Background
Plasma genotyping is an emerging approach for the identification of genetic alterations mediating resistance to anaplastic lymphoma kinase (ALK)–targeted therapy. The authors reviewed ...plasma genotyping and imaging findings to assess the correlation between circulating tumor DNA (ctDNA) burden and disease burden in patients with ALK‐positive lung cancer.
Methods
The authors analyzed 97 plasma specimens from 75 patients with ALK‐positive lung cancer to identify ALK and non‐ALK alterations. Disease burden was estimated by tabulating lesions per organ and calculating lesion diameters, areas, and volumes. Disease burden was correlated with the allelic frequency (AF) of plasma alterations.
Results
The mean interval between plasma collection and imaging was 8 days. ctDNA was detected in approximately 85% of plasma specimens. An ALK fusion and ALK mutation were detected in 79% and 76%, respectively, of plasma specimens. Using the maximum plasma alteration AF and maximum ALK alteration AF as independent surrogates of ctDNA burden, a higher disease burden measurement on imaging was found to be associated with higher ctDNA burden. Total body and extrathoracic tumor volume but not intrathoracic tumor volume correlated with ctDNA burden. Of all the disease sites assessed, the ctDNA burden correlated most with involvement of the liver, bones, and adrenal glands. Despite being the defining alteration in ALK‐positive lung cancer, isolated plasma ALK fusion AF did not perform as well as the maximum plasma alteration AF or maximum ALK alteration AF for correlating tumor burden.
Conclusions
In patients with ALK‐positive lung cancer, the maximum plasma alteration AF and maximum ALK alteration AF correlate with the extrathoracic burden of disease and are more predictive of tumor burden compared with the ALK fusion AF alone.
Lay Summary
Analysis of genetic material shed from cancer cells into the circulation offers insights into the molecular composition of tumors. The circulating tumor DNA (ctDNA) varies over time and across individuals and is impacted by the distribution of disease.
Herein, the authors estimated tumor burden on imaging and correlated it with ctDNA by calculating the maximum allelic frequency.
The current study findings demonstrated that the greatest correlation exists between extrathoracic, extracranial tumor burden (particularly involvement of the liver, adrenal glands, or bones) and ctDNA burden, suggesting a biological basis for the interpatient and temporal intrapatient differences in ctDNA yield that have been described in previous studies.
Plasma genotyping of circulating tumor DNA (ctDNA) has emerged as a clinical tool for the identification of underlying driver mutations and resistance mechanisms in patients with lung cancer. In patients with advanced, ALK‐positive lung cancer, plasma genotyping yields higher quantities of ctDNA in those patients found to have a high extrathoracic disease burden on imaging, particularly within the setting of hepatic, adrenal, and bone metastases.
Aims
Nuclear protein in testis (NUT) carcinoma, an aggressive tumour driven by NUTM1 rearrangements, often involves the lung/mediastinum and shows squamous differentiation. We encountered an index ...patient with a thoracic NUT carcinoma diagnosed by molecular testing, showing extensive pleural involvement and diffuse thyroid transcription factor‐1 (TTF‐1) expression, initially suggestive of lung adenocarcinoma with pseudomesotheliomatous growth. We thus gathered an institutional series of thoracic NUT carcinomas to examine their pathological spectrum.
Methods and results
We searched for thoracic NUT carcinomas in our surgical pathology files and in 2289 consecutive patients with primary thoracic tumours investigated with RNA‐based assays. We performed NUT immunohistochemistry on 425 additional lung adenocarcinomas. Collectively, we identified six patients (five men and one woman; age 31–80 years; four never‐smokers) with thoracic NUT carcinomas confirmed by molecular testing (including five with positive NUT immunohistochemistry). They died at 2.3–12.9 months (median, 2.8 months) after presentation. Two patients were diagnosed by histopathological assessment, and the remaining four (including the index patient) were diagnosed by molecular testing. Analysis of the index case revealed expression of multiple neuroendocrine markers and TTF‐1; no ultrastructural evidence of neuroendocrine differentiation was noted. No additional NUT‐positive cases were found by immunohistochemical screening.
