Next-generation sequencing impact on cancer care: applications, challenges, and future directions.

Fundamentally precision oncology illustrates the path in which molecular profiling of tumors can illuminate their biological behavior, diversity, and likely outcomes by identifying distinct genetic mutations, protein levels, and other biomarkers that underpin cancer progression. Next-generation sequencing became an indispensable diagnostic tool for diagnosis and treatment guidance in current clinical practice. Nowadays, tissue analysis benefits from further support through methods like comprehensive genomic profiling and liquid biopsies. However, precision medicine in the field of oncology presents specific hurdles, such as the cost-benefit balance and widespread accessibility, particularly in countries with low- and middle-income. A key issue is how to effectively extend next-generation sequencing to all cancer patients, thus empowering treatment decision-making. Concerns also extend to the quality and preservation of tissue samples, as well as the evaluation of health technologies. Moreover, as technology advances, novel next-generation sequencing assessments are being developed, including the study of Fragmentomics. Therefore, our objective was to delineate the primary uses of next-generation sequencing, discussing its' applications, limitations, and prospective paths forward in Oncology.

International Cost-Effectiveness Analysis of Durvalumab in Stage III Non-Small Cell Lung Cancer.

Importance: Standard of care for unresectable locally advanced non-small cell lung cancer (NSCLC) involves definitive chemoradiotherapy followed by maintenance therapy with durvalumab. However, the cost of durvalumab has been cited as a barrier to its use in various health systems. Objective: To evaluate the cost-effectiveness of durvalumab vs placebo as maintenance therapy in patients with unresectable stage III NSCLC from 4 international payer perspectives (US, Brazil, Singapore, and Spain). Design, Setting, and Participants: In this economic evaluation, a Markov model was designed to compare the lifetime cost-effectiveness of maintenance durvalumab for unresectable stage III NSCLC with that of placebo, using 5-year outcomes data from the PACIFIC randomized placebo-controlled trial. Individual patient data were extracted from the PACIFIC, KEYNOTE-189, ADAURA, ALEX, and REVEL randomized clinical trials to develop a decision-analytic model to determine the cost-effectiveness of durvalumab compared with placebo maintenance therapy over a 10-year time horizon. Direct costs, adverse events, and patient characteristics were based on country-specific payer perspectives and demographic characteristics. The study was conducted from June 1, 2022, through December 27, 2023. Main Outcomes and Measures: Life-years, quality-adjusted life years (QALYs), lifetime costs, and incremental cost-effectiveness ratios (ICERs) were estimated at country-specific willingness-to-pay thresholds ([data reported in US$] US: $150 000 per QALY; Brazil: $22 251 per QALY; Singapore: $55 288 per QALY, and Spain: $107 069 per QALY). One-way and probabilistic sensitivity analyses were performed to account for parameters of uncertainty. A cost-threshold analysis was also performed. Results: The US base-case model found that treatment with durvalumab was associated with an increased cost of $114 394 and improved effectiveness of 0.50 QALYs compared with placebo, leading to an ICER of $228 788 per QALY. Incremental cost-effectiveness ratios, according to base-case models, were $141 146 for Brazil, $153 461 for Singapore, and $125 193 for Spain. Durvalumab price adjustments to the PACIFIC data improved cost-effectiveness in Singapore, with an ICER of $45 164. The model was most sensitive to the utility of durvalumab. Conclusions and Relevance: In this cost-effectiveness analysis of durvalumab as maintenance therapy for unresectable stage III NSCLC, the therapy was found to be cost-prohibitive from the perspective of various international payers according to country-specific willingness-to-pay thresholds per QALY. The findings of the study suggest that discounted durvalumab acquisition costs, as possible in Singapore, might improve cost-effectiveness globally.

Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio as biomarkers to prognosticate survival in advanced gastric cancer patients in the era of immunotherapy: a systematic review and meta-analysis.

