Understanding the CA-125 Test: What It Can and Can’t Tell a BRCA+ Woman

Jul 31

For women living with a BRCA mutation, navigating surveillance can feel overwhelming, especially when test results don’t come with a clear explanation. This post is about one of the most commonly misunderstood tests in gynaecological care: the CA-125. It’s important to understand what it measures, why it isn’t used as a routine screening tool even in high-risk women, and what questions are worth asking your care team.

What is CA-125?

If you carry a BRCA gene mutation and are at high risk of ovarian cancer, you may have come across the CA-125 test in your research. There is a lot of controversy around the CA-125 test and no doubt you’ve heard mixed information. So, what is it exactly?

CA-125 (Cancer Antigen 125) is a protein produced by certain cells in your body, including cells lining the ovaries, fallopian tubes, uterus, and peritoneum. It can be measured with a simple blood test.

When a woman has been diagnosed with ovarian cancer, CA-125 levels are often elevated. For this reason, it has long been used as a tumour marker, meaning clinicians can use it to help track how well treatment is working in women with a diagnosis and, occasionally, to detect whether cancer has come back after treatment.

Where it gets complicated is when CA-125 is used for a different purpose entirely: trying to screen for cancer in someone who hasn’t been diagnosed yet. This is where the test’s limitations become really important to understand.

Why CA-125 Isn’t Used for Routine Screening, Even in BRCA+ Women

You might reasonably ask: if I’m at high risk of ovarian cancer and CA-125 is a tumour marker for ovarian cancer, shouldn’t my doctor be checking my CA-125 regularly to catch anything early? It seems logical. The honest answer is that the evidence doesn’t support CA-125 as a reliable screening tool, even for high-risk women. But why?

Firstly, the test produces A LOT of false alarms.

CA-125 is not a cancer-specific protein. It is a general marker of inflammation and irritation in the tissues lining the pelvis, abdomen, and other body cavities. Those tissues can be affected by ovarian cancer, but also by many other common gynecological conditions, including endometriosis, fibroids, pelvic inflammatory disease, liver disease, normal menstruation, and pregnancy. Too many common issues cause those tissues to become inflamed, making it very difficult to reliably distinguish cancer from the background noise of everyday biology. This is particularly true for premenopausal women who menstruate regularly.

If you are premenopausal and BRCA+, the threshold of concern was not designed for you.

The most important thing to understand is that the standard 35 U/mL threshold for “positive” CA-125 test was built on studies from healthy postmenopausal women and blood donors. It was never designed for premenopausal women, and it has never been validated in that group. A large NCI-sponsored study of 3,692 women established that the more appropriate threshold of concern in premenopausal women is closer to 50 U/mL, namely because premenopausal women naturally have higher and fluctuating levels of CA-125 due to hormonal activity and the normal functioning of the endometrium.

This means a result between 35 and 50 U/mL in a premenopausal woman may reflect normal biology rather than disease. In practice, though, most labs still flag anything above 35 U/mL as abnormal, and many doctors are more familiar with that cut-off threshold for concern, so a result in this range could be reported as “elevated” and prompt further testing, even when the level may actually be normal for someone of that menopausal status.

Even a result above 50 U/mL in a premenopausal woman is not designed to be a diagnosis. As mentioned, CA-125 is not specific enough to distinguish between cancer and the many benign conditions that also cause it to rise. However, any result above the upper threshold (50 U/mL in premenopausal women and 35 U/mL in postmenopausal women) should trigger a prudent clinical assessment, including symptoms, imaging, and repeat testing over time, before it carries meaningful weight. It is a signal worth paying attention to, but it can’t be understood by itself.

It’s important to mention that these investigations are not benign. They can cause both physical and emotional harm for the patient, which is why triggering unnecessary assessments is something that is avoided in healthcare.

CA-125 also misses too many of the cancers screening is meant to catch.

False alarms are only half the problem. CA-125 also misses a large share of ovarian cancers. Only about half of stage I ovarian cancers produce a raised CA-125, compared with the majority of advanced cancers. This matters enormously for screening, because the whole point of screening is to find disease early. A test that reads normal in roughly half of early cancers cannot reliably do that job.

