EGFR-directed therapies have changed the treatment paradigms in metastatic lung, colorectal, and head and neck cancers and improved outcomes. A better understanding of mechanisms of resistance to these agents is crucial for effective drug development. Predictive biomarkers are being developed to deliver personalized therapies.

Background The incidence and outcomes for patients with colorectal cancer (CRC) varies by age. Younger patients tend to have sporadic cancers not detected by screening and worse survival. To understand if genetic differences exist between age cohorts we sought to characterize unique genetic alterations in patients with CRC. Methods We identified 283 patients with sporadic CRC between 1998 and 2010 and divided them by age into two cohorts: ≤45 years old (younger) or ≥65 years old (older) and performed targeted exome sequencing. Fisher’s Exact test was used to detect differences in mutation frequencies between the two groups. Whole exome sequencing was performed on 21 additional younger patient samples for validation. Findings were confirmed in The Cancer Genome Atlas CRC dataset. Results 246 samples were included for final analysis (195 older, 51 younger). Mutations in FBXW7 were more common in the younger cohort (27.5% vs. 9.7%, p=0.0022) as were mutations in the proofreading domain of POLE (9.8% vs. 1.0%, p= 0.0048). There were similar mutation rates between cohorts with regards to TP53 (64.7% vs. 61.5%), KRAS (43.1% vs. 46.2%), and APC (60.8% vs 73.8%). BRAF mutations were numerically more common in the older cohort, though not statistically significant (2.0% vs 9.7%, p=0.082). Conclusions In this retrospective study, we identified a unique genetic profile for younger CRC patients as compared to patients diagnosed at an older age. These findings should be validated in a larger study and could have an impact on future screening and treatment modalities for younger CRC patients.

202 Background: New therapies are needed for patients (pts) with mCRPC progressing after androgen-receptor signaling inhibitors (ARSIs) and taxane therapies. Niraparib is a once daily highly selective inhibitor of poly (ADP-ribose) polymerase (PARP-1 and 2). Methods: GALAHAD is an ongoing open label Ph 2 study assessing niraparib (300 mg daily) in pts with DRD progressing on/after ARSIs and taxane chemotherapy. Using a validated plasma assay, DRD status was defined as pathogenic mutations (including homozygous deletions) of BRCA1/2, ATM, FANCA, PALB2, CHEK2, BRIP1 or HDAC2. Composite response rate (RR) was defined as an objective response by RECIST 1.1 for measurable disease, circulating tumor cell (CTC) conversion to < 5/7.5 mL blood or prostate-specific antigen (PSA) decline of ≥50% (PSA50). Here, preliminary data on RR and adverse events (AEs) are reported in pts with biallelic DRD. Results: As of 10 Sep 2018, 123 pts with mCRPC and DRD were enrolled, of whom 39 had biallelic DRD (23 BRCA1/2). The median follow-up was 5.7 mo (2.0–23.7). Table depicts RRs for pts with biallelic DRD by BRCA status. Composite and objective RRs were 65% and 38% in pts with biallelic BRCA1/2, respectively. 3/8 pts (38% [2/5 BRCA1/2 and 1/3 non-BRCA]) with measurable visceral metastases showed objective response. Among the 20 biallelic responders, the duration of treatment (tx) has exceeded 4 mo in 13 pts and 6 mo in 8 pts; 14 pts remain on tx. The most common grade 3/4 hematologic AEs were anemia (25%) and thrombocytopenia (15%) (manageable by dose reduction/interruption). The most common grade 3/4 nonhematologic AEs were asthenia (6%) and hypertension (5%). Conclusions: These results suggest niraparib has compelling activity as monotherapy for pts with treatment-resistant mCRPC, particularly those with biallelic BRCA1/2 identified by a blood assay. Clinical trial information: NCT02854436. [Table: see text]

Background Recent data have suggested that regular aspirin use improves overall and cancer-specific survival in the subset of colorectal cancer (CRC) patients harboring PIK3CA mutations. However, the number of PIK3CA-mutated CRC patients examined in these studies was modest. Our collaborative study aims to validate the association between regular aspirin use and survival in patients with PIK3CA-mutated CRC. Patients and methods Patients with PIK3CA-mutated CRC were identified at Moffitt Cancer Center (MCC) in the United States and Royal Melbourne Hospital (RMH) in Australia. Prospective clinicopathological data and survival data were available. At MCC, PIK3CA mutations were identified by targeted exome sequencing using the Illumina GAIIx Next Generation Sequencing platform. At RMH, Sanger sequencing was utilized. Multivariate survival analyses were conducted using Cox logistic regression. Results From a cohort of 1487 CRC patients, 185 patients harbored a PIK3CA mutation. Median age of patients with PIK3CA-mutated tumors was 72 years (range: 34 – 92) and median follow up was 54 months. Forty-nine (26%) patients used aspirin regularly. Regular aspirin use was not associated with improved overall survival (multivariate HR 0.96, p = 0.86). There was a trend towards improved cancer-specific survival (multivariate HR 0.60, p = 0.14), but this was not significant. Conclusions Despite examining a large number of patients, we did not confirm that regular aspirin use was associated with statistically significant improvements in survival in PIK3CA-mutated CRC patients. Prospective evaluation of this relationship is warranted.

