Background Further advances of targeted cancer therapy require comprehensive in-depth profiling of somatic mutations that are present in subpopulations of tumor cells in a clinical tumor sample. However, it is unclear to what extent such intra-tumor heterogeneity is present and whether it may affect clinical decision making. To unravel this challenge, we established a deep targeted sequencing platform to identify potentially actionable DNA alterations in tumor samples. Methods We assayed 515 FFPE tumor samples and matched germline (475 patients) from 11 disease sites by capturing and sequencing all the exons in 201 cancer related genes. Mutations, indels and copy number data were reported. Results We obtained a 1000-fold average sequencing depth and identified 4794 non-synonymous mutations in the samples analyzed, which 15.2% were present at less than 10% allele frequency. Most of these low level mutations occurred at known oncogenic hotspots and are likely functional. Identifying low level mutations improved identification of mutations in actionable genes in 118 (24.84%) patients, among which 47 (9.8%) would otherwise be unactionable. In addition, acquiring ultra-high depth also ensured a low false discovery rate (less than 2.2%) from FFPE samples. Conclusion Our results were as accurate as a commercially available CLIA-compliant hotspot panel, but allowed the detection of a higher number of mutations in actionable genes. Our study revealed the critical importance of acquiring and utilizing high depth in profiling clinical tumor samples and presented a very useful platform for implementing routine sequencing in a cancer care institution.
Our understanding of cancer biology is rapidly increasing, as is the availability and affordability of high throughput technologies for comprehensive molecular characterization of tumors and the individual's own genetic makeup. Thus, the time is right to implement personalized molecular medicine for all patients with cancer. Personalized approaches span the full cancer care spectrum from risk stratification to prevention, screening, therapy, and survivorship programs. Several molecular therapeutics have entered clinical trials creating a huge opportunity to couple genomic markers with this emerging drug tool kit. The number of patients managed in major cancer centers creates a challenge to the implementation of genomic technologies required to successfully deliver on the promise of personalized cancer care. This requires a major investment in infrastructure to facilitate rapid deployment of multiplex, cost-effective, and tissue-sparing assays relevant across multiple tumor lineages in the Clinical Laboratory Improvement Amendments (CLIA) environment. Efforts must be made to ensure that assays are accessible to patients most likely to be enrolled onto molecular-marker–driven trials and that the tests are billable and payable, which will make them accessible to a wide range of patients. As the number of patients and aberrations increase, it will become critical to provide decision support for genomic medicine. Institutional commitment is needed to optimize accessibility and quality of research biopsies and to facilitate novel personalized cancer therapy trials. This article will focus on the challenges and opportunities that accompany the building of infrastructure for personalized cancer therapy.
Agents can enter clinical development for cancer prevention either initially or after previous development for a different indication, such as arthritis, with both approaches consuming many years of development before an agent is fully evaluated for cancer prevention. We propose the following, third approach: Reverse migration, that is, importing agents, targets and study designs to personalize interventions, and concepts developed in advanced cancer to the setting of cancer prevention. Importing these “ready-made” features from therapy will allow reverse migration to streamline preventive-agent development. We recently reported the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial of personalized lung-cancer therapy and now propose the reverse-migration development of personalized lung-cancer prevention based on the BATTLE model.
Synthesized VEGF121/rGel-MNPs as targeted MR imaging contrast agents can be specifically delivered to tumors and bind to KDR-expressing angiogenic tumor vessels.
Purpose: Doxorubicin is standard therapy for advanced soft-tissue sarcoma (STS) with minimal improvement in efficacy and increased toxicity with addition of other cytotoxic agents. Pembrolizumab monotherapy has demonstrated modest activity and tolerability in previous advanced STS studies. This study combined pembrolizumab with doxorubicin to assess safety and efficacy in frontline and relapsed settings of advanced STS. Patients and Methods: This single-center, single-arm, phase II trial enrolled patients with unresectable or metastatic STS with no prior anthracycline therapy. Patients received pembrolizumab 200 mg i.v. and doxorubicin (60 mg/m2 cycle 1 with subsequent escalation to 75 mg/m2 as tolerated). The primary endpoint was safety. Secondary endpoints included overall survival (OS), objective response rate (ORR), and progression-free survival (PFS) based on RECIST v1.1 guidelines. Results: Thirty patients were enrolled (53.3% female; median age 61.5 years; 87% previously untreated) with 4 (13.3%) patients continuing treatment. The study met its primary safety endpoint by prespecified Bayesian stopping rules. The majority of grade 3+ treatment-emergent adverse events were hematologic (36.7% 3+ neutropenia). ORR was 36.7% [95% confidence interval (CI), 19.9–56.1%], with documented disease control in 80.0% (95% CI, 61.4–92.3%) of patients. Ten (33.3%) patients achieved partial response, 1 (3.3%) patient achieved complete response, and 13 (43.3%) patients had stable disease. Median PFS and OS were 5.7 months (6-month PFS rate: 44%) and 17 months (12-month OS rate: 62%), respectively. Programmed cell death ligand-1 (PD-L1) expression was associated with improved ORR, but not OS or PFS. Conclusions: Combination pembrolizumab and doxorubicin has manageable toxicity and preliminary promising activity in treatment of patients with anthracycline-naive advanced STS.