Conclusions
Although NUT carcinoma classically shows squamous differentiation, it can rarely express TTF‐1 (even diffusely) and/or multiple neuroendocrine markers. This immunophenotypic spectrum may lead to diagnostic confusion with pulmonary adenocarcinoma, neuroendocrine tumour, and others. To circumvent this pitfall, NUT immunohistochemistry and/or NUTM1 molecular testing should be considered in primitive‐appearing tumours, regardless of their immunophenotypic features.
NUT carcinoma with diffuse TTF‐1 expression.
Targeted therapies have changed the landscape of treatments for non-small cell lung cancer (NSCLC). Specific targeted therapies have been approved for NSCLC patients harboring genetic alterations in ...four oncogenes, and agents targeting additional oncogenic drivers are under investigation. Standard first-line chemotherapy has been supplanted by these targeted therapies due to superior efficacy and lower toxicity. Despite excellent response rates and durable responses in some cases, most patients experience relapse within a few years due to the development of acquired drug resistance. Next generation targeted therapies are being developed to overcome drug resistance and extend the duration of therapy. In this review, we summarize the current treatment strategies for the major targetable oncogenic mutations/alterations in NSCLC and discuss the mechanisms leading to acquired drug resistance.
A study reported in this issue of The Oncologist examined the utility of next‐generation sequencing (NGS) in detecting ALK rearrangements. NGS may one day become the standard initial test for ...molecular genotyping of patients with advanced cancers, and this new generation of ALK diagnostics is a welcome addition to the current screening repertoire.
Cancer is a dynamic disease. During the course of disease, cancers generally become more heterogeneous. As a result of this heterogeneity, the bulk tumour might include a diverse collection of cells ...harbouring distinct molecular signatures with differential levels of sensitivity to treatment. This heterogeneity might result in a non-uniform distribution of genetically distinct tumour-cell subpopulations across and within disease sites (spatial heterogeneity) or temporal variations in the molecular makeup of cancer cells (temporal heterogeneity). Heterogeneity provides the fuel for resistance; therefore, an accurate assessment of tumour heterogeneity is essential for the development of effective therapies. Multiregion sequencing, single-cell sequencing, analysis of autopsy samples, and longitudinal analysis of liquid biopsy samples are all emerging technologies with considerable potential to dissect the complex clonal architecture of cancers. In this Review, we discuss the driving forces behind intratumoural heterogeneity and the current approaches used to combat this heterogeneity and its consequences. We also explore how clinical assessments of tumour heterogeneity might facilitate the development of more-effective personalized therapies.
Purpose Advanced anaplastic lymphoma kinase ( ALK) fusion-positive non-small-cell lung cancers (NSCLCs) are effectively treated with ALK tyrosine kinase inhibitors (TKIs). However, clinical outcomes ...in these patients vary, and the benefit of TKIs is limited as a result of acquired resistance. Emerging data suggest that the ALK fusion variant may affect clinical outcome, but the molecular basis for this association is unknown. Patients and Methods We identified 129 patients with ALK-positive NSCLC with known ALK variants. ALK resistance mutations and clinical outcomes on ALK TKIs were retrospectively evaluated according to ALK variant. A Foundation Medicine data set of 577 patients with ALK-positive NSCLC was also examined. Results The most frequent ALK variants were EML4-ALK variant 1 in 55 patients (43%) and variant 3 in 51 patients (40%). We analyzed 77 tumor biopsy specimens from patients with variants 1 and 3 who had progressed on an ALK TKI. ALK resistance mutations were significantly more common in variant 3 than in variant 1 (57% v 30%; P = .023). In particular, ALK G1202R was more common in variant 3 than in variant 1 (32% v 0%; P < .001). Analysis of the Foundation Medicine database revealed similar associations of variant 3 with ALK resistance mutation and with G1202R ( P = .010 and .015, respectively). Among patients treated with the third-generation ALK TKI lorlatinib, variant 3 was associated with a significantly longer progression-free survival than variant 1 (hazard ratio, 0.31; 95% CI, 0.12 to 0.79; P = .011). Conclusion Specific ALK variants may be associated with the development of ALK resistance mutations, particularly G1202R, and provide a molecular link between variant and clinical outcome. ALK variant thus represents a potentially important factor in the selection of next-generation ALK inhibitors.
