Nt Ueno

Long-term treatment efficacy in primary inflammatory breast cancer by hormonal receptor- and HER2-defined subtypes

BACKGROUND Subtypes defined by hormonal receptor (HR) and HER2 status have not been well studied in inflammatory breast cancer (IBC). We characterized clinical parameters and long-term outcomes, and compared pathological complete response (pCR) rates by HR/HER2 subtype in a large IBC patient population. We also compared disease-free survival (DFS) and overall survival (OS) between IBC patients who received targeted therapies (anti-hormonal, anti-HER2) and those who did not. PATIENTS AND METHODS We retrospectively reviewed the records of patients diagnosed with IBC and treated at MD Anderson Cancer Center from January 1989 to January 2011. Of those, 527 patients had received neoadjuvant chemotherapy and had available information on estrogen receptor (ER), progesterone receptor (PR), and HER2 status. HR status was considered positive if either ER or PR status was positive. Using the Kaplan-Meier method, we estimated median DFS and OS durations from the time of definitive surgery. Using the Cox proportional hazards regression model, we determined the effect of prognostic factors on DFS and OS. Results were compared by subtype. RESULTS The overall pCR rate in stage III IBC was 15.2%, with the HR-positive/HER2-negative subtype showing the lowest rate (7.5%) and the HR-negative/HER2-positive subtype, the highest (30.6%). The HR-negative, HER2-negative subtype (triple-negative breast cancer, TNBC) had the worst survival rate. HR-positive disease, irrespective of HER2 status, had poor prognosis that did not differ from that of the HR-negative/HER2-positive subtype with regard to OS or DFS. Achieving pCR, no evidence of vascular invasion, non-TNBC, adjuvant hormonal therapy, and radiotherapy were associated with longer DFS and OS. CONCLUSIONS Hormone receptor and HER2 molecular subtypes had limited predictive and prognostic power in our IBC population. All molecular subtypes of IBC had a poor prognosis. HR-positive status did not necessarily confer a good prognosis. For all IBC subtypes, novel, specific treatment strategies are needed in the neoadjuvant and adjuvant settings.

Identifying factors that impact survival among women with inflammatory breast cancer

BACKGROUND The objective of this retrospective study was to determine factors impacting survival among women with inflammatory breast cancer (IBC). METHODS The Surveillance, Epidemiology and End Results Registry (SEER) was searched to identify women with stage III/IV IBC diagnosed between 2004 and 2007. IBC was identified within SEER as T4d disease as defined by the sixth edition of the American Joint Committee on Cancer. The Kaplan-Meier product-limit method was used to describe inflammatory breast cancer-specific survival (IBCS). Cox models were fitted to assess the multivariable relationship of various patient and tumor characteristics and IBCS. RESULTS Two thousand three hundred and eighty-four women with stage IIIB/C and IV IBC were identified. Two-year IBCS among women with stage IIIB, IIIC and IV disease was 81%, 67% and 42%, respectively (P < 0.0001). In the multivariable model, patients with stage IIIB disease and those with stage IIIC disease had a 63% [hazard ratio (HR) 0.373, 95% confidence interval (CI) 0.296-0.470, P < 0.001] and 31% (HR 0.691, 95% CI 0.512-0.933, P = 0.016) decreased risk of death from IBC, respectively, compared with women with stage IV disease. Other factors significantly associated with decreased risk of death from IBC included low-grade tumors, being of white/other race, undergoing surgery, receiving radiation therapy and hormone receptor-positive disease. Among women with stage IV disease, those who underwent surgery of their primary had a 51% decreased risk of death compared with those who did not undergo surgery (HR = 0.489, 95% CI 0.339-0.704, P < 0.0001). CONCLUSIONS Although IBC is an aggressive subtype of locally advanced breast cancer, it is heterogeneous with various factors affecting survival. Furthermore, our results indicate that a subgroup of women with stage IV IBC may benefit from aggressive combined modality management.

