results with therapy associations sample report. for ... · genes tested with indeterminate results...

Final Report

The selection of any, all, or none of the matched therapies resides solely with the discretion of the treating physician. Decisions on patient care and treatment must be based on theindependent medical judgment of the treating physician, taking into consideration all available information concerning the patient's condition, the FDA prescribing information forany therapeutic, and in accordance with the applicable standard of care. Whether or not a particular patient will benefit from a selected therapy is based on many factors and can varysignificantly. All trademarks and registered trademarks are the property of their respective owners.

4610 South 44th Place, Suite 100 • Phoenix, AZ 85040 • (888) 979-8669 • Fax: (866) 479-4925CLIA 03D1019490 • CAP 7195577 • ISO 15189:2012 • Matthew Oberley, MD, PhD, Medical Director • ©2020 Caris Life Sciences. All rights reserved. of 7

Patient Specimen Information Ordered ByName: Patient, TestDate of Birth: XX/Mon/19XXSex: MaleCase Number: TN20-XXXXXXDiagnosis: High-grade serous carcinoma

Primary Tumor Site: Peritoneum, NOSSpecimen Site: OmentumSpecimen ID: ABC-1234-XYZSpecimen Collected: XX-Mon-2020Completion of Testing: XX-Mon-2020

OOOrrrdddeeerrriiinnnggg PPPhhhyyysssiiiccciiiaaannn,,, MMMDDDCancer Center123 Main StreetSpringfield, XY 12345, USA1 (123) 456-7890

Results with Therapy Associations

B I O M A R K E R M E T H O D A N A L Y T E R E S U L T T H E R A P Y A S S O C I A T I O NB I O M A R K E RL E V E L *

. niraparib, olaparib, rucaparib Level 1

.BRCA2 Seq DNA-Tumor Pathogenic Variant

Exon 11 | p.N1784fs B E N E F I Tcarboplatin, cisplatin, oxaliplatin Level 3A

.MSI Seq DNA-Tumor High B E N E F I T pembrolizumab Level 1

.BRAF Seq DNA-TumorPathogenic VariantExon 15 | p.V600E

B E N E F I T dabrafenib, trametinib, vemurafenib Level 3A

.ER IHC Protein Positive | 2+, 100% B E N E F I T endocrine therapy Level 3A

.RET Seq DNA-TumorPathogenic VariantExon 12 | p.C618R

B E N E F I T vandetanib Level 3B

* Biomarker reporting classification: Level 1 - highest level of clinical evidence and/or biomarker association included on the drug label; Level 2 - strong evidence of clinical significanceand is endorsed by standard clinical guidelines; Level 3 - potential clinical significance (3A - evidence exists in patient’s tumor type, 3B - evidence exists in another tumor type).

Important Note

This patient has a potential NCI-MATCH Trial-eligible result. Please see Clinical Trial see page 5

A pathogenic frameshift mutation, p.N1748fs, was detected in BRCA2. Germline pathogenic variants in this gene are causal for hereditary cancers of the breast, ovaries,pancreas, and prostate. Confirmation of the patient's carrier status should be considered.

A BRAF-activating, V600 mutation was detected in this sample. BRAF mutations in ovarian cancers are common in low-grade serous carcinoma (LGSC), a molecularlydistinct subtype of ovarian cancer characterized by activating mutations in the MAPK pathway.

Cancer Type Relevant BiomarkersBiomarker Method Analyte Result

Mismatch RepairStatus

IHC Protein Proficient

NTRK1/2/3 Seq RNA-Tumor Fusion Not Detected

Tumor MutationalBurden Seq DNA-Tumor High | 121 Mutations/

Mb

ATM Seq DNA-Tumor Mutation Not Detected

Biomarker Method Analyte Result

BRCA1 Seq DNA-Tumor Mutation Not Detected

PR IHC Protein Negative | 2+, 1%

RAD51C Seq DNA-Tumor Mutation Not Detected

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PATIENT: Patient, Test (XX-Mon-19XX) TN20-XXXXXX PHYSICIAN: Ordering Physician, MD


Genomic SignaturesBiomarker Method Analyte Result

MicrosatelliteInstability (MSI)

Seq DNA-Tumor High

Tumor MutationalBurden (TMB)

Seq DNA-Tumor

Result: High

7Low 17Intermediate High

121

Genes Tested with Pathogenic or Likely Pathogenic Alterations

Gene Method Analyte Variant Interpretation Protein Alteration Exon DNA Alteration VariantFrequency %

Seq DNA-Tumor Pathogenic Variant p.P1115fs 12 c.3344delC 25ARID1A

Seq DNA-Tumor Pathogenic Variant p.D1850fs 20 c.5548delG 26

ASXL1 Seq DNA-Tumor Pathogenic Variant p.G645fs 13 c.1934delG 21

BRAF Seq DNA-Tumor Pathogenic Variant p.V600E 15 c.2600A>C 16

BRCA2 Seq DNA-Tumor Pathogenic Variant p.N1784fs 11 c.5351delA 26

CREBBP Seq DNA-Tumor Pathogenic Variant c.1824-2A>G 9 c.1824-2A>G 21

EP300 Seq DNA-Tumor Pathogenic Variant p.M1470fs 27 c.4408delA 26

FANCA Seq DNA-Tumor Pathogenic Variant p.E345fs 12 c.1034 _1035delAG 28

HNF1A Seq DNA-Tumor Pathogenic Variant p.P379fs 6 c.1136delC 30

KEAP1 Seq DNA-Tumor Pathogenic Variant p.V512I 5 c.1534G>A 29

KMT2A Seq DNA-Tumor Pathogenic Variant p.D877fs 3 c.2629 _2630delGA 21

KMT2D Seq DNA-Tumor Pathogenic Variant p.G1960fs 28 c.5879delG 11

MSH6 Seq DNA-Tumor Pathogenic Variant p.Y1066fs 5 c.3198 _3199delTA 13

Seq DNA-Tumor Pathogenic Variant p.Y628fs 17 c.1882delT 33NF1

Seq DNA-Tumor Pathogenic Variant p.N2341fs 47 c.7022delA 28

NF2 Seq DNA-Tumor Pathogenic Variant p.P275fs 9 c.824delC 25

NSD1 Seq DNA-Tumor Pathogenic Variant p.F1799fs 16 c.5397delT 26

PIK3CA Seq DNA-Tumor Pathogenic Variant p.H1047R 21 c.3140A>G 24

RET Seq DNA-Tumor Pathogenic Variant p.C618R 12 c.1852T>C 29

RNF43 Seq DNA-Tumor Pathogenic Variant p.G659fs 9 c.1976delG 43

STAT3 Seq DNA-Tumor Likely Pathogenic Variant p.E616del 20 c.1847 _1849delAAG 33

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Genes Tested with Pathogenic or Likely Pathogenic Alterations

Gene Method Analyte Variant Interpretation Protein Alteration Exon DNA Alteration VariantFrequency %

Seq DNA-Tumor Pathogenic Variant p.Y220C 6 c.659A>G 17TP53

Seq DNA-Tumor Pathogenic Variant p.A74fs 4 c.220 _226del7 24

Unclassified alterations for DNA and RNA sequencing can be found in the MI Portal.Formal nucleotide nomenclature and gene reference sequences can be found in the Appendix of this report.Variants of Uncertain Significance can be found in the MI Portal.

