Following the tumour DNA trail to crack the secrets of personalised medicine

There are at least 200 forms of cancer, and many more subtypes.  Every one of them is caused by errors in DNA, known as genetic mutations, that make cells in the body grow abnormally fast. In the last decade, cancer genomics research, based on sequencing the full DNA (or genome) of tumours, has been driven forward by several international initiatives that catalogued countless alterations found in the tumour tissue of tens of thousands of patients. These studies revealed that tumours are made up of several different subsets of molecules, each driven by distinct alterations – which suggested that they could be treated according to their individual molecular landscape.

Susana Aguilar, responsible for the MPP review, said: “When we started the programme, there were 13 phase I trials open at our institute, 11 of which were for drugs that targeted the same gene mutation. By 2017, the number of trials had increased tenfold and targeted a much broader array of alterations – 40% were immunotherapy trials. The MPP grew accordingly, from 207 patients screened in 2010 to 1,168 tumours analysed in 2017.”

Initially, patients were screened using so-called IHC (immunohistochemistry), FISH (fluorescence in situ hybridisation) analyses and hotspot mutation panels to search for alterations in a small number of genes and proteins known to play a role in cancer. In the last three years, next-generation sequencing (NGS) was implemented alongside other multigene assays to allow screening for mutations in as many as 61 genes simultaneously.

By 2017, these new molecular profiling techniques were used in most patients in the MPP: 10% of patients were enrolled in early clinical trials as a result, based on 18 different biomarker matches. “This proportion may seem low, but it is partly due to many other factors that determine patients’ eligibility for a trial, including their overall clinical condition, distance to get to the hospital and treatment alternatives available,” Aguilar explained. “Going forward, the clear trend in favour of immunotherapy trials will guide us in our implementation of new markers and tools to identify them in patients.” 

Carmen Criscitiello of the European Institute of Oncology in Milan, Italy, commented on the findings: “The evolution of sequencing techniques has allowed us to look for a wider array of mutations. For many of these, there is no registered drug available to target them. That’s why a key approach to implementing personalised medicine in the management of advanced-stage cancer is to develop clinical trials that show the effectiveness of drugs in cohorts of patients defined by the same genomic alteration,” she said.

“As these trials target more and more distinct alterations in smaller and smaller populations, the main challenge now is patient accrual: with targeted mutations detectable in less than 10% of tumours, we need to screen huge numbers of individuals to find just a handful of people eligible for a trial. Managing the expectations of the many patients for whom analyses don’t lead to any meaningful treatment options is an issue that oncologists urgently need to address,” Criscitiello added.  

Jane Rogan of the Manchester Cancer Research Centre (MCRC) Biobank, which coordinated sample collection and delivered the project for the Greater Manchester area, explained the initial challenges: “One major topic from the start was the length of the consent form: we needed patient consent not just to store their tissue samples in our biobank, but also to sequence the tumour tissue. The former had to be obtained before the surgery to harvest the sample – a time when some patients didn’t even have confirmation of their diagnosis yet, and many were in a state of distress,” she said. “To avoid subjecting patients to lengthy discussions about genomic consent unnecessarily, we introduced a two-tiered model whereby the second level of consent was requested only after sample eligibility had been confirmed.”

“Another constraint was that only frozen tumour samples could be admitted for analysis. The most common medium for sample preservation is formalin, but this is not ideal for DNA extraction,” said Rogan. “To ensure that as many patients as possible could be recruited while simultaneously minimising sample failure rates – due to improper preservation or insufficient tumour content, for instance – we had to integrate our biobanking activity with standard clinical pathways.”

This included the rollout of a shared patient tracker to record the status of candidates for the project, a process to guarantee the overnight refrigeration of samples collected outside the working hours of pathology departments, and a “biopsy pathway” to give patients access to the project outside of the surgery setting. “To date, about 900 samples from 18 different tumour types have been submitted for whole genome sequencing in Manchester: since we started collecting them, we have been able to reduce failure rates by over 10%,” Rogan reported.

Reflecting on these achievements, she added: “WGS has the potential to change our entire health system. Bringing it into routine cancer care is expensive – but when we spend money on appropriate diagnosis and finding the right treatment, we save money on ineffective therapies that don’t help patients but do have a long-term healthcare cost.”

Criscitiello commented: “The significant number of samples collected and the 10% reduction of failure rates show that the implemented system was successful. The clear takeaway from this is that although it may be feasible to use WGS as a standard clinical tool, it can work only if there is structured cooperation between all the professional players involved: oncologists, pathologists, research facilities, service providers and hospitals.”

According to Criscitiello, however, the major hurdle to this approach is obtaining the tumour tissue required for genetic testing: “Depending on the tumour type and location, neither surgery nor biopsy are safe or even feasible for many patients,” she said. “Liquid biopsies, which would allow us to collect so-called circulating tumour DNA (ctDNA) from a simple blood draw, are the most promising solution to this problem. As a non-invasive procedure, they would also enable us to do repeat analyses throughout a patient’s treatment, and thus potentially target alterations as they occur in continually evolving tumours – their use as a standard of care is continually expanding.”

