**2. Current breast cancer detection modalities and their limitations**

Breast is susceptible to a range of pathologic conditions. The most serious of these is breast cancer, which is widely recognised as the most common cancer in women. Other breast conditions include mastalgia, which is referred to a variety of conditions that cause breast pain, and benign lesions such as fibroadenomas and cysts. These conditions are not fatal but they are a source of undesirable symptoms and considerable anxiety for the patients. Improved methods for early detection and diagnosis of breast disease are essential to decrease mortality rates due to cancer. In addition a greater understanding of the physiology of the breast is needed to aid in the diagnosis of disease and in improving treatments.

The breast cancer detection is a three part procedure. The first part is the identification of the abnormality in the breast tissue either by physical examination or by an imaging technique. Secondly the abnormality is diagnosed as a benign or malignant condition by using additional diagnostic methods or by biopsy and microscopic examination of the tissue morphology. The third part is concerned with biochemical characterisation of the malignant tissue in order to stage the cancer according to the size of the tumour and extent of invasion and metastasis. This then determines the prognosis and appropriate course of treatment. The most commonly used imaging modalities are described in the following sections.

The main strategy of breast cancer detection is based on clinical examination and mammography. Mammography is considered to be the 'gold standard' test for breast cancer detection and diagnosis and is accepted as the most cost-effective imaging modality. The performance of a screening test is evaluated by three related measurements: sensitivity, specificity, and a positive predictive value. The sensitivity of a screening test is the proportion of people with the disease who test positive. Specificity is the proportion of people without the disease who test negative. The positive predictive value is the proportion of individuals with a positive screening test result who actually have the disease. In the development of optimum detection modality, there is often a trade-off between sensitivity and specificity, with an increase in one leading to a decrease in the other. The contribution of mammography continues to be challenged with persistent false-negative rates ranging up to 30%.The clinical examination has been challenged with reported sensitivity rates often below 65%. There is also variability in radiologists' interpretation of mammograms with decreasing sensitivity in younger patients and those on oestrogen replacement therapy. In addition, recent data suggests that denser and less informative mammography images are precisely those associated with an increased cancer risk (Boyd et al, 1995). It has also been suggested that mammography procedure cannot be performed by an inexperienced technician or radiologist. With the current emphasis on earlier detection, there is now renewed interest in the development of complimentary imaging techniques that can also exploit the metabolic, immunological, and vascular changes associated with early tumour growth. While promising, techniques such as Doppler ultrasound and MRI are associated with a number of disadvantages, which include the following:

Duration of the test,

Limited accessibility,

452 Advances in Cancer Therapy

*Benign conditions:* There are many lesions and conditions that are non-cancerous but still affect the health of the breast and could be mistaken for cancer. These include fibroadenomas, cysts, mastalgia, breast calcifications, duct ectasia and periductal mastitis, fat necrosis, hyperplasia, intraductal papilloma, phyllodes tumour and sclerosing adenosis.

Breast is susceptible to a range of pathologic conditions. The most serious of these is breast cancer, which is widely recognised as the most common cancer in women. Other breast conditions include mastalgia, which is referred to a variety of conditions that cause breast pain, and benign lesions such as fibroadenomas and cysts. These conditions are not fatal but they are a source of undesirable symptoms and considerable anxiety for the patients. Improved methods for early detection and diagnosis of breast disease are essential to decrease mortality rates due to cancer. In addition a greater understanding of the physiology of the breast is needed to aid in the diagnosis of disease and in improving

