Richard J. Battafarano

Neoadjuvant PD-1 Blockade in Resectable Lung Cancer

BACKGROUND Antibodies that block programmed death 1 (PD‐1) protein improve survival in patients with advanced non–small‐cell lung cancer (NSCLC) but have not been tested in resectable NSCLC, a condition in which little progress has been made during the past decade. METHODS In this pilot study, we administered two preoperative doses of PD‐1 inhibitor nivolumab in adults with untreated, surgically resectable early (stage I, II, or IIIA) NSCLC. Nivolumab (at a dose of 3 mg per kilogram of body weight) was administered intravenously every 2 weeks, with surgery planned approximately 4 weeks after the first dose. The primary end points of the study were safety and feasibility. We also evaluated the tumor pathological response, expression of programmed death ligand 1 (PD‐L1), mutational burden, and mutation‐associated, neoantigen‐specific T‐cell responses. RESULTS Neoadjuvant nivolumab had an acceptable side‐effect profile and was not associated with delays in surgery. Of the 21 tumors that were removed, 20 were completely resected. A major pathological response occurred in 9 of 20 resected tumors (45%). Responses occurred in both PD‐L1–positive and PD‐L1–negative tumors. There was a significant correlation between the pathological response and the pretreatment tumor mutational burden. The number of T‐cell clones that were found in both the tumor and peripheral blood increased systemically after PD‐1 blockade in eight of nine patients who were evaluated. Mutation‐associated, neoantigen‐specific T‐cell clones from a primary tumor with a complete response on pathological assessment rapidly expanded in peripheral blood at 2 to 4 weeks after treatment; some of these clones were not detected before the administration of nivolumab. CONCLUSIONS Neoadjuvant nivolumab was associated with few side effects, did not delay surgery, and induced a major pathological response in 45% of resected tumors. The tumor mutational burden was predictive of the pathological response to PD‐1 blockade. Treatment induced expansion of mutation‐associated, neoantigen‐specific T‐cell clones in peripheral blood. (Funded by Cancer Research Institute–Stand Up 2 Cancer and others; ClinicalTrials.gov number, NCT02259621.)

Why are patients being readmitted after surgery for esophageal cancer

OBJECTIVE Readmission after surgery is an unwanted adverse event that is costly to the healthcare system. We sought to evaluate factors associated with increased risk of readmission and to characterize the nature of these readmissions in patients who have esophageal cancer. METHODS A retrospective cohort study was performed in 306 patients with esophageal carcinoma who underwent neoadjuvant chemoradiation followed by esophagectomy at Johns Hopkins Hospital between 1993 and 2011. Logistic regression was used to identify factors associated with 30-day readmission. Readmissions were defined as inpatient admissions to our institution within 30 days of discharge. RESULTS The median age at surgery was 61 years; the median postoperative length of stay was 9 days; and 48% of patients had ≥1 postoperative complication (POC). The 30-day readmission rate was 13.7% (42 of 306). In univariate analysis, length of stay and having ≥1 POC were significantly associated with readmission. In multivariate analysis, having ≥1 POC was significantly associated with a >2-fold increase in risk for 30-day readmission (odds ratio 2.35, with 95% confidence interval [1.08-5.09], P = .031) when controlling for age at diagnosis and length of stay. Of the 42 patients who were readmitted, 67% experienced POCs after surgery; 50% of patients who experienced POCs were readmitted for reasons related to their postoperative complication. The most common reasons for readmission were pulmonary issues (29%), anastomotic complications (20%), gastrointestinal concerns (17%), and venous thromboembolism (14%). CONCLUSIONS Complications not adequately managed before discharge may lead to readmission. Quality improvement efforts surrounding venous thromboembolism prophylaxis, and discharging patients nothing-by-mouth, may be warranted.

