End-of-neoadjuvant treatment circulating microRNAs and HER2-positive breast cancer patient prognosis: An exploratory analysis from NeoALTTO

Serena Di Cosimo; Chiara M Ciniselli; Sara Pizzamiglio; Vera Cappelletti; Marco Silvestri; Sarra El-Abed; Miguel Izquierdo; Mohammed Bajji; Paolo Nuciforo; Jens Huober; David Cameron; Stephen Chia; Henry L Gomez; Marilena V Iorio; Andrea Vingiani; Giancarlo Pruneri; Paolo Verderio

doi:10.3389/fonc.2022.1028825

End-of-neoadjuvant treatment circulating microRNAs and HER2-positive breast cancer patient prognosis: An exploratory analysis from NeoALTTO

Front Oncol. 2023 Jan 31:12:1028825. doi: 10.3389/fonc.2022.1028825. eCollection 2022.

Authors

Serena Di Cosimo¹, Chiara M Ciniselli², Sara Pizzamiglio², Vera Cappelletti¹, Marco Silvestri¹, Sarra El-Abed³, Miguel Izquierdo⁴, Mohammed Bajji⁵, Paolo Nuciforo⁶, Jens Huober^{7

8}, David Cameron⁹, Stephen Chia¹⁰, Henry L Gomez^{11

12}, Marilena V Iorio¹³, Andrea Vingiani¹, Giancarlo Pruneri¹, Paolo Verderio²

Affiliations

¹ Department of Advanced Diagnostics, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
² Unit of Bioinformatics and Biostatistics, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
³ Breast International Group, Brussels, Belgium.
⁴ Novartis Pharmaceutical, Basel, Switzerland.
⁵ Institut Jules Bordet and l'Université Libre de Bruxelles (U.LB), Bruxelles, Belgium.
⁶ Molecular Oncology Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
⁷ Breast Center, University of Ulm, Ulm, Germany.
⁸ Breast Center, Cantonal Hospital St.Gallen, St. Gallen, Switzerland.
⁹ University of Leeds, Leeds, United Kingdom.
¹⁰ University of British Columbia, Vancouver, BC, Canada.
¹¹ Department of Medical Oncology, Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru.
¹² Department of Medical Oncology, Universidad Ricardo Palma, Lima, Peru.
¹³ Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Abstract

Background: The absence of breast cancer cells in surgical specimens, i.e., pathological complete response (pCR), is widely recognized as a favorable prognostic factor after neoadjuvant therapy. In contrast, the presence of disease at surgery characterizes a prognostically heterogeneous group of patients. Here, we challenged circulating microRNAs (miRNAs) at the end of neoadjuvant therapy as potential prognostic biomarkers in the NeoALTTO study.

Methods: Patients treated within the trastuzumab arm (i.e., pre-operative weekly trastuzumab for 6 weeks followed by the addition of weekly paclitaxel for 12 weeks; post-operative FEC for 3 cycles followed by trastuzumab up to complete 1 year of treatment) were randomized into a training (n= 54) and testing (n= 72) set. RT-PCR-based high-throughput miRNA profile was performed on plasma samples collected at the end of neoadjuvant treatment of both sets. After normalization, circulating miRNAs associated with event free survival (EFS) were identified by univariate and multivariate Cox regression model.

Results: Starting from 23 circulating miRNAs associated with EFS in the training set, we generated a 3-circulating miRNA prognostic signature consisting of miR-185-5p, miR-146a-5p, miR-22-3p, which was confirmed in the testing set. The 3-circulating miRNA signature showed a C-statistic of 0.62 (95% confidence interval [95%CI] 0.53-0.71) in the entire study cohort. By resorting to a multivariate Cox regression model we found a statistical significant interaction between the expression values of miR-194-5p and pCR status (p.interaction =0.005) with an estimate Hazard Ratio (HR) of 1.83 (95%CI 1.14- 2.95) in patients with pCR, and 0.87 (95%CI 0.69-1.10) in those without pCR. Notably, the model including this interaction along with the abovementioned 3-circulating miRNA signature provided the highest discriminatory capability with a C-statistic of 0.67 (95%CI 0.58-0.76).

Conclusions: Circulating miRNAs are informative to identify patients with different prognosis among those with heterogeneous response after trastuzumab-based neoadjuvant treatment, and may be an exploitable tool to select candidates for salvage adjuvant therapy.

Keywords: HER2-positive breast cancer; MiR-194-5p; circulating microRNA; neoadjuvant treatment; prognosis.

Grants and funding

The NeoALTTO study was sponsored by GlaxoSmithKline; Lapatinib is an asset of Novartis AG as of March 2, 2015. This sub-study was supported by the Italian Ministry of Health to SC. No grant number is applicable, funds were obtained through a law that allows tax-payers to allocate the 5 × 1000 share of their payments to research.