The breast cancer detection is a three part procedure. The first part is the identification of the abnormality in the breast tissue either by physical examination or by an imaging technique. Secondly the abnormality is diagnosed as a benign or malignant condition by using additional diagnostic methods or by biopsy and microscopic examination of the tissue morphology. The third part is concerned with biochemical characterisation of the malignant tissue in order to stage the cancer according to the size of the tumour and extent of invasion and metastasis. This then determines the prognosis and appropriate course of treatment. The most commonly used imaging modalities are described in the following sections. The main strategy of breast cancer detection is based on clinical examination and mammography. Mammography is considered to be the 'gold standard' test for breast cancer detection and diagnosis and is accepted as the most cost-effective imaging modality. The performance of a screening test is evaluated by three related measurements: sensitivity, specificity, and a positive predictive value. The sensitivity of a screening test is the proportion of people with the disease who test positive. Specificity is the proportion of people without the disease who test negative. The positive predictive value is the proportion of individuals with a positive screening test result who actually have the disease. In the development of optimum detection modality, there is often a trade-off between sensitivity and specificity, with an increase in one leading to a decrease in the other. The contribution of mammography continues to be challenged with persistent false-negative rates ranging up to 30%.The clinical examination has been challenged with reported sensitivity rates often below 65%. There is also variability in radiologists' interpretation of mammograms with decreasing sensitivity in younger patients and those on oestrogen replacement therapy. In addition, recent data suggests that denser and less informative mammography images are precisely those associated with an increased cancer risk (Boyd et al, 1995). It has also been suggested that mammography procedure cannot be performed by an inexperienced technician or radiologist. With the current emphasis on earlier detection, there is now renewed interest in the development of complimentary imaging techniques that can also exploit the metabolic, immunological, and vascular changes associated with early tumour growth. While promising, techniques such as Doppler ultrasound and MRI are associated

**2. Current breast cancer detection modalities and their limitations** 

with a number of disadvantages, which include the following:

Duration of the test,

treatments.


These modalities are in fact more suited as the second-line options to pursue the already abnormal screening evaluations. This stepwise approach currently results in the nonrecognition, and thus delayed utilization of any second-line technology in approximately 10% of established breast cancers (Moskowitz, 1995). This view is supported by another study of infrared screening of breast cancer [Keyserlignk & Ahlgren, 1998). A list of the established breast cancer detection modalities approved by FDA is given in Table 1.



Non-Invasive Devices for Early Detection of

**2.2 Magnetic resonance imaging (MRI)** 

additional diagnostic information for this purpose.

Breast Tissue Oncological Abnormalities Using Microwave Radio Thermometry 455

Particularly, the sensitivity is lower for women with dense breast tissue (e.g. younger women) and breast implants can affect the accuracy of mammography, as silicone implants are not transparent to X-rays. The disadvantages of compressing the breast are that it is, at best, uncomfortable and for many women with sensitive breasts it can be very painful. This limits the maximum time feasible for the imaging process. Also the spatial accuracy of the

The risk of radiation-induced breast cancer has long been a concern and has driven the efforts to reduce the radiation dose per examination. Radiation has been shown to cause breast cancer in women, and the risk is proportional to the dose. Especially the younger women are at a greater risk for breast cancer due to the exposure to radiation. Radiation related breast cancers occur at least 10 years after exposure. However, breast cancer as a result of the radiation dose associated with mammography has not been established. Radiation from yearly mammograms during ages 40-49 has been estimated as possibly

The principal imaging modality used for the detection of breast tissue abnormalities is x-ray mammography, which has a high sensitivity, but suffers from a relatively poor specificity for some tumours and breast types, leading to unnecessary biopsies. Thus there is a need for an imaging technique that can non-invasively distinguish between malignant and benign lesions. At the present, magnetic resonance imaging (MRI) and ultrasound (US) can provide

The theory of MRI is based on the fact that the nuclei of some atoms have a property known as spin. Such nuclei act like tiny current loops and consequently generate a magnetic field (or magnetic moment), along the spin axis. Under normal circumstances these moments have no fixed orientation so there is no overall magnetic field. When an external magnetic field is applied, the moments will align in certain directions. In the case of hydrogen nuclei, which are the most abundant nuclei in the human body, two discrete energy levels are created. An MRI detection system consists of a magnet, magnetic gradient coils, a radio frequency transmitter and receiver, and a computer that controls the acquisition of signals and computes the MR images obtained. When an atomic nucleus is exposed to a static magnetic field, it resonates when a varying electromagnetic field is applied at an

