Identification of biomarkers to predict relapse in stage I non-seminomatous testicular germ cell tumours
Lead Research Organisation:
Institute of Cancer Research
Department Name: Molecular Carcinogenesis
Abstract
Testicular cancers are the most common cancer in young Caucasian men. Although largely curable, optimising treatment for individual patients is an important clinical issue.
For some patients it is currently difficult to predict whether their tumours have spread microscopically and need more treatment compared to those that will be cured with less treatment. As treatments can have serious long-term side-effects such as heart problems and risk of developing other cancers, unnecessary over-treatment of patients should be avoided. On the other hand, if patients are under-treated and their cancers reoccur, further more aggressive salvage treatment, with the associated long term side-effects, is required.
Based on the underlying molecular biology of these tumours our pilot work at The Institute of Cancer Research suggests a promising biomarker to predict otherwise undetectable tumour spread. In our proposed study we will test particular testicular cancer samples from former patients who either did or did not require additional treatment. This will allow us to determine whether our marker, and another promising candidate from available reports, can accurately predict which patients had undetectable tumour spread. A marker would allow optimised patient treatment. Whilst maintaining cure, this would avoid the potentially serious health problems later in life that are associated with over-treatment.
For some patients it is currently difficult to predict whether their tumours have spread microscopically and need more treatment compared to those that will be cured with less treatment. As treatments can have serious long-term side-effects such as heart problems and risk of developing other cancers, unnecessary over-treatment of patients should be avoided. On the other hand, if patients are under-treated and their cancers reoccur, further more aggressive salvage treatment, with the associated long term side-effects, is required.
Based on the underlying molecular biology of these tumours our pilot work at The Institute of Cancer Research suggests a promising biomarker to predict otherwise undetectable tumour spread. In our proposed study we will test particular testicular cancer samples from former patients who either did or did not require additional treatment. This will allow us to determine whether our marker, and another promising candidate from available reports, can accurately predict which patients had undetectable tumour spread. A marker would allow optimised patient treatment. Whilst maintaining cure, this would avoid the potentially serious health problems later in life that are associated with over-treatment.
Technical Summary
Testicular Germ Cell Tumours (TGCT) are the most common solid malignancy in young adult Caucasian men. Although largely curable, long-term risks associated with their treatment, including cardiovascular disease and secondary malignancies, raise significant issues in their clinical management. Approximately 25-30% of patients with stage I nonseminomas (NS) will relapse from micrometastatic disease not detectable at presentation. In those with vascular invasion, the best current risk factor, this rises to 35-40% versus 15-20% when absent. Using this relatively poor discriminator to direct adjuvant treatment, 60-65% are unnecessarily over-treated. Better risk stratification is therefore urgently required.
TGCT express the chemokine receptor CXCR4 involved in metastatic progression of various tumours. Our pilot data demonstrate migration of TGCT cells towards SDF1, the ligand for CXCR4, in model systems. We have also shown expression of this ligand in a subset of NS and an association with reduced risk of relapse in stage I patients. In addition, the proliferation rate of primary tumours (for which MIB1 is a marker) is reported to be associated with increased risk of metastases in a range of cancers, although data for stage I NS is limited.
Our aims are:
sum To test the efficacy of SDF1 and MIB1 expression to predict relapse in stage I NS patients monitored by surveillance. We will determine whether these are better than or complementary to vascular invasion.
sum To develop a tissue resource of well-characterised formalin fixed paraffin embedded (FFPE) material associated with the MRC TE08 and TE22 clinical trials for this and future ethically approved studies in our laboratory and biological studies channelled through the NCRI Testis Clinical Studies Group.
We will carry out immunohistochemical analysis of SDF1 and MIB1 on tissue microarrays that we will prepare and are estimated will represent material from at least 80% of the 501 patients on surveillance in the TE08 and TE22 MRC clinical trials. From our previous pilot study of SDF1, we will have high power to detect an independent effect of these factors in multivariate analyses for relapse including vascular invasion.
It is anticipated that the results will lead to SDF1 +/or MIB1 immunohistochemistry being recommended as predictive markers of relapse in stage I NS and therefore of use in clinical practice. This would be conveyed through publication of results, NCRI meetings, websites and literature. The supraregional nature of testicular cancer management within the NHS allows rapid dissemination of practice changing data.
TGCT express the chemokine receptor CXCR4 involved in metastatic progression of various tumours. Our pilot data demonstrate migration of TGCT cells towards SDF1, the ligand for CXCR4, in model systems. We have also shown expression of this ligand in a subset of NS and an association with reduced risk of relapse in stage I patients. In addition, the proliferation rate of primary tumours (for which MIB1 is a marker) is reported to be associated with increased risk of metastases in a range of cancers, although data for stage I NS is limited.
Our aims are:
sum To test the efficacy of SDF1 and MIB1 expression to predict relapse in stage I NS patients monitored by surveillance. We will determine whether these are better than or complementary to vascular invasion.
sum To develop a tissue resource of well-characterised formalin fixed paraffin embedded (FFPE) material associated with the MRC TE08 and TE22 clinical trials for this and future ethically approved studies in our laboratory and biological studies channelled through the NCRI Testis Clinical Studies Group.
We will carry out immunohistochemical analysis of SDF1 and MIB1 on tissue microarrays that we will prepare and are estimated will represent material from at least 80% of the 501 patients on surveillance in the TE08 and TE22 MRC clinical trials. From our previous pilot study of SDF1, we will have high power to detect an independent effect of these factors in multivariate analyses for relapse including vascular invasion.
It is anticipated that the results will lead to SDF1 +/or MIB1 immunohistochemistry being recommended as predictive markers of relapse in stage I NS and therefore of use in clinical practice. This would be conveyed through publication of results, NCRI meetings, websites and literature. The supraregional nature of testicular cancer management within the NHS allows rapid dissemination of practice changing data.