Pre-treatment Amino Acids and Risk of Paclitaxel-induced Peripheral Neuropathy in SWOG S0221.

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a treatment-limiting and debilitating neurotoxicity of many commonly used anti-cancer agents, including paclitaxel. The objective of this study was to confirm the previously found inverse association between pre-treatment blood concentrations of histidine and CIPN occurrence and examine relationships of other amino acids with CIPN severity. Methods: Pre-treatment levels of 20 amino acid concentrations were measured via a targeted mass spectrometry assay in banked serum from the SWOG S0221 (NCT00070564) trial of patients with early-stage breast cancer receiving paclitaxel. The associations between amino acid levels and CIPN occurrence or severity were tested in regression analysis adjusted for paclitaxel schedule, age, self-reported race, and body mass index with Bonferroni correction for multiple comparisons. The network of metabolic pathways of amino acids was analyzed using over-representation analysis in MetaboAnalyst. The partial correlation network of amino acids was evaluated using a debiased sparse partial correlation algorithm and Cytoscape. Results: In the primary analysis, histidine concentration was not associated with CIPN occurrence (odds ratio (OR) = 0.97 [0.83, 1.13], p = 0.72). In a secondary analysis, no amino acid was associated with CIPN occurrence (all p > 0.0025). Higher concentrations of four amino acids, glutamate (ß = 0.58 [0.23, 0.93], p = 0.001), phenylalanine (ß = 0.54 [0.19, 0.89], p = 0.002), tyrosine (ß = 0.57 [0.23, 0.91], p = 0.001), and valine (ß = 0.58 [0.24, 0.92], p = 0.001) were associated with more severe CIPN, but none of these associations retained significance after adjustment. In the over-representation analysis, no amino acid metabolic pathways were significantly enriched (all FDR > 0.05). In the network of enriched pathways, glutamate metabolism had the highest centrality. Conclusions: This analysis showed that pre-treatment serum amino acid concentrations are not strongly predictive of CIPN severity. Future prospectively designed studies that assess non-amino acid metabolomics predictors are encouraged.

A Multimodal Approach to Discover Biomarkers for Taxane-Induced Peripheral Neuropathy (TIPN): A Study Protocol.

Introduction: Taxanes are a class of chemotherapeutics commonly used to treat various solid tumors, including breast and ovarian cancers. Taxane-induced peripheral neuropathy (TIPN) occurs in up to 70% of patients, impacting quality of life both during and after treatment. TIPN typically manifests as tingling and numbness in the hands and feet and can cause irreversible loss of function of peripheral nerves. TIPN can be dose-limiting, potentially impacting clinical outcomes. The mechanisms underlying TIPN are poorly understood. As such, there are limited treatment options and no tools to provide early detection of those who will develop TIPN. Although some patients may have a genetic predisposition, genetic biomarkers have been inconsistent in predicting chemotherapy-induced peripheral neuropathy (CIPN). Moreover, other molecular markers (eg, metabolites, mRNA, miRNA, proteins) may be informative for predicting CIPN, but remain largely unexplored. We anticipate that combinations of multiple biomarkers will be required to consistently predict those who will develop TIPN. Methods: To address this clinical gap of identifying patients at risk of TIPN, we initiated the Genetics and Inflammatory Markers for CIPN (GENIE) study. This longitudinal multicenter observational study uses a novel, multimodal approach to evaluate genomic variation, metabolites, DNA methylation, gene expression, and circulating cytokines/chemokines prior to, during, and after taxane treatment in 400 patients with breast cancer. Molecular and patient reported data will be collected prior to, during, and after taxane therapy. Multi-modal data will be used to develop a set of comprehensive predictive biomarker signatures of TIPN. Conclusion: The goal of this study is to enable early detection of patients at risk of developing TIPN, provide a tool to modify taxane treatment to minimize morbidity from TIPN, and improved patient quality of life. Here we provide a brief review of the current state of research into CIPN and TIPN and introduce the GENIE study design.