Background: Gastric cancer (GC) remains an important global health concern with limited treatment options for advanced cases. Immunotherapy has shown promising results, but identifying predictive biomarkers for treatment efficacy is challenging. Novel inflammatory markers, such as the platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR), derived from complete blood count measurements, have gained attention as potential prognostic indicators. This systematic review and meta-analysis investigates the roles of the PLR and NLR as predictors of overall survival (OS) and progression-free survival (PFS) in advanced GC and gastroesophageal junction cancer (GEJC) patients treated with immunotherapy. Methods: A comprehensive search of the literature was conducted through PubMed, Embase, and Cochrane Library to identify relevant studies. A total of 16 studies involving NLR and 8 studies involving PLR were included. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to assess the association between high biomarker values and poor OS and PFS. Subgroup analyses were performed to explore potential sources of heterogeneity. Poor OS, PFS were defined by each study as statistically significant shorter survival. Results: A high NLR was significantly associated with worse OS (HR: 2.11; 95% CI: 1.70-2.62) and PFS (HR: 1.76; 95% CI: 1.43-2.17). High PLR was also significantly associated with poorer OS (HR: 1.77; 95% CI: 1.44-2.17) and PFS (HR: 1.61; 95% CI: 1.33-1.96). Subgroup analyses and sensitivity analyses supported the robustness of these findings. Publication bias was noted in NLR analysis for OS but not for PFS. PLR analysis showed low publication bias. Conclusions: Elevated NLR and PLR are associated with unfavorable OS and PFS outcomes in advanced GC/GEJC patients on immunotherapy. These findings imply the utility of these easily accessible biomarkers in prognostic assessment. However, standardized cutoff values and further research on interactions with the tumor microenvironment and comorbidities are needed. Additional prospective studies are warranted to validate these findings for both biomarkers.

Challenges and opportunities in building a health economic framework for personalized medicine in oncology.

Personalized medicine has allowed for knowledge at an individual level for several diseases and this has led to improvements in prevention and treatment of various types of neoplasms. Despite the greater availability of tests, the costs of genomic testing and targeted therapies are still high for most patients, especially in low- and middle-income countries. Although value frameworks and health technology assessment are fundamental to allow decision-making by policymakers, there are several concerns in terms of personalized medicine pharmacoeconomics. A global effort may improve these tools in order to allow access to personalized medicine for an increasing number of patients with cancer.

Discrepancies Between the Cost of Advanced Lung Cancer Treatment and How Much Is Reimbursed by the Brazilian Public Healthcare System.

OBJECTIVE: Lung cancer is the leading cause of cancer-related death worldwide, and most patients are diagnosed of advanced disease. Molecular-targeted therapy and immunotherapy increase survival among these patients. In this study, we compared the cost of the best treatments available with the amount reimbursed by the Brazilian public healthcare system (Sistema Único de Saúde [SUS]) to treat advanced lung cancer. METHODS: The authors divided lung cancer into 10 subtypes according to histology and molecular profile. A panel of experts defined the best treatment sequencing for each subtype. The authors considered only drug costs retrieved from the Brazilian Health Regulatory Agency official data. The progression-free survival of each regimen was considered as treatment duration. The cost estimate included all postprogression therapies weighted by each subtype proportional frequency. The amount reimbursed by SUS was the sum of the monthly budget accumulated during the estimated treatment duration and then for the proportional frequency of each subtype. RESULTS: The budget reimbursed by SUS for treating each advanced lung cancer case in Brazil is R$8000.00 in average whereas the cost estimate for the best treatment available is R$729 454.00 per case, which represents a difference of 9118%. The budget impact to ensure the reimbursement needed to acquire the best treatments available was estimated in near R$13 billion annually. CONCLUSIONS: The cost estimate of the best treatment available for advanced lung cancer in Brazil is much higher than the amount reimbursed by SUS. This budgetary gap leads to a major access barrier that may compromise the survival outcomes of SUS users.

Laboratory variables as predictors of progression in gastroenteropancreatic neuroendocrine tumors in different lines of antineoplastic treatments.

