Metastatic Triple-negative Breast Cancer Patients Research Articles

A comparative effectiveness analysis of single-agent cytotoxics in triple-negative metastatic breast cancer patients.

157 Background: There has been considerable progress in treatments for MBC. However, the identification of optimal cytotoxic agents in patients with triple negative disease (negative for hormone receptors, ER/PR and HER-2) remains a therapeutic challenge. A comparative effectiveness analysis of four cytotoxic agents was conducted in patients with TN MBC. Methods: We retrospectively identified 225 patients treated with single agent eribulin (E=47), capecitabine (C=69), gemcitabine (G=56) or vinorelbine (V=53) in 19 community oncology clinics across the US. Data collection included baseline patient characteristics, performance status, duration of current therapy, growth factor use and all dose limiting toxicities. Time to treatment failure (TTF) was measured from the first cycle of chemotherapy until disease progression, discontinuation due to toxicity, or death. TTF was then estimated using the Kaplan-Meier method and Cox proportional hazard modeling adjusted for clustering on the practice site. To control for selection bias that is inherent in observational studies, a propensity score weighted TTF analysis was also conducted. Results: Patients were comparable with respect to age, performance status, duration of disease free survival, presence of comorbidities and hemoglobin level prior to the start of chemotherapy. However, the median lines of therapy for use of C, G, V and E were 2nd, 3rd, 3rd, and 4th, respectively. The median duration of treatment was approximately 2 months with C, G, and E compared to 1.6 months with V. Using eribulin as the reference and adjusting for line of therapy and associated prognostic factors, the propensity score weighted Cox regression analysis did not identify statistically significant differences in TTF: C vs. E: HR = 1.15 (0.75 to 1.76), G vs. E: HR = 0.62 (0.34 to 1.13), V vs. E: HR = 1.0 (0.60 to 1.37). Conclusions: In patients with TN-MBC treated in a community oncology setting, eribulin was utilized in later lines than other agents. However, eribulin demonstrated at least comparable drug activity even when used in more heavily pretreated patients. These findings warrant further analyses in a larger population with an evaluation of biologic heterogeneity.

Platinum-based chemotherapy in triple-negative advanced breast cancer.

The purpose of this study was to evaluate the efficacy of platinum-based chemotherapy (PBC) versus conventional non-PBC regimens in a metastatic triple-negative breast cancer (TNBC)setting. We reviewed the electronic patient records of patients with confirmed metastatic TNBC at four major cancer centres in Canada. All patients were allocated into two groups based on type of chemotherapy received (PBC vs. non-PBC) and line of treatment (first-, second-, or third-line). The primary objective of this study was to evaluate the efficacy of PBC in metastatic TNBC in terms of median duration of overall survival (OS) from diagnosis of distant metastatic disease and compare it with the efficacy of conventional non-platinum-based chemotherapy in metastatic TNBC after controlling for known prognostic factors. A total of 153 metastatic TNBC patients were identified, 58 treated with PBC and 95 with non-PBC. The median time in first-line PBC versus non-PBC was not different between the two groups (2 vs. 2 months, p=0.9), the median time on treatment in second and third-line therapy was longer for the PBC group compared to the conventional treated group (4 vs. 1 months, p=0.004; 4 vs. 0.5 months, p=0.004, respectively). Patients who received PBC had a longer OS compared to those managed conventionally (14.5 vs. 10 months, p=0.041). This study evaluates the survival outcomes in a homogenous group of TNBC metastatic patients treated with or without PBC. Our results confirmed our hypothesis of a better OS among PBC-treated TNBC patients compared to conventionally managed TNBC patients. Currently ongoing Phase III trials assessing the benefit of PBC versus other chemotherapeutic regimens in advanced TNBC will help define the role of these agents for the management of this breast cancer subtype.

Monitoring of circulating tumor DNA in metastatic triple-negative breast cancer patients undergoing chemotherapy.

e22056 Background: Triple negative breast cancer (TNBC) is associated with aggressive histological features, high relapse rates, and poor overall survival. To improve the management of TNBC patient...

