IL289062A

Molecular profiling of tumors

Abstract

This record has no abstract on file.

IL289062A, drawing sheet 1 — Sheet 1 of 64

Term

No projected expiry on record.

49 claims: 12 independent, 37 dependent

1
A method of identifying a candidate treatment for a subject in need thereof, comprising:(a) performing an immunohistochemistry (IHC) analysis on a sample from the subject to determine an IHC expression profile on at least five proteins;(b) performing a microarray analysis on the sample to determine a microarray expression profile on at least ten genes;(c) performing a fluorescent in-situ hybridization (FISH) analysis on the sample to determine a FISH mutation profile on at least one gene;(d) performing DNA sequencing on the sample to determine a sequencing mutation profile on at least one gene;and (e) comparing the IHC expression profile, microarray expression profile, FISH mutation profile and sequencing mutation profile against a rules database, wherein the rules database comprises a mapping of treatments whose biological activity is known against cancer cells that: i. overexpress or underexpress one or more proteins included in the IHC expression profile;ii. overexpress or underexpress one or more genes included in the microarray expression profile;iii. have no mutations, or one or more mutations in one or more genes included in the FISH mutation profile;and/or iv. have no mutations, or one or more mutations in one or more genes included in the sequencing mutation profile;and (f) identifying the candidate treatment if: i. the comparison in step (e) indicates that the treatment should have biological activity against the cancer;and ii. the comparison in step (e) does not contraindicate the treatment for treating the cancer.
2
A method of identifying a candidate treatment for a subject in need thereof, comprising:(a) performing an immunohistochemistry (IHC) analysis on a sample from the subject to determine an IHC expression profile on at least five of: SPARC, PGP, Her2/neu, ER, PR, c- kit, AR, CD52, PDGFR, TOP2A, TS, ERCC1, RRM1, BCRP, TOPO1, PTEN, MGMT, and MRP1;(b) performing a microarray analysis on the sample to determine a microarray expression profile on at least five of: ABCC1, ABCG2, ADA, AR, ASNS, BCL2, BIRC5, BRCA1, BRCA2, CD33, CD52, CDA, CES2, DCK, DHFR, DNMT1, DNMT3A, DNMT3B, ECGF1, EGFR, EPHA2, ERBB2, ERCC1, ERCC3, ESR1, FLT1, FOLR2, FYN, GART, GNRH1, GSTP1, Divisional application from IL 282303/2 HCK, HDAC1, HIF1A, HSP90AA1, IL2RA, HSP90AA1, KDR, KIT, LCK, LYN, MGMT, MLH1, MS4A1, MSH2, NFKB1, NFKB2, OGFR, PDGFC, PDGFRA, PDGFRB, PGR, POLA1, PTEN, PTGS2, RAF1, RARA, RRM1, RRM2, RRM2B, RXRB, RXRG, SPARC, SRC, SSTR1, SSTR2, SSTR3, SSTR4, SSTR5, TK1, TNF, TOP1, TOP2A, TOP2B, TXNRD1, TYMS, VDR, VEGFA, VHL, YES1, and ZAP70;(c) performing a fluorescent in-situ hybridization (FISH) analysis on the sample to determine a FISH mutation profile on EGFR and/or HER2;(d) performing DNA sequencing on the sample to determine a sequencing mutation profile on at least one of KRAS, BRAF, c-KIT and EGFR;and (e) comparing the IHC expression profile, microarray expression profile, FISH mutation profile and sequencing mutation profile against a rules database, wherein the rules database comprises a mapping of treatments whose biological activity is known against cancer cells that: i. overexpress or underexpress one or more proteins included in the IHC expression profile;ii. overexpress or underexpress one or more genes included in the microarray expression profile;iii. have no mutations, or one or more mutations in one or more genes included in the FISH mutation profile;and/or iv. have no mutations, or one or more mutations in one or more genes included in the sequencing mutation profile;and (f) identifying the candidate treatment if: i. the comparison in step (e) indicates that the treatment should have biological activity against the cancer;and ii. the comparison in step (e) does not contraindicate the treatment for treating the cancer.
3
A method of identifying a candidate treatment for a cancer in a subject in need thereof, comprising:(a) performing an immunohistochemistry (IHC) analysis on a sample from the subject to determine an IHC expression profile on at least the group of proteins consisting of: SPARC, PGP, Her2/neu, ER, PR, c-kit, AR, CD52, PDGFR, TOP2A, TS, ERCC1, RRM1, BCRP, TOPO1, PTEN, MGMT, and MRP1;(b) performing a microarray analysis on the sample to determine a microarray expression profile on at least the group of genes consisting of ABCC1, ABCG2, ADA, AR, ASNS, BCL2, BIRC5, BRCA1, BRCA2, CD33, CD52, CDA, CES2, DCK, DHFR, DNMT1, DNMT3A, DNMT3B, ECGF1, EGFR, EPHA2, ERBB2, ERCC1, ERCC3, ESR1, FLT1, FOLR2, FYN, GART, GNRH1, GSTP1, HCK, HDAC1, HIF1A, HSP90AA1, IL2RA, HSP90AA1, KDR, KIT, LCK, LYN, MGMT, MLH1, MS4A1, MSH2, NFKB1, NFKB2, OGFR, PDGFC, PDGFRA, PDGFRB, PGR, POLA1, PTEN, PTGS2, RAF1, RARA, RRM1, RRM2, RRM2B, RXRB, RXRG, SPARC, SRC, SSTR1, SSTR2, SSTR3, SSTR4, SSTR5, TK1, Divisional application from IL 282303/2 TNF, TOP1, TOP2A, TOP2B, TXNRD1, TYMS, VDR, VEGFA, VHL, YES1, and ZAP70;(c) performing a fluorescent in-situ hybridization (FISH) analysis on the sample to determine a FISH mutation profile on at least the group of genes consisting of EGFR and HER2;(d) performing DNA sequencing on the sample to determine a sequencing mutation profile on at least the group of genes consisting of KRAS, BRAF, c-KIT and EGFR;and (e) comparing the IHC expression profile, microarray expression profile, FISH mutation profile and sequencing mutation profile against a rules database, wherein the rules database comprises a mapping of treatments whose biological activity is known against cancer cells that: i. overexpress or underexpress one or more proteins included in the IHC expression profile;ii. overexpress or underexpress one or more genes included in the microarray expression profile;iii. have zero or more mutations in one or more genes included in the FISH mutation profile;and/or iv. have zero or more mutations in one or more genes included in the sequencing mutation profile;and (f) identifying the candidate treatment if: i. the comparison in step (e) indicates that the treatment should have biological activity against the cancer;and ii. the comparison in step (e) does not contraindicate the treatment for treating the cancer.
34
The method of claims 1,2 or 3, wherein the treatment comprises administration of one or more candidate therapeutic agents.
38
The method of claims 1,2, 3 or 4, wherein the subject has been previously treated with one or more therapeutic agents to treat a cancer.
39
The method of claims 1,2, 3 or 4, wherein the subject has not previously been treated with one or more candidate therapeutic agents identified in step (f).
40
The method of claims 1,2 or 3, wherein the cancer comprises a metastatic cancer.
41
The method of claims 1,2, or 3, wherein the cancer is refractory to a prior treatment.
43
The method of claims 1,2 or 3, wherein the cancer comprises a prostate, lung, melanoma, small cell (esopha/retroperit), cholangiocarcinoma, mesothelioma, head and neck (SCO), pancreas, pancreas neuroendocrine, small cell, gastric, peritoneal pseudomyxoma, anal Canal (SCC), vagina (SCC), cervical, renal, eccrine seat adenocarinoma, salivary gland adenocarinoma, uterine soft tissue sarcoma (uterine), GIST (Gastric), or thyroid-anaplastic cancer.
44
The method of claims 1,2 or 3, wherein the cancer comprises a cancer of the accessory, sinuses, middle and inner ear, adrenal glands, appendix, hematopoietic system, bones and joints, spinal cord, breast, cerebellum, cervix uteri, connective and soft tissue, corpus uteri, esophagus, eye, nose, eyeball, fallopian tube, extrahepatic bile ducts, mouth, intrahepatic bile ducts, kidney, appendixcolon, larynx, lip, liver, lung and bronchus, lymph nodes, cerebral, spinal, nasal cartilage, retina, eye, oropharynx, endocrine glands, female genital, ovary, pancreas, penis and scrotum, pituitary gland, pleura, prostate gland, rectum renal pelvis, ureter, peritonem, salivary gland, skin, small intestine, stomach, testis, thymus, thyroid gland, tongue, unknown, urinary bladder, uterus, vagina, labia, and vulva.
45
The method of claims 1,2 or 3, wherein the sample comprises cells selected from the group consisting of adipose, adrenal cortex, adrenal gland, adrenal gland - medulla, appendix, bladder, blood, blood vessel, bone, bone cartilage, brain, breast, cartilage, cervix, colon, colon sigmoid, dendritic cells, skeletal muscle, endometrium, esophagus, fallopian tube, fibroblast, gallbladder, kidney, larynx, liver, lung, lymph node, melanocytes, mesothelial lining, myoepithelial cells, osteoblasts, ovary, pancreas, parotid, prostate, salivary gland, sinus tissue, skeletal muscle, skin, small intestine, smooth muscle, stomach, synovium, joint lining tissue, tendon, testis, thymus, thyroid, Divisional application from IL 282303/2 uterus, and uterus corpus.
46
The method of claims 1,2 or 3, wherein the cancer comprises a breast, colorectal, ovarian, lung, nonsmall cell lung cancer, cholangiocarcinoma, mesothelioma, sweat gland, or GIST cancer.

Independent claims12

2,719 paragraphs in 130 sections, as filed

SPECIAL STUDIES

RESULTSAND INTERPRETATION

INTERPRETATION:

REVIEW OF PATHOLOGY SLIDES. (RECEIVED FROM MAIN HOSPITAL, TUCSON, AZ, ONE PARAFFIN BLOCK LABELED MOI-123 AND FROZEN TISSUE).

PELVIC AND RETROPERITONEAL TUMOR: INFLAMMATORY MYOFIBROLASTIC TUMOR.

POSSIBLE AGENTS THAT MIGHT INTERACT WITH CANDIDATE GONE TARGETS:

<td> ASSAY*</td><td> CANDIDATETARGET</td><td> SIGNIFICANT RESULT</td><td> POSSIBLE AGENT(S)</td>

<td> MICROARRAY</td><td> NFKBIA</td><td> (INCREASED 1.78)**</td><td> VELCADE</td>

<td> IHC</td><td> C-KIT .</td><td> (INCREASED+2t 90%)</td><td> GLEEVEC,SUTENT</td>

<td> MICROARRAY</td><td> PDGFRA</td><td> (INCREASED 4.74)**</td><td> GLEEVEC, SORAFENIB, SUTENT</td>

<td> MICROARRAY</td><td> GART</td><td> (INCREASED 1.90)**</td><td> ALIMTA</td>

<td> MICROARRAY</td><td> VDR</td><td> (INCREASED 3730)**</td><td> . CALCITRIOL</td>

<td> MICROARRAY</td><td> ADA</td><td> (INCREASED 5.26)**</td><td> PENTOSTATIN</td>

<td> MICROARRAY</td><td> T0P1</td><td> (INCREASED 2.78)**</td><td> TOPOTECAN, CAMPTOSAR (CPT11)</td>

<td> MICROARRAY</td><td> HIF1A</td><td> (INCREASED 4.03)**</td><td> AVASTIN, SORAFENIB. SUTENT</td>

<td> MICROARRAY</td><td> DNMT1</td><td> (INCREASED 1.51)**</td><td> VIDAZA (5-AZACYTIDINE)</td>

*IHC=IMMUNOHISTOCHEMISTRY &#1524; INCREASED OR DECREASED ARE RELATIVE TO NORMAL CONTRLS.

FIG.3A

CARIS MPI, INC.

<td rowspan="4"> MOLECULAR PROFILING INSTITUTE</td><td> PATIENT INFORMATION</td><td> PHYSICIAN INFORMATION</td>

<td> NAME: SAMPLE PATIENT SEX: FEMALE DOB: 6/1/1974 SSN#: 1236789־45־</td><td> SOME DOCTOR, M.D. 1234 E. SOUTH ST TUCSON, AX 12345 4567־480-123</td>

<td colspan="2"> REPORT INFORMATION VER 1.6.2:4-25-06</td>

<td colspan="2"> DATE SPECIMEN RECEIVED: 02/01/2006 DATE REPORTED: 02/09/2006 CASE NO. MP-TN06-05040 DATE SPECIMEN COLLECTED AT HOST MEDICAL CENTER.01/24/2006 ־</td>

______________________________SPECIAL STUDIES_______________________ ___________________ RESULTSAND INTERPRETATION________________ .112 ADVANCED IMMUNOHISTOCHEMICAL ANALYSIS: >

<td> GENEEXPRESSED PROTEIN</td><td> CONCLUSION</td><td> SPECIFICITY</td><td> INTENSITY</td><td> %</td><td> TARGET STATUS‘</td>

<td> HER2/NEU</td><td> NEGATIVE</td><td></td><td></td><td></td><td></td>

<td></td><td> NEGATIVE</td><td></td><td></td><td></td><td></td>

<td> PR</td><td> NEGATIVE</td><td></td><td></td><td></td><td></td>

<td> KIT־C .</td><td> POSITIVE,</td><td> SPECIFIC</td><td> 2</td><td> 90</td><td> TARGET</td>

<td> _C0X2־</td><td> NEGATIVE</td><td></td><td></td><td></td><td></td>

<td> ANDROGEN RECEPTOR</td><td> NEGATIVE</td><td></td><td></td><td></td><td></td>

<td> CD52</td><td> NEGATIVE</td><td></td><td></td><td></td><td></td>

<td> PDGFR</td><td> NEGATIVE</td><td> NON-SPECIFIC</td><td></td><td></td><td></td>

<td> ---CD25</td><td> NEGATIVE־-</td><td></td><td></td><td></td><td></td>

108 ^&#1470;—110 * 2+ IHC IN GREATER THAN 30% OF THE TUMOR CELLS HAS BEEN CHOSEN AS A CONSERVATIVE DIVIDING POINT TO REPORTA POTENTIAL TARGETAS POSITIVE TO HELP INCREASE PHARMACOLOGIC EFFECTIVENESS.

