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PU-H71 Enhances Radiosensitivity of Breast Carcinoma Cells Metastasized to Vital Organs
Volume 96 Number 2S Supplement 2016 Materials/Methods: Cases diagnosed from 2010-2012 were obtained from the SEER database with inclusion criteria for women 70 years old and above, diagnosed with T1-2N0M0 as well as known status of hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2). They were grouped for analysis as: HR+/HER2-, HR-/HER2+, HR+/ HER2+, and triple-negative (TN). Kaplan-Meier and Cox multivariate regression analysis of overall survival (OS) and cause specific survival (CSS) was performed. Results: A total of 13736 patients were identified, of whom 9652 (70.3%) received BCT and 4084 (29.7%) underwent mastectomy. Patient distribution was 82.8% HR+/HER2- , 2.2% HR-/HER2+ , 5.9% HR+/HER2+and 9.1% TN. With a median follow-up of 20 months (range, 1-35 months), women undergoing BCT had improved OS (98.0%VS 95.0%, P<0.001) and CSS (99.7%VS 98.8%, P<0.001) when compared to women with mastectomy. When the patients were subdivided by tumor subtypes, the BCT group continued to show better OS and CSS compared with the mastectomy group in all of the subgroups except HR+/HER2+. In the subtype group of HR+/HER2-, OS and CSS was 98.2% and 99.8% after BCT and 95.8% and 99.3% after mastectomy (both P<0.001). The results were similar for HR-/HER2+ and TN subgroups favoring BCT group. However, no significant difference in CSS was observed between BCT and mastectomy for HR+/HER2+ subgroup (P Z 0.873). Cox Regression analysis showed that BCT resulted in OS (HR 0.49, 95% CI 0.40 e 0.61, P<0.001) and CSS (HR 0.41, 95% CI 0.26-0.65, P<0.001) better than that of mastectomy. The CSS benefit with BCT compared to mastectomy was greater among HR+/HER2-subgroup (HR 0.4, 95% CI 0.21e0.77) than among TN subgroup (HR 0.45, 95% CI 0.21e0.99); however, this trend was not observed among the other two subgroups. Conclusion: Elderly patients (70 years old) with early stage breast cancer who underwent BCT have better CSS and OS compared with those treated with mastectomy alone. These results provide confidence that BCT is an effective alternative to mastectomy for elderly patients with early stage disease regardless of tumor subtypes. Further investigation is warranted. Author Disclosure: W. Chen: None. Y. Huang: None. S. Szeja: None. S.S. Hatch: None. A.M. Farach: None. E. Butler: None. B.S. Teh: None.
2069 PU-H71 Enhances Radiosensitivity of Breast Carcinoma Cells Metastasized to Vital Organs S. Kale,1 A.F. Korcum,2 E. Dundar,3 and N. Erin4; 1Akdeniz University, School of Medicine, Department of Pharmacology, Antalya, Turkey, 2 Akdeniz Uni. School of Medicine, Department of Radiation Oncology, Antalya, Turkey, 3Akdeniz University, School of Medicine, Department of Radiation Oncology, Antalya, Turkey, 4Akdeniz University, School of Medicine. Department of Pharmacology, Antalya, Turkey Purpose/Objective(s): HSP90 (Heat shock protein 90) inhibitors are considered as new radiosensitizing agents. PU-H71, a novel HSP90 inhibitor, is under evaluation for treatment of advanced cancer in Phase I trials. It is however not known whether PU-H71 alters radiosensitivity of metastatic breast cancer. The goal of the present study was to evaluate possible anti-tumoral and radiosensitizing effects of PU-H71 on breast carcinoma cells metastasized to vital organs such as liver and brain. Furthermore possible changes in client proteins were also evaluated. Materials/Methods: Effect of PU-H71 in murine aggressive breast carcinoma cells (4T1) and its brain (4TBM), liver (4TLM), heart (4THM) metastatic subsets, as well as non-metastatic 67NR cells were determined using MTT-based cell proliferation assay. Changes in radiation sensitivity were determined by clonogenic assays. Changes in client proteins were examined using Western blotting. Results: PU-H71 alone inhibited ERK1/2, p38, Akt activation, and reduced HER2 which are client proteins of HSP90. The combination of PU-H71 and radiation therapy induced synergistic cytotoxicity and PUH71 showed radiosensitizing effect in vitro. On the other hand PU-H71 and radiation co-treatment increased p38 phosphorylation which is one of the hallmarks of inflammatory response.
Poster Viewing
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Conclusion: These results demonstrate for the first time that PU-H71 may enhance therapeutic effects of radiation therapy especially in highly metastatic breast carcinoma cells and decrease level/activity of tumorigenic client proteins. Author Disclosure: S. Kale: None. A. Korcum: None. E. Dundar: None. N. Erin: None.