Abstract P1-04-01: Significance of circulating tumor cells in metastatic triple negative breast cancer: Results of an open label, randomized, phase II trial of nanoparticle albumin-bound paclitaxel with or without the anti-death receptor 5 tigatuzumab (TBCRC 019)

Abstract Background: Circulating Tumor cells (CTCs) are prognostic at baseline and first follow-up in patients with metastatic breast cancer (MBC). Using the most commonly used assay (CellSearch®), we have previously reported the ability to detect apoptotic vs. non-apoptotic CTCs in patients with MBC. However, there has been concern regarding the performance of the CellSearch® assay in patients with triple negative (TN) MBC. We hypothesized that CellSearch® is an effective assay in patients with TN MBC, and that CTC-apoptosis might further separate prognosis. Therefore, we studied CTCs in patients with TN MBC who participated in a prospective randomized phase II trial testing for activity of tigatuzumab (TIG) in combination with nanoparticle albumin-bound paclitaxel (nab-PAC) conducted by the Translational Breast Cancer Research Consortium (overall results reported by Forero A., et al, ASCO 2013). Methods: Whole blood (WB) was drawn into a CellSave tube at baseline, day 15, and day 29 and CTC counts were determined using the CXC CellSearch® kit. Apoptosis was characterized by staining with a monoclonal antibody that detects a neo-epitope on fragmented cytokeratin (M-30) and independently by visual inspection (nucleic condensation and/or fragmentation, as well as granular cytokeratin). Association between levels of CTCs and CTC-apoptosis with the overall response rate (ORR) and progression free survival (PFS) at baseline, day 15, and day 29 was assessed using logistic regression, Kaplan Meier curves, and Cox proportional hazards modeling. Results: Of the 60 patients entered into the trial, 52 were evaluable for CTCs. Of these, 19/52 (36.5%), 14/52 (26.9%), and 13/49 (26.5%) had elevated CTCs (≥5CTC/7.5 ml WB) at baseline, day 15, and day 29, respectively. Patients with elevated CTCs at each time point had worse PFS than patients with low or no CTCs. Hazard rates (HR) at baseline, day 15, and day 29 were 2.38 (95% CI: 1.27-4.45, p = 0.007), 2.87 (95% CI: 1.46-5.66, p = 0.002), and 3.40 (95% CI: 1.68-6.89, p = 0.001), respectively. The odds of overall response for those who had elevated CTCs compared to those who did not at baseline, day 15, and day 29, were 0.25 (95% CI: 0.073-0.81, p = 0.024), 0.18 (95% CI: 0.04-0.67, p = 0.014), and 0.06 (95% CI: 0.01-0.28, p = 0.001), respectively. There was no apparent prognostic effect comparing the degree of CTC-apoptosis vs. non-apoptosis. Conclusions: Similar to observations in other intrinsic subgroups, CTCs were detected in a large fraction of TN MBC patients at baseline using CellSearch® assay, and reductions in CTC levels reflected response. In these homogenously prospectively enrolled TN MBC patients, regardless of treatment, CTCs are prognostic at baseline, day 15, and day 29. It does not appear that analysis of CTC-apoptosis is prognostic. Supported by Susan G. Komen for the Cure, Veridex, LLC, Fashion Footwear Charitable Foundation of New York/QVC Presents Shoes on Sale™ (DFH), Associazione Sandro Pitigliani and by a studentship from FIRC (CP), Triple Negative Breast Cancer Foundation, The AVON Foundation, and The Breast Cancer Research Foundation. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-04-01.

