Germline alterations other than BRCA in triple negative breast cancer (TNBC) patients who underwent neoadjuvant therapy (NAT) on a prospective clinical trial.

Authors

Banu Arun

Banu Arun

The University of Texas MD Anderson Cancer Center, Houston, TX

Banu Arun , Li Zhao , Roland L. Bassett Jr., Alastair Mark Thompson , Jason B White , Rachel M. Layman , Angelica Gutierrez Barrera , Vicente Valero , Naoto T. Ueno , Jennifer Keating Litton , Jianhua Zhang , Elizabeth Ravenberg , Rosalind P Candelaria , Gaiane M Rauch , Debu Tripathy , Stacy L. Moulder

Organizations

The University of Texas MD Anderson Cancer Center, Houston, TX, Baylor College of Medicine, Houston, TX, The Ohio State University Medical Center James Comprehensive Cancer Center, Columbus, OH, Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX

Research Funding

No funding received
None

Background: Previous studies have related germline BRCA mutations to pathologic complete response (pCR) in TNBC cohorts. However, prospective data is lacking on the frequency of non-BRCA germline mutations and pCR in TNBC patients who received neoadjuvant therapy (NAT). The aim of this study was to describe germline alterations in comparison with pCR in a prospective cohort of TNBC receiving NAT. Methods: Pre-NAT blood was drawn from patients enrolled in a clinical trial of genomically tailored NAT (ARTEMIS: NCT: 02276443, per eligibility patients had to have negative clinical BRCA tetsing). Germline DNA was extracted and sequenced on a HiSeq4000 sequencer (Illumina, coverage 60X). Reads were aligned to human reference hg19. Variants were filtered against public databases of normal cohorts: esp6500, 1000 genome, ExAC with a frequency cutoff at 1% in any ethnicity. Two integrative scores were used to evaluate the deleteriousness of the missense variants and the variants predicted to be damaging by both scores were included in the analyses. A 105 pan-cancer susceptibility gene panel was selected based on literature data and commercially available gene panels. NAT included anthracycline and taxane based chemotherapy +/- targeted therapy based on tumor genomic expression. Univariate logistic regression models were used to fit pCR for individual mutations, excluding genes mutated in fewer than three patients. All statistical analyses were performed using R version 3.6.1. with a significance of p=0.05. Results: Germline results and pCR were available for 152 patients. Median age was 55 yrs (range: 24-77). 7.9% were stage (st) I, 65.8% st II, 26.3% st III. 55 pts (36%) had pan-cancer associated germline mutations, whereas 33 (21%) had a breast-cancer associated mutation. Greater than 1% mutations were seen in seventeen genes (Table). There was no significant difference in pCR rate after NAT among pts with different germline mutations versus without mutation. Conclusions: Breast cancer related germline mutations other than BRCA in TNBC are relatively common supporting at least a breast panel (not only BRCA1/2) testing. Treatment implications of different germline mutations and their impact on pCR is ongoing on an extended series.

Gene% posGene% posGene% pos
APC2.6MSH22SDHA2
BRIP11.3MSH61.3BRCA11.3
ERBB21.3MUTHY2.6TSC24
MITF1.3NTHL11.3WT11.3
MLH33.3PMS12XRCC31.3
PHB1.3PMS22

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Abstract Details

Meeting

2020 ASCO Virtual Scientific Program

Session Type

Poster Session

Session Title

Cancer Prevention, Risk Reduction, and Genetics

Track

Prevention, Risk Reduction, and Genetics

Sub Track

Cancer Genetics

Citation

J Clin Oncol 38: 2020 (suppl; abstr 1546)

DOI

10.1200/JCO.2020.38.15_suppl.1546

Abstract #

1546

Poster Bd #

38

Abstract Disclosures