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Objective & methods: This study tested associations of genotype-predicted activity of CYP3A4, other pharmacogenes, SLC28A7 (rs11648166) and ALPPL2 (rs28845026) with systemic concentrations of the endocrine therapies anastrozole and fulvestrant in SWOG S0226 trial participants. Results: Participants in the anastrozole-only arm with low CYP3A4 activity (i.e. CYP3A4*22 carriers) had higher systemic anastrozole concentrations than patients with high CYP3A4 activity (β-coefficient = 10.03; 95% CI: 1.42, 18.6; p = 0.025). In an exploratory analysis, participants with low CYP2C9 activity had lower anastrozole concentrations and higher fulvestrant concentrations than participants with high CYP2C9 activity. Conclusion: Inherited genetic variation in CYP3A4 and CYP2C9 may affect concentrations of endocrine therapy and may be useful to personalize dosing and improve treatment outcomes.

PurposeEfficient analytical methods are necessary to make reproducible inferences on single-item longitudinal ordinal patient-reported outcome (PRO) data. A thorough simulation study was performed to compare the performance of the semiparametric probabilistic index models (PIM) with a longitudinal analysis using parametric cumulative logit mixed models (CLMM).MethodsIn the setting of a control and intervention arm, we compared the power of the PIM and CLMM to detect differences in PRO adverse event (AE) between these groups using several existing and novel summary scores of PROs. For each scenario, PRO data were simulated using copula multinomial models. Comparisons were also exemplified using clinical trial data.ResultsOn average, CLMM provided substantially greater power than the PIM to detect differences in PRO-AEs between the groups when the baseline-adjusted method was used, and a small advantage in power when using the baseline symptom as a covariate.ConclusionAlthough the CLMM showed the best performance among analytical methods, it relies on assumptions difficult to verify and that might not be fulfilled in the real world, therefore our recommendation is the use of PIM models with baseline symptom as a covariate.

Diffuse large B cell lymphoma (DLBCL) is an aggressive but potentially curable malignancy; however, cure is highly dependent on the ability to deliver intensive, anthracycline-based chemoimmunotherapy. Nearly one third of cases of DLBCL occur in patients over age 75 years, and advanced age is an important adverse feature in prognostic models. Despite this incidence in older patients, there is no clear accepted standard of care due to under-representation of this group in large randomized clinical trials. Furthermore, insufficient assessments of baseline frailty and prediction of toxicity hamper clinical decision-making. Here, we present an ongoing randomized study of R-miniCHOP chemoimmunotherapy with or without oral azacitidine (CC-486, Onureg) for patients age 75 and older with newly diagnosed DLBCL and associated aggressive lymphomas. The incorporation of an oral hypomethylating agent is based on increased tumor methylation as a biologic feature of older patients with DLBCL and a desire to minimize the injection burden for this population. This is the first randomized study in this population conducted in North America by the National Clinical Trials Network (NCTN) and will enroll up to 422 patients including 40 patients in a safety run-in phase. This study incorporates an objective assessment of baseline frailty (the FIL Tool) and a serial comprehensive geriatric assessment (CGA). Key correlative tests will include circulating tumor DNA (ctDNA) assays at pre-specified timepoints to explore if ctDNA quantity and methylation patterns correlate with response. S1918 has the potential to impact future trial design and to change the standard of care for patients 75 years and older with aggressive lymphoma given its randomized design, prospective incorporation of geriatric assessments, and exploration of ctDNA correlatives. Trial registration: The trial is registered with ClinicalTrial.gov Identifier NCT04799275.

