Screening in Breast and Prostate Cancers

Introduction

Currently, people believe that the same level of screening for breast cancer in females should be done for malignancies in males

(Razi, 2004

, p. 241) since mortality rates are very similar. About 15% of women who die from cancer in the UK are due to breast cancer, which is the second type of cancer that causes more deaths in women [1], while prostate cancer causes about 13% of all cancer deaths in men, being as well the second type of cancer that causes more deaths in males [2].

But whereas in the UK breast screening is performed in women between 50 and 70 years old [3], prostate screening is not a routine to detect this kind of cancer [4].

Breast cancer screening

Breast screening is used to detect breast cancers when they cannot even be seen or felt  [3], so they are less difficult to treat               [5] and there is a good chance of recovery [6].

Sometimes, women younger than 50 years old may be entitled for breast screening if they have high probabilities of suffering this cancer [7]. Then a genetic specialist should evaluate the case.

• 
  If there is a family history of breast cancer:
  
  women should start annual screening mammograms from 40 years old. For those who are too young to undergo a mammogram but have an increased risk of breast cancer, MRI scans can be done each year from their thirties.
• 
  If they have a gene mutation:
  
  MRI scans are performed every year from age 20 in females with a TP53 mutation and from age of 30 in those with a mutation in BRCA1 or BRCA2 [3].

The most common and useful screening test to find breast cancer early and lower the risk of dying from this pathology is the mammogram [5]

.

The process consists in placing the breast between two plates that flatten it while two X-rays pass through the breast tissue to take an image of it. Then the same procedure is repeated in the other breast. Although it is a brief process, sometimes women can feel uncomfortable. The results will be received within two weeks [7].

But there are other methods used as adjuncts to mammograms, such as Breast Magnetic Resonance Imaging (MRI) technology, which uses magnetic fields and radio frequency signals to take pictures of the breasts in young woman who have a raised probability for getting breast cancer.

Although there is no evidence that being examined by a specialist reduces the risk of dying from breast cancer, it may be a complementary method to find early signs of cancer, such as lumps.  Also, breast self-awareness [5], which consists in touching breasts to check that everything is normal [8] is recommended as a pre-screening method [5].

Furthermore, new diagnostic techniques can be useful in investigating lesions that are not clear on standard imaging. Also, they may help in decreasing recall rates. But they need to be more developed (Singh

et al.

, 2008 p. 501).

• 
  Sestamibi scans
  
  (Singh
  
  et al.
  
  , 2008, p.501): it is a technique used along with current diagnostic methods, which utilizes a radiopharmaceutical called 99mTc-sestamibi as a tumor imaging agent (Khalkhali
  
  et al.
  
  , 2000, p. 1973). This radioactive material is absorbed by tissues with a high metabolic activity, such as breast cancer tissue, thus allowing the development of scintimammography [9]. This is a new type of mammography that can find cancer signs even in breast implants or dense breast tissue. Moreover, it helps to investigate abnormalities detected in a normal mammography and to determine whether those abnormalities requires biopsy or not, avoiding more invasive procedures [10]. Hence this method has a high specificity for cancer [9].
• 
  Optical imaging
  
  (Singh
  
  et al.
  
  , 2008, p. 501): a set of techniques that have emerged in recent years as a potential pre-screening tool due to its low cost and non-invasive procedure. They complement clinical breast examination (CBE) and self-breast examination (SBE) since these lead to increased false-positives (Godavarty
  
  et al.
  
  , 2015, p. 193). They can provide detailed information about breast cancer tissue, such molecular, functional and morphologic features by using near infrared (NIR) light (700–1000 nm) and visible light (400–700 nm) (Di Leo
  
  et al.
  
  , 2017, p. 230).
• 
  Contrast-enhanced digital mammography (CEM)
  
  [11]: it provides a better sensitivity since it optimizes the lesion-background contrast.  Moreover, this technique allows seeing through the dense breast tissues in younger woman (Singh
  
  et al.
  
  , 2008) (sonography may be useful in these cases as well) (Brooks, 2009, p. 308). Therefore, it is possible to decrease the necessity of repeating scanning, as well as the radiation dose to patients (Singh
  
  et al.
  