Abstract PD5-3: Anti-metastatic activity, chemotherapeutic enhancement and therapeutic potential of targeting Hsp90 with ganetespib in triple negative breast cancer

Abstract Background: While the incidence of triple negative breast cancer (TNBC) is only 10-20%, these tumors show a disproportionate mortality for breast cancer patients. Due to a lack of effective molecular targets in this disease, therapeutic options are largely limited to systemic chemotherapeutic approaches which have shown disappointing efficacy in the metastatic setting. Here we undertook a comprehensive evaluation of the activity of the drug candidate, ganetespib, a potent inhibitor of heat shock protein 90 (Hsp90), in this malignancy. Methods: The sensitivity of TNBC cells to ganetespib was determined in viability assays using a panel of tumor lines. The effects of ganetespib exposure on client proteins and their effector pathways were examined by Western blot and reverse phase protein array analysis. The anti-metastatic activity of ganetespib was evaluated using a 4T1 metastasis model. Combinatorial drug analyses were performed with chemotherapeutic agents. DNA damage and cell cycle disruption were assessed using the comet assay, Western blotting and fluorescence microscopy. The in vivo efficacy of the compound, both as a single agent and in combination, was established using MDA-MB-231 xenograft models. Computed tomography scans were obtained for a metastatic TNBC patient undergoing ganetespib treatment. Results: Ganetespib reduced cell viability in TNBC cell lines with low nanomolar potency. Ganetespib treatment induced robust destabilization of multiple client proteins and oncogenic signaling pathways and suppressed lung metastasis in the experimental model. Ganetespib potentiated the cytotoxic activity of doxorubicin via enhanced DNA damage and mitotic arrest, conferring superior efficacy to the doxorubicin + cyclophosphamide (AC) regimen in MDA-MB-231 xenograft models. Ganetespib also promoted mitotic catastrophe and apoptosis in combination with taxanes in vitro, and these effects translated to significantly improved combinatorial activity in vivo. Marked tumor shrinkage of metastatic lung lesions was seen in the patient while on ganetespib monotherapy. Conclusion: The preclinical activity profile and clinical evidence of tumor regression suggest that ganetespib offers considerable promise as a new therapeutic candidate to target TNBC. In particular, the capacity of ganetespib to potentiate the activity of standard of care chemotherapeutics provides a rationale for the exploration of this agent in novel combinatorial treatment strategies for this disease. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD5-3.

Abstract 2397: Correlation between biomarker status and response to EGFR inhibition in triple-negative breast cancer (TNBC): findings from a Phase II trial.

Abstract Background: Epidermal growth factor receptor (EGFR) inhibition in TNBC has shown promising response in some studies, however, these studies have not investigated the correlation between response to EGFR inhibition and EGFR-related biomarker status. In this study, EGFR-related biomarkers in TNBC including p53 expression, EGFR gene amplification, and signalling pathways including RAS and PI3K were investigated to explore potential biomarkers that may correlate with response to EGFR inhibition. Methods: A total of 71 locally advanced or metastatic TNBC patients with no prior EGFR inhibitor treatment and 0 - 1 prior chemotherapy regimens for metastatic breast cancer were evaluated. All patients received gemcitabine 1500mg/m2 IV, carboplatin AUC = 2.5 IV, and panitumumab 6 mg/kg IV every 2 weeks. Archival tumor tissue was obtained from 68 patients for central biomarker analyses. Protein expression of PTEN and p53 in tumor samples was assessed by Immunohistochemistry (IHC). Fluorescence-in-situ-hybridization (FISH) was used to detect EGFR gene amplification. KRAS (codons 12 and 13 in exon 2) and PI3KCA (exons 9 and 20) mutations were analyzed by direct DNA sequencing using capillary gel electrophoresis and fluorescence detection. Bioinformatics analyses were performed to correlate the status of these biomarkers with objective response rate (ORR), progression free survival (PFS) and overall survival (OS). Results: 27 patients had partial response (PR), median PFS was 4.30 months and median OS was 12.58 months. 12/68 (18%) tumors had EGFR amplification. No KRAS mutations were detected in the 62 samples tested (6 patients not evaluable). 18% of tumors demonstrated PI3KCA mutations (12/67). 5/67 (7%) samples had PTEN loss. 50% of the tumors exhibited p53 loss (34/68). 13/68 (19%) tumors had more than one biomarker alteration. PTEN loss and PI3KCA mutation were mutually exclusive in the 67 tumors evaluated. In univariate analyses, none of these biomarkers significantly correlated with ORR, PFS or OS (all, P>0.05). There was a marginal trend to shorter PFS (P=0.08) with PTEN loss and a marginal trend to longer PFS (P=0.106) with p53 loss. In multivariate analyses, none of the four biomarkers (EGFR, PI3KCA, PTEN and p53) showed prognostic significance on OS (all, P>0.05). Conclusions: We hypothesize that constitutive activation of the PI3K pathway due to PTEN loss and activation of EGFR by p53 loss may be potential mechanisms for the observed responses to panitumumab. This single arm study suggests that EGFR gene amplification may not be a predictor for response to panitumumab in TNBC. Further investigation in a randomized trial with a more homogenous patient population is warranted to confirm these findings. Citation Format: Denise Yardley, Denise Yardley, Zeqiang Ma, Patrick Ward, Carolyn Hendricks, Brooke Daniel, William Harwin, George J. Kannarkat, Mythili Shastry, Nancy Peacock, Shile Liang. Correlation between biomarker status and response to EGFR inhibition in triple-negative breast cancer (TNBC): findings from a Phase II trial. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2397. doi:10.1158/1538-7445.AM2013-2397

