gene fusions are rare but potentially actionable oncogenic drivers that are present in some solid tumors. Details regarding the incidence of these gene rearrangements are lacking. Here, we assessed ...the incidence of
fusions across multiple tumor types and described fusion partners.
Tumor specimens submitted for molecular profiling at a Clinical Laboratory Improvement Amendments (CLIA)-certified genomics laboratory and that underwent fusion testing by anchored multiplex PCR for targeted RNA sequencing were retrospectively identified. The overall and tumor-specific incidence was noted, as was the specific fusion partner.
Out of 21,858 tumor specimens profiled from September 2015 to December 2018, 41 cases (0.2%) harbored an
fusion. Multiple fusion partners were identified. Fusion events were seen across tumor types. The greatest incidence was in non-small cell lung cancer (NSCLC, 25), though this represented only 0.3% of NSCLC cases tested. Other tumor types harboring an
fusion included gallbladder cancer, renal cell carcinoma, bladder cancer, ovarian cancer, pancreatic cancer, breast cancer, neuroendocrine tumor, sarcoma, and colorectal cancer.
fusions can be detected at a low incidence across multiple tumor types with significant heterogeneity in fusion partner.
.
is the most commonly mutated oncogene in NSCLC and development of direct KRAS inhibitors has renewed interest in this molecular variant. Different
mutations may represent a unique biologic context ...with different prognostic and therapeutic impact. We sought to characterize genomic landscapes of advanced,
-mutated non-small cell lung cancer (NSCLC) in a large national cohort to help guide future therapeutic development.Molecular profiles of 17,095 NSCLC specimens were obtained using DNA next-generation sequencing of 592 genes (Caris Life Sciences) and classified on the basis of presence and subtype of
mutations. Co-occurring genomic alterations, tumor mutational burden (TMB), and PD-L1 expression 22C3, tumor proportion score (TPS) score were analyzed by
mutation type.Across the cohort, 4,706 (27.5%) samples harbored a
mutation. The most common subtype was G12C (40%), followed by G12V (19%) and G12D (15%). The prevalence of
mutations was 37.2% among adenocarcinomas and 4.4% in squamous cell carcinomas. Rates of high TMB (≥10 mutations/Mb) and PD-L1 expression varied across
mutation subtypes.
G12C was the most likely to be PD-L1 positive (65.5% TPS ≥ 1%) and PD-L1 high (41.3% TPS ≥ 50%).
was mutated in 8.6% of
wild-type NSCLC but more frequent in
-mutant NSCLC, with the highest rate in G13 (36.2%).
mutations were more frequent in
wild-type NSCLC (73.6%).
mutation subtypes have different co-occurring mutations and a distinct genomic landscape. The clinical relevance of these differences in the context of specific therapeutic interventions warrants investigation.
Because of the well-established therapeutic benefit of boosting antitumor responses through blockade of the T cell inhibitory receptor PD-1, it has been proposed that PD-1 blockade could also be ...useful in infectious disease settings, including
(Mtb) infection. However, in preclinical models, Mtb-infected PD-1
mice mount exaggerated T
1 responses that drive lethal immunopathology. Multiple cases of tuberculosis during PD-1 blockade have been observed in patients with cancer, but in humans little is understood about Mtb-specific immune responses during checkpoint blockade-associated tuberculosis. Here, we report two more cases. We describe a patient who succumbed to disseminated tuberculosis after PD-1 blockade for treatment of nasopharyngeal carcinoma, and we examine Mtb-specific immune responses in a patient with Merkel cell carcinoma who developed checkpoint blockade-associated tuberculosis and was successfully treated for the infection. After anti-PD-1 administration, interferon-γ-producing Mtb-specific CD4 T cells became more prevalent in the blood, and a tuberculoma developed a few months thereafter. Mtb-specific T
17 cells, CD8 T cells, regulatory T cells, and antibody abundance did not change before the appearance of the granuloma. These results are consistent with the murine model data and suggest that boosting T
1 function with PD-1 blockade may increase the risk or severity of tuberculosis in humans.
Hispanics living in the United States have higher rates of Epidermal Growth Factor Receptor (EGFR) mutations compared with Non-Hispanic Whites. While this higher incidence is like Asian patients ...living in the United States, the outcomes for Hispanic patients differ. We looked to compare the variances in mutational profiles between Hispanics and Asians in Los Angeles.
Three hundred ninety three non-small cell lung cancer (NSCLC) patients treated at Los Angeles County + University of Southern California (LAC + USC) Medical Center and Norris Comprehensive Cancer Center who received comprehensive genomic profiling (CGP) were evaluated from July 2017 to August 2020. CGP was done using tissue biopsies (n = 211) from Caris Life Sciences and liquid biopsies (n = 231) from Guardant Health. Multivariate logistic regression evaluated the role of race between Hispanics and Asians.
