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Aim: Reviewing outcomes of regorafenib use in metastatic colorectal cancer using real-world data from the South Australian Metastatic Colorectal Cancer Registry. Methods: A retrospective review of the characteristics and outcomes of patients who received regorafenib in the Registry up to December 2018. The registry started in February 2006. Results: Fifty-three patients received regorafenib therapy since approved by the therapeutic goods administration in November 2013. The median age was 66 (range 34–82). 66% were male, 66% had stage IV disease at diagnosis, 53% had liver only involvement, whereas 13% had liver and lung disease and 6% had lung only involvement. 75% had left-sided primary. KRAS was available in 35/53 patients with 49% of them being WT. BRAF status was known in 8/53 with 25% of them having a mutated variant. MSI testing was known in 14 patients in whom 21% of them had MSI-High tumors. Prior lines of treatment received: one line 4%, two 9%, three 23%, four 26%, >four 37%. Prior biological use: bevacizumab 72%, anti-EGFR 100% (for RAS WT). Median survival from diagnosis was 3.3 years (95% CI, 2.8–3.8 years). Median survival from the start of regorafenib was 7.1 months (95% CI, 4.8–9.4 months) and the 12-month survival rate was 28%. Conclusion: The survival outcome for those patients from our population-based registry who access regorafenib is in keeping with reports from large, randomized trials. Thus, clinicians can quote local real world data when discussing efficacy and access to regorafenib therapy for mCRC patients. Refereed/Peer-reviewed

Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (cetuximab or panitumumab) are today increasingly used in the first- or second-line setting for RAS wild-type metastatic colorectal cancer (CRC) patients. Following progression beyond third- or fourth-line therapy, some patients are unsuitable for further chemotherapy because of poor performance status or patient choice. However, a significant number of patients are still candidates for further therapy despite limited standard options being available. The role of rechallenge with anti-EGFR therapy, particularly in patients who had previously responded, is often considered, but there is limited evidence in the literature to support such a strategy. This retrospective study aims to review the outcome of metastatic CRC patients who had anti-EGFR rechallenge. Patients who had been rechallenged with anti-EGFR therapy were identified from the South Australian metastatic CRC database. Patient characteristics were recorded and tumor response was retrospectively assessed using Response Evaluation Criteria in Solid Tumors (RECIST). Kaplan–Meier analysis was used to assess progression free survival (PFS) for each rechallenge and overall survival (OS). Twenty-two patients were eligible for inclusion in this analysis. Disease control rate (stable disease and partial response) was 45.4% (ten patients) for patients who received rechallenge anti-EGFR. Seven patients received a second rechallenge and disease control rate was 28.6% (two patients). The median interval time between initial anti-EGFR therapy and rechallenge was 13.5 months. The median PFS after rechallenge 1 was 4.1 months and after rechallenge 2 was 3.5 months. The median OS was 7.7 months from date of rechallenge. Anti-EGFR rechallenge provides clinical benefit in patients with RAS wild-type metastatic CRC.

Introduction: Outcomes in metastatic colorectal cancer are improving, due to the tailoring of therapy enabled by better understanding of clinical behavior according to molecular subtype. Areas covered: A review of the literature and recent conference presentations was undertaken on the topic of systemic treatment of metastatic colorectal cancer. This review summarizes expert discussion of the current evidence for therapies in metastatic colorectal cancer (mCRC) based on molecular subgrouping. Expert opinion: EGFR-targeted and VEGF-targeted antibodies are now routinely incorporated into treatment strategies for mCRC. EGFR-targeted antibodies are restricted to patients with extended RAS wild-type profiles, with evidence that they should be further restricted to patients with left-sided tumors. Clinically distinct treatment pathways based on tumor RAS, BRAF, HER2 and MMR status, are now clinically applicable. Evidence suggests therapy for additional subgroups will soon be defined; the most advanced being for patients with KRAS G12 C mutation and gene TRK fusion defects.

Background The sensitive detection of recurrent colorectal cancer (CRC) by the measurement of circulating tumor DNA (ctDNA) might improve the chance of a cure. This study compared a quantitative methylated ctDNA test with carcinoembryonic antigen (CEA) in the setting of surveillance for recurrence. Methods Blood samples collected either during surveillance or within 12 months of the confirmation of recurrence were assayed for ctDNA (methylated branched‐chain amino acid transaminase 1 [BCAT1]/Ikaros family zinc‐finger 1 protein [IKZF1]) and CEA. The optimal ctDNA threshold was determined by receiver operating characteristic analysis, and the test performance for the detection of recurrence was compared with CEA (5 ng/mL threshold). Results The study cohort comprised 144 eligible patients and included 50 recurrence events. The sensitivity of the methylated ctDNA test for recurrence was 66.0% (95% confidence interval [CI], 57.1%‐69.3%), which was significantly higher than the sensitivity of CEA (31.9%; 95% CI, 22.8%‐36.6%; P, An optimal positivity threshold has been determined for an epigenetic circulating tumor DNA panel of biomarkers (methylated BCAT1 and IKZF1), and it has been applied to investigating the panel's utility in the detection of colorectal cancer recurrence. The sensitivity of the circulating tumor DNA test is superior to that of the clinically used carcinoembryonic antigen test for all recurrences (66% vs 32%) and those considered curable (60% vs 20%), with both tests having a very high specificity (98% vs 96%).

Introduction: A comprehensive trimodality approach has become the standard of care for patients with locally advanced rectal cancer. However, the sequencing and duration of chemotherapy and chemoradiotherapy around surgery varies between clinical studies and geographical regions. Growing evidence is also mounting for strategies such as total neoadjuvant therapy and non-operative management for carefully selected patients.Areas covered: We provide a perspective review of the current evidence and controversies in the treatment of locally advanced rectal cancer including the recent updates from the 2020 ASCO annual conference.Expert opinion: With ongoing advances in the management of locally advanced rectal cancer, a multidisciplinary team approach is necessary as treatments could involve multiple approaches. Chemoradiotherapy whether short or long course followed by at least 3 months of systemic chemotherapy may be the preferred option to balance local and distant disease control. Albeit the choice of doublet or triplet chemotherapy is still controversial. As total neoadjuvant treatment becomes part of the standard of care in rectal cancer, modification of the surveillance schedule is needed to detect early recurrences which may be limited by resources and availability of services.

