Dr. Stephanie Graff: Understanding Progression

Essential KnowledgeMedical CommunityChallenges and BarriersMBC Imaging and ProfilingDifficult to TreatNovel TreatmentsObstacles to Better OutcomesDiagnosis and TreatmentEntities of Cancer

Apr 21

Written By Our MBClife

In the inverted language of MBC, “unremarkable” is something we all aspire to, and “progression” is something we dread. Progression means that our current medication regimen is no longer working and cancer is spreading and/or growing. It means that treatment is likely to change—bringing new drugs with new side effects. It also means that we’ve exhausted one of the available treatment options for our disease, leaving fewer remaining lines of treatment. In this episode, breast oncologist Dr. Stephanie Lynn Graff helps us unravel the mysteries of progression and resistance, tissue and liquid biopsies, tumor markers and scans.

Episode Notes

Receptors are molecules that live on the surface of a cancer cell that can be filled (and attract) by a specific ligand, or put another way receptors are proteins or glycoprotein that bind signaling molecules known as first messengers, or ligands. They can initiate a signaling cascade, or chemical response, that induces cell growth, division, and death or opens membrane channels.
This ligand can also colloquially be called “fuel” since when the receptors are filled, that allows the cancer cell to continue to proliferate and take over more healthy cells. If you are interested in learning more about receptors
When a ligand binds to its respective receptor, the shape and/or activity of the ligand is altered to initiate several different types of cellular responses.
Cellular receptors are proteins either inside a cell or on its surface, which receive a signal. In normal physiology, this is a chemical signal where a protein-ligand binds a protein receptor. The ligand is a chemical messenger released by one cell to signal either itself or a different cell.
Receptors are a special class of proteins that function by binding a specific ligand molecule. When a ligand binds to its receptor, the receptor can change conformation, transmitting a signal into the cell. In some cases the receptors will remain on the surface of the cell and the ligand will eventually diffuse awa
Like most, enzyme-linked receptors are transmembrane proteins but they are unique because in addition to receiving signals from chemical messengers they also function as enzymes. Binding of a signaling molecule activates the receptor's enzymatic activity
Tyrosine kinases are a family of enzymes, which catalyzes phosphorylation of select tyrosine residues in target proteins, using ATP.
Receptor tyrosine-protein kinase erbB-2, also known as CD340 (cluster of differentiation 340), proto-oncogene Neu, Erbb2 (rodent), or ERBB2 (human), is a protein that in humans is encoded by the ERBB2 gene.
The main difference between enzyme and protein is that the enzyme is a biological catalyst whereas the protein can involve in the formation of structures, transportation, catalysis, and regulation of biological processes.
Enzymes and proteins are intrinsically linked and often confused. Essentially, an enzyme is a specific type of protein that performs a very specific function. Enzymes function to regulate biochemical reactions in living things, in this sense, they operate solely as a functional protein, while a protein can be either functional or structural. Therefore, all enzymes can be adequately described as globular proteins, however, not all proteins are globular. Proteins are macromolecules, that consist of polymers of amino acids that come to operate as the structural and functional basis for cells within living things. A protein can have multiple functions, including but not limited to enzyme catalysis, defense, transport, storage, and support.
For breast cancer, there are three (3) different receptors that are typically used to describe a subtype and which are often targeted for treatment. They are:
1) Estrogen;
2) Progesterone; and
3) Her2 neu.
For the first two receptors, both hormones made naturally by the body, a pathology report will include a percentage of positivity.
For the last receptor, the pathology reports typically just include positive or negative; however, there is some new data/studies looking at a third category of Her2-low, which opens up some additional treatment options
From the interview transcript: “
I am going to use HER2 as an example.
Remember, at the very beginning of your breast cancer diagnosis, you were probably told that your HER2 was HER2 0, 1+, 2+, or 3+. That means that when we look at your cancer under the microscope and literally dump ink on cells, that's how much ink sticks to your cancer under the microscope. What the ink is sticking to is the HER2 receptors. And the more ink that sticks, the more receptors are on the surface of the cell. And so somebody who has 1+ has more receptors than somebody who is HER2 0 and somebody who has her 2+ has more than somebody who has 1+.
Our definition of positive is 3+. For somebody who's 2+, we typically do the FISH test to look to see if they're amplified, because you can have a medium number of receptors and still have that gene turned on in the cell.
But we know that a lot of breast cancer will have HER2 on the surface. That's why now we're seeing trastuzumab deruxtecan being tested and this new concept. of HER2 low breast cancer
People who are her2 zero, it's not that they don't have any of HEr2, it's that there's not much ink sticking to that cancer cell. So when cancers develop resistance. Interestingly, one of the mechanisms of estrogen resistance is to up-regulate HER2, because there's some crosstalk in the cell.
And so by making more, HER2 on the surface, it can help bypass that estrogen blockade, even if HR2 isn't your cancer's thing. So even if you are HER2 negative, your breast cancer can use HER2 to get around estrogen.
Up-regulation just means that your cancer cell decides to sprout more of that particular pattern on the surface of cancer cells.
Down-regulation is the opposite of that process. Down-regulation is the mechanism that estrogen typically uses. And we see that a lot in tumors. They down-regulate the progesterone receptors. So we see somebody who has ER 95% PR 95% on the future biopsies become ER 80% PR 40%.
