Yongjun Cha

The evolutionary dynamics of cancer genomes at single-cell resolution under therapeutic pressure remain elusive. Hence, we perform whole-genome sequencing of 58 single-cell-derived tumoroids and 18 matched bulk tumors from six patients with metastatic colorectal cancer. High-resolution phylogenies reveal the clonal evolution of cancer with quantitative and qualitative profiling of therapy-associated mutations at the single-cell level. We uncover pronounced inter- and intra-patient heterogeneity in burden and spectrum of chemotherapy-induced mutations, with preferential enrichment in more proliferative lineages, highlighting differential mutagenic effects across co-existing cancer cell populations. Late-stage mutational trajectories uncover strikingly dynamic genomic alterations, including complex structural variants, extrachromosomal DNA amplifications, and LINE-1 retrotranspositions, often involving alterations in cancer driver genes. Together, we show the clonal architecture and mutational landscapes of advanced cancers under therapeutic pressure, providing an important foundation for future studies of late-stage cancer evolution under therapies.

In recent years, next-generation sequencing (NGS)–based genetic testing has become crucial in cancer care. While its primary objective is to identify actionable genetic alterations to guide treatment decisions, its scope has broadened to encompass aiding in pathological diagnosis and exploring resistance mechanisms. With the ongoing expansion in NGS application and reliance, a compelling necessity arises for expert consensus on its application in solid cancers. To address this demand, the forthcoming recommendations not only provide pragmatic guidance for the clinical use of NGS but also systematically classify actionable genes based on specific cancer types. Additionally, these recommendations will incorporate expert perspectives on crucial biomarkers, ensuring informed decisions regarding circulating tumor DNA panel testing.

Plasma circulating tumor DNA (ctDNA) sequencing has demonstrated clinical utility for tumor molecular profiling at initial diagnosis or tumor progression in advanced solid cancers and is being rapidly incorporated into the clinical practice guidelines, including non–small cell lung and breast cancer. Despite relatively low sensitivity, plasma ctDNA sequencing has several advantages over tissue-based assays, including ease of sampling, rapid turnaround time, repeatability, and the ability to overcome spatial heterogeneity, which makes it ideal for investigating acquired resistance and monitoring tumor evolution and dynamics. With technological advancement and declining costs, the clinical application of plasma ctDNA is expanding, and numerous ongoing clinical trials are examining its potential to guide the management of advanced, localized, and even preclinical cancers of various tumor types. The ability of plasma ctDNA analysis to detect minimal residual disease following curative treatment in the absence of clinical disease is among its most promising attributes. Plasma ctDNA sequencing can also facilitate the conduct of clinical trials and drug development, particularly in immunotherapy. In order to incorporate plasma ctDNA sequencing for clinical decision-making, it is important to understand the preanalytical and analytical factors that may affect its sensitivity and reliability.

Considering the high morbidity and mortality of Coronavirus disease 2019 (COVID-19) in patients with malignancy, they are regarded as a priority for COVID-19 vaccination. However, general vaccine uptake rates among cancer patients are known to be lower than in their healthy counterparts. Thus, we aimed to investigate the attitude and acceptance rates for the COVID-19 vaccine in cancer patients and identify predictive factors for vaccination that could be modified to increase vaccine uptake rates, via a paper-based survey (58 items over six domains). A total of 1001 cancer patients participated in this nationwide, multicenter survey between February and April 2021. We observed that 61.8% of respondents were willing to receive the COVID-19 vaccine. Positive predictive factors found to be independently associated with vaccination were male gender, older age, obesity, previous influenza vaccination history, absence of cancer recurrence, time since cancer diagnosis over 5 years, and higher EuroQol Visual Analogue Scale scores. Along with the well-known factors that are positively correlated with vaccination, here, we report that patients’ disease status and current health status were also associated with their acceptance of the COVID-19 vaccination. Moreover, 91.2% of cancer patients were willing to be vaccinated if their attending physicians recommend it, indicating that almost 30% could change their decision upon physicians’ recommendation. Unlike other factors, which are unmodifiable, physicians’ recommendation is the single modifiable factor that could change patients’ behavior. In conclusion, we firstly report that Korean cancer patients’ acceptance rate of the COVID-19 vaccination was 61.8% and associated with disease status and current health status. Physicians should play a major role in aiding cancer patients’ decision-making concerning COVID-19 vaccines.

We set out to determine the usability of serum neurofilament light chain (sNfL), serum glial fibrillary acidic protein (sGFAP), and retinal parameters by using optical coherence tomography (OCT) as reliable biomarkers of the progression of oxaliplatin-induced peripheral neuropathy (OIPN). Forty-three patients scheduled to undergo oxaliplatin-based chemotherapy at the National Cancer Center of Korea between June 2018 and October 2019 were prospectively assessed at baseline, 3 months, and 6 months of chemotherapy. Patients were assessed on clinical scales and underwent OCT, sNfL, and sGFAP level measurement at each follow-up visit. By applying the National Cancer Institute-Common Toxicity Criteria (NCI-CTC), OIPN was classified as grade 1 in 12 (28%) patients, grade 2 in 25 (58%), and grade 3 in 5 (12%) at 6 months of chemotherapy. sNfL levels increased during oxaliplatin administration, while serial sGFAP levels or retinal parameters did not change. Patients with grade-3 OIPN showed significantly higher mean sNfL levels than patients with grade 0–2 OIPN at 6 months of treatment. At 4–6 months after completion of chemotherapy, sNfL levels were significantly reduced compared to the levels at 6 months of chemotherapy. Monitoring of sNfL during chemotherapy can indicate ongoing neuroaxonal injury and the severity of OIPN.

