Craig Heartwell - Academia.edu (original) (raw)

Papers by Craig Heartwell

Commercial genomic and protein-based profiling was performed on tissue from pancreatic cancer pat... more Commercial genomic and protein-based profiling was performed on tissue from pancreatic cancer patients who enrolled in the Pancreatic Cancer Action Network's Know Your Tumor (KYT) service. The service offers molecular profiling for patients with resectable or metastatic disease, in preparation for their next treatment plan. Patients are eligible to enroll at any institution, clinic, or cancer center in the US. Biopsies, tissue retrieval and testing is coordinated by Perthera, Inc. From 6/2014 to 11/2015 tumor biopsies, resected or archived tissue was obtained from 152 (53% male) pancreatic cancer patients and profiling including NGS/FISH (144 patients) and IHC (143 patients) was performed. The median age at biopsy or resection was 63 (25-83), 55% of the tissue came from liver, 16% from pancreas, 7% lung, 4% peritoneum, and 18% from another type of tissue. 87% of the patients were diagnosed with pancreatic ductal adenocarcinoma and the remaining with another form of confirmed or suspected pancreatic cancer. The most identified pathogenic mutations were KRAS (85%), TP53 (72%), CDKN2A (47%), CDKN2B (24%), SMAD4 (22%), ARID1A (10%), STK11 (7%), and BRCA2 (5%). The average number of genomic alterations (likely but not confirmed to be somatic) detected was five per patient from a panel of 320 genes. Molecular modifications that are linked to a treatment option were observed in 44% of patients. Twenty four of 144 patients (17%) had mutations in at least one DNA repair gene potentially benefiting from platinum or PARP inhibitor-based therapies, including BRCA2 (5%), ATM (4%), BAP1 (4%), SMARCA4 (3%), FANC (1%), CHEK2 (1%), and PALB2 (<1%). Other actionable molecular phenotypes observed include anti-HER2 therapies targeting ERBB2 amplifications (3%) and mTOR inhibitors suitable for patients with mutations in STK11/LKB1 (7%), PTEN (3.5%), PIK3R1 (<1%), or PIK3CA (3%). Actionable alterations identified with a low frequency (<2%) include RET fusions, amplifications of FGFR, CRKL, AXL, and mutations in NTRK3, MEN1 (PNET), and BRAF. One patient harbored the BRAF V600E mutation, prompting consideration of off label melanoma-approved therapy. Overexpression of ALK by IHC was observed in one patient who chose to enroll in a ceritinib clinical trial. Six percent of patients were PDL-1 positive, and 22% were positive for PD-1 from tumor infiltrating lymphocytes, suggesting possible activity from immune checkpoint inhibitors. To date, 7 of the 152 patients have enrolled in a clinical trial, 4 were treated with an off label treatment, 67 have yet to make their next treatment decision, and 53 are known to be deceased. KYT has successfully profiled tumors and presented targeted treatment options to patients and physicians in 33 states regardless of a patient's socioeconomic background and geographic location, moving the field a step closer towards a democratized, personalized approach to treating pancreatic cancer. Citation Format: Lola Rahib, Anitra Engebretson, Michael J. Pishvaian, Jonathan R. Brody, William A. Hoos, Emily E. Lyons, Joseph Bender, Emanuel F. Petricoin, Subha Madhavan, Craig Heartwell, Lynn M. Matrisian. Molecular profiling of pancreatic cancer patients from a wide geographical distribution across the US. [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 93.

Cancer Biology & Therapy, Mar 6, 2018

Isocitrate dehydrogenase 1 (IDH1) is a metabolic enzyme implicated in cancer cell metabolic repro... more Isocitrate dehydrogenase 1 (IDH1) is a metabolic enzyme implicated in cancer cell metabolic reprogramming. This is underscored by the detection of functional, somatic IDH1 mutations frequently found in secondary glioblastoma. To our knowledge, there has never been a reported, validated case of an IDH1 mutation in a pancreatic ductal adenocarcinoma (PDA). Herein, we present a case of a patient with metastatic PDA that harbored a potentially actionable, albeit rare, IDH1 mutation. As part of the Know Your Tumor project (Pancreatic Cancer Action Network), a 48-year-old female was diagnosed with metastatic PDA and subsequently started on standard of care chemotherapy, during which her hepatic lesions progressed. Detailed molecular profiling was performed on a biopsy from a liver lesion that demonstrated an IDH1 mutation, R132H. This mutation was confirmed by an independent sequencing reaction from the tumor sample, and by immunohistochemistry using an antibody specific for the IDH1 R132H mutation. The patient subsequently received a mutant IDH1 inhibitor (AG-120, Agios Pharmaceuticals, Cambridge, MA), but with no response. IDH1 mutations are common in certain cancer types, but have not been reported in PDA. We report the first case of an IDH1 mutation in this tumor type, perhaps providing a rare opportunity for a targeted therapy as a treatment option for PDA.

