EGFR Inhibitors in Patients with Advanced Squamous Cell Anal Carcinomas: A Single-Institution Experience.

BACKGROUND: Although squamous cell anal carcinomas are relatively rare, their incidence has been increasing steadily. Because of the limited data, treatment of metastatic disease is a major therapeutic challenge. In this study, we report the safety and efficacy of epidermal growth factor receptor (EGFR) inhibitors in patients with advanced squamous cell anal carcinomas. METHOD: A retrospective analysis was conducted using the Moffitt Cancer Tumor Registry from January 2009 to January 2014. Eligible patients had diagnosis of advanced squamous cell anal carcinomas and received an EGFR inhibitor as part of their treatment. RESULT: A total of 13 patients were identified for analysis. All of them received concurrent chemoradiation as initial treatment and subsequently had recurrence. Five patients received single agent cetuximab or panitumumab, and the others received cetuximab or panitumumab with irinotecan or FOLFIRI. The objective response rate was 30.8% including 1 complete response, and the disease control rate was 46.2%. With a median follow-up of 9.6 months, the median progression-free survival and median overall survival were 4.4 months and 11.4 months, respectively. CONCLUSION: Our analysis suggests that EGFR inhibitors have potential efficacy and are reasonably well tolerated in patients with squamous cell anal carcinomas. These findings warrant further evaluation in a large prospective trial.

Role of Systemic Therapy and Future Directions for Hepatocellular Carcinoma.

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.

Increased incidence of FBXW7 and POLE proofreading domain mutations in young adult colorectal cancers.

BACKGROUND: The incidence and outcomes of patients with colorectal cancer (CRC) varies by age. Younger patients tend to have sporadic cancers that are not detected by screening and worse survival. To understand whether genetic differences exist between age cohorts, the authors sought to characterize unique genetic alterations in patients with CRC. METHODS: In total, 283 patients who were diagnosed with sporadic CRC between 1998 and 2010 were identified and divided by age into 2 cohorts-ages ≤45 years (the younger cohort) and ≥65 years (the older cohort)-and targeted exome sequencing was performed. The Fisher exact test was used to detect differences in mutation frequencies between the 2 groups. Whole exome sequencing was performed on 21 additional younger patient samples for validation. Findings were confirmed in The Cancer Genome Atlas CRC data set. RESULTS: In total, 246 samples were included for final analysis (195 from the older cohort and 51 from the younger cohort). Mutations in the FBXW7 gene were more common in the younger cohort (27.5% vs 9.7%; P = .0022) as were mutations in the proofreading domain of polymerase ε catalytic subunit (POLE) (9.8% vs 1%; P = .0048). There were similar mutation rates between cohorts with regard 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, although the difference did not reach statistical significance (2% vs 9.7%; P = .082). CONCLUSIONS: In this retrospective study, a unique genetic profile was identified for younger patients who have CRC compared with patients who are 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 patients with CRC. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2828-2835. © 2016 American Cancer Society.

Impact of regular aspirin use on overall and cancer-specific survival in patients with colorectal cancer harboring a PIK3CA mutation.

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.

Predictive biomarkers for anti-epidermal growth factor receptor therapy: beyond KRAS testing.

In an era of personalized medicine, an increased effort is being made to identify patients likely to benefit from targeted therapy. By limiting treatment to selected patients, both unnecessary cost and toxicity may be avoided. Restricting the use of anti-epidermal growth factor receptor (anti-EGFR)-targeted agents in metastatic colorectal cancer to only patients with KRAS exon 2 wild-type tumors has become well-established in clinical practice. However, lack of KRAS exon 2 mutations does not necessarily predict response, and a significant proportion of patients with KRAS wild-type tumors do not benefit from therapy with cetuximab or panitumumab. Further characterization is needed of the subset of patients with KRAS exon 2 wild-type tumors who are likely to benefit from anti-EGFR therapy. Recent data suggest that patients with KRAS mutations at loci other than exon 2, and those with other RAS mutations, might not benefit from EGFR-directed therapy. This article briefly reviews established work on KRAS exon 2 mutations, but focuses primarily on emerging data on non-exon 2 KRAS mutations and additional RAS and BRAF mutations and how this information may impact clinical decision-making.

Epidermal growth factor receptor inhibitors: coming of age.

BACKGROUND: Agents targeting the epidermal growth factor (EGFR)-mediated signaling pathway are used in the treatment of various solid tumors, including lung, breast, pancreatic, colorectal, and head and neck cancers. METHODS: Clinical evidence supporting the benefits of targeted agents directed against EGFR/HER1 in various solid tumors is discussed, as well as the survival end points used in the pivotal clinical trials, current applications, and future research directions. Agents reviewed include the monoclonal antibodies cetuximab and panitumumab, both of which block ligand binding to the extracellular domain, and the small-molecule tyrosine kinase inhibitors gefitinib, erlotinib, and afatinib that exert their effects at the intracellular portion of the receptor to prevent tyrosine kinase phosphorylation and the activation of signal transduction pathways. RESULTS: EGFR inhibitors have a mechanism of action distinct from traditional cytotoxic therapies, and combining these agents with chemotherapy produces synergistic anticancer activity without overlapping toxicity profiles. The level of EGFR expression does not correlate with agent response, and many tumors are resistant to treatment. Even if tumors are initially sensitive to these agents, they inevitably acquire resistance through complex, poorly understood molecular mechanisms. CONCLUSIONS: 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.

First-line treatment for advanced pancreatic cancer.

Metastatic pancreatic cancer is a rapidly fatal disease with few therapeutic options. The authors summarize four abstracts (#148, #233, #158, #291) presented at the 2013 ASCO Gastrointestinal Cancers Symposium which were focused on novel agents for metastatic pancreatic cancer.

