What Is a Multi-Cancer Early Detection Test? Understanding True and False Positive and Negative Results

What Is a Multi-Cancer Early Detection Test?

Cancer is one of the world's most important health problems, and early diagnosis is crucial to improving treatment success. Developed for this purpose, multi-cancer early detection tests (MCED = Multi Cancer Early Detection) have the potential to detect several types of cancer from a blood sample. By enabling diagnosis at an early stage, they may improve quality of life and survival. However, the accuracy and reliability of their results are essential. Their potential to produce true positive, false positive, true negative, and false negative results must therefore be assessed.

Related topic: How Close Are We to Multi-Cancer Early Detection from a Single Blood Sample?

A Revolution in Early Detection – Its Importance and the Technologies Used

MCED tests offer a revolutionary innovation in the early detection of cancer.

These tests detect substances released from cancer cells or tumors into body fluids, particularly the bloodstream, including:

• Blood biomarkers,
• DNA fragments,
• Epigenetic changes, and
• Other molecules, using advanced biotechnology methods.

These tests do not attempt early cancer detection through a single biotechnology approach, such as screening only for tumor DNA or cancer cells in the blood. Instead, they use models that combine many biomarkers and seek a particular pattern. Examining combinations of biological signals can thereby provide earlier and more accurate detection.

At present, no MCED test has yet received formal approval from the FDA (United States Food and Drug Administration) or another approving health authority. However, many developers are working intensively on these tests, with approvals expected within the next few years. Clinical studies involving tens of thousands of people worldwide are currently assessing their sensitivity and accuracy.

How MCED Tests Generally Work

The illustration below shows how an MCED blood test using machine learning, a form of artificial intelligence, works: 

The diagram above details the process of early cancer detection and the role of MCED tests. After cancer cells first develop, they begin releasing cell-free DNA (cfDNA) through apoptosis or necrosis. The MCED test isolates and sequences cfDNA in the blood. Analysis using machine learning algorithms provides information about the presence and origin of a cancer signal. If a signal is detected, the test identifies the organ from which it originates. The detection limit and clinical detection points represent thresholds at which cancer can be identified by conventional methods. The diagram emphasizes the ability of MCED tests to detect cancer during the preclinical detectable period, before it becomes clinically apparent.

Types of MCED Tests – Names, Technologies, and Targeted Cancers

The following table lists MCED tests developed by various companies, the technologies they use, and the cancer types they target:

Basic Concepts in Cancer Screening Tests

There are four basic types of results when assessing the reliability of cancer screening tests:

• True Positive: The test is positive and cancer is actually present. This means the test has successfully detected cancer.
• False Positive: The test is positive, but cancer is not actually present. This may cause unnecessary anxiety and additional medical interventions.
• True Negative: The test is negative and cancer is actually absent. This means the patient truly does not have cancer and the test has given the correct result.
• False Negative: The test is negative, but cancer is actually present. This risks leaving the disease undiagnosed and allowing it to progress untreated.

The General Rationale for Cancer Screening

Cancer screening aims to identify cancer early in people of certain ages or with particular characteristics. For example:

• Colorectal Cancer Screening: Performed after age 45 in both women and men using methods such as colonoscopy or fecal occult blood testing.
• Breast Cancer Screening: Performed with mammography in women after age 40.
• Cervical Cancer Screening: Performed with HPV testing or a smear in all women from age 25.
• Lung Cancer Screening: Performed with low-dose chest CT in all women and men who smoke, starting at age 50.
• Prostate Cancer Screening: Performed by measuring blood PSA in all men from age 50.

These age thresholds apply to individuals at average risk. People with hereditary cancer risk may be screened earlier and with more detailed or different methods.

Screening is performed before cancer causes symptoms, enabling early diagnosis and treatment. Its effectiveness is highly important for public health because cancers detected early have much higher treatment success rates.

Until now, separate screening tests have been available for individual cancer types. MCED tests have the potential to detect many different cancers early from a single blood sample.

MCED tests bring a new approach to cancer screening and are an important tool for saving more lives. However, their results must be interpreted with the possibility of false positives and false negatives in mind, and these outcomes must be managed carefully.

What Happens If an MCED Test Is Positive?

If an MCED test is positive, the following steps are taken:

1. Cancer Signal Detected: If a cancer signal is detected, its source is identified to help determine which organ or tissue is producing the cancer.
2. Additional Investigations: After a positive result is confirmed, additional clinical investigations and tests are performed, such as PET/CT, CT alone, or MRI . These are necessary for a more definitive diagnosis and treatment planning.
3. Treatment Planning: An appropriate treatment plan is prepared according to the cancer type and stage identified.

What Happens If an MCED Test Is Negative?

A negative MCED result means that circulating tumor cells (CTCs) or tumor DNA (cfDNA) were not detected in the person's blood. A negative result indicates that the person showed no sign of cancer at the time of testing. However, negative results must be considered with certain qualifications:

1. Absence of Cancer: A negative result indicates that the person does not have cancer at that time. This means they currently have no malignant tumor and may therefore feel less concerned about cancer.

2. Regular Follow-Up: Even after a negative result, regular follow-up is important, particularly for people with a family history of cancer or in high-risk groups. At-risk individuals should continue MCED or other appropriate cancer screening tests at regular intervals.

A Recent Study – Low Cancer Risk After False Positive Results

Cancer screening is crucial for early diagnosis and treatment. However, false positive results, incorrectly indicating cancer, may occur and cause unnecessary anxiety. DETECT-A data show that patients with false positive results from CancerSEEK , a type of MCED test, have a low long-term risk of developing cancer. These findings provide important insights into managing false positive results.

Study Aim and Methods

DETECT-A evaluated the performance of the MCED test CancerSEEK. It enrolled 10,006 women aged 65-75 with no previous cancer history. Patients with positive CancerSEEK results were investigated with PET/CT and clinical assessment to confirm whether cancer was present.

Findings

This analysis evaluated 98 patients with false positive CancerSEEK results. A result was defined as false positive if, within 1 year after the positive test, cancer or a precancerous lesion was not detected . Median follow-up was 3.6 years.

• Among patients with false positive MCED results, the rate of cancer development was 1% after 1 year and 3.4% after 2, 3, and 4 years.
• The annual cancer development rate was calculated as 1%.
• Among 63 patients who had no additional procedure after PET/CT, the cancer development rate was 1.6% at 1 year and 3.6% at 2, 3, and 4 years.

During follow-up, 3 patients were diagnosed with cancer:

1. One patient was diagnosed with stage IIIC ovarian cancer 1.9 years after the false positive result.
2. Two patients had stage I breast cancer detected by routine mammography, after 0.1 years and 1.6 years, respectively.

Reassessment of the PET/CT images was consistent with the original readings. The patient with ovarian cancer died approximately 1 year after surgery and chemotherapy. One breast cancer patient underwent surgery, radiation, and hormone therapy and remained cancer-free during follow-up. The other underwent surgery and radiotherapy, but detailed medical records were not provided.

Conclusions and Recommendations

These findings indicate that patients with false positive MCED results can return to routine care when clinical and imaging assessments do not detect cancer. The study shows that returning to routine follow-up protocols while avoiding unnecessary interventions is safe for these patients. However, the findings need validation across broader age ranges, different sexes, and more diverse racial and ethnic groups.

Earlier DETECT-A results showed that CancerSEEK could detect appendix cancer, breast cancer, colorectal cancer, kidney cancer, lung cancer, lymphoma, ovarian cancer, thyroid cancer, uterine cancer, and cancer of unknown primary.