下午長庚閻紫宸 OI-03 MR/PET in Oncology Imaging
INTEGRATING IMAGING DATA WITH INFORMATION FROM GENOMICS IN ONCOLOGY
Tzu-Chen Yen Molecular Imaging Center, Chang Gung Memorial Hospital and University, Taiwan
As a physician and researcher in medical imaging, we have been fascinated by the rapid and dramatic improvement of imaging capabilities over the past decade. Meanwhile, we have also witnessed an explosive development of the ‘omics’ technologies – genomics, proteomics, metabolomics, etc. over the years. Now that we are living in the “-omics” era, it has become an emergent need to integrate imaging data with the “-omics” data. More importantly, role of imaging should be defined in such integration by identifying its advantages. With such integration, we see a person truly as whole – macroscopically and microscopically. However, such integration is challenging. A few groups have been working on this emergent topic so far, but not too many yet. We initiated our work since 2007 with the start-up project of head and neck cancers for at least two reasons. First, head and neck cancers are important cancers in Taiwan because it is the top ranking cancer in male between 30-60 years old in Taiwan. Second, the treatment regimens for head and neck cancers in our hospital will follow a fixed protocol and most of them will have a radical surgery. Therefore, we may have a chance to study the “-omics” from their bio- and tissue specimens. We hope that through this start-up study, we can achieve a few goals: (1) Promoting the importance of imaging/omics data integration; (2) Letting people know this is feasible as well as what are the state of the arts; (3) Facilitating the interdisciplinary collaboration between different groups for pooling data together and (4) Stimulating the technological developments for such endeavors. Herein, I wish to share with you some of our preliminary data.
INTEGRATING IMAGING DATA WITH INFORMATION FROM GENOMICS IN ONCOLOGY
Tzu-Chen Yen Molecular Imaging Center, Chang Gung Memorial Hospital and University, Taiwan
As a physician and researcher in medical imaging, we have been fascinated by the rapid and dramatic improvement of imaging capabilities over the past decade. Meanwhile, we have also witnessed an explosive development of the ‘omics’ technologies – genomics, proteomics, metabolomics, etc. over the years. Now that we are living in the “-omics” era, it has become an emergent need to integrate imaging data with the “-omics” data. More importantly, role of imaging should be defined in such integration by identifying its advantages. With such integration, we see a person truly as whole – macroscopically and microscopically. However, such integration is challenging. A few groups have been working on this emergent topic so far, but not too many yet. We initiated our work since 2007 with the start-up project of head and neck cancers for at least two reasons. First, head and neck cancers are important cancers in Taiwan because it is the top ranking cancer in male between 30-60 years old in Taiwan. Second, the treatment regimens for head and neck cancers in our hospital will follow a fixed protocol and most of them will have a radical surgery. Therefore, we may have a chance to study the “-omics” from their bio- and tissue specimens. We hope that through this start-up study, we can achieve a few goals: (1) Promoting the importance of imaging/omics data integration; (2) Letting people know this is feasible as well as what are the state of the arts; (3) Facilitating the interdisciplinary collaboration between different groups for pooling data together and (4) Stimulating the technological developments for such endeavors. Herein, I wish to share with you some of our preliminary data.
傍晚院長的Keynote speech:
METABOLISM AND CANCER THERAPEUTICS: TARGETING ARGININE ADDICTION OF CANCERS
Hsing-Jien Kung National Health Research Institutes, Taiwan
There is considerable evidence that tumor and normal cells differ in their metabolic requirements. The most prominent examples are the addiction of tumor cells to glucose (i.e., Warburg effect) and to glutamine. Therapeutics based on selective targeting of these metabolic pathways is under intensive investigations. Recently, we reported that irrespective of androgen receptor status, prostate cancer cells selectively and epigenetically suppress the expression of ASS (arginine succinosythethase), a rate-limiting enzyme for intracellular arginine synthesis. Analysis of over 100 PC specimens showed the complete absence of ASS expression, whereas some normal prostate epitheial cells express ASS. As a result, PC cells, but not normal counterparts become “auxotroph” for and addicted to external arginine. Thus, arginine-deprivation should selectively “starve” the PC cells to death. Indeed, in recent publications, we showed that depletion of external arginine by arginine deiminase (ADI) effectively induces cell death of CRPC cell lines, but not normal prostate epithelial cells in vitro and in vivo. In addition, we reported that ADI synergizes with Taxol in preclinical xenograft model. Based on this finding, a phaseI/II clinical trial is underway at UCD. Intriguingly, we found that ADI killing of cancer cells is associated with aggressive autophagy and appears to be caspase independent. At early phase, autophagy is protective and prolongs the survival of treated cells. Using high-resolution, live imaging, molecular and genetic profiling, we have now characterized in details the arginine-deprived cells undergoing apoptosis. The starved cells showed significant epigenetic reprogramming, excessive autophagy and most remarkably, nuclear rupture. The possible mechanism(s) and its implication will be discussed.
