Phase 1 Dose-Escalation Study of Triweekly Nab-Paclitaxel Combined With S-1 for HER2-Negative Metastatic Breast Cancer

PurposeTo evaluate the efficacy, toxicity, maximum tolerated dose, and recommended dose of triweekly nab-paclitaxel (nab-PTX) and S-1 combination chemotherapy for patients with metastatic breast cancer.Patients and MethodsThis phase 1 study was conducted with a standard 3 + 3 dose escalation design. Every 3 weeks, the patients received nab-PTX at 180-260 mg/m² on day 1 and S-1 at 65-80 mg/m² daily on days 1 to 14.ResultsTen HER2-negative metastatic breast cancer patients were enrolled; their median number of prior chemotherapy regimens was 3. Dose-limiting toxicity was observed in the first patient assigned to level 4; grade 4 febrile neutropenia and grade 3 neurotoxicity such as needing a wheelchair occurred. Therefore, an additional patient was not assigned to level 4. The maximum tolerated dose was considered level 4 (260 mg/m² nab-PTX with 80 mg/m² S-1). The recommended dose determined was level 3 (220 mg/m² nab-PTX with 80 mg/m² S-1). The response rate was 60.0%. The disease control rate was 70.0%.ConclusionThis combination chemotherapy therapy was feasible and safe for patients with HER2-negative metastatic breast cancer.     

Phase II Study of Paclitaxel and Dasatinib in Metastatic Breast Cancer

Background

Overexpression and activation of tyrosine kinase Src has been linked to breast carcinogenesis and bone metastases. We showed the feasibility of combining the SRC inhibitor dasatinib with weekly paclitaxel in patients with metastatic breast cancer (MBC) and herein report the subsequent phase II trial.

国产长春瑞滨联合顺铂治疗转移性乳腺癌的临床观察

目的：观察国产长春瑞滨(盖诺)联合顺铂方案治疗转移性乳腺癌的临床疗效。方法：运用盖诺(25mg／m^2 IV dl，d8)加顺铂(DDP80mg／m^32 IV d1)治疗转移性乳腺癌26例。结果：取得CR3例(11．5％)，PR12例(46．1％)，总有效率RR(CR PR)达57．6％。主要毒副作用为骨髓抑制，胃肠道反应和静脉炎。白细胞减少的发生率100％，其中Ⅲ-Ⅳ度达57．7％。恶心、呕吐的发生率92．3％，Ⅲ-Ⅳ度达11．5％。静脉炎的发生率15．4％。结论：国产长春瑞滨联合顺铂对转移性乳腺癌疗效确切，且毒性可以耐受，可以作为对蒽环类药物治疗后复发，转移乳腺癌患者的二线治疗方案。     

羟基喜树碱、氨甲蝶呤、5-氟脲嘧啶和醛氢叶酸联合化疗治疗晚期复发性乳腺癌

目的：观察包含羟基喜树碱的联合化疗方案治疗晚期复发性乳腺癌的疗效及毒副作用。方法： ４３例乳腺癌患者均为术后或放疗后、并且己行系统化疗结束后复发或转移复治的病例。化疗方案为羟基喜树碱１０ｍｇ／ｍ２静滴,第 １—５ ８;氨甲喋呤 １００ｍｇ静冲,第 １日、醛氢叶酸 １５０ｍｇ／ｍ２第 ２～ ４ 日,静滴; ５－氟脲嘧啶 ５００ｍｇ／ｍ２静滴,第１－５日;每２８日为一周期,连用两个周期以上。结果：总有效率４７％,１年生存率５４％,中位生存期为１９个月。主要毒副作用为轻度的血液和消化道反应。结论：含羟基喜树碱的ＨＭＬＦ方案是治疗晚期复发性乳腺癌有效且毒性较小的联合化疗方案。     

A Real-World Study on Oral Vinorelbine for the Treatment of Metastatic Breast Cancer

Background: Vinorelbine can be used to treat metastatic breast cancer as a single agent or in combination withother chemotherapy agents, although there is little real-world data for its use, particularly the oral form, in China.The current study aimed to explore the efficacy and safety of oral vinorelbine in patients with metastatic breastcancer in real-world clinical practice. Methods: A total of 194 patients with metastatic breast cancer received oralvinorelbine as a treatment between February 2017 and January 2021 at the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciencesand Peking Union Medical College. The efficacy, in terms of progression-free survival and overall survival,and safety of oral vinorelbine were evaluated. Results: At a median follow-up period of 17.0 months, 152 patientsfinally exhibited disease progression, and 55 succumbed to the disease. During the follow-up, 53 patients demonstrated a partial response, and 106 achieved a stable disease, with an objective response rate of 27.3%. Additionally,118 patients demonstrated a partial response or stable disease for ≥24 weeks, with a clinical benefit rate of 60.8%.The median progression-free survival was 6.2 months (95% confidence interval, 5.0–7.4), and the median overallsurvival was not evaluated. No treatment-associated mortalities occurred. The most common adverse eventsincluded leukopenia (73.2%), neutropenia (72.7%), anemia (65.5%), and diarrhea (46.9%). Conclusions: Oral vinorelbine appears to be efficacious for metastatic breast cancer with acceptable toxicity for real-world use in China.     

