Rectal Primaries Research Articles

Identification of somatic alterations associated with brain metastases from a colorectal origin.

210 Background: Colorectal brain metastases (cBM) confer a devastating prognosis with survival of less than 13 months. Identifying genomic signatures to predict and guide treatment for these patients would be a valuable adjunct. This study evaluated genomic and clinicopathological features specific to cBM. Methods: cBM patients from the MSK-MET cohort were evaluated in comparison to other colorectal cancer patients with extracranial metastases (cOM). Clinicopathologic features and genomic alterations were analyzed with MSK-IMPACT, a targeted DNA sequencing panel for solid tumors and matched blood specimens. We considered mutations, copy number alterations, and fusions. Analyses of genomic features were restricted to microsatellite stable (MSS) patients. q-values were computed using Benjamini-Hochberg correction to account for multiple hypothesis testing. Patient record review identified patients with sequenced matched samples from the primary colorectal tumor and the brain metastases, which were then examined for loss and gain of assessed genetic alterations. Results: Of 130 patients with cBM identified from the cohort, 20 samples were from brain metastases, 52 from the primary CRC, and 58 from other metastatic sites. Average time to diagnosis of cBM was 3.5 years after primary colorectal cancer diagnosis and average time to death was 10 months after cBM diagnosis. Compared to the 3,383 cOM patients, cBM patients had significantly higher rates of both MSS CRC primaries (p<0.001, 122/130 cBM were MSS vs. 3,038/3,382 cOM) and primaries that originated in the rectum (p<0.002, with 38/130 cBM primaries from the rectum vs. 695/3,382 cOM rectal primaries). Somatic alterations in the KRAS, BRCA2, CDK8 and ERCC5 genes were significantly more frequent in patients with cBM compared to cOM patients (all p<0.001) (Table 1). Of the 9 patients who had matched primary and metastatic brain tissue sequenced, KRAS alterations were shared between the primary and brain metastasis in 2/9, ERBB3 and ERCC5 in 2/9, p53 in 6/9, and APC in 6/9 patients. In addition, newly acquired private alterations found only in the brain metastasis samples of matched patients included PIK3RI, ARID5B, NOTCH4, CYLD and SMAD4. Conclusions: We identify new genomic and clinical factors in cBM patients, including somatic alterations in potentially clinically actionable targets. To further explore potential clinical utility, these findings require validation in an independent cBM clinicogenomic dataset.[Table: see text]

Atypical (non-V600E) BRAF mutations in metastatic colorectal cancer in population and real-world cohorts.

BRAF-V600E mutation (mt) is a strong negative prognostic and predictive biomarker in metastatic colorectal cancer (mCRC). Non-V600Emt, designated atypical BRAFmt (aBRAFmt) are rare, and little is known about their frequency, co-mutations and prognostic and predictive role. These were compared between mutational groups of mCRC patients collected from three Nordic population-based or real-world cohorts. Pathology of aBRAFmt was studied. The study included 1449 mCRC patients with 51 (3%) aBRAFmt, 182 (13%) BRAF-V600Emt, 456 (31%) RAS&BRAF wild-type (wt) and 760 (52%) RASmt tumours. aBRAFmt were seen in 2% of real-world and 4% of population-based cohorts. Twenty-six different aBRAFmt were detected, 11 (22%) class 2 (serrated adenocarcinoma in 2/9 tested), 32 (64%) class 3 (serrated in 15/25) and 4 (8%) unclassified. aBRAFmt patients were predominantly male, had more rectal primaries, less peritoneal metastases, deficient mismatch repair in one (2%), and better survival after metastasectomy (89% 5-year overall survival [OS]-rate) compared with BRAF-V600Emt. aBRAFmt and BRAF-V600Emt had poorer performance status and received fewer treatment lines than RAS&BRAFwt and RASmt. OS among aBRAFmt (median 14.4 months) was longer than for BRAF-V600Emt (11.2 months), but shorter than for RAS&BRAFwt (30.5 months) and RASmt (23.4 months). Addition of bevacizumab trended for better OS for the aBRAFmt. Nine patients with aBRAFmt received cetuximab/panitumumab without response. aBRAFmt represents a distinct subgroup differing from other RAS/BRAF groups, with serrated adenocarcinoma in only half. OS for patients with aBRAFmt tumours was slightly better than for BRAF-V600Emt, but worse than for RASmt and RAS&BRAFwt. aBRAFmt should not be a contraindication for metastasectomy.

Survival outcomes for patients with colorectal cancer with synchronous liver only metastasis.

Colorectal cancer with synchronous liver-only metastasis is managed with a multimodal approach, however, optimal sequencing of modalities remains unclear. A retrospective review of all consecutive rectal or colon cancer cases with synchronous liver-only metastasis was conducted from the South Australian Colorectal Cancer Registry from 2006 to 2021. This study aimed to investigate how order and type of treatment modality affects overall survival. Data of over 5000 cases were analysed (n = 5244), 1420 cases had liver-only metastasis. There were a greater number of colon than rectal primaries (N = 1056 versus 364). Colonic resection was the preferred initial treatment for the colon cohort (60%). In the rectal cohort, 30% had upfront resection followed by 27% that had chemo-radiotherapy as 1st line therapy. For the colon cohort, there was an improved 5-year survival with surgical resection as initial treatment compared to chemotherapy (25% versus 9%, P < 0.001). In the rectal cohort, chemo-radiotherapy as the initial treatment was associated with an improved 5-year survival compared to surgery or chemotherapy (40% versus 26% versus 19%, P = 0.0015). Patients who were able to have liver resection had improved survival, with 50% surviving over 5 years compared to 12 months in the non-resected group (P < 0.001). Primary rectal KRAS wildtype patients who underwent liver resection and received Cetuximab had significantly worse outcomes compared to KRAS wildtype patients who did not (P = 0.0007). Where surgery is possible, resection of liver metastasis and primary tumour improved overall survival. Further research is required on the use of targeted treatments in patients undergoing liver resection.

