The predictive ability of the 313 variant–based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant

Abstract: Purpose: To evaluate the association between a previously published 313 variant–based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes. Methods: We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk. Results: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06–1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR = 1.15, 95% CI (1.07–1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS313 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively. Conclusion: The PRS313 can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS313 needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making

Potential of adaptive clinical trial designs in pharmacogenetic research, A simulation based on the IPASS trial

Background: An adaptive clinical trial design that allows population enrichment after interim analysis can be advantageous in pharmacogenetic research if previous evidence is not strong enough to exclude part of the patient population beforehand.With this design, underpowered studies or unnecessary large numbers of patients given an inferior/harmful treatment can be avoided. Objectives: Aim of this study was to illustrate the potential benefits of an adaptive trial design using a simulation model based on empirical data. Methods: The simulation was based on data of the IPASS trial, a phase III trial in non-small-cell lung cancer patients, aimed to study the efficacy and safety of gefitinib. A subgroup analysis showed that the tumor response of patients positive for the EGFR mutation was 71.2% with gefitinib versus 47.3% with control, and 1.1% versus 23.5%, respectively, in the mutation-negative subgroup.We simulated two scenarios of an adaptive trial, one using the response rates of the IPASS trial and one assuming an equal response rate (20%) in mutation-negatives, which is a more realistic assumption when planning a trial. The conditional power was calculated to decide at interim analysis whether (1) to continue the trial with the whole population, (2) to continue with only mutation-positive patients, or (3) to stop due to futility. Results: The simulation showed that the overall ±-level was maintained at 2,5% (one-sided). The first scenario resulted in a probability of .91 to continue with only mutation-positive. Continuation with the whole population in this scenario resulted in the largest bias in the treatment effect estimates. Scenario 2 resulted in a probability of .54 to continue with the whole population and .38 to continue with only mutation- positive. Stopping the trial for futility in this scenario lead to the largest bias in the treatment effect estimates. Conclusions: We demonstrated that if an adaptive trial would have been performed in the case of gefitinib, continuation with an enriched population would have been very likely, which would have lead to a smaller trial, with less EGFR mutation-negative patients unnecessarily exposed to the drug

Potential of adaptive clinical trial designs in pharmacogenetic research, A simulation based on the IPASS trial

Background: An adaptive clinical trial design that allows population enrichment after interim analysis can be advantageous in pharmacogenetic research if previous evidence is not strong enough to exclude part of the patient population beforehand.With this design, underpowered studies or unnecessary large numbers of patients given an inferior/harmful treatment can be avoided. Objectives: Aim of this study was to illustrate the potential benefits of an adaptive trial design using a simulation model based on empirical data. Methods: The simulation was based on data of the IPASS trial, a phase III trial in non-small-cell lung cancer patients, aimed to study the efficacy and safety of gefitinib. A subgroup analysis showed that the tumor response of patients positive for the EGFR mutation was 71.2% with gefitinib versus 47.3% with control, and 1.1% versus 23.5%, respectively, in the mutation-negative subgroup.We simulated two scenarios of an adaptive trial, one using the response rates of the IPASS trial and one assuming an equal response rate (20%) in mutation-negatives, which is a more realistic assumption when planning a trial. The conditional power was calculated to decide at interim analysis whether (1) to continue the trial with the whole population, (2) to continue with only mutation-positive patients, or (3) to stop due to futility. Results: The simulation showed that the overall ±-level was maintained at 2,5% (one-sided). The first scenario resulted in a probability of .91 to continue with only mutation-positive. Continuation with the whole population in this scenario resulted in the largest bias in the treatment effect estimates. Scenario 2 resulted in a probability of .54 to continue with the whole population and .38 to continue with only mutation- positive. Stopping the trial for futility in this scenario lead to the largest bias in the treatment effect estimates. Conclusions: We demonstrated that if an adaptive trial would have been performed in the case of gefitinib, continuation with an enriched population would have been very likely, which would have lead to a smaller trial, with less EGFR mutation-negative patients unnecessarily exposed to the drug

Cytochrome P-450 2D6 and 2C19 polymorphisms and consumption of care in psychiatric practice