Journal of Clinical Oncology, Feb 1, 2016

Molecular Biomarker Weighting and the Perthera Drug Scoring Algorithm: Molecular Vector: • Chemot... more Molecular Biomarker Weighting and the Perthera Drug Scoring Algorithm: Molecular Vector: • Chemotherapy markers alone (low rank) à Pathway-level (high score) Disease-Specific Vector: • Untested in that disease (low score) à Clinically proven benefit (high score) Patient History Vector: • Patient has received the agents (low score) à Treatment naïve (high score

Journal of Clinical Oncology, Feb 1, 2017

278 Background: Recent studies have expanded our knowledge of the genomic landscape of PDA. While... more 278 Background: Recent studies have expanded our knowledge of the genomic landscape of PDA. While critical and in some cases, potentially actionable alterations are being identified, limited outcomes data have thus far made it difficult to validate the relevance of these observations. Methods: The Pancreatic Cancer Action Network (PanCAN) and Perthera have facilitated commercial tumor molecular profiling for over 400 PDA pts since 2014 through KYT, and have developed a database of molecular and clinical information useful for data mining of biomarker-survival correlations. The survival significance of biomarkers was assessed using standard statistical methodology including Kaplan-Meier analysis and Cox proportional hazard models. Results: Linked molecular and outcomes data were available for 360 pts, of which 173 had treatment (tx) information available. Pathogenic mutations from targeted NGS, protein expression from IHC, and protein phosphorylation from RPPA were screened for correlations with overall survival (OS) and progression-free survival (PFS) independent of tx received. As shown in the table, mutations in 3 genes were associated with a better OS; while mutations in 8 genes were associated with poorer OS. Only two mutations were correlated with PFS in 1st or 2nd-line tx ( BRCA2 and KDM6A, worse PFS). Positive expression of 7 proteins, including TS, TOP1, and RRM1, were associated with reduced OS but were not correlated with PFS. High levels of phospho-ribosomal protein S6 were associated with both poor OS (HR=10.3, p=0.001) and poor PFS (HR=9.6, p=0.006). Conclusions: Multiple biomarkers had significant correlations with OS in PDA, while fewer were correlated with PFS. Growth of this registry database will further validate tx-specific predictive biomarkers for use in pts with multi-omic profiling data. [Table: see text]

Oncotarget, Nov 8, 2016

Recent improvements in next-generation sequencing (NGS) technology have enabled detection of biom... more Recent improvements in next-generation sequencing (NGS) technology have enabled detection of biomarkers in cell-free DNA in blood and may ultimately replace invasive tissue biopsies. However, a better understanding of the performance of blood-based NGS assays is needed prior to routine clinical use. As part of an IRBapproved molecular profiling registry trial of pancreatic ductal adenocarcinoma (PDA) patients, we facilitated blood-based NGS testing of 34 patients from multiple community-based and high-volume academic oncology practices. 23 of these patients also underwent traditional tumor tissue-based NGS testing. cfDNA was not detected in 9/34 (26%) patients. Overall concordance between blood and tumor tissue NGS assays was low, with only 25% sensitivity of blood-based NGS for tumor tissue NGS. Mutations in KRAS, the major PDA oncogene, were only detected in 10/34 (29%) blood samples, compared to 20/23 (87%) tumor tissue biopsies. The presence of mutations in circulating DNA was associated with reduced overall survival (54% in mutation-positive versus 90% in mutation-negative). Our results suggest that in the setting of previously treated, advanced PDA, liquid biopsies are not yet an adequate substitute for tissue biopsies. Further refinement in defining the optimal patient population and timing of blood sampling may improve the value of a blood-based test.

