Journal of Medicine and Health (JMH) Vol. 4 No. 2 August 2022 e-ISSN: 2442-5257 https://doi.org/10.28932/jmh.v4i2.4554 Research Article The Association between The Patient’s Age Groups with Stage, Grading, and Molecular Subtype of Breast Cancer Hubungan antara Kelompok Usia Pasien dengan Stadium, Derajat Diferensiasi dan Subtipe Molekuler Kanker Payudara Agatha MA Putri1, Tejo Jayadi1,3*, Wiwiek Probowati1,2, Jonathan W Siagian1 1.Faculty of Medicine Duta Wacana Christian University, Yogyakarta Jalan dr. Wahidin Sudirohusodo no. 5-25, Yogyakarta, 55224, Indonesia 2 Internal Medicine of Bethesda Hospital, Yogyakarta Jalan Jend. Sudirman No.70, Kotabaru, Yogyakarta, 55224, Indonesia 3 Pathological Anatomy of Bethesda Hospital Yogyakarta Jalan Jend. Sudirman No.70, Kotabaru, Yogyakarta, 55224, Indonesia *Correspondence author Email: tejo_jayadi@staff.ukdw.ac.id Received: February 25, 2022 Accepted: August 11, 2022 Abstract In 2020, Global Cancer Observatory reported breast cancer incidence was 11.7% and mortality was 6.9%, most presenting a late-stage and delaying diagnosis. The study aimed to assess the breast cancer clinicopathologic characteristics according to the age groups. The research was conducted on 98 Medical Records from Bethesda Hospital Yogyakarta. The variable data were analyzed by univariate and the association between variables were analyzed with binary logistic regression with odds ratio and 95% confidence interval. The presentation of age groups ≤ 30 years (1,02%), 31-40 years (12,24%), 41-50 years (25,51%), 51-60 years (46,94%), and ≥ 61 years (15,31%); right breast (48,98%) and left breast (51,02%); stage I (3,06%), II (28,57%), III (55,10%), dan IV (13,27%); ductal type of breast cancer (89,80%) and others (10,20%); molecular subtype luminal A (43,88%), luminal B (14,29%), HER-2 neu enriched (29,59%), and basal-like/triple-negative (12,24%). There wasn’t any association between age groups and stages (p=0.368). There was an association between age groups and molecular subtype (p=0.013, OR 2.993 CI95% 1.239-7.230). Conclusions: The commonest clinicopathologic characteristic of breast cancer patients were in the age group 51-60 years, left breast, high stage, ductal type, and luminal A. Hormone receptors in breast cancer expressed more common in patients ≤50 years. Keywords: breast cancer; clinicopathology profiles; age group How to Cite: Putri AMA, Jayadi T, Probowati W, Siagian JW. The association between the patient’s age groups with stage, grading, and molecular subtype of breast cancer. Journal of Medicine and Health. 2022; 4(2), 123-30. DOI: https://doi.org/10.28932/jmh.v4i2.4554 © 2022 The Authors. This work is licensed under a Creative Commons AttributionNonCommercial 4.0 International License. J Med Health.2022;4(2):123-30 123 Journal of Medicine and Health Vol. 4 No. 2 August 2022 The Association between The … e-ISSN: 2442-5257 Research Article Abstrak Global Cancer Observatory tahun 2020 melaporkan insidensi kanker payudara sebesar 11,7% dengan kematian sebesar 6,9%, dan sebagian besar pasien sudah stadium lanjut dan ada keterlambatan diagnosis. Tujuan penelitian ini adalah untuk menilai karakteristik klinikopatologi penderita kanker payudara berdasarkan kelompok usia. Penelitian pada 98 Rekam Medik Rumah Sakit Bethesda Yogyakarta, data variabel diolah secara univariat dan bivariat dan hubungan antar variabel dianalisis menggunakan regresi logistic biner, disertai rasio odds dan konfiden interval 95%. Hasil: Presentasi kelompok usia ≤30 tahun (1,02%), 31-40 tahun (12,24%), 41-50 tahun (25,51%), 51-60 tahun (46,94%), dan ≥61 tahun (15,31%); payudara kanan (48,98%) dan kiri (51,02%); stadium I (3,06%), II (28,57%), III (55,10%), dan IV (13,27%); tipe histologi duktal (89,80%) dan non-duktal (10,20%); subtipe