Abstract PD09-03: Impact of BRCA1/2 Mutation Status in TBCRC009: A multicenter phase II study of cisplatin or carboplatin for metastatic triple negative breast cancer.

Abstract Background: Triple negative breast cancer (TNBC) has a poor prognosis compared to other BC subtypes and lacks identified specific therapeutic targets. TNBC is frequent among BRCA1-associated breast cancer. Platinum chemotherapy has activity in TNBC, and several studies have suggested particular efficacy of platinum agents in BRCA-associated breast cancer. TBCRC009 is a multicenter single arm phase II study of single agent platinum in metastatic TNBC. Here we sought to evaluate the impact of BRCA1/2 mutation status on outcomes in this study population. Methods: Eligible metastatic TNBC patients (pts) had measurable disease, available archival tumor, ≤ 1 prior metastatic therapy, and no prior platinum chemotherapy. Pts were assigned by physician choice (limited to equal enrollment in each arm) to cisplatin 75mg/m2 or carboplatin AUC=6 every 21 days with optional extension to 28 days after cycle 1. Co-primary endpoints were: 1) Response Rate (RR) and 2) whether tumor p63/p73 expression predicts response. Secondary endpoints included determination of BRCA1/2 mutation status and exploratory analysis of correlation of BRCA1/2 status with outcomes. Baseline blood samples from all pts were analyzed by Myriad Genetics using BRCAnalysis and BART testing. Results of this exploratory analysis are presented here. Results: 86 TNBC pts enrolled between June 2007-Oct 2010. Results of primary endpoint 1 and patient characteristics were previously presented (ASCO 2011 Annual Meeting, J Clin Oncol 29: 2011 suppl; abstr 1025). In summary, median age=52 (30–78), 64% had ECOG PS=0, and 86% had adjuvant chemotherapy. Overall response rate (RR) was 30.2% (95% CI 20.8%–41.1%), including 4 CR (4.7%), 22 PR (25.6%). Among the 76 pts with BRCA1/2 status available, there were 11 (14.5%) BRCA1/2 carriers (9 BRCA1, 2 BRCA2) and 65 (85.5%) BRCA1/2 wild type (wt). Testing is ongoing for the remaining 10 pts. RR was 54.6% (5 PR, 1 CR) in BRCA1/2 carriers and 26.2% (14 PR, 3 CR) in BRCA1/2 wt (p = 0.0506). There was no significant difference in PFS between BRCA1/2 carriers (median PFS 99 days; 95% CI: 40–215) and BRCA1/2 wt (median PFS 86 days, 95% CI: 46–146). Interestingly, 6 pts (7%), including 5 BRCA1/2 wt and 1 BRCA unknown, remain without progression for 53, 41, 33, 27, 25, and 22 months as of June 2012. Of these 6 pts, 3 pts discontinued study drug due to toxicity and received no additional therapy and 3 pts had major responses and had consolidation therapy with surgery, chemotherapy, or radiation. Conclusion: First or second line single agent platinum is effective in both BRCA1/2-associated and sporadic metastatic TNBC. In this exploratory analysis, we observed a higher RR in BRCA1/2 carriers than in BRCA wt patients, but we did not observe an improved PFS in this small cohort. We observed durable responses in 7% of pts which did not correlate with BRCA1/2 mutations. The lack of a clear relationship between the higher RR in patients with germline BRCA1/2 mutations and PFS is surprising and could be further elucidated by studies in a larger cohort, and our ongoing analyses of additional markers for platinum sensitivity. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD09-03.