OBJECTIVE: To determine the association of red cell blood counts, and liver panel tests to predict outcomes in patients with gastroenteropancreatic neuroendocrine tumors who underwent systemic antineoplastic treatments. METHODS: Patients with gastroenteropancreatic neuroendocrine tumors in systemic treatment were assessed according to laboratory tests within the same period. Progression free survival was determined by the period between the beginning of treatment and the date of progression. We used conditional models (PWP model) to verify the association between laboratory tests and tumor progression. The level of significance used was 5%. RESULTS: A total of 30 treatments given to 17 patients in the intention-to-treat population were evaluated. Treatment included octreotide, lanreotide, everolimus, lutetium, and chemotherapy. We had statistically significant results in chromogranin A, neutrophils and platelets-to-lymphocyte ratio. The risk of progression increases by 2% with the addition of 100ng/mL of chromogranin A (p=0.034), 4% with the increase of 100 neutrophil units (p=0.006), and 21% with the addition of 10 units in platelets-to-lymphocyte ratio (p=0.002). CONCLUSION: Chromogranin A, neutrophils and platelets-to-lymphocyte ratio were associated with disease progression during systemic treatment in gastroenteropancreatic neuroendocrine tumors. Further prospective studies with larger cohorts are necessary to validate our findings.

Cost-effectiveness analysis of Ado-trastuzumab emtansine for the treatment of residual invasive HER2-positive breast cancer.

OBJECTIVE: Human epidermal growth factor receptor 2 (HER2) overexpression occurs in up to 30% of breast cancer cases. Ado-trastuzumab emtansine (T-DM1) is approved to treat residual HER2-positive breast cancer after neoadjuvant therapy. The aim of this study was to determine the quality-adjusted time with symptoms or toxicity and without symptoms or toxicity (Q-TWiST) of T-DM1 compared to trastuzumab for residual invasive HER2-positive breast cancer. METHODS: The authors developed an analytical model extracting individual patient data and estimated invasive disease-free survival and overall survival over a 30-year time horizon. Only direct costs from adjuvant treatment were considered as well as relapse treatment from Brazilian and American payer perspectives. Heart events were considered for utility and cost analysis. RESULTS: The 30-year projection utilizing the Weibull method estimated a mean invasive disease-free survival of 16.4 years for T-DM1 and 10.4 for Trastuzumab, in addition to a mean overall survival of 18.1 and 15.4 years, respectively. We determined a Q-TWiST gain of 3,812 years for the T-DM1 arm when compared to trastuzumab and an Incremental cost-effectiveness ratio per Q-TWiST of US$ 11,467.65 in the United States and US$ 3,332.73 in Brazil. CONCLUSION: Ado-trastuzumab emtansine is cost-effective from both Brazilian and American perspectives.

Predictive genetic biomarkers in immune checkpoint inhibitors for non-small-cell lung cancer.

Immune checkpoint inhibitors improved the overall survival of patients with advanced non-small-cell lung cancer and changed the treatment since the last decade. The duration of response is longer than what is seen with chemotherapy or targeted agents; however, some patients have no benefit or even a progressive disease as best response. Immune checkpoint inhibitor plus chemotherapy combinations are a very useful strategy, but defining precisely who will benefit most from immunotherapy is still a main question. Therefore, understanding the genetics of the tumor microenvironment is a way to determine new predictive biomarkers to replace the only one currently accepted, PD-L1 expression, whose application is surrounded by uncertainties.

Plain language summary Currently, immunotherapy based on immune checkpoint inhibitors represents a crucial tool in the treatment of non-small-cell lung cancer, but not all patients have an adequate response to this therapy, which is not free of side effects and may be difficult to access due to the costs involved; therefore, understanding who will benefit most from this therapy is essential. The biomarker most available nowadays (PD-L1 expression) is surrounded by limitations. An understanding of tumor genetics, in turn, represents a path with great potential to assist in patient selection, which is possible through assessing genomic peculiarities of the tumor.

Palliative Prognostic Index accuracy of survival prediction in an inpatient palliative care service at a Brazilian tertiary hospital.