IMMUNOHISTOCHEMICAL TESTS NOT PERFORMED

IL-2

NF .KAPPA BETA THYMIDYLATE SYNTHASE ERCC3 (HELICASE) THYMIDINE PHOSPHORYLASE NGF

MTAP

MAP KINASE PROTEIN XANTHINE OXIDASE

TOPOISOMERASEI TOPOISOMERASE II .RETINOIC ACID RECEPTOR RXR

ORNITHINE DECARBOXYLASE

SOMATOSTATIN RAS (MUTATED) ASPARAGINE SYNTHETASE

MLH1

MSH2

CD20

P53

CYCUND1

BCL-2

VEGF

FIG.3B

CARIS MPI, INC.

<td colspan="3" rowspan="4"> . MOLECULAR PROFILING INSTITUTE :</td><td colspan="6"> PATIENT INFORMATION</td><td colspan="6"> PHYSICIAN INFORMATION</td><td rowspan="4"></td>

<td colspan="6"> NAME: SAMPLE PATIENT SEX: FEMALE DOB: 6/1/1974 SSN#: 123-45-6789</td><td colspan="6"> SOME DOCTOR, M.D. 1234 E. SOUTH ST. TUCSON, AX 12345 480-123-4567</td>

<td colspan="12"> REPORT INFORMATION VER 1.6.2:4-25-06</td>

<td colspan="12"> )ATE SPECIMEN RECEIVED: 02/01/2006 DATE REPORTED: 02/09/2006 CASE NO. MP-TN06-05040 )ATE SPECIMEN COLLECTEDAT HOST MEDICAL CENTER: 01/24/2006</td>

<td colspan="15"> SPECIAL STUDIES</td><td rowspan="2"></td>

<td colspan="15"> MICROARRAY RESULTS</td>

<td colspan="4"> ‘16 11 ζ MICROARRAY ANALYSIS: J</td><td> 8</td><td colspan="5"> 116 118 s s</td><td></td><td colspan="4"> 116 118 1 S A X</td><td> OO</td>

<td colspan="4"> GENE RATIO EXPRESSION* ANALYSIS</td><td rowspan="24"></td><td colspan="5"> GENE RATIO EXPRESSION*ANALYSIS</td><td rowspan="24"></td><td> GENE</td><td colspan="2"> RATIO EXPRESSIONS</td><td> MALYSIS</td><td rowspan="27"> )L ETIME</td>

<td> AR</td><td> 0.02</td><td> UNDEREXPRESSEE</td><td></td><td> EGFR</td><td> 1.16</td><td> NO CHANGE</td><td colspan="2"></td><td> ZAP70</td><td> 3.00</td><td> NO CHANGE</td><td></td>

<td> ESR1</td><td> 0.09</td><td> UNDEREXPRESSEE</td><td></td><td> OGFR</td><td> 1.17</td><td> NO CHANGE</td><td colspan="2"></td><td> ZAP70</td><td> 3.02</td><td> NO CHANGE</td><td></td>

<td> PGR</td><td> 0.10</td><td> UNDEREXPRESSEE</td><td></td><td> MLH1</td><td> 1.19</td><td> NO CHANGE</td><td colspan="2"></td><td> CD33</td><td> 3.05</td><td> OVER EXPRESSED</td><td></td>

<td> VEGF</td><td> 0.33</td><td> UNDEREXPRESSEE</td><td></td><td> VHL</td><td> 1.22</td><td> NO CHANGE</td><td colspan="2"></td><td> ZAP70</td><td> 3.06</td><td> NO CHANGE</td><td></td>

<td> KIT</td><td> 0.51</td><td> UNDEREXPRESSEE</td><td></td><td> TNF</td><td> 1.29</td><td> NO CHANGE</td><td colspan="2"></td><td> ZAP70</td><td> 3,13</td><td> NO CHANGE</td><td></td>

<td> PDGFC</td><td> 0.53</td><td> UNDEREXPRESSEE</td><td></td><td> RARA</td><td> 1.38</td><td> NO CHANGE</td><td colspan="2"></td><td> ZAP70</td><td> 3.18</td><td> NO CHANGE</td><td></td>

<td> RXRB</td><td> 0.62</td><td> NO CHANGE</td><td></td><td> HSPCA</td><td> 1.42</td><td> NO CHANGE</td><td colspan="2"></td><td> ZAP70</td><td> 3.40</td><td> NO CHANGE</td><td></td>

<td> T0P2B</td><td> 0.62</td><td> UNDEREXPRESSEE</td><td></td><td> TXNRD1</td><td> 1.42</td><td> NO CHANGE</td><td colspan="2"></td><td> CD33</td><td> 3.52</td><td> OVER EXPRESSED</td><td></td>

<td> RAFI</td><td> 0.68</td><td> NO CHANGE</td><td></td><td> ASNS</td><td> 1.44</td><td> NO CHANGE</td><td colspan="2"></td><td> HIF1A</td><td> 3.84</td><td> OVER EXPRESSED</td><td></td>

<td> ERBB2</td><td> 0.69</td><td> NO CHANGE</td><td></td><td> DNMT1</td><td> 1.51</td><td> OVER EXPRESSED</td><td colspan="2"></td><td> HIF1A</td><td> 3.85</td><td> OVER EXPRESSED</td><td></td>

<td> ERCC3</td><td> 0.71</td><td> NO CHANGE</td><td></td><td> NFKB2</td><td> 1.74</td><td> NO CHANGE</td><td colspan="2"></td><td> HIF1A</td><td> 3.88</td><td> OVER EXPRESSED</td><td></td>

<td> BCL2</td><td> 0.71</td><td> NO CHANGE</td><td></td><td> NFKBIA</td><td> 1.78</td><td> OVER EXPRESSED</td><td colspan="2"></td><td> HIF1A</td><td> 3.90</td><td> OVER EXPRESSED</td><td></td>

<td> PDGFRB</td><td> 0.78</td><td> NO CHANGE</td><td></td><td> PTGS2</td><td> 1.81</td><td> NO CHANGE</td><td colspan="2"></td><td> HIF1A</td><td> 3.90</td><td> OVEREXPRESSH)</td><td></td>

<td> BCL2</td><td> 0.80</td><td> NO CHANGE</td><td></td><td> BRCA2</td><td> 1.83</td><td> NO CHANGE</td><td colspan="2"></td><td> HIF1A</td><td> 3.91</td><td> OVER EXPRESSED</td><td></td>

<td> GSTP1</td><td> 0.85</td><td> NO CHANGE</td><td></td><td> GART</td><td> 1.9D</td><td> OVER EXPRESSED</td><td colspan="2"></td><td> HIF1A</td><td> 3.94</td><td> OVER EXPRESSED</td><td></td>

<td> SPARC</td><td> 0.92</td><td> NO CHANGE</td><td></td><td> CDW52</td><td> 2.15</td><td> OVEREXPRESSED</td><td colspan="2"></td><td> HIF1A</td><td> 3.97</td><td> OVER EXPRESSED</td><td></td>

<td> HDAC1</td><td> 0.95</td><td> NO CHANGE</td><td></td><td> 2AP70</td><td> 2.18</td><td> NO CHANGE</td><td colspan="2"></td><td> HIF1A</td><td> 4.01</td><td> OVER EXPRESSED</td><td></td>

<td> POLA</td><td> 0.98</td><td> NO CHANGE</td><td></td><td> F0LR2</td><td> 2.21</td><td> OVEREXPRESSEO</td><td colspan="2"></td><td> HIF1A</td><td> 4.03</td><td> OVER EXPRESSED</td><td></td>

<td> MSH2</td><td> 0.98</td><td> NO CHANGE</td><td></td><td> ZAP70</td><td> 2.76</td><td> NO CHANGE</td><td colspan="2"></td><td> PDGFRA</td><td> 4.74</td><td> OVER EXPRESSED</td><td></td>

<td> CES2</td><td> 1.05</td><td> NO CHANGE</td><td></td><td> T0P1</td><td> 2.78</td><td> OVEREXPRESSEO</td><td colspan="2"></td><td> TK1</td><td> 4.94</td><td> OVER EXPRESSED</td><td></td>

<td> VEGF</td><td> 1.09</td><td> NO CHANGE</td><td></td><td> MS4A1</td><td> 2.86</td><td> NO CHANGE</td><td colspan="2"></td><td> IL2RA</td><td> 5.07</td><td> NO CHANGE</td><td></td>

<td> SSTR1</td><td> 1.11</td><td> NO CHANGE</td><td></td><td> ZAP70</td><td> 2.86</td><td> NO CHANGE</td><td colspan="2"></td><td> ADA</td><td> 5.26</td><td> OVER EXPRESSED</td><td></td>

<td> PTEN</td><td> 1.11</td><td> NO CHANGE</td><td></td><td> ZAP70</td><td> 2.92</td><td> NO CHANGE</td><td colspan="2"></td><td> TOP2A</td><td> 9.34</td><td> NO CHANGE</td><td></td>

<td colspan="4"></td><td></td><td colspan="5"></td><td></td><td> TYMS</td><td> 22.95</td><td> OVER EXPRESSED</td><td></td>

<td colspan="11"></td><td> VDR</td><td> 37.30</td><td> OVER EXPRESSED</td><td></td>

<td colspan="12">1“NO CHANGE' INDICATES THAT THERE IS NO DIFFERENCE IN EXPRESSION FOR THIS GENE BETO TISSUES ATA SIGNIFICANCE LEVEL OF P<=0.001. A SIGNIFICANCE LEVEL OF P<=0.001 HAS BEEN ( THIS THRESHOLD CAN BE VALIDATED AS DIFFERENTIALLY EXPRESSED BY ALTERNATIVE METHOD FIG.3C</td><td> /EENT 1HOSE ISAPF</td><td colspan="2"> TIE TUMOR AND CONTR N SINCE GENES PASSIN ROXIMATELY 95% OF ΤΉ</td>

CARIS MPI, INC.

PATIENT; SAMPLE PATIENT

CASE NO. MP-TN06-0504O

DATE REPORTED: 2/9/2006

L_________________________________CLINICAL INFORMATION __________________________

CLINICAL HISTORY / THEPATIENTWASDIAGNOSEDWiTHINFLAMATORYMYOFIBROBLASTICTUMORINFEB12004.ATTHATTIMEALARGE / MASS WAS REMOVED FROM HER ABDOMEN. THE PATIENT NOWHAS RECURRENT MASSES ON HER LEFT UPPER QUADRANT 120 AND IN THE PELVIS. PER THE PATIENT CHART, DR SOME REVIEWED THIS CASE WITH DR VON HOFF AND IT WAS AGREED

THAT PERFORMING DNA MICROARRAY AND IHC TESTING ON THIS PATIENT MAY PROVIDE INSIGHT INTO FURTHER TREATMENT OPTIONS.

SPECIMENS SUBMITTED / RECEIVED FROM MAIN HOSPITAL, TUCSON, AZ, ONE PARAFFIN BLOCK LABELED MOI-123 AND FROZEN TISSUE WITH THE / ACCOMPANYING SURGICAL PATHOLOGY REPORT.

DISCLAIMER

BY MOLECULAR PROFILING. IT HAS NOT BEEN CLEARED OR APPROVED BY THE U.S. FOOD AND DRUG ADMINISTRATION f0R CLINICAL PURPOSES AND SHOULD NOT BE REGARDED AS PURELY »GATIONAL OR FOR RESEARCH. MOLECULAR PROFILING IS CERTIFIED UNDER THE CLINICAL LABORATORY IMPROVEMENT AMENDMENTS OF 1988 (CL1A) AS QUALIFIED TO PERFORM HIGH-COMPLEXITY CLINICAL TESTING.

KH S INFORMATION CONCERNING THE PATIENT'S CONDITION,

INCLUDING OTHER LABORATORY TESTS, IN ACCORDANCE WITH THE STANDARD OF CARE IN A GIVEN COMMUNITY.

THE FINDING OF A TARGET OOES NOT NECESSARILY INDICATE PHARMACOLOGIC EFFECTIVENESS.

2/9/2006

ROBERTlPENNY.MD.PHpr.PATHOLOGISTANOMEDICALDIRECTOR DATE

FIG.3D

CARIS MPI, INC.

FIG.4

CARIS MPI, INC.

FIG.5

CARIS MPI, INC.

VIEWS OF INTEREST (E.G., STAR SCHEMA) JFIG.6

CARIS MPI, INC.

&#1503; CLINICAL DECISION SUPPORT SYSTEM

FIG.8

CARIS MPI, INC.

FIG.9

CARIS MPI, INC.

CLINICAL STANDARDIZED VOCABULARY

FIG.10

CARIS MPI, INC.

MICROARRAY GENE EXPRESSION DATABASE (MGED)

EXTERNALDATABASES INTERNAIDATABASES

FIG.11

CARIS MPI, INC.

MGED DATAWAREHOUSE

CARIS MPI, INC.

WEB-BASED PERMEDEX SYSTEM (CONT.) MPI PLUS PERMEDEX

FIG.13

CARIS MPI, INC.

CARIS MPI, INC.

CARIS MPI, INC.

CARIS MPI, INC.

CARIS MPI, INC.

CARIS MPI, INC.

CARIS MPI, INC.

<td> I ^FILEMAKER PRO . [MPI DATABASE 7-29-04.FP5]</td><td> _______________________________ΓΠπϊχΙ</td>

<td></td><td> 1-iaixi</td>

PAGE3OF4

<td rowspan="4"> MOLECULAR PROFILING INSTITUTE</td><td></td><td></td><td> lumoiiHW^</td>

<td colspan="2"> NAME: PATIENTSAMPLE SEX: DOB: 4/7/1945 . SSN#: 123-45-6789</td><td> ANYPHYSIC1AN 123 E. NORTH ST. FARGO. N012345 3334^7890</td>

<td colspan="3"> DATE SPECIMEN RECEIVED: DATE REPORTED: CASE NO. MP-TN06-O5186 DATE SPECIMEN COLLECTED AT HOST MEDICAL CENTER:</td>

<td colspan="4"> ..... SPtCIALSIUDItS ־ .</td>

<td colspan="4"> . .. MKRDMWAY RFSULTS</td>

MICROARRAY ANALYSIS:

AUTO-FILITARGETS

TO »[1®, fl

<td> ΙΙ!Ι!ίΜΙΜίΙι|^</td><td></td>

<td> HA 0.52 fc ESSED</td><td></td>

<td> FA Beffl</td><td></td>

<td> Ιί!ΙίΜΟΚ!ΙΙΙ|»β</td><td></td>

<td> AF1A BfcTO</td><td></td>

&#1524;NO CHANGE’ INDICATES THAT THERE IS NO DIFFERENCE IN EXPRESSION FOR THIS GENE BETWEEN

TOTAL GENES: 71 DONE

THE WMOR AND CONTROL TISSUES AT A SIGNIFICANCE LEVEL OF P<=O.OOI. A SIGNIFICANCE LEVEL

OF P<=0.001 HAS BEEN CHOSEN SINCE GENES PASSING THIS THRESHOLD CAN BE VALIDATED AS

DIFFERENI1ALLYPRESSED BY ALTERNATIVE METHODS APPROXIMATELY95%OFTHE TIME.

