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Improvements in early detection, screening and treatment of cancer have resulted in a significant improvement in cancer mortality and an increase in the number of cancer survivors globally. Accordingly, a significant rise in the number of cancer survivors in Ireland has been observed. The surveillance of survivors of gastrointestinal malignancies in Ireland is heterogeneous and represents an unmet need for standardisation.There are currently no national guidelines in Ireland to guide follow-up practices for these patients. The aim of this study was to establish homogeneity nationally with respect to follow-up of these patients by medical oncologists.A consensus group consisting of Irish oncologists with an interest in gastrointestinal malignancies was created to address this issue, and determined that it would be reasonable to adopt the NCCN guidelines for this purpose, but that this recommendation would not be prescriptive, and should be individualised to each patient.We hope that this initiative may help to homogenise survivorship practices in this cohort of Irish patients, and may support the implementation of survivorship initiatives by the National Cancer Control Programme (NCCP).

Purpose:Immune checkpoint inhibitors (ICI) are effective in only a minority of patients with esophagogastric cancer (EGC). Here, we aimed to identify predictors of durable clinical benefit to ICI in EGC.Experimental Design:Patients with advanced EGC treated with ICIs at Memorial Sloan Kettering Cancer Center (New York, NY) were identified. Clinicopathologic variables were assessed. In patients profiled by MSK-IMPACT–targeted sequencing, outcomes were correlated with tumor genomic features.Results:One-hundred sixty-one patients were treated with ICIs (110 with anti–PD-1/PD-L1 antibodies and 51 with anti–CTLA-4 and PD-1/PD-L1 antibodies). The median progression-free survival (PFS) and overall survival (OS) were 1.7 and 4.9 months, respectively. Greater number of disease sites (≥3), liver metastases, treatment with ≥3 prior therapies and ECOG performance status ≥2 were associated with poorer PFS and OS. Patients treated with combination ICI and those with PD-L1–positive tumors had improved outcomes. There was no difference in outcomes between patients treated with antibiotics during or in the 2 months preceding ICI treatment versus those who were not. Occurrence of irAEs was associated with improved OS. In genomically profiled tumors (n = 89), survival was associated with increasing tumor mutation burden (TMB). However, in multivariable analyses and when microsatellite unstable (MSI) patients were excluded, a significant association was no longer observed.Conclusions:In patients with advanced EGC, heavily pretreated patients, those with high-volume disease and/or poor PS were less likely to benefit from ICI. irAEs were associated with improved OS. TMB correlated with improved survival, but this association was not observed when MSI-high patients were excluded.

PFS analysis by gene alteration occurring in 10% or more of MSS patients who received combination therapy

Paclitaxel plus ramucirumab is a standard second-line regimen for patients with advanced gastric adenocarcinoma, but clinical benefit remains modest. One potential resistance mechanism to VEGFR2 inhibition is activation of the PDGF/PDGFR pathway, which can be blocked by the selective inhibitor crenolanib. Therefore, we performed a phase I/Ib study of crenolanib in combination with paclitaxel/ramucirumab.Patients with metastatic esophagogastric adenocarcinoma refractory to first-line therapy received escalating doses of crenolanib [60 mg twice daily (BID) to 100 mg three times daily (TID)] in combination with paclitaxel 80 mg/mWe enrolled 19 patients in the dose escalation phase and 8 patients in the dose expansion phase at the MTD of crenolanib 100 mg BID. Common grade 3/4 treatment-emergent adverse events included leukopenia (19%), anemia (11%) and neutropenia (11%). In the 14 patients treated at the MTD, 6-month PFS was 43% [95% confidence interval (CI) 23-78%] and the objective response rate (ORR) was 42% (95% CI 15-72%). The trial was terminated early due to withdrawal of crenolanib by the sponsor.The addition of crenolanib to paclitaxel/ramucirumab is safe and well-tolerated at a dose level up to 100 mg BID.NCT03193918. June 19, 2017.

Purpose: Immune checkpoint inhibitors (ICI) are effective in only a minority of patients with esophagogastric cancer (EGC). Here, we aimed to identify predictors of durable clinical benefit to ICI in EGC. Experimental Design: Patients with advanced EGC treated with ICIs at Memorial Sloan Kettering Cancer Center (New York, NY) were identified. Clinicopathologic variables were assessed. In patients profiled by MSK-IMPACT–targeted sequencing, outcomes were correlated with tumor genomic features. Results: One-hundred sixty-one patients were treated with ICIs (110 with anti–PD-1/PD-L1 antibodies and 51 with anti–CTLA-4 and PD-1/PD-L1 antibodies). The median progression-free survival (PFS) and overall survival (OS) were 1.7 and 4.9 months, respectively. Greater number of disease sites (≥3), liver metastases, treatment with ≥3 prior therapies and ECOG performance status ≥2 were associated with poorer PFS and OS. Patients treated with combination ICI and those with PD-L1–positive tumors had improved outcomes. There was no difference in outcomes between patients treated with antibiotics during or in the 2 months preceding ICI treatment versus those who were not. Occurrence of irAEs was associated with improved OS. In genomically profiled tumors (n = 89), survival was associated with increasing tumor mutation burden (TMB). However, in multivariable analyses and when microsatellite unstable (MSI) patients were excluded, a significant association was no longer observed. Conclusions: In patients with advanced EGC, heavily pretreated patients, those with high-volume disease and/or poor PS were less likely to benefit from ICI. irAEs were associated with improved OS. TMB correlated with improved survival, but this association was not observed when MSI-high patients were excluded.