Circulating tumor cells in metastatic inflammatory breast cancer

BACKGROUND Inflammatory breast cancer (IBC) is the most aggressive form of breast cancer. Circulating tumor cells (CTCs) are an independent prognostic factor in metastatic breast cancer. The aim of this study was to assess the prognostic value of baseline CTCs in metastatic IBC patients. PATIENTS AND METHODS This retrospective study included 42 metastatic IBC and 107 metastatic non-IBC patients treated with first- or second-line chemotherapy from January 2004 to December 2007 at MD Anderson Cancer Center. CTCs were detected and enumerated before patients started chemotherapy using the CellSearch system. RESULTS Ten (23.8%) IBC patients versus 48 (44.9%) non-IBC patients had baseline CTCs > or =5 per 7.5 ml of peripheral blood. IBC patients had a lower mean +/- SEM CTCs than non-IBC patients (7.6 +/- 2.9 versus 34.2 +/- 9.1; P = 0.02). The estimated median overall survival was 26.5 versus 18.3 months (P = 0.68) in IBC patients and 37.4 versus 18.3 months (P = 0.016) in non-IBC patients with CTCs <5 and CTCs > or =5, respectively. CONCLUSIONS Metastatic IBC patients had a lower prevalence and fewer CTCs in comparison to metastatic non-IBC patients. Survival of metastatic IBC patients with <5 CTCs was not significantly better than that of patients with > or =5 CTCs. Further research is warranted with prospective assessment of CTCs in IBC patients and their biological characterization.

Incidence of and survival following brain metastases among women with inflammatory breast cancer

BACKGROUND The purpose of this study was to determine the incidence of and survival following brain metastases among women with inflammatory breast cancer (IBC). PATIENTS AND METHODS Two hundred and three women with newly diagnosed stage III/IV IBC diagnosed from 2003 to 2008, with known Human epidermal growth factor receptor 2 (HER2) and hormone receptor status, were identified. Cumulative incidence of brain metastases was computed. Survival estimates were computed using the Kaplan-Meier product limit method. Multivariable Cox proportional hazards models were fitted to explore the relationship between breast tumor subtype and time to brain metastases. RESULTS Median follow-up was 20 months. Thirty-two (15.8%) patients developed brain metastases with a cumulative incidence at 1 and 2 years of 2.7% and 18.7%, respectively. Eleven (5.3%) patients developed brain metastases as the first site of recurrence with cumulative incidence at 1 and 2 years of 1.6% and 5.7%, respectively. Compared with women with triple receptor-negative IBC, those with hormone receptor-positive/HER2-negative disease [hazard ratio (HR) = 0.55, 95% confidence interval (CI) 0.19-1.51, P = 0.24] had a decreased risk of developing brain metastases, and those with HER2-positive disease (HR = 1.02, 95% CI 0.43-2.40, P = 0.97) had an increased risk of developing brain metastases, although these associations were not statistically significant. Median survival following a diagnosis of brain metastases was 6 months. CONCLUSION Women with newly diagnosed IBC have a high early incidence of brain metastases associated with poor survival and may be an ideal cohort to target for site-specific screening.

Characterization of Metastatic Breast Cancer Patients with Non-Detectable Circulating Tumor Cells.

Background: Circulating tumor cells (CTC) are independent predictor of progression free and overall survival in metastatic breast cancer patients, with superior prognosis for patients with CTC Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3006.

Abstract P3-12-06: Statin use and outcome among breast cancer patients treated with neoadjuvant systemic chemotherapy

BACKGROUND: Statins are cholesterol-reducing agents that affect intracellular pathways associated with tumorigenesis and inflammation. Preclinical studies have demonstrated that statins have anti-tumor effects and epidemiological studies have suggested that the use of HMG-CoA-reductase inhibitors is associated with improved long-term outcomes among breast cancer patients. In this study we sought to evaluate the effect of statins in the pathologic complete response (pCR) and survival outcomes among breast cancer patients receiving neoadjuvant systemic chemotherapy (NST). METHODS: Retrospective study including patients diagnosed between 1995-2007 with invasive primary breast cancer. All patients received neoadjuvant systemic chemotherapy. Use of statins during NST was identified by review of medical records. We compared pCR rate, relapse-free survival (RFS), disease-specific survival (DSS) and overall survival (OS) between statin-users and non-users. pCR was defined as no evidence of invasive carcinoma in the breast and axillary lymph nodes at the time of surgery. Descriptive statistics and Cox proportional hazards model were used in the analyses. RESULTS: From the 1449 patients included, 74 (5.11%) were treated with statin during NST. Statin users were more likely to be older, overweight/obese and more likely to be also treated with beta-blockers or metformin. No differences in pCR were observed according to statin use (16.2% vs 17.6% p = 0.75). In the multivariable model, the use of statin was not an independent predictor of pCR. With 55 months of follow-up (415 recurrences and 359 deaths), the 5-year RFS was 82% in the statin-treated patients and 70% in the non-statin treated group (p = 0.03), no differences were seen in DSS or OS. Subset analyses according to tumor subtype demonstrated patients with hormone receptor-positive tumors treated with statins had better 5-year RFS (93% vs 76%; p = 0.01). In the multivariable model, no association was observed between statin use and outcome. CONCLUSIONS: In our cohort of patients, statin use during NST was not independently associated with pCR, RFS, DSS and OS. Further studies with larger number of statin-treated patients are warranted to clarify the role of HMG-CoA reductase inhibitors in the treatment of breast cancer patients. In addition future studies should evaluate the effect of prolonged statin use and take the different type of statin subtype into account. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-12-06.

