ABSTRACT
Objective: Risk-reducing therapy with selective estrogen receptor (ER) modulators and aromatase inhibitors reduce breast cancer risk. However, the effects are limited to ER-positive breast cancer. Therefore, new agents with improved toxicity profiles that reduce the risk in ER-negative breast cancers are urgently needed. The aim of this prospective, short-term, prevention study was to evaluate the effect of dasatinib, an inhibitor of the tyrosine kinase Src, on biomarkers in normal (but increased risk) breast tissue and serum of women at high risk for a second, contralateral primary breast cancer. Materials and Methods: Women with a history of unilateral stage I, II, or III ER-negative breast cancer, having no active disease, and who completed all adjuvant therapies were eligible. Patients underwent baseline fine-needle aspiration (FNA) of the contralateral breast and serum collection for biomarker analysis and were randomized to receive either no treatment (control) or dasatinib at 40 or 80 mg/day for three months. After three months, serum collection and breast FNA were repeated. Planned biomarker analysis consisted of changes in cytology and Ki-67 on breast FNA, and changes in serum levels of insulin-like growth factor 1 (IGF-1), IGF-binding protein 1, and IGF-binding protein 3. The primary objective was to evaluate changes in Ki-67 and secondary objective included changes in cytology in breast tissue and IGF-related serum biomarkers. Toxicity was also evaluated. Results: Twenty-three patients started their assigned treatments. Compliance during the study was high, with 86.9% (20/23) of patients completing their assigned doses. Dasatinib was well tolerated and no drug-related grade 3 and 4 adverse events were observed. Since only one patient met the adequacy criteria for the paired FNA sample, we could not evaluate Ki-67 level or cytological changes. No significant change in serum biomarkers was observed among the three groups. Conclusion: Dasatinib was well tolerated but did not induce any significant changes in serum biomarkers. The study could not fulfill its primary objective due to an inadequate number of paired FNA samples. Further, larger studies are needed to evaluate the effectiveness of Src inhibitors in breast cancer prevention.
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BACKGROUND: Selinexor (KPT-330) is a potent inhibitor of exportin 1 (XPO1), in turn inhibiting tumor growth. Selinexor enhances the antitumor efficacy of eribulin in triple-negative breast cancer (TNBC) in vitro and in vivo. Given the unmet medical need in TNBC and sarcoma, the authors explored the safety and efficacy of this combination. METHODS: The authors conducted a phase 1b trial of combined selinexor and eribulin using a 3 + 3 dose-escalation design in patients who had advanced solid tumors and in those who had TNBC in a dose-expansion cohort. RESULTS: Patients with TNBC (N = 19), sarcoma (N = 9), and other cancers (N = 3) were enrolled in the dose-escalation cohort (N = 10) and in the dose-expansion cohort (N = 21). The median number lines of prior therapy received was four (range, from one to seven prior lines). The most common treatment-related adverse events for selinexor were nausea (77%), leukopenia (77%), anemia (68%), neutropenia (68%), and fatigue (48%). One dose-limiting toxicity occurred at the first dose level with prolonged grade 3 neutropenia. The recommended phase 2 dose was 80 mg of selinexor orally once per week and 1 mg/m2 eribulin on days 1 and 8 intravenously every 3 weeks. The objective response rate (ORR) was 10% in three patients. In the dose-escalation cohort, the ORR was 10%, whereas six patients with had stable disease. In the TNBC dose-expansion cohort (n = 18), ORR was 11%, and there were two confirmed partial responses with durations of 10.8 and 19.1 months (ongoing). CONCLUSIONS: Selinexor and eribulin had an acceptable toxicity profile and modest overall efficacy with durable responses in select patients. PLAIN LANGUAGE SUMMARY: Effective therapies for advanced, triple-negative breast cancer and sarcoma represent an unmet need. Exportin 1 is associated with the transport of cancer-related proteins. Preclinical studies have demonstrated tumor growth inhibition and enhanced tumor sensitivity in patients who receive selinexor combined with eribulin. In this phase 1b study, the authors evaluated the safety profile and clinical activity of the combination of selinexor, a potent oral inhibitor of exportin 1, and eribulin in patients with advanced cancers enriched for triple-negative breast cancer or sarcoma. The combination was well tolerated; most adverse events were mild or moderate, reversible, and managed with dose modifications or growth factor support. The combination of selinexor and eribulin produced an antitumor response, particularly in some patients with triple-negative breast cancer. This work lays the foundation for prospective investigations of the role of selinexor and eribulin in the treatment of triple-negative breast cancer.
