Key Lessons Learned from Moffitt's Molecular Tumor Board: The Clinical Genomics Action Committee Experience

The increasing practicality of genomic sequencing technology has led to its incorporation into routine clinical practice. Successful identification and targeting of driver genomic alterations that provide proliferative and survival advantages to tumor cells have led to approval and ongoing development of several targeted cancer therapies. Within many major cancer centers, molecular tumor boards are constituted to shepherd precision medicine into clinical practice

Copy Number Alterations as Novel Biomarkers and Therapeutic Targets in Colorectal Cancer

In colorectal cancer, somatic mutations have played an important role as prognostic and predictive biomarkers, with some also functioning as therapeutic targets. Another genetic aberration that has shown significance in colorectal cancer is copy number alterations (CNAs). CNAs occur when a change to the DNA structure propagates gain/amplification or loss/deletion in sections of DNA, which can often lead to changes in protein expression. Multiple techniques have been developed to detect CNAs, including comparative genomic hybridization with microarray, low pass whole genome sequencing, and digital droplet PCR. In this review, we summarize key findings in the literature regarding the role of CNAs in the pathogenesis of colorectal cancer, from adenoma to carcinoma to distant metastasis, and discuss the roles of CNAs as prognostic and predictive biomarkers in colorectal cancer

An analysis of the use of targeted therapies in patients with advanced Merkel cell carcinoma and an evaluation of genomic correlates of response.

BACKGROUND: The use of targeted therapy remains a treatment consideration for some patients with advanced Merkel cell carcinoma (MCC). However, supportive data on the use of targeted therapy approaches are limited. Thus, we sought to evaluate the responsiveness of targeted agents in patients with advanced MCC. METHODS: An institutional MCC database identified patients who were treated with targeted therapy. For the purpose of this study, targeted therapy was defined as any multi-targeted tyrosine kinase inhibitor or inhibitor of the PI3K-pathway. Clinical benefit was defined as complete response, partial response, or stable disease (SD) ≥6 months. A subset of patient samples underwent next-generation sequencing (NGS), Merkel cell polyomavirus testing, and PD-L1/PD-1 expression testing. RESULTS: Nineteen patients with MCC treated with targeted therapy were identified, 21 targeted therapy regimens were evaluable for response in 18 patients. Four of twenty-one (19%) of evaluable regimens were associated with clinical benefit with the best overall response of SD. The durations of SD were 13.6 months (59 weeks), 9.7 months (42 weeks), 7.6 months (33 weeks), and 7.2 months (31 weeks). Of the four patients who derived clinical benefit, three were treated with pazopanib alone and one was treated with pazopanib plus everolimus. No difference in the rate of clinical benefit between molecular disease subtypes was detected nor was associated with any specific genomic alteration. CONCLUSION: In our series, targeted agents elicited a disease control rate of 19% in patients with advanced MCC, with a best overall response of SD. Pazopanib alone or in combination exhibited a rate of disease control of 36% (4 of 11 with SD ≥6 months)

Key Lessons Learned from Moffitt's Molecular Tumor Board: The Clinical Genomics Action Committee Experience

BACKGROUND. The increasing practicality of genomic sequencing technology has led to its incorporation into routine clinical practice. Successful identification and targeting of driver genomic alterations that provide proliferative and survival advantages to tumor cells have led to approval and ongoing development of several targeted cancer therapies. Within many major cancer centers, molecular tumor boards are constituted to shepherd precision medicine into clinical practice. MATERIALS AND METHODS. In July 2014, the Clinical Genomics Action Committee (CGAC) was established as the molecular tumor board companion to the Personalized Medicine Clinical Service (PMCS) at Moffitt Cancer Center in Tampa, Florida. The processes and outcomes of the program were assessed in order to help others move into the practice of precision medicine. RESULTS. Through the establishment and initial 1,400 patients of the PMCS and its associated molecular tumor board at a major cancer center, five practical lessons of broad applicability have been learned: transdisciplinary engagement, the use of the molecular report as an aid to clinical management, clinical actionability, getting therapeutic options to patients, and financial considerations. Value to patients includes access to cutting‐edge practice merged with individualized preferences in treatment and care. CONCLUSIONS. Genomic‐driven cancer medicine is increasingly becoming a part of routine clinical practice. For successful implementation of precision cancer medicine, strategically organized molecular tumor boards are critical to provide objective evidence‐based translation of observed molecular alterations into patient‐centered clinical action. Molecular tumor board implementation models along with clinical and economic outcomes will define future treatment standards. IMPLICATIONS FOR PRACTICE. It is clear that the increasing practicality of genetic tumor sequencing technology has led to its incorporation as part of routine clinical practice. Subsequently, many cancer centers are seeking to develop a personalized medicine services and/or molecular tumor board to shepherd precision medicine into clinical practice. This article discusses the key lessons learned through the establishment and development of a molecular tumor board and personalized medicine clinical service. This article highlights practical issues and can serve as an important guide to other centers as they conceive and develop their own personalized medicine services and molecular tumor boards

