Predisposing Conditions to Pediatric Hepatocellular Carcinoma and Association With Outcomes: Single-center Experience.

OBJECTIVES: Hepatocellular carcinoma (HCC) has been linked to chronic viral or metabolic liver disease and other conditions. The characteristics of children with HCC have not been fully elucidated and outcomes in children with predisposing liver disease are not well defined. METHODS: Patients ≤21 years old with HCC managed at our institution and through external consultation between 1996 and 2016 were included. Demographics, clinical history, and pathology were tabulated. Fisher exact test and Wilcoxon test were employed for subgroup comparison, and survival differences were evaluated by Kaplan-Meier method. RESULTS: Sixty-one cases of HCC were identified. Seven of 16 patients (44%) at our institution and 18 of 45 consult patients (40%) had a predisposing condition: cryptogenic cirrhosis/steatosis (9), genetic (7), biliary pathology (4), viral hepatitis (1), and other (4). Thirteen of 27 patients with de novo HCC had fibrolamellar HCC. Clinical characteristics were grouped by presence or absence of predisposing conditions: age at diagnosis (7.2 vs 10.2 years, P < 0.05), metastatic disease at presentation (15% vs 44%, P = n.s), and tumor size >4 cm (20% vs 100%, P < 0.05). In patients treated at our institution, 5 of 7 with predisposing conditions received liver transplant and achieved complete remission, whereas only 3 of 9 patients with de novo HCC received curative surgery and this group had decreased median overall survival (P < 0.05). CONCLUSIONS: The majority of children with HCC did not have predisposing liver or associated disease. These patients were diagnosed later with more advanced stage disease and had significantly decreased overall survival.

RAS mutations affect pattern of metastatic spread and increase propensity for brain metastasis in colorectal cancer.

BACKGROUND: RAS and PIK3CA mutations in metastatic colorectal cancer (mCRC) have been associated with worse survival. We sought to evaluate the impact of RAS and PIK3CA mutations on cumulative incidence of metastasis to potentially curable sites of liver and lung and other sites such as bone and brain. METHODS: We performed a computerized search of the electronic medical record of our institution for mCRC cases genotyped for RAS or PIK3CA mutations from 2008 to 2012. Cases were reviewed for patient characteristics, survival, and site-specific metastasis. RESULTS: Among the 918 patients identified, 477 cases were RAS wild type, and 441 cases had a RAS mutation (394 at KRAS exon 2, 29 at KRAS exon 3 or 4, and 18 in NRAS). RAS mutation was significantly associated with shorter median overall survival (OS) and on multivariate analysis independently predicted worse OS (HR, 1.6; P < .01). RAS mutant mCRC exhibited a significantly higher cumulative incidence of lung, bone, and brain metastasis and on multivariate analysis was an independent predictor of involvement of these sites (HR, 1.5, 1.6, and 3.7, respectively). PIK3CA mutations occurred in 10% of the 786 cases genotyped, did not predict for worse survival, and did not exhibit a site-specific pattern of metastatic spread. CONCLUSIONS: The metastatic potential of CRC varies with the presence of RAS mutation. RAS mutation is associated with worse OS and increased incidence of lung, bone, and brain metastasis. An understanding of this site-specific pattern of spread may help to inform physicians' assessment of symptoms in patients with mCRC.

Adjuvant Chemotherapy and Trastuzumab Is Safe and Effective in Older Women With Small, Node-Negative, HER2-Positive Early-Stage Breast Cancer.

INTRODUCTION: The benefit of adjuvant trastuzumab with chemotherapy is well established for women with higher risk human epidermal growth factor receptor 2-positive (HER2+) breast cancer. However, its role in older patients with smaller, node-negative tumors is less clear. We conducted a retrospective, sequential cohort study of this population to describe the impact of trastuzumab on breast cancer outcomes and cardiac safety. PATIENTS AND METHODS: Women ≥ 55 years with ≤ 2 cm, node-negative, HER2+ breast cancer were identified and electronic medical records reviewed. A no-trastuzumab cohort of 116 women diagnosed between January 1, 1999 and May 14, 2004 and a trastuzumab cohort of 128 women diagnosed between May 16, 2006 and December 31, 2010 were identified. Overall survival and distant relapse-free survival were estimated by Kaplan-Meier methods. RESULTS: The median ages of the trastuzumab and no-trastuzumab cohorts were 62 and 64 years, respectively. More patients in the trastuzumab cohort had grade III (P = .001), lymphovascular invasion (P = .001), or estrogen receptor-negative (P < .001) cancers. The majority of the trastuzumab cohort received chemotherapy versus one-half of the no-trastuzumab cohort (98% vs. 53%; P < .0001). The median follow-up was 4 versus 9 years in the trastuzumab versus no-trastuzumab cohorts; therefore, outcomes at 4 years are reported. Despite the higher-risk tumor features in the trastuzumab group, the 4-year overall survival was 99% in both cohorts; the distant relapse-free survival was 99% versus 97% in the trastuzumab versus no-trastuzumab cohorts. Four (3.1%; 95% confidence interval, 1.0%-7.8%) women in the trastuzumab cohort and 1 in the no-trastuzumab cohort developed symptomatic heart failure. There were no cardiac-related deaths in either arm. CONCLUSION: Following adjuvant trastuzumab with chemotherapy, selected older women with small, node-negative, HER2+ breast cancers have excellent disease control. The rate of cardiac events is low.

EGF receptor activates MET through MAPK to enhance non-small cell lung carcinoma invasion and brain metastasis.

MET amplification as a mechanism of acquired resistance to EGF receptor (EGFR)-targeted therapies in non-small cell lung carcinoma (NSCLC) led to investigation of novel combinations of EGFR and MET kinase inhibitors. However, promiscuous interactions between MET and ERBB family members have made it difficult to evaluate the effects of MET on EGFR signaling, both independent of drug treatment and in the context of drug resistance. We addressed this issue by establishing a 32D model cell system wherein ERBBs or MET are expressed alone and in combination. Using this model, we determined that EGFR signaling is sufficient to induce MET phosphorylation, although MET activation is enhanced by coexpression of ERBB3. EGFR-MET cross-talk was not direct, but occurred by a combined regulation of MET levels and intermediary signaling through mitogen-activated protein kinases (MAPK). In NSCLCs harboring either wild-type or mutant EGFR, inhibiting EGFR or MAPK reduced MET activation and protein levels. Furthermore, MET signaling promoted EGFR-driven migration and invasion. Finally, EGFR-MET signaling was enhanced in a highly metastatic EGFR-mutant cell subpopulation, compared with the indolent parental line, and MET attenuation decreased the incidence of brain metastasis. Overall, our results establish that EGFR-MET signaling is critical for aggressive behavior of NSCLCs and rationalize its continued investigation as a therapeutic target for tumors harboring both wild-type and mutant EGFR at early stages of progression.