While recent decades have seen incremental improvements in the treatment of esophageal carcinoma, outcomes remain modest. The five-year overall survival (OS) rate for locally advanced esophageal cancer with surgery alone is 23–33% in contemporary studies (1-3). In locally advanced esophageal cancer, the risk of incomplete (R1) resection, local recurrence and systemic dissemination is significant. Numerous studies have demonstrated that the addition of chemotherapy and/or radiation to surgery improve outcomes, leading to multimodal treatment becoming standard-of-care. In particular, pre-operative chemoradiation has emerged as a standard-of-care in the US and Western Europe (4).

Adjuvant therapy for 6 months is the standard of care for stage III colon cancer. The use of oxaliplatin-based therapy over fluoropyrimidine alone increases toxicity, including dose-dependent peripheral neuropathy. Evaluation of a shorter duration of adjuvant therapy was therefore warranted, aiming to reduce toxicity while maintaining clinical efficacy. The International Duration Evaluation of Adjuvant chemotherapy (IDEA) collaboration was a pivotal prospective pooled analysis of 6 randomized phase III trials across 12 countries. IDEA evaluated the non-inferiority of 3 versus 6 months of adjuvant oxaliplatin-based chemotherapy. The 3-year disease-free survival was very similar between the 3-month and 6-month study arms. Despite this, non-inferiority was not confirmed. However, important differences were observed between FOLFOX and CAPOX regimens, and risk groups within stage III disease, which allow for greater individualization of adjuvant therapy. The IDEA results suggest 3 months of therapy is reasonable in most patients with stage III disease, especially those with low-risk disease. Importantly, 3 months of therapy is associated with a dramatic reduction in peripheral neuropathy. A thorough discussion of the risks and benefits with patients regarding the duration of therapy is required. In this review, we discuss the IDEA findings and the optimal duration of adjuvant chemotherapy in stage III colon cancer.

Although recent decades have witnessed incremental improvements in the treatment of gastroesophageal junction (GEJ) carcinoma, outcomes remain modest. For locally advanced esophageal cancer, the addition of chemotherapy and/or radiation to surgery is considered the standard of care. Chemotherapy remains the primary treatment for metastatic disease and improves survival over best supportive care. However, the prognosis for patients with GEJ cancers, which are treated along the same paradigms as esophageal and gastric carcinomas, remain poor because of the emergence of chemoresistance and limited targeted therapeutic approaches, which include agents that target the HER2 and vascular endothelial growth factor pathways. Evaluation of immune checkpoint inhibitors in the chemorefractory setting have confirmed the activity of immunotherapy in esophagogastric cancer. Ongoing immunotherapeutic strategies are being evaluated in both the locally advanced and metastatic settings. This review focuses on the treatment of locally advanced and metastatic GEJ carcinomas, which encompass all tumors that have an epicenter within 5 cm proximal or distal to the anatomical Z-line (Siewert classification). Because the vast majority of GEJ tumors are adenocarcinoma, the management of adenocarcinoma is the focus of this review. Evolving approaches and areas of clinical equipoise are discussed.

INTRODUCTION: Preoperative or definitive chemoradiation is an accepted treatment for locally advanced esophageal squamous cell carcinoma (ESCC). The MUNICON study showed that positron-emission tomography (PET) response following induction chemotherapy was predictive of outcomes in patients with gastroesophageal junction adenocarcinoma. We evaluated the predictive value of PET following induction chemotherapy in ESCC patients and assessed the impact of changing chemotherapy during radiation in PET nonresponders. METHODS: We retrospectively reviewed all patients with locally advanced ESCC who received induction chemotherapy and chemoradiation; all patients had a PET before and after induction chemotherapy. Survival was calculated from date of repeat PET using Kaplan-Meier analysis and compared between groups using the log-rank test. RESULTS: Of 111 patients, 70 (63%) were PET responders (defined as a 35% or more decrease in maximum standard uptake value) to induction chemotherapy. PET responders received the same chemotherapy during radiation. Of 41 PET nonresponders, 16 continued with the same chemotherapy and 25 were changed to alternative chemotherapy with radiation. Median progression-free survival (70.1 months versus 7.1 months, p < 0.01) and overall survival (84.8 months versus 17.2 months, p < 0.01) were improved for PET responders versus nonresponders. Median progression-free survival and overall survival for PET nonresponders who changed chemotherapy versus those who did not were 6.4 months versus 8.3 months (p = 0.556) and 14.1 versus 17.2 months (p = 0.81), respectively. CONCLUSIONS: PET after induction chemotherapy highly predicts for outcomes in ESCC patients who receive chemoradiation. However, our results suggest that PET nonresponders do not benefit from changing chemotherapy during radiation. Future trials should use PET nonresponse after induction chemotherapy to identify poor prognosis patients for novel therapies.

Summary A 41-year-old male presented to the Emergency Department with a 6-month history of back and hip pain. Skeletal survey revealed bilateral pubic rami fractures and MRI of the spine demonstrated multiple thoracic and lumbar fractures. Secondary work up for osteoporosis was undertaken. There was no evidence of hyperparathyroidism and the patient was vitamin D replete. Testosterone (T) was low at 1.7 nmol/L (8.6–29.0) and gonadotrophins were undetectable. The patient failed a 1 mg dexamethasone suppression test (DST) with a morning cortisol of 570 nmol/L ( Learning points Unexplained osteoporosis requires thorough investigation and the workup for secondary causes is not complete without excluding glucocorticoid excess. MTC should be considered when searching for sources of ectopic ACTH secretion. Resistance to tyrosine kinase inhibitors is well described with MTC and clinicians should have a low threshold for screening for recurrent disease.

