Questions Patients Ask Us

Every week, patients and families send us questions about test results they don't understand, reports full of unfamiliar terms, and decisions they don't want to make alone. Below are some of the questions we hear most often, with the kind of answer we'd give if you asked us directly.

These answers are general. Your situation depends on your cancer type, your treatment history, and the details in your own reports. That's exactly what we look at in a consultation.

My Signatera test came back positive for the first time. What does that mean?

A positive Signatera result means fragments of DNA carrying your tumor's specific mutations were detected in your blood, which usually indicates cancer cells are present somewhere in the body, even if nothing shows up on a scan yet.

Signatera is a "tumor-informed" test. It's built from the sequencing of your own tumor tissue, then tracks a personalized set of mutations in your blood over time. Because it looks only for your tumor's fingerprint, a positive result is taken seriously. It's not a general screening test picking up something random.

That said, a single first positive is the start of a conversation, not a verdict. The questions that matter next are:

  • How high is the level? Results are reported in mean tumor molecules per milliliter (MTM/mL). A very low value and a high value can carry different implications.
  • What's the trend? One result is a snapshot. Two or three results over several weeks tell you whether the level is stable, rising, or falling.
  • Has imaging been done, and what kind? A positive result often leads to a scan to look for a source.
  • What's your cancer type and treatment history? The same number means different things in colorectal cancer after surgery than in breast cancer years after treatment.

What we'd advise against is waiting passively. A positive result often opens a window: time to repeat testing, plan imaging thoughtfully, revisit your genomic profile, and look at clinical trials designed specifically for patients with positive ctDNA. Many of those trials require you to enroll before anything is visible on a scan.

My Signatera is positive but my CT or PET scan is clear. Which one do I believe?

Usually both are telling the truth: ctDNA testing can detect cancer at a level far below what imaging can see, so a positive blood test with a clear scan often means disease that is real but too small to show up yet.

Scans need a tumor to reach a certain physical size before it becomes visible, generally several millimeters at minimum, and more for some locations and scan types. A ctDNA test measures molecules shed into the blood, which can happen when the amount of cancer is tiny. In published studies, ctDNA has often turned positive months before recurrence appeared on imaging.

So a "clear" scan doesn't cancel out a positive Signatera. It tells you there's no disease large enough to see right now. This is sometimes called molecular recurrence or minimal residual disease.

What usually makes sense next:

  • Confirm the result with a repeat test, typically within a few weeks, to establish a trend.
  • Ask whether the right scan was done. Depending on the cancer, a dedicated MRI (for example, of the liver), a PET/CT, or a different protocol may see what a standard CT can't.
  • Shorten the imaging interval rather than waiting for the next routine scan.
  • Look at ctDNA-guided clinical trials. Several trials enroll patients exactly in this situation: ctDNA positive, no visible disease.

The hardest part for most patients is that there may not be a single "right" treatment yet. That's where an informed plan, rather than watchful worry, makes the biggest difference.

What does a "low positive" Signatera result mean?

A low positive, such as a result under 1 MTM/mL, is still a positive result: your tumor's DNA was detected, but at a level that suggests a small amount of disease, and the most important next step is usually a repeat test to see the trend.

Signatera reports results in mean tumor molecules per milliliter of plasma (MTM/mL). A value like 0.1 or 0.3 means very few tumor DNA fragments were found. Patients often hear "low" and assume it doesn't count, or hear "positive" and assume the worst. Neither is quite right.

Here's how we think about a low positive:

  • It is meaningful. The test requires multiple of your tumor-specific mutations to be detected before calling a result positive, which makes random noise less likely.
  • The trend matters more than the number. A level that stays very low, rises steadily, or disappears on retesting each points in a different direction.
  • Low does not mean slow. Some cancers shed less DNA into the blood than others. A low number in one cancer type can mean more than the same number in another.
  • False positives are uncommon but possible. Technical and biological factors can occasionally produce a result that doesn't reflect true recurrence. That's one more reason to confirm before acting.

In practice, a low positive is a signal to get organized: repeat the test on a defined timeline, discuss imaging with your oncologist, and make sure your full molecular profile is up to date in case treatment or a clinical trial becomes the next step.

What is a "variant of unknown significance" on my genomic report, and should I worry?

A variant of unknown significance (VUS) is a change in a gene that the lab detected but can't yet classify as harmful or harmless, and in most cases it should not drive treatment decisions on its own.

Genomic tests like FoundationOne CDx, Tempus, and Caris sequence hundreds of genes. Along the way, they find many small changes. Some are well understood "drivers" with known treatments. Others are common harmless variations. A VUS falls in between: there isn't enough scientific evidence yet to know what it does.

