Clinical subtypes of breast cancer in Thai women: a population-based study of Chiang Mai province

The data used in this study are retrospective data from the cancer registry and the study was approved by the Research Ethics Committee of the Faculty of Medicine, Chiang Mai University (certificate of approval no. 316/2016).

This observational study extracted data of women diagnosed with breast cancer during 2004–2013 and living in Chiang Mai province were collected by the Chiang Mai Cancer Registry using International Classification of Diseases–10th edition (ICD-10) codes C50. The Chiang Mai Cancer Registry is a population-based cancer registry operating in the Maharaj Nakorn Chiang Mai Hospital, Faculty of Medicine, Chiang Mai University. The data were collected from all hospitals in Chiang Mai, including Maharaj Nakorn Chiang Mai Hospital, which is a university hospital, as well as government hospitals, municipal hospitals, private hospitals, and community hospitals. Patient data were systematically collected and carefully verified by cancer registry personnel and using cancer registry software (CanReg5). Cancer registry data included patient profiles, such as date of birth, age at diagnosis, clinical diagnosis, pathological report, clinical extent of disease before treatment, and initial treatment. Immunohistochemical (IHC) status including ER, PR, and HER2 was extracted from the medical record.

The stage of breast cancer was categorized based on the extent of disease of cancer. Localized tumors are restricted to the breast, regional tumors involve axillary lymph nodes, and distant stage involves spreading of cancer to other parts of the body.

According to the population-based cancer registry data for the Chiang Mai population in 2004–2013, the incidence of breast cancer significantly increased [5]. While the proportion of unknown subtype has been decreasing, the proportion of luminal subtype (ER+ and/or PR+) has been increasing, particularly the proportion of luminal A-like (ER+ or PR+ and HER2-). The proportion of HER2 (ER- and PR- and HER2+) subtypes and triple-negative subtypes (ER- and PR-and HER2-) were stable and lower than 20%.

Only a few studies previously reported on the proportion of breast cancer subtypes based on ER/PR and HER2 in the Thai population.

First, a study of patients with invasive ductal carcinomas in Siriraj Hospital reported the proportion of female breast cancer clinical subtypes [10]. Compared to the Siriraj Hospital study, which assessed 324 breast cancer patients diagnosed during 2009–2010, our study found a lower proportion of luminal A-like in our population in 2009–2010 (39% in our study vs. 59% in the Siriraj study), but a higher proportion of luminal B-like and HER2 (22% and 21%, respectively, in our study vs. 12% and 13%, respectively, in the Siriraj Hospital study). However, the proportion of triple-negative in our population was similar to that reported in the Siriraj Hospital study, 18% vs 15%.

Second, a study of the northeastern Thailand population on 294 patients diagnosed with breast cancer at Srinagarind Hospital [12] from January 2004 to June 2006 found that the proportion of luminal A-like (ER+ or PR+ and HER2-), luminal B-like (ER+ or PR+ and HER2+), HER2 (ER- and PR- and HER2+) and triple-negative was 51%, 8%, 19%, and 22%, respectively. Compared to the Srinagarind Hospital study, our study found a slightly lower proportion of luminal A-like (40% vs. 51%) but a significantly higher proportion of luminal B-like (22% vs. 8%). The proportions of HER2 and Triple-negative in our study (17% and 22%, respectively) were similar to that in the Srinagarind Hospital study.

The most recent study in southern Thailand [15] reported, 46%, 28%, 13%, and 13%, respectively, of the subtypes luminal A-like, luminal B-like, HER2, and triple-negative subtypes among 635 female breast cancer patients for whom clinical subtype information was available in 2010–2012. The proportion of luminal A-like in our study was the same as the southern Thailand study. The proportion of luminal B-like was lower in our study (24%), while the proportions of HER2 and triple-negative in our study (16% and 15%, respectively) were slightly higher than the southern Thailand study. A Western-based population study using data of female breast cancer cases diagnosed during 1999–2003 in California, showed a 12% proportion of triple-negative tumors. Women with triple-negative breast cancers were significantly more likely to be under age 40 [8]. Another larger study based on data from 17 population-based cancer registries that participate in the SEER program in the United States reported that among 50,571 cases in patients diagnosed in 2010, 73% were luminal A-like (HR+/ HER2-), 12% were triple-negative (HR-/HER2-), 10% were luminal B-like (HR+/HER2+), and 5% were HER2 (HR-/ HER2+). This study also showed that the proportion of triple-negative tumors was significantly higher in women age <65 [9]. The distribution of female breast cancer subtypes in the US population and our Chiang Mai population are different. The proportion of luminal A-like was much higher and HER2 was moderately lower in the US population compared to our Chiang Mai population, but the distribution of our population was likely closer to other studies among the Thai population [10, 12, 15], despite that these Thai studies were not population-based study and were conducted in different parts of Thailand. Therefore, the distributions of female breast cancer by subtypes using population-based data in different parts of Thailand are recommended.

