Cancerprofiling.com.au

ORDERED BY
Patient Name
Primary Tumor Site: Brain, NOS
Ordering Physician
Case Number: TN13-111111
Specimen Site: Cerebellum
The Cancer Center
Date Of Birth: XX/XX/1995
Specimen Collected: XX/XX/2013
City Gate, St. Jakobsstrasse 123ABC, Basel, CH-4052 Sex: Male
Specimen Received: XX/XX/2013
Initiation of Testing: XX/XX/2013
Completion of Testing: XX/XX/2013
Caris Molecular Intelligence Service Report Summary
Agents Associated with
Agents Associated With
Potential LACK OF BENEFIT
Agents associated with potential benefit or lack of benefit, as indicated above, are based on biomarker results provided in this report, andare based on published medical evidence. This evidence may have been obtained from the studies performed in the cancer type present inthe tested patient's sample or derived from another tumor type.
The selection of any, all or none of the matched agents resides solely with the discretion of the treating physician. Decisions on patient care and treatment mustbe based on the independent medical judgment of the treating physician, taking into consideration all applicable information concerning the patient's condition,such as patient and family history, physical examinations, information from other diagnostic tests, and patient preferences, in accordance with the applicablestandard of care. Decisions regarding care and treatment should not be based on a single test such as this test or the information contained in this report.
** FINAL REPORT **
Patient: Patient Name
Physician: Ordering Physician
4610 South 44th Place / Phoenix, AZ 85040 / (888) 979-8669 / Fax: (866) 479-4925 / CLIA 03D1019490 / Zoran Gatalica, M.D., DSc, Medical Director Caris MPI, Inc. d/b/a Caris Life Sciences

Clinical History
Per the submitted surgical pathology report (XYZ-123), the patient is a 17 year-old male with a history of an unclassifiable malignant
neoplasm of the brain.
Submitted Pathologic Diagnosis
Repeat posterior fossa brain tumour biopsy: Malignant neoplasm, not able to be further classified.
Specimens Received (Gross Description)
The specimens consist of:
1 (A) Paraffin Block - Client ID(XYZ-123) with the corresponding histopathology report labeled "XYZ-123".
** FINAL REPORT **
Patient: Patient Name
Physician: Ordering Physician
4610 South 44th Place / Phoenix, AZ 85040 / (888) 979-8669 / Fax: (866) 479-4925 / CLIA 03D1019490 / Zoran Gatalica, M.D., DSc, Medical Director Caris MPI, Inc. d/b/a Caris Life Sciences

Agents Associated with Potential BENEFIT
Lack of Level* Reference
*The level of evidence for all references is assigned according to the Literature Level of Evidence Framework consistent with the US Preventive Services Task Force described further in the Appendix of this report. The data level of each biomarker-drug interaction is the average level of evidence based on the body of evidence, overall clinical utility, competing biomarker interactions and tumor type from which the evidence was gathered.
= Greater level of evidence = Intermediate level of evidence = Lower level of evidence ✝ Refer to Appendix for detailed Result and Value information for each biomarker, including appropriate cutoffs, unit of measure, etc.
** FINAL REPORT **
Patient: Patient Name
Physician: Ordering Physician
4610 South 44th Place / Phoenix, AZ 85040 / (888) 979-8669 / Fax: (866) 479-4925 / CLIA 03D1019490 / Zoran Gatalica, M.D., DSc, Medical Director Caris MPI, Inc. d/b/a Caris Life Sciences

Agents Associated with Potential LACK OF BENEFIT
Lack of Level* Reference
17, 18, 19
26, 28, 29,
30, 31, 32,
33, 34, 35
26, 27, 28,
29, 30, 31
Wild Type
36, 37, 38
36, 37, 38
41, 42, 43
44, 45, 46
** FINAL REPORT **
Patient: Patient Name
Physician: Ordering Physician
4610 South 44th Place / Phoenix, AZ 85040 / (888) 979-8669 / Fax: (866) 479-4925 / CLIA 03D1019490 / Zoran Gatalica, M.D., DSc, Medical Director Caris MPI, Inc. d/b/a Caris Life Sciences Agents Associated with Potential LACK OF BENEFIT
Lack of Level* Reference
Wild Type
47, 48, 49
Wild Type
50, 51, 52
Wild Type
47, 48, 49
*The level of evidence for all references is assigned according to the Literature Level of Evidence Framework consistent with the US Preventive Services Task Force described further in the Appendix of this report. The data level of each biomarker-drug interaction is the average level of evidence based on the body of evidence, overall clinical utility, competing biomarker interactions and tumor type from which the evidence was gathered.
= Greater level of evidence = Intermediate level of evidence = Lower level of evidence ✝ Refer to Appendix for detailed Result and Value information for each biomarker, including appropriate cutoffs, unit of measure, etc.
** FINAL REPORT **
Patient: Patient Name
Physician: Ordering Physician
4610 South 44th Place / Phoenix, AZ 85040 / (888) 979-8669 / Fax: (866) 479-4925 / CLIA 03D1019490 / Zoran Gatalica, M.D., DSc, Medical Director Caris MPI, Inc. d/b/a Caris Life Sciences Agents Associated with INDETERMINATE BENEFIT
Lack of Level* Reference
Wild Type
*The level of evidence for all references is assigned according to the Literature Level of Evidence Framework consistent with the US Preventive Services Task Force described further in the Appendix of this report. The data level of each biomarker-drug interaction is the average level of evidence based on the body of evidence, overall clinical utility, competing biomarker interactions and tumor type from which the evidence was gathered.
= Greater level of evidence = Intermediate level of evidence = Lower level of evidence ✝ Refer to Appendix for detailed Result and Value information for each biomarker, including appropriate cutoffs, unit of measure, etc.
** FINAL REPORT **
Patient: Patient Name
Physician: Ordering Physician
4610 South 44th Place / Phoenix, AZ 85040 / (888) 979-8669 / Fax: (866) 479-4925 / CLIA 03D1019490 / Zoran Gatalica, M.D., DSc, Medical Director Caris MPI, Inc. d/b/a Caris Life Sciences Expanded Mutational Analysis by Next Generation Sequencing
Genes Tested With Alterations
Interpretation: A pathogenic mutation was detected in BRAF
BRAF encodes a protein belonging to the raf/mil family of serine/threonine protein kinases. This protein plays a role in regulating the
MAP kinase/ERK signaling pathway initiated by EGFR activation, which affects cell division, differentiation, and secretion. BRAF somatic mutations have been found in melanoma (43%), thyroid (39%), biliary tree (14%), colon (12%), and ovarian tumors (12%). Patients with mutated BRAF genes have a reduced likelihood of response to EGFR targeted monoclonal antibodies, such as cetuximab in colorectal cancer. A BRAF enzyme inhibitor, vemurafenib, was approved by FDA to treat unresectable or metastatic melanoma patients harboring BRAF V600E mutations. Various clinical trials (on www.clinicaltrials.gov) investigating agents which target this gene may be available, which include the following: NCT01543698, NCT01352273, NCT01709292.
BRAF inherited mutations are associated with Noonan/Cardio-Facio-Cutaneous (CFC) syndrome, syndromes associated with short stature, distinct facial features, and potential heart/skeletal abnormalities.
Genes Tested Without Alterations
Genes Tested with Indeterminate Results
Electronic Signature ** FINAL REPORT **
Patient: Patient Name
Physician: Ordering Physician
4610 South 44th Place / Phoenix, AZ 85040 / (888) 979-8669 / Fax: (866) 479-4925 / CLIA 03D1019490 / Zoran Gatalica, M.D., DSc, Medical Director Caris MPI, Inc. d/b/a Caris Life Sciences Penson, R.T., M.V. Seiden, et al. (2004). "Expression of multidrug resistance-1 protein inversely correlates with paclitaxel response Yeh, J.J., A. Kao, et al. (2003). "Predicting Chemotherapy Response to Paclitaxel-Based Therapy in Advanced Non-Small-Cell Lung Cancer with P-Glycoprotein Expression." Respiration 70:32-35.
Gao, S., J. Gao, et al. (2012). "Clinical implications of REST and TUBB3 in ovarian cancer and its relationship to paclitaxel resistance." T Ploussard, G., A. de la Taille, et al. (2010). "Class III β-Tubulin Expression Predicts Prostate Tumor Aggressiveness and Patient Response to Docetaxel-Based Chemotherapy Zhang, H.-L., X.-W. Zhou, et al. (2012). "Association between class III β-tubulin expression and response to paclitaxel/vinorelbine- Seve, P., C. Dumontet, et al. (2005). "Class III β-tubulin expression in tumor cells predicts response and outcome in patients with non-small cell lung cancer receiving paclitaxel." Mol Cancer Ther 4(12): 2001-2007.
Kulkarni, S.A., D.T. Ross, et. al. (2009). "TLE3 as a candidate biomarker of response to taxane therapy". Breast Cancer Research.
Lee, S.J., Y.H. Im, et. al. (2010). "Thymidylate synthase and thymidine phosphorylase as predictive markers of capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer." Cancer Chemother. Pharmacol.
Qiu, L.X., M.H. Zheng, et. al. (2008). "Predictive value of thymidylate synthase expression in advanced colorectal cancer patients receiving fluoropyrimidine-based chemotherapy: Evidence from 24 studies." Int. J. Cancer: 123, 2384-2389.