Assessment of complete pathologic response after neoadjuvant immunotherapy for MSI-H gastrointestinal cancers.

43 Background: Immunotherapy (IO) has shown remarkable efficacy in gastrointestinal (GI) cancers with high microsatellite instability (MSI-H). We evaluated real world outcomes of patients treated with neoadjuvant IO for MSI-H colorectal (CRC) and gastroesophageal (GE) cancers. Methods: We queried diagnoses, pathology reports, and clinic notes of patients receiving IO at Massachusetts General Hospital from October 2014 to March 2022 using the Research Patient Data Registry and MATLAB. 1140 patients were identified with esophageal, gastric, colon, or rectal primaries. Of these, 56 were MSI-H and seven received neoadjuvant IO with curative intent. Results: Of the seven patients who received neoadjuvant IO for MSI-H CRC or GE cancers, three patients achieved complete pathologic response (pCR). Three patients had partial responses; one had a single residual lymph node tumor cell, one had residual T1b tumor and negative nodes, and one had residual T3 tumor and positive nodes. All patients with pCR had non-metastatic disease. Three of four patients with partial responses or progression had metastatic disease. Five patients had no recurrence by median follow-up of 10 months post-resection. One patient's cancer recurred 15 months post-resection, and one patient had progressive disease on neoadjuvant IO so did not undergo primary resection. Conclusions: Neoadjuvant IO shows promise for MSI-H GI cancers. Three of seven patients (43%) had pCR and three others (43%) had notable partial responses. There is a need to understand IO-refractory primary tumors and the differing effects of IO in local versus metastatic disease. While our data is limited by sample size, larger clinical trials can establish the safety and utility of neoadjuvant IO, potentially sparing many patients from surgery. We will collaborate with other centers for a larger scale analysis on neoadjuvant IO in MSI-H GI cancers. [Table: see text]

Abstract 3634: Integrative analysis of the contribution of genomic and clinical factors to worse clinical outcomes in non-Hispanic Black patients with colorectal cancer

Abstract Non-Hispanic Black (NHB) patients have higher incidence and higher mortality from colorectal cancer (CRC) than non-Hispanic white (NHW) patients. The extent to which this aggressive behavior in NHB patients is driven by differences in cancer genomics is presently unknown. We analyzed clinical and genomic data from 3,963 CRC patients treated at Memorial Sloan Kettering, including 336 (8%) NHB and 3,627 (92%) NHW patients. Tumors were sequenced using the clinical MSK-IMPACT test, a targeted next-generation DNA sequencing assay that identifies mutations, copy number changes and structural rearrangements in 341-505 genes using solid tissue and matched blood. No significant differences by race were observed for stage at diagnosis or sex. While the difference in median age at diagnosis was small (53.4 for NHB vs. 55 years for NHW patients, p=0.012), significantly fewer NHB patients were diagnosed after 65 years of age (17% vs. 27%, p=0.001). Right-sided colon tumors were more common among NHB patients (37% vs. 25%, p=0.02); the proportion of rectal tumors was similar in both racial groups (31% in NHB vs. 34% in NHW patients, n.s.). Hypermutated tumors, including tumors with microsatellite instability (MSI) and POLE hypermutants, were more frequent among NHW patients (12% vs. 8%, p=0.02). Right-sided tumors were more frequently MSI/hypermutated in the NHW patients (27% vs. 13%, p=0.008), whereas no differences by race were observed for left-sided colon (5% vs. 1%, n.s.) or rectal primaries (4% vs. 5%, n.s.). Genomic analysis of the non-hypermutated tumors revealed no significant differences in tumor mutational burden or fraction of genome altered between racial groups. Tumors in NHB patients were enriched in KRAS mutations (60% vs. 45%, p&amp;lt;0.001), but G12C mutations accounted only for 3% of all driver KRAS mutations in NHB patients vs. 8% of all driver mutations in NHW patients (p=0.01). BRAF mutations were more frequent in non-hypermutated NHW patients (7% vs. 3%, p=0.006), but the overall frequency of RTK/RAS pathway alterations was higher in the NHB group (74% vs. 66%, p=0.004). Even though all patients were treated at the same single institution during the study, NHB patients had shorter overall survival (OS) from the time of sequencing (median 28 months [95% CI 25-38] vs. 50 months [95% CI 47-53], p&amp;lt;0.001). NHB patients also had worse OS [HR 1.64, CI 1.3 - 2.1, p&amp;lt;0.001] in a multivariate analysis using Cox Proportional-Hazards and accounting for age at diagnosis, stage at diagnosis, body mass index, primary tumor location, MSI status and oncogenic alterations in APC, TP53, KRAS, SMAD4, and BRAF. Our data confirms that NHB patients with CRC have worse clinical outcomes than NHW patients. Clinically relevant differences in the frequency of alterations in cancer driver genes are observed based on racial origin, but they do not fully explain the difference in survival. Citation Format: Henry Walch, Anisha Luthra, Walid K. Chatila, Fan Wu, Debyani Chakravarty, Chin-Tung Chen, Rupa Sood, Dana M. Omer, Jesse J. Smith, Nikolaus Schultz, Karuna Ganesh, Julio Garcia-Aguilar, Rona Yaeger, Francisco Sanchez-Vega. Integrative analysis of the contribution of genomic and clinical factors to worse clinical outcomes in non-Hispanic Black patients with colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3634.