FIG.20

CARIS MPI, INC.

CXI

CARIS MPI, INC.

CARIS MPI, INC.

CARIS MPI, INC.

CARIS MPI, INC.

WU Hkll&#9633; BKUTO LrJ______________________________________________________________;_ __

TOR HELP, PRESS Fl - . Π FIG.25

CARIS MPI, INC.

FIG. 26A

<td></td><td colspan="12"> Tumor Type</td>

<td rowspan="2"> me</td><td colspan="2"> Adipose (13)</td><td colspan="2"> Adipose tissue. If not available use fibroblast (1)</td><td colspan="2"> Adrenal Cortex (18)</td><td colspan="2"> Adrenal Gland (1)</td><td colspan="2"> Adrenal Gland ־ Medulla (15)</td><td colspan="2"> Appendix (5)</td>

<td> biomarker flagged as target</td><td> tumor <ype</td><td> biomarker flagged as target</td><td> tumor type</td><td> biomarker flagged as target</td><td> tumor type</td><td> biomarker flagged as target</td><td> tumor type</td><td> biomarker flagged as target</td><td> %in tumor type</td><td> biomarker flagged as target</td><td> tumor type</td>

<td> Androgen Receptor</td><td></td><td> 0.0%</td><td></td><td> 0.0%</td><td> 1</td><td> 1.79%</td><td></td><td> 0.00%</td><td> 1</td><td> 2.22%</td><td></td><td> 0.00%</td>

<td> Cyclin DI</td><td></td><td> 0.0%</td><td></td><td> 0.0%</td><td></td><td> 0.00%</td><td></td><td> 0.00%</td><td></td><td> 0.00%</td><td></td><td> 0.00%</td>

<td> PDGFR</td><td> 7</td><td> 0.0%</td><td></td><td> 0.0%</td><td> 1</td><td> 1.79%</td><td></td><td> 0.00%</td><td> 8</td><td> 17.78%</td><td> 3</td><td> 25.00%</td>

<td> SPARC</td><td> 7</td><td> 23.3%</td><td> 1</td><td> 25.0%</td><td> 17</td><td> 30.38%</td><td> 1</td><td> 33.33%</td><td> 3</td><td> 6.67%</td><td> 1</td><td> 8.33%</td>

<td> Survivin</td><td></td><td> 0.0%</td><td></td><td> 0.0%</td><td></td><td> 0.00%</td><td></td><td> 0.00%</td><td></td><td> 0.00%</td><td></td><td> 0.00%</td>

<td> Topoisomerase II alpha</td><td></td><td> 0.0%</td><td></td><td> 0.0%</td><td> —</td><td> 0.00%</td><td></td><td> 0.00%</td><td></td><td> 0.00%</td><td></td><td> 0.00%</td>

<td> Total Number of ICH Biomarkers Flagged as Target for Tumor Type Samples</td><td> 30</td><td> 100.00%</td><td> 4</td><td> 100.00%</td><td> 56</td><td> 100.00%</td><td> 3</td><td> 100.00%</td><td> 45</td><td> 100.00%</td><td> 12</td><td> 100.00%</td>

CARIS MPI, INC.

FIG. 26B

<td colspan="2"> Bladder (7)</td><td colspan="2"> Blood Vessel Vain (4)</td><td colspan="2"> Bone (2)</td><td colspan="2"> Bone if you have it if not Cartilage (1)</td><td colspan="2"> Brain (2)</td><td colspan="2"> Breast (99)</td><td colspan="2"> Cartilage (5)</td>

<td> biomarker flagged as</td><td> tumor type</td><td> biomarker flagged as target</td><td> % in tumor type</td><td> biomarker flagged as target</td><td> % to tumor type</td><td> # of times biomarker flagged as target</td><td> % In tumor type</td><td> biomarker flagged as target</td><td> % in tumor type</td><td> biomarker flagged as target</td><td> tumor type</td><td> biomarker flagged as</td><td> tumor type</td>

CARIS MPI, INC.

FIG. 26C

<td colspan="2"> Cervix (10)</td><td colspan="2"> Colon (67)</td><td> Colon Si!</td><td> »mold (1)</td><td> Dendritic found in skii lymph nod Mike Bittner of ori</td><td> ells can be 1, the spleen, Let’s get s take on site jin(l)</td><td> Difficult ori| Try skeJeta</td><td> in to define, muscle (1)</td><td colspan="2"> Endometrium (3)</td><td> Esophagus</td>

<td> bioinarker flagged as target</td><td> tumor type</td><td> biomarker flagged as target</td><td> %in tumor type</td><td> #of times bioinarker flagged as target</td><td> %in tumor type</td><td> # of times biomarker flagged as target</td><td> %fn tumor type</td><td> bioinarker flagged as target</td><td> %in tumor type</td><td> # of times biomarker flagged as target</td><td> %in tumor type</td><td> biomarker flagged as target</td>

CARIS MPI, INC.

FIG. 26D

<td> S(9)</td><td colspan="2"> Fallopian Tube (3)</td><td colspan="2"> Fibroblast (7)</td><td colspan="2"> GaUbladder (5)</td><td colspan="2"> Kidney (14)</td><td colspan="2"> Larynx (3)</td><td colspan="2"> Liver (1)</td><td> Lun^</td><td> (74)׳</td><td colspan="2"> Lymph Node (9)</td>

<td> %in tumor lype</td><td> hinmaricgr flagged as target</td><td> %tn tumor type</td><td> Womarker flagged as target</td><td> %tn tumor type</td><td> bfolBarker flagged as target</td><td> %in tumor type</td><td> bktmarker flagged as target</td><td> tumor type</td><td> Momarker flapped as target</td><td> tumor type</td><td> bio mark«. flagged 8s target</td><td> tumor type</td><td> times biomark</td><td> tumor type</td><td> biomarker flagged as</td><td> %in tumor <ype</td>

CARIS MPI, INC.

FIG. 26E

<td colspan="2"> Melanocytes (22)</td><td colspan="2"> Mesothelial Lining (6)</td><td colspan="2"> Myoepithflial cells (1)</td><td colspan="2"> Osteoblasts (2)</td><td colspan="2"> Ovary (40)</td><td colspan="2"> Pancreas(33)</td><td colspan="2"> Parotid (2)</td><td> Prostate (6)</td>

<td> btomarker flagged as target</td><td> % tn tumor type</td><td> bio marker flagged as target</td><td> %ta tumor type</td><td> bio marker flagged as target</td><td> %fn tumor type</td><td> bio marker flagged as target</td><td> %in tumor type</td><td> btomarker flagged as target</td><td> tumor type</td><td> btomarker flagged as target</td><td> tumor type</td><td> btomarker flagged as target</td><td> tumor type</td><td> btomarker flagged as target</td>

CARIS MPI, INC.

FIG. 26F

<td> (6)</td><td colspan="2"> Salivary Gland (5)</td><td colspan="2"> Sinus tissue (1)</td><td colspan="2"> Skeletal Muscles (2)</td><td colspan="2"> Skin (5)</td><td colspan="2"> Small Intestine (4)</td><td colspan="2"> smooth muscle (3)</td><td colspan="2"> Smooth Muscle such as smooth muscle from the intestine without the epithelium, ditto for the uterus ie no endometrium (1)</td>

<td> tumor type</td><td> bio marker flagged as</td><td> tumor type</td><td> biomarker flagged as target</td><td> %ln tumor type</td><td> biomarker flagged as target</td><td> tumor type</td><td> biomarker flagged as</td><td> tumor type</td><td> biomarker flagged as target</td><td> tumor type</td><td> biomarker flagged as target</td><td> tumor type</td><td> # of times biomarker flagged as target</td><td> %ln tumor type</td>

CARIS MPI, INC.

FIG. 26G

<td colspan="2"> Smooth muscle such as Uterine wall but not uterine lining Le^ not endometrium (1)</td><td colspan="2"> Stomach (6)</td><td colspan="2"> Synovium (1)</td><td> Synov joint linin</td><td> ium or g tissue (1)</td><td colspan="2"> Tendon (1)</td><td colspan="2"> Testis (1)</td><td colspan="2"> Thymus (2)</td>

<td> # of times biomarker flagged as target</td><td> % In tumor type</td><td> biomarker flagged as</td><td> % In tumor type</td><td> biomarker flagged as target</td><td> %in tumor type</td><td> # of times biomarker flagged as target</td><td> % in tumor type</td><td> biomarker flagged as target</td><td> % in tumor type</td><td> biomarker flagged as target</td><td> tumor type</td><td> biomarker flagged as</td><td> tumor type</td>

CARIS MPI, INC.

FIG. 26H

<td colspan="2"> Thyroid (4)</td><td colspan="2"> Uterus (3)</td><td colspan="2"> Uterus:corpus (10)</td><td colspan="3"> Overall</td>

<td> biomarker flagged as</td><td> tumor type</td><td> biomarker flagged as</td><td> tumor type</td><td> # of times biomarker flagged as target</td><td> % in tumor type</td><td colspan="3"></td>

<td></td><td> 0.00%</td><td></td><td> 0.00%</td><td> 3</td><td> 6.67%</td><td> 78</td><td> 4.5%</td><td> Androgen Receptor</td>

<td></td><td> 0.00%</td><td></td><td> 0.00%</td><td></td><td> 0.00%</td><td> 0</td><td> 0.0%</td><td> Cyclin DI</td>

<td></td><td> 0.00%</td><td> 1</td><td> 12.50%</td><td> 4</td><td> 8.89%</td><td> 179</td><td> 10.4%</td><td> PDGFR</td>

<td> 1</td><td> 12.50%</td><td> 2</td><td> 25.00%</td><td> 10</td><td> 22.22%</td><td> 244</td><td> 14.2%</td><td> SPARC</td>

<td></td><td> 0.00%</td><td></td><td> 0.00%</td><td></td><td> 0.00%</td><td> 0</td><td> 0.0%</td><td> Survivin</td>

<td></td><td> 0.00%</td><td></td><td> 0.00%</td><td></td><td> 0.00%</td><td> 0</td><td> 0.0%</td><td> Topoisomerase Π alpha</td>

CARIS MPI, INC.

FIG. 27A

<td></td><td colspan="12"> Tumor Type</td>

<td> Gene Name (Microarray)</td><td colspan="2"> Adipose (13)</td><td colspan="2"> Adipose tissue, if not available use fibroblast (1)</td><td colspan="2"> Adrenal Cortex (18)</td><td colspan="2"> Adrenal Gland (1)</td><td colspan="2"> Adrenal Gland ־ Medulla (]5)</td><td colspan="2"> Appendix (5)</td>

<td> Gene</td><td> # of times biomarker flagged as target</td><td> %ln tumor type</td><td> # of times biomarker flagged as target</td><td> % in tumor type</td><td> # of times biomarker flagged as target</td><td> %in tumor type</td><td> # of times biomarker flagged as target</td><td> % in tumor type</td><td> # of times biomarker flagged as target</td><td> %in tumor type</td><td> # of tiroes biomarker flagged as target</td><td> %in tumor type</td>

<td> HSPCA</td><td></td><td> 0.00%</td><td></td><td> 0.00%</td><td></td><td> 0.00%</td><td></td><td> 0.00%</td><td></td><td> 0.00%</td><td></td><td> 0.00%</td>

<td> PDGFC</td><td></td><td> 0.00%</td><td></td><td> 0.00%</td><td></td><td> 0.00%</td><td></td><td> 0.00%</td><td></td><td> 0.00%</td><td></td><td> 0.00%</td>

<td> pdgfra</td><td> 2</td><td> 1.83%</td><td></td><td> 0.00%</td><td></td><td> 0.00%</td><td></td><td> 0.00%</td><td></td><td> 0.00%</td><td> 1</td><td> 1.61%</td>

<td> PDGFRB</td><td> 1</td><td> 0.92%</td><td> 1</td><td> 11.11%</td><td> 1</td><td> 0.82%</td><td> 1</td><td> 10.00%</td><td> 5</td><td> 3.11%</td><td> 4</td><td> 6.45%</td>

<td> SPARC</td><td> 8</td><td> 7.34%</td><td> 1</td><td> 11.11%</td><td> 14</td><td> 11.48%</td><td> 1</td><td> 10.00%</td><td> 2</td><td> 1.24%</td><td> 1</td><td> 1.61%</td>

<td> SPARC*</td><td></td><td> 0.00%</td><td></td><td> 0.00%</td><td></td><td> 0.00%</td><td></td><td> 0.00%</td><td></td><td> 0.00%</td><td></td><td> 0.00%</td>

<td> VEGFA</td><td> 1</td><td> 0.92%</td><td></td><td> 0.00%</td><td> 3</td><td> 2.46%</td><td></td><td> 0.00%</td><td></td><td> 0.00%</td><td> 2</td><td> 3.23%</td>

<td> Total Number of DMA Biomarkers Flagged as Target for Tumor Type Samples</td><td> 109</td><td> 100.00%</td><td> 9</td><td> 100.00%</td><td> 122</td><td> 99.18%</td><td> 10</td><td> 100.00%</td><td> 161</td><td> 100.00%</td><td> 82</td><td> 100.00%</td>

CARIS MPI, INC.

FIG. 27B

<td> # of times biomarker flagged as</td><td> % in tumor type</td><td> # of times biomarker tiagged as target</td><td> % in tumor type</td><td> # of times biomarker flagged as target</td><td> % in tumor type</td><td> # of times biomarker flagged as target</td><td> % in tumor type</td><td> # of times biomarker flagged as target</td><td> %in tumor type</td><td> # of times biomarker flagged as target</td><td> % In tumor type</td><td> # of times biomarker flagged as</td><td> %/n tumor type</td>

CARIS MPI, INC.

