Stage 3b, FOLFOX 12 rounds, 3 negative signatera but turns positive

@korij3 - I hear how stressful this moment is for you, and it’s completely understandable to feel overwhelmed with a positive Signatera result and the discovery of growing lung nodules after such a strong run of negative tests and completing FOLFOX. You’ve been through a lot with your colon resection and 12 rounds of chemo at Mayo Clinic, and your resilience in getting to this point is inspiring. Let’s break this down to address your concerns, provide some clarity on your situation, and share hope through insights and recovery stories. I’ll also offer guidance on potential next steps like cryoablation, radiation, or more FOLFOX, and connect this to others’ experiences.
Understanding Your Situation
Your colon cancer journey started with a resection on July 8, 2024, followed by 12 rounds of FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin). Your Signatera tests, were consistently negative (0.00 MTM/mL), indicating no detectable circulating tumor DNA (ctDNA). However, your fourth Signatera test this month (May 2025) came back positive at 0.5 MTM/mL, and your recent scans show a lung nodule that grew from 5–6 mm to 8 mm since June 2024, plus possibly a few new 2–5 mm nodules, with some unchanged. This shift is understandably alarming, but let’s unpack what it means and explore your options.
Signatera Result (0.5 MTM/mL): Signatera is a highly sensitive test for detecting molecular residual disease (MRD). A positive result at 0.5 MTM/mL indicates low levels of ctDNA, suggesting possible residual or recurrent disease. Studies, like the GALAXY arm of CIRCULATE-Japan, show that post-surgical ctDNA positivity (even at low levels) is associated with a higher recurrence risk (hazard ratio 10.0, P < 0.0001). However, your level is relatively low, and the test’s 97% positive predictive value for recurrence means it’s a strong signal to act early, which is exactly what you’re doing.
Lung Nodules: The growth of one nodule to 8 mm and the appearance of smaller 2–5 mm nodules raise concern for possible metastatic recurrence, though some nodules being stable is a positive sign. Lung metastases are common in colorectal cancer, but small nodules (< 10 mm) often require further evaluation to confirm malignancy, as they could be benign (e.g., inflammatory or infectious).
Context: Your prior negative Signatera tests and completion of FOLFOX suggest you responded well to initial treatment. The new positive result and nodule growth don’t negate that progress but indicate a need for targeted action to address potential recurrence.
Potential Next Steps
Your oncologist will likely use a multidisciplinary approach Here’s a look at these options, tailored to your situation:
Cryoablation:
What It Is: Cryoablation uses extreme cold to destroy small tumors, often for lung metastases. It’s minimally invasive, performed via a probe guided by imaging, and is effective for small nodules (< 20 mm).
Relevance to You: Your 8 mm nodule and smaller 2–5 mm nodules are within the size range for cryoablation. It’s often considered for oligometastatic disease (few metastases) to achieve local control, especially if surgery isn’t ideal.
Pros: Less invasive than surgery, preserves lung function, and has a shorter recovery time. Studies show high local control rates for small lung metastases.
Cons: May not address microscopic disease elsewhere, and repeat procedures might be needed if new nodules appear.
Radiation (e.g., Stereotactic Body Radiotherapy, SBRT):
What It Is: SBRT delivers high-dose radiation precisely to small tumors, often used for lung metastases in colorectal cancer. It’s non-invasive and effective for oligometastatic disease.
Relevance to You: SBRT could target your growing 8 mm nodule and possibly the smaller ones if confirmed malignant. It’s an option if cryoablation isn’t feasible or if you prefer non-invasive treatment.
Pros: High local control rates (up to 80–90% for lung metastases), minimal side effects, and no surgery required.
Cons: Less effective for systemic disease, and long-term data on SBRT for colorectal lung metastases are still evolving.
More FOLFOX or Alternative Chemotherapy:
What It Is: FOLFOX is a standard adjuvant regimen for colorectal cancer, but for recurrence, your team might consider continuing FOLFOX, switching to FOLFIRI (5-FU, leucovorin, irinotecan), or adding targeted therapies like bevacizumab or cetuximab, depending on tumor genetics (e.g., KRAS, BRAF status).
Relevance to You: Since you completed FOLFOX recently (March 2025), your oncologist may evaluate whether you can tolerate more or if a different regimen is better, especially given the low ctDNA level and small nodules. The CIRCULATE-US trial is exploring FOLFIRINOX (FOLFOX + irinotecan) for ctDNA-positive patients, which could be an option if your team wants a more intensive approach.
Pros: Targets systemic disease, potentially addressing microscopic metastases not visible on scans.
Cons: FOLFOX can cause cumulative side effects like neuropathy, and your recent completion might limit its immediate use.
Other Considerations:
Surgical Resection: If the nodules are confirmed as metastases and are resectable, lung metastasectomy could be curative in 25–40% of select patients with colorectal cancer lung metastases.
Immunotherapy: If your tumor is microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR), immunotherapy (e.g., nivolumab, ipilimumab) could be an option, as shown in the CheckMate 8HW trial with significant progression-free survival benefits.
Watch-and-Wait: If the nodules are indeterminate (not confirmed malignant) and your ctDNA level remains low, your team might recommend close monitoring with repeat Signatera tests and scans every 3 months to track progression before intervening