Subject(s)
Neutropenia , Sarcoma , Soft Tissue Neoplasms , Triple Negative Breast Neoplasms , Humans , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/pathology , Prospective Studies , Sarcoma/drug therapy , Soft Tissue Neoplasms/drug therapy , Antineoplastic Combined Chemotherapy Protocols/adverse effectsABSTRACT
BACKGROUND: Human epidermal growth factor 2 (HER2) is an effective therapeutic target in breast cancer; however, resistance to anti-HER2 agents such as trastuzumab and lapatinib develops. In a preclinical model, an HDAC inhibitor epigenetically reversed the resistance of cancer cells to trastuzumab and showed synergistic efficacy with lapatinib in inhibiting growth of trastuzumab-resistant HER2-positive (HER2+) breast cancer. METHODS: A phase 1b, dose escalation study was performed to assess maximum tolerated dose, safety/toxicity, clinical efficacy and explored pharmacodynamic biomarkers of response to entinostat combined with lapatinib with or without trastuzumab. RESULTS: The combination was safe. The MTD was lapatinib, 1000 mg daily; entinostat, 12 mg every other week; trastuzumab, 8 mg/kg followed by 6 mg/kg every 3 weeks. Adverse events included diarrhoea (89%), neutropenia (31%), and thrombocytopenia (23%). Neutropenia, thrombocytopenia and hypokalaemia were noted. Pharmacodynamic assessment did not yield conclusive results. Among 35 patients with evaluable response, PR was observed in 3 patients and CR in 3 patients, 1 maintained SD for over 6 months. DISCUSSION: This study identified the MTD of the entinostat, lapatinib, and trastuzumab combination that provided acceptable tolerability and anti-tumour activity in heavily pre-treated patients with HER2+ metastatic breast cancer, supporting a confirmatory trial.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Breast Neoplasms/drug therapy , Breast Neoplasms/enzymology , Receptor, ErbB-2/metabolism , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Benzamides/administration & dosage , Benzamides/adverse effects , Breast Neoplasms, Male/drug therapy , Breast Neoplasms, Male/enzymology , Dose-Response Relationship, Drug , Drug Resistance, Neoplasm , Drug Synergism , Female , Humans , Lapatinib/adverse effects , Male , Middle Aged , Neoplasm Metastasis , Pyridines/administration & dosage , Pyridines/adverse effects , Survival Rate , Trastuzumab/administration & dosage , Trastuzumab/adverse effectsABSTRACT
Background Imatinib mesylate is a potent inhibitor of the Abl, KIT and platelet derived growth factor (PDGF) receptor tyrosine kinases. Preclinical data suggest that combining imatinib mesylate with anti-estrogen therapy may be synergistic in hormone receptor-positive breast cancer. We report results of the first phase II trial evaluating the efficacy of the novel combination of imatinib mesylate and letrozole in the treatment of postmenopausal women with metastatic breast cancer. Patients and Methods 45 postmenopausal women with hormone receptor-positive metastatic breast cancer whose tumors demonstrated c-kit and/or PDGFR-ß positivity were treated with imatinib mesylate 400 mg PO twice daily and letrozole 2.5 mg PO once daily until disease progression or unacceptable toxicity. Results There were no complete responses and five partial responses for an objective response rate of 11%. An additional 16 patients had stable disease lasting at least 24 weeks for a clinical benefit rate of 46.7%. The median progression-free and overall survival was 8.7 months (95% confidence interval: 3.8-11.4 months) and 44.3 months (95% confidence interval: 34.0-55.3 months), respectively. The most common grade 3 or higher treatment related adverse events were fatigue and diarrhea, occurring in 9 (20%) and 7 patients (16%), respectively. Conclusion The combination of imatinib mesylate and letrozole is well tolerated but appears to have limited efficacy in the treatment of hormone receptor-positive metastatic breast cancer.
Subject(s)
Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Imatinib Mesylate/therapeutic use , Letrozole/therapeutic use , Proto-Oncogene Proteins c-kit/metabolism , Receptor, Platelet-Derived Growth Factor beta/metabolism , Adult , Aged , Aged, 80 and over , Female , Humans , Imatinib Mesylate/adverse effects , Kaplan-Meier Estimate , Letrozole/adverse effects , Middle Aged , Neoplasm Metastasis , Progression-Free Survival , Treatment OutcomeABSTRACT
BACKGROUND: Limited clinical data are available regarding the safety of docetaxel in metastatic breast cancer patients with liver dysfunction. METHODS: Eligible patients had breast cancer with impaired liver function secondary to hepatic metastases and were candidates for docetaxel therapy. They were assigned to one of five groups on the basis of total bilirubin, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels. All other causes of liver dysfunction were excluded, and bile duct obstruction was corrected, if possible, prior to study entry. Patients received docetaxel every three weeks. The chemotherapy dose was chosen on the basis of the patient's level of hepatic dysfunction and escalated as tolerated. The primary outcome of this study was safety. The secondary outcomes were pharmacokinetic data and efficacy in terms of time to disease progression. RESULTS: Twenty-three patients were enrolled. No unexpected toxicities occurred. Grade 3/4 fatigue (65%), neutropenia (30%), myalgias (26%), neutropenic fever (26%), vomiting (9%), and rash (9%) were the most common serious adverse events. The median time to progression was three months (range 1-18 months). Pharmacokinetic results indicated that patients with more severe hepatic dysfunction may have been underdosed based on our conservative dosing strategy. CONCLUSIONS: Docetaxel can be administered to patients with metastatic breast cancer and liver dysfunction after dose attenuation. However, because of a narrow therapeutic index in this clinical setting, therapy should be closely monitored with subsequent dose escalation when possible.
