1. Comprehensive molecular profiling should be the preferred test rather than a molecular cancer classifier assay?
AGAINST:
Dr Natalie Cook
Senior Clinical Lecturer in Experimental Cancer Medicine, University of Manchester
Honorary Consultant in Medical Oncology
Christie NHS Foundation Trust

2. Premise
Tissue agnostic therapeutic approaches are too simplistic Context matters

3. Hereditary cancer syndromes and tissue-specific tumorigenesis
The idea is that germline mutations can predispose to very specific cancer types (left) or more broad (right). The fact that APC mutation promote specific cancers suggests that different tissues have different requirements for genes, and therefore knowing the tissue in which the mutation occurs is important.
Certain genes have tissue specific roles
………..Context Matters
Schneider et al, Nature Reviews Cancer 2017

4. Tissue-specific genetic alterations and differential responses
Tissue-specific genetic alterations and differential responses Different human cancers contain a subset of recurring cancer driver gene mutations and chromosome copy number alterations that are specific for, or enriched in, that tumor type. The underlying tissue-specific epigenetic architecture may differentially determine the responsiveness to oncogenic signals and thus the propensity to acquire alterations that lead to cancer.
…….Context Matters
Kevin M. Haigis et al. Science 2019;363:
Published by AAAS

5. Vemurafenib activity against BRAFV600E tumours
NSCLC
Melanoma
COAD
Other
Sosman et al, NEJM 2012
Tissue-specific activity of vemurafenib against BRAF mutant tumours.
…….Context matters
Hyman et al, NEJM 2015

6. Oncogene vs. Tumour Suppressor gene
Types of context: 1) Tissue
2) Genetic background
3) Tumour stage
…….Context matters
Proto-Oncogenes with Tumour Suppressor Function
Shen et al, Oncogenesis 2018
Some genes have completely different roles in different cancers. Top table is from a paper that tried to systematically identify these genes. Bottom table I made where I take a few examples and show in which tissues they are oncogenes and which are TSG.
Gene
Oncogene in:
Tumour suppressor in:
Therapy
NOTCH
Breast, T-ALL, Ovarian, Lung, Pancreas
HNSC, HCC, Bladder, Oesophagus, Small cell lung
GSI (various)
EZH2
DLBCL, Prostate , CRC, Melanoma
Lung, T-ALL, AML
Tazemetostat
STAT3
GBM, Prostate, Breast, DLBCL
CRC, Salivary
TTI-101, AZD9150

7. The SHIVA Trial: The failure of tissue agnostic precision medicine
SHIVA trial shows no difference between matched and non-matched therapies. Lots of potential issues with this trial, but at least on the surface it supports the idea that tissue-agnostic precision medicine does not work.
LeTourneau et al, Lancet 2015
…….Context matters

8. NGS ignores the non-cell autonomous compartment
Play a critical role in the maintenance of the cancer

9. Practical Aspects AND……..CONTEXT MATTERS
Molecular cancer classifiers are cheaper than NGS
Standard of care limited to certain cancer types (e.g. Immunotherapy)
Many trials will only accept certain cancer types
IDH1 mutation etc on CUPISCO FGFR3
AND……..CONTEXT MATTERS