P-294 Colon carcinoma in adolescents and young adults, not so rare: Experience from an Indian cancer center

The rise of colorectal carcinoma in adolescents and young adults (AYA) is a growing global concern. Limited studies are available which have focused on colon cancer in this population. We aimed to assess clinicopathologic features and outcomes of colon carcinoma in this population. We conducted a retrospective study including patients with colon carcinoma aged 13 to 30 years who presented to Tata Medical Center between 1 Jan 2012 and 31 Dec 2020. Information extracted from electronic medical records (EMR) included demographics, risk factors, stage at presentation, pathologic information, treatment, and follow-up details. Rectal primaries were excluded. Overall survival (OS) was estimated with the Kaplan-Meier method and Cox proportional hazard model was used to identify factors associated with survival. 2845 patients with colon cancer were registered in the hospital during this period. A total of 148 (5.8%) patients belonged to the age group of AYA, with the majority being males (58%). A family history of cancer was present in 36% of cases. Hereditary cancer syndrome was present in 26 (17.6%) patients (Lynch syndrome 10.1%, familial adenomatous polyposis 5.4%, and others 2%). The most common presenting features were bleeding (45.9%) and altered bowel (41.2%). The most common site was sigmoid colon in 76(51.4%) cases, while tumors arising from descending, transverse, and ascending colon were 12.2%, 16.9%, and 19.6%, respectively. The majority of them had signet ring morphology (58%). Sixty-two (49.1%) patients initially presented with metastatic disease. The distribution of patients in stages I, II, III were 4.1%, 16.2%, and 37.8%, respectively. At a median follow-up of 44 (95% confidence interval [CI] 33.8- 61.5) months, 5-year OS was 37.2% (95% CI 31.8-42.8) in the entire cohort. Five-year OS for stages I, II, III, and IV were 100%, 53%, 26%, and 16%. Adverse histology (p=0.001) and higher stage at presentation (p < 0.001) were associated with poorer survival. The proportion of AYA patients with colon carcinoma was more than expected, and they presented with advanced stages and poorer histology. Most patients had sporadic cancers. Five-year OS for stages II-IV was worse than those reported in older patients.

Exact Primary Tumor Location in mCRC: Prognostic Value and Predictive Impact on Anti-EGFR mAb Efficacy.

Simple SummarySidedness of primary tumor is a well-established prognostic marker and is predictive for anti-EGFR efficacy in RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients. As molecular markers change rather continuously throughout the colon, we ask whether the exact primary tumor location (PTL) is a better prognostic marker than sidedness and predictive for anti-EGFR efficacy in RAS/BRAF wild-type mCRC. We retrospectively analyzed five studies containing various therapy protocols concerning primary tumor location, dividing the colorectal frame into six segments. In our cohort, PTL has a prognostic impact on disease spread and overall survival. Only distal segments benefitted when receiving anti-EGFR containing therapy regarding overall survival. Intermediate segments were indifferent and caecal primaries had a detrimental effect receiving anti-EGFR based therapy. Being a retrospective analysis and challenging the standard of basing anti-EGFR treatment on sidedness in RAS/BRAF wild-type mCRC, future studies are necessary to confirm and further investigate our hypothesis-generating results.Primary tumor sidedness (left vs. right) has prognostic and predictive impact on anti-EGFR agent efficacy and thus management of metastatic colorectal cancer (mCRC). This analysis evaluates the relevance of primary tumor location (PTL) in RAS/BRAF wild-type mCRC patients, when dividing the colorectal frame into six segments. This pooled analysis, performed on a single-patient basis of five randomized first-line therapy trials, evaluates the impact of exact PTL classification on baseline characteristics, prognosis and prediction of anti-EGFR antibody efficacy by chi-square and log-rank tests, the Kaplan–Meier method, Cox and logistic regressions. The PTL was significantly associated with metastatic spread: liver (p = 0.001), lung (p = 0.047), peritoneal (p < 0.001) and lymph nodes (p = 0.048). A multivariate analysis indicated an impact on anti-EGFR agent efficacy in terms of overall survival depending on the exact primary tumor location: from detrimental in caecal (HR 2.63), rather neutral effects in the ascending colon (HR 1.24), right flexure/transverse colon (HR 0.99) and left flexure/descending colon (HR 0.91) to clear benefit in sigmoid (HR 0.71) and rectal (HR 0.58) primaries. Exact primary tumor location affects anti-EGFR antibody efficacy in a rather continuous than a dichotomous fashion in RAS/BRAF wild-type mCRC patients. This perspective might help to support clinical decisions when anti-EGFR antibodies are considered.

