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PO135 AT A GLANCE THE BRCAS EPIGENETIC STUDY IN PADANG, WEST SUMATERA, INDONESIA
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Abstracts / The Breast 24 S3 (2015) S21–S75
Family Comprehensive Cancer Center, San Francisco, CA, USA; 3University of California, San Francisco, Hematology/Oncology Department, San Francisco, CA, USA Background: Antitumor immunity may be dampened by the interaction of the PD-1 receptor on tumor infiltrating lymphocytes and PD-L1 on tumor cells. Two recent phase I trials have suggested efficacy of anti-PD-1/PD-L1 antibodies in triple negative (TN) BC. In this study, we investigated associations between primary BC PD-1 and PD-L1 expression, clinical characteristics, and patient outcomes in publically available databases. Methods: We evaluated PD-1 and PD-L1 expression using microarray data from the neoadjuvant I-SPY 1 study (n = 149). Associations with clinical features and chemotherapy response were assessed by KruskalWallis and Wilcoxon rank sum tests, respectively. Recurrence free survival (RFS) associations were assessed by the Cox proportional hazard model. Pearson correlations between PD-1 and expression of PD-L1, HAVCR2, STAT5A, FOXP3, MYC, PGR, and ESR1 were determined in I-SPY 1 and 2 other datasets: METABRIC (n = 1992) and TCGA (n = 817). Results: In I-SPY 1, PD-1 expression was significantly higher in HER2+ and TNBC (p = 0.003), and in grade 2/3 tumors (p = 0.043); this association was also seen in METABRIC. PD-1 expression was associated with pathologic complete response (p = 0.006), but this correlation did not remain significant on subtype correction. PD-1 was not associated with tumor stage, nodal status, lymphovascular invasion or RFS. While PD-L1 did not correlate with tumor features, patients with PD-L1 expression in the lowest quintile had worse RFS, even after subtype adjustment (HR 2.33, p = 0.01). In all 3 datasets, PD-1 significantly correlated with PD-L1, HAVCR2, and STAT5A, and inversely with ESR1. In TCGA and METABRIC, a significant inverse correlation of PD-1 with PGR was noted. In the TN subset of TCGA and METABRIC, PD-1 significantly correlated with PD-L1, HAVCR2, and STAT5A. In TCGA and METABRIC, PD-L1 significantly correlated with HAVCR2 and STAT5A, and this was also seen in the TN subset. In TCGA alone, PD-1 and PD-L1 significantly correlated with FOXP3, and PD-1 with MYC. Conclusions: PD-1 expression is higher in TN and other aggressive BC subtypes. PD-1 and PD-L1 correlate with immune related genes HAVCR2 and STAT5A. Low PD-L1 expression may be an adverse prognostic factor. Trials are underway to investigate the activity of anti-PD-1/PD-L1 antibodies in TNBC and to elucidate markers of response.
PO135 AT A GLANCE THE BRCAS EPIGENETIC STUDY IN PADANG, WEST SUMATERA, INDONESIA Wirsma Arif Harahap1, Dessy Arisanty2,Daan Khambri1,Yanwirasti3, Sofia Mubarikha4 1 Medical Faculty Andalas University/Dr. M. Djamil Hospital, Department of Surgery, Padang West Sumatera, Indonesia; 2Andalas University, Dept of Biochemistry, Padang West Sumatera, Indonesia; 3Medical Faculty Andalas University, Dept. of Biomedical Science, Padang West Sumatera, Indonesia; 4 Faculty of Medicine GMU, Molecular Biology Laboratory, Yogyakarta, Indonesia Background: Sporadic breast carcinoma is the most common cancer among premenopausal women in Padang. There are differences of risk factors and tumor characteristics compared with Caucasian patients such as young age, lactation, multiparity etc. It was assumed that promoter methylationin BRCA1 plays a role in this differences. Materials and Methods: This study is a descriptive analytic study aimed to describe the incidence of promoter methylation in the BRCA1 gene in sporadic premenopausal breast cancer patients in Padang. This research used methylation with bisulfate PCR technique method in the BRCA1 promoter in 60 sporadic premenopausal breast cancer patients at M Djamil Hospital Padang. Stage, tumor grading, mitotic index and immunohistochemical examination (Er, Pr, HER2, Ki67) are examined prognostic factor. Data are analyzed using Chi-Square test. Results: 60 breast cancer patients, 23.3% are stage II, 66.7% are stage III and 10% are stage IV. Cancer subtypes were luminal A in 12 patients
(20%), luminal B in 16 patients (26.7%), HER2 in 10 patients (16.7%) and TNBC in 22 patients (36.7%). Methylation in cancer tissue was found in 39 patients (65%) where 32 patients with advanced stage (82.1%). The result of Chi-Square test found a significant association between methylation of stage (p=0.000) and Ki67 (p=0.000). There was no significant association between methylation of ER (p=0.454), PR (p=0.082), HER-2 (p=2.359). Conclusion: Most patients came for treatment at advanced stage. The frequency of methylation in the promoter gene BRCA1 in sporadic premenopausal by 65% greater than literature reports. Methylation associated with a high degree of proliferation (Ki67>14%) and advanced stage. Breast cancer with promoter methylation in the BRCA1 gene have a worse prognosis. Further research is needed to study the clinical impact of antimethylation in patients with breast cancer with BRCA1 promoter methylation.