390 - Cisplatin, Cyclophosphamide, Methotrexate, and 5-Fluorouracil (PCMF) as First Line Therapy of Metastatic Triple Negative Breast Cancer (MTNBC) in Patients Previously Treated with Adjuvant Anthracyclines and Taxanes: Retrospective Analysis

ABSTRACT Background The purpose of this study was to evaluate the efficacy and toxicity of applied PCMF chemotherapy every four weeks (q4w) in the treatment of MTNBC patients (pts) previously treated with adjuvant anthracyclines and taxanes. Methods We administered cisplatin 30 mg/m2 on day 1 to 3 with regular hydration, cyclophosphamide 400 mg/m2 on day 1 to 5, 5-fluorouracil 500mg/m2 on day 2 and 4, and methotrexate 30mg/m2 on day 1, 3, and 5.The evaluation was performed after 4 cycles. We included 76 pts (median age 58 years, range: 32-71 years). PS medium was 1 (0-2); 21 pts (27.6%) were premenopausal and 55 (62.4%) postmenopausal. Adjuvant anthracyclines (AC or FAC x 4) and taxanes (paclitaxel/w x 12, or docetaxel/3w x 4) therapy was applied in all patients. DFS 12 months in 29 pts (38.2%). Adjuvant radiotherapy was applied in 48 pts (63.2%). Visceral metastases were observed in 51 pts (67.1%), bone metastases in 34 (44.7%), and soft tissue metastases in 11 pts (14.5%). Only one organ was affected in 15 pts (19.7%), in 41 (53.9%) two organs, and in 5 pts (6.6%) three or more. Results We evaluated 76 pts with MTNBC after 4 cycles of PCMF chemotherapy. CR was found in 3 pts (3.9%), PR in 16 pts (21.0%), SD in 11 pts (14.5%), and PD in 39 pts (51.3%); with ORR in 19 pts (24.9%) and TCR in 30 pts (39.5%). Hematological toxicity: grade 3 and 4 anemia was found in 4 pts (5.3%) and leukopenia in 9 pts (11.8%). Non-hematological toxicity: renal grade 3 awas observed in 2 pts (2.6%). Not a single therapy was interrupted due to toxicity, but therapy prolongation was present in 15% of applied cycles. Conclusions The application of PCMF chemotherapy q4w in the treatment of patients previously treated with anthracyclines and taxanes as adjuvant treatment appeared to be effective with ORR in 24.9% and TCR in 39.5% and can be administered with good tolerance.It is today our standard treatment in this pts population. Disclosure All authors have declared no conflicts of interest.

