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Back to Journal »Cancer Management and Research» Volume 13
Author Koonmee S, Somintara O, Intarawichian P, Aphivatanasiri C, Sangkhamanon S, Laohawiriyakamol S, Panawattanakul R, Maantassanapong P, Rattadilok C, Jeeravongpanich P, Krongyute W, Prachumrasee K, Alagheh
Published on November 23, 2021, the 2021 volume: 13 pages 8737-8753
DOI https://doi.org/10.2147/CMAR.S335386
Single anonymous peer review
Editor who approved for publication: Dr. Seema Singh
Video abstract of "Pathum Raksa Project: Differences in Breast Cancer Care in Thailand" [ID 335386].
Supinda Koonmee,1 Ongart Somintara,2 Piyapharom Intarawichian,1 Chaiwat Aphivatanasiri,1 Sakkarn Sangkhamanon,1 Suphawat Laohawiriyakamol,3 Rujira Panawattanakul,4 Phanchanut Mahantassanphiotana,1 Chayanoot, Mahantassanapong,1 Chayanoot, Mahantassanapong,1 Chayanoot, Mahantassanapong,5 Chayanoot, Mahantassanapong,1 Chayanoot, Mahantassanapong, 5 Chayanoot Mahantas Department of Pathology, School of Medicine, Khon Kaen University, Khon Kaen; 2 Department of Surgery, School of Medicine, Khon Kaen University, Khon Kaen, Thailand; 3 Department of General Surgery, Prince of Songkhla University School of Medicine, Songkhla, Thailand; 4 Surgery, Udon Thani Hospital, Udon Thani, Thailand; 5 Department of Anatomy and Pathology, Surin Surin Hospital, Thailand; 6 Department of Surgery, Nopparatrajathanee Hospital, Bangkok, Thailand; 7 Department of Anatomy and Pathology, Songkhla Hospital, Thailand; 8 Surgery, Fort Suranari Hospital, Nakhon Ratchasima, Thailand; 9 Khon Kaen, Thailand Jing University School of Local Administration; 10 Department of Pathology, University of British Columbia School of Medicine, Royal Columbia Hospital, Vancouver, British Columbia, Canada Royal Columbia Hospital, British Columbia, Vancouver, British Columbia, Canada Email [email protected] Purpose: Breast cancer is Thailand’s growing public health challenges. The Pathum Raksa project was launched in 2015 because the incidence of triple-negative breast cancer among Thai women was higher than expected. The purpose of this project is to determine the cause and solve the problem, thereby improving the quality of breast cancer biomarker testing in Thailand. Materials and methods: From 2015 to 2020, a total of 902 breast cancer patients from 19 hospitals across the country participated in this study. The data before and after the Pathum Raksa project is only applicable to Khon Kaen University (KKU) and Udon Thani Hospital in Northeast Thailand. We have formulated a resource stratification strategic plan, including the design of unique specimen containers, the formation of multidisciplinary teams in surgery and pathology, and the use of locally developed innovative technologies to optimize the entire process of breast cancer diagnosis and biomarker detection. Results: The incidence of triple-negative breast cancer in KKU and Udonthani decreased by 52.8% (p = 0.02) and 28.9% (p = 0.48), respectively. After the implementation of Pathum Laksa, the incidence of ER breast cancer in the two hospitals increased by 5%. The HER2-neu (score 3) rate of the two hospitals also increased (especially the KKU increased by 65%). Luminal A/B cancer is the most common subtype in KKU and Udonthani hospitals. Conclusion: The Pathum Raksa project has significantly improved breast cancer biomarker detection in Thailand. Thanks to this national innovation, the false negative rate of breast biomarkers has been significantly reduced, thereby improving the prognosis, treatment and survival rates of breast cancer women in Thailand. Keywords: breast cancer, biomarker, Pathum Raksa, multidisciplinary team, pre-analysis stage
Breast cancer is the most common malignant tumor for women in the world, and it is an increasingly serious public health challenge, especially in economically underdeveloped and developing countries. 1 Breast cancer deaths disproportionately affect individuals in low- and middle-income countries, where most breast cancer deaths occur prematurely (in women under 70). 1 In Thailand, the incidence of breast cancer is increasing significantly in all regions of the country, increasing by 3% to 7% every year. 2 Breast cancer is the most common cancer among Thai women, and it is expected to remain one of the main factors leading to cancer diagnosis by 2025.2
Laboratory services are an indispensable part of clinical decision-making and contribute to all aspects of health services, including cancer diagnosis, treatment decisions, disease monitoring and prevention. 3 Early diagnosis and accurate histological interpretation of breast tumors are the basic pillars of any breast cancer care plan. As we all know, biomarker detection, ER (estrogen receptor), PR (progesterone receptor) and HER2/neu (human epidermal growth factor receptor 2) are essential for correct patient treatment, among which anti-hormonal and HER2 targets Provides significant clinical benefits to treatment. 4,5 Immunohistochemical detection of breast biomarkers is the current standard of care. However, these biomarkers must be properly verified, reproducible, correctly interpreted, and reliably reported. These biomarkers must be tested in appropriately processed samples. To maintain antigenicity and morphology. 5
The Pathum Raksa project, which literally means "better breast cancer treatment", was launched in 2015 because the incidence of triple-negative breast cancer among Thai women was higher than expected. The initial purpose of the project was to determine the cause and solve the problem, thereby improving the quality of breast cancer biomarker testing in Thailand. This article will outline how this national innovation was successfully implemented and how it has a positive impact on the lives of breast cancer patients in Thailand.
