Rencana Strategis Pengembangan Pusat Kanker Nasional Indonesia, Sebuah Studi Kasus

ABSTRAK Kanker merupakan penyakit kronis yang angka kejadiannya terus meningkat di dunia dan menjadi perhatian dalam beberapa dekade belakang ini. Namun, Indonesia belum memiliki Program Pengendalian Kanker Nasional yang komprehensif. Penelitian ini bertujuan untuk menyusun rencana strategis pengembangan Pusat Kanker Nasional yang sesuai dengan kondisi Indonesia. Penelitian dilakukan dengan menggunakan pendekatan operational research selama bulan Maret-Desember 2013 dengan melibatkan berbagai stakeholder dalam Program Pengendalian Kanker di Indonesia. Hasil penelitian menunjukkan bahwa perkembangan penyakit kanker dengan angka kematian akbibat penyakit kanker menduduki urutan ketiga di Indonesia. Pembiayaan untuk penyakit kanker menunjukkan trend yang terus meningkat. Seluruh informan pada penelitian ini menyatakan pentingnya memiliki sebuah lem-baga yang bersifat nasional yang berperan dalam pengendalian kanker secara komprehensif. Lembaga yang paling ideal adalah lembaga non struktural yang untuk mencapainya diperlukan bentuk antara yang disebut Tim Pengem-bangan Pusat Kanker Nasional yang berada dalam wadah yang berkoordinasi dengan Direktur Utama RS Kanker "Dharmais”. Kesimpulan dari penelitian ini adalah pentingya memiliki sebuah lembaga yang bersifat nasional yang berperan dalam pengendalian kanker secara komprehensif. Bentuk lembaga yang paling ideal adalah sebuah Lem-baga Non Struktural. ABSTRACT Cancer is a chronic disease and its prevalence is increasing nowadays. Uptudate, Indonesia doesn’t have a comprehensive program for National Cancer Control. This study aims to develop a strategic plan for the development of National Cancer Center for Indonesia. This study is conducted by using operational research approach, and is conducted during the months of March to December 2013 by involving various stakeholders. In Indonesia, cancer is the third killer disease among the NCD (Non Communicable Disease), the incidence is increasing as well as the funding for cancer treatment. All informants expressed the importance of establishing a national institute that plays a role in cancer control in a comprehensive manner. The most ideal institute is a non structural form and to achieve it, a National Cancer Center Development Team to be formed that coordinates with the Director of Cancer Hospital "Dharmais" which is a top referral center for cancer at this time. In conclusion, it is really important for national institute to take part in a comprehensive cancer control manner. The most ideal form of organization for the above function is a non-structural institution.

Strategy for Diagnosing Breast Cancer in Indonesia during the COVID-19 Pandemic: Switching to Ultrasound-Guided Percutaneous Core Needle Biopsy

In this era of COVID-19, suspected breast cancer patients experience delay in diagnosis due to the fear of contracting the virus and reduction of non-COVID-19 health services. Furthermore, it may lead to potential increase in the incidence of advanced cancers in the future. Ultrasound-guided (US-guided) percutaneous core needle biopsy (CNB) is a great option for the diagnosis of cancer but it is poorly utilized. This study aimed to prove that the US-guided CNBis accurate when performed in a local setting and a potential solution for diagnosing breast cancer patients in this pandemic. In addition, it was a single health center cross-sectional study, and the participants were all breast cancer patients that had US-guided CNB from 2013-2019. The pathology results from US-guided CNB were compared to specimens from post-CNB surgeries. The data were collected from medical records and the immunohistochemistry (IHC) examinations were carried out for malignancy. There were 163 patients who were included in this study, 86 had malignancies and 77 had benign tumor reported in their CNB results. The US-guided CNB had 100% sensitivity and specificity compared to surgery. With its lower cost, time usage, and patient exposure to the hospital environment, US-guided CNB should replace open surgery biopsy for diagnosing suspicious breast cancers during the pandemic in Indonesia

Developing Models to Predict BRAFV600E and RAS Mutational Status in Papillary Thyroid Carcinoma Using Clinicopathological Features and pERK1/2 Immunohistochemistry Expression

