Background: Colorectal cancer (CRC) incidence and mortality rates have been increasing among young patients (YP), for uncertain reasons. It is unclear whether YP have a distinct tumor biology or merit a different treatment approach to older patients (OP). Methods: We reviewed prospectively collected data from consecutive patients with metastatic CRC (MCRC) enrolled in the multi-site Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) Australian registry. Clinicopathological features, treatment and survival outcomes were compared between YP (<50 years) and OP (>= 50 years). Results: Of 3692 patients diagnosed August 2009 - March 2023, 14 % (513) were YP. YP were more likely than OP to be female (52% vs. 40 %, P < 0.0001), have ECOG performance status 0-1 (94% vs. 81 %, P < 0.0001), to have a left-sided primary (72% vs. 63 %, P = 0.0008) and to have fewer comorbidities (90% vs. 60 % Charleston score 0, P < 0.0001). There were no differences in the available molecular status, which was more complete in YP. YP were more likely to have de novo metastatic disease (71% vs. 57 %, P < 0.0001). YP were more likely to undergo curative hepatic resection (27% vs. 17 %, P < 0.0001), to receive any chemotherapy (93% vs. 78 % (P < 0.0001), and to receive 3+ lines of chemotherapy (30% vs. 24 % (P < 0.0034)). Median first-line progression free survival (10.2 versus 10.6 months) was similar for YP vs OP, but overall survival (32.1 versus 25.4 months, HR = 0.745, P < 0.0001) was longer in YP. Conclusion: Known prognostic variables mostly favored YP versus OP with newly diagnosed mCRC, who were also more heavily treated. Consistent with this, overall survival outcomes were improved. This data does not support that CRC in YP represent a distinct subset of mCRC patients, or that a modified treatment approach is warranted.

Background:This study explores the potential benefits of neoadjuvant chemotherapy in borderline resectable (BR) pancreatic adenocarcinoma. Despite neoadjuvant treatment (NAT) increasingly being utilised, uncertainty remains as to the optimal approach. Patients and methods:This study assessed clinical outcomes for 218 consecutive BR patients from the PURPLE registry. We compared initial surgery (IS) to NAT overall, and between different chemotherapy regimens. Results:Of 1314 non-metastatic patients enrolled, 218 (17%) were considered BR. Of 28 planned for IS, 11/28 (39%) had their tumour excised compared to 68/152 (45%) with NAT (P = 0.59). Among those who received NAT and were resected, 52/100 (52%) received FOLFIRINOX (P = 0.234) and 8/28 (29%) received nab-paclitaxel with gemcitabine (nabPGem). There was no difference in median overall survival (OS) [hazard ratio (HR) 0.72, P = 0.199] between pooled NAT versus IS. Neoadjuvant FOLFIRINOX was associated with improved R0 resection rates (26% versus 7%, P = 0.07) and lower perineural invasion (51% versus 82%, P = 0.02) compared to IS in resected specimens. Neoadjuvant FOLFIRINOX improved OS (HR 0.53, P = 0.02), with a 23% improvement in 2-year OS. There was no difference in survival outcomes between IS and nabPGem. Conclusions:The results of our study suggest that neoadjuvant FOLFIRINOX could improve R0 resection rate and OS compared to IS.

Effective treatment options remain an unmet need for patients (pts) with previously treated non-microsatellite instability-high/mismatch repair deficient (non-MSI-H/dMMR) mCRC. We present results from the global, randomized, open-label phase 3 LEAP-017 study (NCT04776148) evaluating the efficacy and safety of lenvatinib + pembrolizumab versus standard-of-care (SOC) in previously treated non-MSI-H/dMMR mCRC.

