A comparison of isolated circulating tumor cells and tissue biopsies using whole-genome sequencing in prostate cancer

Previous studies have demonstrated focal but limited molecular similarities between circulating tumor cells (CTCs) and biopsies using isolated genetic assays. We hypothesized that molecular similarity between CTCs and tissue exists at the single cell level when characterized by whole genome sequencing (WGS). By combining the NanoVelcro CTC Chip with laser capture microdissection (LCM), we developed a platform for single-CTC WGS. We performed this procedure on CTCs and tissue samples from a patient with advanced prostate cancer who had serial biopsies over the course of his clinical history. We achieved 30X depth and ≥ 95% coverage. Twenty-nine percent of the somatic single nucleotide variations (SSNVs) identified were founder mutations that were also identified in CTCs. In addition, 86% of the clonal mutations identified in CTCs could be traced back to either the primary or metastatic tumors. In this patient, we identified structural variations (SVs) including an intrachromosomal rearrangement in chr3 and an interchromosomal rearrangement between chr13 and chr15. These rearrangements were shared between tumor tissues and CTCs. At the same time, highly heterogeneous short structural variants were discovered in PTEN, RB1, and BRCA2 in all tumor and CTC samples. Using high-quality WGS on single-CTCs, we identified the shared genomic alterations between CTCs and tumor tissues. This approach yielded insight into the heterogeneity of the mutational landscape of SSNVs and SVs. It may be possible to use this approach to study heterogeneity and characterize the biological evolution of a cancer during the course of its natural history

High Throughput Interrogation of Somatic Mutations in High Grade Serous Cancer of the Ovary

BACKGROUND:Epithelial ovarian cancer is the most lethal of all gynecologic malignancies, and high grade serous ovarian cancer (HGSC) is the most common subtype of ovarian cancer. The objective of this study was to determine the frequency and types of point somatic mutations in HGSC using a mutation detection protocol called OncoMap that employs mass spectrometric-based genotyping technology. METHODOLOGY/PRINCIPAL FINDINGS:The Center for Cancer Genome Discovery (CCGD) Program at the Dana-Farber Cancer Institute (DFCI) has adapted a high-throughput genotyping platform to determine the mutation status of a large panel of known cancer genes. The mutation detection protocol, termed OncoMap has been expanded to detect more than 1000 mutations in 112 oncogenes in formalin-fixed paraffin-embedded (FFPE) tissue samples. We performed OncoMap on a set of 203 FFPE advanced staged HGSC specimens. We isolated genomic DNA from these samples, and after a battery of quality assurance tests, ran each of these samples on the OncoMap v3 platform. 56% (113/203) tumor samples harbored candidate mutations. Sixty-five samples had single mutations (32%) while the remaining samples had ≥ 2 mutations (24%). 196 candidate mutation calls were made in 50 genes. The most common somatic oncogene mutations were found in EGFR, KRAS, PDGRFα, KIT, and PIK3CA. Other mutations found in additional genes were found at lower frequencies (<3%). CONCLUSIONS/SIGNIFICANCE:Sequenom analysis using OncoMap on DNA extracted from FFPE ovarian cancer samples is feasible and leads to the detection of potentially druggable mutations. Screening HGSC for somatic mutations in oncogenes may lead to additional therapies for this patient population

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease

Is computed tomography a necessary part of a metastatic evaluation for castration-resistant prostate cancer? Results from the Shared Equal Access Regional Cancer Hospital Database

BACKGROUND Metastatic lesions in prostate cancer beyond the bone have prognostic importance and affect clinical therapeutic decisions. Few data exist regarding the prevalence of soft-tissue metastases at the initial diagnosis of metastatic castration-resistant prostate cancer (mCRPC). METHODS This study analyzed 232 men with nonmetastatic (M0) castration-resistant prostate cancer (CRPC) who developed metastases detected by a bone scan or computed tomography (CT). All bone scans and CT scans within the 30 days before or after the mCRPC diagnosis were reviewed. The rate of soft-tissue metastases among those undergoing CT was determined. Then, predictors of soft-tissue metastases and visceral and lymph node metastases were identified. RESULTS Compared with men undergoing CT (n = 118), men undergoing only bone scans (n = 114) were more likely to have received primary treatment (P =.048), were older (P =.013), and less recently developed metastases (P =.018). Among those undergoing CT, 52 (44%) had soft-tissue metastases, including 20 visceral metastases (17%) and 41 lymph node metastases (35%), whereas 30% had no bone involvement. In a univariable analysis, only prostate-specific antigen (PSA) predicted soft-tissue metastases (odds ratio [OR], 1.27; P =.047), and no statistically significant predictors of visceral metastases were found. A higher PSA level was associated with an increased risk of lymph node metastases (OR, 1.38; P =.014), whereas receiving primary treatment was associated with decreased risk (OR, 0.36; P =.015). CONCLUSIONS The data suggest that there is a relatively high rate of soft-tissue metastasis (44%) among CRPC patients undergoing CT at the initial diagnosis of metastases, including some men with no bone involvement. Therefore, forgoing CT during a metastatic evaluation may lead to an underdiagnosis of soft-tissue metastases and an underdiagnosis of metastases in general