2.1 Incidence of breast cancer by age

Compared with women in westernized countries, the peak age of breast cancer incidence is 10 years or more earlier among Chinese females (Figure 2).^{7, 8} Specifically in 2019, the highest age-specific incidence rate in China was 123.7/100,000 observed among women in the 65–69-year-age group, compared to 521.4/100,000 and 386.8/100,000 in 80–84 and 85–89 years old based in the United States and Australia, respectively. This dissimilarity was also shown with the onset age,¹⁰ with the medium age at diagnosis in China (46 years in 2013–2017) being over 10 years earlier than that in Australia (63 years in 2017), United States (63 years in 2014–2018) and Japan (60 years in 2017).^11-14 Like China, South Korea also reported an early onset age of 52 years in 2018.¹⁵

It is important to note however that the peak age of incidence has been gradually shifting to older ages in China.¹⁶ Although, as mentioned above, incidence rates are relatively low before the age of 20, and then increase significantly and plateau in the fifth or sixth decade, the peak age group has moved from 50–54 in 2008¹⁷ to 55–60 in 2013,¹⁸ and 65–69 years in 2019.⁷ Keeping with national trends, regional records of age-specific incidence from Shanghai,¹⁹ Wuhan,²⁰ and Hong Kong Special Administration Region (SAR)²¹ show similar patterns and have reported a 10- to 15-year time shift toward older ages within the last 20 years.

2.2 Urban-rural disparity of incidence

Administratively, urban areas in China are defined as the areas where the local governments of the county (xian) level and above are situated, and the rural areas are the places governed by village authorities (xiang).²² Under these definitions, urban areas are composed of “districts in cities” (chengqu), and “districts in towns” (zhenqu), which are usually located in the center of a city and the surrounding suburbs, respectively.²² Rural areas are remote from the city districts, with less population and under-developed infrastructures, which people residing in are mainly involved in agricultural activities, provided with fewer social and healthcare benefits, and have a lower income compared to those living in urban places.²³

Sourced from the National Central Cancer Registry of China, studies have revealed an incidence disparity among women between urban and rural areas, with ASIRs being higher in urban regions (Figure 3).^{17, 18, 24-29} However, a reduction in this regional discrepancy was observed after 2009 due to the significant increase in incidence rates in rural areas, which may be attributable to the implementation of a free breast screening program in rural regions since 2009, leading to an increase in early detection and diagnosis of breast cancer.³⁰ The recent rural increases may also be attributable to the policy of the public health system which requires rural migrant workers who are diagnosed with breast cancer after being exposed to high risk factors in the city to register as a rural patient in their hometown.³¹

Geographical disparity in the incidence rate of breast cancer was also demonstrated across regions in China, in line with socioeconomic development and industrialization.³¹ Specifically, the average incidence rates during 2010–2015 in the eastern, central, and western regions (divided according to the National Health and Family Planning Statistical Yearbook) were 47.7/100,000, 35.0/100,000 and 29.1/100,000, respectively.³² The higher prevalence of risk factors for breast cancer due to westernized practices, and the higher detection rate of breast cancer due to the greater accessibility to medical resources in the eastern region compared to the central and western regions could be possible explanations for this geographical disparity.^{31, 33}

3.1 Breast cancer mortality by age

Similarly to incidence, breast cancer mortality is highly associated with age (Figure 5).^{7, 8} Generally, the mortality rate of breast cancer increases with age, being the lowest in women under 35 years and the highest in those over 85 years of age in all countries. Before 50–54 years, the mortality rates of breast cancer are almost the same across countries, after which, the mortality risks are divergent, with figures in Australia and the United States increasing substantially compared to a slight increase in China, Japan, and South Korea. This disparity could be explained by the two-disease model of breast cancer, where premenopausal and postmenopausal breast cancers are hypothesized to be two diseases with different pathological mechanisms.³⁸ The “two” diseases themselves demonstrate mortality rates that are different but overlapping in terms of age distribution.³⁸ The relatively high mortality rates after 55 years in Australia and the United States may be due to a higher proportion of post-menopausal breast cancer compared to Asian countries (82.6% in North America, 78.2% in the Australia and New Zealand region, and 64.6% in Eastern Asia).³⁹ Furthermore, this disparity may be related to a higher prevalence of hormone replacement therapy (HRT) in Western than Asian populations. Because the HRT is suggested to increase the risks of breast cancer in post-menopausal women, especially those on combined estrogen/progestin therapy for more than 5 years.⁴⁰ Studies have reported that the proportion of women who used HRT was 2.1% (2012) and 6.3% (2013) in China and South Korea, respectively,^{41, 42} compared to 24% (2013) in Australia.⁴³ However, more comparative studies are needed to investigate the impact of HRT consumption patterns, including estrogen alone versus combined estrogen/progestin therapy, dose and administration method, and treatment duration, on breast cancer development among post-menopausal females from Asian and Western countries.

