Efficacy-effectiveness analysis on survival in a population-based real-world study of BRAF-mutated metastatic colorectal cancer patients treated with encorafenib-cetuximab.

BACKGROUND: Encorafenib-cetuximab has been approved for pretreated BRAFV600E-mutated metastatic colorectal cancer (mCRC) patients based on efficacy demonstrated in the randomized phase III BEACON trial. The aim of this real-world effectiveness study is to improve knowledge on the generalizability of trial results. METHODS: This population-based real-world study includes all mCRC patients in the Netherlands treated with encorafenib-cetuximab since approval. Individual patient data and pathology reports were collected. Overall survival (OS) was compared to BEACON and subgroup analyses were conducted for patients who would have been eligible and ineligible for BEACON. RESULTS: 166 patients were included with a median follow-up time of 14.5 months. Median OS was 6.7 months (95% CI:6.0-8.3) and differed from BEACON (9.3 months; 95% CI:8.0-11.3, p-value 0.002). Thirty-six percent of real-world patients would have been ineligible for the BEACON trial. Trial ineligible subgroups with symptomatic brain metastases and WHO performance status ≥2 had the poorest median OS of 5.0 months (95% CI:4.0-NR) and 3.9 months (95% CI:2.4-NR). CONCLUSION: This real-world cohort of mCRC patients treated with encorafenib-cetuximab showed a clinically relevant efficacy-effectiveness gap for OS. The chance of survival benefit from encorafenib-cetuximab in patients with brain metastases and/or WHO performance status ≥2 is negligible as neither efficacy nor effectiveness has been demonstrated.

Harnessing the Potential of Real-World Evidence in the Treatment of Colorectal Cancer: Where Do We Stand?

OPINION STATEMENT: Treatment guidelines for colorectal cancer (CRC) are primarily based on the results of randomized clinical trials (RCTs), the gold standard methodology to evaluate safety and efficacy of oncological treatments. However, generalizability of trial results is often limited due to stringent eligibility criteria, underrepresentation of specific populations, and more heterogeneity in clinical practice. This may result in an efficacy-effectiveness gap and uncertainty regarding meaningful benefit versus treatment harm. Meanwhile, conduct of traditional RCTs has become increasingly challenging due to identification of a growing number of (small) molecular subtypes. These challenges-combined with the digitalization of health records-have led to growing interest in use of real-world data (RWD) to complement evidence from RCTs. RWD is used to evaluate epidemiological trends, quality of care, treatment effectiveness, long-term (rare) safety, and quality of life (QoL) measures. In addition, RWD is increasingly considered in decision-making by clinicians, regulators, and payers. In this narrative review, we elaborate on these applications in CRC, and provide illustrative examples. As long as the quality of RWD is safeguarded, ongoing developments, such as common data models, federated learning, and predictive modelling, will further unfold its potential. First, whenever possible, we recommend conducting pragmatic trials, such as registry-based RCTs, to optimize generalizability and answer clinical questions that are not addressed in registrational trials. Second, we argue that marketing approval should be conditional for patients who would have been ineligible for the registrational trial, awaiting planned (non) randomized evaluation of outcomes in the real world. Third, high-quality effectiveness results should be incorporated in treatment guidelines to aid in patient counseling. We believe that a coordinated effort from all stakeholders is essential to improve the quality of RWD, create a learning healthcare system with optimal use of trials and real-world evidence (RWE), and ultimately ensure personalized care for every CRC patient.

The Impact of Hospice Care Structures on Care Processes: A Retrospective Cohort Study.

