Comparative genomic analysis of PIK3R1-mutated and wild-type breast cancers.

PURPOSE: The PIK3R1 gene encodes the regulatory subunit-p85a-of the PI3K signaling complex. Prior studies have found that pathogenic somatic alterations in PIK3R1 are enriched in human breast cancers but the genomic landscape of breast cancer patients harboring PIK3R1 mutations has not been extensively characterized. METHODS: We retrospectively analyzed 6,009 patient records that underwent next-generation sequencing (NGS) using the Tempus xT solid tumor assay. All patients had breast cancer with known HER2 (+/-) and hormone receptor (HR; +/-) status and were classified according to the presence of PIK3R1 mutations including short variants and copy number alterations. RESULTS: The frequency of PIK3R1 mutations varied according to subtype: 6% in triple negative (TNBC, 89/1,475), 2% in HER2-/HR+ (80/3,893) and 2.3% in HER2+ (15/641) (p < 0.001). Co-mutations in PTEN, TP53 and NF1 were significantly enriched, co-mutations in PIK3CA were significantly less prevalent, and tumor mutational burden was significantly higher in PIK3R1-mutated HER2- samples relative to PIK3R1 wild-type. At the transcriptional-level, PIK3R1 RNA expression in HER2- disease was significantly higher in PIK3R1-mutated (excluding copy number loss) samples, regardless of subtype. CONCLUSION: This is the largest investigation of the PIK3R1 mutational landscape in breast cancer patients (n = 6,009). PIK3R1 mutations were more common in triple-negative breast cancer (~ 6%) than in HER2 + or HER2-/HR + disease (approximately 2%). While alterations in the PI3K/AKT pathway are often actionable in HER2-/HR + breast cancer, our study suggests that PIK3R1 could be an important target in TNBC as well.

Multinational Study of the Efficacy and Safety of Humanized Anti-HER2 Monoclonal Antibody in Women Who Have HER2-Overexpressing Metastatic Breast Cancer That Has Progressed After Chemotherapy for Metastatic Disease.

PURPOSE: Overexpression of the HER2 protein occurs in 25% to 30% of human breast cancers and leads to a particularly aggressive form of the disease. Efficacy and safety of recombinant humanized anti-HER2 monoclonal antibody as a single agent was evaluated in women with HER2-overexpressing metastatic breast cancer that had progressed after chemotherapy for metastatic disease. PATIENTS AND METHODS: Two hundred twenty-two women, with HER2-overexpressing metastatic breast cancer that had progressed after one or two chemotherapy regimens, were enrolled. Patients received a loading dose of 4 mg/kg intravenously, followed by a 2-mg/kg maintenance dose at weekly intervals. RESULTS: Study patients had advanced metastatic disease and had received extensive prior therapy. A blinded, independent response evaluation committee identified eight complete and 26 partial responses, for an objective response rate of 15% in the intent-to-treat population (95% confidence interval, 11% to 21%). The median duration of response was 9.1 months; the median duration of survival was 13 months. The most common adverse events, which occurred in approximately 40% of patients, were infusion-associated fever and/or chills that usually occurred only during the first infusion, and were of mild to moderate severity. These symptoms were treated successfully with acetaminophen and/or diphenhydramine. The most clinically significant adverse event was cardiac dysfunction, which occurred in 4.7% of patients. Only 1% of patients discontinued the study because of treatment-related adverse events. CONCLUSION: Recombinant humanized anti-HER2 monoclonal antibody, administered as a single agent, produces durable objective responses and is well tolerated by women with HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. Side effects that are commonly observed with chemotherapy, such as alopecia, mucositis, and neutropenia, are rarely seen.

Efficacy and Safety of Trastuzumab as a Single Agent in First-Line Treatment of HER2-Overexpressing Metastatic Breast Cancer.