Chen, C.-Y., P.-C. Yang, et al. (2011). "Thymidylate synthase and dihydrofolate reductase expression in non-small cell lung carcinoma: The association with treatment efficacy of pemetrexed." Lung Cancer 74(1): 132-138.
Gennari, A., P. Bruzzi, et. al (2008) "HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials." J Natl Can Inst. 100:14-20.
Press, M.F., Slamon, D.J., et. al. (2011)."Alteration of topoisomerase II-alpha gene in human breast cancer: association with responsiveness to anthracycline based chemotherapy." J. Clin. Oncol, 29(7):859-67.
Chintamini, J.P., Singh, et. al. (2005). "Role of p-glycoprotein expression in predicting response to neoadjuvant chemotherapy in breast cancer - a prospective clinical study." W Akimoto, M., H, Saisho, et al. (2006). "Relationship between therapeutic efficacy of arterial infusion chemotherapy and expression of P-glycoprotein and p53 protein in advanced hepatocellular carcinoma." World J of Gastroenterol, 12(6), 868-873.
O'Malley, F.P., K.I. Pritchard, et al. (2011). "Topoisomerase II alpha protein and resposiveness of breast cancer to adjuvant chemotherapy with CEF compared to CMF in the NCIC CTG randomized MA.5 adjuvant trial." Breast Can Res Treat. 128, Rodrigo, R.S., C. Axel le, et. al. (2011). "Topoisomerase II-alpha protein expression and histological response following doxorubicin-based induction chemotherapy predict survival of locally advanced soft tissues sarcomas." Eur J of Can. 47, Braun, M.S., M.T. Seymour, et. al. (2008). "Predictive biomarkers of chemotherapy efficacy in colorectal cancer: results from the Ataka, M., K. Katano, et. al. (2007). "Topoisomerase I protein expression and prognosis of patients with colorectal cancer." Yonago Acta medica. 50:81-87 Kostopoulos, I., G. Fountzilas, et. al. (2009). "Topoisomerase I but not thymidylate synthase is associated with improved outcome in patients with resected colorectal cancer treated with irinotecan containing adjuvant chemotherapy." BMC Cancer. 9:339 ** FINAL REPORT **
Patient: Patient Name
Physician: Ordering Physician
4610 South 44th Place / Phoenix, AZ 85040 / (888) 979-8669 / Fax: (866) 479-4925 / CLIA 03D1019490 / Zoran Gatalica, M.D., DSc, Medical Director Caris MPI, Inc. d/b/a Caris Life Sciences Gong, W., J. Dong, et. al. (2012). "RRM1 expression and clinical outcome of gemcitabine-containing chemotherapy for advanced non-small-cell lung cancer: A meta-analysis." Lung Cancer. 75:374-380.
Chinot, O. L., M. Barrie, et al. (2007). "Correlation between O6-methylguanine-DNA methyltransferase and survival in inoperable newly diagnosed glioblastoma patients treated with neoadjuvant temozolomide." J Clin Oncol 25(12): Busch, C., P.E. Lonning, et. al. (2010). "MGMT expression levels predict disease stabilisation, progression-free and overall survival in patients with advanced melanomas treated with DTIC." European Journal of Cancer. 46:2127-2133.
Von Hoff, D.D., M. Hidalgo, et. al. (2011). "Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial." J. Clin. Oncol. DOI: 10.1200/JCO.2011.36.5742.
Desai, N., Soon-Shiong, P., et al. (2009). "SPARC Expression Correlates with Tumor Response to Albumin-Bound Paclitaxel in Head and Neck Cancer Patients." T El Sheikh, S. S., H. M. Romanska, et. al. (2008). "Predictive value of PTEN and AR coexpression of sustained responsiveness to hormonal therapy in prostate cancer--a pilot study Thurlimann, B., A. Goldhirsch, et al. (1997). "Formestane versus Megestrol Acetate in Postmenopausal Breast Cancer Patients After Failure of Tamoxifen: A Phase III Prospective Randomised Cross Over Trial of Second-line Hormonal Treatment (SAKK 20/90). E J Cancer 33 (7): 1017-1024.
Stendahl, M., L. Ryden, et al. (2006). "High progesterone receptor expression correlates to the effect of adjuvant tamoxifen in Stuart, N.S.A., H. Earl, et. al. (1996). "A randomized phase III cross-over study of tamoxifen versus megestrol acetate in advanced and recurrent breast cancer." European Journal of Cancer. 32(1 Cuzick J,LHRH-agonists in Early Breast Cancer Overview group. (2007). "Use of luteinising-hormone-releasing hormone agonists as adjuvant treatment in premenopausal patients with hormone-receptor-positive breast cancer: a meta-analysis of individual patient data from randomised adjuvant trials." The Lancet 369: 1711-1723.
Lewis, J.D., M.J. Edwards, et al. (2010). "Excellent outcomes with adjuvant toremifene or tamoxifen in early stage breast cancer." Dowsett, M., C. Allred, et al. (2008). "Relationship between quantitative estrogen and progesterone receptor expression and human epidermal growth factor receptor 2 (HER-2) status with recurrence in the Arimidex, Tamoxifen, Alone or in Combination trial." J Clin Oncol 26(7): 1059-65.
Bartlett, J.M.S., D. Rea, et al. (2011). "Estrogen receptor and progesterone receptor as predictive biomarkers of response to endocrine therapy: a prospectively powered pathology study in the Tamoxifen and Exemestane Adjuvant Multinational trial." J Coombes, R.C., J.M. Bliss, et al. (2007). "Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomized controlled trial." The Lancet 369:559-570.
Anderson, H., M. Dowsett, et. al. (2011). "Relationship between estrogen receptor, progesterone receptor, HER-2 and Ki67 expression and efficacy of aromatase inhibitors in advanced breast cancer. Annals of Oncology. 22:1770-1776.
Viale, G., M. M. Regan, et al. (2008). "Chemoendocrine compared with endocrine adjuvant therapies for node-negative breast cancer: predictive value of centrally reviewed expression of estrogen and progesterone receptors--International Breast Cancer Study Group." J Clin Oncol 26(9): 1404-10.
Nicolantonio, F.D., A. Bardelli, et. al. (2010). "Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus." The Journal of Clinical Investigation. 120(8):2858-2866.
Moroney, J.W., R. Kurzrock, et. al. (2011). "A phase I trial of liposomal doxorubicin, bevacizumab, and temsirolimus in patients with advanced gynecologic and breast malignancies." Clin. Cancer Res. 17:6840-6846.
Janku, F., R. Kurzrock, et. al. (2011). "PIK3CA mutations in patients with advanced cancers treated with PI3K/AKT/mTOR axis inhibitors." Molecular Cancer Therapeutics. 10(3):558-65.
** FINAL REPORT **
Patient: Patient Name
Physician: Ordering Physician
4610 South 44th Place / Phoenix, AZ 85040 / (888) 979-8669 / Fax: (866) 479-4925 / CLIA 03D1019490 / Zoran Gatalica, M.D., DSc, Medical Director Caris MPI, Inc. d/b/a Caris Life Sciences Yin, W., J. Lu, et. al. (2011). "Trastuzumab in adjuvant treatment HER2-positive early breast cancer patients: A meta-analysis of published randomized controlled trials." PLoS ONE 6(6): e21030. doi:10.1371/journal.pone.0021030.
Bang, Y-J., Y-K. Kang, et. al. (2010). "Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial." Lancet. 376:687-97.
Cortes, J., J. Baselga, et. al. (2012). "Pertuzumab monotherapy after trastuzumab-based treatment and subsequent reintroduction of trastuzumab: activity and tolerability in patients with advanced human epidermal growth factor receptor-2-positive breast cancer." J. Clin. Oncol. 30. DOI: 10.1200/JCO.2011.37.4207.
Slamon, D., M. Buyse, et. al. (2011). "Adjuvant trastuzumab in HER2-positive breast cancer." N. Engl. J. Med. Bartlett, J.M.S., K. Miller, et. al. (2011). "A UK NEQAS ISH multicenter ring study using the Ventana HER2 dual-color ISH assay." Am. J. Clin. Pathol. 135:157-162.
Johnston, S., Pegram M., et. al. (2009). "Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. Journal of Clinical Oncology. Published ahead of print on Amir, E. et. al. (2010). "Lapatinib and HER2 status: results of a meta-analysis of randomized phase III trials in metastatic breast cancer." Cancer T Press, M. F., R. S. Finn, et al. (2008). "HER-2 gene amplification, HER-2 and epidermal growth factor receptor mRNA and protein expression, and lapatinib efficacy in women with metastatic breast cancer." Clin Cancer Res 14(23): Minor, D.R., B.C. Bastian, et. al. (2012). "Sunitinib therapy for melanoma patients with KIT mutations." Clinical Cancer Research.
Guo, J., S. Qin, et. al. (2011). "Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma Carvajal, R.D., G.K. Schwartz, et. al. (2011). "KIT as a therapeutic target in metastatic melanoma." JAMA. 305(22):2327-2334.
Biron, P., P. G. Casali, et al. (2010). "Outcome of patients (pts) with PDGFRA D842V mutant gastrointestinal stromal tumor (GIST) treated with imatinib (IM) for advanced disease." J Clin Oncol 30 (suppl; abstr 10051) Debiec-Rychter, M., I. Judson, et al. (2006). "KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours." Eur J Cancer 42:1093-1 Heinrich, M.C., J.A. Fletcher, et. al. (2008). "Correlation of kinase genotype and clinical outcome in North American Intergroup phase III trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 study by Cancer and Leukemia Group B and Southwest Oncology Group." J Clin Oncol 26(33):5360-5367.
