Next-generation sequencing (NGS) allows sequencing of a high number of nucleotides in a short time frame at an affordable cost. While this technology has been widely implemented, there are no ...recommendations from scientific societies about its use in oncology practice. The European Society for Medical Oncology (ESMO) is proposing three levels of recommendations for the use of NGS. Based on the current evidence, ESMO recommends routine use of NGS on tumour samples in advanced non-squamous non-small-cell lung cancer (NSCLC), prostate cancers, ovarian cancers and cholangiocarcinoma. In these tumours, large multigene panels could be used if they add acceptable extra cost compared with small panels. In colon cancers, NGS could be an alternative to PCR. In addition, based on the KN158 trial and considering that patients with endometrial and small-cell lung cancers should have broad access to anti-programmed cell death 1 (anti-PD1) antibodies, it is recommended to test tumour mutational burden (TMB) in cervical cancers, well- and moderately-differentiated neuroendocrine tumours, salivary cancers, thyroid cancers and vulvar cancers, as TMB-high predicted response to pembrolizumab in these cancers.
Outside the indications of multigene panels, and considering that the use of large panels of genes could lead to few clinically meaningful responders, ESMO acknowledges that a patient and a doctor could decide together to order a large panel of genes, pending no extra cost for the public health care system and if the patient is informed about the low likelihood of benefit. ESMO recommends that the use of off-label drugs matched to genomics is done only if an access programme and a procedure of decision has been developed at the national or regional level. Finally, ESMO recommends that clinical research centres develop multigene sequencing as a tool to screen patients eligible for clinical trials and to accelerate drug development, and prospectively capture the data that could further inform how to optimise the use of this technology.
•ESMO recommends the use of tumour multigene NGS in NSCLC, cholangiocarcinoma, prostate and ovarian cancers.•It is recommended to test TMB in well- and moderately-differentiated neuroendocrine tumours (NETs), cervical, salivary, thyroid and vulvar cancers.•Academic research centres should perform multigene NGS as part of their missions to enable access to innovative treatments.•A large panel of genes could be ordered, considering the benefit for the patient and the cost for the public health care system.
Access to biomolecular technologies has become an essential requirement to ensure optimal and timely treatment of patients with cancer. This study sought to provide a comprehensive overview of the ...availability and accessibility of biomolecular technologies to patients, the status of their use and prescription, barriers to access, and potential economic issues related to cost and reimbursement.
A total of 201 field reporters from 48 European countries submitted data through an electronic survey tool between July and December 2021. The survey methodology mirrored that from previous ESMO studies addressing the availability and accessibility of antineoplastic medicines, in Europe and worldwide. The preliminary data were posted on the ESMO website for open peer-review, and amendments were incorporated into the final report.
Overall, basic single-gene techniques are widely available, whereas access to advanced biomolecular technologies, including large next-generation sequencing panels and complete genomic profiles, is highly heterogeneous. In most countries, advanced biomolecular technologies remain largely inaccessible in clinical practice, are limited to clinical trials or basic research, and associated with progressively increasing cost as the technique becomes more advanced. Differences also exist regarding national sequencing initiatives or molecular tumour boards. The most important barriers to multiple versus single-gene sequencing techniques are the reimbursement of the test (59% versus 24%), and the availability of a suitable medicine, either through reimbursement of treatment (48% versus 30%), off-label treatment (52% versus 35%), or clinical trial enrolment (53% versus 39%).
Cost and availability of both treatment and test are the two main factors limiting patients’ access to advanced biomolecular technologies and as a consequence to innovative anticancer strategies. In the era of precision medicine, tackling the accessibility to biomolecular technologies is a key step to reduce inequalities to transformative cancer care.