PURPOSE: To evaluate the efficacy and safety of first-line, single-agent trastuzumab in women with HER2-overexpressing metastatic breast cancer. PATIENTS AND METHODS: One hundred fourteen women with HER2-overexpressing metastatic breast cancer were randomized to receive first-line treatment with trastuzumab 4 mg/kg loading dose, followed by 2 mg/kg weekly, or a higher 8 mg/kg loading dose, followed by 4 mg/kg weekly. RESULTS: The objective response rate was 26% (95% confidence interval [CI], 18.2% to 34.4%), with seven complete and 23 partial responses. Response rates in 111 assessable patients with 3+ and 2+ HER2 overexpression by immunohistochemistry (IHC) were 35% (95% CI, 24.4% to 44.7%) and none (95% CI, 0% to 15.5%), respectively. The clinical benefit rates in assessable patients with 3+ and 2+ HER2 overexpression were 48% and 7%, respectively. The response rates in 108 assessable patients with and without HER2 gene amplification by fluorescence in situ hybridization (FISH) analysis were 34% (95% CI, 23.9% to 45.7%) and 7% (95% CI, 0.8% to 22.8%), respectively. Seventeen (57%) of 30 patients with an objective response and 22 (51%) of 43 patients with clinical benefit had not experienced disease progression at follow-up at 12 months or later. The most common treatment-related adverse events were chills (25% of patients), asthenia (23%), fever (22%), pain (18%), and nausea (14%). Cardiac dysfunction occurred in two patients (2%); both had histories of cardiac disease and did not require additional intervention after discontinuation of trastuzumab. There was no clear evidence of a dose-response relationship for response, survival, or adverse events. CONCLUSION: Single-agent trastuzumab is active and well tolerated as first-line treatment of women with metastatic breast cancer with HER2 3+ overexpression by IHC or gene amplification by FISH.

Comparison of Radiation With or Without Concurrent Trastuzumab for HER2-Positive Ductal Carcinoma In Situ Resected by Lumpectomy: A Phase III Clinical Trial.

PURPOSE: Preclinical studies report that trastuzumab (T) can boost radiotherapy (RT) effectiveness. The primary aim of the B-43 trial was to assess the efficacy of RT alone vs concurrent RT plus T in preventing recurrence of ipsilateral breast cancer (IBTR) in women with ductal carcinoma in situ (DCIS). PATIENTS AND METHODS: Eligibility: Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, DCIS resected by lumpectomy, known estrogen receptor (ER) and/or progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2) status by centralized testing. Whole-breast RT was given concurrently with T. Stratification was by menopausal status, adjuvant endocrine therapy plan, and nuclear grade. Definitive intent-to-treat primary analysis was to be conducted when either 163 IBTR events occurred or all accrued patients were on study ≥ 5 years. RESULTS: There were 2,014 participants who were randomly assigned. Median follow-up time as of December 31, 2019, was 79.2 months. At primary definitive analysis, 114 IBTR events occurred: RT arm, 63 and RT plus T arm, 51 (hazard ratio [HR], 0.81; 95% CI, 0.56 to 1.17; P value = .26). There were 34 who were invasive: RT arm, 18 and RT plus T arm, 20 (HR, 1.11; 95% CI, 0.59 to 2.10; P value = .71). Seventy-six were DCIS: RT arm, 45 and RT plus T arm, 31 (HR, 0.68; 95% CI, 0.43 to 1.08; P value = .11). Annual IBTR event rates were: RT arm, 0.99%/y and RT plus T arm, 0.79%/y. The study did not reach the 163 protocol-specified events, so the definitive analysis was triggered by all patients having been on study for ≥ 5 years. CONCLUSION: Addition of T to RT did not achieve the objective of 36% reduction in IBTR rate but did achieve a modest but statistically nonsignificant reduction of 19%. Nonetheless, this trial had negative results. Further exploration of RT plus T is needed in HER2-positive DCIS before its routine delivery in patients with DCIS resected by lumpectomy.

Loss of STAT6 leads to anchorage-independent growth and trastuzumab resistance in HER2+ breast cancer cells.

Approximately 20% of breast cancers are HER2-positive. Trastuzumab has improved patient outcomes significantly for these cancers. However, acquired resistance remains a major hurdle in the clinical management of these patients. Therefore, identifying molecular changes that cause trastuzumab resistance is worthwhile. STAT6 is a transcription factor that regulates a variety of genes involved in cell cycle regulation, growth inhibition, and apoptosis. STAT6 expression is lost in approximately 3% of breast cancers, but little work has been done in the context of trastuzumab resistance in breast cancer. In isogenic cell line pairs, we observed that trastuzumab-resistant cells expressed significantly lower levels of STAT6 compared to trastuzumab-sensitive cells. Therefore, in order to study the consequences of STAT6 loss in HER2+ breast cancer, we knocked out both alleles of the STAT6 gene using somatic cell gene targeting. Interestingly, loss of STAT6 resulted in anchorage-independent growth and changes in several genes involved in epithelial to mesenchymal transition. This study suggests that STAT6 may play a role in the pathophysiology of HER2+ human breast cancer.

