Background: P-and A-based regimens are widely used as PST and ACT of early BC. It is unknown whether the efficacy of such combinations is affected by their sequence of administration. The purpose of this retrospective analysis was to assess the clinical outcome of two different sequences of P and A in pts receiving PST and ACT. Methods: We analyzed 3,010 pts (1,414 PST and 1,596 ACT) with stage I — III BC treated between 1994 -2009. These pts were identified through our prospective online MDACC breast cancer database. Pts treated with trastuzumab, docetaxel or adriamycin/cyclophosphamide-regimen were excluded. Pathological complete response (pCR) was defined as no residual invasive disease in breast and ipsilateral axillary lymph nodes. Results: PST cohort included 1.071 pts (75%) with clinical stage I-IIIA and 343 (24.2%) stage IIIB-IIIC BC; 1,188 pts (84%) received the sequence P→A and 226 pts (16%) A→P. In the PST cohort 958 pts (67.7%) and 161 (11.3%) had hormone-receptor (HR) positive (+) and HER-2 + BC, respectively. ACT cohort consisted of 1,503 pts (94%) with pathological stage I-IIIA and 93 (5.82%) stage IIIB-IIIC. 1,196 pts (75%) received the sequence P→A, and 400 pts (25%) A→P. In the ACT cohort 1,122 (70.3%) and 93 (3.9%) had HR+ and HER2+ BC, respectively. Both cohorts of pts were balanced by HR-status, clinical stage, and menopausal status. The combined p-values for ACT and PST cohorts were calculated and they were significant for both RFS (p=0.022) and OS (p=0.002). In univariate analysis the sequence A→P was associated with inferior outcome. In Cox multivariate analysis, after stratification for period at diagnosis and adjustment for age, clinical stage, HR status, grade, and LVI the A→P sequence administered as PST was associated with significantly higher risk of relapse (HR 1.49; CI 1. 10-2.03; p=0.01) but not death (HR 1.28; CI 0.90-1.84; p=0.17). In the ACT cohort, the Cox multivariate analysis, after stratification for age, HR status, HER2 the sequence A→P was significantly associated with higher risk of death (HR 2.02; CI 1.33-3.06; p=0.001) but not relapse (HR 1.21; CI 0.82-1.79; p=0.33). Conclusions: The P→A sequence compared to the A→P sequence is associated with lower risk of relapse and death in PST and ACT, respectively. This retrospective analysis is hypothesis-generating and should lead to a prospective randomized trial to compare the two sequences as PST or ACT in locally advanced or early BC, respectively. Primary Systemic Therapy (N=1,414) Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-10-02.
Background: The detection of more than 5 CTCs/7.5 ml of blood in MBC pts predicts worse progression-free survival (PFS) and overall survival (OS). We investigated time-related clinical trend of CTCs according to types of 1st line therapy (hormonal therapy, HTx; chemotherapy CTx, anti-HER2 therapy; CTx with Bevacizumab) and immunohistochemical (IHC) subtypes of disease. Methods: Enumeration of CTCs was performed by the CellSearch™ technology as standard of care for 235 MBC pts receiving 1st line treatment for MBC. The evaluation of CTCs was performed as follow: baseline CTC value defined as assay taken within 30 days before starting therapy, post-treatment CTC value defined as the lowest CTC value after starting therapy; progression CTC value defined as assay taken within 30 days before documented radiological progression of disease (PD). We analyzed the effect of treatments on CTC count by Wilcoxon matched pair test and the progression CTC value within all subtypes by Kruskal-Wallis one-way analysis of variance. Results: A total of 1,052 CTC assays were performed from September 2004 to June 2010 in 235 MBC pts. One hundred thirty pts (55%) had HR+/HER2- MBC, 20 (9%) HR+/HER2+, 23 (10%) HR-/HER2-, and 62 (26%) triple-negative MBC (TNBC). Forty-seven pts received HTx (25 with available post-treatment CTC, median PFS for all group: 10.6 months), 41 pts were treated with anti-HER2 treatment (30 post-treatment CTC, median PFS: 12 months), 39 received Bevacizumab (31 post-treatment CTC, median PFS: 7.3 months), 87 CTx combination with taxanes/anthracyclines or other (epothilone or platinum salts) (57 post-treatment CTC, median PFS: 9.4 months) and 21 mono-chemotherapy (16 post-treatment CTC, median PFS: 3.6 months). Table 1 describes treatment distribution among subtypes. All administrated 1st line treatments decreased the CTC number with exception of HTx (66% patients decreased post-treatment CTCs value after HTx, p=.31). According to IHC subtypes, post-treatment CTC value decreased in all subtypes, while