Faculty Bibliography

We report a case of crizotinib-induced esophageal ulcers in a 45-year-old woman with metastatic anaplastic lymphoma kinase-positive non-small-cell lung cancer after 10 weeks of therapy. Endoscopic and pathologic findings were consistent with active inflammation with mid-esophageal ulceration and consistent with drug-induced esophagitis. Crizotinib was held and had a complete clinical and radiographic resolution of her symptoms. Patient was started on treatment with another anaplastic lymphoma kinase-targeted agent alectinib and has been tolerating it well without evidence of recurrence of esophagitis.

The majority of small cell lung cancer (SCLC) patients demonstrate initial chemo-sensitivity, whereas a distinct subgroup of SCLC patients, termed chemo-refractory, do not respond to treatment. There is little understanding of how to distinguish these patients prior to disease treatment. Here we used gene expression profiling to stratify SCLC into subgroups and characterized a molecular phenotype that may identify, in part, chemo-refractive SCLC patients. Two subgroups of SCLC were identified in both cell lines and tumors by the reciprocal expression of two genes; INSM1, a neuroendocrine transcription factor, and YAP1, a key mediator of the Hippo pathway. The great majority of tumors expressed INSM1, which was prognostic for increased progression-free survival and associated with chemo-sensitivity in cell lines. YAP1 is expressed in a minority of SCLC tumors and was shown in cell lines to be downstream of the retinoblastoma protein (RB1) and associated with decreased drug sensitivity. RB1 expression in SCLC cell lines sensitizes them to CDK4/6 inhibitors. Wild-type RB1 mutation status, used as a surrogate marker of YAP1 expression, was prognostic for decreased patient survival and increased chemo-refractory tumor response. Thus, the reciprocal expression of INSM1 and YAP1 appears to stratify SCLC into distinct subgroups and may be useful, along with RB1 mutation status, to identify chemo-refractory SCLC patients.

Several non-invasive diagnostic platforms are already being incorporated in routine clinical practice in the work up and monitoring of patients with lung cancer. These approaches have great potential to improve patient selection and monitor patients while on therapy, however several challenges exist in clinical validation and standardization of such platforms. In this review, we summarize the current technologies available for non-invasive diagnostic evaluation from the blood of patients with non-small cell lung cancer (NSCLC), and discuss the technical and logistical challenges associated incorporating such testing in clinical practice.

Identification of patients with early stage non-small cell lung cancer (NSCLC) with high risk of recurrence could help identify patients who would receive additional benefit from adjuvant therapy. In this work, we present a computational histomorphometric image classifier using nuclear orientation, texture, shape, and tumor architecture to predict disease recurrence in early stage NSCLC from digitized H&E tissue microarray (TMA) slides. Using a retrospective cohort of early stage NSCLC patients (Cohort #1, n = 70), we constructed a supervised classification model involving the most predictive features associated with disease recurrence. This model was then validated on two independent sets of early stage NSCLC patients, Cohort #2 (n = 119) and Cohort #3 (n = 116). The model yielded an accuracy of 81% for prediction of recurrence in the training Cohort #1, 82% and 75% in the validation Cohorts #2 and #3 respectively. A multivariable Cox proportional hazard model of Cohort #2, incorporating gender and traditional prognostic variables such as nodal status and stage indicated that the computer extracted histomorphometric score was an independent prognostic factor (hazard ratio = 20.81, 95% CI: 6.42-67.52, P < 0.001).

BACKGROUND:Immunostimulatory therapies targeting immune-suppressive pathways produce durable responses in advanced solid tumors. Indoleamine 2,3-dioxygenase (IDO) is the rate-limiting oxidoreductase that catalyzes the degradation of tryptophan to kynurenine. IDO induces immune tolerance by downregulating CD8+ and effector CD4+ T cell responses. IDO1, the most active isoform, is expressed in diverse tumor types and can be targeted using small molecule inhibitors. We used an objective, in situ assay to measure IDO1 in a collection of hormone receptor-positive breast cancers (HR+ BC). METHODS:and Mann-Whitney tests. Survival was studied using Kaplan-Meier estimator and a proportional hazards model. All tests were two-sided. RESULTS:IDO1 protein was observed in 76.2% of HR+ BC. There was no association between IDO1 and major clinico-pathological characteristics. Increased IDO1 correlated with decreased CD20+ infiltration (P = 0.0004) but not with CD3+, CD8+ or FOXP3 levels. Elevated IDO1 expression was associated with worse 20-year overall survival (log-rank P = 0.02, HR = 1.39, 95% C.I.: 1.05-1.82). IDO1 scores were independently associated with outcome in multivariable analysis. CONCLUSIONS:IDO1 protein is expressed in the majority of HR+ BC and is an independent negative prognostic marker. Additionally, IDO1 expression is negatively associated with tumor B-cell infiltration. Measurement of IDO1 has the potential to identify a population that might derive benefit from IDO1 blockade.

In 1996, Jim Allison demonstrated that blocking the immune regulatory molecule CTLA-4 with anit-CTLA4 antibody led to enhance tumor responses in mice. It would take an additional 15 years for human studies to confirm the potency and clinical efficacy of anti-CTLA4, ultimately leading to US FDA approval of the first checkpoint inhibitor, ipilimumab. Now with a plethora of immune-modulating agents demonstrating single agent safety and benefit across many tumor types, investigation on the optimal combination of immune-based therapies has begun in earnest. While there are many challenges, a central one is how to select which combination for which patient is the best. Here we review the current approaches that a practitioner can use to achieve this therapeutic goal.