Hsing-Jien Kung National Health Research Institutes, Taiwan
There is considerable evidence that tumor and normal cells differ in their metabolic requirements. The most prominent examples are the addiction of tumor cells to glucose (i.e., Warburg effect) and to glutamine. Therapeutics based on selective targeting of these metabolic pathways is under intensive investigations. Recently, we reported that irrespective of androgen receptor status, prostate cancer cells selectively and epigenetically suppress the expression of ASS (arginine succinosythethase), a rate-limiting enzyme for intracellular arginine synthesis. Analysis of over 100 PC specimens showed the complete absence of ASS expression, whereas some normal prostate epitheial cells express ASS. As a result, PC cells, but not normal counterparts become “auxotroph” for and addicted to external arginine. Thus, arginine-deprivation should selectively “starve” the PC cells to death. Indeed, in recent publications, we showed that depletion of external arginine by arginine deiminase (ADI) effectively induces cell death of CRPC cell lines, but not normal prostate epithelial cells in vitro and in vivo. In addition, we reported that ADI synergizes with Taxol in preclinical xenograft model. Based on this finding, a phaseI/II clinical trial is underway at UCD. Intriguingly, we found that ADI killing of cancer cells is associated with aggressive autophagy and appears to be caspase independent. At early phase, autophagy is protective and prolongs the survival of treated cells. Using high-resolution, live imaging, molecular and genetic profiling, we have now characterized in details the arginine-deprived cells undergoing apoptosis. The starved cells showed significant epigenetic reprogramming, excessive autophagy and most remarkably, nuclear rupture. The possible mechanism(s) and its implication will be discussed.
Day 2, May 3 (Saturday)
Morning Section:
Mario Sznol Yale Cancer Center, Yale-New Haven Hospital Smilow Cancer Hospital, USA
ANTAGONISTS OF PD-1-L1 IMMUNE CHECKPOINT PATHWAY FOR CANCER TREATMENT (這是去年AACR 非常夯的題目)
Programmed death-1 (PD-1) is an immune co-inhibitory receptor induced by lymphocyte activation. PD-1 binds to two known ligands, PD-L1 (B7-H1) and PD-L2 (B7-DC). PD-L1 can also suppress immune function by binding to B7.1 (CD80). PD-L1 expression on tumor cells and on other components of the tumor microenvironment can be induced by cytokines, particularly type 2 interferons, and therefore the PD-1/PD-L1 pathway serves as an adaptive mechanism to downmodulate tissue inflammation. Antagonists of PD-1 or PD-L1 increase cytokine production in human mixed lymphocyte cultures and demonstrate anti-tumor activity in some animal tumor models. Several antibodies blocking PD-1 (nivolumab, MK-3475) or PD-L1 (MDX-1105, MPDL3280A, and MEDI-4736) are currently in clinical development. In metastatic melanoma progressing after at least one systemic treatment, the longest follow up was reported for nivolumab; overall objective response rate was 31%, median duration of response was 2 years, and median survival was 16.8 months. Both nivolumab and MK-3475 demonstrated activity in patients whose disease was progressing after prior ipilimumab (anti-CTLA-4). In metastatic RCC, objective response rates for the various agents ranged from 13-29%. In pre-treated patients with NSCLC, nivolumab produced a 17% objective response rate; the median duration of response was 17 months, and median survival was 9.9 months. Similar rates of activity in NSCLC were reported for MK-3475 and MPDL3280. A small subset of patients across diseases experienced prolonged stable disease and unconventional immune related tumor responses which may be associated with clinical benefit. In the phase 1 trials, objective responses were also observed in patients with metastatic colorectal cancer, ovarian cancer, gastric cancer, and head and neck cancer. Blockade of the PD-1/PD-L1 pathway produced a lower incidence and less severe immune inflammatory events compared to literature data from anti-CTLA-4 trials, with the exception of a low rate of severe pneumonitis observed in the large phase 1-2 trial of nivolumab. Anti-PD-1 and anti-PD-L1 are being combined with multiple other agents including other checkpoint inhibitors, costimulatory agonists, cytokines, vaccines, targeted agents, anti-angiogenesis agents, chemotherapy and radiation therapy. In a phase 1 trial for patients with metastatic melanoma, ipilimumab 3 mg/kg was combined with nivolumab (0.3, 1, and 3 mg/kg), q3w x 4, followed by nivolumab q3w x 4, followed by the combination q12w. One additional cohort received ipilimumab 1 mg/kg with nivolumab 3 mg/kg. Among 52 evaluable patients across all 4 dose cohorts, the overall objective response rate was 40%; activity appeared greater with nivolumab doses of at least 1 mg/kg q3w during the combination induction period. Thirty-one percent of all patients achieved at least 80% reduction in WHO tumor measurements, suggesting superior activity for the combination compared to historical data for either single agent. Estimated one year survival for the entire 52-patient cohort was 82%. The incidence of grade 3-4 inflammatory events was > 50%; however, the spectrum of adverse events was similar to ipilimumab and the events were manageable using standard algorithms established for ipilimumab trials. In addition to a phase 3 study in melanoma, the combination of ipilimumab/nivolumab is being evaluated in several advanced malignancies. Clinical data to date have established PD-1/PD-L1 antagonists as the foundation for effective anti-cancer immunotherapy in various advanced malignancies; future development will be prioritized towards combinations which address other mechanisms of immune suppression within the tumor microenvironment, or increase infiltration of tumor antigen-specific T cells into non-inflamed tumors.