Inhibiteurs de la poly(ADP-ribose) polymerase et cancer du sein : bilan et perspectives

Poly(ADP-ribose) polymerase (PARP) family has become a promising therapeutic target in various malignancies including breast cancer. When homologous recombination repair is deficient, as it is observed in BRCA1/2-mutated tumor models, inhibition of PARP was shown to induce massive and selective tumor cell death (the so-called “synthetic lethality”). In breast cancer, PARP inhibitors have been developed as single-agent in BRCA1/2-mutated tumors or in combination with chemotherapy. Recently, a randomized phase III clinical trial failed to demonstrate any survival improvement by combining the iPARP iniparib to chemotherapy in triple-negative metastatic breast cancer patients. This emphasizes the need for future development of this class of compounds to resolve critical issues such as optimal schedule of administration and association to other anticancer treatments, as well as identification of pertinent biomarkers predictive for efficacy.

P5-19-14: Platinum-Based Chemotherapy in Triple-Negative Breast Cancer.

Abstract Background: There is increasing evidence that DNA repair defects characteristic of BRCA1-related cancers and triple negative breast cancer (TNBC) confer sensitivity to certain chemotherapeutic agents, such as platinums. However, prospective and retrospective studies comparing the efficacy of these agents versus conventional treatment in TNBC are lacking. The aim of this study was to evaluate the efficacy of platinum-based chemotherapy (PBC) in metastatic TNBC in terms of median duration of treatment and overall-survival (OS) and compare it to patients treated with conventional chemotherapy. Methods: We performed a retrospective chart review of patients with metastatic TNBC who received PBC from January 2007 to June 2010 treated at the Sunnybrook Odette Cancer Center and the Ottawa Hospital Cancer Centre. This cohort was compared to a control group that included metastatic TNBC treated with conventional agents that included anthracyclines, taxanes, capecitabine, and vinorelbine. Results: A total of 166 metastatic TNBC patients were analyzed: 60 treated with PBC and 106 managed with conventional treatment. Median age at diagnosis was 48 years and distant disease-free interval was 26 months (m) for both groups. Patients on both groups had multiple sites of metastases at diagnosis of recurrence than a single site of metastasis (69% for both groups). Of the 60 patients treated with PBC, 90% received a combination regimen, most commonly weekly cisplatin plus gemcitabine in 37% of patients and cisplatin plus vinorelbine in 17% of patients. The median number of cycles delivered was 4 (1-24). 33% received the PBC as first-line treatment, 38% as second-line, 18% as third-line, 7% as fourth line, and 3% as fifth-line. Only 8 patients (5%) discontinued PBC secondary to toxicity. The median time on treatment in first, second and third-line therapy was longer for the PBC group compared to the conventional group (5 vs. 2 m, p=0.108; 5 vs. 2 m, p=0.01; and 4 vs. 1 m, p=0.026). Patients treated with PBC had a longer OS compared to those managed conventionally (16 vs. 10 m, p=0.039). Conclusions: PBC appears to improve clinical outcomes in patients with metastatic TNBC compared to those treated with conventional chemotherapy regimens. Although this is a retrospective study with its obvious limitations, it adds to the growing body of literature, suggesting the benefit of PBC in TNBC. Prospective trials are needed to confirm its benefit in order to integrate it as part of the routine management of these patients. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-19-14.

A phase II open-label trial to evaluate the efficacy and toxicity of erlotinib in women with metastatic, hormone receptor-negative, and HER2-negative breast cancer.