The Cancer Genome Atlas (TCGA) has classified papillary thyroid carcinoma (PTC) into indolent RAS-like and aggressive BRAF-like based on its distinct driver gene mutations. This retro- spective study aimed to assess clinicopathology and pERK1/2 expression variations between BRAF- like and RAS-like PTCs and establish predictive models for BRAFV600E and RAS-mutated PTCs. A total of 222 PTCs underwent immunohistochemistry staining to assess pERK1/2 expression and Sanger sequencing to analyze the BRAF and RAS genes. Multivariate logistic regression was em- ployed to develop prediction models. Independent predictors of the BRAFV600E mutation include a nuclear score of 3, the absence of capsules, an aggressive histology subtype, and pERK1/2 levels exceeding 10% (X 2 = 0.128, p > 0.05, AUC = 0.734, p < 0.001). The RAS mutation predictive model includes follicular histology subtype and pERK1/2 expression >10% (X 2 = 0.174, p > 0.05, AUC = 0.8, p < 0.001). We propose using the prediction model concurrently with four potential combination group outcomes. PTC cases included in a combination of the low-BRAFV600E-scoring group and high-RAS-scoring group are categorized as RAS-like (adjOR = 4.857, p = 0.01, 95% CI = 1.470–16.049). PTCs included in a combination of the high-BRAFV600E-scoring group and low-RAS-scoring group are categorized as BRAF-like PTCs (adjOR = 3.091, p = 0.001, 95% CI = 1.594–5.995). The different prediction models indicate variations in biological behavior between BRAF-like and RAS-like PTCs. Keywords: papillary thyroid carcinoma; BRAF-like; RAS-like; BRAFV600E; RAS mutation; prediction mode

Hubungan Ekspresi miR-21 dan miR-200c dengan Respons Terapi Sistemik Neoajuvan Pasien Kanker Payudara Stadium Lanjut

Kegagalan terapi pada kanker payudara stadium lanjut dihubungkan dengan ekspresi mikroRNA antara lain miR-21 dan miR-200c. Untuk mengetahui hubungan respons terapi sistemik neoajuvan serta ekspresi miR-21 dan miR-200c pada pasien kanker payudara, dilakukan studi potong lintang di RS Kanker Dharmais dan RSUPN dr. Cipto Mangunkusumo (RSUPNCM) pada bulan Juli 2015 hingga April 2016. Subjek yang memiliki spesimen jaringan segar dan blok parafin serta telah mendapat pengobatan adekuat, dilakukan pengukuran MiR-21 dan miR-200c dengan qRT-PCR. Hasil dinyatakan sebagai perbedaan cycle thresholds (&Delta;Ct) terhadap U6 snRNA. Ekspresi relatif dihitung sebagai perbedaan dua nilai &Delta;Ct (&Delta;&Delta;Ct) dan fold change (2-&Delta;&Delta;Ct). Sebanyak 31 dari 60 subjek mendapat kemoterapi dan 29 mendapat terapi hormonal. Setelah terapi neoajuvan, hanya 46 orang subjek yang dapat menjalani mastektomi. Respons terapi dinilai dengan kriteria Miller Payne dari sediaan operasi. Sebanyak 23 (50%) subjek tidak respons (Miller Payne grade 1). &Delta;Ct miR21 dan &Delta;Ct miR-200c tidak berbeda bermakna pada subjek yang responsif dan tidak responsif, namun subjek yang tidak responsif memperlihatkan peningkatan ekspresi miR-200c (FC=2,375). Berdasarkan jenis terapi neoajuvan ekspresi miR21 maupun miR-200c lebih tinggi pada kelompok tidak respons dengan kemoterapi, sedang pada pemberian hormonal ekspresi miR-21 lebih rendah dan miR-200c cenderung lebih tinggi. Disimpulkan ekspresi miR-21 dan miR-200c tidak dapat digunakan untuk memprediksi respons terapi.&nbsp;Association of Expression of miR-21, miR-200c and response of Neoadjuvan Systemic Therapy in Patients with Breast Cancer &nbsp;Treatment failure in advanced stage breast cancer has been associated with expression of microRNA e.g. miR-21 and miR-200c. To know the association between response neoadjuvant systemic therapy and the expressions of miR-21 and miR-200c in breast cancer patient, a cross-sectional study has been conducted in Dharmais Cancer Hospital and dr. Cipto Mangunkusumo Hospital National (CMHN) from July 2015 to April 2016. Patients had fresh and paraffin-embedded tissues from biopsy specimens and have been treated adequately. MiR-21 and miR-200c were measured using qRT-PCR on fresh tissues. Results were expressed as cycle thresholds difference (&Delta;Ct) against U6 snRNA. Relative expression was calculated as difference of two &Delta;Ct values (&Delta;&Delta;Ct) and fold change (2-&Delta;&Delta;Ct). Treatment response was evaluated histopathologically using Miller-Payne criteria on mastectomy specimens. A total of 60 patients were enrolled, 31 had chemotherapy and 29 had hormonal therapy. After treatment, only 46 patients were eligible for mastectomy. Twenty-three (50%) patients showed no response (Miller-Payne grade 1) after treatment. &Delta;Ct miR-21 and &Delta;Ct miR-200c were not significantly different between responsive and not responsive patients. However, patients with no response showed increased expression of miR-200c (FC=2.375). Based on type of neoadjuvant , in chemotherapy group expression of miR-21 and miR-200c were high(FC=3.67 and 6.16 respectively) but in hormonal group expression miR-21 FC=0.11 and miR-200c FC=1.25). In conclusion, expressions of miR-21 and miR-200c cannot be used to predict treatment response