3.2 Urban–rural disparity of mortality

The urban–rural disparity in breast cancer mortality was in line with the geographical distribution of incidence rates in China, with mortality rates higher among women in urban than in compared to other rural areas during 2003 and 2015 (Figure 6).^{17, 18, 24-29} Other location-dependent variations in mortality rates have been demonstrated, with higher numbers in the southwest compared to northeast China, and in the west compared to eastern and southeastern coastal China.³²

4.1 Survival difference between China and other countries

The breast cancer survival rate is relatively low in China compared to other developed countries. The age standardized 5-year relative survival rate was 82% for breast cancer consumers diagnosed in 2012–2015 in China, compared to that recorded in Japan, South Korea, Australia, and the United States where 5-year relative survival rates exceeded 90% for a similar time period (Table 1).^{12, 44-47} Despite a relatively low survival rate, breast cancer outcomes are improving in China.⁴⁴ Specifically, the 5-year relative survival rate of breast cancer increased from 73.1% to 82.0% for patients diagnosed in 2003–2005 and 2012–2015 (Table 1).⁴⁴ This could be partially due to the national medical reform initiated in 2009, and since then Basic Medical Insurance (BMI) expanded its coverage and the national reimbursement drug list (NRDL) subsidized more essential anticancer drugs.⁴⁸ In particular, 95% of all residents of China were covered under BMI in 2011.⁴⁸

Delayed diagnosis and subsequent late stages at presentation are related to poor breast cancer survival. Unlike populations in some developed countries where a high percentage of breast cancer diagnoses occur in the early stages mainly attributable to breast screening, some Chinese women are commonly not taking advantage of breast screening or do not recognize and respond quickly to breast changes.⁴⁹ This could be due to insufficient cancer awareness,^50-52 breast cancer fatalism, the stigma of having the disease,^53-56 financial concern,^{52, 57} and inaccessibility of screening and diagnostic facilities in less economically developed regions,^{30, 52} which has resulted in a high proportion of females being diagnosed in late stages.⁵⁸

Cross-sectional surveys reported that Chinese women lacked a detailed understanding of breast cancer-related symptoms, risk factors, and detection methods.^50-52 Although most of them understand that breast cancer is common and breast lumps and family history are strongly related to this disease, only around half of the women in the study know other atypical symptoms (e.g., nipple discharge and axillary lump) and risk factors (e.g., a high-fat diet, early menarche and late menopause).^50-52 Regarding cancer detection methods, up to 80% of surveyed women are unaware of the benefits of mammography, which at least partially explains the low utilization rate of breast screening in China (22.5% for women aged 35–69 years in 2013).^{49, 52}

Fatalism and stigma are also related to the delayed diagnosis of breast cancer.^53-56 In China, some people believe that cancer development and progression are predetermined by external forces and that personal intervention will not alter health outcomes.^{55, 56} This fatalistic view negatively affects patients’ health practices, leading to avoidance of breast screening participation, in-adherence to medical treatment, and thus poor outcomes.⁵⁶ Furthermore, people are often stigmatized for having breast cancer, making them reluctant to attend breast screening and delay hospital visits. The stigma often arises from the beliefs in Buddhism that treat cancer as a punishment for the misdeeds of patients or their ancestors, and traditional Chinese medicine that attributes breast cancer to negative personalities, such as jealousy and narrow-mindedness; or traditional Chinese philosophies that associate breast cancer with immoral behaviors.^{53, 55}

The Chinese health authority has launched several breast cancer screening programs. In 2012–2013, a breast screening program was launched, targeting high-risk urban females residing in 14 selected cities from nine provinces in China.⁵⁹ Since 2009, a “two cancers” screening program was implemented, providing government-funded breast and cervical cancer screening for rural and economic-disadvantaged urban females aged 35–64 years and at average risk.³⁰ Despite being free, the reported attendance rate is still low (22.5% for women aged 35–69 years in 2013).⁴⁹ One of the underlying reasons is insufficient medical resources, such as a shortage of general practitioners, mammography, and screening facilities.³⁰ Studies revealed that people are unwilling to attend if the screening site is far away from where they live.³⁰ It is also worth noting that the coverage of the free “two cancers” screening program is limited, and the nontargeted population needs to pay out-of-pocket, which raises financial concerns, leading to delayed diagnosis.⁵²