A few things patients should know:

  • A VUS is not a diagnosis. Most VUS findings are later reclassified as benign.
  • Long VUS lists are normal. Many reports list several. That doesn't mean your tumor is unusually abnormal.
  • Tumor VUS and inherited VUS are different. A VUS on a tumor (somatic) report is about the cancer. A VUS on a germline (inherited) test is about you and possibly your family, and it shouldn't be used to make preventive decisions without genetic counseling.
  • Some VUS are worth a second look. Occasionally a VUS sits in a gene with an active clinical trial, or new research has emerged since the report was issued. This is where an expert review can add value.

The real risk with a VUS isn't the variant itself. It's that a page full of them can bury the findings that actually matter. A careful read of the report separates what's actionable from what's noise.

My genomic report says "no actionable mutations." Does that mean there are no options?

No. "No actionable mutations" usually means the report found no alteration matched to an FDA-approved targeted drug for your cancer type, which is different from having no treatment options, no trial options, or nothing useful in the report.

The phrase is narrower than it sounds. "Actionable" typically refers to a short list of approved, matched therapies. A report can say "no actionable alterations" and still contain:

  • Biomarkers that affect immunotherapy decisions, such as tumor mutational burden (TMB) or microsatellite instability (MSI) status.
  • Alterations with active clinical trials, even without an approved drug yet.
  • Alterations approved in a different cancer type, which may be relevant for trials or for discussions with your oncologist.
  • Findings that tell you what won't work, which is valuable information on its own.

It's also worth asking whether the testing was complete. Was there enough tumor tissue? Was it a tissue test, a blood test, or both? Was RNA sequencing included? Some important alterations, like certain gene fusions, are much easier to detect with RNA. An older report may not reflect therapies approved since it was issued, and the RAS-targeted therapy landscape alone has changed significantly in the past two years.

When a report says "nothing actionable," that's often the moment a second, careful read is most worthwhile.

I have a KRAS mutation. Are there any targeted treatments?

Yes, and the answer has changed a lot recently. Some KRAS mutations now have FDA-approved targeted treatments, and several more are being studied in clinical trials, so the specific variant you have matters.

KRAS is one of the most commonly mutated genes in cancer, especially in pancreatic, colorectal, and lung cancers. For decades it was considered "undruggable." That's no longer true.

Where things stand now:

  • KRAS G12C has FDA-approved targeted therapies in non-small cell lung cancer and, as combination treatments, in colorectal cancer.
  • Pancreatic cancer: In August 2026, the FDA approved daraxonrasib (Rasonque), a RAS inhibitor, for adults with metastatic pancreatic adenocarcinoma who have received at least one prior therapy or can't receive multi-drug chemotherapy. It's the first RAS-targeted therapy approved for pancreatic cancer and is being studied in other cancers as well.
  • KRAS G12D, G12V, and other variants are the focus of several newer drugs in clinical trials, some with encouraging early results.

The details on your report matter: the exact variant (G12C, G12D, G12V, G13D, Q61H, and so on), whether other mutations are present alongside it, and your cancer type. In colorectal cancer, for example, a KRAS mutation also means certain antibody drugs (anti-EGFR therapies) are generally not effective on their own, which shapes the treatment plan.

If you have a KRAS mutation and haven't had a recent conversation about RAS-targeted options or trials, it's worth having one.

How do I find a clinical trial that actually fits my cancer?

Start with your molecular profile, your treatment history, and your willingness to travel, then search for trials that match all three, because most patients who search on their own find trials they don't actually qualify for.

ClinicalTrials.gov lists tens of thousands of cancer studies. Searching by cancer type alone usually returns hundreds of results, most of which won't fit. The trials that matter are the ones where you meet the eligibility criteria and the science matches your tumor.

The information that narrows the search most:

  • Your biomarkers. Specific mutations (KRAS, HER2, BRAF, and others), MSI status, TMB, and ctDNA status. Many newer trials are biomarker-driven.
  • Your prior treatments. Trials often require (or exclude) specific previous therapies, and the order matters.
  • Your current status. Measurable disease on a scan, no visible disease but positive ctDNA, or between treatments. Each opens different trials.
  • Practical factors. Travel distance, organ function, other health conditions, and timing.

A few things patients don't always know: eligibility criteria are long and strict, a trial being listed doesn't mean it's open at every site, and some trials have narrow enrollment windows, including ctDNA trials that require enrollment before recurrence is visible.

Finding the right trial is part science, part logistics. Reading eligibility criteria line by line against your records, then contacting trial sites to confirm openings, is time-consuming. It's also one of the most valuable things you can do.

My oncologist says there's nothing more to do. What else can I ask?

You can ask what has been tested, what hasn't, and what trials have been considered, because "nothing more" sometimes means "nothing more in standard treatment" rather than "no options at all."

This is one of the hardest conversations in cancer care, and it deserves both honesty and thoroughness. Sometimes it truly is time to focus on comfort and quality of life, and that is a valid, important choice. But it's reasonable to make sure every door has been checked before you reach that conclusion.

