ABSTRACT
BACKGROUND: Patients with metastatic triple-negative breast cancer have a poor prognosis. Sacituzumab govitecan is an antibody-drug conjugate composed of an antibody targeting the human trophoblast cell-surface antigen 2 (Trop-2), which is expressed in the majority of breast cancers, coupled to SN-38 (topoisomerase I inhibitor) through a proprietary hydrolyzable linker. METHODS: In this randomized, phase 3 trial, we evaluated sacituzumab govitecan as compared with single-agent chemotherapy of the physician's choice (eribulin, vinorelbine, capecitabine, or gemcitabine) in patients with relapsed or refractory metastatic triple-negative breast cancer. The primary end point was progression-free survival (as determined by blinded independent central review) among patients without brain metastases. RESULTS: A total of 468 patients without brain metastases were randomly assigned to receive sacituzumab govitecan (235 patients) or chemotherapy (233 patients). The median age was 54 years; all the patients had previous use of taxanes. The median progression-free survival was 5.6 months (95% confidence interval [CI], 4.3 to 6.3; 166 events) with sacituzumab govitecan and 1.7 months (95% CI, 1.5 to 2.6; 150 events) with chemotherapy (hazard ratio for disease progression or death, 0.41; 95% CI, 0.32 to 0.52; P<0.001). The median overall survival was 12.1 months (95% CI, 10.7 to 14.0) with sacituzumab govitecan and 6.7 months (95% CI, 5.8 to 7.7) with chemotherapy (hazard ratio for death, 0.48; 95% CI, 0.38 to 0.59; P<0.001). The percentage of patients with an objective response was 35% with sacituzumab govitecan and 5% with chemotherapy. The incidences of key treatment-related adverse events of grade 3 or higher were neutropenia (51% with sacituzumab govitecan and 33% with chemotherapy), leukopenia (10% and 5%), diarrhea (10% and <1%), anemia (8% and 5%), and febrile neutropenia (6% and 2%). There were three deaths owing to adverse events in each group; no deaths were considered to be related to sacituzumab govitecan treatment. CONCLUSIONS: Progression-free and overall survival were significantly longer with sacituzumab govitecan than with single-agent chemotherapy among patients with metastatic triple-negative breast cancer. Myelosuppression and diarrhea were more frequent with sacituzumab govitecan. (Funded by Immunomedics; ASCENT ClinicalTrials.gov number, NCT02574455; EudraCT number, 2017-003019-21.).
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents/therapeutic use , Camptothecin/analogs & derivatives , Cell Adhesion Molecules/antagonists & inhibitors , Immunoconjugates/therapeutic use , Triple Negative Breast Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/adverse effects , Antigens, Neoplasm , Antineoplastic Agents/adverse effects , Camptothecin/adverse effects , Camptothecin/therapeutic use , Drug Resistance, Neoplasm , Female , Humans , Immune Checkpoint Inhibitors/therapeutic use , Immunoconjugates/adverse effects , Male , Middle Aged , Neoplasm Recurrence, Local/drug therapy , Progression-Free Survival , Survival Analysis , Triple Negative Breast Neoplasms/mortality , Tumor BurdenABSTRACT
The successful development of therapies targeting the human epidermal growth factor receptor 2 (HER2) has altered the natural progression of disease among patients with HER2-positive metastatic breast cancer. The monoclonal antibody trastuzumab was the first HER2-directed agent and it was associated with significantly improved outcomes for patients. Subsequently, other HER2-directed agents such as the monoclonal antibody pertuzumab, the tyrosine kinase receptor inhibitor lapatinib, and the immunoconjugate trastuzumab emtansine were developed to overcome resistance to trastuzumab and provide additional treatment options for patients. Recent data have demonstrated that the use of these HER2-directed agents improves outcomes. However, with the emergence of new HER2-targeted agents, the optimal sequencing of treatment remains unclear. Ongoing research is investigating new HER2 combinations, the role of sequencing, novel HER2-directed agents, and combinations with other targeted agents to overcome resistance.