  , 2008). Because of that, with this technique is possible to depict cancers that would otherwise be occult on standard unenhanced mammography [11].
• 
  Tomosynthesis
  
  :  is a more developed mammography in which small doses of x-rays are used [12] to get multiple 3D digital X-ray images (Godavarty
  
  et al.
  
  , 2015, p. 197) for the purpose of detecting cancer early [12].
• 
  PET/CT
  
  (positron emission tomography–computed tomography) (Groves et al., 2012 p. 613): it has a role in detecting tumour recurrence and metastasis in breast cancer patients (Singh
  
  et al.
  
  , 2008, p. 507). With PET imaging, a radiologist injects a small amount of radioactive dye into the patient and then measures the absorption of the dye as it passes through the body [13]. PET discoveries can be localised thanks to the contribution of the CT component
  
  (Groves et al., 2012 p. 613).
  
• 
  Biomarkers
  
  : CA 15-3, carcinoembryonic antigen (CEA), and CA 27 – 29 are serum tumor markers which are used in the clinic for disease surveillance, but they are not useful in detecting early breast cancer, due to their low sensitivity and specificity. Plasma prolactin, circulating insulin-like growth factor (IGF)-1 and IGF binding protein (IGFBP)-3 concentrations are related to a high risk of postmenopausal breast cancer risk in older women, but their use as markers is still being investigated (Brooks, 2009, pp. 309-312).

Benefits of breast screening

In England, breast screening leads to the diagnosis of 18,000 breast cancers each year. They are usually found at an early stage, when they are easier to treat and need less treatment. Almost all women in this situation will be probably cured and most of them will survive for at least 5 years after the cancer is detected [3].

Randomized controlled trials (RCTs) show that females from 50 to 69 who undergo mammography improved their breast cancer survival [14].

Harms of breast screening

• 
  False negative result
  
  [3]: in 6% to 46% of mammograms there may be invasive cancer that was undetected [14]. This may delay finding a cancer and getting treatment [15]. They are more likely for tumours in dense breasts, frequently in young women [14].
• 
  False positive result:
  
  the test detects signs of breast cancer in heathy women. Also, about 7% of females that were submitted to screening are called back to be x-rayed again, if the first mammogram is not clear enough. This can lead to more invasive tests, like a biopsy [3], which can be expensive and time-consuming [15].

• 
  Overdiagnosis and overtreatment
  
  : it happens when cancers that will not ever cause any problems are detected by the test. Currently, it is not possible to distinguish between breast cancers that will develop quickly and those that will disappear on its own. So, the most common procedure is to eliminate it by surgery, and to take other treatments that can be unnecessary. According to a review in 2012, about 4,000 females are overdiagnosed each year in the UK[3].
• 
  Exposure to radiation
  
  [3]: it is extremely unlikely that radiation doses used in a mammography cause cancer. It would be necessary to receive higher doses to cause radiation-induced mutations [14].
• 
  Unnecessary anxiety:
  
  when women are called back for more tests (about 1 in 25) they feel very anxious that they might have cancer, but most of them turn out to be fine (just 1 in 5 of those had breast cancer) [16].

The UK breast screening programme

The first screening programme aimed to detect breast cancer was performed in 1988 by the NHS.

In the year from 2009 to 2010, 1,998,225 females aged 50-70 had breast screening in the UK and 15,517 of these were diagnosed of cancer.

A trial put women into two random groups, one of them was screened and the other one not. The Panel found that in the UK, breast screening can avoid the breast cancer death of 1,300 women each year.  For every 1,000 women screened, about 5 lives are saved while 17 women are overdiagnosed.

The good results yielded in this trial showed that the UK breast screening programme should continue due to its important advantages [16].

Prostate cancer screening

Although the incidence of prostate cancer is increasing, the mortality and morbidity rates have remained constant. Moreover, the disease belongs to old ages and if it is not screened, the danger for the patient is less than that of lung, colorectal, and breast carcinoma. It means that the priority is not given to prostate cancer (Razi, 2004, p. 242).