Subject(s)
Breast Neoplasms/drug therapy , Liver Diseases/drug therapy , Liver Neoplasms/drug therapy , Taxoids/adverse effects , Taxoids/pharmacokinetics , Adult , Aged , Breast Neoplasms/pathology , Docetaxel , Female , Humans , Liver/drug effects , Liver/pathology , Liver Neoplasms/pathology , Liver Neoplasms/secondary , Male , Middle Aged , Pilot ProjectsABSTRACT
BACKGROUND: Radiation is a standard component of treatment for patients with locoregional recurrence (LRR) of breast cancer following mastectomy. The current study reports the results of a 10% radiation dose escalation in these patients. METHODS: 159 patients treated at MD Anderson Cancer Center between 1994-2006 with isolated LRR after mastectomy alone were reviewed. Patients in the standard treatment group (65 pts, 40.9%) were treated to 50 Gy comprehensively plus a boost of 10 Gy. The dose escalated group (94 pts, 59.1%) was treated to 54 Gy comprehensively and a minimum 12 Gy boost. Median dose in the standard dose and dose escalated group was 60 Gy (±1 Gy, 95% CI) and 66 Gy (±0.5 Gy, 95% CI) respectively. Median follow up for living patients was 94 months from time of recurrence. RESULTS: The actuarial five year locoregional control (LRC) rate was 77% for the entire study population. The five year overall survival and disease-free survival was 55% and 41%, respectively. On multivariate analysis, initial tumor size (p = 0.03), time to initial LRR (p = 0.03), absence of gross tumor at the time of radiation (p = 0.001) and Her2 status (p = 0.03) were associated with improved LRC. Five year LRC rates were similar in patients with a complete response to chemotherapy without surgery and patients with a complete surgical excision (77% vs 83%, p = NS), compared to a 63% LRC rate in patients with gross disease at the time of radiation (p = 0.024). LRC rates were 80% in the standard dose group and 75% in the dose escalated group (p = NS). CONCLUSIONS: While LRR following mastectomy is potentially curable, distant metastasis and local control rates remain suboptimal. Radiation dose escalation did not appear to improve LRC. Given significant local failure rates, these patients are good candidates for additional strategies to improve their outcomes.
Subject(s)
Breast Neoplasms/pathology , Breast Neoplasms/radiotherapy , Mastectomy/methods , Neoplasm Recurrence, Local/radiotherapy , Radiometry/methods , Adult , Aged , Breast Neoplasms/mortality , Breast Neoplasms/surgery , Disease-Free Survival , Female , Humans , Middle Aged , Multivariate Analysis , Retrospective Studies , Treatment OutcomeABSTRACT
The mutation pattern of breast cancer molecular subtypes is incompletely understood. The purpose of this study was to identify mutations in genes that may be targeted with currently available investigational drugs in the three major breast cancer subtypes (ER+/HER2-, HER2+, and Triple Negative). We extracted DNA from fine needle aspirations of 267 stage I-III breast cancers. These tumor specimens typically consisted of >80% neoplastic cells. We examined 28 genes for 163 known cancer-related nucleic acid variations by Sequenom technology. We observed at least one mutation in 38 alleles corresponding to 15 genes in 108 (40%) samples, including PIK3CA (16.1% of all samples), FBXW7 (8%), BRAF (3.0%), EGFR (2.6%), AKT1 and CTNNB1 (1.9% each), KIT and KRAS (1.5% each), and PDGFR-α (1.1%). We also checked for the polymorphism in PHLPP2 that is known to activate AKT and it was found at 13.5% of the patient samples. PIK3CA mutations were more frequent in estrogen receptor-positive cancers compared to triple negative breast cancer (TNBC) (19 vs. 8%, p=0.001). High frequency of PIK3CA mutations (28%) were also found in HER2+ breast tumors. In TNBC, FBXW7 mutations were significantly more frequent compared to ER+ tumors (13 vs. 5%, p=0.037). We performed validation for all mutated alleles with allele-specific PCR or direct sequencing; alleles analyzed by two different sequencing techniques showed 95-100% concordance for mutation status. In conclusion, different breast cancer subtypes harbor different type of mutations and approximately 40 % of tumors contained individually rare mutations in signaling pathways that can be potentially targeted with drugs. Simultaneous testing of many different mutations in a single needle biopsy is feasible and allows the design of prospective clinical trials that could test the functional importance of these mutations in the future.
Subject(s)
Breast Neoplasms/genetics , Mutation , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , DNA Mutational Analysis , Female , Genes , Genetic Association Studies , Humans , Molecular Targeted Therapy , Multivariate Analysis , Polymorphism, Single Nucleotide , Receptor, ErbB-2/metabolism , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Signal Transduction/geneticsABSTRACT
PURPOSE: We investigated whether capecitabine and docetaxel followed by fluorouracil, epirubicin, and cyclophosphamide (FEC) or weekly paclitaxel (WP) followed by FEC would improve relapse-free survival (RFS) in operable breast cancer. PATIENTS AND METHODS: In this single-institution study, patients with clinical stages I to IIIC breast cancer were randomly assigned on a 1:1 basis to WP 80 mg/m(2) for 12 weeks followed by fluorouracil 500 mg/m(2), epirubicin 100 mg/m(2), and cyclophosphamide 500 mg/m(2) (FEC-100) every 3 weeks for four cycles or docetaxel 75 mg/m(2) on day 1 and capecitabine (XT) 1,500 mg/m(2) on days 1 through 14 every 3 weeks for four cycles followed by FEC for four cycles and stratified by timing of chemotherapy (preoperative v adjuvant). Accrual was stopped short of 930 patients on the basis of a Bayesian predictive calculation that additional accrual would be unlikely to change the qualitative comparison of the two regimens. RESULTS: After enrollment of 601 patients and a median follow-up of 50 months, we observed no improvement in RFS between XT (87.5%; 95% CI, 82.7% to 91.1%) and WP (90.7%; 95% CI, 86.4% to 93.7%; P = .51). In the preoperative group, the pathologic complete response rate was 19.8% and 16.4% in the XT and WP arms, respectively (P = .45). Rates of breast-conserving surgery were similar between the two groups (P = .48). The XT arm had a significantly higher incidence of stomatitis (P < .001), hand-foot syndrome (P < .001), and neutropenic infection (P < .001). CONCLUSION: There was no difference in efficacy between WP and XT as used in this randomized phase III trial. XT was associated with higher GI, skin, and neutropenic-related toxicities.