Methylation in IKZF1 and BCAT1 are common events in colorectal cancer (CRC). They are often detected in blood as circulating tumor DNA (ctDNA) at diagnosis and disappear after surgery in most CRC patients. A prospective study was conducted to determine the relationship between detection of these markers following surgery and risk for residual disease and for recurrence. ctDNA status with methylated BCAT1 and IKZF1 was determined within 12 months of surgical resection of CRC, and was related to presence of or risk for residual disease (margins involved, metastases present or nature of node involvement), and to recurrence-free survival. Blood was collected from 172 CRC patients after surgery and 28 (16%) were ctDNA positive. Recurrence was diagnosed in 23 of the 138 with clinical follow-up after surgery (median follow-up 23.3 months, IQR 14.3–29.5). Multivariate modeling indicated that features suggestive of residual disease were an independent predictor of post-surgery ctDNA status: cases with any of three features (close resection margins, apical node involved, or distant metastases) were 5.3 times (95% CI 1.5–18.4, p = 0.008) more likely to be ctDNA positive. Multivariate analysis showed that post-surgery ctDNA positivity was independently associated with an increased risk of recurrence (HR 3.8, 1.5–9.5, p = 0.004). CRC cases positive for methylated ctDNA after surgery are at increased risk of residual disease and subsequently recurrence. This could have implications for guiding recommendations for adjuvant therapy and surveillance strategies. Randomized studies are now indicated to determine if monitoring cases with these biomarkers leads to survival benefit.

Aim Observation with close follow-up ("watch and wait") is a recognized treatment option in patients who achieve a complete clinical response to long course chemoradiotherapy. This review of a prospective database aims to evaluate the clinical outcomes among patients with a complete clinical response managed with observation. Methods A prospective study of 32 patients who achieved a complete clinical response was undertaken. The primary outcomes measured were overall and recurrence-free survival, and rate of organ preservation in patients who deferred immediate surgery. Results Seven patients developed local regrowth over a median follow-up period of 38 months (range, 9-91 months). Median time to detection was 12 months. All seven underwent salvage surgery with complete surgical clearance. One patient developed combined local and systemic recurrence following a low anterior resection. Organ preservation was possible in 25 (78%) patients who sustained a complete clinical response with no evidence of local regrowth or disease recurrence. Among the patients who sustained a complete response, two developed isolated systemic disease. Overall and recurrence-free survival was 95.7% and 87.0%, respectively. Conclusion The majority of patients with rectal cancer who achieved a complete clinical response after chemoradiotherapy and managed with a "watch and wait" approach preserved their rectum and did not develop cancer relapse. Salvage surgery was achieved in all patients who developed local regrowth. The study supports a period of observation in rectal cancer patients who achieve a complete clinical response.

// Sing Y. Moorcraft 1 , Thomas Jones 2 , Brian A. Walker 1 , George Ladas 2 , Eleftheria Kalaitzaki 1 , Lina Yuan 1 , Ruwaida Begum 1 , Zakaria Eltahir 1 , Andrew Wotherspoon 1 , Angeles Montero-Fernandez 2 , Larissa S. Teixeira Mendes 1 , David Gonzalez de Castro 1 , Sanna Hulkki Wilson 1 , Paula Proszek 1 , Ye M. To 1 , Eliza Hawkes 1 , Amitesh Roy 1 , David Cunningham 1 , Sheela Rao 1 , David Watkins 1 , Naureen Starling 1 , Anne M. Bowcock 3 and Ian Chau 1 1 The Royal Marsden NHS Foundation Trust, London and Sutton, United Kingdom 2 The Royal Brompton and Harefield NHS Foundation Trust, London, United Kingdom 3 National Heart and Lung Institute, Imperial College, London, United Kingdom Correspondence to: Ian Chau, email: ian.chau@rmh.nhs.uk Keywords: colorectal cancer, heterogeneity, metastasectomy, pulmonary metastases, RAS Received: October 06, 2016 Accepted: March 29, 2017 Published: April 11, 2017 ABSTRACT This study aimed to molecularly characterise colorectal pulmonary metastases (PM) and investigate whether their molecular profiles were concordant with those of the primary tumour. Clinical data and archival formalin fixed paraffin embedded tissue samples were retrospectively collected from patients who underwent ≥ 1 pulmonary metastasectomies for colorectal cancer between 1997–2012. Primary tumour and metastatic samples were analysed using a targeted capture sequencing panel of 46 cancer-associated genes. The 5-year progression-free and overall survival rates for the 81 patients in this study were 32% (95% CI 22–42%) and 77% (95% CI 66–85%) respectively. Fifty-four patients had samples available from ≥ 1 PM, and sequencing data were successfully obtained from 33 PM from 24 patients. The most frequently mutated genes were APC (71%), KRAS (58%) and TP53 (46%). Seventy-three percent of the 15 patients with matched primary and PM samples and 6 of the 7 patients (86%) with data from ≥ 2 PM had concordant molecular profiles. The concordance for KRAS and NRAS was 100%. At our institutions, patients with resectable colorectal PM had a favourable prognosis. RAS mutations were commonly detected in PM and the molecular profiles of colorectal PM were highly concordant with the primary tumour.