The most extended screening test is the PSA test. It involves the measure in the blood of the protein produced by the prostate gland called prostate-specific antigen (PSA). [17]. In men free of disease, who have a normal prostate, a small amount of this protein, leak out into circulation. But the levels of PSA in blood increase significantly when there is a prostate cancer (Stenman

et al.

, 1999, p. 84). However, other non-carcinogenic factors such as the age can also rise the PSA levels in blood [17].

The PSA test has a high fluctuation in specificity and sensitivity (Razi, 2004, p. 243). Although specificity of the test is 60% to 70% (Kim

et al.

, 2015, p. 258) (disease-free cases correctly classified) (Parikh et al., 2008, p. 46) in males with a level of PSA in blood above 4.0 ng/mL, sensitivity is only about 20%. This means that while 20 patients are correctly diagnosed of prostate cancer, 80 patients should be submitted to more invasive procedures such as biopsy, since there will be false negative cases. Therefore, a high number of patients will undergo unnecessary biopsy without detecting prostate cancer (Kim et al., 2015, p. 258). These are some reasons why prostate screening is not performed as a routine in the UK [17]. However, men from 55 to 69 years

(Grossman

et al.

, 2018, p. 1901)

can access the ‘Prostate cancer risk management’ programme

[17

], which allows them to have an appointment with the doctor to be informed about advantages and disadvantages of screening according to family history, race/ethnicity and comorbid medical conditions (Grossman

et al.

, 2018, p. 1901).

If the result of the screening test shows an amount of PSA in the blood of 3ng/ml or higher, the doctor may suggest further test to find out if it is a prostate cancer. Probably it is a sign of

enlarged prostate

,

prostatitis

or

urinary infection

, which are not cancer [17].

Additionally,

Digital Rectal Examination (DRE) test

can help in the diagnosis of the palpable form of disease. But its sensitivity changes from 18% to 68%, due to the different sensitivity of examiners’ fingers (Razi, 2004, p. 242).

Benefits of prostate screening

• According to some studies, not executing this test may raise a risk of reducing well-being as well as longevity in men. One of them done in Quebec, in which 80137 men over 50 years old experienced DRE and PSA, shown that the
  
  mortality rate from prostate cancer decreased noticeably in screened men
  
  in comparison with 38000 controls (5/100000 vs. 48.7/100000) (Razi, 2004, p. 243).
• If the result of the test does not show any abnormality, men who underwent screening may be relieved [17].
• In some cases, it is possible to receive early treatment since it can detect signs of cancer at the beginning of the disease [17].
• 
  Men with PSA levels between 4.1 and 10 ng/ml
  
  are suggested to perform a biopsy. This will lead to diagnosis of cancer in 25% (Razi, 2004, p. 243).

Harms of prostate screening

• Although it is possible to diagnose the disease in early stages, we are unable to differentiate the non-progressive disease from its fatal form (few cases). Because of that, it is probable that screening test may diagnose a benign form of disease, not requiring treatment. Then the patient will suffer from being aware of his illness and should undergo different stages of investigation and treatment, which might be accompanied by morbidities (i.e. incontinency, impotency, intestinal complications, etc.) (Razi, 2004, pp. 241-242).
• It is not possible to know if treatments available for prostate cancer, such as radical prostatectomy, radiotherapy and watchful-waiting will alter the natural course of preclinical disease or not. Moreover, these treatments have complications such as urethral stenosis, injury to intestine, incontinency, and impotence (Razi, 2004, p. 242).
• It is necessary to perform a lot of rectal examinations (289 according to a study) to diagnose one case of clinically significant prostate cancer (Razi, 2004, pp. 242-243).
• False-positive results: sometimes PSA tests can pick up signs of prostate cancer even if it does not exist. About 75% of males who show a raised PSA level do not have prostate cancer [17], but it is necessary to take second line tests such as transrectal ultrasound (TRUS) or transrectal ultrasound-guided biopsy (TRUS-GB) to confirm that (Razi, 2004, p. 243). In recent years it has become more common to offer an MRI scan before that to help avoid invasive tests [17].

