Kevin K. Roggin

Abstract Gastroesophageal adenocarcinoma (GEA) is a lethal disease where targeted therapies, even when guided by genomic biomarkers, have had limited efficacy. A potential reason for the failure of such therapies is that genomic profiling results could commonly differ between the primary and metastatic tumors. To evaluate genomic heterogeneity, we sequenced paired primary GEA and synchronous metastatic lesions across multiple cohorts, finding extensive differences in genomic alterations, including discrepancies in potentially clinically relevant alterations. Multiregion sequencing showed significant discrepancy within the primary tumor (PT) and between the PT and disseminated disease, with oncogene amplification profiles commonly discordant. In addition, a pilot analysis of cell-free DNA (cfDNA) sequencing demonstrated the feasibility of detecting genomic amplifications not detected in PT sampling. Lastly, we profiled paired primary tumors, metastatic tumors, and cfDNA from patients enrolled in the personalized antibodies for GEA (PANGEA) trial of targeted therapies in GEA and found that genomic biomarkers were recurrently discrepant between the PT and untreated metastases. Divergent primary and metastatic tissue profiling led to treatment reassignment in 32% (9/28) of patients. In discordant primary and metastatic lesions, we found 87.5% concordance for targetable alterations in metastatic tissue and cfDNA, suggesting the potential for cfDNA profiling to enhance selection of therapy. Significance: We demonstrate frequent baseline heterogeneity in targetable genomic alterations in GEA, indicating that current tissue sampling practices for biomarker testing do not effectively guide precision medicine in this disease and that routine profiling of metastatic lesions and/or cfDNA should be systematically evaluated. Cancer Discov; 8(1); 37–48. ©2017 AACR. See related commentary by Sundar and Tan, p. 14. See related article by Janjigian et al., p. 49. This article is highlighted in the In This Issue feature, p. 1

BACKGROUND: There is considerable debate about the safety and clinical equivalence of laparoscopic pancreaticoduodenectomy (LPD) and open pancreaticoduodenectomy (OPD) for pancreatic ductal adenocarcinoma (PDCA). STUDY DESIGN: We queried the National Cancer Data Base to identify patients undergoing LPD and OPD for PDCA between 2010 and 2011. Chi-square and Student's t-tests were used to evaluate differences between the 2 approaches. Multivariable logistic regression modeling was performed to identify patient, tumor, or facility factors associated with perioperative mortality. RESULTS: Four thousand and thirty-seven (91%) patients underwent OPD. Three hundred and eighty-four (9%) patients underwent LPD. There were no statistical differences between the 2 surgical cohorts with regard to age, race, Charlson score, tumor size, grade, stage, or treatment with neoadjuvant chemoradiotherapy. Laparoscopic pancreaticoduodenectomy demonstrated a shorter length of stay (10 ± 8 days vs 12 ± 9.7 days; p < 0.0001) and lower rates of unplanned readmission (5% vs 9%; p = 0.027) than OPD. In an unadjusted comparison, there was no difference in 30-day mortality between the LPD and OPD cohorts (5.2% vs 3.7%; p = 0.163). Multivariable logistic regression modeling predicting perioperative mortality controlling for age, Charlson score, tumor size, nodal positivity, stage, facility type, and pancreaticoduodenectomy volume identified age (odds ratio [OR] = 1.05; p < 0.0001), positive margins (OR = 1.45; p = 0.030), and LPD (OR = 1.89; p = 0.009) as associated with an increased probability of 30-day mortality; higher hospital volume was associated with a lower risk of 30-day mortality (OR = 0.98; p < 0.0001). In institutions that performed ≥10 LPDs, the 30-day mortality rate of the laparoscopic approach was equal to that for the open approach (0.0% vs 0.7%; p = 1.00). CONCLUSIONS: Laparoscopic pancreaticoduodenectomy is equivalent to OPD in length of stay, margin-positive resection, lymph node count, and readmission rate. There is a higher 30-day mortality rate with LPD, but this appears driven by a surmountable learning curve for the procedure.