molekuler luminal A (43,88%), luminal B (14,29%), HER-2 positif (29,59%), dan basal like/triple negative (12,24%). Stadium kanker payudara tidak berbeda pada kelompok usia (p=0,368). Subtipe molekuler menunjukkan hubungan dengan kelompok usia, (p=0,013, OR 2,993 CI95% 1,239-7,230). Simpulan: Karakteristik klinikopatologi penderita kanker payudara terbanyak pada kelompok usia 51-60 tahun, sisi payudara kiri, stadium III, tipe histologi duktal, dan subtipe molekular luminal A. Pasien berusia ≤50 tahun lebih banyak menunjukkan ekspresi reseptor hormonal positif. Kata kunci: kanker payudara; profil klinikopatologi; kelompok usia Introduction Cancer is a non-communicable disease characterized by unregulated cell growth. Breast cancer from unregulated breast parenchymal cells, mainly epithelial, growth. 1 Global Burden Disease Study (2019), there are 24.5 million incidents of cancer worldwide in 2017 and the odds of developing cancer during a lifetime (ages 0-79 years) were 1 in 3 in men and 1 in 4 in women.2 Globocan data (2020) in International Agency for Research on Cancer WHO, globally the incidence of breast cancer according to Age-Specific Rate (ASR) in men and women (0-85 years) was 47.8 per 100.000 and the proportion in 5 years was 201,6% of all cancer excluding non-melanoma skin cancer.3 In Indonesia breast cancer incidence is the highest among others cancer, with ASR 43.8 per 100.000 population, mortality ASR 9.4 per 100.000 population, and a proportion was 178.9 per 100.000 population.3 The prevalence of all cancer in Yogyakarta was 4,1o/oo, the highest among other provinces in Indonesia, and breast cancer total cases in Yogyakarta was 4.325 cases.4 Breast cancer is one of the major health burdens in Indonesia. The burdens are different exposures to risk factors, economic settings, lifestyles, access to care and screening,5 delay in seeking help and non-adherence 6, financial toxicity,7,8, and Social Insurance Administration Organization reported that from 1,308,061 inpatient cancer cases treated in 2016, a total of 2.2 trillion rupiahs was spent, amounting to $486,960,633 in the US dollars (purchasing power J Med Health.2022;4(2):123-30 124 Journal of Medicine and Health Vol. 4 No. 2 August 2022 The Association between The … e-ISSN: 2442-5257 Research Article parity 2016).9 There are many breast cancer risk factors profiles studies,10,11 pathologic profile of young age group12, old age group.13 This research is still important because the young age group patients increase with aggressive characteristics, in an older age group patients increase with a worse prognostic outcome, and the majority of breast cancer patients in Indonesia are diagnosed at a high stage,12,14 and in Jogjakarta, almost half have delay presentation, and 64.7% experience delay in diagnosis.15 The study aimed to assess the different clinicopathologic between the young age group and older age group, and this study could provide additional data for later epidemiological, clinical, biomedical studies and to make policies for breast cancer screening. Methods A cross-sectional study used secondary data from the Medical Records (MR) at Bethesda Hospital Yogyakarta, which included all women diagnosed with breast cancer from 1st January 2017 – to 31st December 2020. This research has ethical clearance from Bethesda Hospital Yogyakarta number 42/KEPK-RSB/V/21. Of the 98 Medical records, were collected clinical data including age, and breast cancer side. Using American Joint Commission on Cancer system Tumour Node Metastasis staging of breast cancer; pathologic data include the histological type and molecular subtype of breast cancer. Including criteria were all breast cancer patient records in Bethesda Hospital Medical Record, and the excluding criteria