Mismatch Repair Status Correlates with Survival in Young Adults with Metastatic Colorectal Cancer

BackgroundYoung adults with metastatic colorectal cancer (mCRC) may have higher rates of deficient mismatch repair (dMMR) than older patients. This study sought to assess patterns of MMR-testing and survival among young adult mCRC patients in the National Cancer Database (NCDB), hypothesizing that dMMR correlates with worse survival than in MMR-proficient (pMMR) patients. MethodsStage-IV colorectal cancers were identified in NCDB (2010-2016). Demographic and clinical features were compared between younger (age ≤ 30) and older mCRC patients and tested for association with overall survival. Stage-IV disease without other recorded metastatic sites defined peritoneal metastasis (PM). Fisher-exact tests compared proportions and Cox models tested association with overall survival. ResultsOf 124,587 stage-IV colorectal cancers, 1,123 (0.9%) were in young patients. Young patients were more likely to have mucinous histology, high-grade, rectal primaries, and isolated peritoneal metastases (P < 0.001). Younger patients more often had MMR-testing (29.1 versus 16.6%), with dMMR found at similar rates in young and older patients (21.7 versus 17.1% of those tested, P= 0.4). Despite higher rates of adverse prognostic features, younger patients had better survival (median 20.7 versus 14.8 months, P < 0.001). In MMR-tested patients, dMMR correlated with higher mortality risk compared to pMMR (median 16.6 months versus 25.5 months, P = 0.01). On multivariable analysis, grade and MMR-status remained independently associated with survival. ConclusionsMedian survival was worse with dMMR by 8.9 months compared to pMMR in young adults with mCRC. Despite higher rates of familial syndromes in young patients and recommendations for universal MMR-testing, over 70% of young mCRC patients had no MMR-status recorded.

96P - Incidence, characteristics and prognosis in colorectal cancer with CNS metastases

BackgroundBrain metastases (BM) due to colorectal cancer (CRC) are an infrequent event. Previous research suggests that patients with pulmonary metastases, rectal primaries and KRAS mutations are at an increased risk of BM. Despite multidisciplinary treatment, survival following BM remains poor. We aimed to analyse the incidence, genomic profiling, treatment administered and survival in patients with BM from CRC within our cancer service. MethodsA retrospective analysis of 1346 CRC patients at two comprehensive cancer centres in Western Sydney identified 52 patients with BM. Data was subsequently collected on patient demographics, tumour and treatment characteristics. KRAS and BRAF mutation status from primary colorectal tumour specimens and surgical resection of BM was assessed. Survival data was analysed by the Kaplan-Meier method. ResultsThe incidence of BM in our cohort was 3.9%. The mean age of patients was 66 (35-82) with 48% female and 52% male in the BM group compared to 36% female and 64% male in the non-BM group. 33% of patients were wildtype (WT), 62% had a RAS mutation and 5% were BRAF mutant. The median time between diagnosis of primary CRC and development of BM did not differ between RAS, RAF and WT (37, 50 and 43 months). 70% of WT patients presented with one BM compared to 45% of KRAS mutated patients although this was not statistically significant (p = 0.13). 38% of patients had surgery while 81% had radiotherapy (56% WBRT, 44% SRS) to treat their BM. The median PFS across all groups was 3.2 months and median OS was 3.9 months. Median PFS was significantly longer in patients who received surgery, chemotherapy and radiotherapy following their diagnosis of BM (12.3 months) versus surgery alone (1 month) or surgery and radiotherapy (4.4 months) (p = 0.022). Mutational status or number of BM did not impact on PFS or OS. Patients with synchronous liver metastases had a significantly shorter median OS of 3 months versus 13 months in those without liver metastases (p = 0.008). ConclusionsBrain metastases remains an infrequent event in patients with metastatic colorectal cancer. KRAS and BRAF mutations do not appear to have any effect on prognosis or response to treatment in CRC patients with BM. Survival of CRC patients following BM is poor and novel approaches are needed. Legal entity responsible for the studyThe authors. FundingWestern Sydney Local Health District. DisclosureK.Y.M. Wong: Advisory / Consultancy: Baxalta; Speaker Bureau / Expert testimony: Sirtex; Travel / ccommodation / Expenses: MSD Oncology. All other authors have declared no conflicts of interest.

Stereotactic Ablative Body Radiotherapy to Treat Colorectal Oligometastases

To assess the outcome of all patients with primary colorectal cancer who received SABR (stereotactic ablative body radiotherapy) for oligometastatic disease under the Commissioning through Evaluation program at our institution over a three-year time period. Data were collected retrospectively from our institutional SABR database. All patients with primary colorectal cancer who received SABR to oligometastases (one to three lesions) between 01.01.2016 and 01.01.2019 were included. Patients were treated using a TrueBeam linear accelerator. 19 oligometastases were treated in 16 patients. 13 patients received SABR to one metastasis and three patients had two metastases treated. The median age of patients was 69.5 years (range 36 to 87 years); 11 patients (68.8%) were male and five patients (31.2%) female. Nine patients (56.3%) had a primary colon cancer and seven patients (43.7%) had a primary rectal cancer. 10 (62.5%) patients received treatment to a separate metastasis prior to SABR. The site of metastases treated included 12 (63.2%) lung metastases, 6 (31.6%) lymph node metastases, and 1 (5.2%) liver metastasis. The median biologically effective dose (BED10) delivered was 115.5Gy (range 60 to 151.2Gy). The median follow up was 20.5 months (range 6 to 37 months). No patients experienced grade 3 to 4 toxicity following SABR. 8 (50.0%) patients are currently alive and disease free. Four patients (25.0%) developed local recurrence of their metastasis. The mean time to local recurrence was 10.5 months; three of these patients (75.0%) had a primary rectal cancer and one patient (25.0%) had a primary colon cancer. Three patients (18.8%) developed distant recurrence following SABR. The mean time to distant recurrence was five months; one of these patients had a primary rectal cancer (33.3%) and two patients (66.6%) had a primary colon cancer. Of note one patient developed both local and distant recurrences. Two patients (11.1%) died during the follow up period. This study demonstrated a local failure rate of 25.0% following SABR to colorectal oligometastases within a 20.5 month median follow up. Patients with a rectal primary appeared to have a higher local failure rate (42.9%) than those with a primary colon cancer (11.1%). There was no evidence that SABR adversely affected the quality of life in these patients. Colorectal metastases have a radioresistant phenotype and have been associated with higher local failure rates following SABR compared with different tumor histologies. This potentially highlights the need for dose escalation within this cohort of patients particularly in patients with rectal primaries.

