BRAFV600E-Mutant Metastatic Colorectal Cancer: Current Evidence, Future Directions, and Research Priorities.

BRAFV600E-mutant metastatic colorectal cancer represents a distinct molecular phenotype known for its aggressive biological behavior, resistance to standard therapies, and poor survival rates. Improved understanding of the biology of the BRAF oncogene has led to the development of targeted therapies that have paved the way for a paradigm shift in managing this disease. However, despite significant recent advancements, responses to targeted therapies are short-lived, and several challenges remain. In this review, we discuss how progress in treating BRAFV600E-mutant metastatic colorectal cancer has been made through a better understanding of its unique biological and clinical features. We provide an overview of the evidence to support current treatment approaches and discuss critical areas of need and future research strategies that hold the potential to refine clinical practice further. We also discuss some challenging aspects of managing this disease, particularly the complexity of acquired resistance mechanisms that develop under the selective pressure of targeted therapies and rational strategies being investigated to overcome them.

Adjuvant Chemotherapy for Older Patients With Stage III Colorectal Cancer: A Real-World Analysis of Treatment Recommendations, Treatment Administered and Impact on Cancer Recurrence.

BACKGROUND: A substantial proportion of patients with stage III colorectal cancer (CRC) are older than 70 years. Optimal adjuvant chemotherapy (AC) for older patients (OP) continues to be debated, with subgroup analyses of randomized trials not demonstrating a survival benefit from the addition of oxaliplatin to a fluoropyrimidine backbone. PATIENTS AND METHODS: We analyzed the multisite Australian ACCORD registry, which prospectively collects patient, tumor and treatment data along with long term clinical follow-up. We compared OP (≥70) with stage III CRC to younger patients ([YP] <70), including the proportion recommended AC and any reasons for not prescribing AC. AC administration, regimen choice, completion rates, and survival outcomes were also examined. RESULTS: One thousand five hundred twelve patients enrolled in the ACCORD registry from 2005 to 2018 were included. Median follow-up was 57.0 months. Compared to the 827 YP, the 685 OP were less likely to be offered AC (71.5% vs. 96.5%, P < .0001) and when offered, were more likely to decline treatment (15.1% vs. 2.8%, P < .0001). Ultimately, 60.0% of OP and 93.7% of YP received AC (P < .0001). OP were less likely to receive oxaliplatin (27.5% vs. 84.7%, P < .0001) and to complete AC (75.9% vs. 85.7%, P < .0001). The probability of remaining recurrence-free was significantly higher in OP who received AC compared to those not treated (HR 0.73, P = .04) but not significantly improved with the addition of oxaliplatin (HR 0.75, P = .18). CONCLUSION: OP were less likely than YP to receive AC. Receipt of AC reduced recurrences in OP, supporting its use, although no significant benefit was observed from the addition of oxaliplatin.

Circulating tumour DNA in the evolving treatment landscape of locally advanced rectal cancer: where does it fit in?

The management of locally advanced rectal cancer (LARC) requires multimodality treatment, typically with neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision. However, the treatment landscape is rapidly evolving with total neoadjuvant therapy and non-operative management for selected patients emerging as other novel treatment approaches. With so many treatment options, there is a need for biomarkers to direct a more personalised treatment strategy for patients with LARC. In this review, we summarise the available data regarding the use of circulating tumour DNA (ctDNA) in patients with LARC, as both a marker of treatment response to neoadjuvant therapy and as a marker of minimal residual disease (MRD) after patients have completed definitive local treatment. To date, the ability of ctDNA status to predict for pathologic complete response at any timepoint during multimodality treatment has been variably reported. The most consistent finding across available studies is the ability of ctDNA to detect MRD after CRT and surgery, the presence of which confers a significantly poor prognosis, with increased risk of cancer recurrence and worse overall survival. It is yet to be determined if providing additional therapies to patients with MRD improves outcomes. The available studies assessing the potential utility of ctDNA in LARC are limited by significant heterogeneity in the choice of ctDNA assay, timepoint at which ctDNA was collected, treatment that patients received and length of follow-up, leading to uncertainties about how to implement it into daily clinical practice. As the treatment landscape evolves, larger randomised trials assessing the role of ctDNA in LARC are needed.

Circulating Tumour DNA and Colorectal Cancer: the Next Revolutionary Biomarker?

PURPOSE OF REVIEW: Improving outcomes for patients with colorectal cancer in both the adjuvant and metastatic setting has been challenging. Here, we review the current and future directions for using ctDNA in clinical practice. RECENT FINDINGS: Circulating tumour DNA (ctDNA) with its ability to detect minimal residual disease is beginning to refine the way we assess recurrence risk in the adjuvant setting. We can potentially tailor treatments to reduce recurrence risk and minimize treatment toxicity. In the metastatic setting, ctDNA can provide a less invasive method of detecting clinically important genetic changes to guide molecularly targeted treatment and to identify mechanisms of molecular resistance. ctDNA can be a surrogate marker for treatment response and help guide the timing of anti-EGFR rechallenge. We await the results of the randomized clinical trials assessing clinical utility of ctDNA in both the adjuvant and metastatic setting before incorporating ctDNA into clinical practice.

Intracranial response after extracranial radiation in a patient with rapidly progressing metastatic melanoma.

Growing literature supports the synergistic effect of radiation as a primer for renewed enhanced systemic immunological responses in patients receiving immunotherapy for metastatic melanoma. Radiographic regression of extracranial tumours after treatment of intracranial metastatic lesions has been reported and these observations point to an abscopal effect that traverses the blood-brain barrier. We describe a patient with rapidly progressing metastatic melanoma despite combined immune checkpoint blockade, who achieved a complete metabolic response of both his extracranial and intracranial disease after the commencement of palliative radiation to his axilla. This is the first published case, to our knowledge, of a sustained, complete intracranial abscopal response from extracranial radiation. We discuss potential mechanistic relations between radiation, the blood-brain barrier and the abscopal effect.

Routine Blood Tests in Asymptomatic Patients With Indolent Lymphoma Have Limited Ability to Detect Clinically Significant Disease Progression.

PURPOSE: Patients with indolent non-Hodgkin lymphoma (iNHL) undergo regular active surveillance in between treatment periods to detect disease relapse or progression. As part of surveillance, international guidelines recommend regular routine blood testing, which is based on consensus rather than evidence of utility. METHODS: We conducted a retrospective analysis of all patients older than age 16 years diagnosed with grade 1-3A follicular or marginal zone lymphoma between 2008 and 2017 from 2 Australian cancer centers to assess the utility of full blood examination, lactate dehydrogenase, and ß2-microglobulin in detecting progression events, defined as either disease relapse or progression of disease. RESULTS: One hundred eighty patients attended 1,757 outpatient appointments (median follow-up, 36 months). Routine blood tests (RBTs) were performed before 83% of appointments. Seventy-four progression events occurred in 62 patients. Only 2 events (3%) were detected by RBTs alone, both of which occurred in treatment-naïve patients who subsequently developed symptoms within 3 weeks. The remainder of progression events were suspected clinically (88%) or detected by imaging (9%). RBT results were frequently abnormal in asymptomatic patients (19%), with abnormal results leading to either additional investigations or an increased surveillance frequency in 8% of cases. The overall sensitivity and positive predictive value of abnormal RBT results in detecting progression events were 39% and 9%, respectively. CONCLUSION: RBTs have poor performance characteristics and rarely detect clinically significant disease progression or relapse in asymptomatic patients with iNHL.