Major milestones in translational oncology.

Translational oncology represents a bridge between basic research and clinical practice in cancer medicine. Today, translational research in oncology benefits from an abundance of knowledge resulting from genome-scale studies regarding the molecular pathways involved in tumorigenesis. In this Forum article, we highlight the state of the art of translational oncology in five major cancer types. We illustrate the use of molecular profiling to subtype colorectal cancer for both diagnosis and treatment, and summarize the results of a nationwide screening program for ovarian cancer based on detection of a tumor biomarker in serum. Additionally, we discuss how circulating tumor DNA can be assayed to safely monitor breast cancer over the course of treatment, and report on how therapy with immune checkpoint inhibitors is proving effective in advanced lung cancer. Finally, we summarize efforts to use molecular profiling of prostate cancer biopsy specimens to support treatment decisions. Despite encouraging early successes, we cannot disregard the complex genetics of individual susceptibility to cancer nor the enormous complexity of the somatic changes observed in tumors, which urge particular attention to the development of personalized therapies

Increased serum tumor necrosis factor α levels in patients with lenalidomide-induced hypothyroidism

As the use of lenalidomide expands, the poorly understood phenomenon of lenalidomide-induced thyroid abnormalities will increase. In this study we compared rates of therapy-induced hypothyroidism in 329 patients with DLBCL treated with conventional chemotherapy (DLBCL-c) or conventional chemotherapy plus lenalidomide (DLBCL-len). We measured serum levels of tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), interleukin-6 (IL-6), interleukin-12 (IL-12), and interleukin-15 (IL-15) before and after treatment. We found a significantly higher rate of therapy-induced hypothyroidism in the DLBCL-len group (25.8% vs 1.3%), and we found a statistically significant increase in serum TNF-α in patients with lenalidomide-induced hypothyroidism

Prognostic Impact of KRAS Mutation Subtypes in 677 Patients with Metastatic Lung Adenocarcinomas

BackgroundWe previously demonstrated that patients with metastatic KRAS mutant lung cancers have a shorter survival compared with patients with KRAS wild-type cancers. Recent reports have suggested different clinical outcomes and distinct activated signaling pathways depending on KRAS mutation subtype. To better understand the impact of KRAS mutation subtype, we analyzed data from 677 patients with KRAS mutant metastatic lung cancer.MethodsWe reviewed all patients with metastatic or recurrent lung cancers found to have KRAS mutations over a 6-year time period. We evaluated the associations among KRAS mutation type, clinical factors, and overall survival in univariate and multivariate analyses. Any significant findings were validated in an external multi-institution patient dataset.ResultsAmong 677 patients with KRAS mutant lung cancers (53 at codon 13, 624 at codon 12), there was no difference in overall survival for patients when comparing KRAS transition versus transversion mutations (p = 0.99), smoking status (p = 0.33), or when comparing specific amino acid substitutions (p = 0.20). In our dataset, patients with KRAS codon 13 mutant tumors (n = 53) had shorter overall survival compared with patients with codon 12 mutant tumors (n = 624) (1.1 versus 1.3 years, respectively; p = 0.009), and the findings were confirmed in a multivariate Cox model controlling for age, sex, and smoking status (hazard ratio: 1.52, 95% confidence interval: 1.11–2.08; p = 0.008). In an independent validation set of tumors from 682 patients with stage IV KRAS mutant lung cancers, there was no difference in survival between patients with KRAS codon 13 versus codon 12 mutations (1.0 versus 1.1 years, respectively; p = 0.41).ConclusionsAmong individuals with KRAS mutant metastatic lung cancers treated with conventional therapy, there are no apparent differences in outcome based on KRAS mutation subtype

Eftilagimod alpha (a soluble LAG-3 protein) combined with pembrolizumab in second-line metastatic NSCLC refractory to anti–programmed cell death protein 1/programmed death-ligand 1-based therapy: final results from a phase 2 study

Introduction: Eftilagimod alpha (efti), a soluble lymphocyte activation gene-3 protein, triggers antigen-presenting cell and T-cell (CD4+ and CD8+) activation and helps overcome resistance to programmed cell death protein 1 or programmed cell death-ligand 1 (PD-(L)1) inhibitors. We assessed efti plus pembrolizumab in second-line anti–PD-(L)1-refractory metastatic patients with NSCLC. Methods: After confirmed progression on anti-PD-(L)1-based first-line therapy, patients received efti (30 mg subcutaneously every 2 weeks for eight 3-week cycles and then every 3 weeks for up to 54 weeks) plus pembrolizumab (200 mg intravenously every 3 weeks for up to 105 weeks). The primary endpoint was the objective response rate by modified Response Evaluation Criteria in Solid Tumors version 1.1 for immune-based therapies. Secondary endpoints included disease control rate, progression-free survival, overall survival (OS), and tolerability. Exploratory endpoints included tumor growth kinetics and predefined subgroup analyses. Programmed cell death-ligand 1 tumor proportion score was assessed centrally. Results: Thirty-six patients were enrolled from April 2019 to August 2021 using Simon’s two-stage design. Most patients (81.8%) had low or negative (<50%) PD-(L)1 tumor proportion score. First-line therapy was anti–PD-(L)1-based for all patients, combined with chemotherapy for 66.7%. The confirmed objective response and disease control rates were 8.3% and 33.3%. The median progression-free survival was 2.1 months and the median OS was 9.9 months. Patients exhibiting high PD-(L)1 expression or acquired resistance to PD-(L)1 inhibitors revealed superior response and survival outcomes, and OS was closely correlated with disease control. No treatment-emergent adverse event led to permanent discontinuation of study treatment. Conclusions: Efti plus pembrolizumab was well-tolerated and revealed signs of antitumor activity in patients with NSCLC resistant to PD-(L)1 inhibitors, warranting further investigation. Trial registration number: NCT03625323