Immunohistochemistry ResultsBiomarker Result Biomarker Result

ER Positive | 2+, 100% PD-L1 (SP142) Negative | 1+, 3%

MLH1 Positive | 3+, 100% PMS2 Positive | 1+, 95%

MSH2 Positive | 3+, 100% PR Negative | 2+, 1%

MSH6 Positive | 2+, 95%

Genes Tested with Indeterminate Results by Tumor DNA SequencingFLT3 HDAC1 JAK2 NFE2L2 NPM1 PRKACA PTPN11

Genes in this table were ruled indeterminate due to low coverage for some or all exons.

Genes Tested with Intermediate CNA Results by Tumor DNA SequencingMYC

The results in this report were curated to represent biomarkers most relevant for the submitted cancer type. These include results importantfor therapeutic decision-making, as well as notable alterations in other biomarkers known to be involved in oncogenesis. Additional results,including genes with normal findings, additional variants of uncertain significance and unclassified alterations can be found in the MI Portal atmiportal.carismolecularintelligence.com. If you do not have an MI Portal account, or need assistance accessing it, please contact Caris CustomerSupport at (888) 979-8669.

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Notes of SignificanceS E E A P P E N D I X F O R D E T A I L S

Clinical Trials Connector TM opportunities based on biomarker expression: 58 Chemotherapy Trials | 288 Targeted Therapy Trials. See page 5for details.

Please Note: A pathogenic frameshift mutation, p.N1748fs, was detected in BRCA2. Germline pathogenic variants in this gene are causal forhereditary cancers of the breast, ovaries, pancreas, and prostate. Confirmation of the patient's carrier status should be considered.

Specimen Information

Specimen ID: ABC-12345-XYZ Specimen Collected: Mon/XX/2020

Specimen Received: Mon/XX/2020 Other Testing Initiated: Mon/XX/2020

Gross Description: 1 (A) Paraffin Block - Client ID (ABC-123-XYZ)

Clinical History: Sample comments are added to the Clinical History free text field for testing purposes.

Pathologic Diagnosis: Sample comments are added to the Pathology Diagnosis free text field for testing purposes.

Dissection Information: A laboratory technician harvested targeted tissues for extraction from the marked areas using a dissection microscope. Theareas marked and extracted were reexamined using a microscope and/or digital whole slide image(s) on post-scraped slides and adequacy of scrapingwas reviewed by a board certified Pathologist.

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Clinical Trials ConnectorTM

For a complete list of open, enrolling clinical trials visit MI Portal to access the Clinical Trials Connector . This personalized, real-time web-basedservice provides additional clinical trial information and enhanced searching capabilities, including, but not limited to:

• Location: filter by geographic area• Biomarker(s): identify specific biomarkers associated with open clinical trials to choose from• Drug(s): search for specific therapies• Trial Sponsor: locate trials based on the organization supporting the trial(s)

Visit www.CarisMolecularIntelligence.com to view all matched trials. Therapeutic agents listed below may or may not be currently FDAapproved for the tumor type tested.

N C I M A T C H B I O M A R K E R S U M M A R Y

Description Biomarker Method Analyte Investigational Agent(s)

BRAF non-V600 mutation or fusion /ulixertinib

BRAF Seq DNA-Tumor ulixertinib

This patient has a potential NCI-MATCH Trial-eligible result for enrollment into trial arm "BRAF non-V600 / ulixertinib". Please note that leptomeningealmetastases are not eligible for enrollment into this arm.

Please note that all NCI MATCH arms associated with this case may not be actively recruiting for enrollment, please contact NCI for confirmation.

Please note regarding amplification inclusion criteria: NCI MATCH gene amplification (CNA) thresholds are higher than the Caris reporting thresholds. Asa result, only genes with amplification levels above the NCI MATCH threshold are shown in the table above.

C H E M O T H E R A P Y C L I N I C A L T R I A L S ( 5 8 )

Drug Class Biomarker Method Analyte Investigational Agent(s)

Antifolates (5) MSH6 NGS DNA-Tumor methotrexate, pemetrexed

Anti-hormonal therapy (8) ER IHC Proteinanastrozole, fulvestrant, goserelin, letrozole,leuprolide

Anti-inflammatory agents (2) PIK3CA NGS DNA-Tumor aspirin

DNA minor groove binding agents (1) BRCA2 NGS DNA-Tumor PM01183 (lurbinectedin)

BRCA2 NGS DNA-TumorPlatinum compounds (42)

MSH6 NGS DNA-Tumorcarboplatin, cisplatin, oxaliplatin

T A R G E T E D T H E R A P Y C L I N I C A L T R I A L S ( 2 8 8 )


Akt inhibitors (5) ARID1A NGS DNA-Tumor AZD5363, GDC-0068, ipatasertib

Chk1/Chk2 inhibitors (1) BRCA2 NGS DNA-Tumor LY2606368

( ) = represents the total number of clinical trials identified by the Clinical Trials Connector for the provided drug class or table.

The Clinical Trials Connector may include trials that enroll patients with additional screening of molecular alterations. In some instances, only specific gene variants maybe eligible.

