Tackling Refractory Metastatic Colorectal Cancer: Future Perspectives
by
, , ,
Nicola Personeni
1,2,†
,
Valeria Smiroldo
2,†,
Emilio Francesco Giunta
3,
Maria Giuseppina Prete
1,2,
Lorenza Rimassa
1,2,*
,
Giacomo Bregni
4,‡ and
Francesco Sclafani
4,‡ 1
Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Milan, Italy
2
Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Milan, Italy
3
Medical Oncology Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via Pansini 5, 80131 Naples, Italy
4
Department of Medical Oncology, Institut Jules Bordet–Université Libre de Bruxelles (ULB), Boulevard de Waterloo 121, 1000 Bruxelles, Belgium
*
Author to whom correspondence should be addressed.
†
N.P. and V.S. equally contributed to this work.
‡
G.B. and F.S. equally contributed to this work.
Cancers 2021, 13(18), 4506; https://doi.org/10.3390/cancers13184506
Submission received: 29 July 2021
/
Revised: 1 September 2021
/
Accepted: 1 September 2021
/
Published: 7 September 2021
(This article belongs to the Special Issue Targeted Therapies in Colorectal Cancer: What’s New?)
Simple Summary
Metastatic colorectal cancer (mCRC) accounts for relevant cancer-related morbidity and mortality. Novel investigations have reshaped the molecular makeup of mCRC, emphasizing a high degree of heterogeneity that can be leveraged to establish a new concept of biomarker-guided therapy. In contrast to the old-fashioned, “one-size-fits-all” therapeutic approach, within a precision oncology approach, a deeper molecular selection is indeed felt to improve the efficacy of targeted systemic treatments. Here, we review available treatment options in patients with refractory mCRC, who have already received chemotherapy regimens containing fluoropyrimidines, oxaliplatin, irinotecan, antiangiogenic agents, and, when indicated, epidermal growth factor receptor inhibitors. In addition, we examine those molecular pathways now included among the most promising areas of clinical research that will eventually drive innovative and more individualized treatment strategies.
Abstract
Substantial improvements have characterized the systemic treatment of metastatic colorectal cancer (mCRC) over the past 20 years. Besides strong evidence that supports the use of RAS and BRAF status as prognostic and predictive indicators of disease and response, novel technologies have made possible the incorporation of emerging biomarkers for the management of mCRC. On one hand, the discovery of point mutations, amplifications, fusions, and gene expression profiles highlights the genomic and dynamic complexity of CRC. On the other, such discoveries are leading to newer biomarker-driven strategies that add to existing anti-epidermal growth factor receptor (EGFR) and anti-angiogenic approaches. In addition, the availability of a wide molecular profiling has relevant implications for patient prognosis and treatment benefits. Here, we will review the molecular underpinnings and clinical data supporting novel targeted treatments under development for refractory mCRC harboring BRAF mutations, KRAS G12C mutations, HER2 amplification, and less common molecular alterations, such as the re-arrangements of NTRK, ALK, and ROS1. Additionally, we will discuss novel strategies driving the rechallenge of EGFR antibodies and the incorporation of newer anti-angiogenic agents in the therapeutic armamentarium.
