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Impact of Molecular Subtypes in Patients with Metastatic Breast Cancer at Diagnosis
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Abstracts / The Breast 36 S1 (2017) S19–S76
PR110 IMPACT OF NEXT-GENERATION SEQUENCING (NGS) FOR PRIMARY ENDOCRINE RESISTANCE ON BREAST CANCER PATIENTS Zhenchuan Song1, Ruoyang Li1, Shuo Feng1, Tianli Hui1, Fugen Li2, Jingyu Li2, Jiajia Xu2 1 4th Hospital of Hebei Medical University, Breast Center, Shijiazhuang, China; 2Institute of Precision Medicine, 3D Medicines Inc., Shanghai, China Background: Multiple mechanisms have been detected to account for the acquired resistance to endocrine therapies in breast cancer. Evidence supports that PIK3CA mutation status may contribute to endocrine resistance. However, some clinical trial data show that whether PIK3CA mutate or not does not affect the therapeutic effect of TAM. In this study we retrospectively studied the mechanism of primary endocrine resistance in estrogen receptor (ER) positive breast cancer patients by NGS. Patients and Methods: Tumor specimens and matched blood samples were obtained from twenty-four breast cancer patients at the Fourth Hospital of Hebei Medical University, Shijiazhuang, China. All the patients were estrogen receptor (ER) positive, among which, fifteen patients displayed endocrine resistance (recurrence and/or metastases within 24 months from the beginning of endocrine therapy), and the other nine patients kept sensitive to endocrine therapy for more than 5 years. According to their medical records, all of the 24 patients were invasive breast cancer (T1-2, N1-2, M0). Tumor tissue was obtained from biopsy or surgery upon the initial diagnosis of cancer at the primary site, and tumor genomic DNA was extracted from formalin-fixed and paraffin-embedded (FFPE) tumor tissue blocks. Normal genomic DNA was extracted from peripheral blood mononuclear cells. Sequencing libraries for each samples were prepared followed by targets capturing for 372 genes that are frequently rearranged in cancers. Massive parallel sequencing was then performed using Illumina NextSeq 500, and samples with a mean sequencing depth of 500× were analyzed. Result: Three patients demonstrated HER2 copy number gains by NGS in each group, which was consistent with the IHC and FISH analysis. 8(55%) of 15 patients showed PIK3CA mutation (3 pathogenic variants in kinase domain, 3 pathogenic variants in helical domain, and 2 variants of unknown significance) in the endocrine-resistant group, and 3 (33%) of 9 patients displayed PIK3CA mutation (2 pathogenic variants in kinase domain and 1 pathogenic variant in helical domain) in the endocrine-sensitive group. In the sensitive group, copy number gain of C11orf30 (EMSY) gene, copy number loss of CDH1 (E-cadherin) gene, and a missense mutation of SF3B1 gene were also detected, which were supposed to decline the expression of the ESR1 and contribute to endocrine sensitivity. Conclusion: PIK3CA mutation rate in the resistance group is relatively higher than that in the sensitive group, which indicates that PIK3CA mutation may contribute to breast cancer primary endocrine resistance. If future studies were conducted with a larger spectrum of patients, results might be more conclusive.
PR111 IMPACT OF MOLECULAR SUBTYPES IN PATIENTS WITH METASTATIC BREAST CANCER AT DIAGNOSIS Tânia Madureira, Paulo Luz, David Dias, Raquel Dionísio, Beatriz Gosalbez, Irene Furtado Centro Hospitalar do Algarve, Serviço de Oncologia Médica, Faro, Portugal
Background: The increasing of molecular and genetic knowledge has provided a new understanding of breast cancer as a heterogeneous disease that can be classified into different subtypes with distinct clinical and pathological features, therapeutic response patterns and outcomes. The influence that the molecular subtypes may have in breast cancer is better established in the early-stages, but less is known about the impact in patients presenting with metastatic disease. Objective: The main goal of this study was to evaluate the impact of molecular subtypes in patients with metastatic breast cancer (MBC) at diagnosis. Methods: We performed a retrospective study based in the review of clinical data from patients with MBC at diagnosis, between January of 2009 and December of 2015. Molecular subtypes were defined as Luminal A(LA), Luminal B(LB), Luminal B/HER2 positive (LB/HER2+), Nonluminal/HER2 positive (NL/HER2+) and Triple Negative (TN). Descriptive statistics and Kaplein-Meier survival curves were computed. Data were analysed using SPSS 23.0. Results: Were included 69 patients: 12 LA cases, 24 LB, 13 LB/ HER2+, 14 NL/HER2+ and 6 TN. The mean age at diagnosis was 65 years (34-88). The median overall survival was 18.3 months. In the entire cohort, the most frequently metastatic site observed was bone counting with 42 cases (60,9%) followed by liver with 20 patients (37,7%). Isolated bone metastasis (IBM) were observed in 36.2% of the patients and isolated visceral metastasis (IVM) in 34.8%, with 29% of the cases presenting with plurimetastasis (PM). Concerning to median survival, were registered 26.7 months, 16.1 months and 19.8 months, respectively for each subgroup. Relatively to molecular subtype analyses, the median survival of LA was 26.7 months, LB 16.7, LB/HER2 + 21.9, NL/ HER2 + 6.1 and TN 8.6. It was realized that IBM showed a predominance in Luminal MBC (LA, LB and LB/HER2+) and IVM in NL/HER2+ and TN. Although the reduced cohort, the subtype LA revealed a larger median survival in IBM subgroup. Conclusion: As described in literature, our study confirmed that bone is the most prevalent metastatic site in breast cancer, also with the highest median survival. Luminal subtypes of MBC appear to have a more favourable outcome, with better median survival, compared to NL/HER2+ and TN, which prognostic remains poor. We can conclude that molecular subtypes have impact in patients presenting with MBC. Nevertheless, is imperative to do more research to improve the outcomes of our patients.