This study aimed to assess the usefulness of radiomics features of 18F-FDG PET/CT in patients with locally advanced esophageal cancers (ESCC) in predicting outcomes such as clinical tumor (cT) and nodal (cN) categories, PET response to induction chemotherapy (PET response), progression-free survival (PFS), and overall survival (OS). Pretreatment PET/CT images from patients who underwent concurrent chemoradiotherapy from July 2002 to February 2017 were segmented, and data were split into training and test sets. Model development was performed on the training datasets and a maximum of five features were selected. Final diagnostic accuracies were determined using the test dataset. A total of 86 PET/CTs (58 men and 28 women, mean age 65 years) were segmented. Due to small lesion size, 12 patients were excluded. The diagnostic accuracies as derived from the CT, PET, and combined PET/CT test datasets were as follows: cT category—70.4%, 70.4%, and 81.5%, respectively; cN category—69.0%, 86.2%, and 86.2%, respectively; PET response—60.0%, 66.7%, and 70.0%, respectively; PFS—60.7%, 75.0%, and 75.0%, respectively; and OS—51.7%, 55.2%, and 62.1%, respectively. A radiomics assessment of locally advanced ESCC has the potential to predict various clinical outcomes. External validation of these models would be further helpful.

Pregnancy-associated breast cancer (PABC) is defined as breast cancer diagnosed during the gestational period (gp-PABC) or in the first postpartum year (pp-PABC). Despite its infrequent occurrence, the incidence of PABC appears to be rising due to the increasing propensity for women to delay childbirth. We have established the first retrospective registry study of PABC in Ireland to examine specific clinicopathological characteristics, treatments, and maternal and foetal outcomes. This was a national, multi-site, retrospective observational study, including PABC patients treated in 12 oncology institutions from August 2001 to January 2020. Data extracted included information on patient demographics, tumour biology, staging, treatments, and maternal/foetal outcomes. Survival data for an age-matched breast cancer population over a similar time period was obtained from the National Cancer Registry of Ireland (NCRI). Standard biostatistical methods were used for analyses. We identified 155 patients—71 (46%) were gp-PABC and 84 (54%) were pp-PABC. The median age was 36 years. Forty-four patients (28%) presented with Stage III disease and 25 (16%) had metastatic disease at diagnosis. High rates of triple-negative (25%) and HER2+ (30%) breast cancer were observed. We observed an inferior 5-year overall survival (OS) rate in our PABC cohort compared to an age-matched breast cancer population in both Stage I–III (77.6% vs 90.9%) and Stage IV disease (18% vs 38.3%). There was a low rate (3%) of foetal complications. PABC patients may have poorer survival outcomes. Further prospective data are needed to optimise management of these patients.

Background The COVID-19 pandemic has resulted in radical changes in the delivery of healthcare worldwide. Our oncology service (at an Irish national cancer centre) rapidly transitioned to the use of telemedicine or virtual clinics (VC) to minimise potential risk of exposure to COVID-19 amongst an immunosuppressed, high-risk population. Our study aimed to evaluate the use of VC in this setting. Methods An 18-point questionnaire was designed to investigate the patient experience of VC during the COVID-19 pandemic in Ireland and compliance with guidelines developed in Ireland to conduct VC and the role of VC in the future. Questionnaires were distributed following the receipt of verbal consent from patients during the VC. Descriptive statistics were utilised for data analysis using SPSS®. Results One hundred and four patients returned completed surveys (n = 104/164, 63% response rate). Overall satisfaction levels were high with most patients (n = 58/100, 58%; no answer provided (NAP), n = 4) equally satisfied or nearly equally satisfied with VC in comparison to a usual clinic encounter. The majority of patients felt that there should be a role for VC in the future (n = 84/102, 82%; NAP, n = 2). The majority of patients (n = 61/99, 61%; NAP, n = 5) were very relieved to avoid a hospital visit due to perceived risk of potential exposure to COVID-19. Conclusion The majority of oncology patients were satisfied with a VC encounter. VC may have a role in the future of medical care in Ireland post the COVID-19 pandemic.

TPS237 Background: Molecular characterisation of colorectal cancer (CRC) has demonstrated the regulatory role of epigenetic alterations, such as DNA methylation, in CRC tumorigenesis(1). Robust molecular profiling of CRC has the potential to provide critical diagnostic and prognostic information. The establishment of 4 consensus molecular subtypes (CMSs), developed initially for primary CRC tumours, resulted in the evolving framework for molecularly targeted interventions; the molecular genetic profile characterising mCRC is less well defined(3, 4). Previous pilot work identified a unique tumour-specific methylation sequence, at 376 sites within the DNA of mCRC cells(5). This study will assess whether this methylation sequence drives mCRC pathogenesis and underpins disease phenotype. The primary aim of this study is validation of the diagnostic utility of this novel enhancer signature and identification of key enhancers with the potential to direct targeted treatment development. Secondary aims include CRISPR knockdown library development targeting the enhancers in CRC cells in vitro, evaluating the impact of the knockdown on phenotype in vitro, and identifying the mechanisms by which methylation-sensitive enhancers regulate the mCRC phenotype. Methods: This is a retrospective, non-interventional, single-centre clinical study, including patients > 18 years, with (group A) de novo mCRC (n = 100), (group B) stage III colorectal cancer that subsequently relapsed (n = 100) or (group C) stage III colorectal cancer without radiological evidence of relapse at study enrolment (n = 100). Formalin-fixed, paraffin-embedded ( FFPE) tissue obtained at diagnosis will be analysed. Additionally, 50 stage III patients who have relapsed (group B) will have blood samples collected prospectively at time of consent to enable assessment for the presence of the methylation signature on ctDNA. The presence or absence of the novel methylation signature will be evaluated via the application of a targeted bisulfite sequencing panel consisting of the previously identified differentially methylated enhancer (DME) signature to both tissue and plasma samples; results will be correlated with conventional histological parameters, systemic therapy, and overall survival. Quantitative statistical analysis will be performed using SPSS with linear regression analysis for survival data. Ethical approval was obtained from the MMUH Institutional Review Board; reference 1/378/2188. This study is open and recruiting. Clinical trial information: 1/378/2188.