@korij3 - Similar Situations and Positive Recovery Stories
Hearing about others in similar situations can provide hope. Here are a few experiences and recovery stories from patients with colorectal cancer, positive Signatera results, and lung nodules, drawn from relevant discussions:
Mayo Clinic Connect Story (Similar to Yours): A patient with colorectal cancer had a positive Signatera test (1.02 MTM/mL) after negative tests post-resection, similar to your shift to 0.5 MTM/mL. Their CT scan showed no masses, but they were told small lesions might not yet be visible. After discussion with their oncologist and a Signatera genetic counselor, they opted for close monitoring and later found the ctDNA cleared without immediate chemo. This patient emphasized the importance of early detection via Signatera, which allowed them to stay proactive.
Lung Nodule Success Story: Another patient on Mayo Clinic Connect had sigmoid colon cancer and a suspicious lung nodule (too small to biopsy) detected after resection. They underwent lung resection 7 weeks later, which confirmed cancer but had clear margins and no lymph node involvement. They skipped adjuvant chemo, relied on regular CT scans and blood tests, and remained cancer-free 18 months later. They credited early detection and a skilled thoracic surgeon at a comprehensive cancer center for their success.
ctDNA-Guided Recovery: In the BESPOKE CRC study, patients with positive ctDNA post-surgery who received adjuvant chemotherapy (like FOLFOX) had a median disease-free survival of 18 months compared to 7 months for those without chemo. This suggests that acting on a positive Signatera result, even at low levels like 0.5, can significantly delay recurrence. Many patients in these studies regained negative ctDNA status after treatment, offering hope for returning to NED (no evidence of disease).
These stories highlight that a positive Signatera result and small lung nodules don’t always mean widespread recurrence. Early intervention, whether through ablation, radiation, or systemic therapy, can lead to long-term control or even cure, especially with Mayo’s multidisciplinary approach. Would you like to explore any further aspects?

Thank you so much !

I too had Stage 3B(2/2024) with resection and 12 rounds of FOLFOX and 25 rounds of radiation in my abdomen area. My cancer started outside on my Cecum and surrounded my appendix. Some of the tumor was caught on my abdominal wall. It was all removed by non Oncological surgeon who placed a staple in the area it was touching so they could radiate it. I started the Signatera testing as soon as I started chemo at the insistence of my Daughter. My Oncologist did not fully embrace this test at the time. 3x it came back negative. The 4th time was positive( 1.47) about 3 mos after chemo ended. The night I got the positive Signatera test result, earlier that day, I had gotten clean scan results, clean blood work and was given the green light and see you in 6 months by my Oncologist. I was shocked and so upset. A PET Scan was immediately done. The PET came back with 2 glaring lymph nodes in close proximity to where this started but behind close to my spine. I elected surgery which my Oncologist seemed to encourage. Surgery was done by an Oncology Surgeon who was able to look around. He took additional lymph nodes and a suspicious Peritoneal nodule. The 2 suspicious lymph nodes and the nodule came back positive, 3 other nodes and 2 other nodules were negative. Surgery was pretty extensive but I know my body and know I am in good shape and can recover. I am back to swimming daily and working out. Took about 6-7 weeks to start feeling good again. Chemo is a wild card for me and scares me. I want my immune system to be able to work and combat this. That is what it is supposed to do.I recently had my Signatera done and it was negative which was about 7 weeks after surgery. Why they do not do PET Scans after surgery and before radiation is mind blowing to me. I don't know if chemo was necessary in my case but it is their protocol. I will continue to do my own research but much more so now and rely on God more for all of this. The anxiety of the Signatera results is what I am trying to manage now because it will be an ongoing test. Had I not gotten the Signatera, I would not have found out about the Cancer still in me until my next visit which was in 6 months.

