FDA approves second PARP inhibitor for germline BRCA-mutated Locally Advanced or Metastatic Breast Cancer

Today, the FDA approved approved talazoparib (Talzenna), a drug of the PARP inhibitor class for breast cancer patients who possess harmful (or suspected harmful) BRCA2 mutations in the context of locally advanced or metastatic breast cancer. Importantly, before approval for the new drug, patients must undergo testing with an FDA-approved companion test from Myriad Genetics, the BRACAnalysis CDx test, which was also granted approval. The FDA based its approvals on data from the open-label, phase 3 EMBRACA trial which was designed to evaluate Talzenna compared with chemotherapy in 431 patients with HER2-negative, germline BRCA-mutant locally advanced or metastatic breast cancer. Breast cancer patient participants could have no more than three prior chemotherapy regimens for locally advanced or metastatic disease, and they were required to have received treatment with an anthracycline and/or taxane (unless they were not eligible for that treatment) in the neoadjuvant (before treatment), adjuvant (during treatment) and/or metastatic (Stage IV breast cancer) setting. Estimated average progression-free survival (time to disease progression or death) in the Talzenna arm was 8.6 months compared to 5.6 months in the chemotherapy arm. Talzenna is the second PARP inhibitor to be approved for the treatment of breast cancer. Lynparza (olaparib) was the first drug in the PARP class to be approved for breast cancer. The prescribing information for Talzenna includes warnings and precautions for myelodysplastic syndrome/acute myeloid leukemia, myelosuppression, and embryo-fetal toxicity. The most common side effects were fatigue, anemia, nausea, neutropenia, headache, thrombocytopenia, vomiting, alopecia, diarrhea and decreased appetite.

October 3 is Previvor Day; what is National Hereditary Breast and Ovarian Cancer (HBOC) Week

Today, October 3, we are honoring Previvors of Breast and Ovarian Cancer! Today is National Previvor Day, when we honor people with a predisposition to breast and ovarian cancer who have not had the disease. More previvors than ever before are empowering themselves with the vastly improved resources and prediction models for breast cancer, including genetic counseling, genetic testing, high risk breast programs, chemoprevention, and risk-reducing surgery. This week (September 30 – October 6) is HBOC Week It’s National Hereditary Breast and Ovarian Cancer (HBOC) Week, a time when we create awareness, recognize those with a genetic predisposition to cancer, and work towards a future when hereditary cancer no longer exists, through enhanced population screening, earlier detection, genetic editing, and targeted therapy.  

What is BRCA2 and what cancers are associated with BRCA2 mutations?

BRCA2 is a very large gene that codes for a large protein consisting of 3,418 amino acid building blocks that has known functions in DNA repair and in controlling cell replication (mitosis). It is a tumor suppressor gene, meaning that an intact BRCA2 gene will prevent cancers from developing by repairing any DNA errors and also by halting cell replication if it senses abnormalities in the genetic makeup of the dividing cells. BRCA2 was discovered in 1995, shortly after the discovery of BRCA1. People who carry a mutation (harmful genetic code change) in BRCA2 are at increased risk of breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, and melanoma. The medical literature also shows a slightly increased risk of bone cancer, mouth cancer, pharygeal (throat) cancer, esophageal cancer, gallbladder cancer, bile duct cancer, eye cancer, and stomach cancer. Male breast cancer is significantly associated with a BRCA2 mutation.    

Functional assays for classification of BRCA2 variants of uncertain significance

AUTHORS: Daniel J Farrugia MD PhD, Agarwal MK, Pankratz VS, Deffenbaugh AM, Pruss D, Frye C, Wadum L, Johnson K, Mentlick J, Tavtigian SV, Goldgar DE, Couch FJ. ABSTRACT: The assessment of the influence of many rare BRCA2 missense mutations on cancer risk has proved difficult. A multifactorial likelihood model that predicts the odds of cancer causality for missense variants is effective, but is limited by the availability of family data. As an alternative, we developed functional assays that measure the influence of missense mutations on the ability of BRCA2 to repair DNA damage by homologous recombination and to control centriole amplification. We evaluated 22 missense mutations from the BRCA2 DNA binding domain (DBD) that were identified in multiple breast cancer families using these assays and compared the results with those from the likelihood model. Thirteen variants inactivated BRCA2 function in at least one assay; two others truncated BRCA2 by aberrant splicing; and seven had no effect on BRCA2 function. Of 10 variants with odds in favor of causality in the likelihood model of 50:1 or more and a posterior probability of pathogenicity of 0.99, eight inactivated BRCA2 function and the other two caused splicing defects. Four variants and four controls displaying odds in favor of neutrality of 50:1 and posterior probabilities of pathogenicity of at least 1 x 10(-3) had no effect on function in either assay. The strong correlation between the functional assays and likelihood model data suggests that these functional assays are an excellent method for identifying inactivating missense mutations in the BRCA2 DBD and that the assays may be a useful addition to models that predict the likelihood of cancer in carriers of missense mutations. Read the full article here.

Detection of Splicing Aberrations Caused by BRCA1 and BRCA2 Sequence Variants Encoding Missense Substitutions: Implications for Prediction of Pathogenicity


Logan C. Walker,* Phillip J. Whiley,* Fergus J. Couch, Daniel J. Farrugia, Sue Healey, Diana M. Eccles, Feng Lin, Samantha A. Butler, Sheila A. Goff, Bryony A. Thompson, Sunil R. Lakhani, Leonard M. Da Silva, kConFab Investigators, Sean V. Tavtigian, David E. Goldgar, Melissa A. Brown, and Amanda B. Spurdle


Missense substitutions in high-risk cancer susceptibility genes create clinical uncertainty in the genetic counseling process. Multifactorial likelihood classification approaches and in vitro assays are useful for the classification of exonic sequence variants in BRCA1 and BRCA2, but these currently rely on the assumption that changes in protein function are the major biological mechanism of pathogenicity. This study investigates the potentially pathogenic role of aberrant splicing for exonic variants predicted to encode missense substitutions using patient-derived RNA. No splicing aberrations were identified for BRCA1c.5054C>T and BRCA2c.7336A>G, c.8839G>A, and c.9154C>T. However, RT-PCR analysis identified a major splicing aberration for BRCA1c.4868C>G(p.Ala1623Gly), a variant encoding a missense substitution considered likely to be neutral. Splicing aberrations were also observed for BRCA2c.7988A>T(p.Glu2663Val) and c.8168A>G(p.Asp2723Gly), but both variant and wildtype alleles were shown to be present in full-length mRNA transcripts, suggesting that variant protein may be translated. BRCA2 protein function assays indicated that BRCA2p.Glu2663Val, p.Asp2723Gly and p.Arg3052Trp missense proteins have abrogated function consistent with pathogenicity. Multifactorial likelihood analysis provided evidence for pathogenicity for BRCA1 c.5054C>T(p.Thr1685Ile) and BRCA2c.7988A>T(p.Glu2663Val), c.8168A>G(p.Asp2723Gly) and c.9154C>T(p.Arg3052Trp), supporting experimentally derived evidence. These findings highlight the need for improved bioinformatic prediction of splicing aberrations and to refine multifactorial likelihood models used to assess clinical significance. Read the full article here.