2070 Role of Radiation Therapy and Its Impact on Survival of Male Breast Cancer Patients: Experience From a Tertiary Cancer Center R. Upadhyay,1 D.N. Sharma,1 A.K. Gandhi,1 K. Haresh,2 S. Deo,3 A. Gogia,1 P. Kumar,1 S. Gupta,1 and R. Pandey4; 1All India Institute of Medical Sciences, New Delhi, India, 2All India Institute of Medical Sciences, New Delhi, India, New Delhi, India, 3All India Institute of Medical Sciences, New Delhi, India, 4Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India Purpose/Objective(s): Male breast Cancer (MBC) is a rare disease accounting for about 1% of all malignancies in men and 1% of all breast cancers. These patients are managed similar to female breast cancers. There is limited literature available defining the role of radiation therapy (RT) in management of MBC. We conducted a retrospective analysis to study the impact of adjuvant RT on outcome of MBC patients treated at our center. Materials/Methods: Review of MBC patients presenting to our center from 2005 to 2015 was done. All underwent pre-treatment evaluation in a combined tumor clinic comprising of radiation, surgical and medical oncologist. Most patients were treated with surgery followed by adjuvant therapy and kept on regular follow up. Overall survival (OS) was defined as time duration from pathologic diagnosis to last follow up or death. Disease free survival (DFS) was defined as time duration from diagnosis to first recurrence. Survival rates were estimated by Kaplan-Meier method and outcome was compared using log-rank test. Predictive analytics software was used for all statistical analysis and P-value <0.05 was considered significant. Results: Ninety-six patients of MBC were identified. Median age was 58 years (range 28-83). Patients with clinical stage I, II, III and IV were 8, 27, 39, and 22 respectively. Of 66 patients with known receptor status, 83% were estrogen receptor(ER) positive, 82% were progesterone receptor(PR) positive, 20% were Her-2/neu positive and 7.5% were triple negative. 69 patients underwent (modified) radical mastectomy or wide local excision. 54% were pathologically node positive. Adjuvant RT was delivered to 33 (34%) patients at 1.8-2 Gy per fraction to a median dose of 50 Gy (range 45-60 Gy). The field of radiation comprised of chest wall (25%) or chest wall with regional lymphatics (75%). 39, 42 and 2 patients received adjuvant chemotherapy (CT), Tamoxifen and antiHER-2 therapy respectively. Median follow up was 12 months (range 2-132). Sixteen patients had relapse out of which 4(4%) had local and 13(14%) had distant (most common site bone) metastases after a median duration of 19 months (range 2-108). The 2 year estimated DFS for the entire cohort was 79.2% and 2 year OS was 85.7%. The 2 year DFS in patients undergoing surgery was 86.4% vs 29.2% in those who did not (P Z 0.001). Patients who received adjuvant RT had better 2 year DFS (92.4% vs 52.9%, P Z 0.002). Adjuvant chemotherapy did not significantly affect the 2 year DFS (93.1% vs 73%, P Z 0.123).There was no statistically significant impact on 2 year DFS for patients with age > 50 years, tumor laterality, early (Stage 1-2) disease, ER positive and Her-2/neu negative patients. Conclusion: MBC mostly present in advance stages at our center and harbor HR positive disease with low HER-2 overexpression. Adjuvant RT provided a statistically significant improvement in outcome. Longer follow up of these cohorts of patients is required for accurate evaluation of role of RT in MBC. Author Disclosure: R. Upadhyay: None. D. Sharma: None. A.K. Gandhi: None. K. Haresh: None. S. Deo: None. A. Gogia: None. P. Kumar: None. S. Gupta: None. R. Pandey: None.
2069 PU-H71 Enhances Radiosensitivity of Breast Carcinoma Cells Metastasized to Vital Organs S. Kale,1 A.F. Korcum,2 E. Dundar,3 and N. Erin4; 1Akdeniz University, School of Medicine, Department of Pharmacology, Antalya, Turkey, 2 Akdeniz Uni. School of Medicine, Department of Radiation Oncology, Antalya, Turkey, 3Akdeniz University, School of Medicine, Department of Radiation Oncology, Antalya, Turkey, 4Akdeniz University, School of Medicine. Department of Pharmacology, Antalya, Turkey Purpose/Objective(s): HSP90 (Heat shock protein 90) inhibitors are considered as new radiosensitizing agents. PU-H71, a novel HSP90 inhibitor, is under evaluation for treatment of advanced cancer in Phase I trials. It is however not known whether PU-H71 alters radiosensitivity of metastatic breast cancer. The goal of the present study was to evaluate possible anti-tumoral and radiosensitizing effects of PU-H71 on breast carcinoma cells metastasized to vital organs such as liver and brain. Furthermore possible changes in client proteins were also evaluated. Materials/Methods: Effect of PU-H71 in murine aggressive breast carcinoma cells (4T1) and its brain (4TBM), liver (4TLM), heart (4THM) metastatic subsets, as well as non-metastatic 67NR cells were determined using MTT-based cell proliferation assay. Changes in radiation sensitivity were determined by clonogenic assays. Changes in client proteins were examined using Western blotting. Results: PU-H71 alone inhibited ERK1/2, p38, Akt activation, and reduced HER2 which are client proteins of HSP90. The combination of PU-H71 and radiation therapy induced synergistic cytotoxicity and PUH71 showed radiosensitizing effect in vitro. On the other hand PU-H71 and radiation co-treatment increased p38 phosphorylation which is one of the hallmarks of inflammatory response.
