Derrick S. Haslem

A Retrospective Analysis of Precision Medicine Outcomes in Patients With Advanced Cancer Reveals Improved Progression-Free Survival Without Increased Health Care Costs

Purpose: The advent of genomic diagnostic technologies such as next-generation sequencing has recently enabled the use of genomic information to guide targeted treatment in patients with cancer, an approach known as precision medicine. However, clinical outcomes, including survival and the cost of health care associated with precision cancer medicine, have been challenging to measure and remain largely unreported. Patients and Methods: We conducted a matched cohort study of 72 patients with metastatic cancer of diverse subtypes in the setting of a large, integrated health care delivery system. We analyzed the outcomes of 36 patients who received genomic testing and targeted therapy (precision cancer medicine) between July 1, 2013, and January 31, 2015, compared with 36 historical control patients who received standard chemotherapy (n = 29) or best supportive care (n = 7). Results: The average progression-free survival was 22.9 weeks for the precision medicine group and 12.0 weeks for the control group (P = .002) with a hazard ratio of 0.47 (95% CI, 0.29 to 0.75) when matching on age, sex, histologic diagnosis, and previous lines of treatment. In a subset analysis of patients who received all care within the Intermountain Healthcare system (n = 44), per patient charges per week were

Precision oncology in advanced cancer patients improves overall survival with lower weekly healthcare costs

4,665 in the precision treatment group and

Precision Oncology Strategy in Trastuzumab-Resistant Human Epidermal Growth Factor Receptor 2–Positive Colon Cancer: Case Report of Durable Response to Ado-Trastuzumab Emtansine

5,000 in the control group (P = .126). Conclusion: These findings suggest that precision cancer medicine may improve survival for patients with refractory cancer without increasing health care costs. Although the results of this study warrant further validation, this precision medicine approach may be a viable option for patients with advanced cancer.

Abstract 998: OPeN: the oncology precision network data sharing consortium

The impact of precision oncology on guiding treatment decisions of late-stage cancer patients was previously studied in a retrospective analysis. However, the overall survival and costs were not previously evaluated. We report the overall survival and healthcare costs associated with precision oncology in these patients with advanced cancer. Building on a matched cohort study of 44 patients with metastatic cancer who received all of their care within a single institution, we evaluated the overall survival and healthcare costs for each patient. We analyzed the outcomes of 22 patients who received genomic testing and targeted therapy (precision oncology) between July 1, 2013 and January 31, 2015, and compared to 22 historically controlled patients (control) who received standard chemotherapy (N = 17) or best supportive care (N = 5). The median overall survival was 51.7 weeks for the targeted treatment group and 25.8 weeks for the control group (P = 0.008) when matching on age, gender, histological diagnosis and previous treatment lines. Average costs over the entire period were

Abstract 3650: Multi-pronged approach to establish control standards for somatic mutations in next generation sequencing (NGS) oncology test

2,720 per week for the targeted treatment group and

Abstract 625: The frequency of gene amplifications in cancer revealed by a droplet digital PCR (ddPCR) based pan-cancer gene panel test

3,453 per week for the control group, (P = 0.036). A separate analysis of 1,814 patients with late-stage cancer diagnoses found that those who received a targeted cancer treatment (N = 93) had 6.9% lower costs in the last 3 months of life compared with those who did not. These findings suggest that precision oncology may improve overall survival for refractory cancer patients while lowering average per-week healthcare costs, resource utilization and end-of-life costs.

Abstract 1114: Genomics in cancer patient care: Bench to bedside and beyond

Colorectal cancer is the third most common cancer and the fourth leading cause of cancer death worldwide. Metastatic disease is ultimately identified in the majority of patients with colorectal cancer and, with rare exceptions, is considered incurable. The treatment of metastatic colorectal cancer (mCRC) has historically included the use of fluorouracil in combinationwithother chemotherapeutic agents, including oxaliplatin or irinotecan. Theadditionof theanti–vascularendothelialgrowth factor antibody, bevacizumab, to standard chemotherapyregimenshas improvedtheprogression-free and overall survival of patients with mCRC and has signaled a shift toward the addition of biologic and targeted agents in the treatment of advanced cancer. The transition toward molecularly targeted therapies has gained additional momentum with the US Food and Drug Administration approvalof theanti–epidermalgrowthfactor receptor agents cetuximab and panitumumab for the treatment ofKRASwild-type colorectal cancers. Unfortunately, many patients with mCRC progress through these therapies, or are not candidates to receive themonthebasis of themolecular profile of their particular tumor, and are left with few treatment options. This common scenario, in addition toadvances inmolecular testing,hasacceleratedthe application of precision oncology, which uses molecular profiling of a patient’s tumor to identify potentially actionablemutations to enable targeted treatment.

Precision medicine to improve survival without increasing costs in advanced cancer patients.

