Scott Y. H. Kim

Personalized Oncology Through Integrative High-Throughput Sequencing: A Pilot Study

The mutations present in advanced cancers can be identified by integrative high-throughput sequencing to enable biomarker-driven clinical trials and, ultimately, treatment. First Steps to Personalized Cancer Treatment In an optimistic vision of personalized medicine, each cancer patient is treated with drugs tailored for their particular tumor. This sounds appealing, but is it even possible? Roychowdhury and his colleagues tested this approach by extensively characterizing cancers in several patients and then convening a Sequencing Tumor Board of experts to determine the appropriate treatment. With a combination of whole genome and exome sequencing plus sequencing of transcribed RNA, the authors were able to find informative mutations within 3 to 4 weeks, a short enough time to be useful clinically. To verify that their sequencing strategy would work before testing it on actual patients, they assessed two xenografts established from patients with metastatic prostate cancer. They found that one of these carried the common prostate cancer–specific gene fusion of TMPRSS2 and ERG and another, previously undescribed, gene fusion. Also, the androgen receptor gene was amplified and two tumor suppressors were inactivated. The Board concluded that this pattern of mutations could in theory be treated by combined block of the PI3K and androgen receptor signaling pathways. The authors then turned to an actual patient, a 46 year old with colorectal cancer, who had been unsuccessfully treated. Characterization of his metastatic tumor showed mutations in the oncogene NRAS, the tumor suppressor TP53, aurora kinase A, a myosin heavy chain and the FAS death receptor, plus amplification of CDK8. Of these, the Sequencing Tumor Board concluded that the NRAS and CDK8 aberrations could potentially be matched to clinical trials, although none were available at the time. Similar analysis of another patient with metastatic melanoma revealed a structural rearrangement in CDKN2C and HRas. Although the HRAS mutation has not been described before in melanoma, the Sequencing Tumor Board suggested that combined treatment with PI3K and MEK inhibitors would be suitable for this patient. The good news resulting from these studies was that the patients’ tumors were analyzed with in 24 days for ~

Activating ESR1 mutations in hormone-resistant metastatic breast cancer

3600, well within the cost of routine clinical tests. But aspects need improvement: Additional testing for epigenetic and small RNA variants will allow more informative characterization. Sequencing at higher depth or enrichment methods will be needed for tumors of lower purity. And perhaps most important, we need a broader array of clinical trials, as highlighted by the fact that none was available for these two patients. Individual cancers harbor a set of genetic aberrations that can be informative for identifying rational therapies currently available or in clinical trials. We implemented a pilot study to explore the practical challenges of applying high-throughput sequencing in clinical oncology. We enrolled patients with advanced or refractory cancer who were eligible for clinical trials. For each patient, we performed whole-genome sequencing of the tumor, targeted whole-exome sequencing of tumor and normal DNA, and transcriptome sequencing (RNA-Seq) of the tumor to identify potentially informative mutations in a clinically relevant time frame of 3 to 4 weeks. With this approach, we detected several classes of cancer mutations including structural rearrangements, copy number alterations, point mutations, and gene expression alterations. A multidisciplinary Sequencing Tumor Board (STB) deliberated on the clinical interpretation of the sequencing results obtained. We tested our sequencing strategy on human prostate cancer xenografts. Next, we enrolled two patients into the clinical protocol and were able to review the results at our STB within 24 days of biopsy. The first patient had metastatic colorectal cancer in which we identified somatic point mutations in NRAS, TP53, AURKA, FAS, and MYH11, plus amplification and overexpression of cyclin-dependent kinase 8 (CDK8). The second patient had malignant melanoma, in which we identified a somatic point mutation in HRAS and a structural rearrangement affecting CDKN2C. The STB identified the CDK8 amplification and Ras mutation as providing a rationale for clinical trials with CDK inhibitors or MEK (mitogen-activated or extracellular signal–regulated protein kinase kinase) and PI3K (phosphatidylinositol 3-kinase) inhibitors, respectively. Integrative high-throughput sequencing of patients with advanced cancer generates a comprehensive, individual mutational landscape to facilitate biomarker-driven clinical trials in oncology.

