491P - Comparison of ctDNA profiles from HR+/HER2-low and HR+/HER2-0 advanced breast cancer patients

Background

Despite the substantial progress in systemic treatment of hormone receptor-positive (HR+) breast cancer, a significant proportion of patients has dismal prognosis. A meaningful proportion of these patients has HER2-low disease. Circulating tumor DNA (ctDNA) profiles between HER2-low and HER2-0 have not yet been comprehensively investigated.

Methods

67 plasma samples from 59 metastatic breast cancer patients (HR+/HER2-low, n=53; HR+/HER2-0, n=14) were collected either before starting 1^st line or 2^nd line treatment. Tumor fractions were assessed using an untargeted aneuploidy screening and expressed as z-scores (mFAST-SeqS). The mutational landscape of ctDNA was established using a 77-gene panel (AVENIO ctDNA Expanded). Tumor fractions, the number of somatic variants and variant allele frequencies (VAF) were compared between HER2-low and HER2-0 patients.

Results

HER2-low patients had significantly higher z-scores compared to HER2-0 patients (median 3.22 vs. 1.65, rank-sum p-value 0.025). In contrast, neither the highest nor the average VAF differed significantly between the two groups. HER2-low patients had a median of 3 detected variants (range 1-20), with a median of 2 clonal (range 0-9) and 1 subclonal (range 0-19) variants. HER2-0 patients presented with a median of 5 variants (range 1-12), including a median of 3 clonal (range 1-4) and 1 subclonal (range 0-8) variants. In contrast to previous reports, PIK3CA mutations were more prevalent in HER2-0 patients (57.1%) compared to HER2-low patients (35.8%), whereas TP53 mutations were identified at the same extent with 28.6% in HER2-0 and 22.6% in HER2-low patients.

Conclusions

Our results suggest a significant difference in the tumor fractions in plasma between HER2-0 and HER2-low patients. Moreover, the mutational landscape of our cohort revealed differences from previous reports, indicating that further investigations are needed to elucidate and establish the distinct features of HER2-low breast tumors.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Medical University of Graz.

Funding

AstraZeneca / Daiichi Sankyo.

Disclosure

N. Dandachi: Financial Interests, Personal, Other, travel support: Daiichi Sankyo. E.V. Klocker: Financial Interests, Institutional, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: AstraZeneca, Eli Lilly, Novartis; Financial Interests, Personal, Other, Travel fee: Daiichi Sankyo, Gilead; Financial Interests, Institutional, Other, Travel fee: Pierre Fabre. C. Suppan: Financial Interests, Personal, Advisory Board: Lilly, Pfizer, Novartis, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Roche, Pierre Fabre, AstraZeneca. P.J. Jost: Financial Interests, Personal, Advisory Board: Ariad, AbbVie, Bayer, Novartis, Pfizer, Servier, Roche, BMS and Celgene, CBmed, Janssen; Financial Interests, Personal, Invited Speaker: Boehringer; Financial Interests, Personal, Other, Travel Support: Pierre Fabre; Financial Interests, Personal, Stocks/Shares: Daiichi; Financial Interests, Personal, Royalties, Minimal contribution to Venetoclax patent: The Walter and Eliza Hall Institute; Financial Interests, Institutional, Funding: Boehringer Ingelheim Abbvie, Novartis. E. Heitzer: Financial Interests, Institutional, Research Funding: Servier, Freenome, PreAnalytixX; Financial Interests, Personal, Advisory Board: AstraZeneca, Roche Diagnostics; Financial Interests, Institutional, Product Samples, Provision of reagents: Roche Diagnostics, Illumina. M. Balic: Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, Daiichi Sankyo, MSD, Pierre FABRE, Pfizer, Roche, Gilead; Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo, Eli Lilly, MSD, Novartis, Novartis, Pierre Fabre, Pfizer, Roche, Gilead; Financial Interests, Personal and Institutional, Coordinating PI: AstraZeneca; Financial Interests, Personal, Coordinating PI, Steering Committee Member, Coordinating PI, Advisory role: Roche; Financial Interests, Institutional, Local PI: Roche, MSD, Qiagen, Amgen, Gilead; Financial Interests, Institutional, Coordinating PI: Austrian Breast and Colorectal Cancer Study Group, Pierre FABRE, Novartis, Pfizer. All other authors have declared no conflicts of interest.