Aggressive Subsets of Metastatic Triple Negative Breast Cancer

BackgroundRelative to other metastatic breast cancer subtypes, metastatic triple-negative breast cancer (mTNBC) has a shorter duration of response to therapy and worse overall survival. Among patients with mTNBC, it is hypothesized that inflammatory breast cancer (IBC) and young women have particularly aggressive phenotypes. We investigated clinical and cell-free DNA (cfDNA) characteristics of inflammatory-mTNBC and young-mTNBC.Patients and MethodsWe evaluated 158 patients with mTNBC who were stratified into 3 groups: (1) IBC; (2) patients aged 45 years or younger at primary diagnosis without IBC (non-IBC young); and (3) patients over age 45 at diagnosis without IBC. We evaluated clinicopathologic characteristics, sites of metastasis, survival outcomes, and the fraction of DNA in circulation derived from tumor (TFx).ResultsAnalysis of metastatic sites revealed that young patients without IBC had the most frequent lung metastases (P = .002). cfDNA analyses of first sample showed that TFx was highest in the non-IBC young group but not elevated in the IBC group (analysis of variance P = .056 for first TFx). Individually, median overall survival from metastatic diagnosis for the IBC group was 15.2 months; for the non-IBC young group, 21.2 months, and for the non-IBC over 45 group, 31.2 months. Patients with IBC and young patients without IBC had worse prognosis relative to patients over 45 without IBC (log-rank P = .023).ConclusionsAmong patients with mTNBC in this single-institution cohort, patients with IBC and young patients without IBC had significantly worse overall survival compared with patients over 45 without IBC. Young patients without IBC had significantly higher cfDNA TFx, whereas patients with IBC did not have elevated TFx despite a poor prognosis. These findings demonstrate that further analyses of mTNBC subsets are warranted.     

miRNA-29在正常乳腺、原发性乳腺癌及转移性乳腺癌组织中的表达意义

目的 探讨微小RNA-29 (miRNA-29)在正常乳腺、原发性乳腺癌以及转移性乳腺癌组织中的表达,并分析miRNA-29、基质金属蛋白酶-2(MMP-2)在疾病发生与进展中的作用.方法 选取286例乳腺癌患者,其中原发性乳腺癌205例,转移性乳腺癌81例,同期选取150例无乳腺疾病的健康妇女为对照组.采用RT-PCR检测miRNA-29与MMP-2表达水平.结果 三组乳腺标本中miRNA-29与MMP-2水平比较差异均具有统计学意义(P＜0.05),其miRNA-29与MMP-2表达呈负相关性,而肿瘤大小、病理分期、HER-2及ki-67均与miRNA-29表达具有密切相关性(P＜0.05).结论 miRNA-29与乳腺癌的发生、发展与转移等过程均具相关性,明确其表达水平有助于病情评估及临床治疗.     

Phase I/II Trial of Vinorelbine and Sorafenib in Metastatic Breast Cancer

PurposeWe investigated the efficacy and toxicity of sorafenib, a multikinase inhibitor of vascular endothelial growth factor receptor tyrosine kinase, in combination with vinorelbine therapy in a phase I/II trial in patients with metastatic breast cancer.Patients and MethodsWe enrolled 11 patients in the phase I portion to determine the maximum tolerated dose (MTD) of the combination, followed by 35 extra patients treated at the MTD in phase II. The median age of patients was 54 years old (range, 31-72 years old). Tumors were estrogen receptor and progesterone receptor (ER/PR) positive in 54% (22/54) of patients, and triple negative (ER⁻, PR⁻, HER2⁻) in 41% (17/54) of patients. Of all patients, 22% received sorafenib and vinorelbine as first-line therapy, 37% as second-line therapy, and 41% as third-line therapy.ResultsIn total, 41 patients were treated at the MTD (6 during phase I; 35 in phase II). The observed 44% 4-month progression-free survival rate was similar to the estimated historical rate of 43% with vinorelbine treatment. The combination was tolerated with expected toxicities. Patients treated at the MTD who had received prior bevacizumab treatment received a median of 1.5 cycles (range, 1-10 cycles) compared with a median of 5 cycles (range, 2-12 cycles) for patients without prior bevacizumab treatment.ConclusionFurther evaluation of vinorelbine and sorafenib in bevacizumab-naive patients may be of interest if specific biomarkers guiding patient selection can be identified.     