Enhanced understanding of the molecular events underlying oncogenesis has led to the development of “tumor‐agnostic” treatment strategies, which aim to target a tumor's genomic profile regardless of ...its anatomic site of origin. A classic example is the translocation resulting in an ETV6‐NTRK3 gene fusion, a characteristic driver of a histologically diverse array of cancers. The chimeric ETV6‐NTRK3 fusion protein elicits constitutive activation of the tropomyosin receptor kinase (TRK) C protein, leading to increased cell survival, growth, and proliferation. Two TRK inhibitors, larotrectinib and entrectinib, are currently approved for use in the metastatic setting for the treatment of advanced solid tumors harboring NTRK fusions. Here we report a rare case of recurrent secretory carcinoma of the breast (SCB) with NTRK3 gene fusion. Whereas most cases of SCB represent slow‐growing tumors with favorable outcomes, the case detailed here is the first to the authors' knowledge of recurrence within 1 year of surgery. We review the molecular findings and potential clinical significance.
Key Points
The translocation resulting in the ETV6‐NTRK3 gene fusion is a known oncogenic driver characteristic of secretory carcinoma of the breast (SCB).
Whereas most cases of SCB represent slow‐growing tumors with favorable outcomes, the case here with ETV6‐NTRK3 gene fusion had local recurrence within 1 year of surgery.
Two tropomyosin receptor kinase (TRK) inhibitors, larotrectinib and entrectinib, are approved to treat NTRK fusion–positive tumors, demonstrating sustained high overall response rates in the metastatic setting.
Approval of TRK inhibitors necessitates optimization of NTRK fusion detection assays, including detection with liquid biopsies.
This article reports a rare case of recurrent secretory carcinoma of the breast with NTRK3 gene fusion, detailing the molecular findings and potential clinical significance.
Ten percent of NSCLCs harbor mutations in SMARCA4, the gene encoding the SWItch/Sucrose Non-Fermentable ATPase BRG1. In preclinical models, BRG1 inactivation increases tumor aggressiveness but ...enhances sensitivity to drugs that target oxidative phosphorylation and inhibit SMARCA2, EZH2, CDK4, or CDK6. To facilitate translation of preclinical findings into clinical studies exploiting these therapeutic vulnerabilities, we assessed the clinical features of patients with tumors harboring BRG1-inactivating mutations.
Data sets from Massachusetts General Hospital and Foundation Medicine were reviewed to determine the prevalence of SMARCA4-mutant NSCLC and describe its clinicopathologic characteristics. BRG1 expression was evaluated by immunohistochemistry and correlated with SMARCA4 mutations. Treatment outcomes were retrospectively assessed.
We detected SMARCA4 genomic alterations in 9% (n = 117 of 1422) and 11% (n = 3188 of 27,281) of NSCLCs in the institutional and Foundation Medicine data sets, respectively. In both cohorts, truncating mutations comprised over one-third of SMARCA4 alterations. Twenty-nine of 64 SMARCA4-mutant NSCLCs (45%) assessed for BRG1 expression reported loss of expression, most (90%) of which had truncating SMARCA4 mutations. Overall, 84% (n = 26 of 31) of evaluated NSCLCs with truncating SMARCA4 mutations lacked BRG1 expression. Deficient BRG1 expression was predominantly detected in adenocarcinomas with co-occurring mutations in KRAS, TP53, KEAP1, and STK11. Among patients with BRG1-deficient NSCLC who received first-line platinum doublet chemotherapy (n = 11) or chemotherapy plus immunotherapy (n = 5), median progression-free survival was 38 days and 35 days, respectively.
BRG1 deficiency is enriched in NSCLCs with truncating SMARCA4 mutations. Clinical outcomes are poor in this molecular subgroup, highlighting the importance of developing novel strategies to target unique vulnerabilities associated with the BRG1-deficient state.
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