Subject(s)
Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Receptor, ErbB-2/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Clinical Trials as Topic , Drug Resistance, Neoplasm/drug effects , Female , Humans , Neoplasm Metastasis , Receptor, ErbB-2/genetics , Sequence Analysis, DNAABSTRACT
PURPOSE: Although the 21-gene recurrence score (RS) assay has been validated to assess the risk of distant recurrence in hormone receptor-positive breast cancer patients, the relationship between RS and the risk of locoregional recurrence (LRR) remains unclear. The purpose of this study was to determine if RS is associated with LRR in breast cancer patients and whether this relationship varies based on the type of local treatment [mastectomy or breast-conserving therapy (BCT)]. METHODS: 163 consecutive estrogen receptor-positive breast cancer patients at our institution had an RS generated from the primary breast tumor between August 2006 and October 2009. Patients were treated with lumpectomy and radiation (BCT) (n = 110) or mastectomy alone (n = 53). Patients were stratified using a pre-determined RS of 25 and then grouped according to local therapy type. RESULTS: Median follow-up was 68.2 months. Patients who developed an LRR had stage I or IIA disease, >2 mm surgical margins, and received chemotherapy as directed by RS. While an RS > 25 did not predict for a higher rate of LRR, an RS > 24 was associated with LRR in our subjects. Among mastectomy patients, the 5-year LRR rate was 27.3 % in patients with an RS > 24 versus 10.7 % (p = 0.04) in those whose RS was ≤ 24. RS was not associated with LRR in patients who received BCT. CONCLUSIONS: Breast cancer patients treated with mastectomy for tumors that have an RS > 24 are at high risk of LRR and may benefit from post-mastectomy radiation.
Subject(s)
Breast Neoplasms/surgery , Mastectomy, Segmental , Mastectomy , Neoplasm Recurrence, Local/diagnosis , Adult , Aged , Aged, 80 and over , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Female , Follow-Up Studies , Humans , Middle Aged , Neoplasm Grading , Neoplasm Recurrence, Local/metabolism , Neoplasm Staging , Prognosis , Receptor, ErbB-2/metabolism , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolismABSTRACT
Endocrine therapy has significantly improved outcomes for patients with early- and advanced-stage hormone-receptor (HR)-positive breast cancer. Despite the success of adjuvant endocrine therapy, some patients with early-stage disease will experience relapse. Additionally, all patients with advanced disease will eventually experience disease progression on endocrine therapy due to resistance. Improved understanding of the mechanisms associated with resistance to endocrine agents has recently led to the approval of new therapeutics. Multiple questions remain unanswered, including the optimal duration of adjuvant therapy, the role of ovarian ablation in early-stage breast cancer in premenopausal women, and how to best incorporate targeted agents with endocrine therapy in the metastatic setting. This article reviews the optimization of endocrine therapy in patients with HR-positive breast cancer, focusing on these controversial areas.
Subject(s)
Antineoplastic Agents, Hormonal/therapeutic use , Breast Neoplasms/drug therapy , Aromatase Inhibitors/therapeutic use , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Chemotherapy, Adjuvant , Clinical Trials as Topic , Female , Humans , Neoplasm Metastasis , Neoplasm Staging , Tamoxifen/therapeutic use , Treatment OutcomeABSTRACT
The use of gene expression profiling has impacted our understanding of breast cancer biology and increasingly has played a role in guiding clinical decisions. We have used hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status for years to guide selection of therapy. More recently, gene expression analysis has facilitated the identification of at least five intrinsic subtypes of breast cancer. Potential therapeutic targets have also been identified using genomic profiling. Several tests, such as the 21-gene recurrence score assay (Oncotype DX) and the 70-gene prognosis signature (MammaPrint), have been well validated as prognostic tools for early-stage breast cancer, and have aided in adjuvant therapy decisions for early-stage, HR-positive breast cancer patients. Genomic profiling has the potential to provide additional insight into drug discovery and clinical trial design by identifying appropriate targeted therapies for subtypes of breast cancer.
Subject(s)
Biomarkers, Tumor/genetics , Breast Neoplasms/classification , Breast Neoplasms/genetics , Decision Making , Gene Expression Profiling , Genomics , Breast Neoplasms/drug therapy , Chemotherapy, Adjuvant , Female , Gene Expression Regulation, Neoplastic , Humans , Oligonucleotide Array Sequence Analysis , Practice Guidelines as TopicABSTRACT
PURPOSE: Cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) with endocrine therapy (ET) improves progression-free survival (PFS) and overall survival (OS) in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). Although preclinical and clinical data demonstrate a benefit in changing ET and continuing a CDK4/6i at progression, no randomized prospective trials have evaluated this approach. METHODS: In this investigator-initiated, phase II, double-blind placebo-controlled trial in patients with HR+/HER2- MBC whose cancer progressed during ET and CDK4/6i, participants switched ET (fulvestrant or exemestane) from ET used pre-random assignment and randomly assigned 1:1 to the CDK4/6i ribociclib versus placebo. PFS was the primary end point, defined as time from random assignment to disease progression or death. Assuming a median PFS of 3.8 months with placebo, we had 80% power to detect a hazard ratio (HR) of 0.58 (corresponding to a median PFS of at least 6.5 months with ribociclib) with 120 patients randomly assigned using a one-sided log-rank test and significance level set at 2.5%. RESULTS: Of the 119 randomly assigned participants, 103 (86.5%) previously received palbociclib and 14 participants received ribociclib (11.7%). There was a statistically significant PFS improvement for patients randomly assigned to switched ET plus ribociclib (median, 5.29 months; 95% CI, 3.02 to 8.12 months) versus switched ET plus placebo (median, 2.76 months; 95% CI, 2.66 to 3.25 months) HR, 0.57 (95% CI, 0.39 to 0.85); P = .006. At 6 and 12 months, the PFS rate was 41.2% and 24.6% with ribociclib, respectively, compared with 23.9% and 7.4% with placebo. CONCLUSION: In this randomized trial, there was a significant PFS benefit for patients with HR+/HER2- MBC who switched ET and received ribociclib compared with placebo after previous CDK4/6i and different ET.