PR136 PREDICTIVE VALUE OF MRNA EXPRESSION OF TUBIII GENE IN THE TREATMENT OF LOCALLY ADVANCED BREAST CANCER Tatiana Semiglazova2, Petr Krivorotko3, Ekaterina Busko4, Sergey Novikov4, Veronika Klimenko2, Elena Turkevich5, Anna Belyaeva6, Vladislav Semiglazov1, Evgeniy Imyanitov7, Vladimir Semiglazov3 1 1st Saint-Petersburg State Medical University named after I.P. Pavlov, Oncology, St. Petersburg, Russian Federation; 2N.N. Petrov Research Institute of Oncology, Innovative therapy, St. Petersburg, Russian Federation; 3N.N. Petrov Research Institute of Oncology, Breast cancer, St. Petersburg, Russian Federation; 4N.N. Petrov Research Institute of Oncology, Radiology diagnostics, St. Petersburg, Russian Federation; 5N.N. Petrov Research Institute of Oncology, Pathology, St. Petersburg, Russian Federation; 6N.N. Petrov Research Institute of Oncology, Abdominal oncology, St. Petersburg, Russian Federation; 7N.N. Petrov Research Institute of Oncology, Molecular oncology, St. Petersburg, Russian Federation Background: The most effective drugs in breast cancer treatment are taxanes and anthracycline antibiotics. Knowledge of molecular genetics predictive characteristics of the tumor can help not only in the choice of cytostatic agent, but also to avoid the risk of side effects from obviously ineffective therapy. Methods: Patients with locally advanced breast cancer received by randomization in neoadjuvant taxane-based regimens TAC (“docetaxel 75 mg/m2 + doxorubicin 50 mg/m2 + cyclophosphamide 500 mg/m2”) or TC (“docetaxel 75 mg/m2 and cyclophosphamide 500 mg/m2”). Predictive value of the expression of mRNA of the gene -tubulin class III (TUBIII), as a marker of tumor sensitivity to taxanes, was examined in 140 patients with locally advanced breast cancer. Depending on the expression of TUBIII tumors patients were formed in two subgroups: with low - 61 (43.6%) and high expression - 52 (49.5%). Detection of mRNA expression of the gene TUBIII was carried by semiquantitative polymerase chain reaction (PCR) in real time using a TaqMan-probes. Pathologic response of the tumor and the lymph nodes on taxanecontaining neoadjuvant chemotherapy was evaluated by a scale MillerPayne. Results: Pathologic complete response (pCR) in patients with low expression TUBIII (n = 61) was registered in 19 patients (24.1%; 95% CI: 15,2-34,2), and in the high expression group TUBIII pCR was not registered (p <0.005). A similar correlation between low expression of TUBIII and efficacy obtained by the intergroup analysis of TAC/TC groups. The sensitivity, specificity, overall accuracy, and predictive value of positive and negative results of TUBIII low expression were 94.7%, 50.4%, 56.4%, 23.1% and 98.4%, respectively. At the same time in patients with low expression of the gene TUBIII in tumor before chemotherapy it was marked improvement of 2-year disease-free survival compared with patients whose TUBIII gene expression was high (80.3% vs. 51.9%, p<0.05). Conclusions: Thus, according to the study, low mRNA expression of the gene -tubulin class III in breast cancer tissue can be considered as an important sign of the effectiveness of taxane-containing chemotherapy.
