Faculty Bibliography

INTRODUCTION: We examined the effect of access to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy on survival for Asian female (AF) EGFR mutation-enriched patients with advanced lung adenocarcinoma. MATERIALS AND METHODS: We used the Surveillance Epidemiology and End Results database to study patients with stage IV lung adenocarcinoma diagnosed from 1998 to 2012. We compared survival (lung cancer-specific survival [LCSS] and overall survival) between AFs and non-Asian males (NAMs), an EGFR mutation-enriched and EGFR mutation-unenriched population, respectively, with a diagnosis in the pre-EGFR TKI (1998-2004) and EGFR TKI (2005-2012) eras. We used Cox proportional hazards models to examine the interaction of access to TKI treatment and EGFR enrichment status. RESULTS: Among 3029 AF and 35,352 NAM patients, we found that LCSS was best for AFs with a diagnosis in the TKI era (median, 14 months), followed by AFs with a diagnosis in the pre-TKI era (median, 8 months), NAMs with a diagnosis in the TKI era (median, 5 months), and NAMs with a diagnosis in the pre-TKI era (median, 4 months; log-rank P < .0001). In a multivariable model, the effect of a diagnosis in the TKI era on survival was greater for AFs than for NAMs (LCSS, P = .0020; overall survival, P = .0007). A lung cancer diagnosis in the TKI era was associated with an overall mortality decrease of 26% for AFs (hazard ratio, 0.740; 95% confidence interval, 0.682-0.80) and 15.9% for NAMs (hazard ratio, 0.841; 95% confidence interval, 0.822-0.860). CONCLUSIONS: We found increased survival for lung adenocarcinoma diagnoses made after widespread access to EGFR TKIs, with the greatest increase among AF patients enriched for EGFR mutations. The present analysis eliminated the effect of crossover, which has complicated assessments of the survival advantage in EGFR TKI randomized trials.

PURPOSE: Prognostic models for pleural mesothelioma (MPM) are needed to prevent potentially futile outcomes. We combined MPM plasma biomarkers with validated clinical prognostic indices to determine whether stratification of risk for death in 194 MPM patients improved. PATIENTS AND METHODS: Individuals were recruited from three different centers: a discovery cohort (83 MPM) created by combining patients from two US centers and a separate, independent cohort from Canada (111 MPM). Univariable/multivariable analyses were performed on the initial discovery and independent cohorts separately. In multivariable analyses, prognostic factors were adjusted for the Mesothelioma EORTC Prognostic Index (PI). The prognostic significance of adding plasma biomarker data to the PI was determined using the likelihood ratio test, comparing models with and without the addition of biomarker to the clinical PI. The predictive ability of the biomarker was then assessed formally using Harrell's c-index by applying the fitted model variables of the discovery cohort to the second, independent cohort, including and not including the biomarker with the PI. RESULTS: Higher levels of osteopontin and mesothelin were individually associated with worse prognosis after adjusting for the PI. In the independent cohort, incorporating either plasma osteopontin or mesothelin into the baseline predictive PI model substantively and statistically significantly improved Harrell's c-statistic. In the final prognostic model, log-osteopontin, EORTC CPI, and hemoglobin remained as independently significant predictors, and the entire prognostic model improved the optimism-corrected Harrell's c-index significantly from 0.718 (0.67-0.77) to 0.801 (0.77-0.84). CONCLUSION: These data suggest a possible role for preoperative plasma biomarkers to improve prognostic capability of the MPM EORTC PI.

We prospectively addressed whether EGFR and KRAS mutations, EML4-ALK, ROS1 and RET rearrangements, or wild-type (WT), affects radiosurgery outcomes and overall survival (OS) in non-small cell lung cancer (NSCLC) patients with brain metastases (BM). Of 326 patients with BM treated in 2012-2014 with Gamma Knife radiosurgery (GKRS), 112 NSCLC patients received GKRS as their initial intracranial treatment. OS, intracranial progression-free survival, and time to intracranial failure were determined. Univariate and multivariate analysis were performed to determine factors affecting OS. Toxicity of treatment was evaluated. Median follow-up was 9 months. Patients with EGFR mutant BM had improved survival compared to WT. Median time to development of BM was higher in EGFR mutant patients, but this difference was not significant (2.2 vs 0.9 months; p = 0.2). Median time to distant brain failure was independent of EGFR mutation status. Karnofsky performance status (KPS), non-squamous histopathology, targeted therapy, systemic disease control, EGFR mutation, and low tumor volume were predictive of increased OS on univariate analysis. KPS (p = 0.001) and non-squamous histopathology (p = 0.03) continued to be significant on multivariate analysis. Patients with EGFR mutant BM underwent salvage treatment more often than those without (p = 0.04). Treatment-related toxicity was no different in patients treated with GKRS combined with targeted therapies versus GKRS alone (5 vs 7 %, p = 0.7). Patients with EGFR mutant BM had improved survival compared to a WT cohort. Intracranial disease control following radiosurgery was similar for all tumor subtypes. Radiosurgery is effective for BM and concurrent treatment with targeted therapy appears to be safe.