Abstract PD03-06: Simvastatin radiosensitizes differentiated and stem-like breast cancer cell lines and is associated with improved local control in inflammatory breast cancer patients treated with post-mastectomy radiation

Among women with non-inflammatory triple-negative and triple-negative inflammatory breast cancer (IBC), the 5-yr actuarial rates of local failure after radiation are 11%–35% and 45%, respectively, in part influenced by the contribution of radioresistant cancer stem cells to these cancers. Herein we explored the radiosensitization of breast cancer stem-like cells in vitro and examined the influence on local control after post-mastectomy radiation (PMRT) among IBC patients taking statins. SUM149, SUM159 and MCF-7 cells were cultured in standard monolayer cultures and stem cell enriching anchorage independent clonogenic cultures with simvastatin and treated with increasing concentrations of radiation. Survival curves were generated and t-test was used to compare surviving fraction (SF) of groups. p Simvastatin radiosensitized all cell lines in both types of clonogenic culture assays. The triple-negative IBC cell line SUM149 had the greatest response to combined treatment regardless of the radiation dose used in monolayer cultures (SF2: 0.417 vs 0.319, SF4: 0.136 vs 0.075, SF6: 0.026 vs 0.018, in control vs treated respectively, all p Patients with IBC and triple negative non-IBC breast cancer have the highest rates of local failure and no available known radiosensitizers. Here we report significant improvement in local control after PMRT among statin users with IBC and significant radiosensitization across triple-negative and IBC cell lines of multiple subtypes using simvastatin. Clinical value in patients without hypercholesterolemia remains to be established. These encouraging data suggest simvastatin may be an appropriate radiosensitizing agent for clinical trials. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD03-06.

Predictive Value of Circulating Tumor Cells (CTCs) in Metastatic Breast Cancer Patients Treated by Bevacizumab-Based Therapy.

Background:Circulating tumor cells (CTC) are involved in cancer dissemination and are an independent prognostic factor in metastatic breast cancer (MBC). Antiangiogenic, bevacizumab-based chemotherapy improves response rate and progression free survival in patients with metastatic breast cancer (MBC), without impact on overall survival. Preclinical data suggest the possibility of increased metastatic potential of tumor cells pretreated by anti-angiogenic therapy (Ebos et al. Cancer Cell 2009,15: 232–9). The aim of this study was to determine the prognostic value of CTC in MBC patients treated by bevacizumab-based therapy.Patients and Methods: This retrospective study included 48 MBC treated with bevacizumab combined chemotherapy regimens and 46 patients treated with chemotherapy alone between January 2004 and December 2008 at M.D.Anderson Cancer Center. CTCs were detected and enumerated before patients started therapy using the CellSearch™ system (Veridex, LLC, NJ, USA). Progression free survival (PFS) and overall survival (OS) were calculated from the date of CTC measurement, estimated by the Kaplan-Meier product limit method, and compared between groups with the log-rank test.Results: At a median follow up of 10.1 months (range: 1-26 months), 22 patients (45.8%) had died. The estimated medians of PFS in bevacizumab-treated patients were 8.1 vs. 5.2 months (p = 0.42) in patients with baseline Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3013.