Background: Cytochrome P-450 2D6 (CYP2D6) and 2C19 (CYP2C19) are known to contain functional polymorphisms that can alter the metabolic rate of many antidepressants (AD) and antipsychotics (AP). Individuals with no metabolic activity and with increased activity may be at risk for an unsatisfactory drug response. Objectives: Aim of this study was to assess the influence of CYP2D6 and CYP2C19 phenotypes on the consumption of care in psychiatric patients. Methods: The study was conducted in a psychiatric hospital in the Netherlands, including all admissions from July 2001 until July 2010, of patients genotyped for (at least) the CYP2D6 ∗3 ∗4 and gene multiplication and CYP2C19 ∗2. Patients were classified as poor metabolizers (PM), ultrarapid metabolizers (UM), intermediate metabolizers (IM) and extensive metabolizers (EM). To study the consumption of care, several outcome measures were calculated for PM and UM and compared to EM. Results: 7377 admissions were analyzed, belonging to 3859 unique patients. The total duration of hospital stays with AP and/or AD treatment was longer for CYP2D6 UM than for CYP2D6 EM (66 versus 48 days,

Use of preventive medication and supplements in general practice in patients in their last year of life: a Retrospective cohort study

Background: Several preventive medications and supplements become inappropriate in the last phase of life due to increased risk of adverse events caused by changed pharmacokinetics, drug-drug interactions, and changed care goals. Information on these preventive medication and supplements use in patients with a life-limiting illness in the home-care setting is limited. The primary aim of this study was to assess the use of four different groups of preventive drugs and supplements, which are inappropriate in adult patients with a life-limiting illness, living at home in the last year of life. The secondary aims were to assess reasons for discontinuing these drugs as documented in the general practitioners’ patient file and whether these reasons affected the time between medication discontinuation and death. Methods: We performed a retrospective cohort study using the routine primary care database of the Julius General Practitioners’ Network of the University Medical Centre Utrecht, a database consisting of routine care data from GPs from the city of Utrecht and its vicinity. Patients in the homecare setting with a life-limiting illness, diagnosed at least one year before death, were included. Descriptive analyses were used to describe the study population and the frequency of starting, using, and discontinuing medication and supplements in the last year of life. Results: A total of 458 of 666 included patients (69%) used at least one preventive drug in the last year of life. Vitamins were used by 36% of the patients, followed with 35% using cholesterol-lowering medication, 24% using calcium supplements and 9% using bisphosphonates. Bisphosphonates were discontinued by 70% of the users, calcium supplements by 61%, vitamins by 56% and cholesterol-lowering medication by 48% of the users, with a median interval between day of discontinuation and death of 119, 60, 110 and, 65 days, respectively. The median time between medication or supplement discontinuation and death was longest in patients with side effects and who had medication reviews. Conclusion: Many patients in their last phase of life in the home-care setting use inappropriate medication and supplements. Timely medication review may contribute to optimise medication use in the last year of life

Electronic Health Program to Empower Patients in Returning to Normal Activities After General Surgical and Gynecological Procedures: Intervention Mapping as a Useful Method for Further Development

