The application of genomic profiling assays using plasma circulating tumor DNA (ctDNA) is rapidly evolving in the management of patients with advanced solid tumors. Diverse plasma ctDNA technologies ...in both commercial and academic laboratories are in routine or emerging use. The increasing integration of such testing to inform treatment decision making by oncology clinicians has complexities and challenges but holds significant potential to substantially improve patient outcomes. In this review, the authors discuss the current role of plasma ctDNA assays in oncology care and provide an overview of ongoing research that may inform real‐world clinical applications in the near future.
A rare 5% of cutaneous squamous cell carcinomas (cSCC) metastasize, lack FDA-approved therapies, and carry a poor prognosis. Our aim was to identify recurrent genomic alterations in this ...little-studied population of metastatic cSCCs.
We performed targeted sequencing of 504 cancer-associated genes on lymph node metastases in 29 patients with cSCC and identified mutations and somatic copy-number alterations associated with metastatic cSCC. We determined significantly mutated, deleted, and amplified genes and associated genomic alterations with clinical variables.
The cSCC genome is heterogeneous with widely varying numbers of genomic alterations and does not appear to be associated with human papillomavirus. We found previously identified recurrently altered genes (TP53, CDKN2A, NOTCH1/2) but also a wide spectrum of oncogenic mutations affecting RAS/RTK/PI3K, squamous differentiation, cell cycle, and chromatin remodeling pathway genes. Specific mutations in known oncogenic drivers and pathways were correlated with inferior patient outcomes. Our results suggest potential therapeutic targets in metastatic cSCC, including PIK3CA, FGFR3, BRAF, and EGFR, similar to those reported in SCCs of the lung and head and neck, suggesting that clinical trials could be developed to accrue patients with SCCs from multiple sites of origin.
We have genomically characterized a rare cohort of 29 metastatic cSCCs and identified a diverse array of oncogenic alterations that can guide future studies of this disease.
Opinion statement
Adenoid cystic carcinoma (ACC) is an often-indolent type of salivary gland cancer (SGC). A subset of patients develops progression or aggressive disease warranting systemic therapy ...in the recurrent/metastatic (R/M) setting. We recommend genomic testing for all patients with R/M disease to aid with prognostication and eligibility for potential experimental therapies. Here, we review the currently available treatment options (cytotoxic chemotherapies and vascular endothelial growth factor receptor (VEGFR)-targeting tyrosine kinase inhibitors (TKIs)). Based on limited data, we nominate regimens which may have more favorable efficacy profiles. Among the cytotoxic chemotherapies, several regimens are acceptable when incorporating a platinum agent. Among the VEGFR-targeting TKIs, lenvatinib and axitinib are the preferred options. Larger, randomized studies prioritizing combinations with mechanistic synergism are needed. Predictive biomarkers are critical, as there is currently little evidence to guide sequencing of available options for individual patients. Immunotherapy is an available option, but has been associated with only modest benefit in ACC. We go on to review other therapies that have been studied and nominate those with promise based on early clinical data.
Everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is effective in treating tumors harboring alterations in the mTOR pathway. Mechanisms of resistance to everolimus remain ...undefined. Resistance developed in a patient with metastatic anaplastic thyroid carcinoma after an extraordinary 18-month response. Whole-exome sequencing of pretreatment and drug-resistant tumors revealed a nonsense mutation in TSC2, a negative regulator of mTOR, suggesting a mechanism for exquisite sensitivity to everolimus. The resistant tumor also harbored a mutation in MTOR that confers resistance to allosteric mTOR inhibition. The mutation remains sensitive to mTOR kinase inhibitors.
Tumor mutational burden correlates with response to immune checkpoint blockade in multiple solid tumors, although in microsatellite-stable tumors this association is of uncertain clinical utility. ...Here we uniformly analyzed whole-exome sequencing (WES) of 249 tumors and matched normal tissue from patients with clinically annotated outcomes to immune checkpoint therapy, including radiographic response, across multiple cancer types to examine additional tumor genomic features that contribute to selective response. Our analyses identified genomic correlates of response beyond mutational burden, including somatic events in individual driver genes, certain global mutational signatures, and specific HLA-restricted neoantigens. However, these features were often interrelated, highlighting the complexity of identifying genetic driver events that generate an immunoresponsive tumor environment. This study lays a path forward in analyzing large clinical cohorts in an integrated and multifaceted manner to enhance the ability to discover clinically meaningful predictive features of response to immune checkpoint blockade.