Adjuvant chemotherapy improves breast cancer survival but is associated with bothersome short- and long-term toxicity. Factors associated with toxicity, especially subacute toxicity up to 2 years following chemotherapy, have not been fully elucidated. The NRG Oncology/NSABP B-30 clinical trial compared 3 different doxorubicin-, cyclophosphamide-, and docetaxel-based chemotherapy regimens given over 3-6 months. Patients with hormone receptor-positive breast cancer received subsequent adjuvant endocrine therapy. From baseline through 24 months, 2156 patients completed questionnaires serially. We used multivariable probabilistic index models to identify factors associated with acute (>0-12 months) and subacute (>12-24 months) difficulties with pain, cognition, vasomotor symptoms, and vaginal symptoms. For all symptom domains, presence of symptoms prior to chemotherapy initiation were associated with symptoms in the subacute period (all p

BackgroundGraphical displays and data visualization are essential components of statistical analysis that can lead to improved understanding of clinical trial adverse event (AE) data. Correspondence analysis (CA) has been introduced decades ago as a multivariate technique that can communicate AE contingency tables using two-dimensional plots, while quantifying the loss of information as other dimension reduction techniques such as principal components and factor analysis.MethodsWe propose the application of stacked CA using contribution biplots as a tool to explore differences in AE data among treatments in clinical trials. We defined five levels of refinement for the analysis based on data derived from the Common Terminology Criteria for Adverse Events (CTCAE) grades, domains, terms and their combinations. In addition, we developed a Shiny app built in an R-package, visae, publicly available on Comprehensive R Archive Network (CRAN), to interactively investigate CA configurations based on the contribution to the explained variance and relative frequency of AEs. Data from two randomized controlled trials (RCT) were used to illustrate the proposed methods: NSABP R-04, a neoadjuvant rectal 2 × 2 factorial trial comparing radiation therapy with either capecitabine (Cape) or 5-fluorouracil (5-FU) alone with or without oxaliplatin (Oxa), and NSABP B-35, a double-blind RCT comparing tamoxifen to anastrozole in postmenopausal women with hormone-positive ductal carcinoma in situ.ResultsIn the R04 trial (n = 1308), CA biplots displayed the discrepancies between single agent treatments and their combinations with Oxa at all levels of AE classes, such that these discrepancies were responsible for the largest portion of the explained variability among treatments. In addition, an interaction effect when adding Oxa to Cape/5-FU was identified when the distance between Cape+Oxa and 5-FU + Oxa was observed to be larger than the distance between 5-FU and Cape, with Cape+Oxa and 5-FU + Oxa in different quadrants of the CA biplots. In the B35 trial (n = 3009), CA biplots showed different patterns for non-adherent Anastrozole and Tamoxifen compared with their adherent counterparts.ConclusionCA with contribution biplot is an effective tool that can be used to summarize AE data in a two-dimensional display while minimizing the loss of information and interpretation.

PurposeThe US National Cancer Institute Moonshot initiative calls for improving analysis and reporting of toxicity to inform treatment tolerability. We used existing clinician-reported adverse event (AE) and patient-reported outcome (PRO) questionnaire data from the randomized, double-blind NSABP B-35 clinical trial to explore reasons for anastrozole and tamoxifen discontinuation.MethodsPostmenopausal women with ductal carcinoma in situ treated with breast-conserving therapy were randomly assigned to anastrozole or tamoxifen for 5 years. The primary outcome for this analysis was time to treatment discontinuation. AEs were collected every 6 months post-random assignment from all 3,104 participants and summarized using the Toxicity Index (TI). PRO data were collected at baseline and every 6 months from 1,194 participants. Univariate and multivariable analyses of time to treatment discontinuation were performed using Cox regression models with TIs and PROs as time-dependent covariates.ResultsOf 3,046 analyzed participants, 869 (28.5%) discontinued treatment prematurely. In multivariable analysis, when both baseline PROs and on-treatment AEs were considered, thrombosis and arthralgia AEs were associated with discontinuation of both tamoxifen and anastrozole; additional AEs associated with discontinuation varied by drug. In addition, baseline pain interference, hot flashes, and unhappiness were associated with tamoxifen discontinuation (n = 589; overall Harrell's C-statistic 0.686 [95% CI, 0.640 to 0.732]); no baseline PROs were associated with anastrozole discontinuation (n = 589; overall Harrell's C-statistic 0.656 [95% CI, 0.630 to 0.681]). When only baseline PROs were examined, pain interference, hot flashes, and unhappiness were associated with shorter time to discontinuation of tamoxifen; only hot flashes were associated with discontinuation of anastrozole.ConclusionAnalysis of AEs using the TI yielded important insights into reasons for discontinuation of endocrine therapy that was enhanced by the addition of PRO baseline and treatment-emergent symptoms.