Journal of Clinical Oncology, Feb 1, 2016

282 Background: Emerging insights into the molecular biology of tumors and recent developments in... more 282 Background: Emerging insights into the molecular biology of tumors and recent developments in MoP have led to the identification of targets that can be used for selecting treatment (tx) regimens. Multiple testing platforms are available, though most studies to date have used only next generation DNA sequencing (NGS). Methods: The Pancreatic Cancer Action Network (PanCAN) and Perthera have initiated an IRB-approved registry trial wherein we facilitate commercial MoP on tumor tissue from PDA patients. MoP includes NGS, immunohistochemistry (IHC), and phosphoproteomics (PHO). The results are reviewed by a team of PDA specialists in the context of the pt’s tx history. Tx options are prioritized based on the actionable molecular abnormalities. Pts are being followed longitudinally to assess physician acceptance of the tx options and track survival outcomes. Results: From 06/2014 to 09/2015, Perthera reports were delivered for 117 pts. 44% of the analyses were for second-line tx and 43% for ≥ third-line. Tumor based NGS and IHC were available for 75% and 90% of pts, respectively, and research use only PHO data was available for 20 pts. Actionable findings, defined based on a high response rate in pts with an identified molecular abnormality (in any cancer type), or based on a mechanism/pathway-defined implication of response to tx were identified in 43% of pts, primarily based on NGS. Incorporation of IHC refined and expanded chemotherapy tx options in all pts. PHO revealed pathway activation (e.g. mTOR, JAK-STAT, MET, RET, or EGFR) in 16/20 samples. Interestingly, only 45% of KRAS mutant samples had PHO-defined activation of the MEK-ERK pathway. Conclusions: MoP resulted in actionable findings in 43% of PDA pts using NGS and IHC. Incorporation of PHO data could have a significant impact on MoP-based therapy options. Analysis of the MoP in the context of patient history by a PDA specialist provided a service to treating oncologists in the community that was frequently incorporated into their treatment decisions. Survival outcomes will be presented. As additional testing platforms and results become available, the breadth and confidence of actionable markers is expected to increase.

Proceedings. 36th Annual 2002 International Carnahan Conference on Security Technology

Journal of Clinical Oncology, Feb 1, 2016

279 Background: There has been a significant increase in the utilization of MoP to facilitate the... more 279 Background: There has been a significant increase in the utilization of MoP to facilitate the selection of therapies for pts with advanced cancers. However, coordinated efforts to perform uniform MoP and collect clinical outcomes data have only successfully been executed in limited academic settings. In an effort to “democratize” the availability of MoP for PDA patients in a broad spectrum of clinical settings, The Pancreatic Cancer Action Network (PanCAN) and Perthera initiated the KYT initiative, an academic, industry, and advocacy group collaboration. Methods: PDA pts self-referred to the Patient Central call center at PanCAN. Pts interested in enrolling in an IRB-approved registry trial were then referred to Perthera to facilitate consent, tissue acquisition, and commercial MoP of the pt’s tumor. Test results were reviewed by a team of PDA specialists in the context of the pt’s treatment (tx) history. A report detailing tx options was delivered to the pt’s oncologist. Pts are being actively followed longitudinally to assess physician acceptance of the tx options and to track outcomes. Results: From 06/2014 to 09/2015, 382 pts were enrolled into KYT. Of these, 273 pts from 192 physicians (community and academic) in 38 states were enrolled. Reasons for non-enrollment were: pts no longer interested (67%); pts too ill or not appropriate for KYT (17%); the pt’s physician would not sanction MoP (16%). To date, 162 pt tumor samples have been obtained, and 117 reports delivered. 75% of samples had adequate tissue for genomic profiling (NGS), with 87% of samples harboring a KRAS mutation. Actionable findings (i.e. linked to a specific tx option) identified by NGS included mutations in BRCA2 (5%), PALB2 (1%), ATM (4%); BRAF (2%), PIK3C/PIK3R (7%), STK11 (5%), amplification of ERBB2 (3%), FGFR (2%), PDGFR (2%); and RET fusions (2%). Of the 117 profiles, 43% revealed actionable findings; 58% presented off-label therapy options; and 48% led towards high priority clinical trials. Conclusions: MoP of pts with PDA is feasible irrespective of their geographical location or access to an academic center. Updated information on tx selection and patient outcomes will be provided.

Journal of Clinical Oncology, 2017

Journal of Clinical Oncology, 2016

Cancer biology & therapy, Jan 28, 2016

Proceedings. 36th Annual 2002 International Carnahan Conference on Security Technology, 2002

The latest generation of computer vision technology is revolutionizing concepts, applications, an... more The latest generation of computer vision technology is revolutionizing concepts, applications, and products in video surveillance and CCTV. This is of prime relevance to security for large outdoor facilities such as commercial airfields, refineries, power plants, and office/industrial campuses. Most airfields, for example, have open (unfenced) perimeters, high volume heterogeneous traffic, are easily accessed on foot or by water, and exist in areas where regulations providing a safety buffer are difficult to legislate or enforce. And all airfields require 24x7 outdoor monitoring - snow, fog, rain or shine. Likewise, most high-value facilities appealing to criminals and terrorists are in close proximity to public areas (roads, residences, city, etc.). The appeal of automated real-time surveillance is obvious - maximizing efficiency and effectiveness of security personnel and resources while increasing the probability of preventing a serious security breach. Computer vision based solu...