were not complete Medical Records. The collected data were analysed by univariate statistics to describe the frequency and proportional percentage of clinicopathologic data. The significant difference between the dependent variable (age groups ≤ 50 years and > 50 years) and independent variables (low stage (I & II) - high stage (III & IV) and hormone receptors positive (Lumina A & Luminal B) – hormone receptors negative (HER-2/neu & Triple Negative Breast Cancer (TNBC)). The association between two variables was analysed by binary logistic regression. Results The 98 MR were included in the study. The clinicopathologic data is depicted in Table 1. Age-specific incidence rises steadily from age < 30 years, the highest rate was in the 51-60 years age group and declined after 60 years. The patients aged > 50 years are 62.23%, and 13.26% at the young age group (≤40 years), mean age 52.28 ± 0.944, youngest 24 years and oldest 78 years. Most of the histologic type of patients were invasive ductal carcinoma type (89.80%) rather than invasive lobular carcinoma type or other types. The high stage of cancer J Med Health.2022;4(2):123-30 125 Journal of Medicine and Health Vol. 4 No. 2 August 2022 The Association between The … e-ISSN: 2442-5257 Research Article (III & IV) in this study was found in 67 patients (68.37%). Hormone-positive breast cancer (58.17%) was more than hormone-negative breast cancer (41.83%). The significant differential analysis between low stage – high stage and hormone receptors positive and negative with age group ≤50 years and > 50 years, explained in Table 2. Percentage proportion of age group ≤ 50 years tend to show a higher risk for the advanced stage of breast cancer than age group > 50 years, although not statistically significant (p=0.368). Age group ≤ 50 years had hormone receptors positive, and the age group > 50 years had hormone receptors negative molecular subtype characteristic (p<0.05) in the odds 2.993 (CI 95% 1.239 – 7.230). Table 1 Distribution of Age, Breast Cancer Side, Stage Histopathologic Type, Molecular Subtype Variable Age Breast cancer side Stage Histopathologic type Molecular Subtype ≤ 30 years 31-40 years 41-50 years 51-60 years ≥ 61 years Right Left Stage 0 Stage I Stage II Stage III Stage IV Invasive Ductal Ca. Others Luminal A Luminal B HER-2 positive Basal-like / Triplenegative Breast Ca. Frequency % 1 12 25 45 15 48 50 0 3 28 54 13 88 10 43 14 29 1,02% 12,24% 25,51% 46,92% 15,31% 48,98% 51,02% 0,00% 3,06% 28,57% 55,10% 13,27% 89,80% 10,20% 43,88% 14,29% 29,59% 12 12,24% Table 2 The Difference Between Age Groups with Stage and Molecular Subtype Variable Stage Molecular Subtype Low High Hormone receptor + Hormone receptor - J Med Health.2022;4(2):123-30 Age groups ≤50 years >50 years 10 (32.3%) 21 (67.7%) 28 (41.8%) 39 (58.2%) 28 (49.1%) 29 (50.9%) 10 (24.4%) 31 (75.6%) Significance 0.368 0.013 OR 2.993 CI 95% 1.239 – 7.230 126 Journal of Medicine and Health Vol. 4 No. 2 August 2022 The Association between The … e-ISSN: 2442-5257 Research Article Discussion The incidence of breast cancer increases with age and decreases after age 60 years. A very young adult breast cancer patient in this study was at age of 24 years. Age group ≤ 50 years tend to have a high stage at diagnosis presentation (68.37%) and had hormone receptor-positive molecular subtype characteristic (58.17%). In a study in Sardjito Hospital, the prevalent age of the patient was 46-50 years of age (22.4%), then 51-55 years of age (19.5%).16 In a study at Kariadi Hospital Semarang (2016), there were 372 cases (83.4%) of breast cancer that occurred in age ≥ 40 years of totals 446 cases.1 The study in RSUP Haji Adam Malik Medan (2021) show different results, age group 41 - 50 (38 cases of total 103 cases, 36.9%) was the