Molecular biomarkers are independent of the presence of a detectable tumor mass or even the detection of intact transformed cells. Instead, they represent detection at a distance, using molecular signals in blood or excretia to indicate the presence of a cancer or pre-invasive lesion. These molecular biomarkers fall into four groups (Table 1).

Some are products of the neoplastic process that are shed by the tumors, such as mutated or hypermethylated DNA (‘carcinogenesis markers’). Others are molecular species generated by the host response to the cancer (‘response biomarkers’). Examples include antibodies, protein degradation products,¹² and acute phase reactants.¹³

A third group of biomarkers, like blood in stool or PSA in serum, are released in abnormal amounts as a result of the anatomical or metabolic disruption associated with a tumor (‘released biomarkers’).

The final group of molecular markers comprises factors associated with or supporting the underlying carcinogenesis (‘risk biomarkers’). Examples are high estradiol levels in relation to breast cancer or markers of human papilloma virus in relation to cervical cancer.

These classes of biomarkers will probably behave differently in early detection. Carcinogenesis markers are likely to be relatively specific for invasive or pre-invasive neoplasia, as they are essentially found only in on-going carcinogenesis.

Testing for PSA or blood in stool has already shown that released biomarkers can be non-specific: pathology other than cancer often leads to their release into blood and stool respectively.

Risk biomarkers are often abnormal in individuals without cancer; these are really risk factors, markers of cancer risk rather than markers of cancer itself.

Typically only a minority of individuals with the risk factors actually develop the associated disease.

Thus, just as benign masses can mimic tumors or obscure cancers in anatomical screening, pathological and metabolic processes will affect the specificity of molecular screening, especially if it is not based on carcinogenesis markers. PSA provides many examples: hemodilution of PSA levels in obese men,^{14, 15}distortion of levels by medication,¹⁴ and increases in levels from prostatitis.¹⁶ Inflammation – a risk factor for cancer in many organs — may be a particular problem as it shares molecular mediators with carcinogenesis.

One is that the tests are convenient and safe – typically requiring only the donation of blood, urine or stool. Measuring these molecular biomarkers does not involve tests that deliver radiation, a visit to the clinic, or unpleasant procedures as is needed for colonoscopy. Thus, the use of molecular biomarkers is likely to improve the uptake of screening by the general population and make repeated testing practical and affordable. This would increase the sensitivity of the screening process, and correspondingly increase the chances of detecting early cancers. However, it would also increase the potential for false positives, with the adverse downstream consequence of unnecessary diagnostic follow-ups.

Another advantage of molecular biomarkers is that they can easily be combined into panels using mathematical techniques such as logistic models or recursive partitioning to enhance sensitivity and specificity. Such combinations might be less susceptible to measurement artifacts than the individual markers. Also, the quantitative nature of many molecular markers means that they can potentially be personalized, using age, sex and race-specific norms, for example.

Pre-malignant lesions

Since the molecular defects of early cancer are often similar to those of intraepithelial neoplasia,⁴⁰molecular screening for cancers will likely identify substantial numbers of pre-invasive lesions. In organs such as the colorectum and cervix, these can be removed relatively easily to reduce risk of future cancer. Excision of pre-invasive lesions identified in less accessible tissues, such as the pancreas, entails considerable morbidity. It may not be clear what should be done to address the increased risk of invasive cancer, particularly as the natural history of these screen-detected lesions may not be well characterized.

Some risk biomarkers and some reaction biomarkers (such as antibodies) might remain in the abnormal range even after the responsible lesions are completely removed. For example, long-term hormonal patterns that promoted carcinogenesis presumably would continue, and some antibodies generated by a tumor may persist. Markers that do revert to normal after successful treatment could be used to follow disease recurrence and progression, as PSA (for prostate cancer) CEA (for colorectal cancer) and CA-125 (for ovarian cancer) are used now. Here again, advanced anatomical detection may aid the molecular screen to locate recurrent neoplasia that is not otherwise evident. Ideally, the validation of molecular screening markers would include study of their behavior as markers of disease progression after excision of the tumors that are detected.

In some organs, it may even be a challenge to find the cancers indicated by molecular biomarkers.

Some of the cancers detected may not need to be treated.

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