Programmed death-1 (PD-1) is an immune co-inhibitory receptor induced by lymphocyte activation. PD-1 binds to two known ligands, PD-L1 (B7-H1) and PD-L2 (B7-DC). PD-L1 can also suppress immune function by binding to B7.1 (CD80). PD-L1 expression on tumor cells and on other components of the tumor microenvironment can be induced by cytokines, particularly type 2 interferons, and therefore the PD-1/PD-L1 pathway serves as an adaptive mechanism to downmodulate tissue inflammation. Antagonists of PD-1 or PD-L1 increase cytokine production in human mixed lymphocyte cultures and demonstrate anti-tumor activity in some animal tumor models. Several antibodies blocking PD-1 (nivolumab, MK-3475) or PD-L1 (MDX-1105, MPDL3280A, and MEDI-4736) are currently in clinical development. In metastatic melanoma progressing after at least one systemic treatment, the longest follow up was reported for nivolumab; overall objective response rate was 31%, median duration of response was 2 years, and median survival was 16.8 months. Both nivolumab and MK-3475 demonstrated activity in patients whose disease was progressing after prior ipilimumab (anti-CTLA-4). In metastatic RCC, objective response rates for the various agents ranged from 13-29%. In pre-treated patients with NSCLC, nivolumab produced a 17% objective response rate; the median duration of response was 17 months, and median survival was 9.9 months. Similar rates of activity in NSCLC were reported for MK-3475 and MPDL3280. A small subset of patients across diseases experienced prolonged stable disease and unconventional immune related tumor responses which may be associated with clinical benefit. In the phase 1 trials, objective responses were also observed in patients with metastatic colorectal cancer, ovarian cancer, gastric cancer, and head and neck cancer. Blockade of the PD-1/PD-L1 pathway produced a lower incidence and less severe immune inflammatory events compared to literature data from anti-CTLA-4 trials, with the exception of a low rate of severe pneumonitis observed in the large phase 1-2 trial of nivolumab. Anti-PD-1 and anti-PD-L1 are being combined with multiple other agents including other checkpoint inhibitors, costimulatory agonists, cytokines, vaccines, targeted agents, anti-angiogenesis agents, chemotherapy and radiation therapy. In a phase 1 trial for patients with metastatic melanoma, ipilimumab 3 mg/kg was combined with nivolumab (0.3, 1, and 3 mg/kg), q3w x 4, followed by nivolumab q3w x 4, followed by the combination q12w. One additional cohort received ipilimumab 1 mg/kg with nivolumab 3 mg/kg. Among 52 evaluable patients across all 4 dose cohorts, the overall objective response rate was 40%; activity appeared greater with nivolumab doses of at least 1 mg/kg q3w during the combination induction period. Thirty-one percent of all patients achieved at least 80% reduction in WHO tumor measurements, suggesting superior activity for the combination compared to historical data for either single agent. Estimated one year survival for the entire 52-patient cohort was 82%. The incidence of grade 3-4 inflammatory events was > 50%; however, the spectrum of adverse events was similar to ipilimumab and the events were manageable using standard algorithms established for ipilimumab trials. In addition to a phase 3 study in melanoma, the combination of ipilimumab/nivolumab is being evaluated in several advanced malignancies. Clinical data to date have established PD-1/PD-L1 antagonists as the foundation for effective anti-cancer immunotherapy in various advanced malignancies; future development will be prioritized towards combinations which address other mechanisms of immune suppression within the tumor microenvironment, or increase infiltration of tumor antigen-specific T cells into non-inflamed tumors.