Thailand has a population of nearly 70 million and is considered a middle-income country in Southeast Asia. According to the latest statistics from the World Health Organization (WHO) in 2020, the age-standardized (world) breast cancer incidence and mortality rates for Thai women are 37.8 and 12.7 per 100,000 population, respectively. 6 Estimate the total number of breast cancers in the past and the future. The number of cases will increase from 13,000 in 2012 to 23,000 in 2040. 6 Thailand is a diversified country. Many aspects, including demographics, geography, socio-economic and cultural aspects, lead to different cancer incidence rates and care-related resources in specific areas. 2
A national breast cancer screening campaign was launched in 2002, and the Thai government promoted guidelines on self-breast examinations and clinical breast examinations. 2 It is estimated that Thailand has nearly 2,800 CT, MRI and mammography machines, of which nearly 25% are located in the capital Bangkok, and the rest are located in 76 provinces. 2 In addition, about one-third of these machines are in the private sector, and most Thai women cannot use them. They are covered by the universal health coverage plan. 2
Most pathology laboratories in Thailand are based on hospitals and are facing increasing workload and staff shortage challenges. 7 In Thailand, there are more than 300 hospitals that perform breast surgery, and specimens are examined by internal pathology laboratories or outsourced. It should be noted that there are only 32 pathology laboratories nationwide that have been officially certified and accredited by the Royal Committee of Pathologists in Thailand. The certification also includes immunohistochemistry (for ER, PR and HER2-neu) and in situ hybridization (ISH) for HER2-neu testing. 8
Due to differences in personnel, infrastructure, expertise, and experience, the different resources of the national pathology laboratory may lead to differences in cancer care diagnosis and treatment. Table 1 shows the geographic distribution of anatomical pathologists per 100,000 population in Thailand (source: Royal Thai Pathologists Committee). Obviously, the ratio of anatomic pathologists per 100,000 in the capital Bangkok (3.8/100,000) is comparable to other economically developed countries such as the United States (3.9/100,000) and Canada (4.8/100,000). 9 However, there is a huge gap in the workforce of pathologists in other parts of the country, 0.1 to 0.4 per 100,000 people, resulting in a huge gap in access to surgical pathology-related services including breast cancer diagnosis (at least 10 times smaller) . Table 1 Distribution of anatomical pathologists per 100,000 population in Thailand (Source: Royal Thai Pathologist Committee)
Table 1 Distribution of anatomical pathologists per 100,000 population in Thailand (Source: Royal Thai Pathologist Committee)
The original idea of this national initiative started when the senior author (SK) observed significant differences in life expectancy and the quality of breast cancer diagnosis between economically developed countries and Thailand. In 2003, the senior author (SK) and his colleagues10 conducted a baseline study at the Srinagarin Hospital, Affiliated Hospital of Khon Kaen University (KKU) in Northeast Thailand to examine the status of breast cancer immunohistochemical biomarkers (ER/PR). , HER2-neu). Studies have shown that the incidence of ER breast cancer in this region is 53.1%, which is significantly lower than the expected ER breast cancer incidence of 79-84% globally. 5 In addition, the high incidence of triple-negative breast cancer (22%) is observed in northeastern Thailand.
These shocking findings prompted the Royal Thai Academy of Pathologists' EQA (External Quality Assurance) program and the "SPHeRE Program in the Asia-Pacific Region (HER2 Scientific Partnership for Excellence in Testing)". All surveys similarly identify gaps fixed by the appropriate organization as a key pre-analytical factor.