Safety and Efficacy of Palbociclib and Radiation Therapy in Patients With Metastatic Breast Cancer: Initial Results of a Novel Combination.

PURPOSE: Palbociclib is a selective cyclin-dependent kinase 4/6 inhibitor approved for metastatic ER+/HER2- breast cancer. Preclinical evidence suggests a possible synergistic effect of palbociclib when combined with radiation therapy (RT); however, the toxicity of this pairing is unknown. We report preliminary results on the use of this combination. METHODS AND MATERIALS: Records of patients treated with palbociclib at our institution from 2015 to 2018 were retrospectively reviewed. Patients who received RT for symptomatic metastases concurrently or within 14 days of palbociclib were included. Local treatment effect was assessed by clinical examination and subsequent computed tomography/magnetic resonance imaging. Toxicity was graded based on Common Terminology Criteria for Adverse Events version 5.0. RESULTS: A total of 16 women received palliative RT in close temporal proximity to palbociclib administration. Four patients received palbociclib before RT (25.0%), 5 concurrently (31.3%), and 7 after RT (43.8%). The median interval from closest palbociclib use to RT was 5 days (range, 0-14). The following sites were irradiated in decreasing order of frequency: bone (11 axial skeleton [9 vertebra and 2 other]; 4 pelvis; 3 extremity), brain (4: 3 whole brain RT and 1 stereotactic radiosurgery), and mediastinum (1). The median and mean follow-up time is 14.7 and 17.6 months (range, 1.7-38.2). Pain relief was achieved in all patients. No radiographic local failure was noted in the 13 patients with evaluable follow-up imaging. Leukopenia, neutropenia, and thrombocytopenia were seen in 4 (25.0%), 5 (31.3%), and 1 (6.3%) patient before RT. After RT, 5 (31.3%), 1 (6.3%), and 3 (18.8%) patients were leukopenic, neutropenic, and thrombocytopenic, respectively. All but 2 (grade 2) hematologic toxicities were grade 1. No acute or late grade 2+ cutaneous, neurologic, or gastrointestinal toxicities were noted. Toxicity results did not differ based on disease site, palbociclib-RT temporal association, or irradiated site. CONCLUSIONS: The use of RT in patients receiving palbociclib resulted in minimal grade 2 and no grade 3+ toxicities. This preliminary work suggests that symptomatic patients receiving palbociclib may be safely irradiated.

Somatic loss of PIK3R1 may sensitize breast cancer to inhibitors of the MAPK pathway.

PURPOSE: The PI3K pathway, which includes the PI3K catalytic subunits p110α (PIK3CA) and the PI3K regulatory subunit p85α (PIK3R1), is the most frequently altered pathway in cancer. We encountered a breast cancer patient whose tumor contained a somatic alteration in PIK3R1. Some commercial sequencing platforms suggest that somatic mutations in PIK3R1 may sensitize cancers to drugs that inhibit the mammalian target of rapamycin (mTOR). However, a review of the preclinical and clinical literature did not find evidence substantiating that hypothesis. The purpose of this study was to knock out PIK3R1 in order to determine the optimal therapeutic approach for breast cancers lacking p85α. METHODS: We created an isogenic cellular system by knocking out both alleles of the PIK3R1 gene in the non-tumorigenic human breast cell line MCF-10A. Knockout cells were compared with wild-type cells by measuring growth, cellular signaling, and response to drugs. RESULTS: We observed hyperphosphorylation of MEK in these knockouts, which sensitized PIK3R1-null cells to a MEK inhibitor, trametinib. However, they were not sensitized to the mTOR inhibitor, everolimus. CONCLUSIONS: Our findings suggest that breast cancers with loss of p85α may not respond to mTOR inhibition, but may be sensitive to MEK inhibition.

Hereditary diffuse gastric cancer and lynch syndromes in a BRCA1/2 negative breast cancer patient.