OBJECTIVE: The current study compares outcome after resection of papillary hilar cholangiocarcinoma to that of the more common nodular-sclerosing subtype. METHODS: Clinical, radiologic, histopathologic, and survival data on all patients with hilar cholangiocarcinoma were analyzed. Resected tumors were reexamined and classified as nodular-sclerosing (no component of papillary carcinoma) or papillary (any component of papillary carcinoma); for papillary tumors, the proportion of invasive carcinoma present was determined. Differences in the clinical behavior and histopathologic features of nodular-sclerosing and papillary tumors were assessed. RESULTS: From January 1991 to November 2003, 279 patients were evaluated, 154 men (55.2%) and 125 women (44.8%), with a mean age of 65.4 +/- 0.7 years (median = 68, range 23-87 years). Of the 215 patients explored, 106 (49.5%) underwent a complete gross resection. An en bloc partial hepatectomy (n = 87) and an R0 resection (n = 82) were independent predictors of favorable outcome. Operative mortality was 7.5% but was 2.8% over the last 4 years of the study, and there were no operative deaths in the last 33 consecutive resections. Twenty-five resected tumors (23.6%) contained a papillary component: 12 were minimally or noninvasive (<10% invasive cancer) and 13 had an invasive component ranging from 10% to 95% (> or =10%). Patients with papillary and nodular-sclerosing tumors had similar demographics, operative procedures, and proportion of R0 resections. By contrast, papillary tumors were significantly larger, more often well-differentiated, and earlier stage. Disease-specific survival after resection of papillary tumors (55.7 months) was greater than after resection of nodular-sclerosing lesions (33.5 months, P = 0.013). The papillary phenotype was an independent predictor of survival, although the benefit was more pronounced for less invasive tumors. CONCLUSIONS: The presence of a component of papillary carcinoma is more common than previous reports have suggested and is an important determinant of survival after resection of hilar cholangiocarcinoma.

In Brief Objective: To prospectively evaluate the additional value of geriatric assessment (GA) for predicting surgical outcomes in a cohort of older patients undergoing a pancreaticoduodenectomy (PD) for pancreatic tumors. Background: Older patients are less often referred for possible PD. Standard preoperative assessments may underestimate the likelihood of significant adverse outcomes. The prospective utility of validated GA has not been studied in this group. Methods: PD-eligible patients were enrolled in a prospective outcome study. Standard preoperative assessments were recorded. Elements of validated GA were also measured, including components of Fried's model of frailty, the Vulnerable Elders Survey (VES-13), and the Short Physical Performance Battery (SPPB). All postoperative adverse events were recorded, systematically reviewed, and graded using the Clavien-Dindo system by a surgeon blinded to the GA results. Multivariate regression analyses were conducted. Results: Seventy-six older patients underwent a PD. Significant unrecognized vulnerability was identified at the baseline: Fried's “exhaustion” (37.3%), SPPB <10 (28.5%), and VES-13 >3 (15.4%). Within 30 days of PD, 46% experienced a severe complication (Clavien-Dindo grade ≥III). In regression analyses controlling for age, the body mass index, the American Society of Anesthesiologists score, and comorbidity burden, Fried's “exhaustion” predicted major complications [odds ratio (OR) = 4.06; P = 0.01], longer hospital stays (β = 0.27; P = 0.02), and surgical intensive care unit admissions (OR = 4.30; P = 0.01). Both SPPB (OR = 0.61; P = 0.04) and older age predicted discharge to a rehabilitation facility (OR = 1.1; P < 0.05) and age correlated with a lower likelihood of hospital readmission (OR = 0.94; P = 0.02). Conclusions: Controlling for standard preoperative assessments, worse scores on GA prospectively and independently predicted important adverse outcomes. Geriatric assessment may help identify older patients at high risk for complications from PD. Older adults with pancreatic cancer are at higher risk for complications from surgical treatment. Undetected vulnerabilities related to frailty may adversely affect surgical outcomes. Preoperative comprehensive geriatric assessments may prospectively identify patients at risk for major complications. If sought for and identified, this risk could be managed expectantly, leading to more accurate preoperative counseling, treatment, and in-hospital care.