Yisheng Li

Feasibility of Large-Scale Genomic Testing to Facilitate Enrollment Onto Genomically Matched Clinical Trials

PURPOSE We report the experience with 2,000 consecutive patients with advanced cancer who underwent testing on a genomic testing protocol, including the frequency of actionable alterations across tumor types, subsequent enrollment onto clinical trials, and the challenges for trial enrollment. PATIENTS AND METHODS Standardized hotspot mutation analysis was performed in 2,000 patients, using either an 11-gene (251 patients) or a 46- or 50-gene (1,749 patients) multiplex platform. Thirty-five genes were considered potentially actionable based on their potential to be targeted with approved or investigational therapies. RESULTS Seven hundred eighty-nine patients (39%) had at least one mutation in potentially actionable genes. Eighty-three patients (11%) with potentially actionable mutations went on genotype-matched trials targeting these alterations. Of 230 patients with PIK3CA/AKT1/PTEN/BRAF mutations that returned for therapy, 116 (50%) received a genotype-matched drug. Forty patients (17%) were treated on a genotype-selected trial requiring a mutation for eligibility, 16 (7%) were treated on a genotype-relevant trial targeting a genomic alteration without biomarker selection, and 40 (17%) received a genotype-relevant drug off trial. Challenges to trial accrual included patient preference of noninvestigational treatment or local treatment, poor performance status or other reasons for trial ineligibility, lack of trials/slots, and insurance denial. CONCLUSION Broad implementation of multiplex hotspot testing is feasible; however, only a small portion of patients with actionable alterations were actually enrolled onto genotype-matched trials. Increased awareness of therapeutic implications and access to novel therapeutics are needed to optimally leverage results from broad-based genomic testing.

Mechanisms Linking Socioeconomic Status to Smoking Cessation: A Structural Equation Modeling Approach

OBJECTIVE Although there has been a socioeconomic gradient in smoking prevalence, cessation, and disease burden for decades, these disparities have become even more pronounced over time. The aim of the current study was to develop and test a conceptual model of the mechanisms linking socioeconomic status (SES) to smoking cessation. DESIGN The conceptual model was evaluated using a latent variable modeling approach in a sample of 424 smokers seeking treatment (34% African American; 33% Latino; 33% White). Hypothesized mechanisms included social support, neighborhood disadvantage, negative affect/stress, agency, and craving. MAIN OUTCOME MEASURE The primary outcome was Week 4 smoking status. RESULTS As was hypothesized, SES had significant direct and indirect effects on cessation. Specifically, neighborhood disadvantage, social support, negative affect/stress, and agency mediated the relation between SES and smoking cessation. A multiple group analysis indicated that the model was a good fit across racial/ethnic groups. CONCLUSION The present study yielded one of the more comprehensive models illuminating the specific mechanisms that link SES and smoking cessation. Policy, community, and individual-level interventions that target low SES smokers and address the specific pathways identified in the current model could potentially attenuate the impact of SES on cessation.

The Effect of Tobacco Outlet Density and Proximity on Smoking Cessation

OBJECTIVES We examined the influence of tobacco outlet density and residential proximity to tobacco outlets on continuous smoking abstinence 6 months after a quit attempt. METHODS We used continuation ratio logit models to examine the relationships of tobacco outlet density and tobacco outlet proximity with biochemically verified continuous abstinence across weeks 1, 2, 4, and 26 after quitting among 414 adult smokers from Houston, Texas (33% non-Latino White, 34% non-Latino Black, and 33% Latino). Analyses controlled for age, race/ethnicity, partner status, education, gender, employment status, prequit smoking rate, and the number of years smoked. RESULTS Residential proximity to tobacco outlets, but not tobacco outlet density, provided unique information in the prediction of long-term, continuous abstinence from smoking during a specific quit attempt. Participants residing less than 250 meters (P = .01) or less than 500 meters (P = .04) from the closest tobacco outlet were less likely to be abstinent than were those living 250 meters or farther or 500 meters or farther, respectively, from outlets. CONCLUSIONS Because residential proximity to tobacco outlets influences smoking cessation, zoning restrictions to limit tobacco sales in residential areas may complement existing efforts to reduce tobacco use.