Background: Studies have reported significant differences in baseline characteristics and outcomes of metastatic colorectal cancer (mCRC) patients when managed in private versus public hospitals. Aim: To compare disease, treatment and survival outcomes of patients with mCRC in public versus private hospitals in South Australia. Methods: Analysis of prospectively collected data from the SA mCRC Registry. Patterns of care and outcome data according to location of care and socioeconomic status based on Index of Relative Socio‐Economic Advantage and Disadvantage (IRSAD) were analyzed. Results: 3470 patient's data were analysed during February 2006 ‐ January 2015. Majority (70%) of patients received treatment in public hospitals. Patients in the upper 50% for IRSAD score were more likely to receive treatment at a private hospital (41.2% v 21.5%) compared to 3 lines of treatment had an average survival increase of over 15 months, 15.7 (95% CI 13.41, 17.99, p

Background Microsatellite instability (MSI) is the molecular marker for DNA mismatch repair deficiency (dMMR) in colorectal cancer (CRC) and has been associated with better survival outcomes in early stage disease. In metastatic CRC (mCRC), outcomes for patients with MSI are less clear. There is evolving evidence that treatment pathways forMSI CRC should include programmed-death 1 (PD-1) antibodies. Objective An analysis was performed to explore the impact of MSI status on overall survival (OS) in mCRC. Patients and methods South Australian Metastatic CRC Registry data were analysed to assess patient characteristics and survival outcomes, comparing patients with MSI CRC with those whose tumours were microsatellite stable (MSS). Kaplan–Meier survival analysis was used to assess OS. Cox regression analysis was undertaken to assess the independence of MSI as a prognostic factor. Results Of 4359 patients registered on the database, 598 (14%) had been tested for, and 62 (10.1%) of these patients had, demonstrable MSI. There were significantly higher rates of right-sided primary (p < 0.001), poorly differentiated pathology (p = 0.002), and BRAF V600E mutation (p < 0.001) in the MSI group. The MSI group were also less likely to receive chemotherapy (p < 0.001) or to have liver surgery, but more likely to be diagnosed at an early stage. The median overall survival was 9.5 months for those with MSI CRC versus 21.3 months for MSS CRC patients (p =0.052). Cox regression analysis indicated that MSI was not an independent predictor of OS. Independent predictors of better OS included having liver surgery for metastasis, having chemotherapy, and being initially diagnosed at an early stage. Conclusions Only 14% of patients with mCRC were tested for MSI, and 1 in 10 were found to be MSI high. The clinical characteristics of MSI mCRC are in keeping with those previously reported. MSI in this population-based registry was associated with a numerically lower survival which did not attain statistical significance. Refereed/Peer-reviewed

3579 Background: Recurrence of colorectal cancer has been linked to the presence of epigenetic circulating tumour DNA (ctDNA) in patient plasma after surgery. The prognostic significance of ctDNA prior to treatment remains unknown. This study investigated the correlation between pre-treatment ctDNA and current radiological (MRI) prognostic markers in patients with rectal cancer. Methods: Forty-two patients with rectal cancer were enrolled, with all having staging MRI prior to treatment. Plasma was taken for ctDNA at diagnosis. The presence of either methylated branched-chain amino acid transaminase 1 (BCAT1) or Ikaros family zinc finger (IKZF1) in cell-free DNA from plasma was deemed a positive ctDNA result. Correlation of MRI prognostic indicators and ctDNA results was assessed with chi-square tests. Univariable and multivariable cox regression analyses were performed to determine variables associated with overall survival (OS). Results: Mean age was 64.4 years (SD 12.5) and majority were male (30/42, 71.4%). 11, 13, 9 & 9 patients had stages I, II, III, IV respectively. Patients had a minimum follow-up of 36 months. Thirty-three (78.6%) patients received neoadjuvant chemoradiotherapy. 29 (69.0%) patients underwent surgical resection. 3-year survival rate was 64% in the overall group. 67% (n=28/42) of patients were positive for the methylated ctDNA at diagnosis. 11 out of 12 patients with a positive circumferential resection margin (CRM +) were ctDNA positive (p=0.03). Univariable analysis showed that prognostic indicators for OS were presence of extramural venous invasion (EMVI) (HR 3.0, 95% CI 1.1-8.4), CRM+ (HR 12.2, 95%CI 3.9-37.6), metastatic disease (HR 7.32, 95% CI 2.63-20.37) and ctDNA% methylation (HR 1.1, 95% CI 1.04-1.13) (Table 1). The presence of CRM+ and a positive ctDNA had a HR of 20.5 (95% CI 5.1-82.3). With multivariable analysis, including adjustment for age and EMVI, only CRM+/ctDNA+ variable was an independent predictor for poor survival (HR 20.2, 95% CI 4.5-90.9). Conclusions: In rectal cancer, almost all patients with CRM involvement have ctDNA, and these patients had the worst prognosis. Future studies with longitudinal ctDNA assessment pre and post treatment could potentially inform prognosis and help tailor patients’ treatment.[Table: see text]

3528 Background: Residual disease after treatment for colorectal cancer (CRC) poses a risk for recurrence but imaging and CEA are limited in their capacity to detect residual disease. A simple test is needed for assessing treatment response. This study determined whether levels of methylated BCAT1/IKZF1 DNA in blood correlate with tumor burden and whether post-treatment levels inform efficacy of different treatments for CRC. Methods: Patients with primary CRC had blood collected prior to treatment (n = 282, 59.9% males, median age 68.5y). Cell free DNA (cfDNA) was extracted from plasma and assayed for methylation in BCAT1 and IKZF1. Detection of methylation in either gene deemed a sample positive; levels were expressed as %methylation (average methylation/average cfDNA). Positive patients had additional samples collected post-treatment for early stage CRC (surgery, n = 31), advanced/metastatic CRC (surgery + adjuvant chemotherapy, n = 15), and rectal cancer (neoadjuvant therapy, surgery +/- chemotherapy, n = 6), or following mid-therapy suspension of treatment in advanced CRC (n = 24). Tumor size was expressed as the maximum diameter of the primary (assessed surgically or by MRI). Results: Pretreatment results increased with CRC stage. Positivity by stage was: I, 23.7% (14/59); II, 62.1% (54/87); III, 68.6% (70/102); IV, 85.3% (29/34). Level by stage: I, 0.0%; II, 0.06%; III, 0.07%; IV, 4.07%, p < 0.001). Pretreatment levels correlated significantly with tumor size (r = 0.372, p < 0.001). Post-treatment blood was collected a median 2.4mo (IQR 1.7-3.9) after therapy completion. Positivity decreased after completing treatment (Table), with 88.4% of cases (46/52) becoming ctDNA negative. All cases with complete treatment had a reduction in biomarker levels, whereas in those with incomplete therapy, 54.5% (12/22) remained positive and the pre- and post-treatment levels were not significantly different. Of those positive after treatment, 13 had a further blood sample: 8 had become ctDNA negative and all but one remained disease free. Five remained positive and all had further suspected or confirmed disease. Conclusions: Levels of methylated BCAT1 and IKZF1 DNA in blood correlated with tumor burden; levels became undetectable in the majority of patients following completion of planned curative intent treatment. The methylated ctDNA blood test aids monitoring of responses to therapy and identification of those cases with residual cancer who might benefit from ongoing therapy.[Table: see text]