Successful Treatment and Retreatment With Erdafitinib for a Patient With FGFR3-TACC3 Fusion Squamous NSCLC: A Case Report

FGFR3-TACC3 fusions have been identified in patients with multiple cancer types, and tumors with these alterations are potentially sensitive to selective FGFR inhibitors. However, there are no FGFR inhibitors approved by the U.S. Food and Drug Administration for the treatment of patients with NSCLC with FGFR alterations. Here, we report a case of a patient with FGFR3-TACC3 fusion squamous NSCLC who achieved a radiographic response and disease control for 11 months on initial treatment with erdafitinib and subsequently obtained an additional 8 months of disease control after erdafitinib retreatment after 5 months of intervening chemotherapy. Further investigation into FGFR inhibitor treatment specifically and targeted therapy retreatment for patients with NSCLC may increase our therapeutic options for these patients

Current landscape and future of dual anti-CTLA4 and PD-1/PD-L1 blockade immunotherapy in cancer; lessons learned from clinical trials with melanoma and non-small cell lung cancer (NSCLC)

Abstract Immunotherapy is among the most rapidly evolving treatment strategies in oncology. The therapeutic potential of immune-checkpoint inhibitors is exemplified by the recent hail of Food and Drug Administration (FDA) approvals for their use in various malignancies. Continued efforts to enhance outcomes with immunotherapy agents have led to the formulation of advanced treatment strategies. Recent evidence from pre-clinical studies evaluating immune-checkpoint inhibitors in various cancer cell-lines has suggested that combinatorial approaches may have superior survival outcomes compared to single-agent immunotherapy regimens. Preliminary trials assessing combination therapy with anti-PD-1/PD-L1 plus anti-CTLA-4 immune-checkpoint inhibitors have documented considerable advantages in survival indices over single-agent immunotherapy. The therapeutic potential of combinatorial approaches is highlighted by the recent FDA approval of nivolumab plus ipilimumab for patients with advanced melanoma. Presently, dual-immune checkpoint inhibition with anti-programmed death receptor-1/programmed cell death receptor- ligand-1 (anti-PD-1/PD-L1) plus anti-cytotoxic T lymphocyte associated antigen-4 (anti-CTLA-4) monoclonal antibodies (MoAbs) is being evaluated for a wide range of tumor histologies. Furthermore, several ongoing clinical trials are investigating combination checkpoint inhibition in association with traditional treatment modalities such as chemotherapy, surgery, and radiation. In this review, we summarize the current landscape of combination therapy with anti-PD-1/PD-L1 plus anti-CTLA-4 MoAbs for patients with melanoma and non-small cell lung cancer (NSCLC). We present a synopsis of the prospects for expanding the indications of dual immune-checkpoint inhibition therapy to a more diverse set of tumor histologies

First-line Chemotherapy Responsiveness and Patterns of Metastatic Spread Identify Clinical Syndromes Present Within Advanced KRAS Mutant Non-Small-cell Lung Cancer With Different Prognostic Significance.

BackgroundUnsuccessful KRAS-specific treatment approaches in non-small-cell lung cancer (NSCLC) might reflect underlying disease heterogeneity. We sought to define clinical "syndromes" within advanced KRAS mutant NSCLC to improve future clinical trials and create a clinical framework for future molecular development.Patients and methodsTo test a series of a priori hypotheses regarding KRAS-mutant NSCLC clinical syndromes, we conducted a multi-institutional retrospective medical record review. Survival probabilities were estimated using the Kaplan-Meier model. Between-group differences were assessed using the log-rank test. Multivariate Cox regression analyses and Wilcoxon rank sum testing were used to assess progression-free survival and overall survival (OS) differences.ResultsAmong 218 patients with advanced KRAS-mutant NSCLC, OS and progression-free survival with first-line chemotherapy did not differ by intrathoracic versus extrathoracic spread, smoking intensity, or the specific KRAS mutation. Metastatic disease at diagnosis resulted in significantly worse OS than recurrent, unresectable disease (median OS, 14.6 vs. 40.9 months; P = .001). Among the patients with metastatic disease at diagnosis, nonscalp, soft tissue metastases (syndrome X; 6% of cases; 95% confidence interval [CI], 2.5%-10.1%) signified a poor prognosis (median OS, 7.5 vs. 15.9 months for the controls; P = .021). The response to first-line chemotherapy (syndrome Y; 41% of cases; 95% CI, 32.3%-50.6%) signified a good prognosis (median OS, 26.7 vs. 11.9 months; P = .002). The overlap between these 2 syndromes was minimal (2 of 111). Multivariate analysis confirmed these observations. The hazard ratio for death for syndromes X and Y was 2.64 (95% CI, 1.13-6.14) and 0.45 (95% CI, 0.28-0.76), respectively.ConclusionChemotherapy-responsive disease and nonscalp, soft tissue spread might represent distinct clinical syndromes within KRAS-mutant NSCLC. The molecular biology underlying this heterogeneity warrants future studies