Neoadjuvant talazoparib in patients with germline BRCA1/2 mutation-positive, early-stage triple-negative breast cancer: exploration of tumor BRCA mutational status

• Published in: Breast cancer (Tokyo, Japan) Vol. 31; no. 5; pp. 886 - 897
• Main Authors: Telli, Melinda L., Litton, Jennifer K., Beck, J. Thaddeus, Jones, Jason M., Andersen, Jay, Mina, Lida A., Brig, Raymond, Danso, Michael, Yuan, Yuan, Symmans, William F., Hopkins, Julia F., Albacker, Lee A., Abbattista, Antonello, Noonan, Kay, Mata, Marielena, Laird, A. Douglas, Blum, Joanne L.
• Format: Journal Article
• Language: English
• Published: Singapore Springer Nature Singapore 01-09-2024
• Subjects: Adult; Aged; Biomarkers, Tumor - genetics; BRCA1 Protein - genetics; BRCA2 Protein - genetics; Cancer Research; Female; Germ-Line Mutation; Humans; Loss of Heterozygosity; Medicine; Medicine & Public Health; Middle Aged; Neoadjuvant Therapy - methods; Oncology; Original Article; Phthalazines - administration & dosage; Phthalazines - therapeutic use; Retrospective Studies; Surgery; Surgical Oncology; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - pathology; Neoadjuvant; Talazoparib; Triple-negative breast cancer; BRCA1; BRCA2
• ISSN: 1340-6868; 1880-4233; 1880-4233
• DOI: 10.1007/s12282-024-01603-4

Background
Talazoparib monotherapy in patients with germline
BRCA
-mutated, early-stage triple-negative breast cancer (TNBC) showed activity in the neoadjuvant setting in the phase II NEOTALA study (NCT03499353). These biomarker analyses further assessed the mutational landscape of the patients enrolled in the NEOTALA study.
Methods
Baseline tumor tissue from the NEOTALA study was tested retrospectively using FoundationOne
®
CDx. To further hypothesis-driven correlative analyses, agnostic heat-map visualizations of the FoundationOne
®
CDx tumor dataset were used to assess overall mutational landscape and identify additional candidate predictive biomarkers of response.
Results
All patients enrolled (
N
 = 61) had TNBC. In the biomarker analysis population, 75.0% (39/52) and 25.0% (13/52) of patients exhibited
BRCA1
and
BRCA2
mutations, respectively. Strong concordance (97.8%) was observed between tumor
BRCA
and germline
BRCA
mutations, and 90.5% (38/42) of patients with tumor
BRCA
mutations evaluable for somatic-germline-zygosity were predicted to exhibit
BRCA
loss of heterozygosity (LOH). No patients had non-
BRCA
germline DNA damage response (DDR) gene variants with known/likely pathogenicity, based on a panel of 14 non-
BRCA
DDR genes. Ninety-eight percent of patients had
TP53
mutations. Genomic LOH, assessed continuously or categorically, was not associated with response.
Conclusion
The results from this exploratory biomarker analysis support the central role of
BRCA
and
TP53
mutations in tumor pathobiology. Furthermore, these data support assessing germline
BRCA
mutational status for molecular eligibility for talazoparib in patients with TNBC.