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/surgery , Carcinoma, Intraductal, Noninfiltrating/drug therapy , Carcinoma, Intraductal, Noninfiltrating/surgery , Adult , Breast Neoplasms/mortality , Capecitabine , Carcinoma, Intraductal, Noninfiltrating/mortality , Combined Modality Therapy , Cyclophosphamide/administration & dosage , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Docetaxel , Epirubicin/administration & dosage , Female , Fluorouracil/administration & dosage , Fluorouracil/analogs & derivatives , Follow-Up Studies , Humans , Middle Aged , Paclitaxel/administration & dosage , Survival Rate , Taxoids/administration & dosage , Treatment OutcomeABSTRACT
PURPOSE: Trastuzumab resistance has been linked to activation of the phosphoinositol 3-kinase (PI3K) pathway. Phosphatase and tensin homolog (PTEN) is a dual phosphatase that counteracts the PI3K function; PTEN loss leads to activation of the Akt cascade and the downstream mammalian target of rapamycin (mTOR). Preclinical studies demonstrated that mTOR inhibition sensitized the response to trastuzumab in mice with HER2 overexpressing and PTEN-deficient breast xenografts. Our trial evaluated the safety and efficacy of the combination of everolimus and trastuzumab in women with HER2-overexpressing metastatic breast cancer (MBC) that progressed on trastuzumab-based therapy. PATIENTS AND METHODS: This represents a pooled analysis (n = 47), stemming from two trials that occurred concurrently in The University of Texas MD Anderson Cancer Center, Beth Israel Deaconess Medical Center, and Dana-Farber Cancer Institute. Patients with HER2-overexpressing MBC who had progressed on trastuzumab-based therapy received trastuzumab every 3 weeks in combination with daily everolimus. RESULTS: Among 47 patients, the combination of everolimus and trastuzumab provided partial responses in seven patients (15%) and persistent stable disease (lasting 6 months or longer) in nine patients (19%), resulting in a clinical benefit rate of 34%. The median progression-free survival (PFS) was 4.1 month. Fatigue, infection, and mucositis were the predominant nonhematologic toxicities. Trastuzumab did not have significant influence on the pharmacokinetic profile of everolimus. Patients with PTEN loss demonstrated decreased overall survival (P = .048). However, PFS was not affected by PTEN loss. CONCLUSION: Inhibition of mTOR results in clinical benefit and disease response in patients with trastuzumab-resistant HER2-overexpressing MBC.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Receptor, ErbB-2/biosynthesis , Sirolimus/analogs & derivatives , Adult , Aged , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/pharmacokinetics , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Biomarkers, Tumor/analysis , Breast Neoplasms/metabolism , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Disease-Free Survival , Everolimus , Female , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Middle Aged , Neoplasm Metastasis , PTEN Phosphohydrolase/metabolism , Salvage Therapy/methods , Sirolimus/administration & dosage , Sirolimus/adverse effects , Sirolimus/pharmacokinetics , Sirolimus/therapeutic use , TOR Serine-Threonine Kinases/metabolism , TrastuzumabABSTRACT
CONTEXT: Prediction of high probability of survival from standard cancer treatments is fundamental for individualized cancer treatment strategies. OBJECTIVE: To develop a predictor of response and survival from chemotherapy for newly diagnosed invasive breast cancer. DESIGN, SETTING, AND PATIENTS: Prospective multicenter study conducted from June 2000 to March 2010 at the M. D. Anderson Cancer Center to develop and test genomic predictors for neoadjuvant chemotherapy. Patients were those with newly diagnosed ERBB2 (HER2 or HER2/neu)-negative breast cancer treated with chemotherapy containing sequential taxane and anthracycline-based regimens (then endocrine therapy if estrogen receptor [ER]-positive). Different predictive signatures for resistance and response to preoperative (neoadjuvant) chemotherapy (stratified according to ER status) were developed from gene expression microarrays of newly diagnosed breast cancer (310 patients). Breast cancer treatment sensitivity was then predicted using the combination of signatures for (1) sensitivity to endocrine therapy, (2) chemoresistance, and (3) chemosensitivity, with independent validation (198 patients) and comparison with other reported genomic predictors of chemotherapy response. MAIN OUTCOME MEASURES: Distant relapse-free survival (DRFS) if predicted treatment sensitive and absolute risk reduction ([ARR], difference in DRFS between 2 predicted groups) at median follow-up (3 years). RESULTS: Patients in the independent validation cohort (99% clinical stage II-III) who were predicted to be treatment sensitive (28%) had 56% (95% CI, 31%-78%) probability of excellent pathologic response and DRFS of 92% (95% CI, 85%-100%), with an ARR of 18% (95% CI, 6%-28%). Survival was predicted in ER-positive (30% predicted sensitive; DRFS, 97% [95% CI, 91%-100%]; ARR, 11% [95% CI, 0.1%-21%]) and ER-negative (26% predicted sensitive; DRFS, 83% [95% CI, 68%-100%]; ARR, 26% [95% CI, 4%-48%]) subsets and was significant in multivariate analysis. Other genomic predictors showed paradoxically worse survival for patients predicted to be responsive to chemotherapy. CONCLUSION: A genomic predictor combining ER status, predicted chemoresistance, predicted chemosensitivity, and predicted endocrine sensitivity identified patients with high probability of survival following taxane and anthracycline chemotherapy.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Gene Expression Profiling , Genes, Neoplasm/genetics , Adult , Algorithms , Anthracyclines/therapeutic use , Antineoplastic Agents, Hormonal/pharmacology , Antineoplastic Agents, Hormonal/therapeutic use , Biopsy, Needle , Breast Neoplasms/mortality , Bridged-Ring Compounds/therapeutic use , Disease-Free Survival , Drug Resistance, Neoplasm , Female , Forecasting , Genes, erbB-2 , Genomics , Humans , Middle Aged , Neoadjuvant Therapy , Neoplasm Recurrence, Local , Oligonucleotide Array Sequence Analysis , Predictive Value of Tests , Prognosis , Prospective Studies , Receptors, Estrogen/analysis , Risk , Taxoids/therapeutic useABSTRACT
