Eric H. Bernicker

Next-Generation Sequencing of a Cohort of Pulmonary Large Cell Carcinomas Reclassified by World Health Organization 2015 Criteria.

CONTEXT The classification of pulmonary large cell carcinoma has undergone a major revision with the recent World Health Organization (WHO) 2015 Classification. Many large cell carcinomas are now reassigned to either adenocarcinoma with solid pattern or nonkeratinizing squamous cell carcinoma based on immunopositivity for adenocarcinoma markers or squamous cell carcinoma markers, respectively. Large cell carcinomas that are negative for adenocarcinoma and squamous cell carcinoma immunomarkers are now classified as large cell carcinoma with null immunohistochemical features (LCC-N). Although a few studies investigated the mutation profile of large cell carcinomas grouped by immunostain profile before the publication of the new WHO classification, investigation of tumors previously diagnosed as large cell carcinoma and reclassified according to the 2015 WHO classification has not, to our knowledge, been reported. OBJECTIVE To determine the mutation profiles of pulmonary large cell carcinomas reclassified by WHO 2015 criteria. DESIGN Archival cases of non-small cell lung carcinoma with large cell carcinoma morphology (n = 17) were reclassified according to 2015 WHO criteria. To determine mutation profile, we employed Ion Torrent (Life Technologies, Carlsbad, California)-based next-generation sequencing (50 genes; more than 2800 mutations) in addition to real-time quantitative reverse transcription polymerase chain reaction for ALK translocation detection. RESULTS Two of 17 cases (12%) were reclassified as LCC-N, and both had mutations-BRAF D594N in one case and KRAS G12C in the other case. Seven of 17 cases (41%) were reclassified in the adenocarcinoma with solid pattern group, which showed one KRAS G12C and one EGFR E709K + G719C double mutation in addition to mutations in TP53. Eight of 17 cases (47%) were reclassified in the nonkeratinizing squamous cell carcinoma group, which showed mutations in PIK3CA, CDKN2A, and TP53. No ALK translocations or amplifications were detected. CONCLUSIONS The adenocarcinoma with solid pattern group showed mutations typical of adenocarcinoma, whereas the nonkeratinizing squamous cell carcinoma group showed mutations typical of squamous cell carcinoma. Both LCC-N cases had mutations associated with adenocarcinoma, supporting the hypothesis that LCC-N is related to adenocarcinoma.

Biomarkers for Selection of Therapy for Adenocarcinoma of the Lung

To suggest that the discovery of targetable driver mutations in many patients with advanced adenocarcinoma of the lung has completely transformed the work-up and therapeutic options for this disease would not be hyperbole. Although not curative, small-molecule tyrosine kinase inhibitors directed at oncogene-addicted tumors have led to significantly improved response rates compared with cytotoxic chemotherapy, with often manageable toxicities and better tolerance. However, the absence of reliable clinical predictors has made molecular testing essential to ensure that patients receive the proper medical management. We outline the many recent advances with regard to diagnosis and treatment of oncogene-addicted advanced nonsquamous non-small-cell lung cancer.

Management of pathologic node-positive disease following initial surgery for clinical T1-2 N0 esophageal cancer: patterns of care and outcomes from the national cancer data base

Abstract Purpose: Although clinical T1-2N0 esophageal cancer (EC) is often initially surgically resected (without neoadjuvant therapy), several studies have illustrated substantial rates of discovering pathologically node-positive disease. This study evaluated national practice patterns of adjuvant therapy for this population. Methods: The National Cancer Database (NCDB) was queried (2004–2013) for patients with cT1-2N0M0 EC that received up-front surgery (esophagectomy/local techniques) with subsequent discovery of nodal metastasis. Patients receiving any neoadjuvant therapy were excluded. Multivariable logistic regression determined factors predictive of receiving adjuvant therapy. Kaplan–Meier analysis evaluated overall survival (OS), and Cox proportional hazards modeling determined variables associated with OS. Propensity score matching assessed groups in a balanced manner while reducing indication biases. Results: Altogether, 715 patients met inclusion criteria; 114 (16%) underwent adjuvant chemotherapy, 183 (26%) chemoradiation, 16 (2%) radiotherapy alone, and 402 (56%) observation. Observation was more likely performed with advanced age (p = .002) and at nonacademic centers (p = .001). Median OS in the respective cohorts were 42.6, 35.1, 22.2, and 27.0 months. Both chemotherapy and chemoradiation were statistically similar (p = .462) but superior to observation (p < .05 for both). There was a survival benefit to any adjuvant treatment (median OS 38.5 vs. 27.0 months, p < .001), which persisted after propensity matching (median OS 35.1 vs. 24.3 months, p < .001). On multivariable analysis, any adjuvant treatment was independently associated with improved OS, along with treatment at an academic center (p < .05 for all). Conclusions: In the largest study to date evaluating patterns of care for pN + disease following resection of cT1-2N0 EC, a strikingly high proportion of patients were observed. Adjuvant treatment, ideally chemotherapy or chemoradiation, independently correlated with higher survival, and should be considered in able patients. Treatment at academic facilities also associated with higher survival, which has implications for patient counseling.