Associations between self-reported diet during treatment and chemotherapy-induced peripheral neuropathy in a cooperative group trial (S0221).

BACKGROUND: The pathophysiology of chemotherapy-induced peripheral neuropathy (CIPN) is not well understood. Currently, dose reduction is the only recommendation for alleviating symptoms, often leading to premature treatment cessation. The primary aim of this analysis was to determine the association between components of diet during taxane treatment for breast cancer and change in CIPN symptoms over treatment. METHODS: Women with stage II or III invasive breast cancer were enrolled into an ancillary study to the North American Breast Cancer Intergroup phase III trial (S0221) led by the Southwest Oncology Group (SWOG). Questionnaires including a food frequency questionnaire and the Functional Assessment of Cancer Treatment Gynecologic Oncology Group-Neurotoxicity were administered to assess diet and neuropathic conditions at baseline and during chemotherapy. Ordinal regression was used to estimate odds ratios (ORs) for associations between various food groups and change in neuropathy score (< 10%, 10-30%, > 30%) (n = 900). RESULTS: The odds of worse neuropathy decreased by 21% for each increase in tertile of grain consumption (OR = 0.79, 95% CI 0.66-0.94, p = 0.009). We also observed a nominal 19% increase with higher consumption of citrus fruits (OR = 1.19, 95% CI 1.01-1.40, p = 0.05). CONCLUSIONS: Distinguishing between those who experienced a moderate and a severe change in neuropathy, we found that citrus fruit and grain consumption may play a role in the severity of symptoms. Since there are no existing dietary recommendations for the management of CIPN, further research is needed to investigate whether there may be certain foods that could worsen or alleviate neuropathy symptoms associated with treatment for breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03413761 . Registered retrospectively on 29 January 2018.

Germline genetic variants in ABCB1, ABCC1 and ALDH1A1, and risk of hematological and gastrointestinal toxicities in a SWOG Phase III trial S0221 for breast cancer.

Hematological and gastrointestinal toxicities are common among patients treated with cyclophosphamide and doxorubicin for breast cancer. To examine whether single-nucleotide polymorphisms (SNPs) in key pharmacokinetic genes were associated with risk of hematological or gastrointestinal toxicity, we analyzed 78 SNPs in ABCB1, ABCC1 and ALDH1A1 in 882 breast cancer patients enrolled in the SWOG trial S0221 and treated with cyclophosphamide and doxorubicin. A two-SNP haplotype in ALDH1A1 was associated with an increased risk of grade 3 and 4 hematological toxicity (odds ratio=1.44, 95% confidence interval=1.16-1.78), which remained significant after correction for multiple comparisons. In addition, four SNPs in ABCC1 were associated with gastrointestinal toxicity. Our findings provide evidence that SNPs in pharmacokinetic genes may have an impact on the development of chemotherapy-related toxicities. This is a necessary first step toward building a clinical tool that will help assess risk of adverse outcomes before undergoing chemotherapy.

Genetic predictors of taxane-induced neurotoxicity in a SWOG phase III intergroup adjuvant breast cancer treatment trial (S0221).

