Breast cancer is the most frequently diagnosed cancer in 154 countries and the leading cause of cancer death in over 100 countries1. The standardization of surgery, adjuvant radiotherapy, and systemic therapy has been strongly established based on the understanding that breast cancer is a type of systemic disease. In parallel, advances in genomics have not only deepened the understanding of breast biology but also dramatically impacted the path toward risk reduction. In this review, we summarize global trends in epidemiology, screening, prevention, diagnosis, and therapeutics regarding breast cancer. It would help the readers deepen their understanding of breast cancer, especially its equality and diversity across the world.
Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death among women. According to GLOBOCAN 2018, about 2,100,000 women were estimated to be newly diagnosed with breast cancer, accounting for 24% of all incidences of cancer among women. About 630,000 women were estimated to die due to breast cancer (15% of total cancer deaths)1.
There are substantial differences in breast cancer incidence and mortality depending on region. According to GLOBOCAN 2018 estimates, the incidence is higher in western countries, such as Australia/New Zealand (94.2/100,000), Northern Europe (90.1/100,000), Western Europe (92.6/100,000), Southern Europe (80.3/100,000), and North America (84.8/100,000). Contrastingly, it is lower in South America (56.8/100,000), Africa (27.9–48.9/100,000), and Asia (25.9–45.3/100,000). However, the incidence in the latter regions has been rising quickly over recent decades.
Breast cancer incidence also varies depending on a region’s degree of development. The incidence is significantly higher in countries that score high/very high on the Human Development Index (HDI) compared with countries with low/medium HDI scores (54.4 vs. 31.3 per 100,000). In contrast, the standardized mortality rate is much lower in countries with high/very high HDI scores (11.6 vs. 14.9 per 100,000). This difference is attributed mainly to the prevalence of well-established screening programs and abundant medical services in countries with high HDI scores1.
The onset age of breast cancer also differs across countries. In most western countries, 48% of breast cancer cases are diagnosed at ages 50–692, with the risk of breast cancer progressively increasing around age 503. For instance, in the United States, the median age of diagnosis is 62 years, and 82% of breast cancers are diagnosed in women at age 50 or older. About 90% of breast cancer deaths occur in the same age group4. However, in Asian countries such as China and Japan, the peak of age-standardized incidence occurs at an earlier age than in western countries; most cases are concentrated at ages 45–69 (Fig. 1)5–7.
The incidence and mortality of breast cancer also differ depending on race and ethnicity. In the United States, the incidence is the highest in Whites, followed by Blacks, Hispanics, and Asians/Pacific Islanders. Nevertheless, mortality is highest in Blacks, followed by Whites, Hispanics, and Asians/Pacific Islanders. The mortality rate of Whites and Blacks is more than double that of Asian/Pacific women (Fig. 2)4. A higher proportion of triple-negative breast cancers (TNBCs) in Blacks may partially explain this difference in mortality (Fig. 3)4. A similar trend can be found in African countries where the frequency of TNBCs is significantly high and many women are diagnosed at a young age. Unfortunately, the relevant genetic predisposition that may explain the higher incidence of TNBCs in women having African ancestry has not been identified8–10.
Worldwide, the mean breast cancer mortality rate was estimated to be 13.77/100,000 in 1990, increasing by about 0.7/100,000 a year between 1990 and 2015. The total number of breast cancer deaths is still increasing in many countries, especially in middle- or low-income regions. Therefore, the worldwide increase in mortality may be partially due to the increase of breast cancer incidence in developing countries with insufficient medical resources11–14. In fact, the mortality rate is actually decreasing or stable in high-income countries (Fig. 4)11,15. From 2002 to 2012, breast cancer mortality declined from 17.9/100,000 to 15.2/100,000 in Europe. It is estimated to decrease further in 2020 (13.4/100,000). Mortality also declined in North America and Oceania, where it is predicted to reach 11–12/100,000 in 2020 (vs. 14/100,000 in 2012). No significant changes were observed in mortality in Japan and Korea, where mortality has been relatively low (under 10/100,000)12,13. According to statistics from 2008 to 2012 in China, during which the economy was quickly expanding, breast cancer incidence and mortality were 42.67/100,000 and 10.36/100,000, respectively. While the incidence had increased by 30.56%, the mortality had not increased significantly from 2003 to 201216. An estimate from the United States reported that between 384,000 and 614,500 breast cancer deaths had been averted through mammography screening and improved treatment between 1989 and 201817.
These findings suggest that it is reasonable to establish individualized screening systems based on the age and race characteristics of each country, in addition to other possible factors. To reduce worldwide breast cancer death, it is important to address the unequal distribution of medical resources and funding as well as the gap in accessibility to the latest knowledge on breast cancer management.
