The VAULT study aims to tackle the challenge of intra-tumour heterogeneity in cancer, where multiple genetically distinct subclones exist within the same tumour, complicating accurate molecular profiling and treatment decisions. Current diagnostic practices, which typically analyse a single tumour sample, may not capture this diversity.

To address this, the study explores a novel approach involving the retention and homogenization of leftover formalin-fixed tumour tissue, which is typically discarded after surgery, and is being conducted at The Royal Marsden Hospital (NHS Foundation Trust). This 'blending' method produces a more representative sample of the tumour's genetic landscape, improving the accuracy of DNA sequencing. 

Our pilot RepSeq data in kidney and other cancer types has demonstrated the potential of this methodology for robust mutational calling, accurate determination of cancer cell fraction and the ability to discern clonal from subclonal variants. We have published a STAR protocol on the technique which extends the utility of the technique and makes the technology accessible for researchers in other groups. 

The study's aims include:

  • Assessing Feasibility: determining the proportion of primary tumor cases with sufficient leftover tissue for homogenization across multiple cancer types.
  • Pilot Homogenization: implementing this technique in a pilot study involving 500 cases from various tumours, including breast, endometrial, ovarian, renal cancers, sarcomas, and melanoma lymph nodes.

Additionally, the research team is exploring the extension of this representative sampling method to profile the tumor microenvironment, particularly relevant for patients undergoing immune checkpoint inhibitor therapy. This aspect will be further investigated in the upcoming MANIFEST study, starting in 2025.

Clinical trial identification: NCT03832062

An illustration of a sample from a human figure can be standard or representative.

Figure 1: The three stages of tumour sampling

  1. Surgical tumour resection
  2. Standard sampling: samples are taken from different regions
  3. Representative sampling: the entire tumour is homogenised, sample aliquots are taken from this homogenised solution and representing a comprehensive representation of the tumour's heterogeneity.

Funding

Roche Diagnostics


Collaborators

  • The Royal Marsden Hospital (NHS Foundation Trust)
  • Dr Lisa Gallegos and Dr Nelson Alexander (Roche)