Effective and systematic management of breast cancer plays a significant role in preventing recurrence and metastasis and prolonging survival. In recent years, molecular targeted therapy, including inhibitors of endocrine and human epidermal growth factor receptor 2 (HER2), has transformed conventional breast cancer treatment with reduced toxicity, improved response rates to treatment, and a better prognosis.⁶⁰ However, in China, the use of targeted therapy was partially affected by the unaffordability of patent anticancer drugs that were not covered by medical insurance.^{61, 62} A 2013–2014 nationwide survey on the clinical use of a HER2-targeted drug called trastuzumab found that less than 30% of HER2-positive breast cancer patients received post-surgery adjuvant treatment that included trastuzumab.⁶¹ In particular, the underuse of trastuzumab was more prominent in the less developed regions of China,⁶² this was at least partially due to the high cost of trastuzumab, which was not included in the NRDL until 2017.⁴⁸ Although listed in NRDL, by 2018 only eight provinces had trastuzumab on their local reimbursement drug list (LRDL).⁴⁸ In comparison, the uptake rate of trastuzumab in breast cancer adjuvant therapy has been higher in Australia and New Zealand region and the United States, ranging from 72% to 80.9%.⁶³

The out-of-pocket medical expenses are still substantial even if using the anticancer drugs covered by LRDL, given the high and increasing launch prices and the long-term treatment after cancer diagnosis.⁶⁴ The Chinese cancer survivors spent approximately 48% and 288% of the average monthly income on generic and patented anticancer pharmaceuticals, respectively.⁶⁵ The antibreast cancer drugs cost even more, placing a severe financial burden on cancer patients.⁶⁵ Compared to developed countries, financial hardship is heavier among Chinese cancer patients, although the retail prices of anticancer drugs are lower in China.⁶⁵ For example, in Australia, the monthly expenses of generic and patented anticancer drugs account for 3% and 71% of the average monthly income, respectively.⁶⁵ The lower affordability of cancer treatment may be attributable to the lower per capita spending power in China than that in westernized countries.⁶⁵ Besides, the abuse of traditional Chinese medicine adds to the financial burden of Chinese cancer patients. Since it is reported that some patients rely on traditional Chinese drugs in addition to western medicine to cure cancer; however, the actual benefits of these traditional Chinese drugs are largely unproven.⁶⁴ The considerable financial burden negatively affects their medical adherence, mental health, and quality of life.^{64, 65} Patients with heavier financial difficulties are more likely to quit treatment or reduce the prescribed amount of medication, suffer a mental disorder, and reduce daily necessities expenditures.⁶⁴

4.2 The urban–rural disparity in survival

Adapted to incidence and mortality, there are also urban–rural disparities in breast cancer survival. For women diagnosed in 2012–2015, the 5-year relative survival of breast cancer was 84.9% and 72.9% in urban and rural areas, respectively.⁴⁴ The underlying reason for this discrepancy is multifaceted, including but not limited to lower breast screening participation, more difficulty in accessing tertiary hospitals, and lower reimbursement rates in rural than urban populations.^{66, 67} Rural females demonstrated a greater reluctance to pay and attend screening, which might have led to more delayed diagnoses and undesired prognoses compared to urban females.⁶⁷ Although several free breast screening programs have been introduced for rural and urban women since 2009 and 2013, respectively, the coverage was limited and to date, free screening has not yet completely addressed the urban-rural participation gap.⁶⁸ Regarding the accessibility of tertiary hospitals, rural women had more difficulty accessing urban tertiary hospitals, which are generally better equipped with diagnostic equipment and qualified health providers than rural local hospitals, thus influencing breast cancer outcomes.^{66, 67} Additionally, rural residents receive a lower reimbursement rate than their urban counterparts who are covered by different BMI schemes.⁶⁶ Specifically, rural people are under the New Rural Cooperative Medical System which receives a 44% inpatient reimbursement, while urban residents receive a 48%−68% inpatient reimbursement under Urban Employee Basic Medical Insurance or Urban Resident Basic Medical Insurance.⁶⁶