[Show abstract][Hide abstract] ABSTRACT: Background
With the continuing increase in the use of definitive stereotactic radiosurgery (SRS) for patients with limited brain metastases (BM), clinicians need more specific prognostic tools. We investigated clinical predictors of outcomes in patients with limited breast cancer BM treated with SRS alone.
Methods and Materials
We identified 136 patients with breast cancer and 1-3 BM who underwent definitive SRS for 186 BM between 2000 and 2012. The Kaplan-Meier method was used to assess overall survival (OS), regional failure (RF), and local failure (LF). Associations between clinical factors and outcomes were tested using Cox regression. A point scoring system was used to stratify patients based on OS, and the predictive power was tested with concordance probability estimate (CPE).
The median OS was 17.6 months. The 12-month RF and LF rates were 45% and 10%, respectively. On multivariate analysis, >1 lesion (hazard ratio [HR] = 1.6, P=.02), triple-negative (TN) disease (HR=2.0, P=.006), and active extracranial disease (ED) (HR=2.7, P<.0001) were significantly associated with worse OS. The point score system was defined using proportional simplification of the multivariate Cox proportional hazards regression function. The median OS for patients with 3.0-4.0 points (n=37), 4.5-5.5 points (n=28), 6.0-6.5 points (n=37), and 8-8.5 points (n=34) were 9.2, 15.6, 25.1, and 45.1 months, respectively (P<.0001, CPE = 0.72). Active ED (HR=2.4, P=.0007) was significantly associated with RF. Higher risk for LF was significantly associated with larger BM size (HR=3.1, P=.0001).
Patients with >1 BM, active ED, and TN had the highest risk of death after SRS. Active ED is an important prognostic factor for OS and intracranial control.
International journal of radiation oncology, biology, physics 11/2014; 90(3). DOI:10.1016/j.ijrobp.2014.06.063 · 4.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Breast cancer brain metastases (BCBM) are challenging complications that respond poorly to systemic therapy. The role of the blood-tumor barrier in limiting BCBM drug delivery and efficacy has been debated. Herein, we determined tissue and serum levels of capecitabine, its prodrug metabolites, and lapatinib in women with BCBM resected via medically indicated craniotomy.
Study patients with BCBM requiring surgical resection received either single-dose capecitabine (1250 mg/m(2)) 2-3 h before surgery or 2-5 doses of lapatinib (1250 mg) daily, the last dose 2-3 h before surgery. Serum samples were collected serially on the day of surgery. Drug concentrations were determined in serum and BCBM using liquid chromatography tandem mass spectrometry.
Twelve patients were enrolled: 8 for capecitabine and 4 for lapatinib. Measurable drug levels of capecitabine and metabolites, 5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine, and 5-fluorouracil, were detected in all BCBM. The ratio of BCBM to serum was higher for 5-fluorouracil than for capecitabine. As for lapatinib, the median BCBM concentrations ranged from 1.0 to 6.5 µM. A high variability (0.19-9.8) was noted for lapatinib BCBM-to-serum ratio.
This is the first study to demonstrate that capecitabine and lapatinib penetrate to a significant though variable degree in human BCBM. Drug delivery to BCBM is variable and in many cases appears partially limiting. Elucidating mechanisms that limit drug concentration and innovative approaches to overcome limited drug uptake will be important to improve clinical efficacy of these agents in the central nervous system. Trial registration ID: NCT00795678.
[Show abstract][Hide abstract] ABSTRACT: In two randomized phase III trials of patients with metastatic breast cancer (MBC), gemcitabine-docetaxel (GD) and capecitabine-docetaxel (CD) had similar efficacy, but distinct safety profiles.Methods.Data from two GD versus CD studies were pooled; overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) were determined. Cox proportional hazards models identified prognostic factors associated with improved OS and PFS. Using a multivariate prognostic model incorporating identified adverse prognostic factors, we grouped MBC patients into low-, intermediate-, and high-risk categories. Hazard ratios (HRs) of GD over CD for OS and PFS were determined for subsets of patients.Results.Baseline demographics of the pooled population were mostly well balanced. In the pooled population, there were no significant differences between GD versus CD for OS (HR = 1.02; p = .824), PFS (HR = 1.15; p = .079), and ORR (p = .526). In the pooled crossover population, there were trends toward improved OS (HR = 0.82; p = .171) and PFS (HR = 0.93; p = .557) with GD. Several prognostic factors (including prior adjuvant taxane) for improved OS or PFS were identified; however, there were no significant interactions between treatment arms and prognostic factors for PFS or OS, except number of metastatic sites. In the prognostic model, median OS and PFS were numerically lower in the high-risk group versus the intermediate- and low-risk groups.Conclusion. This analysis confirms the lack of efficacy difference between GD and CD in the pooled population, crossover population, and almost all subpopulations. Several prognostic factors were associated with improved outcomes in the pooled population.