The article focuses on the rapid guideline update for combining endocrine therapy with targeted agents for advanced breast cancer based on biomarker alterations. Topics include selecting between alpelisib and capivasertib for patients with PIK3CA mutations, the appropriateness of monotherapy with endocrine agents, and the impact of treatment toxicity and patient comorbidities on therapy decisions.

PURPOSE: Taxane-induced peripheral neuropathy (TIPN) is a dose-limiting toxicity of paclitaxel in patients with cancer. TIPN prediction is challenging although patients with higher systemic paclitaxel exposure have higher TIPN risk. This study aimed to identify protein predictors of TIPN and paclitaxel pharmacokinetics (PK). METHODS: This is a retrospective analysis of a prospective study of females with early-stage breast cancer receiving weekly paclitaxel. TIPN was assessed using the sensory subscale of the European Organisation for Research and Treatment of Cancer QLQ-Chemotherapy-Induced Peripheral Neuropathy (CIPN)20 (CIPN8). A blood sample was collected within 10 minutes before the end of the first paclitaxel infusion to measure plasma proteins using liquid chromatography-mass spectrometry and to estimate maximum systemic paclitaxel concentration (C max). A second sample was collected approximately 24 hours after the first infusion to estimate paclitaxel time above threshold (T c >0.05). Linear mixed-effect and regression models were used to identify proteins predictive of TIPN and paclitaxel PK parameters, respectively, using a Bonferroni-adjusted α =.0006. RESULTS: Data from 36 participants were included in the analysis testing associations of 83 proteins with TIPN or PK. Higher levels of complement C3 were associated with more severe TIPN trajectories (P =.0002). No proteins were associated with either C max or T c >0.05 (all P >.0006). CONCLUSION: Complement C3 concentration at the end of initial paclitaxel infusion may be useful for identifying patients with breast cancer and potentially other tumor types who could benefit from TIPN prevention strategies to improve long-term treatment outcomes. [ABSTRACT FROM AUTHOR]

Background: Aromatase inhibitors (AI) reduce hormone receptor-positive breast cancer recurrence risk by about 50%. However, half of AI-treated postmenopausal women report new or worsened musculoskeletal symptoms (AIMSS), and 20% discontinue therapy prematurely. Acupuncture is effective for reducing symptoms, but many women are not able to access acupuncture therapy. We hypothesize that self-administered acupressure will reduce AIMSS. Materials and methods: Postmenopausal women who have been receiving treatment with an AI for more than 3 weeks but less than 2 years, and who report new or worsened joint pain or myalgias since starting AI therapy with worst pain of at least 4 out of 10 on a numerical rating scale, are eligible. Fifty participants will be enrolled and randomized 1:1 to treatment with true or sham acupressure for 12 weeks. Participants will self-apply pressure for 3 minutes to each of the 9 acupoints daily. All participants will complete a pain assessment weekly, and a battery of symptom questionnaires every 6 weeks. Optional stool samples will be collected after 0 and 12 weeks of acupressure to examine changes in the gut microbiome. The primary endpoint is change in worst pain on the Brief Pain Inventory-Short Form with 12 weeks of the acupressure intervention, evaluated with generalized estimating equations. Conclusion: Determination that self-administered acupressure reduces AIMSS in this randomized phase 2 pilot trial will lead to a larger randomized phase 3 clinical trial to confirm the efficacy of self-acupressure. Reduction of AI-related arthralgias may improve persistence with breast cancer therapy, breast cancer outcomes, and quality of life for AI-treated patients. Trial registration: Clinicaltrials.gov NCT06228768. [ABSTRACT FROM AUTHOR]

