Paclitaxel-induced neuropathy is an adverse event that often leads to therapeutic disruption and patient discomfort. We attempted to replicate a previously reported association between increased ...neuropathy risk and CYP2C8*3 genotype.
Demographic, treatment, and toxicity data were collected for paclitaxel-treated breast cancer patients who were genotyped for the CYP2C8*3 K399R (rs10509681) variant. A log-rank test was used in the primary analysis of European-American patients. An additional independent replication was then attempted in a cohort of African-American patients, followed by modeling of the entire patient cohort with relevant covariates.
In the primary analysis of 209 European patients, there was an increased risk of paclitaxel-induced neuropathy related to CYP2C8*3 status HR (per allele) = 1.93 (95% CI: 1.05–3.55), overall log-rank P = 0.006. The association was replicated in direction and magnitude of effect in 107 African-American patients (P = 0.043). In the Cox model using the entire mixed-race cohort (n = 411), each CYP2C8*3 allele approximately doubled the patient's risk of grade 2+ neuropathy (P = 0.004), and non-Europeans were at higher neuropathy risk than Europeans of similar genotype (P = 0.030).
The increased risk of paclitaxel-induced neuropathy in patients who carry the CYP2C8*3 variant was replicated in two racially distinct patient cohorts.
Background
Gene expression studies have identified distinct breast cancer subtypes, including luminal A, luminal B, Her2-enriched, and Basal-like, which differ in survival. The impact of subtypes on ...locoregional recurrence (LRR) after neoadjuvant chemotherapy for locally advanced breast cancer is unknown.
Methods
A total of 149 patients with stage II and III breast cancer with known ER, PR, and HER2 who underwent neoadjuvant chemotherapy from 1991 to 2005 were analyzed. We used clinical assays to distinguish luminal A (ER or PR+/HER2−,
n
= 55), luminal B (ER or PR+/HER2+,
n
= 25), HER2 (ER and PR−/HER2+,
n
= 20), and Basal-like (ER, PR, and HER2−,
n
= 49) subtypes. Covariates associated with LRR were evaluated by logistic regression and differences between subtypes tested using Wald χ
2
.
Results
Median follow-up was 55 months. Forty-nine (33%) patients had breast conservation (BCT) with radiation, 82 (55%) had a mastectomy with radiation, and 18 (12%) had a mastectomy alone. Eighty-eight (59%) were clinically node positive. A pathologic complete response was seen in 39 (26%) patients. LRR was identified in 11 (7%) patients: 2 after BCT (4%) and 9 after mastectomy (9%). LRR rates by subtype are as follows: luminal A 2 of 55 (4%), luminal B 1 of 25 (4%), Her2 1 of 20 (5%), and basal-like 7 of 49 (14%). Compared with all other subtypes, basal-like patients were more likely to have a LRR (7/49 (14%) vs. 4/100 (4%),
p
= 0.03).
Conclusions
Molecular subtype predicts LRR with basal-like patients more likely to develop LRR. These patients may be candidates for investigation with novel chemotherapy regimens and radiation sensitizing agents, which may offer improvement in local control.
Women with locally advanced breast cancer (LABC) who are breast conservation (BCT) candidates after neoadjuvant chemotherapy have the best long-term outcome and low local-regional recurrence (LRR) ...rates. However, young women are thought to have a higher risk of LRR based on historical data. This study sought to evaluate LRR rates in young women who undergo BCT after neoadjuvant chemotherapy. We identified 122 women aged 45 years or younger with American Joint Committee on Cancer (AJCC) Stage II to III breast cancer, excluding T4d, treated with neoadjuvant chemotherapy from 1991 to 2007 from a prospective, Institutional Review Board-approved, single-institution database. Data were analyzed using Fisher eExact test, Wilcoxon tests, and the Kaplan-Meier method. Median follow-up was 6.4 years. Fifty-four (44%) patients had BCT and 68 (56%) mastectomy. Forty-six per cent were estrogen receptor-positivity and 28 per cent overexpressed Her2. Mean pretreatment T size was 5.6 cm in the BCT group and 6.7 cm in the mastectomy group (P = 0.04). LRR rates were no different after BCT compared with mastectomy (13 vs 18%, P = 0.6). Higher posttreatment N stage (P < 0.001) and AJCC stage (P = 0.008) were associated with LRR but not pretreatment staging. Disease-free survival was better for patients achieving BCT, with 5-year disease-free survival rates of 82 per cent (95% CI, 69 to 90%) compared with 58 per cent (95% CI, 45 to 69%) for mastectomy (P = 0.03). Young women with LABC who undergo BCT after neoadjuvant chemotherapy appear to have similar LRR rates compared with those with mastectomy. This suggests that neoadjuvant chemotherapy may identify young women for whom BCT may have an acceptable risk of LRR.