Stand Up to Cancer Phase Ib Study of Pan-Phosphoinositide-3-Kinase Inhibitor Buparlisib With Letrozole in Estrogen Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer

PURPOSE Buparlisib, an oral reversible inhibitor of all class I phosphoinositide-3-kinases, has shown antitumoral activity against estrogen receptor (ER)-positive breast cancer cell lines and xenografts, alone and with endocrine therapy. This phase Ib study evaluated buparlisib plus letrozoles safety, tolerability, and preliminary activity in patients with metastatic ER-positive breast cancer refractory to endocrine therapy. PATIENTS AND METHODS Patients received letrozole and buparlisib in two different administration schedules. Outcomes were assessed by standard solid-tumor phase I methods. [(18)F]fluorodeoxyglucose-positron emission tomography/computed tomography ([(18)F]FDG-PET/CT) scans were done at baseline and 2 weeks after treatment initiation. Tumor blocks were collected for phosphoinositide-3-kinase pathway mutation analysis. RESULTS Fifty-one patients were allocated sequentially to continuous or intermittent (five on/two off days) buparlisib administration on an every-4-week schedule. Buparlisibs maximum-tolerated dose (MTD) was 100 mg/d. Common drug-related adverse events included ≤ grade 2 hyperglycemia, nausea, fatigue, transaminitis, and mood disorders. The clinical benefit rate (lack of progression ≥ 6 months) among all patients treated at the MTD was 31%, including two objective responses in the continuous dose arm. Of seven patients remaining on treatment ≥ 12 months, three had tumors with PIK3CA hot-spot mutation. Patients exhibiting metabolic disease progression by [(18)F]FDG-PET/CT scan at 2 weeks progressed rapidly on therapy. CONCLUSION The letrozole and buparlisib combination was safe, with reversible toxicities regardless of schedule administration. Clinical activity was observed independent of PIK3CA mutation status. No metabolic response by [(18)F]FDG-PET/CT scan at 2 weeks was associated with rapid disease progression. Phase III trials of buparlisib and endocrine therapy in patients with ER-positive breast cancer are ongoing.

Financial Strain and Smoking Cessation Among Racially/Ethnically Diverse Smokers

OBJECTIVES We evaluated the influence of financial strain on smoking cessation among Latino, African American, and Caucasian smokers of predominantly low socioeconomic status. METHODS Smokers enrolled in a smoking cessation study (N = 424) were followed from 1 week prequit through 26 weeks postquit. We conducted a logistic regression analysis to evaluate the association between baseline financial strain and smoking abstinence at 26 weeks postquit after control for age, gender, race/ethnicity, educational level, annual household income, marital status, number of cigarettes smoked per day, and time to first cigarette of the day. RESULTS Greater financial strain at baseline was significantly associated with reduced odds of abstinence at 26 weeks postquit among those who completed the study (odds ratio [OR] = 0.77; 95% confidence interval [CI] = 0.62, 0.94; P = .01). There was a significant association as well in analyses that included those who completed the study in addition to those lost to follow-up who were categorized as smokers (OR = 0.78; 95% CI = 0.64, 0.96; P = .02). CONCLUSIONS Greater financial strain predicted lower cessation rates among racially/ethnically diverse smokers. Our findings highlight the impact of economic concerns on smoking cessation and the need to address financial strain in smoking cessation interventions.

Dose-finding in phase I clinical trials based on toxicity probability intervals

Background Most phase I clinical trials conducted at the M. D. Anderson Cancer Center use the algorithmic 3 + 3 design, despite the availability of more advanced model-based designs such as the continual reassessment method. Purpose Through simple statistical modeling and computing, we develop a dose-finding design that can be easily understood and implemented by non-statisticians. Methods We propose a beta/binomial Bayesian model and a probabilistic up-and-down rule that allow all possible dose-assignment actions to be tabulated in a spreadsheet. We have developed an Excel macro (available at http://odin.mdacc. tmc.edu/~yuanj) that generates trial monitoring tables, which contain the dose-assignment actions corresponding to various toxicity outcomes. Results The new design outperforms the 3 + 3 design and performs comparably to other model-based methods in the literature. Limitations The proposed method assumes that the observed toxicity is a binary variable and that toxicity increases with dose level. Conclusion The new dose-finding design enables physicians to readily determine dose assignments for new patients by referencing a trial monitoring table. Clinical Trials 2007; 4: 235—244; http://ctj.sagepub.com

A modified toxicity probability interval method for dose-finding trials.

