Sequential profiling of plasma cell-free DNA (cfDNA) holds immense promise for early detection of patient progression. However, how to exploit the predictive power of cfDNA as a liquid biopsy in the clinic remains unclear. RAS pathway aberrations can be tracked in cfDNA to monitor resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer. In this prospective phase II clinical trial of single-agent cetuximab in wild-type patients, we combine genomic profiling of serial cfDNA and matched sequential tissue biopsies with imaging and mathematical modeling of cancer evolution. We show that a significant proportion of patients defined as wild-type based on diagnostic tissue analysis harbor aberrations in the RAS pathway in pretreatment cfDNA and, in fact, do not benefit from EGFR inhibition. We demonstrate that primary and acquired resistance to cetuximab are often of polyclonal nature, and these dynamics can be observed in tissue and plasma. Furthermore, evolutionary modeling combined with frequent serial sampling of cfDNA allows prediction of the expected time to treatment failure in individual patients. This study demonstrates how integrating frequently sampled longitudinal liquid biopsies with a mathematical framework of tumor evolution allows individualized quantitative forecasting of progression, providing novel opportunities for adaptive personalized therapies. Liquid biopsies capture spatial and temporal heterogeneity underpinning resistance to anti-EGFR monoclonal antibodies in colorectal cancer. Dense serial sampling is needed to predict the time to treatment failure and generate a window of opportunity for intervention. .

There are limited data on circulating, cell-free, tumour (ct)DNA analysis in locally advanced rectal cancer (LARC). Digital droplet (dd)PCR was used to investigate KRAS/BRAF mutations in ctDNA from baseline blood samples of 97 LARC patients who were treated with CAPOX followed by chemoradiotherapy, surgery and adjuvant CAPOX ± cetuximab in a randomised phase II trial. KRAS mutation in G12D, G12V or G13D was detected in the ctDNA of 43% and 35% of patients with tumours that were mutant and wild-type for these hotspot mutations, respectively, according to standard PCR-based analyses on tissue. The detection rate in the ctDNA of 10 patients with less common mutations was 50%. In 26 cases ctDNA analysis revealed KRAS mutations that were not previously found in tissue. Twenty-two of these (84.6%) were detected following repeat tissue testing by ddPCR. Overall, the ctDNA detection rate in the KRAS mutant population was 66%. Detection of KRAS mutation in ctDNA failed to predict prognosis or refine patient selection for cetuximab. While this study confirms the feasibility of ctDNA analysis in LARC and the high sensitivity of ddPCR, larger series are needed to better address the role of ctDNA as a prognostic or predictive tool in this setting.

Introduction Coronavirus disease 2019 (COVID-19) has disrupted the global health care system since March 2020. Lung cancer (LC) patients (pts) represent a vulnerable population highly affected by the pandemic. This multicenter Italian study aimed to evaluate whether the COVID-19 outbreak impacted on access to cancer diagnosis and treatment for LC pts compared to pre-pandemic time. Methods Consecutive newly diagnosed LC pts referred to 25 Italian Oncology Departments between March and December 2020 were included. Access rate and temporal intervals between date of symptoms onset and diagnostic and therapeutic services were compared to the same period in 2019. Differences between the two years were analyzed using chi-square test for categorical variables and Mann-Whitney U test for continuous variables. Results A slight reduction (-6.9%) in newly diagnosed LC cases was observed in 2020 compared with 2019 (1523 vs 1637, p=0.09). Newly LC pts in 2020 were more likely to be diagnosed with stage IV disease (p<0.01) and to be current smokers (p<0.01). The drop in terms of new diagnoses was greater in the lockdown period (percentage drop -12% vs -3.2%) compared to the other months included. More LC pts referred to low/medium volume hospital in 2020 compared to 2019 (p=0.01). No differences emerged in terms of interval between symptoms onset and radiological diagnosis (p=0.94), symptoms onset and cytohistological diagnosis (p=0.92), symptoms onset and treatment start (p=0.40), treatment start and first radiological revaluation (p=0.36). Conclusions Our study pointed out a reduction of new diagnoses with a shift towards higher stage at diagnosis for LC pts in 2020. Despite this, the measures adopted by Italian Oncology Departments ensured the maintenance of the diagnostic-therapeutic pathways of LC pts.

Over the years, a growing body of literature has confirmed as beneficial the implementation of a multidisciplinary approach in the so-often-intricate scenario of cancer patients' management. Together with the consolidation of tumor-board experience in clinical practice, certain aspects have emerged as controversial and a source of current debate. In this systematic literature review, we focused our attention on the impact of multidisciplinary tumor boards, assessing benefits and limitations as a result of the dissemination of such approaches. On the bright side, adherence to clinical guidelines, treatment outcomes, and overall improvement in decision-making processes have been recognized as advantages. On the other side, our analysis highlights a few limitations that should be taken into account to optimize cancer patients' management. Of note, some issues, such as costs, legal responsibility, geographic barriers, and treatment delays, have yet to be resolved. In order partly to address this matter, software platforms and novel methods of computational analysis may provide the needed support. Therefore, the aim of our analysis was to describe the multidisciplinary approach in cancer care in terms of adherence to clinical guidelines, treatment outcomes, and overall improvement in decision-making processes through a systematic review of the literature.