Scott T. Tagawa, MD, FACP, discusses the heterogeneity and features of prostate cancer and provides insight on biomarker testing.
Scott T. Tagawa, MD, FACP: Prostate cancer, like other cancers, has some heterogeneity. This happens within an entire body, meaning different tumors might be different from others either genotypically or phenotypically. And then even within tumors, there may be some differences in one area vs another.
Prostate cancer as a general rule is an adenocarcinoma. The 2 terms are more or less close to synonyms. When we say prostate cancer, we generally mean adenocarcinoma of the prostate. But there are different histologies at diagnosis of primary tumors in the prostate, and there may be some differences over time, with one mechanism being lineage plasticity, meaning starting as adenocarcinoma and then changing histologically to small cell, or neuroendocrine prostate cancer, for instance. That may happen increasingly with increased pressure against the main pathway that we know is active in prostate cancer, the androgen receptor, or AR, pathway. These more potent hormonal agents may change that.
One significant target in prostate cancer is prostate-specific membrane antigen, or PSMA. That has a reciprocal relationship with the androgen receptor, meaning that as there’s more pressure or dysregulation of the androgen receptor pathway, for instance with hormonal therapy blocking that pathway against prostate cancer cells, generally speaking, any prostate cancer cell that’s able to survive that ends up with a higher amount of PSMA, which is a cell surface antigen. That being said, in those types of tumors that happen to lose the AR pathway, ie, small cell or neuroendocrine, those are the tumor types that may also lose PSMA.
We assess prostate cancer, like in other cancers, with a number of different modalities. This includes biopsies, liquid biopsies as in assessment of blood, as well as imaging. Each one of these are different with their own advantages and disadvantages and are complementary. For instance, a biopsy gives us very good histology and a very high level of depth of coverage should we want to look at genomics, transcriptomics, or omics in general. Many of these are now clinically in prime time. But what we learn is what’s in that needle. There may be different areas within what is in that needle, but it doesn’t tell us about the rest of the tumor that was not biopsied within that needle, or other areas. In addition, even though we have better, less-invasive techniques, it’s still an invasive procedure to have a biopsy. And prostate cancer is often located in bone, which for many places outside of academic centers is a little more difficult in terms of handling and processing of the specimen.
With liquid biopsies, we’ll generally look at either circulating tumor cells, which are good for proteins, and RNA, as well as plasma, and cell-free DNA, which in today’s era, I believe the best assays for that also include some control for germline. I won’t go into the great details of that, but these are nice because we’re able to get sequential assays. For instance, PSA [prostate-specific antigen] is a circulating assay, it just doesn’t happen to be a DNA assay. What that tells us is more or less a summary of what’s going on with the patient. It doesn’t tell us if 1 dominant lesion is secreting all of that DNA, or if it’s one-tenth from 10 different lesions that are out there. But this type of test does have the advantage of being minimally invasive and able to be assayed sequentially over time.
Imaging has long told us a lot about cancer in general, including prostate cancer, in terms of location as well as some characteristics, ie, bone, sclerotic or blastic, or whether it’s lytic in nature. Prostate cancer is usually sclerotic or blastic, but prostate cancer that’s lytic in nature tells us something about that. But with molecular imaging, generally speaking of PET [positron emission tomography] imaging, we’re able to get more phenotypic characterization. And unlike a single biopsy, we’re able to look at it lesion by lesion and say, are they appearing on this test homogeneous, or is there some heterogeneity that we see across the body?
I used the terms genotypic and phenotypic. Genotypic is generally what’s in the genes. Generally speaking, that’s DNA. Phenotypic can have some different definitions. That may be how the genes are expressed or subsequently translated in what happens in the actual cells. It may also have to do with histology, as I mentioned. For instance, a tumor may have similar genes, such as a TP53 alteration and an RB [retinoblastoma] alteration, but histologically may look like typical adenocarcinoma or small cell carcinoma. Those are differences between the actual genes and the phenotype.
Transcript Edited for Clarity