Background: Hepatic resection for colorectal (CRC) metastasis is considered a standard of care. Resection of metastasis isolated to lung also is considered potentially curable, although there is still some variation in recommendations. We explore outcomes for patients undergoing lung resection for mCRC, with the liver resection group as the comparator. Methods: South Australian (SA) metastatic CRC registry data were analysed to assess patient characteristics and survival outcomes for patients suitable for lung or liver resection. Results: A total of 3241 patients are registered on the database to December 2014. One hundred two (3.1 %) patients were able to undergo a lung resection compared with 420 (12.9 %) who had a liver resection. Of the lung resection patients, 62 (61 %) presented with lung disease only, 21 % initially presented with liver disease only, 11 % had both lung and liver, and 7 % had brain or pelvic disease resection. Of these patients, 79 % went straight to surgery without any neoadjuvant treatment and 34 % had lung resection as the only intervention. Chemotherapy for metastatic disease was given more often to liver resection patients: 76.9 versus 53.9 %, p = 0.17. Median overall survival is 5.6 years for liver resection and has not been reached for lung resection (hazard ratio 0.82, 95 % confidence interval 0.54–1.24, p = 0.33). Conclusions: Lung resection was undertaken in 3.1 % of patients with mCRC in our registry. These data provide further support for long-term survival after lung resection in mCRC, survival that is at least comparable to those who undergo resection for liver metastasis in mCRC. Refereed/Peer-reviewed

This study aimed to investigate the cancer characteristics,treatments administered and outcomes for nonagenarians and centenarians diagnosed with mCRC using our state-wide population-based mCRC registry to understand the current patterns of care and outcomes in this age subgroup of patients. Refereed/Peer-reviewed

Introduction: Oxaliplatin-based adjuvant chemotherapy has been the standard of care for resected early colon cancer for over a decade. Recent results from the IDEA meta-analysis attempt to address the question of whether 3 or 6months of adjuvant chemotherapy is preferable in Stage III colon cancer.Areas covered: A review of the literature and recent conference presentations was undertaken on the topic of adjuvant therapy for resected early colon cancers. This article reviews the current evidence for adjuvant treatment of Stage II and III colon cancer, as well as up-to-date data regarding optimal duration of therapy. This article reviews the evidence for lifestyle modifications in the management of early colorectal cancer and other future directions for research in early colon cancer.Expert commentary: In recent years, there have been no advances in the development of novel agents for adjuvant therapy in colorectal cancer. Although the IDEA meta-analysis was negative for its primary non-inferiority endpoint, the detailed results provide valuable information that allows personalisation of treatment regimen and duration.

Background: \ud Patients often ask oncologists how long a cancer has been present before causing symptoms or spreading to other organs. The evolutionary trajectory of cancers can be defined using phylogenetic approaches but lack of chronological references makes dating the exact onset of tumours very challenging.\ud \ud Patients and methods: \ud Here, we describe the case of a colorectal cancer (CRC) patient presenting with synchronous lung metastasis and metachronous thyroid, chest wall and urinary tract metastases over the course of 5 years. The chest wall metastasis was caused by needle tract seeding, implying a known time of onset. Using whole genome sequencing data from primary and metastatic sites we inferred the complete chronology of the cancer by exploiting the time of needle tract seeding as an in vivo ‘stopwatch’. This approach allowed us to follow the progression of the disease back in time, dating each ancestral node of the phylogenetic tree in the past history of the tumour. We used a Bayesian phylogenomic approach, which accounts for possible dynamic changes in mutational rate, to reconstruct the phylogenetic tree and effectively ‘carbon date’ the malignant progression.\ud \ud Results: \ud The primary colon cancer emerged between 5 and 8 years before the clinical diagnosis. The primary tumour metastasized to the lung and the thyroid within a year from its onset. The thyroid lesion presented as a tumour-to-tumour deposit within a benign Hurthle adenoma. Despite rapid metastatic progression from the primary tumour, the patient showed an indolent disease course. Primary cancer and metastases were microsatellite stable and displayed low chromosomal instability. Neo-antigen analysis suggested minimal immunogenicity.\ud \ud Conclusion: \ud Our data provide the first in vivo experimental evidence documenting the timing of metastatic progression in CRC and suggest that genomic instability might be more important than the metastatic potential of the primary cancer in dictating CRC fate.

Objective: Brain metastasis is considered rare in metastatic colorectal cancer (mCRC); thus, surveillance imaging does not routinely include the brain. The reported incidence of brain metastases ranges from 0.6% to 3.2%. Methods: The South Australian mCRC Registry (SAmCRC) was analyzed to assess the number of patients presenting with brain metastasis during their lifetime. Due to small numbers, a descriptive analysis is presented. Results: Only 59 patients of 4,100 on the registry at the time of analysis had developed brain metastasis (1.4%). The clinical characteristics of those with brain metastasis were as follows: the median age was 65.3 years and 51% were female. Where the V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation status of the tumor was known, the majority harbored a KRAS mutation (55%); 31 (53%) underwent craniotomy and 55 (93%) underwent whole-brain radiotherapy. The median survival time from diagnosis of brain metastasis was 4.2 months (95% confidence interval 2.9–5.5). Patients who underwent craniotomy and radiotherapy had superior survival compared to those who underwent whole-brain radiotherapy (8.5 months vs. 2.2 months, respectively). Data from the SAmCRC (a population-based registry) confirm that brain metastases are rare and the median time to development is approximately 2 years. Conclusions: Brain metastasis is a rare outcome in advanced CRC. Patients within the registry tended to be female, young in age, and harbored with higher rates of KRAS mutations. Whether routine surveillance brain scanning should be considered remains controversial given the relative rarity of developing brain metastases in mCRC and ultimately, most patients with central nervous system involvement die from their extracranial disease.