Journal of Clinical Oncology, 2016

268 Background: Obtaining an adequate tissue sample for molecular profiling to guide therapy sele... more 268 Background: Obtaining an adequate tissue sample for molecular profiling to guide therapy selection for patients with advanced cancers can be clinically difficult, and/or patients may not want to undergo a biopsy. There has been a growing interest in the use of BB tests, including cell free DNA (cfDNA) and exosome/circulating tumor cell based-analyses as surrogates for tumor tissue (TT) testing. Validation of BB tests in PDA is possible because > 90% of PDAs harbor KRAS mutations – thus providing a reliable “internal control.” Methods: The Pancreatic Cancer Action Network (PanCAN) and Perthera initiated an IRB-approved registry trial for patients with pancreatic cancer wherein we facilitated commercially available, CLIA certified multi-Omic profiling including next generation DNA sequencing (NGS), immunohistochemistry, and phosphoproteomics on patient tumor samples. In a subset of these patients, we incorporated BB testing. Results: A KRAS mutation has been identified in 87% o...

IEEE Aerospace and Electronic Systems Magazine, 2003

... N. Haering & D. Madden. ... Operating Environment Issues Low-level street lamp illuminati... more ... N. Haering & D. Madden. ... Operating Environment Issues Low-level street lamp illumination and vehicle headlights at night Nighttime lighting phenomenon (refinery flare and flashing amber beacon on regular patrols by refinery security vehicles) Film and dust accumulation in ...

Journal of Clinical Oncology, 2016

Oncotarget, Jan 8, 2016

Recent improvements in next-generation sequencing (NGS) technology have enabled detection of biom... more Recent improvements in next-generation sequencing (NGS) technology have enabled detection of biomarkers in cell-free DNA in blood and may ultimately replace invasive tissue biopsies. However, a better understanding of the performance of blood-based NGS assays is needed prior to routine clinical use. As part of an IRB-approved molecular profiling registry trial of pancreatic ductal adenocarcinoma (PDA) patients, we facilitated blood-based NGS testing of 34 patients from multiple community-based and high-volume academic oncology practices. 23 of these patients also underwent traditional tumor tissue-based NGS testing. cfDNA was not detected in 9/34 (26%) patients. Overall concordance between blood and tumor tissue NGS assays was low, with only 25% sensitivity of blood-based NGS for tumor tissue NGS. Mutations in KRAS, the major PDA oncogene, were only detected in 10/34 (29%) blood samples, compared to 20/23 (87%) tumor tissue biopsies. The presence of mutations in circulating DNA was ...

Cancer Biology & Therapy, Mar 6, 2018

Journal of Clinical Oncology, Feb 1, 2016

Journal of Clinical Oncology, Feb 1, 2017

Oncotarget, Nov 8, 2016

Journal of Clinical Oncology, Feb 1, 2016

Proceedings. 36th Annual 2002 International Carnahan Conference on Security Technology

Journal of Clinical Oncology, Feb 1, 2016

Journal of Clinical Oncology, 2017

Journal of Clinical Oncology, 2016

Cancer biology & therapy, Jan 28, 2016

Proceedings. 36th Annual 2002 International Carnahan Conference on Security Technology, 2002

Journal of Clinical Oncology, 2016

IEEE Aerospace and Electronic Systems Magazine, 2003

Journal of Clinical Oncology, 2016

Oncotarget, Jan 8, 2016

Recent improvements in next-generation sequencing (NGS) technology have enabled detection of biom... more Recent improvements in next-generation sequencing (NGS) technology have enabled detection of biomarkers in cell-free DNA in blood and may ultimately replace invasive tissue biopsies. However, a better understanding of the performance of blood-based NGS assays is needed prior to routine clinical use. As part of an IRB-approved molecular profiling registry trial of pancreatic ductal adenocarcinoma (PDA) patients, we facilitated blood-based NGS testing of 34 patients from multiple community-based and high-volume academic oncology practices. 23 of these patients also underwent traditional tumor tissue-based NGS testing. cfDNA was not detected in 9/34 (26%) patients. Overall concordance between blood and tumor tissue NGS assays was low, with only 25% sensitivity of blood-based NGS for tumor tissue NGS. Mutations in KRAS, the major PDA oncogene, were only detected in 10/34 (29%) blood samples, compared to 20/23 (87%) tumor tissue biopsies. The presence of mutations in circulating DNA was ...