In the phase Ib/II EVICT trial, the combination of vemurafenib and erlotinib demonstrated promising efficacy with response rates of 32% (10/31; 16% -5/31 confirmed) in patients (pts) with BRAF V600E mt mCRC and 43% (3/7) in pts with other cancers. The overall clinical benefit rate (partial response + stable disease) was 71% (27/38). Here we report the utility of ctDNA as a biomarker to predict outcomes and understand mechanisms of treatment resistance. Serial plasma samples were available from 25 pts. Paired baseline and progression samples were analyzed by targeted sequencing (AVENIO ctDNA expanded assay, Roche diagnostics). Droplet digital PCR was used to serially monitor mutations of interest. BRAF V600E mt ctDNA was detected at baseline in 21/25 pts (84%). Other frequently altered genes included TP53 (60%), EGFR (52%), and MET (40%), with mutational burden higher in pts who did not derive clinical benefit (P=0.04). MET amplification was associated with inferior overall survival (OS) (median OS 4.9 vs 8.8 months; HR 2.2; [95% CI 0.84-6.0]; P=0.04). Decline in ctDNA levels (copies/mL) between baseline to week 2 was greater in pts who derived clinical benefit (P<0.001). Reduction in ctDNA variant allele fraction at 2 weeks predicted longer progression free survival (PFS) (median PFS 1.8 vs 6.4 months; HR 3.6, 95% CI 1.30-9.76, P<0.001) and OS (median OS 5.6 vs 9.9 months; HR 2.9, 95% CI 1.01-8.36, P<0.01). Of the 18 pts with plasma available at progression, 9/18 (50%) showed emergence of >1 KRAS or NRAS mutation. Polyclonal KRAS mutations were observed in 6/9 pts (67%). Other frequently acquired MAPK pathway alterations included MAP2K1 mutations (22%) and MET amplification (17%). In pts with BRAF V600E mt cancers treated with vemurafenib and erlotinib, baseline ctDNA profile and an early decline in ctDNA were predictive of clinical outcomes. ctDNA analyses provided a mechanistic understanding of intrinsic and acquired resistance, revealing frequent evidence of convergent evolution and MAPK pathway reactivation as the dominant mechanism of therapeutic escape.

Background: Phase 3 trials have identified FOLFIRINOX (Oxaliplatin, Irinotecan, Fluorouracil and Leucovorin) as the most active chemotherapy regimen in metastatic pancreatic ductal adenocarcinoma (PDAC); however, this regimen is not always selected for use by clinicians due to toxicity. It is unknown whether results from FOLFIRINOX in clinical practice in the Australasian population reflect that of the international trials. Methods: An international multi-centre retrospective study of consecutive patients with PDAC was performed using the Australasian Pancreatic cancer registry (PURPLE: Pancreatic cancer: Understanding Routine Practice and Lifting End Results). The database was queried to identify patients receiving FOLFIRINOX. Baseline characteristics including resectability of disease as assessed by the centre, treatment details, toxicity and outcome data were analysed. Efficacy measures included objective response (OR), overall survival (OS) and progression-free (progression/recurrence) survival (PFS). Results: From a total of 774 patients, 55 (7%) received FOLFIRINOX. Median age of FOLFIRINOX-treated patients was 57 yrs (range: 41–80). The ECOG performance score was 0-1 for 96%. FOLFIRINOX was administered for borderline resectable disease (BRD) in 28 cases and for metastatic disease (MD) in 16; the median number of cycles were 6 (range 3-16) and 8 (range 3-12) in patients with BRD and MD respectively. 63% (15/24) of patients had OR, defined by CT following neoadjuvant FOLFIRINOX and 13 of 26 (50%) proceeded to curative intent surgery. Median OS and PFS were 34 and 15 months respectively in patients who had resection compared to 17 and 8 months in patients with unresectable or MD. The most common grade 3/4 toxicities were diarrhoea (25%) and myelosuppression (21%). 35% of patients received GCSF and 46% experienced at least one admission related to FOLFIRINOX toxicity. Conclusions: Our study shows a modest overall uptake of FOLFIRINOX in routine practice. Where FOLFIRINOX is used in patients with BRD the conversion rate to resectable is promising. Survival outcomes in patients with MD approach that seen in clinical trials; however, adverse events are frequent, most notably diarrhoea and haematological toxicities. Legal entity responsible for the study: Systems Biology and Personalised Medicine Division, Walter and Eliza Hall Institute of Medical Research, VIC, Australia. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