Young women with breast cancer (YWBC) represent 7–12% of breast cancer diagnoses and ostensibly have more biologically aggressive subtypes with higher relapse and mortality rates. We studied the clinical and pathological characteristics in YWBC and examined how outcomes and treatment have evolved. YWBC were identified from pathology databases at two tertiary centers. Patients were divided into two cohorts: those diagnosed from 2000 to 2005 (C1) and from 2006 to 2015 (C2). Data were retrieved from clinical, radiology, and histology databases. Statistical analysis was performed using R® (V3.2.0). We identified 345 patients. Median age was 36 years (23–39 years). Mastectomy was performed in 232 patients (67.2%) and axillary lymph node clearance (ALNC) in 207 patients (60% [C1 82.7 vs. C2: 49.4%, p

Liver metastases are the commonest cause of death for patients with colorectal cancer. Growing evidence supports the use of selective internal radiation therapy (SIRT) in combination with conventional chemotherapy regimens for liver-only or liver-dominant unresectable metastatic colorectal cancer. To measure and evaluate outcomes of the first 20 consecutive patients with unresectable colorectal liver metastasis selected for SIRT in addition to their chemotherapy at a single Irish institution. Retrospective case series was performed. Patient charts and medical records were reviewed. All 20 patients (100%) selected for angiographic workup were subsequently successfully treated with radioembolization. All patients were discharged 1 day post-SIRT. At initial imaging evaluation, 12 (60%) had a partial response in their liver, 2 (10%) had stable disease, and 6 (30%) had liver-specific progressive disease. Median follow up was 10 months (range 6–26). At last follow up, 14 (70%) patients were alive and 6 (30%) deceased. Most recent imaging demonstrated 2 (10%) with a complete response, 7 (35%) had a partial response, 2 (10%) had stable disease, and 9 (45%) had progressive disease within their liver. One patient was downstaged to hepatic resection, and one with a complete hepatic response had his primary sigmoid tumor resected 11 months post-SIRT. SIRT is a safe and effective therapy for certain patients with unresectable colorectal liver metastases. This case series supports our opinion that selected patients should be offered SIRT in concert with their medical oncologist, concomitant with their chemotherapy. Larger multi-center studies are required to more clearly define the patient groups that will derive most benefit from SIRT.

Targeting of the immune checkpoints cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed death (PD)-1/PD-ligand 1 (PD-L1) with monoclonal antibodies has been shown to improve outcomes in a number of solid tumors, leading to their routine use in clinical practice. Early phase evaluation of immune checkpoint inhibitors demonstrated encouraging results in esophageal cancer, and studies in the chemorefractory setting have confirmed the activity of immunotherapy in esophageal cancer. Immunotherapeutic strategies continue to be evaluated rapidly in esophageal cancer, in both the locally advanced and metastatic settings. This chapter will focus on the accumulating data regarding the use of immunotherapy in esophageal cancer.

The treatment landscape for metastatic melanoma has been revolutionised by the introduction of immunotherapy and targeted therapies. Despite these advances, some patients exhibit primary or acquired resistance to treatment. We present the case of a resected mucosal melanoma that on relapse underwent transformation to a dedifferentiated state. The relapsed tumour was phenotypically disparate and demonstrated loss of all typical melanoma-associated immunohistochemical markers. Furthermore, it demonstrated aggressive biological behaviour and immunotherapy resistance. We performed genomic profiling of the original and relapsed tumour to further elucidate the mechanisms underlying this rare phenomenon. Mass spectrometry-based single-nucleotide polymorphism genotyping technology was used to screen for mutations in the original and recurrent tumour. Whole-exome sequencing was performed on the original tumour, recurrent tumour and blood. Both the original and recurrent tumour shared a NRAS mutation, a similar aneuploidy profile and proportion of somatic single-nucleotide variants. However, in contrast to the original tumour, the recurrent tumour demonstrated a lower mutational burden and deletions in the CDKN2A/CDKN2B and CHEK2 genes. The genomic similarity between the original and recurrent tumour attests to a common ancestry and the possible existence of nongenomic drivers inciting phenotype plasticity. In contrast, the low mutational load and potential inactivation of tumour suppressor genes in the recurrent tumour may underlie its rapid proliferative rate and immunoresistance. Dynamic treatment models are desired in the future to track the genomic and epigenetic evolution of a tumour to guide optimal therapy choice and sequencing.

Esophageal carcinoma is an aggressive malignancy and outcomes remain poor. Immune checkpoint inhibitors are a standard-of-care in the third-line and beyond settings, although benefit is modest. Herein, we report the case of a patient who achieved a partial response to salvage chemotherapy following treatment with an immune checkpoint inhibitor despite having chemo-refractory disease. A 41-year-old male, with a history of Crohn's disease, was diagnosed with Her2-positive metastatic esophageal adenocarcinoma to lungs and lymph nodes. The patient received multiple lines of systemic therapy including: first-line modified DCF (docetaxel/cisplatin/5-fluorouracil) with trastuzumab, second-line trastuzumab/afatinib on a clinical study, third-line carboplatin/irinotecan/ramucirumab and fourth-line treatment with a Her2 antibody-drug conjugate, DS-8201A, on a phase I study. While the patient was not a candidate for clinical trials evaluating immune checkpoint inhibitors due to his history of Crohn's disease, the latter was well controlled. Thus, the patient commenced pembrolizumab as fifth-line of treatment 2 years since diagnosis. After 3 cycles of therapy, the patient developed grade 3 immune-related colitis and treatment was discontinued. The patient maintained a good performance status and commenced a sixth-line of carboplatin/irinotecan/ramucirumab. Subsequent imaging demonstrated a partial response which was maintained over a 6-month period. This case demonstrates a response to previously administered chemotherapy following immune checkpoint inhibitor therapy, despite prior progression on this chemotherapy regimen. To our knowledge, this has not been previously reported in esophagogastric carcinoma (EGC). Post-immune checkpoint inhibitor chemotherapy may be a feasible treatment strategy. Research is needed to evaluate the role of post-immune checkpoint inhibitor chemotherapy in patients with metastatic EGC.

