Background
The usage of genomic screening to usher the attraction of crab patients is becoming routine. However, its implementation wrong analyzable healthcare systems is not without challenges.
Here we stock the learnings from the CRUK Stratified Medicine Programme 2 (SMP2), a UK-wide genomic screening programme. Funded by Cancer Research UK (CRUK), the National Health Services (NHS) successful the 4 UK Nations, AstraZeneca and Pfizer, SMP2 offered genomic screening to patients with precocious non-small compartment lung crab (NSCLC) for enrolment into the National Lung Matrix Trial (NLMT) [1, 2].
What SMP2 delivered
SMP2 was the archetypal survey of its benignant to beryllium acceptable up wrong the NHS astatine a clip erstwhile next-generation sequencing (NGS) was conscionable becoming clinically disposable [1,2,3,4,5]. The programme was palmy successful demonstrating the feasibility of delivering genomic investigating astatine scale, with 79% of each patients tested having a genomic effect (Fig. 1). This occurrence was owed to the collaborative effort betwixt antithetic stakeholders who worked unneurotic passim the lifespan of the task to place processes hindering it and instrumentality changes to maximise screening success.
a SMP2 consort graph showing implicit numbers and percent of tested patients. Patients not recruited to NLMT included patients connected modular of attraction (SOC) attraction oregon dormant astatine the clip of closure, patients who could not beryllium recruited owed to mediocre show presumption (PS) and patients who stopped attraction owed to toxicity. b Comparison of NGS occurrence rates for the 3 panels. The percentages of samples wherever the indicated fraction of genes was successfully sequenced are shown. All differences betwixt panels are important (p < 0.01). c Types of cistron aberrations detected. The fractions of genes successfully sequenced successful which the indicated aberration was detected over all genes passed are shown. **p < 0.01, Fisher’s nonstop test. d SCNA detection by panel. The fractions of patients wherever an amplification oregon deletion successful the indicated genes was detected implicit the fig of patients wherever the cistron was successfully sequenced are shown. Only genes for which astatine slightest 50 SCNA events person been observed successful the SMP2 cohort are included. ● = **; **p < 0.01, Fisher’s nonstop test.
Indeed, betwixt January 2015 and August 2021, implicit 10,000 patients were consented to SMP2 utilizing a web of >50 hospitals dispersed passim the state crossed divers socio-economic backgrounds. Of these 6787 patients had a illustration sent for investigating portion undergoing first-line standard-of-care (SOC) treatment. The wide turn-around-time (TAT) from diligent consent to merchandise of the genomic results was intimately monitored and optimised to guarantee that a molecular study would beryllium disposable erstwhile patients relapsed connected SOC and could beryllium considered for NLMT enrolment [2] (median = 121 days). Different section processes astatine sites and mediocre illustration prime relationship for astir of the variability successful the clip needed from consent to illustration sent for investigating (median = 28 days, IQR = 27 days, 75% samples sent wrong 55 days), whereas the clip required for investigating astatine the molecular laboratories was unchangeable (median = 19 days, IQR = 11 days, 75% reported wrong 26 days).
The ambition for SMP2 was to person a azygous assay susceptible of detecting each types of aberrations required for NLMT eligibility [2]. Therefore, a bespoke NGS sheet (SMP2v01 panel) was designed by Illumina, covering the 28 genes projected by the pharma partners [2]. The assay required sequencing of tumours and matched mean humor samples and could observe SNVs and indels astatine ≥10% frequence and SCNAs successful samples with >60% tumour content.
To minimise the load connected patients, residual FFPE diagnostic samples were utilized for testing. Because of this, 20% of patients considered for SMP2 could not beryllium tested owed to insufficient tissue, and initially, 34% of samples could not beryllium sequenced owed to insufficient genomic worldly (QC fail). To trim the QC fails and guarantee that we could corroborate the wild-type presumption of immoderate NLMT genes, we acceptable stringent thresholds for tumour content, work extent and sum (20% tumour content, 500 reads crossed minimum 85% exons).
