PTEN Loss Mediates Clinical Cross-Resistance to CDK4/6 and PI3Kα Inhibitors in Breast Cancer.

The combination of CDK4/6 inhibitors with antiestrogen therapies significantly improves clinical outcomes in ER-positive advanced breast cancer. To identify mechanisms of acquired resistance, we analyzed serial biopsies and rapid autopsies from patients treated with the combination of the CDK4/6 inhibitor ribociclib with letrozole. This study revealed that some resistant tumors acquired RB loss, whereas other tumors lost PTEN expression at the time of progression. In breast cancer cells, ablation of PTEN, through increased AKT activation, was sufficient to promote resistance to CDK4/6 inhibition in vitro and in vivo. Mechanistically, PTEN loss resulted in exclusion of p27 from the nucleus, leading to increased activation of both CDK4 and CDK2. Because PTEN loss also causes resistance to PI3Kα inhibitors, currently approved in the post-CDK4/6 setting, these findings provide critical insight into how this single genetic event may cause clinical cross-resistance to multiple targeted therapies in the same patient, with implications for optimal treatment-sequencing strategies. SIGNIFICANCE: Our analysis of serial biopsies uncovered RB and PTEN loss as mechanisms of acquired resistance to CDK4/6 inhibitors, utilized as first-line treatment for ER-positive advanced breast cancer. Importantly, these findings have near-term clinical relevance because PTEN loss also limits the efficacy of PI3Kα inhibitors currently approved in the post-CDK4/6 setting.This article is highlighted in the In This Issue feature, p. 1.

Development of an illustrated medication schedule as a low-literacy patient education tool.

OBJECTIVE: Patients with low health literacy have difficulty understanding prescription drug labels and other medication instructions. This article describes the development, implementation, and preliminary evaluation of an illustrated medication schedule (a "pill card") that depicts a patient's daily medication regimen using pill images and icons. METHODS: Participants in a randomized controlled trial who were assigned to receive the pill card intervention described their use of the card and its perceived effectiveness. Responses were analyzed by level of patient literacy and other characteristics. RESULTS: Among the 209 respondents, 173 (83%) reported using the pill card when they initially received it, though use declined to 60% approximately 3 months later. Patients with inadequate or marginal literacy skills, less than high school education, or cognitive impairment were most likely to refer to the card on a regular basis initially and at 3 months (p<0.05). Most pill card users (92%) rated the tool as very easy to understand, and 94% found it helpful for remembering important medication information, such as the name, purpose, or time of administration. CONCLUSION: Nearly all patients considered an illustrated medication schedule to be a useful and easily understood tool to assist with medication management. Patients with limited literacy skills, educational attainment, or cognitive function referred to the aid with greater frequency. PRACTICE IMPLICATIONS: Picture-based instructions promote better understanding of prescription medications, particularly among patients with limited literacy skills or cognitive impairment, and should be used more widely in practice.

High-Content Biopsies Facilitate Molecular Analyses and Do Not Increase Complication Rates in Patients With Advanced Solid Tumors.

PURPOSE: Precision oncology relies on frequent pathologic, molecular, and genomic assessments of tumor tissue to guide treatment selection, evaluate pharmacodynamic effects of novel agents, and determine drug resistance mechanisms. Newer forms of analyses such as drug screens in cell lines and patient-derived xenografts demand increasing amounts of tissue material. It remains unknown how the need for serial biopsies with large numbers of tumor cores relates to tissue yields and biopsy complication rates. MATERIALS AND METHODS: In this study, we performed a retrospective analysis of 199 focal liver biopsies performed in 143 patients in the setting of oncologic research protocols (research biopsy group) over a 4-year period at a single-intervention oncology service. Practice patterns and complication rates were compared with those related to 1,522 consecutive biopsies performed in 1,154 patients in whom two cores were obtained for standard clinical management of patients (standard biopsy). RESULTS: In the research biopsy group, 1,100 tissue cores (average, 5.5 cores per procedure) were harvested and distributed to trial sponsors, internal research laboratories, and pathology services. The complication rate in this cohort was 0.5% for major complications (one of 199) and 1.0% for minor complications managed conservatively (two of 199). In the standard biopsy control group, major complications were observed in 1.4% of procedures (22 of 1,522) and minor complications in 0.2% (three of 1,522). These complication rates were not statistically different. CONCLUSION: Harvesting extra tissue cores through coaxial needles during focal liver biopsies does not increase complication rates and yields valuable tissue for additional experimental testing.

Use of handheld computers in medical education. A systematic review.