This leads to the single most important point about a normal result. A normal CA-125 does not mean ovarian cancer has been ruled out. For a BRCA+ woman, since CA-125 testing cannot reliably detect the cancers we need it to, it cannot be used to delay or reconsider risk-reducing surgery that has been recommended. High-grade serous cancers can also progress quickly once they take hold, so a normal result at one point in time says little about where things stand months later.

Large screening trials haven’t shown a mortality benefit in using CA-125 as a screening tool.

This leads to the final point about why CA-125 is generally not recommended. It unfortunately can’t reliably prevent deaths from ovarian cancers. The UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) is the largest ovarian cancer screening study ever conducted. It followed over 200,000 postmenopausal women for an average of 16 years, randomly allocating them to either no screening, annual ultrasound, or annual multimodal screening combining CA-125 with ultrasound. What was found is that neither method reduced deaths from ovarian cancer.

What makes this finding particularly worth understanding is what the trial did show along the way. The multimodal screening approach using CA-125 actually did detect cancers at an earlier stage, with significantly more stage I and II cancers found in the screened group. On the face of it, that sounds like exactly what screening should achieve.

But earlier detection did not translate into fewer deaths. The number of women who died from ovarian cancer was virtually identical across all three groups.

Researchers believe this reflects something important about the biology of the most common and deadly form of ovarian cancer, high-grade serous carcinoma, which is the type BRCA+ women are predisposed to. This type of ovarian cancer tends to spread very early in its development, often before it is large enough to be reliably detected by any current test. By the time a CA-125 rise or an ultrasound finding becomes detectable, the cancer is likely to have already seeded microscopic disease beyond the ovaries, even if imaging suggests it looks localised. The PLCO trial in the United States, which followed tens of thousands of women with CA-125 and ultrasound screening over nearly 15 years, confirmed the same finding.

There is a second part to this, and it matters especially for BRCA+ women. Ovarian cancer is not just one disease. The slower-growing, less aggressive types of ovarian tumours (often grouped as type I tumours) tend to have a good outlook regardless of when they are found. But the aggressive high-grade serous cancers (type II) cause most ovarian cancer deaths and account for the large majority of BRCA-related ovarian cancers. CA-125-based screening can pick up both, but by the time the type II cancers show detectable levels, spread has often already taken place. So, part of the earlier-stage detection seen in the trials came from finding cancers that would likely have done well anyway, while the dangerous cancers were still not caught early enough to prevent progression.

It is worth noting that UKCTOCS excluded women with known familial ovarian cancer risk, so its findings apply most directly to average-risk postmenopausal women rather than to a BRCA+ population.

Some clinicians do still choose to offer CA-125 and transvaginal ultrasound in high-risk surveillance programmes, but it’s important to be aware that the evidence does not currently support the idea that this approach reliably catches cancers early enough to reduce deaths, even in a high-risk setting.

So What IS the CA-125 Test Useful For?

We don’t want you to walk away thinking CA-125 is a useless test. In the right context, it provides genuinely valuable information. The key is understanding that context.

Because CA-125 reflects a general inflammatory signal in the tissues lining the pelvis and abdomen, it is difficult to use as a screening tool. But once a diagnosis of ovarian cancer has been made, that same property becomes genuinely useful. Now that we know disease is present, we can therefore infer a relationship between the cancer and the inflammatory signal; CA-125 becomes a way of tracking the inflammatory burden of that disease over time. When cancer responds to chemotherapy, the inflammation subsides, and CA-125 falls. When cancer recurs, inflammation rises again, and CA-125 rises with it, often months before symptoms or imaging changes appear. The test hasn’t changed; what has changed is that we now have a known signal to follow rather than trying to find one in noisy background data.

So, when should we use CA-125?