Immune checkpoint inhibitors have transformed treatment paradigms in several cancers, many of which were previously associated with a poor prognosis, including melanoma and lung cancer. Given the poor outcomes from treatment with chemotherapy and targeted therapies in this disease, there has been strong interest in the evaluation of immunotherapy.

Recent years have seen advances in the management of esophageal cancer, which have led to clinically meaningful improvements in outcome. While surgical resection is the mainstay of treatment for locally advanced esophageal cancer, the addition of chemotherapy and/or radiotherapy are also recognized to be key components of the treatment paradigm. Definitive chemoradiation is standard-of-care for patients with unresectable esophageal cancer, and it is an option for patients with squamous cell carcinoma (SCC), with surgery reserved for patients with persistent/recurrent disease. This chapter focuses on established neoadjuvant and adjuvant therapy in the treatment of localized esophageal cancer. Evolving approaches and areas of clinical equipoise are also discussed.

Despite advances in the treatment of metastatic colorectal cancer (CRC) the 5-year survival of patients with this disease remains low. A small proportion of CRCs overexpress the HER2 oncogene and the effective targeting of this pathway in other malignancies such as breast and gastric cancer has led to efforts to determine if it can also be exploited as a target in CRC. Activation of the HER2 pathway as a bypass signalling pathway has been identified as a mechanism of resistance for antiepidermal growth factor receptor antibody therapy in both the first line and salvage settings. It has also been shown that RAS and BRAF wild type metastatic CRC enriches for the presence of HER2 amplification. This knowledge, in addition to preclinical data providing a rationale for dual anti-HER2 targeted therapy has led to several clinical trials. To date, recently published and presented early phase data provide promising evidence suggesting anti-HER2 therapy may have a potentially beneficial role in the treatment of HER2-positive metastatic CRC. Namely, the HERACLES-A and MyPathway studies have shown benefit in a small number of patients with the use of combination trastuzumab-lapatinib and trastuzumab-pertuzumab, respectively. However, data from larger clinical trials are required before HER2-directed therapy is incorporated into standard treatment paradigms for CRC. This review presents an overview of epidermal growth factor receptor and HER2 pathways in CRC and discusses preclinical and clinical studies carried out in this field to date. There is potential that with continued evolution of data in this area, HER2 may become a validated therapeutic target and thus, anti-HER2 therapy may become an additional treatment option for a small population of patients with metastatic CRC.

4046 Background: Peri-op chemo (ctx) and surgery is a standard in the treatment of GC, based on the MAGIC (NEJM 2006; 355:11) and FLOT4 (J Clin Oncol 35:4004 [abstr]) studies. However, less than half of patients (pts) completed ctx in the MAGIC and FLOT4 studies, mainly from issues delivering post-op therapy. We assessed safety and feasibility of TNT, where all ctx is given pre-op. Methods: We reviewed GC pts who received TNT or peri-op ctx and had surgery; decision for TNT was by physician preference, based on clinical or radiographic benefit to justify completing ctx pre-op. Pt characteristics were compared using Fisher’s exact and Wilcoxon Rank Sum tests. Post-op length of stay (LOS) was calculated from date of surgery (DOS) to date of discharge and surgical morbidity was determined using the Clavien-Dindo classification. Progression free survival (PFS) and overall survival (OS) were calculated from DOS using Kaplan-Meier methods and compared between groups using the log-rank test. Results: 120 pts were identified, median age 63, 62.5% male, 98% ECOG 0/1. 93 pts (77.5%) received peri-op ctx and 27 (22.5%) received TNT. In peri-op pts, 19%, 43% and 38% received FLOT, platinum/fluropyrimidine (FP) and ECF/EOX respectively. In TNT pts, 56%, 37% and 7% received FLOT, platinum/FP and ECF/EOX respectively. 57% had subtotal gastrectomy. Surgical outcomes were similar between groups; median LOS was 6 and 7 days (p = 0.31) in peri-op and TNT pts respectively. There was no significant difference in Clavien Dindo grade I-II or III-IV morbidity between groups (p = 0.103). There were no deaths. TNT pts received higher proportions of planned treatment than peri-op ctx pts: 90% vs. 60% FP (0.001); 85% vs. 41% platinum ( < 0.001); 100% vs. 9% epirubicin (0.015) and 53% vs. 28% docetaxel (p = 0.169). At median follow-up of 19 months, median PFS and OS were not reached. There was no significant difference in PFS (p = 0.089) or OS (p = 0.59) between groups. Conclusions: TNT appears safe with no increase in post-op LOS or surgical morbidity observed. TNT pts had higher percentage drug delivery, suggesting potential benefit for administering all ctx before surgery. While longer survival follow-up is required, TNT may be considered in pts with locally advanced GC who are candidates for ctx.

