Most patients with follicular lymphoma (FL) experience multiple relapses necessitating subsequent lines of therapy. Ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor approved for the treatment of ...several B-cell malignancies, showed promising activity in FL in a phase 1 study. We report the results of a phase 2 trial evaluating ibrutinib in recurrent FL. Forty patients with recurrent FL were treated with ibrutinib 560 mg/d until progression or intolerance. The primary end point was overall response rate (ORR). Exploratory analyses included correlations of outcome with recurrent mutations identified in a cancer gene panel that used next-generation sequencing in pretreatment biopsies from 31 patients and results of early interim positron emission tomography/computed tomography scans in 20 patients. ORR was 37.5% with a complete response rate of 12.5%, median progression-free survival (PFS) of 14 months, and 2-year PFS of 20.4%. Response rates were significantly higher among patients whose disease was sensitive to rituximab (52.6%) compared with those who were rituximab refractory (16.7%) (P = .04). CARD11 mutations were present in 16% of patients (5 of 31) and predicted resistance to ibrutinib with only wild-type patients responding (P = .002). Maximum standardized uptake value at cycle 1 day 8 correlated with response and PFS. Ibrutinib was well-tolerated with a toxicity profile similar to labeled indications. Ibrutinib is a well-tolerated treatment with modest activity in relapsed FL. Evaluation of BTK inhibitors in earlier lines of therapy may be warranted on the basis of improved response rates in rituximab-sensitive disease. Somatic mutations such as CARD11 may have an impact on response to ibrutinib, may inform clinical decisions, and should be evaluated in larger data sets. This trial was registered at www.clinicaltrials.gov as #NCT01849263.
•Ibrutinib has modest activity in FL with low response rates in rituximab-refractory patients.•CARD11 mutations predict for lack of response to ibrutinib.
Follicular lymphoma (FL) is the most common form of indolent non-Hodgkin lymphoma, yet it remains only partially characterized at the genomic level. To improve our understanding of the genetic ...underpinnings of this incurable and clinically heterogeneous disease, whole-exome sequencing was performed on tumor/normal pairs from a discovery cohort of 24 patients with FL. Using these data and mutations identified in other B-cell malignancies, 1716 genes were sequenced in 113 FL tumor samples from 105 primarily treatment-naive individuals. We identified 39 genes that were mutated significantly above background mutation rates. CREBBP mutations were associated with inferior PFS. In contrast, mutations in previously unreported HVCN1, a voltage-gated proton channel-encoding gene and B-cell receptor signaling modulator, were associated with improved PFS. In total, 47 (44.8%) patients harbor mutations in the interconnected B-cell receptor (BCR) and CXCR4 signaling pathways. Histone gene mutations were more frequent than previously reported (identified in 43.8% of patients) and often co-occurred (17.1% of patients). A novel, recurrent hotspot was identified at a posttranslationally modified residue in the histone H2B family. This study expands the number of mutated genes described in several known signaling pathways and complexes involved in lymphoma pathogenesis (BCR, Notch, SWitch/sucrose nonfermentable (SWI/SNF), vacuolar ATPases) and identified novel recurrent mutations (EGR1/2, POU2AF1, BTK, ZNF608, HVCN1) that require further investigation in the context of FL biology, prognosis, and treatment.
•FLs harbor more recurrent mutations in the BCR signaling pathway, SWI/SNF complex, and histone genes than previously known.•Novel recurrent mutations affecting BTK, SYK, and HVCN1 may have therapeutic and prognostic implications for FL.
Here we report targeted sequencing of 83 genes using DNA from primary breast cancer samples from 625 postmenopausal (UBC-TAM series) and 328 premenopausal (MA12 trial) hormone receptor-positive (HR+) ...patients to determine interactions between somatic mutation and prognosis. Independent validation of prognostic interactions was achieved using data from the METABRIC study. Previously established associations between MAP3K1 and PIK3CA mutations with luminal A status/favorable prognosis and TP53 mutations with Luminal B/non-luminal tumors/poor prognosis were observed, validating the methodological approach. In UBC-TAM, NF1 frame-shift nonsense (FS/NS) mutations were also a poor outcome driver that was validated in METABRIC. For MA12, poor outcome associated with PIK3R1 mutation was also reproducible. DDR1 mutations were strongly associated with poor prognosis in UBC-TAM despite stringent false discovery correction (q = 0.0003). In conclusion, uncommon recurrent somatic mutations should be further explored to create a more complete explanation of the highly variable outcomes that typifies ER+ breast cancer.