Monitoring known cancer. This is where CA-125 is most valuable: tracking ovarian cancer that has already been diagnosed, measuring whether treatment is working, and detecting biochemical signs of recurrence early.
Investigating symptoms alongside imaging. If a woman has symptoms that might suggest ovarian cancer (persistent bloating, pelvic pain, feeling full quickly) and a pelvic mass is identified on ultrasound, CA-125 can contribute useful information alongside imaging, particularly in postmenopausal women.
As part of a broader risk assessment. Some clinicians use CA-125 alongside other markers (such as HE4) and imaging as part of a multi-modal approach in high-risk women. The keyword is “alongside.” A single CA-125 number, read in isolation, tells you very little.
Trending over time. A consistently rising trend may be more meaningful than any individual reading. This is the principle behind tools like the Risk of Ovarian Cancer Algorithm (ROCA), which tracks how CA-125 changes across multiple tests rather than comparing a single result to a fixed threshold.

What About Menstrual Cycle Timing?

Some evidence suggests that CA-125 levels may be somewhat higher during menstruation, which could, in theory, push a borderline result above a threshold. The research on this is less settled than it is sometimes presented, though. Studies in healthy women without conditions like endometriosis suggest the rise during menstruation is generally modest at a population level, and at least one larger study concluded the effect is not clinically significant for most women.

Cycle timing is worth mentioning to your doctor when discussing a result, particularly if blood was taken during your period. It may be one factor among several to consider. But it is not a reliable explanation for an elevated result on its own, and it should never be used to dismiss a result that warrants proper follow-up. If your care team considers timing relevant, they may suggest a repeat test at a different point in your cycle. That decision sits with them, informed by the full clinical picture.

Questions Worth Asking Your Doctor

Understanding your surveillance plan puts you in a much better position when results come back. Here are some questions worth raising:

“What threshold are you using to interpret my CA-125, and is it adjusted for my age and menopausal status?” The standard 35 U/mL threshold was derived from postmenopausal and general population data. Evidence from large studies suggests a higher threshold, around 50 U/mL, may be more appropriate for premenopausal women.
“If my CA-125 is elevated, what will the next steps be and why?” Knowing the pathway in advance helps you hold a borderline result in perspective rather than waiting anxiously for a call.
“Are you tracking my CA-125 over time, or interpreting a single reading in isolation?” A rising trend is more meaningful than any individual number.
“Is CA-125 being used alongside other tools, like transvaginal ultrasound?” Multi-modal assessment is more informative than any single marker.
“What would prompt you to be genuinely concerned about a result, versus wanting to repeat or monitor it?” Understanding where the threshold for action lies can make a real difference to how you process results.

The Bottom Line

CA-125 is a frequently discussed test in the BRCA+ community. It has real and well-documented limitations, particularly for premenopausal women, and the reference range most labs still use was not designed with a BRCA+ and premenopausal population in mind.

Unfortunately, there is currently no screening test, CA-125 included, that has been shown to reduce deaths from ovarian cancer, in the general population or in high-risk women. For BRCA+ women, risk-reducing surgery remains the only established way to lower the risk of dying from ovarian cancer. Some care teams may still choose to use CA-125 as part of a broader surveillance plan. If yours does, the questions above will help you understand what the results can, and cannot, tell you.

The use of CA-125 for screening is not recommended by the BC Cancer Hereditary Cancer Program. This post is for informational purposes and does not constitute medical advice. Please discuss your individual surveillance plan and any test results with your care team.

References

1. CA-125 as marker of ovarian malignancy; stage-specific sensitivity (elevated in about 50% of early-stage tumours, mostly type I, and 92% of advanced-stage tumours, mostly type II); comparison with HE4. Charkhchi P, et al. CA125 and Ovarian Cancer: A Comprehensive Review. Cancers (Basel). 2020;12(12):3730. https://pmc.ncbi.nlm.nih.gov/articles/PMC7763876/

2. Reference range of 35 U/mL derived from postmenopausal/blood donor populations; revised upper limit of 50 U/mL for premenopausal women (NCI-sponsored study, n=3,692). Skates SJ, et al. Large Prospective Study of Ovarian Cancer Screening in High-Risk Women: CA125 Cut-point Defined by Menopausal Status. Cancer Prev Res. 2011;4(9):1401-8. https://pmc.ncbi.nlm.nih.gov/articles/PMC3172691/