4047 Background: In the US, FOLFOX is the most widely used 1L treatment for advanced EGA. We evaluated if FOLFOX resistance (FR) impacted subsequent therapy and characterized the clinical and molecular factors that predict resistance to 1L FOLFOX. Methods: We reviewed pts with advanced Her2-negative EGA treated with 1L FOLFOX from Jan 2013 to Aug 2017. Response or stable disease (SD) at time of first restaging scan defined pts as FOLFOX sensitive (FS); progression defined FR. Pt characteristics were compared using Fisher’s exact and Wilcoxon Rank-Sum tests. Outcomes were correlated with clinical variables and MSK-IMPACT data. Microsatellite instable (MSI) pts were excluded from gene and pathway analysis. Overall survival (OS) was calculated from start of FOLFOX using Kaplan-Meier methods. Landmark analysis (2 months [mo] after starting FOLFOX) was used to compare OS between groups. Results: We identified 311 pts, median age 62, 73% male, 82% ECOG 0/1. 246 pts (79%) were FS and 65 (21%) were FR. FR pts had a higher number of metastatic sites, p = 0.001. Median OS was 13.4 mo in FS pts vs 4.3 mo in FR pts (p < 0.001). At time of analysis, 213 pts (172 FS pts and 41 FR pts) and 110 pts (90 FS pts and 20 FR pts) had received 2nd-line (2L) and 3rd-line (3L) chemo respectively. In pts who received 2L chemo (ctx), there was no difference in ctx duration between FS and FR pts (2.1 vs 1.4 mo, p = 0.67). However, in pts who received 3L ctx, the duration was longer in FS vs FR pts (1.6 vs 0.5 months, p = 0.002). In IMPACT tested pts (n = 130), univariate analysis identified EGFR (33.3% vs 10.7%, p = 0.032) and WNT pathway (26.7% vs 4.9%, p = 0.015) alterations more frequently in FR pts vs FS pts. 12 pts were MSI, all were FS (3 SD, 8 PR, 1 CR). Of 63 pts who had IMPACT germline testing, 7 (11%) had germline mutations identified, including CDH1 (n = 2) and ATM (n = 1), all were FS. No pts were enrolled on genotype-matched trials as a result of IMPACT testing. Conclusions: From time of first restaging scan, FR pts have inferior OS to FS pts. The duration of 3L ctx was longer in FS vs FR pts. Higher number of metastatic sites and EGFR and WNT pathway alterations were associated with FR; MSI was not. IMPACT did not facilitate enrolment on genotype-matched studies.

117 Background: The role of IP CTX in pts with GC and PC is unclear. The PHOENIX-GC phase III study (J Clin Oncol 2018;35:1922) did not show overall survival (OS) benefit for IP CTX plus systemic CTX while a retrospective French study suggested benefit for IP CTX and cytoreductive surgery (J Clin Oncol 36:8 [abstr]). Prolonged survival may be possible in pts with chemosensitive disease (dz). Methods: We reviewed GC pts diagnosed with PC (+ve cytology and/or gross dz) at diagnostic laparoscopy (DL). We identified pts treated with gastrectomy and IP floxuridine 1,000mg/ m2/leucovorin 240 mg/m2 ×3d q14d and pts who had CTX alone. Pts with visible dz on imaging were excluded. Progression-free survival (PFS) and OS were calculated from surgery date and estimated using Kaplan-Methods in surgery + IP CTX pts. Pt characteristics were compared using Fisher’s exact test and Wilcoxon Rank-Sum tests. Results: From 2000-2017, 18 pts had surgery + IP CTX (IP); 45 pts received CTX alone. Median age was 50 in IP pts and 65 in CTX only pts (p = 0.002); 94% of IP pts were ECOG PS 0/1 vs. 78% in CTX only pts (p = 0.16). 56% and 67% of pts had gross dz at DL in IP and CTX only pts respectively; remaining pts had +ve cytology only. IP pts received CTX (72% 5-FU/platinum based) for a median 3.3 months before repeat DL. 14/18 pts cleared dz; four pts with residual dz (1 +ve cytology only) had gross dz at baseline. Fourteen pts had R0 resection; 83% of tumors were ypT3-4N+. 4 pts had R1 resection; three had residual gross PC at DL. Pts received IP CTX for a median of 1 month post surgery. Median PFS and OS were 12.4 and 23 months respectively in surgery + IP CTX pts. While there was no difference in PFS in pts with -ve vs. persistently +ve cytology at repeat DL following CTX (15.5 vs. 4.7 months, p = 0.3), median OS was improved in pts who cleared cytology (29 vs. 8 months, p = 0.01). Median PFS and OS were 7 and 13.5 months respectively in CTX only pts. Conclusions: Surgery and IP CTX may have a role in highly select pts with GC and +ve cytology or small-volume gross dz. While survival was encouraging, no pt had OS > 5 years. Surgery and IP CTX may be considered in pts who have a -ve repeat DL after initial CTX. Survival in CTX only pts is comparable with stage IV pts enrolled on clinical trials.

116 Background: PTX/RAM as 2L tx for patients (pts) with EGA is a standard-of-care based on the RAINBOW trial (Lancet Oncol 2014;15:1224). However, benefit is modest. Upregulation of the platelet-derived growth factor (PDGF)/PDGF receptor-β (PDGFR-β) pathway causes resistance to VEGF inhibition. Crenolanib is a selective inhibitor of PDGFR-β. We report initial results of the dose escalation phase of a study of crenolanib plus RAM/PTX in pts with previously treated advanced EGA. Methods: This phase I/Ib study is enrolling ECOG PS 0-1 EGA pts with progression on first-line chemo. PTX 80 mg/m2/ day on day 1, 8, 15 and RAM 8mg/kg q 14 days were administered with escalating doses of crenolanib (60, 80, 100 mg BID) after a 7 day “run-in” of crenolanib to assess crenolanib-related toxicities. The primary objective was to determine the maximum tolerated dose (MTD) of crenolanib plus RAM/PTX. Safety and preliminary efficacy were examined. Results: 15 pts were treated; 12 male, median age 58 (32-73), 66% were ECOG PS 1. Primary site was gastric in nine pts, GEJ in 4 pts and esophageal in two pts. Three pts each received crenolanib 60mg BID and 80mg BID, six pts received 100mg BID and three pts received higher doses. At data cutoff, eight pts continued on treatment. 12 pts have completed the DLT evaluation period across 3 dose levels (60 to 100 mg BID). Median treatment duration was 76 days (35-191). The combination was well tolerated, with no DLTs or serious adverse events (SAEs) attributed to study drug. Treatment related adverse events occurred in two pts (17%), all grade 1. These were fatigue, nausea, vomiting and hypertension. Disease progression was the most common reason for treatment discontinuation; no pt discontinued due to study drug related AEs. Nine pts were evaluable for response. One pt had objective response; the disease control rate was 78%. Median PFS and OS were 4.1 and 11.9 months respectively. Conclusions: Crenolanib plus RAM/PTX appears well tolerated at a dose level of 100mg BID. Further evaluation is needed to determine efficacy. Accrual is ongoing at higher doses. Once the MTD is defined, the dose expansion phase will enroll 25 pts. Updated data with pharmacokinetics and biomarkers will be presented. Clinical trial information: NCT03193918.

