Lewis, Mark A.

Abstract Abstract 4259 Background: Patients with defective DNA repair mechanisms are at higher risk for developing cancer. BRCA1 and BRCA2 are proteins that coordinate DNA repair by homologous-recombination. Mutations in BRCA1 and BRCA2 are associated with an increased risk of cancers, namely breast, ovarian, and pancreatic, thus making these patients more likely to receive chemo- or radiation therapy. Additionally, secondary malignancies can be an unfortunate consequence of treatment with chemo- or radiation therapy. Although tumors with defective DNA repair mechanisms may be more susceptible to therapy, we hypothesized that patients with BRCA mutations that underwent chemotherapy or radiotherapy for treatment of breast or ovarian cancer would be at a higher risk of developing therapy- related myelodysplastic syndrome (t-MDS) or acute myeloid leukemia (t-AML). Methods: We accessed patient data from our institution maintained by the Mayo Clinic Life Sciences System using the Data Discovery and Query Builder. We searched for patients whose notes and diagnoses included the terms BRCA, and breast or ovarian cancer, and myelodysplastic syndrome or acute myeloid leukemia. We searched our records from 1/1/1995–7/15/2011. We cross-referenced our findings to a database of patients who were diagnosed with a BRCA mutation through our department of medical genetics. Secondly, we searched the National Cancer Institute's Surveillance Epidemiology and End Results (SEER) database for female patients who developed AML after the diagnosis or breast or ovarian cancer from the years 1973–2008 using ratio and multiple primaries standardized incidence ratios sessions. Results: We identified 220 patients with a BRCA mutation, of which 73 received chemotherapy. There were two patients with BRCA mutations that developed t-AML following treatment for breast cancer, and one patient with a BRCA mutation who developed t-AML following treatment for ovarian cancer (Table 1). Manual data extraction from the list of patients with BRCA mutations diagnosed at our institution only identified one of these patients, as two obtained their testing through another institution. We did not identify any patients with BRCA mutations who developed t-MDS following treatment for breast or ovarian cancer. The latency between diagnosis of the primary cancer and the diagnosis or t-AML was 24 months for two patients, and 22 years for the other. From our search of the SEER database we found 649 patients who developed AML after a diagnosis of breast cancer, and 98 patients who developed AML after a diagnosis of ovarian cancer. These patients represented 0.1% and 0.2% of evaluable breast and ovarian cases respectively. The latency from time of diagnosis of the primary cancer to that of AML was 58 months (29–113 interquartile range) for breast cancer and 47 months (29–91) for ovarian cancer. The observed number of patients with AML following the diagnosis of breast or ovarian cancer was 1.68 and 4.74 times higher than that expected of the general population, respectively (both p<0.05). We were not able to stratify patients based on the presence of a BRCA mutation due to the limitations of the database. Conclusions: We identified three patients with confirmed BRCA mutations and t-AML at our institution. Although this does not represent a strong association, patients at risk for BRCA mutations do not always undergo testing. Thus, our results may not fully represent whether there is an association with BRCA mutations and t-MDS or t-AML. Using the SEER database, we confirmed that patients who were diagnosed with breast or ovarian cancer subsequently had a higher incidence of AML than the general population, although we were not able to test if patients with BRCA mutations are at higher risk of t-MDS or t-AML. Disclosures: No relevant conflicts of interest to declare.

Although HER2‐positive breast cancers demonstrate a propensity for central nervous system (CNS) metastasis, it is unknown whether other HER2‐positive tumors, including adenocarcinomas of the esophagus/gastroesophageal junction (EAC), share this characteristic. Insight into this association may inform the development of HER2‐targeted therapies that penetrate the blood‐brain barrier. We examined HER2 overexpression and gene amplification in 708 patients with EAC who underwent curative‐intent surgery during a time period (1980–1997) when no patient received HER2‐targeted therapy. We identified patients whose site of first cancer recurrence was CNS and those who had a CNS relapse at any time. After a median follow‐up of 61.2 months, 3.4% (24/708) of patients developed CNS relapse (all involved the brain). Patients with HER2‐positive (vs ‐negative) primary tumors showed a higher 5‐year cumulative incidence of CNS relapse as first recurrence (5.8% vs. 1.2%; p = 0.0058) and at any time (8.3% vs. 2.4%; p = 0.0062). In a multivariable model that included covariates previously associated with HER2 or with CNS relapse in breast cancer, HER2 positivity was the only variable that was statistically significantly associated with shorter time to CNS relapse as first recurrence (p = 0.0026) or at any time (hazard ratio 4.3 [95% confidence interval 1.8 to 10.3]; p = 0.001). These are the first data in a non‐breast cancer to demonstrate an association between HER2 positivity and higher CNS relapse risk after surgery, and suggest that HER2‐positive EACs have a predilection for CNS metastases.