progression CTC at radiological PD increased in pts with HR+/HER2- and TNBC (45% and 51% pts had < 5 progressing CTCs, respectively, p<.05), but remained low in HER2+ subtypes (92% pts had < 5 progressing CTCs, p>.05). Conclusion: This large retrospective study showed that monitoring of CTCs is an appropriate tool for predicting response to different types of treatments, but is least useful for pts receiving HTx. Clinical trend of CTC value consistently reflects disease course in pts with HR+/HER2- and TNBC, while pts with HER2+ MBC treated with trastuzumab or lapatinib presented a low number of CTCs at PD. Our data may suggest phenotypical heterogeneity of CTCs in pts with HER-2 amplified and HR+ disease. Table 1 Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD04-02.
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 < .001). DMFS and OS were shorter in patients with stage III IBC than in those with stage III non-IBC (2.5 vs. 6.9 years, P < .001; and 4.7 vs. 8.9 years, P < .001; respectively). However, there was no significant difference in OS after development of distant metastasis between stage III IBC and non-IBC (median for both 1.3 years, 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.
BACKGROUND: A review of the literature identifies high levels of anxiety and depression as adverse effects of oncology diagnosis and treatment, even for patients with curable cancers such as early stage breast cancer (ESBC). Studies have reported that music therapy yields remarkable, multi-dimensional benefits on an individual's mood and state of mind. The purpose of this trial is to evaluate the impact of personalized music therapy (PMT) in reducing anxiety and other adverse mental health symptoms experienced by patients receiving chemotherapy treatment for ESBC. ELIGIBILITY: Females ≥ 18 years diagnosed with ESBC (Stage I-III) initiating intravenous chemotherapy as their only oncology treatment modality who report anxiety ≥ 4 on a numerical rating scale of 0-10. TRIAL DESIGN: This is a 4-week, two-arm, randomized (1:1) trial evaluating the anti-anxiety benefits of PMT for women with ESBC initiating intravenous (IV) chemotherapy. The patients randomized to the experimental group will participate in 30-minute PMT sessions conducted by a Licensed Musical Therapist (LMT). Initial PMT will occur within 1 hour of the patient's first chemotherapy infusion (C1D1), then once weekly for the remaining 3 weeks of the trial. Patients randomized to the control group will be referred to the medical oncologist for standard of care (SOC) anxiety treatment. Outcomes will be measured via the Generalized Anxiety Disorder Assessment (GAD-7), the Center for Epidemiologic Studies Depression Scale (CES-D), the Pittsburgh Sleep Quality Index (PSQI), and the Symptom Inventory Tool-M.D. Anderson Symptom Inventory (SIT-MDASI) to be completed by both cohorts at baseline and regular intervals for the duration of the study. AIMS: The primary endpoint is to determine the impact of PMT during chemotherapy treatment on patient reported anxiety (GAD-7). Secondary endpoints will determine the impact of PMT during chemotherapy treatment on patient reported depression (CES-D), sleep disturbances (PSQI), and quality of life (SIT-MDASI). STATISTICAL METHODS/TARGET ACCRUAL: Patients will be randomized to receive either PMT or SOC using the Pocock-Simon dynamic allocation method to balance tumor stage between the arms. With 30 patients in each arm and approximate target accrual of 60, the study achieves 80.0% power to detect a 0.65 standard deviation unit effect size of the change in scale measure between baseline and 4 weeks at the 0.05 significance level using a one-sided two-sample t-test. GAD-7 change will be compared between the two arms using a two-sample t-test (Pooled Standard error or Satterthwaite approximation as appropriate). The secondary outcomes include CES-D, PSQI, and SIT-MDASI for which a longitudinal analysis of subscale scores will be conducted using a generalized linear mixed-effects model with fixed effects for treatment group and time. All statistical analyses will be conducted using SAS 9.3 [SAS Institute Inc., Cary, NC, USA]. Statistical significance will be defined as p < 0.05. Citation Format: Toole Jr. M, Bendinger GM, Ensor Jr. JE, Alvarez Tapias C, Smith E, McGuire E, Rados K, McNight JE, Pabbathi H, Panicker R, Johnson AT, Lammersfeld C, Alvarez RH. A randomized study of personalized music therapy for patients with early stage breast cancer receiving chemotherapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT3-08-01.