• False-negative results: many men are not diagnosed of prostate cancer since about 15% of cases do not have high levels of PSA in blood [17].
• Case finding expenses should be equivalent to medical care expenses but in the case of prostate cancer, screening expenditure is much higher than medical care expenses (Razi, 2004, p. 243).
• The screening test is not all accepted by the community, since many patients are embarrassed with DRE (Razi, 2004, p. 243).
• There is no agreement that early diagnosis can decrease mortality rate with appropriate treatment. Many studies such as the one from Massachusetts hospital, disagree with the results of the study done in Quebec, which showed a reduced mortality rate from prostate cancer in screened patients (Razi, 2004, p. 243).

Because of the large number of disadvantages of PSA test and its controversial use, some prostate cancer biomarkers are being investigated currently. The testing of urine, serum, or prostate tissue for molecular signs of prostate cancer can provide information of diagnosis (Alford

et al.

, 2017, p. 222).

• 
  Kallikreins
  
  : there is a test that measures the plasma levels of four of these proteins which are expressed in the prostate. Human kallikrein-3 (PSA) and human kallikrein-2 (hK2) are the dominant forms and their levels are increased in circulation when the tumor is poorly differentiated. The number of biopsies can be reduced by 49% to 57% among men being screened for the first time with this test (Alford
  
  et al.
  
  , 2017, p. 223).
• 
  Autoantibodies
  
  : the humoral immune response to cancer consists of the production of autoantibodies against several tumor antigens. The blood test Apifiny measures the expression of eight PCa-specific autoantibodies. It is marketed for men with PSA 2.5 ng/mL who are considering initial biopsy (Alford
  
  et al.
  
  , 2017, p. 224).
• 
  PCA3 (DD3):
  
  it is a long noncoding RNA overexpressed in 90% of prostate cancers.

The Progensa PCA3 assay is a test that measures the concentration of this molecule. Lower PCA3 levels are associated with a low-grade disease (Alford

et al.

, 2017, p. 224).

Screening programs: differences among countries

• 
  Breast cancer:
  
  mammography is the standard screening method in the 26 countries that organize screening programs for woman, according to the National Cancer Institute. Nevertheless, there are some differences depending on the country since there is no agreement for a unique performance of this screening. In general, it is conducted every two years (United States, Sweden), although the United Kingdom recommends screening at three-year interval and Uruguay offers it every year.

There are also variations in the onset age of mammography. While most programs are offered to women between 50-70 years old, in China, Japan, Australia, South Korea, Sweden, Uruguay, Iceland, Saudi Arabia, and the United States, patients start to be screened in their forties.

Finally, in terms of participation rates, less than 20% women undergo mammography in Japan and Saudi Arabia; around 50% in France, Switzerland and Canada and above 80% in Finland and the Netherlands [18].

• 
  Prostate cancer:
  
  the controversial use of PSA test as a screening tool means that there is no agreement among all the countries on how to carry it out (Ebell, Thai and Royalty, 2018, pp. 4-5).

Most of the countries does not have a national guideline currently. They are limited to recommending an appointment with the doctor (such as Belgium, Luxembourg, Switzerland and Iceland) or do not make any recommendation. Furthermore, according to the United States Preventive Services Task Force (USPSTF), Spain, Sweden, United Kingdom, United States, New Zealand, France, Canada and Australia advise men against prostate cancer screening (Ebell, Thai and Royalty, 2018, pp. 5-8).

Regarding US American Cancer Society’s information, men with levels of PSA in blood over 2.5 ng/Ml should be screened every year. However, it should be offered at the age of 40-45 to those men who have a high risk of prostate cancer. This is the age of starting screening ‘regularly’ in Austria

(Ebell, Thai and Royalty, 2018, p. 8).

Conclusion

As we can see, breast cancer screening is a routine in the UK, as well as in many other countries, to decrease effectively deaths due to breast cancer. A large number of studies have confirmed that performing breast screening in women over 40-50 years old has more benefits than harms. However, there is no evidence that a PSA test for prostate cancer screening has the same effect reducing mortality rates caused by this type of cancer. In fact, some experts believe that its disadvantages exceed its advantages, based on the reasons mentioned above. Therefore, PSA test should be used as a screening tool in specific cases but not routinely.

Recently, new techniques that can be helpful for the screening and diagnosis of both types of cancer have emerged, however there is still much to investigate and improve.

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