Clinical Cancer Research最新文献

Purpose: The prognosis of patients with unresectable hepatocellular carcinoma (HCC) and compensated cirrhosis is influenced by cancer progression. Data on the incidence and the prognostic role of clinical hepatic decompensation (CHD) following immune checkpoint inhibitor therapy are lacking. We aimed to assess whether early CHD within 3 months from commencement of systemic therapy affects overall survival (OS) of patients treated with atezolizumab plus bevacizumab or sorafenib.

Patients and methods: Individual patient data from the IMbrave150 trial were analyzed. Cumulative incidence of CHD was assessed by competing risk analysis against HCC radiologic progression. Early CHD and HCC radiologic progression were assessed as predictors of OS by the time-dependent Cox model.

Results: The 3- and 12-month rates of CHD were 7% and 12%, respectively, whereas the 3- and 12-month rates of HCC radiologic progression were 23% and 52%, respectively. Albumin-bilirubin grade 2 [subdistribution HR (sHR) = 1.79, 95% confidence interval (CI), 1.01-3.19; P = 0.049], INR (sHR = 1.97, 95% CI, 1.64-2.37; P < 0.001), and presence of neoplastic macrovascular invasion (sHR = 2.01, 95% CI, 1.14-3.54; P = 0.020) were independently associated with higher risk of CHD. Early CHD (HR = 7.56, 95% CI, 4.47-12.8) and early HCC radiologic progression (HR = 5.92, 95% CI, 4.03-8.69), as first events, were independently associated with higher mortality.

Conclusions: This study provides robust evidence that early CHD is associated with the highest risk of death in patients with unresectable HCC undergoing systemic treatment. Within well-compensated participants, albumin-bilirubin, INR, and macrovascular invasion identify a population at higher risk of decompensation. Inclusion of clinical decompensation events in future prospective clinical trials may improve characterization of OS from systemic therapy of HCC.

Purpose: Effective therapy for recurrent head and neck squamous cell carcinoma (HNSCC) that is refractory to chemotherapy and immunotherapy is a considerable need. Aurora kinase A inhibition leads to apoptosis and immunogenic cell death in preclinical models of human papilloma virus (HPV)-driven cancers.

Patients and methods: Alisertib was administered orally twice daily on days 1-7 and pembrolizumab on day 1 of a 21-day cycle to adults with advanced solid tumors (phase I) or with immunotherapy- and platinum-resistant, HPV-positive HNSCC (phase II).

Results: The recommended phase II alisertib dose was 40 mg, which had only the expected toxicity including cytopenia that led to dose reductions in two phase II patients at cycles 13 and 16. We saw no objective responses, but the combination led to prolonged stable disease (SD) in several patients, including two of 10 phase I patients (8 and 27 months). Eight of the 15 HPV-positive patients had SD, of which four (heavily pretreated) had ≥6 months, with median overall and progression-free survival durations of 16.8 and 1.4 months, respectively. In circulating immune cells and plasma, patients with SD had markedly higher levels of HLA de novo resistance-expressing NK cells than did progressive disease patients who demonstrated a more immunosuppressive and inflammatory profile. Pharmacokinetics did not indicate any significant drug-drug interactions between pembrolizumab and alisertib.

Conclusions: The combination of alisertib and pembrolizumab was well tolerated and led to prolonged SD in some immunotherapy-resistant patients, supporting our hypothesis that Aurora kinase A inhibition can reverse immunotherapy resistance of retinoblastoma protein-deficient HNSCC.

The management of children with syndromes associated with an increased risk of benign and malignant neoplasms is a complex challenge for health care professionals. The 2023 American Association for Cancer Research Childhood Cancer Predisposition Workshop provided updated consensus guidelines on cancer surveillance in these syndromes, aiming to improve early detection and intervention and reduce morbidity associated with such neoplasms. In this article, we review several of the rare conditions discussed in this workshop. Ollier disease and Maffucci syndrome are enchondromatoses (disorders featuring benign bone lesions) with up to 50% risk of malignancy, including chondrosarcoma. These patients require surveillance with baseline whole-body MRI and routine monitoring of potential malignant transformation of bony lesions. Hereditary multiple osteochondromas carry a lower risk of chondrosarcoma (<6%) but still require lifelong surveillance and baseline imaging. Related syndromes of benign bone lesions are also described. Hereditary leiomyomatosis and renal cell carcinoma syndrome, associated with fumarate hydratase pathogenic variants, is discussed in detail. Surveillance for renal cell carcinoma in pediatric age is recommended, as well as prompt intervention when a lesion is detected. Schinzel-Giedion syndrome and Rubinstein-Taybi syndrome are described for their associated malignancies and other complications, as well as expert consensus on the need for childhood cancer surveillance. Clinical recommendations, including imaging modalities and frequency of screenings, are proposed and are tailored to each syndrome's age-specific tumor risk profile. In all syndromes, patients and their families should be educated about the potential malignancy risk and advised to seek medical care for rapid growth of a mass, persistent pain, or other unexplained symptoms.