Background: Our in vitro and in vivo preclinical data showed that entinostat enhances the efficacy of lapatinib in HER2 positive (HER2+) breast cancer cells via FOXO3-mediated Bim1 expression, which resulted in enhanced apoptosis in HER2 targeted therapy (lapatinib and trastuzumab)-resistant breast cancer (IBC and non-IBC) cells [Lee et al.]. Based on these findings, we conducted a phase 1b trial of entinostat to determine the maximal tolerated dose (MTD) in combination with lapatinib alone and in combination with lapatinib and trastuzumab for metastatic HER2+ breast cancer patients (pts), who progressed on trastuzumab. Method: This was a single-center, open-label phase 1b study to evaluate the dose limiting toxicity (DLT) and determine MTD. 3+3 dose escalation schedule was used for Cohorts 1 and 2. Pts received lapatinib and entinostat (Cohort 1) or entinostat, lapatinib, and trastuzumab (Cohort 2). Initial dose of lapatinib 1250mg in Cohort 1 and 1000mg for Cohort 2 to match standard dose in combination with trastuzumab dose. In Cohort 1, entinostat was given PO on day 1 and 15 every 28 days cycle at dose levels 10 mg (level 0), 12 mg (level 1), or 15 mg (level 2). The dose levels for Cohort 2 were 12 mg (co-level 0) or 15 mg (co-level 1) on day 1 and 15 every 28 days cycle. While lapatinib and entinostat were given 28 days cycle due to entinostat dosing, the dosing of trastuzumab followed approved schedule every 21 days starting at 8mg/kg loading followed by 6mg/kg q 3 wks in Cohort 2 and 3. After the MTD of entinostat in cohort 2 was determined at 12mg, an expansion cohort of 10 pts (cohort 3) was conducted. Results: Median age was 52 (26-69 yrs). Median number of prior trastuzumab-based regimens was 2 (1-6), 8 pts had lapatinib containing treatment prior to the trial, including 5 pts who had clinical benefit. 16 had ER+ and 13 ER negative, and 9 had IBC. Clinical efficacy and toxicity of treatment is summarized in table 1. Out of 14 pts who had clinical benefit (CR, PR, SD), 6 had IBC. Three pts are still on therapy (1CR, 1PR, 1SD). Table 1. Clinical Efficacy, Toxicity of combination Receptor StatusResponseGrade 3 toxicityGrade 4 toxicityCohort 1HER2+/ER- (N=8) HER2+/ER+ (N=7)CR (N=1; 8M), SD (N=4;1,2,4M)Lapatinib dose reduction: 3 pts Rash (2) Abdominal pain + dyspnea (1)Entinostat dose reduction: 2pts Neutropenia (1 at 12mg, 1 at 15mg)Cohort 2/3HER2+/ER- (N=8) HER2+/ER+ (N=6)CR (N=2; 3,6M), PR (N=2;4,5M) SD (N=5;1,2,4,6M)Lapatinib dose reduction: 2 pts Diarrhea (N=1 at 12mg N=1 at 10mg) Entinostat dose reduction: 5 pts Neutropenia (N=2 at 12 mg) Leukopenia (N=1 at 12mg) Anemia (N=1 at 12mg)Entinostat dose reduction: 2pts Hypokalemia (N=1 at 12mg) Thrombocytopenia (N=1 at 15mg)CR: complete response, PR: partial response, SD: stable disease, N=number of pts, M=months Conclusion: MTD was reached at 12mg q 2wkly entinostat, lapatinib 1000 mg daily and trastuzumab 8 mg/kg followed by 6mg/kg q 3 wks. This combination was safe and had promising clinical efficacy in patients with trastuzumab-resistant metastatic HER2+ breast cancer including IBC, warranting further study. Citation Format: Lim B, Jackson S, Alvarez RH, Ibrahim NK, Willey JS, Murthy RK, Booser DJ, Giordano SH, Barcenas CH, Brewster A, Walters RS, Brown PH, Tripathy D, Valero V, Ueno NT. A single-center, open-label phase 1b study of entinostat, and lapatinib alone, and in combination with and trastuzumab in patients with HER2+ metastatic breast cancer after progression on trastuzumab. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-22.
Background: Germline mutation screening of BRCA1 and BRCA2 genes is performed in suspected familial breast cancer cases, but a causative mutation is found in only 30% of patients. The development of additional methods to identify good candidates for BRCA1 and BRCA2 analysis would therefore increase the efficacy of diagnostic mutation screening. With this in mind, we developed a study to determine molecular signatures of BRCA1—or BRCA2—mutated breast cancers. Materials and Methods: Array-cgh (comparative genomic hybridization) and transcriptomic analysis were performed on a series of 103 familial breast cancers. The series included 7 breast cancers with a BRCA1 mutation and 5 breast cancers with a BRCA2 mutation. The remaining 91 cases were obtained from 73 families selected on the basis of at least 3 affected first-degree relatives or at least 2 affected first-degree relatives with breast cancer at an average age of 45 years. Array-cgh analyses were performed on a 4407 BAC-array (CIT-V8) manufactured by IntegraGen. Transcriptomic analyses were performed using an Affymetrix Human Genome U133 Plus 2.0 chip. Results: Using supervised clustering analyses we identified two transcriptomic signatures: one for BRCA1-mutated breast cancers consisting of 600 probe sets and another for BRCA2-mutated breast cancers also consisting of 600 probes sets. We also defined cgh-array signatures, based on the presence of specific genomic rearrangements, one for BRCA1-mutated breast cancers and one for BRCA2-mutated breast cancers. Conclusions: This study identified molecular signatures of breast cancers with BRCA1 or BRCA2 germline mutations. Genes present in these signatures could be exploited to find new markers for such breast cancers. We also identified specific genomic rearrangements in these breast cancers, which could be screened for in a diagnostic setting using fluorescence in situ hybridization, thus improving patient selection for BRCA1 and BRCA2 molecular genetic analysis.