Metastatic Breast Cancer: Therapeutic Options According to Molecular Subtypes and Prior Adjuvant Therapy

In spite of advances in treatment strategies, about 25%–40% of patients with breast cancer still eventually develop metastatic disease that is largely incurable. Treatment goals vary from symptom control to lengthening survival, mainly on the basis of patient age and performance status, tumor biology, site and extent of disease, and prior therapies. In particular, breast cancer molecular characterization allows for the identification of breast cancer subtypes with distinct biological features, a distinct clinical course, and distinct treatment sensitivity. Endocrine manipulation is the cornerstone of therapy in hormone receptor–positive tumors; anti–human epidermal growth factor receptor (HER)‐2 agents are essential in the management of HER‐2⁺ tumors; and chemotherapy is the only available option so far for the triple‐negative subtype. In each of these subtypes, the more efficacious agents have been progressively incorporated into adjuvant treatment. As a consequence, the choice of the optimal therapeutic strategy for patients with metastatic disease is largely influenced by prior exposure to adjuvant therapies. This review contextualizes the data from clinical trials into different clinical scenarios of metastatic disease, taking into account the molecular subtype and prior adjuvant treatments.     

Paclitaxel and Mitoxantrone in the Treatment of Metastatic Breast Cancer: A Phase II Trial of the Minnie Pearl Cancer Research Network

Background and rationale: The combination of paclitaxel and doxorubicin is highly active in the treatment of metastatic breast cancer, but is associated with substantial toxicity. In this phase II trial, we evaluated the combination of paclitaxel and mitoxantrone in an attempt to maintain efficacy and improve tolerability of this regimen.

Patients and methods: Sixty-three patients with metastatic breast cancer were treated with paclitaxel 200 mg/m², 1 hr IV infusion, and mitoxantrone 10 mg/m² IV, every 21 days. Responding patients received at least six courses of therapy. Ninety-three percent of patients in this trial were receiving first-line treatment for metastatic breast cancer; 62% of patients had received previous adjuvant chemotherapy, and 26% had received previous doxorubicin.

Results: Objective responses were seen in 24 of 61 evaluable patients (39%). Median response duration was 9 months (range 4-37+ months); actuarial 1-, 2-, and 3-year survivals were 62, 32, and 25%, respectively. The treatment was generally well tolerated; 78% of patients had grade 3 or 4 leukopenia at sometime during their treatment course, but only 14 hospitalizations for neutropenia and fever were necessary (4% of courses). Grade 3 fatigue was experienced by 30% of patients. Cardiotoxicity was not observed.

Conclusions: The combination of paclitaxel and mitoxantrone is active, easily administered, and well tolerated in the treatment of metastatic breast cancer. Its activity appears similar to several other taxane-based combination regimens recently evaluated for the treatment of advanced breast cancer.     

Phase I study of docetaxel and cyclophosphamide in patients with advanced or recurrent breast cancer

BACKGROUND: A phase I clinical study of combination chemotherapy with docetaxel and cyclophosphamide (CPA) was performed to determine the maximum tolerated dose (MTD), the incidence and severity of toxicities and the pharmacokinetics in patients with advanced or recurrent breast cancer. METHODS: Docetaxel was administered by intravenous drip infusion over 60 minutes, followed by intravenous bolus injection of CPA every 3-4 weeks. The dosage of docetaxel/CPA was 40/200, 40/400, 50/400, or 60/400 mg/m(2)/day. RESULTS: Fifteen patients were enrolled and received a total of 33 cycles of the combined therapy. The dose limiting toxicities (DLTs) were leukopenia, neutropenia and thrombocytopenia. The MTD was estimated to be docetaxel 60 mg/m(2) in combination with CPA 400 mg/m(2) per day. Plasma clearance of both drugs was similar regardless of dose. The recommended doses of docetaxel/CPA for a phase Utrial are 50/400 mg/m(2)/day every 3-4 weeks. CONCLUSION: The MTD of this combined therapy was docetaxel 60 mg/m(2) and CPA 400 mg/m(2). Neutropenia and leukopeina were common and severe. It is important to stress the need for modification of the dosing scheme.     

