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User Guide for FOUNDATIONONE models including: CDx, CDx Approved as Companion Diagnostic to Lynparza in Ovarian Cancer, Approved as Companion Diagnostic to Lynparza in Ovarian Cancer, Companion Diagnostic to Lynparza in Ovarian Cancer, Diagnostic to Lynparza in Ovarian Cancer, Lynparza in Ovarian Cancer, Ovarian Cancer, Cancer
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DocumentDocumentGuide to FoundationOne®CDx and FoundationOne®Liquid CDx Reports Professional Services Summary Page 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. FOUNDATIONONE ® LIQUIDCDx PATIENT TUMOR TYPE Prostate cancer (NOS) COUNTRY CODE REPORT DATE ORDERED TEST# ABOUT THE TEST FoundationOne® 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. zI- DISEASE Prostate cancer (NOS) NAME Not given DATE OF BIRTH Not given SEX Not given MEDICAL RECORD# Not given u z < ORDERING PHYSICIAN Not given MEDICAL FACILITY Not given v:>zi-: ADDITIONAL RECIPIENT Not given MEDICAL FACILITY ID Not given Q. PATHOLOGIST Not given uz w w SPECIMEN ID Not given SPECIMEN TYPE Not given DATE OF COLLECTION Not given Q. SPECIMEN RECEIVED Not given SAMPLE COVERAGE Not given Biomarker Findings Blood Tumor Mutational Burden -10 Muts/Mb Microsatellite status -MSI-High Not Detected Tumor Fraction - Cannot Be Determined Genomic Findings For a complete list of the genes assayed, please refer to the Appendix. BRCA2 L1908fs*2 CHEK2 L481* PIK3CA Hl047R 1 Report Highlights · There are positive Companion Diagnostic Findings identified for this patient. See the FDA Approved section. · Targeted therapies with NCCN categories of evidence in this tumor type: Olaparib (p. 6), Rucaparib (p. 6) · Variants that may inform nontargeted 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 germline testing in the appropriate clinical context: BRCA2 L1908fs*2 (p. 3) · Variants that may represent clonal hematopoiesis and may originate from non-tumor sources: CHEK2 L481* (p. 4) BIOMARKER FINDINGS Blood Tumor Mutational Burden - 10 M Muts/Mb THERAPIES WITH CLINICAL BENEFIT (IN PATIENT'S TUMOR TYPE) None THERAPIES WITH CLINICAL BENEFIT (IN OTHER TUMOR TYPE) None 10 Trials see p. 9 Microsatellite status - MSI-High Not Detected MSI-High not detected. No evidence of microsatellite instability in this sample (see Appendix section). 4 Tumor Fraction - Cannot Be Determined GENOMIC FINDINGS · Tumor fraction is an estimate of the percentage of circulating-tumor DNA (ctDNA) present in a cell-free DNA (cfDNA) sample based on observed aneuploid instability. 2 THERAPIES WITH CLINICAL BENEFIT (IN PATIENT'S TUMOR TYPE) THERAPIES WITH CLINICAL BENEFIT (IN OTHER TUMOR TYPE) BRCA2 L1908fs*2 47.8% Olaparib [j] Niraparib Rucaparib Talazoparib 10 Trials see p. 11 3 D NCCN Category 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 Shakti Ramkissoon, 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 1 of 2 PROFESSIONAL SERVICES SUMMARY - PAGE 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, germline 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 Consensus1 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 your patient's unique genomic profile with page number for quick reference. Pertinent Negatives Identifies important negative results on FoundationOne CDx that can be used for patient management when applicable. Pertinent negatives do not appear for FoundationOne Liquid CDx. Continued FDA-Approved Claims Page 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). PATIENT TUMOR TYPE Prostate cancer (NOS) PATIENT DISEASE NAME DATE OF BIRTH SEX MEDICAL RECORD # PHYSICIAN ORDERING PHYSICIAN MEDICAL FACILITY ADDITIONAL RECIPIENT MEDICAL FACILITY ID PATHOLOGIST SPECIMEN SPECIMEN ID SPECIMEN TYPE DATE OF COLLECTION SPECIMEN RECEIVED 1 Companion Diagnostic (CDx) Associated Findings GENOMIC FINDINGS DETECTED FDA-APPROVED THERAPEUTIC OPTIONS BRCA2 L1908fs*2 LYNPARZA® (olaparib) RUBRACA® (rucaparib) REPORT DATE ORDERED TEST # 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 cfDNA CHEK2 L481* # OTHER BIOMARKERS WITH POTENTIAL CLINICAL SIGNIFICANCE PIK3CA H1047R # Variants in this gene may be derived from a nontumor source such as clonal hematopoiesis (CH). The efficacy of targeting such nontumor somatic alterations (e.g., CH) is unknown. Refer to the appendix for additional details. Please refer to appendix for Explanation of Clinical Significance Classification and for variants of unknown significance (VUS). 1 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 FoundationOneCDx and FoundationOne Liquid CDx reports and should not be used for patient diagnosis or treatment decisions. Sample report images last updated December 2021. © 2021 Foundation Medicine, Inc. All rights reserved. ABOUT THE TEST FoundationOne®Liquid CDx is a next generation sequencing (NGS) assay that identifies clinically relevant genomic alterations in circulating cell-free DNA. Electronically signed by Richard Huang, M.D. | Julia Elvin, M.D., Ph.D., Laboratory Director CLIA: 22D2027531 Shakti Ramkissoon, M.D., Ph.D., M.M. Sc, Laboratory Director CLIA: 34D2044309 Foundation Medicine, Inc. | 1.888.988.3639 Sample Preparation: 150 Second St., 1st Floor, Cambridge, MA 02141 · CLIA: 22D2027531 Sample Analysis: 150 Second St., 1st Floor, Cambridge, MA 02141 · CLIA: 22D2027531 Post-Sequencing Analysis: 150 Second St., 1st Floor. Cambridge, MA 02141 · CLIA: 22D2027531 1 of 1 FDA APPROVED CLAIMS - PAGE 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 FoundationOneCDx and FoundationOne 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. ORDERED TEST # 1 Variant Allele Frequency Percentage (VAF%) PATIENT 10% increments 0.5% increments TUMOR TYPE Prostate cancer (NOS) REPORT DATE 1 FoundationOne 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 FoundationOne CDx reports, VAF values are displayed in the Genomic Findings section of Professional Services, alongside other variant information. HISTORIC PATIENT FINDINGS Blood Tumor Mutational Burden Microsatellite status Tumor Fraction BRCA2 CHEK2 PIK3CA L1908fs*2 L481* H1047R FoundationOne®Liquid CDx VAF% 10 Muts/Mb MSI-High Not Detected Cannot Be Determined 47.8% 5.8% 1.3% IMPORTANT NOTE This comparison table refers only to genes and biomarkers assayed by prior FoundationOne®Liquid CDx, FoundationOne®Liquid, FoundationOne®, or FoundationOne®CDx tests. Up to five previous tests may be shown. For some genes in FoundationOne Liquid CDx, only select exons are assayed. Therefore, an alteration found by a previous test may not have been confirmed despite overlapping gene lists. Please refer to the Appendix for the complete list of genes and exons assayed. The gene and biomarker list will be updated periodically to reflect new knowledge about cancer biology. As new scientific information becomes available, alterations that had previously been listed as Variants of Unknown Significance (VUS) may become reportable. Tissue Tumor Mutational Burden (TMB) and blood TMB (bTMB) are estimated from the number of synonymous and non-synonymous single-nucleotide variants (SNVs) and insertions and deletions (indels) per area of coding genome sampled, after the removal of known and likely oncogenic driver events and germlinePSANTPIsE. TNisTsue TMB is calculated based on variaTntUs MwiOthRanTaYllePleEfrequency of 5%, and bTMB is calculatRedEbPaOseRd TonDvaAriTanEts with an allele frequency of 0.5%. Prostate cancer (NOS) Not Tested = not baited, not reported on test, or test preceded addition of biomarker or gene Not Detected = baited but not detected on test Detected = present (VAF% is