The role of pelvic radiotherapy in stage IV rectal cancer—still working in the dark!

Approximately 20% of patients with colorectal cancer (CRC) are found to have metastatic colorectal cancer (mCRC) at diagnosis, but only 20% of these are usually considered to be potentially resectable (de Haas 2011) (1). Early stage disease in rectal cancer confers a relatively favourable prognosis, but stage IV or metastatic disease is associated with a five-year survival of only 10–15%, despite major advances in multimodality treatment. Individual outcomes are influenced by the site and number of metastases and the specific metastatic sites involved. Patients with rectal primaries are also more likely to present with synchronous lung metastases than patients with colon cancer (Robinson 2018) (2), which then can lead to a different natural history with bone and brain metastases.

A Curative-Intent Trimodality Approach for Isolated Abdominal Nodal Metastases in Metastatic Colorectal Cancer: Update of a Single-Institutional Experience.

The purpose of this study was to define survival rates in patients with isolated advanced abdominal nodal metastases secondary to colorectal cancer (CRC), treated with curative-intent trimodality therapy. Sixty-five patients received trimodality therapy, defined as chemotherapy delivered with external beam radiotherapy (EBRT) followed by lymphadenectomy and intraoperative radiotherapy (IORT). Infusional 5-fluorouracil was the most common radiosensitizer used (63%, 41 patients). The median dose of EBRT was 50 Gy, and the median dose of IORT was 12.5 Gy. We evaluated time to distant metastasis, toxicities, local failure within the EBRT field, recurrence within the IORT field, and survival. Fifty-two percent of patients were male; patients' median age was 50.5 years. All patients had an Eastern Cooperative Oncology Group score ≤1. Twenty-nine patients had right-sided colon cancer, 22 had left-sided colon cancer, and 14 had rectal primaries. The median time from initial CRC diagnosis to development of abdominal nodal metastatic disease was 20.6 months (95% confidence interval [CI], 21.2-40.8 months). Seventy-eight percent (51 patients) had para-aortic nodal metastases, 15% (10 patients) had mesenteric nodal metastases, and 6% (4 patients) had both. With a median follow-up of 77.6 months, the median overall survival and 5-year estimated survival rate were 55.4 months (95% CI, 47.2-80.9 months) and 45%, respectively. The median progression-free survival was 19.3 months (95% CI, 16.5-32.8 months). Twenty-six (40%) patients never developed distant disease. The outcome was not affected by disease sidedness or rectal primary. Treatment was well tolerated without grade 3 or 4 toxicities. Trimodality therapy produces sustainable long-term survival in selected patients with metastatic CRC presenting with isolated retroperitoneal or mesenteric nodal relapse. This article reports a unique trimodality approach incorporating external beam radiotherapy with radiosensitizing chemotherapy, surgical resection, and intraoperative radiotherapy provides durable survival benefit with significant curative potential for patients with metastatic colorectal cancer who present with isolated abdominal nodal (mesenteric and/or retroperitoneal) recurrence.

Impact of age on clinical and pathological features as well as outcome in Egyptian patients with colorectal cancer (CRC).

600 Background: The incidence of early onset CRC is rising. Little is known about the clinicopathological differences between younger and older Egyptian (EGY) adults with CRC. Herein we explore these differences. Methods: A retrospective review of younger EGY adult (YA; ≤ 46 years) and older EGY adult (OA; &gt; 65 years) patients (pts) with CRC was performed. T and Fisher’s exact tests were used for comparative analyses. Kaplan-Meier methodology estimated survival. Results: In total, 997 EGY pts with CRC were studied, including 443 YA (median age 35 years; range 15-46) and 153 OA pts (median 70 years range 65-84).There were no statistically significant differences with respect to gender, degree of tumor differentiation, extracolonic extension, stage at presentation, or patterns of metastasis between the two groups. YA pts had more rectal primaries compared with OA pts (49% vs. 31%, p &lt; 0.001), whereas older pts had more colon primaries (69% vs. 51%, p &lt; 0.001). Additionally YA pts had more left-sided tumors (78% vs. 62%, p &lt; 0.001) compared with OA pts, whereas older pts had more right-sided tumors (32% vs. 17%, p &lt; 0.001). YA pts were more likely to have mucin-producing tumors (40% vs. 23%, p = 0.003). Although there were no differences in the proportion of pts presenting with metastatic disease (28% [YA] vs. 32% [OA], p = 0.615), or the pattern of metastasis to the liver, lung, or peritoneum (40% vs. 50%, p = 0.288; 5% vs. 6%, p = 1.00, 16% vs. 17%, p = 1.00), YA were more likely to have CRC-related lymph node (LN) involvement (mean: 3.2 vs. 1.6, p = 0.006). There were no differences in PFS (Median: 12 months for YA vs. 13 months for OA) or OS (median: 76 months for YA vs. not reached for OA) between the two groups. However male YA pts had a better OS that female pts (median OS not reached in males, 72 months in females). Conclusions: Significant differences were evident between YA and OA pts with CRC, notably locations of primary tumors. Male had improved outcome compared to female YA patients. Additional evaluation of the molecular features of CRC in young and older patients in Egypt is warranted.