It should be noted that according to the American Society of Clinical Oncology/American College of Pathologists (ASCO/CAP) practice guidelines, if core biopsies of breast tumors are representative of the tumor (grade and type), they are the preferred samples for biomarker testing5 Unfortunately, the guidelines have not been consistently followed or practiced in Thailand, mainly due to lack of infrastructure, resources and personnel. In small and remote hospitals that are mainly located in the "periphery" (away from Bangkok and/or other major university centers), biomarker testing is mainly performed on surgical specimens, which creates challenges before analysis and leads to high false-negative biomarkers (ER/PR /HER2-neu) results.
Ideally, according to the latest 2020 ASCO/CAP Guidelines5, the time from tissue collection to fixation should be as short as possible, and samples used for biomarker testing should be fixed in 10% neutral buffered formalin (NBF) 6-72 hours. After proper gross examination and margin assignment, the specimen should also be sectioned at 5 mm intervals and placed in an NBF of sufficient volume to allow sufficient tissue penetration. In addition, when the tumor comes from a remote area, the tumor should be divided into two, taken out and sent to a pathology laboratory soaked in a sufficient amount of NBF. In addition, the cold ischemia time, the type of fixative, and the time the sample was placed in the NBF must be recorded.
After identifying the problem, its scope and potential root causes, the research team developed a resource stratification strategic plan to address the problems in the most affected areas of the country. The plan includes the design of unique and professional specimen containers, a multidisciplinary team composed of surgery and pathology departments, and the use of locally developed innovative technologies to optimize the entire process of breast cancer diagnosis and biomarker detection.
In order to solve the problem of poor formalin tissue fixation, a special specimen container was designed in 2012 (Figure 1A-C). As far as we know, this innovative design is the first in Southeast Asia and other low- and middle-income countries. Figure 1 (A) Breast specimen (Pathum Raksa) container size 14×20×12cm with lid locking system to prevent NBF leakage. (B) The acrylic barrier plate has at least 3 holes with a diameter of 0.5 cm to allow the free flow of NBF between the parts. (C) Continuously cut the surgical specimens of breast tumors to a thickness of 3 cm, and then put them in a special container. Note: Figure 1C is used with permission from Thaomani Ruaysoongnern; copyright Squamosa 2013.
Figure 1 (A) Breast specimen (Pathum Raksa) The container size is 14×20×12cm, with a lid locking system to prevent NBF leakage. (B) The acrylic barrier plate has at least 3 holes with a diameter of 0.5 cm to allow the free flow of NBF between the parts. (C) Continuously cut the surgical specimens of breast tumors to a thickness of 3 cm, and then put them in a special container.
Note: Figure 1C is used with permission from Thaomani Ruaysoongnern; copyright Squamosa 2013.
The size of the container is 20 cm (length) x 14 cm (width) x 12 cm (height), with a lid locking system to prevent NBF from overflowing during transportation. The container may be divided into 2 to 4 compartments, using acrylic barriers, while maintaining a sample thickness of 3 cm. The plate design also has at least three 0.5 cm diameter holes, allowing NBF to flow freely between the compartments. A customized surgical application form, pink paper (compared to conventional white paper surgical applications) was developed to visually identify specimens and ensure that key demographic, clinical, and pre-analytical factors (Figure 2) are consistently recorded. The specialized breast container is a unique and innovative solution used in Thailand. In Thailand, most breast specimens come from remote hospitals and need to be transferred to the central and main referral pathology laboratory, causing serious delays before reaching the pathology laboratory. Before the implementation of this special specimen container, many samples arrived in the laboratory with poor tissue fixation, which ultimately led to potential errors in biomarker detection. Figure 2 A special surgical application form, which is visible in pink, is used to record demographic, clinical and pre-examination data-analysis factors. Note: The image was provided and developed by the Department of Pathology, Khon Kaen University School of Medicine.
Figure 2 The pink special surgery application form used to record demographic, clinical, and preanalytical factor data.
Note: The image was provided and developed by the Department of Pathology, Khon Kaen University School of Medicine.
In order to put the breast specimen into a container (with multiple compartments), the surgeon slices the sample in series with a thickness of 3-4 cm, allowing the NBF tissue to penetrate (Figure 3). Guidelines have been developed to ensure that the specimen orientation remains intact during the transport of specimens in the container from the operating room (OR) to the pathology laboratory. The mastectomy specimen is oriented by the surgeon, and the upper and lateral edges are marked with a single short and long surgical silk suture, respectively. For the lumpectomy sample, the third suture line marked the leading edge with a double surgical wire (Figure 4). Figure 3 Serial sections of breast tumors separated by acrylic barrier plates. Figure 4 The edges of the mastectomy specimen are marked on the top and side with a single short and long surgical silk suture. For lumpectomy specimens, the third edge (front) is marked with a double-layer surgical wire.