Increased Frequency of IDH1/2 Mutations in Extramedullary Acute Myeloid Leukemia

Abstract Introduction The identification of somatic genomic alterations in cancer has brought forth a paradigm change in the personalized management of patients with acute myeloid leukemia (AML). This is exemplified by the recent FDA approvals with the targeted small molecule inhibitors of mutant IDH1 (ivosidenib) and IDH2 (enasidenib) for patients with relapsed/refractory AML. IDH1/2 mutations have been reported to occur in approximately 16-20% of patients with AML based on the largest published cohorts to date (Dinardo et al., Am J Hematol, 2015; Papaemmanuil et al., NEJM, 2016). However, there remains a paucity of data on the frequency of IDH1/2 and other targetable mutations in extramedullary manifestations of AML (i.e. myeloid sarcoma and leukemia cutis; EM-AML). We sought to characterize the mutational landscape of EM-AML, with a focus on determining the frequency of IDH1/2 mutations. Methods This is a multi-institutional retrospective analysis of patients diagnosed with EM-AML, who were treated at Moffitt Cancer Center or Memorial Healthcare System and underwent next-generation sequencing (NGS). All patients were evaluated for IDH1/2 mutations and up to 435 additional genes. Clinical variables and outcomes of EM-AML patients were characterized at the time of sample procurement. Additionally, we acquired additional de-identified NGS data on EM-AML patients who underwent sequencing of the EM site at Genoptix. We describe the mutational landscape of patients and compared the frequency of IDH1/2 mutations to historical controls in AML from the published literature using Fisher's exact test. Kaplan-Meier curves were used to estimate overall survival (OS) and analyzed from the date of mutation identification. Results Thirty-five patients with EM-AML were identified (22 in the clinical cohort and 13 in the Genoptix cohort) and are included in this analysis. The distribution of EM-AML diagnoses were myeloid sarcoma in 71% of cases (n=25) and leukemia cutis in 29% (n=10). The sequenced samples were from an extramedullary site for 63% (n=22) of the cases. The median age of the cohort was 64 (IQR 52 - 72) with a male predominance (55%). Of the clinical cohort, 68% (n=15) were non-Hispanic White, 23% (n=5) were Hispanic, and 9% (n=2) were Black. The molecular landscape of the cohort is shown in Figure 1. The frequency of IDH1/2 mutations was 31% (11/35), with IDH1 and IDH2 mutations reported in 17% (n=6) and 14% (n=5) of cases, respectively. All IDH1 mutations were at position R132 (4 R132H and 2 R132C) and all IDH2 mutations were at R140 (4 R140Q and 1 R140G). The other most frequent genomic alterations were DNMT3A (29%), NPM1 (26%), FLT3 (23%; ITD in 18% and TKD in 5%; 11% in IDH wildtype), NRAS (21%), TET2 (17%), and ASXL1 (17%). Mutations in DNA methylation occurred in 54% of patients (n=19). Co-occurring NRAS/KRAS mutations were more frequent in IDH mutant patients (45%; 5/11) compared to 12% (3/24) of IDH wild type patients (P=0.01). DNMT3A mutations were reported in 45% (5/11) of IDH mutant cases compared to 21% (5/24) of IDH wildtype cases, although this was not statistically significant (P=0.23). In comparison to a historical frequency of IDH1/2 mutations in AML patients of 17.4% (n=2366), EM-AML patients had an increased frequency of 31% (P=0.04). The median OS of the cohort was 13.6 months. Within the clinical cohort 50% (4/8) of the IDH1/2 mutant patients were treated with an IDH inhibitor with CR in 1 patient, CRi in 1 patient, and stable disease in 2 patients. The patient who achieved CR developed widespread leukemia cutis during cycle 1 of enasidenib which resolved over 6 months and is in durable CR for 15 months. Conclusion Overall, EM-AML patients had targetable mutations (i.e. IDH1/IDH2/FLT3) in 40% of cases with an increased frequency of IDH1/2 mutations (31%) in comparison to the general AML population. IDH mutant EM-AML patients achieved clinical benefit to specific inhibitors. These data support mutational analysis of EM-AML patients in order to personalize therapeutic options for our patients. Figure 1. Figure 1. Disclosures Bhagat: Genoptix: Employment. Watts:Takeda: Research Funding; Jazz Pharma: Consultancy, Speakers Bureau. Sweet:Novartis: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Jazz: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Jazz: Speakers Bureau; BMS: Honoraria; Astellas: Consultancy; Celgene: Honoraria, Speakers Bureau; Astellas: Consultancy; Agios: Consultancy; Agios: Consultancy; Phizer: Consultancy; Phizer: Consultancy; BMS: Honoraria. Komrokji:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Sallman:Celgene: Research Funding, Speakers Bureau