highest rate of breast cancer,2 and also in RSUP Sanglah Bali,17,18 and RSUP Dr. R.D. Kandau Manado.19 Increasing age is one of the breast cancer risk factors, but peaking age groups in one region to others are different. In Korea, the peaking incidence rate in the 45- 49year age group,3 Japan 50-54year age group,4 the United States 55-59 age group,4 Australia 65-69 age group,20 and in the world 49% 50-69 years age group.21 The menopausal and postmenopausal are prevalent breast cancer patients in some regions but the other premenopausal patients are prevalent. Demographic differences with fewer old women in some regions and lower prevalence of risk factors of postmenopausal cancer are the most likely explanation for the lower mean age at diagnosis in those regions.22 In this study, the left lateralization of the right and left breast cancer was almost the same. In the study in St. Rita Medical Centre Ohio United States (2014), most patients had unilateral breast cancer in, the upper outer quadrant, and left breast side.23 In the study at Affiliated Hospital of Guangdong Medical University China (2018), the left side of breast cancer was the dominant breast side in the≥ 40 year age group and the right side of breast cancer in the < 40 year age group.24 Predominance lateralization on the left breast side could be explained by breast asymmetry in women, as measured on mammography, the left breast was noted to be larger than the right in 55% of healthy women. Breast hypertrophy was reported to be more common on the left side.23 In this study, stage III was the most of breast cancer stage. In a study conducted at RSUP Sanglah Bali (2020), most patients’ stage presentation was stage III (64,06%),17,18 and stage IV (63.6%) in RSUP Dr. RD. Kandau Manado.19 The factors of delay in seeking treatment are caused by lacking breast cancer knowledge, the major cause, cost of treatment, culture and spiritual belief, and seeking complementary and alternative medicine (CAM). 17 In the study conducted at RSUP Prof. Dr. R.D. Kandau Manado (2018) and RSUP Sanglah Bali, the most histopathology type is invasive ductal carcinoma (96% and 84.7%). 18,19 Invasive Ductal J Med Health.2022;4(2):123-30 127 Journal of Medicine and Health Vol. 4 No. 2 August 2022 The Association between The … e-ISSN: 2442-5257 Research Article Carcinoma No Specific Type (IDC NST) constitute 40-75% and invasive lobular carcinoma accounts for 10-15% of all breast cancers. The clinicopathologic presentations of IDC NST usually show a wide scope of morphological variation and clinical behaviors, such as tumor size, grade, the relative proportion of tumor cell and stroma, and types of margins. IDC NST shows heterogeneous growth, including diffuse sheets, nests, cords, or singly distributed cells with a variable amount of ductal differentiation.25 A molecular subtype of breast cancer is a determinant factor for overall survival (OS), favourable molecular subtypes (Luminal A and Luminal B) can expect an OS above 95% and a local recurrent rate of almost 100% above 5 years. On the other hand, the outcome of patients with HER-2/neu and TNBC subtype remains poor.26 In this study hormonal receptor subtypes are predominant. In the study conducted in RSUP Sanglah Bali (2014), Luminal A and TNBC were the most molecular subtype,27 in RSUP Dr. M. Djamil Padang (2016), Luminal B and TNBC were the most molecular subtype,28 In RSUD Madiun (2021), Luminal B is the most molecular subtype than TNBC., Luminal A, and HER-2/neu.29 Systematic Review study by Simbolon and Pohan (2021), molecular the subtype most molecular subtype was Luminal A (57.5%), Luminal B (17.7%), TNBC (14.3%), and Her-2/neu (10.1%). Luminal A subtype presents low histopathologic grade, special histologic type (tubular, mucinous, and