Unmatched Therapy Research Articles

Genomic Assessment of Blood-Derived Circulating Tumor DNA in Patients With Colorectal Cancers: Correlation With Tissue Sequencing, Therapeutic Response, and Survival.

PurposeGenomic alterations in blood-derived circulating tumor DNA (ctDNA) from patients with colorectal cancers were correlated with clinical outcomes.Patients and MethodsNext-generation sequencing of ctDNA (54- to 73-gene panel) was performed in 94 patients with colorectal cancer.ResultsMost patients (96%) had metastatic or recurrent disease at the time of blood draw. The median number of nonsynonymous alterations per patient was three (range, zero to 30). The most frequently aberrant genes were TP53 (52.1% of patients), KRAS (34%), and APC (28.7%). Concordance between tissue and blood next-generation sequencing ranged from 63.2% (APC) to 85.5% (BRAF). Altogether, 74 patients (79%) had one or more nonsynonymous alterations, 69 (73%) had one or more potentially actionable alterations, and 61 (65%) had an alteration actionable by a drug approved by the US Food and Drug Administration (on or off label). Lung metastases correlated with improved survival from diagnosis in univariable analysis. ctDNA of 5% or more from blood tests as well as EGFR and ERBB2 (HER2) nonsynonymous alterations correlated with worse survival (but only ERBB2 remained significant in multivariable analysis). No two patients had identical molecular portfolios. Overall, 65% versus 31% of patients treated with matched (n = 17) versus unmatched therapy (n = 18) after ctDNA testing achieved stable disease for 6 months or more, partial response, or complete response (P = .045); progression-free survival, 6.1 versus 2.3 months (P = .08); and survival not reached versus 9.4 months (P = .146; all by multivariable analysis).ConclusionPatients with colorectal cancer have heterogeneous ctDNA profiles, and most harbor potentially actionable ctDNA alterations. Matched therapy yielded higher rates of stable disease for 6 months or more, partial response, or complete response. ctDNA assessment may have clinical utility and merits further investigation.

Estimated Cost of Anticancer Therapy Directed by Comprehensive Genomic Profiling in a Single-Center Study.

PurposeComprehensive genomic profiling (CGP) detects several classes of genomic alterations across numerous genes simultaneously and can match more patients with genomically targeted therapies than conventional molecular profiling. The current study estimated the costs of anticancer drugs and overall survival (OS) for patients who were treated with matched and unmatched therapy.MethodsCosts were estimated for patients with complete data (188 of 500 patients) from a prospective, nonrandomized study of patients with diverse refractory cancers who underwent CGP and were treated with matched or unmatched therapy. We assessed mean time to treatment failure (TTF) and mean observed OS. Patient-specific drug and administration costs were imputed for the first regimen after CGP on the basis of drug classes, unit costs, and time on treatment.ResultsPatients on matched (n = 122) versus unmatched (n = 66) therapy had longer mean TTF (+1.5 months) and observed OS (+2.4 months) and higher drug costs (+$38,065; all P < .01). Increased drug costs were largely attributable to the longer duration of therapy associated with extended TTF (66.3%) rather than higher monthly drug costs (33.7%). Incremental increases in TTF (+1.9 months v +1.2 months) and observed OS (+2.5 months v +2.1 months) between matched and unmatched therapies were larger for those who underwent CGP in earlier- versus later-line therapy. Incremental increases in drug costs between matched and unmatched therapies were lower for earlier- compared with later-line therapy (+$27,000 v +$43,000, respectively).ConclusionMatched therapy was associated with longer TTF, increased OS, and manageable incremental cost increases compared with unmatched therapy. Most of these increased costs were a result of the longer duration of therapy rather than higher monthly drug costs. The benefits of matching were numerically greater in earlier versus later lines of therapy, which is consistent with the value of early use of CGP.

Molecular Profiling of Patients with Pancreatic Cancer: Initial Results from the Know Your Tumor Initiative.

Purpose: To broaden access to and implementation of precision medicine in the care of patients with pancreatic cancer, the Know Your Tumor (KYT) program was initiated using a turn-key precision medicine system. Patients undergo commercially available multiomic profiling to determine molecularly rationalized clinical trials and off-label therapies.Experimental Design: Tumor samples were obtained for 640 patients from 287 academic and community practices covering 44 states. College of American Pathologists/Clinical Laboratory Improvement Amendments-accredited laboratories were used for genomic, proteomic, and phosphoprotein-based molecular profiling.Results: Tumor samples were adequate for next-generation sequencing in 96% and IHC in 91% of patients. A tumor board reviewed the results for every patient and found actionable genomic alterations in 50% of patients (with 27% highly actionable) and actionable proteomic alterations (excluding chemopredictive markers) in 5%. Actionable alterations commonly found were in DNA repair genes (BRCA1/2 or ATM mutations, 8.4%) and cell-cycle genes (CCND1/2/3 or CDK4/6 alterations, 8.1%). A subset of samples was assessed for actionable phosphoprotein markers. Among patients with highly actionable biomarkers, those who received matched therapy (n = 17) had a significantly longer median progression-free survival (PFS) than those who received unmatched therapy [n = 18; PFS = 4.1 vs. 1.9 months; HR, 0.47; 95% confidence interval (CI): 0.24-0.94; P adj = 0.03].Conclusions: A comprehensive precision medicine system can be implemented in community and academic settings, with highly actionable findings observed in over 25% of pancreatic cancers. Patients whose tumors have highly actionable alterations and receive matched therapy demonstrated significantly increased PFS. Our findings support further prospective evaluation of precision oncology in pancreatic cancer. Clin Cancer Res; 24(20); 5018-27. ©2018 AACR.