Wells, S.A., M.J. Schlumberger, et al. (2012). "Vandetanib in Patients with Locally Advanced or Metastatic Medullary Thyroid Cancer: A Randomized, Double-Blind Phase III T Sosman, J.A., A.K. Joe, et. al. (2012). "Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib." N. Engl.
Chapman, P.B., G.A. McArthur, et. al. (2011). "Improved survival with vemurafenib in melanoma with BRAF V600E mutation." N.
Engl. J. Med. This article (10.1056/NEJMoa1103782) was published on June 5, 2011, at nejm.org.
** FINAL REPORT **
Patient: Patient Name
Physician: Ordering Physician
4610 South 44th Place / Phoenix, AZ 85040 / (888) 979-8669 / Fax: (866) 479-4925 / CLIA 03D1019490 / Zoran Gatalica, M.D., DSc, Medical Director Caris MPI, Inc. d/b/a Caris Life Sciences All of the individual assays that are available through Caris Life Sciences® Molecular Intelligence™ Services (Caris Molecular Intelligence) were developed and validated by Caris MPI, Inc. d/b/a Caris Life Sciences and their test performance characteristics were determined and validated by Caris Life Sciences pursuant to the Clinical Laboratory Improvements Amendments and accompanying regulations ("CLIA"). Some of the assays that are part of Caris Molecular Intelligence have been cleared or approved by the U.S. Food and Drug Administration (FDA). The clinical reference laboratory of Caris MPI, Inc. is certified under CLIA to perform high complexity testing, including all of the assays that are part of the Caris Molecular Intelligence.
The CLIA certification number of each Caris MPI, Inc. laboratory performing testing in connection with Caris Molecular Intelligence can be found at the bottom of each page. This Report includes information about therapeutic agents that appear to be associated with clinical benefit based on NCCN Compendium guidelines, relevance of tumor lineage, level of published evidence and strength of biomarker expression, as available, reviewed and assessed by Caris Life Sciences. The agents are not ranked in order of potential or predicted efficacy. The finding of a biomarker expression does not necessarily indicate pharmacologic effectiveness or lack thereof. The agents identified may or may not be suitable for use with a particular patient and the report does not guarantee or suggest that any particular agent will be effective with the treatment of any particular condition. Caris Life Sciences expressly disclaims and makes no representation or warranty whatsoever relating, directly or indirectly, to this review of evidence or identified scientific literature, the conclusions drawn from it or any of the information set forth in this Report that is derived from such review, including information and conclusions relating to therapeutic agents that are included or omitted from this Report.
The decision to select any, all or none of the matched agents resides solely with the discretion of the treating physician. Decisions on patient care and treatment must be based on the independent medical judgment of the treating physician, taking into consideration all applicable information concerning the patient's condition, such as patient and family history, physical examinations, information from other diagnostic tests, and patient preferences, in accordance with the applicable standard of care. Decisions regarding care and treatment should not be based on a single test such as this test or the information contained in this report.
The information presented in the Clinical Trials Connector™ section of the Report is compiled from sources believed to be reliable and current. We have used our best efforts to make this information as accurate as possible. However, the accuracy and completeness of this information cannot be guaranteed. The contents are to be used for clinical trial guidance and may not include all relevant trials. Current enrollment status for these trials is unknown. The clinical trials information present in the biomarker description was compiled from www.clinicaltrials.gov. The contents are to be used only as a guide, and health care providers should employ clinical judgment in interpreting this information for individual patients.
Specific entrance criteria for each clinical trial should be reviewed as additional inclusion criteria may apply. Caris Life Sciences makes no promises or guarantees that a healthcare provider, insurer or other third party payor, whether private or governmental, will provide reimbursement (instead of coverage) for any of the tests performed.
The next generation sequencing assay performed by Caris Life Sciences examines tumor tissue only and does not examine normal tissues such as tumor adjacent tissue or whole/ peripheral blood. As such, the origin of any mutation detected by our assay may either be a somatic (not inherited) or a germline mutation (inherited) and will not be distinguishable by this assay. It is recommended that results be considered within the clinical context and history of the patient. If a germline inheritance pattern is suspected then counseling by a board certified genetic counselor is recommended.
Electronic Signature ** FINAL REPORT **
Patient: Patient Name
Physician: Ordering Physician
4610 South 44th Place / Phoenix, AZ 85040 / (888) 979-8669 / Fax: (866) 479-4925 / CLIA 03D1019490 / Zoran Gatalica, M.D., DSc, Medical Director Caris MPI, Inc. d/b/a Caris Life Sciences Note: The initial pages of this Appendix contain patient
specific Result and Value information for each biomarker,
including appropriate cutoffs, unit of measure, etc.
** FINAL REPORT **
Patient: Patient Name
Physician: Ordering Physician
4610 South 44th Place / Phoenix, AZ 85040 / (888) 979-8669 / Fax: (866) 479-4925 / CLIA 03D1019490 / Zoran Gatalica, M.D., DSc, Medical Director Caris MPI, Inc. d/b/a Caris Life Sciences Note: Please refer to the "Expanded Mutational Analysis by Next Gen Sequencing" section
of the report for information on the additional mutations offered in the expanded panel
Next Generation Sequencing: Direct sequence analysis was performed on genomic DNA isolated from a formalin-fixed paraffin-embedded tumor sample
using the Illumina MiSeq platform. Specific regions of the genome were amplified using the Illumina TruSeq Amplicon Cancer Hotspot panel. This panel only sequences selected regions of 44 genes and the amino acids sequenced by this assay can be found at www.carislifesciences.com. All variants reported by this are detected with >99% confidence based on the frequency of the mutation present and the amplicon coverage. This test is not designed to distinguish between germ line inheritance of a variant or acquired somatic mutation. This test has a sensitivity to detect as low as approximately 10% population of cells containing a mutation a sequenced amplicon. This test has not been cleared or approved by the United States Food and Drug Administration (FDA) as such approval is not necessary. All performance characteristics were determined by Caris Life Sciences. Insertions or deletions larger than 27 bp will not be detected by this assay. Benign and non-coding variants are not included in this report but are available upon request.
** FINAL REPORT **
Patient: Patient Name
Physician: Ordering Physician
4610 South 44th Place / Phoenix, AZ 85040 / (888) 979-8669 / Fax: (866) 479-4925 / CLIA 03D1019490 / Zoran Gatalica, M.D., DSc, Medical Director Caris MPI, Inc. d/b/a Caris Life Sciences IHC Biomarker Detail
Threshold *
Staining Intensity Percent Staining
=0+ or <50% or <2+ or ≥2+ and ≥50% <30% or <2+ or ≥2+ and ≥30% =0+ or <30% or <2+ or ≥2+ and ≥30% =0+ or <10% or ≥1+ and ≥10% <30% or <2+ or ≥2+ and ≥30% <30% or <2+ or ≥2+ and ≥30% <30% or <2+ or ≥2+ and ≥30% =0+ or ≤50% or ≥1+ and >50% =0+ or ≤35% or ≥1+ and >35% =0+ or ≤3+ and <10% or ≥1+ and ≥10% =0+ or <10% or ≥1+ and ≥10% =0+ or <10% or ≥1+ and ≥10% ≤1+ or =2+ and <10% or ≥3+ and ≥10% =0+ or <10% or ≥1+ and ≥10% =0+ or <10% or ≥1+ and ≥10% <50% or <2+ or ≥2+ and ≥50% These tests were developed and their performance characteristics determined by Caris Life Sciences, Inc.
* Caris Life Sciences has defined threshold levels of reactivity of IHC to establish cutoff points based on published evidence. Clones used: RRM1(polyclonal), SPARC Monoclonal(122511), TOPO1(1D6), TOP2A(3F6), TLE3(M-201), SPARC Polyclonal(polyclonal), TUBB3(Neuronal Class III Beta-Tubulin Polyclonal), PTEN(6H2.1), MGMT(MT23.3), TS(TS106/4H4B1), Androgen Receptor(AR318), ER(SP1), Her2/ Neu(4B5), PGP(C494), PR(100), cMET(CONFIRM anti-Total cMET (SP44)).
Electronic Signature ** FINAL REPORT **
Patient: Patient Name
Physician: Ordering Physician
4610 South 44th Place / Phoenix, AZ 85040 / (888) 979-8669 / Fax: (866) 479-4925 / CLIA 03D1019490 / Zoran Gatalica, M.D., DSc, Medical Director Caris MPI, Inc. d/b/a Caris Life Sciences ANALYSIS BY CISH FOR AMPLIFICATION
nuc ish (D17Z1x1-2,HER2x1-2)[/30] Reference Range: Her2/Neu:CEP 17 signal ratio of >= 2.0; and non-amplification as <2.0 per
Ventana INFORM HER2 CISH Package insert.