These changes dramatically reduced the fraction of samples that could not beryllium sequenced from 34 to 15%, highlighting the value of capable illustration processing. However, we inactive observed a important NGS nonaccomplishment rate, with >10% of samples failing each 28 genes (sequencing sum threshold not met) and an further 25% failing up to 50% of the genes (Fig. 1b). Moreover, immoderate genes failed importantly much often than others (p < 0.01), including RB1, which negatively impacted patients’ enrolment onto the NLMT arsenic its wild-type presumption confirmation was an exclusion criterion for 1/3 of the cohorts [2].
In March 2017, the SMP2 sheet was upgraded to SMP2v02 to optimise its show and adhd people regions for a caller NLMT arm. The upgrade included further probes to amended sum for genes with the highest nonaccomplishment rates and for calling SCNAs, less probes successful highly repetitive intronic regions to trim off-target effects and probes targeting SNPs to let recognition of blood-tumour mismatches. We besides reduced the minimum allele frequence threshold from 10% to 5% and partially automated the investigation pipeline.
These changes resulted successful a important betterment successful sheet performance, with the wide cistron nonaccomplishment complaint (OFR) reducing from 36 to 28%. Also, the fraction of samples passing each genes markedly accrued (35 to 48%) and the fractions of samples with >50% genes failed importantly decreased (Fig. 1b, each p < 0.01).
The request to let caller molecular arms for NLMT triggered a further sheet upgrade successful November 2019. We selected the Illumina TruSight Tumor 170 assay (TST170) arsenic it queried DNA and RNA from the aforesaid sample, enabling the detection of cistron fusions, reducing the request for FISH and the TAT. At the outset, though investigating for each 170 genes, the molecular laboratories reported lone 43 genes. The implementation of the TST170 sheet required a important alteration successful illustration mentation to alteration some DNA and RNA workflows and did not necessitate sequencing of the matched humor sample.
The caller sheet performed good with a further simplification of the OFR to 15%, an summation successful the fraction of samples that passed each genes (48 to 57%) and a alteration of samples that failed >50% of the genes (27 to 12%, Fig. 1b, each p < 0.01). Overall, 88% of samples tested passed astatine slightest 50% of the genes compared to 73% connected SMP2v02 sheet and 65% connected SMP2v01 sheet (p < 0.01). This betterment is adjacent much significant, considering that the fig of genes reported connected the caller sheet had astir doubled.
While the TST170 sheet showed betterment successful SNV calling (p < 0.01; Fig. 1c), it did not execute arsenic good arsenic the SMP2v02 sheet for SCNAs successful immoderate genes often amplified oregon deleted successful NSCLC (all p < 0.01; Fig. 1d); however, we accepted this regulation arsenic the payment of including much targets outweighed the imaginable nonaccomplishment successful sensitivity.
Conclusions
In summary, SMP2 demonstrated that regular genomic investigating for NSCLC patients could beryllium delivered astatine standard successful a clinically applicable timeframe wrong a nationalist wellness system. This has been achieved done an extended infrastructure dispersed passim the state to guarantee entree for each patients.
Our observations connected processes for exertion implementation, illustration quality, logistics and reporting connection a utile assets to different groups mounting up akin approaches [6].
From a technological constituent of view, our results item the value of successive iterations of the screening pipeline to amended NGS occurrence complaint based connected some biologic and technological advances. Over the people of SMP2 we achieved this by taking a flexible attack to the benignant of sheet and investigation utilized and by moving collaboratively to instrumentality changes successfully.
The main rule driving the occurrence of SMP2 was putting the patients astatine the halfway of the research, and by facilitating entree to the latest molecular diagnostics, patients could payment from entree to much personalised crab treatments.
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Acknowledgements
We gratefully admit each the members of the SMP2 consortium for helping present the programme done diligent consent, illustration processing and providing diligent objective information for analysis. Most importantly we convey each our patients for donating their samples and their information passim the programme.
Funding
This enactment has been funded by grants from CRUK to each objective hospitals and molecular laboratories progressive successful the survey (references: CRUK A26798, A22801, A22802, A22786, A22787, A26796, A22792, A22793, A22788, A22790, A26794, A22791, A26792, A22808, A26790, A22796, A22795, A22803, A26797, A22797, A22798, A22794, A22800, A31319, A31320, A31318).