Programmed Death Ligand-1 (PD-L1) Expression in Either Tumor Cells or Tumor-Infiltrating Immune Cells Correlates With Solid and High-Grade Lung Adenocarcinomas

CONTEXT - Programmed death ligand-1 (PD-L1) expression in non-small cell lung carcinoma (NSCLC) is heterogeneous and known to be underestimated on small biopsies. Correlation of PD-L1 expression with clinicopathologic features may provide additional useful information. To our knowledge, the clinicopathologic features of NSCLC have not been reported for subsets defined by PD-L1 expression in either tumor cells or tumor-infiltrating immune cells. OBJECTIVE - To investigate the clinicopathologic characteristics of NSCLC subsets defined by PD-L1 expression in either tumor cells or tumor-infiltrating immune cells. DESIGN - PD-L1 immunohistochemistry with the SP142 clone was performed on whole-tissue sections and given semiquantitative scores (0/1/2/3) according to percent of PD-L1+ tumor cells (TCs) and percent tumor area with PD-L1+ tumor-infiltrating immune cells (ICs). RESULTS - Adenocarcinoma cases that were scored either TC 1/2/3 or IC 1/2/3 included most (22 of 34; 65%) high-histologic grade cases and most (25 of 36; 69%) solid subtype cases. Compared with the adenocarcinoma TC 0 and IC 0 subset, the TC 1/2/3 or IC 1/2/3 subset correlated with higher histologic grade (P = .005, χ2 test for trend) and solid subtype (P < .001, Fisher exact test). Compared with the adenocarcinoma TC 0/1 or IC 0/1 subset, the TC 2/3 or IC 2/3 subset correlated with higher histologic grade (P = .002, χ2 test for trend), solid subtype (P < .001, Fisher exact test), and higher smoking pack-years (P = .01, Mann-Whitney test). CONCLUSIONS - Lung adenocarcinoma subsets defined by PD-L1 expression in either tumor cells or tumor-infiltrating immune cells correlated with high histologic grade, solid subtype, and high smoking pack-years.

Chemotherapy in non-small cell lung cancer: opportunities for advancement

Locally advanced non-small cell lung cancer (NSCLC) continues to be a challenging disease to treat. With high rates of both local and distant failures, there is significant interest in finding more biologically active chemotherapy regimens that can contribute to reduce both failures. The phase III PROCLAIM trial, recently published in the Journal of Clinical Oncology entitled “PROCLAIM: randomized phase III trial of pemetrexed–cisplatin or etoposide–cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer”, compared two different chemotherapy regimens given concurrently with radiotherapy in patients with stage III non-squamous lung cancer: pemetrexed plus cisplatin versus cisplatin plus etoposide. Both groups received consolidation chemotherapy. After enrolling 598 of planned 600 patients, the study was stopped early due to futility as no difference was seen in the primary end-point of overall survival. Since PROCLAIM was designed as a superiority trial, these results suggest that pemetrexed regimens do not offer a clinical advantage over standard cisplatin plus etoposide. There are some subpopulations who might still benefit from pemetrexed, especially if clinicians are concerned about myelosuppression-related adverse events. Future trials are needed to investigate novel biologic agents and irradiation techniques that can result in more durable local and distant disease control in locally advanced NSCLC.

Practice Patterns and Outcomes in Elderly Stage I Non–Small-cell Lung Cancer: A 2004 to 2012 SEER Analysis