lobular), low proliferation index, and low recurrent rate than other subtypes.30 Conclusion Our study concluded that the 51-60 years age group was the most prevalent age group of breast cancer, and incidence declined after 60. Laterality of left breast side of breast cancer found almost the same with right breast side. Most patients presented a high stage of invasive ductal carcinoma. Hormone receptor-positive was the predominant subtype of breast cancer. Hormone receptor-positive subtypes were characteristic of patients ≤ 50 years old, 2.993 more prevalent than > 50 years, while hormone receptor-negative subtypes were characteristic of patients > 50 years old. References 1. 2. 3. 4. Firasi AA, Jkd Y, Yudhanto E. Hubungan usia terhadap derajat diferensiasi kanker payudara pada wanita. Diponegoro Med J (Jurnal Kedokt Diponegoro). 2016;5(4):327–36. Mardiah H, Ginting RNA, Rahmadhany H, Sitorus ERD. Correlation between age and body mass index (BMI) with histopathological features of breast cancer patients in RSUP Haji Adam Malik Medan. Indones J Cancer 2021;15(2):46–53. Park B, Ma SH, Shin A, Chang MC, Choi JY, Kim S, et al. Korean risk assessment model for breast cancer risk prediction. PLoS One. 2013;8(10). Saika K, Sobue T. Epidemiology of breast cancer in Japan and the US Descriptive Epidemiology number of new J Med Health.2022;4(2):123-30 128 Journal of Medicine and Health Vol. 4 No. 2 August 2022 The Association between The … e-ISSN: 2442-5257 Research Article 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. cases and incidence rate of breast cancer Information on cancer morbidity. J Japan Med Assoc. 52(1):657–61. Fitzmaurice C, Abate D, Abbasi N, Abbastabar H, Abd-Allah F, Abdel-Rahman O, et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted lifeyears for 29 cancer groups, 1990 to 2017: A Systematic analysis for the global burden of disease study. JAMA Oncol. 2019;5(12):1749. Iskandarsyah A, de Klerk C, Suardi DR, Soemitro MP, Sadarjoen SS, Passchier J. Psychosocial and cultural reasons for delay in seeking help and nonadherence to treatment in Indonesian women with breast cancer: A qualitative study. Heal Psychol. 2014;33(3):214–21. Susilowati M, Afiyanti Y. The socio-demographic factors correlated with financial toxicity among patients with breast cancer in Indonesia. J Public health Res [Internet]. 2021 [Cited 2022 Apr 20];10(s1). Available from: https://pubmed.ncbi.nlm.nih.gov/34060753/ Coughlin SS, Ayyala DN, Tingen MS, Cortes JE. Financial distress among breast cancer survivors. Curr cancer reports]. 2020;2(1):48–53. Nasional Tempo. BPJS 2016 tanggung perawatan 1,3 juta kasus kanker - [Internet]. [Cited 2022 Apr 20]. Available from: https://nasional.tempo.co/read/841873/2016-bpjs-tanggung-perawatan-13-juta-kasuskanker/full&view=ok Aryandono T, Harijadi, Soeripto. Survival from operable breast cancer: Prognostic factors in Yogyakarta, Indonesia. Asian Pacific J Cancer Prev. 2006;7(3):455–9. Nindrea RD, Aryandono T, Lazuardi L. Breast cancer risk from modifiable and non-modifiable risk factors among women in Southeast Asia: A Meta-Analysis. Asian Pac J Cancer Prev. 2017;18(12):3201–6. Anwar SL, Raharjo CA, Herviastuti R, Dwianingsih EK, Setyoheriyanto D, Avanti WS, et al. Pathological profiles and clinical management challenges of breast cancer emerging in young women in Indonesia: A hospital-based study. BMC Womens Health. 