Clinical Issues: Surgical Oncology
PO112 BREAST CANCER LIVER METASTASES: WHEN TO OPERATE Vítor Devezas, André Costa Pinho, Fabiana Sousa, Fernando Osório, Susy Costa, André Magalhães, Henrique Mora, Luis Afonso Graça, José Luis Fougo, José Costa-Maia Centro Hospitalar de São João, General Surgery, Porto, Portugal Introduction: Treatment of metastatic breast cancer has undergone considerable changes and recent advances in systemic therapies significantly increased survival. Regarding breast cancer liver metastasis (LM), selected patients may benefit from combining systemic therapies with liver therapies, namely resection. Objective: Comparing survival after LM diagnosis among those who did metastasectomy and those who did not. Material and Methods: Retrospective review of the clinical files of 55 female patients with breast cancer (mean age of 48 years), treated to histologically proven LM, from 2011 to 2016 in a single institution. The median follow up was 73 [10-316] months. Data were analyzed using SPSS®22.
Abstracts / The Breast 36 S1 (2017) S19–S76
PR110 IMPACT OF NEXT-GENERATION SEQUENCING (NGS) FOR PRIMARY ENDOCRINE RESISTANCE ON BREAST CANCER PATIENTS Zhenchuan Song1, Ruoyang Li1, Shuo Feng1, Tianli Hui1, Fugen Li2, Jingyu Li2, Jiajia Xu2 1 4th Hospital of Hebei Medical University, Breast Center, Shijiazhuang, China; 2Institute of Precision Medicine, 3D Medicines Inc., Shanghai, China Background: Multiple mechanisms have been detected to account for the acquired resistance to endocrine therapies in breast cancer. Evidence supports that PIK3CA mutation status may contribute to endocrine resistance. However, some clinical trial data show that whether PIK3CA mutate or not does not affect the therapeutic effect of TAM. In this study we retrospectively studied the mechanism of primary endocrine resistance in estrogen receptor (ER) positive breast cancer patients by NGS. Patients and Methods: Tumor specimens and matched blood samples were obtained from twenty-four breast cancer patients at the Fourth Hospital of Hebei Medical University, Shijiazhuang, China. All the patients were estrogen receptor (ER) positive, among which, fifteen patients displayed endocrine resistance (recurrence and/or metastases within 24 months from the beginning of endocrine therapy), and the other nine patients kept sensitive to endocrine therapy for more than 5 years. According to their medical records, all of the 24 patients were invasive breast cancer (T1-2, N1-2, M0). Tumor tissue was obtained from biopsy or surgery upon the initial diagnosis of cancer at the primary site, and tumor genomic DNA was extracted from formalin-fixed and paraffin-embedded (FFPE) tumor tissue blocks. Normal genomic DNA was extracted from peripheral blood mononuclear cells. Sequencing libraries for each samples were prepared followed by targets capturing for 372 genes that are frequently rearranged in cancers. Massive parallel sequencing was then performed using Illumina NextSeq 500, and samples with a mean sequencing depth of 500× were analyzed. Result: Three patients demonstrated HER2 copy number gains by NGS in each group, which was consistent with the IHC and FISH analysis. 8(55%) of 15 patients showed PIK3CA mutation (3 pathogenic variants in kinase domain, 3 pathogenic variants in helical domain, and 2 variants of unknown significance) in the endocrine-resistant group, and 3 (33%) of 9 patients displayed PIK3CA mutation (2 pathogenic variants in kinase domain and 1 pathogenic variant in helical domain) in the endocrine-sensitive group. In the sensitive group, copy number gain of C11orf30 (EMSY) gene, copy number loss of CDH1 (E-cadherin) gene, and a missense mutation of SF3B1 gene were also detected, which were supposed to decline the expression of the ESR1 and contribute to endocrine sensitivity. Conclusion: PIK3CA mutation rate in the resistance group is relatively higher than that in the sensitive group, which indicates that PIK3CA mutation may contribute to breast cancer primary endocrine resistance. If future studies were conducted with a larger spectrum of patients, results might be more conclusive.