Abstract
Background: Paclitaxel-induced neuropathy is a common, severe adverse event that seems to be related to cumulative drug exposure. Examining a neoadjuvantly treated cohort, we previously ...found increased neuropathy risk in patients carrying the CYP2C8*3 variant, which is associated with altered paclitaxel metabolism. To confirm this association, we examined the univariate association of CYP2C8*3 genotype and paclitaxel-induced neuropathy first in an independent cohort, then as a combined multivariable analysis.
Methods: CYP2C8*3 is more common in Caucasians (Allele Frequency AF=0.14) than other racial groups (African-American AF=0.04). To avoid potential issues with population stratification, initial univariate analysis was performed on 209 self-reported Caucasian breast cancer patients from a prospective cohort study (LCCC 9830) who were treated with paclitaxel-based regimens and had not been previously analyzed. The CYP2C8*3 (K399R) variant was genotyped on the Affymetrix DMET™ Plus Chip (Affymetrix, Inc., Santa Clara, CA, USA) at Gentris Corp. (Gentris Corp. Morrisville, NC) from germline DNA collected at diagnosis. The primary endpoint was the dose-at-grade 2+ neuropathy as defined by NCI CTC criteria. Statistical analysis was carried out using the log-rank test across the three genotype groups (*1/*1, *1/*3, *3/*3). The Caucasian cohort was then combined with 78 Caucasian patients from our previous neoadjuvant study and 124 non-Caucasian patients to build a multivariate Cox proportional hazards model. We performed model selection using backward elimination with AIC on a main effects model that included potential covariates: race, age, diabetes, paclitaxel schedule, and supplemental neuropathy therapy. A standard alpha=0.05 was used as the significance threshold for the primary log-rank analysis.
Results: The allele frequencies were similar to that expected and the distribution of alleles conformed to Hardy-Weinberg proportions for the Caucasian and non-Caucasian cohorts. 209 Caucasian breast cancer patients treated with paclitaxel were evaluated in the primary analysis, 35 (17%) of whom experienced grade 2+ peripheral neuropathy. The risk of neuropathy was significantly associated with CYP2C8*3 in the primary analysis (log-rank p = 0.006). A combined cohort of 411 patients were evaluable in the Cox model, 76 (18%) of whom experienced grade 2+ neuropathy during treatment. After backward elimination of covariates that did not contribute to the Cox model, increased age (HR = 1.02 95% CI: 1.00–1.04, p = 0.102), non-Caucasian race (HR = 1.76 1.05–2.93, p = 0.031), and CYP2C8*3 (Additive Model: HR=1.98 1.25–3.13, p = 0.004, no model assumed: p = 0.023) were associated with increased risk of paclitaxel-induced neuropathy.
Conclusions: We have replicated in an independent population the finding that patients carrying CYP2C8*3 are at increased risk of paclitaxel-induced neuropathy, with risk approximately doubling for each *3 variant carried. After adjusting for CYP2C8 genotype we detected an increase in neuropathy risk for non-Caucasians which is consistent with a previous finding and supports the need to better understand the overall etiology of neuropathy risk.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD10-07.
Abstract only
1076
Background: At present, effects of heterogeneity among breast cancer subtypes on timing and patterns of relapse are not fully understood. We characterized timing and patterns of ...distant recurrence among subtypes in women followed from initial diagnosis of breast cancer. Methods: 345 pts with newly diagnosed predominantly stage II-III breast cancer were treated with multiagent neoadjuvant therapy and subtyped by IHC: LumA (ER/PR+, HER2-); LumB (-ER/PR+, HER2+); Basal (triple neg); HER2 (HER2+,ER/PR-). Site-specific patterns of distant metastasis (DM) were examined among pts with single site of first DM. Sites of relapse were bone, CNS, viscera, lymph node, and soft tissue. Time to progression (TTP) was from date of initial diagnosis. Results: 108 patients developed metastatic disease; 65 demonstrated a single site of first DM. Basal subtype was associated with greater CNS and visceral metastases and fewer bone metastases than other subtypes. LumA subtype was associated with fewer CNS and greater bone metastases than other subtypes. See table. Dichotomizing as Basal v. non-Basal, bone v. no bone and CNS v. no CNS revealed identical trends with increased significance (p=0.01–0.03). TTP trended toward Basals demonstrating earliest DM and LumA latest. Excluding pts with DM at diagnosis, TTP differed between Basals and non-Basals within viscera (p=0.002, n=14/21, median TTP=10/21); CNS (p=0.047, n=8/7, median TTP=11/27); and bone (p=0.002, n=8/31, median TTP=9/21). Conclusions: Subtypes exhibit distinct timing and patterns of relapse within this largely homogeneous cohort of pts with predominantly locally advanced breast cancer, despite modern multiagent neoadjuvant therapy. Specifically, Basal cancers exhibit earlier recurrence and greater involvement of sites more difficult to treat than non-Basals. Within individual sites TTP differences between Basal and non-Basal tumors persist and are even more pronounced, suggesting that tumor microenvironment does not appear to be driving these differences.
