Table_1_The Use of Circulating Tumor DNA for Prognosis of Gastrointestinal Cancers.docx

<p>Gastrointestinal cancers, including oesophageal, gastric and colorectal cancers (CRC) have high rates of disease recurrence despite curative resection. There are a number of recent studies that have investigated the use of circulating tumor DNA (ctDNA) for prognostic value in these cancers. We reviewed studies that had been published prior to March 2018 that assessed the prognostic values of ctDNA in patients with oesophageal and gastric cancers, gastrointestinal stromal tumors (GIST) and CRC. We identified 63 eligible clinical studies that focussed on recurrence and survival. Studies assessed investigated various ctDNA biomarkers in patients with different stages of cancer undergoing surgical resection, chemotherapy and no treatment. For oesophageal squamous cell carcinoma and oesophageal adenocarcinoma, methylation of certain genes such as APC and DAPK have been highlighted as promising biomarkers for prognostication, but these studies are limited and more comprehensive research is needed. Studies focusing on gastric cancer patients showed that methylation of ctDNA in SOX17 and APC were independently associated with poor survival. Two studies demonstrated an association between ctDNA and recurrence and survival in GIST patients, but more studies are needed for this type of gastrointestinal cancer. A large proportion of the literature was on CRC which identified both somatic mutations and DNA methylation biomarkers to determine prognosis. ctDNA biomarkers that identified somatic mutations were more effective if they were personalized based on mutations found in the primary tumor tissue, but ctDNA methylation studies identified various biomarkers that predicted increased risk of recurrence, poor disease free survival and overall survival. While the use of non-invasive ctDNA biomarkers for prognosis is promising, larger studies are needed to validate the clinical utility for optimizing treatment and surveillance strategies to reduce mortality from gastrointestinal cancers.</p

OS outcomes for EGFR-I by chemotherapy backbone.

<p>OS outcomes for EGFR-I by chemotherapy backbone.</p

OS outcomes for EGFR-I by chemotherapy backbone—extended RAS analysis.

<p>OS outcomes for EGFR-I by chemotherapy backbone—extended RAS analysis.</p

Fluoropyrimidine subgroup analysis for PFS–combining EGFR-I with oxaliplatin-based chemotherapy.

<p>Fluoropyrimidine subgroup analysis for PFS–combining EGFR-I with oxaliplatin-based chemotherapy.</p

List of included trials.

<p>Abbreviations: Cet—Cetuximab, Pan—Panitumumab, Bev—Bevacizumab, XB—Capecitabine + Bevacizumab, Cape—Capecitabine</p><p>List of included trials.</p

PFS outcomes for anti-angiogenic agents by chemotherapy backbone.

<p>PFS outcomes for anti-angiogenic agents by chemotherapy backbone.</p

PRISMA flow diagram.

<p><i>From</i>: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). <i>P</i>referred <i>R</i>eporting <i>I</i>tems for <i>S</i>ystematic Reviews and <i>M</i>eta-<i>A</i>nalysis: The PRISMA Statment. PLoS Med 6(6): e1000097. doi:<a href="http://dx.doi.org/10.1371/journal.pmed1000097" target="_blank">10.1371/journal.pmed1000097</a> For more information, visit <a href="http://www.prisma-statement.org" target="_blank">www.prisma-statement.org</a>.</p

The survival outcome of patients with metastatic colorectal cancer based on the site of metastases and the impact of molecular markers and site of primary cancer on metastatic pattern

<p><b>Background:</b> Pattern of spread in patients with metastatic colorectal cancer (mCRC) is variable and may reflect different biology in subsets of patients. This is a retrospective study to explore the outcome of patients with mCRC based on their site of metastasis at diagnosis and to explore the association between tumor characteristics [KRAS/RAS, BRAF, mismatch repair (MMR) status, site of primary] and the site of metastasis.</p> <p><b>Methods:</b> Patients from two Australian databases were divided into six groups based on site of metastasis at time of diagnosis of metastatic disease; lung-only, liver-only, lymph node-only or any patients with brain, bone or peritoneal metastases. Primary endpoint was overall survival (OS) of each cohort compared with the rest of the population. A Mantel–Haenszel chi-squared test used to explore the association between site of metastasis and selected tumor characteristics.</p> <p><b>Results:</b> Five thousand nine hundred and sixty-seven patients were included. In a univariate analysis, median OS was significantly higher when metastases were limited to lung or liver and shorter for those with brain, bone or peritoneal metastases (<i>p</i> < .001) in both datasets. BRAF mutation was strongly associated with peritoneal metastases (relative risk = 1.8, <i>p</i> < .001) with lower incidence of lung (RR = 0.3, <i>p</i> = .004) and liver (RR = 0.7, <i>p</i> = .005) limited metastases. Lung-only metastases were more frequent with KRAS/RAS mutation (RR = 1.4, <i>p</i> = .007). Left colon tumors were associated with bone (RR = 1.6, <i>p</i> < .001) and lung-only metastases (RR = 2.3, <i>p</i> = .001) while peritoneal spread was less frequent compared with right colon tumors (RR = 0.6, <i>p</i> < .001). Rectal cancer was associated with brain, bone and lung metastases (RR = 1.7; <i>p</i> = .002, 1.7; <i>p</i> < .001, 2.0; <i>p</i> < .001). Liver-only metastases were less frequent in deficient MMR tumors (RR = 0.7, <i>p</i> = .01).</p> <p><b>Conclusion:</b> Survival duration with mCRC is related to the site of metastases with lung limited disease showing a more favorable survival outcome compared to other single metastatic site disease. The BRAF mutation and primary rectal cancer were associated with poor prognostic metastatic sites.</p