Adjuvant chemotherapy and outcomes in esophageal carcinoma.

BACKGROUND: Standard treatment for locally advanced esophageal cancer is neoadjuvant chemoradiation followed by surgery. The role of postoperative chemotherapy is unclear. We sought to determine the indications, patterns, and outcomes for adjuvant chemotherapy in esophageal carcinoma. METHODS: This single institution retrospective review included patients with esophageal cancer who received neoadjuvant chemoradiation and surgery at Moffitt. We identified patients in this cohort who additionally received adjuvant chemotherapy. Medical records were reviewed for demographic/clinical information. Survival was estimated using the Kaplan-Meier method and compared by log-rank. Case-control analysis was performed using a 2:1 nearest neighbor propensity score matching algorithm, which included 92 without adjuvant chemotherapy and 46 with adjuvant chemotherapy. RESULTS: We identified 382 patients, 46 of whom received adjuvant chemotherapy. Patients who received adjuvant chemotherapy were younger (60.2 vs. 63.8 years; P=0.047), more likely to have adenocarcinoma (91% vs. 85%; P=0.034), had more advanced ypT and ypN classifications (P<0.001), less response to neoadjuvant therapy (P<0.001), and more margin positivity (15% vs. 4%; P=0.007). With propensity score matching analysis, no variables were significantly different between the two matched groups. Median follow-up times for the entire cohort and for case-control analysis were 2.9 and 2.4 years, respectively. There were no significant differences in overall or recurrence-free survival (RFS) between groups in either analysis. CONCLUSIONS: The role of adjuvant chemotherapy following neoadjuvant chemoradiation and surgery in esophageal cancer is unclear. We found no significant difference in survival based on adjuvant chemotherapy. Future prospective studies should further investigate potential survival benefits and morbidity.

Outcomes in patients with brain metastasis from esophageal carcinoma.

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. METHODS: We retrospectively identified 49 patients with brain metastasis from stage I-IV primary esophageal cancer treated with surgery, radiation, or a combination of modalities at our tertiary referral center between 1998 and 2015. Medical records were reviewed to collect demographic and clinical information. RESULTS: Median age at diagnosis of the primary esophageal cancer was 60 years. Forty-one (84%) patients were male and forty patients (82%) had adenocarcinoma. Median overall survival (MS) following esophageal cancer diagnosis was 24 months (range, 3-71 months), and median survival after the identification of brain metastases was 5 months (range, 1-52 months). On univariate analysis, only patients with poor Karnofsky performance status (KPS <70), recursive partitioning analysis (RPA) classification (III), or 3 or more brain metastases were found to have worsened survival after the diagnosis of brain metastases (all P<0.01). Factors not associated with survival were age, gender, histology (adenocarcinoma vs. other), palliative-intent treatment of the primary tumor, time to diagnosis of brain metastases from initial diagnosis, uncontrolled primary tumor at time of brain metastasis diagnosis, or extracranial metastases. On multivariate analysis (MVA, KPS excluded), patients with RPA class I (MS, 14.6 months) or II (MS, 5.0 months) disease had significantly improved overall survival compared to class III disease (MS, 1.6 months, P<0.01). Also on MVA, patients with 1 (MS, 10.7 months) or 2 (MS, 4.7 months) brain metastases had significantly improved overall survival compared to patients with 3 or more brain metastases (MS, 0.3 months, P<0.01). For the 36 patients with 1-2 brain metastases and KPS ≥70, MS was 11.1 months. 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.

Current status of novel agents in advanced gastroesophageal adenocarcinoma.

Gastroesophageal (GE) adenocarcinomas are highly lethal malignancies and despite multiple chemotherapy options, 5-year survival rates remain dismal. Chemotherapy is the mainstay of treatment but patients are often limited by toxicity and poor performance status. Because of molecular heterogeneity, it is essential to classify tumors based on the underlying oncogenic pathways and develop targeted therapies that act on individual tumors. Trastuzumab, a human epidermal growth factor receptor type 2 (HER2) monoclonal antibody, was the first such agent shown to improve response rate, progression free survival (PFS), and overall survival (OS) when added to cisplatin based chemotherapy in patients with HER2 over-expressing GE junction (GEJ) and gastric adenocarcinomas. However, HER2 over expressing GE tumors are in the minority and the need for additional targeted agents is urgent. Though many agents are in development, incorporating targeted therapy in the treatment of GE cancers comes with a unique set of challenges. In this review, we outline oncogenic pathways relevant to GE adenocarcinomas, including HER2, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), hepatocyte growth factor (HGF), and c-Met, and discuss recent trials with agents targeting these pathways.

PET/CT Fusion Scan Prevents Futile Laparotomy in Early Stage Pancreatic Cancer.

BACKGROUND: Surgical resection with negative margins is the only curative approach for pancreatic cancer. A paucity of data exists in using PET/CT scan as staging workup in resectable pancreatic cancer. The aim of this study is to determine if PET/CT prevents futile laparotomy by detecting occult metastatic disease in patients with resectable or borderline resectable pancreatic cancer. METHODS: Patients were included using 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 characteristics were evaluated. The impact of PET/CT on patient management was estimated by calculating the percentage of patients whose treatment plan was altered secondary to PET/CT. RESULTS: We identified 285 patients with early stage pancreatic cancer who received PET/CT as part of initial staging workup. Upon initial workup (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 the patients (95% CI, 8%-15%). Metastatic lesions were confirmed with biopsy in 19 patients (61%). The proportion of change in treatment plan was significantly higher in patients who were initially considered to have borderline resectable compared with resectable malignancy (17% vs 7%, P = 0.019). In 199 patients who underwent 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.

Comparison of KRAS mutation analysis of colorectal cancer samples by standard testing and next-generation sequencing.

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.