Background: Palliative care is subject to substantial variations in care, which may be shaped through adapting the organisational structures through which care is provided. Whilst the goal of these structures is to improve patient care, there is a lack of evidence regarding their effect on care processes and patient outcomes. Aims: This study aims to describe the relationship between care structures and the quantity and domains of care processes in hospice care. Design: Retrospective cohort study. Settings/Participants: Data were collected from Dutch hospice patient's clinical records and hospice surveys, detailing hospice structures, patient clinical characteristics and care processes. Results: 662 patients were included from 42 hospices, mean age 76.1 years. Hospices were categorised according to their care structures - structured clinical documentation and multidisciplinary meetings. Patients receiving care in hospices with structured multidisciplinary meetings had an increased quantity of documented care processes per patient on admission through identification (median 4 vs 3, P < .001), medication (2 vs 1, P = .004) and non-medication (1 vs 0, P < .001) interventions, monitoring (2 vs 1, P < .001) and evaluation (0 vs 0, P = .014), and prior to death. Similar increases were identified for patients who received care in hospices with structured documentation upon admission, but these changes were not consistent prior to death. Conclusions: This study details that the care structures of documentation and multidisciplinary meetings are associated with increased quantity and breadth of documentation of care processes in hospice care. Employing these existing structures may result in improvements in the documentation of patient care processes, and thus better communication around patient care.

Survival of Patients with Deficient Mismatch Repair Versus Proficient Mismatch Repair Metastatic Colorectal Cancer Receiving Curative-Intent Local Treatment of Metastases in a Nationwide Cohort.

BACKGROUND: It is unclear whether curative-intent local therapy of metastases is of similar benefit for the biological distinct subgroup of patients with deficient mismatch repair (dMMR) metastatic colorectal cancer (mCRC) compared with proficient mismatch repair (pMMR) mCRC. PATIENTS AND METHODS: In this nationwide study, recurrence-free (RFS) and overall survival (OS) were analyzed in patients with dMMR versus pMMR mCRC who underwent curative-intent local treatment of metastases between 2015 and 2018. Subgroup analyses were performed for resection of colorectal liver metastases (CRLM) and cytoreductive surgery ± hyperthermic intraperitoneal chemotherapy (CRS ± HIPEC). Multivariable regression was conducted. RESULTS: Median RFS was 11.1 months [95% confidence interval (CI) 8.5-41.1 months] for patients with dMMR tumors compared with 8.9 months (95% CI 8.1-9.8 months) for pMMR tumors. Two-year RFS was higher in patients with dMMR versus pMMR (43% vs. 21%). Results were similar within subgroups of local treatment (CRLM and CRS ± HIPEC). Characteristics differed significantly between patients with dMMR and pMMR mCRC; however, multivariable analysis continued to demonstrate dMMR as independent factor for improved RFS [hazard ratio (HR): 0.57, 95% CI 0.38-0.87]. Median OS was 33.3 months for dMMR mCRC compared with 43.5 months for pMMR mCRC, mainly due to poor survival of patients with dMMR in cases of recurrence in the preimmunotherapy era. CONCLUSION: Patients with dMMR eligible for curative-intent local treatment of metastases showed a comparable to more favorable RFS compared with patients with pMMR, with a clinically relevant proportion of patients remaining free of recurrence. This supports local treatment as a valuable treatment option in patients with dMMR mCRC and can aid in shared decision-making regarding upfront local therapy versus immunotherapy.

Prognostic value of Lynch syndrome, BRAFV600E , and RAS mutational status in dMMR/MSI-H metastatic colorectal cancer in a pooled analysis of Dutch and French cohorts.