Micro‐Abstract We reviewed the population‐based outcomes for elderly patients with stage I non–small‐cell lung cancer (NSCLC) treated after the widespread adoption of stereotactic body radiation therapy (SBRT). Using the Surveillance, Epidemiology, and End Results database, biopsy‐proven stage I NSCLC cases diagnosed from 2004 to 2012 were identified (n = 62,213). With advancing age, radiation replaced surgery as the most used local therapy for early‐stage NSCLC. Concurrent with the widespread adoption of SBRT, overall and cancer‐specific survival improved significantly for elderly stage I NSCLC patients treated with SBRT alone. Background: We reviewed the population‐based treatment patterns and outcomes for elderly patients with stage I non–small‐cell lung cancer (NSCLC) treated from 2004 to 2012. Patients and Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified biopsy‐proven stage I NSCLC cases diagnosed from 2004 to 2012. The patients were divided into 5‐year age subsets (60‐64, 65‐69, 70‐74, 75‐79, 80‐84, 85‐89, and ≥ 90 years). The demographic data, therapy, and survival were compared by year. Trends in overall survival (OS), cancer‐specific survival (CSS), and practice patterns were analyzed. Results: A total of 62,213 cases were identified. The use of surgery declined sharply with age. Patients aged 60 to 64 years had a surgical rate of 81% compared with 21% for those aged ≥ 90 years (P < .0001). Radiation use increased (from 11% to 39%; P < .0001), as did the receipt of neither surgery nor radiation (from 7% to 40%; P < .0001). When analyzing the annual trends, radiation use increased, with fewer patients forgoing treatment from 2004 to 2012 (P < .0001). From 2004 to 2011, CSS at 2 years improved significantly for patients treated with radiation alone (from 48% to 72%; P < .0001) and more subtly for those receiving surgery alone (from 87% to 91%; P < .0001). The outcomes were stable for those receiving neither surgery nor radiation (38% to 45%; P = NS). Surgical outcomes declined with advancing age (P < .0001); however, the radiation outcomes did not (P = NS). Conclusion: With advancing age, radiation replaces surgery as the most used treatment for early‐stage NSCLC. OS and CSS have improved significantly for elderly stage I NSCLC patients treated with radiation alone during a timeline concurrent with the widespread adoption of stereotactic body radiation therapy. Dedicated prospective studies are indicated, because these findings are limited by the inherent biases of using the SEER database alone.

Next-Generation Sequencing and Immunotherapy Biomarkers: A Medical Oncology Perspective

The two most important scientific developments of the past decade regarding therapies for patients with non-small cell lung cancer are the ability to exploit particular genetic mutations with targeted therapies and the discovery of drugs that can help the patients own immune system attack the cancer. Despite these advances, many patients do not yet benefit from either approach. To maximize patient benefit, clinicians and pathologists will need to rationally apply the growing scientific knowledge to best characterize a patients tumor and possible driver mutations. A growing understanding of host-tumor immune interactions will hopefully help expand our therapeutic options. Lastly, the still elusive identification of immunotherapy biomarkers will hopefully help identify patients most likely to derive a therapeutic response to immune checkpoint inhibitors, and promises to be an important field of study for years to come.

Impact of recent developments in lung cancer on the practice of pathology

Landmark events in the field of lung cancer in the past year have the potential to significantly alter the practice of pathology. Three key events are (1) approval of payment for low-dose computed tomography screening for lung cancer, (2) publication of an extensively revised World Health Organization classification of lung cancers, and (3) approval of immunohistochemistry based companion diagnostics by the US Food and Drug Administration. We briefly review these milestones in the context of their impact on the practice of pathology.

Targeted Therapies for Lung Cancer

The impressive advances in understanding the genomic changes driving many lung carcinomas, especially adenocarcinomas, have led to a growing number of small-molecule drugs that often have meaningful clinical activity against advanced cancer. In many cases, therapy selected on the basis on a driver mutation has considerably more activity than standard cytotoxic chemotherapy. However for patients to receive the full potential benefit of this knowledge, the correct testing must be performed to identify those likely to benefit from targeted therapy. This chapter will review the current field of targeted agents for advanced lung cancer, the methods of identification of the genomic mutations, the corresponding clinical features, and the activity of particular agents that have been approved or about to be approved for use in patients.

Hybrid capture-based genomic profiling of circulating tumor DNA from patients with advanced non-small cell lung cancer

Introduction: Genomic profiling informs selection of matched targeted therapies as part of routine clinical care in NSCLC. Tissue biopsy is the criterion standard; however, genomic profiling of blood‐derived circulating tumor DNA (ctDNA) has emerged as a minimally invasive alternative. Methods: Hybrid capture–based genomic profiling of 62 genes was performed on blood‐based ctDNA from 1552 patients with NSCLC. Results: Evidence of ctDNA was detected in 80% of samples, and in 86% of these cases, at least one reportable genomic alteration (GA) was detected. Frequently altered genes were tumor protein p53 gene (TP53) (59%), EGFR (25%), and KRAS (17%). Comparative analysis with a tissue genomic database (N = 21,500) showed similar frequencies of GAs per gene, although KRAS mutation and EGFR T790M were more frequent in tissue and ctDNA, respectively (both p < 0.0001), likely reflecting the use of liquid versus tissue biopsy after relapse during targeted therapy. In temporally matched ctDNA and tissue samples from 33 patients with evidence of ctDNA in their blood, 64% of GAs detected in tissue were also detected in ctDNA, including 78% of short variants (58 of 74) and 100% of rearrangements (four of four), but only 16% of amplifications (four of 25). Conclusions: Genomic profiling of ctDNA detected clinically relevant GAs in a significant subset of NSCLC cases. Most alterations detected in matched tissue were also detected in ctDNA. These results suggest the utility of ctDNA testing in advanced NSCLC as a complementary approach to tissue testing. Blood‐based ctDNA testing may be particularly useful at the time of progression during targeted therapy.