BACKGROUND Previous reports have described differences in biology and outcome for colorectal cancer based on whether the primary is right or left sided. Further division by right, left, and rectum or even exact primary site has also been explored. Possible differences in response to biological agents have also been reported based on side of primary lesion. METHODS We explored the South Australian registry for metastatic colorectal cancer to assess if there were any differences in patient characteristics, prognostic markers, and treatment received and outcomes based on whether the primary was right or left sided. We also explored if differences exist based on left colon and rectum and by exact primary site. RESULTS Two thousand nine hundred seventy-two patients were analyzed. Thirty-five percent had a right-sided primary. The median overall survival for the entire group right versus left was 9.6 versus 20.3 months (P

e15173 Background: PROMs have not been adequately studied in LARC pts who are managed with W&W after a clinical complete response to CRT. The objectives of this study were to evaluate: quality of life measures, bowel function, Fear of Cancer Recurrence (FCR) and survivors’ needs, in this population. Methods: Data were collected from the Flinders Medical Centre W&W prospective database. Questionnaires including Self-Administered Comorbidity (SCQ), EORTC QLQ-C30 and -CR29, EQ-5D-5L, MSKCC Bowel Function Instrument (MBFI), Low Anterior Resection Syndrome (LARS) score, Fear of Cancer Recurrence Inventory-Short Form (FCRI-SF), Cancer Survivors’ Unmet Needs (CaSUN) and Response Efficacy Score (RES) were sent via mail to eligible pts according to a Tailored Design Method. Descriptive statistical analyses were conducted. Results: Of 40 eligible pts, 21 (52.5%) responded: 15 (71%) were male, median age at diagnosis was 66 years (34-81). 5 developed local re-growth (1 had local excision and 4 had ultra-low anterior resection). Median time from end of CRT to data collection was 39.8 months (6.0-77.5). The mean SCQ score was 5.7 (SD 5.5). Mean EQ-5D-5L utility score was 0.84 (SD 0.13), mean EQ-VAS score was 81.9 (SD 12.7) and mean EORTC QLQ global health status score was 76.2 (SD 19.2). The most common symptoms were fatigue (90%), pain (67%) and flatulence (67%). In pts without a re-growth (n = 16), the mean MBFI total score was 27.9 (SD 7.7); based on LARS score: 6 (38%) had no LARS, 5 (31%) had minor LARS and 5 (31%) had major LARS. Mean FCRI-SF score was 11.8 (SD 6.1), clinical level FCR was reported by 2 (9.5%) [cut-off 22] and 4 (19%) pts [cut-off 16]. 10 (47%) reported unmet needs: the most common area was Comprehensive Cancer Care n = 9 (42%). On RES, of 20 responders, 19 (95%) believed W&W was a worthwhile and effective strategy. Conclusions: The most commonly reported symptoms included fatigue, pain and flatulence. LARS was common: in the absence of surgery, LARS is due to CRT. Clinical FCR was uncommon. The majority believed W&W was worthwhile and effective. Larger comparative studies are needed in this group of pts.

Background: Colorectal cancer (CRC) is a common malignancy. There is growing evidence that CRC incidence is increasing in the younger population. There is controversy surrounding the prognosis of young patients with CRC. In this study we reviewed Australian patients with metastatic CRC (mCRC) who were younger than 40 years of age at the time of diagnosis of metastatic disease. To our knowledge this is the first study to focus on this age group with mCRC. Patients and methods: This was a retrospective study using data from the South Australian Metastatic Colorectal Cancer database. We compared patient and disease characteristics, management approaches, and outcomes for age groups < 40 and ≥ 40. A multivariate Cox proportional hazards model was fitted to compare the survival outcomes (death from all causes) between the 2 groups. Results: From 3318 patients, 46 (1.4%) were younger than 40 years of age. In a comparison of patients in the younger than 40-year-old group with the older group, a greater proportion had synchronous metastatic disease (80.4% vs. 64.4%, respectively; P = .04) and disease originating from the left colon (71.7% vs. 61.7%, respectively; P = .035); also a larger proportion in the younger than 40-year-old group received chemotherapy compared with the older group (82.6% vs. 58.7%, respectively; P < .01). In the adjusted multivariate model, survival was not significantly different between the 2 groups (hazard ratio, 0.81; 95% confidence interval, 0.56-1.16; log rank P = .25). Conclusion: Young-onset mCRC patients, when defined as aged younger than 40 years, have equivalent survival compared with their older counterparts. This is despite differences in disease characteristics and management approach between the 2 groups. Refereed/Peer-reviewed

e15510Background: Microsatellite instability (MSI) has been associated with better survival outcomes in early stage CRC. In mCRC MSI is a smaller subgroup (3-5%). There is evolving evidence that tr...

3596Background: The methylated ctDNA biomarkers BCAT1 and IKZF1 are common events in colorectal cancer (CRC), play a role in its development and drugs targeting BCAT1 are available. As these biomar...

739 Background: The benefit of primary tumour resection (PTR) in patients with synchronous mCRC is not clear. The influence of tumour location on PTR benefit is also uncertain. Methods: SAMCRC is a population based registry collating data from all patients in South Australia diagnosed with mCRC from February 2006. We examined outcomes according to whether the primary colorectal tumour was excised within 3 months of diagnosis or remained in situ; we also examined whether outcomes were affected by tumour side (right v left). Registry data was included for patients with synchronous metastic adenocarcinoma from colon or rectum. Exclusion criteria included metastasectomy, tumour resection within 7 days or death within 3 months of mCRC diagnosis. Kaplan Meier analysis was used for Survival. Tumour sidedness and PTR were analysed with a multivariate Cox proportional hazards model. Survival was measured from the landmark date (3 months from date of diagnosis). Results: 2575 patients with synchronous mCRC have entered the database, of which 1869 patients were eligible for the PTR analysis. 50.2% (n = 938) underwent PTR. 481 patients (51.3%) of the PTR analysis group had left-sided primary tumours whilst 436 had right sided tumours (46.5%) which was significant (p < 0.001). 63% of the PTR cohort were male (n = 1006). Site and age metastases were included in the multivariate analysis. PTR was associated with improved survival from landmark compared to no resection (15.0 mo vs 11.2 mo, 95% CI 15.0 – 16.3 vs 11.2 – 12.3, p = 0.031). In the entire synchronous mCRC group, left-sided tumours (62.1%) had a longer median survival (17.8 mo vs 10.4 mo, 95% CI 15.7 – 19.5 vs 10.4 – 11.7 p = < 0.001). An interaction test was performed for sidedness and was not significant. Conclusions: PTR was associated was associated with improvement in survival in this large population based registry. This finding did not differ signifcantly between right and left sided tumours. Survival was superior for patients with left sided tumours, in keeping with established data. Criteria for selection of patients with mCRC who benefit from PTR need to be defined.