Taxanes have resulted in improved survival for breast cancer patients, but often cause neurological toxicities. Identification of biomarkers related to toxicities could be important for dictating treatment regimen. We evaluated single nucleotide polymorphisms (SNPs) in the Fanconi Anemia (FA)/BRCA pathway in relation to grade 3/4 neurotoxicities in patients (n = 888) from SWOG0221, a phase III adjuvant trial for breast cancer of 4 dose/schedules of cyclophosphamide (C), doxorubicin (A), and paclitaxel (T). In a separate cohort, we measured the correlation of significant FANCD2 SNPs with corresponding gene expression. For FANCD2, permutation testing revealed that 4 (out of 20) SNPs were significantly associated with an almost two-fold increased risk of toxicity. Two FANCD2 haplotypes were also associated with neurological toxicity, with odds ratios (OR) in the overall population of 1.8 (95% confidence interval (CI) 1.3, 2.5) and 1.7 (95% CI, 1.2, 2.4). Although numbers were small, an African-American-specific haplotype was associated with an almost 3-fold increase in risk of neurologic toxicity (OR = 2.84, 95% CI = 1.2, 6.9). Expression analyses revealed that significant FANCD2 SNPs were associated with FANCD2 expression levels (P = 0.03). There were no associations between SNPs in BRCA1 and neurotoxicities. In this trial of CA+T for breast cancer, SNPs in FANCD2, but not in BRCA1, were associated with a 70-80% increase in the odds of grade 3/4 neurological toxicities and increased expression of the gene. If replicated, women with these genotypes should be closely monitored for toxicities and could be targeted for preventive measures or alternative therapeutic approaches.

Subcutaneous implantable venous access device erosion through the skin in patients treated with anti-vascular endothelial growth factor therapy: a case series.

Subcutaneous implantable venous access devices (IVADs) are commonly used in oncology practice. They facilitate the administration of chemotherapy, fluids and blood products. The incidence of IVAD-related complications is not uncommon, and includes infection, thrombosis and bleeding. IVAD erosion through the skin has been reported secondary to infection or inexperienced handling. We report three cases of IVAD erosion through the skin in patients treated with anti-vascular endothelial growth factor therapy. Anti-vascular endothelial growth factor agents are increasingly used in the treatment of solid tumors. This class of drugs has been associated with delayed wound healing and thromboembolism. To our knowledge, this is the first case series of IVAD erosion through skin, in patients receiving such therapy.

A data model to predict HER2 status in breast cancer based on the clinical and pathologic profiles of a large patient population at a single institution.

Recently published clinical trial data have produced compelling evidence for increased survival when Herceptin is administered to patients whose tumors are HER2 amplified. Therefore, the accuracy of HER2 status is essential to determine which patients should or should not receive Herceptin. Although HER2 results obtained by FISH and IHC are often in agreement, there is a persistent group of cases in which results are discordant, particularly among tumors with intermediate results. A multivariable analysis was undertaken to determine relative significance of various clinical and pathologic findings for patients diagnosed with infiltrating ductal carcinoma, and a data model was produced that predicts which patients are most likely to have HER2 amplified tumors. Correlates of HER2 amplification were higher Scarff-Bloom-Richardson grade, younger age at diagnosis, and a comedo ductal carcinoma in situ component.

A Southwest Oncology Group Randomized Phase II Study of doxorubicin and paclitaxel as frontline chemotherapy for women with metastatic breast cancer.

PURPOSE: To evaluate whether the high complete response (CR) rates for the combination of doxorubicin and paclitaxel in metastatic breast cancer observed in two European studies could be replicated in a multi-institutional cooperative group trial. PATIENTS AND METHODS: This was a phase II study with 91 patients randomized between either doxorubicin (60 mg/m(2)) followed immediately by paclitaxel (200 mg/m(2) over 3 h) (AT), or with doxorubicin (60 mg/m(2)) followed immediately by cyclophosphamide (600 mg/m(2)) (AC). Treatment was limited to six cycles of therapy for the doxorubicin and paclitaxel combination. Left ventricular ejection fraction was evaluated at on study and after four and six cycles of treatment on AT. RESULTS: Estimates of overall objective response were 31% (with 9% CR) and 39% (with 11% CR) for patients on the AT and AC regimens, respectively. Response was lower than anticipated on the standard AC arm. On average the reduction of LVEF was similar in the two groups, with no patients developing congestive heart failure during the six cycles of therapy, although one patient in the AT group died of delayed congestive heart failure. CONCLUSIONS: The results of this multi-institutional study in patients with metastatic breast cancer suggest that the combination of doxorubicin and paclitaxel is well tolerated with relatively low rates of cardiac toxicity if the total dose of doxorubicin is held to