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.
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To update the 2006 American Society of Clinical Oncology guideline on the use of hematopoietic colony-stimulating factors (CSFs).
The American Society of Clinical Oncology convened an Update ...Committee and conducted a systematic review of randomized clinical trials, meta-analyses, and systematic reviews from October 2005 through September 2014. Guideline recommendations were based on the review of the evidence by the Update Committee.
Changes to previous recommendations include the addition of tbo-filgrastim and filgrastim-sndz, moderation of the recommendation regarding routine use of CSFs in older patients with diffuse aggressive lymphoma, and addition of recommendations against routine dose-dense chemotherapy in lymphoma and in favor of high-dose-intensity chemotherapy in urothelial cancer. The Update Committee did not address recommendations regarding use of CSFs in acute myeloid leukemia or myelodysplastic syndromes in adults.
Prophylactic use of CSFs to reduce the risk of febrile neutropenia is warranted when the risk of febrile neutropenia is approximately 20% or higher and no other equally effective and safe regimen that does not require CSFs is available. Primary prophylaxis is recommended for the prevention of febrile neutropenia in patients who are at high risk on the basis of age, medical history, disease characteristics, and myelotoxicity of the chemotherapy regimen. Dose-dense regimens that require CSFs should only be used within an appropriately designed clinical trial or if supported by convincing efficacy data. Current recommendations for the management of patients exposed to lethal doses of total-body radiotherapy, but not doses high enough to lead to certain death as a result of injury to other organs, include the prompt administration of CSFs.
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.
The risk for development of a second primary lung cancer (SPLC) after treatment of an initial primary lung cancer (IPLC) is around 1% to 2% per patient per year. The present screening and ...surveillance guidelines do not adequately address this particular patient population.
We retrospectively reviewed patients in the Surveillance, Epidemiology, and End Results database from 1992 to 2007 to assess the frequency of occurrence of SPLC with regard to multiple patient demographics and calculated standardized incidence ratios (SIRs).
The SIRs for SPLCs were high for both men and women at any age but highest if the IPLC occurred at a younger age. Women had the highest SIR values irrespective of age and race, with the highest SIR reported for the youngest age group (20–49 years) (SIR = 15.26, 95% confidence interval: 12.81–18.04). The rate of SPLC development was 1.10% per patient per year, with median time intervals between the IPLC and SPLC diagnoses of 59 and 62 months, respectively, for men and women. The cumulative risk for development of SPLC increased over time and did not plateau.
These findings suggest that there is a continued risk for development of SPLC. Surveillance strategies for this population must be addressed.
Abstract Mutations in the epidermal growth factor receptor gene ( EGFR ) are frequently observed in non–small-cell lung cancer (NSCLC), occurring in about 40% to 60% of never-smokers and in about 17% ...of patients with adenocarcinomas. EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, have transformed therapy for patients with EGFR -mutant NSCLC and have proved superior to chemotherapy as first-line treatment for this patient group. Despite these benefits, there are currently 2 key challenges associated with EGFR inhibitor therapy for patients with NSCLC. First, only 85% to 90% of patients with the EGFR mutation derive clinical benefit from EGFR TKIs, with the remainder demonstrating innate resistance to therapy. Second, acquired resistance to EGFR TKIs inevitably occurs in patients who initially respond to therapy, with a median duration of response of about 10 months. Mutant EGFR activates various subcellular signaling cascades, including the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, which demonstrates maintained activity in a variety of TKI-resistant cancers. Given the fundamental role of the PI3K/Akt/mTOR pathway in tumor oncogenesis, proliferation, and survival, PI3K pathway inhibitors have emerged as a possible solution to the problem of EGFR TKI resistance. However resistance to EGFR TKIs is associated with considerable heterogeneity and complexity. Preclinical experiments investigating these phenomena suggest that in some patients, PI3K inhibitors will have to be paired with other targeted agents if they are to be effective. This review discusses the preclinical data supporting PI3K/Akt/mTOR pathway inhibitor combinations in EGFR TKI-resistant NSCLC from the perspective of the various agents currently being investigated in clinical trials.
To update the 2000 American Society of Clinical Oncology guideline on the use of hematopoietic colony-stimulating factors (CSF).
The Update Committee completed a review and analysis of pertinent data ...published from 1999 through September 2005. Guided by the 1996 ASCO clinical outcomes criteria, the Update Committee formulated recommendations based on improvements in survival, quality of life, toxicity reduction and cost-effectiveness.
The 2005 Update Committee agreed unanimously that reduction in febrile neutropenia (FN) is an important clinical outcome that justifies the use of CSFs, regardless of impact on other factors, when the risk of FN is approximately 20% and no other equally effective regimen that does not require CSFs is available. Primary prophylaxis is recommended for the prevention of FN in patients who are at high risk based on age, medical history, disease characteristics, and myelotoxicity of the chemotherapy regimen. CSF use allows a modest to moderate increase in dose-density and/or dose-intensity of chemotherapy regimens. Dose-dense regimens should only be used within an appropriately designed clinical trial or if supported by convincing efficacy data. Prophylactic CSF for patients with diffuse aggressive lymphoma aged 65 years and older treated with curative chemotherapy (CHOP or more aggressive regimens) should be given to reduce the incidence of FN and infections. Current recommendations for the management of patients exposed to lethal doses of total body radiotherapy, but not doses high enough to lead to certain death due to injury to other organs, includes the prompt administration of CSF or pegylated G-CSF.
fusions are oncogenic drivers of various tumors, including non-small cell lung cancers (NSCLC). The safety and antitumor activity of the multikinase RET inhibitor RXDX-105 were explored in a phase ...I/Ib trial. A recommended phase II dose of 275 mg fed daily was identified. The most common treatment-related adverse events were fatigue (25%), diarrhea (24%), hypophosphatemia (18%), maculopapular rash (18%), and nonmaculopapular rash (17%). In the phase Ib cohort of RET inhibitor-naïve patients with
fusion-positive NSCLCs, the objective response rate (ORR) was 19% (95% CI, 8%-38%,
= 6/31). Interestingly, the ORR varied significantly by the gene fusion partner (
< 0.001, Fisher exact test): 0% (95% CI, 0%-17%,
= 0/20) with
(the most common upstream partner for
fusion-positive NSCLC), and 67% (95% CI, 30%-93%,
= 6/9) with non-
partners. The median duration of response in all
fusion-positive NSCLCs was not reached (range, 5 to 18+ months). SIGNIFICANCE: Although
is the most common
fusion in NSCLCs, RET inhibition with RXDX-105 resulted in responses only in non-
-containing cancers. Novel approaches to targeting
-containing tumors are needed, along with a deeper understanding of the biology that underlies the differential responses observed.
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•Novel therapies are needed for the treatment of malignant pleural mesothelioma (MPM).•Agents targeting angiogenesis such as bevacizumab have a role in the treatment of MPM.•Nintedanib had modest ...activity involving prolonged stable disease in a small group of patients.•Immunotherapy is now important in the treatment of MPM but angiogenesis inhibitors in combination with immunotherapy and/or chemotherapy may still have a role.•It is very important to discover biomarkers that can help with patient selection to individualize treatment.•Participation in clinical trials evaluating novel agents remains very important in advancing treatment strategies.
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