Prostate Cancer Lab #26: Clinical Guidance from Proteomics (Sheeno Thyparambil)

Most cancer patients these days get a genomic analysis (DNA sequencing) of their tumor tissue. Some get translational analysis (RNA sequencing), even though few oncologists may know how to interpret the RNA results. Few patients get proteomic analysis, so most are missing this opportunity for additional treatment guidance. There are biomarkers that can be identified through proteomic analysis, such as HER2, that can point to targeted drugs with better patient outcomes than standard treatments.

Depending on genomics analysis alone to guide treatment can introduce errors. When you go from DNA to RNA to protein, how much information is lost? When you go from DNA to RNA, let’s say 50% of your information is transmitted. And then from RNA to protein, maybe 30% of the information is translated. So, when you go from DNA to proteins (gene expression), we know there is a loss of information. Yet all drugs are acting against proteins, so the question becomes, should I measure the levels of proteins to see what’s actually being expressed, either through mass spectrometry or immunohistochemistry, to know if the proteins are being expressed? This can be super helpful.

Dr. Sheeno Thyparambil is the Senior Director (R&D) of the mProbe Precision Oncology division. He has extensive experience in developing and deploying clinical diagnostics products, especially the use of mass spectrometry for clinical tests. He describes how mass spectrometry-based clinical proteomics can guide treatment decisions, providing arguments advanced cancer patients can use with their oncologists to liberate some of their tissue (FFPE) for this test. It’s important to be able to distinguish the additional information that is gained from proteomics, especially beyond genomic testing.

A main reason why a lot of oncologists and patients are interested in mass spectrometry-derived proteomic tests is helping with chemotherapy decisions. Many tests help inform targeted therapy decisions, or whether you need chemo or not, but few help decide what type of chemo regimen to choose. For example, mass spectrometry-derived protein biomarker reports will say, “This patient is likely to respond to some chemotherapies, like epirubicin or doxorubicin, or they will have a resistance to other drugs, such as a cisplatin- or oxaliplatin-based drug.”

On the targeted therapy side, the most popular protein biomarkers are HER2 (human epidermal growth factor receptor 2, an important protein in breast and gastric cancer) and PDL1 (programmed death ligand-1, a protein that helps keep immune cells from attacking non-harmful cells in the body), but there are others, especially for prostate cancer, such as AR TROP2 (androgen receptor trophoblast cell-surface antigen-2, an important target for antibody-drug conjugates), which point to new drugs. Another example: 15% of all glioblastomas tend to have very high levels of the biomarker TOPO1, which you can treat with a drug (irinotecan). Brian McCloskey has a high expression of B7-H3, for which there are targeted treatments. Knowing his TOPO1 levels could be useful. For patients with metastatic castrate resistant prostate cancer, you should find out what your TROP2 levels are, and if they are high enough, you should consider enrolling in one of two clinical trials of drugs that bind to TROP2.

Proteomic identification of biomarkers can also steer treatment to a clinical trial. For example, a patient showed a very high level of a biomarker (MET, mesenchymal epithelial transition factor receptor), then after a round of chemotherapy, the biomarker jumped. The oncologist decided to switch the patient’s treatment to a phase one clinical trial targeted on the biomarker, which was very successful.

HER2 levels can point to treatments outside of gastric and breast cancers. A patient with pancreatic cancer usually has less than a year of survival. In one case, a pancreatic cancer patient with unusually high HER2 was given an anti-HER2 drug, and this patient is 180 weeks out and still doing very well. HER2 can also be relevant for prostate cancer. In 71 prostate cancer samples, about three to five patients had high levels of HER2. They would want to enroll in an anti-HER2 clinical trial. Even with low HER2, there is a clinical trial that is going on in prostate cancer, which is a combination of a drug for low HER2 – Enhertu or trastuzumab deruxtecan – and a PARP inhibitor.

Mass spectrometry from FFPE tissue can also predict the overall survival of patients. For example, outcomes were accurately predicted in a study of breast cancer patients with high HER2 expression.

The inputs for the test process are relatively straightforward, and the results arrive relatively fast. Once mProbe receives two slides of tumor tissue (FFPE), five days later a clinical report goes to the oncologist with the levels of 72 biomarkers.

What’s next for proteomics? Having examined a few targets in prostate cancer to see what the distribution is, it is surprising to see the number of treatment opportunities, especially for TROP2 and HER2. We can go back at some point and examine the 72 biomarkers to see what else we can find. Not all patients are unique. For every patient, what works? What are the options if something is not working?