PURPOSE: The Palliative Prognostic Index (PPI) was developed to improve survival prediction for advanced cancer patients. However, there is limited data about the PPI application in a real-world scenario. This study aimed to assess the accuracy of PPI > 6 in predicting survival of cancer inpatients. METHODS: A prospective observational cohort in an inpatient palliative care service at a tertiary hospital in São Paulo-SP, Brazil, between May 2011 and December 2018. RESULTS: We included 1,376 critically ill cancer inpatients. Patients were divided into three PPI subgroups: PPI ≤ 4, PPI 4-6, and PPI ≥ 6. Their respective medium overall survival values were 44 days (95% confidence interval [CI] 35.52-52.47), 20 days (95% CI 15.40-24.59), and 8 days (95% CI 7.02-8.98), (p < 0.001). PPI ≥ 6 predicted survival of <3 weeks with a positive predictive value (PPV) of 72% and an negative predictive value (NPV) of 68% (sensitivity 67%, specificity 72%). PPI > 4 predicted survival of <6 weeks with a PPV of 88% and an NPV of 36% (sensitivity 74%, specificity 59%). When PPI was <4, the mortality rate over 3 weeks was 39% with a relative risk (RR) of 0.15 (95% CI 0.11-0.20; p < 0.001), and the 6-week mortality rate was 63% with a RR of 0.18 (95% CI 0.13-0.25; p < 0.001) compared to PPI ≥ 4. CONCLUSIONS: PPI was a good discriminator of survival among critically ill cancer inpatients and could assist in hospital discharge decision. PPI may help healthcare policymakers and professionals in offering high-quality palliative care to patients.

Comparative Efficacy and Safety of Programmed Death-1 Pathway Inhibitors in Advanced Gastroesophageal Cancers: A Systematic Review and Network Meta-Analysis of Phase III Clinical Trials.

Background: The use of checkpoint inhibitors has changed the treatment landscape for gastroesophageal cancer in the third-line setting. However, success rates in earlier treatment lines are highly variable across trials. Herein, we compare the efficacy and safety of the different anti-PD-1/PD-L1 regimens with or without chemotherapy; Methods: We performed a network meta-analysis (NMA) of anti-PD-1/PD-L1 monotherapy or combined with chemotherapy (chemoimmunotherapy) for gastroesophageal cancers without ERBB2 overexpression; Results: The first-line NMA included four trials (N = 3817), showing that chemoimmunotherapy improved OS and PFS without significant safety difference: Nivolumab-chemotherapy, OS (HR: 0.83 [95% CI, 0.75-0.92]), PFS (HR 0.68 [95% CI, 0.57-0.81]), Pembrolizumab-chemotherapy: OS (HR 0.77 [95% CI, 0.67-0.88]), PFS (HR: 0.72 [95% CI, 0.60-0.85]. Pembrolizumab monotherapy was the safest first-line treatment, SAE (OR 0.02 [95% CI, 0.00-0.2]) but showed no survival benefit. The second-line NMA encompassed four trials (N = 2087), showing that anti-PD-1 significantly improved safety but not survival: camrelizumab, SAE (OR 0.37; [95% CI, 0.24-0.56]); nivolumab, SAE (OR 0.13, [95% CI, 0.08-0.2]) pembrolizumab, SAE (OR 0.4; [95% CI, 0.30-0.53]); Conclusions: chemoimmunotherapy improves OS and PFS in previously untreated gastroesophageal cancers. Anti-PD-1 monotherapies improve safety in refractory disease, with no significant survival benefit.

Cost-effectiveness and affordability of anticancer treatment in Brazil.

The cost of anticancer treatments has increased in recent years. This is a threat to the sustainability of health systems. The number and relevance of pharmacoeconomic studies has increased, although their interpretation has become more complex. In a majority of cases, the benefit provided by new drugs is not enough to consider them cost-effective. In other cases, the treatment can be cost-effective, but the budget impact is unaffordable. Both cases deserve a deep discussion on how to make these treatments available to patients.