BACKGROUND Building on earlier work, the toxicity probability interval (TPI) method, we present a modified TPI (mTPI) design that is calibration-free for phase I trials. PURPOSE Our goal is to improve the trial conduct and provide more effective designs while maintaining the simplicity of the original TPI design. METHODS Like the TPI method, the mTPI consists of a practical dose-finding scheme guided by the posterior inference for a simple Bayesian model. However, the new method proposes improved dose-finding decision rules based on a new statistic, the unit probability mass (UPM). For a given interval and a probability distribution, the UPM is defined as the ratio of the probability mass of the interval to the length of the interval. RESULTS The improvement through the use of the UPM for dose finding is threefold: (1) the mTPI method appears to be safer than the TPI method in that it puts fewer patients on toxic doses; (2) the mTPI method eliminates the need for calibrating two key parameters, which is required in the TPI method and is a known difficult issue; and (3) the mTPI method corresponds to the Bayes rule under a decision theoretic framework and possesses additional desirable large- and small-sample properties. LIMITATION The proposed method is applicable to dose-finding trials with a binary toxicity endpoint. CONCLUSION The new method mTPI is essentially calibration free and exhibits improved performance over the TPI method. These features make the mTPI a desirable choice for the design of practical trials.Background Building on earlier work, the toxicity probability interval (TPI) method, we present a modified TPI (mTPI) design that is calibration-free for phase I trials. Purpose Our goal is to improve the trial conduct and provide more effective designs while maintaining the simplicity of the original TPI design. Methods Like the TPI method, the mTPI consists of a practical dose-finding scheme guided by the posterior inference for a simple Bayesian model. However, the new method proposes improved dose-finding decision rules based on a new statistic, the unit probability mass (UPM). For a given interval and a probability distribution, the UPM is defined as the ratio of the probability mass of the interval to the length of the interval. Results The improvement through the use of the UPM for dose finding is threefold: (1) the mTPI method appears to be safer than the TPI method in that it puts fewer patients on toxic doses; (2) the mTPI method eliminates the need for calibrating two key parameters, which is required in the TPI method and is a known difficult issue; and (3) the mTPI method corresponds to the Bayes rule under a decision theoretic framework and possesses additional desirable largeand smallsample properties. Limitation The proposed method is applicable to dose-finding trials with a binary toxicity endpoint. Conclusion The new method mTPI is essentially calibration free and exhibits improved performance over the TPI method. These features make the mTPI a desirable choice for the design of practical trials. Clinical Trials 2010; 7: 653–663. http://ctj.sagepub.com

A Phase Ib Study of Alpelisib (BYL719), a PI3Kα-Specific Inhibitor, with Letrozole in ER+/HER2− Metastatic Breast Cancer

Purpose: Alpelisib, a selective oral inhibitor of the class I PI3K catalytic subunit p110α, has shown synergistic antitumor activity with endocrine therapy against ER+/PIK3CA-mutated breast cancer cells. This phase Ib study evaluated alpelisib plus letrozoles safety, tolerability, and preliminary activity in patients with metastatic ER+ breast cancer refractory to endocrine therapy. Experimental Design: Twenty-six patients received letrozole and alpelisib daily. Outcomes were assessed by standard solid-tumor phase I methods. Tumor blocks were collected for DNA extraction and next-generation sequencing. Results: Alpelisibs maximum-tolerated dose (MTD) in combination with letrozole was 300 mg/d. Common drug-related adverse events included hyperglycemia, nausea, fatigue, diarrhea, and rash with dose-limiting toxicity occurring at 350 mg/d of alpelisib. The clinical benefit rate (lack of progression ≥6 months) was 35% (44% in patients with PIK3CA-mutated and 20% in PIK3CA wild-type tumors; 95% CI, 17%–56%), including five objective responses. Of eight patients remaining on treatment ≥12 months, six had tumors with a PIK3CA mutation. Among evaluable tumors, those with FGFR1/2 amplification and KRAS and TP53 mutations did not derive clinical benefit. Overexpression of FGFR1 in ER+/PIK3CA mutant breast cancer cells attenuated the response to alpelisib in vitro. Conclusions: The combination of letrozole and alpelisib was safe, with reversible toxicities. Clinical activity was observed independently of PIK3CA mutation status, although clinical benefit was seen in a higher proportion of patients with PIK3CA-mutated tumors. Phase II and III trials of alpelisib and endocrine therapy in patients with ER+ breast cancer are ongoing. Clin Cancer Res; 23(1); 26–34. ©2016 AACR.

