A B S T R A C T PurposeWe 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 MethodsStandardized 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. ResultsSeven hundred eighty-nine patients (39%) had at least one mutation in potentially actionable genes. Eighty-three patients (11%) with potentially actionable mutations went on genotypematched 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. ConclusionBroad 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.

Purpose Alpelisib, a selective oral inhibitor of the class I PI3K catalytic subunit p110α, has shown synergistic anti-tumor activity with endocrine therapy against ER+/PIK3CA mutated breast cancer cells. This phase Ib study evaluated alpelisib plus letrozole’s safety, tolerability and preliminary activity in patients with metastatic ER+ breast cancer refractory to endocrine therapy. Patients and Methods 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 Alpelisib’s 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. Conclusion 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.

In this simulation modeling study that projected trends in breast cancer mortality rates among US women, decreases in overall breast cancer mortality from 2000 to 2012 were associated with advances in screening and in adjuvant therapy, although the associations varied by breast cancer molecular subtype.

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 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 individuallevel 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.

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.