nab-Paclitaxel for the Treatment of Aggressive Metastatic Breast Cancer

Despite advances in early diagnosis, prevention, and treatment, breast cancer remains the second-leading cause of cancer-related deaths in women. The 5-year survival rate for patients with metastatic breast cancer (MBC) is just 24%. However, some forms of MBC appear to be more aggressive than others. Triple-negative breast cancer (TNBC; lacking overexpression of human epidermal growth factor receptor 2 [HER2] and expression of estrogen and progesterone receptors) and breast cancers that overexpress HER2 are the 2 biologically defined subtypes with the worst prognoses. Although a number of effective options have been developed for the treatment of HER2-overexpressing disease, TNBC remains a difficult-to-treat subtype. In addition to hormone receptor and HER2 status, multiple other factors are predictive of relatively poorer clinical outcomes, including visceral metastasis, short disease-free interval between the end of treatment for early-stage disease and diagnosis of MBC, and higher number of metastatic sites. There is an urgent need to improve therapy for patients with aggressive forms of breast cancer. Taxanes are considered among the most active classes of compounds against breast cancer. This review specifically examines the clinical trials in which nab-paclitaxel was used to treat patients with MBC and factors associated with poor prognosis.     

中等剂量卡培他滨单药治疗转移性乳腺癌的疗效及安全性

目的观察中等剂量［2 000 mg/(m²·d)］卡培他滨治疗转移性乳腺癌的疗效和不良反应。方法卡培他滨单药治疗43例转移性乳腺癌,2000 mg/(m²·d),d1～14,每3周为1周期。结果43例患者平均行8周期卡培他滨治疗,客观缓解率（CR+PR）为18.6%,临床获益率（CR+PR+SD）为86.0%。整体的中位无进展生存期（PFS）为7.1月（95%CI：5.8～8.4）,在一线治疗、二线治疗和三线及以上治疗亚组中差异无统计学意义,分别为7.1月、6.1月和8.1月（P=0.390）。在蒽环类药物与紫杉类药物治疗均失败的患者中,PFS明显缩短（6.1月 vs.7.1月,P=0.038）。大于65岁的患者PFS显著延长（8.1月 vs.6.1月,P=0.045）。主要不良反应为手足综合征19例（44.2%）。结论中等剂量［2 000 mg/(m²·d)］卡培他滨单药治疗转移性乳腺癌安全、有效。     

A Phase 1 dose-escalation trial of glufosfamide in combination with gemcitabine in solid tumors including pancreatic adenocarcinoma

Absract Purpose To evaluate safety and pharmacokinetics and to establish the maximum tolerated dose of glufosfamide when administered in combination with gemcitabine in advanced solid tumors. Methods This Phase 1 dose-escalation study evaluated the combination of glufosfamide + gemcitabine in patients with advanced solid tumors. Cohorts of three to six patients were treated with glufosfamide doses from 1,500 to 4,500 mg/m² IV over 4 h on Day 1 and gemcitabine 1,000 mg/m² IV over 30 min on Days 1, 8 and 15 of every 28-day cycle. Detailed PK sampling was performed on days 1 and 8 of the first two cycles. Results Nineteen patients were enrolled. Two patients had dose-limiting toxicity: Grade 3 fatigue at 2,500 mg/m² and Grade 4 thrombocytopenia at 4,500 mg/m². Five patients completed six cycles and one patient remained on study for ten cycles. Two patients discontinued for adverse events. Grade 3/4 neutropenia and thrombocytopenia occurred in seven patients and five patients, respectively. The CrCL fell below 60 mL/min in two patients. There was one unconfirmed partial response and 10 of 19 (52.6%) patients had stable disease or better at 8 weeks and three patients had continuing stable disease at 24 weeks. Pharmacokinetic analyses suggest no interaction between glufosfamide and gemcitabine. Conclusion Phase I data indicate that full dose glufosfamide (4,500 mg/m²) can be given safely in combination with gemcitabine. A Phase II study in patients with pancreatic adenocarcinoma is ongoing. Presented in part at the 2006 ASCO Gastrointestinal Symposium. Research supported by Threshold Pharmaceuticals, Inc.     

Genetic Markers in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) accounts for 15% to 20% of breast cancer cases and is characterized by the absence of estrogen, progesterone, and human epidermal growth factor 2 receptors. Though TNBC is a highly heterogenic and aggressive disease, TNBC patients have better response to neoadjuvant therapy compared to other breast cancer subtypes. Nevertheless, patients with residual disease have a very poor prognosis, with higher probability of relapse and lower overall survival in the first years after diagnosis. TNBC has 6 subtypes with distinct molecular signatures with different prognoses and probably different responses to therapy. The precise stratification of TNBC is therefore crucial for the development of potent standardized and targeted therapies. In spite of intensive research into finding new molecular biomarkers and designing personalized therapeutic approaches, BRCA mutational status is the only clinically validated biomarker for personalized therapy in TNBC. Recent studies have reported several promising biomarkers that are currently being validated through clinical trials. The objective of this review was to summarize the clinically relevant genetic markers for TNBC that could serve as diagnostic, prognostic, or predictive or could improve personalized therapeutic strategies.     

