Paclitaxel-containing Regimens Research Articles

Retrospective evaluation of Penguin Cold Caps for chemotherapy-induced alopecia

BackgroundScalp cooling is an increasingly recognized non-pharmacologic approach to minimize chemotherapy-induced alopecia (CIA). Several commercially available machine-based and manual scalp cooling systems are available; however, literature reports of effectiveness are highly variable. The purpose of this study was to determine real-world tolerability and subjective effectiveness of a manual cold capping system in minimizing CIA across a variety of patient race and hair types. This study was a single-institution review of outcomes from manual cold capping.MethodsWe identified retrospective cohort of adult patients who presented to discuss cold capping between January 14, 2019, and March 31, 2022. Data collected from medical records included demographics, decision to pursue/continue cold capping, diagnoses, chemotherapy regimens, hair characteristics (length, thickness, coarseness, type), and subjective perception of percentage of hair retained. Those with successful vs. unsuccessful cold capping (≥ 50% vs. < 50% of hair retained) were compared based on the patient-level factors of interest.FindingsA total of 100 patients initiated cold capping during the study period, and 95% of them completed cold capping. The majority of patients who started cold capping completed it. The median-reported percentage of hair maintained was 75%, and 82/89 (92.1% of patients) had favorable results, defined as ≥ 50% of hair retained. The only patient-level factor associated with favorable response was chemotherapy regimen, with fewer patients receiving doxorubicin-containing regimens having successful hair retention compared to other chemotherapy types (71.4% successful results vs. 95.7% for those receiving paclitaxel-containing regimens and 96.6% for those receiving docetaxel-containing regimens (p = 0.018). There was no difference in success based on patient race/ethnicity or hair characteristics.InterpretationThe overall effectiveness (92.1%) in this study is consistent to higher than many literature reports. One possible reason for the high success in our cohort is compliance with cold capping protocols, meaning applying the cap in the appropriate manner and wearing the cap for the prescribed durations, which may impact effectiveness.

Is ranitidine necessary as premedication for regimens containing paclitaxel? A non-inferiority study

ABSTRACT Background Histamine type-2-receptor antagonist drugs (H2-antagonists) have been used as standard treatment to prevent hypersensitivity reactions (HRs) in paclitaxel-containing regimens, however, their use has been strongly questioned. Ranitidine has been the most widely used H2-antagonist. Therefore, especially after its withdrawal from the market, the objective of this study is to determine the impact of its elimination from premedication on HR incidence. Methods A cohort, multicenter, observational, prospective, and non-inferiority study, including paclitaxel-naïve cancer patients, designed to determine the incidence of HRs of any grade associated with paclitaxel administration and analyze non-inferiority against the incidence estimated in the literature (20%), with 5% as the maximum difference (Δ). Patients with a solid neoplasm of any type/stage, who initiated treatment with paclitaxel without H2-antagonists in the premedication regimen were enrolled. Results A total of 441 patients were included, of whom 50 presented 54 HRs of any grade. The cumulative incidence was 11.3% (95%CI 8.5–14.7), thus fulfilling the hypothesis of non-inferiority. Of the overall HRs detected, 15 were grade ≥ 3 with a cumulative incidence of 3.4% (95%CI 1.9–5.5). Conclusions This study demonstrates that the elimination of ranitidine from paclitaxel premedication schedules is non-inferior in the development of HRs of any grade compared to the administration of H2-antagonists.

Plasma Cytokine Levels and Cytokine Genetic Polymorphisms in Patients with Metastatic Breast Cancer Receiving High-Dose Chemotherapy

Differences in the baseline levels of serum cytokines or in single-nucleotide polymorphisms (SNPs) in cytokine genes may be useful to predict outcomes for patients being treated for metastatic breast cancer. We have measured the plasma levels and characterized individual SNPs for IL-1RA, IL-1β, IL-2, IL-6 and TNFα in 130 patients with metastatic breast cancer treated with high-dose chemotherapy. Patients were treated with high-dose cyclophosphamide (Group 1, 74 patients) or high-dose paclitaxel-containing regimens (Group 2, 56 patients). A high plasma level of IL-1RA and a SNP in the IL-1RA gene indicated a better prognosis for patients in Group 1 (but not Group 2). However, the level of plasma IL-1RA did not correlate with the SNP genotype. A high plasma level of IL-6 or TNFα indicated a poorer outcome for patients in Group 1 although the SNP genotypes for the IL-6 and TNFα SNPs were not associated with differences in outcome. The plasma levels of IL-1β and IL-2 and the genotype of the IL-1β SNPs did not indicate differences in outcome. Although, individually, plasma levels of cytokine or “risk” SNP genotypes may not indicate outcome, in combination there was an increased trend to predict outcome for patients treated with high-dose cyclophosphamide but not high-dose paclitaxel. These results suggest that the immune cytokines may be useful as prognostic biomarkers in the treatment of patients with metastatic breast cancer treated with different types of chemotherapy.

