IMPORTANCE: Cancer is caused by a diverse array of somatic and germline genomic aberrations. Advances in genomic sequencing technologies have improved the ability to detect these molecular ...aberrations with greater sensitivity. However, integrating them into clinical management in an individualized manner has proven challenging. OBJECTIVE: To evaluate the use of integrative clinical sequencing and genetic counseling in the assessment and treatment of children and young adults with cancer. DESIGN, SETTING, AND PARTICIPANTS: Single-site, observational, consecutive case series (May 2012-October 2014) involving 102 children and young adults (mean age, 10.6 years; median age, 11.5 years, range, 0-22 years) with relapsed, refractory, or rare cancer. EXPOSURES: Participants underwent integrative clinical exome (tumor and germline DNA) and transcriptome (tumor RNA) sequencing and genetic counseling. Results were discussed by a precision medicine tumor board, which made recommendations to families and their physicians. MAIN OUTCOMES AND MEASURES: Proportion of patients with potentially actionable findings, results of clinical actions based on integrative clinical sequencing, and estimated proportion of patients or their families at risk of future cancer. RESULTS: Of the 104 screened patients, 102 enrolled with 91 (89%) having adequate tumor tissue to complete sequencing. Only the 91 patients were included in all calculations, including 28 (31%) with hematological malignancies and 63 (69%) with solid tumors. Forty-two patients (46%) had actionable findings that changed their cancer management: 15 of 28 (54%) with hematological malignancies and 27 of 63 (43%) with solid tumors. Individualized actions were taken in 23 of the 91 (25%) based on actionable integrative clinical sequencing findings, including change in treatment for 14 patients (15%) and genetic counseling for future risk for 9 patients (10%). Nine of 91 (10%) of the personalized clinical interventions resulted in ongoing partial clinical remission of 8 to 16 months or helped sustain complete clinical remission of 6 to 21 months. All 9 patients and families with actionable incidental genetic findings agreed to genetic counseling and screening. CONCLUSIONS AND RELEVANCE: In this single-center case series involving young patients with relapsed or refractory cancer, incorporation of integrative clinical sequencing data into clinical management was feasible, revealed potentially actionable findings in 46% of patients, and was associated with change in treatment and family genetic counseling for a small proportion of patients. The lack of a control group limited assessing whether better clinical outcomes resulted from this approach than outcomes that would have occurred with standard care.
Patients with advanced non-small cell lung cancer (NSCLC) whose tumors harbor anaplastic lymphoma kinase (
gene fusions benefit from treatment with ALK inhibitors (ALKi). Analysis of cell-free ...circulating tumor DNA (cfDNA) may provide a noninvasive way to identify
fusions and actionable resistance mechanisms without an invasive biopsy.
The Guardant360 (G360; Guardant Health) deidentified database of NSCLC cases was queried to identify 88 consecutive patients with 96 plasma-detected
fusions. G360 is a clinical cfDNA next-generation sequencing (NGS) test that detects point mutations, select copy number gains, fusions, insertions, and deletions in plasma.
Identified fusion partners included
(85.4%),
(6%), and
, and
(totaling 8.3%). Forty-two
-positive patients had no history of targeted therapy (cohort 1), with tissue
molecular testing attempted in 21 (5 negative, 5 positive, and 11 tissue insufficient). Follow-up of 3 of the 5 tissue-negative patients showed responses to ALKi. Thirty-one patients were tested at known or presumed ALKi progression (cohort 2); 16 samples (53%) contained 1 to 3
resistance mutations. In 13 patients, clinical status was unknown (cohort 3), and no resistance mutations or bypass pathways were identified. In 6 patients with known
activating mutations, an
fusion was identified on progression (cohort 4; 4
, 1
one both
and
); five harbored
T790M.
In this cohort of cfDNA-detected
fusions, we demonstrate that comprehensive cfDNA NGS provides a noninvasive means of detecting targetable alterations and characterizing resistance mechanisms on progression.
.
To analytically and clinically validate microsatellite instability (MSI) detection using cell-free DNA (cfDNA) sequencing.