Robotic Versus Thoracoscopic Resection for Lung Cancer: Early Results of a New Robotic Program

BACKGROUND Robot-assisted surgical techniques have been introduced in recent years as an alternative minimally invasive approach for lung surgery. While the advantage of video-assisted thoracoscopic surgery (VATS) over thoracotomy for anatomical lung resection has been extensively reported, the results of robotic video-assisted thoracoscopic surgery (RVATS) compared to VATS are still under investigation. METHODS We performed a retrospective review of lung cancer patients, undergoing minimally invasive segmentectomy or lobectomy between December 2007 and May 2014. A robotic program was introduced in 2011. Relevant early surgical outcomes were compared between VATS and RVATS, including mortality, morbidity, conversion to thoracotomy, length of stay (LOS), and reoperation. RESULTS Eighty (60.2%) patients underwent VATS resection, while 53 (39.8%) had a RVATS procedure. The two groups presented no meaningful differences at baseline, in terms of age, race, body mass index, and preoperative comorbidities. Adenocarcinoma was the most common histology in both groups. Patients in the RVATS group had significantly more segmentectomies (11.3% versus 1.2%, P = .016). There were no postoperative deaths. RVATS appeared to be associated with fewer conversions to open (13.2% versus 26.2%, P = .025) and more lymph nodes retrieved (9 versus 7, P = .049). We found no significant differences in terms of other individual complications, including tracheostomy, reintubation, pneumonia, pulmonary embolism, and cerebrovascular events. CONCLUSIONS According to our results, the introduction of a robotic program did not negatively affect the early surgical outcomes of a well-established oncologic minimally invasive thoracic program. Potential advantages of RVATS still need to be explored in terms of long-term outcomes.

Abstract 4455: DNA methylation as biomarkers to predict early recurrence of T1-2N0 lung cancer

Purpose: Many patients die of recurrent NSCLC. Current clinical and molecular tests fail to predict patients at high risk for recurrence. We investigated the relationship between gene promoter methylation and recurrence of NSCLC and its prediction accuracy. Materials and Methods: We prospectively enrolled patients who underwent surgery for T1-2N0 NSCLC. We collected primary tumors, regional lymph nodes (RLN) and mediastinal lymph nodes (MLN). A total of 112 patients were included; cases (n = 39) and controls (n = 73) were defined based on cancer recurrence within 40 months of surgery. Promoter methylation of eight cancer-related genes (CDO1, TAC1, SOX17, p16, CDH13, RASSF1A, APC and MGMT) was obtained by using nanoparticle-based DNA extraction followed by qMSP. Logistic regression analysis adjusted by age, gender, race, tumor size and pack year was used to study the relationship between the gene promoter methylation and the risk of recurrence of NSCLC; machine learning assessed its prediction accuracy. Results: Cases had significantly higher p16 methylation levels than controls in all three tissue types by univariate and multivariate analysis after adjusting for confounders (age, gender, race, tumor size, smoking history, and other gene methylation levels). SOX17 was significantly methylated among cases in both RLN and MLN samples, and remained significant in MLN after adjusting for confounders. Table 1 shows the prediction accuracy of p16 and SOX17 using tumor tissue alone and combined with RLN and/or MLN. Prediction accuracies were increased after adding biomarkers from lymph nodes. Conclusion: Increased methylation status in the promoter region of p16 and SOX17 is associated with an increased risk of cancer recurrence among patients with T1-2N0 NSCLC treated with curative resection. Adding molecular analyses of lymph nodes to primary tumor samples significantly increased the diagnostic accuracy of predicting recurrence in these patients. Citation Format: Chen Chen, Andrew Yang, Devlin Danielle, Kristen Rodgers, Peng Huang, Zhihao Lu, Candace Griffin, Beverly Lee, Richard Battafarano, Fenglei Yu, Tza-Huei Wang, Stephen Baylin, James Herman, Alicia Hulbert, Malcolm Brock. DNA methylation as biomarkers to predict early recurrence of T1-2N0 lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4455.