Their cancer starts to turn down how much estrogen and progesterone is being expressed, and that's a way it's developing resistance.
A tumor marker is a biomarker found in blood, urine and body tissue. It could be produced by the tumor itself or by the body's response to the tumor. In breast cancer, there are tumor markers in the blood that your doctor may measure serially. Serial measurements show how the level of a marker changes over time. In some people, a decrease in the level of a specific marker may mean the tumor is responding to treatment while an increase could mean the opposite. The usefulness of the information these tumor markers provide depends on various factors, including the subtype of breast cancer.
They may have less usefulness in HER2 positive and TNBC subtypes and the individual patient. The most frequent serial measured tumor markers in the blood for breast cancer are
1. CEA Which is a marker that's often used for colorectal cancer, but it can be useful in monitoring treatment response in breast cancer, too
2. CA 15-3 and CA 27-29 CA stands for Cancer Antigen are related tumor markers that are made by breast cancer cells. So finding them in the blood, it can signal breast cancer or lack of treatment effectiveness.
3. CA-125 is associated with both ovarian cancer and breast cancer
Tumor markers like these can be elevated for reasons, unrelated to breast cancer, such as another type of cancer or benign condition.
They are one of the tools our doctors can use to see what is happening, but on their own, they aren't sufficient to monitor for progression or treatment effectiveness.
Liquid biopsy is the use of a patient fluid sample rather than a tissue sample for the same kind of clinical utility one would get from a traditional biopsy. It has been shown that during tumor progression, the tumor can shed a few biomarkers into the bloodstream, including cells, proteins, and nucleic acids. These are linearly related to the size of the tumor and can provide a snapshot in time of the tumor status due to short biomarker half-life.
Some of the most commonly used biomarkers for liquid biopsy are circulating tumor cells (CTCs). CTCs are whole cells that shed off of the tumor and can be captured in a simple blood draw It has been shown that the concentration of CTCs correlates with disease severity, and that the surface receptors and molecular contents of the CTC are reflective of the tumor One of the major challenges with CTC capture and detection is that they are extremely rare, with typically fewer than 10 CTCs in a standard blood draw, making their separation from background blood components a challenge Once captured, CTCs can provide a wealth of information about the tumor, including an understanding of surface antigens and genetic profiling.
Another biomarker of interest is circulating tumor DNA (ctDNA). ctDNA is DNA that sheds out of the tumor through secretion, apoptosis, or necrosis It is widely believed that ctDNA can be detected sooner than other circulating biomarkers due to its larger fragment number in the blood ctDNA poses a challenge for capture and detection because it is relatively small and low in concentration. One of the biggest challenges with ctDNA capture and analysis is differentiating tumor DNA from healthy cell DNA. This requires that the technology can distinguish relatively low concentrations of mutant ctDNA in a wild type background.
The liquid biopsy represents in a more exhaustive way than the tissue biopsy the molecular heterogeneity of the disease containing, at least potentially, tumor DNA deriving from the different areas of the same tumor and possible disease locations. Moreover, the liquid biopsy can be repeated over time to monitor the molecular evolution of the disease, although there is no evidence to date to change the therapeutic choice, in the absence of clinical progression.
Response evaluation criteria in solid tumors or RECIST is the gold standard to evaluate treatment response by using a standard measurement to evaluate the changes in the dimensions of a metastatic leasion. By using these rules, clinicians can determine when patients improve, stay the same or stable, or worsen on a treatment.
The RECIST criteria have gained widespread adoption and a widely used in oncology clinical trials. But there lies the problem. They're based on the anatomic measurement of solid tumors. . Bone metastases are typically difficult to measure with rulers
Bone metastasis are classified as blastic, lytic, and sclerotic, and they can even be mixed. Blastic lesions fill the bone with extra cells, whereas lytic lesions destroy those cells. When we see sclerotic lesion on our scans, it's typically talking about hardening of the bone in response to treatment representing healing.
NCCN stands for National Comprehensive Cancer Network. It's a set of guidelines that are updated periodically and accepted widely. They're used to guide providers to consider best practice treatment options. When planning a treatment regimen, practitioners will keep the guidelines into consideration, but we'll also review the most recent advances as well as patient circumstances to come up with an individualized plan.
Traditional PET scans rely on a glucose based imaging agent that is taken up by cancer cells to diagnose metastatic sites and disease activity Syriana, which is also. F-18, Flouroestrodiol or FES for short. is a new type of PET scan that uses a contrast agent that binds to the estrogen receptor on cancers.
So only the cells that are positive for estrogen receptor will light up on the FES scan your doctor can see if you are all ER positive, partially ER positive or not at all, which will guide treatment decisions. If the FES scan shows that all metastatic sites seen on PET pet scan are also lighting up as ER positive, typo might not need to do a tissue biopsy because you'd be a candidate for estrogen blockade therapies. If however, the metastatic sites seen on PET scan do not then show up as ER positive on the FES scan, a tissue biopsy is needed to determine the molecular makeup. So. It's typically the next step to inform the best treatment for your disease.