PR111 IMPACT OF MOLECULAR SUBTYPES IN PATIENTS WITH METASTATIC BREAST CANCER AT DIAGNOSIS Tânia Madureira, Paulo Luz, David Dias, Raquel Dionísio, Beatriz Gosalbez, Irene Furtado Centro Hospitalar do Algarve, Serviço de Oncologia Médica, Faro, Portugal
Background: The increasing of molecular and genetic knowledge has provided a new understanding of breast cancer as a heterogeneous disease that can be classified into different subtypes with distinct clinical and pathological features, therapeutic response patterns and outcomes. The influence that the molecular subtypes may have in breast cancer is better established in the early-stages, but less is known about the impact in patients presenting with metastatic disease. Objective: The main goal of this study was to evaluate the impact of molecular subtypes in patients with metastatic breast cancer (MBC) at diagnosis. Methods: We performed a retrospective study based in the review of clinical data from patients with MBC at diagnosis, between January of 2009 and December of 2015. Molecular subtypes were defined as Luminal A(LA), Luminal B(LB), Luminal B/HER2 positive (LB/HER2+), Nonluminal/HER2 positive (NL/HER2+) and Triple Negative (TN). Descriptive statistics and Kaplein-Meier survival curves were computed. Data were analysed using SPSS 23.0. Results: Were included 69 patients: 12 LA cases, 24 LB, 13 LB/ HER2+, 14 NL/HER2+ and 6 TN. The mean age at diagnosis was 65 years (34-88). The median overall survival was 18.3 months. In the entire cohort, the most frequently metastatic site observed was bone counting with 42 cases (60,9%) followed by liver with 20 patients (37,7%). Isolated bone metastasis (IBM) were observed in 36.2% of the patients and isolated visceral metastasis (IVM) in 34.8%, with 29% of the cases presenting with plurimetastasis (PM). Concerning to median survival, were registered 26.7 months, 16.1 months and 19.8 months, respectively for each subgroup. Relatively to molecular subtype analyses, the median survival of LA was 26.7 months, LB 16.7, LB/HER2 + 21.9, NL/ HER2 + 6.1 and TN 8.6. It was realized that IBM showed a predominance in Luminal MBC (LA, LB and LB/HER2+) and IVM in NL/HER2+ and TN. Although the reduced cohort, the subtype LA revealed a larger median survival in IBM subgroup. Conclusion: As described in literature, our study confirmed that bone is the most prevalent metastatic site in breast cancer, also with the highest median survival. Luminal subtypes of MBC appear to have a more favourable outcome, with better median survival, compared to NL/HER2+ and TN, which prognostic remains poor. We can conclude that molecular subtypes have impact in patients presenting with MBC. Nevertheless, is imperative to do more research to improve the outcomes of our patients.
Clinical Issues: Surgical Oncology
PO112 BREAST CANCER LIVER METASTASES: WHEN TO OPERATE Vítor Devezas, André Costa Pinho, Fabiana Sousa, Fernando Osório, Susy Costa, André Magalhães, Henrique Mora, Luis Afonso Graça, José Luis Fougo, José Costa-Maia Centro Hospitalar de São João, General Surgery, Porto, Portugal Introduction: Treatment of metastatic breast cancer has undergone considerable changes and recent advances in systemic therapies significantly increased survival. Regarding breast cancer liver metastasis (LM), selected patients may benefit from combining systemic therapies with liver therapies, namely resection. Objective: Comparing survival after LM diagnosis among those who did metastasectomy and those who did not. Material and Methods: Retrospective review of the clinical files of 55 female patients with breast cancer (mean age of 48 years), treated to histologically proven LM, from 2011 to 2016 in a single institution. The median follow up was 73 [10-316] months. Data were analyzed using SPSS®22.