Ethics declarations
Competing interests
SMM has received compensation arsenic a subordinate of the technological advisory committee of AstraZeneca. GM received honoraria for advisory boards/speaker engagements from BMS, MSD, AZ, Roche, D2G, Servier and Merck Serono. Prof Swanton acknowledges assistance enactment from Pfizer, AstraZeneca, BMS, Roche-Ventana, Boehringer-Ingelheim, Invitae (previously Archer Dx Inc)—collaboration successful minimal residual illness sequencing technologies, and Ono Pharmaceutical, and is an AstraZeneca Advisory Board subordinate and Chief Investigator for the AZ MeRmaiD 1 and 2 objective trials and is besides Co-Chief Investigator of the NHS Galleri proceedings funded by GRAIL and a paid subordinate of GRAIL’s Scientific Advisory Board. He receives advisor fees from Achilles Therapeutics (also SAB member), Bicycle Therapeutics (also a SAB member), Genentech, Medicxi, Roche Innovation Centre—Shanghai, Metabomed (until July 2022) and the Sarah Cannon Research Institute C.S has received honoraria from Amgen, AstraZeneca, Pfizer, Novartis, GlaxoSmithKline, MSD, Bristol Myers Squibb, Illumina and Roche-Ventana; had banal options successful Apogen Biotechnologies and GRAIL until June 2021, and presently has banal options successful Epic Bioscience, Bicycle Therapeutics, and has banal options and is co-founder of Achilles Therapeutics (Patents: C.S. holds patents relating to assay exertion to observe tumour recurrence (PCT/GB2017/053289); to targeting neoantigens (PCT/EP2016/059401), identifying patent effect to immune checkpoint blockade (PCT/EP2016/071471), determining HLA LOH (PCT/GB2018/052004), predicting endurance rates of patients with crab (PCT/GB2020/050221), identifying patients who respond to crab attraction (PCT/GB2018/051912), US patent relating to detecting tumour mutations (PCT/US2017/28013), methods for lung crab detection (US20190106751A1) and some a European and US patent related to identifying insertion/deletion mutation targets (PCT/GB2018/051892)). SP reported receiving consultancy honoraria and probe backing from Amgen, AstraZeneca, Blueprint, BMS, Boehringer Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Guardant Health, Janssen, Lilly, MSD, Roche, Seattle Genetics, Takeda, Turning Point Therapeutics; consultancy honoraria from Bayer, BeiGene, EQRx, Merck KGaA, Novartis, Pfizer and Sanofi; helium is an advisor for ALK Positive UK, Lung Cancer Europe, Ruth Strauss Foundation; portion of the committee of directors of Mesothelioma Applied Research Foundation and enactment for BTOG Steering Committee, ETOP Foundation Council. MR and DMB are employees of Illumina, a nationalist institution that develops and markets systems for familial analysis. SNH is an worker of Pfizer. SH is simply a full-time worker of AstraZeneca and holds banal successful AstraZeneca and Roche/Genentech. JP was an worker of Illumina during the programme. The remaining authors state nary competing interests.
Ethical approval
Research involving quality subjects, quality materials oregon quality information person been performed successful accordance with the Declaration of Helsinki and person been approved by the NRES Committee East of England—Cambridge Central (REC notation 11/EE/0202). All patients progressive successful the survey provided informed consent for the usage of their worldly and data.
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Unaffiliated authors: Catrin Middleton, Abdullah Alvi.
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Cite this article
Cerone, M.A., Mills, T.C., Sharpe, R. et al. The Cancer Research UK Stratified Medicine Programme arsenic a exemplary for delivering personalised crab care. Br J Cancer (2023). https://doi.org/10.1038/s41416-022-02107-8
Received: 16 November 2022
Revised: 25 November 2022
Accepted: 06 December 2022
Published: 04 January 2023
DOI: https://doi.org/10.1038/s41416-022-02107-8
English (US)