Short-Term Biomarker Modulation Study of Dasatinib for Estrogen Receptor-Negative Breast Cancer Chemoprevention.

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.

Phase 1 trial of ADI-PEG 20 and liposomal doxorubicin in patients with metastatic solid tumors.

BACKGROUND: Arginine depletion interferes with pyrimidine metabolism and DNA damage repair pathways. Preclinical data demonstrated that depletion of arginine by PEGylated arginine deiminase (ADI-PEG 20) enhanced liposomal doxorubicin (PLD) cytotoxicity in cancer cells with argininosuccinate synthase 1 (ASS1) deficiency. The objective of this study was to assess safety and tolerability of ADI-PEG 20 and PLD in patients with metastatic solid tumors. METHODS: Patients with advanced ASS1-deficient solid tumors were enrolled in this phase 1 trial of ADI-PEG 20 and PLD following a 3 + 3 design. Eligible patients were given intravenous PLD biweekly and intramuscular (IM) ADI-PEG 20 weekly. Toxicity and efficacy were evaluated according to the Common Terminology Criteria for Adverse Events (version 4.0) and Response Evaluation Criteria in Solid Tumors (version 1.1), respectively. RESULTS: Of 15 enrolled patients, 9 had metastatic HER2-negative breast carcinoma. We observed no dose-limiting toxicities or treatment-related deaths. One patient safely received 880 mg/m2 PLD in this study and 240 mg/m2 doxorubicin previously. Treatment led to stable disease in 9 patients and was associated with a median progression-free survival time of 3.95 months in 15 patients. Throughout the duration of treatment, decreased arginine and increased citrulline levels in peripheral blood remained significant in a majority of patients. We detected no induction of anti-ADI-PEG 20 antibodies by week 8 in one third of patients. CONCLUSION: Concurrent IM injection of ADI-PEG 20 at 36 mg/m2 weekly and intravenous infusion of PLD at 20 mg/m2 biweekly had an acceptable safety profile in patients with advanced ASS1-deficient solid tumors. Further evaluation of this combination is under discussion.

A Randomized Phase II Study of Sequential Eribulin Versus Paclitaxel Followed by FAC/FEC as Neoadjuvant Therapy in Patients with Operable HER2-Negative Breast Cancer.

LESSONS LEARNED: The combination of eribulin with 5-fluorouracil, either doxorubicin or epirubicin, and cyclophosphamide (FAC/FEC) was not superior to the combination of paclitaxel with FAC/FEC and was associated with greater hematologic toxicity. Eribulin followed by an anthracycline-based regimen is not recommended as a standard neoadjuvant therapy in nonmetastatic operable breast cancer. BACKGROUND: Neoadjuvant systemic therapy is the standard of care for locally advanced operable breast cancer. We hypothesized eribulin may improve the pathological complete response (pCR) rate compared with paclitaxel. METHODS: We conducted a 1:1 randomized open-label phase II study comparing eribulin versus paclitaxel followed by 5-fluorouracil, either doxorubicin or epirubicin, and cyclophosphamide (FAC/FEC) in patients with operable HER2-negative breast cancer. pCR and toxicity of paclitaxel 80 mg/m2 weekly for 12 doses or eribulin 1.4 mg/m2 on days 1 and 8 of a 21-day cycle for 4 cycles followed by FAC/FEC were compared. RESULTS: At the interim futility analysis, in March 2015, 51 patients (28 paclitaxel, 23 eribulin) had received at least one dose of the study drug and were thus evaluable for toxicity; of these, 47 (26 paclitaxel, 21 eribulin) had undergone surgery and were thus evaluable for efficacy. Seven of 26 (27%) in the paclitaxel group and 1 of 21 (5%) in the eribulin group achieved a pCR, and this result crossed a futility stopping boundary. In the paclitaxel group, the most common serious adverse events (SAEs) were neutropenic fever (grade 3, 3 patients, 11%). In the eribulin group, nine patients (39%) had neutropenia-related SAEs, and one died of neutropenic sepsis. The study was thus discontinued. For the paclitaxel and eribulin groups, the 5-year event-free survival (EFS) rates were 81.8% and 74.0% (hazard ratio [HR], 1.549; 95% confidence interval [CI], 0.817-2.938; p = .3767), and the 5-year overall survival (OS) rates were 100% and 84.4% (HR, 5.813; 95% CI, 0.647-52.208; p = .0752), respectively. CONCLUSION: We did not observe a higher proportion of patients undergoing breast conservation surgery in the eribulin group than in the paclitaxel group. The patients treated with eribulin were more likely to undergo mastectomy and less likely to undergo breast conservation surgery, but the difference was not statistically significant. As neoadjuvant therapy for operable HER2-negative breast cancer, eribulin followed by FAC/FEC is not superior to paclitaxel followed by FAC/FEC and is associated with a higher incidence of neutropenia-related serious adverse events.