Pan-cancer MSI detection using Guardant360 was analytically validated ...according to established guidelines and clinically validated using 1,145 cfDNA samples for which tissue MSI status based on standard-of-care tissue testing was available. The landscape of cfDNA-based MSI across solid tumor types was investigated in a cohort of 28,459 clinical plasma samples. Clinical outcomes for 16 patients with cfDNA MSI-H gastric cancer treated with immunotherapy were evaluated.
cfDNA MSI evaluation was shown to have high specificity, precision, and sensitivity, with a limit of detection of 0.1% tumor content. In evaluable patients, cfDNA testing accurately detected 87% (71/82) of tissue MSI-H and 99.5% of tissue microsatellite stable (863/867) for an overall accuracy of 98.4% (934/949) and a positive predictive value of 95% (71/75). Concordance of cfDNA MSI with tissue PCR and next-generation sequencing was significantly higher than IHC. Prevalence of cfDNA MSI for major cancer types was consistent with those reported for tissue. Finally, robust clinical activity of immunotherapy treatment was seen in patients with advanced gastric cancer positive for MSI by cfDNA, with 63% (10/16) of patients achieving complete or partial remission with sustained clinical benefit.
cfDNA-based MSI detection using Guardant360 is highly concordant with tissue-based testing, enabling highly accurate detection of MSI status concurrent with comprehensive genomic profiling and expanding access to immunotherapy for patients with advanced cancer for whom current testing practices are inadequate.
.
Complete and timely tissue genotyping is challenging, leading to significant numbers of patients with newly diagnosed metastatic non-small cell lung cancer (mNSCLC) being undergenotyped for all eight ...genomic biomarkers recommended by professional guidelines. We aimed to demonstrate noninferiority of comprehensive cell-free DNA (cfDNA) relative to physician discretion standard-of-care (SOC) tissue genotyping to identify guideline-recommended biomarkers in patients with mNSCLC.
Prospectively enrolled patients with previously untreated mNSCLC undergoing physician discretion SOC tissue genotyping submitted a pretreatment blood sample for comprehensive cfDNA analysis (Guardant360).
Among 282 patients, physician discretion SOC tissue genotyping identified a guideline-recommended biomarker in 60 patients versus 77 cfDNA identified patients (21.3% vs. 27.3%;
< 0.0001 for noninferiority). In tissue-positive patients, the biomarker was identified alone (12/60) or concordant with cfDNA (48/60), an 80% cfDNA clinical sensitivity for any guideline-recommended biomarker. For FDA-approved targets (
) concordance was >98.2% with 100% positive predictive value for cfDNA versus tissue (34/34
or
-positive patients). Utilizing cfDNA, in addition to tissue, increased detection by 48%, from 60 to 89 patients, including those with negative, not assessed, or insufficient tissue results. cfDNA median turnaround time was significantly faster than tissue (9 vs. 15 days;
< 0.0001). Guideline-complete genotyping was significantly more likely (268 vs. 51;
< 0.0001).
In the largest cfDNA study in previously untreated mNSCLC, a validated comprehensive cfDNA test identifies guideline-recommended biomarkers at a rate at least as high as SOC tissue genotyping, with high tissue concordance, more rapidly and completely than tissue-based genotyping.
.
Prostate cancer has been described as a component tumor of Lynch syndrome (LS), with tumors obtained from mutation carriers demonstrating the DNA mismatch repair deficiency phenotype. Previous ...studies quantifying prostate cancer risk in LS have provided conflicting results.
We examined cancer histories of probands and their first- through fourth-degree relatives for 198 independent mutation-positive LS families enrolled in two US familial cancer registries. Modified segregation analysis was used to calculate age-specific cumulative risk or penetrance estimates, with accompanying Wald-type CIs. Cumulative lifetime risks and hazard ratio (HR) estimates for prostate cancer were calculated and compared with those of the general population.