Hypoxia is a common feature of solid tumors and is associated with a poor response to anticancer therapies. Hypoxia also induces metabolic changes, such as a switch to glycolysis. This glycolytic switch causes acidification of the tumor microenvironment (TME), thereby attenuating the anticancer immune response. A promising therapeutic strategy to reduce hypoxia and thereby sensitize tumors to irradiation and/or antitumor immune responses is pharmacological inhibition of oxidative phosphorylation (OXPHOS). Several OXPHOS inhibitors (OXPHOSi) have been tested in clinical trials. However, moderate responses and/or substantial toxicity has hampered clinical implementation. OXPHOSi tested in clinical trials inhibit the oxidative metabolism in tumor cells as well as healthy cells. Therefore, new strategies are needed to improve the efficacy of OXPHOSi while minimizing side effects. To enhance the therapeutic window, available OXPHOSi have, for instance, been conjugated to triphenylphosphonium (TPP+) to preferentially target the mitochondria of cancer cells, resulting in increased tumor uptake compared to healthy cells, as cancer cells have a higher mitochondrial membrane potential. However, OXPHOS inhibition also induces reactive oxygen species (ROS), and subsequent antioxidant responses, which may influence the efficacy of therapies, such as platinum-based chemotherapy and radiotherapy. Here, we review the limitations of the clinically tested OXPHOSi metformin, atovaquone, tamoxifen, BAY 87-2243 and IACS-010759 and the potential of mito-targeted OXPHOSi and their influence on ROS production. Furthermore, the effect of the mitochondria-targeting moiety TPP+ on mitochondria is discussed as this affects mitochondrial bioenergetics.

Purpose: Preclinical data motivate clinical evaluation of inhibitors of MAPK-interacting kinases 1 and 2 (MNK1/2). We conducted a phase 1b clinical trial to study target engagement and safety of tomivosertib, a MNK1/2 inhibitor, alone and in combination with paclitaxel.

Patients and methods: Eligible patients had metastatic breast cancer resistant to standard-of-care treatments. Biopsies were obtained at baseline and during treatment with tomivosertib, and then tomivosertib was continued with the addition of paclitaxel until disease progression or toxicity. Serum drug levels were measured, and pharmacodynamic endpoints included IHC, proteomics, translatomics, and imaging mass cytometry.

Results: Tomivosertib alone and in combination with paclitaxel was well tolerated. There was no pharmacokinetic interaction between the drugs. We observed a clear reduction in phosphorylation of eIF4E at S209, a major substrate of MNK1/2, and identified tomivosertib-induced perturbations in the proteome, translatome, and cellular populations of biopsied metastatic breast cancer tissue.

Conclusions: We conclude that tomivosertib effectively inhibits MNK1/2 activity in metastatic breast cancer tissue and that it can safely be combined with paclitaxel in future phase II studies. We demonstrate feasibility of using proteomic profiles, translatomic profiles, and spatial distribution of immune cell infiltrates for clinical pharmacodynamic studies.

Purpose: We evaluated whether indoleamine 2,3-dioxygenase (IDO1) inhibitor (IDOi) BMS986205 + PD-1 inhibitor nivolumab enhanced T-cell activity and augmented immune-mediated antitumor responses in untreated, resectable head and neck squamous cell carcinoma (HNSCC). We employed response-adaptive surgical timing to identify responders to immunotherapy and enhance their response.

Patients and methods: Patients with HNSCC were 3:1 randomized to receive nivolumab with or without BMS986205 orally daily (NCT03854032). In the combination arm, BMS986205 was initiated 7 days prior to nivolumab. Patients were stratified by human papillomavirus (HPV) status. Response-adaptive surgical timing involved response assessment by radiographic criteria 4 weeks after treatment with nivolumab in both arms. Nonresponders underwent surgical resection, whereas responders received 4 more weeks of randomized therapy before surgery. Biomarker analysis utilized pathologic treatment response (pTR) and RNA sequencing.