PURPOSE: We hypothesize that measurement of gene expression related to estrogen receptor α (ER; gene name ESR1) within a breast cancer sample represents intrinsic tumoral sensitivity to adjuvant endocrine therapy. METHODS: A genomic index for sensitivity to endocrine therapy (SET) index was defined from genes coexpressed with ESR1 in 437 microarray profiles from newly diagnosed breast cancer, unrelated to treatment or outcome. The association of SET index and ESR1 levels with distant relapse risk was evaluated from microarrays of ER-positive breast cancer in two cohorts who received 5 years of tamoxifen alone as adjuvant endocrine therapy (n = 225 and 298, respectively), a cohort who received neoadjuvant chemotherapy followed by tamoxifen and/or aromatase inhibition (n = 122), and two cohorts who received no adjuvant systemic therapy (n = 208 and 133, respectively). RESULTS: The SET index (165 genes) was significantly associated with distant relapse or death risk in both tamoxifen-treated cohorts (hazard ratio [HR] = 0.70, 95% CI, 0.56 to 0.88, P = .002; and HR = 0.76, 95% CI, 0.63 to 0.93, P = .007) and in the chemo-endocrine-treated cohort (HR = 0.19; 95% CI, 0.05 to 0.69, P = .011) independently from pathologic response to chemotherapy, but was not prognostic in two untreated cohorts. No distant relapse or death was observed after tamoxifen alone if node-negative and high SET or after chemo-endocrine therapy if intermediate or high SET. CONCLUSION: The SET index of ER-related transcription predicted survival benefit from adjuvant endocrine therapy, not inherent prognosis. Prior chemotherapy seemed to enhance the efficacy of adjuvant endocrine therapy related to SET index.
Subject(s)
Antineoplastic Agents, Hormonal/therapeutic use , Biomarkers, Tumor/genetics , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Estrogen Receptor alpha/genetics , Gene Expression Regulation, Neoplastic , Genomics , Aromatase Inhibitors/therapeutic use , Biomarkers, Tumor/metabolism , Breast Neoplasms/mortality , Breast Neoplasms/secondary , Chemotherapy, Adjuvant , Chi-Square Distribution , Disease-Free Survival , Estrogen Receptor alpha/metabolism , Female , Gene Expression Profiling , Genomics/methods , Humans , Middle Aged , Neoplasm Staging , Oligonucleotide Array Sequence Analysis , Patient Selection , Proportional Hazards Models , Risk Assessment , Risk Factors , Survival Analysis , Tamoxifen/therapeutic use , Time Factors , Transcription, Genetic , Treatment OutcomeABSTRACT
BACKGROUND: A combination of uracil and ftorafur (UFT) was developed to combine the cytotoxic effects of 5-fluorouracil (5-FU) with convenient oral dosing. Leucovorin was combined with UFT to further potentiate the effect of 5-FU on tumor cells. Orally administered UFT and leucovorin provided higher peak plasma concentrations of 5-FU and prolonged therapeutic 5-FU concentrations compared with continuous infusion of 5-FU. METHODS: Ninety-one patients with metastatic breast cancer who had been previously treated with anthracyclines and/or taxanes were treated with UFT and leucovorin, given orally, for the first 28 days of a 35-day cycle. The total daily dose of UFT was 300 mg/m(2), administered in 3 doses of 100 mg/m(2) each every 8 hours. The primary endpoint was time to disease progression (TTP). Secondary objectives included overall tumor response rate (overall response equals complete response plus partial response) and overall survival. RESULTS: Of the 91 patients enrolled, 70 were evaluable for efficacy. Although no complete responses were observed, 7 patients had partial responses, for an overall response rate of 10% in the evaluable population. The median TTP for the evaluable population was 10 weeks, and the proportion of patients who were free of disease progression at 6 months was 23%. The median overall survival was 59.4 weeks for all patients enrolled. Common, drug-related > or = grade 3 adverse events (graded according to National Cancer Institute Common Toxicity Criteria, version 2) included diarrhea, vomiting, abdominal pain, and nausea. CONCLUSIONS: The combination of UFT and leucovorin administered orally in a 3-times-daily regimen was found to have modest activity. Grade 3 toxicities were manageable with appropriate dose adjustments in patients with metastatic breast cancer previously treated with anthracyclines and/or taxanes.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/pathology , Drug Administration Schedule , Female , Humans , Leucovorin/administration & dosage , Middle Aged , Neoplasm Metastasis , Recurrence , Retreatment , Tegafur/administration & dosage , Uracil/administration & dosageABSTRACT
BACKGROUND: This study was performed to evaluate the outcomes of patients with locally advanced breast cancer (LABC) who were treated with a multidisciplinary approach including primary systemic chemotherapy and noncross-resistant adjuvant chemotherapy. METHODS: Patients with LABC received 4 or 6 cycles of doxorubicin and docetaxel (DT) as primary systemic chemotherapy (PST) every 21 days. Patients with adequate response underwent surgery followed by adjuvant chemotherapy according to pathologic response: complete (pCR), 2 more cycles of DT; partial (pPR), 2 more cycles of DT followed by 6 cycles of cyclophosphamide, methotrexate, and 5-fluorouracil (5-FU) (CMF); and minor (pMR), 6 cycles of CMF. Patients then received radiation and tamoxifen (hormone receptor-positive patients only). RESULTS: Eighty-eight patients were evaluable. Seventy-four patients had an adequate response to DT and were considered operable, and 72 underwent surgery. Ten patients (13.9%) achieved a pCR, 22 (30.5%) achieved a pPR, and 40 achieved a pMR (55.5%). Fourteen patients were considered nonoperable after DT and underwent salvage CMF therapy. Five of these patients underwent surgery and 1 had achieved a pCR. The estimated 5-year recurrence-free survival (RFS) rates for patients with pCR, pPR, and pMR were 80%, 77%, and 59%, respectively, and the estimated 5-year overall survival (OS) rates were 90%, 91%, and 74%, respectively. The 5-year OS rates were 82% for initially operable and 21% for initially inoperable patients (P < or = .001) CONCLUSIONS: Multidisciplinary therapy that includes PST with DT and adjuvant therapy with CMF administered according to the clinical and pathologic response is associated with high long-term RFS and OS rates in patients with LABC. Clinical or pathologic PR or CR to DT predicts improved RFS and OS.