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Immune microenvironment in clear cell type renal cell carcinoma with loss of PBRM1 protein expression
abstracts
Annals of Oncology MO1 8 3
The Correlation of Nottingham Prognostic Index with Immunoexpression of ER, PR, HER2, and Ki67 in Breast Cancer Tissue
Chetana Ruangpratheep1, Supakorn Piyaisrakul2 Department of Pathology, Phramongkutklao College of Medicine, Bangkok, Thailand, 2 Division of Pathology, Bhumibol Adulyadej Hospital, Bangkok, Thailand
1
MO1 8 4
Baseline neutrophil to lymphocyte ratio is predictor of longer OS of metastatic BC patients treated with eribulin
Shota Kusuhara1, Takahiro Kogawa1, Mototsugu Shimokawa2, Sumito Shingaki1, Yumi Fujimoto1, Kenichi Harano1, Nobuaki Matsubara1, Yoichi Naito1, Ako Hosono1, Hirofumi Mukai1, Toru Mukohara1 1 Department of Breast and Medical Oncology, National Cancer Center Hospital East, 2 Cancer Biostatistics Laboratory, Clinical Research Institute, National Kyushu Cancer Center Background: Eribulin demonstrated longer overall survival for pretreated metastatic breast cancer. Several factors are reported to be associated with their survival outcomes of breast cancer patients, and scarce of predictors are determined for each agent. Previous reports have demonstrated that high neutrophil to lymphocyte ratio (NLR) is related to poor survival outcomes of cancer. We hypothesized that low NLR is predictor of longer survival of breast cancer patients. We investigated whether baseline NLR before chemotherapy is associated with overall survival, and explored possible mechanism of better survival in patients with metastatic breast cancer. Methods: We extracted female patients with metastatic breast cancer who received Eribulin for metastatic disease at NCCHE. We included HER2-negative disease, and those treated with standard chemotherapy including eribulin. We retrieved patient and disease characteristics; age, disease location, de novo stage IV or recurrent disease, hormone receptor status. Result: We identified 135 patients between July 2012 and December 2018 with a median age of 57.9 (34-77), of which 106 (78.5%) had HR positive disease, 104 (77.0%) had recurrent disease, and 114 (84.4%) had visceral disease. Log rank test showed hormone receptor status and visceral disease were significant variable for candidate for multivariate analysis. COX regression model demonstrated that decreasing of NLR was associated with better OS [HR ¼ 1.145, 95% confidence interval (95% CI)¼1.0731.223]. We showed low NLR at the administration of eribulin was independent predictor of OS [HR ¼ 1.048, 95% confidence interval (95% CI)¼1.004-1.093]. Conclusion: We showed low NLR is better prognostic factor of any chemotherapy for metastatic breast cancer. Our exploratory research also showed low NLR at eribulin administraton was suspected to be better OS indicator regardless of pretreated chemotherapy.
Volume 30 | Supplement 6 | October 2019
Development of diagnostic kit for in vitro diagnostics of the TP53 signature in early breast cancer
Shin Takahashi1,7, Youichiro Kakugawa2, Tadashi Nomizu3, Tatsuro Saito4, Yuan Yuan4, Shinji Ohno5, Masakazu Toi6, Chikashi Ishioka1,7 1 Department of Medical Onocology, Tohoku Unuversity Hospital, 2Department of Breast Oncology, Miyagi Cancer Center, 3Department of Surgery, Hoshi General Hospital, 4RIKEN GENESIS CO., LTD, 5Center of Breast Oncology, The Cancer Institute Hospital of JFCR, 6Department of Breast Surgery, Graduate School of Medicine Kyoto University, 7Department of Clinical Oncology, IDAC, Tohoku University Background: Diagnostic tests based on gene expression signatures identified by transcriptome analyses have been developed and these have been used for predicting prognosis, recurrence and/or effect of anticancer drugs including endocrine therapies in clinical practice of breast cancer, ahead of other cancer types. We have previously reported that TP53 signature, which has the ability to determine TP53 mutation status, are an independent prognostic factor of breast cancer, and also shown that the TP53 signature has better predictability of prognosis and efficacy on chemotherapies than the TP53 mutation status and other known clinic-pathological factors. Objects: The aim of this study is to develop the diagnostic kit for in vitro diagnostics based on the TP53 signature. Methods: We adopted an nCounter system (NanoString) because it has robust ability to analyze a gene expression signature of the TP53 signature from a small amount of RNA derived from archival FFPE tissues. Results: We have designed a specific probe set for IVD of the TP53 signature and programed a new algorithm to determine the status of TP53 signature from the identified expression data. The algorithm has the characteristic that is hard to be affected by the outliers than previous algorithm (the algorithm cannot be disclosed). Using this method, we determined status of TP53 signature of 220 stage I-II breast cancers. The predictability of recurrence by the IVD of the TP53 signature will be shown in this study. We are also conducting a retrospective-prospective analysis of over 500 breast cancers as the validation study of the IVD under cooperation of JBCRG, OOTR. From this study, the predictability of the pathological CR (pCR) after neoadjuvant chemotherapies and the prognosis by the IVD will be also shown. Conclusion: The TP53 signature diagnostic kit is expected to be a clinically useful biomarker for prediction of prognosis, recurrence and efficacy of perioperative chemotherapy in breast cancer.
