Breast cancer is the most common malignancy in women worldwide. Although there is evidence that some chemopreventive drugs such as triamcinolone and Anastrozole can reduce the incidence of breast cancer in high-risk groups, there is still no primary prevention measure that can effectively control the occurrence of breast cancer. Therefore, at present and for quite some time to come, striving for early diagnosis remains a fundamental strategy for breast cancer control. In the last three decades, with the development of breast imaging technology and the popularization of cancer prevention knowledge, the early diagnosis of breast cancer has made considerable progress, especially in countries and regions with high incidence of breast cancer. Although China is a country with low incidence of breast cancer, the incidence rate has been on the rise in recent years, especially in the economically developed coastal cities.
I. Definition of early diagnosis of breast cancer and methods of effect evaluation
Breast cancer is a tumor on the surface of the body, and it is easily detected by patients themselves when it increases to a certain size, which is called the clinical occurrence of the tumor. The so-called early diagnosis of breast cancer is to obtain the diagnosis before the clinical occurrence of breast cancer (i.e. asymptomatic period), which includes two inseparable parts: early detection of suspected lesions (Detection) and further determination of the nature of the lesions. The effectiveness of early diagnostic measures should be evaluated in terms of their impact on disease outcome, diagnostic sensitivity and specificity, and cost-effectiveness ratio.
The impact of early diagnosis on breast cancer outcome is the most fundamental component of the evaluation of its effectiveness. The most compelling indicator is the ability of early diagnostic measures to reduce mortality from breast cancer in the population. Since the 1960s, a series of studies have been conducted in North America, Northern Europe and Western Europe on screening mammography in high-risk groups, and the results have confirmed that screening mammography can reduce breast cancer mortality by 20%-40% in patients aged 50-69 years, and by 20% in patients aged 40-49 years. The above results led to the WHO’s decision to include breast cancer screening in the list of breast cancer screening programs. These results have led the WHO to rank breast cancer as one of the few human tumors for which cancer screening is effective.
The evaluation of the accuracy of early diagnostic measures includes two major indicators: sensitivity and specificity. Low sensitivity will lead to a large number of missed tumors and lose the significance of early diagnosis; low specificity will affect the efficiency of early diagnosis and also lose its application value. Therefore, in the case of incompatibility, multiple diagnostic measures can be used. Cost-effectiveness ratio is the most important indicator to measure the practical value of a public health measure. Factors affecting the cost-effectiveness of early diagnosis of breast cancer include the incidence of breast cancer in the population, the false-positive rate of early diagnostic measures, and the investment in all screening measures (including the cost of screening, the time and labor cost of screening, and the subsequent unnecessary investment and psychological harm to false-positive individuals).
II. Basic measures for early diagnosis of breast cancer
There are three basic measures for early diagnosis of breast cancer that are commonly used worldwide: mammography screening, clinical examination and self-examination.
(I) Mammography screening
As mentioned earlier, regular mammography screening can reduce the mortality rate of breast cancer in women over 40 years of age and is therefore the only breast screening measure that has been proven to be effective to date. The immediate signs of breast cancer on X-ray include mainly masses and microcalcifications, and the latter are particularly important in the early diagnosis of breast cancer, since about half of the breast cancers not detected on mammography and about 70 percent of breast cancers not detected on mammography are not detected on mammography. The latter is particularly important in the early diagnosis of breast cancer, as approximately half of all breast cancers without a lump and 70% of breast cancers in situ are detected thanks to the detection of microcalcifications on X-ray.
Despite the high value of mammography in the early detection of breast cancer, it may be missed and its use in determining the benignity of abnormal lesions is very limited. There is no valid method to distinguish whether the occurrence of breast cancer during the interval between mammograms is a missed diagnosis or a new case, but the literature generally considers any breast cancer occurring within 1 year after a negative screening result as a missed diagnosis. Based on this definition, the sensitivity of screening mammography for women aged 40-49 years has been reported in the literature to be 53%-81%; for women aged 50 years and older, 73%-88%. In addition, the literature reports a 5%-7% chance of detecting suspicious abnormalities on mammography, of which 70% are benign lesions. Therefore, mammography screening must be combined with one or more other screening measures to further improve the sensitivity and specificity of early diagnosis.
