Mike Janicek, MD, and Bradley J. Monk, MD, FACS, FACOG, prepared useful Practice Aids pertaining to DDR-mutant cancers and PARP inhibitors for this CME activity titled, "Targeting Pathogenic Mutations in the DNA Damage Response Pathway: Genetic Testing and Counseling in the Era of Precision Medicine and Next-Generation Sequencing." For the full presentation, complete CME information, and to apply for credit, please visit us at https://bit.ly/2T8MPzj. CME credit will be available until May 26, 2021.

1. FDA-Approved PARP Inhibitors
for the Treatment of Solid Tumors
Access the activity, “Targeting Pathogenic Mutations in the DNA Damage Response Pathway: Genetic Testing
and Counseling in the Era of Precision Medicine and Next-Generation Sequencing” at PeerView.com/XUK40
PRACTICE AID
AML: acute myeloid leukemia; ALT: alanine transaminase; AST: aspartate aminotransferase; BRCA: breast cancer gene; CR: complete response; gBRCAmut: germline BRCA mutation; HER2: human epidermal growth factor receptor 2;
HRD: homologous recombination deficiency; HRR: homologous recombination repair; MDS: myelodysplastic syndromes; PARP: poly(ADP)-ribose polymerase; PR: partial response; sBRCAmut: somatic BRCA mutation; tx: treatment.
a
Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine therapy.
1. Zejula (niraparib) Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208447lbl.pdf. 2. Lynparza (olaparib) Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/
label/2018/208558s001lbl.pdf. 3. Rubraca (rucaparib) Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209115s003lbl.pdf. 4. Talzenna (talazoparib) Prescribing Information. https://www.
accessdata.fda.gov/drugsatfda_docs/label/2018/211651s000lbl.pdf. 5. https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm301431.htm.
Agent
Niraparib
Patients with advanced ovarian cancer who have
been treated with ≥3 prior chemotherapy
regimens and whose cancer is associated with
HRD-positive status
HRD status testing using
myChoice CDx
None
None
BRCA1/2 testing using
BRACAnalysis CDx or
next-gen sequencing using
FoundationOne CDx
BRCA1/2 testing using
BRACAnalysis CDx or
next-gen sequencing using
FoundationOne CDx
BRCA1/2 testing using
BRACAnalysis CDx
or next-gen sequencing using
FoundationFocus CDx BRCA or
FoundationOne CDx
BRCA1/2 testing using
BRACAnalysis CDx
BRCA1/2 testing using
BRACAnalysis CDx
Maintenance treatment in patients with gBRCAmut
or sBRCAmut advanced ovarian cancer following
response to first-line platinum-based chemotherapy
Patients with gBRCAmut or sBRCAmut
advanced ovarian cancer previously treated
with ≥2 chemotherapies
Maintenance treatment in patients with
recurrent ovarian cancer, achieving CR or PR
to platinum-based chemotherapy
Patients with gBRCAmut, HER2-negative,
metastatic breast cancer who have been treated
with chemotherapy in the neoadjuvant, adjuvant,
or metastatic settinga
Maintenance treatment in patients with
recurrent ovarian cancer, achieving CR or PR
to platinum-based chemotherapy
Patients with gBRCAmut advanced ovarian cancer
previously treated with ≥3 chemotherapies
Patients with gBRCAmut, HER2-negative,
locally advanced or metastatic breast cancer
Common AEs
Hematologic: anemia, thrombocytopenia, neutropenia, lymphocytopenia
Gastrointestinal: nausea, vomiting, diarrhea, constipation, abdominal pain, dysgeusia,
decreased appetite
Constitutional: fatigue, asthenia, dyspnea
Laboratory abnormalities: elevated creatinine, ALT, AST, and cholesterol
Serious AEs
Bone marrow suppression and MDS/AML
Lung-related: pneumonitis
Cardiovascular effects: hypertension and hypertensive crisis
Embryo-fetal toxicity