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Breast Neoplasms/therapy , Doxorubicin/administration & dosage , Taxoids/administration & dosage , Adult , Aged , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Breast Neoplasms/radiotherapy , Breast Neoplasms/surgery , Chemotherapy, Adjuvant , Combined Modality Therapy , Cyclophosphamide , Disease-Free Survival , Docetaxel , Drug Administration Schedule , Female , Fluorouracil , Humans , Methotrexate , Middle Aged , Radiotherapy, AdjuvantABSTRACT
PURPOSE: This study sought to quantify the extent of downstaging after preoperative chemotherapy for stage III breast cancer, to assess the feasibility of breast-conserving therapy (BCT) after preoperative chemotherapy, to determine the effectiveness of this multimodal treatment as measured by disease-free survival (DFS) and overall survival (OS), and to evaluate toxicities. PATIENTS AND METHODS: Patients were treated with 4 preoperative courses of 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC). They were then evaluated for response to go to mastectomy or BCT. After local therapy, patients with an excellent response were treated with 4 additional cycles of FAC, whereas patients with a moderate response received 4 cycles of MV (methotrexate and vinblastine). A total of 203 patients were registered; 194 patients (96%) underwent surgery after chemotherapy. RESULTS: The 5-year OS and progression-free survival rates were 89.8% and 81.6%, respectively, for patients with an excellent response to therapy compared with 67.2% and 63.5%, respectively, for patients with a moderate response and 55.3% and 48.8%, respectively, for patients considered nonresponders (P=.0005 for OS; P<.0001 for DFS). Cytopenia, nausea/vomiting, and stomatitis were the most common toxicities. Preoperative chemotherapy with FAC downstaged 88.6% of patients, and BCT was possible in >25%. CONCLUSION: Response to preoperative chemotherapy was a prognostic factor in improved long-term survival.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/surgery , Adolescent , Adult , Aged , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Combined Modality Therapy , Disease-Free Survival , Female , Humans , Middle Aged , Young AdultABSTRACT
PURPOSE: Preclinical data showed enhancement of breast cancer cell death when G3139 was combined with anthracyclines and taxanes. We evaluated the efficacy and safety of a Bcl-2 antisense oligonucleotide, G3139, in combination with doxorubicin (A) and docetaxel (T) in patients with locally advanced breast cancer (LABC). EXPERIMENTAL DESIGN: Following a brief phase I to determine the phase II dose, patients with locally advanced breast cancer received G3139 administered by continuous i.v. infusion for 5 to 7 days with bolus A (50 mg/m2) and T (75 mg/m2) administered on either day 3 or 6 of therapy with G3139. Cycles were repeated every 21 days x 6 in the neoadjuvant setting. Serial plasma samples were obtained for pharmacokinetic analysis. Tissue samples were obtained before and after therapy for pharmacodynamic analysis of Bcl-2 expression. RESULTS: Thirty patients (median age, 49 years; range, 24-71 years) received 160 cycles. During the phase I portion of the trial, the dose of G3139 was escalated from 3 to 7 mg/kg/d (i.v. for 5 days) in combination with AT. During the phase II portion of the trial, several doses and schedules of G3139 were evaluated. There were no pathologic complete responses. Pharmacodynamic studies showed limited Bcl-2 down-regulation in the primary tumors. CONCLUSIONS: G3139 in combination with doxorubicin and docetaxel is well tolerated. No pathologic complete response was seen and pharmacodynamic studies showed very little down-regulation of Bcl-2 in primary tumors, perhaps related to issues with insufficient drug delivery to the intact tumor.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Proto-Oncogene Proteins c-bcl-2/drug effects , Thionucleotides/administration & dosage , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Docetaxel , Doxorubicin/administration & dosage , Doxorubicin/adverse effects , Female , Humans , Middle Aged , Proto-Oncogene Proteins c-bcl-2/biosynthesis , Reverse Transcriptase Polymerase Chain Reaction , Taxoids/administration & dosage , Taxoids/adverse effects , Thionucleotides/adverse effects , Thionucleotides/pharmacokineticsABSTRACT
There is limited prognostic information to identify breast cancer patients who are at risk for late recurrences after adjuvant or neoadjuvant systemic therapy (AST). We evaluated the residual risk of recurrence and prognostic factors of 2838 patients with stage I-III breast cancer who were treated with AST between January 1, 1985, and November 1, 2001, and remained disease free for 5 years. Residual recurrence-free survival was estimated from the landmark of 5 years after AST to date of first recurrence or last follow-up using the Kaplan-Meier method. The log-rank test (two-sided) was used to compare groups. Residual recurrence-free survival rates at 5 and 10 years were 89% and 80%, respectively, and 216 patients developed a recurrence event. The 5-year residual risks of recurrence for patients with stage I, II, and III cancers were 7% (95% confidence interval [CI] = 3% to 15%), 11% (95% CI = 9% to 13%), and 13% (95% CI = 10% to 17%), respectively (P = .02). In multivariable analysis, stage, grade, hormone receptor status, and endocrine therapy were associated with late recurrences. Breast cancer patients have a substantial residual risk of recurrence, and selected tumor characteristics are associated with late recurrences.