BACKGROUND: Over the past decade, handheld computers (or personal digital assistants [PDAs]) have become a popular tool among medical trainees and physicians. Few comprehensive reviews of PDA use in medicine have been published. OBJECTIVE: We systematically reviewed the literature to (1) describe medical trainees' use of PDAs for education or patient care, (2) catalog popular software applications, and (3) evaluate the impact of PDA use on patient care. DATA SOURCES: MEDLINE (1993 to 2004), medical education-related conference proceedings, and hand search of article bibliographies. REVIEW METHODS: We identified articles and abstracts that described the use of PDAs in medical education by trainees or educators. Reports presenting a qualitative or quantitative evaluation were included. RESULTS: Sixty-seven studies met inclusion criteria. Approximately 60% to 70% of medical students and residents use PDAs for educational purposes or patient care. Satisfaction was generally high and correlated with the level of handheld computer experience. Most of the studies included described PDA use for patient tracking and documentation. By contrast, trainees rated medical textbooks, medication references, and medical calculators as the most useful applications. Only 1 randomized trial with educational outcomes was found, demonstrating improved learning and application of evidence-based medicine with use of PDA-based decision support software. No articles reported the impact of PDA use on patient outcomes. CONCLUSION: Most medical trainees find handhelds useful in their medical education and patient care. Further studies are needed to evaluate how PDAs impact learning and clinical outcomes.

Predictors of medication self-management skill in a low-literacy population.

BACKGROUND: Patients' ability to manage medications is critical to chronic disease control. Also known as medication management capacity (MMC), it includes the ability to correctly identify medications and describe how they should be taken. OBJECTIVE: To evaluate the effects of low literacy, medication regimen complexity, and sociodemographic characteristics on MMC. DESIGN: Cross-sectional analysis of enrollment data from participants in a randomized trial. PARTICIPANTS: Patients with coronary heart disease in an inner-city clinic. MEASUREMENTS: Medication management capacity was measured with the Drug Regimen Unassisted Grading Scale (DRUGS), which scores subjects' ability to identify, open, describe the dose, and describe the timing of their medications. DRUGS overall and component scores were compared by literacy, Mini Mental State Exam score, regimen complexity (number of prescription medications), and sociodemographic characteristics. RESULTS: Most of the 152 participants were elderly (mean age 65.4 years), women (54.6%), and African American (94.1%). Approximately half (50.7%) had inadequate literacy skills, and 28.9% had marginal skills. In univariate analysis, MMC was significantly associated with literacy (P<.001), and this effect was driven by the ability to identify medications. In multivariable models, patients with inadequate literacy skills had 10 to 18 times the odds of being unable to identify all of their medications, compared with those with adequate literacy skills (P<.05). CONCLUSIONS: Adults with inadequate literacy skills have less ability to identify their medications. Techniques are needed to better educate low-literacy patients about their medications, as a potential strategy to enhance adherence.

Medication use among inner-city patients after hospital discharge: patient-reported barriers and solutions.

OBJECTIVES: To better characterize medication-related problems among inner-city patients after hospital discharge and to suggest potential interventions. PATIENTS AND METHODS: Between August 9, 2005, and April 3, 2006, we interviewed 84 patients hospitalized with acute coronary syndromes at Grady Memorial Hospital in downtown Atlanta, GA, and contacted them by telephone about 2 weeks later. English-speaking patients who managed their own medications were studied. Patients reported their adherence with filling prescriptions and taking medications after discharge, as well as barriers to and potential enablers of proper medication use. RESULTS: Most of the 84 respondents were African American (74 [88%]), male (49 [58%]), and middle-aged (mean age, 54.5 years). Only 40% of patients filled their prescriptions on the day of discharge, 20% filled them 1 or 2 days later, and 18% waited 3 to 9 days; 22% had not filled their prescriptions by the time of the follow-up telephone call (median, 12 days; interquartile range, 8-18 days). Transportation, cost, and wait times at the pharmacy were cited as the main barriers. Many patients reported it was somewhat or very difficult to understand why they were prescribed medications (21%), how to take them (11%), or how to reconcile them with the medications they had been taking before hospitalization (16%). About half the patients (40 [48%]) reported some degree of nonadherence after discharge. Patients noted that several forms of assistance could improve medication use after discharge, including lower medication costs (75%), a follow-up telephone call (68%), transportation to the pharmacy (65%), pharmacist counseling before discharge (64%), and a pillbox (56%). CONCLUSION: Patients often delay filling prescriptions and have difficulty understanding medication regimens after hospital discharge. Interventions that reduce medication costs, facilitate transportation, improve medication counseling, and supply such organizing aids as pillboxes might be beneficial.