Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer.

BACKGROUND: In an earlier analysis of this phase 3 trial, ribociclib plus fulvestrant showed a greater benefit with regard to progression-free survival than fulvestrant alone in postmenopausal patients with hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Here we report the results of a protocol-specified second interim analysis of overall survival. METHODS: Patients were randomly assigned in a 2:1 ratio to receive either ribociclib or placebo in addition to fulvestrant as first-line or second-line treatment. Survival was evaluated by means of a stratified log-rank test and summarized with the use of Kaplan-Meier methods. RESULTS: This analysis was based on 275 deaths: 167 among 484 patients (34.5%) receiving ribociclib and 108 among 242 (44.6%) receiving placebo. Ribociclib plus fulvestrant showed a significant overall survival benefit over placebo plus fulvestrant. The estimated overall survival at 42 months was 57.8% (95% confidence interval [CI], 52.0 to 63.2) in the ribociclib group and 45.9% (95% CI, 36.9 to 54.5) in the placebo group, for a 28% difference in the relative risk of death (hazard ratio, 0.72; 95% CI, 0.57 to 0.92; P = 0.00455). The benefit was consistent across most subgroups. In a descriptive update, median progression-free survival among patients receiving first-line treatment was 33.6 months (95% CI, 27.1 to 41.3) in the ribociclib group and 19.2 months (95% CI, 14.9 to 23.6) in the placebo group. No new safety signals were observed. CONCLUSIONS: Ribociclib plus fulvestrant showed a significant overall survival benefit over placebo plus fulvestrant in patients with hormone-receptor-positive, HER2-negative advanced breast cancer. (Funded by Novartis; MONALEESA-3 ClinicalTrials.gov number, NCT02422615.).

Safety and impact of dose reductions on efficacy in the randomised MONALEESA-2, -3 and -7 trials in hormone receptor-positive, HER2-negative advanced breast cancer.

BACKGROUND: This pooled analysis of MONALEESA trials evaluated the safety of ribociclib plus endocrine therapy (RIB + ET) with a focus on dose reductions in first-line patients. METHODS: In the dose reduction analysis, data were pooled from MONALEESA-2 (all patients), MONALEESA-3 (patients receiving treatment as first-line ET) and MONALEESA-7 (patients receiving combination therapy with an NSAI as initial ET). Efficacy was analysed by ribociclib relative dose intensity (DI). Safety was analysed in all patients in the trials (except those receiving tamoxifen in MONALEESA-7) and those with/without ≥1 ribociclib dose reduction. RESULTS: Of 818 women who received first-line RIB + ET, 41.8% required ≥1 dose reduction due to AEs (most commonly, neutropenia). Median RIB relative DI in patients without and with dose reductions was 99.3% and 65.6% in MONALEESA-2, 98.4% and 67.8% in MONALEESA-3 and 98·0% and 66·3% in MONALEESA-7. Median PFS was 24.8, 24.9 and 29.6 months for patients who received ≤71% (30th percentile), 72-96% (60th percentile) and 97-100% (90th percentile) RIB relative DI, respectively. No new safety signals emerged in the pooled safety analysis. CONCLUSIONS: This analysis provides reassuring data showing that the clinical benefit of RIB is preserved when dose modifications are undertaken to manage AEs. TRIAL REGISTRATION: MONALEESA-2 (NCT01958021) first posted October 8, 2013; MONALEESA-3 (NCT02422615) first posted April 21, 2015; MONALEESA-7 (NCT02278120) first posted October 29, 2014.

Trastuzumab emtansine plus atezolizumab versus trastuzumab emtansine plus placebo in previously treated, HER2-positive advanced breast cancer (KATE2): a phase 2, multicentre, randomised, double-blind trial.