Vitamin D insufficiency as a peripheral neuropathy risk factor in white and black patients in SWOG 0221.

12023 Background: Peripheral neuropathy (PN) is a treatment-limiting toxicity of paclitaxel. Black patients have higher rates of PN and vitamin D insufficiency, and our prior work suggests vitamin D insufficiency increases risk of paclitaxel-induced PN. The objective of this study was to validate that patients with vitamin D insufficiency have higher risk of paclitaxel-induced PN and investigate whether this explains racial disparities in PN risk. Methods: This retrospective validation study was conducted in the phase III SWOG 0221 (NCT00070564) trial comparing paclitaxel-containing chemotherapy regimens for early-stage breast cancer. Pre-treatment 25-hydroxy-vitamin D was quantified in cryopreserved serum. Males and patients who received less than a third of the paclitaxel treatment were excluded. The association between vitamin D insufficiency (≤20 ng/mL) and grade 3+ sensory PN was tested via logistic regression and then adjusted for self-reported race, age, paclitaxel schedule (QW vs Q2W), and body mass index. Results: Of the 1,116 female patients in the analysis, 169 (15.1%) experienced PN and 376 (33.7%) had vitamin D insufficiency. Vitamin D insufficiency was associated with higher PN risk (19.4% vs 13.0%, OR = 1.62, p = 0.005, Data Table). The association was borderline significant (OR = 1.44, p = 0.056) after adjustment for black race (OR = 2.41, p = 0.001), paclitaxel schedule (OR = 2.22, p &lt; 0.001), and age (OR = 1.03, p = 0.005). Compared with white patients (n = 943), black patients (n = 99) had more prevalent vitamin D insufficiency (77.8% vs 28.6%, OR = 8.72, p &lt; 0.001) and increased PN risk (29.3% vs 13.5%, OR = 2.66, p &lt; 0.001); adjusting for vitamin D insufficiency decreased but did not eliminate the higher PN risk in black patients (OR = 2.23, p = 0.002). Conclusions: Vitamin D insufficiency increases risk of paclitaxel-induced PN and partially explains the higher risk of PN in black patients. Prospective trials are needed to test whether vitamin D supplementation lessens PN and reduces disparities in treatment outcomes. [Table: see text]

Clinical information and management status of de novo stage IV breast cancer patients: a Chinese multicenter investigation (CSBrS-002).

Background:Although de novo stage IV breast cancer is so far incurable, it has entered an era of individualized treatment and chronic disease management. Based on systemic treatment, whether the surgical resection of primary or metastatic foci of de novo stage IV breast cancer can bring survival benefits is currently controversial. We aimed to explore the clinicopathological factors and current status of the management of de novo stage IV breast cancer in China to provide a reference for clinical decisions.Methods:Based on the assistance of Chinese Society of Breast Surgery, a retrospective study was conducted to analyze the clinical data of patients with de novo stage IV breast cancer in 33 centers from January 2017 to December 2018. The relationship between basic characteristic (age, menstrual status, family history, reproductive history, pathological type, estrogen receptor [ER] status, progesterone receptor [PR] status, human epidermal growth factor receptor 2 [HER2] status, Ki-67 percentage, and molecular subtype), and metastasis sites (lung metastasis, liver metastasis, and bone metastasis) was examined by Pearson Chi-square tests.Results:A total of 468 patients with de novo stage IV breast cancer were enrolled. The median age of the enrolled patients was 51.5 years. The most common pathological type of primary lesion was invasive carcinoma (97.1%). Luminal A, luminal B, HER2 overexpressing, and triple-negative subtypes accounted for 14.3%, 51.8%, 22.1%, and 11.8% of all cases, respectively. Age, PR status, and HER2 status were correlated with lung metastasis (χ2 = 6.576, 4.117, and 8.643 and P = 0.037, 0.043, and 0.003, respectively). Pathological type, ER status, PR status, and molecular subtype were correlated with bone metastasis (χ2 = 5.117, 37.511, 5.224, and 11.603 and P = 0.024, <0.001, 0.022, and 0.009, respectively). Age, PR status, HER2 status, Ki-67 percentage, and molecular subtype were correlated with liver metastasis (χ2 = 11.153, 13.378, 10.692, 21.206, and 17.684 and P = 0.004, <0.001, 0.001, <0.001, and 0.001, respectively). Combined treatment with paclitaxel and anthracycline was the most common first-line chemotherapy regimen for patients with de novo stage IV breast cancer (51.7%). Overall, 91.5% of patients used paclitaxel-containing regimens. Moreover, 59.3% of hormone receptor-positive patients underwent endocrine therapy.Conclusions:In 2018, 1.07% of patients from all studied centers were diagnosed with de novo stage IV breast cancer. This study indicated that 95.1% of patients received systemic therapy and 54.2% of patients underwent surgical removal of the primary lesion in China.

