MPM is an aggressive disease with an immunosuppressive tumor microenvironment, and interest in exploring immunotherapy in this disease has been increasing. In the first line of treatment, the ...combination of nivolumab and ipilimumab demonstrated an improvement in survival over chemotherapy. The presence of TILs has been recognized as a marker of antitumor immune response to chemotherapy in solid tumors. The aim of our study is to identify the effect of treatment on immune cells and the immune gene profile in MPM. We investigated the changes in expression of TILs in 10 human MPM paired tumor tissues using immunohistochemistry and gene expression analysis from paired untreated and treated samples. In this small series, we demonstrated that during the evolution of disease without any treatment there was an increase in the inflammatory component in tumor samples. After systemic treatment there was a decrease in the number of TILs. We observed that after systemic treatment or disease progression immune gene signatures were suppressed. Our integrated analysis of paired samples with immune profile and genomic changes on MPM suggested that during the evolution of the disease the immune system tends to switch, turning off with treatment.
The search for understanding immunotherapy response has sparked interest in diverse areas of oncology, with artificial intelligence (AI) and radiomics emerging as promising tools, capable of ...gathering large amounts of information to identify suitable patients for treatment. The application of AI in radiology has grown, driven by the hypothesis that radiology images capture tumor phenotypes and thus could provide valuable insights into immunotherapy response likelihood. However, despite the rapid growth of studies, no algorithms in the field have reached clinical implementation, mainly due to the lack of standardized methods, hampering study comparisons and reproducibility across different datasets. In this review, we performed a comprehensive assessment of published data to identify sources of variability in radiomics study design that hinder the comparison of the different model performance and, therefore, clinical implementation. Subsequently, we conducted a use-case meta-analysis using homogenous studies to assess the overall performance of radiomics in estimating programmed death-ligand 1 (PD-L1) expression. Our findings indicate that, despite numerous attempts to predict immunotherapy response, only a limited number of studies share comparable methodologies and report sufficient data about cohorts and methods to be suitable for meta-analysis. Nevertheless, although only a few studies meet these criteria, their promising results underscore the importance of ongoing standardization and benchmarking efforts. This review highlights the importance of uniformity in study design and reporting. Such standardization is crucial to enable meaningful comparisons and demonstrate the validity of biomarkers across diverse populations, facilitating their implementation into the immunotherapy patient selection process.
The COVID-19 pandemic remains a public health emergency of global concern. Determinants of mortality in the general population are now clear, but specific data on patients with cancer remain limited, ...particularly in Latin America.
A longitudinal multicenter cohort study of patients with cancer and confirmed COVID-19 from Oncoclínicas community oncology practice in Brazil was conducted. The primary end point was all-cause mortality after isolation of the SARS-CoV-2 by Real-Time Polymerase Chain Reaction (RT-PCR) in patients initially diagnosed in an outpatient environment. We performed univariate and multivariable logistic regression analysis and recursive partitioning modeling to define the baseline clinical determinants of death in the overall population.
From March 29 to July 4, 2020, 198 patients with COVID-19 were prospectively registered in the database, of which 167 (84%) had solid tumors and 31 (16%) had hematologic malignancies. Most patients were on active systemic therapy or radiotherapy (77%), largely for advanced or metastatic disease (64%). The overall mortality rate was 16.7% (95% CI, 11.9 to 22.7). In univariate models, factors associated with death after COVID-19 diagnosis were age ≥ 60 years, current or former smoking, coexisting comorbidities, respiratory tract cancer, and management in a noncurative setting (
< .05). In multivariable logistic regression and recursive partitioning modeling, only age, smoking history, and noncurative disease setting remained significant determinants of mortality, ranging from 1% in cancer survivors under surveillance or (neo)adjuvant therapy to 60% in elderly smokers with advanced or metastatic disease.
Mortality after COVID-19 in patients with cancer is influenced by prognostic factors that also affect outcomes of the general population. Fragile patients and smokers are entitled to active preventive measures to reduce the risk of SARS-CoV-2 infection and close monitoring in the case of exposure or COVID-19-related symptoms.
INTRODUCTION: Immunotherapy led to increased survival in advanced non-small cell lung cancer; however, it has also increased treatment costs. In this study, real-world data was used to evaluate the ...average cost of treatment of patients with lung cancer. MATERIAL AND METHODS: This is a retrospective study that extracted patient-level data from a Brazilian Oncology Group database. The inclusion criteria were patients with non-small cell lung cancer from stage I-IV, and that received at least one line of treatment from 2018 to 2019. The primary endpoint was the average cost of treatment according to the disease stage, and secondary endpoints were the average cost of each line of treatment among patients with advanced disease, and the percentage of this amount that was related to immunotherapy acquisition. The study also assessed overall survival and the cost-effectiveness of immunotherapy at first-line versus immunotherapy at second-line or beyond, that was presented as the incremental cost effectiveness ratio per quality-adjusted life years. RESULTS: Fifty patients were included, being four (8%) at early-stage (I and II), 10 (20%) at locally advanced disease (III) and 36 (72%) at advanced-stage (IV). The average costs of treatment for each disease stage were respectively US$30,040, US$52,162, and US$95,607 =0.071). Among patients with advanced disease that received IO, the average cost of the entire treatment was highest with immunotherapy at first line (US$116,623) compared with immunotherapy at second-line (US$112,967) or third-line (US$37,279). Immunotherapy at first-line resulted in an estimated additional 0.26 quality-adjusted life years compared to immunotherapy at second-line (US$19,240). CONCLUSION: The cost of treating non-small cell lung cancer is higher as more advanced is the neoplasm stage at diagnosis. Regarding immunotherapy, the cost of treatment is higher as earlier the treatment is performed, even tough, the cost-effectiveness ratio for first-line treatment seems to be favorable compared to second-line treatment.