Abstracts / The Breast 24 S3 (2015) S21–S75
Family Comprehensive Cancer Center, San Francisco, CA, USA; 3University of California, San Francisco, Hematology/Oncology Department, San Francisco, CA, USA Background: Antitumor immunity may be dampened by the interaction of the PD-1 receptor on tumor infiltrating lymphocytes and PD-L1 on tumor cells. Two recent phase I trials have suggested efficacy of anti-PD-1/PD-L1 antibodies in triple negative (TN) BC. In this study, we investigated associations between primary BC PD-1 and PD-L1 expression, clinical characteristics, and patient outcomes in publically available databases. Methods: We evaluated PD-1 and PD-L1 expression using microarray data from the neoadjuvant I-SPY 1 study (n = 149). Associations with clinical features and chemotherapy response were assessed by KruskalWallis and Wilcoxon rank sum tests, respectively. Recurrence free survival (RFS) associations were assessed by the Cox proportional hazard model. Pearson correlations between PD-1 and expression of PD-L1, HAVCR2, STAT5A, FOXP3, MYC, PGR, and ESR1 were determined in I-SPY 1 and 2 other datasets: METABRIC (n = 1992) and TCGA (n = 817). Results: In I-SPY 1, PD-1 expression was significantly higher in HER2+ and TNBC (p = 0.003), and in grade 2/3 tumors (p = 0.043); this association was also seen in METABRIC. PD-1 expression was associated with pathologic complete response (p = 0.006), but this correlation did not remain significant on subtype correction. PD-1 was not associated with tumor stage, nodal status, lymphovascular invasion or RFS. While PD-L1 did not correlate with tumor features, patients with PD-L1 expression in the lowest quintile had worse RFS, even after subtype adjustment (HR 2.33, p = 0.01). In all 3 datasets, PD-1 significantly correlated with PD-L1, HAVCR2, and STAT5A, and inversely with ESR1. In TCGA and METABRIC, a significant inverse correlation of PD-1 with PGR was noted. In the TN subset of TCGA and METABRIC, PD-1 significantly correlated with PD-L1, HAVCR2, and STAT5A. In TCGA and METABRIC, PD-L1 significantly correlated with HAVCR2 and STAT5A, and this was also seen in the TN subset. In TCGA alone, PD-1 and PD-L1 significantly correlated with FOXP3, and PD-1 with MYC. Conclusions: PD-1 expression is higher in TN and other aggressive BC subtypes. PD-1 and PD-L1 correlate with immune related genes HAVCR2 and STAT5A. Low PD-L1 expression may be an adverse prognostic factor. Trials are underway to investigate the activity of anti-PD-1/PD-L1 antibodies in TNBC and to elucidate markers of response.
PO135 AT A GLANCE THE BRCAS EPIGENETIC STUDY IN PADANG, WEST SUMATERA, INDONESIA Wirsma Arif Harahap1, Dessy Arisanty2,Daan Khambri1,Yanwirasti3, Sofia Mubarikha4 1 Medical Faculty Andalas University/Dr. M. Djamil Hospital, Department of Surgery, Padang West Sumatera, Indonesia; 2Andalas University, Dept of Biochemistry, Padang West Sumatera, Indonesia; 3Medical Faculty Andalas University, Dept. of Biomedical Science, Padang West Sumatera, Indonesia; 4 Faculty of Medicine GMU, Molecular Biology Laboratory, Yogyakarta, Indonesia Background: Sporadic breast carcinoma is the most common cancer among premenopausal women in Padang. There are differences of risk factors and tumor characteristics compared with Caucasian patients such as young age, lactation, multiparity etc. It was assumed that promoter methylationin BRCA1 plays a role in this differences. Materials and Methods: This study is a descriptive analytic study aimed to describe the incidence of promoter methylation in the BRCA1 gene in sporadic premenopausal breast cancer patients in Padang. This research used methylation with bisulfate PCR technique method in the BRCA1 promoter in 60 sporadic premenopausal breast cancer patients at M Djamil Hospital Padang. Stage, tumor grading, mitotic index and immunohistochemical examination (Er, Pr, HER2, Ki67) are examined prognostic factor. Data are analyzed using Chi-Square test. Results: 60 breast cancer patients, 23.3% are stage II, 66.7% are stage III and 10% are stage IV. Cancer subtypes were luminal A in 12 patients
(20%), luminal B in 16 patients (26.7%), HER2 in 10 patients (16.7%) and TNBC in 22 patients (36.7%). Methylation in cancer tissue was found in 39 patients (65%) where 32 patients with advanced stage (82.1%). The result of Chi-Square test found a significant association between methylation of stage (p=0.000) and Ki67 (p=0.000). There was no significant association between methylation of ER (p=0.454), PR (p=0.082), HER-2 (p=2.359). Conclusion: Most patients came for treatment at advanced stage. The frequency of methylation in the promoter gene BRCA1 in sporadic premenopausal by 65% greater than literature reports. Methylation associated with a high degree of proliferation (Ki67>14%) and advanced stage. Breast cancer with promoter methylation in the BRCA1 gene have a worse prognosis. Further research is needed to study the clinical impact of antimethylation in patients with breast cancer with BRCA1 promoter methylation.