Background Compared with the general population, the incidence of young-onset (YO) colorectal cancer (CRC) is increasing. However, a significant knowledge gap exists in the clinical characteristics, treatment patterns, and outcomes for these patients. Materials and Methods Six international tertiary cancer centers conducted a retrospective study. Patients with YO CRC (aged 18-44 years) and LO CRC (aged > 44 years) diagnosed with histologically proven colorectal adenocarcinoma from June 2003 to June 2014 were enrolled. Patients were randomly chosen from each center's database, and the patient demographics and treatment information were collected. The data were then centralized, and the final analysis was performed at a single institution. Cox proportional hazards models were used to estimate the crude and adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for progression-free survival and mortality, and YO was compared with LO. Site-specific HRs were pooled using a random-effects meta-analysis. Results Overall, 498 patients, including 224 with YO (129 men; mean age, 37 ± 5.5 years) and 274 with LO (167 men; mean age, 64.8 ± 9.5 years) CRC, were included. At the diagnosis, 137 patients (61.2%) and 122 patients (44.5%) with YO and LO CRC had metastatic disease, respectively. For both cohorts, the 3 most common presenting symptoms were pain, hematochezia, and weight loss. Surgery was performed in 141 YO (63.0%) and 219 LO (79.9%) patients. The longitudinal noncurative treatment patterns were similar, but more biologic therapy was used for these YO patients. The pooled progression-free survival analysis results for first-line noncurative treatment favored LO (HR, 1.96; 95% CI, 1.04-3.68). The mortality analysis showed no significant differences between the 2 groups (YO: HR, 1.53; 95% CI, 0.91-2.58). Conclusion Despite similar treatment patterns and survival outcomes, YO disease might be clinically more aggressive.

4056Background: Immune checkpoint inhibitors (nivolumab and pembrolizumab) have clear activity in EGC. However, benefit is modest in an unselected population. TMB may be of value as a quantitive ma...

4055Background: Pre-operative or definitive CRT is standard for locally advanced (LA) ESCC. We previously showed that PET response after induction chemo and prior to CRT and surgery strongly predic...

60 Background: Due to rising incidence and improved outcomes the number of CRC survivors in Ireland is approaching 20,000, and this figure is climbing. It is now recognized by leading organizations such as ASCO and NCCN, that survivorship is a distinct phase along the cancer care continuum and that supporting patients throughout their survivorship is vital. We aimed to assess the variability in surveillance practices in Ireland, and pilot the use of SCPs in CRC patients. Methods: A two phase approach was taken to complete this study. Firstly an online survey was issued to medical oncologists treating CRC in the 8 designated regional cancer centres in Ireland. This comprised 10 questions addressing surveillance practices and use of guidelines. We subsequently piloted the SCP in a cohort of our CRC patients, and followed up with a questionnaire assessing patient views. Results: The online survey was completed by 13 medical oncologists, comprising the lead treating physicians for the Irish regional cancer centres and their satellite centres. Routine surveillance of CRC is practiced by 77% (n = 10). Of those who practice follow up, 90% (n = 9) do so for 5 years. Guidelines for follow up are utilized by 77% (n = 10). The most commonly used guideline is NCCN, by 60% (n = 6). 91.6% think that the SCP is useful in enabling alternative methods of follow up and 69.2% think that nurse-led surveillance clinics should be introduced. 16 patients responded to the follow up survey. 81% (n = 13) felt the SCP was useful, and 81% (n = 13) also believed it reduced anxiety around their diagnosis. 88% (n = 14) reported that the SCP helped them feel in control of their follow up. 69% of patients (n = 11) felt the SCP aided communication and coordination of their care. Conclusions: Surveillance practices in Ireland are heterogeneous. Which guidelines are used to follow patients is physician and hospital dependent. The SCP is a useful tool for streamlining follow up practices so that they are more uniform. Physicians and patients both feel that SCPs are beneficial. Widespread use of SCPs may provide a mechanism to move CRC surveillance out of busy oncology clinics to a more appropriate setting, such as nurse-led clinics and primary care.