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Clinical Trials ConnectorTM

T A R G E T E D T H E R A P Y C L I N I C A L T R I A L S ( 2 8 8 )


BRAF NGS DNA-TumorERK inhibitors (2)

NF1 NGS DNA-TumorBVD-523 (ulixertinib)

FAK inhibitors (3) NF2 NGS DNA-Tumor PF-04554878, defactinib

KEAP1 NGS DNA-TumorGlutaminase Inhibitor (4)

NF1 NGS DNA-TumorCB-839

MSH6 NGS DNA-Tumor

MSI NGS DNA-TumorImmunomodulatory agents (181)

TMB NGS DNA-Tumor

MEDI4736, MK-3475, MPDL3280A, MSB0010718C,atezolizumab, avelumab, cemiplimab, durvalumab,ipilimumab, mRNA-4157, nivolumab, pembrolizumab

BRAF NGS DNA-TumorMEK inhibitors (14)

NF1 NGS DNA-Tumor

ARRY-162, GDC-0973, XL518, binimetinib, selumetinib,trametinib

BRAF NGS DNA-Tumor

NF1 NGS DNA-TumorMultikinase inhibitors (23)

RET NGS DNA-Tumor

AZD1775, GSK2118436 (dabrafenib), LGX818,LOXO-292 (selpercatinib), LXH254, MGCD516,Ponatinib, cabozantinib, encorafenib, lenvatinib,regorafenib, sorafenib, sunitinib, vemurafenib

BRCA2 NGS DNA-TumorPARP inhibitors (30)

FANCA NGS DNA-Tumor

BGB-290, BMN-673, MK4827, niraparib, olaparib,rucaparib, talazoparib, veliparib

NF1 NGS DNA-Tumor

NF2 NGS DNA-TumorPI3K/Akt/mTor inhibitors (25)

PIK3CA NGS DNA-Tumor

AZD5363, BAY80-6946, GDC-0068, GSK2636771,INK1117, MLN0128, MLN1117, PF-05212384,everolimus, ipatasertib, sapanisertib, sirolimus,taselisib, temsirolimus

( ) = represents the total number of clinical trials identified by the Clinical Trials Connector for the provided drug class or table.

The Clinical Trials Connector may include trials that enroll patients with additional screening of molecular alterations. In some instances, only specific gene variants maybe eligible.

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DisclaimerDecisions on patient care and treatment must be based on the independent medical judgment of the treating physician, taking into consideration allavailable information concerning the patient's condition, the FDA prescribing information for any therapeutic, and in accordance with the applicablestandard of care. Drug associations provided in this report do not guarantee that any particular agent will be effective for the treatment of any patientor for any particular condition. Caris Life Sciences expressly disclaims and makes no representation or warranty whatsoever relating, directly or indirectly,to the conclusions drawn from its review of scientific literature, including information and conclusions relating to therapies that are included or omittedfrom this report. Whether or not a particular patient will benefit from a selected therapy is based on many factors and can vary significantly. The selectionof therapy, if any, resides solely in the discretion of the treating physician.

Individual assays that are available through Caris Molecular Intelligence® include both Laboratory Developed Tests (LDT) and U.S. Food and DrugAdministration (FDA) approved or cleared tests. Caris MPI, Inc. d/b/a Caris Life Sciences® is certified under the Clinical Laboratory ImprovementAmendments (CLIA) as qualified to perform high complexity clinical laboratory testing, including all of the assays that comprise the Caris MolecularIntelligence®. The LDTs were developed and their performance characteristics determined by Caris. The LDTs have not been cleared or approved by theU.S. Food and Drug Administration. Caris’ CLIA certification number is located at the bottom of each page of this report. Certain tests have not beencleared or approved by the FDA. The FDA has determined that clearance or approval is not necessary for certain laboratory developed tests. Caris LDTsare used for clinical purposes. They are not investigational or for research.

The information presented in the Clinical Trials Connector™ section of this report, if applicable, is compiled from sources believed to be reliable andcurrent. However, the accuracy and completeness of the information provided herein cannot be guaranteed. The clinical trials information present in thebiomarker description was compiled from www.clinicaltrials.gov. The contents are to be used only as a guide, and health care providers should employtheir best comprehensive judgment in interpreting this information for a particular patient. Specific eligibility criteria for each clinical trial should bereviewed as additional inclusion criteria may apply.

Caris Molecular Intelligence is subject to Caris’ intellectual property. Patent www.carislifesciences.com/ip.

Electronic Signature

Mon/XX/2020

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4610 South 44th Place, Suite 100 • Phoenix, AZ 85040 • (888) 979-8669 • Fax: (866) 479-4925CLIA 03D1019490 • CAP 7195577 • ISO 15189:2012 • Matthew Oberley, MD, PhD, Medical Director • ©2020 Caris Life Sciences. All rights reserved. Appendix 1 of 14

Mutational Analysis by Next-Generation Sequencing (NGS)T U M O R M U T A T I O N A L B U R D E N

Mutations / Megabase Result

121 High

TMB Methods

Tumor Mutational Burden was performed based on Next Generation Sequencing (NGS) analysis from genomic DNA isolated from a formalin-fixedparaffin-embedded tumor sample. NGS was developed and its performance characteristics determined by Caris Life Sciences.

Tumor Mutational Burden is calculated using only missense mutations that have not been previously reported as germline alterations. A highmutational burden is a potential indicator of immunotherapy response (Le et al., NEJM, 2015; Rizvi et al., Science, 2015; Rosenberg et al., Lancet, 2016;Snyder et al., NEJM, 2014). Caris Life Sciences has defined threshold levels for Tumor Mutational Burden and establish cutoff points based on publishedevidence and internal data/experience:

● High: greater than or equal to 17 mutations/Megabase (≥17 mutations/Mb). Approximately 7% of Caris Molecular Intelligence cases reported aHigh result.

● Intermediate: greater than or equal to 7 but fewer than 17 mutations/ Megabase (≥7 and <17 mutations/Mb). Approximately 34% of CarisMolecular Intelligence cases reported an Intermediate result.

● Low: less than or equal to 6 mutations/Megabase (≤6 mutations/Mb). Approximately 59% of Caris Molecular Intelligence cases reported a Lowresult.

M I C R O S A T E L L I T E I N S T A B I L I T Y A N A L Y S I S

Test Interpretation Result

Major microsatellite instability detected. High

MSIProcedure: NGS

Microsatellite Instability Analysis

Microsatellite instability status by NGS (MSI-NGS) is measured by the direct analysis of known microsatellite regions sequenced in the CMI NGS panel. Toestablish clinical thresholds, MSI-NGS results were compared with results from over 2,000 matching clinical cases analyzed with traditional, PCR-basedmethods. Genomic variants in the microsatellite loci are detected using the same depth and frequency criteria as used for mutation detection. Onlyinsertions and deletions resulting in a change in the number of tandem repeats are considered in this assay. Some microsatellite regions with knownpolymorphisms or technical sequencing issues are excluded from the analysis. The total number of microsatellite alterations in each sample are countedand grouped into three categories: High, Equivocal and Stable. MSI-Low results are reported in the Stable category. Equivocal results have a total numberof microsatellite alterations in between High and Stable.