FIG. 27C

<td colspan="2" rowspan="2"> Cervix (10)</td><td colspan="2" rowspan="2"> Colon (66)</td><td colspan="2" rowspan="2"> Colon Sigmoid (1)</td><td colspan="2" rowspan="2"> Dendritic cells can be found in skin, the spleen, lymph node. Let’s get Mike Bittner’s take on site of origin (1)</td><td colspan="2"> Difficult origin to define.</td><td colspan="2" rowspan="2"> Endometrium (3)</td><td rowspan="2"> Esophagus</td>

<td> Try skeleta</td><td> muscle (1)</td>

<td> # of times biomarker flagged as target</td><td> %in tumor type</td><td> # of times biomarker flagged as target</td><td> %in tumor type</td><td> # of times biomarker flagged as target</td><td> % In tumor type</td><td> # of times biomarker flagged as target</td><td> % in tumor type</td><td> # of times biomarker flagged as target</td><td> % in tumor type</td><td> # of times biomarker flagged as target</td><td> % in tumor type</td><td> biomarker flagged as target</td>

CARIS MPI, INC.

FIG. 27D

<td> S(9)</td><td colspan="2"> Fallopian Tube (3)</td><td colspan="2"> Fibroblast (7)</td><td colspan="2"> Gallbladder (5)</td><td colspan="2"> Kidney (14)</td><td colspan="2"> Larynx (3)</td><td colspan="2"> Uver(l)</td><td colspan="2"> Lung (74)</td><td colspan="2"> Lympb Node (9)</td>

<td> % In tumor type</td><td> # of times btomarker flagged as target</td><td> %in tumor type</td><td> # of times btomarker flagged as target</td><td> % In tumor type</td><td> #of times btomarker flagged as target</td><td> % in tumor type</td><td> # of times btomarker flagged as target</td><td> % In tumor type</td><td> # of times btomarker flagged as target</td><td> % tn tumor type</td><td> # of times btomarker flagged as target</td><td> %ln tumor type</td><td> # of times biomark</td><td> % tn tumor type</td><td> # of times btomarker flagged as</td><td> %in tumor type</td>

CARIS MPI, INC.

FIG. 27E

<td colspan="2"> Melanocytes (22)</td><td colspan="2"> Mesothelial Lining (6)</td><td colspan="2"> Myoepithilial cells (1)</td><td colspan="2"> Osteoblasts (2)</td><td colspan="2"> Ovary (39)</td><td colspan="2"> Pancreas (31)</td><td colspan="2"> Parotid (2)</td><td> Prostate («)</td>

<td> #of hinmarirM» flagged as target</td><td> % in tumor type</td><td> # of times biomarker flagged as target</td><td> % in tumor type</td><td> # of times biomarker flagged as target</td><td> %ln tumor type</td><td> # of times biomarker flagged as target</td><td> % in tumor type</td><td> #of times biomarker flagged as target</td><td> % in tumor type</td><td> # of times bfomarfcer flagged as target</td><td> %in tumor type</td><td> # of times biomarker flagged as target</td><td> % in tumor type</td><td> # of times biomarker flagged as target</td>

CARIS MPI, INC.

FIG. 27F

<td> (6)</td><td colspan="2"> Salivary Gland (5)</td><td colspan="2"> Sinus tissue (1)</td><td colspan="2"> Skeletal Musdes (2)</td><td colspan="2"> Skin (5)</td><td colspan="2"> Small Intestine (4)</td><td colspan="2"> smooth muscle (3)</td><td colspan="2"> Smooth Musde such as smooth muscle from the intestine without the epithelium, ditto for the uterus te no endometrium (1)</td>

<td> %ln tumor type</td><td> # of times biomarker flagged as</td><td> %ln tumor type</td><td> # of times btomarka* flagged as target</td><td> %ln tumor type</td><td> # of times biomarker flagged as target</td><td> %ln tumor type</td><td> #of times biomarker flagged as</td><td> %ln tumor type</td><td> # of times blomarker flagged as target</td><td> %ln tumor type</td><td> # of times blomarker flagged as target</td><td> %in tumor type</td><td> # of times blomarker flagged as target</td><td> %in tumor .yp«</td>

CARIS MPI, INC.

FIG. 27G

<td colspan="2"> Smooth muscle such as Uterine wall but not uterine lining Le., not endometrium (1)</td><td colspan="2"> Stomach (5)</td><td colspan="2"> Synovium (1)</td><td colspan="2"> Synovium or joint lining tissue (1)</td><td colspan="2"> Tendon (1)</td><td colspan="2"> Testis (1)</td><td colspan="2"> Thymus (2)</td>

<td> # of times biomarker flagged as target</td><td> % in tumor type</td><td> # of times biomarker flagged as</td><td> %in tumor type</td><td> # of times biomarker flagged as target</td><td> %ta tumor type</td><td> # of times biomarker flagged as target</td><td> % in tumor type</td><td> # of times biomarker flagged as target</td><td> % in tumor type</td><td> # of times biomarker flagged as target</td><td> % in tumor type</td><td> # of times biomarker flagged as</td><td> % in tumor type</td>

CARIS MPI, INC.

FIG. 27H

<td colspan="2"> Thyroid (4)</td><td colspan="2"> Uterus (3)</td><td colspan="2"> Uterus:corpus (10)</td><td></td><td colspan="2"> Overall</td>

<td> # of times biomarker flagged as</td><td> 70 in tumor type</td><td> # of times biomarker flagged as</td><td> 70 in tumor type</td><td> # of times biomarker flagged as target</td><td> 70 in tumor type</td><td></td><td></td><td></td>

<td> 3</td><td> 4.11%</td><td> 2</td><td> 4.88%</td><td> 7</td><td> 5.47%</td><td> 234</td><td> 3.8%</td><td> HIFLA</td>

<td></td><td> 0.00%</td><td></td><td> 0.00%</td><td></td><td> 0.00%</td><td> 15</td><td> 0.2%</td><td> HSPCA</td>

<td> 3</td><td> 4.11%</td><td> 2</td><td> 4.88%</td><td> 6</td><td> 4.69%</td><td> 261</td><td> 4.2%</td><td> NFKBIA</td>

<td></td><td> 0.00%</td><td></td><td> 0.00%</td><td></td><td> 0.00%</td><td> 6</td><td> 0.1%</td><td> PDGFC</td>

<td></td><td> 0.00%</td><td></td><td> 0.00%</td><td> 1</td><td> 0.78%</td><td> 39</td><td> 0.6%</td><td> PDGFRA</td>

<td> 3</td><td> 4.11%</td><td></td><td> 0.00%</td><td> 1</td><td> 0.78%</td><td> 159</td><td> 2.6%</td><td> PDGFRB</td>

<td> 1</td><td> 1.37%</td><td></td><td> 0.00%</td><td></td><td> 0.00%</td><td> 143</td><td> 2.3%</td><td> SPARC</td>

<td></td><td> 0.00%</td><td></td><td> 0.00%</td><td></td><td> 0.00%</td><td> 0</td><td> 0.0%</td><td> SPARC*</td>

<td> 3</td><td> 4.11%</td><td></td><td> 0.00%</td><td> 4</td><td> 3.13%</td><td> 162</td><td> 2.6%</td><td> VEGFA</td>

CARIS MPI, INC.

FIG. 28A

<td></td><td colspan="2"> Accessory, Sinuses. Middle & Inner Ear</td><td colspan="3"> Adrenal Glands .</td>

<td> IHC</td><td> Number of times biomarfcer flagged as target</td><td> % in tumor type</td><td colspan="2"> Number of times biomarker flagged as target</td><td> % in tumor type</td>

<td> Androgen Receptor</td><td></td><td></td><td colspan="2"> 2</td><td> 1.60%</td>

<td> Cyclin D1</td><td></td><td> 0.00%</td><td colspan="2"></td><td> 0.00%</td>

<td> PDGFR</td><td> 1</td><td> 9.09%</td><td colspan="2"> Θ ־</td><td> 4.80%</td>

<td> SPARC</td><td> 3</td><td> 27.27%</td><td colspan="2"> 36</td><td> 28.80%</td>

<td> Survivin</td><td></td><td> 0.00%</td><td colspan="2"></td><td> 0.00%</td>

<td> Grand Total</td><td> 11</td><td> 100.00%</td><td colspan="3"> 125| 100.00%</td>

CARIS MPI, INC.

FIG. 28B

<td colspan="2"> Appendix</td><td colspan="2"> Hematopoietic Sys</td><td colspan="2"> Bones & Joints</td><td colspan="2"> Spinal Cord, (Excl.</td>

<td> Number of times biomarker flagged as target</td><td> % in tumor type</td><td> Number of times biomarker flagged as target</td><td> % in tumor type</td><td> Number of times biomarker flagged as target</td><td> % In tumor type</td><td> Number of times biomarker flagged as target</td><td> % in tumor type</td>

CARIS MPI, INC.

FIG. 28C

<td colspan="2"> Breast</td><td colspan="2"> Cerebellum</td><td colspan="2"> Cervix Uteri</td><td colspan="2"> Connective & Soft Tissue</td>

<td> Number of times biomarker flagged as target</td><td> % In tumor type</td><td> Number of times biomarker flagged as target</td><td> % in tumor type</td><td> Number of times biomarker flagged as target</td><td> % in tumor type</td><td> Number of times biomarker flagged as target</td><td> % in tumor type</td>

CARIS MPI, INC.

FIG. 28D

<td colspan="2"> Corpus Uteri</td><td colspan="2"> Esophagus</td><td colspan="2"> Eye, Nos</td><td colspan="2"> Eyeball</td>

<td> Number of times biomarker flagged as target</td><td> % in tumor type</td><td> Number of times biomarker flagged as target</td><td> % in tumor type</td><td> Number of times biomarker flagged as target</td><td> % in tumor type</td><td> Number of times biomarker flagged as target</td><td> % in tumor type</td>

<td></td><td></td><td></td><td></td><td> gam</td><td> γΤΪΜΡ.“.ΤγιΠγ3^</td><td></td><td></td>

CARIS MPI, INC.

FIG. 28E

<td colspan="2"> Fallopian Tube</td><td colspan="2"> Extrahepatic Bile Ducts</td><td colspan="2"> Other Mouth</td><td colspan="2"> Intrahepatlc Bile Ducts</td>

<td> Number of times biomarker flagged as target</td><td> % in tumor type</td><td> Number of times biomarker flagged as target</td><td> % in tumor type</td><td> Number of times biomarker flagged as target</td><td> % in tumor type</td><td> Number of times biomarker flagged as target</td><td> % In tumor type</td>

CARIS MPI, INC.

FIG. 28F

<td colspan="2"> Kidney</td><td colspan="2"> AppendixpColon</td><td colspan="2"> Larynx</td><td colspan="2"> Up</td>

<td> Number of times biomarker flagged as target</td><td> % in tumor type</td><td> Number of times biomarker flagged as target</td><td> % in tumor type</td><td> Number of times biomarker flagged as target</td><td> % in tumor type</td><td> Number of times biomarker flagged as target</td><td> % in tumor type</td>

CARIS MPI, INC.

FIG. 28G

<td colspan="2"> Liver</td><td colspan="2"> Lung & Bronchus</td><td colspan="2"> Lymph Nodes</td><td colspan="2"> (Cerebral,Spinal)</td>

<td colspan="2">;ר : U?; &48; ‘ ‘ זי ׳:; ri' .״.i‘* י י '>./ .-.»43» *‘. *e'.nr.׳;</td><td colspan="2"></td><td colspan="2"> ''WOiVAlFT w׳\</td><td colspan="2"> * to׳« .y</td>

<td> Number of times biomarker flagged as target</td><td> % In tumor type</td><td> Number of times blamarker flagged as target</td><td> % In tumor type</td><td> Number of times biomarker flagged as target</td><td> % In tumor type</td><td> Number of times blomarkcr flagged as target</td><td> % in tumor type</td>

CARIS MPI, INC.

FIG. 28H

<td colspan="2"> Nasal Cartilage)</td><td colspan="2"> (Excl. Retina, Eye, Nos)</td><td colspan="2"> Orophamyx</td><td colspan="3"> Other Endocrine Glands</td>

<td> Number of times biomarker flagged as target</td><td> % In tumor type</td><td> Number of times biomarker flagged as target</td><td> % in tumor type</td><td> Number of times biomarker flagged as target</td><td> % in tumor type</td><td colspan="2"> Number of times biomarker flagged as target</td><td> % in tumor type</td>

CARIS MPI, INC.

FIG. 281

<td colspan="2"> Other Female Genital</td><td colspan="2"> Ovary</td><td colspan="2"> Pancreas</td><td colspan="2"> Penis & Scrotum</td>

CARIS MPI, INC.

FIG. 28J

<td colspan="2"> Pituitary Gland</td><td colspan="2"> Pleura</td><td colspan="2"> Prostate Gland</td><td colspan="2"> Rectum</td>

<td> Number of times biomarker flagged as target</td><td> % in tumor type</td><td> Number of times biomarker flaggod as target</td><td> % in tumor type</td><td> Number of times biomarker flagged as target</td><td> % in tumor type</td><td> Number of times biomarker flagged as target</td><td> % in tumor type</td>

CARIS MPI, INC.

FIG. 28K

<td colspan="2"> Renal Pelvis, Ureter</td><td colspan="2"> Peritoneum</td><td colspan="2"> Salivary Gland</td><td colspan="2"> Skin</td>

<td> Number of times biomarker flagged as target</td><td> % in tumor type</td><td> Number of times biomarker flagged as target</td><td> % in tumor type</td><td> Number of times biomarkcr flagged as target</td><td> % in tumor type</td><td> Number of times biomarker flagged as target</td><td> % in tumor type</td>

CARIS MPI, INC.

FIG. 28L

<td colspan="2"> Small Intestine</td><td colspan="2"> Stomach</td><td colspan="2"> Testis</td><td colspan="2"> Thymus</td>

<td> Number of times biomarker flagged as target</td><td> % in tumor type</td><td> Number at times biomarker flagged as target</td><td> % in tumor type</td><td> Number of times biomarker flagged as target</td><td> % in tumor type</td><td> Number of times biomarker flagged as target</td><td> % in tumor type</td>

CARIS MPI, INC.

FIG. 28M

<td colspan="2"> Thyroid Gland</td><td colspan="2"> Tongue</td><td colspan="2"> Unknown</td><td colspan="2"></td>

<td> Number of times biomarker flagged as target</td><td> % in tumor type</td><td> Number of times biomarker flagged as target</td><td> % In tumor type</td><td> Number of times biomarker flagged as target</td><td> % in tumor type</td><td> Number of times biomarker flagged as target</td><td> % In tumor type</td>

CARIS MPI, INC.