As reported in several studies [8, 9], our study found similar results that the most common subtype in all age groups was luminal A-like, which was likely to have a higher proportion in the elderly group compared to other groups. Our previous study showed a significant increase of breast cancer incidence in the elderly [6]; in the present study, we also found the increase of median age over time (Table 1). This might explain the larger proportion of luminal A-like subtype over time (Figure 1).

Moreover, an association between mammographic screening and detection of breast cancer with hormone positive, that is, ER+ has been shown [16, 17]. In the present study, percentage of localized tumor has been significantly increased (P = 0.04) and may represent the increased coverage of screening. Although organized mammographic screening has not been established in Thailand, the percentage of coverage increased in different regions of the country. According to the National Health and Welfare Survey in 2007 and the Reproductive Health Survey in 2009 [18], the screening coverage was found to be stable in Bangkok (13%) with moderate increase in the North, Northeast, and South (from 4% to 9%, 5% to 9%, and 7% to 10%, respectively). The coverage of mammo-graphic screening was highest in Bangkok, followed by the South region [18]. This might explain the higher proportion of luminal subtypes in Bangkok and the South compared to our Chiang Mai population, but our results were similar to what was found in the Northeast in the corresponding period of study.

IHC analyses including ER, PR, HER2, and Ki-67, define the luminal A, luminal B, HER2, and Basal-like subtypes [19]. However, our study only used ER, PR, and HER2 status to classify clinical subtype of breast cancer because Ki-67 information is not routinely collected and was unavailable. Therefore, we used the available IHC status to approximate the breast cancer subtype into the four subtypes: luminal A-like, luminal B-like, HER2, and triple-negative. However, we found this distribution of approximated subtypes of breast cancer using IHC was similar to what was reported in an Asian-population study that was based on molecular data [20], in which the luminal subtypes (luminal A+luminal B), HER2, and triple-negative subtypes were 65%, 14%, and 13%, respectively. Thus, this IHC classification may be more precise in distinguishing breast cancer subtypes if the luminal A-like and luminal B-like subtypes are merged into a single luminal subtype.

At the beginning period of our study, HER2 status that was necessary for IHC classification was not routinely examined. Therefore, clinical subtypes were not able to classify in such periods in this population. This can lead to an underestimation of the proportion of clinical subtypes. However, age distribution of unknown subtype was not significantly different from known subtype (P = 0.6). Fortunately, in recent years, subtypes of breast cancer have been classified more accurately with less unknown subtype. The change of subtype distribution overtime could be more accurately determined to observe the most three recent periods, which had <25% unknown subtype.

Moreover, our study has lack of tumour, node, metastasis (TNM) staging data defined by American Joint Committee on Cancer (AJCC) because of incomplete staging from some sources of data. The extent of disease which is commonly applied for population-based cancer registry data was therefore used instead.

Another limitation of our study is the delay of data collection. These are population-based data with active method of collection which has delay time around 2 years. Some additional time was spent for IHC status review of all individual record from all hospitals in Chiang Mai province because these data were not routinely collected by the cancer registry. Inclusion of these essential clinical data in the cancer registry would be encouraged for less time delay. However, our study is the first population-based study that describes the proportions of female breast cancer by clinical subtype and the change over time of those proportions in the Thai population. Moreover, this population-based data were collected by the active method, so we consider the data to be generally high quality, with more than 95% having histology verification (%HV) and <1% is death certificate only cases (%DCO).

As found in the results of hospital-based studies [10, 12, 15], the proportions of clinical subtypes of breast cancer were different in different parts of Thailand. Thus, the trends in incidence of breast cancer by clinical subtypes are likely to be different between sets of regions. In the future, when the classification of clinical subtype of breast cancer could become more stably accurate, the incidence estimation of female breast cancer by clinical subtypes using population-based data from different parts of Thailand is encouraged to determine the distribution of clinical subtype nationally and sub-nationally. The results of our study may guide for the better treatment plan considering the breast cancer subtypes. Since the proportion of hormone positive subtypes has been increasing, the inclusion of treatment facilities with a variety of hormone therapies as essential medicines for universal health coverage should be considered.

In the last decade, increased ability to identify subtypes has led to better treatment planning. Although the proportion of breast cancer with HER2 and triple-negative subtypes has remained stable at <20% in our population, anti-HER2 therapies should be made available. The proportion of hormone positive subtypes, luminal A-like, and luminal B-like has been increasing. Therefore, in the future, treatment facilities with a variety of hormone therapies should be provided in order to improve the efficacy and coverage of treatment for this population.