Guide to Foundation One® CDx and
Foundation One® Liquid CDx Reports

Professional Services Summary

As the first page of the report (page 1), the Professional Services summary page provides information for all of the reported biomarker and genomic findings upfront. It serves as the overview for clinicians to help ensure no findings are missed.
This section is not reviewed or approved by the FDA.
PATIENT
TUMOR TYPE  REPORT DATE
Prostate cancer (NOS)
COUNTRY CODE
ORDERED TEST #

ABOUT THE TEST Foundation One®
Liquid CDx is a next generation sequencing (NGS) assay that identifies clinically relevant genomic alterations in circulating cell-free DNA. Interpretive content on this page and subsequent pages is provided as a professional service, and is not reviewed or approved by the FDA.
ATNT
DISEASE Prostate cancer (NOS)
NAME Not given
DATE OF BIRTH Not given
SEX Not given
MEDICAL RECORD# Not given
PHYSICIAN
ORDERING PHYSICIAN Not given
MEDICAL FACILITY Not given
ADDITIONAL RECIPIENT Not given
MEDICAL FACILITY ID Not given
PATHOLOGIST Not given
SPECIMEN
SPECIMEN ID Not given
SPECIMEN TYPE Not given
DATE OF COLLECTION Not given
SPECIMEN RECEIVED Not given
SAMPLE COVERAGE Not given
Biomarker Findings
Blood Tumor Mutational Burden -10 Muts/Mb Micro satellite status -ISM-High Not Detected Tumor Fraction  Cannot Be Determined
Genomic Findings
For a complete list of the genes assayed, please refer to the Appendix.
BRCA2 L1908fs2
CHEK2 L481
PIK3CA Hl047R

Report Highlights

• There are positive Companion Diagnostic Findings identified for this patient. See the FDA Approved section.
• Targeted therapies with NC categories of evidence in this tumor type: Paramaribo (p. 6), Caparison (p. 6)
• Variants that may inform non targeted treatment approaches (e.g., chemotherapy) in this tumor type: BRCA2 L1908fs*2 (p. 3)
• Evidence-matched clinical trial options based on this patient’s genomic findings: (p. 11)
• Variants in select cancer susceptibility genes to consider for possible follow-up germ line testing in the appropriate clinical context: BRCA2 L 1908fs*2 (p. 3)
• Variants that may represent clonal hematologists and may originate from non-tumor sources: CHEK2 L481* (p. 4)

The content provided as a professional service by Foundation Medicine, Inc., has not been reviewed or approved by the FDA.
Electronically signed by Erik Williams, M.D. I
Julia Elvin, M.D., Ph.D., Laboratory Director CUA: 2202027531
Tisha Kissogram, M.D., Ph.D., M.M. Sc, Laboratory Director CUA: 34D2044309
Foundation Medicine, Inc. I 1-888-988-3639
© 2021 Foundation Medicine, Inc. All rights reserved.
Sample Preparation: 150 Second St., 1st Floor, Cambridge, MA 02141  CUA: 2202027531
Sample Analysis: 150 Second St., 1st Floor, Cambridge, MA 02141  CUA: 2202027531
Post-Sequencing Analysis: 150 Second St., 1st Floor. Cambridge, MA 02141  CUA: 2202027531
PROFESSIONAL SERVICES SUMMARY – PAGE 1 of 2

1. Report Highlights
   This feature distills important genomic insights in one easy-to-find place, helping you focus on the key actionable results to inform your patient’s treatment plan.
   Such key findings may include targeted therapies with potential resistance,germ line implications, non-targeted therapy implications and more depending on each patient case.

2. Therapies with Clinical Benefit Therapies for each associated genomic finding are listed in the therapy table.  On the left are therapies within your patient’s tumor type, and on the right  are those with proven clinical benefit in other tumor types. Therapy resistance based on your patient’s genomic profile  will also be indicated.

3. National Comprehensive Cancer Network® (NCCN®) Categories of Evidence and Consensus Associated NCCN Category that has been assigned to the therapy listed within your patient’s tumor type.

4. Clinical Trials
   Identifies number of trials based on outpatients unique genomic profile with page number for quick reference.