Subject(s)
Breast Neoplasms , Humans , Female , Breast Neoplasms/pathology , Cyclin-Dependent Kinase 4 , Prospective Studies , Receptor, ErbB-2/metabolism , Double-Blind Method , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cyclin-Dependent Kinase 6ABSTRACT
Angiogenesis, the process of new blood vessel formation, is required for tumor growth and metastasis. There is substantial preclinical and clinical evidence supporting the central role of angiogenesis in tumor formation and metastasis. Thus, the inhibition of angiogenesis may provide more effective treatment for patients with advanced breast cancer. Several chemotherapeutic and hormonal agents routinely used in the treatment of advanced breast cancer have antiangiogenic properties. Novel antiangiogenic agents targeting the vascular endothelial growth factor (VEGF) ligand and receptor tyrosine kinase inhibitors are being developed. Recently, a large phase III clinical trial demonstrated a significant benefit in progression-free survival with the addition of anti-VEGF monoclonal antibody bevacizumab to paclitaxel for first-line treatment of advanced breast cancer. This study established that antiangiogenic therapy is effective in breast cancer, and additional studies of bevacizumab and other antiangiogenic agents are underway. This article reviews the evidence for the role of angiogenesis in breast cancer pathogenesis, the challenges of developing antiangiogenic agents, and current agents in clinical trials.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Antineoplastic Agents/therapeutic use , Breast Neoplasms/blood supply , Breast Neoplasms/drug therapy , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Angiogenesis Inhibitors/pharmacology , Antineoplastic Agents/pharmacology , Breast Neoplasms/metabolism , Female , Humans , Neovascularization, PathologicABSTRACT
The microtubule-targeting agents have made significant contributions to cancer therapy over the past 50 years. The vinca alkaloids and taxanes have been used to treat a broad range of malignancies, including leukemias and lymphomas and many types of solid tumors. The taxanes have been frequently used in the treatment of advanced ovarian, breast, lung, head and neck, and prostate cancer, and they are increasingly being used in early stage disease. This chapter reviews the pharmacology, clinical indications, and toxicities associated with the vinca alkaloids and taxanes.
Subject(s)
Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Microtubules/drug effects , Neoplasms/drug therapy , Antineoplastic Agents/adverse effects , Humans , Molecular Conformation , Taxoids/adverse effects , Taxoids/pharmacology , Taxoids/therapeutic use , Vinca Alkaloids/adverse effects , Vinca Alkaloids/pharmacology , Vinca Alkaloids/therapeutic useABSTRACT
Among breast cancer patients treated with neoadjuvant chemotherapy (NAC) and mastectomy, locoregional recurrence (LRR) rates are unclear in women with ER+ tumors treated with adjuvant endocrine therapy without postmastectomy radiation (PMRT). To determine if PMRT is needed in these patients, we compared LRR rates of patients with ER+ tumors (treated with adjuvant endocrine therapy) with women who have non-ER+ tumors. 85 consecutive breast cancer patients (87 breast tumors) treated with NAC and mastectomy without PMRT were reviewed. Patients were divided by residual nodal disease (ypN) status (ypN+ versus ypN0) and then stratified by receptor subtype. Among ypN+ patients (n = 35), five-year LRR risk in patients with ER+, Her2+, and triple negative tumors was 5%, 33%, and 37%, respectively (p = 0.02). Among ypN+/ER+ patients, lymphovascular invasion and grade three disease increased the five-year LRR risk to 13% and 11%, respectively. Among ypN0 patients (n = 52), five-year LRR risk in patients with ER+, Her2+, and triple negative tumors was 7%, 22%, and 6%, respectively (p = 0.71). In women with ER+ tumors and residual nodal disease, endocrine therapy may be sufficient adjuvant treatment, except in patients with lymphovascular invasion or grade three tumors where PMRT may still be indicated.