Incidence of Hypersensitivity Reactions to Carboplatin or Paclitaxel in Patients With Ovarian, Fallopian Tube, or Primary Peritoneal Cancer With or Without BRCA1 or BRCA2 Mutations.

The association of BRCA mutation status with hypersensitivity reactions (HSRs) to carboplatin has gained interest in recent years, particularly in patients with ovarian, fallopian tube, and primary peritoneal cancer. The primary objective of this study is to determine whether the presence of BRCA mutations increased the likelihood of HSRs to carboplatin. The incidence of HSRs to paclitaxel and symptom grade based on the Common Terminology Criteria for Adverse Events, version 4.0, were explored as secondary endpoints. A retrospective chart review of patients with ovarian, fallopian tube, or primary peritoneal cancer at the University of Arizona Cancer Center who underwent treatment with carboplatin-containing regimens and received genetic testing was performed. Institutional review board approval was obtained for this study. Fisher’s exact test was used to analyze the primary outcome. Out of 167 initial patients, 62 with germline test results constituted the evaluable sample. 15 of 62 (24.2%) BRCA-tested patients were treated with carboplatin monotherapy, while 44 of 62 (71.0%) patients were treated with paclitaxel-containing regimens. Hypersensitivity reactions occurred in 4 of 13 (30.8%) BRCA-mutated patients and 22 of 49 (44.9%) BRCA wild-type patients (p = .5291). Hypersensitivity reactions to paclitaxel occurred in 1 of 13 (7.7%) BRCA-mutated patients and 26 of 49 (53.1%) BRCA wild-type patients (p = .0039). Overall, there were 11 grade 1 reactions, 14 grade 2 reactions, and 16 grade 3 reactions to carboplatin. All reactions to carboplatin in BRCA-mutated patients were grade 1. All paclitaxel reactions manifested as grade 2. The sample size was the main study limitation. The presence of BRCA mutations was not statistically significantly associated with a higher incidence of HSRs to carboplatin, but was statistically significant with regards to paclitaxel.

Frequency of Immune Cell Subtypes in Peripheral Blood Correlates With Outcome for Patients With Metastatic Breast Cancer Treated With High-Dose Chemotherapy

BackgroundThe frequency of circulating leukocytes has been shown to be a prognostic factor in patients being treated for different types of cancer. In breast cancer, tumor-infiltrating leukocytes may predict patient outcome, but few studies have investigated such associations for circulating leukocytes. Patients and MethodsMultiparametric flow cytometry was used to examine the immunophenotypes of circulating peripheral blood mononuclear cells for 88 patients with metastatic breast cancer, which was then correlated to breast cancer–specific survival. Patients had been treated either with high-dose cyclophosphamide-containing regimens (group 1, n = 51 patients) or high-dose paclitaxel-containing regimens (group 2, n = 37 patients). ResultsThe frequency of peripheral blood CD14+ monocytes indicated prognosis for patients in group 1 (but not group 2), while higher levels of CD11c+ dendritic cells indicated a better prognosis for patients in group 2 (but not group 1). The frequency of a number of different CD4+ or CD8+ T cell subtypes also predicted prognosis for patients in group 2. For example, patients in group 2 with a higher frequency of circulating CD4+ or CD8+ naive T cells (CD45RA+CD95−CD27+CD28+) showed a poorer prognosis. In contrast, T cells were not associated with prognosis for patients in group 1. ConclusionCirculating leukocytes can predict clinical outcome for patients with breast cancer. Prediction of clinical outcome in this cohort of metastatic breast cancer patients was specific to the type of chemotherapy, and this finding is likely to apply to other therapies.