Sequencing of tumors is now routine and guides personalized cancer therapy. Mutant allele fractions (MAFs, or the ‘mutation dose’) of a driver gene may reveal the genomic structure of tumors and ...influence response to targeted therapies. We performed a comprehensive analysis of MAFs of driver alterations in unpaired primary and metastatic colorectal cancer (CRC) at our institution from 2010 to 2015 and studied their potential clinical relevance. Of 763 CRC samples, 622 had detailed annotation on overall survival in the metastatic setting (OSmet) and 89 received targeted agents matched to KRAS (MEK inhibitors), BRAF (BRAF inhibitors), or PIK3CA mutations (PI3K pathway inhibitors). MAFs of each variant were normalized for tumor purity in the sample (adjMAFs). We found lower adjMAFs for BRAFV600E and PIK3CA than for KRAS, NRAS, and BRAF non‐V600 variants. TP53 and BRAFV600E adjMAFs were higher in metastases as compared to primary tumors, and high KRAS adjMAFs were found in CRC metastases of patients with KRAS wild‐type primary tumors previously exposed to EGFR antibodies. Patients with RAS‐ or BRAFV600E‐mutated tumors, irrespective of adjMAFs, had worse OSmet. There was no significant association between adjMAFs and time to progression on targeted therapies matched to KRAS, BRAF, or PIK3CA mutations, potentially related to the limited antitumor activity of the employed drugs (overall response rate of 4.5%). In conclusion, the lower BRAFV600E and PIK3CA adjMAFs in subsets of primary CRC tumors indicate subclonality of these driver genes. Differences in adjMAFs between metastases and primary tumors suggest that approved therapies may result in selection of BRAFV600E‐ and KRAS‐resistant clones and an increase in genomic heterogeneity with acquired TP53 alterations. Despite significant differences in prognosis according to mutations in driver oncogenes, adjMAFs levels did not impact on survival and did not help predict benefit with matched targeted agents in the metastatic setting.
A comprehensive analysis of mutant allele fractions of driver oncogene mutations in colorectal cancer suggests that (i) some events, including BRAFV600E, may be subclonal; (ii) standard chemotherapies and EGFR antibodies may change the genomic structure of metastatic lesions, with acquired gene alterations and selection of resistant clones; and (iii) the clonality of events does not affect patient outcome or response to matched targeted agents.
PURPOSE
Mutations of the KIT gene are the molecular hallmark of most GI stromal tumors (GISTs). Imatinib has revolutionized GIST treatment. Adjuvant imatinib for 3 years is the standard of care for ...high-risk resected GIST. However, the GIST molecular biologic profile has found different responses to this approach. Despite this, genetic testing at diagnosis is not a routine and empirical adjuvant imatinib remains the rule. Barriers to genetic profiling include concerns about the cost and utility of testing. This analysis aims to determine whether targeted genetic testing reduces costs as an ancillary tool for a limited-resource scenario instead of adjuvant empirical imatinib in patients with resected high-risk GIST.
METHODS
The cost evaluation analysis of molecular testing for GIST was based on the Cost of Preventing an Event (COPE), considering the Number Needed to Treat and the costs of each test compared with the cost of 3-year empirical adjuvant imatinib and real treatment costs (median number of cycles) from the public and private Brazilian Healthcare System's perspective. The analysis compared the costs of the molecular tests (broad next-generation sequencing NGS, GS Infinity DNA/RNA assay, and targeted NGS: GS Focus GIST and the Fleury GIST Tumor DNA sequencing panel), costs of drug acquisition, considering discounts (imatinib mesylate and Glivec), and the costs of supportive care.
RESULTS
In both scenarios, public and private, regardless of the use of imatinib or Glivec, tailoring adjuvant treatment reduced costs, irrespective of the number of cycles. The only exception was the combination of the broad NGS test and imatinib in the Public Healthcare System.
CONCLUSION
The molecularly tailored adjuvant imatinib reduced costs considering the COPE of available NGS tests for both the public and private Brazilian health care systems.
In the Brazilian context, molecularly tailored adjuvant imatinib reduces costs over empirical treatment for GISTs.