The INFORM DUAL HER2 ISH Assay (Ventana Medical Systems, Inc.) has been cleared by the US Food and Drug Administration (FDA) for enumerating the ratio of Her2/Chr 17 in Breast Cancer samples.The cMET CISH test was carried out using a probe specific for cMET and a probe for the pericentromeric region of chromosome 7 (Ventana). The cMET probe and HER2 probe for cancer lineages other than breast have been developed and their performance characteristics determined by Caris MPI, Inc. (d/b/a Caris Life Sciences), and have not been cleared or approved by the FDA. The FDA has determined that such clearance or approval is not currently necessary. These tests should not be regarded as investigational or research as they are used for clinical purpose and determined to be medically necessary by the ordering physician, who is not employed by Caris MPI, Inc. or its affiliates. This laboratory is certified under Clinical Laboratory Improvement Amendment of 1988 (CLIA-88) and is qualified to perform high complexity testing. CLIA 03D1019490 Electronic Signature ** FINAL REPORT **
Patient: Patient Name
Physician: Ordering Physician
4610 South 44th Place / Phoenix, AZ 85040 / (888) 979-8669 / Fax: (866) 479-4925 / CLIA 03D1019490 / Zoran Gatalica, M.D., DSc, Medical Director Caris MPI, Inc. d/b/a Caris Life Sciences ABL1 Most CML patients have a chromosomal abnormality due to a fusion between Abelson (Abl) tyrosine kinase gene at chromosome 9 and break point cluster (Bcr) gene at chromosome 22 resulting in constitutive activation of the Bcr-Abl fusion gene. Imatinib is a Bcr-Abl tyrosine kinase inhibitor commonly used in treating CML patients. Mutations in the ABL1 gene are common in imatinib resistant CML patients which occur in 30-90% of patients.
However, more than 50 different point mutations in the ABL1 kinase domain may be inhibited by the second generation kinase inhibitors, dasatinib, bosutinib and nilotinib. The gatekeeper mutation, T315I that causes resistance to all currently approved TKIs accounts for about 15% of the mutations found in patients with imatinib resistance. BCR-ABL1 mutation analysis is recommended to help facilitate selection of appropriate therapy for patients with CML after treatment with imatinib fails. Various clinical trials (on www.clinicaltrials.gov) investigating agents which target this gene may be available, which include the following: NCT01528085.
AKT1 gene (v-akt murine thymoma viral oncogene homologue 1) encodes a serine/threonine kinase which is a pivotal mediator of the PI3K-related signaling pathway, affecting cell survival, proliferation and invasion. Dysregulated AKT activity is a frequent genetic defect implicated in tumorigenesis and has been indicated to be detrimental to hematopoiesis. Activating mutation E17K has been described in breast (2-4%), endometrial (2-4%), bladder cancers (3%), NSCLC (1%), squamous cell carcinoma of the lung (5%) and ovarian cancer (2%). This mutation in the pleckstrin homology domain facilitates the recruitment of AKT to the plasma membrane and subsequent activation by altering phosphoinositide binding. A mosaic activating mutation E17K has also been suggested to be the cause of Proteus syndrome. Mutation E49K has been found in bladder cancer, which enhances AKT activation and shows transforming activity in cell lines. Various clinical trials (on www.clinicaltrials.gov) investigating AKT inhibitor MK-2206 in patients carrying AKT mutations may be available, which include the following: NCT01277757, NCT01425879.
ALK rearrangements indicates the fusion of ALK (anaplastic lymphoma kinase) gene with the fusion partner, EML4. EML4-ALK fusion results in the pathologic expression of a fusion protein with constitutively active ALK kinase, resulting in aberrant activation of downstream signaling pathways including RAS-ERK, JAK3-STAT3 and PI3K-AKT. Patients with an EML4-ALK rearrangement are likely to respond to the ALK-targeted agent crizotinib.
The androgen receptor (AR) is a member of the nuclear hormone receptor superfamily. Prostate tumor dependency on androgens / AR signaling is the basis for hormone withdrawal, or androgen ablation therapy, to treat men with prostate cancer. Androgen receptor antagonists as well as agents which block androgen production are indicated for the treatment of AR expressing prostate cancers.
APC or adenomatous polyposis coli is a key tumor suppressor gene that encodes for a large multi-domain protein. This protein exerts its tumor suppressor function in the Wnt/b-catenin cascade mainly by controlling the degradation of b-catenin, the central activator of transcription in the Wnt signaling pathway.
The Wnt signaling pathway mediates important cellular functions including intercellular adhesion, stabilization of the cytoskeleton, and cell cycle regulation and apoptosis, and it is important in embryonic development and oncogenesis. Mutation in APC results in a truncated protein product with abnormal function, lacking the domains involved in b-catenin degradation. Somatic mutation in the APC gene can be detected in the majority of colorectal tumors (80%) and it is an early event in colorectal tumorigenesis. APC wild type patients have shown better disease control rate in the metastatic setting when treated with oxaliplatin, while when treated with fluoropyrimidine regimens, APC wild type patients experience more hematological toxicities. APC mutation has also been identified in oral squamous cell carcinoma, gastric cancer as well as hepatoblastoma and may contribute to cancer formation.
Various clinical trials (on www.clinicaltrials.gov) investigating agents which target this gene and/or its downstream or upstream effectors maybe available, which include the following: NCT01351103. Germline mutation in APC causes familial adenomatous polyposis, which is an autosomal dominant inherited disease that will inevitably develop to colorectal cancer if left untreated. COX-2 inhibitors including celecoxib may reduce the recurrence of adenomas and incidence of advanced adenomas in individuals with an increased risk of CRC. Turcot syndrome and Gardner's syndrome have also been associated with germline APC defects. Germline mutations of the APC have also been associated with an increased risk of developing desmoid disease, papillary thyroid carcinoma and hepatoblastoma.
ATM or ataxia telangiectasia mutated is activated by DNA double-strand breaks and DNA replication stress. It encodes a protein kinase that acts as a tumor suppressor and regulates various biomarkers involved in DNA repair, which include p53, BRCA1, CHK2, RAD17, RAD9, and NBS1. Although ATM is associated with hematologic malignancies, somatic mutations have been found in colon (18%), head and neck (14%), and prostate (12%) cancers.
Patients with inactivating ATM mutations have been shown to respond poorly to DNA-damaging agents, as shown in a recent cohort of patients with leukemia, and therefore may potentially be more susceptible to PARP inhibitors. Various clinical trials (on www.clinicaltrials.gov) investigating agents which target this gene and/or its downstream or upstream effectors may be available, which include the following: NCT01434316. Germline mutations in ATM are associated with ataxia-telangiectasia (also known as Louis-Bar syndrome) and a predisposition to malignancy.
BRAF encodes a protein belonging to the raf/mil family of serine/threonine protein kinases. This protein plays a role in regulating the MAP kinase/ERK signaling pathway initiated by EGFR activation, which affects cell division and differentiation. Patients with mutated BRAF genes are less likely to respond to EGFR targeted monoclonal antibodies. A BRAF enzyme inhibitor, vemurafenib, was approved by FDA to treat unresectable or metastatic melanoma patients harboring BRAF V600E mutations.
CDH1 (epithelial cadherin/E-cad) encodes a transmembrane calcium dependent cell adhesion glycoprotein that plays a major role in epithelial architecture, cell adhesion and cell invasion. Loss of function of CDH1 contributes to cancer progression by increasing proliferation, invasion, and/or metastasis.
Various somatic mutations in CDH1 have been identified in diffuse gastric, lobular breast, endometrial and ovarian carcinomas; the resultant loss of function of E-cad may contribute to tumor growth and progression. Germline mutations in CDH1 cause hereditary diffuse gastric cancer and colorectal cancer; affected women are predisposed to lobular breast cancer with a risk of about 50%. CDH1 mutation carriers have an estimated cumulative risk of gastric cancer of 67% for men and 83% for women, by age of 80 years.
c-Kit is a cytokine receptor expressed on the surface of hematopoietic stem cells as well as other cell types. This receptor binds to stem cell factor (SCF, a cell growth factor). As c-Kit is a receptor tyrosine kinase, ligand binding causes receptor dimerization and initiates a phosphorylation cascade resulting in changes in gene expression. These changes affect proliferation, apoptosis, chemotaxis and adhesion. c-Kit is inhibited by multi-targeted agents including imatinib, sunitinib and sorafenib.
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4610 South 44th Place / Phoenix, AZ 85040 / (888) 979-8669 / Fax: (866) 479-4925 / CLIA 03D1019490 / Zoran Gatalica, M.D., DSc, Medical Director Caris MPI, Inc. d/b/a Caris Life Sciences C-Met is a tyrosine kinase receptor for hepatocyte growth factor (HGF) or scatter factor (SF) and is overexpressed and amplified in a wide range of tumors. cMET overexpression has been associated with a more aggressive biology and a worse prognosis in many human malignancies. Amplification or overexpression of cMET has been implicated in the development of acquired resistance to erlotinib and gefitinib in NSCLC.
CSF1R or colony stimulating factor 1 receptor gene encodes a transmembrane tyrosine kinase, a member of the CSF1/PDGF receptor family. CSF1R mediates the cytokine (CSF-1) responsible for macrophage production, differentiation, and function. Although associated with hematologic malignancies, mutations of this gene are associated with cancers of the liver (21%), colon (13%), prostate (3%), endometrium (2%), and ovary (2%). It is suggested patients with CSF1R mutations could respond to imatinib. Various clinical trials (on www.clinicaltrials.gov) investigating agents which target this gene and/ or its downstream or upstream effectors may be available, which include the following: NCT01346358, NCT01440959. Germline mutations in CSF1R are associated with diffuse leukoencephalopathy, a rapidly progressive neurodegenerative disorder.