296 Background: There is limited success with current therapies for triple negative (TN) breast cancer. Epidermal growth factor receptor (EGFR) is a therapeutic target in solid tumors. Overexpression of EGFR has been linked to an aggressive breast tumor phenotype with a poor prognosis. Previous work at RUSH showed that 64% of 66 TN tumors were EGFR positive (Siziopikou SABCS 2004). To date, the use of EGFR tyrosine kinase inhibitors (TKIs) in metastatic breast cancer (MBC) has been disappointing. These trials enrolled refractory patients and did not select for EGFR expression. We hypothesized that if selected for EGFR expression, there may be a cohort of TN MBC patients who benefit from an EGFR TKI. This is a phase II study of erlotinib in TN-EGFR-positive MBC. Methods: Eligible patients had TN-EGFR-positive MBC. EGFR positivity was defined as staining in >10% of tumor cells by IHC (Dako). Patients required measurable disease, prior treatment with anthracycline and taxane (adjuvant or metastatic setting) and ≤1 prior chemotherapy for MBC. Patients received erlotinib 150mg daily. Primary endpoint was progression-free survival (PFS). Initially, 18 patients were to be accrued. If ≥ 3 patients were progression-free at 4 months, accrual would continue to 43. Results: The study was terminated prematurely due to poor accrual. In total, 11 patients enrolled, 10 were treated. Mean age 56.7y, 18% African-American. Four patients had prior chemotherapy for MBC. Most patients progressed rapidly, median PFS was 29 days (95% CI 25.90 – 32.10). However, 2 patients had stable disease for 225 and 476 days. Treatment was well-tolerated. Toxicities in the 2 patients with stable disease included grade 2 rash, grade 1 diarrhea, grade 1 nausea, grade 2 weight loss and grade 1 diarrhea. Conclusions: Although most patients progressed rapidly, 2/10 patients had prolonged stable disease. This suggests there may be a subset of TN, EGFR positive MBC for whom EGFR-directed therapy may be suitable or that the natural history of their disease was indolent. Future studies to determine molecular and clinical profiles of patients likely to benefit from EGFR-TKI therapy in this population are warranted.

TBCRC009: A multicenter phase II study of cisplatin or carboplatin for metastatic triple-negative breast cancer and evaluation of p63/p73 as a biomarker of response.

1025 Background: Triple-negative breast cancer (TNBC) has a poor prognosis compared to other BC subtypes and lacks specific therapeutic targets. Platinum chemotherapy (CTx) may be active in this population. The p53 family members p63 and p73 are expressed in about 40% of TNBC and may predict response to platinum. TBCRC009 is a multicenter single arm phase II study of single agent platinum in metastatic TNBC. Methods: Eligible metastatic TNBC patients (pts) had measurable disease, available archival tumor, ≤ 1 prior metastatic therapy, and no prior platinum CTx. Pts were assigned by physician choice (limited to equal enrollment in each arm) to cisplatin 75mg/m2 or carboplatin AUC=6 every 21 days with optional extension to 28 days after cycle 1. Co-primary endpoints were: 1) Response Rate (RR) and 2) whether tumor p63/p73 expression by qRT-PCR predicts response. Results for endpoint 1 are presented. Results: 86 TNBC pts enrolled between June 2007-Oct 2010. Med age=52 (30−78), 80% White, 8% Black. 64% had ECOG PS=0, 86% had adjuvant CTx, 70% had prior anthracycline and 73% prior taxane. Mean # of disease sites = 2.4; lymph nodes (52), lung (41), bone (25), liver (24). Optional research biopsies were collected from 8 pts. Overall RR was 30.2% (95% CI 22.1%−39.4%), including 4 CR (4.7%), 22 PR (25.6%). All 4 CRs remain progression-free 156, 71, 44, and 24 weeks since study entry, and 3 stopped treatment after 6 cycles. The CBR (CR+PR+SD>6 mo) was 34%. Exploratory subgroup analysis of RR: Cis 37%, Carbo 23%; 1st line 31.7%, 2nd line 20%. Med # cycles = 4 (range 1−19), with 10 pts ≥ 10 cycles. Med PFS = 89 days and 4 pts remain on study at abstract submission. 33% of pts progressed by 6 weeks, but 33% remained on study for ≥ 6 mos. 51 treatment related grade 3/4 toxicities occurred: Gr 4 included neutropenia (1) and HTN (1); Gr3 included fatigue (8), neutropenia (6), anemia (5), hyponatremia (4). Conclusions: First or second line single agent platinum is active and well tolerated in metastatic TNBC with durable CRs and PRs. p63/p73 analysis, additional correlative studies, and BRCA mutation analysis is ongoing. Final updated efficacy analysis for primary endpoint 1 will be presented.