BACKGROUND: Support for guiding and monitoring postoperative recovery and resumption of activities is usually not provided to patients after discharge from the hospital. Therefore, a perioperative electronic health (eHealth) intervention ("ikherstel" intervention or "I recover" intervention) was developed to empower gynecological patients during the perioperative period. This eHealth intervention requires a need for further development for patients who will undergo various types of general surgical and gynecological procedures. OBJECTIVE: This study aimed to further develop the "ikherstel" eHealth intervention using Intervention Mapping (IM) to fit a broader patient population. METHODS: The IM protocol was used to guide further development of the "ikherstel" intervention. First, patients' needs were identified using (1) the information of a process evaluation of the earlier performed "ikherstel" study, (2) a review of the literature, (3) a survey study, and (4) focus group discussions (FGDs) among stakeholders. Next, program outcomes and change objectives were defined. Third, behavior change theories and practical tools were selected for the intervention program. Finally, an implementation and evaluation plan was developed. RESULTS: The outcome for an eHealth intervention tool for patients recovering from abdominal general surgical and gynecological procedures was redefined as "achieving earlier recovery including return to normal activities and work." The Attitude-Social Influence-Self-Efficacy model was used as a theoretical framework to transform personal and external determinants into change objectives of personal behavior. The knowledge gathered by needs assessment and using the theoretical framework in the preparatory steps of the IM protocol resulted in additional tools. A mobile app, an activity tracker, and an electronic consultation (eConsult) will be incorporated in the further developed eHealth intervention. This intervention will be evaluated in a multicenter, single-blinded randomized controlled trial with 18 departments in 11 participating hospitals in the Netherlands. CONCLUSIONS: The intervention is extended to patients undergoing general surgical procedures and for malignant indications. New intervention tools such as a mobile app, an activity tracker, and an eConsult were developed. TRIAL REGISTRATION: Netherlands Trial Registry NTR5686; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=5686

Genetic susceptibility to radiation-induced breast cancer after Hodgkin lymphoma.

Female Hodgkin lymphoma (HL) patients treated with chest radiotherapy (RT) have a very high risk of breast cancer. The contribution of genetic factors to this risk is unclear. We therefore examined 211 155 germline single-nucleotide polymorphisms (SNPs) for gene-radiation interaction on breast cancer risk in a case-only analysis including 327 breast cancer patients after chest RT for HL and 4671 first primary breast cancer patients. Nine SNPs showed statistically significant interaction with RT on breast cancer risk (false discovery rate, <20%), of which 1 SNP in the PVT1 oncogene attained the Bonferroni threshold for statistical significance. A polygenic risk score (PRS) composed of these SNPs (RT-interaction-PRS) and a previously published breast cancer PRS (BC-PRS) derived in the general population were evaluated in a case-control analysis comprising the 327 chest-irradiated HL patients with breast cancer and 491 chest-irradiated HL patients without breast cancer. Patients in the highest tertile of the RT-interaction-PRS had a 1.6-fold higher breast cancer risk than those in the lowest tertile. Remarkably, we observed a fourfold increased RT-induced breast cancer risk in the highest compared with the lowest decile of the BC-PRS. On a continuous scale, breast cancer risk increased 1.4-fold per standard deviation of the BC-PRS, similar to the effect size found in the general population. This study demonstrates that genetic factors influence breast cancer risk after chest RT for HL. Given the high absolute breast cancer risk in radiation-exposed women, these results can have important implications for the management of current HL survivors and future patients

Genetic susceptibility to radiation-induced breast cancer after Hodgkin lymphoma.

Female Hodgkin lymphoma (HL) patients treated with chest radiotherapy (RT) have a very high risk of breast cancer. The contribution of genetic factors to this risk is unclear. We therefore examined 211 155 germline single-nucleotide polymorphisms (SNPs) for gene-radiation interaction on breast cancer risk in a case-only analysis including 327 breast cancer patients after chest RT for HL and 4671 first primary breast cancer patients. Nine SNPs showed statistically significant interaction with RT on breast cancer risk (false discovery rate, <20%), of which 1 SNP in the PVT1 oncogene attained the Bonferroni threshold for statistical significance. A polygenic risk score (PRS) composed of these SNPs (RT-interaction-PRS) and a previously published breast cancer PRS (BC-PRS) derived in the general population were evaluated in a case-control analysis comprising the 327 chest-irradiated HL patients with breast cancer and 491 chest-irradiated HL patients without breast cancer. Patients in the highest tertile of the RT-interaction-PRS had a 1.6-fold higher breast cancer risk than those in the lowest tertile. Remarkably, we observed a fourfold increased RT-induced breast cancer risk in the highest compared with the lowest decile of the BC-PRS. On a continuous scale, breast cancer risk increased 1.4-fold per standard deviation of the BC-PRS, similar to the effect size found in the general population. This study demonstrates that genetic factors influence breast cancer risk after chest RT for HL. Given the high absolute breast cancer risk in radiation-exposed women, these results can have important implications for the management of current HL survivors and future patients