Phase I Study of Everolimus, Letrozole, and Trastuzumab in Patients with Hormone Receptor-positive Metastatic Breast Cancer or Other Solid Tumors.

PURPOSE: Doublets of everolimus with letrozole or trastuzumab have demonstrated activity against HER2-positive breast cancer, suggesting that the triple combination can have synergistic anticancer activity. PATIENTS AND METHODS: This first-in-human dose-escalation study (NCT02152943) enrolled patients with hormone receptor- positive, HER2-positive (defined by amplification, overexpression, or mutation) treatment-refractory advanced cancers to receive escalating doses (3+3 design) of daily oral letrozole (days 1-21), daily oral everolimus (days 1-21), and intravenous trastuzumab (day 1) every 21 days to determine dose-limiting toxicities (DLT) and MTD or recommended phase II dose (RP2D). RESULTS: A total of 32 patients with hormone receptor-positive, HER2-positive (amplification, n = 27; overexpression, n = 1; and mutation, n = 4) advanced breast cancer (n = 26) or other cancers (n = 6) were enrolled. The most frequent grade ≥3 adverse events included hyperglycemia (n = 4), anemia (n = 3), thrombocytopenia (n = 2), and mucositis (n = 2). DLTs included grade 3 mucositis and grade 4 neutropenia, and trastuzumab given as an 8 mg/kg loading dose on day 1 of cycle 1 followed by a 6 mg/kg maintenance dose on day 1 of subsequent cycles plus 10 mg everolimus daily and 2.5 mg letrozole daily every 21 days was declared as RP2D. Five patients with breast cancer (four with HER2 amplification and one with HER2 mutation) had partial responses. HER2 amplification in circulating cell-free DNA at baseline was associated with shorter progression-free and overall survival durations (P < 0.05). CONCLUSIONS: Everolimus, letrozole, and trastuzumab have a favorable safety profile and elicit encouraging signals of anticancer activity in patients with heavily pretreated hormone receptor- and HER2-positive advanced cancers.

Efficacy and safety of the combination of metformin, everolimus and exemestane in overweight and obese postmenopausal patients with metastatic, hormone receptor-positive, HER2-negative breast cancer: a phase II study.