CTNNB1 or cadherin-associated protein, beta 1, encodes for β-catenin, a central mediator of the Wnt signaling pathway which regulates cell growth, migration, differentiation and apoptosis. Mutations in CTNNB1 (often occurring in exon 3) prevent the breakdown of β-catenin, which allows the protein to accumulate resulting in persistent transactivation of target genes, including c-myc and cyclin-D1. Somatic CTNNB1 mutations occur in 1-4% of colorectal cancers, 2-3% of melanomas, 25-38% of endometrioid ovarian cancers, 84-87% of sporadic desmoid tumors, as well as the pediatric cancers, hepatoblastoma, medulloblastoma and Wilms' tumors. A growing number of compounds that suppress the Wnt/β-catenin pathway are available in clinical trials (on www.clinicaltrials.gov) including PRI-724 for advanced solid tumors (NCT01302405) and LGK974 for melanoma and lobular breast cancer EGFR (epidermal growth factor receptor) is a receptor tyrosine kinase and its abnormalities contribute to the growth and proliferation of many human cancers. Sensitizing mutations are commonly detected in NSCLC and patients harboring such mutations may respond to EGFR-targeted tyrosine kinase inhibitors including erlotinib and gefitinib. Lung cancer patients overexpressing EGFR protein are known to respond to EGFR monoclonal antibody, cetuximab. Increased gene expression of EGFR is associated with response to irinotecan containing regimen in colorectal cancer patients.
The estrogen receptor (ER) is a member of the nuclear hormone family of intracellular receptors which is activated by the hormone estrogen. It functions as a DNA binding transcription factor to regulate estrogen-mediated gene expression. Estrogen receptors overexpressing breast cancers are referred to as "ER positive." Estrogen binding to ER on cancer cells leads to cancer cell proliferation. Breast tumors over-expressing ER are treated with hormone- based anti-estrogen therapy.
ERBB2 (HER2) or v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian) encodes a member of the epidermal growth factor (EGF) receptor family of receptor tyrosine kinases. This gene binds to other ligand-bound EGF receptor family members to form a heterodimer and enhances kinase-mediated activation of downstream signaling pathways, leading to cell proliferation. Most common mechanism for activation of HER2 is gene amplification, seen in approximately 15% of breast cancers. However, somatic mutations are rare and found in colon (4%), endometrium (4%), prostate (3%), ovarian (3%), breast (2%) and gastric (2%) cancers. Mutations are present in 2-4% of lung adenocarcinomas, with case reports involving NSCLC patients responding to trastuzumab or afatinib. Various clinical trials (on www.clinicaltrials.gov) investigating agents which target this gene may be available, which include the following: NCT01306045.
ERBB4 is a member of the Erbb receptor family known to play a pivotal role in cell-cell signaling and signal transduction regulating cell growth and development. The most commonly affected signaling pathways are the PI3K-Akt and MAP kinase pathways. Erbb4 was found to be somatically mutated in 19% of melanomas and Erbb4 mutations may confer "oncogene addiction" on melanoma cells. Erbb4 mutations have also been observed in various other cancer types, including, gastric carcinomas (2%), colorectal carcinomas (1-3%), non-small cell lung cancer (2-5%) and breast carcinomas (1%), however, their biological impact is not uniform or consistent across these cancers. Based on activity of lapatinib in vitro, there is an active clinical trial (on www.clinicaltrials.gov) investigating lapatinib in stage IV melanoma patients with Erbb4 mutations, which includes NCT01264081.
FBXW7 or E3 ligase F-box and WD repeat domain containing 7, also known as Cdc4, encodes three protein isoforms which constitute a component of the ubiquitin-proteasome complex. Mutation of FBXW7 occurs in hotspots and disrupts the recognition of and binding with substrates which inhibits the proper targeting of proteins for degradation (e.g. Cyclin E, c-Myc, SREBP1, c-Jun, Notch-1, mTOR and MCL1). Mutation frequencies identified in cholangiocarcinomas, acute T-lymphoblastic leukemia/lymphoma, and carcinomas of endometrium, colon and stomach are 35%, 31%, 9%, 9%, and 6%, respectively. Targeting an oncoprotein downstream of FBXW7, such as mTOR or c-Myc, may provide a novel therapeutic strategy. Tumor cells with mutated FBXW7 are particularly sensitive to rapamycin treatment, suggesting FBXW7 loss (mutation) may be a predictive biomarker for treatment with inhibitors of the mTOR pathway. In addition, it has been proposed that loss of FBXW7 confers resistance to tubulin-targeting agents like paclitaxel or vinorelbine, by interfering with the degradation of MCL1, a regulator of apoptosis.
FGFR1 or fibroblast growth factor receptor 1, encodes for FGFR1 which is important for cell division, regulation of cell maturation, formation of blood vessels, wound healing and embryonic development. Somatic activating mutations are rare, but have been documented in melanoma, glioblastoma, and lung tumors. Other aberrations of FGFR1 including protein overexpression and gene amplification are common in breast cancer, squamous cell lung cancer, colorectal cancer, and, to a lesser extent in adenocarcinoma of the lung. Recently, it has been shown that osteosarcoma and advanced solid tumors that exhibit FGFR1 amplification are sensitive to the pan-FGFR inhibitor, NVP-BGJ398. Other FGFR1-targeted agents under clinical investigation (on www.clinicaltrials.gov) include dovitinib (NCT01440959). Germline, gain-of-function mutations in FGFR1 result in developmental disorders including Kallmann syndrome and Pfeiffer syndrome.
** FINAL REPORT **
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Physician: Ordering Physician
4610 South 44th Place / Phoenix, AZ 85040 / (888) 979-8669 / Fax: (866) 479-4925 / CLIA 03D1019490 / Zoran Gatalica, M.D., DSc, Medical Director Caris MPI, Inc. d/b/a Caris Life Sciences FGFR2 is a receptor for fibroblast growth factor. Activation of FGFR2 through mutation and amplification has been noted in a number of cancers. Somatic mutations of the fibroblast growth factor receptor 2 (FGFR2) tyrosine kinase are present in endometrial carcinoma, lung squamous cell carcinoma, cervical carcinoma, and melanoma. In the endometrioid histology of endometrial cancer, the frequency of FGFR2 mutation is 16% and the mutation is associated with shorter disease free survival in patients diagnosed with early stage disease. Loss of function FGFR2 mutations occur in about 8% melanomas and contribute to melanoma pathogenesis. Functional polymorphisms in the FGFR2 promoter are associated with breast cancer susceptibility. Various clinical trials (on www.clinicaltrials.gov) investigating agents which target this gene may be available, which include the following: NCT01379534. Germline mutations in FGFR2 are associated with numerous medical conditions that include congenital craniofacial malformation disorders, Apert syndrome and the related Pfeiffer and Crouzon syndromes.
FLT3 or Fms-like tyrosine kinase 3 receptor is a member of class III receptor tyrosine kinase family, which includes PDGFRA/B and KIT. Signaling through FLT3 ligand-receptor complex regulates hematopoiesis, specifically lymphocyte development. The FLT3 internal tandem duplication (FLT3-ITD) is the most common genetic lesion in acute myeloid leukemia (AML), occurring in 25% of cases. FLT3 mutations are rare in solid tumors; however they have been documented in breast cancer. Several small molecule multikinase inhibitors targeting the RTK-III family are available (on www.clinicaltrials.gov) including phase II trials for crenolanib in AML (NCT01657682), famitinib for nasopharyngeal carcinoma (NCT01462474), dovitinib for GIST (NCT01440959), and phase I trial for PLX108-01 in solid tumors (NCT01004861).
GNA11 is a proto-oncogene that belongs to the Gq family of the G alpha family of G protein coupled receptors. Known downstream signaling partners of GNA11 are phospholipase C beta and RhoA and activation of GNA11 induces MAPK activity. Over half of uveal melanoma patients lacking a mutation in GNAQ exhibit somatic mutations in GNA11. Activating mutations of GNA11 have not been found in other malignancies. Various clinical trials (on www.clinicaltrials.gov) investigating agents which target this gene may be available, which include the following: NCT01587352, NCT01390818, GNAS (or GNAS complex locus) encodes a stimulatory G protein alpha-subunit. These guanine nucleotide binding proteins (G proteins) are a family of heterotrimeric proteins which couple seven-transmembrane domain receptors to intracellular cascades. Stimulatory G-protein alpha-subunit transmits hormonal and growth factor signals to effector proteins and is involved in the activation of adenylate cyclases. Mutations of GNAS gene at codons 201 or 227 lead to constitutive cAMP signaling. GNAS somatic mutations have been found in pituitary (28%), pancreatic (20%), ovarian (11%), adrenal gland (6%), and colon (6%) cancers. SNPs in GNAS1 are a predictive marker for tumor response in cisplatin/fluorouracil-based radiochemotherapy in esophageal cancer. Patients with somatic GNAS mutations may derive benefit from MEK inhibitors. Germline mutations of GNAS have been shown to be the cause of McCune-Albright syndrome (MAS), a disorder marked by endocrine, dermatologic, and bone abnormalities. GNAS is usually found as a mosaic mutation in patients. Loss of function mutations are associated with pseudohypoparathyroidism and pseudopseudohypoparathyroidism.