759 Background: Microsatellite instability (MSI) has been associated with improved survival outcomes in early stage CRC. In stage IV disease, MSI represents only 3-5% of cases and currently the prognostic implications are less clear. There is however evolving evidence that treatment pathways should include anti-PD-1 antibodies given the encouraging results in heavily pre-treated MSI mCRC patients. We undertook an analysis of the South Australian mCRC population based registry to explore the relevance of MSI status in this population based registry. Methods: The registry was analysed to assess patient characteristics and survival outcomes comparing patients with MSI or microsatellite stable (MSS) disease. K-M survival analysis was used to assess OS. Results: 4359 patients are registered on the data base. 598 (14%) patients had been tested for MSI. 62 (10.1%) of these patients had demonstrable MSI. Patient characteristics and outcomes are summarized in the table. There are statistically higher rates of right sided primary, poorly differentiated pathology and BRAF mutation in the MSI group associated with a trend to reduced survival. Chemotherapy and biological therapy received in the MSI v MSS groups was as follows; 5FU 31% v 25%, 5FU/irinotecan 17% v 12%, 5FU/oxaliplatin 52% v 58%, bevacizumab 31% v 42%, anti-EGFR 0 v 4.6%. Conclusions: The patient characteristics of MSI mCRC are in keeping with those previously reported. MSI in this population based mCRC registry is not associated with a favorable outcome as seen in earlier stage disease compared to patients with MSS disease. The trend to poorer outcomes may support routine testing and potentially an alternate treatment pathway, which may include PD-1 inhibitors.[Table: see text]

701 Background: Management of rectal cancer with synchronous liver metastasis is not clear. Optimal timing of radiotherapy, chemotherapy, resection of primary and liver metastasis is debated. Methods: The South Australian Registry for metastatic colorectal cancer has entered all patients with mCRC since 1st February 2006. Registry data were analyzed to assess patient characteristics, therapy received and outcomes for patients with liver only metastasis and synchronous rectal or colon primary. KM analysis was used for survival outcomes. Results: 2677 patents had synchronous mCRC. 42% (n = 1125) had liver only metastasis (primary: 275 rectal/850 colon). The main differences between rectal/liver vs. colon/liver were: more males (68.7% v 57.8%, p = 0.001), younger age (65.8 v 73.3 years, p < 0.001) and less poorly differentiated histology (14.2% v 24.1%, p = 0.003). The rate of no surgery on the primary was 21.4% for rectal cancers v. 36% for colon (p ≤ 0.001). Liver surgery rates in both groups was similar (28.4% v 23.0% (p = 0.075). Out of the 275 rectal cancer patients, 100 (36.3%) had rectal surgery, 83 (30%) had chemo-RT and 47 (17%) had chemotherapy +/- targeted therapy as initial treatment, 45 (16%) patients had no treatment. Median OS of rectal cancer patients based on their initial treatment was 33.2m (Chemo-RT) vs. 22.2m (surgery) vs. 19.2m (chemotherapy +/- targeted therapy, p < 0.001). The mOS for rectal group was 22.8m v. 14.8m (p = 0.001) for colon group. For patients who had liver surgery mOS was 60.7m vs. 67.1m respectively. Survival was better if primary was rectum or left colon vs. right colon (mOS 18.3m vs 18.8m vs 10.2m respectively p < 0.001). Resection of the primary occurred first in all patients who had liver resection. Conclusions: Patients with synchronous rectal cancer with liver only metastases have better survival compared to those with colon cancer and liver only metastases. Where surgery is possible, OS is equivalent between the two groups and in our registry population surgery on the rectal primary or chemo-RT were found to be the preferred initial treatment for rectal cancer patients with synchronous liver metastases.

752 Background: With improved healthcare we now face an ageing population worldwide. More patients with metastatic colorectal cancer (mCRC) will present at advanced age. Patients with mCRC now have the potential of living longer due to surgery, chemotherapeutic agents and monoclonal antibodies. Australian data (2011) indicated 1.3% of the population are aged over 90 years*. Medical oncologists are now being referred patients in their 90’s and the optimal management for this group is unknown. Methods: The population based South Australian Clinical Registry for mCRC includes all patients with metastatic CRC diagnosed since the 1st February 2006. We examined cancer characteristics, treatments administered and outcomes for patients aged > 90 years. Results: 130 patients of 4199 (3%) were aged 90 years or older. The median age was 92.1 years (range 90-104.8 years). 61% were female, 70% presented with synchronous disease. Organ involvement was as follows; 58% liver, 32% lung, 8% peritoneal and 7% bone. Primary site was: right 46%, left 28%, rectum 20%, unknown 6%. Only 4 patients had KRAS testing (all WT). 44.6% overall have had no surgery for their CRC primary. 24% of those with synchronous disease at diagnosis had resection of primary lesion and 3% had stoma formed for palliation. One patient had lung resection for metastasis. Only 4 patients received systemic therapy (age range 90-93). Lines of therapy delivered; one in 2 patients, two lines in one and 4 lines in one. Aside single agent 5FU, combination therapy (oxaliplatin/FU+/- bevacizumab) was given to two patients and cetuximab single agent in 2 (WT one, unknown one). The median survival overall was 3 months (95% CI 1.4-4.6 months). Two year survival was 10%. Conclusions: This analysis gives us some insight into the management of the very old. Female sex and right sided cancers are more frequent. Systemic therapy is rarely offered and the outlook is poor. Further research to understand whether active therapy is possible or warranted in this age group should be considered. *http://www.abs.gov.au/ausstats/abs@.nsf