Background Increased adiposity is thought to result in worse clinical outcomes in patients with breast cancer through increased estrogen production, hyperinsulinemia, insulin resistance, and activation of the phosphatidylinositol-3-kinase/AKT/mammalian target of rapamycin (mTOR) pathway. Thus, we hypothesized that the addition of metformin to everolimus and exemestane, could lead to better outcomes in overweight and obese patients with metastatic, hormone receptor-positive, HER2-negative breast cancer. We conducted a phase II trial to evaluate the efficacy and safety of the combination of metformin, everolimus and exemestane in overweight and obese postmenopausal women with metastatic, hormone receptor-positive, HER2-negative breast cancer. Methods Twenty-two patients with a body mass index ≥25 kg/m2 were treated with metformin 1000 mg twice daily, everolimus 10 mg daily and exemestane 25 mg daily. Median progression-free (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Results Median PFS and OS were 6.3 months (95% confidence interval [CI]: 3.8-11.3 months) and 28.8 months (95% CI: 17.5-59.7 months), respectively. Five patients had a partial response and 7 had stable disease for ≥24 weeks yielding a clinical benefit rate of 54.5%. Compared with overweight patients, obese patients had an improved PFS on univariable (p = 0.015) but not multivariable analysis (p = 0.215). Thirty-two percent of patients experienced a grade 3 treatment-related adverse event (TRAE). There were no grade 4 TRAEs and 7 patients experienced a grade 3 TRAE. Conclusion The combination of metformin, everolimus and exemestane was safe and had moderate clinical benefit in overweight and obese with patients metastatic, hormone receptor-positive, HER2-negative breast cancer.

Rapid Breast Cancer Disease Progression Following Cyclin Dependent Kinase 4 and 6 Inhibitor Discontinuation.

Background: CDK 4 and 6 inhibitors (CDK4/6i), which arrest unregulated cancer cell proliferation, show clinical efficacy in breast cancer. Unexpectedly, a patient treated on a CDK4/6i-based trial, as first-line therapy in metastatic breast cancer, developed rapid disease progression following discontinuation of study drug while receiving standard second-line therapy off trial. We thus sought to expand this observation within a population of patients treated similarly at The University of Texas MD Anderson Cancer Center. Methods: Using an IRB-approved protocol, 4 patients previously enrolled on CDK4/6i trials were analyzed for outcomes after discontinuing study drug. These patients were treated on a randomized trial of first-line endocrine therapy +/- a CDK4/6i. Rapid disease progression was defined as progression occurring within 4 months of CDK4/6i discontinuation. Results: In total, 4 patients developed rapid disease progression and died; 2 of whom died within 6 months of CDK4/6i discontinuation. Conclusion: This case series suggests a potential for rapid disease progression following CDK4/6i discontinuation. However, the clinical course following progression must be validated in large CDK4/6i clinical trials and standard-of-care cohorts. If confirmed, such observations may alter the algorithm for subsequent therapy in patients with disease progression on CDK4/6i. Nevertheless, the need remains to define a mechanistic basis for this rapid progression and formulate alternative therapeutic strategies.

Targeting the PI3K/AKT/mTOR Pathway for the Treatment of Mesenchymal Triple-Negative Breast Cancer: Evidence From a Phase 1 Trial of mTOR Inhibition in Combination With Liposomal Doxorubicin and Bevacizumab.