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Mutational Analysis by Next-Generation Sequencing (NGS)G E N E S T E S T E D W I T H A L T E R A T I O N S

Gene Analyte Variant Interpretation Protein Alteration Exon DNAAlteration

VariantFrequency % Transcript ID

ARID1A DNA-Tumor Pathogenic Variant p.P1115fs 12 c.3344delC 25 NM_006015

Interpretation: A pathogenic frameshift mutation was detected in ARID1A.

This gene encodes a member of the SWI/SNF family, whose members have helicase and ATPase activities and are thought to regulate transcription of certain genes byaltering the chromatin structure around those genes. Inactivating mutations of ARID1A, a member of the SWI/SNF chromatin-remodeling complex, have been identifiedin a long list of cancers, including ovarian clear-cell carcinoma, gastric, hepatocellular, breast and so on. Mutational and functional data suggest ARID1A is a bona fidetumor suppressor. ARID1A may contribute to tumor suppression via effects on the SWI/SNF complex, control of cell proliferation and differentiation, and/or effects onhistone ubiquitylation.



ARID1A DNA-Tumor Pathogenic Variant p.D1850fs 20 c.5548delG 26 NM_006015

Interpretation: A pathogenic frameshift mutation was detected in ARID1A.



ASXL1 DNA-Tumor Pathogenic Variant p.G645fs 13 c.1934delG 21 NM_015338

Interpretation: A common truncating mutation, p.G645fs, was detected in ASXL1. Pathogenic somatic ASXL1 mutations are frequent in myeloidneoplasms and solid tumors, such as colorectal adenocarcinomas (Balasubramani 2015 Cancer-associated ASXL1 mutations may act as gain-of-function mutations of the ASXL1-BAP1 complex. Nat Commun 6:7307).

The protein is a member of the Polycomb group of proteins, which are necessary for the maintenance of stable repression of homeotic and other loci. The protein isthought to disrupt chromatin in localized areas, enhancing transcription of certain genes while repressing the transcription of other genes. The protein encoded by thisgene functions as a ligand-dependent co-activator for retinoic acid receptor in cooperation with nuclear receptor coactivator 1. Mutations in this gene are associated withmyelodysplastic syndromes and chronic myelomonocytic leukemia.



BRAF DNA-Tumor Pathogenic Variant p.V600E 15 c.2600A>C 16 NM_004333

Interpretation: The oncogenic p.V600E mutation was detected in BRAF.

BRAF encodes a protein belonging to the raf/mil family of serine/threonine protein kinases. This protein plays a role in regulating the MAP kinase/ERK signaling pathwayinitiated by EGFR activation, which affects cell division, differentiation, and secretion. BRAF somatic mutations have been found in melanoma (43%), thyroid (39%), biliarytree (14%), colon (12%), and ovarian tumors (12%). BRAF inherited mutations are associated with Noonan/Cardio-Facio-Cutaneous (CFC) syndrome, syndromes associatedwith short stature, distinct facial features, and potential heart/skeletal abnormalities.

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BRCA2 DNA-Tumor Pathogenic Variant p.N1784fs 11 c.5351delA 26 NM_000059

Interpretation: A pathogenic frameshift mutation, p.N1748fs, was detected in BRCA2. Germline pathogenic variants in this gene are causal forhereditary cancers of the breast, ovaries, pancreas, and prostate.

BRCA2 or breast cancer type 2 susceptibility gene encodes a protein involved in cell growth, cell division, and DNA-damage repair. It is a tumor suppressor gene whichplays an important role in mediating double-strand DNA breaks by homologous recombination (HR). Tumors with BRCA2 mutation may be more sensitive to platinumagents and PARP inhibitors.



CREBBP DNA-Tumor Pathogenic Variant Intron Splice Variant 9 c.1824-2A>G 21 NM_004380

Interpretation: A pathogenic mutation that disrupts an intron splice site was detected in CREBBP.

CREBBP encodes a protein involved in the transcriptional co-activation of many different transcription factors. This gene is known to play critical roles in embryonicdevelopment, growth control, and homeostasis. The protein encoded by this gene has intrinsic histone acetyltransferase activity and also acts as a scaffold to stabilizeadditional protein interactions with the transcription complex. Mutations in this gene cause Rubinstein-Taybi syndrome (RTS). Chromosomal translocations involving thisgene have been associated with acute myeloid leukemia.



EP300 DNA-Tumor Pathogenic Variant p.M1470fs 27 c.4408delA 26 NM_001429

Interpretation: A pathogenic frameshift mutation was detected in EP300.

EP300 encodes the adenovirus E1A-associated cellular p300 transcriptional co-activator protein. It functions as histone acetyltransferase that regulates transcription viachromatin remodeling and is important in the processes of cell proliferation and differentiation. It mediates cAMP-gene regulation by binding specifically to phosphorylatedCREB protein. This gene has also been identified as a co-activator of HIF1A (hypoxia-inducible factor 1 alpha), and thus plays a role in the stimulation of hypoxia-inducedgenes such as VEGF. Defects in this gene are a cause of Rubinstein-Taybi syndrome and may also play a role in epithelial cancer.



FANCA DNA-Tumor Pathogenic Variant p.E345fs 12c.1034

_1035delAG28 NM_000135

Interpretation: A loss of function pathogenic frameshift mutation was found.

The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI,FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a geneticallyheterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defectiveDNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclearprotein complex. This gene encodes the protein for complementation group A. Mutations in this gene are the most common cause of Fanconi anemia.

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HNF1A DNA-Tumor Pathogenic Variant p.P379fs 6 c.1136delC 30 NM_000545

Interpretation: A pathogenic frameshift mutation was detected in HNF1A.

HNF1A or hepatocyte nuclear factor 1 homeobox A encodes a transcription factor that is highly expressed in the liver, found on chromosome 12. It regulates a large numberof genes, including those for albumin, alpha1-antitrypsin, and fibrinogen. HNF1A has been associated with an increased risk of pancreatic cancer. HNF1A somatic mutationsare found in liver (30%), colon (15%), endometrium (11%), and ovarian (3%) cancers. Its prognostic and predictive value is under investigation. Germline mutations ofHNF1A are associated with maturity-onset diabetes of the young type 3.