3. CA-125 sensitivity and specificity; performance lower in premenopausal women. Cancer Antigen 125. StatPearls, NIH National Library of Medicine. 2024. https://www.ncbi.nlm.nih.gov/books/NBK562245/

4. Age-specific annual ovarian cancer incidence in BRCA1 and BRCA2 carriers (prospective study, n=5,689). Kotsopoulos J, et al. Age-specific ovarian cancer risks among women with a BRCA1 or BRCA2 mutation. Gynecol Oncol. 2018;150(3):406-410. https://pubmed.ncbi.nlm.nih.gov/29793803/

5. Cumulative ovarian cancer risk by age 80: 44% BRCA1, 17% BRCA2 (prospective cohort, n=9,856). Kuchenbaecker KB, et al. Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers. JAMA. 2017;317(23):2402-2416. https://jamanetwork.com/journals/jama/fullarticle/2632503

6. UKCTOCS: no mortality reduction from CA-125 plus ultrasound screening despite earlier stage detection (n=202,638, median follow-up 16 years). Menon U, et al. Ovarian cancer population screening and mortality after long-term follow-up in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Lancet. 2021;397(10290):2182-2193. https://pubmed.ncbi.nlm.nih.gov/33991479/

7. PLCO trial: no ovarian cancer mortality benefit from CA-125 and ultrasound screening (median follow-up 14.7 years). Pinsky PF, et al. Extended Mortality Results for Ovarian Cancer Screening in the PLCO Trial. Gynecol Oncol. 2016;143(2):270-275. https://pmc.ncbi.nlm.nih.gov/articles/PMC5077651/

8. High-grade serous carcinoma biology and why earlier detection does not reduce mortality (exploratory UKCTOCS analysis). Menon U, et al. Why Did Downstaging in UKCTOCS Not Result in a Mortality Benefit? SSRN preprint. 2023. https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4451250

9. Menstrual cycle variation in CA-125: effect modest in healthy women; not clinically significant at population level. O'Neill C, et al. The effect of the menstrual cycle on serum CA 125 levels: A population study. Am J Obstet Gynecol. 2013. https://www.sciencedirect.com/science/article/abs/pii/S0002937811917207

10. CA-125 levels elevated during menstruation; sampling during menstruation not recommended for cancer diagnosis. Haga Y, et al. Serum CA 125 levels during the menstrual cycle. Fertil Steril. 1990. https://pubmed.ncbi.nlm.nih.gov/2223685/

11. Lifetime ovarian cancer risk: 39-58% BRCA1, 13-29% BRCA2. National Cancer Institute. BRCA Gene Changes: Cancer Risk and Genetic Testing Fact Sheet. Updated 2024. https://www.cancer.gov/about-cancer/causes-prevention/genetics/brca-fact-sheet

12. Population prevalence of BRCA2 approximately twice that of BRCA1. Anglian Breast Cancer Study Group. Prevalence and penetrance of BRCA1 and BRCA2 mutations in a population-based series of breast cancer cases. Br J Cancer. 2000;83(10):1301-1308. https://pubmed.ncbi.nlm.nih.gov/11044354/

13. ROCA algorithm for longitudinal CA-125 interpretation. Skates SJ. Ovarian Cancer Screening: Development of the Risk of Ovarian Cancer Algorithm (ROCA) and ROCA Screening Trials. Int J Gynecol Cancer. 2012;22(Suppl 1):S24-S26.

14. Preclinical natural history and rapid growth of high-grade serous ovarian cancer; short window of screen-detectability before advanced stage. Brown PO, Palmer C. The Preclinical Natural History of Serous Ovarian Cancer: Defining the Target for Early Detection. PLoS Med. 2009;6(7):e1000114. https://journals.plos.org/plosmedicine/article/info:doi/10.1371/journal.pmed.1000114

15. Histology-specific progression; type I subtypes (low-grade serous, mucinous, clear cell, endometrioid) progress more slowly than high-grade serous carcinoma. Development and Validation of a Histology-Specific Natural History Model of Ovarian Cancer. Am J Obstet Gynecol. 2025. https://pubmed.ncbi.nlm.nih.gov/40618976/

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