IMPORTANCE: Triple-negative breast cancer (TNBC) classified by transcriptional profiling as the mesenchymal subtype frequently harbors aberrations in the phosphoinositide 3-kinase (PI3K) pathway, raising the possibility of targeting this pathway to enhance chemotherapy response. Up to 30% of mesenchymal TNBC can be classified histologically as metaplastic breast cancer, a chemorefractory group of tumors with a mixture of epithelial and mesenchymal components identifiable by light microscopy. While assays to identify mesenchymal TNBC are under development, metaplastic breast cancer serves as a clinically identifiable surrogate to evaluate potential regimens for mesenchymal TNBC. OBJECTIVE: To assess safety and efficacy of mammalian target of rapamycin (mTOR) inhibition in combination with liposomal doxorubicin and bevacizumab in patients with advanced metaplastic TNBC. DESIGN, SETTING, AND PARTICIPANTS: Phase 1 study with dose escalation and dose expansion at the University of Texas MD Anderson Cancer Center of patients with advanced metaplastic TNBC. Patients were enrolled from April 16, 2009, to November 4, 2014, and followed for outcomes with a cutoff date of November 1, 2015, for data analysis. INTERVENTIONS: Liposomal doxorubicin, bevacizumab, and the mTOR inhibitors temsirolimus or everolimus using 21-day cycles. MAIN OUTCOMES AND MEASURES: Safety and response. When available, archived tissue was evaluated for aberrations in the PI3K pathway. RESULTS: Fifty-two women with metaplastic TNBC (median age, 58 years; range, 37-79 years) were treated with liposomal doxorubicin, bevacizumab, and temsirolimus (DAT) (N = 39) or liposomal doxorubicin, bevacizumab, and everolimus (DAE) (N = 13). The objective response rate was 21% (complete response = 4 [8%]; partial response = 7 [13%]) and 10 (19%) patients had stable disease for at least 6 months, for a clinical benefit rate of 40%. Tissue was available for testing in 43 patients, and 32 (74%) had a PI3K pathway aberration. Presence of PI3K pathway aberration was associated with a significant improvement in objective response rate (31% vs 0%; P = .04) but not clinical benefit rate (44% vs 45%; P > .99). CONCLUSIONS AND RELEVANCE: Using metaplastic TNBC as a surrogate for mesenchymal TNBC, DAT and DAE had notable activity in mesenchymal TNBC. Objective response was limited to patients with PI3K pathway aberration. A randomized trial should be performed to test DAT and DAE for metaplastic TNBC, as well as nonmetaplastic, mesenchymal TNBC, especially when PI3K pathway aberrations are identified.

Phase I biomarker modulation study of atorvastatin in women at increased risk for breast cancer.

Selective estrogen receptor modulators (SERMs), tamoxifen, and raloxifene that reduce the risk of breast cancer are limited to only estrogen receptor-positive (ER(+)) breast cancer. In addition, patient acceptance of SERMs is low due to toxicity and intolerability. New agents with improved toxicity profile that reduce risk of ER-negative breast cancer are urgently needed. Observational studies show that statins can reduce breast cancer incidence and recurrence. The objective of this prospective short-term prevention study was to evaluate the effect of a lipophilic statin, atorvastatin, on biomarkers in breast tissue and serum of women at increased risk. Eligible participants included women with previous history of carcinoma in situ, or atypical hyperplasia, or 5 year breast cancer projected Gail risk >1.67 %, or lifetime breast cancer risk >20 % calculated by models including Claus, Tyrer-Cuzick, Boadicea, or BRCAPRO. Patients underwent baseline fine needle aspiration (FNA) of the breast, blood collection for biomarker analysis, and were randomized to either no treatment or atorvastatin at 10, 20, or 40 mg/day dose for 3 months. At 3 months, blood collection and breast FNA were repeated. Biomarkers included C-reactive protein (CRP), lipid profile, atorvastatin, and its metabolites, Ki-67, bcl-2, EGFR, and pEGFR. Baseline genotype for 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoAR) was also measured. Among 60 patients evaluated, a significant reduction in serum CRP, cholesterol and low-density lipoprotein (LDL), and increase in atorvastatin metabolites in serum and breast FNAs was demonstrated. No changes were observed in other tissue biomarkers. This study shows that atorvastatin and its metabolites are detectable in breast samples and may lower serum CRP among women without hyperlipidemia.

TBCRC-010: Phase I/II Study of Dasatinib in Combination with Zoledronic Acid for the Treatment of Breast Cancer Bone Metastasis.