Subject(s)
Antineoplastic Agents/therapeutic use , Breast Neoplasms/therapy , Mastectomy , Neoplasm Recurrence, Local/prevention & control , Adult , Analysis of Variance , Antineoplastic Agents, Hormonal/therapeutic use , Breast Neoplasms/ethnology , Breast Neoplasms/pathology , Breast Neoplasms/prevention & control , Chemotherapy, Adjuvant , Confidence Intervals , Female , Humans , Kaplan-Meier Estimate , Mastectomy/methods , Middle Aged , Neoadjuvant Therapy/methods , Neoplasm Staging , Odds Ratio , Prognosis , Proportional Hazards Models , Radiotherapy, Adjuvant , Research Design , Risk Assessment , Risk Factors , Time Factors , United States/epidemiologyABSTRACT
BACKGROUND: : Primary systemic therapy (PST) is the standard approach to the management of patients with locally advanced breast cancer (LABC). The authors hypothesized that the intratumoral administration of a nonreplicating adenoviral vector (Ad5) that contains the human wild-type p53, AdCMV-p53, combined with chemotherapy, could increase the efficacy of PST as measured by pathologic complete response. METHODS: : In a prospective, open-label, Phase II trial, 13 patients with LABC were treated with 6 3-week cycles of PST, which consisted of intratumoral injections of Ad5CMV-p53 for 2 consecutive days plus docetaxel and doxorubicin followed by surgery. p53 status was determined at baseline and was assessed immediately after the first injection (up to 48 hours). Clinical response was assessed by clinical and radiologic methods. RESULTS: : The trial was terminated early, because none of the patients achieved a pathologic complete response. The median age was 56 years (range, 39-71 years), and the median tumor size was 8 cm (range, 5-11 cm). Eight patients (73%) had a p53 mutation. Serial biopsies showed an increase in p53 messenger RNA (mRNA) and p21(WAF1/Cip1) mRNA. All 12 evaluable patients achieved an objective clinical response. The surgical specimens revealed scattered tumor cells with extensive tumor-infiltrate leukocytes (predominantly T-lymphocytes). At a median follow-up of 37 months (range, 30-41 months), 4 patients (30%) developed systemic recurrence, and 2 patients died. The estimate breast cancer-specific survival rate at 3 years was 84% (95% confidence interval, 65.7-100%). There was no increase in systemic toxicity. CONCLUSIONS: : Ad5CMV-p53 combined with PST is safe, active, and associated with local immunomodulatory effects. The promising clinical activity of this combination deserves further investigation in randomized studies.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/therapy , Genes, p53 , Genetic Therapy , Adenoviruses, Human/genetics , Adult , Aged , Breast Neoplasms/immunology , Breast Neoplasms/surgery , Combined Modality Therapy , Docetaxel , Doxorubicin/administration & dosage , Female , Gene Transfer Techniques , Genetic Vectors , Humans , Lymphocytes, Tumor-Infiltrating/immunology , Middle Aged , Survival Rate , Taxoids/administration & dosage , TransgenesABSTRACT
BACKGROUND: The authors previously reported results from a randomized trial of standard-dose chemotherapy with combined 5-fluorouracil (1000 mg/m2 per cycle), doxorubicin (50 mg/m2 per cycle), and cyclophosphamide (500 mg/m2 per cycle) (FAC) versus FAC followed by high-dose chemotherapy (HDCT) and autologous stem cell support (ASCS) for patients with high-risk primary breast carcinoma. After a median follow-up of 6.5 years, no significant differences were observed in recurrence-free survival (RFS) or overall survival (OS) between the 2 arms. This report updates the survival analyses. METHODS: Patients with >or=10 positive axillary lymph nodes after primary surgery or >or=4 positive lymph nodes at surgery after neoadjuvant chemotherapy were eligible. All patients were to receive 8 cycles of FAC. Patients were assigned randomly to receive either no further chemotherapy or 2 cycles of combined high-dose cyclophosphamide (5250 mg/m2 per cycle), etoposide (1200 mg/m2 per cycle), and cisplatin (165 mg/m2 per cycle) with ASCS. Primary endpoints were RFS and OS. RFS and OS were calculated by using the Kaplan-Meier method. The log-rank statistic was used to compare treatment arms. RESULTS: Between 1990 and 1997, 78 patients were registered, and 39 patients were assigned randomly to each arm. The median follow-up for all patients who were alive at last follow-up was 142.5 months (range, 45-169 months). An intention-to-treat analysis showed no significant difference between the 2 arms in terms of RFS (at 10 years: 40% with FAC vs. 26% with FAC plus HDCT; P=.11) or OS (at 10 years: 47% with FAC vs. 42% with FAC plus HDCT; P=.13). CONCLUSIONS: With a median follow-up of nearly 12 years for patients who remained alive, this trial continued to demonstrate no RFS or OS advantage for patients with high-risk primary breast carcinoma treated with HDCT after standard-dose FAC chemotherapy.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/therapy , Hematopoietic Stem Cell Transplantation , Adult , Aged , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Chemotherapy, Adjuvant , Cisplatin/administration & dosage , Cyclophosphamide/administration & dosage , Disease-Free Survival , Dose-Response Relationship, Drug , Etoposide/administration & dosage , Female , Follow-Up Studies , Humans , Middle Aged , Neoadjuvant Therapy , Survival Rate , Transplantation, Autologous , Treatment OutcomeABSTRACT