Abstract A101: The MetAction trial: long-lasting responses to molecularly matched therapy in end-stage cancer

Abstract Background: The first phase of the MetAction trial established the required diagnostic infrastructure, implemented security-approved systems for handling of sensitive information, educated the Trial Team within the context of tumor boards, and estimated costs of the initiative within public health services. The endeavor enabled expedited and safe mutation profiling of metastatic tumors in order to offer molecularly matched medication for end-stage cancer (Ree et al., ESMO Open 2017;2:e000158). The aim of the second trial phase was to investigate the utility of the MetAction pipeline in clinical practice. Procedures: An eligible patient with end-stage metastatic disease from any origin had been on the previous line of systemic therapy for 6 or more weeks with radiologic evaluation intervals of 6-12 weeks and disease progression according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Biopsy-sampled metastatic tissue was analyzed by DNA sequencing (Ion Oncomine™ Comprehensive Panel), where called variants were filtered prior to assessment and prioritization, supplemented with fluorescence in situ hybridization to cover relevant biomarkers. The Molecular Tumor Board interpreted the findings within the likelihood of signaling pathway activity, for the sequential Clinical Tumor Board to conclude on potential systemic tumor-directed medication. On study therapy, radiologic work-up was performed every 8 weeks. The primary objective was to compare progression-free survival (PFS) on study treatment, termed Period-B, with PFS for the most recent therapy, termed Period-A. If Period-B/Period-A was ≥1.3, the study therapy was deemed to be of benefit. The incidence of diagnostic adverse events and treatment-related grade 3-5 Common Terminology Criteria for Adverse Events (CTCAE) toxicities was secondary end points. Results: 26 patients were enrolled. Biopsy procedures were undertaken at lung or pleural sites (6 cases), liver or peritoneal sites (19 cases), and an inguinal lymph node (1 case), and did not cause adverse events. Histologic entities were 18 adenocarcinomas (AC), 2 undifferentiated carcinomas, 1 case each of cholangiocarcinoma and squamous cell carcinoma, and 4 different sarcoma entities. 13 patients were found eligible for off-label use of molecularly matched therapy (inhibitor of ALK-, BRAF-, EGFR-, FGFR-, mTOR-, PARP-, ROS1-, or PD-1-mediated signaling). Among the 10 individuals who received study treatment until radiologic evaluation, 5 met the primary end point. The patient with cholangiocarcinoma and a patient with rectal AC primaries, both given crizotinib, obtained Period-B/Period-A outcome slightly better than 1.3. Notably, 3 patients with colon AC primaries, receiving either a combination of panitumumab with vemurafenib or chemotherapy or single-agent pembrolizumab, obtained long-lasting responses. In addition, 1 colon AC patient receiving pembrolizumab with RECIST progression (i.e., primary end point failure) before a long-lasting response to off-protocol continuation, reported CTCAE grade 3 toxicity (a colitis event that immediately resolved on high-dose prednisolone). Conclusion: MetAction procedures and treatments were safe. 15% (4/26) of patients with progressing end-stage cancer had the disease course substantially reversed by this biomarker-directed therapy approach. Citation Format: Anne Hansen Ree, Kjersti Flatmark, Vigdis Nygaard, Daniel Heinrich, Kjetil Boye, Svein Dueland, Vegard Nygaard, Eivind Hovig, Klaus Beiske, Marius Lund-Iversen, Vivi A. Flørenes, Christin Johansen, Inger Riise Bergheim, Menaka Sathermugathevan, Sigve Nakken, Gry A. Geitvik, Ole C. Lingjærde, Anne-Lise Børresen-Dale, Hege G. Russnes, Gunhild M. Mælandsmo. The MetAction trial: long-lasting responses to molecularly matched therapy in end-stage cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A101.

608P - Variations in clinicopathological features, treatment patterns, and outcomes of young adults with colorectal cancer in the United States and Egypt