5. Pertinent Negatives Identifies important negative results on Foundation One CDx that can be used for patient management when applicable.
   Pertinent negatives do not appear for Foundation One Liquid CDx.

FDA-Approved Claims

Any FDA-approved claims for companion diagnostic (CDx) findings will appear on the FDA-approved claims page,  which comes directly after the Professional Services Summary page(s).

1. Companion Diagnostic (CDx) Associated Findings
   GENOMIC FINDINGS DETECTED| FDA- APPROVED THERAPEUTIC OPTIONS
   ---|---
   BRCA2 L1908fs*2| PARALYZE® (caparison)
   ABRACADABRA® (caparison)

OTHER SHORT VARIANTS AND SELECT REARRANGEMENTS AND COPY NUMBER ALTERATIONS IDENTIFIED
Results reported in this section are not prescriptive or conclusive for labeled use of any specific therapeutic product.
See professional services section for information on the alterations listed in this section as well as any additional detected copy number alterations, gene rearrangements, or biomarkers.
BIOMARKERS WITH EVIDENCE OF CLINICAL SIGNIFICANCE IN TISSUE SUPPORTED BY ANALYTICAL VALIDATION USING cDNA CHEK2 CHEK2 L481*
OTHER BIOMARKERS WITH POTENTIAL CLINICAL SIGNIFICANCE PIK3C PIK3CAA H1047R

Variants in this gene may be derived from a non tumor source such as clonal

hematologists (CH). The efficacy of targeting such non tumor somatic alterations (e.g., CH) is unknown.
Refer to the appendix for additional details.
Please refer to appendix for Explanation of Clinical Sign Cassi and for variants of unknown sign (VUS).

FDA-Approved CDx Claims
List of FDA-approved companion diagnostics associated with your  patient’s findings.
A companion diagnostic provides  essential information for the safe and effective use of a corresponding drug  or biological product.
NOTE: The images shown on this piece are of a sample report and do not represent actual test results. This information is intended to educate healthcare providers on the Foundational and  Foundation One Liquid CDx reports and should not be used for patient diagnosis or treatment decisions.
Sample report images last updated December 2021.

Professional Services Continued

Medical Case Consulting
You can find the remaining of the professional services section after the FDA- approved claims page.
PATIENT
TUMOR TYPE REPORT DATE
Prostate cancer (NOS)
ORDERED TEST #
Variant Allele Frequency Percentage (VAF%)

Blood Tumor
Mutational Burden| 10 Nuts/Mb
---|---
Micro satellite status| ISM-High Not Detected
Tumor Fraction| | Cannot Be Determined
BRCA2| L1908fs2| 48.%
CHEK2| L481| 6.%
PIK3CA| H1047R| 1.%