208 Background: It is estimated that within ten years of primary treatment for prostate cancer up to 40% of patients post radical prostatectomy, and up to 50% of patients post radiotherapy will develop disease recurrence. While monitoring of PSA levels is informative of biochemical recurrence, it may precede radiologically detectable recurrence by months to years, and cannot differentiate local/regional recurrence from systemic disease. This represents a management dilemma for treating physicians. The incorporation of PET probes targeting prostate-specific membrane antigen (PSMA) for prostate cancer shows promise for improving the management of patients with prostate cancer, when used alongside existing imaging techniques, like CT, MRI and bone scans. Methods: Retrospective review of all patients referred from our institution for PSMA imaging was carried out. Baseline clinical features were determined and we analyzed impact of PSMA imaging on management outcomes and survival data. Results: 33 patients referred for 68Ga-PSMA-PET imaging were identified. Median age at diagnosis was 65 years (51 -75). The indication for referral in all patients was biochemical recurrence in the absence of radiological evidence of disease by CT imaging and bone scan. Median PSA at time of referral for PSMA scan was 7.3ug/L (1.4ug/L to 87.7ug/L). 100% of patients (n = 33) were upstaged following PSMA imaging, and 30% (n = 10) had more than one site of metastatic disease identified. Most common sites of metastasis were lymph node and bone. Median number of sites of metastatic disease identified by PSMA imaging was one. These results led to a change in management for 96% patients (n = 32). All patients at the time of this review are alive with a median follow up of 13 months, and median progression-free survival of 11 months. Conclusions: PSMA PET-CT directly led to an alteration in the treatment of the majority of patients in this study. This real world data reflects the growing role of PSMA imaging in influencing clinical decisions for prostate cancer patients with biochemical recurrence. Prospective data from randomized studies are awaited to further validate the role of PSMA PET-CT in this patient cohort.

827 Background: The last 15 years have seen significant improvements in the outcomes of patients (pts) with CRC. More effective systemic therapy (Rx) and wider use of surgery (Sx) in stage IV disease (Dx) are key drivers of this. We evaluated the impact of intense surveillance in concert with greater use of metastasectomy and improved systemic Rx on CRC outcomes. Methods: This is a retrospective review of the clinical, radiologic and histological records for consecutive pts with CRC who were referred to the multi-disciplinary CRC team from 2003-2016. Pts with stage I/II Dx were included when referred for adjuvant Rx for high-risk features. We recorded pt characteristics, Rx received and outcomes. Survival was assessed using Kaplan-Meier analysis. Results: We identified 600 pts. Median age was 65 (22-97 years). 71.2% (n=427) of pts had left sided CRC and 25.7% (n=154) had right sided Dx. 211 pts (35.2%) had de novo metastatic Dx. 163 of 389 pts (41.9%) with stage II/III disease relapsed. Median Dx-free interval was 16 months. Of 163 relapses, 121 (74%) were detected by radiologic surveillance and 14 (9%) by rise in CEA. Symptomatic relapse occurred in 20 pts (12%). Median overall survival (OS) was significantly improved in pts with relapse detected by CT, PET/CT or CEA rise (54, 53 and 54 months respectively) vs pts with symptomatic relapse (4 months, p

172 Background: Pre-op CRT with carboplatin (C)/paclitaxel (P) and radiation (RT) for locally advanced esophageal cancer is a standard of care, based on the CROSS trial (NEJM 2012;366:2074). However, outcomes remain poor. Early data suggest activity of durvalumab (D) in GEJ/gastric cancer [Ann Oncol 25:iv361-372; 2014]. In a pilot study, we assessed safety of D + C/P + RT as pre-op therapy. Methods: Patients (Pts) had TanyN+ or T3-4NanyM0 esophageal and Siewert Type I/II GEJ adenocarcinoma staged by EUS, PET/CT and CT. Pts received D 1500mg x 1 dose and 4 weeks later C AUC2 and P 50mg/m2 weekly x 5 with RT (1.8Gy daily fractions to 50.4Gy). Pts also received D 1,500mg at first dose of C/P and RT. PET/CT was repeated 21-27 days post D and 4-6 weeks post CRT. Esophagectomy was planned 6-8 weeks after CRT. Pts who had R0 resections received adjuvant D 1,500mg 4 weekly x 6 doses. Initially, 6 patients were treated and followed for 30 days after surgery to assess for unacceptable toxicities. Results: 6 pts were enrolled: 3 Siewert I (50%), 2 Siewert II (33%), 1 esophageal (17%); 5 T3N1-2, 1 T4aN1. 5 pts (83%) underwent sx. 1 pt was retrospectively assessed to have metastases after induction D and taken off-study. Pathologic response was 60% in 2 pts, 90% in 1 pt, 80% in 1 pt and 40% in 1 pt; no complete response was seen. Significant grade 3/4 toxicity observed during D and CRT was neutropenia in 1 pt (17%). Adverse events (AEs) of any grade in ≥20%: lymphopenia (5 pts), thrombocytopenia (5 pts), leucopenia (4 pts), fatigue (3 pts), anemia (3 pts), neutropenia (3 pts) and abdominal pain (2 pts). Immune-related AEs were hypothyroidism (grade 2; 1 pt) and nephritis (grade 2; 1 pt). Surgical complications: 2 esophageal strictures, 1 pneumonia and 1 anastomotic leak with airway fistula, successfully treated with a stent. Immune correlative analyses from tumor blocks and whole blood are ongoing and will be reported in the poster. Conclusions: The addition of D to pre-op CRT in esophageal and GEJ adenocarcinoma appears feasible and safe. We observed no unacceptable toxicity. The study is being modified to incorporate use of induction chemo and PET (based on CALGB 80803 results) and expanded to a multicenter setting. Clinical trial information: NCT02962063.

The use of [ 18 F]-2-fluoro-deoxy-D-glucose positron emission tomography (FDG-PET) imaging is emerging as an important tool in the treatment of esophageal cancer. Over a decade ago, the MUNICON investigators first incorporated metabolic assessment by PET into clinical trial design and evaluated the strategy of taking patients with locally advanced gastroesophageal junction (GEJ) adenocarcinomas, who had a suboptimal response to two weeks of induction chemotherapy with 5-fluorouracil (FU)/cisplatin directly to surgery (1).

e20091 Background: Despite optimal local Rx 35-50% of pts with OM develop metastasis (MM), most frequently in the liver. Systemic Rx for MM is very unsatisfactory and the median overall survival (O...

e14692 Background: Contrary to the general population, incidence of CRC in AYA is on the rise. However, their clinical outcomes and treatment (tx) efficacy remains somewhat abstruse. A MIRR was per...