Olaparib
Rucaparib
Talazoparib
Spectrum of
Adverse Events
With PARP
Inhibitors1-4
Indicated for/in1-4 Companion
Diagnostic5
None
Maintenance treatment in patients with recurrent
epithelial ovarian cancer who are in a complete or
partial response to platinum-based chemotherapy
BRCA1/2testing using
BRACAnalysis CDx
First-line maintenance treatment in patients with
gBRCAmut metastatic pancreatic cancer whose
disease has not progressed on at least 16 weeks
of platinum-based chemotherapy
None
Maintenance treatment in patients with advanced
ovarian cancer following CR or PR to first-line
platinum-based chemotherapy
HRD status testing using
myChoice CDx
Maintenance treatment in combination with
bevacizumab in patients with advanced epithelial
ovarian, fallopian tube, or primary peritoneal
cancer who responded to first-line platinum-based
chemotherapy and whose cancer is HRD positive
None
Patients with gBRCAmut or sBRCAmut metastatic
castration-resistant prostate cancer previously
treated with androgen receptor-directed therapy
and a taxane-based chemotherapy
HRR testing using
FoundationOne CDx
Patients with recurrent germline or somatic HRR
gene–mutated metastatic prostate cancer
previously treated with enzalutamide or abiraterone

2. Genetic/Familial High-Risk Testing Guidelines for Breast,
Ovarian, Pancreatic, and Prostate Cancers1,2
PRACTICE AID
Access the activity, “Targeting Pathogenic Mutations in the DNA Damage Response Pathway: Genetic Testing
and Counseling in the Era of Precision Medicine and Next-Generation Sequencing,” at PeerView.com/XUK40
EOC: epithelial ovarian cancer; FTC: fallopian tube cancer; PPC: primary peritoneal cancer; TNBC: triple-negative breast cancer.
1. NCCN Clinical Practice Guidelines in Oncology. Genetic/Familial High Risk Assessment: Breast, Ovarian, and Pancreatic. Version 1.2020. 2. https://www.breastsurgeons.org/docs/statements/Consensus-Guideline-on-Genetic-Testing-for-Hereditary-Breast-Cancer.pdf.
Which patients with ovarian cancer should I test for BRCA1/2 mutations?
NCCN Guidelines
• All patients with ovarian cancer (EOC), peritoneal cancer (PPC), and fallopian tube cancer (FTC)
• Insurance will cover appropriate patients
Which patients with pancreatic or prostate cancer should I test for BRCA1/2 mutations?
NCCN Guidelines
Patients with:
• Exocrine pancreatic cancer at any age
• Metastatic or intraductal prostate cancer at any age
• High-grade (Gleason score ≥7) prostate cancer with:
– Ashkenazi Jewish ancestry; or
– ≥1 close relative with breast cancer at age ≤50 y or ovarian, pancreatic, or metastatic or intraductal prostate
cancer at any age; or
– ≥2 close relatives with breast or prostate cancer (any grade) at any age
• Consider pancreatic cancer screening beginning at 50 years of age (or 10 years younger than the earliest
exocrine pancreatic cancer diagnosis in the family; whichever is earlier)
Which patients with breast cancer should I test for BRCA1/2 mutations?
NCCN Guidelines
Patients with or who are:
• Aged ≤45 y, or ≤50 y if from a small family with few women
• TNBC, aged ≤60 y
• Ashkenazi Jewish history
• Male
• Bilateral breast cancer, with the first appearance when the patient was aged ≤50 y
• Aged ≤50 y with ≥1 relative with breast, pancreatic, or prostate cancer
• Any age with
– ≥2 relatives with breast, pancreatic, or prostate cancer
– ≥1 relative with ovarian cancer
– ≥1 relative with breast cancer diagnosed when aged ≤50 y
– ≥1 male relative with breast cancer
ASBrS Guidelines
• Genetic testing should be made available to all patients with a personal history of breast cancer