MO1 9 2
Immune microenvironment in clear cell type renal cell carcinoma with loss of PBRM1 protein expression
Yuji Miura1, Takanobu Motoshima2, Naoko Inoshita3, Toshikazu Okaneya4, Toshimi Takano1, Yoshihiro Komohara5 1 Department of Medical Oncology, Toranomon Hospital, 2Department of Urology, Graduate School of Medical Sciences, Kumamoto University, 3Department of Pathology, Toranomon Hospital, 4Department of Urology, Toranomon Hospital, 5 Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University Background: Polybromo-1 (PBRM1) is a chromatin-modifying gene and its mutation is detected in approximately 40% of clear cell type renal cell carcinoma (ccRCC). It has been recently reported that PBRM1 mutation was positively associated with the efficacy of immune checkpoint inhibitors. Previously, our group demonstrated the tumor heterogeneity of PBRM1 and tumor associated macrophages (TAMs) differentiation between primary and metastatic site of ccRCC, separately. Here, we evaluated the relationship between the protein expression of PBRM1 in tumor cells and their immune microenvironment. Methods: We performed immunohistochemistry (IHC) for PBRM1, CD8, Iba1, which is a common pan-macrophage marker, CD163 and CD204, which are considered to be a M2 macrophage marker using tissue microarray samples of both primary and matched metastatic sites in 41 metastatic ccRCC patients. Results: Thirty-three paired samples were available for IHC assessment. The density of CD8þ T cells was significantly lower in PBRM1 protein expression-negative tumor than -positive tumor (average 6 standard error [SE] density in PBRM1-positive vs. negative tumor was 367 6 94/m2 vs. 650 6 71/m2, P ¼ 0.023) in metastatic site. The density of CD163þ TAMs was significantly higher in PBRM1 protein expression-negative tumor than -positive tumor (average 6 standard error [SE] density in PBRM1positive vs. -negative tumor was 693 6 74/m2 vs. 471 6 56/m2, P ¼ 0.023) in metastatic site. By the contrast, no significant relationship between PBRM1 protein expression and the density of CD8þ T cells or TAM was observed in primary site. Conclusion: TAMs were polarized towards an M2-like phenotype and CD8þ T cells density decreased in metastatic lesion of PBRM1 protein expression-negative ccRCC. Further investigation with large sample size is warranted.
doi:10.1093/annonc/mdz338 | vi93
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_6/mdz338.016/5583153 by guest on 28 October 2019
Background: In the underdeveloped and developing countries, the application of immunohistochemistry (IHC) to assess the status of oestrogen receptor (ER), progesterone receptor (PR), HER2 receptor, and Ki67 proteins in formalin-fixed, paraffinembedded tissue sections of primary invasive breast carcinoma is utterly hindered by high cost, long procedure, and need for both skilled operator and pathologist. The objective of this study was to evaluate the correlation of Nottingham prognostic index (NPI) with immunoexpression of ER, PR, HER2, and Ki67 proteins in the formalinfixed, paraffin-embedded tissue sections of primary invasive breast carcinoma. The ethical approval reference number is IRBRTA 306/2560. Methods: Two hundred and forty primary invasive breast carcinoma cases were determined their NPI which was calculated as [0.2 maximum tumour diameter in cm] þ tumour grade þ axillary lymph node score. Tumour grade was given a score 1 to 3 based on the Nottingham Combined Histologic Grade system (Elston-Ellis modification of Scarff-Bloom-Richardson grading system) of primary invasive breast carcinoma. Axillary lymph node metastasis (ALNM) was given a score 1 if no ALNM, a score 2 if 1 to 3 metastatic nodes, and a score 3 if at least 4 nodal involvement. The correlation between NPI and the IHC status of ER, PR, HER2, and Ki67 was analysed at the 95% confidence interval. Results: The NPI had a significant association with the immunoexpression of ER, PR, and Ki67 proteins. There was no correlation with HER2 immunohistochemical reactivity. The proposed NPI score less than 4.5 will significantly correlate with positive immunoexpression of ER and PR. The NPI score greater than or equal to 4.5 will correlate with high Ki67. Conclusion: The NPI might have a role in predicting the results of ER, PR and Ki67 expression in the formalin-fixed, paraffin-embedded tissue sections of primary invasive breast carcinoma, if immunohistochemical method is unavailable.