PURPOSE: Osteoclast-mediated bone resorption through src kinase releases growth factors, sustaining bone metastases. This trial determined the recommended phase II dose (RP2D) and clinical efficacy of the src kinase inhibitor dasatinib combined with zoledronic acid in bone predominant, HER2-negative breast cancer metastases. EXPERIMENTAL DESIGN: A 3+3 lead in phase I design confirmed the RP2D allowing activation of the single-arm, phase II trial. Zoledronic acid was administered intravenously on day 1, and dasatinib was given orally once daily for 28 days each cycle as twice daily administration caused dose-limiting toxicity (DLT). Response was assessed every three cycles. N-telopeptide (NTx) was serially measured. RESULTS: A total of 25 patients were enrolled. No DLTs were noted at the RP2D of dasatinib = 100 mg/d. Common adverse events were grade 1-2: rash (9/25, 36%), fatigue (9/25, 36%), pain (9/25, 36%), nausea (6/25, 20%). The objective response rate in bone was 5/22 (23%), all partial responses (PR). The clinical benefit rate [PRs + stable disease (SD) ≥ 6 months] in bone was 8/22 (36%). Median time to treatment failure was 2.70 months [95% confidence interval (CI), 1.84-5.72] in the general cohort, 3.65 months (95% CI, 1.97-7.33) in patients with hormone receptor (HR)-positive breast cancer and 0.70 months (95% CI, 0.30-NA) in those with HR-negative disease. Factors associated with response in bone included lower tumor grade, HR-positive status, and pretreatment high NTx levels. CONCLUSIONS: Combination therapy was well tolerated and produced responses in bone in patients with HR-positive tumors. Clin Cancer Res; 22(23); 5706-12. ©2016 AACR.

Docetaxel Alone or in Combination With a Therapeutic Cancer Vaccine (PANVAC) in Patients With Metastatic Breast Cancer: A Randomized Clinical Trial.

IMPORTANCE: Previous phase 1 and 2 trials of PANVAC, a poxviral-based cancer vaccine, have suggested clinical efficacy in some patients with breast, ovarian, and colorectal cancer and have shown evidence of immunologic activity. Preclinical data have shown that docetaxel can modify tumor phenotype, making tumor cells more amenable to T cell-mediated killing. OBJECTIVE: The goal of this study was to determine if the treatment combination of docetaxel and PANVAC improves clinical outcomes in patients with metastatic breast cancer compared with docetaxel treatment alone. DESIGN, SETTING, AND PARTICIPANTS: Between May 2006 and February 2012, this open-label, phase 2 randomized clinical trial enrolled 48 patients with metastatic breast cancer of all subtypes, without limitation on other lines of previous therapy, to receive treatment with either docetaxel with PANVAC (arm A) or docetaxel alone (arm B). Final clinical data were collected on September 16, 2013. All patients were treated at either the National Cancer Institute or the Department of Breast Medical Oncology, MD Anderson Cancer Center. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival (PFS), using a phase 2.5 statistical design, with the intent of identifying a trend toward benefit (defined as 1-sided P≤.10) to guide a larger trial design. Secondary end points included safety and immunologic correlative studies. RESULTS: Forty-eight participants were enrolled: 25 were randomized to the combination treatment arm A, and 23 to arm B. No patient remained in the study at the time of the final analysis. Patient and tumor characteristics were well matched. Analysis of adverse events in both treatment arms demonstrated very little difference between the 2 groups. In the combination treatment arm (arm A), statistically significant increases were noted in the frequency of grades 1 and 2 edema (P=.02, likely related to greater median number of docetaxel cycles) and injection-site reactions (P<.001). In the final data analysis, median PFS was 7.9 months in arm A vs 3.9 months in arm B (hazard ratio, 0.65 [95% CI, 0.34-1.14]; P=.09). CONCLUSIONS AND RELEVANCE: The results suggest that the combination of PANVAC with docetaxel in metastatic breast cancer may provide a clinical benefit. This study was hypothesis generating and provides both rationale and statistical assumptions for a larger definitive randomized study. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00179309.

Phase II Randomized Study of Ixabepilone Versus Observation in Patients With Significant Residual Disease After Neoadjuvant Systemic Therapy for HER2-Negative Breast Cancer.

