Lab Tests, Biomarkers & ctDNA

Every time you turn around, it seems there is another test of some kind that needs to be run, or interpreted, or repeated. The amount of testing that patients undergo during and after cancer treatment could easily put a cramming-for-finals college student to shame. Even though all of this testing is necessary, valuable, relatively simple, and regularly occurring, it's can also be stressful, confusing, and just downright mysterious. What do the results mean? Am I okay? Is that result bad? Good? What do we do with this information? How can I do better on this test next time? Is high good? Is positive bad? Does anything need to change because of these test results? Why do we run this test so frequently? Why can't we run this other test more often? (It's because of insurance, isn't it? Ugh. I knew it.) and so on. 

Trying to keep track of what test is what, what it's for, what the results can and can't tell us, and how often you need to have it done can be a real brain jumbler. It may be helpful to organize the different tests you'll receive into one (or more) of four categories—based on how your doctor will likely use the test & test results to influence or inform various aspects of your care. 

Four Categories of Cancer Tests by Purpose***

1. Tests used for screening, diagnosis, prognosis and/or staging
2. Tests used for treatment guidance & selection
3. Tests used for measuring treatment response & monitoring for recurrence
4. Tests used to check how your body is tolerating treatment and if you're cleared for continued treatment

Some tests fall into more than one category, and these multitasking tests are the ones with which you will become most familiar.  A CT scan fits both Category 1 and Category 3. A biopsy fits into Categories 1 and 2, and sometimes Category 3. A tumor marker test may fit Categories 1, 2, and 3. A Complete Blood Count (CBC) panel usually fits best into Category 4, and a ctDNA test fits Category 3, and can also fit Category 1. Routine bloodwork is most often a Category 4 test.

Simply knowing how your doctor intends to use the test results can put things into perspective and ease the mind a bit. If your doctor runs a Category 2 test, you likely don't need to hold your breath because it's being conducted to help determine which treatments may work best for you, and it's not measuring your cancer burden. And when you have blood drawn prior to a chemotherapy infusion, it's likely being used as a Category 4 test to make sure your body is in good enough shape to endure another infusion. Category 1 tests are nerve-racking at the beginning, but it's Category 3 tests that usually bring about the most palpable fear and anxiety because those are the ongoing cancer-detecting tests. ~sigh~

When your doctor orders a test, ask them how they plan to apply the results. You do not need to memorize their responses because one test can be used for different purposes at different times. Just ask them what they're using it for and make a note for this test, this time. 

Are you ordering this test for diagnostic, prognostic, or staging purposes? Is it going to determine my eligibility for a specific therapy? Is it to look for or measure cancer? Are you ordering this bloodwork to get a snapshot of how my body is handling everything, or are you looking for something in particular? 

***If you ask a doctor if they are giving you "a Category 2 or 3 test," they may look at you like you've sprouted horns and wings. The category numbers mean absolutely nothing to healthcare professionals because they were assigned (by me) indiscriminately for the purposes of the discussion on this page. It was easier to type "Category 1" instead of typing the full description repeatedly. Use the above paragraph as a model for how to inquire about the purpose of tests so your doctor doesn't mistake you for a Griffin. :) 

For the majority of blood-based lab tests, there is a reference range, or "normal" range, associated with each test to guide clinicians in their interpretations of the results. Values outside of this range can either be high or low, and the clinical significance of the value is specific to each test and the lab that performed the analysis. Reference ranges can vary from lab to lab so be sure you are comparing your results to the reference ranges listed on your lab report. "Normal" ranges are based on averages, but what's normal for you may be slightly higher or lower than the reference range. You can establish what's typical for your body along with your doctor, likely over the course of several successive tests. Furthermore, when you are going through cancer treatment, your "normal" may shift while your body adjusts to, metabolizes, and reacts to the treatment. 

Lab work values in the "normal" range do not always mean "healthy with no underlying concerns," and values outside of the "normal" range do not always indicate illness, disease, or dysfunction. Lab work tells us part of the story, but not always the whole story. 

