Background
In the developing world, cancer is projected to increase by 70% over the next 20–25 years. Breast cancer represents 20–30% of cancer among women and is likely to account for a major part of that increase [
1]. These expectations are anticipated because the populations of developing countries are ageing and cancer is largely a disease of older people. Life-style changes are likely to contribute, because transitions from a traditional to a Westernized life-style expose women to higher individual risk [
2].
The world can be divided into low-risk and high-risk regions on the basis of differences in breast cancer incidence [
1,
2]. Those at high-risk consists of the developed countries of Northern Europe, North American, Uruguay, Argentina, Australia and New Zealand. In these areas, age standardized incidence exceeds 80-100/100,000 women. In the developing world, age standardized incidence (ASI) varies from 20-60/100,000 women, and in parts of Central and Southeast Asia and sub-Saharan Africa, estimates are less than 20/100,000 [
1,
2].
Breast cancer in all parts of the world begins to be seen at about 20 years of age [
3]. Afterward, age specific incidence steadily rises until the menopause when geographic differences begin to be seen. In the developing world, a flattening and then a decline occur about 10–15 years after the menopause. In developed countries, the age specific incidence accelerates after the menopause, and at age 70 and above doubles that seen at 45–49 years old [
3‐
5]. The life-style changes contributing to increased post-menopausal breast cancer are largely premenopausal and include obesity, low rates of childbirth, infrequent or no lactation, early menarche, and late menopause [
2]. These factors, that are common in high-risk countries, promote a state of relative hyperestrogenism and the development of estrogen responsive tumors [
3‐
5]. The life-style factors are becoming more common in countries considered low-risk particularly in their growing urbanized communities [
6].
Molecular subtyping has defined at least four categories of breast cancer with the most prevalent type and that being most closely related to increased estrogen exposure being estrogen receptor (ER) positive and negative for the Her-2-neu (HER2) proto-oncogene [
3]. ER positive tumors are further subtyped into low proliferation rate luminal A and higher proliferation rate luminal B tumors with the luminal A tumors being more frequently seen in older women in regions of the world at high-risk for breast cancer [
3].
Breast cancer rates in Iraq and its Kurdish region were generally stable between 2000 to 2009, but newer data from the Iraqi Cancer Registry reveal rising rates since 2009 with women after age 50 making the major contribution to the increase [
5,
7‐
9]. In this study, demographic changes are explored together with tumor ER and HER2 subtyping. The aim of the study was to determine whether age related shifts may be occurring in ER and HER2 subtypes that may offer insight into potential increases of breast cancers in culturally transitional Middle-Eastern countries.
Discussion
Molecular breast cancer subtyping is widely used clinically to identify patients at low risk for metastasis and can be roughly inferred on the basis of IHC testing [
12,
13]. While the 2015 St Gallen’s consensus considered the IHC designation of molecular subtypes as being impractical for guiding treatment, the assignment may be valuable from an epidemiologic standpoint [
3,
13]. In the West, the average age of newly diagnosed breast cancer patients is > 60 years old, and the high rates of breast cancer are the result of a several-fold increase in the age specific incidence of ER+/HER2- tumors in post-menopausal women [
3‐
5].
In US women, on the basis of IHC with parallel PAM50 molecular testing, luminal B breast cancers were found to be more common than luminal A tumors by a factor of 2.48 under 40 years of age with the ratio decreasing to 1.27 at 40–49 years old [
16]. At 50–59 years of age, the proportions reached parity, and at > 60 years old, luminal A exceeded luminal B tumors by 25-50% [
16]. In terms of age specific density, this created a bimodal frequency for ER+ tumors in which there is a minor peak mainly of luminal B tumors at about age 50 and a major peak due to the late contribution of luminal A tumors near age 70 [
3].
This is not seen in Sulaimaniyah for Kurdish or Arab breast cancer patients where the average is < 50 years old for both ethnic groups. In these Iraqi patients, luminal B tumors were the predominant subtype from the beginning of breast cancer development in the early 20s and remained predominant at all later ages. The age distribution of both luminal A and luminal B tumors was unimodal and closely overlapping with no suggestion of a late peak for ER+ tumors.
On the basis of both molecular testing and IHC surrogates, this greater proportion of luminal B over luminal A breast cancers has been observed in other low incidence countries, including Colombia [age standardized incidence (ASI), 39.7] and China (ASI, 31.7) [
17‐
19]. In reports of Middle-Eastern patients in which luminal A were distinguished from ER+/PR+ luminal B tumors on the basis of a low Ki67 index, a > 3:1 predominance of luminal B over luminal A was found in Saudi Arabia (ASI, 24.7) and in Moroccan Arab immigrants to Belgium [
20,
21]. In the Belgium study, Moroccan and European women were compared [
21]. The mean age of Moroccan women was 49 ± 11 years old. European women who averaged 60 years old showed a contrasting all age parity in the proportion of luminal A and B tumors.