IMPORTANT NOTE This comparison table refers only to genes and biomarkers assayed by prior Foundation One®Liquid CDx, Foundation One°Liqu id, Foundation One®, or Foundation One®CDx tests. Up to five previous tests may be shown.
GENE
 BRCA2
ALTERATION 1.1908fC2
TRANSCRIPT ID NM_000059
CODING SEQUENCE EFFECT 5722_5723cleICT
POTENTIAL TREATMENT STRATEGIES
Alterations that inactivate SRC/it or BRCA2 may confer sensitivity to PARP inhibitors36-9 or to ATR inhibitors84-55. Clinical responses to PARP inhibitors have been reported for patients with either germ line or somatic BRCA1/2 mutations9A2ASS2-9 and for patients with platinum-resistant or -refractory disease36,1101851. In a case study, a patient with therapy-induced endocrinology prostate cancer and an inactivating BRCA2 rearrangement experienced a CR ongoing for 20 months to the ATR inhibitor berzosertib55. Clinical studies of BRCA1/2 inactivation in T-cell acute scholastically leukemia (T-ALL)56, ovarian carcinoma57, and triple-negative breast cancer (INBC)58 showing reduced cell viability and increased DNA damage during ATR treatment further support the sensitivity of BRCA2-deficient cells to ATR inhibitors. The Phase 3 Profound study for patients with metastatic castration-resistant prostate cancer (CRPC) who had progressed on a new hormonal agent reported improved radio graphic PFS with parabola compared with physician’s choice of aberration/prednisone or sulfonamides for patients with BRCA2/2 or ATM
alterations (7.4 vs. 3.6 mo., HR=o.34)9. Inactivation of BRCA2 may also predict sensitivity to DNA-damaging drugs such as contradicted, disconnected, and the platinum chemo therapies splatting and carboplatins8-28.
FREQUENCY at PROGNOSIS
BRCA2 mutations have been identified in 3-6% of primary and 6-7% of metastatic prostate cancer specimens21-23, with deleterious germline BRCA2 mutations present in 5% of men with metastatic prostate cancerm. The positive predictive value of prostate specific antigen (PSA) levels was found to be higher in patients with SRC/i1/2 mutations than in the general population75. BRCA2 germline mutations have been associated with attributes of aggressive prostate cancer at diagnosis, including high Gleason score, nodal involvement, advanced tumor stage, and metastatic spreads. Germaine BRCA2 mutation carriers had a significantly shorter cause-specific survival (CSS, to vs. 15.7 years) than noncancerous. Following radical conventional treatment for localized prostate cancer, patients with germ line BRCA1/2 mutations experienced significantly shorter metastasis-free survival (HR=2.36) and CSS (HR=2.17) than non carriers”. For patients with metastatic castration-resistant prostate cancer (McCray). germ line BRCA2 mutations were an independent marker of poor prognosis (CSS 17.4 vs. 33.2 months, HR=2.12) in 1 study28. Germaine BRCA2 mutations in McCray were associated with relative benefit from first-line aberration or sulfonamides compared with tannest (CSS 24.o vs.17.0 months, PFS on the second systemic therapy 1841 vs. 8.6 months) in a large prospective cohort study28. Three patients with non-endocrinology prostate cancer harboring BRCA2
mutations derived clinical benefit from treatment with platinum-based chemotherapy”-80.
FINDING SUMMARY
The BRCA2 tumor suppressor gene encodes a protein that regulates the response to DNA damage81. Inactivating mutations in BRCA2 can lead to the inability to repair DNA damage and loss of cell cycle checkpoints, which can lead to tumorigenesis82. Alterations such as seen here may disrupt BRCA2 function or expression81.8348.
POTENTIAL GERM LINE IMPLICATIONS
One or more of the BRCA2 variants observed here has been described in the Invar database as a likely pathogenic or pathogenic germ line mutation (by an expert panel or multiple submitter with no conflicts) associated with hereditary breast and ovarian cancer syndrome (ClinVar, Sep acao)99. Follow-up germ line testing would be needed to distinguish whether the finding in this patient is somatic or germ line. Inactivating germ line mutations in Br Cat or BRCA2 are associated with lysosomal dominant hereditary breast and ovarian cancer18°-181, and the lifetime risk of breast and ovarian cancer in BRCA2 mutation carriers has been estimated to be as high as >8o% and 23%. respectively182. Elevated risk for other cancer types, including gastric, pancreatic, prostate, and correctional, has also been identified, with an increase in risk ranging from 20 to 643%183. The estimated prevalence of deleterious germ line BRCA1/2 mutations in the general population is between 1:400 and 1:8o0, with an approximately to-fold higher prevalence in the Ashkenazim Jewish population102104-109. In the appropriate clinical context, germ line testing of BRCA2 is recommended.

1. Foundation One Liquid CDx Variant Allele Frequency Percentage (VAF%) Graph and Table
   Shows the detected VAF% and where applicable in the patient’s biomarkers and/or genomic signatures. Up to 5 previous tests may be shown. For Foundation One CDx reports, VAF values are displayed in the Genomic Findings section of Professional Services,  alongside other variant information.

2. Biomarker and Genomic Findings
   Following the initial pages of the report, the professional services section goes into more detail about your patient’s findings.

