Applications of cell-free circulating tumor DNA detection in EGFR mutant lung cancer.

Analyses of cell-free tumor DNA (ctDNA) have provided a non-invasive strategy for cancer diagnosis, the identification of molecular aberrations for treatment identification, and evaluation of tumor response. Sensitive and specific ctDNA sequencing strategies have allowed for implementation into clinical practice for the initial genotyping of patients and resistance monitoring. The specific need for EGFR mutation detection for the management of lung cancer patients has been an early imperative and has set the stage for non-invasive molecular profiling across other oncogenic drivers. Ongoing efforts are demonstrating the utility of ctDNA analyses in the initial genotyping of patients, the monitoring resistance clones, and the initial evaluation of response.

Vitiligoid hypopigmentation associated with pembrolizumab in metastatic head and neck cancer.

Cutaneous adverse events are common with the use of immunotherapy. Although only 5% of patients develop severe reactions, about half will develop mild to moderate cutaneous adverse events. Vitiligo has been seen in melanomas treated with checkpoint inhibitors (CPI). We describe the first known case of Vitiligoid irAE (immune-related adverse event) in a non-melanoma solid cancer treated with pembrolizumab.

Circulating tumor DNA analyses predict progressive disease and indicate trastuzumab-resistant mechanism in advanced gastric cancer.

BACKGROUND: Circulating tumor DNA (ctDNA) isolated from plasma contains genetic mutations that can be representative of those found in primary tumor tissue DNA. These samples can provide insights into tumoral heterogeneity in patients with advanced gastric cancer (AGC). Although trastuzumab has been shown to be effective in first-line therapy for patients with metastatic gastric cancer with overexpression of human epidermal growth factor receptor 2 (HER2), the mechanism of AGC resistance is incompletely understood. METHODS: In this prospective study, we used targeted capture sequencing to analyze 173 serial ctDNA samples from 39 AGC patients. We analyzed cancer cell fractions with PyClone to understand the clonal population structure in cancer, and monitored serial samples during therapy. Serial monitoring of ctDNA using the molecular tumor burden index (mTBI), identified progressive disease before imaging results (mean: 18 weeks). FINDINGS: We reconstructed the clonal structure of ctDNA during anti-HER2 treatment, and identified 32 expanding mutations potentially related to trastuzumab resistance. Multiple pathways activating in the same patients revealed heterogeneity in trastuzumab resistance mechanisms in AGC. In patients who received chemotherapy, mTBI was validated for the prediction of progressive disease, with a sensitivity of 94% (15/16). A higher mTBI (≥1%) in pretreatment ctDNA was also a risk factor for progression-free survival. CONCLUSIONS: Analysis of ctDNA clones based on sequencing is a promising approach to clinical management, and may lead to improved therapeutic strategies for AGC patients. FUND: This work was supported by grants from the National International Cooperation Grant (to J.X.; Project No. 2014DFB33160).

Novel Third-Generation EGFR Tyrosine Kinase Inhibitors and Strategies to Overcome Therapeutic Resistance in Lung Cancer.

EGFR-activating mutations are observed in approximately 15% to 20% of patients with non-small cell lung cancer. Tyrosine kinase inhibitors have provided an illustrative example of the successes in targeting oncogene addiction in cancer and the role of tumor-specific adaptations conferring therapeutic resistance. The compound osimertinib is a third-generation tyrosine kinase inhibitor, which was granted full FDA approval in March 2017 based on targeting EGFR T790M resistance. The compound has received additional FDA approval as first-line therapy with improvement in progression-free survival by suppressing the activating mutation and preventing the rise of the dominant resistance clone. Drug development has been breathtaking in this space with other third-generation compounds at various stages of development: rociletinib (CO-1686), olmutinib (HM61713), nazartinib (EGF816), naquotinib (ASP8273), mavelertinib (PF-0647775), and AC0010. However, therapeutic resistance after the administration of third-generation inhibitors is complex and not fully understood, with significant intertumoral and intratumoral heterogeneity. Repeat tissue and plasma analyses on therapy have revealed insights into multiple mechanisms of resistance, including novel second site EGFR mutations, activated bypass pathways such as MET amplification, HER2 amplification, RAS mutations, BRAF mutations, PIK3CA mutations, and novel fusion events. Strategies to understand and predict patterns of mutagenesis are still in their infancy; however, technologies to understand synthetically lethal dependencies and track cancer evolution through therapy are being explored. The expansion of combinatorial therapies is a direction forward targeting minimal residual disease and bypass pathways early based on projected resistance.