MO1 8 6
Annals of Oncology MO1 8 3
The Correlation of Nottingham Prognostic Index with Immunoexpression of ER, PR, HER2, and Ki67 in Breast Cancer Tissue
Chetana Ruangpratheep1, Supakorn Piyaisrakul2 Department of Pathology, Phramongkutklao College of Medicine, Bangkok, Thailand, 2 Division of Pathology, Bhumibol Adulyadej Hospital, Bangkok, Thailand
1
MO1 8 4
Baseline neutrophil to lymphocyte ratio is predictor of longer OS of metastatic BC patients treated with eribulin
Shota Kusuhara1, Takahiro Kogawa1, Mototsugu Shimokawa2, Sumito Shingaki1, Yumi Fujimoto1, Kenichi Harano1, Nobuaki Matsubara1, Yoichi Naito1, Ako Hosono1, Hirofumi Mukai1, Toru Mukohara1 1 Department of Breast and Medical Oncology, National Cancer Center Hospital East, 2 Cancer Biostatistics Laboratory, Clinical Research Institute, National Kyushu Cancer Center Background: Eribulin demonstrated longer overall survival for pretreated metastatic breast cancer. Several factors are reported to be associated with their survival outcomes of breast cancer patients, and scarce of predictors are determined for each agent. Previous reports have demonstrated that high neutrophil to lymphocyte ratio (NLR) is related to poor survival outcomes of cancer. We hypothesized that low NLR is predictor of longer survival of breast cancer patients. We investigated whether baseline NLR before chemotherapy is associated with overall survival, and explored possible mechanism of better survival in patients with metastatic breast cancer. Methods: We extracted female patients with metastatic breast cancer who received Eribulin for metastatic disease at NCCHE. We included HER2-negative disease, and those treated with standard chemotherapy including eribulin. We retrieved patient and disease characteristics; age, disease location, de novo stage IV or recurrent disease, hormone receptor status. Result: We identified 135 patients between July 2012 and December 2018 with a median age of 57.9 (34-77), of which 106 (78.5%) had HR positive disease, 104 (77.0%) had recurrent disease, and 114 (84.4%) had visceral disease. Log rank test showed hormone receptor status and visceral disease were significant variable for candidate for multivariate analysis. COX regression model demonstrated that decreasing of NLR was associated with better OS [HR ¼ 1.145, 95% confidence interval (95% CI)¼1.0731.223]. We showed low NLR at the administration of eribulin was independent predictor of OS [HR ¼ 1.048, 95% confidence interval (95% CI)¼1.004-1.093]. Conclusion: We showed low NLR is better prognostic factor of any chemotherapy for metastatic breast cancer. Our exploratory research also showed low NLR at eribulin administraton was suspected to be better OS indicator regardless of pretreated chemotherapy.
Volume 30 | Supplement 6 | October 2019
Development of diagnostic kit for in vitro diagnostics of the TP53 signature in early breast cancer
Shin Takahashi1,7, Youichiro Kakugawa2, Tadashi Nomizu3, Tatsuro Saito4, Yuan Yuan4, Shinji Ohno5, Masakazu Toi6, Chikashi Ishioka1,7 1 Department of Medical Onocology, Tohoku Unuversity Hospital, 2Department of Breast Oncology, Miyagi Cancer Center, 3Department of Surgery, Hoshi General Hospital, 4RIKEN GENESIS CO., LTD, 5Center of Breast Oncology, The Cancer Institute Hospital of JFCR, 6Department of Breast Surgery, Graduate School of Medicine Kyoto University, 7Department of Clinical Oncology, IDAC, Tohoku University Background: Diagnostic tests based on gene expression signatures identified by transcriptome analyses have been developed and these have been used for predicting prognosis, recurrence and/or effect of anticancer drugs including endocrine therapies in clinical practice of breast cancer, ahead of other cancer types. We have previously reported that TP53 signature, which has the ability to determine TP53 mutation status, are an independent prognostic factor of breast cancer, and also shown that the TP53 signature has better predictability of prognosis and efficacy on chemotherapies than the TP53 mutation status and other known clinic-pathological factors. Objects: The aim of this study is to develop the diagnostic kit for in vitro diagnostics based on the TP53 signature. Methods: We adopted an nCounter system (NanoString) because it has robust ability to analyze a gene expression signature of the TP53 signature from a small amount of RNA derived from archival FFPE tissues. Results: We have designed a specific probe set for IVD of the TP53 signature and programed a new algorithm to determine the status of TP53 signature from the identified expression data. The algorithm has the characteristic that is hard to be affected by the outliers than previous algorithm (the algorithm cannot be disclosed). Using this method, we determined status of TP53 signature of 220 stage I-II breast cancers. The predictability of recurrence by the IVD of the TP53 signature will be shown in this study. We are also conducting a retrospective-prospective analysis of over 500 breast cancers as the validation study of the IVD under cooperation of JBCRG, OOTR. From this study, the predictability of the pathological CR (pCR) after neoadjuvant chemotherapies and the prognosis by the IVD will be also shown. Conclusion: The TP53 signature diagnostic kit is expected to be a clinically useful biomarker for prediction of prognosis, recurrence and efficacy of perioperative chemotherapy in breast cancer.