Ninety-seven cases of prostate cancer were observed in 4,127 men. Median age at prostate cancer diagnosis was 65 years (range, 38 to 89 years), with 11.53% of affected individuals diagnosed before age 50 years. The cumulative risk of prostate cancer at ages 60 and 80 years was 6.30% (95% CI, 2.47 to 9.96) and 30.0% (95% CI, 16.54 to 41.30), as compared with the population risk of 2.59% and 17.84%, respectively. The overall prostate cancer HR among carriers was 1.99 (95% CI, 1.31 to 3.03).
The cumulative lifetime risk of prostate cancer in individuals with LS is two-fold higher than in the general population and is slightly higher in carriers diagnosed before age 60 years (HR, 2.48; 95% CI, 1.34 to 4.59). These estimates are clinically valuable to quantify risk for both patients and providers.
is an emerging oncogenic target showing promise in phase I/II clinical trials. An understudied aspect of
-driven cancers is the extent to which co-occurring genomic alterations exist and how they may ...impact prognosis or therapeutic response.
Somatic activating
alterations were identified among 32,989 consecutive patients with metastatic solid tumors tested with a clinical cell-free circulating tumor DNA (cfDNA) assay. This comprehensive next-generation sequencing (NGS) assay evaluates single-nucleotide variants, and select indels, fusions, and copy number gains in 68-73 clinically relevant cancer genes.
A total of 176 somatic activating
alterations were detected in 170 patients (143 fusions and 33 missense mutations). Patients had non-small cell lung (NSCLC,
= 125), colorectal (
= 15), breast (
= 8), thyroid (
= 8), or other (
= 14) cancers. Alterations in other oncogenic signaling pathway genes were frequently identified in
-positive samples and varied by specific
fusion gene partner.
fusions involving partners other than
were enriched for alterations in MAPK pathway genes and other bona fide oncogenic drivers of NSCLC, particularly
. Molecular and clinical data revealed that these variants emerged later in the genomic evolution of the tumor as mechanisms of resistance to EGFR tyrosine kinase inhibitors.
In the largest cancer cohort with somatic activating
alterations, we describe novel co-occurrences of oncogenic signaling pathway aberrations. We find that
-
fusions are highly specific for NSCLC. In our study, only non-
-
fusions contributed to anti-
therapy resistance. Knowledge of specific
fusion gene partner may have clinical significance.
Although patients with advanced-stage non-small cell lung cancers (NSCLC) harboring
exon 14 skipping mutations (
ex14) often benefit from MET tyrosine kinase inhibitor (TKI) treatment, clinical ...benefit is limited by primary and acquired drug resistance. The molecular basis for this resistance remains incompletely understood.
Targeted sequencing analysis was performed on cell-free circulating tumor DNA obtained from 289 patients with advanced-stage
ex14-mutated NSCLC.
Prominent co-occurring RAS-MAPK pathway gene alterations (e.g., in
) were detected in NSCLCs with
ex14 skipping alterations as compared with
-mutated NSCLCs. There was an association between decreased MET TKI treatment response and RAS-MAPK pathway co-occurring alterations. In a preclinical model expressing a canonical
ex14 mutation, KRAS overexpression or NF1 downregulation hyperactivated MAPK signaling to promote MET TKI resistance. This resistance was overcome by cotreatment with crizotinib and the MEK inhibitor trametinib.
Our study provides a genomic landscape of co-occurring alterations in advanced-stage
ex14-mutated NSCLC and suggests a potential combination therapy strategy targeting MAPK pathway signaling to enhance clinical outcomes.
Treatment outcomes for patients with advanced pancreatic ductal adenocarcinoma (PDAC) remain dismal. There are unmet needs for understanding the biologic basis of this malignancy using novel ...next-generation sequencing technologies. Herein, we investigated the clinical utility of circulating tumor DNA (ctDNA) (the liquid biopsy) in this malignancy.
ctDNA was analyzed in 112 patients with PDAC (54-73 genes) and tissue DNA in 66 patients (315 genes) (both clinical-grade next-generation sequencing). Number of alterations, %ctDNA, concordance between ctDNA and tissue DNA, and correlation of ctDNA results with survival were assessed.