FIG. 28N

<td colspan="2"> Urinary Bladder</td><td colspan="2"> Uterus, Nas</td><td colspan="2"> Vagina & Labia</td><td colspan="2"> Vulva, Nos</td>

CARIS MPI, INC.

FIG. 280

<td colspan="2"> (blank)</td><td rowspan="2"> Grand Total</td>

<td> Number of times biomarker flagged as target</td><td> % in tumor type</td><td> Number of times biomarker flagged as target</td><td> % In tumor type</td><td> IHC</td>

<td> 3</td><td> 5.45%</td><td> 187</td><td> 4.82%</td><td> Androgen Receptor</td>

<td></td><td> 0.00%</td><td> 1</td><td> 0.03%</td><td> Cydin D1</td>

<td> 4</td><td> 7.27%</td><td> 439</td><td> 11.32%</td><td> PDGFR</td>

<td> 10</td><td> 18.18%</td><td> 569</td><td> 14.67%</td><td> SPARC</td>

<td></td><td> 0.00%</td><td> 7</td><td> 0.18%</td><td> Survivln</td>

<td> 55</td><td> 100.00%</td><td> 3878</td><td> 100.00%</td><td> Grand Total</td>

CARIS MPI, INC.

FIG. 29

Biomarkers Tagged as Target in Order of Frequency

<td> Number of times biomarker flagged as target</td><td> % in tumor type</td><td> IHC</td>

<td> 3878</td><td> 100.00%</td><td> Grand Total</td>

<td> 569</td><td> 14.67%</td><td> SPARC</td>

<td> 439</td><td> 11.32%</td><td> PDGFR</td>

<td> 187</td><td> 4.82%</td><td> Androgen Receptor</td>

<td> 7</td><td> 0.18%</td><td> Survivin</td>

<td> 1</td><td> 0.03%</td><td> Cyclin D1</td>

CARIS MPI, INC.

FIG. 30A

<td></td><td colspan="2"> Accessory, sinuses, Middle & Inner Ear</td><td colspan="2"> Adrenal Glands</td><td colspan="2"> Anal Canal & Anus</td>

<td> :Countof Case S '</td><td colspan="2"> /׳ . ־ ’;׳W 1h״1™</td><td colspan="2"> .»-«.«.It». -t-7־ : </td><td colspan="2"> ״.e . . A- . ! 6 * ' ' .*.1 Ά' '</td>

<td> Gene .</td><td> Number or Umas biomarker flagged as</td><td> % in tumor type</td><td> Numocror times btomerkfir flagged as</td><td> % in tumor type</td><td> Number at limes biomarker flagged as</td><td> % In tumor type</td>

<td> ΟΝΜπβ</td><td> t</td><td> 7.14%</td><td> 13</td><td> 7.18%</td><td> 2</td><td> 4.26%</td>

<td> ERCCJ</td><td></td><td> 0.00%</td><td></td><td> 0.00%</td><td></td><td> 0.00%</td>

<td> HSPCA</td><td></td><td> 0.00%</td><td></td><td> 0.00%</td><td></td><td> 060%</td>

<td> MFKBIA</td><td> 1</td><td> 7.14%</td><td> 5</td><td> 2.76%</td><td> 3</td><td> 636%</td>

<td> PDGFC</td><td></td><td> 0.00%</td><td> 2</td><td> 1.10%</td><td></td><td> 0.00%</td>

<td> PDGFRA</td><td> 1</td><td> 7.14%</td><td></td><td> 0.00%</td><td></td><td> 0.00%</td>

<td> PDGFRB</td><td> 1</td><td> 7.14%</td><td> 5</td><td> 2.76%</td><td> 2</td><td> 4.26%</td>

<td> SPARC</td><td> 1</td><td> 7.14%</td><td> 23</td><td> 1271%</td><td> 1</td><td> 2.13%</td>

<td> VEGFA</td><td></td><td> 0.00%</td><td> 4</td><td> 2.21%</td><td> 2</td><td> 4.26%</td>

<td> Grand Total</td><td> 14</td><td> 100.00%</td><td> 181</td><td> 100.00%</td><td> 47</td><td> 100.00%</td>

CARIS MPI, INC.

FIG. 30B

<td colspan="2"> Appendix</td><td colspan="2"> Blood, Bono Marrow, & Hematopoietic Sys</td><td colspan="2"> Bones & Joints</td><td colspan="2"> Brain, & Cranial Nerves, 8 Spinal Card, (Exci. Ventricle, Cerebellum)</td>

<td> Number or times biomarkcr Ragged aa</td><td> % in tumor typo</td><td> Number ot times biomarker Seeped as</td><td> % tn tumor type</td><td> Number or times bloniarker flagged as</td><td> % tn tumor type</td><td> Number oi times biomarker flagged as</td><td> % In tumor type</td>

CARIS MPI, INC.

FIG. 30C

<td colspan="2"> Breast</td><td colspan="2"> Cerebellum</td><td colspan="2"> Cervix Uteri</td><td colspan="2"> Connective & Soft Tissue</td>

<td> Number or times biomarker flagged as</td><td> % In tumor type</td><td> Number of times biomarker flagged as</td><td> % In tumor typo</td><td> Number or time» biomarker flagged as</td><td> % in tumor typo</td><td> Number or times biomarker flagged as</td><td> % In tumor type</td>

CARIS MPI, INC.

FIG. 30D

<td colspan="2"> Corpus Uteri</td><td colspan="2"> Esophagus</td><td colspan="2"> Eye, Nos</td><td colspan="2"> Eyeball</td>

<td> Number of times bio marker flagged as</td><td> % in tumor type</td><td> Number 01 times bio marker flapped as</td><td> % hi tumor type</td><td> Number 01 times btomarkar flagged as</td><td> % in tumor typo</td><td> Number or times Nomarker flagged as</td><td> % in tumor type</td>

CARIS MPI, INC.

FIG. 30E

<td colspan="2"> Fallopian Tube</td><td colspan="2"> Gallbladder & Extrahepatic Bile Ducts</td><td colspan="2"> Gum, Floor Of Mouth, 8 OUier Mouth</td><td colspan="2"> Intrahcpaflc Bile Ducts</td>

<td> Number or times biomarker flanged as</td><td> % In tumor type</td><td> Number ol limes biomarker flagged es</td><td> % In tumor typo</td><td> Number ot times biomarker flagged as</td><td> % in tumor typo</td><td> Number at times biomarker flagged ae</td><td> % In tumor type</td>

CARIS MPI, INC.

FIG. 30F

<td colspan="2"> Kidney</td><td colspan="2"> Large Intestine, (Excl. AppendlxhColon</td><td colspan="2"> Larynx</td><td colspan="2"> up</td>

<td> Number or times biomarter flagged as</td><td> % in tumor type</td><td> Number or times biomaricer flagged as</td><td> % tn tumor type</td><td> Number or times btomarKcr Ragged as</td><td> % tn tumor type</td><td> Number or times blomarter flagged as</td><td> % in tumor type</td>

CARIS MPI, INC.

FIG. 30G

<td colspan="2"> Uver</td><td colspan="2"> Lung & Bronchus</td><td colspan="2"> Lymph Nodes</td><td colspan="2"> Meninges (Cerebral ,8 Pinal)</td>

<td> Humber 01 times bio marker flagged as</td><td> % in tumor type</td><td> Number or tones biomarker flagged as</td><td> % In tumor type</td><td> Number or times blomarker flagged»</td><td> % In tumor typo</td><td> Num Derot times blomarker flagged as</td><td> % In tumor type</td>

CARIS MPI, INC.

FIG. 30H

<td></td><td colspan="2"></td><td> fem iciW®«., KS'-'i</td><td></td><td> ΜϋτίΓϋ'Λ -1</td><td></td><td></td>

<td colspan="2"> Nasal Cavity (including Nasal Cartilage)</td><td colspan="2"> Ort1it& Lacrimal Gland, (Excl Retina, Eye, Nos)</td><td colspan="2"> Orophamyx</td><td colspan="2"> Other Endocrine Glands</td>

<td> Number of times biomarker flagged as</td><td> % In tumor type</td><td> Number of times biomarker flagged as</td><td> % In tumor type</td><td> Number of times biomarker flagged as</td><td> % In tumor type</td><td> Number ot times biomarker nagged as</td><td> % in tumor type</td>

CARIS MPI, INC.

FIG. 301

<td colspan="2"> Other Female Genital</td><td colspan="2"> Orary</td><td colspan="2"> Pancreas</td><td colspan="2"> Penis & Scrotum</td>

<td> Number of Umas biomarker flagged as</td><td> % In tumor type</td><td> Number 0J limes blomarker flagged 8s</td><td> % In tumor type</td><td> Number of times biomarker flanged as</td><td> % in tumor typo</td><td> Number 01 time* blomarker flagged as</td><td> % in tumor type</td>

CARIS MPI, INC.

FIG. 30J

<td colspan="2"> Pituitary Gland</td><td colspan="2"> Pleura</td><td colspan="2"> Prostate Gland</td><td colspan="2"> Rectum</td>

<td> Number of times biomarker (tagged as</td><td> % in tumor typ«</td><td> Number of times bio marker flagged 05</td><td> % in tumor type</td><td> Number זס times biomarker fleggod as</td><td> % In turner type</td><td> Number of times biomarker flagged as</td><td> % In tumor type</td>

CARIS MPI, INC.

FIG. 30K

<td colspan="2"> Renal Pelvis, Urotor</td><td colspan="2"> Rctroperitoneum & Peritoneum</td><td colspan="2"> Salivary Gland</td><td colspan="2"> Skin</td>

<td> Number 01 times triomarkar Ragged as</td><td> % In tumor type</td><td> Number or times biomarker flagged as</td><td> % In tumor type</td><td> Number 01 Ums biomarker flagnodas</td><td> % In tumor type</td><td> Number ol times btomarker flagged as</td><td> % tn tumor typo</td>

CARIS MPI, INC.

FIG. 30L

<td colspan="2"> Small Intestine</td><td colspan="2"> Stomach</td><td colspan="2"> Testi*</td><td colspan="2"> Thymus</td>

<td> Number of times blomarker Ragged as</td><td> % in tumor typo</td><td> Number or times biomarker flagged as</td><td> % in tumor type</td><td> Number ol times biomarker Ragged as</td><td> % In tumor type</td><td> Number of times biomarker flagged as</td><td> % In tumor type</td>

CARIS MPI, INC.

FIG. 30M

<td colspan="2"> Thyroid Gland</td><td colspan="2"> Tongue</td><td colspan="2"> Unknown</td><td colspan="2"> Unspecified Digest. Organs</td>

<td> Number or time* biomarker flapped a*</td><td> % in tumor type</td><td> Number ci times btomarknr flapped as</td><td> % in tumor type</td><td> Number at time* bio marker named as</td><td> % In tumor type</td><td> Number cl times biemarker nagged as</td><td> % In tumor typo</td>

CARIS MPI, INC.

FIG. 30N

<td colspan="2"> Urinary Bladder</td><td colspan="2"> Uterus. Nos</td><td colspan="2"> Vagina & Labia</td><td colspan="2"> Vuhra, Nos</td>

<td> Number 01 ttmoe biomarker «agape a* -</td><td> % In tumor typo</td><td> Number of times biomarker flagged as</td><td> % in tumor t»»</td><td> Number 01 times biomarker flagged as</td><td> % in tumor typo</td><td> Number 01 Umas biomarker flagged as</td><td> % in tumor typo</td>

CARIS MPI, INC.

FIG. 300

<td> Numoeror Ιΰηο» biamarksr flagged as</td><td> % In tumor type</td><td> Grand Total</td><td> % in tumor type</td><td> Gene</td>

<td> 1</td><td> 1.20%</td><td> 61</td><td> 039%</td><td> HSPCA</td>

<td> 4</td><td> 4.82%</td><td> 395</td><td> 4.36%</td><td> NFKBIA</td>

<td></td><td> 0.00%</td><td> 41</td><td> 0.45%</td><td> PDGFC</td>

<td></td><td> 0.00%</td><td> 71</td><td> 0.78%</td><td> PDGFRA</td>

<td></td><td> 0.00%</td><td> 229</td><td> 2.53%</td><td> PDGFRB</td>

<td> 2</td><td> 2.41%</td><td> 260</td><td> 2.87%</td><td> SPARC</td>

<td> 2</td><td> 231%</td><td> 181</td><td> 200%</td><td> VEGFA</td>

<td> 83</td><td> 100.60%</td><td> 9085</td><td> 100.00%</td><td> Grand Total</td>

CARIS MPI, INC.

FIG. 31

<td> -;;ך! ז יזF/Γ - ' Grand rToialr.</td><td> % ώturriortype</td><td> Gene.</td>

<td> ׳v,-u5<;.'80e6</td><td> 100.00% <־:?'.<-־</td><td> Grand Totel.«;-״׳</td>

<td> 395</td><td> 4.36%</td><td> NFKBIA</td>

<td> 260</td><td> 2.67%</td><td> SPARC</td>

<td> 229</td><td> 2.53%</td><td> PDGFRB</td>

<td> 181</td><td> 2.00%</td><td> VEGFA</td>

<td> 81</td><td> 0.89%</td><td> HSPCA</td>

<td> 71</td><td> 0.78%</td><td> PDGFRA</td>

<td> 41</td><td> 0.45%</td><td> POGFC</td>

CARIS MPI, INC.

FIG. 32

CARIS MPI, INC.

Treat patients according to Treat patient with

MP Findings. ______clinician's choice

CARIS MPI, INC.

FIG. 34

Patients consented and evaluated for the study= 106

Treated According to MP =66 Treated Not According to MP=2 Note: Median time for MP results available to a clinician = 16 days from biopsy and 8 days from reception of tissue samples for analyses

CARIS MPI, INC.

FIG. 35

Patients with PFS ratio > 1.3

CARIS MPI, INC.

FIG. 36

ooogooooooo Ο 00 <O CM CM to CO O !Individual patients je^eweip UO!IS9| )SfSJllB) paiuwns euijeseq W04 e6ueq&#9633; jusojad wnwixeyy

CARIS MPI, INC.

FIG. 37

CARIS MPI, INC.

FIG. 38

Overall Survival (months)

CARIS MPI, INC.

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CARIS MPI, INC.

TARGET®NOW.