Molecular annotation of extramedullary acute myeloid leukemia to identify prevalence of targetable mutations

7024 Background: Extramedullary (EM) involvement, including myeloid sarcoma (MS) and leukemia cutis (LC), is uncommon in patients with acute myeloid leukemia (AML). Mutational landscape of EM-AML is not well characterized, including concordance of sequencing data from EM vs. non-EM site (blood or bone marrow) and the potential for personalized targeted therapy in this patient cohort. Methods: In a multicenter retrospective study, clinical and genomic data were collected on EM-AML patients treated at Moffitt Cancer Center, Memorial Healthcare System, and University of Miami, as well as sequenced cases at a central laboratory. Next generation sequencing (NGS) data come from panels that interrogated 24- 406 genes, with 15 genes covered by all panels, including notably, IDH1, IDH2, KIT, KRAS, NPM1, NRAS, and TP53. Survival estimates using Kaplan-Meier statistics and multivariate analysis with Cox-regression were performed in SPSS (v.26). Results: Our study included 58 patients with EM-AML. Median age at diagnosis was 62 years; 55% of patients were males. In our cohort, 34 (59%) patients had MS, and 19 (33%) had LC. EM-AML was noted during relapse in 60% of evaluable patients (n=45), and 31% had isolated EM disease. Patients with LC had a significantly worse median overall survival (OS) than those with MS (5.7 months vs. 21.9 months, p= 0.008); Pattern of EM involvement (MS vs. LC) remained an independent prognostic factor for OS (p= 0.04) in a multivariate analysis including disease setting (new diagnosis vs. relapse) and ELN risk category. Results of NGS performed during EM presentation were available in 48 patients, 19 of which had NGS data from EM site. Most commonly mutated genes were NRAS on EM site NGS (37%) and NPM1 on non-EM site NGS (28%). Based on EM NGS, 52% patients had a targetable genomic alteration, with 37% mutations in IDH, 21% NPM1, 5% FLT3, and 11% MLL-PTD. Five (two with concurrent M+EM disease) out of nine evaluable patients had significant discordance in targetable mutations between EM and non-EM NGS at EM-AML. Three of four patients who received treatment with IDH1/2 inhibitors based on EM NGS achieved complete response. Conclusions: EM-AML has a distinct molecular architecture with an inferior OS in LC vs. MS patients. We conclude that EM site NGS is critical in patients with EM-AML, as 52% have potentially targetable mutations and could benefit from specific targeted therapies.[Table: see text