Poster Viewing
E29
Conclusion: These results demonstrate for the first time that PU-H71 may enhance therapeutic effects of radiation therapy especially in highly metastatic breast carcinoma cells and decrease level/activity of tumorigenic client proteins. Author Disclosure: S. Kale: None. A. Korcum: None. E. Dundar: None. N. Erin: None.
2070 Role of Radiation Therapy and Its Impact on Survival of Male Breast Cancer Patients: Experience From a Tertiary Cancer Center R. Upadhyay,1 D.N. Sharma,1 A.K. Gandhi,1 K. Haresh,2 S. Deo,3 A. Gogia,1 P. Kumar,1 S. Gupta,1 and R. Pandey4; 1All India Institute of Medical Sciences, New Delhi, India, 2All India Institute of Medical Sciences, New Delhi, India, New Delhi, India, 3All India Institute of Medical Sciences, New Delhi, India, 4Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India Purpose/Objective(s): Male breast Cancer (MBC) is a rare disease accounting for about 1% of all malignancies in men and 1% of all breast cancers. These patients are managed similar to female breast cancers. There is limited literature available defining the role of radiation therapy (RT) in management of MBC. We conducted a retrospective analysis to study the impact of adjuvant RT on outcome of MBC patients treated at our center. Materials/Methods: Review of MBC patients presenting to our center from 2005 to 2015 was done. All underwent pre-treatment evaluation in a combined tumor clinic comprising of radiation, surgical and medical oncologist. Most patients were treated with surgery followed by adjuvant therapy and kept on regular follow up. Overall survival (OS) was defined as time duration from pathologic diagnosis to last follow up or death. Disease free survival (DFS) was defined as time duration from diagnosis to first recurrence. Survival rates were estimated by Kaplan-Meier method and outcome was compared using log-rank test. Predictive analytics software was used for all statistical analysis and P-value <0.05 was considered significant. Results: Ninety-six patients of MBC were identified. Median age was 58 years (range 28-83). Patients with clinical stage I, II, III and IV were 8, 27, 39, and 22 respectively. Of 66 patients with known receptor status, 83% were estrogen receptor(ER) positive, 82% were progesterone receptor(PR) positive, 20% were Her-2/neu positive and 7.5% were triple negative. 69 patients underwent (modified) radical mastectomy or wide local excision. 54% were pathologically node positive. Adjuvant RT was delivered to 33 (34%) patients at 1.8-2 Gy per fraction to a median dose of 50 Gy (range 45-60 Gy). The field of radiation comprised of chest wall (25%) or chest wall with regional lymphatics (75%). 39, 42 and 2 patients received adjuvant chemotherapy (CT), Tamoxifen and antiHER-2 therapy respectively. Median follow up was 12 months (range 2-132). Sixteen patients had relapse out of which 4(4%) had local and 13(14%) had distant (most common site bone) metastases after a median duration of 19 months (range 2-108). The 2 year estimated DFS for the entire cohort was 79.2% and 2 year OS was 85.7%. The 2 year DFS in patients undergoing surgery was 86.4% vs 29.2% in those who did not (P Z 0.001). Patients who received adjuvant RT had better 2 year DFS (92.4% vs 52.9%, P Z 0.002). Adjuvant chemotherapy did not significantly affect the 2 year DFS (93.1% vs 73%, P Z 0.123).There was no statistically significant impact on 2 year DFS for patients with age > 50 years, tumor laterality, early (Stage 1-2) disease, ER positive and Her-2/neu negative patients. Conclusion: MBC mostly present in advance stages at our center and harbor HR positive disease with low HER-2 overexpression. Adjuvant RT provided a statistically significant improvement in outcome. Longer follow up of these cohorts of patients is required for accurate evaluation of role of RT in MBC. Author Disclosure: R. Upadhyay: None. D. Sharma: None. A.K. Gandhi: None. K. Haresh: None. S. Deo: None. A. Gogia: None. P. Kumar: None. S. Gupta: None. R. Pandey: None.