A 2013 report from Jordan showed that despite an increasing incidence of breast cancer in older women, the median age of all Jordanian breast cancer patients was still 50 years old [
22]. The authors claimed a predominance of luminal A tumors, but the cancers were not identified as luminal A based upon the St. Gallen’s guidelines and included all luminal subtypes except those that were HER2 positive [
22].
The 2013 St Galen’s guidelines recommended that luminal A be defined as ER+/PR+/HER2- tumors with a Ki67 index ≤ 14% and PR expression in > 20% of cells [
12]. Higher proliferation rate ER+ tumors including the triple positive ER+/PR+/HER2+ subtype are considered luminal B. The 2015 guidelines suggested a Ki67 index ≤ 20% or a Ki67 index less than the laboratory average for ER+/HER2- tumors [
13]. Regardless of the specific Ki67 criteria, a low proliferation rate is needed to reasonably replicate a luminal A molecular phenotype.
In Sulaimaniyah patients, triple negative and ER-/HER2+ were nearly evenly distributed throughout all age groups at a frequency approximately half that of luminal A tumors. This is representative of triple negative and ER-/HER2+ subtypes in other low incidence countries and illustrates their relatively low contribution to the total breast cancer burden compared to luminal tumors [
5,
18,
19,
23,
24]. Triple negative tumors are unusually common in sub-Saharan and African American women [
3,
24,
25]. However, in other racial groups they seem to have a relatively constant frequency of about 10-15% and increase proportionately across all ages as the general rate of breast cancer rises [
3,
5,
17‐
19,
24‐
26].
The relatively higher rates of luminal B breast cancers in developing countries may be a reflection of the younger populations and the relatively small proportions of aging women exposed to premenopausal hyperestrogenism. We have previously reported that the age specific incidence of the common ER+/HER2- breast cancer is similar in Kurdish and US women under 50 years old [
5]. The difference in the two populations is the absence in Kurdistan of the marked increase in the rates of ER+/HER2- tumors in older women that is seen in the US [
5]. This lends credibility to a concept of a prolonged population exposure being needed for the development of luminal A tumors. Nevertheless, it is worth mentioning that the age of the population by itself is not the determining factor. China has a huge, aging population but a low breast cancer age standardized rate and low rates of luminal A tumors [
17,
23]. In addition, low parity, that is considered a risk factor for post-menopausal tumors in the West, has been public policy in China for decades.
Our findings show that breast cancer incidence was essentially the same in the Kurdish region and in the south of Iraq before 2010 with an age standardized rate of approximately 30 per 100,000 women. After 2009, rates increased to 40.0/100,000 women in the south of Iraq and with a smaller change in Sulaimaniyah. This seems to be following the pattern observed over the past decade in Jordan (ASI, 53.8), Lebanon (ASI, 55.4), and several Gulf States including Kuwait (ASI, 48.0) and Qatar (ASI, 45.0) and may be an early phase in the transition toward higher breast cancer rates [
2].
It is not obvious whether the increasing age standardized rate of breast cancer in Iraq and other Middle-Eastern countries is a true biological transition or whether it reflects the increased utilization of urban cancer centers [
5,
19,
26,
27]. With a more general awareness of breast cancer, financially able women may selectively be traveling for a level of care that is not within the means of many families. In 2011, 60.1% of breast cancer among Jordanian women was diagnosed in Amman where the crude incidence rate was 47.8/100,000 [
28]. This compared with the outlying Governates where crude incidence varied from 11.7 to 22.7/100,000 women. In the Sulaimaniyah Governate, a similar clustering of breast cancer diagnosis was found in central Sulaimaniyah city. This may indicate urban/rural differences in incidence but as likely represents patterns of accessing cancer care.
The technology and specialization needed for modern cancer care necessitates its centralization but also has the potential for creating demographic artifacts. With mammography and MRI, central facilities have the ability to detect small and in-situ breast cancer that may not be found by clinical practice outside of major centers. In addition, women taking advantage of these facilities may be more likely to have risk factors associated with post-menopausal disease.
In many if not most Middle-East countries, luminal subtypes represent more than 60% of breast cancers of all ages and more than 70% after age 60 [
5,
6,
20‐
22,
26,
27]. Whether the pattern of increasing rates of breast cancer in older patients is taking a direction that will resemble the West remains to be seen, and it will be valuable to understand the relationships between cancer subtypes in the region. If the Western pattern is followed, age standardized rate should continue to rise, the average age of breast cancer patients should increase, and luminal A should exceed the frequency of luminal B tumors at around 60–70 years of age.
Acknowledgements
The authors thank the histology department of Shorsh Pathology laboratory for their extra work in preparing the high quality of sections and immunohistochemistry from the many breast specimens. MDH particularly thanks Mr. Adalan Abdulmajeed Mustafa, the supervisor of medical records at Hiwa Hospital, who tirelessly searched files to confirmed diagnoses and establish the ethnicity and residence of breast cancer patients.