PAGE 1 0110

<td> PATIENT</td><td> PHYSICIAN</td><td> 1 SPECIMEN</td>

<td> Case Number ΜΡ-ΤΝ00-00000</td><td> Test Ordering Physician, MD</td><td> Primary Tumor Site: Ovary</td>

<td> Patient: Jane Doe</td><td> Test Organization</td><td> Specimen Site: Connective tissue</td>

<td> Date Of Birth: OW VI950</td><td> 1234 Man Street</td><td> Specimen Collected: 01/16/2000</td>

<td> Sex: Female</td><td> Dallas, TX 75133</td><td> Specimen Received: 1/5/2000</td>

<td> SSN: 123-456-7890</td><td> 7890־456(123)</td><td> Date Reported: 1/01/2000</td>

Interpretation: Received one pa^affin block labeled 123456-Al from Test University Metical Center, Greenvale, SC. with the corresponding surgical pathology report disclosing'.

Mass right back, excision: Metastatic adenocarcinoma, extending to inked resection margins.

Interpretation is done by Dr. Ashfaq and signed outby Dr. Gupta for Dr. Ashfaq.

Clinical History: Per the submitted patient history, the patient is a 50-year-dd female with ahistory 01 cancer of unknown primary, She underwent a back mass excision in January 2000 showing metastatic adenocarcinoma. No history of prior therapies were provided.

_________TARGET NOW* SUMMARY &#1470; Agents Associated with CUNICAL BENEFIT

Ths role 0( Target Now is to identify bbmarkers and therapies associated with «finical benefit or lack cl clinical benefit for cancer patents. The selection of any. all or none of the matched agents resides with he discretion of the treating physician If a patient's tumor has previously progressed on an agent identified as associated with clinical benefit on this report, the patient should not be recreated with this agent_________________________________

<td> Biomarker</td><td> Assay</td><td> Results</td><td> Agents Associated With CLINICAL BENEFIT 1</td>

<td> TOPO1</td><td> IHC</td><td> Significant (+2. 85%)</td><td> Irinotecan</td>

<td> PDGFR</td><td> IHC</td><td> Significant (+2, 80%)</td><td> Imatinlb</td>

<td> C-Mt</td><td> IHC</td><td> Significant (+2, 50%)</td><td> . Imatinlb</td>

<td> SPARC</td><td> IHC</td><td> Significant (+2, 50%)</td><td> nab-paclitaxei</td>

<td> ER</td><td> IHC</td><td> Significant (+1,20%)</td><td> tamoxifen, aromatase Inhibitors (anastreede, tetrazole)</td>

<td> PTGS2</td><td> Mier ca tray</td><td> Increased (9.21)</td><td> celecoxib</td>

<td> HJF1A</td><td> Microarray</td><td> Increased (1.64)</td><td> sorafenib, sunltinlb, bevaclzumab</td>

<td> GART</td><td> Microarray</td><td> Decreased (.55)</td><td> pemetrexed</td>

* Car is 0» ftss det neo threshold levels of reactivity tor 1HC ossad on publtsned evidence.

FIG. 40A

CARIS MPI, INC.

TARGETSNOW HSA&l

PAGE 2 of 10

PATIENT INFORMATION

Patient: Jane Doe Case Number: MP-TN00-OO000 Ordering Physician: Test Ordering Physician, MD

TARGET NOW® SUMMARY

<td> Biomarker</td><td> Assay</td><td> Results</td><td> Agents Associated With LACK OFCUMCAL BENEFIT</td>

<td> MGMT</td><td> IHC</td><td> Significant (+3. 50%)</td><td> temozolomide .</td>

<td> MGMT</td><td> Microarray</td><td> Increased (1.73)</td><td> temozolomide</td>

<td> ERCC1</td><td> IHC</td><td> Significant (+2 80%)</td><td> cisplatin; carboplatin</td>

<td> BCRP</td><td> IHC</td><td> Significant (+2 60%)</td><td> cisplatin; carboplatin</td>

<td> RRM1</td><td> IHC</td><td> Significant (+2. 80%)</td><td> gemcitabine</td>

<td> MRP1</td><td> IHC</td><td> Significant (+2 40%)</td><td> etoposide, vincristine</td>

<td> PGP</td><td> IHC</td><td> Significant (+1, 10%)</td><td> etoposide, vincristine</td>

<td> TS</td><td> IHC</td><td> Significant (+2 35%)</td><td> fluoropyrimidines</td>

FIG. 40B

CARIS MPI, INC.

TARGET©NOW

HHHH Lirt > k, 11 U c ג

PAGE 3 or 10

PATIENT INFORMATION

Patient: Jane Doe Case Number: MP-TN00-O000O Ordering Physician: Test Ordering Physician, MD

<td> Biomarker |</td><td> Information on Therapeutic Impact from Literature</td><td> Literature Level of Evidence</td>

<td> SPARC</td><td> High SPARC protein was assodatod with response to nab-paditaxel-based corrbi nation therapy</td><td> III/Good</td>

<td> TOPO1</td><td> High «pression of TOPO1 has been associated with a higher response rate when treated with irinotecan</td><td> IF3/Fair</td>

<td> PGP</td><td> High expression of P-glycoprotein has been assodatod with tock of response to Etoposide and Vincristine.</td><td> IF31 Fair</td>

<td> BCRP</td><td> High expression of BCRP has boon associated with shorter profession-free (PFS) and overall survival (OS), when treated with platinum based combination chemotherapy.</td><td> 11-3/Good</td>

<td> MRP1</td><td> High expression of MR PI has been associated with tack of response to Etoposido and Vincristine</td><td> 11-3/Fair</td>

<td> TS</td><td> High TS expression levels are associated with poor response to fiuoropynmidtnes and shorter 06 and DFS.</td><td> 11-3/Good</td>

<td> ERCC1</td><td> High expression of ERCC1 has been assodatod with lower response rates and a significartly shorter median progression-free and overall survival when treated with platinum-based chemotherapy.</td><td> IL3/G00d</td>

<td> RRMt</td><td> High RRM1 expression was assodatod with lack of response to gemcitabine treatment and poor outcome</td><td> IL3/G00d</td>

<td> MGMT</td><td> High expression of MGMT has been associated with resistance to temozotomide-basod therapy</td><td> 11-3/Good</td>

<td> c- Mt</td><td> Hi^t expression of c־Ki has been associated with significantly better survival, when treated withlmatinib</td><td> 11-2 / Fair</td>

<td> PDGFR</td><td> High expression al PDGFR a has been assodatod with response to imatinib treatment</td><td> lil fFear</td>

<td> ER</td><td> High expressionof ER has been associated with response to endocrine therapy.</td><td> 11-3 /Good</td>

<td> GART</td><td colspan="2" rowspan="4"> Biomarker associations with drugs based on microanay results have been identified by mechanistic association</td>

FIG. 40C

CARIS MPI, INC.

TARGET®NOW.

PAGE 4 of 10

PATIENT INFORMATION

Patient: Jane Doe Case Number: MP-TN00-OO00O Ordering Physician: Test Ordering Physician, MD

IHC Biomarker Detail

<td> Biomarker</td><td> Significant Result ~</td><td colspan="2"> । Patient Tumor Staining Intensity! Percent Staining</td><td> Threshold' Biomarker tntensity/Percentage</td>

<td> PDGFR</td><td></td><td> 2</td><td> 80</td><td> 22+and 230%</td>

<td> SPARC .“</td><td></td><td> 2</td><td> 50</td><td> 22+ and 230%</td>

<td> Androgen Receptor</td><td></td><td> 0</td><td> 100</td><td> 21+ and 210% or =0+ and =100%</td>

*Caris Dx has defined threshold levels of reactivity for IHC to estabish cutoff points based on pubfished evidence.

~ AH significant results are reflected in the Target Now Summary.

— SPARC results reflect analyses performed with both monoclonal and polyclonal antibodes.

FIG. 40D

CARIS MPI, INC.

TARGET®NOW.

PAGE 5 of 10

PATIENT INFORMATION

Patient: Jane Doe Case Number: ΜΡ-ΤΝ00-00000 Ordering Physician: Test Ordering Physician, MD

Microarray Analysis of RNA Expression on Formalin-Fixed Tissue

<td> 1 Gene</td><td> Ratio</td><td colspan="2"> Expression 1 1</td><td> Gene</td><td> I Ratio |</td><td> Expression</td><td> i</td><td> Gene</td><td> Ratio</td><td> Expies״«־ I</td>

<td> KIT</td><td> Ni</td><td> Not Intormativo</td><td></td><td> RRM1</td><td> 0.79</td><td> No Change</td><td></td><td> 3HFR</td><td> 1.27</td><td> No Change</td>

<td> ΓΟΡ2Β</td><td> 0.22</td><td> Under Expressed</td><td></td><td> PDGFRB</td><td> 0.81</td><td> No Change</td><td></td><td> XBCG2</td><td> 1.28</td><td> No Change</td>

<td> GGFR</td><td> Nl</td><td> Not Intormativo</td><td></td><td> NFKB1</td><td> 0.93</td><td> No Change</td><td></td><td> TNF</td><td> Nl</td><td> Not Informative</td>

<td> WLH1</td><td> Nl</td><td> Not Intormativo</td><td></td><td> LYN</td><td> 094</td><td> No Change</td><td></td><td> MFKB2</td><td> Nl</td><td> Not Informative</td>

<td> CD33</td><td> Nl</td><td> Not Informative</td><td></td><td> DNMT3A</td><td> Nl</td><td> Not informative</td><td></td><td> GDA</td><td> 1.33</td><td> No Change</td>

<td> SSTR2</td><td> Nl</td><td> Not Informative</td><td></td><td> CD52</td><td> NJ</td><td> Not Informative</td><td></td><td> 1SP9QAA1</td><td> 1.34</td><td> No Change</td>

<td> Ml</td><td> Nl</td><td> Not Informative</td><td></td><td> TOP2A</td><td> Nl</td><td> Not Intormativo</td><td></td><td> flARA</td><td> Nl</td><td> Not Informative</td>

<td> -RCC3</td><td> Nl</td><td> Not Informative</td><td></td><td> RXRG</td><td> Nl</td><td> Not Informative</td><td></td><td> GES2</td><td> 1.44</td><td> No Change</td>

<td> POGFRA</td><td> 0.44</td><td> Under Expressed</td><td></td><td> HCK</td><td> 0.97</td><td> No Change</td><td></td><td> TYMS</td><td> Nl</td><td> Not Intormativo</td>

<td> SPARC</td><td> 0.45</td><td> Under Expressed</td><td></td><td> PTEN</td><td> 1.01</td><td> No Change</td><td></td><td> 1IF1A</td><td> 1.64</td><td> Ocr Expressed .X’</td>

<td> PGR</td><td> Nl</td><td> Not Informative</td><td></td><td> BRCA1</td><td> NJ</td><td> Not Informative</td><td></td><td> SRC</td><td> Nl</td><td> Not Intormativo</td>

<td> RAFI</td><td> 0.90</td><td> Under Expressed</td><td></td><td> FLT1</td><td> NI</td><td> Not Informative</td><td></td><td> MGMT</td><td> 1.73</td><td> Over Expressed</td>

<td> GART</td><td> 0.55</td><td> Under Expressed</td><td></td><td> DNMT3B</td><td> NJ</td><td> Not Informative</td><td></td><td> </DR</td><td> Nl</td><td> Not Informative</td>

<td> OLR2</td><td> 0.57</td><td> Under Expressed</td><td></td><td> SSTR3</td><td> Nl</td><td> Not Intormativo</td><td></td><td> 3SIP1</td><td> 1.84</td><td> Over Expressed</td>

<td> WA</td><td> 0.57</td><td> Under Expressed</td><td></td><td> DNMT1</td><td> 1.11</td><td> No Change</td><td></td><td> EGFR</td><td> Nl</td><td> Not Informative</td>

<td> POLA1</td><td> Nl</td><td> Not Informative</td><td></td><td> IL2RA</td><td> Nl</td><td> Not Infotmatlvo</td><td></td><td> ΓΚ1</td><td> 1.94</td><td> Over Expressed</td>

<td> ΣΑΡ70</td><td> N)</td><td> Not Informative</td><td></td><td> SSTR4</td><td> Nl</td><td> Not Intormativo</td><td></td><td> S1RC5</td><td> Nl</td><td> Not Informative</td>

<td> ESRI</td><td> Nl</td><td> Not Informative</td><td></td><td> BRCA2</td><td> Nl</td><td> Not Informative</td><td></td><td> MSH2</td><td> Nl</td><td> Not Intormativo</td>

<td> LCK</td><td> Nl</td><td> Not Informative</td><td></td><td> HDhCl</td><td> 1.17</td><td> No Change</td><td></td><td> ✓EGFA</td><td> 2.22</td><td> C^er Expressed</td>

<td> rXNRDI</td><td> Nl</td><td> Not Informative</td><td></td><td> GNRH1</td><td> 1.18</td><td> No Change</td><td></td><td> ΞΡΗΑ2</td><td> Nl</td><td> Not informative</td>

<td> SSTR1</td><td> Nl</td><td> Not Informative</td><td></td><td> ERCC1</td><td> Nl</td><td> Not Informative</td><td></td><td> /Ht</td><td> 2.75</td><td> Over Expressed</td>

<td> KDR</td><td> Nl</td><td> Not Informative</td><td></td><td> RRM2B</td><td> 1.19</td><td> No Change</td><td></td><td> SSTR5</td><td> Nl</td><td> Not Intormativo</td>

<td> PDGFC</td><td> 0.68</td><td> No Change</td><td></td><td> RXRB</td><td> 1.20</td><td> No Charge</td><td></td><td> *boci</td><td> Nl</td><td> Not Informative</td>

<td> FYN</td><td> 0.71</td><td> No Change</td><td></td><td> MS4A1</td><td> Nl</td><td> Not Infotmativo</td><td></td><td> ECGF1</td><td> 4.08</td><td> Over Expressed</td>

<td> GCK</td><td> 0.71</td><td> No Change</td><td></td><td> ERBB2</td><td> 1.23</td><td> No Change</td><td></td><td> RRM2</td><td> Nl</td><td> Not Informative</td>

<td> ^SNS</td><td> 0.75</td><td> No Change</td><td></td><td> TOPI</td><td> Nl</td><td> Not Informative</td><td></td><td> PTGS2</td><td> 9.21</td><td> Over Expressed</td>

<td> 3CL2</td><td> Nl</td><td> Not Informative</td><td></td><td> YES1</td><td> 1.25</td><td> No Change</td><td colspan="4"></td>

No Change indicates that there is no difference in expression tor ths gone between the tumor and control tissues at a significance level of p<°0.001. A sigrificance level of p<e0.00l has been chosen since genes passing this threshold can bo vaSdated as differentially expressed by alternative methods approximately 95* of the time.

