Tumor Heterogeneity

“Tumor Heterogeneity” (TH) is a phrase that often comes up in discussions with my medical team and with researchers as we all attempt to understand and anticipate the behavior of the cancer cells. From some of my discussions with other patients on social media, there does seem to be a lot of confusion about this phrase and I’ve not always been clear on its meaning or implications myself. And so I’ve taken some time to delve into the definition and why it impacts our treatment for Stage IV Metastatic Breast Cancer (MBC). I’ve linked some articles below for anyone to read more and if I’ve not explained well, please feel free to ask questions.

Let’s start with the more unfamiliar work, “heterogenous:”

Heterogenous (adjective) means: “Diverse in character or content.”

https://www.lexico.com/en/definition/heterogeneous

The way I remember this is to think of being heterosexual means that there is a male and a female in a relationship. With tumor heterogeneity, it is the understanding that a tumor/lesion is made up of a variety of cancer cells that are different.

Here’s an explanation from Wikipedia:

Tumour heterogeneity describes the observation that different tumour cells can show distinct morphological and phenotypic profiles, including cellular morphology, gene expression, metabolism, motility, proliferation, and metastatic potential.^[1]

https://en.wikipedia.org/wiki/Tumour_heterogeneity

In breast cancer, we get as much information about our subtypes, the receptors, the mutations in order to determine the best treatment, the best nutrition, the best supplements. For example, for those of of us with a high percentage of estrogen receptors, we do our best to avoid anything that acts like estrogen as well. I’ve written before about how we are often segregated into groups based on our subtypes because the cancer acts differently and the treatments are often substantially different.

But tumor heterogeneity tells us that this classification isn’t static, that the cells can be very different within the tumor as well as between tumors. Here’s a few other terms: 1) inter-tumor heterogeneity, which means that different tumors within the same body may have different characteristics; and 2) intra-tumor heterogeneity, which means different cells within the same tumor (this is usually what is meant by tumor heterogeneity, but it’s important to understand that it might not be the whole story).

Why does this happen?

A minimal level of intra-tumour heterogeneity is a simple consequence of the imperfection of DNA replication: whenever a cell (normal or cancerous) divides, a few mutations are acquired^[2]—leading to a diverse population of cancer cells.^[3]

https://en.wikipedia.org/wiki/Tumour_heterogeneity

One of the basic reason that cancer cells are so insidious is that the brakes are turned off. Cells divide, cells replicate, and then cells die all over the body all the time every day. But cancer cells are different. They divide and replicate like mad and then do it all over again and again and again without a natural end or brake. This behavior and the speed at which it happens means that some or all of the new cells are likely different from the parent cells and there’s no way to predict how other than to know that there will be differences.

As new technology improves our understanding of tumor heterogeneity, there are implications in the treatment and clinical guidelines. An article that does a pretty good job of explaining the overview of how can be found here. Unfortunately, since we can’t test or understand each individual cell, doctors and researchers do have to rely on trends and statistics and some generalities.

For instance, when I recently had progression to my liver and three different lesions lit up more significantly than the other tiny ones, I initially wanted the interventional radiologist to biopsy all three. After discussions with the director of the department and my medical oncologist, we ended up taking samples from two that were close together because of the risk of bleeding and because the likelihood of the tumors/lesions that appeared in the same progression were statistically likely to be the same. The balancing act between my desire for more information and the likelihood that information would be something we could do something about was a little infuriating, to be honest.

Here are some of the ways that tumor heterogeneity can affect the experience of MBC:

• Information gained from a biopsy may be different from the pathology of the entire tumor. Depending on where the interventional radiologist took the sample from the tumor (center, outside, etc.) the results of the biopsy might be different from when the pathologist tests the entire tumor. This is why staging and diagnosis isn’t finalized until the pathology of a tumor that has been removed is finalized.
• Gaining or losing receptors with progression. I wrote recently about Receptors and my experience of losing the Progesterone receptor. It is not uncommon for metastasis to be different from the original tumor by losing a part or characteristic of the original tumor that has been targeted with treatment. For those of us who have received years of hormonal or endocrine treatment, losing the receptor that has been targeted with these medications is likely a result of the cancer mutating to ensure that the medication is no longer effective, meaning mutating to stay alive.
• Biopsies/pathology may show that different tumors have different subtypes. It is not impossible to have a tumor that is triple negative (meaning no hormonal or HER2neu receptors) and a tumor that is hormone positive at the same time. I know people who have had this happen to them. Having more than one subtype means that both subtypes must be treated and this can get complicated. Again, just shows you how the cancer can mutate around the treatment in order to proliferate more.
• Mutations appear and disappear. Somatic mutations, which are acquired by specific cells, can appear and disappear. I wrote recently about how the mutations that showed up in the liquid biopsy I had recently are similar to mutations that showed up in the past and some are new, some are targetable and some are not. Again, a result of the copies of the cancer cells mutating and changing due to treatments.
• If multiple tumors in both breasts are homogeneous, that can indicate a germline/genetic mutation. For those of us who carry an inherited mutation embedded in our DNA, the cancer can behave in a more homogenous way, at least initially. Many of my friends who carry a BRCA mutation have this happen at diagnosis and many doctors who have been around for a bit will say that a homogenous tumor in both breasts is a pretty good indication that a germline mutation is present.

As I continue to learn and read and talk with experts, I am fascinated more about the workings of the human body and I understand more about what we don’t know. There are no easy answers. There are no easy results. And just when we think we understand the cancer cells, there is a new progression, a new mutation, a new behavior.

The biggest practical takeaway for me is to insist upon as much testing as possible as often as possible. Any time there is a progression, getting a biopsy if we can is key. Any time there is progression or tumor markers are on the rise, getting a liquid biopsy is key. Any time there is a new algorithm being tested for the possibility of learning more about our DNA, our makeup, I’m signing up. The more we know about the cancer, it’s makeup, and anticipating it’s behavior, the better.