Myelodysplastic syndromes (MDS) are hematopoietic stem cell disorders that often progress to chemotherapy-resistant secondary acute myeloid leukemia (sAML). We used whole-genome sequencing to perform ...an unbiased comprehensive screen to discover the somatic mutations in a sample from an individual with sAML and genotyped the loci containing these mutations in the matched MDS sample. Here we show that a missense mutation affecting the serine at codon 34 (Ser34) in U2AF1 was recurrently present in 13 out of 150 (8.7%) subjects with de novo MDS, and we found suggestive evidence of an increased risk of progression to sAML associated with this mutation. U2AF1 is a U2 auxiliary factor protein that recognizes the AG splice acceptor dinucleotide at the 3' end of introns, and the alterations in U2AF1 are located in highly conserved zinc fingers of this protein. Mutant U2AF1 promotes enhanced splicing and exon skipping in reporter assays in vitro. This previously unidentified, recurrent mutation in U2AF1 implicates altered pre-mRNA splicing as a potential mechanism for MDS pathogenesis.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Hyperactivation of AKT is common and associated with endocrine resistance in estrogen receptor-positive (ER
) breast cancer. The allosteric pan-AKT inhibitor MK-2206 induced apoptosis in
-mutant ER
...breast cancer under estrogen-deprived condition in preclinical studies. This neoadjuvant phase II trial was therefore conducted to test the hypothesis that adding MK-2206 to anastrozole induces pathologic complete response (pCR) in
mutant ER
breast cancer.
Potential eligible patients with clinical stage II/III ER
/HER2
breast cancer were preregistered and received anastrozole (goserelin if premenopausal) for 28 days in cycle 0 pending tumor
sequencing. Patients positive for
mutation in the tumor were eligible to start MK-2206 (150 mg orally weekly, with prophylactic prednisone) on cycle 1 day 2 (C1D2) and to receive a maximum of four 28-day cycles of combination therapy before surgery. Serial biopsies were collected at preregistration, C1D1 and C1D17.
Fifty-one patients preregistered and 16 of 22 with
-mutant tumors received study drug. Three patients went off study due to C1D17 Ki67 >10% (
= 2) and toxicity (
= 1). Thirteen patients completed neoadjuvant therapy followed by surgery. No pCRs were observed. Rash was common. MK-2206 did not further suppress cell proliferation and did not induce apoptosis on C1D17 biopsies. Although AKT phosphorylation was reduced, PRAS40 phosphorylation at C1D17 after MK-2206 persisted. One patient acquired an
mutation at surgery.
MK-2206 is unlikely to add to the efficacy of anastrozole alone in
-mutant ER
breast cancer and should not be studied further in the target patient population.
.
Myelodysplastic syndromes (MDS) are the most common adult myeloid blood cancers in the US. Patients have increased apoptosis in their bone marrow cells leading to low peripheral blood counts. The ...full complement of gene mutations that contribute to increased apoptosis in MDS remains unknown. Up to 25% of MDS patients harbor and acquired interstitial deletion on the long arm of chromosome 5 del(5q), creating haploinsufficiency for a large set of genes including HSPA9. Knockdown of HSPA9 in primary human CD34+ hematopoietic progenitor cells significantly inhibits growth and increases apoptosis. We show here that HSPA9 knockdown is associated with increased TP53 expression and activity, resulting in increased expression of target genes BAX and p21. HSPA9 protein interacts with TP53 in CD34+ cells and knockdown of HSPA9 increases nuclear TP53 levels, providing a possible mechanism for regulation of TP53 by HSPA9 haploinsufficiency in hematopoietic cells. Concurrent knockdown of TP53 and HSPA9 rescued the increased apoptosis observed in CD34+ cells following knockdown of HSPA9. Reduction of HSPA9 below 50% results in severe inhibition of cell growth, suggesting that del(5q) cells may be preferentially sensitive to further reductions of HSPA9 below 50%, thus providing a genetic vulnerability to del(5q) cells. Treatment of bone marrow cells with MKT-077, an HSPA9 inhibitor, induced apoptosis in a higher percentage of cells from MDS patients with del(5q) compared to non-del(5q) MDS patients and normal donor cells. Collectively, these findings indicate that reduced levels of HSPA9 may contribute to TP53 activation and increased apoptosis observed in del(5q)-associated MDS.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Precision oncology involves analysis of individual cancer samples to understand the genes and pathways involved in the development and progression of a cancer. To improve patient care, knowledge of ...diagnostic, prognostic, predisposing, and drug response markers is essential. Several knowledgebases have been created by different groups to collate evidence for these associations. These include the open-access Clinical Interpretation of Variants in Cancer (CIViC) knowledgebase. These databases rely on time-consuming manual curation from skilled experts who read and interpret the relevant biomedical literature.
