Part 1, The Sequel: Attack of the Clones

Cancer as a “disease” is incredibly complex, and patient care for a cancer diagnosis is complex as a result. I’m starting to explore some of these difficulties in a series of articles: “Why Treating Cancer is So Difficult.” Previously published in this series:

Previously published in this series: Part 1, Your Tumor is Not a Clone. Part 2, Cancer Cells are Still Cells. Part 3, Resistance is Not Futile. Part 4, There is No Google Translate for Science. Part 5, Is This Thing On?

Part 1, The Sequel // Attack of the Clones

It’s been more than 8 months since I posted the first article in the “Why Treating Cancer is So Difficult” series, and I was delighted when I saw this on Twitter a few days ago:

// A quick recap

In Part 1, I talked about how tumors are not “clones.” In other words, not every cell in a tumor is exactly the same. First of all, tumors are made up of many different types of cells, including the cancer cells, cells from your immune system, and other cell types as well. Second, it is possible that not every cancer cell in a tumor is identical. Some cells may have different mutations or other characteristics, which could mean that not every cancer cell in a tumor responds to a cancer therapy in the same way. Since normally patients have a single biopsy of a tumor taken to help doctors evaluate which treatment to receive, it is possible that doctors see an incomplete picture of the “mutational load” (all of the different mutations in a tumor). Since a personalized medicine approach to cancer therapy is based on selecting a cancer therapy for a patient’s specific mutations, it is possible that only some cells will be impacted if that particular mutation is not in all of the cancer cells.

 

I ended the article with several questions that researchers are in the process of investigating:

Is it possible to biopsy and examine multiple parts of a tumor, and then combine therapies based on a patient’s unique and varied tumor characteristics?

These are great questions that researchers are seeking to answer. Now that sequencing (looking at the genetic code of a tissue) is becoming more commonplace in cancer treatment, patients and doctors can move closer to the idea of personalized medicine.

// The research update: “Detecting truly clonal arterations from multi-region profiling of tumours

Werner, B. et al. Detecting truly clonal alterations from multi-region profiling of tumours. Sci. Rep. 7, 44991; doi: 10.1038/srep44991 (2017).

In this recent publication, researchers highlighted the need to take multiple biopsies for improved cancer patient treatment and care. This has been well-documented before, that multiple samples from multiple regions within a tumor provides a better “big picture” view of the tumor, but this paper establishes a mathematical basis for how many different biopsies are needed.

“Ideally, the sampling strategy should be adjusted to account for each tumour’s individual evolutionary trajectory.”

(Spoiler alert: this can vary from tumor type to tumor type and from patient to patient, so more analysis will be needed.)

Mutations for one patient with renal clear cell carcinoma. Posted with permission from Nature Publishing Group.

So what does it mean to identify “clonal” versus “sub-clonal” mutations in a tumor? To visualize this, we use an evolutionary “tree” to represent how the tumor has evolved over time. The “trunk” of the tree would represent mutations that occur in all of the cancer cells in a tumor, and every time the tree “branches,” these are points where only some of the cells have particular mutations while others do not. The “trunk” mutations are called “clonal” (every cancer cell has them, so they are like “clones”), while the “branch” mutations are called “sub-clonal” (in this case meaning they are not like clones because not every cell has them).

// Why is it important that doctors treat “clonal” mutations and not “sub-clonal” ones?

Imagine the tree of mutations above. If doctors prescribe a cancer therapy based on one of the “branches” of the tree, it means that only that part of the tree (the cancer cells with those mutations) will die, while the others will continue to grow. So even if you see a change in the tumor size, for example, the treatment is still not effective on the whole tumor because only a part of the tumor is being treated.

// Do patients who received treatment for “sub-clonal” mutations have a greater risk of cancer progression or metastasis?

This is a really important question, and one that is not yet fully understood. However, the authors of this publication suggest that it’s possible that patients receiving a targeted therapy might need to have a larger number of biopsies to correctly identify the “clonal” mutations in the tumor for the best therapeutic strategy. It also may be more important for patients who are relapsing to have a larger number of biopsies than patients with tumors that are developing for the first time.

// Part 1, Redux: What are the new questions moving forward?

In the same way that I ended Part 1 with a list of questions, I will do the same for this Part 1 update. What are some important questions that researchers are focusing on now, with respect to personalized medicine in cancer therapy?

Should there be a standard way and number of biopsies for every patient, or should it vary from patient to patient? (In reality we already know that it should vary from patient to patient, we just don’t yet know how.)

Does the number of biopsies needed depend on the tumor size, or stage, or some other clinical factor?

Is it best to evaluate multiple biopsies before any treatment begins? Should it be repeated at any point during the therapy?

// Want to learn more?

Why don’t we have a cure for cancer? Check out this podcast, starting around 22:40.

What is Precision Medicine and how is it helping people? Check out information from President Obama’s Personalized Medicine Initiative.

How are researchers tackling the issue of tumor heterogeneity? conversation with Dr. Scott W. Lowe, head of the Geoffrey Beene Cancer Research Center at the Memorial Sloan Kettering Cancer Center in NYC.

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