However great the difficulties of putting all the pieces of the personalised medicine puzzle together, there is promise of a greater reward. Patients are already benefiting from the first tailored therapies that target their tumours’ genetic mutations: BRCA1 and BRCA2 genes, for example, are important for repairing the damage to DNA that occurs routinely throughout a cell’s life-cycle. Mutations of these genes within a cell can lead to DNA repair errors and ultimately to the cell’s death. In ovarian and breast cancers where such alterations are present, targeted drugs are used successfully to accelerate the death of tumour cells.

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J. Henry¹, J.A. Radford^2 
1MCRC Biobank, The Christie NHS Foundation Trust, Manchester, UK, ²The Christie NHS Foundation Trust, Manchester, UK

Background: The 100,000 Genomes Project is a central element of NHS England’s Personalised Medicine Strategy, which aims to progress the move from a ‘one size fits all’ approach to patient treatment to more effective personalised therapies. The driver for this lies in the relative inefficacy of generic treatments; leading to at least 40% of patients receiving treatments that have no clinical benefit. This project is an NHS transformation initiative and aims to embed operational processes for Whole Genome Sequencing (WGS) of patient samples into routine clinical practice.

Methods: The Manchester Cancer Research Centre (MCRC) Biobank has been coordinating central sample collection in Greater Manchester since 2008. Historically, this activity has fallen outside of routine clinical practice, however integration of Biobanking activity and clinical pathways has enabled Manchester to deliver this national project. Steps taken include: Introducing methods in histopathology for routine frozen sample processing and tumour content assessment Roll-out of a shared patient tracker to faciliate recruitment A two-tier consent model enabling biobank consent at the time of surgery, followed by a more detailed genomic consent once sample eligibility has been confirmed Detailed data capture of sample ‘failure’ reasons to improve sample conversion rate Routine refrigeration of ‘out-of-hours’ specimens so that frozen tissue can be collected the following day Development of a ‘biopsy pathway’ to ensure learning can be main-streamed for real life clinical utility post project

Results: To date, Manchester have submitted ~900 samples for Whole Genome Sequencing. Key achievements include: Samples submitted from 18 distinct tumour types Reduction of sample failure rates by >10% Successful introduction of remote consenting model

Conclusions: Delivery of the 100,000 Genomes Project in Manchester is a clear demonstration of holistic working between research infrastructure and clinical service, which will ultimately transform personalised medicine for cancer patients in England.

Funding: Has NOT received any funding
Disclosure: All authors have declared no conflicts of interest.

S. Aguilar, A. Vivancos, P. Nuciforo, C. Viaplana, F. Ruiz-Pace, E. Sanchez, J. Rodon, J. Tabernero, E. Garralda, R. Dienstmann 
Vall dHebron Institute of Oncology, Barcelona, Spain

Background: Since 2010, when the Molecular Prescreening Program (MPP) was established at VHIO, we have adapted the techniques and procedures to improve the identification of genomic alterations in tumors from patients (pts) eligible to Early Clinical Trials (ECTs). Here we report the clinical utility of our program given the evolving molecular testing landscape and trends in drug development.

Methods: In the last 8 years, 5,775 formalin fixed paraffin embedded tumor samples were analyzed: from 2010 to 2014 we used a hotspot mutation panel (Sequenom, 20 oncogenes) plus FISH/IHC of selected markers; from 2015 to 2017 we moved to a custom amplicon-based NGS panel (MiSeq, 61 genes), a copy number (CN) panel (Nanostring, 44 genes) and a fusion + gene expression (exp) panel (Nanostring, 26 genes) with additional FISH/IHC in selected cases, including PDL1 and MSI status.

Results: We found a stepwise increase in the MPP, from 207 pts in 2010 to 1168 pts in 2017. Most common tumors were colorectal, lung, breast, gynecologic, pancreatobiliary, head & neck and gastric. In the last 8 years, the number of ECTs increased tenfold: from 13 in 2010 (11 PI3K inhibitor [inh]) to 137 in 2017 (including 55 immunotherapy [IMT], 11 RAF/MEK/ERK inh, 9 FGFR inh, 8 PI3K inh, 6 EGFR/HER2 inh and 6 antibody-drug conjugates). Inclusion rate in ECTs with targeted agents reduced from 2016 to 2017 (228 to 133), while IMT trial recruitment increased (179 to 245). In 2017, 862 tumors had NGS, 708 tested with IHC, 267 CN panel and 342 fusion + exp assay. As a result of this molecular profiling, 116 pts (10%) were enrolled in ETCs with 18 diffent biomarker matches (5.5% mandatory, 4.5% enrichment) and 220 pts (19%) were recruited in unmatched trials.

Conclusions: The MPP at VHIO is constantly adapting to the needs of our ECTs portfolio. Biomarker matched trials evolved from a “few targets/ large populations” scenario to a complex situation with “many targets/ small populations”. Moreover, the substantial increase of IMT trials had a major impact in trial prioritization, and will guide clinical implementation of new markers currently under development, such as tumor mutational load and inflammatory gene exp signatures.

Funding: Has NOT received any funding
Disclosure: All authors have declared no conflicts of interest.