The signal in MRI arises from the rotating magnetisation, but it decays due to two different relaxation processes. The first process is the spin-lattice relaxation. The second relaxation process is the spin-spin relaxation. During spin-spin relaxation, the detected signal decays over a period of time. However, the spins are also subject to inhomogeneities in the magnetic field causing the signal to decay faster than the natural time period. Part of the signal can be obtained due to the spin-echo effect. This involves the application of a further RF pulse which causes the spins to be flipped by 180°. This means that the phase-position of each spin has been inverted and so nuclei that were precessing faster are now behind spins that were precessing at a slower rate. At the echo time *TE*, the spins will catch each other up and a peak in the signal will be detected. An MRI exam of the breast typically takes between 30 and 60 minutes. Diffusion and perfusion MRI are relatively new procedures. Diffusion MRI measures the mobility of water protons whereas perfusion MRI measures the rate at which blood is delivered to tissue. Both of these factors vary in malignant tissues as

appropriate frequency and an image is computed from the resonance signals.

compared with benign tissue and therefore can be used as indicators for cancer.

image can be distorted so that it is difficult to exactly locate an identified lesion.

causing one additional breast cancer death per 10,000 women.

#### **2.1 X-ray mammography**

X-ray mammography is the most common method of imaging the breast at present. The technique involves the breast being compressed between two plates with an x-ray film placed underneath and low energy x-rays are then passed through the breast and the images are recorded. The best contrast between soft tissues is achieved at low energies and hence these are used in x-ray mammography. The x-rays are produced by an electron beam irradiating either a tungsten or molybdenum target depending on the size of the breast to be imaged. At low energies, the transmission is low causing a high dose to the patient. Thus a compromise between contrast and dose is necessary. This problem is reduced by compression of the breast. The breast is compressed to between 2 and 8 cm enabling a high contrast whilst keeping the dose within an acceptable level. Contrast is dependent on the thickness of the breast and the difference in linear attenuation coefficient (*μ)* between the tissue types. The value of *μ* is dependent on the atomic number of the material. Thus tissues with higher atomic numbers will produce a higher attenuation than others (e.g. microcalcifications).

The established sensitivity of mammography is higher than 91% (Brem et al 2003), which is greater than any other imaging modality for breast cancer detection. This is the main reason for the use of mammography in screening programmes. The reported specificity of the technique is quite variable and is considered to be in the region of 72% (Bone et al 1997). This means that nearly a quarter of the benign lesions are diagnosed as suspicious, which leads to unnecessary invasive procedures, biopsies, in order to establish the true nature of the lesion. Furthermore, the sensitivity of mammography for younger women is lower than that for older women. Younger women have denser breasts and less adipose tissue. Adipose tissue provides a greater contrast to calcifications than denser fibrous tissue and so mammography is more successful in older women.

Nearly one quarter of all invasive breast cancers are not detected by x-ray mammography in women aged between 40-49 years. However, the statistics for women above the age of 50 years are significantly better (1 in 10). Treatment of women with undetected invasive cancers, because of false-negative results, may be delayed. Many mammographic abnormalities may not be cancer, but will prompt additional testing and anxiety. Approximately 10 percent of all screening mammograms are read as abnormal. This will result in additional diagnostic tests such as diagnostic mammography, ultrasound, needle aspiration, core biopsy, or surgical biopsy. Given the lower incidence of breast cancer in 40 to 49-year-old women compared with that in older women, false-positive examinations are more common in younger women and the proportion of true-positive examinations increases with increasing age. There is concern that women having abnormal mammograms, both true-positive and false-positive, experience psychosocial stresses, including anxiety, fear, and inconvenience. There is the concern that experiencing a falsepositive mammogram may affect subsequent willingness of the patient to undergo future screening mammography at ages when it is of greatest benefit.

The main advantages of x-ray mammography are that the technique has good resolution and microcalcifications can easily be observed. Furthermore, the relatively fast imaging time allows many women to be scanned in one screening session. The major drawbacks of the modality are the use of ionising radiation, which is potentially harmful for the patient and the operator, and interpreting mammograms can be difficult due to differences in the appearance of the normal breast for each woman. The sensitivity is high (91.4% (Brem et al, 2003) but is not 100% and also the specificity is relatively low for some types of tumours. Particularly, the sensitivity is lower for women with dense breast tissue (e.g. younger women) and breast implants can affect the accuracy of mammography, as silicone implants are not transparent to X-rays. The disadvantages of compressing the breast are that it is, at best, uncomfortable and for many women with sensitive breasts it can be very painful. This limits the maximum time feasible for the imaging process. Also the spatial accuracy of the image can be distorted so that it is difficult to exactly locate an identified lesion.