Figure 3 Serial sections of breast tumors separated by acrylic barrier plates.
Figure 4 The edges of the mastectomy specimen are marked on the top and side with a single short and long surgical silk suture. For lumpectomy specimens, the third edge (front) is marked with a double-layer surgical wire.
In this study, pre-analysis factors such as cold ischemia time, fixation type, and collection time are recorded on the surgical application form. According to ASCO/CAP clinical practice guidelines,5 samples used for biomarker testing should be fixed in NBF for 6 to 72 hours. In some hospitals participating in the project, the geographic distance between the operating room and the outsourced pathology laboratory in the mainland hospital is more than 300 miles. Obviously, this leads to excessive fixation of the specimen, which may affect the testing of biomarkers. In order to solve this problem, the research team cooperated with the KKU Department of Electrical Engineering to develop a monitoring tool based on the concept of the Internet of Things (IoT), which allows monitoring of a fixed time.
The Internet of Things is a network of physical objects ("things", such as the breast container in this case) embedded with sensors, software, and other technologies, with the purpose of connecting and exchanging data with other devices and systems via the Internet. In addition, a notification function is also designed and integrated to assist in informing the laboratory staff of the gaze time and prevent potential over-gaze. Facts have proved that the notification function is very useful, especially in laboratories with heavy workloads and staff shortages. This innovative technology enables laboratories to prioritize the general examination of breast cancer specimens, ensuring that all specimens are processed before the recommended fixed time of 72 hours.
From a logistical point of view, the designed electronic equipment was placed and installed in OR and pathology laboratories. The labeled breast cancer specimen container is scanned twice by a radio frequency identification (RFID) technology reader: 1) after placing the specimen in the NBF and before leaving the operating room, and 2) after reaching the pathology laboratory, as shown in Figure 5. Once the breast container is initially scanned in the operating room, the data (date/time, hospital, container number) is sent to the server and a notification message is sent to the laboratory staff. A web-based application tool was also designed to monitor specimen fixation time (Figure 6). Figure 5 The breast specimen container is scanned by a sensor reader in the operating room (left picture) and the pathology laboratory (right picture). Figure 6 Fixed-time monitoring, using a network-based application system.
Figure 5 The breast specimen container is scanned by a sensor reader in the operating room (left picture) and the pathology laboratory (right picture).
Figure 6 Fixed-time monitoring, using a network-based application system.
The first step in the successful implementation of the project requires the establishment of support and alliances with surgeons in order to come up with the idea of using specially designed containers to better handle breast cancer cases. This was achieved through a successful collaboration with the former chairman of the Royal Thai Surgeons Council (Professor Vajarabhongsa Bhudhisawasdi), who advocated high-quality breast cancer biomarker reporting, especially in hospitals in northeastern Thailand.
In 2013, a pilot study was conducted in hospitals in the two northeastern provinces of Kalasin and Roi Et, and surgeons agreed to cooperate and implement innovations. The two hospitals sent their breast specimens to Chiang Mai (the largest city in northern Thailand and the capital of Chiang Mai province) and Bangkok for pathological examinations, with an average geographic distance of 300-400 miles. It should be noted that in addition to poor tissue fixation and poor biomarker testing quality, the turnaround time for breast cancer reports in these two provinces is also a concern for surgeons and oncologists. With the support and priority of the Thai government, the country’s key performance indicators for breast cancer care require up to 2 weeks to release the pathology report after the biopsy, and to receive treatment within 4 weeks after the pathology report. This is certainly not the case in these two provinces, which further led to their choice in the pilot phase.
An educational briefing was held with surgeons, OR nurses and pathologists in each hospital. The introduction will include a one-hour seminar and online video training, covering the pre-analytical factors and logistical aspects of the project, including the use of containers, sectioning, orientation, and handling of breast surgery specimens. A post-training assessment tool was developed that requires surgeons and OR nursing staff to have a passing score of at least 70%, and pathologists to have a passing score of 80%. It should be noted that all pathology laboratories participating in the project (including pilot and follow-up laboratories) need to be certified for breast cancer biomarker testing and be accredited by the Royal Thai Board of Pathologists.
Provided professional breast containers and breast surgery application forms to two pilot hospitals, and decided to redirect breast specimens from these two provinces to the KKU Pathology Department of Srinagar Hospital, with an average distance of 40-70 miles. Shorter geographic distances combined with the use of dedicated containers lead to faster turnaround times, improved tissue fixation quality, and accurate biomarker results (unpublished data).