Background: Entinostat is a novel, potent, orally bioavailable, class I selective histone deacetylase inhibitor. Pre-clinical data has shown that Entinostat can enhance the activity of Lapatinib in HER2+ metastatic inflammatory and non-inflammatory breast cancer. The primary objective of the phase I portion of this study is to determine the recommended phase II dose for Entinostat in combination with Lapatinib in patients who have received Trastuzumab for HER2+ metastatic breast cancer. Methods: This is a single center, open-label study to evaluate the safety and tolerability of every other week entinostat in combination with a 28-day cycle of Lapatinib. Patients with metastatic breast cancer in whom trastuzumab has failed were included. The phase I portion of the study is a conventional 3+3 dose-escalation design. Dose levels include 0 (starting dose) Entinostat 10 mg orally every other week, I Entinostat 12 mg, and II Entinostat 15 mg. Lapatinib 1,250 mg orally is given every day without dose escalation. Toxicities are evaluated at the end of each cycle. Results: Here we report the phase I portion of the study. To date, 9 patients were enrolled, 3 were in level 0, and 6 were in level I. In Level 0, 2 patients were taken off study due to disease progression (PD) at the end of cycle one and 1 patient was taken off study due to PD at the end of cycle two. In Level I, 1 patient was taken off study due to PD at the end of cycle one and 2 patients were taken off study due to PD at the end of cycle 2. 1 patient had stable disease. The median age is 41 (range, 26–69). Seven of the nine patients are evaluable for toxicity. Most common toxicities reported by the patients are nausea grade 3 (1), fatigue grade 3 (1), muscle aches/pain grade 2 (3), skin rash grade 3 (1), paresthesias grade 2 (2), heartburn grade 1 (4), and diarrhea Grade 2 (1). Lapatinib dose was reduced in 2 patients. The most common hematological toxicities were neutropenia grade 1 (3), anemia grade 2 (1), and thrombocytopenia grade 4 (1). Conclusions: Overall, patients have tolerated the combination regimen relatively well. We have not reached the maximum tolerated dose, so patient enrollment will continue until the phase I portion of the study is complete, most likely in July 2012. We plan to proceed with phase II portion in two parallel cohorts (HER2+ inflammatory and non-inflammatory metastatic breast cancer). Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-20-13.
Background: Inflammation contributes to the increased invasiveness and poor prognosis in breast cancer (BC) patients. Specifically, the expression of the proinflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor alpha (TNFα) and interleukin-1 (IL-1) have all been linked to increased invasiveness and poor prognosis. Interestingly, the increased invasiveness was associated with an increase in the acquisition of markers of epithelial-mesenchymal transition (EMT). Therefore, we determined whether the levels of circulating proinflammatory cytokines (IL-1, IL-6, TNFα) and antiinflammatory cytokines (IL10) were correlated with the induction of EMT transcription factors (TFs), Snail1, Zeb1, Twist1, in breast cancer patients. Materials and Methods: From two laboratory-based ongoing studies at the MD Anderson Cancer Center, 41 BC patients were assessed for EMT-TFs in circulating CD45-ve cells (EMT-CTCs) and for serum proinflammatory cytokines before starting any treatment. 32 of 41 patients assessed for EMT had metastatic BC. EMT-CTCs were detected by qRT-PCR for the EMT-TFs Snail1, Zeb1 and Twist1 (Mego 2011; PMID 21387303) and serum cytokines were measured by Luminex bead array assay (MILLIPLEX™ MAP Human Cytokine/Chemokine Panel). Cytokine serum concentrations were compared with the median cytokine levels of healthy donors (HD). We examined the association of serum cytokines above the median HD levels and the presence of EMT-CTCs by non-parametric Mann-Whitney test with a statistical significance for p<.05. Results: Of the 41 patients assessed for both serum cytokines and EMT-CTCs, 14 (34%) were positive for at least one EMT-TF, including 3 of 9 (33%) patients with no-metastatic BC and 11 of 32 (34%) patients with metastatic BC. We found that serum levels of IL1a, IL2, TGFα, and TNFβ in patients that were above the median levels of HD sera were higher in patients with EMT-CTCs in the blood (higher IL1a concentration in patients with over expression of Snail1, Zeb1, and Twist1; IL2 with Zeb1; TGFα with Snail1; TNFβ with Zeb1, and Twist1). Further, the higher ratio of proinflammatory/anti-inflammatory cytokines, was associated with the presence of at least one EMT-TF, e.g., IL8/IL10 (p=.005) and TNFα/IL10 (p=.037). Discussion: Patients with proinflammatory cytokine (IL1a, IL2, TGFα, and TNFβ) levels above the median levels of HD or who had a predominantly proinflammatory cytokine profile were more likely to have at least one EMT-TF in their blood. These data are consistent with the hypothesis that proinflammatory cytokines promote EMT, which may be involved in tumor aggressiveness and disease progression. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-02-07.
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