•Access to biomolecular technologies is essential to ensure optimal and timely treatment of patients with cancer.•Challenges to access to biomolecular technologies limit patient access to targeted and innovative medicines.•This study provides an overview of availability, accessibility, and costs of genomic testing in oncology in Europe.•It highlights existing disparities in access to biomolecular technologies across countries in Europe.•ESMO aims at reducing inequalities and increasing access to cost-effective biomolecular technologies and relevant therapies.
Objectives
Although high-throughput sequencing is revolutionising medicine, data on the actual cost of whole exome sequencing (WES) applications are needed. We aimed at assessing the cost of WES at a ...French cancer institute in 2015 and 2018.
Methods
Actual costs of WES application in oncology research were determined using both micro-costing and gross-costing for the years 2015 and 2018, before and after the acquisition of a new sequencer. The entire workflow process of a WES test was tracked, and the number and unit price of each resource were identified at the most detailed level, from library preparation to bioinformatics analyses. In addition, we conducted an ad hoc analysis of the bioinformatics storage costs of data issued from WES analyses.
Results
The cost of WES has decreased substantially, from €1921 per sample (i.e. cost of €3842 per patient) in 2015 to €804 per sample (i.e. cost of €1,608 per patient) in 2018, representing a decrease of 58%. In the meantime, the cost of bioinformatics storage has increased from €19,836 to €200,711.
Conclusion
This study suggests that WES cost has decreased significantly in recent years. WES has become affordable, even though clinical utility and efficiency still need to be confirmed.
In the phase III PAOLA-1 study, the addition of maintenance olaparib to bevacizumab in patients with newly diagnosed high-grade ovarian cancer (HGOC) resulted in prolonged progression-free survival ...(PFS), particularly for homologous recombination deficiency-positive tumors, including those with a BRCA mutation (BRCAm). The magnitude of benefit from olaparib and bevacizumab according to the location of mutation in BRCA1/BRCA2 remains to be explored.
Patients with advanced-stage HGOC responding after platinum-based chemotherapy + bevacizumab received maintenance therapy bevacizumab (15 mg/kg q3w for 15 months) + either olaparib (300 mg b.i.d. for 24 months) or placebo. PFS was analyzed in the subgroup of patients with BRCA1m/BRCA2m according to mutation location in the functional domains of BRCA1 Really Interesting Gene (RING), DNA-binding domain (DBD), or C-terminal domain of BRCA1 (BRCT) and BRCA2 RAD51-binding domain (RAD51-BD); DBD.
From 806 randomized patients, 159 harbored BRCA1m (19.7%) and 74 BRCA2m (9.2%). BRCA1m in RING, DBD, and BRCT domains was detected in 18, 40, and 33 patients, and BRCA2m in RAD51-BD and DBD in 36 and 13 patients, respectively. After a median follow-up of 25.5 months, benefit from maintenance olaparib + bevacizumab was observed irrespective of location of BRCAm. The benefit was particularly high for those with BRCA1m located in the DBD, with 24-month PFS estimated to be 89% and 15% olaparib + bevacizumab versus placebo + bevacizumab hazard ratio = 0.08 (95% confidence interval 0.02-0.28); interaction P = 0.03. In BRCA2m patients, 24-month PFS rates for those with mutations located in the DBD were 90% and 100% (olaparib + bevacizumab versus placebo + bevacizumab), respectively.
Advanced-stage BRCA-mutated HGOC patients reported PFS benefit from maintenance olaparib and bevacizumab regardless of mutation location. The benefit is particularly high for patients with mutations located in the DBD of BRCA1. Mutations located in the DBD of BRCA2 are also associated with excellent outcome.
•PFS benefit from ola + bev maintenance in BRCA-mutated advanced stage OC was observed irrespective of mutation location.•The benefit from ola + bev was particularly high among patients with BRCA1 mutations located in the DBD.•OC patients with BRCA2 mutations located in the DBD had excellent outcomes.•BRCA1 mutations located in the RING or BRCT domains were enriched in missense and splicing mutations.•Benefit from ola + bev maintenance in advanced-stage OC with BRCAm was observed irrespective of type of mutation.