The Oncologist 04/2014; 19(5). DOI:10.1634/theoncologist.2013-0428 · 4.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
For patients with progressive breast cancer brain metastasis (BCBM) after whole brain radiotherapy (WBRT), few options exist. Patupilone is an epothilone that crosses the blood-brain barrier. We hypothesized that patupilone would produce a 35% 3-month CNS progression-free survival in women with BCBM after WBRT.Methods
This multicenter phase II trial included 2 cohorts. Group A included women with progressive BCBM after WBRT. Group B was an exploratory cohort of patients with either leptomeningeal metastases or untreated brain metastases. The primary goal was to observe a 35% 3-month CNS progression-free survival in Group A. The sample size was 45 for Group A and 10 for Group B. Patients received patupilone 10 mg/m(2) once every 3 weeks until progression. Responses were scored according to the Macdonald criteria.ResultsFifty-five patients (45 in Group A, 10 in Group B) enrolled. In Group A, the 3-month CNS progression-free survival was 27%, the median overall survival was 12.7 months, and the overall response rate was 9%. In Group B, which enrolled 5 patients with leptomeningeal disease and 5 with no prior WBRT, no responses occurred and 8 patients had CNS progression before 3 months. Systemic responses occurred in 15% of patients, including a complete response in liver metastases. Diarrhea occurred in 87% of patients; 25% had grade 3 and 4 adverse events.Conclusions
Patupilone in patients with BCBM did not meet the efficacy criteria and had significant gastrointestinal toxicity. Further study of brain-penetrant agents is warranted for patients with CNS metastases from breast cancer.
[Show abstract][Hide abstract] ABSTRACT: Brain metastases (BM) portend a poor prognosis among breast cancer patients. The management of breast cancer with brain metastases (BCBM) is multi-modal with local therapy consisting of radiation and/or surgery, albeit without durable responses, and systemic therapy playing an increasingly important role. Further clinical research is warranted to improve prognosis for BCBM. However, there are several challenges in studying this population. This review provides a general overview of BCBM and discusses unique aspects of conducting clinical trials and ongoing/future research in BCBM.
Current Breast Cancer Reports 12/2013; 5(4). DOI:10.1007/s12609-013-0120-1
[Show abstract][Hide abstract] ABSTRACT: Nanoparticle albumin-bound paclitaxel (nab-P) and bevacizumab have each demonstrated efficacy in patients with MBC. This trial was designed to further develop nab-P by evaluating its efficacy and safety using every 3 weeks (q3w), every 2 weeks (q2w), or weekly scheduling in combination with bevacizumab as first-line treatment of MBC.
This open-label phase II study randomized patients to nab-P 260 mg/m(2) q3w (arm A) vs. 260 mg/m(2) q2w with filgrastim (arm B) vs. 130 mg/m(2) weekly uninterrupted, all with bevacizumab (15 mg/kg q3w arm A, 10 mg/kg q2w arms B and C). The primary endpoints were overall response rate (ORR) and toxicity. Time to tumor progression (TTP) and overall survival were secondary endpoints.
Of 212 patients randomized, 208 (arm A, 75; arm B, 54; arm C, 79) were treated. Arm B was closed early due to toxicity, with more grade ≥ 2 fatigue (arm A, 46%; arm B, 62%; arm C, 62%) and bone pain (arm A, 11%; arm B, 23%; arm C, 5%). Neurotoxicity grade ≥ 2 was equivalent across the arms (> 50%) and reversible for most patients. Febrile neutropenia occurred in ≤ 3% of patients in all arms. ORR was similar among the arms (arm A, 45%; arm B, 41%; arm C, 46%). Median TTP was slightly longer in arm C (9.0 months) vs. arms A (8.0 months) and B (5.8 months) (overall, P = .105).
Significant antitumor activity was observed in all the arms. Weekly nab-P with bevacizumab appeared to have the highest therapeutic index. However, sensory neuropathy was treatment limiting, which suggests that a 3 weeks on and 1 week off schedule should be explored.
Clinical Breast Cancer 08/2013; 13(4):239-246.e1. DOI:10.1016/j.clbc.2013.02.008 · 2.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Fifty-five patients with breast cancer were analyzed for electrophysiological characteristics of taxane-induced polyneuropathy. Based on the electrodiagnostic criteria, sensory motor polyneuropathy was found in 67% (37/55) of patients ranging between mild degree and moderate to severe degree. The polyneuropathy is predominantly axonal with three unique features: (1) frequent asymmetry, (2) high sural and radial sensory amplitude ratio in patients with mild polyneuropathy, and (3) slow conduction velocity seen only at the common entrapment sites, such as the carpal tunnel. The severity of polyneuropathy correlated positively with the cumulative dose received. Our study supports the clinical utility of electrodiagnostic study in both diagnosis and monitoring of taxane-induced polyneuropathy.