Table: see text
No significant financial relationships to disclose.
Abstract only
576
Background: Adjuvant trials suggest that taxane (T) after doxorubicin and cyclophosphamide (AC) has little benefit in hormone receptor positive (HR+) patients compared to hormone ...receptor negative (HR-) patients, particularly if HER2 negative. Primary chemotherapy sensitivity is best determined from the neoadjuvant setting, therefore we sought to determine if HR+ primary tumors are less sensitive to taxane chemotherapy than HR- tumors. Methods: Clinical stage II-III breast cancer patients from the UNC Neoadjuvant Database who received sequential AC and T chemotherapy were evaluated. Clinical and radiographic responses were determined after AC and again after T allowing intrapatient sensitivity comparison, and included RECIST-defined complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). Hormone receptor status was determined at diagnosis, and subtypes included ER or PR positive, HER2 negative (HR+), ER and PR negative, HER2 positive (HER2+/ER-), and ER, PR and HER2 negative (TN). The ER or PR+, HER2+ group was too small for analysis. Patients who received neoadjuvant trastuzumab were excluded. Relationships of subtype and clinical response to AC and to T were assessed using Fisher's exact test. Results: 157 patients received neoadjuvant AC sequentially followed by T and were eligible for analysis. The majority of TN patients had PR to AC (56%), while the majority of HR+ patients had SD (54%). Of those with measurable disease after AC (n=127), a higher proportion of TN and HER2+/ER- patients had CR to T (43% and 45%, respectively) than HR+ patients (13%, p = 0.008 and p = 0.0393, respectively). While the majority of HR+ patients again had SD (52%), 42% responded to T. Conclusions: Our data suggests that TN and HER2+/ER- patients benefit more from neoadjuvant taxane chemotherapy than HR+ patients, however HR+ patients clearly derived benefit from T administered after AC.
Table: see text
No significant financial relationships to disclose.
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.
PURPOSE/BACKGROUND: The objective of this study was to create and test the interrater reliability of an Action Research Arm Test (ARAT) training program. The ARAT is a standardized assessment of ...upper extremity function used to measure occupational therapy (OT) outcomes for people who have experienced a stroke (1,2). Despite the use of the ARAT as an outcome measure, there is no training program for administration and scoring of the assessment, and few ARAT research studies report the use of training for the ARAT and most do not assess their interrater reliability. To obtain accurate results, the ARAT must have high interrater reliability, described as demonstrating that "with adequate training, practice, and recalibration, two different raters will consistently arrive at essentially the same score" (3). This calls into question the accuracy of the results of these studies. This study addresses this deficit by creating, training, testing and analyzing the ARAT training program. RESEARCH QUESTION: Do OT graduate students perform the ARAT, with high interrater reliability, after receiving a standardized training? DESIGN: A quantitative, pre-experimental, single group, pretest-posttest research design with a convenience sample of 15 OT graduate students with no prior knowledge of the ARAT. METHOD: Participants were provided with standardized written instructions of the ARAT, one week later they scored 3 pre-recorded client videos completing the ARAT. Two in-person training sessions followed including pictorial examples, detailed charts, a reviewed quiz, client video analysis, interaction with assessment tool, and Q&A of researchers. The final session participants scored 3 pre-recorded client videos (different clients from pre-testing videos) completing the ARAT. Data scoring sheets from each of the participants were entered into a secure database. Intraclass Correlation Coefficient (ICC) model 2 was used on IBMR SPSS for single item measures of each rater and for average rater scores and correct answers (determined by experienced researchers). RESULTS: The total interrater reliability using ICC (2,1) for the pre-training was 0.868 (95% confidence interval: .817-.910, F=117.468, P <.001) and post-training was 0.808 (95% confidence interval: .746-.865, F=65.17, P<.001). The total mean and correct scores ICC (2, k) pre-training: 0.929 (95% confidence interval: .880-.958, F=14.066, P<.001) and post-training: 0.959 (95% confidence interval: .931-.976, F=24.779, P<.001). CONCLUSION: The interrater reliability of the overall pre-training scores may have been higher because the participants scored the clients similarly pre-training but did not score