Phase II Trial of Cabozantinib Plus Nivolumab in Patients With Non-Clear-Cell Renal Cell Carcinoma and Genomic Correlates
Cabozantinib plus nivolumab showed promising efficacy in most non-clear-cell RCC variants tested in this trial, particularly those with prominent papillary features, whereas treatment effects were limited in chromophobe RCC.
KEY FINDINGS: Cabozantinib plus nivolumab showed promising efficacy in most non–clear-cell RCC variants tested in this trial, particularly those with prominent papillary features, whereas treatment effects were limited in chromophobe RCC. Genomic findings in non–clear-cell RCC variants warrant further study as predictors of response.
BACKGROUND: Objective of this trial is to assess the efficacy and safety of cabozantinib plus nivolumab in a phase II trial in patients with non–clear-cell renal cell carcinoma (RCC).
DETAILS: Patients had advanced non–clear-cell renal carcinoma who underwent 0-1 prior systemic therapies excluding prior immune checkpoint inhibitors. Patients received cabozantinib 40 mg once daily plus nivolumab 240 mg once every 2 weeks or 480 mg once every 4 weeks. Cohort 1 enrolled patients with papillary, unclassified, or translocation-associated RCC; cohort 2 enrolled patients with chromophobe RCC. The primary end point was objective response rate (ORR) by RECIST 1.1; secondary end points included progression-free survival, overall survival, and safety. Next-generation sequencing results were correlated with response. A total of 47 patients were treated with a median follow-up of 13.1 months. Objective response rate for cohort 1 (n= 40) was 47.5% (95% CI, 31.5 to 63.9), with median progression-free survival of 12.5 months (95% CI, 6.3 to 16.4) and median overall survival of 28 months (95% CI, 16.3 to not evaluable). In cohort 2 (n= 7), no responses were observed; one patient had stable disease > 1 year. Grade 3/4 treatment-related adverse events were observed in 32% treated patients. Cabozantinib and nivolumab were discontinued because of toxicity in 13% and 17% of patients, respectively. Common mutations included NF2 and FH in cohort 1 and TP53 and PTEN in cohort 2. Objective responses were seen in 10/12 patients with either NF2 or FH mutations.
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Source: Lee, C., Voss, M. H., Carlo, M. I., et al. (2022). Phase II Trial of Cabozantinib Plus Nivolumab in Patients With Non–Clear-Cell Renal Cell Carcinoma and Genomic Correlates. Journal of Clinical Oncology. 2021; 40(21): 2333-2341. Published: July 20, 2022. DOI: 0.1200/JCO.21.01944.
Lysosomal Function and Intracellular Position Determine the Malignant Phenotype in Malignant Melanoma
Rab7a overexpression is accompanied by reduced migration capacity. Taken together, the study emphasizes that alterations in lysosomal properties facilitate the malignant phenotype and declares the targeting of lysosomal function as a future therapeutic approach.
KEY FINDINGS: In addition, Rab7a overexpression is accompanied by reduced migration capacity. Taken together, the study emphasizes that alterations in lysosomal properties facilitate the malignant phenotype and declares the targeting of lysosomal function as a future therapeutic approach.
BACKGROUND: Lysosomes are central in cell homeostasis and participate in macromolecular degradation, plasma membrane repair, exosome release, cell adhesion/migration, and apoptosis. In cancer, alterations in lysosomal function and spatial distribution may facilitate disease progression.
DETAILS: In this study, authors show enhanced lysosomal activity in malignant melanoma cells compared with that in normal human melanocytes. Most lysosomes show perinuclear location in melanocytes, while they are more dispersed in melanoma, with retained proteolytic activity and low pH also in the peripheral population. Rab7a expression is lower in melanoma cells than in melanocytes, and by increasing Rab7a, lysosomes are relocated to the perinuclear region in melanoma. Exposure to the lysosome-destabilizing drug L-leucyl-L-leucine methyl ester causes higher damage in the perinuclear subset of lysosomes in melanomas, whereas differences in subpopulation susceptibility cannot be found in melanocytes. Interestingly, melanoma cells recruit the endosomal sorting complex required for transport-III core protein CHMP4B, involved in lysosomal membrane repair, rather than initiate lysophagy. However, when the perinuclear lysosomal position is promoted by Rab7a overexpression or kinesore treatment, lysophagy is increased.
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Copyright © The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology. All rights reserved.
