Clonal hematopoiesis in older patients with breast cancer receiving chemotherapy.

BACKGROUND: The expansion of hematopoietic stem cells carrying recurrent somatic mutations, termed clonal hematopoiesis (CH), is common in elderly individuals and is associated with increased risk of myeloid malignancy and all-cause mortality. Though chemotherapy is a known risk factor for developing CH, how myelosuppressive therapies affect the short-term dynamics of CH remains incompletely understood. Most studies have been limited by retrospective design, heterogeneous patient populations, varied techniques to identifying CH, and analysis of single timepoints. METHODS: We examined serial samples from 40 older women with triple-negative or hormone receptor-positive breast cancer treated on the prospective ADjuVANt Chemotherapy in the Elderly trial to evaluate the prevalence and dynamics of CH at baseline and throughout chemotherapy (6 and 12 weeks). RESULTS: CH was detected in 44% of patients at baseline and in 53% at any timepoint. Baseline patient characteristics were not associated with CH. Over the course of treatment, mutations exhibited a variety of dynamics, including emergence, expansion, contraction, and disappearance. All mutations in TP53 (n = 3) and PPM1D (n = 4), genes that regulate the DNA damage response, either became detectable or expanded over the course of treatment. Neutropenia was more common in patients with CH, particularly when the mutations became detectable during treatment, and CH was significantly associated with cyclophosphamide dose reductions and holds (P = .02). CONCLUSIONS: Our study shows that CH is common, dynamic, and of potential clinical significance in this population. Our results should stimulate larger efforts to understand the biological and clinical importance of CH in solid tumor malignancies. TRIAL REGISTRATION: ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT03858322). Clinical trial registration number: NCT03858322.

Older adult participation in cancer clinical trials: A systematic review of barriers and interventions.

Cancer is a disease of aging and, as the world's population ages, the number of older persons with cancer is increasing and will make up a growing share of the oncology population in virtually every country. Despite this, older patients remain vastly underrepresented in research that sets the standards for cancer treatments. Consequently, most of what we know about cancer therapeutics is based on clinical trials conducted in younger, healthier patients, and effective strategies to improve clinical trial participation of older adults with cancer remain sparse. For this systematic review, the authors evaluated published studies regarding barriers to participation and interventions to improve participation of older adults in cancer trials. The quality of the available evidence was low and, despite a literature describing multifaceted barriers, only one intervention study aimed to increase enrollment of older adults in trials. The findings starkly amplify the paucity of evidence-based, effective strategies to improve participation of this underrepresented population in cancer trials. Within these limitations, the authors provide their opinion on how the current cancer research infrastructure must be modified to accommodate the needs of older patients. Several underused solutions are offered to expand clinical trials to include older adults with cancer. However, as currently constructed, these recommendations alone will not solve the evidence gap in geriatric oncology, and efforts are needed to meet older and frail adults where they are by expanding clinical trials designed specifically for this population and leveraging real-world data.

A bimodular PKS platform that expands the biological design space.

Traditionally engineered to produce novel bioactive molecules, Type I modular polyketide synthases (PKSs) could be engineered as a new biosynthetic platform for the production of de novo fuels, commodity chemicals, and specialty chemicals. Previously, our investigations manipulated the first module of the lipomycin PKS to produce short chain ketones, 3-hydroxy acids, and saturated, branched carboxylic acids. Building upon this work, we have expanded to multi-modular systems by engineering the first two modules of lipomycin to generate unnatural polyketides as potential biofuels and specialty chemicals in Streptomyces albus. First, we produce 20.6 mg/L of the ethyl ketone, 4,6 dimethylheptanone through a reductive loop exchange in LipPKS1 and a ketoreductase knockouts in LipPKS2. We then show that an AT swap in LipPKS1 and a reductive loop exchange in LipPKS2 can produce the potential fragrance 3-isopropyl-6-methyltetrahydropyranone. Highlighting the challenge of maintaining product fidelity, in both bimodular systems we observed side products from premature hydrolysis in the engineered first module and stalled dehydration in reductive loop exchanges. Collectively, our work expands the biological design space and moves the field closer to the production of "designer" biomolecules.

Chemoinformatic-Guided Engineering of Polyketide Synthases.

Polyketide synthase (PKS) engineering is an attractive method to generate new molecules such as commodity, fine and specialty chemicals. A significant challenge is re-engineering a partially reductive PKS module to produce a saturated ß-carbon through a reductive loop (RL) exchange. In this work, we sought to establish that chemoinformatics, a field traditionally used in drug discovery, offers a viable strategy for RL exchanges. We first introduced a set of donor RLs of diverse genetic origin and chemical substrates  into the first extension module of the lipomycin PKS (LipPKS1). Product titers of these engineered unimodular PKSs correlated with chemical structure similarity between the substrate of the donor RLs and recipient LipPKS1, reaching a titer of 165 mg/L of short-chain fatty acids produced by the host Streptomyces albus J1074. Expanding this method to larger intermediates that require bimodular communication, we introduced RLs of divergent chemosimilarity into LipPKS2 and determined triketide lactone production. Collectively, we observed a statistically significant correlation between atom pair chemosimilarity and production, establishing a new chemoinformatic method that may aid in the engineering of PKSs to produce desired, unnatural products.

Barriers to Participation in Therapeutic Clinical Trials as Perceived by Community Oncologists.