Cost-effectiveness analysis of abiraterone, docetaxel or placebo plus androgen deprivation therapy for hormone-sensitive advanced prostate cancer.

OBJECTIVE: To evaluate the cost-effectiveness of the addition of chemotherapy or abiraterone to androgen deprivation. METHODS: We developed an analytical model to determine the cost-effectiveness of the addition of docetaxel or abiraterone versus androgen deprivation therapy alone. Direct and indirect costs were included in the model. The effects were expressed in Quality-Adjusted Life Years adjusted for side effects. RESULTS: Compared to androgen deprivation therapy alone, the addition of chemotherapy and of abiraterone generated 0.492 and 0.999, respectively, in Quality-Adjusted Life Years. Abiraterone led to a Quality-Adjusted Life Years gain of 0.506 compared to docetaxel. The incremental costs per Quality-Adjusted Life Years were R$ 133.649,22 for docetaxel, R$ 330.828,70 for abiraterone and R$ 571.379,42 for abiraterone compared to docetaxel, respectively. CONCLUSION: The addition of chemotherapy to androgen deprivation therapy is more cost-effective than the addition of abiraterone to androgen deprivation therapy. However, discounts on abiraterone cost might improve cost-effectiveness.

A paradigm shift for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer: a review of CDK inhibitors.

In the last 3 years, a novel class of targeted therapy has been approved for patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer. There are currently three approved agents, which are oral cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. All of the approved drugs exhibit progression-free survival benefit when compared to standard of care and generally have less adverse events compared to traditional chemotherapeutic options. The treatment of HR+/HER2- advanced breast cancer is a continuously evolving landscape, and the addition of CDK4/6 inhibitors is the newest mechanism for treatment. In this review, we summarize all available data, highlight the unanswered questions, and discuss pharmacological differences between each CDK4/6 inhibitor.

Immune checkpoint inhibitors for advanced non-small cell lung cancer: emerging sequencing for new treatment targets.

Lung cancer is the leading cause of cancer-related deaths in the world. Immune checkpoint inhibitors (ICI) stimulate cytotoxic lymphocyte activity against tumour cells. These agents are available for the treatment of non-small cell lung cancer (NSCLC) after failure of platinum-based therapy. One recent study has demonstrated that ICI monotherapy was superior to platinum-based chemotherapy for first-line treatment. Nevertheless, this benefit was only for a minority of the population (30%) whose tumour programmed death receptor ligand-1 (PD-L1) expression was above 50%. Therefore, several strategies are under investigation. One option for patients with PD-L1 expression lower than 50% may be the combination of ICI with platinum-based chemotherapy or with ICIs against different targets. However, all of these combinations are at an early stage of investigation and may be very expensive or toxic, producing several harmful adverse events.

Cost effectiveness of chemohormonal therapy in patients with metastatic hormone-sensitive and non-metastatic high-risk prostate cancer.

OBJECTIVE: To assess the cost-effectiveness of chemohormonal therapy in patients with metastatic hormone-sensitive and non-metastatic high-risk prostate cancer. METHODS: An analytical decision model was developed to determine the cost-effectiveness of chemohormonal therapy versus androgen deprivation therapy alone in patients with metastatic hormone-sensitive prostate cancer and patients with non-metastatic high-risk prostate cancer. The cost-effectiveness in metastatic patients with a high-volume disease was assessed separately. The model used data from randomized clinical trials and drug acquisition costs in Brazil. In addition, the costs of post-progression therapies have been included in this model. The benefits to health are expressed as the quality-adjusted life-years, and the incremental cost-effectiveness ratios were calculated. RESULTS: Chemohormonal therapy may be associated with improved quality-adjusted life-years for all patient. The improvement was more than six times greater for patients with high-volume metastatic disease. In these patients, the incremental cost-effectiveness ratios were up to 74% lower than the incremental cost-effectiveness ratios of patients with non-metastatic disease. CONCLUSION: Chemohormonal therapy has been more cost-effective in patients with high-volume metastatic disease.