accurately. Alternatively, the interrater reliability between the mean rater scores and correct scores improved from pre-to-post training. The participants scored much closer to the correct scores and therefore, were more accurate. This indicates that the ARAT training increased the interrater reliability and scoring accuracy. An ARAT training program can influence the accuracy of scoring for OT graduate students. IMPACT STATEMENT: This project contributes to the OT profession by showing the importance of advanced training for the accuracy of scoring and administering of assessments. OT practice may benefit from this evidence with the addition of an ARAT training protocol promoting the use of the ARAT. It may encourage the creation of similar trainings for other clinical assessments for increased accuracy and trustworthiness. HIGH INTERRATER RELIABILITY: ICC of 0.90 and above is considered reasonable reliability (4). INTERRATER RELIABILITY: The degree to which two or more raters can obtain the same ratings for a given variable (4).
The purpose of this paper was to investigate patterns of health care utilization leading up to diagnosis of necrotizing soft tissue infections of the genitalia and to identify risk factors associated ...with potential diagnostic delay.
IBM MarketScan Research Databases (2001-2020) were used to identify index cases of necrotizing soft tissue infections of the genitalia. We identified health care visits for symptomatically similar diagnoses (eg, penile swelling, cellulitis) that occurred prior to necrotizing soft tissue infections of the genitalia diagnosis. A change-point analysis identified the window before diagnosis where diagnostic opportunities first appeared. A simulation model estimated the likelihood symptomatically similar diagnosis visits represented a missed opportunity for earlier diagnosis. Patient and provider characteristics were evaluated for their associations with delay.
We identified 8,098 patients with necrotizing soft tissue infections of the genitalia, in which 4,032 (50%) had a symptomatically similar diagnosis visit in the 21-day diagnostic window, most commonly for "non-infectious urologic abnormalities" (eg, genital swelling; 64%): 46% received antibiotics; 16% saw a urologist. Models estimated that 5,096 of the symptomatically similar diagnosis visits (63%) represented diagnostic delay (mean duration 6.2 days; mean missed opportunities 1.8). Risk factors for delay included urinary tract infection history (OR 2.1) and morbid obesity (OR 1.6). Visits to more than 1 health care provider/location in a 24-hour period significantly decreased delay risk.
Nearly 50% of insured patients who undergo debridement for, or die from, necrotizing soft tissue infections of the genitalia will present to a medical provider with a symptomatically similar diagnosis suggestive of early disease development. Many of these visits likely represent diagnostic delay. Efforts to minimize logistic and cognitive biases in this rare condition may lead to improved outcomes if they lead to earlier interventions.
Background
Regional anesthesia allows for opioid‐sparing and enhanced recovery after many major surgeries. Erector spinae blockade, with reduced bleeding risk and the option for continuous infusion, ...offers an opportunity to promote this principle in pediatric liver transplant patients. Our goal was to evaluate pain scores, opioid use, and return of bowel function following continuous ESP blockade in pediatric liver transplant recipients.
Methods
This retrospective cohort study included extubated patients who received a liver transplant at St. Louis Children's Hospital from July 2016 to July 2021. The control group, which did not meet the criteria for ESP blockade and received standard analgesia regimens, was compared to the group receiving continuous ESP blockade. Measured outcomes included pain scores, opioid consumption through postoperative day two, date of first bowel movement, and length of stay in the ICU and the hospital.
Results
Patient demographics between control and ESP groups showed no significant differences. Pain scores between control and ESP groups also showed no significant differences. Intraoperative and postoperative opioid requirements, studied in oral morphine equivalents per kilogram (OME/kg), were significantly lower for patients with ESP blockade. Time to first bowel movement was also significantly earlier for the ESP group. No significant differences were found in length of ICU or hospital stay. There were no safety concerns or complications related to ESP blockade.
Conclusions
Use of continuous ESP blockade resulted in reduced opioid consumption through postoperative day two and earlier return of bowel function.
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