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. 2024 Oct;131(6):1060-1067.
doi: 10.1038/s41416-024-02804-6. Epub 2024 Aug 2.

Copy number alterations in metastatic and early breast tumours: prognostic and acquired biomarkers of resistance to CDK4/6 inhibitors

Marie-Paule Sablin #  1 , Pierre Gestraud #  2 , Sarah Flora Jonas #  3   4 , Constance Lamy  1 , Magali Lacroix-Triki  5 , Thomas Bachelot  6 , Thomas Filleron  7 , Ludovic Lacroix  8   9 , Alicia Tran-Dien  10 , Pascal Jézéquel  11 , Marjorie Mauduit  12 , Janice Barros Monteiro  13 , Marta Jimenez  12 , Stefan Michiels  3   4 , Valery Attignon  14 , Isabelle Soubeyran  15 , Keltouma Driouch  16 , Nicolas Servant  2 , Christophe Le Tourneau  1   2 , Maud Kamal  1 , Fabrice André  17 , Ivan Bièche  18
Affiliations

Copy number alterations in metastatic and early breast tumours: prognostic and acquired biomarkers of resistance to CDK4/6 inhibitors

Marie-Paule Sablin et al. Br J Cancer. 2024 Oct.

Abstract

Background: Copy number alterations (CNA) are acquired during the evolution of cancers from their early stage to metastatic stage. This study aims at analysing the clinical value of the identified metastasis-associated CNAs both in metastatic breast cancers (mBCs) and early breast cancers (eBCs).

Methods: Single-nucleotide polymorphism (SNP)-array was performed on 926 biopsies from mBC patients, enrolled in SAFIR02-BREAST prospective trial. CNA profiles of eBCs from The Cancer Genome Atlas Breast Invasive Carcinoma (n = 770), Molecular Taxonomy of Breast Cancer International Consortium (n = 1620) and PACS04 trial (n = 243) cohorts were used as references for comparing mBCs and eBCs CNA profiles. Overall survival was the considered survival endpoint.

Results: Among the twenty-one genes frequently altered in ER + /HER2- mBCs: focal amplification of TERT was associated with poor outcome in the ER + /HER2- mBC population. Among the ER + /HER2- mBCs patients for whom CDK4/6 inhibitors information before biopsies collection was available: we identified seven genes on post-treatment biopsies, including the cyclin-dependent kinase 4 (CDK4), which was amplified in 9.8% of the ER + /HER2- mBCs pretreated population, as compared to 1.5% in the ER + /HER2- mBCs unpretreated population (P = 2.82E-04) as well as the 3 eBC populations. CDK4 amplification was associated with poor outcome in the ER + /HER2- eBCs.

Conclusions: This study provides insights into the biology of mBCs and identifies clinically useful genomic features for future improvement of breast cancer patient management.

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Conflict of interest statement

FA received research funding and served as speaker/advisor (compensated to the hospital) for Roche, AstraZeneca, Daiichi Sankyo, Pfizer, Novartis and Lilly. TB received research funding and served as speaker/advisor (compensated to the hospital) for Roche, Novartis, Pfizer, Seattle Genetic, Lilly and AstraZeneca. TF received research funding and served as speaker/advisor (compensated to the hospital) for Roche, Janssen, and Lilly. SM received Personal fees for DSMB or scientific committee study membership for Kedrion, Sensorion, Biophytis, Servier, Yuhan, Roche, outside the scope of the submitted work. CLT received research funding and served as speaker/advisor (compensated to the hospital) for Roche, Seattle Genetics, Rakuten, Nanobiotix, MSD, BMS, Merck Serono, AstraZeneca, GlaxoSmithKline, Novartis, Celgene, Exscientia, ALX Oncology and Seattle Genetics. The following authors have no disclosures: MPS, PG, SFJ, CL, MLT, LL, ATD, PJ, MM, MJ, VA, IS, KD, NS, MK and IB.

Figures

Fig. 1
Fig. 1. Study design.
Genes frequently altered in mBC and eBC populations in the ER + /HER2− or TNBC sub-populations.
Fig. 2
Fig. 2. Genes frequently altered in mBC and eBC populations in the ER + /HER2- or TNBC sub-populations.
a ER + /HER2− mBCs genes frequently altered in comparison to ER + /HER2− eBCs. b mTNBC genes frequently altered in comparison to eTNBC. c ER + /HER2- mBCs CDKi treatment before biopsies collection genes frequently altered in comparison to ER + /HER2− mBCs CDKi untreated before samples collection.
Fig. 3
Fig. 3. TERT amplification analysis in ER + /HER2− eBC and ER + /HER2− mBC.
a TERT amplification frequency (%). b Overall survival in univariable analysis in ER + /HER2− mBC. c Overall survival in multivariable analysis in ER + /HER2− mBC.
Fig. 4
Fig. 4. CDK4 amplification analysis in ER + /HER2- mBC and ER + /HER2− eBC.
a CDK4 amplification frequency (%) in ER + /HER2− mBC patients treated or not by CDK4/6i before samples collection and in ER + /HER2− eBC patients. b CDK4 RNA expression by real-time quantitative RT-PCR stratified according the CDK4 amplification status in ER + /HER2− mBC population. c Overall survival in univariable analysis in ER + /HER2− eBC. d Overall survival in multivariable analysis in ER + /HER2− eBC.
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