Current State of Research on Decision-Making Competence of Cognitively Impaired Elderly Persons

Breast cancer is the most prevalent cancer in women, and over two-thirds of cases express estrogen receptor-α (ER-α, encoded by ESR1). Through a prospective clinical sequencing program for advanced cancers, we enrolled 11 patients with ER-positive metastatic breast cancer. Whole-exome and transcriptome analysis showed that six cases harbored mutations of ESR1 affecting its ligand-binding domain (LBD), all of whom had been treated with anti-estrogens and estrogen deprivation therapies. A survey of The Cancer Genome Atlas (TCGA) identified four endometrial cancers with similar mutations of ESR1. The five new LBD-localized ESR1 mutations identified here (encoding p.Leu536Gln, p.Tyr537Ser, p.Tyr537Cys, p.Tyr537Asn and p.Asp538Gly) were shown to result in constitutive activity and continued responsiveness to anti-estrogen therapies in vitro. Taken together, these studies suggest that activating mutations in ESR1 are a key mechanism in acquired endocrine resistance in breast cancer therapy.

Trends in the prevalence and mortality of cognitive impairment in the United States: Is there evidence of a compression of cognitive morbidity?

As the number of cognitively impaired elderly persons increases, the need for evidence-based assessments of their capacity to consent to medical treatment and research participation will grow. The authors conducted an electronic and manual literature search for all English-language articles examining the decision-making capacity of elderly persons with dementia or cognitive impairment, reviewing articles in relation to key areas of methodological, clinical, and policy importance. The 32 relevant studies identified were highly heterogeneous, even in their definitions and measurements of decisional capacity. Although incapacity is common, many persons with dementia are capable of making their own medical and research decisions. In Alzheimer disease, memory and executive-function deficits predict decisional impairment. Still, at least in early stages of dementia, interventions may improve decisional abilities. Short and simple cognitive screening may be useful by identifying persons in need of more intensive evaluations. The use of expert judgment-based methods may mitigate the problem of a lack of a criterion standard for competence. Research into the decision-making competence of cognitively impaired elderly persons is a growing field. It is beginning to yield findings with practical implications for preserving the autonomy and welfare of this group of vulnerable elderly patients.

The ability of persons with Alzheimer disease (AD) to make a decision about taking an AD treatment.

Recent medical, demographic, and social trends might have had an important impact on the cognitive health of older adults. To assess the impact of these multiple trends, we compared the prevalence and 2‐year mortality of cognitive impairment (CI) consistent with dementia in the United States in 1993 to 1995 and 2002 to 2004.

Potential research participants’ views regarding researcher and institutional financial conflicts of interest

Objective: To examine the severity of impairments in the decision-making abilities (understanding, appreciation, reasoning, and choice) and competency to make a decision to use an Alzheimer disease (AD)-slowing medication in patients with AD and the relationships between these impairments, insight, and overall cognition. Methods: Semistructured in-home interviews were conducted with 48 patients with very mild to moderate AD and 102 family caregivers of patients with mild to severe AD recruited from the Memory Disorders Clinic of an AD center. The interview measured performance on the decision-making abilities and three expert psychiatrists’ judgment of competency based on their independent review of the patient interviews. Results: There was considerable variation in patients’ performance on the measures of decision-making abilities. Three expert raters found 19 of 48 (40%) of the subjects competent. Competent patients were more likely to show awareness of their symptoms, prognosis, and diagnosis. A sensitivity analysis suggests that a MMSE score is helpful in discriminating capacity from incapacity only when below 19 or above 23. Conclusions: Persons with mild to moderate Alzheimer disease (AD) have notable impairments in their ability to make an AD treatment decision, especially persons with moderate AD and persons who lack awareness of symptoms, prognosis, or diagnosis.

Broad Consent for Research With Biological Samples: Workshop Conclusions.