Results: Forty-two patients were enrolled, and the addition of IDOi to nivolumab did not result in greater rate of radiographic response (P = 0.909). Treatment was well tolerated, with only 2 (5%) patients experiencing grade 3 immune-related adverse events. The addition of IDOi augmented rates of pTR in patients with high baseline IDO1 RNA expression (P < 0.05). Response-adaptive surgical timing demonstrated reliability in differentiating pathologic responders versus nonresponders (P = 0.009). A pretreatment NK cell signature, PD-L1 status, and IFN-γ expression in the HPV- cohort correlated with response. The HPV+ cohort found B-cell and cancer-associated fibroblast signatures predictive of response/nonresponse.

Conclusions: Response-adaptive surgical timing enhanced treatment response. IDOi BMS986205 augmented pTR in patients with high IDO1 expression in baseline samples, indicating a need for identifying and targeting resistant nodes to immunotherapy. HPV status-dependent signatures predicting response to immunotherapy in HNSCC warrant further study.

Purpose: Next-generation sequencing assays for circulating tumor DNA analysis are routinely used in the care of patients with advanced non-small cell lung cancer. However, variable assay sensitivities in detection of fusions have been reported. Here we report on the performance of detecting RET rearrangements in plasma across three commercial NGS laboratories.

Methods: Banked plasma from the phase 3 LIBRETTO-431 trial was studied. For each patient (n=60) with a known RET fusion by local tumor tissue genotyping, pretreatment plasma was divided into two 3mL aliquots and tested on 2 of 3: Guardant Health's Guardant360®, Foundation Medicine's FoundationOne®Liquid CDx, and Resolution Bioscience's ctDx-FirstTM. A round-robin comparison was performed across vendors using three pairwise comparisons of 20 patients each. On an exploratory basis, agreement of fusion breakpoint calling between plasma and tissue and determinants of false negatives in plasma were assessed.

Results: Of 40 samples received by each laboratory, 100% (40/40), 92.5% (37/40), and 90% (36/40) were successfully sequenced by Guardant360, FoundationOne Liquid CDx, and ctDx-First, with a RET-fusion or rearrangement detected in 60% (24/40), 67.6% (25/37), and 63.9% (23/36) of cases, respectively. Discordant results included rare and common RET translocations but were usually below allelic frequency of 0.5%. Of samples with a RET fusion detected in plasma and a reported fusion partner by tumor assay, the same fusion partner was identified in tissue and liquid 81-89% of the time.

Conclusion: Our results support the utility of ctDNA assays concurrently with tissue testing for detection of translocations, with opportunities to further optimize performance.

Purpose: Non-invasive prognostic biomarkers to inform clinical decision-making are an urgent unmet need for the management of patients with glioblastoma (GBM). We previously showed that higher circulating cell-free DNA concentration [ccfDNA] is associated with worse survival in GBM. However, the biology underlying this is unknown.

Experimental design: We prospectively enrolled 129 patients with treatment-naïve GBM with blood drawn prior to initial resection (baseline) and at time of first post-radiotherapy MRI. We performed ccfDNA methylation deconvolution to determine cellular sources of ccfDNA. ELISA was performed to detect citrullinated H3 (citH3), a marker of neutrophil extracellular traps (NETs). Multiplex proteomic analysis was used to measure soluble inflammatory proteins.

Results: We found that neutrophils contributed the highest proportion of prognostic ccfDNA. The percentage of ccfDNA derived from neutrophils was correlated with total [ccfDNA], but only in patients receiving pre-operative corticosteroids. At baseline and on-therapy, [citH3] was significantly higher in the plasma of patients with GBM receiving corticosteroids compared to corticosteroid-naïve GBMs or no-cancer controls. Unsupervised hierarchical clustering of ccfDNA methylation patterns yielded two clusters, with one enriched for patients with the NETosis phenotype and who received corticosteroids. Unsupervised clustering of circulating inflammatory proteins yielded similar results.

Conclusions: These data suggest neutrophil-mediated NETosis is the dominant source of prognostic ccfDNA in patients with GBM and may be associated with glucocorticoid exposure. If further studies show that pharmacological inhibition of NETosis can mitigate the deleterious effects of corticosteroids, these plasma markers will have important clinical utility as non-invasive correlative biomarkers.