Pathologic diagnosis and molecular subtyping
In the latest update of breast cancer classification by the World Health Organization, the importance of molecular subtyping is emphasized, primarily based on estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 (HER2) status18. Meanwhile, traditional prognostic indicators, such as tumor size (T), lymph node status (N), and the Nottingham grading system, are still deemed important19.
Molecular subtyping can sufficiently predict the biological behavior of tumors. Based on gene expression profiling, breast cancers have been classified into at least 4 subtypes: luminal-A and B, basal-like, normal breast-like, and ERBB2+ subtype20. Generally, due to the availability and cost effectiveness of gene expression profiling, immunohistochemistry is commonly used as an alternative. The St. Gallen International Expert Consensus Meeting from 2007 to 2011 highlighted the classification of breast cancer based on the immunohistochemistry of estrogen receptor, progesterone receptor, HER2, and Ki-67 labeling index and its usefulness in risk prediction and tailoring adjuvant treatment21. In 2011, a multigene assay known as oncotype DX was proposed as a useful tool to better predict the benefit of adjuvant chemotherapy for the luminal subtype21,22. Currently, oncotype DX and MammaPrint tests, with a higher level of evidence, are recommended by guidelines of the National Comprehensive Cancer Network (NCCN), the American Society of Clinical Oncology, and the European Society of Medical Oncology (ESMO)23–25.
To date, various studies have been performed to further classify breast cancer subtypes, especially for TNBCs in which the proper molecular target has not been identified. TNBCs are currently recognized as highly heterogenous. Based on the gene expression profiling of 21 breast cancer data sets and 587 TNBC cases, Lehmann et al26 identified 6 TNBC subtypes exhibiting different responses to therapy: basal-like 1/2 (BL1 and BL2), mesenchymal, immunomodulatory, mesenchymal stem-like, and luminal androgen receptor subtype. Jiang et al27 classified TNBCs into 4 subtypes: luminal androgen receptor, immunomodulatory, basal-like immune-suppressed, and mesenchymal-like, which could provide the opportunity for subtype-specific treatment. They also uncovered ethnic differences in the distribution of these subtypes by comparing the Chinese cohort to the Cancer Genome Atlas (TCGA) cohort. This may be partially attributed to a diversity of country-specific outcomes. Identification via proper subtyping and type-specific targeted treatment for this malignant subgroup are warranted. The advances in molecular phenotyping and pathology are intensively reviewed elsewhere, please refer to previously published reviews28–32.
As discussed, the decrease in breast cancer mortality observed in western countries has been achieved mainly through advances in screening and adjuvant therapy33,34. A breast screening program should include breast awareness, risk assessment, clinical examination, mammography, and magnetic resonance imaging (MRI) for selected patients35. Presently, multiple guidelines have recommend routine mammography instead of physical examination lacking in sufficient evidence36–38. All organizational guidelines have equally recommended mammography for women aged between 50 and 69 years (once every 1 to 2 y). However, for women aged between 40 and 49 years, some guidelines have begun to stop regularly recommending mammography due to a lack of sufficient evidence for this age group. The clinical benefit of mammography for women under 40 and over 75 years is similarly in question. In order to determine the proper age for active screening, clinicians must take into account the patient’s personal risk (dense breast, genetic background, familial history, etc.) and the age-specific pattern of breast cancer incidence in the country of residence36–38.
Besides conventional mammography, the feasibility of using ultrasonography (US), digital breast tomosynthesis (DBT), and MRI for screening a specific population has been questioned. An American observational cohort study reported that the cancer detection and interval cancer rates were not different between mammography screening alone and mammography plus US; and mammography plus US showed a higher false-positive biopsy rate and lower positive prediction values. The authors concluded that the benefits of supplemental ultrasonography screening do not seem to outweigh the associated harms for a relatively young population39. However, the Japan Strategic Anti-cancer Randomized Trial, a randomized controlled trial that compared mammography alone to mammography plus US, showed that the adjunctive US increased the sensitivity and detection rate of early cancers in Japanese women aged 40–49. Therefore, US should be considered as a screening method for Japanese and possibly Asian women, in general, in this age group. For other women, a risk estimate would be very important. Since US is largely dependent on the skills of technicians, its usefulness should be further examined with respect to each specific country or region40,41.
DBT, a new mammography technology equipped with 3-dimensional image reconstruction, has shown improved specificity and cancer detection rates across all age and breast density groups. Compared with conventional mammography, DBT can detect invasive cancer at an earlier stage, particularly for women aged 40–4942. However, due to the increased radiation dose it employs, DBT may be potentially harmful. Overall, DBT and contrast MRI have been recognized as an alternative for the confirmed high-risk group. NCCN guidelines recommend an annual MRI and DBT specifically for women with a known genetic predisposition to breast cancer or other confirmed risk factors. It is important to note that physicians should take into account the potential harm related to gadolinium-based contrast when considering MRI for breast screening.