Background: A recent American Cancer Society study showed that the rate of colorectal cancer (CRC) in young American adults is rising. There are limited data on young Arabian adults with CRC. Herein we explore differences between American and Egyptian young adults with CRC. Methods: A retrospective review of young (≤46 years old) patients (pts) with CRC in the United States (US-pts) and Egypt (EGY-pts) was undertaken. T and Fisher’s exact tests were used for comparative analyses. Kaplan-Meier methodology estimated survival. Results: In total, 504 pts with CRC were studied, incorporating 62 US-pts (median age 38 yrs, range 20-46) and 442 EGY-pts (35 yrs, 15-46). US-pts were more commonly female (66% vs 41%, p < 0.001) and had more colon primaries (75% vs 50%, p = 0.001). EGY-pts had more left-sided tumors (78% vs 61%, p = 0.008), of which 49% were rectal primaries (vs 24% for US-pts, p < 0.001). US-pts had more well-differentiated tumors (25% vs 3%, p < 0.001), whereas EGY-pts had more mucin-producing tumors (40% vs 26%, p = 0.042). US-pts were more likely to have bowel obstruction (64% vs 17%, p < 0.001) and present with metastatic (met) disease (66% vs 28%, p < 0.001), particularly in the liver, lung, and peritoneum (56% vs 40%, p = 0.04; 35% vs 5%, p < 0.001; 48% vs 16%, p < 0.001). Comparing pts with met disease, EGY-pts tended to have rectal primaries (33% vs 22%), while US-pts had more right-sided tumors (38% vs 18%). US-pts were more likely to undergo palliative resection or metastatectomy (41% vs 26%, p = 0.039) and receive bevacizumab (69% vs 1%, p < 0.001). EGY-pts received more 5-FU alone (39% vs 2%, p < 0.001) or 5-FU + radiation (40% vs 0%, p < 0.001), whereas US-pts received more FOLFOX/FOLFIRI (64% vs 13%, p < 0.001). There was no statistically significant difference in median overall survival between US-pts (Not Reached) and EGY-pts (76 months (mos), p = 0.6), nor median progression free survival between US-pts (20 mos) and EGY-pts (13 mos, p = 0.202). Conclusions: Significant differences were observed among young US-pts and EGY-pts with CRC, particularly primary tumor location, patterns of metastasis, and treatment used. Further evaluation of the environmental and ethnic impact on disease biology and treatment outcomes is warranted. Legal entity responsible for the study: Georgetown University IRB Funding: None Disclosure: All authors have declared no conflicts of interest.

A curative intent trimodality approach for advanced isolated abdominal nodal metastasis in metastatic colorectal cancer: Update of a single-institutional experience.

3556 Background: To define and update survival rates and relapse patterns in patients (pts) with isolated advanced abdominal nodal metastasis secondary to colorectal cancer (CRC), treated with curative intent using aggressive trimodality therapy. Methods: Fifty-seven pts with isolated advanced abdominal lymph node metastasis (retroperitoneal and mesenteric) secondary to colorectal cancer received trimodality therapy defined as chemotherapy delivered in conjunction with external beam radiotherapy (EBRT) followed by lymphadenectomy and intraoperative radiotherapy (IORT). Infusional 5-FU was the most common radiosensitizer used (66%, 38 pts). The median dose of EBRT was 50 Gy &amp; the median dose of intraoperative radiotherapy was 12.5 Gy. End points included distant metastasis, toxicities, local failure within EBRT field, recurrence within the intraoperative radiotherapy field, and survival. Results: 49% of pts were male, median age 50.5 yrs. All patients had ECOG ≤ 1. 27 pts had primary right sided colon cancer, 16 left sided colon cancer and 14 rectal primaries. Median time from initial CRC diagnosis to development of abdominal lymph node metastatic disease was 24 months (95% CI, 23.5-45.1 months). 84% (48 pts) had paraaortic nodal metastases, 12% (7 pts) had mesenteric nodal metastases, and 3% (2 pts) had both. With a median follow up of 89.4 months, the median overall survival and 5-year estimated survival rate were 53.2 months (95% CI, 46.4-78.8 months) and 42%, respectively. Median progression free survival was 19.3 months (95% CI, 15.6-32.8 months). 21 (37%) pts never developed distant disease. Outcome was not affected by disease sidedness, rectal primary, or mutational profile. Treatment was well tolerated without any grade 3/4 toxicities. Conclusions: The use of trimodality therapy including EBRT with radiosensitizing chemotherapy, lymphadenectomy and IORT produces sustainable long-term survival in selected metastatic CRC pts presenting with isolated retroperitoneal/mesenteric nodal relapse.

Stage IV colorectal cancer primary site and patterns of distant metastasis

BackgroundAlthough colorectal cancer (CRC) usually metastasizes to the liver and/or lungs, factors influencing the anatomic pattern of metastases remain poorly understood. MethodsWe assessed the relationship between primary CRC site and pattern of synchronous metastasis among 1202 individuals diagnosed with incident metastatic CRC between 2010 and 2014 and identified through the Seattle-Puget Sound Surveillance, Epidemiology, and End Results (SEER) registry. Polytomous logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between primary tumor site and synchronous metastatic pattern. ResultsCompared to patients with proximal colon primaries, patients with rectal primaries were more likely to present with lungs-only or liver and lungs metastases versus liver-only metastases (ORlungs–onlyvs.liver-only: 2.39, 95% CI: 1.35–4.24, ORliver+lungsvs.liver-only: 2.20, 95% CI: 1.46–3.32). ConclusionThese findings suggest that patients with rectal primaries are more likely than patients with colon primaries to present with synchronous lung metastases.

Right versus left: Impact of primary location on survival and cure in patients undergoing hepatic resection for metastatic colon cancer.

