Ninety-four common genetic variants are confirmed to be associated with breast cancer. This study tested the hypothesis that breast cancer susceptibility variants may also be associated with ...chemotherapy-induced toxicity through shared mechanistic pathways such as DNA damage response, an association that, to our knowledge, has not been previously investigated. The study included breast cancer patients who received neoadjuvant/adjuvant chemotherapy from the Pharmacogenetic SNPs (PGSNPS) study. For each patient, a breast cancer polygenic risk score was created from the 94 breast cancer risk variants, all of which were genotyped or successfully imputed in PGSNPS. Logistic regression was performed to test the association with two clinically important toxicities: taxane- related neuropathy (n = 1279) and chemotherapy-induced neutropenia (n = 1676). This study was well powered (≥96%) to detect associations between polygenic risk score and chemotherapy toxicity. Patients with high breast cancer risk scores experienced less neutropenia compared to those with low risk scores (adjusted p-value = 0.06). Exploratory functional pathway analysis was performed and no functional pathways driving this trend were identified. Polygenic risk was not associated with taxane neuropathy (adjusted p-value = 0.48). These results suggest that breast cancer patients with high genetic risk of breast cancer, conferred by common variants, can safely receive standard chemotherapy without increased risk of taxane-related sensory neuropathy or chemotherapy-induced neutropenia and may experience less neutropenia. As neutropenia has previously been associated with improved survival and may reflect drug efficacy, these patients may be less likely to benefit from standard chemotherapy treatment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The complexity of neoplasia and its treatment are a challenge to the formulation of general criteria that are applicable across solid cancers. Determining the number of prior lines of therapy (LoT) ...is critically important for optimising future treatment, conducting medication audits, and assessing eligibility for clinical trial enrolment. Currently, however, no accepted set of criteria or definitions exists to enumerate LoT. In this article, we seek to open a dialogue to address this challenge by proposing a systematic and comprehensive framework to determine LoT uniformly across solid malignancies. First, key terms, including LoT and 'clinical progression of disease' are defined. Next, we clarify which therapies should be assigned a LoT, and why. Finally, we propose reporting LoT in a novel and standardised format as LoT N (CLoT + PLoT), where CLoT is the number of systemic anti-cancer therapies (SACT) administered with curative intent and/or in the early setting, PLoT is the number of SACT given with palliative intent and/or in the advanced setting, and N is the sum of CLoT and PLoT. As a next step, the cancer research community should develop and adopt standardised guidelines for enumerating LoT in a uniform manner.
To evaluate in patients with advanced colorectal cancer (CRC) three treatment regimens of oral capecitabine in order to select the most appropriate regimen for testing in phase III.
Three ...capecitabine schedules were evaluated in a randomized phase II design: arm A, 1,331 mg/m(2)/d bid continuously; arm B, 2,510 mg/m(2)/d bid intermittently (2 weeks on/1 week off); and arm C, 1,657 mg/m(2)/d plus oral leucovorin 60 mg/d bid intermittently (2 weeks on/1 week off).
One hundred nine patients were randomized; 39 patients were assessable for efficacy in arm A, 34 in arm B, and 35 in arm C. Patient characteristics were balanced in the arms. Confirmed tumor responses (partial response PR + complete response CR) were reported for eight patients with two CRs (21%; 95% confidence interval CI, 9% to 36%) in arm A, eight patients with one CR (24%; 95% CI, 11% to 41%) in arm B, and eight patients with two CRs (23%; 95% CI, 10% to 40%) in arm C. Median times to progression (TTP) in arms A, B, and C were 127, 230, and 165 days, respectively. Overall, more toxicity was seen with capecitabine plus leucovorin, particularly diarrhea and hand-foot syndrome. There was no grade 3 or 4 marrow toxicity.
Capecitabine offers a new, effective treatment option as an oral single agent in advanced CRC. Promising overall response rates were reported for all three regimens. The addition of leucovorin to the intermittent regimen had no marked effect on tumor response or median TTP. The intermittent single-agent capecitabine schedule is proposed for phase III evaluation, based on considerations of toxicity, dose-intensity, response rate, and TTP.
Purpose
We investigated whether the pharmacokinetics and tolerability of gefitinib were altered in patients with hepatic impairment due to cirrhosis or hepatic metastases in two open, parallel-group, ...multicenter studies.
Methods
In Study 1, subjects with normal hepatic function or mild, moderate, or severe hepatic impairment (Child-Pugh criteria) due to cirrhosis received single-dose gefitinib 250 mg (
n
= 10 per group). In Study 2, patients with solid malignant tumors with normal liver biochemistry (
n
= 18), moderate (
n
= 16), or severe (
n
= 7) hepatic impairment (liver biochemistry tests) due to metastases received gefitinib 250 mg daily for 28 days.
Results
In Study 1, the geometric mean area under the plasma concentration–time curve (AUC) for gefitinib was significantly higher in patients with hepatic impairment compared with healthy subjects; hepatic impairment was associated with reduced gefitinib plasma clearance, longer half-life, and reduced plasma metabolite levels. In Study 2, the geometric mean gefitinib steady-state AUC during the 24-h dosing interval was slightly, but not significantly, higher in patients with moderate hepatic impairment; there were, however, no significant differences between groups in gefitinib and metabolite pharmacokinetic parameters. In both studies, gefitinib was well tolerated across all cohorts.