169P - Apatinib reverses resistance of paclitaxel-containing regimens in advanced gastric cancer: A phase II study

Background: In the previous observational study, apatinib plus paclitaxel (PTX)-based regimens showed a progression-free survival (PFS) benefit of 4.1 months in 7 gastric cancer patients (pts) resistant to PTX-contained chemotherapy (ASCO-GI 2017, abstr. 89). Hence, we conducted a single-arm phase II clinical trial (Ahead-G323) to confirm apatinib in reversing resistance of PTX-containing regimens. The intermediate analysis has been reported in ASCO 2018 (abstr. e16055). Herein, we further released the updated data. Methods: Advanced or metastatic gastric cancer pts with measurable lesions resistant to PTX-containing regimens (disease progression during or within 3 months after chemotherapy) were recruited. According to ECOG performance status (PS) and drug resistance profile, pts received apatinib (850 mg or 750 mg, po, qd) combined with PTX alone (80 mg/m2, d1, d8, and d15; q4w), POF (PTX 135 mg/m2, oxaliplatin 85 mg/m2, and leucovorin 400 mg/m2, d1; 5-FU 2400 mg/m2 for 46 h; q2w) or other PTX-containing regimen. Results: As of 6/21/2018, all 20 preplanned pts were enrolled. The baseline characteristics are shown in the table. Seventeen pts were available for response evaluation: 5 got partial response, 9 had stable disease, and 3 had progressive disease, resulting in an overall response rate of 29.4% and a disease control rate of 82.4%%, at best response. The median PFS was 4.2 (95%CI, 2.0–6.8) months. The 6-month PFS was 34.6% (95%CI, 9.7%–59.5%). Pts were still in follow-up. Moreover, the most common adverse events (AEs) were neutropenia (80.0%), leukopenia (75.0%), and hypoproteinemia (65.0%). The most common grade 3/4 AEs include neutropenia (30.0%), leukopenia (30.0%), and hypertensionTable169P Baseline characteristicsCharacteristicsN (%)Total20Age, yearsMedian (range)54.50 (45.5, 61.0)GenderFemale8 (40.0%)ECOG PS05 (25.0%)115 (75.0%)Metastatic lesion≤212 (60.0%)>28 (40.0%)Prior chemotherapy, lines17 (35.0%)28 (40.0%)35 (25.0%) Open table in a new tab (30.0%). Conclusions: This study demonstrated that apatinib combined with PTX-containing regimen could bring benefit on responses and survival for advanced or metastatic gastric cancer pts resistant to PTX-containing regimen. Clinical trial identification: NCT02697838, March 3, 2016. Legal entity responsible for the study: Fujian Cancer Hospital. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

A phase II study of apatinib on reversing resistance of paclitaxel-containing regimens in advanced gastric cancer (AGC).

e16055Background: Preclinical study has showed apatinib, an inhibitor of VEGFR-2, could reverse ABC-mediated multidrug resistance by downregulating ABC expression [Zhu, J, et al. 2017 WCLC]. Our pr...

The advantage of pemetrexed combined with platium chemotherapy treatement for advanced nonsquamous non-small-cell lung cancer (NSCLC) patients without drive oncogene.

e20527 Background:Platinum-based chemotherapy is the standard first-line treatment for non-squamous NSCLC patients without driver oncogene (EGFR, KRAS, and ALK mutations). However, it remains unknown that from which chemotherapy regimens can those patients get more benefit. Therefore, the study explore whether pemetrexed combined with platinum chemotherapy is superior to the other platinum-based chemotherapy regimens.Methods:We performed a retrospective study on 114 histologically or cytologically advanced IIIB-IV NSCLC patients admitted to Cancer Hospital from 1 Jan 2013 to 30 Dec 2015. The primary endpoint was the median progression free survival (PFS) and the disease control rate (DCR). And objective response was evaluated every two cycles by imaging according to the Response Evaluation Criteria In Solid Tumors (RECIST version 1.0). The multivariate logistic analyses were carried out by SPSS version 16.0. Results:114 patients received platinum-base doublet as first-line treatment. Among them, 59 patients underwent pemetrexed-containing regimens, and 55 patients received non-pemetrexed-containing regimens (38 patients for paclitaxel-containing regimens, 13 patients for gemcitabine-containing regimens, and 4 patients for other regimens.). The baseline characteristics between two groups were comparable ( p&gt;0.05). The median PFS of pemetrexed-containing regimens was significantly longer compared with that of non-pemetrexed-containing regimens (7.2 months [95% CI: 5.3–9.1] vs. 4.9 months [95% CI: 3.2–6.6], p%0.05). DCR of pemetrexed-containing regimens was better than that of non-pemetrexed-containing regimens in the multivariate logistic analysis (89.8% vs.74.5%, p%0.05).Conclusions:Pemetrexed-containing regimens displayed more benefit than the other chemotherapy regimens for non-squamous NSCLC patients without driver oncogene. However, large scale perspective study is warranted in the future.