Frank Kuo (台大醫學系畢業生、與下一個speaker是同班同學) Pathology Informatics, Department Of Pathology, Brigham and Women’s Hospital, USA
IMPLEMENTING COMPREHENSIVE TUMOR GENOTYPING IN ACADEMIC MEDICAL CENTERS-EXPERIENCE AT DANA FARBER/BRIGHAM AND WOMEN’S CANCER CENTER
Tumors are caused by the cumulative effects of multiple genetic alterations. Comprehensive genotyping of tumor samples will allow us to gain insight into the alterations that drive tumor formation and identify potential therapeutic targets. At Dana Farber/Brigham and Women’s Cancer Center (DF/BWCC) in Boston, we initiated a collaborative project called “Profile” in 2010 to develop and implement a comprehensive tumor genotyping assay to offer to all cancer patients of DF/BWCC. The first version of the Profile test “OncoMap” was launched in September 2011 as a research study. Between September of 2011 and July 2013, we performed OncoMap testing for over 5,000 patients who have consented to participate in the study. OncoMap is based on Mass Spectrometry and interrogates 471 mutation “hotspots” in 41 genes. In July 2013, the second version of Profile test “OncoPanel” was launched. OncoPanel uses Nextgeneration Sequencing (NGS) technology and sequences the entire coding regions of 270 genes as well as selected intronic sequences of 20 genes. From these data, single nucleotide variations (SNV), small insertion/deletions (Indel), large insertion/deletions, chromosomal rearrangements involving the selected introns, and copy number variations (CNV) can be identified and reported. Since its inception, we have completed and reported over 2,000 OncoPanel tests for patients with all tumor types. We identified clinically significant variations in ~20% of the samples that are instructive in therapeutic decisions. Another ~30% of samples have findings that allow enrollment into clinical trials. About 20% of the samples have findings that provide prognostic information. Less than 10% of the samples failed testing. Thus far, Profile tests are paid by the generous donations of philanthropists with no cost to patients. Currently, because OncoMap and OncoPanel are offered as research tests, their reports are not available in electronic medical record (EMR) system and are viewed through a password-controlled, dedicated result viewer. Transition of OncoPanel from a research test to a clinical test is under way to incorporate OncoPanel report into EMR. Despite the overwhelming benefit of targeted-therapy and academic interest, the decision for academic medical centers to develop its own capacity to perform comprehensive tumor genotyping testing is not an easy one. There are several important factors to consider. First, there is significant hardware (sequencing machines and other laboratory equipment) and IT infrastructure (storage, computing power and database) investment involved. Second, recruiting and training laboratory personnel to manage large data set and perform data analysis is needed. Third, molecular pathologists and other professional staff need education and training to interpret, report and understand complex tumor genotyping results. Our experience shows that in addition to institutional commitment and capital investment, a close collaboration among pathologists, oncologists, surgeons, geneticists, bioinformaticists and biomedical researchers is the best way to ensure a comprehensive, successful tumor genotyping effort.
Ming-Tseh Lin (林敏哲醫師)Molecular Diagnostic Lab, Department of Pathology, Johns Hopkins Hospital, USA
MOLECULAR PATHOLOGY TO GUIDE CANCER TREATMENT, EXPERIENCE FROM JOHN HOPKINS
UNIVERSITY
UNIVERSITY
Most cancers are driven by genomic alterations that dysregulate key oncogenic pathways. Over the past few years, the convergence of discovery, technology and therapeutic development has created the opportunity to test the hypothesis of genomics driven cancer medicine: knowledge of genomic information from individual cancers can improve clinical outcome by targeting the druggable genomic alterations. To select targeted therapy, cancer patients must undergo stratification based on their individual tumor genomic alterations. A variety of technologies have been developed to detect different categories of mutations. The advent of massively parallel sequencing or next generation sequencing (NGS) technology has revolutionized genome discovery. NGS will eventually be the most cost-effective sequencing platform for clinical diagnostic laboratories. The recent advance of NGS technologies and the rapid expansion of targeted agents had also changed our approached in molecular diagnostics laboratories. We are currently moving from the traditional single gene test to the multiplex platform assay to test a group of targeted genes for a specific tumor type. In the future, the prospect is to use NGS to allow detection of a more comprehensive spectrum of genomic alterations. In January 2013, we validated the KRAS, BRAF and EGFR genes within the Ion AmpliSeq Cancer Hotspot Panel using the Ion Torrent Personal Genome Machine™. We developed a statistical model to determine the read depth needed for a given percent tumor cellularity and number of functional genomes. By using 16 formalin-fixed paraffinembedded (FFPE) cancer-free specimens and 118 cancer specimens with known mutation status, we validated the 6 traditional analytic performance characteristics (accuracy, recision, analytic sensitivity, analytic specificity, reportable range and reference ranges) recommended by the Next-generation Sequencing: Standardization of Clinical Testing Working-group. Baseline noise is consistent with spontaneous and FFPE induced C:G → T:A deamination mutations. In April 2014, we expanded the validation process to include the lung cancer panel (AKT, BRAF, EGFR, ERBB4, KRAS, NRAS and PIK3CA), colorectal cancer panel (BRAF, KRAS, NRAS and PIK3CA), melanoma panel (BRAF, KIT, NRAS and PIK3CA) and gastrointestinal stromal tumor panel (KIT and PDGFRA). Between January 2013 and March 2014, approximately 450 specimens with lung cancer, 250 specimens with colorectal cancer and 80 specimens with melanoma have been tested using NGS platform in our CLIA-certified molecular diagnostics laboratory. Recently, we also validate the whole panel. We conclude that redundant bioinformatic pipelines are essential for clinical molecular diagnosis, as a single analysis pipeline gives false negative and false positive results. NGS is sufficiently robust for clinical detection of gene mutations, with attention to potential artifacts.