BACKGROUND: Colorectal cancer (CRC) develops through the alteration of several critical pathways. This study was aimed at evaluating the influence of critical pathways on survival outcomes for patients with CRC.METHODS: Targeted next‐generation sequencing of 40 genes included in the 5 critical pathways of CRC (WNT, P53, RTK‐RAS, phosphatidylinositol‐4,5‐bisphosphate 3‐kinase [PI3K], and transforming growth factor β [TGF‐β]) was performed for 516 patients with stage III or high‐risk stage II CRC treated with surgery followed by adjuvant fluoropyrimidine and oxaliplatin chemotherapy. The associations between critical pathway mutations and relapse‐free survival (RFS) and overall survival were analyzed. The associations were further analyzed according to the tumor location.RESULTS: The mutation rates for the WNT, P53, RTK‐RAS, PI3K, and TGF‐β pathways were 84.5%, 69.0%, 60.7%, 30.0%, and 28.9%, respectively. A mutation in the PI3K pathway was associated with longer RFS (adjusted hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.36‐0.99), whereas a mutation in the RTK‐RAS pathway was associated with shorter RFS (adjusted HR, 1.60; 95% CI, 1.01‐2.52). Proximal tumors showed a higher mutation rate than distal tumors, and the mutation profile was different according to the tumor location. The mutation rates of Kirsten rat sarcoma viral oncogene homolog (KRAS), phosphatidylinositol‐4,5‐bisphosphate 3‐kinase catalytic subunit α (PIK3CA), and B‐Raf proto‐oncogene serine/threonine kinase (BRAF) were higher in proximal tumors, and the mutation rates of adenomatous polyposis coli (APC), tumor protein 53 (TP53), and neuroblastoma RAS viral oncogene homolog (NRAS) were higher in distal tumors. The better RFS with the PI3K pathway mutation was significant only for proximal tumors, and the worse RFS with the RTK‐RAS pathway mutation was significant only for distal tumors.CONCLUSIONS: A PI3K pathway mutation was associated with better RFS for CRC patients treated with adjuvant chemotherapy, and an RTK‐RAS pathway mutation was associated with worse RFS. The significance of the prognostic impact differed according to the tumor location. Cancer 2017;123:3513‐23. © 2017 American Cancer Society.

Asian population has different body mass index (BMI) profile compared to Caucasian population. However, the effect of obesity and body weight gain in Asian colorectal cancer patients treated with adjuvant chemotherapy has not been studied thus far. We have analyzed the association between disease-free survival (DFS) and obesity/body weight change during treatment in Korean stage III or high-risk stage II colorectal cancer patients treated with adjuvant 5-fluorouracil/ leucovorin/oxaliplatin. BMI was classified according to WHO Asia-Pacific classification. Weight change was calculated by comparing body weights measured at the last chemotherapy cycle and before surgery. Among a total of 522 patients, 35.7 % of patients were obese (BMI ≥ 25 kg/m2) and 29.1 % were overweight (BMI, 23–24.9 kg/m2) before surgery. 18.0 % of patients gained ≥ 5 kg and 26.1 % gained 2–4.9 kg during the adjuvant chemotherapy period. Baseline BMI or body weight change was not associated with DFS in the overall study population. However, body weight gain (≥5 kg) was associated with inferior DFS (adjusted hazard ratio 2.04, 95 % confidence interval 1.02–4.08, p = 0.043) in overweight and obese patients (BMI ≥ 23.0 kg/m2). In Korean colorectal cancer patients treated with adjuvant FOLFOX chemotherapy, body weight gain during the treatment period has a negative prognostic influence in overweight and obese patients.

Metastatic cancer is a significant cause of death worldwide, despite continuing advances in research on diagnostics and therapy. To overcome unsuccessful drug delivery to the tumor tissue, several different nanoprobes have been designed, of which some have combined diagnostic and therapeutic properties. It is an advantage to use non-toxic, biodegradable materials in the design of nanoprobes, as such compounds are easily eliminated from the body. In this work we report for the first time the use of a recently developed nanoprobe to label melanoma metastatic cell lines, for multimodal imaging of cellular uptake and drug delivery. Our nanoprobe consisted of a backbone of glycogen, where the red fluorescent marker Dyo-615 for fluorescence microscopy and Gadolinium for MRI were incorporated. Fluorescence microscopy showed effective labeling of human melanoma metastatic cells over 24 hours and cell viability was not affected by the labeling. The nanoprobe was found in the cytosol of the cells, and a gradual degradation of the probe inside the lysosomes could be observed. In vitro MRI relaxivity measurements showed significant reduction in T1 mapping times, compared to unlabeled cells. In vivo MRI studies showed that subcutaneous melanoma tumors in mice could be effectively visualized with T1 weighted MRI after intravenous injection of the nanoprobe, and the contrast enhancement was comparable to what was seen after using standard Omniscan contrast agent. In summary, our biodegradable glycogen nanoprobe shows a high potential to be used further as a theranostic entity. The nanoprobe may offer additional advantages over MRI contrast agents, as tumor uptake of pharmaceuticals attached to the nanoprobe can be traced in real-time in vivo. Citation Format: Synnøve N. Aasen, Tilo W. Eichler, Martin Hruby, Aneta Pospisilova, Petr Stepanek, Endy Spriet, Daniel Jirak, Kai Ove Skaftnesmo, Frits Thorsen. A novel, multimodal theranostic nanoprobe is effectively incorporated into melanoma brain metastatic cells. []. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl): nr 5195. doi:10.1158/1538-7445.AM2015-5195