A Pilot, Prospective, Observational Study to Investigate the Value of NGS in Liquid Biopsies to Predict Tumor Response After Neoadjuvant Chemo-Radiotherapy in Patients With Locally Advanced Rectal Cancer: The LiBReCa Study

Raffaello Roesel; Samantha Epistolio; Francesca Molinari; Piercarlo Saletti; Sara De Dosso; Mariacarla Valli; Alessandra Franzetti-Pellanda; Letizia Deantonio; Maira Biggiogero; Paolo Spina; Sotirios Georgios Popeskou; Alessandra Cristaudi; Francesco Mongelli; Luca Mazzucchelli; Federico Mattia Stefanini; Milo Frattini; Dimitri Christoforidis

doi:10.3389/fonc.2022.900945

A Pilot, Prospective, Observational Study to Investigate the Value of NGS in Liquid Biopsies to Predict Tumor Response After Neoadjuvant Chemo-Radiotherapy in Patients With Locally Advanced Rectal Cancer: The LiBReCa Study

Front Oncol. 2022 Jun 28:12:900945. doi: 10.3389/fonc.2022.900945. eCollection 2022.

Authors

Raffaello Roesel¹, Samantha Epistolio², Francesca Molinari², Piercarlo Saletti^{3

4

5}, Sara De Dosso^{5

6}, Mariacarla Valli⁷, Alessandra Franzetti-Pellanda⁸, Letizia Deantonio^{5

7}, Maira Biggiogero³, Paolo Spina^{2

9}, Sotirios Georgios Popeskou¹, Alessandra Cristaudi¹, Francesco Mongelli¹, Luca Mazzucchelli^{2

5}, Federico Mattia Stefanini¹⁰, Milo Frattini², Dimitri Christoforidis^{1

5

11}

Affiliations

¹ Department of Visceral Surgery, Regional Hospital of Lugano, Ente Ospedaliero Cantonale, Lugano, Switzerland.
² Istituto Cantonale di Patologia, Ente Ospedaliero Cantonale, Locarno, Switzerland.
³ Clinical Research Unit, Clinica Luganese Moncucco, Lugano, Switzerland.
⁴ Medical Oncology Clinic, Clinica Luganese Moncucco, Lugano, Switzerland.
⁵ Faculty of Biomedical Sciences, University of Southern Switzerland, Lugano, Switzerland.
⁶ Istituto Oncologico della Svizzera Italiana, Ente Ospedaliero Cantonale, Bellinzona, Switzerland.
⁷ Radiation Oncology Clinic, Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland.
⁸ Service of Radiotherapy, Clinica Luganese Moncucco, Lugano, Switzerland.
⁹ Department of Health Sciences, University of Eastern Piedmont, Novara, Italy.
¹⁰ Faculty of Science and Technology-ESP, University of Milan, Milano, Italy.
¹¹ Department of Visceral Surgery, Lausanne University Hospital, Lausanne, Switzerland.

Abstract

Introduction: Circulating tumor DNA (ctDNA) correlates with the response to therapy in different types of cancer. However, in patients with locally advanced rectal cancer (LARC), little is known about how ctDNA levels change with neoadjuvant chemoradiation (Na-ChRT) and how they correlate with treatment response. This work aimed to explore the value of serial liquid biopsies in monitoring response after Na-ChRT with the hypothesis that this could become a reliable biomarker to identify patients with a complete response, candidates for non-operative management.

Materials and methods: Twenty-five consecutive LARC patients undergoing long-term Na-ChRT therapy were included. Applying next-generation sequencing (NGS), we characterized DNA extracted from formalin-fixed paraffin embedded diagnostic biopsy and resection tissue and plasma ctDNA collected at the following time points: the first and last days of radiotherapy (T₀, T_end), at 4 (T₄), 7 (T₇) weeks after radiotherapy, on the day of surgery (T_op), and 3-7 days after surgery (T_post-op). On the day of surgery, a mesenteric vein sample was also collected (T_IMV). The relationship between the ctDNA at those time-points and the tumor regression grade (TRG) of the surgical specimen was statistically explored.

Results: We found no association between the disappearance of ctDNA mutations in plasma samples and pathological complete response (TRG1) as ctDNA was undetectable in the majority of patients from Tend on. However, we observed that the poor (TRG 4) response to Na-ChRT was significantly associated with a positive liquid biopsy at the T_op.

Conclusions: ctDNA evaluation by NGS technology may identify LARC patients with poor response to Na-ChRT. In contrast, this technique does not seem useful for identifying patients prone to developing a complete response.

Keywords: LARC; circulating tumor DNA (ctDNA); liquid biopsy; next-generation sequencing; rectal cancer (RC); watch and wait approach.

Copyright © 2022 Roesel, Epistolio, Molinari, Saletti, De Dosso, Valli, Franzetti-Pellanda, Deantonio, Biggiogero, Spina, Popeskou, Cristaudi, Mongelli, Mazzucchelli, Stefanini, Frattini and Christoforidis.