Enrichment of kinase fusions in ESR1 wild-type, metastatic breast cancer revealed by a systematic analysis of 4854 patients.

BACKGROUND: Kinase fusions are rare and poorly characterized in breast cancer (BC). We aimed to characterize kinase fusions within a large cohort of advanced BC. PATIENTS AND METHODS: A total of 4854 patients with BC were analyzed by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) targeted DNAseq and MSK-Fusion targeted RNAseq during the study time period. RESULTS: Twenty-seven of 4854 (0.6%) patients harbored fusions: 11 FGFR (five FGFR2, three FGFR3, three FGFR1), five BRAF, four NTRK1, two RET, two ROS1, one ALK, one ERBB2, and one MET. A history of endocrine therapy was present in 15 (56%) of fusion-positive BC; eight of the 15 cases had available pre-treatment samples, of which six were fusion-negative. None of the fusion-positive BC samples harbored ESR1 hotspot mutations. Two patients with acquired LMNA-NTRK1 fusions and metastatic disease received larotrectinib and demonstrated clinical benefit. CONCLUSION: Kinase fusions in BC are extremely rare, and appear to be enriched in hormone-resistant, metastatic carcinomas and mutually exclusive with ESR1 mutations. The present study expands the spectrum of genetic alterations activating mitogen-activated protein kinase (MAPK) signaling that can substitute for ESR1 mutations in this setting. Molecular testing at progression after endocrine therapy should include fusion testing, particularly in the absence of ESR1 hotspot alterations, in an effort to identify additional therapeutic options which may provide substantial clinical benefit.

Ultra-deep next-generation sequencing of plasma cell-free DNA in patients with advanced lung cancers: results from the Actionable Genome Consortium.

BACKGROUND: Noninvasive genotyping using plasma cell-free DNA (cfDNA) has the potential to obviate the need for some invasive biopsies in cancer patients while also elucidating disease heterogeneity. We sought to develop an ultra-deep plasma next-generation sequencing (NGS) assay for patients with non-small-cell lung cancers (NSCLC) that could detect targetable oncogenic drivers and resistance mutations in patients where tissue biopsy failed to identify an actionable alteration. PATIENTS AND METHODS: Plasma was prospectively collected from patients with advanced, progressive NSCLC. We carried out ultra-deep NGS using cfDNA extracted from plasma and matched white blood cells using a hybrid capture panel covering 37 lung cancer-related genes sequenced to 50 000× raw target coverage filtering somatic mutations attributable to clonal hematopoiesis. Clinical sensitivity and specificity for plasma detection of known oncogenic drivers were calculated and compared with tissue genotyping results. Orthogonal ddPCR validation was carried out in a subset of cases. RESULTS: In 127 assessable patients, plasma NGS detected driver mutations with variant allele fractions ranging from 0.14% to 52%. Plasma ddPCR for EGFR or KRAS mutations revealed findings nearly identical to those of plasma NGS in 21 of 22 patients, with high concordance of variant allele fraction (r = 0.98). Blinded to tissue genotype, plasma NGS sensitivity for de novo plasma detection of known oncogenic drivers was 75% (68/91). Specificity of plasma NGS in those who were driver-negative by tissue NGS was 100% (19/19). In 17 patients with tumor tissue deemed insufficient for genotyping, plasma NGS identified four KRAS mutations. In 23 EGFR mutant cases with acquired resistance to targeted therapy, plasma NGS detected potential resistance mechanisms, including EGFR T790M and C797S mutations and ERBB2 amplification. CONCLUSIONS: Ultra-deep plasma NGS with clonal hematopoiesis filtering resulted in de novo detection of targetable oncogenic drivers and resistance mechanisms in patients with NSCLC, including when tissue biopsy was inadequate for genotyping.

Variable risk of second primary malignancy in multiple myeloma patients of different ethnic subgroups.

Second primary malignancies (SPMs) among multiple myeloma (MM) patients have been reported with an estimated incidence varying from 1 to 15%. We have previously reported that significant disparity exists in MM survival across patients of different ethnicities. We undertook a Surveillance Epidemiology and End Results-based analysis to describe the incidence of SPMs among MM patients of different ethnicities, to explore the variable impact that SPMs might have on MM outcomes of patients across racial subgroups. We found that the risk of developing SPMs among MM patients is variable depending on the patient's ethnic background. This warrants further exploration of the impact of SPMs on outcomes of MM patients across different racial subgroups, especially in the form of prospective data collection and analyses.

Patterns of second primary malignancy risk in multiple myeloma patients before and after the introduction of novel therapeutics.