In the Hispanic cohort (n = 90), 50.0% were male, median age of diagnosis was 62, 54.5% were non-smokers, and 85.5% had adenocarcinoma. In Asians (n = 142), 47.5% were male, median age of diagnosis was 65, 59.6% were non-smokers, and 83.8% had adenocarcinoma. Hispanic patients had greater prevalence of Kirsten rat sarcoma virus (KRAS) mutations (odds ratio OR 4.42, 95% confidence interval 95% CI: 1.63-12.83) and lesser prevalence of EGFR mutations (OR 0.31, 95% CI: 0.16-0.59). There were a greater proportion of Hispanic smokers with KRAS mutations (14/41; 34.1%) than Asian smokers (4/58; 6.9%).
We saw a greater percentage of Hispanics with KRAS mutations despite similar smoking percentages along with a greater percentage of Asians with EGFR mutations. This study shows that ethnic and racial backgrounds of the patient can influence the effects of potentially carcinogenic exposures leading to variances of mutation frequency of NSCLC among different ethnicities.
We sought to compare the variances in mutational profiles between Hispanics and Asians in Los Angeles comparing 393 patients who received comprehensive genomic profiling. We saw a greater percentage of Hispanics with Kirsten rat sarcoma virus mutations despite similar smoking percentages and a greater percentage of Asians with Epidermal Growth Factor Receptor mutations. These findings highlight the idea that ethnic and racial backgrounds can influence the effects of potentially carcinogenic exposures leading to variances of mutation frequency of non-small cell lung cancer among different ethnicities.
Activating fusions of the NTRK1, NTRK2 and NTRK3 genes are drivers of carcinogenesis and proliferation across a broad range of tumour types in both adult and paediatric patients. Recently, the FDA ...granted tumour-agnostic approvals of TRK inhibitors, larotrectinib and entrectinib, based on significant and durable responses in multiple primary tumour types. Unfortunately, testing rates in clinical practice remain quite low. Adding plasma next-generation sequencing of circulating tumour DNA (ctDNA) to tissue-based testing increases the detection rate of oncogenic drivers and demonstrates high concordance with tissue genotyping. However, the clinical potential of ctDNA analysis to identify NTRK fusion-positive tumours has been largely unexplored.
We retrospectively reviewed a ctDNA database in advanced stage solid tumours for NTRK1 fusions.
NTRK1 fusion events, with nine unique fusion partners, were identified in 37 patients. Of the cases for which clinical data were available, 44% had tissue testing for NTRK1 fusions; the NTRK1 fusion detected by ctDNA was confirmed in tissue in 88% of cases. Here, we report for the first time that minimally-invasive plasma NGS can detect NTRK fusions with a high positive predictive value.
Plasma ctDNA represents a rapid, non-invasive screening method for this rare genomic target that may improve identification of patients who can benefit from TRK-targeted therapy and potentially identify subsequent on- and off-target resistance mechanisms.
Previous studies on Hispanic thyroid cancer cases show sex disparities and an increased prevalence of large tumor sizes and nodal involvement. Here, we characterized Hispanic thyroid cancer cases in ...California.
We identified thyroid cancer cases from 2010 to 2020 using the California Cancer Registry by sex, race/ethnicity, histology, TNM stage, tumor size, lymph node involvement, and Charlson comorbidity score. The age-adjusted incidence rate (AAIR) and age-adjusted mortality rate (AAMR) for all causes of death were calculated. A Cox proportional hazards regression analysis was performed to evaluate the mortality risk from all causes of death by race.
Overall, 56,838 thyroid cancer cases were identified, including 29.75% in Hispanics. Hispanics had the highest female-to-male incidence rate ratio (IRR 3.54) and the highest prevalence of T3/T4 tumor size (28.71%), the highest N1 nodal status (32.69%), and the highest AAMR (0.79 per 100,000 people). After adjusting for demographic and tumor covariates, compared to non-Hispanic White people, Hispanic ethnicity, with an HR of 1.22 (95% CI 1.18-1.25,
< 0.0001), remained a significant independent contributor to mortality risk.
Hispanics had the greatest female-to-male IRR ratio, a greater prevalence of advanced disease features at diagnosis, along with the highest AAMR and increased mortality risk despite adjustments for demographic and tumor covariates. Further investigation into other risk factors is needed.
