Ajaz Bulbul

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.

Lacrimal gland adenocarcinoma responding to checkpoint inhibition and androgen deprivation

Abstract 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.

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

PurposenDesmoplastic 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.nnnMethodsnThirty-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.nnnResultsnThe 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.nnnConclusionnThe 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.

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.xa0Our 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.

The Conundrum of Adjuvant HER2 Treatment Options

Improving outcomes in HER2 over-expressing breast cancer has been an impressive success story over the years. Remarkable clinical benefit and large hazard ratios in earlier metastatic and adjuvant trials rendered hope to more contemporary adjuvant trials of a similar large-scale benefit. Recent FDA approvals of dual HER2-blockade with trastuzumab plus pertuzumab and neratinib based on the APHINITY and ExteNET trials, respectively, were modest and rather underwhelming. Future trials need to focus on identifying robust biomarkers and clinical parameters that can best define the subset of patients where the anticipated toxicities and cost of therapy are justified.

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 9–11u2009months (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.