RESUMO
ABSTRACT: Recently, organ preservation with total neoadjuvant therapy resulted in substantial progress in the management of locally advanced rectal cancer (LARC). The PROSPECT trial showed noninferiority of de-escalation of radiotherapy for patients with low-risk LARC who do not need abdominoperineal resection. Although these escalation and de-escalation approaches offer more personalized therapeutic approaches, the current state of care for patients with rectal cancer is far from individualized management. Circulating tumor DNA (ctDNA) is known to be one of the most powerful prognostic factors for early relapse and has been investigated in several interventional clinical trials to offer more precise treatment algorithms. In this review article, we discuss recent updates from studies examining the role of ctDNA for the prediction of treatment response and recurrence for patients with rectal cancer. We also elaborate on the future potential use of ctDNA in treatment escalation and de-escalation approaches for more personalized therapeutic interventions.
Assuntos
Biomarcadores Tumorais , DNA Tumoral Circulante , Neoplasias Retais , Humanos , Neoplasias Retais/terapia , Neoplasias Retais/genética , Neoplasias Retais/sangue , Neoplasias Retais/diagnóstico , Neoplasias Retais/patologia , DNA Tumoral Circulante/sangue , Biomarcadores Tumorais/sangue , Terapia Neoadjuvante/métodos , Prognóstico , Recidiva Local de Neoplasia/genética , Medicina de Precisão/métodos , Gerenciamento Clínico , Resultado do TratamentoRESUMO
KRAS mutations are common driver oncogenes associated with the development of several solid tumors. KRAS oncogene has been considered a highly challenging target for drug development because of structural features, including the lack of deep groove on its catalytic unit. However, by leveraging cysteine residues, covalent KRAS inhibitors irreversibly trap KRAS G12C mutants in their inactive GDP-bound state. These agents have resulted in significant clinical responses among patients with KRAS G12C-mutant solid tumors, including patients with colorectal cancer (CRC). Other allele-specific inhibitors of KRAS oncogene and panKRAS and panRAS inhibitors are also currently being investigated in clinical trials. This review article overviews recent clinical progress on KRAS G12C targeting for the management of patients with KRAS G12C-mutant CRC and provides an update on other RAS targeting approaches. We also discuss the unique biological features of RAS-mutant CRC, which require the combination of KRAS inhibitors and anti-epidermal growth factor receptor therapy, and elaborate on resistance mechanisms and novel therapeutic avenues that may define future treatment paradigms of patients with RAS-mutant CRC.
RESUMO
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment paradigm of mismatch repair-deficient/microsatellite instability-high (MMMR-D/MSI-H) colorectal cancer (CRC). Unique molecular features of MMR-D/MSI-H CRC with frameshift alterations, which result in mutation-associated neoantigen (MANA) generation, create an ideal molecular framework for MANA-driven T-cell priming and antitumor immunity. These biologic characteristics of MMR-D/MSI-H CRC resulted in rapid drug development with ICIs for patients with MMR-D/MSI-H CRC. Observed deep and durable responses with the use of ICIs in advanced-stage disease have stimulated the development of clinical trials with ICIs for patients with early-stage MMR-D/MSI-H CRC. Most recently, neoadjuvant dostarlimab monotherapy for nonoperative management of MMR-D/MSI-H rectal cancer and neoadjuvant NICHE trial with nivolumab and ipilimumab for MMR-D/MSI-H colon cancer resulted in groundbreaking results. Although nonoperative management of patients with MMR-D/MSI-H rectal cancer with ICIs will potentially define our current therapeutic approach, therapeutic goals of neoadjuvant ICI therapy for patients with MMR-D/MSI-H colon cancer may differ given that nonoperative management has not been well established for colon cancer. Herein, we overview recent advancements in ICI-based therapies for patients with early-stage MMR-D/MSI-H colon and rectal cancer and elaborate on the future treatment paradigm of this unique subgroup of CRC.