BACKGROUND: Residual disease (RD) after neoadjuvant chemotherapy carries an increased risk for recurrence. Ixabepilone has activity in anthracycline/taxanes-resistant breast cancer. We explored adjuvant ixabepilone in patients with significant RD HER2-negative breast cancer. METHODS: A phase II study in patients with residual cancer burden II or III randomized to ixabepilone versus observation was conducted. Circulating tumor cells (CTCs) were measured at baseline and at 9 and 18 weeks. Survival probabilities were estimated by Kaplan-Meier product limit. Toxicities were reported as proportions in the ixabepilone arm. RESULTS: Accrual was stopped because of ixabepilone toxicity. Sixty-seven patients were registered; 43 were randomized, 19 received ixabepilone, and 24 went to observation. One patient (9.1%) in the observation arm versus 2 patients (18.2%) in the ixabepilone arm had CTCs at 18 weeks (P = 1.0). Three-year recurrence-free survival and overall survival were 94% and 82%, and 100% and 79% in the observation and ixabepilone arms (P = .35 and .18), respectively. Most common adverse events (AEs) included fatigue, pain, neuropathy, constipation, nausea, rash, anorexia, and diarrhea. Serious AEs included pain (63.2%), fatigue (31.6%), and neuropathy (31.6%). CONCLUSIONS: Adjuvant ixabepilone in patients with significant RD after neoadjuvant chemotherapy was difficult to administer because of AEs and did not change the presence of CTC or affect survival outcomes. NCT00877500.

Combined Antiangiogenic and Mammalian Target of Rapamycin Inhibitor Targeted Therapy in Metaplastic Breast Cancer Harboring a PIK3CA Mutation.

Metaplastic breast cancer (MpBC) is an extremely rare breast cancer subtype, characterized by a heterogeneous phenotype. MpBC aggressive biology is attributed to its stem cell-like characteristics. Since these tumors are largely chemoresistant, novel targeted therapies should be explored. Herein, we report the clinical course of a 59-year-old African American woman with MpBC with a PIK3CA mutation in codon 545, exon 10 (GAG to AAG; p.Glu545Lys) and a TP53 mutation in codon 286, exon 8 (GAA to AAA; p.Glu286Lys). The same mutations were observed in the primary and secondary sites. The patient was treated with a molecularly matched therapy using a combined antiangiogenic and mammalian target of rapamycin kinase inhibitor strategy that included liposomal doxorubicin, bevacizumab, and temsirolimus. Partial remission was achieved. In this report, the scientific rationale underlying the activity of this combination was explored. In conclusion, patients may benefit from being offered molecular profiling early during the course of the disease to receive a therapy guided accordingly.

Effect of adjuvant/neoadjuvant trastuzumab on clinical outcomes in patients with HER2-positive metastatic breast cancer.

BACKGROUND: The purpose of the current study was to describe the outcomes of patients with human epidermal growth factor receptor 2 (HER2)-overexpressed/amplified (HER2+) early breast cancer who received adjuvant or neoadjuvant trastuzumab-based therapy and were subsequently retreated with trastuzumab for metastatic disease. METHODS: A total of 353 patients with metastatic HER2+ breast cancer who were treated with trastuzumab as part of their first-line treatment for metastatic disease were identified. A total of 75 patients had received adjuvant or neoadjuvant trastuzumab-based therapy for early breast cancer, and 278 had not. Clinical outcomes of patients who had or had not received prior trastuzumab were compared using Cox proportional hazards regression and logistic regression analyses. Survival was estimated using the Kaplan-Meier method. RESULTS: The clinical benefit (complete response, partial response, or stable disease of ≥ 6 months) rates were 71% in the group who did not receive prior trastuzumab and 39% in the group previously treated with trastuzumab. The adjusted odds ratios were 0.28 (95% confidence interval [95% CI], 0.13-0.59; P = .0009) for clinical benefit rates and 0.39 (95% CI, 0.18-0.82; P = .038) for objective (complete or partial) response rates. In the univariate analysis, the median overall survival rate was longer in the group who did not receive prior trastuzumab (36 months vs 28 months) (hazards ratio, 1.47; 95% CI, 1.07-2.01 [P = .022]). The multivariate analysis found no significant difference in overall survival. CONCLUSIONS: When treated with trastuzumab for metastatic disease, patients with HER2+ breast cancer without prior exposure to trastuzumab were found to have superior clinical outcomes to those with prior exposure. Prior trastuzumab exposure should be considered in treatment algorithms and in HER2-targeted clinical trial enrollment for metastatic disease.