Mammography has the advantages of simple operation, rapid diagnosis, easy image retention and review, and is therefore suitable for large-scale population screening. In recent years, the use of digital imaging technology has improved the clarity of mammography images and increased the detection rate of abnormal lesions, while further reducing the cost of each examination. Considering the possible radiological damage of mammography, it is not advisable to perform frequent examinations; while in young women, the breast is more dense and the diagnostic sensitivity of X-ray is not high. Therefore, the interval between examinations and age limits are generally specified in the guidelines for mammography screening (see Table 1).
(ii) Clinical physical examination
Although mammography is the most effective tool for early detection of breast cancer, there are still some early breast cancers that cannot be detected by x-ray and are detected by clinical physical examination alone. Early stage breast cancer does not necessarily have typical clinical manifestations, so it is easy to miss the diagnosis. Therefore, we cannot use “lump” as the primary sign essential for the diagnosis of breast cancer. Li Shuling et al. reported 77 cases of early breast cancer without lumps, mainly due to local glandular thickening, nipple discharge and nipple erosion, which were found after further examination. In addition, such as mild nipple retraction, mild indentation of the breast skin and mild edema of the areola are all valuable clinical manifestations. Since clinical examination is relatively convenient and economical, it is generally recommended to combine it with mammography for breast cancer screening. The recommended time interval for receiving clinical physical examination for those at high risk of breast cancer (see Table 1).
1. Premenopausal women should choose 9-11 days after the onset of menstruation (when breast tissue is least affected by hormones in the body); postmenopausal women should choose a day that is easy to remember, such as the first day of the month.
2.Seriously high-risk women are those who have obvious tendency of family history of breast cancer, first-degree relatives with bilateral breast cancer before menopause, positive for breast cancer-related genes (such as BRCAl/2) and previous history of breast cancer, intraductal breast cancer, lobular carcinoma in situ, or atypical hyperplasia.
(C) Self-examination
Self-examination of the breast is a voluntary and conscious part of self-care for women. It has the advantages of being economical, convenient, rarely limited in time, and non-invasive to the body. The effectiveness of breast self-examination is still controversial, and although some studies suggest that self-examination can help detect small or lymph node negative breast cancers, results of large prospective controlled studies have shown no difference in mortality from breast cancer between the self-examination and control groups. It should be recognized, however, that there are many factors that can affect the accuracy of outcome evaluation. For example, in addition to selection bias when establishing a control group, there may be “control group contamination” in that some patients in the control group may also be consciously performing breast self-examination or regular clinical examinations. In addition, women’s mastery and compliance with breast self-examination methods are also important influencing factors. A study on breast self-examination in Beijing showed that the detection rate of early breast cancer was higher among intellectuals. In addition, we need to educate women about the basic knowledge of breast cancer, including the influence of menstrual cycle on breast, clinical manifestations of breast cancer, significance of early detection of breast cancer, etc.
Other measures for early diagnosis of breast cancer
(I) Ultrasound examination of breast
Ultrasound examination is the most acceptable breast examination method because of its quick, safe and convenient features. With the upgrading of ultrasound imaging technology and the introduction of color Doppler technology in recent years, the accuracy of breast ultrasound in diagnosing substantial breast lumps has been greatly improved. However, most experts currently have a negative opinion on the use of breast ultrasound for mass screening. The main reason for this is that breast ultrasound has the following drawbacks compared to x-ray examination.