The biology of breast cancer response to neoadjuvant therapy is underrepresented in the literature and provides a window-of-opportunity to explore the genomic and microenvironment modulation of ...tumours exposed to therapy. Here, we characterised the mutational, gene expression, pathway enrichment and tumour-infiltrating lymphocytes (TILs) dynamics across different timepoints of 35 HER2-negative primary breast cancer patients receiving neoadjuvant eribulin therapy (SOLTI-1007 NEOERIBULIN-NCT01669252). Whole-exome data (N = 88 samples) generated mutational profiles and candidate neoantigens and were analysed along with RNA-Nanostring 545-gene expression (N = 96 samples) and stromal TILs (N = 105 samples). Tumour mutation burden varied across patients at baseline but not across the sampling timepoints for each patient. Mutational signatures were not always conserved across tumours. There was a trend towards higher odds of response and less hazard to relapse when the percentage of subclonal mutations was low, suggesting that more homogenous tumours might have better responses to neoadjuvant therapy. Few driver mutations (5.1%) generated putative neoantigens. Mutation and neoantigen load were positively correlated (R
= 0.94, p = <0.001); neoantigen load was weakly correlated with stromal TILs (R
= 0.16, p = 0.02). An enrichment in pathways linked to immune infiltration and reduced programmed cell death expression were seen after 12 weeks of eribulin in good responders. VEGF was downregulated over time in the good responder group and FABP5, an inductor of epithelial mesenchymal transition (EMT), was upregulated in cases that recurred (p < 0.05). Mutational heterogeneity, subclonal architecture and the improvement of immune microenvironment along with remodelling of hypoxia and EMT may influence the response to neoadjuvant treatment.
High prevalence of placental-derived complications, such as preeclampsia and intrauterine growth restriction, has been reported in women with breast cancer (BC) treated with chemotherapy during ...pregnancy (PBC-CHT).
To ascertain whether PBC-CHT is associated with an imbalance of angiogenic factors, surrogate markers for placental insufficiency, that could explain perinatal outcomes.
Prospective study between 2012 and 2016 in a single institution. Soluble fms-like tyrosine kinase (sFlt-1), placental growth factor (PlGF), and soluble endoglin (sEng) in maternal blood were assessed throughout pregnancy in 12 women with BC and 215 controls.
Cancer patients were treated with doxorubicin-based regimes and with taxanes. Ten PBC-CHT (83%) developed obstetrical complications. At the end of the third trimester, significantly higher levels of sFlt-1; sFlt-1/PGF ratio, and sEng levels were observed in BC women as compared to controls. Moreover; there was a significant correlation between plasma levels of sFlt-1 and the number of chemotherapy cycles administered. Besides, more chemotherapy cycles correlated with lower birthweight and head circumference at birth.
Women with BC treated during pregnancy showed an antiangiogenic state compatible with placental insufficiency. Angiogenic factors could be useful in the clinical obstetric management of these patients; although further studies will be required to guide clinical decision-making.
Monoclonal antibodies have become an important new class of therapeutic agents approved for use in solid tumors. They function through several different mechanisms including inhibition of ...tumor-related signal transduction, induction of apoptosis, inhibition of angiogenesis, enhancing host immune response against cancer and targeted delivery of cytotoxic agents to the tumor site. Several monoclonal antibodies have now received regulatory approval--trastuzumab, cetuximab, panitumumab, bevacizumab, catumaxomab, ipilimumab and denosumab--across multiple solid tumor types, including breast, colorectal, head and neck, non-small cell lung cancers and melanomas, amongst others. These agents are employed clinically in some neoadjuvant/adjuvant and radical treatment settings, as well as more extensively in the metastatic and palliative settings. Current research is focused on innovative compound design, novel targets, predictive biomarker discovery, enriched patient populations, and combination strategies in order to overcome resistance and prolong disease control. Here we provide an overview of monoclonal antibodies approved for use in clinical oncology and those currently in clinical development.
Bulk transcriptional profiles of early colorectal cancer (CRC) can fail to detect biological processes associated with disease-free survival (DFS) if the transcriptional patterns are subtle and/or ...obscured by other processes' patterns. Consensus-independent component analysis (c-ICA) can dissect such transcriptomes into statistically independent transcriptional components (TCs), capturing both pronounced and subtle biological processes.
In this study we (1) integrated transcriptomes (n = 4228) from multiple early CRC studies, (2) performed c-ICA to define the TC landscape within this integrated data set, 3) determined the biological processes captured by these TCs, (4) performed Cox regression to identify DFS-associated TCs, (5) performed random survival forest (RSF) analyses with activity of DFS-associated TCs as classifiers to identify subgroups of patients, and 6) performed a sensitivity analysis to determine the robustness of our results RESULTS: We identify 191 TCs, 43 of which are associated with DFS, revealing transcriptional diversity among DFS-associated biological processes. A prominent example is the epithelial-mesenchymal transition (EMT), for which we identify an association with nine independent DFS-associated TCs, each with coordinated upregulation or downregulation of various sets of genes.
This finding indicates that early CRC may have nine distinct routes to achieve EMT, each requiring a specific peri-operative treatment strategy. Finally, we stratify patients into DFS patient subgroups with distinct transcriptional patterns associated with stage 2 and stage 3 CRC.
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