754 Background: Questions over the impact of 1st line bevacizumab on subsequent sensitivity to anti-EGFR therapy have been raised with authors hypothesizing that up-front anti-VEGF agent’s use influences biological changes that increase the risk of acquired resistance to subsequent EGFR inhibitors. Methods: Aretrospective cohort study was performed to compare the characteristics and survival of patients who were treated with an anti-EGFR therapy 2nd line and beyond by two groups defined by the 1st line therapy; 1. chemotherapy (chemo) plus bevacizumab (bev) and 2. chemo alone. Pearson chi test analysis was performed to determine whether receiving 1st line bev was associated with worse OS. Results: 348 mCRC patients who received chemo with or without bev and then an anti-EGFR therapy were studied. Patient characteristics are summarised in table. The significant differences between group 1. Vs. 2. were as follows; median age, lower use of single agent FU, KRAS status not tested, and where BRAF MT status was known (11%); BRAF MT rate. Median OS for the 2 groups was 34.2 mths, and 28.2 mths respectively (p = 0.12). Conclusions: Survival was not significantly different between the two groups, and the trend was towards higher OS with chemo plus bev suggesting that in our registry population, bev administration in first line therapy with chemo did not lead to a worse outcome for those patients subsequently receiving anti-EGFR therapy. [Table: see text]

HER2 is an established therapeutic target in breast and gastric cancers. The role of HER2 in rectal cancer is unclear, as conflicting data on the prevalence of HER2 expression in this disease have been reported. We evaluated the prevalence of HER2 and its impact on the outcome of high-risk rectal cancer patients treated with neoadjuvant CAPOX and CRT +/- cetuximab in the EXPERT-C trial. Eligible patients with available tumour tissue for HER2 analysis were included. HER2 expression was determined by immunohistochemistry (IHC) in pre-treatment biopsies and/or surgical specimens (score 0-3+). Immunostaining was scored according to the consensus panel recommendations on HER2 scoring for gastric cancer. Tumours with equivocal IHC result (2+) were tested for HER2 amplification by D-ISH. Tumours with IHC 3+ or D-ISH ratio >= 2.0 were classified as HER2+. The impact of HER2 on primary and secondary end points of the study was analysed. Of 164 eligible study patients, 104 (63%) biopsy and 114 (69%) surgical specimens were available for analysis. Only 3 of 104 (2.9%) and 3 of 114 (2.6%) were HER2+, respectively. In 77 patients with paired specimens, concordance for HER2 status was found in 74 (96%). Overall, 141 patients were assessable for HER2 and 6 out of 141 (4.3%) had HER2 overexpression and/or amplification. The median follow-up was 58.6 months. HER2 was not associated with a difference in the outcome for any of the study end points, including in the subset of 90 KRAS/BRAF wild-type patients treated +/- cetuximab. Based on the low prevalence of expression as recorded in the EXPERT-C trial, HER2 does not appear to represent a useful therapeutic target in high-risk rectal cancer. However, the role of HER2 as a potential predictive biomarker of resistance to anti-EGFR-based treatments and a therapeutic target in anti-EGFR refractory metastatic colorectal cancer (CRC) warrants further investigation. Trial registration: ISRCTN Register: 99828560.

3603 Background: The management of LARC involves NCRT followed by resection +/- adjuvant chemotherapy. Rectal resection has associated short and long-term morbidity and functional compromise. Compl...

e14675 Background: The impact of primary tumor resection on survival in pts with mCRC and unresectable synchronous metastases is unclear. We aimed to examine the association of primary tumor resect...

708 Background: Hepatic resection for CRC metastasis is now considered a standard of care and perioperative chemotherapy may improve outcomes. Resection of metastasis isolated to lung is also considered potentially curable, although there is still some variation in recommendations and no evidence for perioperative or adjuvant chemotherapy. Here, we explore patient characteristics and outcomes for patients undergoing lung resection for mCRC, with the liver resection group as the comparator. Methods: SA mCRC registry data were analysed to assess patient characteristics and survival outcomes between patients suitable for lung or liver resection. K-M survival analysis was used to assess OS. Results: 3,241 patient are registered on the database. 102 (3.1%) patients were able to undergo a lung resection compared to 420 (12.9%) a liver resection. Of the lung resection patients, 21% initially presented with liver only disease, 11% both lung and liver, and 7% brain or pelvic disease. 62 (61%) presented with lung only disease. Of these patients, 79% went straight to surgery and 34% had lung resection as the only intervention. When comparing the groups, they were balanced for age and sex, liver v lung; 67.7 years v 69.5 years, 63.6% v 57.8% male. There was no difference in pathological grade or KRAS MT rate when tested (36% liver v 32% lung). Compared to patients undergoing liver resection, those having lung resection were more likely to be metachronous (75.5% v 44%, p=

Aim: Previous reports have described differences in biology and outcome based on whether the primary bowel cancer is right (R) or left (L) sided. Some authors have, however, argued that separating into right and left is too limited and that different patterns still exist within each sub group. Here we aimed to look at each individual primary site and outcomes from the SA mCRC registry to test this hypothesis. Methods: We assessed for differences in patient characteristics and outcomes based on the standard divisions of primary sites; caecum, ascending (AC), hepatic flexure (HF), transverse (TC), splenic flexure (SF), descending (DC), sigmoid (SC), rectosigmoid (RS) or rectal. Kaplan Meier was used for survival outcomes and a descriptive analysis was undertaken for prognostic markers. Results: 2877 patients were analysed. Primary site frequency was as follows; Caecum 14.6%, AC 9.2%, HF 3.1%, TC 6.2%, SF 2.8%, DC 3.9%, SC 21.9%, RS 6.8% and 26.7% rectum (4% unknown). Differences between sites were age, female sex, rates of poorly differentiated pathology, and rate of lung metastasis. There were no subgroups within the R & L division that stood out as behaving differently. Median age was 76.3 yrs for caecum compared with 69.3 yrs for rectum. Female sex was highest in caecum 52.5% vs. 34.9% rectum. Poorly diff pathology, caecum to SF 30-40.7% vs. DC to rectum 18.3-20.9%. Lung metastasis, caecum to SF 3-6% vs. DC to rectum 9.6-12.8%. There was variation in KRAS mutation; highest 59% in caecum, 48% for DC and Conclusions: Cancer of the caecum had the highest proportion of females, poorly differentiated pathology and KRAS exon 2 mutation. Lung metastases were observed more commonly in cancers that originate from the distal colon to rectum as compared to more proximal cancers. R sided primary sites have a poorer outcome consistently than those designated L. Overall, the SA mCRC data supports a distinction between metastatic tumors of right versus left sides origin, with the transition point being at the splenic flexure. Disclosure: All authors have declared no conflicts of interest.