BACKGROUND: Current knowledge on prognostic biomarkers (especially BRAFV600E /RAS mutations) in metastatic colorectal cancer (mCRC) is mainly based on mCRC patients with proficient mismatch repair (pMMR) tumors. It is uncertain whether these biomarkers have the same prognostic value in mCRC patients with deficient mismatch repair (dMMR) tumors. METHODS: This observational cohort study combined a population-based Dutch cohort (2014-2019) and a large French multicenter cohort (2007-2017). All mCRC patients with a histologically proven dMMR tumor were included. RESULTS: In our real-world data cohort of 707 dMMR mCRC patients, 438 patients were treated with first-line palliative systemic chemotherapy. Mean age of first-line treated patients was 61.9 years, 49% were male, and 40% had Lynch syndrome. BRAFV600E mutation was present in 47% of tumors and 30% harbored a RAS mutation. Multivariable regression analysis on OS showed significant hazard rates (HR) for known prognostic factors as age and performance status, however showed no significance for Lynch syndrome (HR: 1.07, 95% CI: 0.66-1.72), BRAFV600E mutational status (HR: 1.02, 95% CI: 0.67-1.54), and RAS mutational status (HR: 1.01, 95% CI: 0.64-1.59), with similar results for PFS. CONCLUSION: BRAFV600E and RAS mutational status are not associated with prognosis in dMMR mCRC patients, in contrast to pMMR mCRC patients. Lynch syndrome is also not an independent prognostic factor for survival. These findings underline that prognostic factors of patients with dMMR mCRC are different of those with pMMR, which could be taken into consideration when prognosis is used for clinical decision-making in dMMR mCRC patients and underline the complex heterogeneity of mCRC.

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.

Hospice Care Access: a national cohort study.

OBJECTIVES: Hospice care in the Netherlands is provided in three different types of hospice facilities: volunteer-driven hospices (VDH), stand-alone hospices (SAHs) and hospice unit nursing homes (HU). The organisational structures range from care directed by trained volunteers in VDH to care provided by multiprofessional teams in SAH and HU units.This study aims to characterise the patient populations who access Dutch hospices and describe the patient profiles in different hospice types. METHODS: A retrospective cohort study using clinical records of adult hospice inpatients in 2017-2018 from a random national sample of hospices. RESULTS: In total 803 patients were included from 51 hospices, mean age 76.1 (SD 12.4). 78% of patients had a primary diagnosis of cancer, 3% identified as non-Dutch cultural background and 17% were disorientated on admission. At admission, all patients were perceived to have physical needs. Psychological needs were reported in 37%, 36% and 34%, social needs by 53%, 52% and 62%, and existential needs by 23%, 30% and 18% of patients in VDH, SAH, HU units, respectively. 24%, 29% and 27% of patients from VDHs, SAHs and HUs had care needs in three dimensions, and 4%, 6% and 3% in all four dimensions. CONCLUSIONS: People who access Dutch hospices predominantly have cancer, and have a range of physical, psychological, social and existential needs, without substantial differences between hospice types. Patients with non-malignant disease and non-Dutch cultural backgrounds are less likely to access hospice care, and future policy would ideally focus on facilitating their involvement.

Patient-Reported Outcomes During Checkpoint Inhibition: Insight into Symptom Burden in Daily Clinical Practice.

CONTEXT: While praised for inducing durable anti-tumour responses, immune checkpoint inhibitors (ICI) also cause immune-related adverse events (irAEs) that can vary in severity and affect health-related quality of life (HRQL). OBJECTIVES: This study was performed to provide insight into the course of symptoms and the influence of irAEs on HRQL measured with the treatment-specific Utrecht Symptom Diary Immunotherapy (USD-I). METHODS: In this observational cohort study, melanoma or non-small lung cancer (NSCLC) patients treated with PD(L)1-inhibitors between February 2016 and December 2018 were included. Data on symptoms, wellbeing and influence of side effects on HRQL were obtained using the patient-scored, treatment-specific USD-I, which was completed as part of routine care. Patients scored symptom intensity on a 0-10 numeric rating scale (NRS); NRS≥3 considered clinically relevant. RESULTS: A total of 162 melanoma (55%) or NSCLC (45%) patients completed 1493 USDs (median seven per patient). Most common patient-reported clinically relevant symptoms were: inactivity, fatigue, pain, cough and sleeping problems. Symptom prevalence decreased during treatment. Patients generally reported a low influence of side effects on HRQL. A higher number of clinically relevant symptoms at a certain time point correlated with poorer wellbeing. CONCLUSIONS: These data illustrate that ICI-treatment is generally well tolerated. However, especially the number of clinically relevant symptoms can impact patients wellbeing. Systematic use of an ICI-tailored PROM could create a window to discuss symptoms in a structured way which may promote personalized care during treatment.