Conclusions
We conclude that the effect of hepatic impairment on gefitinib pharmacokinetics depends on the underlying etiology of that impairment and its classification.
Objectives To quantify the use of sunbeds in young people across England, identify geographical variation, and explore patterns of use, including supervision.Design Two random location sampling ...surveys.Setting National Prevalence Study in England; Six Cities Study in Liverpool, Stoke/Stafford, Sunderland, Bath/Gloucester, Oxford/Cambridge, and Southampton.Participants 3101 children aged 11-17 in the National Prevalence study and 6209 in the Six Cities study.Results In the National Prevalence Study 6.0% (95% confidence interval 5.1% to 6.8%) of those aged 11-17 had used a sunbed. Use was higher in girls than in boys (8.6% (7.2% to 10.0%) v 3.5% (2.6% to 4.4%), respectively), in those aged 15-17 compared with those aged 11-14 (11.2% (9.5% to 12.9%) v 1.8% (1.2% to 2.4%), respectively), and in those from lower rather than higher social grades (7.6% (5.7% to 9.5%) v 5.4% (4.5% to 6.3%), respectively). Sunbed use was higher in the “north” (11.0%, 8.9% to 13.0%) than in the “midlands” (4.2%, 2.5% to 5.8%) and the “south” (4.2%, 3.3% to 5.2%). In the Six Cities Study, sunbed use was highest in Liverpool and Sunderland (20.0% (17.5% to 22.4%) and 18.0% (15.6% to 20.3%), respectively), with rates especially high in girls, those aged 15-17, or from lower social grades. Mean age of first use was 14, and 38.4% (34.7% to 42.1%) of children used a sunbed at least once a week. Nearly a quarter (23.0%, 19.8% to 26.1%) of children had used a sunbed at home (including home of friends/relatives), and 24.7% (21.0% to 28.4%) said they had used sunbeds unsupervised in a tanning/beauty salon or gym/leisure centre.Conclusions Sunbed use by children is widespread in England, is often inadequately supervised, and is a health risk. National legislation is needed to control sunbed outlets.
Highlights • In the era of targeted treatments, chemotherapy remains the backbone for treatment of breast cancer being an option for all molecular subtypes of the disease. This review is intended to: ...• Give a practical guideline for treating women with metastatic breast cancer (MBC) helping clinicians to make evidence based decisions following treatment with an anthracycline and a taxane. • Provide an update on cytotoxic drugs recently evaluated in late line MBC. • Identify priorities in the development of new cytotoxics for women with MBC.
Trastuzumab improves survival outcomes for patients with HER2-positive (HER2+) breast cancer, yet not all such women receive this important therapy. Trastuzumab was approved by the US Food and Drug ...Administration in 1998 and the European Medicines Agency in 2000 as treatment for HER2+ metastatic breast cancer (MBC). Observational studies between 2000 and 2015 in patients with HER2+ MBC suggest that nearly 12% in the United States, 27% to 54% in Europe, and 27.1% to 49.2% in China did not receive trastuzumab or any other HER2-targeted agent as first- and/or later-line for treatment of metastatic disease. In 2006, both agencies approved trastuzumab as adjuvant therapy for patients with HER2+ early breast cancer (EBC). Observational studies on real-world treatment patterns for HER2+ EBC between 2005 and 2015 suggest that 19.1% to 59.5% of patients across regions of North America, Europe, Australia, New Zealand, and China did not receive (neo)adjuvant trastuzumab. Data suggest that some patient subgroups, including older patients, those with HER2+/hormone receptor-positive disease, and women with small and/or node-negative HER2+ tumors, were less likely to receive anti-HER2 therapy. Barriers to accessing trastuzumab are multifactorial and include issues related to drug funding and high treatment costs for patients that have been reported worldwide. Herein, we review available literature on the use of, and barriers to, treatment with trastuzumab in patients with HER2+ breast cancer. We also discuss how the availability of safe and effective biosimilars might increase access to trastuzumab and allow greater use of anti-HER2 therapy, potentially improving patient outcomes.
How to identify optimal phase II trial designs Providing a practical guide containing the information needed to make crucial decisions regarding phase II trial designs, A Practical Guide to Designing ...Phase II Trials in Oncology sets forth specific points for consideration between the statistician and clinician when designing a phase II trial, including issues such as how the treatment works, choice of outcome measure and randomization, and considering both academic and industry perspectives. A comprehensive and systematic library of available phase II trial designs is included, saving time otherwise spent considering multiple manuscripts, and real-life practical examples of using this approach to design phase II trials in cancer are given. A Practical Guide to Designing Phase II Trials in Oncology: * Offers a structured and practical approach to phase II trial design * Considers trial design from both an academic and industry perspective * Includes a structured library of available phase II trial designs * Is relevant to both clinical and statistical researchers at all levels * Includes real life examples of applying this approach For those new to trial design, A Practical Guide to Designing Phase II Trials in Oncology will be a unique and practical learning tool, providing an introduction to the concepts behind informed decision making in phase II trials. For more experienced practitioners, the book will offer an overview of new, less familiar approaches to phase II trial design, providing alternative options to those which they may have previously used.
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