We identified amplification of RICTOR, a key component of the mTORC2, as the sole actionable genomic alteration in an 18-year-old never smoker with lung adenocarcinoma. It occurs in 13% of lung cancers (1016 cases) in TCGA and at a similar frequency in an independent cohort of 1,070 patients identified by genomic profiling. In the latter series, 11% of cases harbored RICTOR amplification as the only relevant genomic alteration. Its oncogenic roles were suggested by decreased lung cancer cell growth both in vitro and in vivo with RICTOR ablation, and the transforming capacity of RICTOR in a Ba/F3-cell system. The mTOR1/2 inhibitors were significantly more active against RICTOR-amplified lung cancer cells as compared to other agents targeting the PI3K/AKT/mTOR pathway. Moreover, an association between RICTOR amplification and sensitivities to mTOR1/2 inhibitors was observed. The index patient has been treated with mTOR1/2 inhibitors that led to tumor stabilization for over 18 months. SIGNIFICANCE: RICTOR amplification may define a novel and unique molecular subset of lung cancer patients who may benefit from treatment with mTOR1/2 inhibitors.

Reactivation of Mycobacterium tuberculosis can occur in patients with latent tuberculosis (TB) with risk factors including chronic disease (i.e., malignancy). We herein describe the case of an immigrant from Hong Kong with lung cancer and no known TB disease who presents with reactivation of TB in the setting of chemotherapy and radiation therapy.

BACKGROUND: An abscopal response describes radiotherapy-induced immune-mediated tumour regression at sites distant to the irradiated field. Granulocyte-macrophage colony-stimulating factor is a potent stimulator of dendritic cell maturation. We postulated that the exploitation of the pro-immunogenic effects of radiotherapy with granulocyte-macrophage colony-stimulating factor might result in abscopal responses among patients with metastatic cancer. METHODS: Patients with stable or progressing metastatic solid tumours, on single-agent chemotherapy or hormonal therapy, with at least three distinct measurable sites of disease, were treated with concurrent radiotherapy (35 Gy in ten fractions, over 2 weeks) to one metastatic site and granulocyte-macrophage colony-stimulating factor (125 mug/m2 subcutaneously injected daily for 2 weeks, starting during the second week of radiotherapy). This course was repeated, targeting a second metastatic site. A Simon's optimal two-stage design was chosen for this trial: an additional 19 patients could be enrolled in stage 2 only if at least one patient among the first ten had an abscopal response. If no abscopal responses were seen among the first ten patients, the study would be deemed futile and terminated. The primary endpoint was the proportion of patients with an abscopal response (defined as at least a 30% decrease in the longest diameter of the best responding abscopal lesion). Secondary endpoints were safety and survival. Analyses were done based on intention to treat. The trial has concluded accrual, and is registered with ClinicalTrials.gov, number NCT02474186. FINDINGS: From April 7, 2003, to April 3, 2012, 41 patients with metastatic cancer were enrolled. In stage 1 of the Simon's two-stage design, ten patients were enrolled: four of the first ten patients had abscopal responses. Thus, the trial proceeded to stage 2, as planned, and an additional 19 patients were enrolled. Due to protocol amendments 12 further patients were enrolled. Abscopal responses occurred in eight (27.6%, 95% CI 12.7-47.2) of the first 29 patients, and 11 (26.8%, 95% CI 14.2-42.9) of 41 accrued patients (specifically in four patients with non-small-cell lung cancer, five with breast cancer, and two with thymic cancer). The most common grade 3-4 adverse events were fatigue (six patients) and haematological (ten patients). Additionally, a serious adverse event of grade 4 pulmonary embolism occurred in one patient. INTERPRETATION: The combination of radiotherapy with granulocyte-macrophage colony-stimulating factor produced objective abscopal responses in some patients with metastatic solid tumours. This finding represents a promising approach to establish an in-situ anti-tumour vaccine. Further research is warranted in this area. FUNDING: New York University School of Medicine's Department of Radiation Oncology and Cancer Institute.

Interleukin-1 (IL-1) is a cytokine critical to inflammation, immunological activation, response to infection, and bone marrow hematopoiesis. Cyclophosphamide downmodulates immune suppressor cells and is cytotoxic to a variety of tumors. A phase I trial of IL-1 and cyclophosphamide was conducted by the Eastern Cooperative Oncology Group. This study evaluated 3 dose levels and 3 schedules in patients with solid tumors. The goal was to evaluate the hematopoietic supportive care effect and possible antitumor effect. Toxicity was fever, chills, hypotension, nausea/emesis, hepatic, and neutropenia. Toxicity increased with dose increases of interleukin-1. Treatment at all dose levels resulted in significant increases in total white blood cell (WBC) counts above baseline. Nadir WBC and nadir absolute neutrophil counts were not significantly different by dose level of IL-1 or schedule of IL-1. Toxicity due to IL-1 at higher doses prohibited further evaluation of this agent for hematopoietic support, particularly in view of the activity and tolerability of more lineage-specific hematopoietic cytokines. Therapeutic interventions in the role of IL-1 in inflammatory conditions and cancer may be further informed by our definition of its clinical and biological effects in this evaluation of dose and schedule.