When assessing lab results, it can be challenging not to fixate on the value of a single routine test, or get derailed by several results listed in red text or inside of red boxes. Yikes! What does that mean?!  A test result of 38 that jumps to 41 a month later, for example, may not be cause for concern. On the other hand, small rises or falls on other tests may be of more concern. Each test has different thresholds of acceptable variation. Too often, a patient or caregiver gets wound up and stressed about an out-of-range lab result but their doctor is nonchalant and unbothered by the same result. We need to get on the same page with our doctors so we know what means what. 

Ask your doctor what's acceptable and worrisome to them in terms of out-of-range lab results for each routine test so you're not thrown for a loop every time you get lab results outside of the reference range. Some tests may only be worrisome if they are out-of-range on the high side, others if they are out-of-range on the low side, while others may signal concern if they are out-of-range on either side, low or high. Some tests may have more wiggle room for fluctuation, and other tests may require close attention to, what appear to be, mild/slight elevations or drops. 

Not all lab tests have a low-normal-high reference range. Some tests require a result to be above X or below X to be considered "normal." For example, on Test D, a "normal" result is anything above 20, and on Test E, a "normal" result is anything below 4.5. Other tests may not have a reference range or specific value (number) associated with them, but instead are simply reported as positive or negative. Keep in mind that the word negative does not always have a bad/poor connotation in medicine and oncology, and positive does not always have a good connotation. You can be negative for cancer (great news!) or positive for cancer recurrence (not great). Talk to your doctor about how you can best understand what your lab test results mean. 

For tests that have a reference range, you can ask your oncologist to use an upper limit of normal (ULN) or a lower limit of normal (LLN) multiple to guide your understanding of the severity or relevancy of abnormal results. 

Here's an example: Let's say TEST A has a reference range of 50-100. We can find the limit multiple by dividing the result by the limit. If your result is high, you will use the top of the reference range, and if your test result is low, you will use the lower end of the range for your calculation.     TEST RESULT / UPPER OR LOWER LIMIT = LIMIT MULTIPLE

• A test result of 200 would be considered high in this example so we will use the high end of the reference range, 100, as our limit number. (200 divided by 100= 2) In this example, the test result is two times (2x) the upper limit of normal (ULN). 
• A result of 350 would be 3.5x the ULN (350 / 100 = 3.5)
• A test result of 25 would be considered low in this example so we will use the low end of the reference range, 50, as our limit number. (25 divided by 50= 1/2) In this example, the test result is one-half times (1/2x) the lower limit of normal (LLN). (25/50= 1/2)

Now that the math is figured out, we can use this information to communicate with doctors about an out-of-range result and whether or not it's concerning. You can ask your doctor something like, "I see that my liver enzyme ALT test came back high and is two times the upper limit of normal. Does that worry you? If not, at what point would you be worried? 4x ULN? 6x ULN?" You can then jot down their response and refer back to it after future blood draws. Dr. Grey is not concerned until TEST B is 5x the ULN or greater.  Please note: This is specific to each and every test, and is also subjective. It can be different depending on the doctor you ask, their specialty, the relevancy of the test to their specialty, etc. If TEST C is high, you will also need to ask your doctor what multiple of the ULN or LLN is acceptable or worrisome on this test from their perspective. With a few conversations, you may be able to create a cheat sheet that summarizes your doctor's parameters of concern for each routine lab test, or for the routine tests that, for you, most often come back too high or too low. 

Sample Lab Test Cheat Sheet

Dr. Grey says not to worry until...