After implementing a pilot project in two provinces in the northeast and our successful initiatives in addressing differences in breast cancer care in Thailand, the project was recognized by the country and led to the addition of many new hospitals across the country. It is worth noting that surgeons and oncologists from different regions of the country have a clear need for timely access to pathology reports and high-quality biomarker testing to help expand the scope of their tasks. In fact, the Pathum Raksa project was subsequently supported and endorsed by the Thai Breast Disease Society (TBS) in 2017, which led to changes in the national clinical practice guidelines to adopt serial sections of breast specimens before sending them to the pathology laboratory. TBS’s support also facilitated the expansion of the project nationwide, allowing hospital administrators to access, adopt, and utilize project resources. Therefore, cancer centers (universities, government, and military) and community hospitals have access to the program and its resources. This also includes private pathology laboratories mainly located in Bangkok, most of which are outsourced laboratories of hospitals that can use the program.
Since the implementation of the Pathum Raksa project in 2013, 19 hospitals across the country have officially joined the plan, and 6 of them have agreed to share data. Figure 7 shows the geographic distribution of participating hospitals across Thailand. Figure 7 The geographical distribution of 19 participating hospitals using Pathum Raksa containers.
Figure 7 The geographical distribution of 19 participating hospitals using Pathum Raksa containers.
Of all 19 participating hospitals, 6 agreed to share their data (Table 2), so there were 902 patients undergoing breast cancer surgery (ie, mastectomy) during the 6-year study period (2015-2020). The data before and after Pathum Raksa are only applicable to KKU and Udonthani hospitals in northeastern Thailand, so these two hospitals were included in the analysis. The data collection period is from 2015 to 2020, including the first 3 years of Pathum Laksa (2015-2017) and the last 3 years of Pathum Laksa (2018-2020), and comparative analysis and research have been conducted. Table 2 Characteristics of 6 of the 19 participating hospitals with data sharing agreements
Table 2 Characteristics of 6 of the 19 participating hospitals with data sharing agreements
A total of 595 patients with primary invasive breast cancer undergoing surgery (405 from KKU and 190 from Udonthani Hospital) were enrolled. The biomarker test was conducted inside KKU, while the specimens in Udon Thani Hospital were tested at the National Institute of Pathology, the government pathology laboratory in the capital Bangkok. The immunohistochemistry platform used by KKU is Ventana, while Leica is used in Udonthani. Table 2 shows the antibodies used in each immunohistochemistry laboratory.
According to ASCO/CAP guidelines, when at least 1% of tumor cells show clear nuclear staining, the tumor is considered positive for ER and PR. 11 According to the membrane staining pattern and the percentage of stained malignant cells, HER2-neu is scored as follows: 0, ≤10% of the cells are not stained or weakly stained; 1,> 10% of the cells are weakly stained; 2. Weak to moderately complete staining in> 10% of cells; and 3, complete staining in> 10% of cells. Only a score of 3 is considered positive. The score of proliferating cells is based on a count of at least 500 tumor cells. The Ki67 value is expressed as the percentage of positive (nuclear staining) cells in each case. Positive nuclei> 15% of the cases were classified as Ki67 high expression, and <15% of the cases were classified as Ki67 low expression. 12,13
We used the clinicopathological alternative definition of breast cancer subtype adopted by the expert panel of the 13th St. Gallen International Breast Cancer Conference (2013), based on the immunohistochemical measurement results of ER, PR, HER2-neu and Ki67. Where appropriate, in situ hybridization was performed to confirm. 14 This includes luminal A, with hormone receptor expression, no HER2-neu expression and low Ki67; luminal B, with hormone receptor and HER2-neu expression or high Ki67; rich in HER2, no hormone receptor expression and HER2-neu Expression; triple negative, no hormone receptor or HER2-neu expression. It should be noted that the Ki67 proliferation index of the KKU sample and Udonthani sample has been checked; mainly, it has not been implemented. Therefore, we did not include the Ki67 marker index to determine the breast cancer subtype of Udonthani specimens. The suspected HER2-neu selected at KKU was further analyzed by double in situ hybridization (DISH) analysis (scoring 2). This is because in KKU, core biopsy and surgical specimens are tested for biomarkers in accordance with institutional policies; therefore, according to relevant clinical indications, DISH testing is performed on some ambiguous HER2-neu. On the other hand, we have no data on the ambiguous HER2-neu at Udonthani Hospital.