Recent studies have reported an increased risk of second primary malignancies (SPM) following multiple myeloma (MM) diagnosis associated with novel anti-myeloma treatments. We evaluated the risk of SPM among 36 491 MM cases reported to the Surveillance, Epidemiology, and End Results program (SEER) between 1973 and 2008. We calculated overall and site-specific standardized incidence ratio (SIR) and 95% confidence intervals (CI) for 2012 SPM cases diagnosed within the 35-year follow-up. There was no significant overall risk of SPM (SIR=0.98; 95% CI=0.94-1.02); however, there were multiple site-specific risk patterns. The risk of breast and prostate cancer was significantly decreased overall and across age, latency and the year of diagnosis strata. There was an ∼50% increased risk of colorectal cancer 5 years after MM diagnosis (Ptrend<0.001). The risk of hematological malignancies was significantly increased, notably for acute myeloid leukemia (AML; SIR=6.51; 95% CI=5.42-7.83). There was a significant decreasing trend for AML over time, particularly for patients 65. However, no significant change in risk was noted after the introduction of autologous stem cell transplant among younger patients (<65 years). On the basis of observed trends for overall SPM as well as AML, no association between the introduction of novel therapies and SPM following MM has emerged in this large population-based study.

Unsuspected pulmonary emboli adversely impact survival in patients with cancer undergoing routine staging multi-row detector computed tomography scanning.

BACKGROUND: While symptomatic venous thromboembolism adversely impacts survival among cancer patients, the outcome of cancer patients with unsuspected pulmonary embolism (UPE) found on routine cancer staging multi-row detector computed tomography (MDCT) scans is unknown. OBJECTIVE: To determine whether UPE detected on routine staging MDCT scans impacts overall survival among cancer patients. PATIENTS AND METHODS: We performed a matched cohort study of cancer patients diagnosed with UPE on routine staging scans between May 2003 and August 2006. Two controls (n = 137) were individually matched by age (± 5 years), cancer type and stage for each UPE patient (n = 70). We used Cox's proportional hazard models to compare the mortality between UPE patients and their matched controls. RESULTS: The hazard ratio (HR) for death among UPE patients was 1.51 (95% CI 1.01-2.27, P = 0.048). Compared with their matched controls, patients with UPE more proximal than the subsegmental arterial branches had a HR for death at 6 months of 2.28 (95% CI 1.20-4.33, P = 0.011) and an overall HR of 1.70 (95% CI 1.06-2.74, P = 0.027). Survival among UPE patients with isolated subsegmental PE (ISSPE) was not significantly different than that of matched controls (HR 1.04 95% CI 0.44-2.39, P = 0.92). CONCLUSIONS: UPE identified more proximal than the subsegmental arterial branches has a significant negative impact on survival among cancer patients.

Esophageal exfoliative cytology samplers. A comparison of three types.

OBJECTIVE: To compare three types of esophageal exfoliative cytology samplers in terms of patient acceptability, ease of use, final destination of the sampler tip in the gastrointestinal tract and cellular yield. STUDY DESIGN: A controlled, single-blind, cross-over study was undertaken to compare the balloon, sponge and sponge-mesh samplers in healthy volunteers. After completing the three procedures in random order, participants were asked about their preferred method. Ease of use was defined as the technician's ability to perform the intubation successfully. Final destination of the samplers was assessed fluoroscopically. Cytopathologists determined the cellular yield of each sampler using the Bethesda System. RESULTS: Sixty-two volunteers participated. The two encapsulated samplers were significantly preferred over the balloon (P < .0001). There was no significant difference in ease of use, final destination or cellular yield of the three techniques. All three samplers were successfully intubated on the first attempt and retrieved adequate numbers of squamous and glandular cells in > 78% of cases. CONCLUSION: All three samplers obtained satisfactory yields of squamous and glandular cells, but the encapsulated samplers were more patient acceptable. The sponge-mesh sampler may be the least complicated sampler for field screening use. Larger-scale studies will be required to test the accuracy of these three samplers for detecting esophageal dysplasia and carcinoma.

Identification of arylamine N-acetyltransferase activity in the bovine lens.

Arylamine N-acetyltransferase (NAT) activity was identified and partially characterized in the bovine lens. According to size-exclusion HPLC, the molecular mass of the arylamine NAT is approximately 30-kDa. Based upon substrate specificity analysis, it is best described as an arylamine NAT which has some ability to N-acetylate arylalkylamines. This arylamine NAT acetylates para-aminobenzoic acid thereby demonstrating a monomorphic pattern of N-acetylation. It demonstrates low sensitivity to methotrexate inhibition as indicated by the relatively high IC50 value (470 microM). NAT could be involved in lenticular detoxification of both endogenous amines and exogenous drugs.