Along with advances in imaging technology for breast screening, we must consider the variations in epidemiological characteristics, economics, and diagnostic performance (ie, number and skill level of breast radiologists and pathologists) within each country. Furthermore, we need to keep in mind that improvement in breast cancer detection does not necessarily translate into survival benefit. For instance, a recent study suggested that both the detection of low-grade ductal carcinoma in situ and its subsequent surgery were unlikely to yield survival benefit43. How best to minimize the potential harms stemming from overtreatment needs to be further investigated.
Breast cancer prevention approaches include lifestyle modifications, chemoprophylaxis, and prophylactic mastectomies for specific populations. To date, obesity (especially in postmenopausal women), height in adulthood, radiation exposure, benign tumor disease (proliferative lesion with atypia), family history of breast cancer, hormone replacement therapy, and mammographic density are recognized as risk factors for breast cancer44. Growing evidence suggests that women may be able to reduce their risk by choosing a healthy lifestyle that involves avoiding alcohol, quitting smoking, exercising, changing food preferences (eg, increasing soy intake), and proper sleep45–48. Studies have also suggested that ambient air pollution and consumption of sugary drinks and red meat were positively associated with an increased risk49–51. However, it should be noted that these findings may be biased due to factors such as study population and exposure period—further confirmation is needed. In addition, parity, younger age at first birthing, and lactation can reduce the risk of breast cancer. However, some studies have suggested that first parity at an older age (over 30 y) could result in an increased breast cancer risk lasting at least 10 years after delivery52,53. It should be noted that the age of first parity tends to be delayed in many countries.
For the specific population with familial/genetic risk factors or those judged as high-risk by adequate cancer risk assessment models, pharmacological or surgical prevention could be considered. Based on the results of the National Surgical Adjuvant Breast and Bowel Project prevention trial, the Study of Tamoxifen and Raloxifene trial, the Mammary Prevention 3 trial, and the International Breast Cancer Intervention Studies-II trial, the NCCN guideline recommends the use of tamoxifen in premenopausal or postmenopausal women at least 35 years old with a ≥1.7% 5-year risk for breast cancer determined by the modified Gail model—or who have a history of lobular carcinoma in situ. Other studies report that anastrozole and exemestane could be considered for postmenopausal women54–57. In addition, proper monitoring of patients is essential to detect breast cancer or associated adverse events and to deliver timely adequate management.
Mutations in known breast cancer risk genes such as BRCA1/2, TP53, and PTEN are strong indicators for surgical prevention (Table 1)58–60. The distribution of these genetic predispositions may be slightly different across countries. The frequency of BRCA1 and BRCA2 mutations in unselected breast cancer patients has been reported as 3.2% and 3.1% in the United States, 1.0% and 1.9% in Italy, 1.45% and 2.71% in Japan, and 1.8% and 3.5% in China, respectively61–64. Several risk models have been developed to date: the modified Gail model, the Claus model, the BRCAPRO model, the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm, and the Tyrer-Cuzick model65–69. Different models have their adaptive populations. For example, the Gail model, which is most commonly used, is not applicable for with a significant family history45. Each risk model is developed from a retrospective epidemiological dataset collected from a particular country. Thus, a model’s performance could vary depending on the applied population. Each country or region should test which model would be most applicable to its residents, or consider developing a risk model based on its own epidemiological characteristics.
Table 1 -
Known genetic predispositions associated with breast cancer and ovarian cancer.
ATM, BRCA1*, BRCA2*, CDH1*, PALB2*, PTEN*, STK11*, TP53*
BRCA1, BRCA2, BRIP1, MSH2, MLH1, MSH6, PMS2, EPCAM, RAD51C, RAD51D, STK11
|Potential or controversial
BARD1, CHEK2, NBN, NF1, RAD51D
|Unknown or unrelated
BRIP1, MSH2, MLH1, MSH6, PMS2, EPCAM, RAD51C
BARD1, NBN, PALB2
The table was created based on the information of Brisken and colleagues53–55
*Indicates genes with an over 5-fold relative risk of breast cancer. Surgical risk reduction may be considered for this segment of the population under full discussion.
Currently, the NCCN, ESMO, Chinese, and Japanese breast cancer societies have recommended considering risk-reducing mastectomy (RRM) for women with the pathogenic variants, such as BRCA1/2 mutation44,45,70,71. Some guidelines have stated that RRM for women without a known genetic predisposition is worth considering if they are estimated to be high-risk (ie, women with a relevant family history, a past history of thoracic radiotherapy, etc.). Because of lack of high-quality evidence in this area, precise assessment of lifetime risk and careful discussion regarding potential benefits and harms with patients is important. When considering RRM, proper breast reconstruction should be offered upon the patients’ request whenever possible.