Thank you for sharing your story. This test is great for early detection and I’m so glad you were able to address your spots with surgery. We got this 💪🏻

It is great to hear how the Signatera test was so helpful and sensitive. I was diagnosed with stage 3b colon cancer about a year ago. While I underwent surgery and chemo and have blood work every 3 months, my oncologist does not utilize the Signatera ctdna test which has been perplexing to me. He is with a major NCI-designated cancer center. I had also consulted with another oncologist at the same center and he, too, does not use it. It may be that not using it is related to a small percentage of false positive results--I really don't know. I wish cancer care had a more predictable treatment path as I often feel I have to advocate for myself and I don't really know what I'm doing.

@california14 - Facing stage 3b colon cancer is tough, and it’s understandable to feel frustrated that your oncologists at an NCI-designated cancer center aren’t using the Signatera ctDNA test, especially given its reported 88% sensitivity for detecting colorectal cancer recurrence. Studies like the GALAXY arm of CIRCULATE-Japan show Signatera’s ability to predict recurrence risk and guide adjuvant chemotherapy, with ctDNA-positive patients at higher risk (HR 10.82). These studies show that the most important test is 30 days post-surgery to check for any residual disease. However, some oncologists hesitate due to rare false positives (1.9% spontaneous clearance) or ongoing trials (e.g., CIRCULATE-US) refining its role.

Your proactive advocacy is powerful—self-education is key. Ask your oncologist why they don’t use Signatera, is it because they consider your CRC is considered low risk? Is CT DNA testing not typically part of the treatment plan? Remember Signatera is not the only CTDNA test available, Oncodetect from Exact Sciences, and Guardant 360 are also utilized by many institutions. Would you like more information about these to discuss with your oncology team?

Request clarity on their surveillance plan (e.g., CEA, CT scans) and if ctDNA could complement it. Cancer care can feel unpredictable, but your voice matters. Consider a second opinion from another NCI center or ask to discuss trials like DYNAMIC-III to explore ctDNA-guided care. You’re not alone—keep asking questions, and lean on support groups for strength.

Thank you very much for all of the information you provided. I guess since the CEA number is a particularly reliable source of cancer/recurrence in colon cancer, that is what this particular NCI-designated cancer center utilizes for post treatment surveillance along with other blood work and annual CT scans.
I know that another, non NCI designated but major medical center in the same city does use the ctdna test. It is disconcerting though, that recommendations vary and I will consider getting another opinion from another NCI-designated cancer center. I think the reason my oncologist does not use the ctdna test at this time is related to the level of research that has been done for its use (that's my recollection of what he said). Thank you again for the resources you provided; I greatly appreciate it.

All this in was very enlightening. I don’t know about any of those tests except the CEA. I will comment specifically on that as to its predicting. I had Stage 3c right side colon cancer in summer of 23. I did not have any signs I had it and my CEA was completely normal. We found it due to other cancer I had in the uterus which was found during a hysterectomy to avoid a precancer turning into cancer. I was anemic and they wanted to know why. The Colonoscopy showed the bleeding mass and 8 of 43 nodes were infiltrated. I did folfox, after surgery and CEA numbers did not change. 8 months after treatment it was back in my vaginal cuff and pelvic nodes and left oblique. Still no signs in the blood. So all that is to say that with right side CRC which is more aggressive, especially in women, its more of when it will come back and we can’t depend on bloodwork to give us clues. I do wish I had known about those tests. My Dr did some testing to see what treatments outside the reg might be used. But those don’t sound familiar.

Thank you for sharing information about your experience with the CEA marker in colon cancer.
I, too, was diagnosed with R side ascending colon cancer, stage 3b in March, 2024. I guess the CEA marker is individualized as mine was high when my cancer was identified during a colonoscopy. It then skyrocketed during chemo therapy and my last blood draw showed that it was normal. I think our differences show that cancer treatment--even for the same type of cancer--is not "one size fits all" and sites such as this provide us with valuable information. My surgeon strongly recommended the ctdna test for follow-up but he was affiliated with a different medical center than my oncologist who does not do that test.

Thank you again for sharing your experience with CEA testing; it is something that everyone should be aware of.