The risk of radiation-induced breast cancer has long been a concern and has driven the efforts to reduce the radiation dose per examination. Radiation has been shown to cause breast cancer in women, and the risk is proportional to the dose. Especially the younger women are at a greater risk for breast cancer due to the exposure to radiation. Radiation related breast cancers occur at least 10 years after exposure. However, breast cancer as a result of the radiation dose associated with mammography has not been established. Radiation from yearly mammograms during ages 40-49 has been estimated as possibly causing one additional breast cancer death per 10,000 women.

#### **2.2 Magnetic resonance imaging (MRI)**

454 Advances in Cancer Therapy

X-ray mammography is the most common method of imaging the breast at present. The technique involves the breast being compressed between two plates with an x-ray film placed underneath and low energy x-rays are then passed through the breast and the images are recorded. The best contrast between soft tissues is achieved at low energies and hence these are used in x-ray mammography. The x-rays are produced by an electron beam irradiating either a tungsten or molybdenum target depending on the size of the breast to be imaged. At low energies, the transmission is low causing a high dose to the patient. Thus a compromise between contrast and dose is necessary. This problem is reduced by compression of the breast. The breast is compressed to between 2 and 8 cm enabling a high contrast whilst keeping the dose within an acceptable level. Contrast is dependent on the thickness of the breast and the difference in linear attenuation coefficient (*μ)* between the tissue types. The value of *μ* is dependent on the atomic number of the material. Thus tissues with higher atomic numbers will produce a higher attenuation than others (e.g.

The established sensitivity of mammography is higher than 91% (Brem et al 2003), which is greater than any other imaging modality for breast cancer detection. This is the main reason for the use of mammography in screening programmes. The reported specificity of the technique is quite variable and is considered to be in the region of 72% (Bone et al 1997). This means that nearly a quarter of the benign lesions are diagnosed as suspicious, which leads to unnecessary invasive procedures, biopsies, in order to establish the true nature of the lesion. Furthermore, the sensitivity of mammography for younger women is lower than that for older women. Younger women have denser breasts and less adipose tissue. Adipose tissue provides a greater contrast to calcifications than denser fibrous tissue and so

Nearly one quarter of all invasive breast cancers are not detected by x-ray mammography in women aged between 40-49 years. However, the statistics for women above the age of 50 years are significantly better (1 in 10). Treatment of women with undetected invasive cancers, because of false-negative results, may be delayed. Many mammographic abnormalities may not be cancer, but will prompt additional testing and anxiety. Approximately 10 percent of all screening mammograms are read as abnormal. This will result in additional diagnostic tests such as diagnostic mammography, ultrasound, needle aspiration, core biopsy, or surgical biopsy. Given the lower incidence of breast cancer in 40 to 49-year-old women compared with that in older women, false-positive examinations are more common in younger women and the proportion of true-positive examinations increases with increasing age. There is concern that women having abnormal mammograms, both true-positive and false-positive, experience psychosocial stresses, including anxiety, fear, and inconvenience. There is the concern that experiencing a falsepositive mammogram may affect subsequent willingness of the patient to undergo future

The main advantages of x-ray mammography are that the technique has good resolution and microcalcifications can easily be observed. Furthermore, the relatively fast imaging time allows many women to be scanned in one screening session. The major drawbacks of the modality are the use of ionising radiation, which is potentially harmful for the patient and the operator, and interpreting mammograms can be difficult due to differences in the appearance of the normal breast for each woman. The sensitivity is high (91.4% (Brem et al, 2003) but is not 100% and also the specificity is relatively low for some types of tumours.

**2.1 X-ray mammography** 

microcalcifications).

mammography is more successful in older women.

screening mammography at ages when it is of greatest benefit.

The principal imaging modality used for the detection of breast tissue abnormalities is x-ray mammography, which has a high sensitivity, but suffers from a relatively poor specificity for some tumours and breast types, leading to unnecessary biopsies. Thus there is a need for an imaging technique that can non-invasively distinguish between malignant and benign lesions. At the present, magnetic resonance imaging (MRI) and ultrasound (US) can provide additional diagnostic information for this purpose.