Background: The advent of Next-Generation Sequencing (NGS), and other molecular diagnostic technologies, has enabled the use of genomic information to guide targeted treatment in cancer patients. While this precision oncology approach can yield exciting clinical outcomes, the innumerable genomic variants identified in individual tumors effectively establishes each case as a unique N=1 clinical presentation. This scenario is contrary to a basic dogma of medical practice where historical cases and treatment outcomes guide future management and therapeutic decisions. Aggregation of large data sets, on a multi-institutional basis, has the potential to overcome the N=1 paradox and yield management insights in the implementation of precision oncology. Methods: We have formed the Oncology Precision Network (OPeN), an oncology data sharing consortium, to aggregate big data sets consisting of clinical, genomic, pharmacological, and treatment response data from diverse patient cases. Data from Intermountain Healthcare, Stanford University, and Swedish Cancer Institute-Providence St. Joseph Health, as well as other institutions, comprises the database and is derived from 79 hospitals, over 800 physician clinics and more than 50,000 annual cases. Results: The OPeN database can be interrogated by variant type, specific therapeutics, clinical outcomes, and by grouped variables, in a structured data format. The overarching IT platform is a cloud based, open source, triple store precision oncology solution, Syapse. These data are yielding valuable insights, including tumor mutational burden (TMB) scores and their correlation to immunotherapy response, clinical response in various drug-gene combinations, and therapy-specific adverse events. Conclusions: We anticipate this resource will be used by the Molecular Tumor Boards of contributing institutions for clinical interpretation, and by treating providers to overcome the N=1 challenge associated with precision oncology. Citation Format: Lincoln Nadauld, Derrick Haslem, Paul D. Tittel, Mariko Tameishi, Thomas Brown, James Ford. OPeN: the oncology precision network data sharing consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 998. doi:10.1158/1538-7445.AM2017-998

DNA damage repair (DDR) pathway defects in gastrointestinal (GI) malignancies.

In recent years, somatic mutation testing via Next Generation Sequencing (NGS) has emerged as a powerful tool to detect targetable mutations in diseases such as cancer. These include mutations such as BRAF V600E, which can lead to targeted drug therapy; therefore, improving the standard of care in cancer diagnostics. To generate clinically meaningful results, we need to define standards that can be applied to laboratories performing somatic testing on tumor samples. With ongoing debate about the use of positive or negative controls in somatic testing assays, we designed an experiment to test the concordance of clinically actionable mutations commonly seen in tumor testing. We use cell line controls and commercially engineered DNA to validate concordance of mutations at specific allelic ratios. Our results depict an experiment design to determine if a genomic test can detect actionable mutations with high levels of accuracy and precision. In this study, we designed a multi-pronged approach to evaluate the need for control standards by the ICG100 clinical NGS panel. To establish a baseline negative control, we performed concordance testing on the NA12878 cell line. We compared SNPs, insertions and deletions found using our methodology to the variants reports by NIST. We found our results to be concordant with NIST at a sensitivity of 92% and a specificity of 93%. To establish a baseline for positive controls, we utilized commercially engineered DNA which contains variants spiked-in at known allelic frequencies. This allowed us to determine if the ICG100 panel was able to retrieve specific somatic mutations. We were able to detect high confidence somatic mutations, such as BRAFV600E, as well as BRAF V600G which was spiked in at a lower expect allelic frequency of 4%. Moreover, we are able to detect with high confidence mutations such as ALK F1174L, EGFR G719S, PIK3CA H1047R, and MET Y1247D, and we were able to reproduce the results across multiple cell lines. Overall, our results show the need to utilize controls as standard protocol which can help assess the proficiency of a clinical assay. With rapid advances is NGS testing methodologies, there is a need for establishing standardized controls that asses the performance of a somatic tumor testing. Citation Format: Christopher Johnson, Sharanya Raghunath, Jackie Wayne, Aimee Shamo, Patrick Bradley, Moises Hernandez, David Loughmiller, Jason Gillman, Derrick Haslem, Gary Stone, Lincoln Nadauld, Pravin J. Mishra. Multi-pronged approach to establish control standards for somatic mutations in next generation sequencing (NGS) oncology test. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3650.

Implementation of a precision cancer program in an integrated health care system.

The development of molecular assays designed to detect gene amplifications has largely been hampered by technical challenges such as limited DNA quantity and tumor heterogeneity, which demand methods of very high precision and sensitivity. The recent introduction of affordable digital PCR platforms, such as droplet digital PCR (ddPCR), that are capable of providing single molecule resolution of target abundances thus provides a unique opportunity to address this gap in molecular diagnostics. A ddPCR-based test was therefore developed under CLIA-CAP guidelines to determine the amplification status of 12 commonly amplified genes targeted by FDA approved drugs. Termed the Amplinome Test, this test was applied to 49 clinical samples received over a period of 6 months and compared to the results obtained from a commercially available clinical sequencing test applied that also reports copy number alterations (CNAs). An overall concordance rate of 90% (532/588 calls) was observed between the two tests across the entire gene set, 5 of which were identified as amplified. There were 56 discordant copy number amplifications between the two testing modalities. The vast majority (55/56) of discordant calls arose from gene amplifications identified by the Amplinome test, but not detected by sequencing, indicating an 11-fold increase in sensitivity in detecting amplifications. One discordant call (HER3) was identified as amplified via sequencing, but confirmed to be unamplified via FISH. At the patient level, the Amplinome test identified 5-fold more patients as having actionable amplifications in at least one of the 12 assayed genes versus clinical sequencing (29 vs. 6). Clinical management was altered in 14 of the 29 patients with an actionable CNA identified on the Amplinome test; those patients received targeted therapy directed against the amplified gene. The ddPCR-based Amplinome test thus provides a highly sensitive method for measuring gene amplifications in cancer that alters patient management, and suggests that the prevalence of actionable amplifications may be significantly underestimated by standard clinical next-generation sequencing tests. Citation Format: Austin P. So, Amy Wong, Jennifer Pecson, Girish Putcha, Gregory Jensen, Michael Lucero, Gary Stone, Jason Gillman, Pravin Mishra, David Loughmiller, Derrick S. Haslem, Lincoln Nadauld. The frequency of gene amplifications in cancer revealed by a droplet digital PCR (ddPCR) based pan-cancer gene panel test. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 625. doi:10.1158/1538-7445.AM2015-625