Afternoon Section:
REGIONAL CHALLENGES IN HORMONAL RECEPTOR POSITIVE ADVANCED BREAST CANCER AND REALWORLD EXPERIENCE OF PATIENT MANAGEMENT IN TAIWAN
Ching-Hung Lin
Division of Oncology, National Taiwan University Hospital, Taiwan
Ching-Hung Lin
Division of Oncology, National Taiwan University Hospital, Taiwan
RECENT ADVANCE IN THE MANAGEMENT OF BREAST CANCER WITH BRAIN METASTASES
Yen Shen Lu
Department of Internal Medicine, National Taiwan University College of Medicine, Taiwan
Yen Shen Lu
Department of Internal Medicine, National Taiwan University College of Medicine, Taiwan
PROGNOSTIC FACTORS IN EPSTEIN-BARR VIRUSASSOCIATED STAGE I-III GASTRIC CARCINOMA: A
SINGLE-INSTITUTE EXPERIENCE
Shih-Chiang HUANG1, Kwai-Fong NG1, Kuang-Hua CHEN1, Ta-Sen YEH2*,
Tse-Ching CHEN1
1 Department Of Pathology, Chang Gung Memorial Hospital, Taiwan
2 Department Of Surgery, Chang Gung Memorial Hospital, Taiwan
SINGLE-INSTITUTE EXPERIENCE
Shih-Chiang HUANG1, Kwai-Fong NG1, Kuang-Hua CHEN1, Ta-Sen YEH2*,
Tse-Ching CHEN1
1 Department Of Pathology, Chang Gung Memorial Hospital, Taiwan
2 Department Of Surgery, Chang Gung Memorial Hospital, Taiwan
CURRENT CONTROVERSIES IN THER MANAGEMENT OF LOCALLY ADVANCED PANCREATIC ADENOCARCINOMA
Hui-Ju Ch’ang (常慧如醫師)
National Institute of Cancer Research, National Health Research Institute, Taiwan
Hui-Ju Ch’ang (常慧如醫師)
National Institute of Cancer Research, National Health Research Institute, Taiwan
CO-EXPRESSION OF CANCER STEM CELLS AND TUMOR ASSOCIATED MACROPHAGES IS A PREDICTOR OF SURVIVAL IN PANCREATIC DUCTAL ADENOCARCINOMA
Yan-Shen SHAN1 (沈延盛醫師),2*,Ying-Jui CHAO1.2, Ya-Chin HOU3, Hao-Chen WANG3, Hui-
Ling TUNG1.2
1 Department Of Surgery, National Cheng Kung University Hospital,Taiwan,
2 Institute Of Clinical Medicine, College Of Medicine, National Cheng Kung University, Taiwan
3 Institute Of Basic Medical Sciences, College Of Medicine, National Cheng Kung University,Taiwan,
Yan-Shen SHAN1 (沈延盛醫師),2*,Ying-Jui CHAO1.2, Ya-Chin HOU3, Hao-Chen WANG3, Hui-
Ling TUNG1.2
1 Department Of Surgery, National Cheng Kung University Hospital,Taiwan,
2 Institute Of Clinical Medicine, College Of Medicine, National Cheng Kung University, Taiwan
3 Institute Of Basic Medical Sciences, College Of Medicine, National Cheng Kung University,Taiwan,
COMPARISION OF SERUM BIOMARKER CYFRA 21-1 AND CA19-9 IN BILIARY MALIGNANCY
Bikal GHIMIRE1, Yogendra SINGH1
1 Department of Surgery, Maharajgung Medical Campus, Institute of Medicine, Tribhuvan University
Teaching Hospital, Nepal
Bikal GHIMIRE1, Yogendra SINGH1
1 Department of Surgery, Maharajgung Medical Campus, Institute of Medicine, Tribhuvan University
Teaching Hospital, Nepal
TUMOR BIOLOGY OF BREAST CANCER IN NEPALESE YOUNG WONEN
Yogendra SINGH1*, Gita SAYAMI2, Prakash SAYAMI1 (on p.235)
1 Department Of Surgery, Tribhuvan University Teaching Hospital, Nepal
2 Department Of Pathology, Tribhuvan University Teaching Hospital, Nepal
Yogendra SINGH1*, Gita SAYAMI2, Prakash SAYAMI1 (on p.235)
1 Department Of Surgery, Tribhuvan University Teaching Hospital, Nepal
2 Department Of Pathology, Tribhuvan University Teaching Hospital, Nepal
Purpose: Breast carcinomas in <40 2007="" 2007to="" 2013.="" advanced="" age="" aggressive="" aim="" among="" analysis="" and="" are="" at="" biological="" biology.="" breast="" cancer="" center.="" clinico-pathological="" div="" done="" er="" evaluate="" features="" for="" from="" group="" her2="" ignored="" immunohistochemical="" nbsp="" of="" our="" pr="" present="" since="" stage="" study="" the="" this="" to="" tumor="" usually="" was="" with="" women="" years="" young="">
Materials and Methods: Retrospective analysis of 87 breast cancer patients below the age of 40 years out of the total 335 patients (26%) over a period of 7 years was carried out at the Department of Surgery, Tribhuvan University Teaching Hospital, Kathmandu, Nepal.