Toward a socio-spiritual approach? A mixed-methods systematic review on the social and spiritual needs of patients in the palliative phase of their illness.

BACKGROUND: Patients express a variety of needs, some of which are labeled social and spiritual. Without an in-depth exploration of patients' expressions of these needs, it is difficult to differentiate between them and allocate appropriate healthcare interventions. AIM: To gain insight into the social and spiritual needs of patients with a life-limiting illness and the distinction between these needs, as found in the research literature. DESIGN: A mixed-methods systematic review and meta-aggregation were conducted following the Joanna Briggs Institute (JBI) approach to qualitative synthesis and the PALETTE framework and were reported according to the PRISMA statement. This review was registered in PROSPERO (CRD42019133571). DATA SOURCES: The search was conducted in PubMed, EMBASE, CINAHL, Scopus, and PsycInfo. Eligible studies reported social and spiritual needs from the patients' perspective and were published between January 1st 2008 and October 2020. The quality of evidence was assessed using JBI Critical Appraisal Tools. RESULTS: Thirty-four studies (19 qualitative, 1 mixed-methods, and 14 quantitative) were included. The five synthesized findings encompassing social and spiritual needs were: being autonomous, being connected, finding and having meaning, having a positive outlook, and dealing with dying and death. CONCLUSION: What literature labels as social and spiritual needs shows great similarities and overlap. Instead of distinguishing social from spiritual needs based on patients' linguistic expressions, needs should always be explored in-depth. We propose a socio-spiritual approach that honors and preserves the multidimensionality of patients' needs and enables interdisciplinary teamwork to allocate patient-tailored care.

Validation of the Dutch version of the Edmonton Symptom Assessment System.

BACKGROUND: The Utrecht Symptom Diary (USD) is a Dutch and adapted version of the Edmonton Symptom Assessment System, a patient-reported outcome measurement (PROM) tool to asses and monitor symptoms in cancer patients. This study analyses the validity and responsiveness of the USD and the cutoff points to determine the clinical significance of a symptom score. METHODS: Observational longitudinal cohort study including adult in- and outpatients treated in an academic hospital in the Netherlands who completed at least one USD as part of routine care (2012-2019). The distress thermometer and problem checklist (DT&PC) was used as a reference PROM. Content, construct and criterion validity, responsiveness, and cutoff points are shown with prevalences, area under receiver operating characteristic (ROC) curve, Chi-squared test, Wilcoxon signed-rank test, and positive and negative predictive values, respectively. RESULTS: A total of 3913 patients completed 22 400 USDs. Content validity was confirmed for all added USD items with prevalences of ≥22%. All USD items also present on the DT&PC demonstrated a good criterion validity (ROC >0.8). Construct validity was confirmed for the USD as a whole and for the items dry mouth, dysphagia and well-being (P < .0001). USD scores differed significantly for patients when improving or deteriorating on the DT&PC which confirmed responsiveness. Optimal cutoff points (3 or 4) differed per symptom. CONCLUSION: The USD is a valid 12-item PROM for the most prevalent symptoms in cancer patients, which has content, criterion, and construct validity, and detects clinically important changes over time, in both curative and palliative phase.

Predicting Anxiety in Hospitalized Cancer Patients.