3. Specifications of Homologous Recombination Deficiency Tests1
PRACTICE AID
Access the activity, “Targeting Pathogenic Mutations in the DNA Damage Response Pathway: Genetic Testing
and Counseling in the Era of Precision Medicine and Next-Generation Sequencing,” at PeerView.com/XUK40
Germline PVsSpecimen Somatic PVs HRD
myChoice CDx
MyTumorSeek
(~592 genes)
FoundationOne CDx
(~324 genes)
Tissue Biopsy HRD Tests
Offering
MSK-IMPACT
(468 genes)
xT Assay
(~648 genes)
TumorNext-HRD
Germline PVs MSI PD-L1
or TMB
FDA-Approved
Therapy
FFPE tumor
FFPE tumor
FFPE tumor
FFPE tumor
PB and
FFPE tumor
PB and
FFPE tumor
+ germ
panels
Validate if NEG
Pair with any of
their other panels
BRCA1/2 only
(for PLUS:
90 genes)
BRCA1/2 + 322
additional genes
648 genes
fusion/
rearrange/CNV
11 HRD genes
LOH + TAI + LST
= GIS
Inferred NGS:
LOH with WES
LOH high ≥16%
Inferred NGS
LOH
Inferred from
11 HRD gene
mutations
With PLUS
MMRP IHC
(optional)
MMRP IHC
(optional)
TMB
(PD-L1 optional)
TMB/PD-L1
(optional)
TMB
TMB/PD-L1
(optional)
Approved: HRD+
niraparib 4th line (QUADRA)
olaparib + bev 1st line (PAOLA)
None for HRD
Rucaparib 3rd line, germline
or somatic
Olaparib 4th line, germline
and 1st line, germline or
somatic
First FDA-approved
commercial tumor-
profiling test
(Nov. 2017)
None for HRD
None for HRD

4. Specifications of Homologous Recombination Deficiency Tests1
PRACTICE AID
Access the activity, “Targeting Pathogenic Mutations in the DNA Damage Response Pathway: Genetic Testing
and Counseling in the Era of Precision Medicine and Next-Generation Sequencing,” at PeerView.com/XUK40
ABL1: v-abl Abelson murine leukemia viral oncogene homolog 1; ALK: analplastic lymphoma kinase; BCR: breakpoint cluster region protein; CD: cluster of differentiation; CNV: copy-number variation; EGFR: epidermal growth factor receptor; ETV6: ETS variant transcription factor
6; EWSRI: Ewing sarcoma breakpoint region 1; FFPE: formalin-fixed paraffin-embedded; FGFR: fibroblast growth factor receptor; GIS: genomic instability score; HRD: homologous recombination deficiency; IHC: immunohistochemistry; LOH: loss of heterozygosity; LST: large-scale
state transitions; MMRP: mismatch repair protein; MSI: microsatellite instability; NGS: next-generation sequencing; NRGI: neuregulin I; NTRK1: neurotrophic receptor tyrosine kinase 1; PAX8: paired box gene 8; PB: peripheral blood; PDGFRA: platelet-derived growth factor receptor
alpha; PDGFRB: platelet-derived growth factor receptor beta; PML: promyelocytic leukemia protein; PRKACA: protein kinase cAMP-activated catalytic subunit alpha; PV: pathogenic variant; RARA: retinoic acid receptor alpha; SNV: single-nucleotide polymorphism; TAI: telomere
allelic imbalance; TMB: tumor mutational burden; TMPRSS2: transmembrane serine protease 2; VAF: variant allele fraction; WES: whole-exome sequencing.
1. Provided courtesy of Mike Janicek, MD.
Germline PVsSpecimen Somatic PVs HRD
FoundationOne Liquid
(~70 genes)
ATLAS
(~600 genes)
Liquid Biopsy HRD Tests
Offering
xF Liquid
Biopsy Assay
Guardant Liquid
Biopsy Assay
(~73 genes)
Germline PVs MSI PD-L1
or TMB
Fusions and
Rearrangements
PB
PB
PB
PB
Inferred from
VAF ~50%
Inferred from
VAF ~50%
500x coverage
fusion/
rearrange/CNV
SNVs, CNVs,
fusions,andindels
Via NGS
Inferred from
limited HRD
genes
MMRP IHC
(optional)
TMB/PD-L1
(optional)
TMB
ALK,CD74,EGFR,FGFR1,
FGFR2,FGFR3,MET,
PDGFRA,PDGFRB,PRKACA,
RET,ROS1,NTRK1
ABL1,ALK, BCR,BRAF,EGFR,
ETV6,EWSRl,FGFR2,FGFR3,
MYB,MYC,NRGl,NTRK1,
NTRK3,PAX8,PDGFRA,PML,
RARA,RET,ROS1,TMPRSS2
ALK, FGFR2, FGFR3,
NTRK1, RET, ROS1
ALK,EGFR,FGFR2,FGFR3,
PDGFRA,RET,ROS1
(not NTRK1as of Feb. 2020)
TMB
(PD-L1viaXassay)
Inferred NGS