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Pictogramme horloge December 2014

Genetic studies of solid tumours have led to an understanding of mechanisms of carcinogenesis that are specific to each solid tumour. The concept of targeted therapy is based on this principle: target a specific molecular alteration in the tumour cell and inhibit its proliferation. This idea of targeting requires the establishment of biological tests known as “companion diagnostics” or “biomarker testing” to identify the molecular defect for which a targeted therapy can be proposed. In 2014, targeted therapies are available for patients whose disease has become metastatic. In cases of breast cancer, ovarian cancer and cancers of the colon, lungs and stomach, as well as in melanoma and GIST, personalised drug-based therapy can be offered.

These tests to predict therapeutic response represent an area of a close collaboration between clinicians, pathologists, cytogeneticists and molecular biologists, and biostatisticians are about to join the fray. It is important to point out one issue: for the result of a biomarker test to be interpreted properly, it is essential to respect the pre-analytical processing conditions for the biopsy or tumour fragment.

These biological tests, which determine access to a targeted therapy, are distinct from cancer predisposition tests (oncogenetics) and tests to determine the diagnosis and/or prognosis of solid tumours.

There are 2 classes of drug, and these are divided based on their level of action on tumour cells:

  • Drugs with the suffix -mab (which stands for “monoclonal antibody”) target and block a receptor on the surface of tumour cells,
  • Drugs with the suffix -nib (for “inhibitor”) inhibit the tyrosine kinase activity of intracellular proteins involved in cell signalling pathways, hence the name TKI (tyrosine-kinase inhibitors).

A new class of drug that acts at the level of DNA repair mechanisms (anti-PARP antibodies) has recently emerged in the field of targeted therapy for ovarian and breast cancer.

The techniques used for companion diagnostics are varied and involve three biological disciplines: immunohistochemistry or IHC (e.g. IHC HER2 in breast cancer), fluorescence in situ hybridization or FISH (e.g. FISH HER2 in breast cancer or FISH ALK in non-small cell lung cancer) and molecular biology techniques (e.g. KRAS and NRAS in colon cancer, EGFR in lung cancer). The range of molecular biology techniques is broad: HRM, pyrosequencing, Sanger sequencing, SNaPshot or allelic discrimination using the Taqman probe, etc.). Next-generation sequencing techniques (NGS) allow more sensitive analysis, at higher speed and lower cost. In the near future, they will revolutionise the routine conduct of these companion tests.

To provide an example (not an exhaustive list), the tests that can be performed to determine access to a targeted therapy for which marketing authorisation has been granted are presented in the following table:

 

 DISEASE
 BIOMARKER
 ANOMALY INVESTIGATED
 TARGETED TREATMENT
 Breast cancer HER2

  Overexpression (IHC)

Amplification (FISH)

 

Trastuzumab

Pertuzumab
Lapatinib

 Stomach cancer HER2

  Overexpression (IHC)

Amplification (FISH)

 Trastuzumab
 Colorectal cancer

 KRAS

NRAS

 Absence of mutation

 Panitumumab

Cetuximab

 Non-small cell
lung cancer

 EGFR

(KRAS)

 

ALK

ROS

 

 Presence of an activating
mutation(TKI resistance)Overexpression (IHC)

Gene rearrangement
(FISH)

 Gefitinib
Erlotinib
Afatinib
Crizotinib
 Melanoma BRAF Presence of an activating
mutation		 Vemurafenib
Dabrafenib
 GIST C-KIT Presence of an activating
mutation		 Imatinib
 Ovarian cancer BRCA
PDFGRA		 Mutation Olaparib

The prognostic value of some biomarkers (e.g. BRAF in colorectal cancer: a mutation in this gene is associated with a poor prognosis irrespective of the treatments administered)
The notion of resistance to targeted therapies (e.g. KRAS in non-small cell lung cancer; this mutation is associated with resistance to TKIs).

In the future, prescription of a targeted therapy will therefore most likely involve investigation of a “panel” of mutations/biomarker changes, hence the avid interest in the scientific community for new technologies such as NGS.

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