*Not Informative’ indicates that the data obtained tor cither the patient sample or the control sample wore not of high enough quality to confidently make a caff on the expression level of that particular RNA transcript. Therefore, tho expression ratios were notintormatwe (Nl).

Microarray Comment

RNA extracted from this patient was of acceptable quality for performance of this test

The expression proflies obtained with FFPE samples show more variability and may differ from expression profiles obtained with fresh frozen samples.

Methodology

Total RNA is extracted from tumor tissue and is converted to cDNA. This cDNA sample is then subjected to a whole genome (24K) microarray analysis using Illumina cDNA-mediated anneaing, selection, extension and ligation (DASL) process. The expression of a subset of 80 genes are then compared to a tissue specific normal control and the relative expression ratios of these 80 target genes is determined as well as the statistical significance of the differential expression.

FIG.40E

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PATIENT INFORMATION

Patient: Jane Doe Case Number: MP-TN0O-O000O Ordering Physician: Test Ordering Physictan, MD

Appendix

BIOMARKER DESCRIPTION

Target

BCRP

Biomarker Description

Breast cancer resistance protein (BCRPI, is a member or the superfamily at ABC transporter proteins, also known as mrtorantronerefi fiance protein. ABCP, and ABCG2. was identified m3 cancer cell line selected for resource to daunorubidh. Elevated expression of 0CRP in vitro causes resistance to anticancer drugs, inducing topotecan, irinotecan, mtoxantrone, and dcxwuoori.

<td> c -kil</td><td> c>Ka is a cytoMne receptor expressed on the surface 01 hematopoietic stem celts as well as other cell types. This receptor binds to stem celt tactor (SCF, a ceil growth tactor). As c-Kn is 8 receptor tyrosine «nase, ligand anang causes receipt omenzes andinaates a phospreryi311on cascade resulting tn changes in gene expression, These changes affect proliferation, apopfesis, chemotaws and adhesion c*K 11 is inhibited by the drugs imafintb. suwniPano so ratenib</td>

<td> ER</td><td> The estrogen receptor (ER) is a member of the nuclear hormone terrify at tntraceDu tar receptors which is activated by the hormone estrogen IB main function is as a ONA binding transcription tactor to regulate estrogen mediated gene expression ER ts expressed in breast ovanan and endometrial tissue. Efirogen ano its receptors are esse rm 1 for sexual development and reproductive function, but also play a rote mother tissues such as bone. Estrogen receptors are over ex pressed in many breast cancer cases, referred to as *ER positive.־Estrogen bindtngto ER on cancer celts leads to cancer cell proliferation, Brea a tumors marked by ER positive/currently term the basis of selecting patients wnc win receive and benefit from hormone based therapy.</td>

<td> ERCC1</td><td> Nucieotkte excision repair (NER)is a DNA repair mechanism necessary for the repair of DNA damage from a vast variety of sources including therricaB anduRrawotet(UV) light tram the sun. NER is a patticularty importart mechanism by which cells preveri unwanted and potential!/ cancer-causing mutations. ERCC1 (erosion repair cross-complementation group 1) aan important enzyme in tneNER pathway Some anticancer drugs tert cancer ceils by causing DNA damage and hence need» overcome the effeasolihe ONA repair pathways» be effective For example, platinum based drugs induce DNA cross-links that interfere witn DNA replication and transcription Tumors with low ERCC1 expression a re more like!/ ט benefit from platinum based DMA damaging agents white tumors »at overex press ERCC1 are ניזז re uiety to be resistant» such drugs</td>

<td> MGMT</td><td> O*6*methylguar1ine-DNA methyifransrerase (MGMT) encodes 3 DNA repeir enzyme Loss of MGMT expression leads to compromsed DNA repair in cells and may playa sigrtficart role tn cancer formation Low MGMT expression has been correlated witn response to temozolomide,</td>

<td> MRP1</td><td> MRM (muttidrugresistance-associated protein 11is one 01 several drug restfiance proteins identified to date and Ban important mediate ref the Multi Drug Resistance (MDR) phenotype in cancer celts MRP1 is found to confer a tack of response to anthracydznes (eg daunorubian. doxorubicin), vinca alkaloids (vincristine, vinblastine), epipodophytotowns (etoposide and tempo side), and mitoertrone, but probably not ta xanes (Padnaxd, Docetael), by causing the eftta of ghkatnioneconjugated natural product agerts (glutathione is a peptide composed of 3amno«ackis). Elevate die vets of MR Pl have been observed in relapsed acute myelogenous leukemia, chronic lymphatic leutenu, small .cell and norv-smalbceo tung cancer, and neuroblastoma a rro ng other malignancies.</td>

<td> PDGFR</td><td> Plafelet«demedgrowlhtac»rs(PDGFs)areimportan1taaorareguteting many important ceiMar (unctions related to cancer development These grow» factors bind toprotein tyrosine kinase receptors including PDGFR-alo transmit extracellular signals. Ligand bound receptors form dimers and transpho sphoiytate tyrosine residuesonthe receptor leading to activation and changes in gene expression. Ima סותם is a drug that targets »e tyrosine kinase domain or several fyro fine kinase receptors, including PDGFRs. imatimb competitively lnh1t«sPDGFR.Qaaivstion. Sorafenib and Smtinib are two additional tyrosine kinase inhibitors which can also block PDGFR-a</td>

<td> PGP</td><td> P glycoprotein (MDR1, ABC81) is an ATP<dependent, transmembrane drug efflux pump with broad substrate specificity, which pumps antitumor drug scut of cells us expression is often induced by chemotherapydrugsands thought to be a major mechanism of chemotherapy resistance. Overexpression of pgpcan be a negative predict Ne factor for various drugs such as antnrac־ytres(dc®nC»cin, epirubkan), pacbtexel, wnbtesune etc. P-gp remains the most important and dominant representative of Mufti Drug Resistance phenotype and is correlated with disease state and resistant phenotype.</td>

<td> RRMt</td><td> Ribonucleotide reductase subunit Ml (RRM1) is a component of the ribonucleotide reductase noIoenzyme confistingot Mi and M3 subunits. The ribonucleotide reauctase is 3 rate-timangemyme involved in the production at nucleotides required for 0na syranests Gemote bine ts8 aeaxyd&chne analogue which inhibits nbonudeattde reductase activity. Ba secton the literature, RRM1 levels are a predictor of patten! response when treated wen gemcitabine.</td>

SPARC

SPARC (secrated protein add» and rich tn cysteine) is a ceidum.blnding mamceftuiar gfyccprot eln secreted Oy many types 01 ceils, it has a normal role in wound repair, cell migration, and eell-matni interactions. IB over expression ts thought to have a role in tumor invasion and angiogenesis. A tew studies indicate that SPARC over-expression impraves the response to the anticancer drug, nab-pacieaxei. The improved response »thought to be related 10 SPARCs rote inaccumuteiing aJOurrinsnaalbumin targetea agents within tumor tissue.

FIG. 40F

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PATIENT INFORMATION

Patient: Jane Doe Case Number: MP-TN0OOC000 Ordering Physician: Test Ordering Physician, MD

Appendix

BIOMARKER DESCRIPTION

Target I Biomarker Description

Topotsorrerace &#1493; is an enzyme that anera the superooilingofdoubie-strandeo DW Topol acts by transiently cusing one strand of the CNA & relax the art! ana extend the CNA molecule. The regulation of CNA supercctling is essential to DNA transcription ana reputation, when me DNA helix must unwind to Serrnn the proper function or the enzymatic machinery involved tn these processes, Higher expression of Topol has been associated with response to tlret 1e chemotherapy containing irinotecan, a Topol inruator

TS

Thymidylate syntheuse CIS) is an enzyme that generates thymidine monophosphate (OTMP), which get phosphorylated to thymidine triphosphate (cfTTP) for use tn DNA synthesisana repair, Tnereacoonscatatyzed by TS also yield dnvirotolate as a secondary product As anarti-cancer chemotherapy target, thymidylate synthetase canbelnhiWed bytlucropynrndineor certain route analogues, High TS hasbeen associated with lack of response to IkXffopynmdine whereas tow or no TS expression has been associated with irrpraved clinical response tortuoropynmidme.

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PATIENT INFORMATION

Patient: Jane Doe Case Number: ΜΡ-ΤΝ00-00000 Ordering Physician: Test Ordering Physician, MD

LITERATURE LEVEL of EVIDENCE

<td> Target</td><td> Reference</td><td> Level of Evidence</td>

<td> BCRP</td><td> Yoh, K., G Ishii, et at. (2004). *Beast cancer resistance protein imp-aas clinical outcome in ptatinumbaseachemotherapy ter advanced non-smaO cell lung cancer. Clin Cancer Res 10(5)' 1691-7.</td><td> W/Feir</td>

<td> BCRP</td><td> Hu, Y., D M un, etal. (2006) ־pciluancesot PC cetKienvea growth factor and breast cancer resistance protein on«* curative effects 01 platinum-based chemotherapeuocregimens toradvencednon-sneOceO time cancer!.“ Zhonghua Y1 Xue Za Zhi 66(37): 2611-4</td><td>/Fair</td>

<td> C * kit</td><td> Hang, $. m , 1. Hwar^etat (2007). “Oinkai and prognostic significances ot nuclear ana cytoplasmic KIT expressions in extrarepete bile duct cerdnomas“ Moa Pathol 20(5): 562-9.</td><td> a-3JQ00d</td>

<td> C-kit</td><td> Kindler. T, F. Beitenbuecher. etal. (2004). *Efficacy ano safety of imatinib in aautt patients wan c-kit-pos we acute myeloid teukerma Btoixl 103(10)1 364454</td><td> B-3/Good</td>

<td> ER</td><td> Yamashita, H . Y. Yando, et al. (2006). immunohistochemical evaluationof hormone receptor status tor prediding response to endocrine therapy In metastatic breast cancer, Breast Cancer 13(1): 74-83</td><td> 0-3/Good</td>

<td> ER</td><td> Viale, G. Μ. M Regan, etal. (2008) Chemoendoainecomparedwtfhendacrine adjuvant therapies tat node-negative breast cancer predetfve value of centrally reviewed expression ot estrogen and progesterone r&ceptora-fnfe material Brea d Cancer Study Group JChn Oncol 26(9) 1404- סד</td><td> 0-2/Good</td>

<td> ER</td><td> Baselga, J , et al, Phase 8 genomics study 01 txabepitone as neoadjuvant treatment tor breast cancer, J Clin Oncol, 2009,27 (¢ p¾.¾4</td><td> fl-2/Good</td>

<td> ERCC1</td><td> Kwon, HC, et al., Prognostic value ot expresstonof ERCC1, thymidylate syrchase. and glutathione S4ransferase Pl tor 5lluorourabuoxaliplaan chemotherapy in advanced gastric cancer. AnnOnocl, 2007.18(3) p 504-9,</td><td> 8-3/Good</td>

<td> ERCC1</td><td> Lee, MW, etal. Expression of excision repair aoss^ompiemersation group 1 protein predicts poef outcome in patients wan smell cell lung cancer. Lung Cancer, 2008 59(1 )p 95-104</td><td> 0-3/Good</td>

<td> ERCC1</td><td> Loro R v. ,el al, ־Low ERCC1 expression correlates wen prolonged simrivai after aspiatin plus gemcitabine chemotherapy in non-smaaceO tung cancer. Ctin Cancer Res, 2002.6(7). p 2256-94</td><td> 0-21 Good</td>

<td> MGMT</td><td> Kovacs, K. B W. Scheithauer et al (2006), *MGMT immunoexpresaon predicts responsiveness of pituftary timors to temosnrrMe therapy Acta Neuropathy! 415(2)- 261 >2.</td><td> 111/Fak</td>

<td> MGMT</td><td> Levin, N, J, Lavon, etal. (2006). Progressivetow-gfade oligodendrogliomas response to temozolomide and correlation between genetic profile and O6-mettyiguanine DNA methyttransferase protein expresaon’Cancer 106(6) 1759-65.</td><td> 8-3/Good</td>

<td> MGMT</td><td> Chmot, O. L, M Barrie, et al. (2007) Correlation between O6-meihyiguantoe-DNAmethy&8nster«e andsurvvaf in inoperable newfy diagnosed gicbtastomB patients treated wnnneoa^uvanttemozotomde JChnOno« 25(12): 14705</td><td> 8-3/Good</td>

<td> MRP1</td><td> Ohsawa, Μ,, Y. Ikura, et al (2005) immunohistochemical expression of muttitrrug resistance proteins as a predictor of poor response to chemotherapy and prognosis in patients with nodal amuse large B-celi lymphoma Oncology 66(4-6): 42231־.</td><td> 0-3/Good</td>

<td> MRP1</td><td> Oshika y., Y. Ueyama. Mutadnjg resiflance 8׳ssoci3ted protein and mutant p53 protein expression in non smstioeOft/ng cancer. Mod Pathol 1998 11(11):1059-1063,</td><td> fl-3/Good</td>

<td> MRP1</td><td> Diestra, J£, MA. tzquiefdo, et al. (2003) *Expression of muttidrug resistance proteins P-^ycoprotein, miAidnjg resistance protem 1, breast cancer resistance protein anaung resistance related protein irdocatty advanced bladder cancer treated with neoadlirvant chemotherapy־ biological anacbnical implications*. The jot Urol 170:1383-87.</td><td> 1-3/Good</td>

<td> POGFRa</td><td> VidaFS, KA, Arantes A, Geiger A, VaeconceltosC, Passes V, Barrios CH, Phase ll trialot high dose imatinib in recurrent glioblastoma muattorrre (GBMjwdhpiataietaenved growth tactw receptor (PDGFR) expression JcumslotainicaiOncology, 200 7 A SCO Annual Meeting Proceed ngs Part t. 2007, 2S(18S (June 20 Supplement)): P 2056</td><td> 01 (Good</td>

<td> POGFRA</td><td> Sevinc, A, C, Camo, et al. (2007). *The diagnosis d C-kt negative GST by POGFRA saining clinical, pathological, anti nuclear metkeire perspedtverOnKitogie 30(12) 6454.</td><td> lU/Fax</td>

<td> PDGFRA</td><td> De Pas, T, F. Torn torio, et at. (2008) *Brief report activity of imatinib in a patient with piateietderrvedgrowtMactor receptor posrtrve malignant solitary fibrous tumor ot the pleura J Thorac Oncol 3(5):938-41.</td><td> 81/Good</td>