Questions worth asking, respectfully:

  • "Has my tumor had comprehensive genomic testing, and how recently?" Tumors change over time and with treatment. An older test may miss new alterations.
  • "Was RNA testing or a liquid biopsy done?" Each can find things the other misses.
  • "Are there biomarker-matched clinical trials I might qualify for, here or elsewhere?"
  • "Would a second opinion at a major cancer center add anything?" Most good oncologists welcome this.
  • "Have any new therapies been approved for my cancer type or mutation recently?" The field moves quickly.

Asking these questions isn't a challenge to your oncologist. It's part of being an informed participant in your own care. If the answers confirm that options are truly exhausted, you'll have that certainty. If they don't, you may find a path that wasn't visible before.

Reader questions

Shared with permission. Questions have been paraphrased and identifying details removed. Answers are general educational information, not individual medical advice.

How soon after a lumpectomy should I have a Signatera test?

There is not one waiting period that is right for everyone. The reason for ordering the test, the surgery date, and any planned chemotherapy or radiation all affect the timing. Surgery can temporarily increase non-tumor cell-free DNA in the blood, which can affect detection. Your oncologist and the testing laboratory should agree on when the first blood draw would be informative.

Signatera also needs tumor tissue to build the personalized test. Ask whether your tissue has been received and whether the assay is ready before arranging the blood draw.

For early-stage breast cancer, ctDNA surveillance is not an established routine basis for changing treatment. A negative result does not prove that no cancer cells remain, and a positive result does not by itself establish which treatment will help. The most useful question is: What would we do differently depending on this result, and is that approach supported by evidence or part of a clinical trial?

My breast cancer blood tests were previously zero, but the latest result is 4. What does that mean?

Before interpreting the number, I would want to see the test name, the units, the laboratory's positive or negative designation, and the dates of the earlier results. A value of 4 on a ctDNA report means something different from a value of 4 on another blood test. We cannot tell what happened from the number alone.

If this is a Signatera result reported as positive at 4 MTM/mL, it means the assay detected DNA carrying the tumor's tracked mutations. It does not measure tumor size, tell us where disease is located, or establish a growth rate. A new positive result warrants a timely conversation with your oncologist about the full report, your treatment history, whether repeat testing is appropriate, and what imaging is indicated.

In breast cancer, using ctDNA alone to choose a new treatment is not established routine care. Ask: Does this result change the recommended evaluation, and is there a relevant clinical trial? Do not stop or change treatment based on the number alone.

Are there other options for locally advanced cervical cancer after chemotherapy, radiation, and brachytherapy?

The first distinction is whether treatment has just finished, cancer remains after treatment, or cancer has returned later. Those are different situations. Chemotherapy with external-beam radiation and brachytherapy can be given with curative intent; completing those treatments does not itself mean that another treatment is needed.

Your team should explain when and how they will assess the response. If cancer persists or recurs, the location and extent of disease, prior drugs and radiation, overall health, and treatment goals determine the next discussion. Depending on those details, options may include specialist evaluation for local treatment, systemic therapy, or a clinical trial. Immunotherapy may be relevant in some settings, but eligibility depends on the treatment setting, prior therapy, biomarkers, and local approvals.

I would start with the pathology report, treatment summary, and most recent imaging. Ask your gynecologic oncologist: Is there evidence of active cancer now? If so, what options fit its location and my prior treatment, and would a specialist second opinion add anything?

My lung adenocarcinoma NGS report found no targetable mutations. Could broader testing find something?

Possibly, but a second test is not automatically more useful. First, I would check what the original panel covered, whether the tissue contained enough tumor, whether quality checks passed, and whether the test assessed relevant gene fusions as well as other alterations. A negative result from a limited or technically inadequate test is different from a negative result from a comprehensive, successful test.

RNA testing can help detect some gene fusions that DNA testing may miss. A blood-based genomic test can sometimes complement tissue testing when tissue is limited or a repeat biopsy is difficult. However, a negative blood test does not rule out a targetable alteration because some tumors release too little DNA into the blood. Your oncologist can decide whether additional tissue testing, RNA analysis, or a liquid biopsy would address a specific gap.

Finding a target is not guaranteed, and no targetable finding does not mean there are no treatment options. PD-L1 and other clinical factors remain part of the treatment discussion. Ask: Was my testing complete and technically adequate, and would another test change the plan? Additional testing should be coordinated with your treating team so it does not unnecessarily delay needed care.

Have a question about your own results?

General answers can only go so far. Your reports, your history, and your options are specific to you. MITOTICS® provides independent scientific interpretation of genomic and ctDNA results, biomarker strategy, and clinical trial navigation for patients nationwide via telehealth.

As much as we'd like to help everyone, we take on a limited number of cases so each patient gets our utmost attention.

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The information on this page is for general educational purposes and is not medical advice. It does not replace consultation with your oncologist or other qualified healthcare provider. MITOTICS® provides scientific interpretation and advocacy services and does not diagnose, treat, or prescribe. Treatment approvals and clinical trial availability change frequently; information is current as of October 2026.