BACKGROUND:The Australian National Bowel Cancer Screening Program (NBCSP) has been offering age-based faecal occult blood testing since 2006. With the rapid expansion of this programme, the NBCSP will ultimately offer biennial screening to all 50-74 years old by 2020. Participation rates remain low. Previous reports have described an increased proportion of earlier stage cancers in patients with NBCSP-detected tumours.METHODS:Data on consecutive patients enrolled into a prospective, comprehensive, multidisciplinary database at six Victorian hospitals were examined. Clinicopathologic and outcome data were compared for NBCSP and symptomatic presentation patients.RESULTS:We identified 3743 patients that presented with colorectal cancer (CRC) at participating hospitals since May 2006. Of 1930 patients aged between 50 and 70 years, 141 (7.3%) had a NBCSP detected cancer, 1441 (74.7%) presented with symptoms and 266 (13.8%) were diagnosed through screening outside of the NBCSP. Based on the American Society of Anaesthesiology score, the NBCSP patients were fitter. They had an earlier stage of diagnosis and were more likely to be female and less likely to have lymphovascular invasion or to present as an emergency. NBCSP detected patients had a lower rate of recurrence (HR 0.17, P = 0.0001) and fewer deaths (HR 0.19, P = 0.005).CONCLUSIONS:Patients with NBCSP-detected CRC have a markedly reduced risk of CRC recurrence and death compared with patients with a symptomatic presentation. The dominant driver of this appears to be earlier stage at diagnosis. Increased promotion of the impact of the NBCSP, including data related to the survival impact, should be undertaken to increase participation rates and achieve further survival gains.

BACKGROUND:Prior studies have suggested improved outcomes for cancer patients managed in private centres, despite universal healthcare within Australia.AIMS:To compare patient, disease, treatment and survival data for metastatic colorectal cancer (mCRC) managed in private versus public centres.METHODS:Analysis of prospectively collected registry data for consecutive patients with mCRC managed at 16 participating centres from July 2009.RESULTS:Data for 1065 patients were examined. Age, gender and Charlson comorbidity score were similar for public and private patients. Private patients were more commonly Eastern Cooperative Oncology Group performance score 0-1 (85% vs 78%, P = 0.008), in the highest Index of Relative Socioeconomic Advantage and Disadvantage quintile (57% vs 18%, P < 0.001) or had a single metastatic site (62% vs 54%, P = 0.009). Patients treated in private were more likely to receive chemotherapy (84% vs 70%, P < 0.001), bevacizumab (59% vs 50%, P = 0.008), be treated with curative intent (37% vs 26%, P < 0.001) and undergo metastasectomy (30% vs 22%, P = 0.001). These management differences remained statistically significant after adjusting for baseline characteristics. Management in the private setting was associated with superior overall survival (median 27.9 vs 20 months, hazard ratio 0.7, 95% confidence interval: 0.57 to 0.86, P = 0.001), significant in multivariate analysis adjusting for all baseline covariates.CONCLUSIONS:Significant differences in baseline characteristics were noted for private versus public patients. However, these do not explain the higher rates of treatment delivery in the private setting, which likely contributed towards the observed survival difference. Further studies are required to determine if the increased likelihood of intervention in the private setting is driven by patient, clinician and/or institutional factors.