Rare Tumor Clinic: The University of California San Diego Moores Cancer Center Experience with a Precision Therapy Approach.

Patients with rare tumors may lack approved treatments and clinical trial access. Although each rare tumor is uncommon, cumulatively they account for approximately 25% of cancers. We recently initiated a Rare Tumor Clinic that emphasized a precision medicine strategy. We investigated the first 40 patients presenting at the Rare Tumor Clinic. Next-generation sequencing (NGS) of tissue and plasma-derived, circulating-tumor DNA (ctDNA), and protein markers were assessed. Median age was 58 years (range, 31-78 years); 70% (28/40) were women; median number of previous systemic therapies was 2 (range 0-7). The most common diagnoses were sarcoma (n = 7) for solid tumors and Erdheim-Chester disease (n = 5) for hematologic malignancies. Twenty distinct diagnoses were seen. Examples of ultrarare tumors included ameloblastoma, yolk sac liver tumor, ampullary cancer, and Castleman's disease. Altogether, 32 of 33 patients (97%) with tissue NGS and 15 of 33 (45%) with ctDNA sequencing harbored ≥1 alteration. Overall, 92.5% of patients (37/40) had ≥1 actionable target based on either genomic (n = 32) or protein (n = 27) markers. In total, 52.5% (21/40) received matched therapy; 52.4% (11/21) achieved stable disease (SD) ≥6 months (n = 3), partial remission (PR; n = 6), or complete remission (CR; n = 2). Matched therapy resulted in significantly longer progression-free survival compared with last prior unmatched therapy (hazard ratio 0.26, 95% confidence interval 0.10-0.71, p = .008). Identifying genomic and protein markers in patients with rare/ultrarare tumors was feasible. When therapies were matched, >50% of patients attained SD ≥6 months, PR, or CR. Further precision medicine clinical investigations focusing on rare and ultrarare tumors are urgently needed. Although rare tumors are infrequent by definition, when all subtypes of rare cancers are combined, they account for approximately 25% of adult malignancies. However, patients with rare tumors may lack approved treatments and clinical trial access. This paper describes an institutional a Rare Tumor Clinic focused on a precision medicine strategy. Performing genomics and protein analyses was feasible amongst patients with rare cancers. Over 50% of patients attained SD ≥6 months, PR, or CR when they received matched therapy (genomically targeted and/or immunotherapy). Further studies investigating the efficacy of the precision therapy approach among rare tumors are warranted.

Estimated cost of anticancer therapy directed by comprehensive genomic profiling (CGP) in a single-center study.

6605 Background: Accumulating evidence supports the clinical benefit of targeted therapies matched to cancer patients based on genomic alterations. CGP, which detects all classes of alterations (base pair substitutions, copy number, insertions/deletions, and rearrangements), can match more patients with available and investigational therapies. This study estimated anti-cancer drug costs and overall survival (OS) for matched vs. unmatched therapy. Methods: Costs were estimated for patients with complete data (N = 188/500) from a prospective, nonrandomized, phase I oncology center study of patients with diverse refractory cancers who underwent CGP and were treated with matched or unmatched therapy (PMID: 27197177). Average time to treatment failure and average OS were assessed during the observation period. Patient-specific drug and administration costs were imputed for the first regimen after CGP based on drug classes, unit costs, and times to treatment failure. Results: Patients onmatched (N = 122) vs. unmatched (N = 66) therapy had, on average, longer time on treatment (+1.5 mos), longer observed survival (+2.4 mos), and higher anti-cancer drug costs (+$38K) (all p &lt; 0.01); 66% of increased drug costs were attributable to longer time on treatment as opposed to higher monthly drug costs. Combination therapy was used for 71% of matched and 53% of unmatched patients. Those undergoing CGP in earlier-line (1-3; N = 58) vs. later-line (4+; N = 130) therapy had numerically larger incremental increases in average times on treatment (+1.9 vs. +1.2 mos) and survival (+2.5 vs. +2.1 mos), and numerically lower incremental drug costs (+$27K vs. +$43K), with matched vs. unmatched therapy. Conclusions: For patients cared for in a phase I clinic, matched vs. unmatched therapy was associated with longer treatment durations, longer survival times, and manageable incremental costs. Despite frequent use of combination therapy, most of the increased costs of matched therapy were due to longer treatment times rather than higher monthly drug costs. Benefits of matching were numerically greater in earlier- vs. later-lines, consistent with the value of earlier-line use of CGP to guide treatment.

