418P - Concordance of PI3K-AKT pathway alterations between tumor and ctDNA in metastatic breast cancer

Background

Circulating tumor DNA (ctDNA) next generation sequencing (NGS) allows for non-invasive detection of actionable genomic alterations (alts) and can overcome sampling bias due to tumor spatial heterogeneity. However, its performance can be affected by clinical and analytical factors. Considering the recent approval of capivasertib for HR+/HER2- metastatic breast cancer (MBC) harboring PI3K-AKT pathway alts based on tissue NGS, we assessed the concordance of tissue and ctDNA NGS for PIK3CA, AKT1, PTEN as well as ESR1.

Methods

We identified 367 HR+/HER2- MBC pts treated at MSK with tissue NGS by MSK-IMPACT within 60 days of ctDNA NGS by either Guardant360 or MSK-ACCESS, without intervening therapy. Only oncogenic alts per OncoKB were included in analyses. Test agreement was determined via Cohen’s kappa coefficient.

Results

Median interval between tissue and ctDNA collection was 15 days. Oncogenic alts in PIK3CA were detected in 39% of pts (n = 142; 69% tissue and ctDNA, 23% tissue, 8% ctDNA; 88% agreement, k = 0.73), AKT1 (predominantly E17K) in 4.9% of pts (n = 18; 61% both, 22% tissue, 17% ctDNA; 98% agreement, k = 0.75) and PTEN in 8.2% of pts (n = 30; 23% both, 60% tissue, 17% agreement, k = 0.35). Expectedly, ESR1 alts were more prevalent in ctDNA (n = 69; 54% in both, 13% tissue, 33% ctDNA; 91% agreement, k = 0.65). There was variability in agreement by alteration; PIK3CA H1047R had a higher concordance rate than E545K and E542K mutations. Agreement for PTEN SNVs and indels was relatively high, while both ctDNA assays were not able to detect PTEN homozygous deletions due to assay design. Polyclonality was more frequent in ctDNA mainly affecting ESR1 and certain PIK3CA mutations such as those associated with APOBEC mutagenesis (e.g. E542K, E545K).

Conclusions

Tissue-ctDNA concordance for the detection of any oncogenic alteration was high for PIK3CA, AKT1, moderate for ESR1, and low for PTEN. More alts were detected in ctDNA for ESR1 and in tissue for PTEN, reflecting acquired ESR1 alts after estrogen deprivation and the current lack of ctDNA assay PTEN copy number loss detection. Additional correlative analyses (e.g. agreement by ctDNA fraction, prior treatment exposure, sites of metastatic disease) will be presented.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

AstraZeneca.

Disclosure

A.R. Brannon: Financial Interests, Personal, Licencing Fees or royalty for IP, intellectual rights: SOPHiA Genetics; Financial Interests, Personal, Stocks/Shares: J&J. C. Weipert: Financial Interests, Personal, Full or part-time Employment: Guardant Health; Financial Interests, Personal, Stocks/Shares: Guardant Health. M. Chaki: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. M. Benrashid: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. S. Puri: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. S. Chandarlapaty: Financial Interests, Personal, Advisory Board: Novartis, AstraZeneca, Lilly, Effector Therapeutics, Nuvalent, SAGA Diagnostics, Neogenomics; Financial Interests, Personal, Stocks/Shares: Odyssey Biosciences, Effector Therapeutics, Totus Medicines; Financial Interests, Institutional, Research Grant: Daiichi Sankyo, Lilly, AstraZeneca. S.B. Maron: Financial Interests, Personal, Speaker, Consultant, Advisor: Novartis, Amgen, Elevation Oncology, Pinetree Therapeutics, Purple Oncology, Bolt Therapeutics, Daiichi Sankyo; Financial Interests, Institutional, Research Funding: Conquer Cancer Foundation, AstraZeneca, Paige.AI.; Financial Interests, Personal, Funding, research travel support: AstraZeneca. P. Razavi: Financial Interests, Personal, Advisory Board: Odyssey Biosciences, Myriad Genetics; Financial Interests, Personal, Advisory Role: Guardant Health, Paige.AI., SAGA Diagnostics, Tempus, Natera, Inivata, Foundation Medicine, Epic Sciences, Prelude Therapeutics, Lilly/Loxo, Pfizer, AstraZeneca, Novartis; Financial Interests, Institutional, Funding: Myriad Genetics, Personalis, Guardant Health, Biovica, Inivata, Tempus, Biotheranostics, Invitae/ArcherDx, Epic Sciences, AstraZeneca, Novartis, Illumina, Grail. All other authors have declared no conflicts of interest.