Genetic heterogeneity beyond CYP2C8*3 does not explain differential sensitivity to paclitaxel-induced neuropathy

The development of paclitaxel-induced peripheral neuropathy (PIPN) is influenced by drug exposure and patient genetics. The purpose of this analysis was to expand on a previous reported association of CYP2C8*3 and PIPN risk by investigating additional polymorphisms in CYP2C8 and in hundreds of other genes potentially relevant to paclitaxel pharmacokinetics. Clinical data was collected prospectively in an observational registry of newly diagnosed breast cancer patients. Patients treated with paclitaxel-containing regimens were genotyped using the Affymetrix DMET™ Plus chip. Patients who carried the CYP2C8*2, *3, or *4 variant were collapsed into a low-metabolizer CYP2C8 phenotype for association with PIPN. Separately, all SNPs that surpassed quality control were assessed individually and as a composite of genetic ancestry for associations with PIPN. 412 paclitaxel-treated patients and 564 genetic markers were included in the analysis. The risk of PIPN was significantly greater in the CYP2C8 low-metabolizer group (HR = 1.722, p = 0.018); however, the influences of the *2 and *4 SNPs were not independently significant (*2: p = 0.847, *4: p = 0.408). One intronic SNP in ABCG1 (rs492338) surpassed the exploratory significance threshold for an association with PIPN in the Caucasian cohort (p = 0.0008) but not in the non-Caucasian replication group (p = 0.54). Substantial genetic variability was observed within self-reported racial groups but this genetic variability was not associated with risk of grade 2+ PIPN. The pharmacogenetic heterogeneity within a cohort of breast cancer patients is dramatic, though we did not find evidence that this heterogeneity directly influences the risk of PIPN beyond the contribution of CYP2C8*3.

Randomized Phase II Study of Ixabepilone or Paclitaxel Plus Carboplatin in Patients With Non–Small-Cell Lung Cancer Prospectively Stratified by Beta-3 Tubulin Status

Retrospective studies have reported that tumor expression of the beta-3 tubulin (β3T) isoform is an unfavorable prognostic factor in non-small-cell lung cancer (NSCLC) treated with tubulin-inhibiting chemotherapy. Ixabepilone is a tubulin-inhibiting agent with low susceptibility to multiple resistance mechanisms including β3T isoform expression in several tumor models. This randomized phase II study evaluated ixabepilone-based chemotherapy in stage IIIb/IV NSCLC, compared with paclitaxel-based chemotherapy. Tumor specimens were prospectively evaluated for β3T expression. Patients were stratified by β3T status (positive v negative) and randomly assigned at a ratio of 1:1 to receive ixabepilone (32 mg/m(2)) and carboplatin (area under concentration-time curve [AUC], 6) or paclitaxel (200 mg/m(2)) and carboplatin (AUC, 6) for up to six cycles. The primary end point was progression-free survival (PFS) in the β3T-positive subgroup. Ninety-five patients (β3T positive, 52; β3T negative, 43) received ixabepilone plus carboplatin; 96 patients (β3T positive, 49; β3T negative, 47) received paclitaxel plus carboplatin. No significant differences in median PFS were observed between arms for either subgroup (β3T positive, 4.3 months in both arms; β3T negative, 5.8 v 5.3 months). Ixabepilone did not significantly improve overall survival (OS) for the β3T-positive subset or the overall population. Adverse events were similar between the two arms and comparable with those in previous studies. There was no predictive value of β3T in differentiating clinical activity of ixabepilone- or paclitaxel-containing regimens. Ixabepilone did not improve PFS or OS in patients with β3T-positive tumors. β3T-positive patients had worse PFS relative to β3T-negative patients, regardless of treatment; hence, β3T expression seems to be a negative prognostic factor, but not a predictive factor, in advanced NSCLC treated with either ixabepilone or paclitaxel platinum-based doublets.

Abstract P2-10-11: Prognostic performance of the EndoPredict score in node-positive chemotherapy-treated ER+/HER2− breast cancer patients: results from the GEICAM/9906 trial.