Source: Eriksson, I., Vainikka, L., Waster, P., et al. (2023). Lysosomal Function and Intracellular Position Determine the Malignant Phenotype in Malignant Melanoma. Journal of Investigative Dermatology. 2023; 143 (9): 1769-1778. Published: September, 2023. DOI: 10.1016/j.jid.2023.01.036.
The Association of Metformin With Heart Failure in Patients With Diabetes Mellitus Receiving Anthracycline Chemotherapy
The use of metformin was associated with a lower incidence of HF and overall mortality in patients with DM receiving anthracyclines. The findings should be further confirmed by randomized control trials.
KEY FINDINGS: The present study demonstrates that the use of metformin in patients with cancer is associated with a decreased incidence of HF in the year following anthracycline chemotherapy. The findings are consistent with previous experimental studies and provide impetus to develop further randomized controlled trials investigating the benefits of metformin in anthracycline-induced cardiotoxicity.
BACKGROUND: The prevention of heart failure (HF) is an important issue in patients treated with anthracyclines. Metformin, widely used to treat diabetes mellitus (DM), protects from anthracycline-induced cardiotoxicity in vitro and in animal models. The aim of the study was to test the association of metformin with the occurrence of symptomatic HF in patients with DM receiving anthracyclines.
DETAILS: A total of 561 patients with DM received new anthracycline therapy between 2008 and 2021 in a tertiary care center; propensity score matching was used to compare patients with or without metformin treatment. The primary outcome was new onset symptomatic HF occurring within 1 year of the initiation of anthracyclines. A total of 315 patients (65 ± 11 years of age, 33.7% male) were included. Patients with and without metformin were well matched for age, sex, type of cancer, medications, and cardiovascular risk factors. Six patients treated with metformin and 17 matched patients developed HF within 1 year of anthracycline initiation. The incidence of HF in patients treated with metformin was lower than patients without metformin within 1 year after anthracyclines (cumulative incidence: 3.6% vs 10.5%; P = 0.022; HR: 0.35; 95% CI: 0.14-0.90; P = 0.029). The use of metformin (HR: 0.71; 95% CI: 0.50-1.00; P = 0.049), was also associated with lower mortality.
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Source: Onoue, T., Kang, Y., Lefebvre, B., et al. (2023). The Association of Metformin With Heart Failure in Patients With Diabetes Mellitus Receiving Anthracycline Chemotherapy. J Am Coll Cardiol CardioOnc. Published: August 29, 2023. DOI: 10.1016/j.jaccao.2023.05.013.
Pediatric Tumors and Developmental Anomalies
In the first Tumeur Et Developpement analysis, 3 major themes have been identified: (1) germline mutations with or without known cancer predisposition, (2) postzygotic events responsible for genomic mosaicism, (3) coincidental associations. New pathways involved in cancer development need to be investigated to improve our understanding of childhood cancers.
KEY FINDINGS: In the first Tumeur Et Developpement analysis, 3 major themes have been identified: (1) germline mutations with or without known cancer predisposition, (2) postzygotic events responsible for genomic mosaicism, (3) coincidental associations. New pathways involved in cancer development need to be investigated to improve our understanding of childhood cancers.
BACKGROUND: Purpose of the study is to assess the associations between congenital abnormalities and pediatric malignancies and evaluate the potential underlying molecular basis by collecting information on pediatric patients with cancer and congenital abnormalities.
DETAILS: Tumeur Et Developpement is a national, prospective, and retrospective multicenter study recording data of children with cancer and congenital abnormalities. When feasible, blood and tumoral samples are collected for virtual biobanking. From June 2013 to December 2019, 679 associations between pediatric cancers and congenital abnormalities were recorded. The most represented cancers were central nervous system tumors (n = 139; 20%), leukemia and myelodysplastic syndromes (n = 123; 18.1%), and renal tumors (n = 101; 15%). Congenital abnormalities were not related to any known genetic disorder in 66.5% of cases. In this group, the most common anomaly was intellectual disability (22.3%), followed by musculoskeletal (14.2%) and genitourinary anomalies (12.4%). Intellectual disability was mostly associated with hematologic malignancies. Embryonic tumors (neuroblastoma, Wilms tumor, and rhabdomyosarcoma) were associated with consistent abnormalities, sometimes with a close anatomical neighborhood between the abnormality and the neoplasm.