ErbB2/Her2 encodes a member of the epidermal growth factor (EGF) receptor family of receptor tyrosine kinases. Her2 has no ligand-binding domain of its own and, therefore, cannot bind growth factors. It does, however, bind tightly to other ligand-bound EGF receptor family members to form a heterodimer and enhances kinase-mediated activation of downstream signaling pathways leading to cell proliferation. Her2 is overexpressed in 15-30% of newly diagnosed breast cancers. Clinically, Her2 is a target for the monoclonal antibodies trastuzumab and pertuzumab which bind to the receptor extracellularly; the kinase inhibitor lapatinib binds and blocks the receptor intracellularly.
HNF1A or hepatocyte nuclear factor 1 homeobox A encodes a transcription factor that is highly expressed in the liver, found on chromosome 12. It regulates a large number of genes, including those for albumin, alpha1-antitrypsin, and fibrinogen. HNF1A has been associated with an increased risk of pancreatic cancer. HNF1A somatic mutations are found in liver (30%), colon (15%), endometrium (11%), and ovarian (3%) cancers. Its prognostic and predictive value is under investigation. Germline mutations of HNF1A are associated with maturity-onset diabetes of the young type 3.
HRAS (homologous to the oncogene of the Harvey rat sarcoma virus), together with KRAS and NRAS, belong to the superfamily of RAS GTPase. RAS protein activates RAS-MEK-ERK/MAPK kinase cascade and controls intracellular signaling pathways involved in fundamental cellular processes such as proliferation, differentiation, and apoptosis. Mutant Ras proteins are persistently GTP-bound and active, causing severe dysregulation of the effector signaling. HRAS mutations have been identified in cancers from the urinary tract (10%-40%), skin (6%) and thyroid (4%) and they account for 3% of all RAS mutations identified in cancer. RAS mutations (especially HRAS mutations) occur (5%) in cutaneous squamous cell carcinomas and keratoacanthomas that develop in patients treated with BRAF inhibitor vemurafenib, likely due to the paradoxical activation of the MAPK pathway. Various clinical trials (on www.clinicaltrials.gov) investigating agents which target this gene and/or its downstream or upstream effectors may be available, which include the following: NCT01306045. Germline mutation in HRAS has been associated with Costello syndrome, a genetic disorder that is characterized by delayed development and mental retardation and distinctive facial features and heart abnormalities.
IDH1 encodes for isocitrate dehydrogenase in cytoplasm and is found to be mutated in 60-90% of secondary gliomas, 75% of cartilaginous tumors, 17% of thyroid tumors, 15% of cholangiocarcinoma, 12-18% of patients with acute myeloid leukemia, 5% of primary gliomas, 3% of prostate cancer, as well as in less than 2% in paragangliomas, colorectal cancer and melanoma. Mutated IDH1 results in impaired catalytic function of the enzyme, thus altering normal physiology of cellular respiration and metabolism. IDH1 mutation can also cause overproduction of onco-metabolite 2-hydroxy-glutarate, which can extensively alter the methylation profile in cancer. In gliomas, IDH1 mutations are associated with lower-grade astrocytomas and oligodendrogliomas (grade II/III), as well as secondary glioblastoma. IDH gene mutations are associated with markedly better survival in patients diagnosed with malignant astrocytoma; and clinical data support a more aggressive surgery for IDH1 mutated patients because these individuals may be able to achieve long-term survival. In contrast, IDH1 mutation is associated with a worse prognosis in AML. In glioblastoma, IDH1 mutation has been associated with significantly better response to alkylating agent temozolomide. Various clinical trials (on www.clinicaltrials.gov) investigating agents which target this gene and/or its downstream or upstream effectors may be available, which include the following: NCT01534845.
** FINAL REPORT **
Patient: Patient Name
Physician: Ordering Physician
4610 South 44th Place / Phoenix, AZ 85040 / (888) 979-8669 / Fax: (866) 479-4925 / CLIA 03D1019490 / Zoran Gatalica, M.D., DSc, Medical Director Caris MPI, Inc. d/b/a Caris Life Sciences JAK2 or Janus kinase 2 is a part of the JAK/STAT pathway which mediates multiple cellular responses to cytokines and growth factors including proliferation and cell survival. It is also essential for numerous developmental and homeostatic processes, including hematopoiesis and immune cell development.
Mutations in the JAK2 kinase domain result in constitutive activation of the kinase and the development of chronic myeloproliferative neoplasms such as polycythemia vera (95%), essential thrombocythemia (50%) and myelofibrosis (50%). JAK2 mutations were also found in BCR-ABL1-negative acute lymphoblastic leukemia patients and the mutated patients show a poor outcome. Various clinical trials (on www.clinicaltrials.gov) investigating agents which target this gene and/or its downstream or upstream effectors may be available for patients carrying JAK2 mutation, which include the following: NCT01038856. Germline mutations in JAK2 have been associated with myeloproliferative neoplasms and thrombocythemia.
JAK3 or Janus activated kinase 3 is an intracellular tyrosine kinase involved in cytokine signaling, while interacting with members of the STAT family. Like JAK1, JAK2, and TYK2, JAK3 is a member of the JAK family of kinases. When activated, kinase enzymes phosphorylate one or more signal transducer and activator of transcription (STAT) factors, which translocate to the cell nucleus and regulate the expression of genes associated with survival and proliferation. JAK3 signaling is related to T cell development and proliferation. This biomarker is found in malignancies like head and neck (21%) colon (7%), prostate (5%), ovary (4%), breast (2%), lung (1%), and stomach (1%) cancer. Various clinical trials (on www.clinicaltrials.gov) investigating agents which target this gene and/or its downstream or upstream effectors may be available, which include the following: NCT01590459. Germline mutations of JAK3 are associated with severe, combined immunodeficiency disease (SCID).
KDR (VEGFR2) or Kinase insert domain receptor gene, also known as vascular endothelial growth factor receptor-2 (VEGFR2), is involved with angiogenesis and is expressed on almost all endothelial cells. VEGF ligands bind to KDR, which leads to receptor dimerization and signal transduction.
Besides somatic mutations in angiosarcoma (10%), somatic KDR mutations have also been found in colon (13%), skin (13%), gastric (5%), lung (3%), renal (2%), and ovarian (2%) cancers. Several VEGFR antagonists are either FDA-approved or in clinical trials (i.e. bevacizumab, regorafenib, pazopanib, and vandetanib). Various clinical trials (on www.clinicaltrials.gov) investigating agents which target this gene and/or its downstream or upstream effectors may be available, which include the following: NCT01068587 and NCT01283945.
Proto-oncogene of the Kirsten murine sarcoma virus (KRAS) is a signaling intermediate involved in many signaling cascades including the EGFR pathway. Mutations at activating hotspots are associated with resistance to EGFR tyrosine kinase inhibitors (erlotinib, gefitinib) and monoclonal antibodies O-6-methylguanine-DNA methyltransferase (MGMT) encodes a DNA repair enzyme. MGMT expression is mainly regulated at the epigenetic level through CpG island promoter methylation which in turn causes functional silencing of the gene. MGMT methylation and/or low expression has been correlated with response to alkylating agents like temozolomide and dacarbazine.
MLH1 or mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli) gene encodes a mismatch repair (MMR) protein which repairs DNA mismatches that occur during replication. Although the frequency is higher in colon cancer (10%), MLH1 somatic mutations have been found in esophageal (6%), ovarian (5%), urinary tract (5%), pancreatic (5%), and prostate (5%) cancers. Its prognostic and predictive utility is under investigation. Germline mutations of MLH1 are associated with Lynch syndrome, also known as hereditary non-polyposis colorectal cancer (HNPCC). Patients with Lynch syndrome are at increased risk for various malignancies, including intestinal, gynecologic, and upper urinary tract cancers and in its variant, Muir-Torre syndrome, with sebaceous tumors.
MPL or myeloproliferative leukemia gene encodes the thrombopoietin receptor, which is the main humoral regulator of thrombopoiesis in humans. MPL mutations cause constitutive activation of JAK-STAT signaling and have been detected in 5-7% of patients with primary myelofibrosis (PMF) and 1% of those with essential thrombocythemia (ET).
NOTCH1 or notch homolog 1, translocation-associated, encodes a member of the Notch signaling network, an evolutionary conserved pathway that regulates developmental processes by regulating interactions between physically adjacent cells. Notch signaling modulates interplay between tumor cells, stromal matrix, endothelial cells and immune cells. Mutations in NOTCH1 play a central role in disruption of micro environmental communication, potentially leading to cancer progression. Due to the dual, bi-directional signaling of NOTCH1, activating mutations have been found in acute lymphoblastic leukemia and chronic lymphocytic leukemia, however loss of function mutations in NOTCH1 are prevalent in 11-15% of head and neck squamous cell carcinoma. NOTCH1 mutations have also been found in 2% of glioblastomas, 1% of ovarian cancers, 10% lung adenocarcinomas, 8% of squamous cell lung cancers and 5% of breast cancers. Notch pathway-directed therapy approaches differ depending on whether the tumor harbors gain or loss of function mutations, thus are classified as Notch pathway inhibitors or activators, respectively. Some Notch pathway modulators are being investigated (on www.clinicaltrials.gov) in phase I/II clinical trials, including MK0752 for advanced solid tumors (NCT01295632) and panobinostat (LBH589) for various refractory hematologic malignancies and many types of solid tumors including thyroid cancer (NCT01013597) and melanoma (NCT01065467).
NPM1 or nucleophosmin is a nucleolar phosphoprotein belonging to a family of nuclear chaperones with proliferative and growth-suppressive roles.