Hepatocellular carcinoma (HCC) is an aggressive tumor that often arises in the setting of liver cirrhosis. Although early-stage disease is often amenable for surgical resection, transplant, or locoregional therapies, many patients are diagnosed at an advanced stage or have poor liver reserve. Systemic therapy is the mainstay of treatment for these patients. At present, the only approved therapy for the treatment of advanced disease is the tyrosine multikinase inhibitor sorafenib. Candidacy for treatment is based on liver reserve. Novel agents for the treatment of this disease are urgently needed. In this article, we review systemic therapy trials and upcoming data for the treatment of HCC.

Aims Based on KRAS testing, the subset of patients with metastatic colorectal cancer (CRC) that could benefit from anti-EGFR therapy can be better delineated. Though KRAS testing has become significantly more prevalent over the last few years, methods for testing remain heterogeneous and discordance has been reported between methods. Methods In this study, we examined a CRC patient population and compared KRAS testing done in Clinical Laboratory Improvement Amendments (CLIA) approved laboratories as part of standard clinical care and by next-generation sequencing (NGS) using the Illumina platform. Discordances were further evaluated with manual review of the NGS testing. Results Out of 468 CRC patient samples, 77 had KRAS testing done by both CLIA assay and NGS. There were concordant results between testing methodologies in 74 out of 77 patients, or 96% (95% CI 89% to 99%). There were three patient samples that showed discordant results between the two methods of testing. Upon further investigation of the NGS results for the three discordant cases, one sample showed a low level of the mutation seen in the standard testing, one sample showed low tumour fraction and a third did not show any evidence of the mutation that was found with the standard assay. Five patients had KRAS mutations not typically tested with standard testing. Conclusions Overall there was a high concordance rate between NGS and standard testing for KRAS. However, NGS revealed mutations that are not tested for with standard KRAS assays that might have clinical impact with regards to the role for anti-EGFR therapy.

Background In pancreatic cancer, early detection and complete surgical resection with negative margins offers the only cure for the disease. Work up to evaluate resectability includes triple phase helical scan CT of the pancreas and endoscopic ultrasound (EUS). A paucity of data exists in using PET/CT scan as staging work up in early resectable pancreatic cancer. The objective of our study was to determine if PET/CT prevents futile laparotomy by detecting occult metastatic disease in patients with resectable/borderline pancreatic cancer. Methods We looked at our institutional PET/CT data base incorporating National Oncologic PET Registry with diagnosis of resectable or borderline resectable pancreatic cancer from 2005 to 2012. Clinical, radiographic, and pathologic follow-up was evaluated, including age, gender, evidence of metastatic disease, and initial CA 19–9 levels. The impact of PET/CT on patient management was estimated by calculating the percentage of patients whose treatment plan was altered due to PET/CT. The confidence interval was computed using the exact binomial distribution. The effect on the change was evaluated by the multiple logistic regression model. The final model was selected using the backward elimination method. Results We identified 285 patients with early stage (resectable or borderline) pancreatic cancer who received PET/CT as part of initial staging workup. Upon initial work up (CT + EUS), 62% of patients were considered resectable and 38% were borderline resectable. Addition of PET/CT scan changed the management in 10.9% (n=31) of patients (95% CI: 7.5%–15.1%). Median time from EUS to PET/CT was 5 days. Metastatic lesions were confirmed with biopsy in 19 (61%) patients. The proportion in the change in treatment plan is significantly higher in patients who were initially considered to have borderline resectable compared to resectable malignancy (16.5% vs. 7.4%). In 199 patients who were taken to surgery, 18.1% (n=36) were found to have metastatic disease intraoperatively. Conclusions PET/CT helped improve detection of occult metastases, ultimately sparing these patients a potentially unnecessary surgery. The role of PET/CT scan should be validated in prospective study.

Background: Brain metastases from esophageal carcinoma have historically been rare and associated with poor prognosis. With improvements in systemic disease control, the incidence of brain metastases is expected to rise. To better inform management decisions, we sought to identify factors associated with survival in patients with brain metastasis from esophageal cancer. Conclusions: While the prognosis for esophageal cancer metastatic to brain remains poor overall, we found that patients with good performance status and limited number of brain lesions have superior survival.Aggressive management may further improve outcomes in these patients.