How Does Testing Impact Treatment Decision

How Does Testing Impact Treatment Decisions Related to PARP Inhibitors and DNA Damaging Agents?

It starts with Homologous Recombination

What is Homologous Recombination (HR)? Homologous recombination (HR) is a critical DNA repair pathway.

It is the only error-free DNA repair pathway that functions in the repair of double strand breaks and unrepaired single strand breaks. DNA damage occurs constantly through normal cellular processes and exposure to carcinogens. There are many genes in the HR pathway, including BRCA1 and BRCA2.

What is Homologous Recombination Deficiency (HRD)?

Homologous recombination deficiency (HRD) occurs when the homologous recombination pathway is disrupted.

This can occur by many mechanisms including genetic mutation, promoter methylation, as well as other yet to be defined causes. When a tumor is HR deficient it can’t repair its DNA reliably and must use a different, less effective, pathway to repair DNA. This leads to the tumor’s genetic makeup becoming very unstable (also called genomic instability). HR deficient tumors are more susceptible to therapies that further damage DNA, both directly and indirectly.1,2

How does a BRCA1/2 Mutation Cause Homologous Recombination Deficiency (HRD)?

Normally, the proteins produced by the BRCA1 and BRCA2 genes prevent cells from developing into cancer by aiding in the repair of mutations in other genes through a process known as double-stranded DNA repair. When one of these genes becomes ineffective due to a deleterious mutation, the cell can no longer perform double-stranded repair DNA and are homologous recombination deficient. HR deficiency can increase the risk for cancer, but is also a biomarker for certain targeted therapies to treat cancer when it develops.

Approximately 7% of breast cancer and 11 – 15% of ovarian cancer cases are caused by germline mutations in BRCA1 or BRCA2.

Breast Cancer

Ovarian Cancer

Why Test Tumors for BRCA1/2 or HRD?

Once a tumor’s genetic makeup becomes unstable it becomes vulnerable to specific treatments.

Cancer cells with HRD due to a BRCA1/2 mutation or other causes are more susceptible to treatments that directly or indirectly damage DNA such as PARP inhibitor therapy or DNA damaging chemotherapy. Identifying tumors with a BRCA1/2 mutation or HRD makes it possible to utilize targeted therapy to more precisely identify and attack cancer cells. Testing for BRCA1/2 or HRD allows therapy to be personalized based on the biology of a patient’s tumor.1-6

PARP inhibitor therapy and DNA damaging chemotherapies are less effective at killing cancer cells that have intact BRCA1/2 genes or homologous recombination (HR) pathway, because they can still repair DNA via the HR pathway.

PARP inhibitor therapy and DNA damaging chemotherapies are more effective at killing cancer cells that have HR deficiency or a BRCA1/2 mutation because DNA damage goes unrepaired, causing cancer cell death.

What data supports the clinical utility of BRCA/HRD testing?

Myriad Products that Assess Homologous Recombination Deficiency (HRD)

Myriad myChoice HRD

Treatment Decision: PARP inhibitors*, DNA-damaging chemotherapy
Assay: Tumor BRCA1 and BRCA2 assessment, Genomic Instability Status to determine whether homologous recombination deficiency is present in the tumor
Sample Type: Tumor (FFPE)
Mutations Identified: Tumor mutations (inclusive of germline and somatic)†
 
 
 
 
 
 


†Follow-up testing on a blood or saliva sample is recommended to determine whether a tumor BRCA1/2 mutation is germline (inherited) or somatic (isolated to the tumor).

Myriad Products that Assess BRCA1/2 Status

BRACAnalysisCDx

Treatment Decision:Lynparza® (olaparib) treatment for patients with breast or ovarian cancer. Zejula® (niraparib) maintence therapy for patients with ovarian cancer.1,2,3
Assay: Full gene sequencing and large rearrangement analysis of BRCA1 and BRCA2
Sample Type: Blood
Mutations Identified: Germline (in every cell of the body)
Myriad myRisk

Treatment Decision: PARP inhibitors*, DNA-damaging chemotherapy, family implications
Assay: Full gene sequencing and large rearrangement analysis of BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS2, EPCAM, APC, MUTYH, CDKN2A, CDK4, TP53, PTEN, STK11, CDH1, BMPR1A, SMAD4, PALB2, CHEK2, ATM, NBN, BARD1, BRIP1, RAD51C, RAD51D, POLD1, POLE, GREM1
Sample Type: Blood/Saliva
Mutations Identified: Germline (in every cell of the body)
Myriad myChoice HRD

Treatment Decision: PARP inhibitors*, DNA-damaging chemotherapy
Assay: Tumor BRCA1 and BRCA2 assessment, Genomic Instability Status to determine whether homologous recombination deficiency is present in the tumor
Sample Type: Tumor (FFPE)
Mutations Identified: Tumor mutations (inclusive of germline and somatic)†
BRACAnalysis

Treatment Decision: PARP inhibitors, DNA-damaging chemotherapy, family implications
Assay: Full gene sequencing and large rearrangement analysis of BRCA1 and BRCA2
Sample Type: Blood/Buccal
Mutations Identified: Germline (in every cell of the body)

 

* BRACAnalysis CDx has been approved by the FDA for patients with breast and ovarian cancer who are or may become eligible for treatment with the PARP inhibitor Lynparza® (olaparib). BRACAnalysis CDx can also identify patients with ovarian cancer who may experience enhanced progression-free survival (PFS) from Zejula® (niraparib) maintenance therapy. myRisk, myChoice HRD and BRACAnalysis have not been reviewed or approved by the FDA.1,2

†Follow-up testing on a blood or saliva sample is recommended to determine whether a tumor BRCA1/2 mutation is germline (inherited) or somatic (isolated to the tumor).

Sources:
  1. Watkins et al. Breast Ca Res (2014) 16:211
  2. Brown et al. ASCO 2015
  3. o Robson et al. Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation. N Engl J Med (2017). 377:523-533
  4. Mirza et al. N Engl J Med (2016). 375:2154-2164.
  5. Lheureux et al. J Clin Oncol (2015). 33 (suppl;abstr 5566).
  6. Kristeleit et al. Presented at European Cancer Congress 2016 (Abstract 8560).
  7. Intended Use: BRACAnalysis CDx® is an in vitro diagnostic device intended for the qualitative detection and classification of variants in the protein coding regions and intron/exon boundaries of the BRCA1 and BRCA2 genes using genomic DNA obtained from whole blood specimens collected in EDTA. Single nucleotide variants and small insertions and deletions (indels) are identified by polymerase chain reaction (PCR) and Sanger sequencing. Large deletions and duplications in BRCA1 and BRCA2 are detected using multiplex PCR.

    Results of the test are used as an aid in identifying breast and ovarian cancer patients with deleterious or suspected deleterious germline BRCA variants, who are or may become eligible for treatment with Lynparza® (olaparib). Detection of deleterious or suspected deleterious germline BRCA variants by the BRACAnalysis CDx test in ovarian cancer patients is also associated with enhanced progression-free survival (PFS) from Zejula® (niraparib) maintenance therapy. This assay is for professional use only and is to be performed only at 320 Wakara Way, Salt Lake City, UT 84108.
  8. For more detailed information about Lynparza and its safety and efficacy please go to lynparza.com
  9. For more detailed information about Zejula and its safety and efficacy please go to zejula.com
Lynparza is a registered trademark of the AstraZeneca group of companies. Zejula is a registered trademark of Tesaro, Inc.