Results: The average age of young patients was 34.5±6.2 years. The youngest patient was 22-year old female. The majority of the patients (90%) with a painless breast lump presented to the hospital quite late (mean 7.6±6.5 months). These patients had experienced menarche 1 year earlier (13.5±1.4 years) than the older age group. Three of the young patients had a positive history of breast carcinoma in the family. Mammography was performed less frequently in younger patients (60%) with a diagnostic benefit in only 19%. At diagnosis, the mean tumor diameter was 5±2.5 vs 4.5±2.4 cm. Three quarters of the patients had axillary lymph node metastasis. The proportion of stage III or IV disease was higher in younger patients (55%). Infiltrating ductal carcinoma was the commonest histological type (90.8%) and 56.3% of the tumors were grade 2 or 3 tumors. Lymphatic and vascular invasion was more common (63.2% and 40.2%) in younger women. Lower estrogen and/or progesterone receptor expression (34.5%) was seen in younger women. The proportion of triple negative tumors in younger age group was higher (23% vs 12.9%).
Results: The average age of young patients was 34.5±6.2 years. The youngest patient was 22-year old female. The majority of the patients (90%) with a painless breast lump presented to the hospital quite late (mean 7.6±6.5 months). These patients had experienced menarche 1 year earlier (13.5±1.4 years) than the older age group. Three of the young patients had a positive history of breast carcinoma in the family. Mammography was performed less frequently in younger patients (60%) with a diagnostic benefit in only 19%. At diagnosis, the mean tumor diameter was 5±2.5 vs 4.5±2.4 cm. Three quarters of the patients had axillary lymph node metastasis. The proportion of stage III or IV disease was higher in younger patients (55%). Infiltrating ductal carcinoma was the commonest histological type (90.8%) and 56.3% of the tumors were grade 2 or 3 tumors. Lymphatic and vascular invasion was more common (63.2% and 40.2%) in younger women. Lower estrogen and/or progesterone receptor expression (34.5%) was seen in younger women. The proportion of triple negative tumors in younger age group was higher (23% vs 12.9%).
Conclusion: Breast cancer in young Nepalese women represents over one quarter of all female breast cancers, many being diagnosed at an advanced stage. Tumors in young women exhibit more aggressive biological features. Hence, breast cancer in young women is worth special attention for earlier detection. Keyword: Breast carcinoma, Tumor biology, Young women
Day 3, May 4 (Sunday)
早上Head and Neck section
SHIFTING PARADIGMS OF ORAL CANCERS
AK D’Cruz Department of Head & Neck Services, Taka Memorial Hospital, India
Oral carcinoma is a global disease with a higher prevalence in the Asian region due to the peculiar habit of tobacco and areca nut chewing. Majority of the patients present late even though the site is accessible to easy examination. The role of screening has not been clearly defined despite a number of trials. The only randomized control screening trial with mortality as an end point conducted in India did show a decreased rate in high risk individuals (tobacco and alcohol users). Diagnostic aids and chemoprevention are also not of benefit due to the lack of robust evidence supporting their use. Novel agents such as curcumin have been explored but have not lived up to the initial promise demonstrated in preclinical studies. However there is some emerging data to show promise of auto florescence and salivary diagnostics. Emphasis therefore needs to be focused on high risk patients, early detection and appropriate management. Paramount to proper management is that a distinction must be made between gingivobuccal (alveolar, buccal and RMT) and tongue & floor of mouth cancers. While broad principles are the same there are finer nuances in the treatment of these two distinct groups which have a bearing on the ultimate outcome. We have also demonstrated some differences in molecular changes and different route of involvement of mandible in these cancers. Surgery is the mainstay of treatment for early cancers with a limited role for radiotherapy. Surgery needs to be performed meticulously as margins have an impact on loco regional control. Locally advanced cancers warrant multimodality treatment. There is a need to identify high risk lesions that require intensification of the adjuvant treatment given the morbidity associated with the same. The role of cost effective strategies using
fractionated radiotherapy and weekly platinum dosing needs to be established particularly in the Asian continent. Advances in reconstruction and rehabilitation with the micro vascular free flap have decreased the morbidity associated with these surgeries significantly. There is emerging data to suggest the possible role of the neoadjuvant chemotherapy for borderline operable tumours as well as down staging and making tumours amenable to more conservative resections. Adjuvant chemo radiotherapy is established for patients with perinodal extension and close or positive margins. There has been evolution in the management of neck in the form of sentinel node biopsy, need of level IIB dissection and selective vs. modified neck dissection. Level IIa seems to be an important nodal station that dictates management of the neck. There is some evidence suggesting the possible role of photodynamic therapy and targeted therapy in locally advanced incurable oral cancers. Multidisciplinary team approach is needed for the best chance of cure with best functional outcome in these cases.
