2MO - Development of a prognostic gene-expression signature for early stage HER2-positive breast cancer patients

Background

With increasing evidence showing the complexity of HER2-positive breast cancer, this study aimed to identify a gene-expression signature with potential prognostic value to assist therapeutic decision in the early disease setting.

Methods

Gene-expression profiles of NeoALTTO tumor biopsies before and after 2 weeks of neoadjuvant treatment were generated by microarrays (Clariom S, ThermoFisher). Genes associated with event free survival (EFS) were selected at the two time points with Cox univariate analysis and combined by multivariate approaches. Independent technical and clinical validation were sought.

Results

Overall, 180 patients were analyzed (NeoALTTO cohort, median follow-up 6.7 yrs [IQR 6.1-6.8]; 53 events). The expression of 18 genes combined by principal component analysis (S18) was significantly associated with EFS in the trastuzumab (T)-arm (Hazard Ratio for each unit increment [HR] 2.4, 95%Confidence Interval [CI] 1.6-3.5) and in the entire NeoALTTO cohort (HR 1.7, CI 1.4-2.2). Notably, S18 showed no overlap with HER2 and/or ESR1 genes and/or their signaling. A more parsimonious signature of five genes (S5) was next developed. Both S18 and S5 retained their prognostic value independently of pathological complete response, age, tumor size, estrogen receptor and node status both in the T-arm and in the entire NeoALTTO cohort. The prognostic value of S18 was technically confirmed by RNAseq in the T-arm (HR 2.1, CI 1.4-3.1) and entire cohort (HR1.3, CI 1.03-1.7) whereas the S5 was confirmed within the T-arm alone (HR 1.5, CI 1.1-1.9). An additional technical validation is currently ongoing by customized open arrays. The prognostic capability of S18 was clinically confirmed by in silico analysis of the Italian GHEA expanded access study of adjuvant trastuzumab (HR 1.9,CI 1.2-2.9). Currently, we are seeking to validate the prognostic value of S5 in the NSABP B-31 study and results are expected to be presented at the congress.

Conclusions

These findings hold the potential to accurately identify patients with early HER2-positive breast cancer at low risk of relapse when treated with trastuzumab-based therapy and may be useful to select patients for single or dual anti-HER2 therapies.

Legal entity responsible for the study

Serena Di Cosimo.

Funding

Fondazione Associazione Italiana Ricerca contro il Cancro (AIRC) IG 20774 to Serena Di Cosimo.

Disclosure

Y. Wang: Financial Interests, Personal, Funding: Wang. All other authors have declared no conflicts of interest.