INTRODUCTION: Genetic counseling and testing is recommended for women with a personal and/or family history of breast and other cancers (ovarian, pancreatic, male breast and others). Mutations in the BRCA1 and BRCA2 genes (BRCA1/2) are the most common causes of hereditary breast and ovarian cancer. Additional genetic counseling and testing with a multi-gene panel may be considered in breast cancer patients who tested negative for mutations in these two genes. In about 11% of BRCA1/2-negative patients, further genetic testing reveals pathogenic mutations in other high or moderate cancer risk genes. In 0.2% of cases, an individual may carry pathogenic mutations in more than one high penetrance gene (a double heterozygote). Finding one or more pathogenic mutations is important for cancer prevention in patients and/or their families. CASE PRESENTATION: Here we present a case of a breast cancer patient who did not have a pathogenic mutation in BRCA1/2 and had a family history of breast and stomach cancers. On an additional multi-gene panel testing, she was found to carry pathogenic mutations in the CDH1 and PMS2 genes, which cause Hereditary Diffuse Gastric Cancer and Lynch syndromes, respectively. To our knowledge, this is the first description of such a double heterozygote. DISCUSSION: Clinical manifestations, genetics, and management of both syndromes are reviewed, including prophylactic surgery and screening for unaffected family members. Management challenges for a mutation carrier with advanced breast cancer are discussed. Our case supports the clinical utility of additional multi-gene panel testing for breast cancer patients who do not have a pathogenic mutation in BRCA1/2 genes.

Mutations in PIK3CA sensitize breast cancer cells to physiologic levels of aspirin.

A review of the literature finds that women diagnosed with breast cancer, who were on an aspirin regimen, experienced a decreased risk of distant metastases and death. Several recent studies have reported an improvement in overall survival in colorectal cancer patients who harbored mutations in the oncogene PIK3CA and received a daily aspirin regimen. Breast cancer patients on a daily aspirin regimen experienced decreased risk of distant metastases and death. PIK3CA is the most frequently mutated oncogene in breast cancer, occurring in up to 45 % of all breast cancers. In order to determine if mutations in PIK3CA sensitized breast cancers to aspirin treatment, we employed the use of isogenic cellular clones of the non-tumorigenic, breast epithelial cell line MCF-10A that harbored mutations in either PIK3CA or KRAS or both. We report that mutations in both PIK3CA and KRAS are required for the greatest aspirin sensitivity in breast cancer, and that the GSK3ß protein was hyperphosphorylated in aspirin-treated double knockin cells, but not in other clones/treatments. A more modest effect was observed with single mutant PIK3CA, but not KRAS alone. These observations were further confirmed in a panel of breast cancer cell lines. Our findings provide the first evidence that mutations in PIK3CA sensitize breast cancer cells to aspirin.

Preliminary results of centralized HER2 testing in ductal carcinoma in situ (DCIS): NSABP B-43.

NSABP B-43 is the first prospective, randomized phase III multi-institution clinical trial targeting high-risk, HER2-positive DCIS. It compares whole breast irradiation alone with WBI given concurrently with trastuzumab in women with HER2-positive DCIS treated by lumpectomy. The primary aim is to determine if trastuzumab plus radiation will reduce in-breast tumor recurrence. HER2-positive DCIS was previously estimated at >50 %, occurring primarily in ER-negative, comedo-type DCIS of high nuclear grade. There has been no documented centralized multi-institutional HER2 analysis of DCIS. NSABP B-43 provides a unique opportunity to evaluate this in a large cohort of DCIS patients. Patients undergoing lumpectomy for DCIS without evidence of an invasive component are eligible. A central review of each patient's pure DCIS lesion is carried out by immunohistochemistry analysis. If the lesion is 2+, FISH analysis is performed. Patients whose tumors are HER2 3+ or FISH-positive are randomly assigned to receive two doses of trastuzumab during WBI or WBI alone. NSABP B-43 opened 11/9/08. As of 7/31/2013, 5,861 patients have had specimens received centrally, and 5,645 of those had analyzable blocks; 1,969 (34.9 %) were HER2 positive. A total of 1,428 patients have been accrued, 1,137 (79.6 %) of whom have follow-up information. The average follow-up time for the 1,137 patients is 23.3 months. No grade 4 or 5 toxicity has been observed. In NSABP B-43 the HER2-positive rate for pure DCIS among patients undergoing breast-preserving surgery is 34.9 %, lower than the previously reported rate. No trastuzumab-related safety signals have been observed. Interest in this trial has been robust.

Prognostic and predictive value of tumor vascular endothelial growth factor gene amplification in metastatic breast cancer treated with paclitaxel with and without bevacizumab; results from ECOG 2100 trial.