Cancer immunotherapy, which seeks to stimulate a patient's own immune system to combat cancer, is quickly becoming a central pillar of cancer therapeutics and has resulted in the development of many ...novel anticancer therapies. One subtype of cancer immunotherapy, immune checkpoint inhibitors (ICIs), has revolutionized cancer treatment and changed the standard of care for multiple indications. However, the advent of ICIs has produced a wide variety of inflammatory side effects termed immune‐related adverse events (IRAEs), including ICI‐induced Sicca syndrome. This article outlines the clinical features of ICI‐induced Sicca syndrome and assesses its reported incidence in clinical trials, case series, and case reports across numerous cancers and treatment modalities. Presentations of ICI‐induced Sicca syndrome in patients with pre‐existing Sjӧgren's disease and with extra‐glandular manifestations will also be explored. The pathophysiological mechanisms underlying IRAEs, including ICI‐induced Sicca syndrome, will be evaluated through an examination of existing literature. Finally, the various treatment and management strategies as well as aims for future work will be discussed and reviewed.
Background
To the authors' knowledge, there are no approved therapies for recurrent, metastatic (R/M) salivary gland carcinoma (SGC), but molecularly targeted therapies warrant ongoing investigation. ...In the current study, the authors have reported on the efficacy of tipifarnib in patients with aggressive HRAS‐mutant, R/M SGC.
Methods
The current prospective, nonrandomized, multicenter, international cohort study involved 8 centers and was conducted from May 2015 to June 2019. The median follow‐up was 22 months (range, 6‐55 months). Subjects with HRAS‐mutant R/M SGC (any histology) and disease progression within the last 6 months were enrolled. Tipifarnib was dosed orally twice daily. The authors determined the objective response rate using Response Evaluation Criteria in Solid Tumors (version 1.1), duration of response, and molecular predictors of response.
Results
A total of 13 patients with R/M SGC were enrolled; all had received prior systemic therapy (1‐3 regimens). One objective response was observed; an additional 7 of 12 evaluable patients (58%) had stable disease as their best response with a median duration of 9 months (range, 3‐14 months). Five of 7 patients had >10% tumor regression and 6 of 7 had stable disease lasting >6 months. Q61R was the most frequent activating HRAS mutation noted (7 of 13 patients; 54%), but gene variant and allele frequency did not correlate with outcomes. The median progression‐free survival was 7 months (95% confidence interval, 5.9‐10.1 months), and the median overall survival was 18 months (95% confidence interval, 9.6‐22.4 months) with approximately 58.6% of patients alive at 1 year. Survival was similar regardless of HRAS mutant variant or co‐occurring PIK3CA alterations. No participant discontinued treatment because of toxicity.
Conclusions
Tipifarnib resulted in modest clinical activity with a promising disease control rate among patients with HRAS‐mutant, R/M SGC who developed disease progression within the last 6 months.
In this prospective, multicenter cohort study that includes 13 adults, 1 patient (8%) is found to achieve a partial response to therapy, and an additional 58% of patients demonstrate stable disease (the majority with >10% tumor regression), with responses often found to last >6 months. Tipifarnib demonstrates a meaningful and often durable disease control rate among patients with a more aggressive subgroup of HRAS‐mutant salivary gland cancers, with evidence of a potential benefit across several variant HRAS mutational genotypes and allele frequencies.
NUT carcinoma (NC) shows very aggressive clinical behavior, occurs predominantly in the thorax and head and neck region of children and adults, and is defined by the presence of NUT (aka NUTM1) ...rearrangement, mostly BRD4‐NUTM1 fusion resulting from t(15;19)(q13; p13.1). So‐called “NUT variants” harbor alternate fusions between NUTM1 and BRD3, NSD3, ZNF532, or unknown partners. Rare cases of pediatric tumors with CIC‐NUTM1 fusion were recently reported in somatic soft tissue, brain, and kidney. However, such cases have not been identified in adult patients and the presence of a fusion between CIC, characteristic of CIC‐rearranged sarcoma, and NUTM1—a defining feature of NC—poses a diagnostic challenge. We herein report a case of malignant epithelioid neoplasm with myoepithelial features harboring CIC‐NUTM1 fusion arising in soft tissue of the head in a 60‐year‐old man. Immunohistochemistry revealed strong expression of NUT, but only weak ETV4 staining and negativity for keratins, EMA, p40, CD99, and WT1. SMARCB1 expression was retained. Fluorescence in situ hybridization and targeted next‐generation sequencing identified a CIC‐NUTM1 fusion resulting from t(15;19)(q14;q13.2). In light of morphologic features that overlap with those of NC from typical anatomical sites we have seen previously, the tumor was best classified as falling within the NC spectrum rather than CIC‐associated sarcoma. This case highlights the emerging diagnostic challenges generated by newly detected gene fusions of unknown clinical and biologic significance. Careful integration of cytogenetic, molecular, and immunohistochemical findings with morphologic appearances in the diagnostic workup of undifferentiated neoplasms is essential.
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