Abstract Background: The EndoPredict (EP) score is an RNA-based multigene test to predict the likelihood of distant recurrence in ER-positive (ER+), HER2-negative (HER2−) breast cancer (BC) patients treated with adjuvant endocrine therapy. Results from two large randomized phase III trials involving endocrine therapy only (n &amp;gt; 1700) demonstrated a prognostic power of the EP score beyond what can be achieved by combining the commonly used clinicopathological parameters (Filipits M, 2011). The performance of the EP in chemotherapy-treated patients has not been evaluated yet. Here, we analyzed the EndoPredict score in node-positive ER+/HER2− BC patients from the GEICAM-9906 trial, treated with adjuvant chemotherapy followed by hormonal therapy. Methods: Patients included in this study participated in the GEICAM/9906 trial and were either treated with fluorouracil, epirubicin, and cyclophosphamide (FEC) or with FEC followed by weekly paclitaxel (FEC-P) (Martin M, 2008). ESR1 and ERBB2 gene expression were assessed by qRT-PCR in 800 formalin-fixed paraffin embedded (FFPE) tumor samples out of 1246 patients included in the GEICAM/9906 trial. The EndoPredict score (including eight prognostic genes) was successfully determined in 555 out of the 566 ER+/HER2− patients. Patients were assigned into two categories (high/low), according to the predefined EP cut-off value (Filipits M, 2011). The primary endpoint for the analysis was distant metastasis. Metastasis rates were estimated using the Kaplan–Meier method. Multivariate analysis was performed using Cox regression. Interaction between treatment effects and EP was tested as well. Results: Twenty-five percent of patients (n = 141) were classified as EP-low-risk. Kaplan Meier analysis demonstrated that the metastasis-free survival (MFS) was 92% in the EP-low risk vs. 69% in the EP-high-risk group (absolute difference of 23%, HR 4.4 (2.3–8.4) p &amp;lt; 0.0001). Multivariate analysis showed that EP is an independent prognostic parameter after adjustment for age, grade, lymph node status and tumor size. EP was found to be prognostic in pre- (p = 0.0002, HR = 5.5 (2.2–13.6)) and postmenopausal (p = 0.0129, HR = 3.3 (1.3–8.2)) BC patients. There were not statistically significant differences in MFS between treatment arms (FEC vs. FEC-P) neither in the high nor in the low-risk groups. Interaction test between chemotherapy arm and EP score was not significant. Conclusions: The results of this study shows that the EndoPredict score is an independent prognostic parameter in node-positive, ER+/HER2− BC patients treated with adjuvant chemotherapy followed by hormonal therapy. EndoPredict was not found to be predictive of weekly paclitaxel efficacy. Novel predictive biomarkers are needed to identify the small subset of patients with ER+/HER2− tumors that actually benefit from weekly paclitaxel-containing regimens. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-11.

Interrogation of polymorphisms in drug metabolism or transport genes and peripheral neuropathy during paclitaxel treatment.

10515 Background: Peripheral neuropathy is the most common severe toxicity in patients treated with paclitaxel. Putative genetic mutations in genes relevant to drug metabolism, distribution, and elimination may explain the differences in risk of neurotoxicity among patients. Using a genotyping platform that interrogates nearly 2,000 known variants in drug exposure genes, we hypothesized that polymorphisms could be identified which modulate a patient’s risk of neuropathy during paclitaxel treatment. Methods: Subjects included in this study were treated for breast cancer with paclitaxel-containing regimens. Clinical data, including patient characteristics and toxicity, was collected prospectively in an observational registry. Blood was collected at diagnosis and genotyped using the Affymetrix DMET Plus chip at Gentris. The primary endpoint was grade 2+ neuropathy as defined by NCI CTC criteria. Statistical analysis was carried out using Fisher’s exact test for each SNP, without assumption of a specific genetic model. For this hypothesis-generating study, a p-value of &lt;0.001 was selected for significance. Results: 412 breast cancer patients treated with paclitaxel were included in the analysis. The median age was 50, 107 (26%) were African-American, and 48 (12%) had preexisting diabetes. The prevalence of grade 2+ neuropathy was 18.5% in the cohort. After exclusion of SNPs based on call rate, Hardy-Weinberg equilibrium, and allele frequency, 564 SNPs were interrogated for an association with grade 2+ neuropathy. Two SNPs, rs3788007 (ABCG1_43706676G&gt;A[Intron]) and rs6163 (CYP17A1_195G&gt;T[S65S]), were associated with grade 2+ neurotoxicity p=0.0003 (OR=3.54, 95% CI: 1.77-7.72) and p=0.0008 (OR=0.35, 95%CI: 0.18-0.66), respectively. Conclusions: We identified two SNPs, both in genes not previously investigated in paclitaxel pharmacogenetic studies, which were associated with modified risk of paclitaxel-induced neuropathy. Both genes are implicated in endogenous steroid biology, which is thought to be relevant to neuropathy development, and one SNP (rs6163) is in high LD (r2=0.93) with a SNP recently reported to be associated with bortezomib-induced neuropathy.