Phase I trial of exemestane in combination with metformin and rosiglitazone in nondiabetic obese postmenopausal women with hormone receptor-positive metastatic breast cancer.

PURPOSE: Obese women with breast cancer have worse prognosis than women with normal body mass index. Endocrine therapy resistance is in part mediated by insulin resistance in obese women with breast cancer. We investigated the tolerability and pharmacokinetics of exemestane in combination with metformin and rosiglitazone in nondiabetic overweight and obese postmenopausal women with hormone receptor-positive metastatic breast cancer. METHODS: Patients had previously received chemotherapy and endocrine therapy for breast cancer. Exemestane was given as 25 mg orally per day. Metformin (M) and rosiglitazone (R) were given twice daily. Dose level 1 consisted of M 1,500 mg/day and R 6 mg/day. Dose level 2 consisted of M 2,000 mg/day and R 8 mg/day. Plasma concentrations of exemestane were measured on days 1, 8, and 15. RESULTS: Twenty patients were enrolled. Fourteen patients received exemestane, metformin, and rosiglitazone. Six patients received exemestane with metformin only (2,000 mg/day). Both regimens were well tolerated at the highest doses tested, and there were no notable changes in plasma exemestane levels. Six patients (30%) had stable disease for 6 months or longer. CONCLUSIONS: Oral daily administration of exemestane (25 mg) and metformin (2,000 mg) with and without rosiglitazone (8 mg) daily was well tolerated. Exemestane pharmacokinetics were not altered by metformin and rosiglitazone.

Estrogen receptor (ER) mRNA and ER-related gene expression in breast cancers that are 1% to 10% ER-positive by immunohistochemistry.

PURPOSE: We examined borderline estrogen receptor (ER) -positive cancers, defined as having 1% to 10% positivity by immunohistochemistry (IHC), to determine whether they show the same global gene-expression pattern and high ESR1 mRNA expression as ER-positive cancers or if they are more similar to ER-negative cancers. PATIENTS AND METHODS: ER status was determined by IHC in 465 primary breast cancers and with the Affymetrix U133A gene chip. We compared expressions of ESR1 mRNA and a 106 probe set ER-associated gene signature score between ER-negative (n = 183), 1% to 9% (n = 25), 10% (n = 6), and more than 10% (n = 251) ER-positive cancers. We also assessed the molecular class by using the PAM50 classifier and plotted survival by ER status. RESULTS: Among the 1% to 9%, 10%, and more than 10% ER IHC-positive patients, 24%, 67%, and 92% were also positive by ESR1 mRNA expression. The average ESR1 expression was significantly higher in the ≥ 10% ER-positive cohorts compared with the 1% to 9% or ER-negative cohort. The average ER gene signature scores were similar for the ER-negative and 1% to 9% IHC-positive patients and were significantly lower than in ≥ 10% ER-positive patients. Among the 1% to 9% ER-positive patients, 8% were luminal B and 48% were basal-like; among the 10% ER-positive patients, 50% were luminal. The overall survival rate of 1% to 9% ER-positive patients with cancer was between those of patients in the ≥ 10% ER-positive and ER-negative groups. CONCLUSION: A minority of the 1% to 9% IHC ER-positive tumors show molecular features similar to those of ER-positive, potentially endocrine-sensitive tumors, whereas most show ER-negative, basal-like molecular characteristics. The safest clinical approach may be to use both adjuvant endocrine therapy and chemotherapy in this rare subset of patients.