Background: Annual or biennial breast cancer screenings are recommended for women 40 and older. Women residing in rural areas have worse breast cancer survival rates than urban women, but no study has focused on rural versus urban residence in Utah regarding breast cancer screening and mortality. Methods: Cases (n = 14,516) were women aged > 39 diagnosed with a first primary invasive breast cancer between 1998 and 2017 in Utah. Controls (n = 63,117) without a history of breast cancer were matched to cases by birth year and birth state. Mammography screening status was identified by Current Procedural Terminology (CPT) codes. Logistic regression was used to assess the odds of breast cancer diagnosis. The Cox proportional hazards model was used to assess survival outcomes for rural and urban breast cancer patients based on screening status. Results: Screening mammography usage among rural patients diagnosed with breast cancer was lower (17.7%) than urban usage (20.7%). Usage of screening mammograms resulted in higher odds of breast cancer diagnosis at localized stage rather than at a regional and distant stage. Rural breast cancer cases had a higher proportion of deaths, and a lower proportion screened, than urban breast cancer cases. Hazard ratios showed that screening mammography usage was associated with better survival among both rural (HR = 0.50, 95% CI = 0.44–0.57) and urban (HR = 0.56, 95% CI = 0.39–0.82) breast cancer cases. Conclusion: Screening mammography usage was associated with better overall survival regardless of place of residence. Removing barriers and improving information regarding breast cancer screenings are needed in both rural and urban settings in Utah to increase mammography usage, with the overall goal of increasing early detection and outcomes of breast cancer. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the validity of the Utah statewide All‐Payer Claims Database (APCD), we compared breast cancer‐specific treatments and dosages with gold‐standard abstraction of medical records. Study Design: In this pilot study, breast cancer treatments were abstracted by a certified tumor registrar at the Utah Cancer Registry (UCR) for patients diagnosed in 2013 with breast cancer. The abstraction of medical records was the gold standard for comparison with treatments identified in the APCD. The reliability and agreement between the treatment identified in the APCD and abstraction data were measured with sensitivity and specificity. Dose consistency was measured with the intraclass correlation coefficients (ICC). Results: Compared with the 186 abstractions, the sensitivity of the APCD to identify chemotherapy agents was high: 89% for any agent, 91% for carboplatin, 83% for docetaxel, 82% for doxorubicin, or 94.7% for biologic therapy. The consistency between the chemotherapy dosage identified in the claims and the abstraction varied from 63% to 76%. For radiotherapy, the sensitivity of the claims to identify the completed radiotherapy regimen was 66%. The ICC between radiotherapy doses identified in the claims and the abstraction was 54% (95% confidence interval [CI], 48%, 67%). Conclusions: Employing these novel methods, the claims were highly reliable in identifying cancer treatment agents overall, namely carboplatin, docetaxel, and trastuzumab. The claims were of moderate utility in capturing the treatment dose information. In addition to the APCD, the use of multiple data sources improved the completeness of cancer treatment information. [ABSTRACT FROM AUTHOR]

Purpose: Few studies have specifically targeted symptom management interventions for adolescent and young adult (AYA) cancer survivors. A greater understanding of AYA cancer survivors' experiences with cancer treatment-related symptoms would help develop age-appropriate oncology symptom management interventions. The purpose of this qualitative analysis was to explore AYA cancer survivors' experience with cancer treatment-related symptoms. Methods: Nineteen post-treatment AYA cancer survivors (18–39 years old) who self-reported moderate–severe cancer treatment-related symptom severity participated in video conferencing or telephone interviews. The questions in the interview guide queried participants to share their experience with cancer treatment-related symptoms. Inductive content analysis was used to identify themes from the interviews. Results: The themes that emerged from the interviews included (1) cancer treatment-related symptoms negatively affected AYA cancer survivors' quality of life (e.g., symptoms served as a reminder of cancer recurrence possibility); (2) AYA cancer survivors' attitudes and feelings about communicating cancer treatment-related symptom concerns to clinicians (e.g., patient–clinician communication was bolstered when AYAs perceived that symptoms were being taken seriously); (3) AYA cancer survivors are interested in oncology symptom management clinical trials, but logistical challenges are barriers to participation; and (4) AYA cancer survivors are interested in nonpharmacological treatments for symptom management. Conclusion: Results highlight the burden of cancer treatment-related symptoms on day-to-day life among post-treatment AYA cancer survivors. Future work is needed to identify nonpharmacological symptom management interventions, strategies to improve patient–clinician communication about symptoms, and strategies to increase the visibility and accessibility of symptom management clinical trials for AYA cancer survivors. [ABSTRACT FROM AUTHOR]