PURPOSE: Despite considerable research on the barriers to enrollment in cancer therapeutic trials, few studies have elicited barriers from the perspective of community physicians, who provide the majority of cancer care. The purpose of this study was to characterize barriers to and facilitators of cancer therapeutic trials as perceived by oncologists in community practices. METHODS: Twenty semistructured interviews were conducted with oncologists at six community sites affiliated with City of Hope National Medical Center from March to June 2018. Responses were recorded digitally and transcribed. Data were analyzed using qualitative content analysis. RESULTS: Of the 20 participants, 4 (20%) were women, 13 (65%) had > 10 years of practice experience, and 16 (80%) reported that < 5% of their patients were enrolled in a therapeutic trial. Participants identified four system-level barriers: lack of appropriate trials for community-based settings, insufficient infrastructure support, restrictive eligibility criteria, and financial limitations; three physician-level barriers: lack of awareness of available trials, lack of knowledge of trial details, and lack of time; and two patient-level barriers: patient burden and negative beliefs/attitudes toward research. Efforts aimed to increase trial availability, clinical trial support personnel, and physician knowledge were identified as major facilitators. CONCLUSION: Community oncologists face numerous complex, multifaceted barriers to cancer therapeutic trial enrollment. Although expanding clinical research beyond the academic setting allows access to a larger and more diverse patient population, increasing generalizability and relevance of trial findings, there remains a substantial need for new strategies to improve cancer research delivery in the community.

Barriers to clinical trial enrollment of older adults with cancer: A qualitative study of the perceptions of community and academic oncologists.

OBJECTIVES: Oncologists can be one of the major barriers to older adult's participation in research. Multiple studies have described academic clinicians' concerns for not enrolling older adults onto trials. Although the majority of older adults receive their cancer care in the community, few studies have examined the unique challenges that community oncologists face and how they differ from oncologist-related barriers in academia. METHODS: Semi-structured interviews were conducted by telephone or face-to-face with 44 medical oncologists (24 academic-based and 20 community-based) at City of Hope from March to June 2018. Interviews explored oncologists' perceptions of barriers to clinical trial enrollment of older adults with cancer. Data were analyzed using qualitative content analysis. RESULTS: Of the 44 participants, 36% were women and 68% were in practice for >10 years. Among the entire sample, stringent eligibility criteria (n = 20) and oncologist concerns for treatment toxicities (n = 15) were the most commonly cited barriers. Compared to academic oncologists, community oncologists more often cited patient attitudes, beliefs, and understanding (n = 9 vs. n = 2) and caregiver burden (n = 6 vs. n = 0). In contrast, compared to community oncologists, academic oncologists more often cited oncologist bias (n = 10 vs. n = 3) and insufficient time/support (n = 4 vs. n = 1). CONCLUSIONS: Differences in perceptions among academic and community oncologists about trials suggest that barriers are multifaceted, complex, and vary by practice setting. Interventions to increase trial accrual among older adults with cancer may benefit from being tailored to address the unique barriers of different practice settings.

Physician Perceptions of the Use of Social Media for Recruitment of Patients in Cancer Clinical Trials.

Importance: Social media campaigns have been successfully implemented in nontherapeutic trials. However, evidence to support their utility in cancer therapeutic trials is limited. Objective: To examine physician attitudes toward and perceptions of social media use for therapeutic trial recruitment of patients with cancer. Design, Setting, and Participants: This qualitative study engaged 44 physicians (24 academic based and 20 community based) at the main academic and 6 affiliated community sites of City of Hope in Duarte, California. Semistructured interviews were conducted in person or by telephone from March to June 2018. An interview guide was developed to explore perceptions of social media use for accrual of cancer therapeutic trials. Responses were recorded digitally and transcribed. Data were analyzed using qualitative content analysis. Main Outcomes and Measures: Physicians' perceptions of the advantages and disadvantages of using social media for clinical trial recruitment, strategies to improve uptake of social media in clinical trials, and the barriers and facilitators to social media use for professional purposes in general. Results: Of the 44 participants, 16 (36%) were women, 30 (68%) had more than 10 years of practice experience, 24 (55%) practiced in academia, and 20 (45%) practiced in the community. Physicians most commonly cited increased trial awareness and visibility as an advantage of using social media for trial recruitment. Cited disadvantages were increased administrative burden and risk of misinformation. Physicians also reported a need for institutional-level interventions (eg, restructuring of clinical trial offices to include personnel with social media expertise), increased evidence-based approaches to social media use, and more physician training on the use of social media. Perceived facilitators to professional social media use were networking and education; barriers included lack of time and lack of evidence of benefit. Conclusions and Relevance: In this qualitative study, physicians recognized the benefits of using social media for clinical trial recruitment but noted that barriers, including increased administrative burden, increased time, and the risk of misinformation, remain. Future interventions to address these concerns are a required first step in increasing digital engagement for clinical trial accrual purposes.

Examining Public Communication About Kidney Cancer on Twitter.

PURPOSE: Several studies have described the content of Twitter conversations about lung, breast, and prostate cancer, but little is known about how the public uses Twitter to discuss kidney cancer. We sought to characterize the content of conversations on Twitter about kidney cancer and the participants engaged in these dialogues. METHODS: This qualitative study analyzed the content of 2,097 tweets that contained the key words kidney cancer from August 1 to 22, 2017. Tweets were categorized by content domain of conversations related to kidney cancer on Twitter and user types of participants in these dialogues. RESULTS: Among the 2,097 kidney cancer-related tweets analyzed, 858 (41.4%) were authored by individuals, 865 (41.2%) by organizations, and 364 (17.4%) by media sites. The most common content discussed was support (29.3%) and treatment (26.5%). Among the 2,097 tweets, 825 were unique tweets, and 1,272 were retweets. The most common unique tweets were about clinical trials (23.9%), most often authored by media sites. The most common retweets were about treatment (38.5%), most often authored by organizations. CONCLUSION: Twitter dialogues about kidney cancer are most commonly related to support and treatment. Our findings provide insights that may inform the design of new interventions that use social media as a tool to improve communication of kidney cancer information. Additional efforts are needed to improve our understanding of the value and direct utility of social media in improving kidney cancer care.