The value of the continuous parameter is calculated as the mean ± standard deviation (SD). Pearson's χ2 test is used for categorical variables. All tests are two-tailed, and p <0.05 is considered the statistical significance level. All descriptive and inferential statistical analyses were performed using the Social Science Statistics Package (SPSS) version 19.0 (Chicago, Illinois, USA).
The average (±SD) patient age at KKU Hospital was 55±10.9 years (median was 55 years), and the range was 26 to 92 years. The corresponding figure for Udon Thani Hospital is 53.5±11.3 years (median is 53 years), and the range is 26 to 82 years. In KKU, 2 out of 405 patients were male, while only 1 out of 190 patients in Udonthani Hospital was male. The clinicopathological characteristics of KKU and Udonthani hospital patients are shown in Table 3. Table 3 Clinicopathological characteristics of breast cancer patients in KKU and Udonthani hospitals
Table 3 Clinicopathological characteristics of breast cancer patients in KKU and Udonthani hospitals
Table 4 shows the distribution of biomarker tests before and after Pathum Raksa. The incidence of ER breast cancer in KKU Hospital has a tendency to rise from 59.3% to 65.0%. Similarly, the incidence of ER breast cancer in Udon Thani Hospital rose from 58.3% to 63.6%. The incidence of PR breast cancer in the two hospitals also increased (Udonthani's increase rate was statistically significant, from 43.7% to 59.1%, p = 0.040). The incidence of HER2 breast cancer in the two hospitals increased significantly from 16.9% of KKU to 28.0% (p = 0.001), and the incidence of Udonthani increased from 22.3% to 24.7% (p = 0.635). Interestingly, the incidence of HER2-neu (score 2) in KKU breast cancer decreased from 35.6% to 15.9% (p = 0.001). The corresponding figure for Udon Thani Hospital dropped slightly from 10.7% to 7.1% (p = 0.635). Table 4 2015-2020 KKU and Udonthani Hospital's biomarker breast cancer detection before and after Raksa in Klang
Table 4 2015-2020 KKU and Udonthani Hospital's biomarker breast cancer detection before and after Raksa in Klang
Table 5 shows the distribution of alternative breast cancer subtypes before and after Baton Laksa. During the study period, Luminal A/B was the most common breast cancer subtype in KKU and Udonthani (before and after Pathum Raksa). The incidence of triple-negative breast cancer in the two hospitals decreased significantly from 26.9% to 12.7% (p = 0.02) in KKU, and from 22.8% to 16.2% in Udonthani (p = 0.48). The incidence of HER2-rich breast cancer in Udonthani remained unchanged, while after the implementation of the Pathum Raksa project, the incidence of KKU increased (from 13.5% to 20.1%, p = 0.33). Table 5 2015-2020 Alternative breast cancer subtypes in KKU and Udonthani hospitals before and after Raksa in Klang
Table 5 2015-2020 Alternative breast cancer subtypes in KKU and Udonthani hospitals before and after Raksa in Klang
Figures 8 and 9 show the distribution of alternative breast cancer subtypes by age group for each hospital (before and after Pathum Laksa). The incidence of luminal tumors (lumen A/B) increases with age in Udon Thani, but is relatively stable in all age groups of KKU. Similarly, the incidence of triple-negative cancer in Udon Thani decreases with age. Figure 8 The age-specific distribution of subtypes of alternative breast cancers before and after KKU (2015-2020). Figure 9 The age-specific distribution of alternative breast cancer subtypes in Udonthani before and after Pathum Laksa (2015-2020).
Figure 8 The age-specific distribution of subtypes of alternative breast cancers before and after KKU (2015-2020).
Figure 9 The age-specific distribution of alternative breast cancer subtypes in Udonthani before and after Pathum Laksa (2015-2020).
Breast cancer continues to be a growing public health challenge in Thailand, and its incidence has increased significantly in all regions of the country. 2 The incidence of breast cancer in northeastern Thailand is 19.4 cases per 100,000 people. This rate is lower than other regions such as the northern, central, and southern regions, which are 32.4, 33.9, and 27.4 cases per 100,000 population, respectively. 15 However, it is expected to increase by 2030 and be comparable to other regions. 15 On the other hand, the ratio of active practicing pathologists per 100,000 in the region is one of the lowest in the country (0.2 in the Northeast, compared to 3.8 per 100,000 in Bangkok).
Biomarker testing (ER/PR/HER2-neu) is an important prognostic and predictive indicator in the management of breast cancer patients and is included in the ASCO/CAP treatment guidelines. 5 Patients with ER tumors generally have a better prognosis and longer survival time. 16 Patients with receptor-positive tumors (ER /PR) are more likely to receive adjuvant endocrine therapy and are more likely to benefit from this treatment. 16,17 Therefore, accurate assessment of biomarkers for the best treatment of breast cancer.