The theory of MRI is based on the fact that the nuclei of some atoms have a property known as spin. Such nuclei act like tiny current loops and consequently generate a magnetic field (or magnetic moment), along the spin axis. Under normal circumstances these moments have no fixed orientation so there is no overall magnetic field. When an external magnetic field is applied, the moments will align in certain directions. In the case of hydrogen nuclei, which are the most abundant nuclei in the human body, two discrete energy levels are created. An MRI detection system consists of a magnet, magnetic gradient coils, a radio frequency transmitter and receiver, and a computer that controls the acquisition of signals and computes the MR images obtained. When an atomic nucleus is exposed to a static magnetic field, it resonates when a varying electromagnetic field is applied at an appropriate frequency and an image is computed from the resonance signals.

The signal in MRI arises from the rotating magnetisation, but it decays due to two different relaxation processes. The first process is the spin-lattice relaxation. The second relaxation process is the spin-spin relaxation. During spin-spin relaxation, the detected signal decays over a period of time. However, the spins are also subject to inhomogeneities in the magnetic field causing the signal to decay faster than the natural time period. Part of the signal can be obtained due to the spin-echo effect. This involves the application of a further RF pulse which causes the spins to be flipped by 180°. This means that the phase-position of each spin has been inverted and so nuclei that were precessing faster are now behind spins that were precessing at a slower rate. At the echo time *TE*, the spins will catch each other up and a peak in the signal will be detected. An MRI exam of the breast typically takes between 30 and 60 minutes. Diffusion and perfusion MRI are relatively new procedures. Diffusion MRI measures the mobility of water protons whereas perfusion MRI measures the rate at which blood is delivered to tissue. Both of these factors vary in malignant tissues as compared with benign tissue and therefore can be used as indicators for cancer.

Non-Invasive Devices for Early Detection of

**2.4 Scintimammography** 

gamma camera.

lymph nodes.

properties as listed in Table 2.

differentiate between certain types of solid breast masses.

Breast Tissue Oncological Abnormalities Using Microwave Radio Thermometry 457

a fluid-filled cyst has a different sound signature than a solid mass, radiologists can reliably use ultrasound to identify cysts, which are commonly found in breasts. The technique can be used for younger women and women with breast implants and is entirely safe, and can be used repeatedly. The main disadvantages of the modality are the lack of fine detail, difficulty in detection of microcalcifications, poor ability to see deep lesions and inability to

Scintimammography or nuclear medicine imaging is sometimes used alongside x-ray mammography in the diagnosis of breast disease since this technique is able to determine if a located lesion is malignant. The technique involves injection of a radioactive tracer into the patient. The tracer emits radiation, which is detected using a gamma camera. Appropriate image reconstruction algorithms enable the distribution of the tracer within the body to be mapped. Since the tracer accumulates differently in malignant and benign tissues it can be used to distinguish between the two conditions. Several radioactive compounds have been investigated, although only one, technetium-99m sestamibi (MIBI), is approved by FDA for use in breast imaging. A nuclear medicine investigation of the breast usually takes between 45 and 60 minutes. In a typical examination, the radioactive tracer (Tc-99m sestamibi) is injected into the patient's arm. The patient lies face down on a special table with her breast suspended through a hole. The images of the breast are taken from several angles using a

The advantages of scintimammography are that it can be used on patients with dense breasts and it can image large palpable lesions that do not appear with other imaging modalities. The modality involves the use of ionising substance that is injected into a patient (invasive) and is time consuming. Whilst it is 90% accurate for abnormalities over 1cm it is only 40- 60% accurate for smaller size abnormalities. The technique can be used to test tissue remaining from a mastectomy and can also be used to check for metastases in the auxiliary

There are several modalities that are at early stages of development but have a considerable potential as breast cancer detection devices. Majority of the imaging technologies for the breast are based on physical, mechanical, electrical, chemical and biological characteristics of the breast tissue. These detection techniques are based on their response to various tissue