3540 Background: Previous reports have described differences in biology and outcome based on R or L sided primary bowel cancer. Possible differences in response to biological agents have also been ...

e17584 Background: Colorectal cancer is less common in those younger than 40. Some studies suggest that young patients (pts) with mCRC have more aggressive disease with worse outcomes. Methods: We analysed data from the South Australian Metastatic Colorectal Cancer database, a population based registry that collects data from all pts diagnosed with mCRC in the Australian state of South Australia from February 2006. We studied pts with mCRC who are younger than 40 years (y) and compared them with pts who were 40 y or older. Results: From 2,862 pts, 36 (1.3 %) were younger than 40 y (17.4 -39.7 y, median 35.7 y) and 2826 (98.7%) were 40 y or older (40 – 105.4 y, median 72.7 y). There were no significant differences in pt sex or living in metropolitan versus (vs) rural areas. Disease characteristics including synchronous vs metachronous metastases, site of primary disease (rectal vs colon), grade of the tumour, number of metastatic sites involved (2 or less vs more than 2) and frequency of KRAS mutation were...

e14616 Background: HER-2 is a well established therapeutic target in breast and gastric cancer. The role of HER-2 in rectal cancer is unclear, as conflicting data on prevalence of HER-2 expression have been reported. Preclinical data indicate a potential role of HER-2 in mediating resistance of rectal cancer to chemoradiotherapy and cetuximab. This analysis evaluates the prevalence of HER-2 and its impact on the outcome of high risk rectal cancer patients treated with neoadjuvant CAPOX and CRT ± cetuximab in EXPERT-C. Methods: Eligible patients with available tumour tissue for HER-2 analysis were included. HER-2 expression was determined by immunohistochemistry (IHC) in biopsy and/or surgical specimens (score 0 to 3+). Tumours with equivocal IHC result (2+) were tested for HER-2 amplification by B-DISH. Tumours with IHC 3+ or B-DISH ratio ≥2.0 were classified as HER-2 positive. The impact of HER-2 on primary (CR) and secondary endpoints (RR, PFS, OS) of the study was analyzed. Results: Of 164 eligible study patients, 104 (63%) biopsy and 114 (69%) surgical specimens were available for analysis. Only 3/104 (2.9%) and 3/114 (2.6%) were HER-2 positive, respectively. In 77 patients with paired specimens, concordance for HER-2 status was found in 74 (96%). Overall 141 patients were assessable for HER-2; 6/141 (4.3%) had a HER-2 positive tumour in at least 1 specimen. The median follow-up was 58.7 months. HER-2 expression or amplification was not associated with a difference in outcome for any of the study endpoints, including in the subset of 90 KRAS/BRAF wild type patients treated ± cetuximab. In an exploratory analysis, 44 IHC 0/1+ random specimens were tested by B-DISH and HER-2 amplification was found in 3/38 (7.9%, insufficient material in 6 cases). Conclusions: Based on the low prevalence of expression (according to the classical criteria for defining HER-2 positivity) as recorded in EXPERT-C, HER-2 does not appear to represent a useful therapeutic target for high risk rectal cancer. We did not confirm the role of HER-2 as prognostic factor or potential predictive biomarker for cetuximab-based treatment.

596 Background: Previous reports have described differences in biology and outcome based on whether the primary is R or L sided. Possible differences in response to biological agents have also been reported based on side of primary lesion (SY Brule et al., JCO31, 2013 (supp #3528). Methods: We explored the SA mCRC registry to assess if there were any differences in patient characteristics, treatment received and outcomes based on whether the primary was R (caecum to transverse colon) or L (splenic flexure to rectum) sided (JA Bufill, Ann Int Med. 113, 1990, 779-788). KM was used for survival outcomes and Cox proportional hazards regression modeling was used to assess defined prognostic markers. Results: 2,877 patients were analysed. 33% had R sided primary. Major differences between R and L respectively are as follows; Female 51.3% vs. 37.9% (p =

Background: Patients with metastatic colorectal cancer (mCRC) with BRAF mutation (BRAF MT) generally have a poorer prognosis. BRAF MT may also have implications for treatment strategy. Despite this, inclusion of BRAF in routine molecular testing varies. Here we report the frequency of BRAF reporting in the South Australian (SA) mCRC registry reflecting community practice, together with the survival outcomes based on mutation status. Methods: The SA population-based mCRC registry was analysed to assess the number of patients where a BRAF MT result was available. The patient characteristics are reported and overall survival was analysed using the Kaplan–Meier method. Results: Of the 3639 patients who have been entered in the registry, only 6.2 % (227) have BRAF MT results available. Of the patients tested, the BRAF MT rate is 12.7 %. The mutation rate was highest in rightsided primary; right colon 23 versus left colon 8.9 % and rectum 7 %. There was no significant difference in median age or male/female proportion. The median overall survival (mOS) for BRAF MT versus wild-type (WT) patients is 14.0 versus 32.9 months (p = 0.003). For patients who have chemotherapy (plus or minus surgery) the mOS is 14.6 months BRAF MT versus 36.1 months (p ≤ 0.001) WT. Liver or lung resection was performed on only 8 % of the BRAF MT group versus 26.5 % of the WT group. Conclusion: Results in a population setting confirm our understanding that BRAF MT is more frequently right sided and of lower frequency in rectal cancer. Survival is lower for patients with mCRC that have BRAF MT, regardless of the therapy. BRAF testing is currently performed infrequently in an Australian setting despite its importance as a significant prognostic factor, and the implications for alternate therapeutic approaches. Refereed/Peer-reviewed