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Proffered Paper session: Breast cancer, metastatic

210O - Mutational signature analysis reveals patterns of genomic instability linked to resistance to endocrine therapy (ET) +/- CDK 4/6 inhibition (CDK4/6i) in estrogen receptor-positive/HER2-negative (ER+/HER2-) metastatic breast cancer (MBC)


09 Sep 2022


Proffered Paper session: Breast cancer, metastatic


Cancer Biology;  Endocrine Therapy;  Targeted Therapy

Tumour Site

Breast Cancer


Antonio Marra


Annals of Oncology (2022) 33 (suppl_7): S88-S121. 10.1016/annonc/annonc1040


A. Marra1, A. Gazzo1, A. Gupta2, P. Selenica1, E.M. Da Silva1, F. Pareja1, X. Pei3, Y. Zhu1, P. Razavi4, A. Safonov4, E. Ferraro4, R. Harris5, N. Riaz3, J.S. Reis-Filho1, S. Chandarlapaty4

Author affiliations

  • 1 Department Of Pathology, Memorial Sloan Kettering Cancer Center, 10065 - New York/US
  • 2 Human Oncology And Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 10065 - New York/US
  • 3 Department Of Radiation Oncology, Memorial Sloan Kettering Cancer Center, 10065 - New York/US
  • 4 Breast Medicine Service, Department Of Medicine, Memorial Sloan Kettering Cancer Center, 10065 - New York/US
  • 5 Department Of Biochemistry, Molecular Biology And Biophysics, University of Minnesota, 55455 - Minneapolis/US


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Abstract 210O


APOBEC mutagenesis is enriched in MBCs. The predictive role of APOBEC and other mutational processes on standard regimens in the MBC setting is largely unknown.


We retrieved clinical and genomic data of 4,595 BCs that underwent targeted sequencing by an FDA-cleared panel comprising >400 genes. Mutational signatures were computed by the SigMA algorithm for samples with at least 5 single nucleotide variants and manually reviewed. BCs were classified as APOBEC+, HRD+ or APOBEC-/HRD- based on the dominant mutational process as defined by SigMA. Progression-free survival (PFS) to any line (L) of therapy was assessed using univariate and multivariate Cox models.


APOBEC+ and HRD+ were found at higher proportion in MBCs than in primary tumors (24% and 24% vs 15% and 13%; p<0.001). APOBEC+ were highly represented in ER+/HER2- (19%) and HER2+ (47%) subtypes, while HRD+ in triple-negative (36%). Lobular BCs had a higher proportion of APOBEC+ than HRD+ and APOBEC-/HRD- (34% vs 10% vs 21%, p<0.001). ER+/HER2- MBCs with APOBEC displayed lower ESR1 hotspot mutations (p<0.001). Survival analyses were restricted to patients with available pre-treatment samples. In ER+/HER2- MBCs treated with 1L or 2L ET monotherapy (n=395), APOBEC+ tumors were independently associated to shorter mPFS (HR 1.6, 95%CI 1.2-2.2, p=0.001), regardless of the ET agent. APOBEC+ and HRD+ MBCs were associated with lower mPFS on 1L CDK4/6i+ET (n=419) than APOBEC-/HRD- (HR 1.5, 95%CI 1.1-2, p=0.01 and HR 1.7, 95%CI 1.2-2.5, p=0.006, respectively), regardless of ET partner. HRD+ BCs had a reduced mPFS on 2L (n=207) and 3L (n=372) of CDK4/6i+ET (HR 2.1, 95%CI 1-4.1, p=0.03 and HR 1.8, 95%CI 1.3-2.5, p=0.001, respectively).


Patients with APOBEC+ and HRD+ ER+/HER2- MBCs experience shorter survival on ET +/- CDK4/6i, suggesting that the genomic instability conferred by APOBEC and HRD results in early resistance. Novel treatments tailored on these BC subgroups are needed. Additional genomic analyses to unravel mutational patterns related to APOBEC and HRD in this setting are underway.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Memorial Sloan Kettering Cancer Center.


Has not received any funding.


P. Razavi: Financial Interests, Personal, Advisory Board: Novartis, AstraZeneca, Foundation Medicine, Natera, Epic Science, Inivata; Financial Interests, Institutional, Funding: Grail Inc, Novartis; Non-Financial Interests, Advisory Role: Tempus. N. Riaz: Financial Interests, Personal and Institutional, Funding, Research support: REPARE Therapeutics, Repertoire Immune Medicines, Pfizer, BMS. J.S. Reis-Filho: Financial Interests, Personal, Other, Consultant: Goldman Sachs, Eli Lilly; Financial Interests, Personal, Other, Member of the Scientific Advisory Board and Consultant: Repare Therapeutics, Paige.AI; Financial Interests, Personal, Advisory Board: Personalis, Roche Tissue Diagnostics; Financial Interests, Personal, Invited Speaker: Grupo Oncoclinicas; Financial Interests, Personal, Stocks/Shares: Repare Therapeutics; Financial Interests, Personal, Other, Stock options: Paige.AI. S. Chandarlapaty: Financial Interests, Personal, Advisory Board: Sanofi, Lilly, Novartis, Inivata, AstraZeneca, Ultivue, Totus Medicines; Financial Interests, Institutional, Research Grant: Daiichi Sankyo, Paige.ai, AstraZeneca; Financial Interests, Institutional, Invited Speaker: Lilly, Novartis, Sanofi. All other authors have declared no conflicts of interest.

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