Reasoning the effect of immunotherapy after chemoradiation in the PACIFIC trial.

Durvalumab consolidation after chemoradiation has been a giant leap in the treatment of stage III non-small-cell lung cancer with an unprecedented 16.8-month median progression-free survival. PACIFIC trial is a new foray into chemoimmunotherapy trials where we apply our knowledge of 'immunogenic cell death' and 'Abscopal' effect of radiation in the clinic. Our understanding of immunotherapy after chemoradiation treatment and application of immunogenic cell death biomarkers in future trials may be the approach we need to maximize benefit of these treatments in the appropriate patients.

Lacrimal gland adenocarcinoma responding to checkpoint inhibition and androgen deprivation.

Although the histologically diverse classification of salivary gland tumors can be successfully applied to the epithelial lacrimal gland neoplasms, it is not clear whether the molecular makeup differs between these two different tumor types. Adenocarcinomas have known to have driver mutations in non-small cell lung cancer, however, besides HER2 expression not much is known regarding molecular drivers in lacrimal tumors. Androgen receptor (AR) expression and deprivation combined with checkpoint inhibition (CPI) have not been described before in lacrimal gland adenocarcinoma. To our knowledge, this is the first case report describing a prolonged response to CPI and AR inhibitors.

First-Line Treatment in EGFR Mutant Non-Small Cell Lung Cancer: Is There a Best Option?

First generation or second generation EGFR tyrosine kinase inhibitors are currently the standard of care for the first-line management of non-small cell lung cancer (NSCLC) patients with activating mutations within the kinase domain of the epidermal growth factor receptor gene (1, 2). Resistance to targeted therapy can develop after 9-11 months (3-8). Third generation inhibitors were developed to target the EGFR T790M clone, which is the most common dominant second site resistance mutation after first or second generation inhibitors. Osimertinib received full FDA approval for the second-line treatment of advanced NSCLC based on a phase III study comparing the compound to chemotherapy. Recent data demonstrates an important impact for osimertinib in the front-line space based on results comparing the compound to first-generation erlotinib or gefitinib therapy.

Systemic Treatment Options for Brain Metastases from Non-Small-Cell Lung Cancer.

Brain metastases are common in patients with non-small-cell lung cancer (NSCLC). Because of associated poor prognosis and limited specific treatment options, there is a real need for the development of medical therapies and strategies for affected patients. Novel compounds for epidermal growth factor receptor-dependent and anaplastic lymphoma kinase-dependent lung cancer have demonstrated blood-brain barrier permeability and have led to important improvements in central nervous system outcomes. Studies of targeted therapies for oncogene-driven tumors and of immunotherapies in patients with brain metastases have shown promise and, allied with novel radiation techniques, are driving a rapid evolution in treatment and prognosis for NSCLC brain metastases.

Genomic and Proteomic Alterations in Desmoplastic Small Round Blue-Cell Tumors.

PURPOSE: Desmoplastic small round blue-cell tumors (DSRCTs) are sarcomas that contain the t(11;22) (p13;q12) translocation EWS-WT1 fusion protein. Because this is a rare tumor type, prospective clinical trials in DSRCT are challenging. Patients are treated in a manner similar to those with Ewing sarcoma; however, differences in prognosis and clinical presentation suggest fundamental differences in biology and potentially different therapeutic implications. This study aimed to characterize the molecular characteristics of DSRCT tumors to explore unique therapeutic options for this extremely rare and aggressive cancer type. METHODS: Thirty-five DSRCT tumors were assessed using next-generation sequencing, protein expression (immunohistochemistry), and gene amplification (chromogenic in situ hybridization or fluorescence in situ hybridization). Three patients had tumor mutational load, which was calculated as somatic nonsynonymous missense mutations sequenced with a 592-gene panel. Gene expression data were obtained for an additional seven DSRCT tumors. Molecular alterations were compared with 88 Ewing sarcomas. RESULTS: The most common alterations that distinguished DSRCTs from Ewing sarcoma included higher androgen receptor (AR), TUBB3, epidermal growth factor receptor, and TOPO2A expression. Independent analysis by RNA sequencing confirmed higher AR expression from an independent data set of EWS-WT1 fusion-positive DSRCTs compared with Ewing sarcoma and a pan-cancer analysis. DSRCTs had somatic mutations that were identified in TP53 and FOXO3, averaged five mutations per megabase, and no programmed death-ligand 1 expression was detected in any DSRCT samples. CONCLUSION: The current analysis provides the first comparative analysis, to our knowledge, of molecular aberrations that distinguish DSRCT from Ewing sarcoma. High AR expression seems to be a defining event in these malignancies, and additional investigation of the responsiveness of AR inhibitors in this disease is encouraged.