PURPOSE: To determine the impact a change in schedule of paclitaxel administration from once every 3 weeks to frequent administration would have on the pathologic complete response (pCR) rate in the breast and lymph nodes for patients with invasive breast cancer treated with primary systemic chemotherapy (PST). PATIENTS AND METHODS: Patients with clinical stage I-IIIA breast cancer were randomly assigned to receive PST of paclitaxel doses administered either weekly (for a total of 12 doses of paclitaxel) or once every 3 weeks (four cycles), followed by four cycles of fluorouracil/doxorubicin/cyclophosphamide (FAC) in standard doses every 3 weeks. Two different doses of paclitaxel were used based on lymph node status defined by ultrasound and fine needle aspiration. Clinical response and extent of residual disease in the breast and lymph nodes was assessed after completion of all chemotherapy. RESULTS: A total of 258 patients were randomly assigned to receive doses of paclitaxel administered either weekly or once every 3 weeks, followed by FAC. Of these 258 patients, 110 patients had histologic lymph node involvement and 148 patients had clinical N0 disease. Weekly paclitaxel followed by FAC was administered to 127 patients and once-every-3-weeks paclitaxel followed by FAC was administered to 131 patients. Clinical response to treatment was similar between groups (P = .25). Patients receiving weekly paclitaxel had a higher pCR rate (28.2%) than patients treated with once-every-3-weeks paclitaxel (15.7%; P = .02), with improved breast conservation rates (P = .05). CONCLUSION: The change in schedule of paclitaxel from once every 3 weeks to a more frequent administration significantly improved the ability to eradicate invasive cancer in the breast and lymph nodes.
Subject(s)
Antineoplastic Agents, Hormonal/administration & dosage , Antineoplastic Agents, Hormonal/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Paclitaxel/administration & dosage , Paclitaxel/therapeutic use , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Breast Neoplasms/pathology , Breast Neoplasms/surgery , Cyclophosphamide/administration & dosage , Doxorubicin/administration & dosage , Drug Administration Schedule , Female , Fluorouracil/administration & dosage , Humans , Middle Aged , Neoplasm Invasiveness , Treatment OutcomeABSTRACT
BACKGROUND: Accurate assessment of HER-2 status is necessary prior to anti-HER-2 antibody (trastuzumab) therapy for metastatic breast carcinoma. However, controversy exists regarding whether to assess HER-2 status in the primary tumor or in metastatic lesions. It is also unclear whether HER-2 status can change during disease progression or after chemotherapy. METHODS: Breast carcinoma samples from 60 women with known HER-2 status in both primary tumors and paired metastases (locoregional disease, n = 43 patients; distant disease, n = 17 patients) were reviewed retrospectively. Thirty-two patients underwent chemotherapy before their metastatic lesions were sampled, including 18 patients who received neoadjuvant chemotherapy and 14 patients who received adjuvant chemotherapy. The HER-2 gene was examined by fluorescence in situ hybridization either in paraffin-embedded tissue samples (48 primary tumors and 9 metastatic tumors) or in fine-needle aspirates (12 primary tumors and 51 metastatic tumors). HER-2 gene amplification was defined as a HER-2:chromosome 17 signal ratio >/= 2.0. RESULTS: The HER-2 status of primary and metastatic tumors agreed in 58 of 60 patients (97%), including 18 (30%) amplified tumors and 40 (67%) nonamplified tumors. A discrepancy in HER-2 status was observed in specimens from two patients in which HER-2 amplification was detected in the primary tumor but not the metastatic tumors. In one patient, three foci of tumor nodules were found in the same breast; the HER-2 status was assessed in only one of them, which showed amplification; however, HER-2 amplification was not detected in the axillary lymph node metastasis. In another patient, the HER-2 gene was amplified in the primary tumor but not in the liver metastasis. No metastases showed HER-2 amplification without amplification in the primary tumor. Locoregional and distant metastases demonstrated similar concordance rates with their corresponding primary tumors (98% and 94%, respectively). Complete concordance of HER-2 status was found between primary tumors prior to chemotherapy and metastases that were sampled after chemotherapy. CONCLUSIONS: The HER-2 status in breast carcinoma generally was stable during metastasis, whether to locoregional or distant sites. Chemotherapy did not modify the HER-2 status in metastatic lesions. Therefore, HER-2 amplification can be evaluated reliably in material from either primary or metastatic tumors in most patients. Further study with larger series is warranted to elucidate the significance of discordant results.