CYP2C8*3 predicts benefit/risk profile in breast cancer patients receiving neoadjuvant paclitaxel

Paclitaxel is one of the most frequently used chemotherapeutic agents for the treatment of breast cancer patients. Using a candidate gene approach, we hypothesized that polymorphisms in genes relevant to the metabolism and transport of paclitaxel are associated with treatment efficacy and toxicity. Patient and tumor characteristics and treatment outcomes were collected prospectively for breast cancer patients treated with paclitaxel-containing regimens in the neoadjuvant setting. Treatment response was measured before and after each phase of treatment by clinical tumor measurement and categorized according to RECIST criteria, while toxicity data were collected from physician notes. The primary endpoint was achievement of clinical complete response (cCR) and secondary endpoints included clinical response rate (complete response+partial response) and grade 3+ peripheral neuropathy. The genotypes and haplotypes assessed were CYP1B1*3, CYP2C8*3, CYP3A4*1B/CYP3A5*3C, and ABCB1*2. A total of 111 patients were included in this study. Overall, cCR was 30.1% to the paclitaxel component. CYP2C8*3 carriers (23/111, 20.7%) had higher rates of cCR (55% vs. 23%; OR=3.92 [95% CI: 1.46-10.48], corrected p=0.046). In the secondary toxicity analysis, we observed a trend toward greater risk of severe neuropathy (22% vs. 8%; OR=3.13 [95% CI: 0.89-11.01], uncorrected p=0.075) in subjects carrying the CYP2C8*3 variant. Other polymorphisms interrogated were not significantly associated with response or toxicity. Patients carrying CYP2C8*3 are more likely to achieve clinical complete response from neoadjuvant paclitaxel treatment, but may also be at increased risk of experiencing severe peripheral neurotoxicity.

Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Abstract PD07-10: Breast Cancer Patients Carrying the CYP2C8*3 Variant Are More Likely To Achieve Clinical Complete Response from Neoadjuvant Paclitaxel Treatment

Abstract Background: Complete response to neoadjuvant chemotherapy is a good prognostic indicator in breast cancer patients. Neoadjuvant treatment has shown comparable efficacy to adjuvant treatment while providing an opportunity to evaluate tumor response to therapy. Paclitaxel is one of the most frequently used chemotherapeutic agents in the neoadjuvant setting. Using a candidate gene approach, we hypothesized that polymorphisms in genes relevant to the metabolism and transport of paclitaxel are associated with treatment efficacy and toxicity. Materials and Methods: Subjects included in this study were treated with paclitaxel-containing regimens in the neoadjuvant setting. Most received sequential anthracycline-and taxane-based therapy in which clinical response to each phase was collected separately. Clinical data, including patient and tumor characteristics and treatment outcomes, was collected prospectively in an observational registry. Treatment response was measured before and after each phase of treatment by clinical tumor measurement and categorized according to RECIST criteria while toxicity data was collected from physician notes. The primary endpoint of this study was achievement of clinical complete response (cCR) during taxane treatment. Secondary endpoints included clinical response rate (cRR, complete response + partial response, cPR), any grade 3 or higher toxicity, and grade 3 or higher neuropathy from paclitaxel treatment. Blood was collected at diagnosis and genotyped using pyrosequencing. The genotypes assessed were CYP1B1*3, CYP2C8*3, CYP3A4*1b, CYP3A5*3C, ABCB1 1236, ABCB1 2677, and ABCB1 3435. Results: 112 breast cancer patients treated with neoadjuvant paclitaxel were included in this analysis. The median age was 50, 28 were African-American, tumor stage included II (42 patients), III (60 patients), and presenting stage IV (10 patients), 60 were grade 3, 57 were ER+, and 32 were HER2+, of whom 21 received trastuzumab as part of the paclitaxel regimen. Response rate was 27.7% cCR, 31.3% cPR to the paclitaxel component. CYP2C8*3 carriers (23/112, 20.5%) had higher rates of clinical complete response to neoadjuvant paclitaxel treatment (55% versus 22%; p=.006). This association remained significant after adjustment for race, tumor grade, ER status, and whether paclitaxel treatment was preceded by another phase of chemotherapy. There were trends for increased clinical response rate (cRR; p=.052) and greater risk of grade 3 or higher peripheral neuropathy (p=.072) in subjects carrying the CYP2C8*3 variant. On multivariate analysis, other paclitaxel drug-metabolizing enzyme polymorphisms did not appear related to either response or toxicity. Discussion: CYP2C8 is the primary enzyme responsible for paclitaxel metabolism, and the *3 variant has demonstrated decreased catalytic activity toward paclitaxel in vivo, leading to increased exposure of the patient to the active parent compound. Our results demonstrate that patients carrying CYP2C8*3 are more likely to achieve clinical complete response from neoadjuvant paclitaxel treatment, but may also be at increased risk of experiencing severe peripheral neurotoxicity. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD07-10.