Major recent advances in breast cancer treatment can be summarized as follows: (1) implementation of minimally invasive surgery, (2) optimization of systemic treatment under the guidance of molecular diagnosis, and (3) establishment of a multidisciplinary team for decision-making. Here, we will briefly review the advances in current therapeutics and discuss the importance of multidisciplinary networking to improve breast cancer outcomes on a global scale. More comprehensive and detailed information on recent advances in therapeutics are discussed in elsewhere30–32,72–77.
The application of breast-conserving surgery (BCS) and sentinel lymph node biopsy are recent developments in breast surgery78. Nevertheless, several issues remain to be unanswered. Regarding BCS, a novel approach that facilitates precise tumor localization and margin assessment is warranted to reduce re-excision rates as well as local recurrence, especially after neoadjuvant treatment79,80. Introduction of sentinel lymph node biopsy has massively reduced the number of unnecessary axillary clearances. Moreover, the Austrian Breast and Colorectal Cancer Study Group Z0011 trial reported a further decrease of axillary clearances in node-positive patients who underwent BCS81. However, whether a similar strategy is applicable for patients with advanced cases, patients who underwent mastectomy without radiation, and patients who underwent BCS after neoadjuvant treatment is unknown79.
For HER2-positive breast cancers, the emergence of a HER2-targeted antibody, trastuzumab, dramatically changed the prognosis82. Currently, based on the results of the Adjuvant Paclitaxel and Trastuzumab and HER plus taxotere and cyclophosphamide trial, chemotherapy regimens tend to be weakened for low-risk populations83,84. However, for high-risk populations (commonly defined as node-positive), the addition of pertuzumab, another HER2-targeting antibody, to trastuzumab in adjuvant treatment significantly improved invasive-disease–free survival85. The addition of pertuzumab in neoadjuvant therapy has significantly improved the pathologic complete response (pCR) rate although its survival benefit remains to be further explored86–88. Patients who did not achieve pCR by neoadjuvant chemotherapy with trastuzumab can benefit from switching to trastuzumab emtansine, an antibody-drug conjugate targeting HER289.
Dose-dense chemotherapy regimens based on combinations of taxanes and anthracyclines are currently the standard treatment for TNBCs90. Neoadjuvant treatment is preferred for advanced patients in order to better predict their prognosis23. For patients who did not achieve pCR, the addition of capecitabine could improve survival. Poly ADP ribose polymerase inhibitors have improved disease progression of metastatic TNBC patients with germline BRCA1/2 mutations91,92. Use of an immune checkpoint inhibitor combined with chemotherapy is expected to improve the outcomes of TNBCs, but it is still under investigation. For advanced/metastatic TNBCs, the combination of a PD-L1 inhibitor, atezolizumab, and nab-paclitaxel improved survival for PD-L1-positive TNBCs93. The addition of a PD-1 inhibitor, pembrolizumab, significantly increased the pCR rate (64.8% vs. 51.2%) of neoadjuvant treatment for early TNBCs94.
A major recent advancement in adjuvant radiation therapy is hypo-fractionated whole breast irradiation (HF-WBI, typically 40–42.5 Gy in 15–16 fractions). The NCCN and American Society for Radiation Oncology guidelines have recommended HF-WBI; its use is now expanding to patients of any age, stage, and those who have undergone neoadjuvant chemotherapy23,95,96. The FAST-Forward study revealed that 26 Gy in 5 fractions was equivalent to 40 Gy in 15 fractions with respect to local tumor control and safety profile97. Recently, a gene expression–based prediction model for radiation sensitivity has been proposed to further optimize radiation dose98.
Finally, a multidisciplinary team (MDT) could be established to support patients as well as doctors in the process of decision-making. MDT has been proven to optimize the therapeutic schedule, shorten treatment time, improve patient satisfaction, and even improve their survival and quality of life99–102. To further expand the benefits of networking and cooperation, cross-regional MDT through international networking may also be beneficial. Because of the geographic, racial, ethnic, and cultural diversities within breast cancer, such a framework could bring equality and further individualization for breast management, as well as improvement of breast cancer prognosis on a global scale.
This is a systematic review of breast cancer in global health and no ethical approval is required.
Sources of funding
L.L. is funded by the China Scholarship Council. M.K. and M.T. are funded by the Ministry of Health, Labor and Welfare KAKENHI Japan.
L.L. collected the relevant literature. L.L., M.K., and M.T. drafted the manuscript. All authors read and approved the final manuscript.
Conflict of interest disclosures
The authors declare that they have no financial conflict of interest with regard to the content of this report.
Research registration unique identifying number (UIN)
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