AK D’Cruz Department of Head & Neck Services, Taka Memorial Hospital, India
Oral carcinoma is a global disease with a higher prevalence in the Asian region due to the peculiar habit of tobacco and areca nut chewing. Majority of the patients present late even though the site is accessible to easy examination. The role of screening has not been clearly defined despite a number of trials. The only randomized control screening trial with mortality as an end point conducted in India did show a decreased rate in high risk individuals (tobacco and alcohol users). Diagnostic aids and chemoprevention are also not of benefit due to the lack of robust evidence supporting their use. Novel agents such as curcumin have been explored but have not lived up to the initial promise demonstrated in preclinical studies. However there is some emerging data to show promise of auto florescence and salivary diagnostics. Emphasis therefore needs to be focused on high risk patients, early detection and appropriate management. Paramount to proper management is that a distinction must be made between gingivobuccal (alveolar, buccal and RMT) and tongue & floor of mouth cancers. While broad principles are the same there are finer nuances in the treatment of these two distinct groups which have a bearing on the ultimate outcome. We have also demonstrated some differences in molecular changes and different route of involvement of mandible in these cancers. Surgery is the mainstay of treatment for early cancers with a limited role for radiotherapy. Surgery needs to be performed meticulously as margins have an impact on loco regional control. Locally advanced cancers warrant multimodality treatment. There is a need to identify high risk lesions that require intensification of the adjuvant treatment given the morbidity associated with the same. The role of cost effective strategies using
fractionated radiotherapy and weekly platinum dosing needs to be established particularly in the Asian continent. Advances in reconstruction and rehabilitation with the micro vascular free flap have decreased the morbidity associated with these surgeries significantly. There is emerging data to suggest the possible role of the neoadjuvant chemotherapy for borderline operable tumours as well as down staging and making tumours amenable to more conservative resections. Adjuvant chemo radiotherapy is established for patients with perinodal extension and close or positive margins. There has been evolution in the management of neck in the form of sentinel node biopsy, need of level IIB dissection and selective vs. modified neck dissection. Level IIa seems to be an important nodal station that dictates management of the neck. There is some evidence suggesting the possible role of photodynamic therapy and targeted therapy in locally advanced incurable oral cancers. Multidisciplinary team approach is needed for the best chance of cure with best functional outcome in these cases.
陳所長早上10:55
UPDATE MEDICAL TREATMENT OF ADVANCED BILILARY TRACT CANCER
Li-Tzong Chen National Institute of Cancer Research, National Health Research Institutes, Taiwan
Biliary tract cancer (BTC) accounts for approximately 3% of all gastrointestinal malignancies and has dismal clinical outcome with 5-year survival of less than 5%. The overall incidence of BTC appears to increasing over the last 3 decade, notably intrahepatic cholangiocarcinoma. Chemotherapy has been the mainstay treatment in advanced biliary tract cancer (ABTC) patients. Etoposide, fluoropyrimdine, gemcitabine, and platinum have been reported to exhibit some degree of anti-tumor activity in previous clinical studies, but standard of care was not really established until very recently. In the phase III ABC-02 study (Valle et al, NEJM 2010) patients received gemcitabine and cisplatin (GC) combination had superior overall survival and progression-free survival than those with gemcitabine alone, 11.7 months vs. 8.1 months; hazard ratio=0.64; 95% CI, 0.52-0.80; P < 0.001, and 8.0 months vs. 5.0 months; hazard ratio=0.63; 95% CI, 0.51-0.77; P < 0.001, respectively. A phase II trial subsequently showed a similar magnitude of superiority for the doublet GC chemotherapy in Asian population. (Okusaka et al, BJC 2010) Based on the encouraging result, gemcitabine in combination with platinum has been considered as first-line standard of care for patients with ABTC.
Li-Tzong Chen National Institute of Cancer Research, National Health Research Institutes, Taiwan
Biliary tract cancer (BTC) accounts for approximately 3% of all gastrointestinal malignancies and has dismal clinical outcome with 5-year survival of less than 5%. The overall incidence of BTC appears to increasing over the last 3 decade, notably intrahepatic cholangiocarcinoma. Chemotherapy has been the mainstay treatment in advanced biliary tract cancer (ABTC) patients. Etoposide, fluoropyrimdine, gemcitabine, and platinum have been reported to exhibit some degree of anti-tumor activity in previous clinical studies, but standard of care was not really established until very recently. In the phase III ABC-02 study (Valle et al, NEJM 2010) patients received gemcitabine and cisplatin (GC) combination had superior overall survival and progression-free survival than those with gemcitabine alone, 11.7 months vs. 8.1 months; hazard ratio=0.64; 95% CI, 0.52-0.80; P < 0.001, and 8.0 months vs. 5.0 months; hazard ratio=0.63; 95% CI, 0.51-0.77; P < 0.001, respectively. A phase II trial subsequently showed a similar magnitude of superiority for the doublet GC chemotherapy in Asian population. (Okusaka et al, BJC 2010) Based on the encouraging result, gemcitabine in combination with platinum has been considered as first-line standard of care for patients with ABTC.
陳所長下午 Kobayashi Arardee 14:00-15:30
CLINICAL TRIAL-GUIDING TREATMENT STRATEGIES FOR
PANCREATIC ADENOCARCINOMA IN TAIWAN
Li-Tzong Chen
National Institute of Cancer Research, National Health Research Institutes, Taiwan
Pancreatic duct adnocarcinoma (PDAC) is a devastating malignancy with limited long-term survivors. One of the factors to cause the poor outcome of PDAC is the undefined best treatment strategies in various stage of PDAC. For exampe, after the demonstration of its superiority over 5-FU, gemctaibine has been the standard of care for patients with advnced pancreatic cancer (APC) in the past 15 years. However, its efficacy was largely considered as modest. In addition, the role of radiotherapy and optimal chemotherapy in patients with locally advanced and post-resection PDAC also remain unelucidated.