11519 Background: Doxorubicin has been the traditional standard therapy for treatment of advanced soft tissue sarcoma (STS). The addition of cytotoxic agents leads to increased toxicity with minimal improvement in efficacy. Pembrolizumab monotherapy has demonstrated activity and tolerability in previous study of advanced STS. This study combined pembrolizumab with doxorubicin to determine safety and efficacy in the frontline setting. Methods: This single-center, single-arm, phase 2 trial enrolled subjects with unresectable or metastatic STS and no prior anthracycline therapy. Subjects were treated with pembrolizumab 200 mg IV and doxorubicin 60 mg/m2 (75 mg/m2 dose escalation per investigator discretion) IV every 3 weeks. The primary endpoint of safety, based on Bayesian stopping rules, evaluated if the severe or life-threatening treatment emergent adverse event (TEAE) rate exceeded 0.55. Secondary endpoints included overall survival (OS), objective response rate (ORR), and progression free survival (PFS). Efficacy and safety were based on RECIST 1.1 and CTCAE v 4.0, respectively. Kaplan-Meier methods evaluated time to event outcomes. Results: From 4/2017 to 12/2019, 30 subjects (53% female, median age 61.5 years, 10 patients > 70 years (33%)) were enrolled in the study with 6 (20%) patients still on treatment and 27 evaluable for response. The most common histologic subtypes were leiomyosarcoma (33%) and liposarcoma (23%), and a majority of patients demonstrated high grade disease (60%). Current analysis shows a median follow-up of 9.9 months. One subject experienced a stopping rule event (grade 3 autoimmune disorder). ORR was 33% (95% CI 17-54%), with documented disease control in 78% (95% CI 57.7-91.4%) of patients. Eight (30%) patients achieved a partial response, one (4%) patient achieved a complete response and 12 (44%) patients had stable disease. Preliminary results demonstrate median PFS of 6.9 months (PFS-6 mo: 52%) and median OS of 15 months (OS-6 mo: 81%) compared to historical PFS-6mo of 4.6 months and OS of 12.8 months with doxorubicin alone.1 Most common grade 3+ TEAEs included neutropenia (11 [37%]), febrile neutropenia (6 [20%]), anemia (5 [17%]), and nausea (4 [13%]). Molecular and biomarker analysis is currently in progress. Conclusions: The combination of pembrolizumab with doxorubicin has manageable toxicity and preliminary promising activity in the treatment of anthracycline-naive advanced soft tissue sarcomas. Ref: 1. Lancet Oncol. 2014 Apr; 15(4):415-23. Clinical trial information: NCT03056001 .
PURPOSE Clinical trials of novel and targeted agents increasingly require biomarkers for eligibility. Precision oncology continues to evolve, but challenges hamper broad use of molecular profiling (MP) that could increase the number of patients benefiting from targeted therapy. We implemented an integrated clinical genomics program (CGP), including a virtual Molecular Tumor Board (MTB), and examined its impact on MP use and impact on clinical trial accrual in a multisite regional-based cancer system with an emphasis on effects for isolated clinicians. METHODS We assessed MP and MTB use from 2010 to 2020 by practice location, physician experience, and patient characteristics. Use of MTB-recommended treatments was assessed. Clinical trial enrollment was evaluated for patients with MP versus MP and MTB review. RESULTS After CGP implementation, the number of physicians using MP and the number of MP tests increased ≥ 10-fold. The proportion of Hispanic patients with MP was the same as that in the system (both 2%) with marginal differences observed in the proportion of African Americans tested compared with the system population (16% v 19%). Physicians followed MTB treatment recommendations in 74% of cases. Rapid clinical decline was the most common reason why physicians did not follow MTB recommendations. Clinical trial accrual was 15% (669 of 4,459) for patients with MP alone and 28% (94 of 334) with both MP and MTB review. Clinical trial availability and patient out-of-pocket costs affected MP use. CONCLUSION Integrating CGP into clinical workflow with decision support tools, trial matching, and management of patient costs led to increased use of MP by physicians with all levels of experience, enhanced clinical trial accrual, and has the potential to reduce disparities in MP.
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