Collaborative research efforts between Canada and Australia have led to a better pathological understanding of aggressive prostate cancers, which could serve as an indicator for the genetic mutation, BRCA2.
The findings are part of a larger study published online this week in Nature Communications, showing that BRCA2- associated prostate tumours are pre-set to be resistant to standard therapies due to abnormalities in genes responsible for regulating cell growth and division.
Dr. Theodorus Van der Kwast, genitourinary pathologist, Laboratory Medicine Program, University Health Network and lead pathologist of the Canadian Prostate Cancer Genome Network (CPC-GENE) study, co-authored the publication and has since helped outline the role of pathology, sharing important characteristics of BRCA2 associated prostate cancer.
“Linking pathological properties of prostate cancer with genetic findings is a necessary step to developing therapies,” says Dr. Van der Kwast. “And the genetic findings of this study will likely affect clinicians’ decisions when patients show possible indicators of BRCA2.”
Intraductal and invasive carcinomas
A key pathologic component of the study is the distinction between intraductal carcinoma and invasive carcinoma, two cancerous cell structures that may be seen in prostate cancer. Because each is not mutually exclusive of each other there has been significant questioning regarding their development.
To investigate the properties of each, pathologists microdissected the prostate samples containing intraductal carcinoma, separating the two carcinoma components from each other and preserving each for individual genetic testing.
Through this, the research team discovered new information about the carcinomas’ development and proved two commonly held hypotheses wrong.
The first, being that the intraductal carcinoma spreads beyond the prostate ducts into surrounding tissue and becomes invasive carcinoma. The other, suggesting the opposite – that the invasive carcinoma pushes its way into the prostate ducts becoming intraductal carcinoma.
“What we found was that both carcinoma components by essence were distinctly different from each other,” say Dr. Van der Kwast. “The study showed that a common precursor cancer cell diverges into both intraductal and invasive carcinoma. This would mean that prostate cancers with intraducal carcinoma are entirely separate entities from those without.”
The role of pathology – step by step
- The first step for Dr. Van der Kwast and fellow pathology staff was finding, diagnosing and grading prostate cancer samples to ensure a high level of cellularity and consistency among all samples used in the study.
- Pathologists then identified which tissue samples have intraductal carcinoma present and ensured they were assigned for microdissection.
- Using laser microdissection equipment, the tissue sample, about the size of a dime, is dissected, allowing the intraductal carcinoma to be separated from the invasive carcinoma. The dissection process is precise down to the micrometer and uses a laser so thin target cells are left undamaged.
- Once the tissue sample has been micro dissected, both the intraductal carcinoma and the invasive carcinoma for each patient is sent to the genetics team for DNA, RNA and epigenetic testing.
How clinical decisions could be affected
Though inherited BRCA2 affects less than 2 per cent of men with prostate cancer, findings from the study may lead to earlier diagnoses, particularly for younger patients due to intraductal carcinoma being a potential indicator of the mutation.
Of the 14 prostate cancer samples from patients with BRCA2, approximately 57 per cent had intraductal carcinoma present, and of the 500 non-BRCA2 cases studied, just 27 per cent had intraductal carcinoma present.
“For pathologists this means that when a younger patient, below the age of 50 has prostate cancer containing intraductal carcinoma, there is reason to believe they could have the inherited BRCA2 mutation and genetic testing may be a consideration,” says Dr. Van der Kwast.
The genetic findings of the study will likely lead to new treatment options for patients with BRCA2 as well.
Co-principal investigator Dr. Robert Bristow, clinician-scientist at Princess Margaret Cancer Centre, University Health Network says, “We now know we need to explore the use of novel therapies to offset the BRCA2-associated aggressiveness earlier on in the treatment of these men and improve survival in an otherwise lethal tumour. This might include different types of chemotherapy or the use of molecular-targeted drugs that specifically target the changes associated with BRCA2 mutation.”
A team effort
The study required the collaboration of researchers from Toronto, Quebec City and Melbourne, Australia to collect the necessary amount of frozen tissue samples needed for the study.
“Due to the characteristics of prostate cancer, it can be very challenging to locate the cancerous area of the prostate in surgical specimens,” says Dr. Van der Kwast. He says because of this, pathology staff reviewed over 1,000 different frozen tissue samples in order to collect the 514 samples used in the study.
“It takes immense collaboration to produce a study of this magnitude,” says Dr. Van der Kwast, “and everybody plays an important role.”
“As a pathologist, this type of investigation provides the opportunity to ask fundamental questions from a pathology perspective that can go on to affect future studies.”
Additionally, he says because the study is part of the CPC-GENE Sequencing Project, the genomic and pathologic data collected from every sample will be made available to fellow researchers from around the world.