Matthew Croxford

Optimizing targeted therapeutic development: Analysis of a colorectal cancer patient population with the BRAFV600E mutation

BRAFV600E mutations are found in 10% of colorectal cancers (CRCs). The low frequency of this mutation therefore makes it a challenging target for drug development, unless subsets of patients with higher rates of BRAFV600E can be defined. Knowledge of the concordance between primary–metastasis pairs and the impact of BRAFV600E on outcome would also assist in optimal drug development. We selected primary CRCs from 525 patients (stages I–IV) evenly matched for age (<70 and ≥70), gender and tumor location (right, left and rectum), and 81 primary–metastasis pairs. BRAFV600E, KRAS mutation and microsatellite instability (MSI) were determined and correlated with clinical features and patient outcomes. In multivariate analyses, increasing patient age (p = 0.04), female gender (p = 0.0005) and right‐sided tumor location (p < 0.0001) were independently associated with BRAFV600E. The prevalence of BRAFV600E was considerably higher in older (age > 70) females with KRAS wild‐type right‐sided colon cancers (50%) compared to the unselected cohort (10%). BRAFV600E was associated with inferior overall survival in metastatic CRC (HR = 2.02; 95% CI 1.26–3.26), particularly evident in patients treated with chemotherapy, and is independent of MSI status. BRAF status was concordant in all primary tumors and matched metastases (79 wild‐type pairs and two mutant pairs). Clinicopathological and molecular features can identify CRC patients with a higher prevalence of BRAFV600E. Patients with BRAFV600E wild‐type primary tumor do not appear to acquire the mutation in their metastases, and BRAFV600E is associated with poorer outcomes in metastatic patients. Our findings are timely and will help inform the rational development of BRAFV600E inhibitors in CRC.

Managing fistula-in-ano with ligation of the intersphincteric fistula tract procedure: the Western Hospital experience

Aim  To review the preliminary results of the ligation of the intersphincteric fistula tract (LIFT) technique in treating complex anal fistulas at our hospital.

Biallelic pms2 Mutations and a Distinctive Childhood Cancer Syndrome

Biallelic mutations in PMS2, a gene usually associated in heterozygous form with hereditary nonpolyposis colorectal cancer (HNPCC), results in a recently described childhood cancer syndrome. The tumor spectrum encompasses atypical brain cancers, hematologic malignancies, and colonic polyposis and cancer. Cutaneous stigmata resembling café-au-lait macules with more diffuse margins are frequently seen. Onset is as young as 2 years. The risk of second malignancy is high. Evidence exists for surveillance for bowel cancer, but surveillance for the wider tumor spectrum is of uncertain benefit. We report a consanguineous Australian-Lebanese family with multiple affected individuals shown to be homozygous for a PMS2 exon 7 deletion. We also review published cases of biallelic mutations in HNPCC-related genes. Early recognition of this familial cancer syndrome is critical, and should prompt investigation for familial HNPCC mutations.

Analysis of local chronic inflammatory cell infiltrate combined with systemic inflammation improves prognostication in stage II colon cancer independent of standard clinicopathologic criteria

In Stage II colon cancer, multiple independent studies have shown that a dense intratumoural immune infiltrate (local inflammation) is associated with improved outcomes, while systemic inflammation, measured by various markers, has been associated with poorer outcomes. However, previous studies have not considered the interaction between local and systemic inflammation, nor have they assessed the type of inflammatory response compared with standard clinicopathologic criteria. In order to evaluate the potential clinical utility of inflammatory markers in Stage II colon cancer, we examined local and systemic inflammation in a consecutive series of patients with resected Stage II colon cancer between 2000 and 2010 who were identified from a prospective clinical database. Increased intratumoural chronic inflammatory cell (CIC) density, as assessed by pathologist review of hematoxylin and eosin stained slides, was used to represent local inflammation. Neutrophil‐to‐lymphocyte ratio (NLR) >5, as calculated from pre‐operative full blood counts, was used to represent systemic inflammation. In 396 eligible patients identified, there was a non‐significant inverse relationship between local and systemic inflammation. Increased CIC density was significantly associated with improved overall (HR 0.45, p = 0.001) and recurrence‐free survival (HR 0.37, p = 0.003). High NLR was significantly associated with poorer overall survival (HR 2.56, p < 0.001). The combination of these markers further stratified prognosis independent of standard high‐risk criteria, with a dominant systemic inflammatory response (low CIC/high NLR) associated with the worst outcome (5‐year overall survival 55.8%). With further validation this simple, inexpensive combined inflammatory biomarker might assist in patient selection for adjuvant chemotherapy in Stage II colon cancer.

Comparing oncological outcomes of laparoscopic versus open surgery for colon cancer: Analysis of a large prospective clinical database.

Oncological outcomes of laparoscopic colon cancer surgery have been shown to be equivalent to those of open surgery, but only in the setting of randomized controlled trials on highly selected patients. The aim of this study is to investigate whether this finding is generalizable to real world practice.