IDH1 DNA-Tumor Likely Benign Variant p.N213fs 6 c.638delA 7 NM_005896

Interpretation: This variant creates a frameshift which would likely result in IDH1 loss of function. As most IDH1 pathogenic variants arise from gainof function, this frameshift mutation is likely to be benign.

IDH1 encodes for isocitrate dehydrogenase in cytoplasm and is found to be mutated in 60-90% of secondary gliomas, 75% of cartilaginous tumors, 17% of thyroid tumors,15% of cholangiocarcinoma, 12-18% of patients with acute myeloid leukemia, 5% of primary gliomas, 3% of prostate cancer, as well as in less than 2% in paragangliomas,colorectal cancer and melanoma. Mutated IDH1 results in impaired catalytic function of the enzyme, thus altering normal physiology of cellular respiration and metabolism.IDH1 mutation can also cause overproduction of onco-metabolite 2-hydroxy-glutarate, which can extensively alter the methylation profile in cancer.



KEAP1 DNA-Tumor Pathogenic Variant p.V512I 5 c.1534G>A 29 NM_012289

Interpretation:

This gene encodes a protein containing KELCH-1 like domains, as well as a BTB/POZ domain. Kelch-like ECH-associated protein 1 interacts with NF-E2-related factor 2 in aredox-sensitive manner and the dissociation of the proteins in the cytoplasm is followed by transportation of NF-E2-related factor 2 to the nucleus. This interaction resultsin the expression of the catalytic subunit of gamma-glutamylcysteine synthetase.



KMT2A DNA-Tumor Pathogenic Variant p.D877fs 3c.2629

_2630delGA21 NM_005933


This gene encodes a transcriptional coactivator that plays an essential role in regulating gene expression during early development and hematopoiesis. The encodedprotein contains multiple conserved functional domains. This protein is processed by the enzyme Taspase 1 into two fragments, MLL-C and MLL-N. These fragmentsreassociate and further assemble into different multiprotein complexes that regulate the transcription of specific target genes, including many of the HOX genes. Multiplechromosomal translocations involving this gene are the cause of certain acute lymphoid leukemias and acute myeloid leukemias.

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KMT2D DNA-Tumor Pathogenic Variant p.G1960fs 28 c.5879delG 11 NM_003482

Interpretation: A pathogenic frameshift mutation was detected in KMT2D.

The protein encoded by this gene is a histone methyltransferase that methylates the Lys-4 position of histone H3. The encoded protein is part of a large protein complexcalled ASCOM, which has been shown to be a transcriptional regulator of the beta-globin and estrogen receptor genes. Mutations in this gene have been shown to bea cause of Kabuki syndrome.



MSH6 DNA-Tumor Pathogenic Variant p.Y1066fs 5c.3198

_3199delTA13 NM_000179

Interpretation: A pathogenic frameshift mutation was detected in MSH6.

This gene encodes a member of the DNA mismatch repair MutS family. Mutations in this gene may be associated with hereditary nonpolyposis colon cancer, colorectalcancer, and endometrial cancer. THe protein product is a component of the DNA mismatch repair system (MMR), and heterodimerizes with MSH2 to form MutS alpha,which binds to DNA mismatches thereby initiating DNA repair.MutS alpha may also play a role in DNA homologous recombination repair. Recruited on chromatin in G1and early S phase via its PWWP domain that specifically binds trimethylated 'Lys-36' of histone H3 (H3K36me3): early recruitment to chromatin to be replicated allowinga quick identification of mismatch repair to initiate the DNA mismatch repair reaction.



NF1 DNA-Tumor Pathogenic Variant p.Y628fs 17 c.1882delT 33 NM_001042492

Interpretation: A pathogenic mutation was detected in NF1. Germline mutations in the NF1 gene are causal for Neurofibromatosis type 1.

The NF1 gene encodes neurofibromin, a protein that activates RAS GTP-ase, causing inactivation of RAS and serving as a negative regulator of the RAS pathway. Preclinicalstudies suggest that mutations in NF1 are associated with a decreased sensitivity to EGFR inhibitory drugs in lung cancer, perhaps due to an increased level of RAS activitythat allows the tumor to escape the negative regulation of EGFR. Further preclinical studies have shown that NF1 mutations/deletions cause sensitivity to MEK inhibitors insarcoma cell lines and resistance to RAF inhibition in melanoma cell lines. NF1 mutations have been observed in urothelial, ovarian, lung and triple negative breast cancer.



NF1 DNA-Tumor Pathogenic Variant p.N2341fs 47 c.7022delA 28 NM_001042492


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NF2 DNA-Tumor Pathogenic Variant p.P275fs 9 c.824delC 25 NM_000268


This gene product, a tumor suppressor, has been shown to interact with cell-surface proteins, proteins involved in cytoskeletal dynamics and proteins involved in regulatingion transport. This gene is expressed at high levels during embryonic development; in adults, significant expression is found in Schwann cells, meningeal cells, lens andnerve cells. Mutations in this gene are associated with neurofibromatosis type II which is characterized by nervous system and skin tumors and ocular/hearing abnormalities.



NSD1 DNA-Tumor Pathogenic Variant p.F1799fs 16 c.5397delT 26 NM_022455


This gene encodes a protein containing a SET domain, 2 LXXLL motifs, 3 nuclear translocation signals (NLSs), 4 plant homeodomain (PHD) finger regions, and a proline-rich region. The encoded protein enhances androgen receptor (AR) transactivation, and this enhancement can be increased further in the presence of other androgenreceptor associated coregulators. This protein may act as a nucleus-localized, basic transcriptional factor and also as a bifunctional transcriptional regulator. Mutationsof this gene have been associated with Sotos syndrome and Weaver syndrome. One version of childhood acute myeloid leukemia is the result of a cryptic translocationwith the breakpoints occurring within nuclear receptor-binding Su-var, enhancer of zeste, and trithorax domain protein 1 on chromosome 5 and nucleoporin, 98-kd onchromosome 11.



PIK3CA DNA-Tumor Pathogenic Variant p.H1047R 21 c.3140A>G 24 NM_006218

Interpretation: The common oncogenic p.H1047R mutation was detected in PIK3CA (Burke 2012 Proc Natl Acad Sci USA 109:15259).