Economic Analysis of Psychosocial Group Therapy in Women with Metastatic Breast Cancer

Purpose

Metastatic breast cancer is associated with psychological distress in one-third of patients. We examined the impact of group psychosocial support on health care costs in metastatic breast cancer. Psychosocial interventions have been shown to reduce psychological distress in these patients. In other diseases, depression and anxiety have been associated with higher health care system resource utilization.

Methods

Data on health care system resources utilization were collected as part of a Canadian multicenter randomized controlled trial of a supportive-expressive group support in metastatic breast cancer. Costs were obtained from one tertiary care hospital in Toronto. A cost minimization analysis was conducted since there was no survival difference; the primary endpoint of the study. Cost-effectiveness analyses were conducted for mood and pain.

Results

Total health care utilization costs (including costs of the group therapy intervention) for the intervention and control groups were $31,715 and $28,189, respectively per patient. The difference in total costs between groups ($3,526) was not statistically significant (P = 0.53). The cost-effectiveness analysis for mood showed the intervention group to have an increased cost of $5,550 per patient for an effect size of 0.5 on the POMS scale. The corresponding cost for pain was $4,309. An exploratory analysis on patients who were more distressed at baseline showed a non-significant decrease in cost in favor of the intervention arm (difference of $3,911 P = 0.66).

Conclusion

Psychosocial intervention, in the form of supportive-expressive group support for metastatic breast cancer, does not lower health care system resource utilization.     

Irinotecan as a Palliative Therapy for Metastatic Breast Cancer Patients after Previous Chemotherapy

Background: This analysis was conducted to evaluate the efficacy and safety of irinotecan based chemotherapyfor treatment of patients with metastatic breast cancer (MBC) who experienced disease progression after one tothree chemotherapy regimens, including at least one anthracycline- or taxane-based. Methods: Clinical studieswere identified using a predefined search strategy. Pooled response rates (RR) to treatment were calculated.Results: As irinotecan based regimens, 5 clinical studies which including 217 patients with refractory MBC wereconsidered eligible for inclusion, with irinotecan, cisplatin, capecitabine, or TS-1. Systemic analysis suggestedthat, in all patients, pooled RR was 48.8% (106/217) with irinotecan based regimens. Thrombocytopenia andleukocytopenia were the main side effects. No grade III or IV renal or liver toxicity was observed. No treatmentrelated deaths occurred. Conclusion: This systemic analysis suggests that irinotecan based regimens are beneficialand safe for treating patients with MBC after other chemotherapy.     

Analysis of MET Genetic Aberrations in Patients With Breast Cancer at MD Anderson Phase I Unit

Backgroundc-MET is a receptor tyrosine kinase whose phosphorylation activates important proliferation pathways. MET amplification and mutation have been described in various malignancies, including breast cancer (BC), and c-MET overexpression is associated with worse survival outcomes in patients with BC. We describe MET mutation and amplification rates in a BC cohort of patients referred to a Phase I Unit.MethodsWe reviewed the electronic medical records of all patients with advanced BC tested for MET amplification, mutation, or both who were referred to the Department of Investigational Cancer Therapeutics at MD Anderson.ResultsA total of 107 patients with advanced BC were analyzed for MET mutation/variant (88 patients) or amplification (63 patients). Of these, 49 were tested for both genetic abnormalities. Three of 63 patients (4.7%) demonstrated MET gene amplification by fluorescence in situ hybridization (2 in primary tissue; 1 in metastatic site). MET mutation/variant was detected in 8 of 88 patients (9%). High-grade tumors were characteristic of all patients harboring MET amplification and were present in 7 of 8 (87.5%) of those with MET mutation. Metastatic sites were greater in MET-amplified compared with wild-type patients (median of 7 vs. 3 sites). Five of 8 patients (62.5%) with MET mutations had triple negative BC compared with 46% in controls. In addition, patients with positive test results for MET aberrations (n = 11) had inferior overall survival (OS) from Phase I consult compared with wild-type patients (n = 37), although this was not statistically significant (median OS = 9 vs. 15 months, P = .43).ConclusionsIn this cohort of patients with BC who were referred to our Phase I Department, MET aberrations were associated with higher metastatic burden and high-grade histology. We could not demonstrate differences in survival outcomes because of a small sample size.