In several hematological malignancies, the NPM locus is lost or translocated, leading to expression of oncogenic proteins. NPM1 is mutated in one- third of patients with adult acute myeloid leukemia (AML) and leads to aberrant localization in the cytoplasm leading to activation of downstream pathways including JAK/STAT, RAS/ERK, and PI3K, leading to cell proliferation, survival and cytoskeletal rearrangements. In addition, the most common translocation in anaplastic large cell lymphoma (ALCL) is the NPM-ALK translocation which leads to expression of an oncogenic fusion protein with constitutive kinase activity. Although there are few NPM-directed therapies currently being investigated, research shows AML tumor cells with mutant NPM are more sensitive to chemotherapeutic agents, including daunorubicin and camptothecin. Further, ALK-targeted therapies like crizotinib are under clinical investigation (on www.clinicaltrials.gov) for ALK-NPM positive ALCL (NCT00939770).
NRAS is an oncogene and a member of the (GTPase) ras family, which includes KRAS and HRAS. This biomarker has been detected in multiple cancers including melanoma, colorectal cancer, AML and bladder cancer. Evidence suggests that an acquired mutation in NRAS may be associated with resistance to vemurafenib in melanoma patients. In colorectal cancer patients NRAS mutation is associated with resistance to EGFR-targeted monoclonal antibodies.
** FINAL REPORT **
Patient: Patient Name
Physician: Ordering Physician
4610 South 44th Place / Phoenix, AZ 85040 / (888) 979-8669 / Fax: (866) 479-4925 / CLIA 03D1019490 / Zoran Gatalica, M.D., DSc, Medical Director Caris MPI, Inc. d/b/a Caris Life Sciences PDGFRA is the alpha-type platelet-derived growth factor receptor, a surface tyrosine kinase receptor structurally homologous to c-KIT, which activates PIK3CA/AKT, RAS/MAPK and JAK/STAT signaling pathways. PDGFRA mutations are found in 5-8% of patients with gastrointestinal stromal tumors (GIST) and increases to 30% in KIT wildtype GIST. PDGFRA mutations in exons 12, 14 and 18 confer imatinib sensitivity, while the substitution mutation in exon 18 (D842V) shows resistance to imatinib. A novel PDGFRA mutation in the extracellular domain was shown to identify a subgroup of DIPG (diffuse intrinsic pontine glioma) patients with significantly worse outcome. Various clinical trials (on www.clinicaltrials.gov) investigating multikinase inhibitors which include PDGFRA as one of the targets for GIST, including dovitinib (NCT01478373), crenolanib for D842V-mutated GIST (NCT01243346) and pazopanib (NCT01524848). Germline mutations in PDGFRA have been associated with Familial gastrointestinal stromal tumors and Hypereosinophillic Syndrome (HES).
P-glycoprotein (MDR1, ABCB1) is an ATP-dependent, transmembrane drug efflux pump with broad substrate specificity, which pumps antitumor drugs out of cells. Its expression is often induced by chemotherapy drugs and is thought to be a major mechanism of chemotherapy resistance. Overexpression of p-gp is associated with resistance to anthracylines (doxorubicin, epirubicin). P-gp remains the most important and dominant representative of Multi- Drug Resistance phenotype and is correlated with disease state and resistant phenotype.
The hot spot missense mutations in the gene PIK3CA are present in various malignancies including breast, colon and NSCLC resulting in activation of the PI3 kinase pathway. This pathway is an active target for drug development. PIK3CA mutations have been associated with benefit from mTOR inhibitors (everolimus, temsirolimus). Evidence suggests that breast cancer patients with activation of the PI3K pathway due to PTEN loss or PIK3CA mutation/ amplification have a significantly shorter survival following trastuzumab treatment. PIK3CA mutated (exon 20) colorectal cancer patients are less likely to respond to EGFR targeted monoclonal antibody therapy.
The progesterone receptor (PR or PGR) is an intracellular steroid receptor that specifically binds progesterone, an important hormone that fuels breast cancer growth. PR positivity in a tumor indicates that the tumor is more likely to be responsive to hormone therapy by anti-estrogens, aromatase inhibitors and progestogens.
PTEN (phosphatase and tensin homolog) is a tumor suppressor gene that prevents cells from proliferating. Loss of PTEN protein is one of the most common occurrences in multiple advanced human cancers. PTEN is an important mediator in signaling downstream of EGFR, and its loss is associated with reduced benefit to trastuzumab and EGFR-targeted therapies. Intra-tumoral PTEN loss has been associated with benefit from mTOR inhibitors PTPN11 or tyrosine-protein phosphatase non-receptor type 11 is a proto-oncogene that encodes a signaling molecule, Shp-2, which regulates various cell functions like mitogenic activation and transcription regulation. PTPN11 gain-of-function somatic mutations have been found to induce hyperactivation of the Akt and MAPK networks. Because of this hyperactivation, Ras effectors, such as Mek and PI3K, are potential targets for novel therapeutics in those with PTPN11 gain-of-function mutations. PTPN11 somatic mutations are found in hematologic and lymphoid malignancies (8%), gastric (2%), colon (2%), ovarian (2%), and soft tissue (2%) cancers. Germline mutations of PTPN11 are associated with Noonan syndrome, which itself is associated with juvenile myelomonocytic leukemia (JMML). PTPN11 is also associated with LEOPARD syndrome, which is associated with neuroblastoma and myeloid leukemia.
RB1 or retinoblastoma-1 is a tumor suppressor gene whose protein regulates the cell cycle by interacting with various transcription factors, including the E2F family (which controls the expression of genes involved in the transition of cell cycle checkpoints). Besides ocular cancer, RB1 mutations have also been detected in other malignancies, such as ovarian (10%), bladder (41%), prostate (8%), breast (6%), brain (6%), colon (5%), and renal (2%) cancers. RB1 status, along with other mitotic checkpoints, has been associated with the prognosis of GIST patients. Germline mutations of RB1 are associated with the pediatric tumor, retinoblastoma. Inherited retinoblastoma is usually bilateral. Studies indicate patients with a history of retinoblastoma are at increased risk for secondary malignancies.
RET or rearranged during transfection gene, located on chromosome 10, activates cell signaling pathways involved in proliferation and cell survival. RET mutations are found in 23-69% of sporadic medullary thyroid cancers (MTC), but RET fusions are common in papillary thyroid cancer, and more recently have been found in 1-2% of lung adenocarcinoma. Amongst RET mutations in sporadic MTC, 85% involve the M918T mutation which is associated with a higher response rate to vandetanib in comparison to M918T negative patients. Further, a 10-year study notes that medullary thyroid cancer patients with somatic RET mutations have a poorer prognosis. Various clinical trials (on www.clinicaltrials.gov) investigating multikinase inhibitors which include RET as one of the targets may be available, including vandetanib for advanced cancers (NCT01582191) or cabozantinib for medullary thyroid cancer (NCT01683110). Germline activating mutations of RET are associated with multiple endocrine neoplasia type 2 (MEN2), which is characterized by the presence of medullary thyroid carcinoma, bilateral pheochromocytoma, and primary hyperparathyroidism. Germline inactivating mutations of RET are associated with Hirschsprung's disease.
Ribonucleotide reductase subunit M1 (RRM1) is a component of the ribonucleotide reductase holoenzyme consisting of M1 and M2 subunits. The ribonucleotide reductase is a rate-limiting enzyme involved in the production of nucleotides required for DNA synthesis. Gemcitabine is a deoxycitidine analogue which inhibits ribonucleotide reductase activity. High RRM1 level is associated with resistance to gemcitabine.
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Patient: Patient Name
Physician: Ordering Physician
4610 South 44th Place / Phoenix, AZ 85040 / (888) 979-8669 / Fax: (866) 479-4925 / CLIA 03D1019490 / Zoran Gatalica, M.D., DSc, Medical Director Caris MPI, Inc. d/b/a Caris Life Sciences PAGE A-10 of A-12 SMAD4 or mothers against decapentaplegic homolog 4, is one of eight proteins in the SMAD family, involved in multiple signaling pathways and are key modulators of the transcriptional responses to the transforming growth factor-β (TGFβ) receptor kinase complex. SMAD4 resides on chromosome 18q21, one of the most frequently deleted chromosomal regions in colorectal cancer. Smad4 stabilizes Smad DNA-binding complexes and also recruits transcriptional coactivators such as histone acetyltransferases to regulatory elements. Dysregulation of SMAD4 occurs late in tumor development, and occurs through mutations of the MH1 domain which inhibits the DNA-binding function, thus dysregulating TGFβR signaling. Mutated (inactivated) SMAD4 is found in 50% of pancreatic cancers and 10-35% of colorectal cancers. Recent studies have shown that preservation of SMAD4 through retention of the 18q21 region, leads to clinical benefit from 5-fluorouracil-based therapy. In addition, various clinical trials investigating agents which target the TGFβR signaling axis are available (on www.clinicaltrials.gov), including PF-03446962 for advanced solid tumors including NCT00557856. Germline mutations in SMAD4 are associated with juvenile polyposis (JP) and combined syndrome of JP and hereditary hemorrhagic teleangiectasia (JP-HHT).