PIK3CA or phosphoinositide-3-kinase catalytic alpha polypeptide encodes a protein in the PI3 kinase pathway. This pathway is an active target for drug development.PIK3CA somatic mutations have been found in breast (26%), endometrial (23%), urinary tract (19%), colon (13%), and ovarian (11%) cancers. Somatic mosaic activatingmutations in PIK3CA are said to cause CLOVES syndrome.



POLE DNA-Tumor Likely Benign Variant p.K995E 25 c.2983A>G 27 NM_006231

Interpretation: Given that only specific missense mutations at other positions in the POLE protein have been reported to promote tumorigenesis,this rare variant is predicted to be of no clinical significance in the tumor.

This gene encodes the catalytic subunit of DNA polymerase e (epsilon) or POLE. The enzyme is involved in DNA repair and chromosomal DNA replication. Mutations in thisgene have been associated with colorectal cancer 12 and facial dysmorphism, immunodeficiency, livedo, and short stature (FILS). POLE-mutated endometrial carcinomashave been associated with elevated tumor infiltrating and peritumoral lymphocytes.SAMPLE

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RET DNA-Tumor Pathogenic Variant p.C618R 12 c.1852T>C 29 NM_020975

Interpretation: An activating missense mutation was found in RET. This mutation along with other similar mutations at amino acid Cys618 have beenreported in both sporadic thyroid cancers and as germline in families with Multiple endocrine neoplasia type 2A (PMID 24928018, 8675603).

RET or rearranged during transfection gene, located on chromosome 10, activates cell signaling pathways involved in proliferation and cell survival. RET mutations arefound in 23-69% of sporadic medullary thyroid cancers (MTC), but RET fusions are common in papillary thyroid cancer, and more recently have been found in 1-2% of lungadenocarcinoma. Germline activating mutations of RET are associated with multiple endocrine neoplasia type 2 (MEN2), which is characterized by the presence of medullarythyroid carcinoma, bilateral pheochromocytoma, and primary hyperparathyroidism. Germline inactivating mutations of RET are associated with Hirschsprung's disease.



RNF43 DNA-Tumor Pathogenic Variant p.G659fs 9 c.1976delG 43 NM_017763

Interpretation: A pathogenic frameshift mutation was detected in RNF43. This specific mutation frequently occurs as a somatic mutation in tumorswith microsatellite instability.

E3 ubiquitin-protein ligase that acts as a negative regulator of the Wnt signaling pathway by mediating the ubiquitination, endocytosis and subsequent degradation ofWnt receptor complex components Frizzled. Acts on both canonical and non-canonical Wnt signaling pathways. Acts as a tumor suppressor in the intestinal stem cellzone by inhibiting the Wnt signaling pathway, thereby resticting the size of the intestinal stem cell zone.



STAT3 DNA-Tumor Likely Pathogenic Variant p.E616del 20c.1847

_1849delAAG33 NM_139276

Interpretation: This inframe deletion mutation in STAT3 is presumed to be pathogenic due to its recurrence in somatic cancers.

The protein encoded by this gene is a member of the STAT protein family.. This protein is activated through phosphorylation in response to various cytokines and growthfactors including IFNs, EGF, IL5, IL6, HGF, LIF and BMP2. This protein mediates the expression of a variety of genes in response to cell stimuli, and thus plays a key rolein many cellular processes such as cell growth and apoptosis. The small GTPase Rac1 has been shown to bind and regulate the activity of this protein. PIAS3 protein isa specific inhibitor of this protein.

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TP53 DNA-Tumor Pathogenic Variant p.Y220C 6 c.659A>G 17 NM_000546

Interpretation: The pathogenic p.Y220C mutation in TP53 is one of the most common mutations detected in cancers; it has been reported as agermline mutation, causal for Li-Fraumeni syndrome (Monti 2007 Clin Cancer Res 13:3789).

TP53, or p53, plays a central role in modulating response to cellular stress through transcriptional regulation of genes involved in cell-cycle arrest, DNA repair, apoptosis,and senescence. Inactivation of the p53 pathway is essential for the formation of the majority of human tumors. Mutation in p53 (TP53) remains one of the most commonlydescribed genetic events in human neoplasia, estimated to occur in 30-50% of all cancers. Generally, presence of a disruptive p53 mutation is associated with a poorprognosis in all types of cancers, and diminished sensitivity to radiation and chemotherapy. Germline p53 mutations are associated with the Li-Fraumeni syndrome (LFS)which may lead to early-onset of several forms of cancer currently known to occur in the syndrome, including sarcomas of the bone and soft tissues, carcinomas of thebreast and adrenal cortex (hereditary adrenocortical carcinoma), brain tumors and acute leukemias.



TP53 DNA-Tumor Pathogenic Variant p.A74fs 4c.220

_226del724 NM_000546

Interpretation: A pathogenic frameshift mutation was detected in TP53.

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Mutational Analysis by Next-Generation Sequencing (NGS)C O M P L E T E L I S T O F G E N E S T E S T E D W I T H I N D E T E R M I N A T E * R E S U L T S B Y T U M O R D N A S E Q U E N C I N G

FLT3 JAK2 NPM1 PTPN11

HDAC1 NFE2L2 PRKACA

Genes in this table were ruled indeterminate due to low coverage for some or all exons.

For a complete list of genes tested, visit www.CarisMolecularIntelligence.com/profilemenu.

NGS Methods

Next Generation Sequencing for WES (Whole Exome Sequencing): Direct sequence analysis was performed on genomic DNA isolated from a micro-dissected, formalin-fixed paraffin-embedded tumor sample using the Illumina NovaSeq 6000 sequencers. A hybrid pull-down panel of baits designedto enrich for more than 700 clinically relevant genes at high coverage and high read-depth was used, along with another panel designed to enrichfor an additional >20,000 genes at lower depth. A 500Mb SNP backbone panel (Agilent Technologies) was added to assist with gene amplification/deletion measurements and other analyses. The performance of the CMI WES assay was validated for sequencing variants, copy number alteration,tumor mutational burden and micro-satellite instability. The test was validated to 50ng of input and has a PPV of 0.99 against a previously validatedNGS assay. CMI WES can detect variants with tumor nuclei as low as 20%, and will detect variants down to 5% variant frequency with an averagedepth of at least 500x. This test has a sensitivity to detect as low as approximately 10% population of cells containing a mutation in all exons fromthe high read-depth clinical genes and 99% of all exons in the 20K whole exome regions. CMI WES is currently validated to detect <44bp indels. Thereference genome for the transcript ID is hg38 with hg19 liftOver calculations performed for the high read-depth gene panel. While the vast majorityof exons in the exome are covered by the assay, technical constraints preclude the coverage of every exon. Of the high read-depth genes with themost relevance to cancer, the following have only partial exon coverage: ARID1B, ASXL2, CDH23, CDKN1C, CHEK2, CYP2D6, DIS3L2, EIF1AX, FAT3, FLT4,FOXO3, HSP90AA1, HSP90AB1, KMT2C, MAGI2, MAML2, MDS2, MLLT3, NCOR1, NOTCH2, NSD3, PDE4DIP, PMS2, RAC1, RAD52, RANBP2, RHEB, RPL10,RPL22, SBDS, SET, SMC3, SRSF3, STAT5B, SUZ12, TCEA1, TOP3B, TSHZ3, USP6, and ZFHX3. For a complete list of what is covered, please contact CarisCustomer Support.