Background Epithelial ovarian cancer (EOC) mortality rates have remained unchanged in 30 years. The most common EOC subtype, high-grade serous ovarian carcinoma (HG-SOC), can be divided into four subgroups on the basis of molecular characteristics. The C5 subgroup is defined by MYCN pathway activation and carries a poor prognosis. The commonly used EOC cell lines are poor models of HG-SOC, whereas patient-derived xenografts (PDX) retain pathological and immunohistochemical features of primary tumour, providing a valuable preclinical resource for therapeutic exploration. Methods Fourteen "C5-like" HG-SOC PDX were generated from tumour tissue transplanted into NOD/SCIDIL2Rγnull mice. Three were from a consecutive cohort of HG-SOC PDX identified by qRT-PCR of the MYCN pathway and the rest from a separate cohort by gene expression analysis. Molecular analysis done included qRT-PCR for MYCN, HMGA2, LIN28B, and sequencing of DNA repair genes. In-vivo response to cisplatin (intraperitoneal on days 1, 8, and 18) is underway, because platinum response provides prognostic information. Tumour volume is measured twice weekly and mice with tumours larger than 0.7 cm3 are euthanised. PDX are deemed sensitive if response is maintained for 100 or more days; resistant if they had stable disease or relapsed in less than 100 days; and refractory if they progressed on treatment. Investigation of in vivo response to compounds targeting the MYCN pathway is underway and each response is considered in light of molecular phenotype. Findings Preliminary data revealed six "C5-like" PDX overexpressed LIN28B and eight overexpressed MYCN. Three overexpressed CCNE1 (drug resistance marker) and three PDX harboured mutations in DNA repair genes (marker of platinum sensitivity). Two PDX were sensitive to cisplatin, two were resistant, four were refractory, and one showed mixed response. Interpretation This cohort of "C5-like" HG-SOC PDX depicts molecular complexity and treatment response heterogeneity. Use of these molecularly annotated PDX to demonstrate novel effective therapies targeting the MYCN pathway will inform clinical trial design. Epithelial ovarian cancer (EOC) mortality rates have remained unchanged in 30 years. The most common EOC subtype, high-grade serous ovarian carcinoma (HG-SOC), can be divided into four subgroups on the basis of molecular characteristics. The C5 subgroup is defined by MYCN pathway activation and carries a poor prognosis. The commonly used EOC cell lines are poor models of HG-SOC, whereas patient-derived xenografts (PDX) retain pathological and immunohistochemical features of primary tumour, providing a valuable preclinical resource for therapeutic exploration. Fourteen "C5-like" HG-SOC PDX were generated from tumour tissue transplanted into NOD/SCIDIL2Rγnull mice. Three were from a consecutive cohort of HG-SOC PDX identified by qRT-PCR of the MYCN pathway and the rest from a separate cohort by gene expression analysis. Molecular analysis done included qRT-PCR for MYCN, HMGA2, LIN28B, and sequencing of DNA repair genes. In-vivo response to cisplatin (intraperitoneal on days 1, 8, and 18) is underway, because platinum response provides prognostic information. Tumour volume is measured twice weekly and mice with tumours larger than 0.7 cm3 are euthanised. PDX are deemed sensitive if response is maintained for 100 or more days; resistant if they had stable disease or relapsed in less than 100 days; and refractory if they progressed on treatment. Investigation of in vivo response to compounds targeting the MYCN pathway is underway and each response is considered in light of molecular phenotype. Preliminary data revealed six "C5-like" PDX overexpressed LIN28B and eight overexpressed MYCN. Three overexpressed CCNE1 (drug resistance marker) and three PDX harboured mutations in DNA repair genes (marker of platinum sensitivity). Two PDX were sensitive to cisplatin, two were resistant, four were refractory, and one showed mixed response. This cohort of "C5-like" HG-SOC PDX depicts molecular complexity and treatment response heterogeneity. Use of these molecularly annotated PDX to demonstrate novel effective therapies targeting the MYCN pathway will inform clinical trial design.

A range of treatments are available for patients with metastatic colorectal cancer (mCRC). An initial period without active treatment, a 'watch and wait approach', is variably employed in routine practice; however, there is no data to support this approach.We prospectively collected data regarding clinician treatment recommendations for patients with newly diagnosed mCRC in addition to subsequent treatment and outcomes. Follow-up and management was according to standard protocols.Seven hundred and thirty-six patients (59.1% male, 40.9% female) with mCRC (January 2003-December 2010) were analysed; the median age was 67.9 years (range 26.2-95.5). Three hundred and seventy-seven patients (51.2%) received immediate chemotherapy. For 133 (18.1%), treatment was considered inappropriate. 34 patients (4.6%) declined therapy. For 192 (26.1%), a watch and wait policy was adopted and 168 (87.5%) of these received treatment, at a median of 3.7 months (range 2-35 months) from diagnosis. Compared with patients immediately treated, the number receiving all active chemotherapy agents (30.4 versus 39.3%) was similar and median survival (27 versus 17 months, P = 0.0008) was superior.Our study demonstrates that a substantial minority of patients underwent an initial watch and wait approach. Ultimately, they received a similar treatment exposure to patients treated immediately and the survival outcomes were not compromised.

