-Anemia pathway may be important for neurological sensitivity to taxanes, and that genotypic markers might be able to be used to identify patients at increased risk for severe taxane-induced neuropathy. Further studies will elucidate potential associations with survival outcomes. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2001.

Techniques for the neurological examination of taxane-induced neuropathy

Taxanes are considered to be the key drugs in the treatment of breast cancer. Although physicians who treat patients with breast cancer have rarely seen patients with neuropathy as an adverse effect of treatment before the advent of taxanes, patients with breast cancer who are treated with taxanes frequently exhibit peripheral neuropathy. As peripheral neuropathy often causes deterioration of the quality of life of patients, it is very important to precisely assess the extent of peripheral neuropathy at an early stage. Clinical oncologists should be familiar with the techniques of neurological examination. In this article we describe the basic techniques for the neurological examination of patients with taxane-induced peripheral neuropathy. In the hope of facilitating the precise evaluation of taxane-induced peripheral neuropathy, the items of neurological examinations in this article are described with reference to the physician neuroexamination form (PNEF) designed by BioNumerik Pharmaceuticals Inc.