not applicable) VAF% = variant allele frequency percentage ORCDaEnnRoEt BDe TDeEteSrTmi#ned = Sample is not of sufficient data quality to confidently determine biomarker status 2 GENOMIC FINDINGS GENE alterations (7.4 vs. 3.6 mo., HR=0.34)59. BRCA2 Inactivation of BRCA2 may also predict sensitivity to DNA-damaging drugs such as trabectedin, AL1L9T0TEh8RefAsco*Tn2ItOenNt provided as a professional service by Foundation Medicine, lurbinectedin, and the platinum Inc.chiasspnloattbienenarenvidewcead robr aoppprloavteidnb6y0th-7e0F.DA. chemotherapies TRANSCRIPT ID NM_000059 CODING SEQUENCE EFFECT 5722_5723delCT POTENTIAL TREATMENT STRATEGIES Alterations that inactivate BRCA1 or BRCA2 may confer sensitivity to PARP inhibitors36-53 or to ATR inhibitors54-55. Clinical responses to PARP inhibitors have been reported for patients with either germline or somatic BRCA1/2 mutations37,42,45,52-53 and for patients with platinum-resistant or -refractory disease36,41,48,51. In a case study, a patient with therapy-induced neuroendocrine prostate cancer and an inactivating BRCA2 rearrangement experienced a CR ongoing for 20 months to the ATR inhibitor berzosertib55. Preclinical studies of BRCA1/2 inactivation in T-cell acute lymphoblastic leukemia (T-ALL)56, ovarian carcinoma57, and triple-negative breast cancer (TNBC)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 radiographic PFS with olaparib compared with physician's choice of abiraterone/prednisone or enzalutamide for patients with BRCA1/2 or ATM FREQUENCY & PROGNOSIS BRCA2 mutations have been identified in 36% of primary and 67% of metastatic prostate cancer specimens71-73, with deleterious germline BRCA2 mutations present in 5% of men with metastatic prostate cancer74. The positive predictive value of prostate specific antigen (PSA) levels was found to be higher in patients with BRCA1/2 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 spread76. Germline BRCA2 mutation carriers had a significantly shorter cause-specific survival (CSS, 8.6 vs. 15.7 years) than noncarriers76. Following radical conventional treatment for localized prostate cancer, patients with germline BRCA1/2 mutations experienced significantly shorter metastasis-free survival (HR=2.36) and CSS (HR=2.17) than noncarriers77. For patients with metastatic castration-resistant prostate cancer (mCRPC), germline BRCA2 mutations were an independent marker of poor prognosis (CSS 17.4 vs. 33.2 months, HR=2.11) in 1 study78. Germline BRCA2 mutations in mCRPC were associated with relative benefit from first-line abiraterone or enzalutamide compared with taxanes (CSS 24.0 vs. 17.0 months, PFS on the second systemic therapy 18.9 vs. 8.6 months) in a large prospective cohort study78. Three patients with nonneuroendocrine prostate cancer harboring BRCA2 mutations derived clinical benefit from treatment with platinum-based chemotherapy79-80. FINDING SUMMARY The BRCA2©tu20m21oFrousnudaptpiorneMsesdoicringe,eInnce. Aellnricgohtds eresseraved. 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 can1 lead 6to tumorigenesis82. Alterations such as seen here may disrupt BRCA2 function or expression81,83-98. POTENTIAL GERMLINE IMPLICATIONS One or more of the BRCA2 variants observed here has been described in the ClinVar database as a likely pathogenic or pathogenic germline mutation (by an expert panel or multiple submitters with no conflicts) associated with hereditary breast and ovarian cancer syndrome (ClinVar, Sep 2020)99. Follow-up germline testing would be needed to distinguish whether the finding in this patient is somatic or germline. Inactivating germline mutations in BRCA1 or BRCA2 are associated with autosomal dominant hereditary breast and ovarian cancer100-101, and the lifetime risk of breast and ovarian cancer in BRCA2 mutation carriers has been estimated to be as high as >80% and 23%, respectively102. Elevated risk for other cancer types, including gastric, pancreatic, prostate, and colorectal, has also been identified, with an increase in risk ranging from 20 to 60%103. The estimated prevalence of deleterious germline BRCA1/2 mutations in the general population is between 1:400 and 1:800, with an approximately 10-fold higher prevalence in the Ashkenazi Jewish population102,104-109. In the appropriate clinical context, germline testing of BRCA2 is recommended. 