Desmoplastic Small Round Blue Cell Tumor: A Review of Treatment and Potential Therapeutic Genomic Alterations.

Desmoplastic small round blue cell tumors (DSRCTs) originate from a cell with multilineage potential. A molecular hallmark of DSRCT is the EWS-WT1 reciprocal translocation. Ewing sarcoma and DSRCT are treated similarly due to similar oncogene activation pathways, and DSRCT has been represented in very limited numbers in sarcoma studies. Despite aggressive therapy, median survival ranges from 17 to 25 months, and 5-year survival rates remain around 15%, with higher survival reported among those undergoing removal of at least 90% of tumor in the absence of extraperitoneal metastasis. Almost 100% of these tumors contain t(11;22) (p13;q12) translocation, and it is likely that EWS-WT1 functions as a transcription factor possibly through WT1 targets. While there is no standard protocol for this aggressive disease, treatment usually includes the neoadjuvant HD P6 regimen (high-dose cyclophosphamide, doxorubicin, and vincristine (HD-CAV) alternating with ifosfamide and etoposide (IE) chemotherapy combined with aggressively attempted R0 resection). We aimed to review the molecular characteristics of DSRCTs to explore therapeutic opportunities for this extremely rare and aggressive cancer type.

Epidermal Growth Factor Receptor, Excision-Repair Cross-Complementation Group 1 Protein, and Thymidylate Synthase Expression in Penile Cancer.

OBJECTIVE: To describe the expression of tissue epidermal growth factor receptor (EGFR), excision-repair cross-complementation group 1 protein (ERCC1), and thymidylate synthase (TS) in patients with penile cancer and explore their association with stage and outcome. METHODS: A total of 52 patients with penile squamous cell cancer who were treated at the University of Southern California from 1995 to 2010 were identified. Paraffin-embedded tissue underwent mRNA quantitation and immunohistochemistry for expression of EGFR, ERCC1, and TS. KRAS mutations were evaluated using polymerase chain reaction-based sequencing. RESULTS: EGFR overexpression was common by mRNA (median, 5.09; range, 1.92-104.5) and immunohistochemistry. EGFR expression > 7 was associated with advanced stage and poor differentiation (P = .01 and .034 respectively) but not with survival in multivariate analysis. ERCC1 mRNA expression was a median of 0.65 (range, 0.21-1.87). TS expression was a median of 1.88 (range, 0.54-6.47). ERCC1 and TS expression were not associated with grade, stage, or survival. There were no KRAS mutations identified. A total of 17 men received chemotherapy; 8 (47%) had an objective response, including 1 with a pathologic complete response. There was a trend for lower expression of EGFR corresponding to a higher likelihood of response (response rate [RR]) to chemotherapy: 67% RR in EGFR mRNA < 7 versus 33% RR in EGFR > 7 (P = .31). CONCLUSIONS: High expression of EGFR mRNA in squamous cell carcinoma of the penis is associated with advanced stage and poor differentiation, but not survival. In our small heterogeneous subset, molecular marker expression did not show a correlation with the likelihood of chemotherapy response. A prospective evaluation of the role of the EGFR pathway and its regulatory environment in penile cancer is warranted. Given the rarity of this cancer, collaborative prospective cohort evaluations and trials need to be encouraged.