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Source: Semeraro, M., Fouquet, C., Vial, Y.t al. (2023). Pediatric Tumors and Developmental Anomalies: A French Nationwide Cohort Study. The Journal of Pediatrics. 2023; 259: 13451. Published: August, 2023. DOI: 10.1016/j.jpeds.2023.113451.
Primary Retroperitoneal Lymph Node Dissection for Stage II Seminoma: Is Surgery the New Path Forward?
CS II seminoma can be treated with surgery to avoid rigors of chemotherapy or radiotherapy. Patients with delayed development of CS II disease (more than 12 months) had the best surgical results.
KEY FINDINGS: CS II seminoma can be treated with surgery to avoid rigors of chemotherapy or radiotherapy. Patients with delayed development of CS II disease (> 12 months) had the best surgical results. Patients may present with borderline CS II disease, and careful surveillance may avoid overtreatment. Further study on patient selection and extent of dissection remains uncertain and warrants further investigation.
BACKGROUND: On the basis of National Comprehensive Cancer Network guidelines, clinical stage (CS) II seminoma is treated with radiotherapy or chemotherapy. Primary retroperitoneal lymph node dissection (RPLND) demonstrated recent success as first-line therapy for RP-only disease. Our aim was to confirm surgical efficacy and evaluate recurrences after primary RPLND for CS IIA/IIB seminoma to determine if various clinical factors could predict recurrences.
DETAILS: Patients who underwent primary RPLND for seminoma from 2014 to 2021 were identified. All patients had at least 6 months of follow-up. Nineteen patients were part of a clinical trial. Patients receiving adjuvant chemotherapy were excluded from Kaplan-Meier recurrence-free survival (RFS) analysis. Researchers identified 67 patients who underwent RPLND for RP-only seminoma. One patient had pN0 disease. Median follow-up time after RPLND was 22.4 months (interquartile range, 12.3-36.1 months) and 11 patients were found to have a recurrence. The 2-year RFS for RPLND-only patients without adjuvant chemotherapy was 80.2%. Patients who developed RP disease for a period > 12 months had the lowest chance of recurrence, with a 2-year RFS of 92.2%. Seven initial CS II patients were on surveillance for 3-12 months before surgery and no patients experienced recurrence. Pathologic nodal stage and high-risk factors such as tumor size > 4 cm or rete testis invasion of the orchiectomy specimen did not affect recurrence.
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Source: Tachibana, I., Alabd, A., Tong, Y., et al. (2023). Primary Retroperitoneal Lymph Node Dissection for Stage II Seminoma: Is Surgery the New Path Forward?. J Clinical Oncology. 2023; 41(23): 3930-3938. Published: August 10, 2023. DOI: 10.1200/JCO.22.01822.
A Reflex Testing Protocol Using Two Multivariate Index Assays Improves the Risk Assessment for Ovarian Cancer in Patients With an Adnexal Mass
Reflexing samples with intermediate OVA1 scores significantly decreases the false-positive rate, thereby reducing unnecessary surgical referrals.
KEY FINDINGS: Reflexing samples with intermediate OVA1 scores significantly decreases the false-positive rate, thereby reducing unnecessary surgical referrals.
BACKGROUND: Patients with adnexal masses suspicious for malignancy benefit from referral to oncology specialists during presurgical assessment of the mass. OVA1 is a multivariate assay using a five-biomarker panel which offers high overall and early-stage sensitivity. However, OVA1 has a high false-positive rate for benign masses. Overa, a second-generation multivariate index assay was developed to reduce the false-positive rate. The aim of the present study was to use Overa as a reflex for OVA1 and increase specificity.
DETAILS: OVA1 cut-off scores were established to place patients into three categories: low, intermediate, and high cancer risk. Samples with intermediate-risk OVA1 scores were reflexed to the Overa and defined as high or low risk. This protocol was tested with 1035 prospectively collected serum samples and validated with an independent prospectively collected sample set (N = 207). Thirty-five per cent (359) of samples had intermediate OVA1 scores. Reflexing these to Overa eliminated 58% of the false-positives and improved the overall specificity from 50% to 72%. This finding was confirmed in the independent dataset, in which the specificity increased from 56% to 73%.
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Source: Fritsche, H. A. and Bullock, R. G. (2023). A Reflex Testing Protocol Using Two Multivariate Index Assays Improves the Risk Assessment for Ovarian Cancer in Patients With an Adnexal Mass. Intl J Gynecol Obstet.. 2023; 162(2): 485-492. Published: August, 2023. DOI: 10.1002/ijgo.14733.
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