The most common genes altered in ctDNA were TP53 (46% of patients, N = 51) and KRAS (44%, N = 49). Median number of characterized ctDNA alterations per patient was 1 (range, 0-6), but patients with advanced PDAC had significantly higher numbers of ctDNA alterations than those with surgically resectable disease (median, 2 versus 0.5, P = 0.04). Overall, 75% (70/94) of advanced tumors had ≥ 1 ctDNA alteration. Concordance rate between ctDNA and tissue DNA alterations was 61% for TP53 and 52% for KRAS. Concordance for KRAS alterations between ctDNA and tissue DNA from metastatic sites was significantly higher than between ctDNA and primary tumor DNA (72% vs 39%, P = 0.01). Importantly, higher levels of total %ctDNA were an independent prognostic factor for worse survival (hazard ratio, 4.35; 95% confidence interval, 1.85-10.24 multivariate, P = 0.001). A patient with three ctDNA alterations affecting the MEK pathway (GNAS, KRAS, and NF1) attained a response to trametinib monotherapy ongoing at 6 months.
Our findings showed that ctDNA often harbored unique alterations some of which may be targetable and that significantly greater numbers of ctDNA alterations occur in advanced versus resectable disease. Furthermore, higher ctDNA levels were a poor prognostic factor for survival.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Adrenocortical carcinoma (ACC) is an endocrine malignancy with a poor prognosis. The association of adult-onset ACC with inherited cancer predisposition syndromes is poorly understood. Our study ...sought to define the prevalence of Lynch syndrome (LS) among patients with ACC.
One hundred fourteen patients with ACC were evaluated in a specialized endocrine oncology clinic and were prospectively offered genetic counseling and clinical genetics risk assessment (group 1). In addition, families with known mismatch repair (MMR) gene mutations that were recorded in the University of Michigan Cancer Genetics Registry were retrospectively reviewed for the presence of ACC (group 2). ACC tumors from patients with LS were tested for microsatellite instability and immunohistochemistry (IHC) to evaluate for MMR deficiency.
Ninety-four (82.5%) of 114 patients with ACC underwent genetic counseling (group 1). Three individuals (3.2%) had family histories suggestive of LS. All three families were found to have MMR gene mutations. Retrospective review of an additional 135 MMR gene-positive probands identified two with ACC (group 2). Four ACC tumors were available (group 1, 3; group 2, 1). All four tumors were microsatellite stable; three had IHC staining patterns consistent with germline mutation status.
The prevalence of LS among patients with ACC is 3.2%, which is comparable to the prevalence of LS in colorectal and endometrial cancer. Patients with ACC and a personal or family history of LS tumors should be strongly considered for genetic risk assessment. IHC screening of all ACC tumors may be an effective strategy for identifying patients with LS.
Abstract Research has demonstrated an inconsistent relationship between suicide ideation and personality traits. This is the first study to empirically examine the relationship of the Five Factor ...Model of personality with current, past and no suicide ideation, and with the two interpersonal risk factors of suicide: thwarted belongingness and perceived burdensomeness (Joiner, T., 2005. Why people die by suicide. Cambridge, MA, US: Harvard University Press). Results indicate that high neuroticism was associated with both current ideation and a history of suicide ideation and extraversion was associated with current ideation. Neuroticism was positively related to thwarted belongingness and perceived burdensomeness, while extraversion was negatively related to these interpersonal predictors of suicide. Agreeableness was negatively related to thwarted belongingness but not perceived burdensomeness, indicating differentiated patterns of relationships between this personality domain and the two suicide constructs. Furthermore, these personality domains predicted 23.82% of variance for thwarted belongingness and 15.07% of the variance for perceived burdensomeness, above and beyond demographic variables associated with suicide ideation. This study, which was conducted with a college sample, demonstrates the potential benefit of identifying predispositional risk factors for suicide ideation and interpersonal predictors of suicide. This may have implications for the development of upstream preventative measures against suicide.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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