Journal of clinical neurophysiology: official publication of the American Electroencephalographic Society 04/2013; 30(2):199-203. DOI:10.1097/WNP.0b013e3182767d3b · 1.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hepatic failure from breast cancer liver metastases (BCLM) is a major cause of morbidity and mortality. We reviewed the treatment histories and outcomes of nine patients with heavily treated BCLM, who received hepatic arterial infusion (HAI) of floxuridine (FUDR)/dexamethasone (Dex) and systemic chemotherapy at our institution. Patients received a median of five (range 1-15) HAI treatments. There were seven (78%) objective responses. Four patients had grade 3 elevations in liver enzymes attributable to HAI. There were no treatment-related deaths. Median hepatic and extrahepatic time to progression on HAI were both 6 months. Median survival after starting HAI was 17 months (range 1-115). Median overall survival from the original breast cancer diagnosis was 110 months (range 52-248). One patient is alive with stable disease on systemic therapy alone. HAI and systemic chemotherapy is feasible and can benefit selected patients with BCLM, who have progressed on prior therapies. Patients require close monitoring for treatment-limiting toxicities.
The Breast Journal 11/2012; 19(1). DOI:10.1111/tbj.12050 · 1.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A consensus conference was held in order to provide guidelines for the use of adjuvant therapy in patients with Stage I carcinoma of the breast, using traditional information, such as tumor size, microscopic character, Nottingham index, patient age and co-morbidities, but also incorporating steroid hormone and Her-2-neu data as well as other immunohistochemical markers. The role of the genetic analysis of breast cancer and proprietary gene prognostic signatures was discussed, along with the molecular profiling of breast cancers into several groups that may predict prognosis. These molecular data are not currently sufficiently mature to make them part of decision making algorithms of recommendations for the treatment of individual patients.
The Breast Journal 07/2012; 18(4):303-11. DOI:10.1111/j.1524-4741.2012.01264.x · 1.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pregnancy-associated breast cancer (PABC) may be defined as breast cancer diagnosed during pregnancy or within 1 year of giving birth. Conflicting data exist regarding the impact of pregnancy on clinical features and prognosis of breast cancer.
A single-institution retrospective chart review was performed of 99 patients identified with PABC between 1992 and 2007. Non-PABC controls were matched 2:1 to PABC cases by year of diagnosis and age. The differences in clinical features were compared between cases and controls using chi-square tests. Univariate and multivariate analyses were performed to assess the effect of PABC on survival.
Of the 99 PABC cases, breast cancer was diagnosed during pregnancy in 36 patients, and after delivery in 63. PABC cases were more likely than controls to be negative for estrogen receptor (59% vs 31%, P < .0001) and negative for progesterone receptor (72% vs 40%, P < .0001). Cases were also more likely to have advanced T class (P = .0271) and N class (P = .0104) and higher grade tumors (P = .0115). With a median follow-up of 6.3 years for cases and 4.7 years for controls, overall survival did not differ between cases and controls (P = .0787). On multivariate analysis, the independent prognostic factors for overall survival were estrogen receptor status (P = .0031) and N class (P = .0003). The diagnosis of PABC was not an independent prognostic factor (P = .1317).
PABC is associated with more adverse tumor features than non-PABC matched for age and year of diagnosis. After correcting for pathologic features, the diagnosis of PABC is not in itself an adverse prognostic factor for survival.
Cancer 07/2012; 118(13):3254-9. DOI:10.1002/cncr.26654 · 4.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Patients with breast cancer, which lacks ER, PR, and HER2; "triple negative" (TNBC), are at increased risk of brain metastases (BMs). However, the impact of modern therapy on the risk of BMs and outcomes remains largely unknown. In this retrospective, single-institution study we assessed the incidence of BMs, the therapeutic options, and overall survival, in a recent cohort of patients with TNBC. Women diagnosed with early stage TNBC from January 1, 1998 to December 31, 2007 were identified through institutional databases. Electronic medical records were reviewed to assess patterns of recurrence, treatment, and survival. In total, 1,323 patients, median age 53 years (range 20-91), were identified. There were 298 patients (23%) who developed metastatic disease, of whom, 99 (33%) developed BMs, representing 7.5% of the entire cohort. Following BM diagnosis, treatment consisted of: radiotherapy 87 (88%) patients, resection 26 (26%) patients, and systemic chemotherapy 70 (71%) patients, with a median of 1.0 (range 0-8) chemotherapy regimens. The actuarial median survival from diagnosis of BMs is 5 months (95% CI 4-7 months). This single-institution, retrospective study confirms that the prognosis for patients with BMs from TNBC remains poor. This group of patients urgently needs improved therapies.
The Breast Journal 05/2012; 18(4):345-50. DOI:10.1111/j.1524-4741.2012.01246.x · 1.41 Impact Factor