The distinction between separate primary lung carcinomas (SPLCs) and intrapulmonary metastases (IPMs) is crucial to accurate cancer staging. Histopathology-based classification cannot always ...determine the relatedness of multiple tumors taken from the lung. Recently, next-generation sequencing (NGS) has been used for biomarker determination, but it also has the potential to inform clonality determination among multiple tumors. Here we present a patient with three lung tumors, each diagnosed as adenocarcinoma by histopathology with a differential diagnosis of SPLC versus IPM. We pursued molecular profiling by NGS, which revealed three unique mutational patterns ruling out the possibility of clonal relatedness among the cancers. Our case supports the utility of NGS in supplementing histopathological methods to distinguish between SPLCs and IPMs and to guide treatment decisions.The distinction between separate primary lung carcinomas (SPLCs) and intrapulmonary metastases (IPMs) is crucial to accurate cancer staging. Histopathology-based classification cannot always determine the relatedness of multiple tumors taken from the lung. Recently, next-generation sequencing (NGS) has been used for biomarker determination, but it also has the potential to inform clonality determination among multiple tumors. Here we present a patient with three lung tumors, each diagnosed as adenocarcinoma by histopathology with a differential diagnosis of SPLC versus IPM. We pursued molecular profiling by NGS, which revealed three unique mutational patterns ruling out the possibility of clonal relatedness among the cancers. Our case supports the utility of NGS in supplementing histopathological methods to distinguish between SPLCs and IPMs and to guide treatment decisions.
The Seneca Valley virus (NTX-010) is an oncolytic picornavirus with tropism for SCLC. This phase II double-blind, placebo-controlled trial evaluated NTX-010 in patients with extensive-stage (ES) SCLC ...after completion of first-line chemotherapy.
Patients with ES SCLC who did not progress after four or more cycles of platinum-based chemotherapy were randomized 1:1 to a single dose of NTX-010 or placebo within 12 weeks of chemotherapy. The primary end point was progression-free survival (PFS). A prespecified interim analysis for futility was performed after 40 events. Viral clearance and the development of neutralizing antibodies were followed.
From January 15, 2010, to January 10, 2013, a total of 50 patients were randomized and received therapy on study (26 received NTX-010 and 24 received placebo). At the specified interim analysis, the median PFS was 1.7 months (95% confidence interval CI: 1.4–3.1 months) for the NTX-010 group versus 1.7 months (95% CI: 1.4–4.3 months) for the placebo group (hazard ratio = 1.03, p = 0.92), and the trial was terminated owing to futility. In the NTX-010 group, PFS was shorter in patients with detectable virus at days 7 and 14 versus in those in whom it was not detected after treatment (1.0 month 95% CI: 0.4–1.5 months versus 1.8 months 95% CI: 1.3–5.5 months, p = 0.008 and 0.9 months 95% CI: 0.4–2.6 months versus 1.3 months 95% CI: 1.0–5.3 months, respectively p = 0.04).
Patients with ES SCLC did not benefit from NTX-010 treatment after chemotherapy with a platinum doublet. Persistence of NTX-010 in the blood 1 or 2 weeks after treatment was associated with a shorter PFS.
Background
The incidence of lung cancer in the US has been decreasing but a bigger decline has been observed in men despite similar declines in tobacco use between men and women. Multiple theories ...have been proposed, including exposure to exogenous estrogens. Our study seeks to understand the relationship between hormone receptors (HR), gender, and the genomic landscape of non-small lung cancer (NSCLC).
Methods
3,256 NSCLC tumor samples submitted for molecular profiling between 2013-2018 were retrospectively identified and assessed for HR expression. Hormone receptor (HR+) was defined as ≥ 1% nuclear staining of estrogen receptor-alpha (ER-a) or progesterone receptor (PR) by immunohistochemistry. DNA sequencing by NGS included cases sequenced by the Illumina MiSeq hot spot 47 gene panel (n=2753) and Illumina NextSeq 592 gene panel (n=503). An adjusted p-value (q-value) <0.05 was determined significant.
Results
HR+ was identified in 18.3% of NSCLC. HR+ occurred more commonly in women compared to men (19.6% vs 11.4%, p <0.0001, q <0.0001).
EGFR
mutations occurred more commonly in HR+ NSCLC than HR- NSCLC (20.2% vs. 14.6%, p = 0.002, q=0.007). Overall, men with
EGFR
mutations were affected by HR status with a higher prevalence in HR+ NSCLC while such differences were not seen in women. However, in women ages ≤45, there was a trend towards greater prevalence HR+ NSCLC (25.25% vs. 11.32%, q= 0.0942) and 10/25 (40.0%) of HR+ cases in young women were found to be
EGFR
mutated.
KRAS
mutations and ALK+ IHC expression occurred more in HR+ NSCLC whereas
TP53
mutations occurred more in HR- NSCLC.
Conclusions
Women were more likely to have HR+ NSCLC than men and
EGFR
and
KRAS
mutations occurred more commonly in HR+ NSCLC. Additional studies with more strict inclusion criteria for HR+ are warranted to see if there is benefit to targeting HR in these subgroups.
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