Concurrent and post-radiotherapy temozolomide (T) significantly improves survival in patient with newly diagnosed glioblastoma multiforme. We aimed to assess the activity of the combination of T and pegylated liposomal doxorubicin (PLD) in this population. A combination of T (days 1-5, 200mg/m(2) orally) and PLD (day 1, 40 mg/m(2) intravenous) was given every 4 weeks for six cycles following chemo-radiotherapy as a post-operative treatment. The primary endpoint was 6-month progression free survival (6PFS). Of the 40 patients who enrolled (53 years median age, 73% male), the 6PFS was 58% (95% confidence interval [CI], 41-72%). The median time to progression was 6.2 months (95% CI, 5.6-8.0 months) and overall survival (OS) was 13.4 months (95% CI, 12.7-15.8 months). Thirty-four patients had measurable disease: one had a complete response (3%), 28 had stable disease (82%), and five had progressive disease (15%). Treatment was well tolerated: hematological toxicity included grade 3 neutropenia (8%). Grade 3 non-hematologic toxicity included nausea and vomiting (8%) and palmar-plantar toxicity (5%). We concluded that combination T and PLD is well tolerated but does not add significant clinical benefit regarding 6PFS and OS.

e15046 Background: Randomised studies have defined adjuvant chemotherapy as standard treatment for stage III colon cancer (SIIICC), with multiple options available. For stage II (SII) disease, the selection of patients for adjuvant treatment remains controversial. There remains limited data on clinician decision making regarding adjuvant chemotherapy in routine clinical practice. Methods: A review of patients treated with SII & IIICC at 4 hospitals, utilising data from BioGrid Australia, where clinician choice and rationale were prospectively documented. Results: 372 patients (37%) with SII and 307 (30%) with SIIICC were identified from 1015 CC patients treated from January 2003 till November 2008. Median age was 68 years, 51% were male; 49% female. 66 (25%) of patients with SIIICC were not offered chemotherapy, predominantly due to advanced age or co-morbidity. Since oxaliplatin and capecitabine became widely available in 2005, 66% of treated patients have received oxaliplatin based therapy, 15% bolus 5-FU alone and 19% capecitabine. For SII disease, overall 81 (26%) pts received adjuvant chemotherapy. Age was the dominant influence on treatment choice with 41% aged 70 (p<0.001) receiving treatment. Patients with high risk features were also more likely to receive adjuvant therapy. (p= 0.006 for those with lymphovascular invasion and p= 0.0068 for those with T4 tumours). Dose reductions and completion rates were similar for SII and III disease, and for older and younger patients. Conclusions: Over 25% of patients with SIIICC do not receive adjuvant chemotherapy in routine practice, with physicians basing non-treatment recommendations predominantly on patient age and co-morbidity. Where treatment is used, oxaliplatin-based therapy is the dominant regimen, except in older patients. In SIICC, adjuvant chemotherapy is used in one in four patients, more frequently in younger patients and those with high risk features. No significant financial relationships to disclose.

Objective The optimal strategy for elective distant staging of colorectal carcinoma (CRC) has yet to be defined, with current guidelines based on small and limited series. One specific issue requiring review is the value of routine computerized tomographic (CT) chest examination. Also lacking is data on current routine clinical practice.Method A retrospective chart review of consecutive cases of elective surgery for CRC from five hospitals.Results Two hundred and fifty-seven cases were reviewed, 128 colon and 129 rectal primaries. 164 (64%) of patients overall, ranging from 45% to 88% across the individual centres, had a preoperative serum CEA level performed. CT abdomen/pelvis was performed in 222 (86%) of cases, ranging from 69% to 98% per centre. CT chest was performed in 95 (37%) of cases, 47% of rectal vs 29% of colon cancers (P = 0.004). In 17 cases (18%) CT chest examinations revealed abnormalities suspicious for metastatic disease, leading to a change in management in six (35%) of these cases. Of the 17 cases with an abnormal CT chest, in only 5 of the 14 (36%) where carcinoembryonic antigen (CEA) levels were also recorded was this increased, and in only three (21%) was this markedly (> 10 mu g/l) elevated.Conclusions Substantial variability exists in the preoperative evaluation of patients with CRC. Many patients do not have a CEA and/or abdominal imaging performed. Where performed, CT chest revealed suspicious findings in a significant number of patients, the vast majority of whom had a normal or near normal CEA. Future studies are required to define optimal preoperative staging.