ER, PR, and HER2-neu are heat-labile proteins, and their expression can be changed by exposure to room temperature for a long time before fixation or the length of fixation time, and in fixation types. 16 Many studies from Thailand examined the profile of cancer biomarkers in different regions of the breast (Table 6). 10,18–25 Similar to the index study conducted by Koonmee et al. 10 Most Thai studies show that ER is quite low and the incidence of triple-negative breast cancer is higher than expected. Thai women. The range of ER cancer is as low as 50%, and the triple-negative rate ranges from 13% to 23%. ER breast cancer is the most common alternative subtype, with an average global incidence of 79-84%, while the incidence of triple-negative breast cancer is estimated to be about 10-15%. 5 Table 6 The Thai study examines breast cancer biomarkers
Table 6 The Thai study of detecting breast cancer biomarkers
When interpreting the data on breast biomarkers in the Thai study (Table 6), it is important to note that the diagnostic criteria for immunohistochemical biomarkers change over time. ASCO/CAP changed the threshold standard for ER/PR from 10% to 1%, and the cut-off standard for HER2-neu (score 3) from 30% to 10%. Despite the changes in the diagnostic criteria of the above-mentioned biomarkers, the problem of low ER and high triple-negative breast cancer, especially in northern and northeastern Thailand, is still a clinical and pathological quality issue that has a negative impact on patient care. We believe that one of the main pre-analytical reasons for high false-negative biomarker breast detection in this area is related to poor tissue fixation. The Pathum Raksa project was launched in 2015 with the aim of addressing the country’s differences in breast cancer care through innovations that specifically target specific pre-analytical factors. This includes designing innovative processes through a variety of methods, processing surgical specimens according to local needs and available resources in Thailand, Thailand’s demographic data, geographical areas where care is received, hospital manpower and pathology laboratory expertise are unevenly distributed.
The design and proper engineering of the special breast container in this project is innovative and is one of the foundations for solving the problem of poor breast tissue fixation. Involving surgical teams across the country to join the project and coordinating their efforts with pathology laboratories is also an important step in achieving the success of this country's innovation. Therefore, currently 19 hospitals in 13 provinces across the country (South: 3 in 2 provinces, Northeast: 9 in 6 provinces, North: 2 in 2 provinces, Central: 5 in 3 provinces) have joined the Pathum Raksa project.
The main goal of organizational processing and preparation is to ensure adequate organizational preservation, which has been successfully achieved in this project. Inaccurate results due to impaired tissue quality may lead to false positive or false negative results, resulting in treatment consequences that may harm patients and affect their final results. 26 In the general practice of most cancers, the fixed time is usually still poorly controlled, 27 but we were able to use the concept of the Internet of Things in this project to implement an effective and efficient system for monitoring the fixed time. We believe that the cooperation between the surgical and pathology departments of various institutions across the country to actively transfer specimens to the laboratory has been proven to successfully achieve the goal of standardization organization processing, rather than trying to expect or promote the already busy OR staff. Provide specimens in a timely manner.
In this study, we examined the data before and after Pathum Laksa from two hospitals in northeastern Thailand (KKU and Udonthani) to assess the impact of the project on key biomarker performance indicators. Both hospitals conducted internal histological examinations. As for biomarker testing, breast specimens are performed inside KKU, while they are outsourced to the Udon Thani government laboratory in the capital Bangkok, because the province’s pathology laboratory does not have the immunohistochemistry infrastructure and capabilities.
The preferred specimens for KKU biomarker testing are core biopsy and surgical specimens, while Udonthani is mainly (approximately 90%) surgical specimens. After the implementation of Pathum Laksa, the incidence of ER breast cancer in the two hospitals has increased by an average of 5%. Similar results were observed in the PR test. Due to the implementation of the Pathum Raksa project, our research results are consistent with the improved ER/PR biomarker profile. Our research team recently used real-time PCR to compare the DNA quality of formalin-fixed paraffin-embedded (FFPE) breast cancer specimens between Pathum Raksa project participants and KKU laboratory routine service participants. The analysis showed that the DNA quality of the Pathum Laksa sample was significantly higher than that of the regular service [unpublished data].