In the care of patients with hepatic neuroendocrine metastases, medical oncologists should work in multidisciplinary fashion with surgeons, interventional radiologists, and radiation oncologists to assess the potential utility of liver-directed and systemic therapies. This paper addresses the various roles and evidence basis for cytoreductive surgery, thermal ablation (radiofrequency, microwave, and cryoablation), and embolization (bland embolization (HAE), chemoembolization (HACE), and radioembolization) as liver-directed therapies. Somatostatin analogues, cytotoxic chemotherapy, and the newer agents everolimus and suntinib are discussed as a means for controlling intra- and extrahepatic disease, along with peptide receptor radiotherapy (PRRT). Finally, the experience with orthotopic liver transplant for neuroendocrine tumors is described.

Purpose There is increasing recognition of the existence of intratumoral heterogeneity of the human epidermal growth factor receptor (HER2), which affects interpretation of HER2 positivity in clinical practice and may have implications for patient prognosis and treatment. We determined the frequency and prognostic impact of heterogeneous HER2 gene amplification and polysomy 17 in patients with esophageal adenocarcinoma (EAC). Patients and Methods HER2 amplification (by fluorescence in situ hybridization) was examined in surgical EAC specimens (n = 675). HER2 heterogeneity was defined according to consensus guidelines as gene amplification (HER2/CEP17 ratio ≥ 2.0) in more than 5% but less than 50% of cancer cells. No patient received neoadjuvant or HER2-targeted therapy. Cox models were used to assess disease-specific survival (DSS) and overall survival (OS). Results Overall, 117 EACs (17%) demonstrated HER2 amplification, of which 20 (17%) showed HER2 heterogeneity. All HER2-heterogeneous tumors were amplified. Among HER2-amplified tumors, heterogeneous tumors had significantly higher frequency of poor histologic grade and polysomy 17. In multivariable models that included number of metastatic lymph nodes, grade, tumor stage, and polysomy 17, only HER2 heterogeneity and node number were prognostic among HER2-amplified tumors, with heterogeneity showing worse DSS (hazard ratio, 2.04; 95% CI, 1.09 to 3.79; P = .025) and OS (P = .026). Among HER2-nonamplified EACs, polysomy 17 was independently associated with worse DSS (P = .012) and OS (P = .023). Conclusion Among HER2-amplified EACs, 17% show HER2 heterogeneity, which independently predicts for worse cancer-specific death. Among HER2-nonamplified EACs, polysomy 17 is independently associated with worse survival. These novel findings demonstrate aggressive subgroups in HER2-amplified and -nonamplified EACs that have important implications for HER2 analysis and determination of benefit from HER2-targeted therapy.

AbstractLearning Objectives:After completing this course, the reader will be able to:Identify the components of the “postembolization syndrome”: elevated liver function tests, right upper quadrant pain, nausea and vomiting, and fever.Distinguish the postembolization syndrome from rare complications of embolization that would merit an extended hospitalization.CME This article is available for continuing medical education credit at CME.TheOncologist.comBackground.There is scant evidence to guide the management of patients after hepatic artery embolization (HAE). We examined length of stay (LOS), laboratory patterns, medication usage, morbidity, and mortality of patients hospitalized after HAE for metastatic neuroendocrine tumors.Methods.Data were abstracted retrospectively from electronic medical records on LOS, liver function tests (LFTs), i.v. antibiotics, analgesia, peak temperature, bacteremia, hepatic abscess formation, carcinoid crisis, and metastatic burden on cross-sectional imaging.Results.In 2005–2009, 72 patients underwent 174 HAEs for carcinoid and islet cell tumors. The median LOS was 4 days (range, 1–8 days). There was no correlation between peak LFTs and tumor burden. Declines in LFTs were not uniform before hospital discharge; 25%, 37%, 30%, 53%, and 67% of patients were discharged before their respective aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and total and direct bilirubin levels began to decline, with no readmissions for acute hepatic failure. The median i.v. analgesia dose was 60 mg oral morphine equivalents (range, 3–1,961 mg). Pre-HAE i.v. antibiotics were administered in 99% of cases; post-HAE fever occurred in 37% of patients, with no documented bacteremia. One patient developed a hepatic abscess after HAE. There were two carcinoid crises. The single in-hospital death was associated with air in the portal veins.Conclusions.The duration and intensity of in-hospital care following HAE should be managed on an individual basis. A downward trend in LFTs is not required before discharge. Modest use of i.v. analgesia suggests that many patients could exclusively receive oral analgesics. Given the rarity of serious complications, hospital stays could be shortened, thereby reducing costs and nosocomial risks.