(1) The sensitivity of existing ultrasound instruments to detect small calcified foci in the breast is not high, which leads to some early breast cancers being missed;
②However, breast ultrasonography still has a greater application in the early diagnosis of breast cancer. It is usually used for further screening of abnormal lesions detected by mammography or physical examination screening because of its obvious advantages in identifying cystic and parenchymal breast masses. In addition, a group of 3,626 women with dense breasts who had no abnormalities on physical examination or mammography were reported to have undergone ultrasound, resulting in the detection of 11 cases of breast cancer (0.30%), thus increasing the detection rate of this breast cancer screening by 17%. It is clear that breast ultrasound is an adjunct or supplement to routine breast screening.
(ii) MRI of the breast
Many reports have shown that breast magnetic resonance imaging (MRI) with contrast is more sensitive than mammography and ultrasound in the early diagnosis of breast cancer.
However, MRI should be used as a breast cancer diagnostic tool. Nevertheless, there are many limitations to the use of MRI as a screening tool for breast cancer. Most notably, MRI is more expensive and takes significantly longer than mammography; in addition, it requires the injection of contrast into the blood vessels, which is an invasive test and therefore not suitable for large population screening. Currently, breast MRI is mainly used for breast cancer screening in women with a significant family history of breast cancer or at high risk of carrying breast cancer-related genes, and also for pre- and post-treatment evaluation of breast cancer.
(C) Nipple discharge screening
Nipple discharge is a common symptom in mammography clinics, and approximately 1% of breast cancers are clinically diagnosed with nipple discharge as the first symptom. Studies have confirmed that early detection of breast cancer can be achieved by screening a large number of patients with clinically inapparent nipple discharge. The commonly used methods include nipple discharge cytology, mammography, and another screening technique developed since the 1990s, breast ductal endoscopy.
A ductal endoscope is a light catheter with an inner diameter of less than lmm that can be inserted from the nipple overflow duct opening to observe and record the situation inside the breast duct through endoscopic imaging technology. The advantage of ductal endoscopy over cytology or biochemistry of the overflow is not only the higher diagnostic sensitivity (>90%), but also the accurate localization for histological biopsy. Thus, for patients with clinically non-palpable nipple discharge, ductal endoscopy can be used for early diagnosis of breast cancer in combination with cytological examination of the discharge smear, etc.
In addition to screening of patients with spontaneous nipple discharge, some foreign scholars are now trying to detect breast cancer early by collecting ductal fluid from asymptomatic patients for exfoliative cytology or molecular markers. However, this method is still a long way from practical application, especially in the selection of screening subjects and the number of ducts to be flushed, which are still controversial.
(iv) Image-guided minimally invasive biopsy
Histological examination is the gold standard for the confirmation of breast cancer diagnosis and the last step in early diagnosis. With the popularization of breast imaging screening, a large number of lesions detected by X-ray or ultrasound without a lump on physical examination have been detected and require definitive diagnosis. However, 60%-90% of the surgical biopsy results are diagnosed as benign lesions, which imposes a huge medical cost burden on the early diagnosis of breast cancer. In addition, surgical biopsy has the disadvantages of greater damage and aesthetic scars. Compared with surgical biopsy, fine-needle aspiration cytology (FNA) is a safe, convenient, and minimally invasive pathological examination method, but it can only provide cytological diagnosis and cannot distinguish pathologically between breast cancer in situ and invasive cancer, nor can it make definite judgment on certain cell morphological abnormalities, thus there are many uncertainties. Previous studies have found that the sensitivity of FNA in diagnosing lesions with clinically undetectable masses is only about 80%.
In the mid-1990s, vacuum-assisted minimally invasive breast biopsy was introduced, which is different from empty needle biopsy (see Table 2), and its diagnostic accuracy has been significantly improved. At the same time imaging-guided equipment has also developed toward high precision, intelligence and humanized design, making the histological diagnosis of subclinical lesions take about 20 minutes to complete successfully in an outpatient setting and leave no obvious scars.