Abstract P6-12-02: Survival differences between patients with metastatic inflammatory and non-inflammatory breast cancer

Background: Very little is known about the survival of patients with inflammatory breast cancer (IBC) and distant metastasis. Furthermore, the American Joint Committee on Cancer classification of breast cancer does not recognize metastatic IBC as a distinct entity within stage IV. We hypothesized that the survival of patients with IBC and distant metastasis is worse than the survival of patients with stage-matched non-IBC. Patients and Methods: We retrospectively reviewed 5314 consecutive patients with stage III or IV breast cancer (IBC or non-IBC) who were treated at our institution between 1986 and 2012. A total of 1079 patients presented with IBC (stage III: 861; stage IV: 218) and 4235 non-IBC (stage III: 2781; stage IV: 1454). We compared the time to distant metastasis from initial diagnosis, distant metastasis–free survival (DMFS), and overall survival (OS) in stage-matched patients with IBC or non-IBC. Results: The median follow-up periods were 3.3 years for patients with stage III disease (range, 0-32.2 years) and 1.8 years for patients with stage IV disease (range, 0-19.9 years). The total number of recorded events (metastasis/death) was 1657 for stage III, while the numbers of deaths for stage III and IV were 1337 and 973, respectively. In patients with stage III, the time to distant metastasis was shorter in IBC than in non-IBC (median 1.3 vs. 1.7 years, P P P P = .83). In multivariate analysis, the diagnosis of IBC remained significantly associated with mortality after adjusting for potential confounders. De novo stage IV IBC presented more frequently with multiple sites of metastasis than de novo stage IV non-IBC ( P = .02). In patients with de novo stage IV disease, OS was shorter in IBC than in non-IBC (2.3 vs. 3.4 years, P = .004). In the multicovariate Cox model, while ethnicity, tumor grade, hormone receptor status and HER2 status, site of metastasis, number of sites of metastasis, and definitive breast surgery by 1 year were all significant factors in OS for stage IV breast cancer, the diagnosis of IBC conferred a hazard ratio of 1.33 (95% confidence interval: 1.05 - 1.69) in multivariate analysis. Conclusion: Our findings suggest that IBC patients with metastasis at diagnosis have worse outcomes than stage-matched non-IBC patients. IBC patients presenting with de novo stage IV disease should be considered as a separate subcategory of stage IV in the tumor-node-metastasis classification because their clinical course and prognosis are different from those of patients with stage IV non-IBC. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-12-02.

Abstract PD03-08: Statin use and improved outcome in primary inflammatory breast cancer: retrospective cohort study

Background Inflammatory breast cancer (IBC) is the most aggressive type of breast cancer. HMG-CoA reductase inhibitors (statins) are cholesterol reducing agents with pleiotropic effects, including antitumorigenic and anti-inflammatory properties. We hypothesized that statins reduce the metastatic potential in primary IBC. Methods We retrospectively reviewed 724 patients diagnosed with and treated for primary IBC at The University of Texas MD Anderson Cancer Center between Jan. 12, 1995 and Jan. 27, 2011. Patients with records indicating statin use at the time of IBC diagnosis on the electronic medical record were compared with those without. We further compared outcomes stratified by statin type (hydrophilic [H] versus lipophilic [L]). We used the Kaplan-Meier method to estimate the median disease-free survival (DFS) after surgery, overall survival (OS), and disease specific survival (DSS), followed by Cox proportional hazards regression model to test statistical significance of several potential prognostic factors. Results For primary IBC patients who had information on their statin use status at IBC diagnosis, the median DFS time were 4.88 years, 2.47 years and 1.76 years (P= 0.04); the median OS time 5.05 years, 3.79 years and 4.32 years (P= 0.35); and the median DSS time 5.10 years, 3.79 years and 4.52 years (P= 0.37), for patients who took “ H”, “L” and no statin, respectively. In multivariable Cox model stratified by radiation therapy, ER/PR status and HER2 status, statin “H” use was associated with significantly improved DFS compared to no statin use (HR=0.49; 95% CI: 0.28–0.84; p Conclusions Hydrophilic statin use was associated with improved DFS. There was a trend for reduced HR in OS and DSS among primary IBC patient who used hydrophilic statins. A prospective randomized study to evaluate the potential survival benefits of statins in primary IBC population is warranted. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD03-08.