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Copy Number Alterations by Next-Generation Sequencing (NGS)G E N E S T E S T E D W I T H I N T E R M E D I A T E C N A R E S U L T S

MYC

C O M P L E T E L I S T O F G E N E S W I T H I N D E T E R M I N A T E C N A R E S U L T S

FLT3 JAK2 TPM4

CNA Methods

The copy number alteration (CNA) of each exon is determined by a calculation using the average sequencing depth of the sample along with thesequencing depth of each exon and comparing this calculated result to a pre-calibrated value. If all exons within the gene of interest have an averageof ≥3 copies and the average copy number of the entire gene is ≥6 copies, the gene result is reported as amplified. If an average of ≥ 4, but < 6 copiesof a gene are detected, or if the average copy number of the gene is ≥6 copies, but contains exons with an average of < 3 copies, the gene result isreported as intermediate. If an average of < 4 copies of a gene are detected, the gene result is reported as no amplification detected. A complete list ofcopy number alteration genes are available upon request.

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Gene Fusion and Transcript Variant Detection by RNA SequencingGene Fusion Methods

Gene fusion and variant transcript detection were performed on mRNA isolated from a formalin-fixed paraffin-embedded tumor sample using theAgilent SureSelectXT Low Input Library prep chemistry, optimized for FFPE tissue, in conjunction with the SureSelect Human All Exon V7 bait panel(48.2 Mb) and the Illumina NovaSeq. This assay is designed to detect fusions occurring at known and novel breakpoints within genes. Only a portionof genes tested are included in this report. The genes included in this report represent the subset of genes most commonly associated with cancer.All results can be provided by request. Analytical validation of this test demonstrated ≥97% Positive Percent Agreement (PPA), ≥99% Negative PercentAgreement (NPA) and ≥99% Overall Percent Agreement (OPA) with a validated comparator method.The versioned reference identifier used for the transcript ID was Feb.2009 (GRCh37/hg19).The complete list of unclassified alterations for RNA Whole Transcriptome Sequencing are available by request.

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Protein Expression by Immunohistochemistry (IHC)Patient Tumor Thresholds*

Biomarker Staining Intensity(0, 1+, 2+, 3+) Percent of cells Result Conditions for a Positive Result:

ER 2 + 100 PositiveIntensity of ≥3+ with ≥50% or≥2+ with ≥75% of cells stained

MLH1 3 + 100 Positive Intensity ≥1+ and ≥1% of cells stained

MSH2 3 + 100 Positive Intensity ≥1+ and ≥1% of cells stained

MSH6 2 + 95 Positive Intensity ≥1+ and ≥1% of cells stained

PD-L1 (SP142) 1 + 3 Negative Intensity ≥2+ and ≥5% of cells stained

PMS2 1 + 95 Positive Intensity ≥1+ and ≥1% of cells stained

PR 2 + 1 Negative Intensity ≥1+ and ≥10% of cells stained

Clones used: ER (SP1), PR (1E2), MLH1 (M1), MSH2 (G219-1129), MSH6 (44), PMS2 (A16-4), PD-L1 (SP142).

Electronic Signature

Mon/XX/2020

IHC Methods

The Laboratory Developed Tests (LDT) immunohistochemistry (IHC) assays were developed and their performance characteristics determined by CarisLife Sciences. These tests have not been cleared or approved by the US Food and Drug Administration. The FDA has determined that such clearance orapproval is not currently necessary. Interpretations of all immunohistochemistry (IHC) assays were performed manually by a board certified pathologistusing a microscope and/or digital whole slide image(s).

The following IHC assays were performed using FDA-approved companion diagnostic or FDA-cleared tests consistent with the manufacturer’sinstructions: ALK (VENTANA ALK (D5F3) CDx Assay, Ventana), ER (CONFIRM anti-Estrogen Receptor (ER) (SP1), Ventana), PR (CONFIRM anti-ProgesteroneReceptor (PR) (1E2), Ventana), HER2/neu (PATHWAY anti-HER-2/neu (4B5), Ventana), Ventana), PD-L1 22c3 (pharmDx, Dako), PD-L1 SP142 (VENTANA,Ventana in urothelial carcinomas and breast carcinoma; drug association only in urothelial and triple negative breast cancers), and PD-L1 28-8 (pharmDx,Dako).

HER2 results and interpretation follow the ASCO/CAP scoring criteria.

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References# Drug Biomarker Reference

1 vandetanib RETWells, S.A., M.J. Schlumberger, et al. (2012). "Vandetanib in Patients with Locally Advanced orMetastatic Medullary Thyroid Cancer: A Randomized, Double-Blind Phase III Trial." J Clin Oncol 30:134-141. View Citation Online

2 endocrine therapy ERRamirez, P.T., D.M. Gershenson, et. al. (2008). "Efficacy of letrozole in the treatment of recurrentplatinum- and taxane-resistant high-grade cancer of the ovary or peritoneum." GynecologicOncology. 110:56-59. View Citation Online

3 endocrine therapy ERArgenta PA, R Ghebre, et al. (2009). "A phase II study of fulvestrant in the treatment of multiply-recurrent epithelial ovarian cancer". Gynecol Oncol. 113(2):205-9. View Citation Online

4 endocrine therapy ERSmyth J.F., S.P. Langdon, et. al. (2007). "Antiestrogen therapy is active in selected ovarian cancer cases:The Use of Letrozole in Estrogen Receptor ^Positive Patients." Clin. Cancer Res. 13(12):3617-3622.View Citation Online

5 niraparib, olaparib, rucaparib BRCA2Swisher, E.M., I.A. McNeish, et al. (2016). "Rucaparib in relapsed, platinum-sensitive high-grade ovariancarcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial". Lancet. Publishedonline November 28, 2016. View Citation Online