Immunoinformatics Approach for Epitope-Based Vaccine Design: Key Steps for Breast Cancer Vaccine

Vaccines are an upcoming medical intervention for breast cancer. By targeting the tumor antigen, cancer vaccines can be designed to train the immune system to recognize tumor cells. Therefore, along with technological advances, the vaccine design process is now starting to be carried out with more rational methods such as designing epitope-based peptide vaccines using immunoinformatics methods. Immunoinformatics methods can assist vaccine design in terms of antigenicity and safety. Common protocols used to design epitope-based peptide vaccines include tumor antigen identification, protein structure analysis, T cell epitope prediction, epitope characterization, and evaluation of protein&ndash;epitope interactions. Tumor antigen can be divided into two types: tumor associated antigen and tumor specific antigen. We will discuss the identification of tumor antigens using high-throughput technologies. Protein structure analysis comprises the physiochemical, hydrochemical, and antigenicity of the protein. T cell epitope prediction models are widely available with various prediction parameters as well as filtering tools for the prediction results. Epitope characterization such as allergenicity and toxicity can be done in silico as well using allergenicity and toxicity predictors. Evaluation of protein&ndash;epitope interactions can also be carried out in silico with molecular simulation. We will also discuss current and future developments of breast cancer vaccines using an immunoinformatics approach. Finally, although prediction models have high accuracy, the opposite can happen after being tested in vitro and in vivo. Therefore, further studies are needed to ensure the effectiveness of the vaccine to be developed. Although epitope-based peptide vaccines have the disadvantage of low immunogenicity, the addition of adjuvants can be a solution

ALDH1 Cancer Stem Cell Marker as a Prognostic Factor in Triple-Negative Breast Cancer

Breast cancer is the most common cancer with an increasing incidence in Asia. About 20% of all breast cancers are triple-negative breast cancers (TNBCs). BCSC is a subset of tumor cells that has stem cell-like characteristics, such as a high capacity for self-renewal and tumor initiation, which implies that BCSC may cause aggressiveness of TNBC. ALDH1 has a role in early stem cell differentiation through its function in the oxidation of retinol to retinoic acid, proposed to be a strong candidate for breast cancer stem cells. Various studies have shown that ALDH1 is one of the markers of CSC that can be used as a prognosis indicator because it can be a biological marker for poor prognostic factors in TNBC. This study assessed the prognostic survival rate with a retrospective cohort method in TNBC patients. A total of 54 of 55 patients treated at RSCM were tested for the expression of ALDH1 through an immunohistochemistry assay of breast cancer tissue using ALDH1 staining. Survival analysis was done to obtain the prognostic data of ALDH1. Positive ALDH1 expression was obtained at 38.89% in TNBC patients. One-year survival and three years of survival in TNBC patients with positive ALDH1 expression were 42.9% and 33.3%, respectively. In this study, ALDH1 can be used as a poor survival prognostic factor with HR 2.636 and p value 0.013. The conclusion of this study is that ALDH1 can be used as a poor prognostic factor in TNBC patients although it cannot be an independent prognostic factor

Amino Acid Profile of Luminal A and B Subtypes Breast Cancer

BACKGROUND: Amino acids are important for proliferation and maintenance of tumor cells. Breast cancer patients were found to have significant changes in the number of amino acids, which are assumed to be correlated with the molecular subtypes of breast cancer. Therefore, current study was conducted to analyze plasma amino acids in breast cancer patients with luminal A and B subtypes.METHODS: Breast cancer and control subjects were recruited, and venous blood was collected for the measurement of plasma amino acids. Total 19 plasma amino acids were measured using reverse-phase high-performance liquid chromatography with C18 column. Mean comparison for normally distributed and homogeneous data was further analzyed using independent sample T-test, with p<0.05 was considered as significant.RESULTS: From total 19 amino acids, only 7 amino acids; cysteine, glutamic acid, histidine, ornithine, threonine, tyrosine, valine, were statistically different between the healthy control and breast cancer subjects. Eventhough no amino acids was found to be statistically different between breast cancer subjects with luminal A and B subtypes, but some amino acids were found to be significantly different when correlated to various breast cancer risk factors.CONCLUSION: Amino acid profile of patients with Luminal A and B subtypes of breast cancer differs compared to healthy controls and is also correlated with breast cancer risk factors. Increase in cysteine level in Luminal A subtype patients and decrease of alanine and leucine in Luminal B subtype patients can be used as a biomarker.KEYWORDS: amino acid, plasma, breast cancer, risk factor, biomarke