Disparities in cancer epidemiology and care delivery among Brazilian indigenous populations.

OBJECTIVE:: To assess aspects related to cancer in indigenous population. METHODS:: This is a retrospective study developed in a public university hospital. We included patients with 18 or more years of age, diagnosed with solid tumors, and followed between 2005 and 2015. Clinical features were assessed by descriptive statistics, and survival was evaluated by Kaplan-Meier curves and multivariate Cox regression. RESULTS:: Fifty patients were included. The cancer incidence was 15.73 per 100,000. The mean age at diagnosis was 54 years and most patients were female (58%). Cancer of the cervix (28%) and prostate (16%) were the most common. The mean time between the onset of symptoms and the diagnosis was 9 months and from diagnosis to the treatment was 3.4 months. Disease diagnosed at stage IV (17%) had worse overall survival (HR: 11.4; p<0.05). The 5-year survival rate ranged from 88% for prostate cancer to 0% for lung cancer. All 5-year survival rates were lower as compared to other populations. CONCLUSION:: The most prevalent cancer sites were cervix and prostate. Disease stage and primary site were prognostic factors. OBJETIVO:: Avaliar os aspectos relacionados a câncer em populações indígenas. MÉTODOS:: Estudo retrospectivo conduzido em um hospital universitário público. Foram incluídos pacientes com 18 anos ou mais, diagnosticados com tumores sólidos e acompanhados entre 2005 e 2015. Os aspectos clínicos foram avaliados por meio de estatística descritiva, e a sobrevida foi avaliada por meio de curvas de Kaplan-Meier e regressão multivariada de Cox. RESULTADOS:: Foram incluídos 50 pacientes. A incidência de câncer foi 15,73 por 100 mil. A média de idade ao diagnóstico foi 54 anos, e a maioria era do sexo feminino (58%). O câncer de colo uterino (28%) e o de próstata (16%) foram os mais frequentes. O tempo médio entre o início dos sintomas e o diagnóstico foi 9 meses, e entre o diagnóstico e o tratamento, de 3,4 meses. Doença diagnosticada no estágio IV (17%) resultou em pior sobrevida global (HR: 11,4; p<0,05). A sobrevida em 5 anos variou de 88% para o câncer de próstata a 0% para pulmão. Todas as taxas de sobrevida em 5 anos foram menores em comparação a outras populações. CONCLUSÃO:: Os locais mais frequentes de neoplasia foram colo de útero e próstata. O estágio da doença e o sítio primário foram fatores prognósticos.

Definitive chemoradiotherapy for squamous head and neck cancer: cisplatin versus carboplatin? A meta-analysis.

AIM: Concomitant chemoradiotherapy (with cisplatin or carboplatin) is an option of definitive treatment for squamous head and neck cancer. We aimed to perform a meta-analysis comparing those two platinum agents. MATERIALS & METHODS: We carried out a systematic search on English literature between 1990 and 17 April 2015 according to the Cochrane review guidelines. RESULTS: Five of 60 studies fulfilled inclusion criteria with 491 patients. There was no difference in response rate. Cisplatin tends to be more active systemically than carboplatin, without statistically significance; 5-year survival rate: 30 and 27%, respectively (p = 0.33). CONCLUSION: Despite the trend to improved outcomes in using cisplatin, carboplatin is also active and can be a reasonable option to treat patients.

Current advances in targeted therapies for metastatic gastric cancer: improving patient care.

In this article, we review the literature on the current advances in targeted therapies for metastatic gastric cancer aimed at improving patient care. We conclude that the key to guiding targeted therapy is individual biomarkers, which are not completely elucidated. HER2 overexpression is the only predictive biomarker currently in use. Furthermore, it is necessary to understand that gastric tumors are heterogeneous; therefore, is impossible to evaluate a novel biological compound without evaluating personal biomarkers. The selection of patients who are able to receive each treatment is paramount for improving advanced gastric cancer survival and reducing unnecessary costs.