CONTEXT: Anxiety in patients with cancer is highly prevalent; yet it remains underestimated and inadequately assessed. Little is known about predictors for anxiety in hospitalized patients with cancer. Insight in predictors should improve recognition and enable a targeted approach. OBJECTIVES: To determine the prevalence of anxiety and predictors for anxiety in hospitalized patients with cancer at different stages of disease. METHODS: A cross-sectional analysis of patients with cancer admitted to the Utrecht University Medical Center in 2015-2018 was conducted. The Utrecht Symptom Diary, an adapted Dutch version of the Edmonton Symptom Assessment System, was used to assess symptom burden on a numeric rating scale (0 = no symptom and 10 = worst possible symptom). Scores ≥4 were considered clinically relevant. All patients completed the Utrecht Symptom Diary as part of routine care. The first questionnaire after admission was selected. Using multivariable linear regression, the predictive value of potential predictors on anxiety was analyzed. RESULTS: In total, 2144 patients were included, of which 22% reported clinically relevant anxiety. The prevalence of anxiety was highest (36%) in patients receiving symptom-directed palliation only. In the total group, female gender, younger age, depressed mood, sleeping problems, dyspnea, and cancer of the head and neck were predictive of anxiety. Throughout all stages of disease, depressed mood was consistently the strongest predictor. CONCLUSION: We found a high prevalence of anxiety in hospitalized patients with cancer. It is recommended to explore anxiety in hospitalized patients with cancer, in particular when they experience depressed mood. Structural use of a symptom diary during hospitalization facilitates the recognition of anxiety and concurrent symptoms.

What do Future Hospice Patients Expect of Hospice Care: Expectations of Patients in the Palliative Phase Who Might be in Need of Hospice Care in the Future: A Qualitative Exploration.

INTRODUCTION: Hospice care (HC) in the Netherlands is available for patients with life expectancies <3 months. Little is known about expectations of patients who might be in need of HC. This study aims to gain insight into expectations of patients regarding HC in order to ameliorate HC to become driven by patient needs. DESIGN: A generic qualitative study, using semistructured interviews and thematic analysis, is performed in the Netherlands from January to June 2018. A purposeful sample of 13 participants was drawn. RESULTS: Participants expected hospice admission only when the burden became unbearable and a home death cannot be reached. Participants expected a homely atmosphere, where one can continue the life lived at home as much as possible. Participants supposed empathic professional caregivers, capable of providing appropriate care. The general practitioner is expected to stay involved in the care process due to the mutual trust. Medical and daily care are required to be provided by competent professionals, where volunteers are expected to provide supportive care. All caregivers are supposed to provide a listening ear and "being there" for participants. Social care and spiritual care are generally projected to be private matters, unless it is requested. CONCLUSIONS: Patients in the palliative phase who might be in need of HC have specific expectations. Perceptions of HC in the public domain should be nuanced in response to these expectations, and information provision on HC should be improved. Then, expectations could be met to make HC more driven by patient needs and future oriented.

Who Are Hospice Patients and What Care Is Provided in Hospices? A Pilot Study.

BACKGROUND: Hospices provide multidimensional care. In the Netherlands, patients with <3 months estimated life expectancy have access to hospice care. Insight into patients admitted to hospices and the care provided is lacking. In preparation for a national multicenter study, a pilot study was performed. OBJECTIVE: The primary objective was to test the appropriateness of the study procedures and the availability of hospice patient records (HPRs), and patient and care characteristics. METHOD: A cross-sectional pilot study was performed using a descriptive exploratory design. Sixteen hospices were invited to participate, and HPRs from 8 deceased patients per hospice were selected. Data were collected using self-developed electronic case report forms. OUTCOMES: (1). Appropriateness of procedures: availability of HPRs and identified barriers and strategies. (2) Availability of patient and care characteristics in HPRs. RESULTS: In total, 104 HPRs of patients from 13 hospices were enrolled. Various types of HPRs were found with different availabilities: nurses' records were most available (98%) compared to volunteers' records (62%). Overarching barriers were as follows: ethical issues, lack of knowledge, and lack of communication. Information about the illness was most available (97%), whereas descriptions of experienced symptoms were least available (10%). CONCLUSION: Collecting HPRs is difficult and time-consuming. Specifically, data from separate records of home care nurses and general practitioners were difficult to come by. Patient and care characteristics were alternately present, which led to an extension of data collection in HPRs to 3 time periods. Piloting is essential to adjust study procedures and outcome measures to ensure a feasible national multicenter hospice study.

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.

No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer.