ABSTRACT
BACKGROUND: Neoadjuvant chemotherapy is widely used to downstage breast cancers before surgery and is an accepted standard of care among patients with early-stage breast cancer in whom adjuvant chemotherapy would be recommended. Pathologic complete response (pCR) rate is a robust predictor of outcome for certain breast cancer subtypes, including Her2-overexpressing breast cancer. The incorporation of Her2-targeted therapies has significantly increased the pCR rate in the neoadjuvant setting. Although regimens composed of trastuzumab, nab-paclitaxel, and vinorelbine have demonstrated clinical efficacy in patients with metastatic breast cancer, few studies have examined this combination in early-stage Her2+ breast cancer. We hypothesized that the combination of neoadjuvant nab-paclitaxel followed by vinorelbine could represent a nonanthracycline-based treatment option for early-stage Her2-overexpressing breast cancer. PATIENTS AND METHODS: Patients received 4 cycles of nab-paclitaxel 260 mg/m(2) intravenously (IV) every 14 days for 4 cycles followed by vinorelbine 25 mg/m(2) IV weekly for 12 weeks with concurrent trastuzumab (4 mg/kg loading dose, and then 2 mg/kg/wk). The primary endpoint was the rate of pCR. Secondary endpoints included clinical response, toxicity, and survival rates. RESULTS: A total of 27 patients were accrued to the trial. The median tumor size was 4.0 cm, and more than 50% of patients had axillary lymph node involvement. The pCR rate was 48.1%. Among the 40% of patients who had hormone receptor-positive disease, the pCR rate was 18.2%, compared with 68.8% among patients with estrogen receptor/progesterone receptor-negative tumors. CONCLUSIONS: The combination of trastuzumab with nab-paclitaxel followed by vinorelbine was well tolerated and had promising activity in the neoadjuvant setting.
Subject(s)
Albumins/administration & dosage , Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Paclitaxel/administration & dosage , Vinblastine/analogs & derivatives , Adult , Albumins/adverse effects , Antibodies, Monoclonal, Humanized/adverse effects , Breast Neoplasms/metabolism , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Female , Humans , Middle Aged , Neoadjuvant Therapy , Neoplasm Staging , Paclitaxel/adverse effects , Receptor, ErbB-2/metabolism , Recurrence , Remission Induction , Survival Analysis , Trastuzumab , Treatment Outcome , Vinblastine/administration & dosage , Vinblastine/adverse effects , VinorelbineABSTRACT
Long-term outcomes for early-stage breast cancer have continued to improve, and more patients are becoming long-term survivors. In addition to patients' concern about risk of developing recurrent disease, they are also concerned about potential toxicities of treatment. Current guidelines for long-term follow-up are reviewed. Potential toxicities of tamoxifen and aromatase inhibitors are reviewed. Management of menopausal symptoms, cancer-related fatigue, and cognitive function is discussed.
Subject(s)
Breast Neoplasms/pathology , Breast Neoplasms/mortality , Early Detection of Cancer , Female , Humans , Neoplasm Staging , Practice Guidelines as Topic , Survival RateABSTRACT
BACKGROUND: The combination of docetaxel and capecitabine has been demonstrated to improve progression-free survival (PFS) and overall survival (OS) in patients with metastatic breast cancer compared with docetaxel alone. We hypothesized that the combination of docetaxel and capecitabine, given concomitantly or sequentially, would present a nonanthracycline-based treatment option for patients with early stage and locally advanced breast cancer. PATIENTS AND METHODS: Patients with stage I to stage IIIC, human epidermal growth factor receptor 2-negative (HER2(-)) breast cancer were randomly assigned to receive either docetaxel followed by capecitabine (D â C) or docetaxel administered concomitantly with capecitabine (DC). RESULTS: Between April 2007 and July 2009, 51 patients were accrued to the trial at an academic center, a county hospital, and community sites. Median tumor size was 3.8 cm and > 70% of patients had axillary lymph node involvement. Fifty-seven percent of patients accrued were African American. Twenty-one of the 51 subjects had triple-negative breast cancer. The pathologic complete response (pCR) rate was 8% in the D â C arm; 12% in the DC arm. The pCR rate among patients with triple-negative breast cancer was 19%. CONCLUSION: The combination of docetaxel and capecitabine has modest activity in the neoadjuvant setting. These results are consistent with other trials using this combination in the neoadjuvant setting.