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. Continued Professional Services Continued PATIENT TUMOR TYPE Prostate cancer (NOS) ORDERED TEST # 3 GENE BRCA2 A LT E R AT I O N L1908fs*2 RATIONALE BRCA2 loss or inactivating alterations may predict sensitivity to PARP inhibitors or to ATR inhibitors. NCT02975934 PHASE 3 A Study of Rucaparib Verses Physician's Choice of Therapy in Patients With Metastatic Castrationresistant Prostate Cancer and Homologous Recombination Gene Deficiency TARGETS CYP17, PARP, AR LOCATIONS: Connecticut, New York, Massachusetts, Delaware, Maryland NCT03748641 A Study of Niraparib in Combination With Abiraterone Acetate and Prednisone Versus Abiraterone Acetate and Prednisone for Treatment of Participants With Metastatic Prostate Cancer PHASE 3 TARGETS CYP17, PARP LOCATIONS: Connecticut, New York, Massachusetts, New Jersey, Pennsylvania, Maryland, Kingston (Canada) NCT04123366 PHASE 2 Study of Olaparib (MK-7339) in Combination With Pembrolizumab (MK-3475) in the Treatment of Homologous Recombination Repair Mutation (HRRm) and/or Homologous Recombination Deficiency (HRD)-Positive Advanced Cancer (MK-7339-007/KEYLYNK-007) TARGETS PARP, PD-1 LOCATIONS: New York, New Jersey, Montreal (Canada), Virginia, Ohio, Moncton (Canada), Kentucky, Georgia NCT03810105 A Study of Olaparib and Durvalumab in Prostate Cancer PHASE 2 TARGETS PARP, PD-L1 LOCATIONS: New York, New Jersey, Michigan, Illinois, California NCT02595931 PHASE 1 ATR Kinase Inhibitor VX-970 and Irinotecan Hydrochloride in Treating Patients With Solid Tumors That TARGETS Are Metastatic or Cannot Be Removed by Surgery ATR LOCATIONS: Connecticut, Massachusetts, Pennsylvania, North Carolina, Tennessee, Missouri, Florida, California NCT03395197 Talazoparib + Enzalutamide vs. Enzalutamide Monotherapy in mCRPC (TALAPRO-2) PHASE 3 TARGETS PARP LOCATIONS: New York, New Jersey, Pennsylvania, Sherbrooke (Canada), Montreal (Canada), Virginia REPORT DATE CLINICAL TRIALS 3 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. Medical Case Consulting The content provided as a professional service by Foundation Medicine, Inc. has not been reviewed or approved by the FDA. © 2021 Foundation Medicine, Inc. All rights reserved. For additional help with report interpretation, select the "Ask An Expert" feature on your provider portal or contact client services at (888) 988-3639. 16 To learn more about our FDA-approved portfolio, go to foundationmedicine.com/portfolio FoundationOne®CDx and FoundationOne®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. FoundationOne CDx utilizes FFPE tissue and analyzes 324 genes as well as genomic signatures. FoundationOne 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 FoundationOne CDx when archival tissue is not available which may pose a risk. Patients who are tested with FoundationOne Liquid CDx and are negative for companion diagnostic mutations should be reflexed to tumor tissue testingand 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 NCCN.org. NCCN 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. | Foundation Medicine® and FoundationOne® are registered trademarks of Foundation Medicine, Inc. www.foundationmedicine.com | Tel 888.988.3639 | Fax 617.418.2290 | US-PF-2100005 V4.0