One of the most important key performance indicators examined in this study is the change in the incidence of triple-negative breast cancer. Thanks to the Pathum Raksa project, the incidence of triple-negative breast cancer in KKU has dropped by 52.8%. Udonthani's corresponding figures show a similar pattern, with the incidence of triple-negative breast cancer falling by 28.9%. At the population level, this means that approximately 50 women with breast cancer and 15 women with breast cancer in Khon Kaen and Udon Thani provinces each year can prevent inaccurate biomarker results and subsequent improper treatment (data : Thailand Cancer Registry). We believe this is one of the most important key clinical impacts of the Pathum Raksa project. It reduces the false negative rate of triple-negative breast cancer, thereby significantly changing the prognosis, treatment and potential survival rates of these women. It is worth noting that due to the failure of endocrine and targeted therapies, triple-negative breast cancer is often more aggressive and lethal than non-triple-negative breast cancer subtypes (luminal tumors). 28,29
After Pathum Raksa, the HER2-neu (score 3) rate of the two hospitals also increased. This is more obvious for KKU, where HER2-neu increased by more than 65% (score 3). At the population level, it is estimated that approximately 40 women with breast cancer in Khon Kaen Province may be eligible for HER2 targeted therapy (data: Thailand Cancer Registry). Interestingly, the ambiguous HER2-neu (score 2) rate in KKU decreased by 54%, while the HER2 enrichment rate increased by approximately 50%. This is a clinically significant finding because trastuzumab is the most common targeted therapy used to treat patients with HER2-positive breast cancer. HER2-positive breast cancer is composed of intrinsic molecular subtypes luminal A, luminal B, and HER2-rich subtypes. The HER2-rich subtypes have the function of activating the EGFR-HER2 pathway. Previous studies have shown that patients rich in HER2 subtypes will benefit the most from certain treatment options, such as dual HER2 blockers. 30
As expected, luminal tumors are the most common breast cancer subtype in this study, which is similar to other Thai studies10, 15, 21, 23 and global literature. 31 Lumen B was found to be the most common breast cancer subtype in KKU before and after Baton Laksa, while Lumen A cancer was the most common subtype of Udon Thani. According to the 2013 St. Gallen Consensus14, luminal B subtypes account for nearly 40% of all breast cancers, which is similar to the implementation of Pathum Raksa after KKU (44%). We investigated this issue further in the 74 breast core biopsy cohorts of KKU during the study and found that 55.4% (41/74) of them were lumen B. We believe that the difference in the distribution of luminal tumors between the two provinces is due to the unavailability of Ki67 index data in Udonthani (unlike KKU). As a limitation of the study, this may lead to differences in the characteristics of luminal breast cancer between the two provinces. Further analysis of Udonthani's data, we found that Ki67 index has only 6 breast cancers, of which 2/6 (33%) are luminal A and 4/6 (67%) are luminal B. This further supports the above-mentioned the possibility of this difference.
The Pathum Raksa project is a national innovation initiative that has had a significant impact on the lives of breast cancer patients in Thailand. The project demonstrated a successful example of how the combination of a national public health vision and resource stratification planning can solve the problem of disparities in breast cancer care in Thailand. Thanks to this innovation, the false-negative rate of breast biomarkers has been significantly reduced, leading to significant changes in the prognosis, treatment and survival rates of breast cancer women in Thailand.
The study was conducted in accordance with the guidelines of the Declaration of Helsinki, and was approved by the Human Research Ethics Committee of Khon Kaen University (HE601284), and written informed consent was obtained from all patients.
We would like to thank Professor Vajarabhongsa Bhudhisawasdi, former Chairman of the Royal Thai Surgeons Committee, Dr. Paiboon Pensuwan, Deputy Dean of Roi Et Hospital, Dr. Chanthit Phunlap, Director of Surgery, Roi Et Hospital, and Dr. Thanasit Praipong, Deputy Dean of Kalasin Hospital for their since 2012 Valuable support and assistance to project management since.
All authors participated in data analysis, drafting and/or revising the article, finally approved the version to be published, agreed to the journal to be submitted, and agreed to be responsible for all aspects of the work.
We would like to thank the deans of the three medical schools of Chiang Mai University, Prince of Songkhla University and Khon Kaen University for their financial support for this project, and the Thai Breast Disease Association for funding participating hospitals.
Dr. Supinda Koonmee and Dr. Krisada Prachumrasee reported a beautiful patent granted to 9256 and a beautiful patent granted to 16424. Dr. Sakkarn Sangkhamanon reported a beautiful patent number. 9256 came from Thailand's Ministry of Intellectual Property, submitted works outside; in addition, Dr. Sakkarn Sangkhamanon reported the Pretty patent number. 9256 Royalties paid to new medical technology companies. The authors report that there are no other potential conflicts of interest for this work.
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