2019;19(1):1–8. Sutandyo Noowati, Kurniawati Sri A., Siregar Nia N. SNK. Three years survival of elderly cancer patients in Indonesia: Do we need a different approach? | Sutandyo | Acta Medica Indonesiana [Internet]. [Cited 2022 Apr 20]. Available from: http://www.actamedindones.org/index.php/ijim/article/view/1150/pdf Sinaga ES, Ahmad RA, Shivalli S, Hutajulu SH. Age at diagnosis predicted survival outcome of female patients with breast cancer at a tertiary hospital in Yogyakarta, Indonesia. [Cited 2022 Apr 20]. Available from: www.panafrican-med-journal.com Hutajulu SH, Prabandari YS, Bintoro BS, Wiranata JA, Widiastuti M, Suryani ND, et al. Delays in the presentation and diagnosis of women with breast cancer in Yogyakarta, Indonesia: A retrospective observational study. PLoS One. 2022;17(1). Fathoni MIA, Gunardi, Adi-Kusumo F, Hutajulu SH, Purwanto I. Characteristics of breast cancer patients at dr. Sardjito Hospital for early anticipation of neutropenia: Cross-sectional study. Ann Med Surg [Internet]. 2022 Jan 1 [cited 2022 Apr 21];73. Available from: https://doi.org/10.1016/j.amsu.2021.103189 Narisuari IDAPM, Manuaba IBTW. Prevalensi dan gambaran karakteristik penderita kanker payudara di poliklinik bedah onkologi RSUP Sanglah, Bali, Indonesia tahun 2016. Intisari Sains Medis. 2020 Mar 24;11(1):183. Diahpradnya Oka Partini P, Niryana IW, Anda Tusta Adiputra P. Karakteristik kanker payudara usia muda di Subbagian Bedah Onkologi Rumah Sakit Umum Pusat Sanglah tahun 2014-2016. Intisari Sains Medis. 2018 Apr 30;9(1). Rondonuwu IA, Haroen H, Wantania FE. Profil kanker payudara RSUP Prof. Dr. R. D. Kandou Manado tahun 2013 – 2014. e-CliniC [Internet]. 2016 [Cited 2022 Apr 21];4(1). Available from: https://ejournal.unsrat.ac.id/index.php/eclinic/article/view/10972 Canberra Health Service, Australian Capital Territories. Focus on breast cancer an overview of breast cancer in the act. 2018 [Cited 2022 Apr 21]; Available from: https://health.act.gov.au/sites/default/files/201909/Focus%20On%20Breast%20Cancer%202018.pdf. World Health Organization (WHO). WHO position paper on mammography screening. 2014 [Cited 2022 Apr 21]; Available from: www.who. Ghiasvand R, Adami HO, Harirchi I, Akrami R, Zendehdel K. Higher incidence of premenopausal breast cancer in less developed countries; myth or truth? BMC Cancer. 2014;14(1):343. Amer MH. Genetic factors and breast cancer laterality. Cancer Manag Res. 2014;6(1):191–203. Cheng SA, Liang LZ, Liang QL, Huang ZY, Peng XX, Hong XC, et al. Breast cancer laterality and molecular subtype likely share a common risk factor. Cancer Manag Res. 2018;10:6549–54. Makki J. Diversity of breast carcinoma: Histological subtypes and clinical relevance. Clin Med Insights Pathol. 2015;8(1):23. Hennigs A, Riedel F, Gondos A, Sinn P, Schirmacher P, Marmé F, et al. Prognosis of breast cancer molecular subtypes in routine clinical care: A large prospective cohort study. BMC Cancer. 2016;16(1). Wiguna NIP, Manuaba IBTW. Karakteristik pemeriksaan imunohistokimia pada pasien kanker payudara di RSUP Sanglah Periode 2003-2012. E-Jurnal Medika Udayana, [S.l.] [Internet], sep. 2014. [Cited 2022 Apr 21]. Available from: . Resti V, Firdaus P, Asri A, Khambri D, Harahap WA. Hubungan grading histopatologi dan infiltrasi limfovaskular dengan subtipe molekuler pada kanker payudara invasif di bagian bedah RSUP. Dr. M. Djamil J Med Health.2022;4(2):123-30 129 Journal of Medicine and Health Vol. 4 No. 2 August 2022 The Association between The … e-ISSN: 2442-5257 Research Article Padang. J Kesehat Andalas. 2016. [Cited 2022 Apr 21];5(1). Available from: http://jurnal.fk.unand.ac.id/index.php/jka/article/view/463 29. Subiyanto D, Ariyati Kadi T, Abdurrahman N, Prasetyo Utomo Y, Reynaldi Alifiansyah A, Ika Fidianingsih dan, et al. Subtipe molekuler kanker payudara di RSUD Madiun dan Hubungannya dengan Grading Histopatologi. Media Penelit dan Pengemb Kesehat. 2021;31(3):193–202. 30. Simbolon YY, Pohan PU. Hubungan infiltrasi limfovaskular dengan subtipe molekuler pasien kanker payudara invasif : telaah sistematis. JIMKI: Jurnal Ilmiah Mahasiswa Kedokteran Indonesia. 2021;9(1): 15-22. J Med Health.2022;4(2):123-30 130