Characteristics of triple-negative metastatic breast cancer among older adults: A population-based analysis.

1092 Background: The prognosis for women with metastatic breast cancer (MBC) is worse for those who have triple negative MBC (TNMBC). Few reports have examined TNMBC in an elderly population. The US National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database provides information on estrogen receptor (ER) status and progesterone receptor (PR) status but does not record human epidermal growth factor receptor 2 (HER2) status, making identification and analysis of TNMBC patients challenging. Methods: Females over the age of 65 with stage IV breast cancer were identified in the SEER-Medicare database. Patients with a prior history of breast cancer were excluded. Those who were (1) ER negative, (2) PR negative, (3) had an administrative claim for HER2 test, and (4) did not receive trastuzumab were classified as potential TNMBC (p-TNMBC). Results: Of 1,755 MBC patients who met the inclusion/exclusion criteria, 313 (17.8%) were p-TNMBC. p-TNMBC were younger than other MBC (76.0 vs. 77.6 years, p<0.01). The proportion of p-TNMBC among African-American women was higher than in non-African-American women (22.2% vs. 17.2%; p=0.06). Compared to other MBC, p-TNMBC were more likely to have consulted with a medical oncologist (83.1% vs. 72.6%, p<0.01). Unadjusted median survival time was 7 months for both p-TNMBC and other MBC patients. Comparisons were similar when we excluded 218 patients who were classified as other MBC (not p-TNMBC); these MBC women were ER negative and PR negative but HER2 status was questionable since they did not have an administrative claim for a HER2 test and did not receive trastuzumab. Conclusions: As defined in this study, TNMBC occurred in approximately 18% of elderly MBC patients. TNMBC patients were younger and were more likely to have consulted a medical oncologist. TNMBC rates were slightly higher among African-Americans than other races. Unadjusted median survival was similar among p-TNMBC and other MBC. Knowledge of characteristics of TNMBC in the “real world” contributes to the understanding of the epidemiology and need for research and development of treatment strategies. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration sanofi-aventis Amgen, Bayer, Genentech, Lilly, Novartis, Pfizer, sanofi-aventis sanofi-aventis Pfizer, sanofi-aventis Novartis, Pfizer, sanofi-aventis

A specific nomogram to predict subsequent brain metastasis in metastatic triple-negative breast cancer patients

1028 Background: The development of brain metastases is usually a fatal event in the history of breast cancer patients with metastatic disease other than brain (MDOB). We previously developed a global nomogram that includes immune-histochemical phenotype to predict the occurrence of brain metastasis (BM). We hypothesized that a nomogram specific to triple negative tumor (TN) could improve prediction BM occurrence in patients with MDOB, thus allowing allocation of preventive treatment more efficiently. Methods: Patients with metastatic BC presenting between 2000 and February 2007 treated at M. D. Anderson Cancer Center were included in this retrospective analysis. We tested 17 variables and developed a multivariate model to predict occurrence of subsequent BM in TN tumors and created a nomogram that could be used for individual prediction. The model was cross-validated by bootstrapping and compared to the global nomogram. Results: Among 2,136 patients with metastatic breast cancer including 641 patients with TN tumors, 362 developed BM during follow-up: young age, histological characteristics, short delay between initial diagnosis and MDOB, number of metastatic sites and initial number of metastatic nodes were significantly and independently associated with subsequent BM. The nomogram to predict BM developed on the TN population provided a better discrimination (area under the ROC curve [AUC] = 0.62) than the global nomogram (AUC = 0.58) for the TN tumors. Prediction with the specific nomogram and the global nomogram were highly correlated (correlation factor = 0.67, p &lt; 0.0001). However, when a threshold at 15% was used, we observed 27% of discordant cases and the sensitivity of the specific nomogram was better. Conclusions: We developed a specific tool to predict subsequent BM in patients with metastatic TN breast cancer. This nomogram outperformed a global nomogram. No significant financial relationships to disclose.