To aid in this curation and provide the greatest coverage for these databases, particularly CIViC, we propose the use of text mining approaches to extract these clinically relevant biomarkers from all available published literature. To this end, a group of cancer genomics experts annotated sentences that discussed biomarkers with their clinical associations and achieved good inter-annotator agreement. We then used a supervised learning approach to construct the CIViCmine knowledgebase.
We extracted 121,589 relevant sentences from PubMed abstracts and PubMed Central Open Access full-text papers. CIViCmine contains over 87,412 biomarkers associated with 8035 genes, 337 drugs, and 572 cancer types, representing 25,818 abstracts and 39,795 full-text publications.
Through integration with CIVIC, we provide a prioritized list of curatable clinically relevant cancer biomarkers as well as a resource that is valuable to other knowledgebases and precision cancer analysts in general. All data is publically available and distributed with a Creative Commons Zero license. The CIViCmine knowledgebase is available at http://bionlp.bcgsc.ca/civicmine/.
BackgroundSince the available predictive biomarkers of response to immune checkpoint inhibitors (ICIs) have limited predictive power, additional biomarkers are needed. Neurotrophic tropomycin ...receptor kinase (NTRK) fusions are rare. Therefore, their association with response to ICIs is not well understood. NTRK variants of unknown significance (VUS’s) are common, but their clinical relevance is unknown. Here, we explored the association between NTRK VUS’s and the response to ICIs in solid tumors.MethodsThe cBioCancer Genomics Portal was used to obtain genomics data. The association between NTRK VUS’s and median overall survival (mOS) was explored in ICI-treated cohort comprising a total of 166 patients. The cohort includes patients with cancers of the skin (melanoma), colon, rectum, lung, unknown primary, bladder, head and neck, stomach, esophagus, brain, breast and kidney who had received at least one dose of ICIs. The log rank test was used to compare Kaplan-Meier survival curves.ResultsAmong the 1661 patients included in this cohort, 144 patients (8.7%) NTRK VUS’s. NTRK1, NTRK2 and NTRK3 VUS’s were reported in 39 (2.3%), 24 (1.4%) and 52 (3.1%) patients, respectively. Co-occurrence of more than 1 NTRK VUS’s was reported in 29 (1.7%) patients. Only 2 patients had NTRK fusions (LMNA-NTRK1 and ZNF710-NTRK3). All other patients had NTRK VUS’s including missense, nonsense, nonstop, splice site and frameshift deletion alterations. The mOS in patients with NTRK VUS’s was better than patients without NTRK VUS’s (34 m vs. 17 m, p<0.0001). Compared to patients without NTRK VUS’s, mOS was better in patients with NTRK3 VUS’s (not reached (NR) vs. 17 m, p<0.0001) and a trend for better mOS was seen in patients with NTRK1 and NTRK2 VUS’s (23 m vs. 17 m, p=0.754) and (23 m vs. 17 m, p=0.904), respectively. Controlling for age, a multivariable Cox regression model showed that besides NTRK3 VUS’s (HR: 0.65, p=0.0078), tumor type (melanoma vs. non-melanoma) (HR: 0.5, p<0.0001) and absence of liver metastasis (HR: 0.57, p<0.0001) were other factors associated with better mOS.ConclusionsNTRK VUS’s were associated with better mOS in patients with solid tumors treated with ICIs. The statistical significance was limited to NTRK3 alterations but a trend for better mOS was evident in NTRK1 and NTRK2. Propsective validation and efforts to understand the underlying mechansims are warranted.Ethics ApprovalThis study was performed utilizing retrospective, de-identified clinical data. Therefore, this study is considered institutional review board (IRB) exempt.ConsentThis study was performed utilizing retrospective, de-identified clinical data. Therefore, no patient consent was necessary from the subject.
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