In an article about controversy over breast cancer screening, Reidy argued that death from malignancy rather than detection of malignancy should be a point of reference in evaluating any screening modality, since fast growing tumours, although detected while small, may have already metastasised. As a result, the number of malignancy related deaths have not altered regardless of their detection stage (Reidy, 1988). This has led to the view that the development of any new breast cancer detection modality must recognise the existence of three biologically distinct breast cancer patient subgroups. Firstly, there is a group of patients, which have slow-growing population of malignant cells that show ability to metastasise until very late. The second group comprises of patients with rapidly growing tumours that can lead to the development of micrometastases long before the tumour is detectable using the current modalities. Finally, there is the group of patients that have

**3. Techniques under development for breast cancer detection** 

The injection of a contrast agent can enhance the ability of MRI to detect specific features or in the case of dynamic contrast-enhancement MRI the functionality of the tissue can be investigated. The contrast agents used are paramagnetic agents with gadolinium (Gd-DTPA) being the most common. The increased vascularity of tumours produces a preferential uptake of contrast agent and the technique can be used to improve their contrast from surrounding normal tissue. In dynamic contrast-enhancement MRI, scans are repeatedly acquired following the contrast injection and the dynamic nature of contrast uptake can be examined, which may improve the differentiation of benign and malignant disease.

The main advantages of MRI are that the modality is suitable for women with denser breasts and the technique is non-ionising. It is possible to take images in any orientation and determine multi-focal cancers. The technique can also show breast implants and ruptures. The disadvantages of MRI are that a contrast agent is required to provide adequate specificity and that it is immobile, expensive, and unsuitable for some women. The modality cannot image calcifications and can induce feelings of claustrophobia, and require long scan times in comparison to x-ray mammography.

#### **2.3 Ultrasound**

Ultrasound is defined as a frequency of sound above the threshold of human hearing (i.e. > 20 kHz). The frequency range used in medical ultrasound imaging is 1 – 15 MHz. This allows wavelengths less than 1 mm to be measured and thus produces good spatial resolution. Ultrasound waves interact with tissue in a variety of ways but it is the reflection and transmission at interfaces between tissues of different acoustic impedance that is utilised in medical imaging. If there is a large acoustic mismatch between two tissues then a large fraction of the ultrasound intensity will be reflected. If there is a small difference in the acoustic impedance then most of the intensity will be transmitted. The time between pulse generation and the detection of an echo provides the depth of the reflecting interface, and thus images can be generated. Measuring the magnitude and time difference between different reflected signals can be used to determine the type, depth and size of different tissues.

Ultrasound pulses are generated and detected by a hand-held transducer, based on an array of small piezoelectric crystals. The very low acoustic impedance of air means that any boundary between air and tissue results in a near 100% reflection, so to ensure that the ultrasound waves are coupled into the body an impedance matching gel is used between the breast and the transducer. As there is a large difference between the acoustic impedance of a liquid filled cyst and normal breast tissue, around 23% of the ultrasound wave is reflected at such a boundary, making this technique particularly useful for the diagnosis of such a lesion. The small differences in acoustic impedance between adipose tissue and glandular tissue mean that this technique is of particular use for younger women with denser breasts, where x-ray mammography is often unsuitable. Doppler ultrasound utilises Doppler shifts from Rayleigh backscattered ultrasound waves to determine the velocity at which red blood cells are moving. Doppler ultrasound can be used to monitor blood flow and as a result can be used as an indicator of vascularisation of a malignant tumour in the breast.

Ultrasound is relatively inexpensive and a versatile technique. It can provide excellent contrast resolution, which means suspicious areas are easy to differentiate from normal tissue. X-ray mammograms are frequently followed up with ultrasound imaging to determine whether a lesion that appeared on a mammogram is a cyst or a solid mass. Since a fluid-filled cyst has a different sound signature than a solid mass, radiologists can reliably use ultrasound to identify cysts, which are commonly found in breasts. The technique can be used for younger women and women with breast implants and is entirely safe, and can be used repeatedly. The main disadvantages of the modality are the lack of fine detail, difficulty in detection of microcalcifications, poor ability to see deep lesions and inability to differentiate between certain types of solid breast masses.