PURPOSE: Clinically validated biomarkers for anti-angiogenesis agents are not available. We have previously reported associations between candidate VEGFA single-nucleotide polymorphisms (SNP) and overall survival (OS) in E2100. The associations between tumor VEGFA amplification and outcome are evaluated here. EXPERIMENTAL DESIGN: E2100 was a phase III trial comparing paclitaxel with or without bevacizumab for patients with metastatic breast cancer. FISH to assess gene amplification status for VEGFA was conducted on paraffin-embedded tumors from 363 patients in E2100. Evaluation for association between amplification status and outcomes was conducted. RESULTS: Estrogen receptor (ER)+ or progesterone receptor (PR)+ tumors were less likely to have VEGFA amplification than ER/PR- tumors (P = 0.020). VEGFA amplification was associated with worse OS (20.2 vs. 25.3 months; P = 0.013) in univariate analysis with a trend for worse OS in multivariate analysis (P = 0.08). There was a significant interaction between VEGFA amplification, hormone receptor status, and study arm. Patients with VEGFA amplification and triple-negative breast cancers (TNBC) or HER2 amplification had inferior OS (P = 0.047); amplification did not affect OS for those who were ER+ or PR+ and HER2-. Those who received bevacizumab with VEGFA amplification had inferior progression-free survival (PFS; P = 0.010) and OS (P = 0.042); no association was seen in the control arm. Test for interaction between study arm and VEGFA amplification with OS was not significant. CONCLUSION: VEGFA amplification in univariate analysis was associated with poor outcomes; this was particularly prominent in HER2+ or TNBCs. Additional studies are necessary to confirm the trend for poor OS seen on multivariate analysis for patients treated with bevacizumab.

Adjuvant endocrine therapy for breast cancer.

Endocrine therapy is a critical part of adjuvant therapy in women with hormone receptor-positive breast cancer, and has been shown to reduce the risk of recurrence and death from breast cancer. For decades, 5 years of tamoxifen has been the standard treatment. For premenopausal women, it remains so, and we await the results of ongoing trials to define the role of ovarian suppression or ablation with endocrine therapy. If a woman becomes postmenopausal during treatment, consideration should be given to extended adjuvant therapy with an aromatase inhibitor (AI) for another 5 years. In postmenopausal women, trials have shown that AIs are more beneficial than tamoxifen in preventing disease recurrence.They have been compared as upfront treatment for 5 years, as sequential therapy after 2 to 3 years of tamoxifen, and as extended treatment for 5 years after 5 years of tamoxifen. Among the questions still being studied are the optimal duration of extended adjuvant therapy with AIs, how one AI performs compared to another, and whether there is a benefit to intermittent extended adjuvant treatment.

Other options in the treatment of advanced breast cancer.

Many cytotoxic therapies are available for patients with metastatic breast cancer, but response rates are low and acquired or de novo resistance is virtually universal. Among the agents that are used in the treatment of pretreated metastatic breast cancer are vinorelbine, gemcitabine, nab-paclitaxel, pemetrexed, platinum salts (eg, cisplatin, carboplatin), pegylated liposomal doxorubicin, etoposide, and irinotecan. Therapies that improve overall survival in patients with anthracycline- and taxane-resistant metastatic breast cancer are needed.

Impact of exploratory biomarkers on the treatment effect of bevacizumab in metastatic breast cancer.

PURPOSE: The addition of bevacizumab to cytotoxic chemotherapy has demonstrated a progression-free survival (PFS) benefit in the first-line and second-line treatment of advanced or metastatic breast cancer (MBC). However, the addition of bevacizumab to capecitabine in heavily pretreated MBC patients did not show a PFS benefit (AVF2119g phase III trial). The aim of this study was to evaluate the expression of novel putative biomarkers as predictors of benefit from bevacizumab in retrospective subset analyses of the AVF2119g trial. EXPERIMENTAL DESIGN: In the AVF2119g trial, 462 patients with MBC were randomly assigned to receive capecitabine or capecitabine plus bevacizumab. Primary tumor tissue and outcome data were available for 223 patients. Biomarker expression was assessed by in situ hybridization (VEGF-A, VEGF-B, thrombospondin-2 and Flt4) or immunohistochemistry (VEGF-C, PDGF-C, neuropilin-1, delta-like ligand (Dll) 4, Bv8, p53 and thymidine phosphorylase) on formalin-fixed, paraffin-embedded tissue. PFS was associated with these variables in retrospective subset analyses. RESULTS: Patients with low scores for Dll4, VEGF-C, and neuropilin-1 showed trends toward improvement in PFS associated with the addition of bevacizumab to capecitabine (P values = 0.01, 0.05, and 0.07, respectively). These observations were not statistically significant following correction for multiple hypothesis testing. CONCLUSION: These retrospective subset analyses suggest that expression of Dll4, VEGF-C, and neuropilin-1 may predict benefit from bevacizumab. Such observations are not conclusive but warrant additional testing.