AbstractBackgroundMany serologic and radiographic modalities are used for monitoring multiple endocrine neoplasia type 1 (MEN 1) patients for pancreaticoduodenal neuroendocrine tumors (PNETs). We compared serum markers and imaging studies obtained preoperatively with the gross pathology and immunohistochemical findings and correlated preoperative testing with postoperative outcome.MethodsFrom 2000 to 2008, 52 MEN 1 patients [32 (62%) female; median age = 43 years, range 19–74 years] underwent 56 pancreatic operations [49 (88%) distal pancreatectomies] for suspected PNETs. Preoperative serum markers [human pancreatic polypeptide (HPP), gastrin, and glucagon] and imaging [CT, 111In pentetreotide scintigraphy, and endoscopic ultrasound (EUS)] were compared to the pathologic findings. Postoperative serum markers and survival were followed.ResultsHuman pancreatic polypeptide had the highest agreement between an elevated serum level and positive tumor immunostaining (83% vs. 50% agreement for gastrin vs. 67% agreement for glucagon). Preoperative CT had 81% sensitivity and positive predictive value (PPV) of 97% for PNETs. 111In pentetreotide scintigraphy had 84% sensitivity and PPV of 96%. Preoperative endoscopic ultrasonography (EUS) had 100% sensitivity and PPV, with close correlation (rs = 0.93) between the largest lesion seen on EUS and pathology. Median follow‐up was 4.3 years (range = 0.1–10.9 years). Overall survival was 89% at 5‐year follow‐up.ConclusionsOur study substantiates EUS as providing the highest preoperative sensitivity and PPV in assessing the presence of PNETs in MEN 1 patients. CT and octreotide scintigraphy can yield both false‐positive and false‐negative results. HPP, gastrin, and glucagon were the most commonly measured tumor markers in our series but did not always correlate with immunostaining. With an aggressive surgical approach, satisfactory rates of biochemical improvement and long‐term survival were observed.

A preponderance of patients with neuroendocrine tumors (NETs) will experience hepatic metastases during the course of their disease. Many diagnoses of NETs are made only after the neoplasms have spread from their primary gastroenteropancreatic sites to the liver. This paper reviews current evidence-based treatments for neuroendocrine hepatic metastases, encompassing surgery, hepatic artery embolization (HAE) and chemoembolization (HACE), radioembolization, hepatic artery infusion (HAI), thermal ablation (radiofrequency, microwave, and cryoablation), alcohol ablation, and liver transplantation as therapeutic modalities. Consideration of a multidisciplinary approach to liver-directed therapy is strongly encouraged to limit morbidity and mortality in this patient population.

Purpose Given that smoking affects body mass index (BMI) and survival, stratification by smoking status may be required to determine the true prognostic impact of BMI. Although obesity increases risk for developing esophageal adenocarcinoma (EAC), the prognostic influence of obesity and its potential modification by smoking status is unknown in this disease. Patients and Methods All patients (N = 778) underwent potentially curative esophagectomy. BMI was calculated using measured height and weight at surgery and categorized as obese (≥ 30 kg/m 2 ), overweight (25 to 29.9 kg/m 2 ), or normal (18.5 to 24.9 kg/m 2 ). Cigarette smoking was categorized as never or ever. The association of BMI with disease-specific survival (DSS), disease-free survival (DFS), and overall survival (OS) was determined by Cox regression. Results Excess BMI was significantly associated with DSS in a manner that differed substantially by smoking status (P for interaction = .023). Among never smokers, obesity was significantly associated with adverse DSS (hazard ratio [HR] = 2.11; 95% CI, 1.31 to 3.43; P = .002), DFS (HR = 2.03; 95% CI, 1.30 to 3.18; P = .002), and OS (HR = 1.97; 95% CI, 1.24 to 3.14; P = .004), as compared with normal weight, after adjusting for covariates. By contrast, among ever smokers, obesity was not prognostic, and overweight status was significantly associated with favorable survival in univariate, but not multivariate, analysis. Conclusion Obesity among never smokers was independently associated with two-fold worsening of DSS, DFS, and OS after surgery for EAC, after adjusting for known prognostic factors. These data, in one of the largest reported resected EAC cohorts, are the first to show an adverse prognostic impact of obesity in EAC.