PANCREATIC ADENOCARCINOMA IN TAIWAN
Li-Tzong Chen
National Institute of Cancer Research, National Health Research Institutes, Taiwan
Pancreatic duct adnocarcinoma (PDAC) is a devastating malignancy with limited long-term survivors. One of the factors to cause the poor outcome of PDAC is the undefined best treatment strategies in various stage of PDAC. For exampe, after the demonstration of its superiority over 5-FU, gemctaibine has been the standard of care for patients with advnced pancreatic cancer (APC) in the past 15 years. However, its efficacy was largely considered as modest. In addition, the role of radiotherapy and optimal chemotherapy in patients with locally advanced and post-resection PDAC also remain unelucidated.
Advanced (metastatic) diseases: In Taiwan, the attempt to improve the therapetic efficacy of chemotherapy for patients with APC was starting from gemcitabinecontaining doublet (gemcitabine followed by 24-hour infusion of high-dose fluorouracil and leucovorin, the Gem-HDFL regimen, in 1997. We then have devoted to investigating the feasibility and efficacy of triplet chemotherapy in APC since 2002. We firstly emonstrated that triplet chemotherapy consisting of gemcitabine 800 mg/m2 (10mg/m2/min) followed by oxpliplatin 85 mg/m2 and 48-hour infusion of 5-FU/LV 3000 and 300 mg/m2 Q 2 weeks, the GOFL regimen, is feasible and active for patients with APC. With the disclosure of the GEST trial, which showing S-1 is non-inferior to gemcitabine for APC patients, we recently conducted a phase I/II trial to investigate the feasibiltiy of replacing infusional 5-FU/LV in GOFL regimen with oral S-1/leucovorin, the SLOG (gemcitabine, oxaliplatin plus oral S-1/leucovorin) regimen, in patients with metastatic pancreatic cancer in T1210 study. The phase II part of the study is tsill ongoing!
Locally advanced diseases: Based on the observation of prolonged survival in patients with locally advanced diseases (LAPC) who had salvage or consolidation concurrent chemoradiotherapy (CCRT) after GOFL in the subgroup analysis of phase II GOFL trial and the report of GERCOR retropsective study, we further investigated the feasiblity and therapeutic efficacies of induction GOFL followed by CCRT and maintenance GOFL in LAPC patients in T1204 study. The median progression-free survival and overall survival in 30 out of 50 mostly definitively unresectable LAPC patients who were able to complete ICT plus CCRT is 14.7 months and 18.3 months, respectively. With the emrgence of FOLFIRINOX as one of the standard chemotherapy in patients with metastatic diseases, we are currently conducting a randomized pahse II trial to comparing induction GOFL versus modified FOLFIRINOX followed by CCRT in patients with LAPC, T2212 study. The study not only aims to validate the therapeutic efficacy of induction triplet chemotherapy followed by CCRT for LAPC in T1204 trial but also to evaluate the feasibility and therapeutic efficacy of FOLFIRINOX in Asian population.
Post-operative minimal residual diseases : Adjuvant chemotherapy with either 5-FU or gemcitabine is the standard of care in patients with curative-intent resected PDAC; while the role of CCRT in adjuvant setting remains controversial. However, because local progression is uncommon in patients who had CCRT after induction GOFL in T1204 study, we are convinced that CCRT is an effective modality for local control in patient with localized pancreatic cancer. We therefore conducted a randomized phase III trial to evaluate whether combining CCRT will further enhance the efficacy of adjuvant gemcitabine in patients with post-operative PDAC, the T3207 study.
Gemcitabine-refractory diseases : In addition, based on the observation of high disease-control rate for patietns with standard therapy-refractory APC in a first-inhuman, phase I trial of PEP02 (PEP0201 study), a liposome-encapsulated irinotecan, we further evaluated and demonstrated its efficacy in a multi-national, phase II trial (PEP0208 study). We then successfully push it into a global randomized phase III trial versus infusional 5-FU/LV as second-line therapy for patients with metastatic, gemcitabine-refractory PDAC, the NAPOLI trial. The trial has completed patient acrual and is pending for the results of final analysis.
Conclusions: In conclusion, in the past 20 years we put effort trying to develop novel treatment strategies for patients with various stage of PDAC through mostly investigator-initiated, multi-center trials in Taiwan. Although some of the results of completed trials are exciting, but in general, the progress is relateively limited as what have been achieved from rest par tof the world. Seeking alternative treatment options through enhacing the transition of novel basic research findings into clinical application and through international collaboration for new drug development shall provide the best chance to leap forward the treatment outcomes in patients with pancreatic cancer.
Conclusions: In conclusion, in the past 20 years we put effort trying to develop novel treatment strategies for patients with various stage of PDAC through mostly investigator-initiated, multi-center trials in Taiwan. Although some of the results of completed trials are exciting, but in general, the progress is relateively limited as what have been achieved from rest par tof the world. Seeking alternative treatment options through enhacing the transition of novel basic research findings into clinical application and through international collaboration for new drug development shall provide the best chance to leap forward the treatment outcomes in patients with pancreatic cancer.