Accessing Targeted Therapies: A Potential Roadblock to Implementing Precision Oncology?

PURPOSE: Advances in genomic techniques have led to increased use of next-generation sequencing (NGS). We evaluated the extent to which these tests guide treatment decisions. METHODS: We developed and distributed a survey assessing NGS use and outcomes to a survey pool of ASCO members. Comparisons between groups were performed with Wilcoxon two-sample, chi-square, and Fisher's exact tests. RESULTS: Among 178 respondents, 62% were male, 54% White, and 67% affiliated with academic centers. More than half (56%) indicated that NGS provided actionable information to a moderate or great extent. Use was highest (median ≥ 70% of cases) for lung and gastric cancer, and lowest (median < 25% of cases) in head and neck and genitourinary cancers. Approximately one third of respondents reported that, despite identification of an actionable molecular variant, patients were sometimes or often unable to access the relevant US Food and Drug Administration-approved therapy. When NGS did not provide actionable results, individuals reporting great or moderate guidance overall from NGS in treatment recommendations were more likely to request the compassionate use of an unapproved drug (P < .001), enroll on a clinical trial (P < .01), or treat off-label with a drug approved for another indication (P = .02). CONCLUSION: When NGS identifies an actionable result, a substantial proportion of clinicians reported encountering challenges obtaining approved therapies on the basis of these results. Perceived overall impact of NGS appears associated with clinical behavior unrelated to actionable NGS test results, including pursuing off-label or compassionate use of unapproved therapies or referring to a clinical trial.

Tumor Genomic Profiling Practices and Perceptions: A Survey of Physicians Participating in the NCI-MATCH Trial.

PURPOSE: To identify factors that may influence physician participation in tumor profiling studies and to assess the routine use of tumor profiling in clinical practice. METHODS: Physicians in the National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH) were invited to participate in an electronic survey consisting of 73 questions related to participation in genomic profiling studies, tumor profiling practices and education during usual patient care, and physician background and practice characteristics. RESULTS: The survey response rate was 8.9% (171 surveys returned of 1,931 sent). A majority of respondents practiced in academic medical centers (AMCs). Participation in NCI-MATCH increased workload and cost but resulted in increased professional satisfaction, confidence in treatment recommendation, and subsequent use of tumor profiling. Barriers to patient participation included length of wait time for results and lack of a therapeutic option from the testing. Physicians who worked in AMCs reported a higher use of tumor profiling than did those who worked in non-AMC settings (43% v 18%; P = .0009). Access to a molecular tumor board was perceived as valuable by 56%. The study identified a need for educational materials to guide both physicians and patients in the field of genomic profiling. CONCLUSION: Physicians who participate in NCI-MATCH perceive value to patient treatment that outweighs the additional effort required; survey results help identify barriers that may limit participation. The current findings have implications for the design of future genomic and other profiling studies.

Patient familiarity with, understanding of, and preferences for clinical trial endpoints and terminology.

BACKGROUND: Although there is increased attention to designing and explaining clinical trials in ways that are clinically meaningful for patients, there is limited information on patient preferences, understanding, and perceptions of this content. METHODS: Maximum difference scaling (MaxDiff) methodology was used to develop a survey for assessing patients' understanding of 19 clinical terms and perceived importance of 9 endpoint surrogate phrases used in clinical trials and consent forms. The survey was administered electronically to individuals with metastatic breast cancer affiliated with the Metastatic Breast Cancer Alliance. Analyses were performed using Bayesian P values with statistical software. RESULTS: Among 503 respondents, 77% had a college degree, 70% were diagnosed with metastatic disease ≥2 years before survey completion, and 77% had received ≥2 lines of systemic therapy. Less than 35% of respondents reported understanding "fairly well" the terms symptomatic progression, duration of disease control, time to treatment cessation, and endpoints. Income level and time since onset of metastatic disease correlated with comprehension. Patients who had received ≥6 lines of therapy perceived that time until serious side effects (P < .001) and time on therapy (P < .001) were more important compared with those who had received only 1 line of therapy. Positively phrased parameters were associated with increased perceived importance. CONCLUSIONS: Even among educated, heavily pretreated patients, many commonly used clinical research terms are poorly understood. Comprehension and the perceived importance of trial endpoints vary over the course of disease. These observations may inform the design, discussion, and reporting of clinical trials.

Discerning the clinical relevance of biomarkers in early stage breast cancer.