Reaching and treating Spanish-speaking smokers through the National Cancer Institute's Cancer Information Service. A randomized controlled trial.

Although the prevalence of smoking is lower among Hispanics than among the general population, smoking still levies a heavy public health burden on this underserved group. The current study, Adiós al Fumar (Goodbye to Smoking), was designed to increase the reach of the Spanish‐language smoking cessation counseling service provided by the National Cancer Institutes Cancer Information Service (CIS) and to evaluate the efficacy of a culturally sensitive, proactive, behavioral treatment program among Spanish‐speaking smokers. Adiós was a 2‐group randomized clinical trial evaluating a telephone‐based smoking cessation intervention. Spanish‐speaking smokers (N = 297) were randomized to receive either standard counseling or enhanced counseling (EC). Paid media was used to increase the reach of the Spanish‐language smoking cessation services offered by the CIS. The Adiós sample was of very low socioeconomic status (SES), and more than 90% were immigrants. Calls to the CIS requesting smoking cessation help in Spanish increased from 0.39 calls to 17.8 calls per month. The unadjusted effect of EC only approached significance (OR = 2.4, P = .077), but became significant after controlling for demographic and tobacco‐related variables (OR = 3.8, P = .048). Adiós al Fumar demonstrated that it is possible to reach, retain, and deliver an adequate dose of treatment to a very low SES population that has traditionally been viewed as difficult to reach and hard to follow. Moreover, the findings suggest that a proactive, telephone‐counseling program, based on the Treating Tobacco Use and Dependence Clinical Practice Guideline and adapted to be culturally appropriate for Hispanics, is effective. Cancer 2007.

Low-level smoking among Spanish-speaking Latino smokers: Relationships with demographics, tobacco dependence, withdrawal, and cessation

INTRODUCTION Although recent research indicates that many Latino smokers are nondaily smokers or daily smokers who smoke at a low level (<or =5 cigarettes/day), almost no research has investigated the characteristics of low-level smokers because such individuals are typically excluded from clinical trial research. METHODS The present study examined the associations of daily smoking level and demographics, tobacco dependence, withdrawal, and abstinence during a specific quit attempt among 280 Spanish-speaking Latino smokers (54% male) who participated in a clinical trial of a telephone counseling intervention. Daily smokers were classified as low-level (1-5 cigarettes/day; n = 81), light (6-10 cigarettes/day; n = 99), or moderate/heavy smokers (> or =11 cigarettes/day; n = 100). Data were collected prior to the quit attempt and at 5 and 12 weeks postquit. RESULTS Results yielded three key findings. First, smoking level was positively associated with the total score and 12 of 13 subscale scores on a comprehensive, multidimensional measure of tobacco dependence. Low-level smokers consistently reported the least dependence, and moderate/heavy smokers reported the most dependence on tobacco. Second, low-level smokers reported the least craving in pre- to postcessation longitudinal analyses. Third, despite significant differences on dependence and craving, low-level smoking was not associated with abstinence. Smoking level was not associated with demographic variables. DISCUSSION This is a preliminary step in understanding factors influencing tobacco dependence and smoking cessation among low-level Spanish-speaking Latino smokers, a subgroup with high prevalence in the Latino population.