Background: Financial conflict of interest in clinical research is an area of active debate. While data exist on the perspectives and roles of academic institutions, investigators, industry sponsors, and scientific journals, little is known about the perspectives of potential research participants. Methods: The authors surveyed potential research participants over the internet, using the Harris Interactive Chronic Illness Database. A potential research participant was defined by: (1) self report of diagnosis by a health care professional and (2) willingness to participate in clinical trials. Email invitations were sent to 20 205 persons with coronary artery disease, breast cancer, or depression; a total of 6363 persons were screened; of these, 86% or 5478 met inclusion criteria and completed the survey. The outcome measures were respondents’ ratings on: importance of knowing conflict of interest information, whether its disclosure ought to be required, and its effect on willingness to participate—across seven widely discussed scenarios of financial conflicts of interest (ranging from commercial funding to equity ownership). Results: Majority responded that knowing conflict of interest information was “extremely” or “very” important; a larger majority felt financial conflicts of interest should be disclosed as part of informed consent (64% to 87%). In all seven scenarios, a majority was still willing to participate but in some scenarios a sizable minority would be wary of participation. Respondents were more wary of individual than institutional conflicts of interest. Illness group and sociodemographic factors had modest effects and did not affect the main trends. Conclusions: The prevailing practice of non-disclosure of financial conflicts of interest in clinical research appears contrary to the values of potential research participants.

Informed Consent for Pragmatic Trials — The Integrated Consent Model

Different types of consent are used to obtain human biospecimens for future research. This variation has resulted in confusion regarding what research is permitted, inadvertent constraints on future research, and research proceeding without consent. The National Institutes of Health (NIH) Clinical Centers Department of Bioethics held a workshop to consider the ethical acceptability of addressing these concerns by using broad consent for future research on stored biospecimens. Multiple bioethics scholars, who have written on these issues, discussed the reasons for consent, the range of consent strategies, and gaps in our understanding, and concluded with a proposal for broad initial consent coupled with oversight and, when feasible, ongoing provision of information to donors. This article describes areas of agreement and areas that need more research and dialogue. Given recent proposed changes to the Common Rule, and new guidance regarding storing and sharing data and samples, this is an important and timely topic.

What do people at risk for Alzheimer disease think about surrogate consent for research

The authors argue that informed consent is ethically necessary in pragmatic trials that randomly assign individual patients to treatments, even when treatment options are within the standard of care. They propose integration of a streamlined consent process into routine practice.

Decision-making capacity for research participation among individuals in the CATIE schizophrenia trial

Background: Research involving decisionally incapable adults remains an unsettled and controversial policy issue, especially for protocols that involve significant risk to participants. Few data exist to guide policymakers and IRBs Objective: Survey the views of persons at heightened risk for dementia regarding the acceptability of surrogate consent for biomedical research of varying levels of risks and potential benefits. Methods: Using a mail survey, the authors surveyed the participants at one of the sites of the Alzheimer’s Disease Anti-inflammatory Prevention Trial (all participants are 70 years old or older with at least one first-degree relative with dementia) and measured responses regarding the acceptability of surrogate consent for 10 research scenarios of varying degrees of risks and benefits (ranging from an observation study to a gene transfer protocol), given from the perspectives of social policy, personal preferences for self, and preferences when deciding on behalf of a loved one. Results: Two hundred twenty-nine of 259 eligible participants responded (88%). A large majority (>90%) found minimal risk studies as well as randomized clinical trials of new medications acceptable for surrogate consent. A smaller majority found the more invasive studies acceptable. Participants were more cautious when deciding for a loved one. General attitude toward biomedical research and scenario-specific risk perception were strong independent predictors. Demographic and personal history variables had relatively little effect. Conclusions: Laypersons at heightened risk of Alzheimer disease discriminate among research scenarios of varying risks and burdens. They are supportive of surrogate consent-based research even when the risks and burdens are significant to the subjects; these opinions appear to be based in part on their assessment of risks as well as on their general attitude toward biomedical research.