MO1 9 2
Immune microenvironment in clear cell type renal cell carcinoma with loss of PBRM1 protein expression
Yuji Miura1, Takanobu Motoshima2, Naoko Inoshita3, Toshikazu Okaneya4, Toshimi Takano1, Yoshihiro Komohara5 1 Department of Medical Oncology, Toranomon Hospital, 2Department of Urology, Graduate School of Medical Sciences, Kumamoto University, 3Department of Pathology, Toranomon Hospital, 4Department of Urology, Toranomon Hospital, 5 Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University Background: Polybromo-1 (PBRM1) is a chromatin-modifying gene and its mutation is detected in approximately 40% of clear cell type renal cell carcinoma (ccRCC). It has been recently reported that PBRM1 mutation was positively associated with the efficacy of immune checkpoint inhibitors. Previously, our group demonstrated the tumor heterogeneity of PBRM1 and tumor associated macrophages (TAMs) differentiation between primary and metastatic site of ccRCC, separately. Here, we evaluated the relationship between the protein expression of PBRM1 in tumor cells and their immune microenvironment. Methods: We performed immunohistochemistry (IHC) for PBRM1, CD8, Iba1, which is a common pan-macrophage marker, CD163 and CD204, which are considered to be a M2 macrophage marker using tissue microarray samples of both primary and matched metastatic sites in 41 metastatic ccRCC patients. Results: Thirty-three paired samples were available for IHC assessment. The density of CD8þ T cells was significantly lower in PBRM1 protein expression-negative tumor than -positive tumor (average 6 standard error [SE] density in PBRM1-positive vs. negative tumor was 367 6 94/m2 vs. 650 6 71/m2, P ¼ 0.023) in metastatic site. The density of CD163þ TAMs was significantly higher in PBRM1 protein expression-negative tumor than -positive tumor (average 6 standard error [SE] density in PBRM1positive vs. -negative tumor was 693 6 74/m2 vs. 471 6 56/m2, P ¼ 0.023) in metastatic site. By the contrast, no significant relationship between PBRM1 protein expression and the density of CD8þ T cells or TAM was observed in primary site. Conclusion: TAMs were polarized towards an M2-like phenotype and CD8þ T cells density decreased in metastatic lesion of PBRM1 protein expression-negative ccRCC. Further investigation with large sample size is warranted.
doi:10.1093/annonc/mdz338 | vi93
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_6/mdz338.016/5583153 by guest on 28 October 2019
Background: In the underdeveloped and developing countries, the application of immunohistochemistry (IHC) to assess the status of oestrogen receptor (ER), progesterone receptor (PR), HER2 receptor, and Ki67 proteins in formalin-fixed, paraffinembedded tissue sections of primary invasive breast carcinoma is utterly hindered by high cost, long procedure, and need for both skilled operator and pathologist. The objective of this study was to evaluate the correlation of Nottingham prognostic index (NPI) with immunoexpression of ER, PR, HER2, and Ki67 proteins in the formalinfixed, paraffin-embedded tissue sections of primary invasive breast carcinoma. The ethical approval reference number is IRBRTA 306/2560. Methods: Two hundred and forty primary invasive breast carcinoma cases were determined their NPI which was calculated as [0.2 maximum tumour diameter in cm] þ tumour grade þ axillary lymph node score. Tumour grade was given a score 1 to 3 based on the Nottingham Combined Histologic Grade system (Elston-Ellis modification of Scarff-Bloom-Richardson grading system) of primary invasive breast carcinoma. Axillary lymph node metastasis (ALNM) was given a score 1 if no ALNM, a score 2 if 1 to 3 metastatic nodes, and a score 3 if at least 4 nodal involvement. The correlation between NPI and the IHC status of ER, PR, HER2, and Ki67 was analysed at the 95% confidence interval. Results: The NPI had a significant association with the immunoexpression of ER, PR, and Ki67 proteins. There was no correlation with HER2 immunohistochemical reactivity. The proposed NPI score less than 4.5 will significantly correlate with positive immunoexpression of ER and PR. The NPI score greater than or equal to 4.5 will correlate with high Ki67. Conclusion: The NPI might have a role in predicting the results of ER, PR and Ki67 expression in the formalin-fixed, paraffin-embedded tissue sections of primary invasive breast carcinoma, if immunohistochemical method is unavailable.
MO1 8 6