Total and Intratumoral CD8+ T Cell Expressions are Correlated with Miller Payne Grading and WHO Clinical Response of Neoadjuvant Chemotherapy

BACKGROUND: Chemotherapy has reported to stimulate immune system through direct activation of cluster of differentiation (CD)8+ T cells. Neoadjuvant chemotherapy (NAC) is known to improve the clinical response of locally advanced breast cancer (LABC) patients. However, the immune response-related factor evaluation of NAC in LABC patients has not been routinely performed. Therefore, current study was conducted to evaluate the correlation of NAC-induced CD8+ T cell with chemotherapy response based on Miller Payne grading and World Health Organization (WHO) criteria.METHODS: LABC patients were recruited and data regarding age, gender, tumor, nodal stages, histopathological grade, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and Ki67 were obtained. Biopsy and mastectomy tissues were collected and processed for hematoxylin-eosin and CD8 immunohistochemical staining. CD8+ T cell expression in peritumoral and intratumoral areas were documented and measured. Clinical responses based on Miller Payne grading and WHO were analyzed and correlated with CD8+ T cell expression.RESULTS: There were more subjects with high expression of total (80%), intratumoral (82.5%) and peritumoral (65%) CD8+ T cell expressions. The total (p=0.013) and intratumoral (p=0.015) CD8+ T cell expression, but not peritumoral CD8+ T cell expression, were significantly correlated with Miller Payne Grading. The total (p=0.009) and intratumoral (p=0.001) CD8+ T cell expressions were also significantly correlated with WHO clinical response.CONCLUSION: Total and intratumoral CD8+ T cell expressions are correlated with Miller Payne grading and WHO clinical response of NAC. Therefore, total and intratumoral CD8+ T cell expressions could be suggested as a predictive marker for clinical response of NAC.KEYWORDS: breast cancer, neoadjuvant chemotherapy, CD8, clinical response, Miller Payne, intratumoral, peritumoral

The Association of Immune Cell Infiltration with Metastasis Location in De Novo Metastatic Triple Negative Breast Cancer: A Multicenter Cross-Sectional Study in Indonesia

Background: Triple-negative breast cancer (TNBC) is an aggressive cancer subtype, with limited treatments and a high metastasis risk. The varying location of metastasis in TNBC patients often leads to in prognosis in breast cancer. Therefore, this study aimed to investigate the potential association between immune cells profiles in the tumor microenvironment and metastatic patterns. Methods: We conducted a multicenter cross-sectional study in 2022 to examine formalin-fixed paraffin-embedded (FFPE) and medical record data from 2015 to 2020 in de novo metastatic TNBC patients. The medical records provided crucial information about the sites of metastasis. Immunohistochemistry (IHC) analysis was carried out on primary breast tumor tissues to evaluate the expressions of cluster of differentiation (CD)4 T-cells, CD8 T-cells, CD163, FOXP3 Tregs, and programmed death-ligand 1 (PD-L1), along with immune cells ratios showing antitumor-to-protumor activity (CD4/FOXP3, CD8/FOXP3, CD4/CD163, CD8/CD163). Metastatic locations were grouped into bone-only, visceral, lung, liver, and brain metastasis.  Results: A total of 120 metastatic TNBC patients were documented for their metastatic location and IHC report. The clinical and histopathological characteristics showed that the majority of the patients were within the 40-65 years old group, and 34.2% had standard body mass index (BMI). Furthermore, the majority (89.22%) of the patients showed No Special Type (NST), (56.7%) had histopathology grade III, high Ki-67 ≥20% (85.8%), and positive PD-L1 expression (30.8%), with visceral metastasis indicating the highest proportion of 75.8%. Patients with a high CD8/FOXP3 and CD4/FOXP3 ratio were significantly prone to have bone-only metastasis compared to visceral metastasis (p= 0.028 and p=0.024, respectively).  Conclusion: The ratio of antitumor to protumor T-lymphocytes had a significant relevance in the metastatic location patterns in TNBC