OBJECTIVE: Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3' UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. METHODS: Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). RESULTS: We found no association with risk of ovarian cancer (OR=0.99, 95% CI 0.94-1.04, p=0.74) or breast cancer (OR=0.98, 95% CI 0.94-1.01, p=0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR=1.09, 95% CI 0.97-1.23, p=0.14, breast cancer HR=1.04, 95% CI 0.97-1.12, p=0.27; BRCA2, ovarian cancer HR=0.89, 95% CI 0.71-1.13, p=0.34, breast cancer HR=1.06, 95% CI 0.94-1.19, p=0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR=0.94, 95% CI 0.83-1.07, p=0.38), breast cancer (HR=0.96, 95% CI 0.87-1.06, p=0.38), and all other previously-reported associations. CONCLUSIONS: rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.

Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers.

BACKGROUND: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes. METHODS: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. RESULTS: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. CONCLUSION: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. IMPACT: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.

Optimizing trial design in pharmacogenetics research: comparing a fixed parallel group, group sequential, and adaptive selection design on sample size requirements.

Two-stage clinical trial designs may be efficient in pharmacogenetics research when there is some but inconclusive evidence of effect modification by a genomic marker. Two-stage designs allow to stop early for efficacy or futility and can offer the additional opportunity to enrich the study population to a specific patient subgroup after an interim analysis. This study compared sample size requirements for fixed parallel group, group sequential, and adaptive selection designs with equal overall power and control of the family-wise type I error rate. The designs were evaluated across scenarios that defined the effect sizes in the marker positive and marker negative subgroups and the prevalence of marker positive patients in the overall study population. Effect sizes were chosen to reflect realistic planning scenarios, where at least some effect is present in the marker negative subgroup. In addition, scenarios were considered in which the assumed 'true' subgroup effects (i.e., the postulated effects) differed from those hypothesized at the planning stage. As expected, both two-stage designs generally required fewer patients than a fixed parallel group design, and the advantage increased as the difference between subgroups increased. The adaptive selection design added little further reduction in sample size, as compared with the group sequential design, when the postulated effect sizes were equal to those hypothesized at the planning stage. However, when the postulated effects deviated strongly in favor of enrichment, the comparative advantage of the adaptive selection design increased, which precisely reflects the adaptive nature of the design.

Consent in psychiatric biobanks for pharmacogenetic research.

In psychiatric practice, pharmacogenetics has the potential to identify patients with an increased risk of unsatisfactory drug responses. Genotype-guided treatment adjustments may increase benefits and reduce harm in these patients; however, pharmacogenetic testing is not (yet) common practice and more pharmacogenetic research in psychiatric patients is warranted. An important precondition for this type of research is the establishment of biobanks. In this paper, we argue that, for the storage of samples in psychiatric biobanks, waiving of consent is not ethically justifiable since the risks cannot be considered minimal and the argument of impracticability does not apply. An opt-out consent procedure is also not justifiable, since it presumes competence while the decisional competence of psychiatric patients needs to be carefully evaluated. We state that an enhanced opt-in consent procedure is ethically necessary, i.e. a procedure that supports the patients' decision-making at the time when the patient is most competent. Nevertheless, such a procedure is not the traditional exhaustive informed consent procedure, since this is not feasible in the case of biobanking.

Potential of adaptive clinical trial designs in pharmacogenetic research.

Adaptive trial designs can be beneficial in pharmacogenetic research when prior uncertainty exists regarding the exact role and clinical relevance of genetic variability in drug response. This type of design enables us to learn about the effect of the genetic variability on drug response and to immediately use this information for the remainder of the study. For different types of adaptive trial designs, we discuss when and how the designs are suitable for pharmacogenetic research: adaptation of randomization, adaptation of patient enrollment and adaptive enrichment. To illustrate the potential benefits of an adaptive design over a fixed design, we simulated an adaptive trial based on the results of the IPASS trial. With a simple model we show that for this example an adaptive enrichment design would have led to a smaller trial, with less EGF receptor mutation-negative patients unnecessarily exposed to the drug, without compromising the α level or reducing power.