GENE
BRBRCA2CA2
ATTENTION
L1908fs*2
RA RATIONALE
BRCA2 loss or inactivating alterations may predict sensitivity to PAR inhibitors or to ATR

A Study of Caparison Verses Physician’s Choice of Therapy in Patients With Metastatic Castration- resistant Prostate Cancer and Homologous Recombination Gene Deficiency| TARGETS CYP17, PAR, AR
LOCATIONS: Connecticut, New York, Massachusetts, Delaware, Maryland
NCT03748641| PHASE 3
A Study of Paramaribo in Combination With Aberration Acetate and Prednisone Versus Aberration Acetate and Prednisone for Treatment of Participants With Metastatic Prostate Cancer| TARGETS
CYP17, PAR
LOCATIONS: Connecticut, New York, Massachusetts, New Jersey, Pennsylvania, Maryland, Kingston (Canada)
NCT04123366| PHASE 2
Study of Paramaribo (MK-7339) in Combination With Embolization (MK-3475) in the Treatment of Homologous Recombination Repair Mutation (Hr Rm) and/or Homologous Recombination Deficiency (HRD)-Positive Advanced Cancer (MK-7339-007/KEYLYNK-007)| TARGETS
PAR, PD-1
LOCATIONS: New York, New Jersey, Montreal (Canada), Virginia, Ohio, Monotonic (Canada), Kentucky,Georgia|
NCT03810105| PHASE 2
A Study of Paramaribo and Undervalue in Prostate Cancer| TARGETS
PAR, PD-1:1
LOCATIONS: New York, New Jersey, Michigan, Illinois, California
NCTO2595931| PHASE 1
ATR Kinase Inhibitor VX-970 and Antineutrino Hydrochloride in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery| TARGET
LOCATIONS: Connecticut, Massachusetts, Pennsylvania, North Carolina, Tennessee, Missouri, Florida,| California
NCT03395197| PHASE 3
Paramaribo + Sulfonamides vs. Sulfonamides Mono therapy in McCray (TALAPRO-2)| SPARTANBURG
LOCATIONS: New York, New Jersey, Pennsylvania, Brushstroke (Canada), Montreal (Canada), Virginia

Medical Case Consulting
For additional help with report interpretation, select the “Ask An Expert” feature on your provider portal or contact client services at 888-988-3639.
Clinical Trial Information
Detailed information about the clinical  trials your patient has been matched to, ranked for the patient based on location and trial phase.
To learn more about our FDA-approved portfolio, go to foundationmedicine.com/portfolio

Foundation One® CDx and Foundation One®Liquid CDx are qualitative next- generation sequencing based in vitro diagnostic tests for advanced cancer patients with solid tumors and are for prescription use only. Foundation One CDx utilizes FFPE tissue and analyzes 324 genes as well as genomic signatures. Foundation One Liquid CDx analyzes 324 genes utilizing circulating cell-free DNA and is FDA-approved to report short variants in 311 genes. The tests are companion diagnostics to identify patients who may benefit from treatment with specific therapies in accordance with the therapeutic product labeling. Additional genomic findings may be reported and are not prescriptive or conclusive for labeled use of any specific therapeutic product. Use of the tests does not guarantee a patient will be matched to a treatment. A negative result does not rule out the presence of an alteration. Some patients may require a biopsy for testing with Foundation One CDx when archival tissue is not available which may pose a risk. Patients who are tested with Foundation One Liquid CDx and are negative for companion diagnostic mutations should be reflexes to tumor tissue testing and mutation status confirmed using an  FDA- approved tumor tissue test, if feasible.
For the complete label, including companion diagnostic indications and important risk information, please visit www.F1CDxLabel.com and www.F1LCDxLabel.com.
References:

1. Referenced with permission from the National Comprehensive Cancer Network, Inc. © National Comprehensive Cancer Network, Inc. 2021. All rights reserved. To view the most recent and complete version of the recommendations, go online to NC.org. NC makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

© 2022 Foundation Medicine, Inc.
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One® are registered trademarks of Foundation Medicine, Inc.
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Tel 888.988.3639
Fax 617.418.2290
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References

• Compare Our Tests | Foundation Medicine
• National Comprehensive Cancer Network - Home
• F1CDxLabel.com
• F1LCDxLabel.com
• Foundation Medicine | A World-leading Molecular Insights Company

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