Biomarkers Play Important Roles in Cancer Detection and Patient Follow-up
Written by Professor Joe Duffy UCD Clinical Research Centre, St. Vincent’s University Hospital, Dublin and UCD School of Medicine, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin
Biomarkers play an important and sometimes vital role in cancer detection and patient management (i.e., follow-up of patients following a diagnosis of cancer). Thus, in well or asymptomatic individuals, some biomarkers may be used in screening for early cancer. Following a diagnosis of cancer, biomarkers can help in planning the most appropriate therapy for a specific patient, in detecting the early emergence of cancer spread and in monitoring the effectiveness of an ongoing therapy. Below, I discuss the use of biomarkers in these different settings.
Biomarkers in Screening for Early Cancer
The aim of screening for cancer is to detect it at an early stage before it causes symptoms and when it may be easier to treat successfully. It is widely accepted that the earlier a cancer is detected, the better the outcome. An effective cancer screening test should therefore reduce mortality from the particular cancer being screened for.
One of the most widely used biomarkers in cancer screening is PSA which is used for detecting early prostate cancer. Although opportunistic screening with PSA is widely performed, this practice is highly controversial with arguments for and against the practice. Although a large trial carried out across 8 European countries showed that screening men 55-69 years of age with PSA significantly reduced mortality from prostate cancer, the trial also showed that many men had a prostate malignancy detected that might not have caused any problems, i.e., screening led to many cases of overdiagnosis of non-life-threatening disease. The problem with overdiagnosis is the possibility of overtreatment with further potential for harm. Overdiagnosis of prostate cancer however, can be reduced by performing additional tests such as multiparametric magnetic resonance imaging (mpMRI).
Another problem with the PSA test is that abnormal values are not confined to men with prostate cancer but may also occur when benign prostate hypertrophy (BPH) or prostatitis is present. Differentiation between BPH and prostate cancer necessitates a prostate biopsy with the possibility for complications such as infection, pain, bleeding, urinary retention or haematuria.
Since PSA is less than an ideal screening test for prostate cancer, most guidelines published by international expert panels are opposed to mass population screening for the disease. Many guidelines however, recommend screening in men 55 to 69 years of age under specific conditions such as following the practice of shared decision making and informed consent. The shared decision making should include a discussion between the man and his doctor about the potential harms and benefits of the screening process and the likely ensuing impact on the man’s health and quality of life.
Another biomarker that is used in screening for cancer is faecal occult blood testing (FOBT) for colorectal cancer (CRC). In contrast to PSA screening for prostate cancer, most countries have organized screening programmes for CRC using FOBT. Several years ago, an early version of the FOBT, known as the guaiac test, was shown to reduce mortality from colorectal cancer in several different large randomized trials. In Ireland, the National Screening Service (NSS) currently offers an improved version of the original FOBT, known as a faecal immunochemical test (FIT), to all individuals aged 60 to 69. Individuals in this age range are contacted by post and invited to participate in the programme. The small numbers of individuals with positive results are then offered a colonoscopy.
Use of Biomarkers in Guiding the Most Appropriate Therapy
Few if any of the currently available drug-related treatments for disease are effective in all of those receiving it. This certainly applies in cancer treatment, especially with some of the newer molecularly therapies and immunotherapy where response are usually confined to a minority of patients. In addition, most cancer treatments can cause unpleasant side-effects. Clearly, in such a situation, biomarkers that predict response in advance of starting the treatment are important to identify those most likely to benefit.
One of the cancers in which such biomarkers are widely used is breast cancer. Currently, when a woman is diagnosed with breast cancer, 3 important biomarkers are measured, estrogen receptors (ER), progesterone receptors (PR) and HER2. Depending on which of these biomarkers are positive, a particular therapy may be administered. For example, if ER or PR is present, the woman is likely to receive some type of endocrine therapy such as tamoxifen or an aromatase inhibitor. If however, the woman is HER2-positive, she is likely to receive the drug, Herceptin. If all 3 biomarkers are negative, i.e., the tumor is triple-negative, chemotherapy is the treatment of choice. However, it should be stated that there is currently intensive ongoing research into developing new non-chemotherapy treatments for patients with the triple-negative type of breast cancer. One of the most promising of these new treatments is immunotherapy which boosts ones’ immune system to fight the cancer.
Another cancer in which biomarkers are widely used in selecting the optimum treatment is a form of lung cancer known as non-small cell lung cancer (NSCLC). Lung cancer is the most common cancer world-wide and causes of most cancer-related deaths. Traditionally, this cancer was difficult to treat with the only form of drug-related therapy been chemotherapy. However, in the last few years, a large range of new treatments have become available, including immunotherapy and drugs which block genes involved in driving the growth of the cancer. To determine the most appropriate drug for an individual patient, a series of biomarkers may be measured and depending on which biomarker is present, a particular drug is recommended.
Monitoring Patients Following a Diagnosis of Cancer
Following initial diagnosis of a cancer, most patients are now followed up at regular intervals, a practice referred to as surveillance. The main aim of surveillance is to detect any emerging recurrent/ metastatic disease at a potentially curable stage, the assumption being that early detection followed by the initiation of treatment will result in better outcome than starting treatment when a recurrence is clinically evident. Indeed, in several different cancer types, regular measurement of biomarkers can predict the presence of early recurrent/ metastatic disease and provide a lead-time vis-à-vis clinical
or radiological findings. Some examples of biomarkers that can identify the emergence of early recurrences include PSA in prostate cancer, CEA in colorectal cancer, AFP and HCG in patients with germ cell tumors of the testis (non-seminomatous type), CA 15-3 in breast cancer and CA 125 in ovarian cancer.
Unfortunately, some of the patients being following-up will develop recurrent or metastatic disease and will have to undergo further therapy. Although radiological imaging is the gold standard method for monitoring response to therapy, the use biomarkers is considerable more convenient for patients and is less expensive.
Generally, decreasing levels of biomarkers following the initiation of therapy correlate with tumor shrinkage while increasing levels tend to predict disease deterioration. The biomarkers used in monitoring therapy are the same as those mentioned above for postoperative surveillance
Conclusion
From above, it is clear that biomarkers are making a major contribution to cancer detection therapy selection and patient monitoring. Hopefully, the use of biomarkers in these different settings is helping with personalized treatment and improved outcome. Looking to the future, one of the most exciting research areas currently is in the development of a blood-based pan-cancer screening test. These tests involve analysing genetically altered DNA shed by tumor cells into the blood stream. Thus, with a sample of blood, it may in the future be possible to screen for up to 50 different cancer types, simultaneously. If so, the holy grail of a simple blood test for early cancer may finally be achieved.
Acknowledgement: MJD’s research is funded by the Cancer Clinical Research Trust
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