Phase III double-blind, placebo-controlled, prospective randomized trial of adjuvant tamoxifen vs. tamoxifen and fenretinide in postmenopausal women with positive receptors (EB193): an intergroup trial coordinated by the Eastern Cooperative Oncology Group.

Fenretinide and tamoxifen have additive antitumor effects preclinically. We performed a randomized, placebo-controlled, double-blind adjuvant trial in breast cancer patients treated for 5 years with tamoxifen, with or without fenretinide. Between October 1995 and October 1999, 426 postmenopausal women with hormone receptor-positive breast cancer were randomized. Patients were monitored for efficacy and toxicity. Four hundred and nineteen patients were evaluable. The study was terminated early due to slow accrual. There were no significant differences between treatment groups in DFS, TTR or survival. More patients stopped treatment early on the fenretinide arm than on placebo (P = 0.02). Grade 3/4 toxicities, including visual problems and musculoskeletal complaints were more common in patients receiving fenretinide (P = 0.007). A Night Blindness Questionnaire was used to monitor nyctalopia, which was slightly, but not significantly, more common on fenretinide. In this underpowered study, no significant difference was observed in efficacy between treatment groups. This trial provides important toxicity information about fenretinide, a retinoid that has been used in the prevention setting, because it is the only placebo-controlled, double-blind randomized study ever performed.

ACR appropriateness criteria on postmastectomy radiotherapy expert panel on radiation oncology-breast.

This summary focuses on the role of postoperative radiation therapy in patients treated with modified radical mastectomy for invasive breast cancer, particularly in patients receiving systemic therapy.

Efficacy and safety of erlotinib in patients with locally advanced or metastatic breast cancer.

PURPOSE: To evaluate the efficacy and safety of erlotinib in advanced breast cancer. Experimental design Multicenter, phase II study of erlotinib (150 mg orally daily). Cohort 1: progression after anthracyclines, taxanes, and capecitabine (n = 47). Cohort 2: progression after >1 chemotherapy for advanced-stage disease (n = 22). Primary endpoint was response rate (World Health Organization criteria). Secondary endpoints were safety, time to progression, and survival. RESULTS: One patient in each cohort (n = 2, 3.0%) had a partial response. Response duration was 17 weeks for the Cohort 1 patient and 32 weeks for the Cohort 2 patient. Median time to progression was 43 days for Cohort 1 (range 1-204) and 43 days for Cohort 2 (range 25-419). Common adverse events were diarrhea, rash, dry skin, asthenia, nausea, anorexia. CONCLUSION: Erlotinib had minimal activity in unselected previously treated women with advanced breast cancer. Predictive factors are needed to identify breast cancer patients who may derive benefit from erlotinib treatment.

Phase II study of sunitinib malate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane.

PURPOSE: Sunitinib is an oral, multitargeted tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor, stem cell factor receptor (KIT), and colony-stimulating factor-1 receptor. This phase II, open-label, multicenter study evaluated sunitinib monotherapy in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Sixty-four patients previously treated with an anthracycline and a taxane received sunitinib 50 mg/d in 6-week cycles (4 weeks on, then 2 weeks off treatment). The primary end point was objective response rate. Plasma samples were obtained for pharmacokinetic and biomarker analysis. RESULTS: Seven patients achieved a partial response (median duration, 19 weeks), giving an overall response rate of 11%. Three additional patients (5%) maintained stable disease for >or= 6 months. Median time to progression and overall survival were 10 and 38 weeks, respectively. Notably, responses occurred in triple negative tumors and HER2-positive, trastuzumab-treated patients. Thirty-three patients (52%) required dose interruption during >or= 1 cycle, and 25 patients required dose reduction (39%). Thirty-six patients (56%) had dose modifications due to adverse events (AEs). Treatment was associated with increases in plasma VEGF and decreases in soluble VEGFRs and KIT. The most common AEs were fatigue, nausea, diarrhea, mucosal inflammation, and anorexia. Most AEs were mild to moderate (grade 1 to 2) in severity and were effectively managed with dose delays or reductions. CONCLUSION: Sunitinib is active in patients with heavily pretreated MBC. Most AEs were of mild-to-moderate severity and manageable with supportive treatment and/or dose modification. Further studies in breast cancer are warranted.