664 Background: Recent prospective studies in metastatic colorectal cancer (mCRC) have demonstrated an association between left-sided primaries and improved overall (OS) and progression-free survival (PFS). Primary location (right vs left colon) has not been well studied in patients undergoing potentially curative hepatic resection. Methods: A single-institution database was queried for all initial hepatic resections for mCRC 1992-2004. Postoperative deaths and patients with no followup after 90 days were excluded. Primary location determined by chart review (Right = cecum to transverse; Left = splenic flexure to sigmoid). Rectal cancer (distal 16cm), multiple primaries, and unknown location were excluded. Kaplan Meier and Cox regression methods were used. Cure was defined as actual 10-year survival with no recurrence or resected recurrence with at least 3 years of disease-free followup. Results: 907 patients were included with a median followup of 11 years. 578 patients (64%) had left-sided and 329 (36%) had right-sided primary. Median OS for patients with a left-sided primary was 5.2 years (95% CI: 4.6-6.0) versus 3.6 years (95% CI: 3.2-4.2) for right-sided (p = 0.004). The hazard ratio (HR) for right-sided tumors was 1.22 (95% CI: 1.02-1.45, p = 0.028) after adjusting for age, CEA &gt; 200, DFI &lt; 12 months, hepatic tumor &gt; 5cm, &gt; 1 tumor, lymph node status, margin, and extrahepatic disease. Recurrence-free survival (RFS) was marginally different stratified by primary location (p = 0.065). Estimated cure rates were 22% for left and 20% for right-sided tumors. Conclusions: Among patients selected for hepatic resection of metastatic colon cancer, left-sided primary tumors were associated with an improved OS but not RFS. This difference in OS was independent of common prognostic variables. Estimated cure rates were not statistically different. Patients with left-sided primary tumors display a prolonged clinical course after recurrence suggestive of more indolent biology. [Table: see text]

535P - Concordance of KRAS, NRAS and BRAF status between primary colorectal tumors and paired metastasis (mts)

It is well established that patients with RAS-mutant colorectal cancer (CRC) are resistant to anti-EGFR therapies and it is suggested that BRAF mutations may also have a predictive value. However, it is not known which is the most suitable specimen for mutation testing. Although it has been postulated a high concordance of KRAS status between primary tumors (pt) and liver mts, there are contradictory results. In this study we investigated the concordance of KRAS, NRAS and BRAF between pt and matched hepatic and extrahepatic mts. We examined 31 pairs of pt and mts (liver, lung, peritoneum, lymph nodes,ovary and pleura samples) of patients with CRC treated at Costa del Sol Hospital. DNA was extracted from formalin-fixed, paraffin-embedded specimens, using the DNA Tissue Kit (Qiagen). After verifying the quality of DNA, CLART CMA KRAS-BRAF Kit and Therascreen Kit or Therascreen KRAS RGQ PCR Kit, exon 15 BRAF sequencing and Therascreen Pyro Kit were employed to detect mutations in KRAS, NRAS and BRAF. To evaluate concordance differences, we used Fisher Test for independent cualitative variables, and U Mann-Whitney Test for cuantitative variables. Concordance rate of KRAS, NRAS and BRAF mutational status between pt and mts of any location was 79.1% (95% Confidence Interval: CI 65.7-92.4).Tabled 1Pt-Liver mtsPt- Extrahepatic mtsPt-Any location mtsKRAS78.9% (15/19)72.7% (8/11)76.7% (95% CI 59.9-93.5)NRAS66.7% (4/6)71.4% (5/7)71.4% (95% CI 29.0-96.3)BRAF100% (5/5)100% (1/1)100% (95% CI 54.1-100) Open table in a new tab We found that discordant pairs of pt-liver mts for KRAS showed more frequently a percentage of tumor cells in pt samples <70% (60% of cases versus 40% for concordant cases; p 0.044). Moreover, a trend for higher concordance of KRAS was showed for colon compared to rectal primaries (86.7% versus 50%; p 0.178). Concordance rate of approximately 80% can be found between pt and corresponding mts in unselected population of CRC patients. Percentage of tumor cells in samples can affect results. More studies are needed to clarify causes for discordance in mutational status of different samples from the same patient.

Trends in multimodal treatment and long-term outcomes of patients with resected colorectal liver metastases in a Brazilian Cancer Center

Introduction: Advances in systemic treatment and perioperative care improved the results of surgical treatment of colorectal liver metastases around the world. The aim of this study was to analyze the evolution of multimodal and surgical treatments of colorectal liver metastases in a Brazilian referral cancer center. Methods: A retrospective analyzes of medical records from patients with colorectal liver metastases who underwent curative liver resections from 1998 to 2012 was performed. The study period was divided in tree 5-year intervals. Multimodal treatment strategies, surgical morbimortality and survival outcomes were analyzed through time. Results: In the study period, 346 liver resections were performed in 285 patients. An increasing number of rectal primaries tumors were observed, without difference in lymph node metastases. Through these intervals, synchronous, multinodular and bilobar metastases become more frequent. Probably due to these factors, the use of multimodal treatment, mostly perioperative chemotherapy increased along time, reaching 72% of patients in the last 5-year period. Regarding surgical procedures, the proportion of major hepatectomies and simultaneous liver and primary resections increased, without significant increment in operative time, blood transfusion rate, morbidity and mortality. Both overall and disease free survivals were similar in the three groups (Table 1).Table1998 to 20022003 to 20072008 to 2012pMultimodal treatment66.6%89.7%94.0%<0.001Preoperative chemotherapy21.4%46.5%72.0%<0.001Major liver resections64.2%50.0%66.0%0.047Primary simultaneous resection04.5%11.2%0.045Blood transfusion37.0%34.0%31.3%0.800Postoperative complications53.5%53.4%65.6%0.116Mortality03.4%5.3%0.6175 year OS48.1%72.8%76.0%0.1265 year DFS38.5%28.9%24.2%0.503[Comparison between periods] Open table in a new tab [Comparison between periods] Conclusion: Our cohort showed that multimodal treatment has been more frequently used and similar surgical and survival outcomes could be observed even with the increasing number of patients with non-favorable prognostic factors through this 15-year period.