SMARCB1 also known as SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily b, member 1, is a tumor suppressor gene implicated in cell growth and development. Loss of expression of SMARCB1 has been observed in tumors including epithelioid sarcoma, renal medullary carcinoma, undifferentiated pediatric sarcomas, and a subset of hepatoblastomas. Germline mutation in SMARCB1 causes about 20% of all rhabdoid tumors which makes it important for clinicians to facilitate genetic testing and refer families for genetic counseling. Germline SMARCB1 mutations have also been identified as the pathogenic cause of a subset of schwannomas and meningiomas.
SMO (smoothened) is a G protein-coupled receptor which plays an important role in the Hedgehog signaling pathway. It is a key regulator of cell growth and differentiation during development, and is important in epithelial and mesenchymal interaction in many tissues during embryogenesis. Dysregulation of the Hedgehog pathway is found in cancers including basal cell carcinomas (12%) and medulloblastoma (1%). A gain-of-function mutation in SMO results in constitutive activation of hedgehog pathway signaling, contributing to the genesis of basal cell carcinoma. SMO mutations have been associated with the resistance to SMO antagonist GDC-0449 in medulloblastoma patients by blocking the binding to SMO. SMO mutation may also contribute partially to resistance to SMO antagonist LDE225 in BCC. Various clinical trials (on www.clinicaltrials.gov) investigating SMO antagonists may be available, which include the following: NCT01529450.
SPARC Monoclonal (secreted protein acidic and rich in cysteine) is a calcium-binding matricellular glycoprotein secreted by many types of cells. It has a normal role in wound repair, cell migration, and cell-matrix interactions. Its over-expression is thought to have a role in tumor invasion and angiogenesis.
A few studies indicate that SPARC over-expression improves the response to the anti cancer drug, nab-paclitaxel. The improved response is thought to be related to SPARC's role in accumulating albumin and albumin targeted agents within tumor tissue.
SPARC Polyclonal (secreted protein acidic and rich in cysteine) is a calcium-binding matricellular glycoprotein secreted by many types of cells. It has a SPARC Polyclonal normal role in wound repair, cell migration, and cell-matrix interactions. Its over-expression is thought to have a role in tumor invasion and angiogenesis.
A few studies indicate that SPARC over-expression improves the response to the anti cancer drug, nab-paclitaxel. The improved response is thought to be related to SPARC's role in accumulating albumin and albumin targeted agents within tumor tissue.
STK11 also known as LKB1, is a serine/threonine kinase. It is thought to be a tumor suppressor gene which acts by interacting with p53 and CDC42.
It modulates the activity of AMP-activated protein kinase, causes inhibition of mTOR, regulates cell polarity, inhibits the cell cycle, and activates p53.
Somatic mutations in this gene are associated with a history of smoking and KRAS mutation in NSCLC patients. The frequency of STK11 mutation in lung adenocarcinomas ranges from 7%-30%. STK11 loss may play a role in development of metastatic disease in lung cancer patients. Mutations of this gene also drive progression of HPV-induced dysplasia to invasive, cervical cancer and hence STK11 status may be exploited clinically to predict the likelihood of disease recurrence. Various clinical trials (on www.clinicaltrials.gov) investigating agents which target this gene may be available, which include the following: NCT01578551. Germline mutations in STK11 are associated with Peutz-Jeghers syndrome which is characterized by early onset hamartomatous gastro-intestinal polyps and increased risk of breast, colon, gastric and ovarian cancer.
TLE3 is a member of the transducin-like enhancer of split (TLE) family of proteins that have been implicated in tumorigenesis. It acts downstream of APC and beta-catenin to repress transcription of a number of oncogenes, which influence growth and microtubule stability. Studies indicate that TLE3 expression is associated with response to taxane therapy in breast, ovarian and lung cancers.
TOPOIIA is an enzyme that alters the supercoiling of double-stranded DNA and allows chromosomal segregation into daughter cells. Due to its essential role in DNA synthesis and repair, and frequent overexpression in tumors, TOPOIIA is an ideal target for antineoplastic agents. In breast cancer, co- amplification of TOPOIIA and HER2 has been associated with benefit from anthracycline-based therapy. In HER2 negative breast cancers, patients with low gene expression of TOPOIIA may derive benefit from anthracycline-based therapy.
Topoisomerase I is an enzyme that alters the supercoiling of double-stranded DNA. TOPOI acts by transiently cutting one strand of the DNA to relax the coil and extend the DNA molecule. Higher expression of TOPOI has been associated with response to TOPOI inhibitors including irinotecan and topotecan.
TP53, or p53, plays a central role in modulating response to cellular stress through transcriptional regulation of genes involved in cell-cycle arrest, DNA repair, apoptosis, and senescence. Inactivation of the p53 pathway is essential for the formation of the majority of human tumors. Mutation in p53 (TP53) remains one of the most commonly described genetic events in human neoplasia, estimated to occur in 30-50% of all cancers with the highest mutation rates occurring in head and neck squamous cell carcinoma and colorectal cancer. Generally, presence of a disruptive p53 mutation is associated with a poor prognosis in all types of cancers, and diminished sensitivity to radiation and chemotherapy. In addition, various clinical trials (on www.clinicaltrials.gov) investigating agents which target p53's downstream or upstream effectors may have clinical utility depending on the p53 status. For p53 mutated patients, Chk1 inhibitors in advanced cancer (NCT01115790) and Wee1 inhibitors in ovarian cancer (NCT01164995, NCT01357161) are being investigated. For p53 wildtype patients with sarcoma, mdm2 inhibitors (NCT01605526) are being investigated. Germline p53 mutations are associated with the Li-Fraumeni syndrome (LFS) which may lead to early-onset of several forms of cancer currently known to occur in the syndrome, including sarcomas of the bone and soft tissues, carcinomas of the breast and adrenal cortex (hereditary adrenocortical carcinoma), brain tumors and acute leukemias.
** FINAL REPORT **
Patient: Patient Name
Physician: Ordering Physician
4610 South 44th Place / Phoenix, AZ 85040 / (888) 979-8669 / Fax: (866) 479-4925 / CLIA 03D1019490 / Zoran Gatalica, M.D., DSc, Medical Director Caris MPI, Inc. d/b/a Caris Life Sciences PAGE A-11 of A-12 Thymidylate synthase (TS) is an enzyme involved in DNA synthesis that generates thymidine monophosphate (dTMP), which is subsequently phosphorylated to thymidine triphosphate for use in DNA synthesis and repair. Low levels of TS are predictive of response to fluoropyrimidines and other folate analogues.
Class III β-Tubulin (TUBB3) is part of a class of proteins that provide the framework for microtubules, major structural components of the cytoskeleton.
Due to their importance in maintaining structural integrity of the cell, microtubules are ideal targets for anti-cancer agents. Low expression of TUBB3 is associated with potential clinical benefit to taxanes and vinca alkaloids in certain tumor types.
VHL or von Hippel-Lindau gene encodes for tumor suppressor protein pVHL, which polyubiquitylates hypoxia-inducible factor in an oxygen dependent manner. Absence of pVHL causes stabilization of HIF and expression of its target genes, many of which are important in regulating angiogenesis, cell growth and cell survival. VHL somatic mutation has been seen in 20-70% of patients with sporadic clear cell renal cell carcinoma (ccRCC) and the mutation may imply a poor prognosis, adverse pathological features, and increased tumor grade or lymph-node involvement. Renal cell cancer patients with a 'loss of function' mutation in VHL show a higher response rate to therapy (bevacizumab or sorafenib) than is seen in patients with wild type VHL, however the mutation is not associated with improvement in progression free survival or overall survival. Various clinical trials (on www.clinicaltrials.gov) investigating angiogenesis inhibitors in various cancer types may be available, which include the following: NCT00693992. Germline mutations in VHL cause von Hippel-Lindau syndrome, associated with clear-cell renal-cell carcinomas, central nervous system hemangioblastomas, pheochromocytomas and pancreatic tumors.
** FINAL REPORT **
Patient: Patient Name
Physician: Ordering Physician
4610 South 44th Place / Phoenix, AZ 85040 / (888) 979-8669 / Fax: (866) 479-4925 / CLIA 03D1019490 / Zoran Gatalica, M.D., DSc, Medical Director Caris MPI, Inc. d/b/a Caris Life Sciences PAGE A-12 of A-12 LITERATURE LEVEL OF EVIDENCE ASSESSMENT FRAMEWORK*
Study Design
of Design
The study is judged to be valid and relevant as Evidence obtained from at least one properly regards results, statistical analysis, and conclusions designed randomized controlled trial.
and shows no significant flaws.
Evidence obtained from well-designed controlled trials The study is judged to be valid and relevant as Evidence obtained from well-designed cohort or
regards results, statistical analysis, and conclusions, case-control analytic studies, preferably from more
but contains at least one significant but not fatal flaw.
than one center or research group.
Evidence obtained from multiple time series with The study is judged to have a fatal flaw such that the conclusions are not valid for the purposes of this test.
or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type * Adapted from Harris, T., D. Atkins, et al. (2001). "Current Methods of the U.S. Preventive Services of evidence.
Task Force." Am J Prev Med 20(3S)9 Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert ** FINAL REPORT **
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Physician: Ordering Physician
4610 South 44th Place / Phoenix, AZ 85040 / (888) 979-8669 / Fax: (866) 479-4925 / CLIA 03D1019490 / Zoran Gatalica, M.D., DSc, Medical Director Caris MPI, Inc. d/b/a Caris Life Sciences

Source: http://www.cancerprofiling.com.au/wp-content/uploads/2014/08/CMI-De-Identified-Report-Brain.pdf