Use of growth factors associated with docetaxel and paclitaxel in patients with early-stage breast cancer in a community oncology center

e17548 Background: Docetaxel and paclitaxel are widely used in treating breast cancer (BC), and both have hematologic toxicity commonly managed by costly growth factors (GFs). However, the extent of GFs use in real-world clinical practice has not been well documented. Methods: The Georgia Oncology Specialist Database was used and contained chemotherapy, medical and pharmacy claims, and lab results for nearly 170,000 patients with various types of cancer (2003–2008). Patients with stage I-III BC receiving docetaxel- or paclitaxel-containing regimens as adjuvant therapy were followed from 1 week prior to docetaxel or paclitaxel (index drug) initiation to the earliest of death, loss to follow-up, switch in taxane, or end of 90-day period post last dose of index drug. Incidence of GFs use per person-year was compared using univariate negative binomial (NB) model, median time to first GFs use was compared using Wilcoxon test. Multivariate analyses were performed on number of utilizations and time to first utilization adjusting for potential confounders. Results: Compared with paclitaxel (n = 433), docetaxel cohort (n = 216) had lower incidence per person-year of erythroid stimulating agents (ESAs) use (8.01 vs. 11.72, p = 0.008), while similar incidence of myeloid growth factors (MGFs) use (8.51 vs. 5.07, p = 0.541). Lower MGFs utilization in docetaxel patients (ratio of number of utilization = 0.821, p = 0.033), and similar ESAs utilization (ratio of number of utilization = 0.920, p = 0.305) were found. While descriptive analysis showed paclitaxel patients received first ESAs sooner than docetaxel patients (median length: 23 vs. 7 days, p &lt; 0.001), and no difference in time to first MGFs use (median 8 days for both); multivariate analyses found docetaxel patients received first MGFs sooner (ratio of days = 0.828, p = 0.039), and no difference in time to first ESAs use (ratio of days = 1.091, p = 0.419). Conclusions: This analysis suggests that docetaxel is associated with lower utilization of MGFs. Studies examining the economic impact of GFs use associated with taxanes will need to be conducted. A potential limitation of this study is that the potential selection bias may not be fully adjusted. [Table: see text]

Impact of Third-Generation Drugs on the Activity of First-Line Chemotherapy in Advanced Non-Small Cell Lung Cancer: A Meta-Analytical Approach

The therapeutic equivalence of different third-generation agents in the first-line treatment of advanced non-small cell lung cancer (NSCLC) has long been accepted, although recent studies seem to suggest some superiority of gemcitabine- or docetaxel-containing regimens over other third-generation doublets. To assess the relative impact of different third-generation drugs on the activity of first-line chemotherapy in advanced non-small cell lung cancer by considering both response and progressive disease (PD) rates as outcome measures. Published and unpublished data were collected from randomized trials comparing a gemcitabine-, docetaxel-, vinorelbine- or paclitaxel-containing regimen with one or more gemcitabine-, docetaxel-, vinorelbine- or paclitaxel-free combinations. For each study, 2 x 2 tables were constructed for both response and immediate progression. Pooled odds ratios were calculated using a general variance-based method. Forty-five trials (11,867 patients) were eligible. The odds of obtaining an objective response to treatment were similar across different regimens. Gemcitabine-based chemotherapy was associated with a 14% lower risk for immediate progression, whereas patients receiving paclitaxel showed a 22% higher risk for having PD as the best response. Docetaxel treatment provided a nonsignificant 9% lower odds for progression. These data demonstrate that different third-generation regimens have comparable activity in chemotherapy-naïve patients with advanced NSCLC. Gemcitabine-based chemotherapy provides better disease control, whereas the risk for immediate progression is significantly higher when paclitaxel-containing regimens are used.

Parkin regulates paclitaxel sensitivity in breast cancer via a microtubule‐dependent mechanism

Parkin is an E3 ubiquitin ligase encoded by the Parkin gene (also called PARK2, located at 6q25.2-q27) and is involved in the pathogenesis of Parkinson's disease and the development of cancer. Recently, Parkin has been demonstrated to interact with the microtubule cytoskeleton. However, the biological implication of the Parkin-microtubule axis has been poorly explored. In this study, we report for the first time that Parkin modulates sensitivity of the chemotherapeutic agent paclitaxel in breast cancer, via a microtubule-dependent mechanism. Our data reveal that Parkin binds to the outer surface of microtubules and increases paclitaxel-microtubule interaction, resulting in enhanced paclitaxel-induced microtubule assembly and stabilization. Our data further show that Parkin promotes the activity of paclitaxel to trigger multinucleation and apoptosis, rendering breast cancer cells more sensitive to this drug. Moreover, Parkin expression correlates with the pathological response of tumours to preoperative paclitaxel-containing chemotherapy. In addition, expression of Parkin also correlates with the sensitivity of paclitaxel in primary cultures of breast cancer cells. Our results identify Parkin as a novel mediator of paclitaxel sensitivity in breast cancer. In addition, our study suggests that patients harbouring tumours with high Parkin level would be more likely to benefit from paclitaxel-containing regimens.