PURPOSE: Prior data suggest that breast cancer patients accept significant toxicity for small benefit. It is unclear whether personalized estimations of risk or benefit likelihood that could be provided by biomarkers alter treatment decisions in the curative setting. METHODS: A choice-based conjoint (CBC) survey was conducted in 417 HER2-negative breast cancer patients who received chemotherapy in the curative setting. The survey presented pairs of treatment choices derived from common taxane- and anthracycline-based regimens, varying in degree of benefit by risk of recurrence and in toxicity profile, including peripheral neuropathy (PN) and congestive heart failure (CHF). Hypothetical biomarkers shifting benefit and toxicity risk were modeled to determine whether this knowledge alters choice. Previously identified biomarkers were evaluated using this model. RESULTS: Based on CBC analysis, a non-anthracycline regimen was the most preferred. Patients with prior PN had a similar preference for a taxane regimen as those who were PN naïve, but more dramatically shifted preference away from taxanes when PN was described as severe/irreversible. When modeled after hypothetical biomarkers, as the likelihood of PN increased, the preference for taxane-containing regimens decreased; similarly, as the likelihood of CHF increased, the preference for anthracycline regimens decreased. When evaluating validated biomarkers for PN and CHF, this knowledge did alter regimen preference. CONCLUSIONS: Patients faced with multi-faceted decisions consider personal experience and perceived risk of recurrent disease. Biomarkers providing information on likelihood of toxicity risk do influence treatment choices, and patients may accept reduced benefit when faced with higher risk of toxicity in the curative setting.

Genome-Wide Association Studies for Taxane-Induced Peripheral Neuropathy in ECOG-5103 and ECOG-1199.

PURPOSE: Taxane-induced peripheral neuropathy (TIPN) is an important survivorship issue for many cancer patients. Currently, there are no clinically implemented biomarkers to predict which patients might be at increased risk for TIPN. We present a comprehensive approach to identification of genetic variants to predict TIPN. EXPERIMENTAL DESIGN: We performed a genome-wide association study (GWAS) in 3,431 patients from the phase III adjuvant breast cancer trial, ECOG-5103 to compare genotypes with TIPN. We performed candidate validation of top SNPs for TIPN in another phase III adjuvant breast cancer trial, ECOG-1199. RESULTS: When evaluating for grade 3-4 TIPN, 120 SNPs had a P value of <10(-4) from patients of European descent (EA) in ECOG-5103. Thirty candidate SNPs were subsequently tested in ECOG-1199 and SNP rs3125923 was found to be significantly associated with grade 3-4 TIPN (P = 1.7 × 10(-3); OR, 1.8). Race was also a major predictor of TIPN, with patients of African descent (AA) experiencing increased risk of grade 2-4 TIPN (HR, 2.1; P = 5.6 × 10(-16)) and grade 3-4 TIPN (HR, 2.6; P = 1.1 × 10(-11)) compared with others. An SNP in FCAMR, rs1856746, had a trend toward an association with grade 2-4 TIPN in AA patients from the GWAS in ECOG-5103 (OR, 5.5; P = 1.6 × 10(-7)). CONCLUSIONS: rs3125923 represents a validated SNP to predict grade 3-4 TIPN. Genetically determined AA race represents the most significant predictor of TIPN.

Examining and predicting drug preferences of patients with metastatic breast cancer: using conjoint analysis to examine attributes of paclitaxel and capecitabine.

The purpose of the study was to examine variables that influence patients' decisions to undergo treatment for metastatic breast cancer as part of a larger effort to understand the utility of biomarkers in treatment decisions. An online survey containing treatment scenarios for a conjoint analysis was e-mailed to members of breast cancer support organizations. The survey contained 14 different scenarios in which survey respondents with a history of metastatic breast cancer were asked to choose between two treatments and whether or not they would undergo the treatment. The scenarios were designed based on paclitaxel and capecitabine profiles related to medication format, likelihood of benefit, and side effects. The likelihood of benefit and likelihood/severity of side effects associated with these two drugs were varied based on the range of predictability afforded by current biomarkers. Most of the 641 respondents indicated that they would opt to undergo a treatment with 27 or 33 % likelihood of benefit regardless of the toxicity scenario presented. In general, a high percentage of respondents indicated that they would choose treatment in all of the scenarios (e.g., for an intravenous medication with a 20-50 % likelihood of benefit and a 20-60 % likelihood of moderate peripheral neuropathy for 1 year, 65-94 % of respondents indicated that they would choose treatment). The conclusion is that this study found that likelihood of benefit was more important than toxicity when considering particular benefit and toxicity ranges associated with common treatment options for metastatic breast cancer.