Preliminary analysis of the cost-effectiveness of the National Bowel Cancer Screening Program: demonstrating the potential value of comprehensive real world data

Background/Aim:  The complexity and cost of treating cancer patients is escalating rapidly and increasingly difficult decisions are being made regarding which interventions provide value for money. BioGrid Australia supports collection and analysis of comprehensive treatment and outcome data across multiple sites. Here, we use preliminary data regarding the National Bowel Cancer Screening Program (NBCSP) and stage‐specific treatment costs for colorectal cancer (CRC) to demonstrate the potential value of real world data for cost‐effectiveness analyses (CEA).

Primary Tumor Resection in Patients With Metastatic Colorectal Cancer Is Associated With Reversal of Systemic Inflammation and Improved Survival

BACKGROUND The true survival benefit of noncurative primary tumor resection in patients with de novo metastatic colorectal cancer (mCRC) remains uncertain. The present study examined the effect of primary tumor resection on systemic inflammation and survival in patients with mCRC. MATERIALS AND METHODS Consecutive patients with de novo mCRC who had undergone primary tumor resection were identified from a prospective database. Patients were excluded if they had undergone resection of metastases, had undergone delayed primary resection, or if blood samples were unavailable. The neutrophil/lymphocyte ratio (NLR) was used as a biomarker of systemic inflammation. Overall survival (OS) was compared between patient groups according to the pre- and postprimary resection NLR. The associations between the reversal of an elevated NLR and primary tumor bulk or performance status were explored. RESULTS A total of 145 eligible patients were identified from the database, with a median age of 70 years. The baseline NLR was elevated (> 5) in 65 patients, 36 (55%) of whom had a low NLR after surgery. The reversal of an elevated NLR was associated with significantly improved OS (hazard ratio, 0.53; P = .017). A similar benefit was seen after excluding patients undergoing emergency primary resection. NLR reversal was more frequent in patients with larger primary tumors or good performance status. CONCLUSION The present study is the first to demonstrate a relationship between the reversal of a systemic inflammatory response and the improved survival after primary resection in those with mCRC. A greater effect was seen in patients with large primary tumors. If validated, these observations could guide clinical decision-making in patients with mCRC at presentation.

ORIGINAL ARTICLE: Linking data from hospital and cancer registry databases: should this be standard practice?

Background: Varying amounts of data related to cancer diagnosis, treatment and/or outcome are routinely collected by many disparate groups. Routinely combining data from these sources could improve data quality and utility for audit and research purposes. The aim of this study is to demonstrate the benefits of linkage between oncology databases.

Linking data from hospital and cancer registry databases: should this be standard practice?

Background: Varying amounts of data related to cancer diagnosis, treatment and/or outcome are routinely collected by many disparate groups. Routinely combining data from these sources could improve data quality and utility for audit and research purposes. The aim of this study is to demonstrate the benefits of linkage between oncology databases.

Serial circulating tumour DNA analysis during multimodality treatment of locally advanced rectal cancer: a prospective biomarker study

Objective For patients with locally advanced rectal cancer (LARC), adjuvant chemotherapy selection following surgery remains a major clinical dilemma. Here, we investigated the ability of circulating tumour DNA (ctDNA) to improve risk stratification in patients with LARC. Design We enrolled patients with LARC (T3/T4 and/or N+) planned for neoadjuvant chemoradiotherapy. Plasma samples were collected pretreatment, postchemoradiotherapy and 4–10 weeks after surgery. Somatic mutations in individual patient’s tumour were identified via massively parallel sequencing of 15 genes commonly mutated in colorectal cancer. We then designed personalised assays to quantify ctDNA in plasma samples. Patients received adjuvant therapy at clinician discretion, blinded to the ctDNA results. Results We analysed 462 serial plasma samples from 159 patients. ctDNA was detectable in 77%, 8.3% and 12% of pretreatment, postchemoradiotherapy and postsurgery plasma samples. Significantly worse recurrence-free survival was seen if ctDNA was detectable after chemoradiotherapy (HR 6.6; P<0.001) or after surgery (HR 13.0; P<0.001). The estimated 3-year recurrence-free survival was 33% for the postoperative ctDNA-positive patients and 87% for the postoperative ctDNA-negative patients. Postoperative ctDNA detection was predictive of recurrence irrespective of adjuvant chemotherapy use (chemotherapy: HR 10.0; P<0.001; without chemotherapy: HR 22.0; P<0.001). Postoperative ctDNA status remained an independent predictor of recurrence-free survival after adjusting for known clinicopathological risk factors (HR 6.0; P<0.001). Conclusion Postoperative ctDNA analysis stratifies patients with LARC into subsets that are either at very high or at low risk of recurrence, independent of conventional clinicopathological risk factors. ctDNA analysis could potentially be used to guide patient selection for adjuvant chemotherapy.