PR136 PREDICTIVE VALUE OF MRNA EXPRESSION OF TUBIII GENE IN THE TREATMENT OF LOCALLY ADVANCED BREAST CANCER Tatiana Semiglazova2, Petr Krivorotko3, Ekaterina Busko4, Sergey Novikov4, Veronika Klimenko2, Elena Turkevich5, Anna Belyaeva6, Vladislav Semiglazov1, Evgeniy Imyanitov7, Vladimir Semiglazov3 1 1st Saint-Petersburg State Medical University named after I.P. Pavlov, Oncology, St. Petersburg, Russian Federation; 2N.N. Petrov Research Institute of Oncology, Innovative therapy, St. Petersburg, Russian Federation; 3N.N. Petrov Research Institute of Oncology, Breast cancer, St. Petersburg, Russian Federation; 4N.N. Petrov Research Institute of Oncology, Radiology diagnostics, St. Petersburg, Russian Federation; 5N.N. Petrov Research Institute of Oncology, Pathology, St. Petersburg, Russian Federation; 6N.N. Petrov Research Institute of Oncology, Abdominal oncology, St. Petersburg, Russian Federation; 7N.N. Petrov Research Institute of Oncology, Molecular oncology, St. Petersburg, Russian Federation Background: The most effective drugs in breast cancer treatment are taxanes and anthracycline antibiotics. Knowledge of molecular genetics predictive characteristics of the tumor can help not only in the choice of cytostatic agent, but also to avoid the risk of side effects from obviously ineffective therapy. Methods: Patients with locally advanced breast cancer received by randomization in neoadjuvant taxane-based regimens TAC (“docetaxel 75 mg/m2 + doxorubicin 50 mg/m2 + cyclophosphamide 500 mg/m2”) or TC (“docetaxel 75 mg/m2 and cyclophosphamide 500 mg/m2”). Predictive value of the expression of mRNA of the gene -tubulin class III (TUBIII), as a marker of tumor sensitivity to taxanes, was examined in 140 patients with locally advanced breast cancer. Depending on the expression of TUBIII tumors patients were formed in two subgroups: with low - 61 (43.6%) and high expression - 52 (49.5%). Detection of mRNA expression of the gene TUBIII was carried by semiquantitative polymerase chain reaction (PCR) in real time using a TaqMan-probes. Pathologic response of the tumor and the lymph nodes on taxanecontaining neoadjuvant chemotherapy was evaluated by a scale MillerPayne. Results: Pathologic complete response (pCR) in patients with low expression TUBIII (n = 61) was registered in 19 patients (24.1%; 95% CI: 15,2-34,2), and in the high expression group TUBIII pCR was not registered (p <0.005). A similar correlation between low expression of TUBIII and efficacy obtained by the intergroup analysis of TAC/TC groups. The sensitivity, specificity, overall accuracy, and predictive value of positive and negative results of TUBIII low expression were 94.7%, 50.4%, 56.4%, 23.1% and 98.4%, respectively. At the same time in patients with low expression of the gene TUBIII in tumor before chemotherapy it was marked improvement of 2-year disease-free survival compared with patients whose TUBIII gene expression was high (80.3% vs. 51.9%, p<0.05). Conclusions: Thus, according to the study, low mRNA expression of the gene -tubulin class III in breast cancer tissue can be considered as an important sign of the effectiveness of taxane-containing chemotherapy.