<td> PGP</td><td> Yeh. J 4, N. Y. Hsu, etal. (2005). *Comparison of chemotherapy response with P-gtyoc protein, miAiaug resistance-related protein-1, and lungreestance-related protein expression in umreated small ceo lung cancer.'Lung 183(3): 177-83,</td><td> 1-3/Good</td>

<td> PGP</td><td> Michiel! Μ, M. Baacaraniet al *P-glycoprotein, lung resistance rata tad protein and muftidrug resistance associated protein in de novo acute non lymphocytic leukaemias; biological and d1nicailm|jllcations,Br J Haematol 1999104(2) 328-35,</td><td> 1-3/Fair</td>

<td> RRM1</td><td> Bepier.G. I. Kusmartseva, etal. (2005). RRM1 modulated in vitro and in vko efficacy of gemcitabine and platinum m nonsmeh-ceii lung cancer״ J CUn Oncol 24(29) 4731-7.</td><td> 0-3/Good</td>

<td> RRM1</td><td> Rosea, R , £ Felip, etal. (2004) Gene expression as a predictive marier of oiscome in stage l&BIA-DBnorvsmailcen lung cancer after induction gemcitibine-ba sea chemotherapy followed by resectional surgery.Clin Cancer Res 10(12 Pt 2)421 ׳½</td><td> 83־/Good</td>

<td> RRM1</td><td> Nakahira. S. S Naka mon, el al (2007), involvement of ribonucleotide reductase Ml subunit overexpression in gemcitabine res^anoe al human pencrestc cancer m j Cancer 120(6)1355-63 ־</td><td> 8-3/Good</td>

<td> SPARC</td><td> Reef sky. E, et al. Phase 0 study of neoadtuvars bevaetzumab ana trastuzumab adntnts&red with alburnn-boixxi peditaxe! (nab pa dftax el) and carpopiatin 1nHER2♦ locally advanced breast career. J Clin Oncol (May20suppl;ab6tr627), 2008</td><td> 81 /Good</td>

FIG. 40H

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PATIENT INFORMATION

Patient: Jane Doe Case Number: ΜΡ-ΤΝ00-00000 Ordering Physician: Test Ordering Physician, MD

LITERATURE LEVEL of EVIDENCE

<td> Target</td><td> Reference</td><td> Level of Evidence</td>

<td> SPARC</td><td> Yard«/, DA. er al Phase Π auovoin&oadiMangemMabtm, earuoon, andeiOurnn-doundnaopectesei (GEA) intocaify advanced Dreas cancer with SPARC tumor assessments j Clin Oncol (May 20 suppijaoss 603), 2008. S</td><td> U/Good</td>

<td> TOPO1</td><td> Braun, M.S., et al. PredictNebtamartersotcnenwnerapy efficacy in colorectal cancer; results from the uk mrc FOCUS tnal. J Clin Oncol. 2008 26(16): p 2690*8.</td><td> a-1 / Good</td>

<td> TOPO1</td><td> Nawa, J, dal, Genetic diagnosis tor chemosensrtMry wnnorug-reastancegenes In epithelial Osetian cancer, int J Gynecol Cancer, 2007.17(1): p 76-82</td><td> 0-3/Good</td>

<td> TS</td><td> Paradiso. A, G Simone, et ar, (2000). Thymidylafe synthase andp53 pnmary tumour e> pres&wn as predictive factors tor advanced colorectal cancer patients Br J Cancer 82(3): 560*7.</td><td> D 3־/Good</td>

<td> TS</td><td> Mu, Y, C, R. A Komorowski et at (20031 -Thymidylate synthase expression prediasthe response to 5-rtucrouracU־based adjuvant therapy in pancreatic cancer. Qin Cancer Res 9(11): 4165*71.</td><td> 0-3 !Good</td>

<td> TS</td><td> Johnsen, P, G., R. Mick, et al (1997). “Tnymldytate synthase expressonano response to neoadjuvant chemotherapy in patents withadva need head and neck cancer. JNan Cancer ins 89(4): 308*13</td><td> B-3/Good</td>

FIG. 401

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PATIENT INFORMATION

Patient: Jane Doe Case Number: MP-TNO0-00O0O Ordering Physician: Test Ordering Physician. MD

LITERATURE LEVEL OF EVIDENCE ASSESSMENT FRAMEWORK*

Study Design

<td> Hierarchy of Design</td><td> Criteria</td>

<td> 1</td><td> Evidence obtained from at least one properly designed randomized controlled trial</td>

<td> 11-1</td><td> Evidence obtained from well-designed controlled trials without random teation.</td>

<td> tl-2</td><td> Evidence obtained from well-designed cohort or casecontrol analytic studies, preferably from more than ono center or research grotp.</td>

<td> II-3</td><td> Evidence obtained from mdtipto timo series with or wtthoti tho irtervention. Dramatic results in uncortrotlod triale might also t>0 regarded as this typo of evidence.</td>

<td> III</td><td> Opinions of respected authorities, based on c Eni cal experience, descriptive studies, or reports of expert committees.</td>

<td colspan="2"> Study Validity</td>

<td> Grade</td><td> Criteria</td>

<td> Good</td><td> The study is judged to be valid ami relevant as regards results, statistical analysis, and conclusions and shows no significant flaws.</td>

<td> Fair</td><td> The study is judged to bo valid and relevant as regards results, statistical analysis, and conclusions, but contains at least ono significant but not fatal flaw.</td>

<td> Poor</td><td> The study is judged to have a fatal flaw such that the conclusions are not valid for the purposes of this test.</td>

*Adapted from Harris, T, D A0<ins. & at. (2001) *Curreri MethocSof the U S Preventive Services T ask Faroe ,* Am j Prev Med 20{3S) *

Disclaimer

Ibis test was developed by Caris MP1 and their performance ch3raaens4ic was determined by Cans MPI, ft has not been ctearedor approved by the U.S Food and Drug Administration (FDA), These tests are perrrufiea tor dincsl purposes and shotiOnoi be regarded as purely InvestfgaHartsl or tor research onfy.CansMPf is certified under the Clinical Laboratory improvement Amendment 5 of 1988 (CUA) as qualified to perform high-corrplexty clinical testing.

By requesting and/or utilizing this test and the report, you agree that trie associated anaysa, interpretation, and intellectual property generated by the utiirzstnnor included in tre report is copyright protected, proprietary, and owned by Caris MPI. Cans MPI grants to the physiOana limned ngnt to use the information to care far the associated patient, but tor no other purpose, including but not tinned to validating ar creating a smilartest program, or report, whien is strictly prohibited unless Oy tne express wnsen permission or Cans MP1 are with appropriate patient consents. By requesungancuof utilizing this report, you agree that in the event 01 a breach of these provisions, Caris MPI shan be entitled to receive asliquicoted damages an immediate payment of 8100,000 tar each violation and 1% of the total amount tor each day that such a breach continues while a cknowiedglrv} and agreeing that actual damages tor such a breach woufo be drtficutt to calculate, and that such an amount conswes a reasonable estimate necessary to compensate Cans MPI far the damage suffered by rt as a result of the breach of ihese provisions that are intended tolimt the use of the test for vie care at the associated patient.

Decisions an careand treatment should be based an the independent medical judgment of the treating physician taking into consideration all available information concerning the patient's condition, including other laboratory tests, in accordance wiih the standard of care ma given community. Decisions regarding careand treatment should not be based on a single test such as Ms test The finding of a biamarke: «spiession does not necessity indicate pharmacologic effectiveness ar lack thereof. If a patient's tuner fas previously progressed on an agent identified as associated with clinical benefit on this report, the patient should not be re-treated with tnis agent

FIG. 40J

Divisional application from IL 282303/2

Contents130

191 members in 17 offices

This recordMember, by publication datePriority claim7 more offices are in the list below

Priority claims19

Priority claims
Document	Office	Kind	Date
15175809	United States of America	P	2009-02-11
15175809	United States of America	P	2009-02-11
61151758	United States of America	–	2009-02-11
17056509	United States of America	P	2009-04-17
17056509	United States of America	P	2009-04-17
61170565	United States of America	–	2009-04-17
22968609	United States of America	P	2009-07-29
22968609	United States of America	P	2009-07-29
61229686	United States of America	–	2009-07-29
2010000407	United States of America	W	2010-02-11
2010000407	United States of America	W	2010-02-11
61151758	–	–	–
61170565	–	–	–
61229686	–	–	–
PCTUS2010000407	–	–	–
US20090151758P	–	–	–
US20090170565P	–	–	–
US20090229686P	–	–	–
WO2010US00407	–	–	–

Members191

Family members, oldest first
Document	Office	Kind
AU2007253740A1	Australia	A1	2007-11-29
CA2651995A1	Canada	A1	2007-11-29
WO2007137187A2	World Intellectual Property Organization (WIPO)	A2	2007-11-29
US2008014146A1	United States of America	A1	2008-01-17
WO2007137187A3	World Intellectual Property Organization (WIPO)	A3	2008-03-13
KR20090013198A	Republic of Korea	A	2009-02-04
EP2032980A2	European Patent Office (EPO)	A2	2009-03-11
MX2008014608A	Mexico	A	2009-03-31
CN101449162A	China	A	2009-06-03
IL195266A0	Israel	A0	2009-08-03
IL195266D0	Israel	D0	2009-08-03
JP2009537154A	Japan	A	2009-10-29
ZA200809783B	South Africa	B	2010-02-24
US2010069298A1	United States of America	A1	2010-03-18
CO6141496A2	Colombia	A2	2010-03-19
WO2010033597A2	World Intellectual Property Organization (WIPO)	A2	2010-03-25
CA2739675A1	Canada	A1	2010-04-22
WO2010045318A2	World Intellectual Property Organization (WIPO)	A2	2010-04-22
US2010113299A1	United States of America	A1	2010-05-06
RU2008146868A	Russian Federation	A	2010-06-27
WO2010033597A3	World Intellectual Property Organization (WIPO)	A3	2010-07-22
CA2751888A1	Canada	A1	2010-08-19
CA3161998A1	Canada	A1	2010-08-19
WO2010045318A3	World Intellectual Property Organization (WIPO)	A3	2010-08-19
WO2010093465A1	World Intellectual Property Organization (WIPO)	A1	2010-08-19
US2010304989A1	United States of America	A1	2010-12-02
CA2779223A1	Canada	A1	2011-05-12
WO2011056688A2	World Intellectual Property Organization (WIPO)	A2	2011-05-12
IL212349A0	Israel	A0	2011-06-30
IL212349D0	Israel	D0	2011-06-30
EP2347009A2	European Patent Office (EPO)	A2	2011-07-27
BRPI0711011A2	Brazil	A2	2011-08-23
WO2011116181A1	World Intellectual Property Organization (WIPO)	A1	2011-09-22
IL214400A0	Israel	A0	2011-09-27
IL214400D0	Israel	D0	2011-09-27
WO2011056688A3	World Intellectual Property Organization (WIPO)	A3	2011-10-06
CN102232117A	China	A	2011-11-02
EP2396661A1	European Patent Office (EPO)	A1	2011-12-21
EP2032980A4	European Patent Office (EPO)	A4	2012-01-04
US2012015843A1	United States of America	A1	2012-01-19
CN102439454A	China	A	2012-05-02
AU2010315400A1	Australia	A1	2012-05-24
EP2347009A4	European Patent Office (EPO)	A4	2012-05-30
JP2012517238A	Japan	A	2012-08-02
EP2494077A2	European Patent Office (EPO)	A2	2012-09-05
US2013072389A1	United States of America	A1	2013-03-21
JP2013127477A	Japan	A	2013-06-27
CN101449162B	China	B	2013-07-31
EP2494077A4	European Patent Office (EPO)	A4	2013-08-21
EP2396661A4	European Patent Office (EPO)	A4	2013-10-30
CN103424541A	China	A	2013-12-04
US2014018254A1	United States of America	A1	2014-01-16
AU2014200048A1	Australia	A1	2014-01-23
KR101356305B1	Republic of Korea	B1	2014-01-28
US2014038846A1	United States of America	A1	2014-02-06
US2014057986A1	United States of America	A1	2014-02-27
US8700335B2	United States of America	B2	2014-04-15
US2014113837A1	United States of America	A1	2014-04-24
US2014121121A1	United States of America	A1	2014-05-01
US2014149136A1	United States of America	A1	2014-05-29
US2014149137A1	United States of America	A1	2014-05-29
US2014149138A1	United States of America	A1	2014-05-29
US2014155298A1	United States of America	A1	2014-06-05
US2014156199A1	United States of America	A1	2014-06-05
US2014172319A1	United States of America	A1	2014-06-19
US8768629B2	United States of America	B2	2014-07-01
US2014221221A1	United States of America	A1	2014-08-07
US2014221222A1	United States of America	A1	2014-08-07
US2014235511A1	United States of America	A1	2014-08-21
US2014244182A1	United States of America	A1	2014-08-28
US2014244183A1	United States of America	A1	2014-08-28
US8831890B2	United States of America	B2	2014-09-09
US8880350B2	United States of America	B2	2014-11-04
US8914239B2	United States of America	B2	2014-12-16
US2014370582A1	United States of America	A1	2014-12-18
US2014371111A1	United States of America	A1	2014-12-18
US2015080268A1	United States of America	A1	2015-03-19
US2015080269A1	United States of America	A1	2015-03-19
CN102439454B	China	B	2015-05-13
US9053224B2	United States of America	B2	2015-06-09
US9058418B2	United States of America	B2	2015-06-16
US9064045B2	United States of America	B2	2015-06-23
US9092392B2	United States of America	B2	2015-07-28
US2015227718A1	United States of America	A1	2015-08-13
CN104878086A	China	A	2015-09-02
JP2015200678A	Japan	A	2015-11-12
US2015361508A1	United States of America	A1	2015-12-17
JP2016027803A	Japan	A	2016-02-25
US2016054325A1	United States of America	A1	2016-02-25
IL195266A	Israel	A	2016-02-29
US9292660B2	United States of America	B2	2016-03-22
AU2016201396A1	Australia	A1	2016-03-24
IL214400A	Israel	A	2016-04-21
IL243717A0	Israel	A0	2016-04-21
IL243717D0	Israel	D0	2016-04-21
IL243718A0	Israel	A0	2016-04-21
IL243718D0	Israel	D0	2016-04-21
IL243719A0	Israel	A0	2016-04-21
IL243719D0	Israel	D0	2016-04-21
US9322067B2	United States of America	B2	2016-04-26

Showing 100 of 191