Scott T. Tagawa, MD, FACP: Prostate cancer, like other cancers, presents a certain heterogeneity. It occurs in an entire body, which means that different tumors can be genotypically or phenotypically different from each other. And then, even within tumors, there can be differences in one area compared to another.

Prostate cancer is usually an adenocarcinoma. The 2 terms are more or less close to synonyms. When we say prostate cancer, we usually mean adenocarcinoma of the prostate. But there are different histologies when diagnosing primary prostate tumors, and there may be some differences over time, one of the mechanisms being lineage plasticity, i.e. starting with adenocarcinoma then changing histologically to small cell or neuroendocrine prostate cancer, for example. This can happen more and more with increased pressure against the main pathway that we know is active in prostate cancer, the androgen receptor pathway, or AR. These more powerful hormonal agents can change that.

An important target in prostate cancer is the prostate specific membrane antigen, or PSMA. This has a reciprocal relationship with the androgen receptor, which means that as there is more pressure or deregulation of the androgen receptor pathway, for example with hormone therapy blocking this pathway against prostate cancer cells, Generally speaking, any prostate cancer cell that is able to survive ends up with a higher amount of PSMA, which is a cell surface antigen. That being said, in the types of tumors that lose the AR pathway i.e. small cells or neuroendocrines, these are the types of tumors that can lose PSMA as well.

We assess prostate cancer, like other cancers, with a number of different modalities. This includes biopsies, liquid biopsies such as in blood assessment, as well as imaging. Each of them is different with its own advantages and disadvantages and is complementary. For example, a biopsy gives us very good histology and a very high level of depth of coverage if we want to look at genomics, transcriptomics, or omics in general. Many of them are now clinically in prime time. But what we learn is what’s in that needle. There may be different areas in what’s in that needle, but that doesn’t tell us about the rest of the tumor that was not biopsied in that needle, or other areas. In addition, although we have better and less invasive techniques, biopsy remains an invasive procedure. And prostate cancer is often localized in the bones, which for many places outside of academic centers is a bit more difficult in terms of handling and processing the sample.

With liquid biopsies, we’ll usually be looking at either circulating tumor cells, which are good for protein, and RNA, as well as plasma, and cell-free DNA, which in today’s era, I think. that the best tests for this also include some germ line testing. I won’t go into details on this, but these are interesting because we are able to get sequential analyzes. For example, PSA [prostate-specific antigen] is a circulating test, it just isn’t a DNA test. What this tells us is more or less a summary of what is going on with the patient. It doesn’t tell us if one dominant lesion secretes all that DNA, or if it’s a tenth of 10 different lesions that exist. But this type of test has the advantage of being minimally invasive and of being able to be dosed sequentially over time.

Imaging has long told us about cancer in general, including prostate cancer, in terms of location as well as certain characteristics, namely, bony, sclerotic or blast, or whether it is lytic in nature. Prostate cancer is usually sclerotic or blastic, but prostate cancer of a lytic nature tells us something about it. But with molecular imaging, in general PET [positron emission tomography] imaging, we are able to obtain a more phenotypic characterization. And unlike a single biopsy, we’re able to look at it lesion by lesion and say, do they show up on this test evenly, or is there some heterogeneity that we see across the body?

I used the terms genotypic and phenotypic. Genotyping is generally what is in the genes. Generally speaking, it is DNA. The phenotypic can have different definitions. Perhaps this is how genes are expressed or subsequently translated into what happens in actual cells. It may also have to do with histology, as I mentioned. For example, a tumor may have similar genes, such as a TP53 alteration and an RB [retinoblastoma] alteration, but histologically may resemble a typical adenocarcinoma or small cell carcinoma. These are differences between the actual genes and the phenotype.

Transcription edited for clarity


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