Circulating tumor DNA (ctDNA) sequencing is a promising approach for tailoring therapy in patients with cancer. We report hereby the results from a prospective study where we investigated the impact ...of comprehensive molecular profiling of ctDNA in patients with advanced solid tumors.
Genomic analysis was performed using the FoundationOne Liquid CDx Assay 324 genes, tumor mutational burden (TMB), microsatellite instability status. Each individual genomic report was reviewed and discussed weekly by a multidisciplinary tumor board (MTB). Actionable targets were classified by ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) tier leading to molecular-based treatment suggestions wherever it was possible.
Between December 2020 and November 2021, 1772 patients with metastatic solid tumors underwent molecular profiling. Median time to assay results was 12 days. Results were contributive for 1658 patients (94%). At least one actionable target was detected in 1059 patients (64%) with a total of 1825 actionable alterations including alteration of the DNA damage repair response pathway (n = 336, 18%), high TMB (>16 mutations/Mb; n = 243, 13%), PIK3CA mutations (n = 150, 8%), ERBB family pathway alterations (n = 127, 7%), PTEN alterations (n = 95, 5%), FGFR alterations (n = 67, 4%) and MET activations (n = 13, 0.7%). The MTB recommended a matched therapy for 597 patients (56%) with a total of 819 therapeutic orientations: clinical trials (n = 639, 78%), off-label/compassionate use (n = 81, 10%), approved drug (n = 51, 6%), and early access program (n = 48, 6%). In total, 122 patients (21%) were treated. Among the assessable patients (n = 107), 4 (4%) had complete response, 35 (33%) had partial response, 27 (25%) had stable disease, and 41 (38%) a progressive disease as best response. The median progression-free survival and median overall survival were 4.7 months (95% confidence interval 2.7-6.7 months) and 8.3 months (95% confidence interval 4.7-11.9 months) respectively.
ctDNA sequencing with a large panel is an efficient approach to match patients with advanced cancer with targeted therapies.
•ctDNA sequencing is increasingly used in clinical practice to characterize genomic tumor profile.•We report here the largest study evaluating the clinical value of ctDNA profiling in patients with advanced cancer.•ctDNA sequencing with a large is an efficient approach to detect actionable alterations in patients with advanced cancer.
Advancements in the field of precision medicine have prompted the European Society for Medical Oncology (ESMO) Precision Medicine Working Group to update the recommendations for the use of tumour ...next-generation sequencing (NGS) for patients with advanced cancers in routine practice.
The group discussed the clinical impact of tumour NGS in guiding treatment decision using the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) considering cost-effectiveness and accessibility.
As for 2020 recommendations, ESMO recommends running tumour NGS in advanced non-squamous non-small-cell lung cancer, prostate cancer, colorectal cancer, cholangiocarcinoma, and ovarian cancer. Moreover, it is recommended to carry out tumour NGS in clinical research centres and under specific circumstances discussed with patients. In this updated report, the consensus within the group has led to an expansion of the recommendations to encompass patients with advanced breast cancer and rare tumours such as gastrointestinal stromal tumours, sarcoma, thyroid cancer, and cancer of unknown primary. Finally, ESMO recommends carrying out tumour NGS to detect tumour-agnostic alterations in patients with metastatic cancers where access to matched therapies is available.
Tumour NGS is increasingly expanding its scope and application within oncology with the aim of enhancing the efficacy of precision medicine for patients with cancer.
•ESMO updates the recommendations for the use of tumour NGS in patients with advanced cancers in routine practice.•ESMO expands tumour NGS recommendation to advanced breast cancer, GIST, sarcoma, thyroid cancer, and cancer of unknown primary.•ESMO recommends tumour NGS for detecting tumour-agnostic alterations where matched therapies are accessible.•Tumour NGS should be done in clinical research centres and may be discussed under specific circumstances with patients.
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