6 niraparib, olaparib, rucaparib BRCA2Oza, A.M., M. Friedlander, et.al. (2015). "Olaparib combined with chemotherapy for recurrent platinum-sensitive ovarian cancer: a randomised phase 2 trial." Lancet Oncol. 16:87-97 View Citation Online

7 niraparib, olaparib, rucaparib BRCA2Mirza, M.R., ENGOT-OV16/NOVA Investigators, et. al, (2016) "Niraparib Maintenance Therapy inPlatinum-Sensitive, Recurrent Ovarian Cancer.", N Engl J Med. 375(22):2154-2164 View Citation Online

8 niraparib, olaparib, rucaparib BRCA2Ledermann, J., U. Matulonis, et.al. (2014). "Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCAstatus in a randomised phase 2 trial." Lancet Oncol. 15(8):852-61. View Citation Online

9 niraparib, olaparib, rucaparib BRCA2National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. OvarianCancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer Version 1.2019

10 niraparib, olaparib, rucaparib BRCA2Kaufman, B., S.M. Domcheck, et al. (2015). "Olaparib monotherapy in patients with advanced cancerand a germline BRCA1/2 mutation". J Clin Oncol. 33(3): 244-250. View Citation Online

11 niraparib, olaparib, rucaparib BRCA2Kondrashova, O., C.L. Scott (2017) "Secondary Somatic Mutations Restoring RAD51C and RAD51DAssociated with Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade OvarianCarcinoma" Cancer Discov. 7(9):984-998. View Citation Online

12 niraparib, olaparib, rucaparib BRCA2Christie, E.L., and D. Bowtell (2017) "Reversion of BRCA1/2 Germline Mutations Detected in CirculatingTumor DNA From Patients With High-Grade Serous Ovarian Cancer" J Clin Oncol 35:1274-1280 ViewCitation Online

13 carboplatin, cisplatin, oxaliplatin BRCA2Swisher, E.M., T. Tangiguchi, et al. (2008) "Secondary BRCA1 mutations in BRCA1-mutated ovariancarcinomas with platinum resistance." Cancer Res. 2008 Apr 15;68(8):2581-6. View Citation Online

14 carboplatin, cisplatin, oxaliplatin BRCA2Tan, D.S.P., M.E. Gore, et. Al. (2008) ""BRCAness" syndrome in ovarian cancer: a case-control studydescribing the clinical features and outcome of patients with epithelial ovarian cancer associated withBRCA1 and BRCA2 mutations." J Clin Oncol. 26(34):5530-6 View Citation Online

15 carboplatin, cisplatin, oxaliplatin BRCA2Byrski, T., S. Narod, et. Al. (2009) "Pathologic complete response rates in young women with BRCA1-positive breast cancers after neoadjuvant chemotherapy." J Clin Oncol. 28(3):275-9. View CitationOnline

16 carboplatin, cisplatin, oxaliplatin BRCA2

Tan, D., M. Gore, et al. (2008). ""BRCAness" Syndrome in Ovarian Cancer: A Case-Control StudyDescribing the Clinical Features and Outcome of Patients With Epithelial Ovarian Cancer AssociatedWith BRCA1 and BRCA2 Mutations" Journal of Clinical Oncology 26:34, 5530-5536 View CitationOnline

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References# Drug Biomarker Reference

17 carboplatin, cisplatin, oxaliplatin BRCA2Weigelt, B., N.C. Turner, et al (2017) "Diverse BRCA1 and BRCA2 Reversion Mutations in Circulating Cell-Free DNA of TherapyResistant Breast or Ovarian Cancer" Clin Cancer Res; 23(21); 6708-20 View CitationOnline

18 carboplatin, cisplatin, oxaliplatin BRCA2Hennessy, B.T., G.B. Mills, et al. (2010) "Somatic mutations in BRCA1 and BRCA2 could expand thenumber of patients that benefit from poly (ADP ribose) polymerase inhibitors in ovarian cancer" J ClinOncol. 28(22):3570-6 View Citation Online

19 carboplatin, cisplatin, oxaliplatin BRCA2Pennington, K.P., E.M. Swisher, et al. (2014). "Germline and somatic mutations in homologousrecombination genes predict platinum response and survival in ovarian, fallopian tube, and peritonealcarcinomas". Clin Cancer Res. 20(3):764-775.

20 carboplatin, cisplatin, oxaliplatin BRCA2Lowery, M.A., E.M. O'Reilly, et.al. (2011) "An emerging entity: pancreatic adenocarcinoma associatedwith a known BRCA mutation: clinical descriptors, treatment implications, and future directions."Oncologist. 16(10):1397-402. View Citation Online

21dabrafenib, trametinib,vemurafenib

BRAFMendivil, A.A., B. H. Goldstein, et al. (2018). "Dramatic clinical response following dabrafenib andtrametinib therapy in a heavily pretreated low grade serous ovarian carcinoma patient with a BRAFV600E mutation." Gynecol Oncol Rep 26:41-44. View Citation Online


BRAFHyman, D.H., J. Baselga, et al. (2015). "Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600Mutations." NEJM 373(8):726-736. View Citation Online


BRAFStover, E.H., N.I. Lindeman, et al. (2018). "Targeted Next-Generation Sequencing Reveals ClinicallyActionable BRAF and ESR1 Mutations in Low-Grade Serous Ovarian Carcinoma." JCO Precis Oncol2018. doi: 10.1200/PO.18.00135. View Citation Online


BRAFCombe, P., E. Pujade-Lauraine, et al., (2015). "Sustained response to vemurafenib in a low grade serousovarian cancer with a BRAF V600E mutation."Invest New Drugs 33(6): 1267-70. View Citation Online


BRAFMoujaber, T., A. deFazio, et al. (2018). "BRAF Mutations in Low-Grade Serous Ovarian Cancer andResponse to BRAF Inhibition." JCO Precis Oncol 2018: 2, 1-14 View Citation Online

26 pembrolizumab MSILe, DT, LA Diaz, et al. (2017). ""Mismatch repair deficiency predicts response of solid tumors to PD-1blockade"". Science. 357:409-413. View Citation Online

27 pembrolizumab MSILe, D.T., L.A. Diaz, et al. (2015). "PD-1 blockade in tumors with mismatch-repair deficiency". N Engl JMed. 372:2509-2520. View Citation Online

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