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. 2022 Dec:86:104316.
doi: 10.1016/j.ebiom.2022.104316. Epub 2022 Nov 1.

Circulating tumour DNA characterisation of invasive lobular carcinoma in patients with metastatic breast cancer

Andrew A Davis  1 , Lorenzo Gerratana  2 , Katherine Clifton  1 , Arielle J Medford  3 , Marko Velimirovic  3 , Whitney L Hensing  1 , Leslie Bucheit  4 , Ami N Shah  5 , Paolo D'Amico  5 , Carolina Reduzzi  5 , Qiang Zhang  5 , Charles S Dai  6 , Elyssa N Denault  6 , Nusayba A Bagegni  1 , Mateusz Opyrchal  7 , Foluso O Ademuyiwa  1 , Ron Bose  1 , William J Gradishar  5 , Amir Behdad  5 , Cynthia X Ma  1 , Aditya Bardia  3 , Massimo Cristofanilli  8
Affiliations

Circulating tumour DNA characterisation of invasive lobular carcinoma in patients with metastatic breast cancer

Andrew A Davis et al. EBioMedicine. 2022 Dec.

Abstract

Background: Limited data exist to characterise molecular differences in circulating tumour DNA (ctDNA) for patients with invasive lobular carcinoma (ILC). We analysed metastatic breast cancer patients with ctDNA testing to assess genomic differences among patients with ILC, invasive ductal carcinoma (IDC), and mixed histology.

Methods: We retrospectively analysed 980 clinically annotated patients (121 ILC, 792 IDC, and 67 mixed histology) from three academic centers with ctDNA evaluation by Guardant360™. Single nucleotide variations (SNVs), copy number variations (CNVs), and oncogenic pathways were compared across histologies.

Findings: ILC was significantly associated with HR+ HER2 negative and HER2 low. SNVs were higher in patients with ILC compared to IDC or mixed histology (Mann Whitney U test, P < 0.05). In multivariable analysis, HR+ HER2 negative ILC was significantly associated with mutations in CDH1 (odds ratio (OR) 9.4, [95% CI 3.3-27.2]), ERBB2 (OR 3.6, [95% confidence interval (CI) 1.6-8.2]), and PTEN (OR 2.5, [95% CI 1.05-5.8]) genes. CDH1 mutations were not present in the mixed histology cohort. Mutations in the PI3K pathway genes (OR 1.76 95% CI [1.18-2.64]) were more common in patients with ILC. In an independent cohort of nearly 7000 metastatic breast cancer patients, CDH1 was significantly co-mutated with targetable alterations (PIK3CA, ERBB2) and mutations associated with endocrine resistance (ARID1A, NF1, RB1, ESR1, FGFR2) (Benjamini-Hochberg Procedure, all q < 0.05).

Interpretation: Evaluation of ctDNA revealed differences in pathogenic alterations and oncogenic pathways across breast cancer histologies with implications for histologic classification and precision medicine treatment.

Funding: Lynn Sage Cancer Research Foundation, OncoSET Precision Medicine Program, and UL1TR001422.

Keywords: Circulating tumour DNA; Genomics; Invasive lobular carcinoma; Metastatic breast cancer.

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Conflict of interest statement

Declaration of interests A. A. Davis reports participating in a scientific advisory board for Pfizer, Inc. L. Gerratana reports consulting fees from Eli Lilly & Co, Novartis, and AstraZeneca. K. Clifton reports research funding from the Cancer and Aging Research Group Pilot Grant outside this work and consulting fees from Biotheranostics. F. O. Ademuyiwa reports research funding from Pfizer, ImmunoMedics, NeoImmuneTech, RNA diagnostics, and Astellas. She reports fees from Teladoc Health, Pfizer, AstraZeneca, QED Therapeutics, Immunomedics, Cardinal Health, Athenex, and Biotheranostics. L. Bucheit is an employee of Guardant Health and has received stock/stock options in the company. A. Shah reports serving on an advisory board for AstraZeneca. P. D'Amico reports grants or contracts from Roche and the American Italian Cancer Foundation and planned employment with Merck. N. Bagegni reports institutional research support from Daiichi Sankyo, Seattle Genetics Inc., Sermonix, Xcovery Holding Company LLC, Pfizer, Inc., AstraZeneca, Sarah Cannon Development Innovations, Ambrx, and Novartis Pharmaceuticals outside this work. She has also received honoraria from OncLive. M. Opyrchal reports receiving grants from Bayer and Eli Lilly & Co outside this work and consulting fees from AstraZeneca and Novartis. R. Bose reports institutional research funding from Puma and consulting fees from Genentech. A. Behdad reports serving as a speaker or receiving honoraria from Foundation Medicine, China, Lily, Bayer, and Thermofisher Scientific. He also reports serving on an advisory board and receiving honoraria from Leica. C.X. Ma holds consultant or advisory roles from Puma, Pfizer, Seattle Genetics, AstraZeneca, Natera, Oncosignal, Olaris, Athenex, Eisai, Philips Electronics, Agendia, Biovica, Jacobio, Inivata, Sanofi, Bayer HealthCare, Eli Lilly, and Gilead. She has received honoraria from PlusOne Health GmbH and UpToDate. She has also received research funding from Pfizer and Puma Biotechnology. A. Bardia reports consulting or advisory roles with Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics/Gilead, Astra Zeneca/Daiichi Sankyo, and Eli Lilly. He reports research funding from Pfizer, Novartis, Genentech, Merck, Radius Health, ImmunoMedics/Gilead, AstraZeneca/Daiichi Sankyo, Phillips, Eli Lilly & Co, and Foundation Medicine outside this work. M. Cristofanilli reports consulting fees from AstraZeneca, Eli Lilly & Co, Ellipses, and Menarini. He has received honoraria from Pfizer and participated in advisory boards for Merck and AstraZeneca. The remaining authors report no conflicts of interest.

Figures

Fig. 1
Fig. 1
Landscape of detectable alterations in ctDNA in patients with ILC (a), IDC (b), and mixed (MXD) histologies (c). Incidence of alterations [copy number variations (CNV), fusions (Fus), deletions (Del), insertions (Ins), frameshift (FS), splicing variants (Spl), premature termination codons (PTC) and single nucleotide variation (SNV)] is represented on the left with ordered frequency based on the sum of all variants in a particular gene. The mutant allele frequency (MAF) of each mutation is shown in the middle. Effect [gain of function (GOF), loss of function (LOF) and switch of function (SOF)] and pathogenicity [yes, no, unknown (Ukn) and inconclusive (Inc)] of all the detected alterations are show on the right. The frequency of alterations is reflected as the number in parenthesis of the colour scale bar. N = 980.
Fig. 2
Fig. 2
Overall survival based on histology for patients with HR+ HER2 negative metastatic breast cancer. Overall survival (OS) was compared for patients across each histology. No significant differences were observed across patients with ILC, IDC, and MXD histologies (log-rank test; P = 0.98). N = 655.
Fig. 3
Fig. 3
Landscape of CDH1 mutations in blood and tissue and CDH1 co-mutations in blood.CDH1 mutations were assessed in nearly 7000 breast cancer patients using the 83-gene Guardant360™ with an observed frequency of 10.8% in blood (a) and 11.0% in tissue based on TCGA (b). Splice mutations were not included in the lollipop plots. The 10 most significant co-mutated alterations with CDH1 are shown (c). Synonymous alterations, variants of unknown significance, and germline alterations were removed for this analysis. Only the first ctDNA test was included for patients with multiple samples.
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