Rare tumor clinic: The UCSD Moores Cancer Center experience with a precision therapy approach.

11578 Background: Rare tumors have an incidence of &lt; 15/100,000 per year; utra-rare, prevalence &lt; 2000 in the USA. Patients (pts) may lack approved treatments and clinical trial access. Although each rare tumor is uncommon, cumulatively they account for &gt; 20% of cancers. We recently initiated a Rare Tumor Clinic that emphasized a precision medicine strategy (genomic and proteomic analysis and individualized therapy). We report our preliminary experience. Methods: We investigated outcome among the first 40 pts presenting to the Rare Tumor Clinic at UC San Diego Moores Center for Personalized Cancer Therapy. Whenever possible, next-generation sequencing (NGS) of tissue and plasma-derived circulating tumor DNA (ctDNA) as well as proteomic markers were assessed. Results: Median age was 58 (range, 31 – 78 yo); 70% (28/40) were women; median number of previous systemic therapies, 2 (range, 0-7). The most common diagnoses were sarcoma (N = 7) for solid tumors; Erdheim-Chester disease (N = 5), for hematologic malignancies. Twenty distinct diagnoses were seen. Examples of ultra-rare tumors included ameloblastoma, yolk sac liver tumor, ampullary cancer, Castleman's disease, and desmoid tumor. 82.5% of pts (33/40) had tissue NGS (182 to 405 genes); 7.5% (3/40), inadequate tissue. The median number of characterized tissue alterations was 3 (range, 0 to 24); 32 pts (80%) had ≥1 characterized genomic alteration. 33 pts (82.5%) had ctDNA analysis; 15 pts had ≥1 characterized alteration. Among those 15 pts, median number of characterized alterations was 3 (range, 1 to 14). 92.5% (37/40) of pts had ≥ 1 actionable target based on either genomic (32 pts) or proteomic markers (27 pts) (FDA-approved [mostly off-label] or investigational agent). 52.5% (21/40) received matched therapy; 52.4% (11/21) achieved SD≥6 months (N = 3)/CR (N = 2)/PR (N = 6). Matched therapy resulted in significantly longer PFS compared to last prior unmatched therapy (HR: 0.26, 95% CI: 0.10 – 0.71 [p = 0.008]). Conclusions: Identifying genomic and proteomic markers in pts with rare and ultra-rare tumors was feasible. When therapies were matched, &gt; 50% of pts attained SD≥6 months/CR/PR. Further clinical investigations focusing on rare and ultra-rare tumors are urgently needed.

Derivation and validation phase for the development of clinical prediction rules for rehabilitation in chronic nonspecific low back pain patients: study protocol for a randomized controlled trial.

BackgroundThere is a consensus that exercise therapy should be used as a therapeutic approach in chronic low back pain (CLBP) but little consensus has been reached about the preferential type of therapy. Due to the heterogeneity of the population no clear effect of specific therapy interventions are found. Probably a specific subgroup of the investigated population will benefit from the intervention and another subgroup will not benefit, looking at the total investigated population no significant effects can be found. Therefore there is a need for the development of clinical prediction rules (CPRs). Objectives for this trial are first, the derivation of CPRs to predict treatment response to three forms of exercise therapy for patients with nonspecific CLBP. Secondly, we aim to validate a CPR for the three forms of exercise therapy for patients with nonspecific CLBP.Methods/DesignThe study design is a randomized controlled trial. Patients with nonspecific CLBP of more than three months duration are recruited at the Antwerp University Hospital (Belgium) and Apra Rehabilitation Hospital. After examination, patients are randomly assigned to one of three intervention groups: motor control therapy, general active exercise therapy and isometric training therapy. All patients will undergo 18 treatment sessions during nine weeks. Measurements will be taken at baseline, nine weeks, six months and at one year. The primary outcome used is the Modified Oswestry Disability Questionnaire score. For each type of exercise therapy a CPR will be derived and validated. For validation, the CPR will be applied to divide each treatment group into two subgroups (matched and unmatched therapy) using the baseline measurements. We predict a better therapeutic effect for matched therapy.DiscussionA randomized controlled trial has not previously been performed for the development of a CPR for exercise therapy in CLBP patients. Only one CPR was described in a single-arm design for motor control therapy in sub-acute non-radicular LBP patients. In this study, a sufficiently large sample will be included in both the derivation and validation phase.Trial registrationThis trial was registered with Clinicaltrials.gov on 10 February 2014, registration number: NCT02063503.Electronic supplementary materialThe online version of this article (doi:10.1186/1745-6215-16-4) contains supplementary material, which is available to authorized users.