• TEST A is 3x ULN or greater
• TEST B is 1.5x ULN or greater
• TEST C is 1/2 LLN or lower
• TEST D is 5x ULN or greater
• TEST F is outside of the normal/reference range (no wiggle room high or low)
• TEST G is at all high/above the ULN (1x)
• TEST H is at all low/below the LLN (1x)
• TEST J is 2x ULN or greater

Using multiples of ULN and LLN from your doctor may make it easier, clearer, or faster to assess whether or not your out-of-range lab test results require additional consideration or immediate attention. If your lab test results pop up in your patient portal at night, you can cross-reference your cheat sheet for peace of mind. If all of the out-of-range results are within acceptable multiples, as determined through conversations with your doctor, you can continue to enjoy your evening. If a result happens to fall outside of this "acceptable multiple window," you can send a message to your doctor through your portal or call the office the next morning for follow-up. You may save yourself some unnecessary stress and anxiety by gathering this information in advance of your next test.

Specificity and sensitivity are quantitative measures of a test's clinical performance, meaning how good is the test at doing what it's designed to do for patients? 

These concepts can get a little fuzzy given the way they're often described, so we won't focus too much on all the details right now. Instead, we'll discuss how a test's sensitivity or specificity correlates with its results and what that means for you. 

Where's My Unicorn Test?

If you're looking for a test, be it a scan, blood test, or other lab test, to have 100% specificity and 100% sensitivity, you're going to be disappointed because it's not a thing. This would be considered a unicorn and, even though researchers and test developers strive for 100+100 in theory, in practice it's not realistically achievable. As you can imagine, there is give-and-take when designing these tests and factors like cost, time, availability of resources, feasibility, safety, reliability, and accuracy all come into play. Each of these factors can have an impact on the test's sensitivity and specificity, usually in an inverse relationship to each other.  If one goes up, the other goes down. You can see the tug-of-war that can arise when designing a test and trying to determine the avenue (100% specificity or 100% sensitivity) that ultimately provides the most benefit and least harm to patients.  Since there are no perfect tests, we have to work with the ones we've got so let's take a look at these two measures of clinical performance: specificity and sensitivity. 

Up first...

SPECIFICITY

How specific is that test? is another way of saying...

• How likely will the test differentiate between a patient with cancer and one without?
• How likely will the test be negative when I don't have cancer?
• If I do not have cancer, how many times out of 10 will this test give a negative result?

• If the test's specificity is 87% it means that 87% of people tested who do not have cancer will have a negative test result. This is called a true negative. It is true that the patient with the negative test does not have cancer. 

• If a test is more specific, it will result in fewer false positives.
• If a test has lower specificity, it will produce more false positives. If you happen to take a test that has low specificity, it may be helpful to keep in mind that there is a greater chance you may receive a false positive which would indicate that you DO have cancer even if you do not. This can definitely cause some unnecessary stress if you mistakenly believe the cancer is back.

SENSITIVITY

How sensitive is that test? is another way of saying...

• How likely will the test identify cancer that is there? 
• How likely will the test be positive when I do have cancer?
• If I have cancer, how many times out of 10 will this test pick it up? 

• If the test's sensitivity is 87% it means that 87% of people tested who do have cancer will have a positive test result. This is called a true positive. It is true that the patient with the positive test result does have cancer. 

• If a test is more sensitive, it will result in fewer false negatives. 
• If a test has lower sensitivity, it will result in more false negatives. If you happen to take a test that has low sensitivity, it may be helpful to keep in mind that there is a greater chance you may receive a false negative which would indicate that you do NOT have cancer when you actually do. This scenario can mislead you to believe the cancer is gone when, unfortunately, that is not the case. 

Another way to describe test results: 

True positive- test is positive and patient does have cancer

True negative- test is negative and patient does not have cancer

False negative- test is negative but patient does have cancer

False positive- test is positive but patient does not have cancer

Please don't worry that every test result is inaccurate or misleading. These are the best tests we have and they are reliable MUCH more often than not. Plus, there are multiple ways to test for most things which means there are likely tests out there that can step in and double-check the work of the previous test.

When your doctor orders a test, ask them if it's more likely to produce a false positive (tells me I have it when I don't) or false negative (tells me I don't have it when I actually do). By knowing that information, you can shift your expectations as needed about the test results. If you're concerned about a result, you can ask your doctor how confident they are in the result, if you can retake it and/or if there is another test out there that could provide similar information.