BACKGROUND: HER2-positive metastatic breast cancer is incurable and new treatments are needed. Addition of atezolizumab to trastuzumab emtansine might potentiate anticancer immunity and enhance the HER2-targeted cytotoxic activity of trastuzumab emtansine. We aimed to test this combination in HER2-positive advanced breast cancer that had progressed after previous treatment with trastuzumab and a taxane. METHODS: The KATE2 study is a randomised, double-blind, placebo-controlled, phase 2 study at 68 centres from nine countries across Asia, Australia, North America, and western Europe. Eligible patients were adults (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1 and centrally confirmed, measurable, HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane. Patients were randomly assigned (2:1) either trastuzumab emtansine (3·6 mg/kg of bodyweight) plus atezolizumab (1200 mg) or trastuzumab emtansine plus placebo; all study drugs were administered by intravenous infusion every 3 weeks. Randomisation was done via an interactive voice and web response system using a permuted block scheme (block size of six) and was stratified by PD-L1 status, world region, and liver metastases. Patients, investigators, and study team members were masked to treatment allocation. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02924883, and the study has been completed. FINDINGS: Between Sept 26, 2016, and Aug 7, 2017, 330 patients were screened for the study, of whom 202 were randomly allocated either atezolizumab (n=133) or placebo (n=69). At the recommendation of the independent data monitoring committee, treatment assignment was unmasked on Dec 11, 2017, due to futility and the numerically higher frequency of adverse events among patients assigned atezolizumab. This date was set as the clinical cutoff for the primary analysis. Median follow-up was 8·5 months (IQR 6·1-11·5) for patients assigned atezolizumab and 8·4 months (5·3-11·1) for those assigned placebo. Median progression-free survival was 8·2 months (95% CI 5·8-10·7) for patients assigned atezolizumab versus 6·8 months (4·0-11·1) for those assigned placebo (stratified hazard ratio 0·82, 95% CI 0·55-1·23; p=0·33). The most common grade 3 or worse adverse events were thrombocytopenia (17 [13%] among 132 patients who received atezolizumab vs three [4%] among 68 who received placebo), increased aspartate aminotransferase (11 [8%] vs two [3%]), anaemia (seven [5%] vs 0), neutropenia (six [5%] vs three [4%]), and increased alanine aminotransferase (six [5%] vs two [3%]). Serious adverse events occurred in 43 (33%) of 132 patients who received atezolizumab and 13 (19%) of 68 patients who received placebo. One patient who received atezolizumab died due to a treatment-related adverse event (haemophagocytic syndrome). INTERPRETATION: Addition of atezolizumab to trastuzumab emtansine did not show a clinically meaningful improvement in progression-free survival and was associated with more adverse events. Further study of trastuzumab emtansine plus atezolizumab is warranted in a subpopulation of patients with PD-L1-positive, HER2-positive advanced breast cancer. FUNDING: F Hoffman-La Roche.

Immunotherapy and targeted therapy combinations in metastatic breast cancer.

Immunotherapy is emerging as a new treatment modality in breast cancer. After long-standing use of endocrine therapy and targeted biological therapy, improved understanding of immune evasion by cancer cells and the discovery of selective immune checkpoint inhibitors have created novel opportunities for treatment. Single-drug therapies with monoclonal antibodies against programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) have shown little efficacy in patients with metastatic breast cancer, in part because of the low number of tumour-infiltrating lymphocytes in most breast cancers. There is growing interest in the development of combinations of immunotherapy and molecularly targeted therapies for metastatic breast cancer. In this Personal View, we review the available data and ongoing efforts to establish the safety and efficacy of immunotherapeutic approaches in combination with HER2-targeted therapy, inhibitors of cyclin-dependent kinases 4 and 6, angiogenesis inhibitors, poly(ADP-ribose) polymerase inhibitors, as well as chemotherapy and radiotherapy.

Breast cancer risk in relation to plasma metabolites among Hispanic and African American women.

PURPOSE: The metabolic etiology of breast cancer has been explored in the past several years using metabolomics. However, most of these studies only included non-Hispanic White individuals. METHODS: To fill this gap, we performed a two-step (discovery and validation) metabolomics profiling in plasma samples from 358 breast cancer patients and 138 healthy controls. All study subjects were either Hispanics or non-Hispanic African Americans. RESULTS: A panel of 14 identified metabolites significantly differed between breast cancer cases and healthy controls in both the discovery and validation sets. Most of these identified metabolites were lipids. In the pathway analysis, citrate cycle (TCA cycle), arginine and proline metabolism, and linoleic acid metabolism pathways were observed, and they significantly differed between breast cancer cases and healthy controls in both sets. From those 14 metabolites, we selected 9 non-correlated metabolites to generate a metabolic risk score. Increased metabolites risk score was associated with a 1.87- and 1.63-fold increased risk of breast cancer in the discovery and validation sets, respectively (Odds ratio (OR) 1.87, 95% Confidence interval (CI) 1.50, 2.32; OR 1.63, 95% CI 1.36, 1.95). CONCLUSIONS: In summary, our study identified metabolic profiles and pathways that significantly differed between breast cancer cases and healthy controls in Hispanic or non-Hispanic African American women. The results from our study might provide new insights on the metabolic etiology of breast cancer.

Prognosis in different subtypes of metaplastic breast cancer: a population-based analysis.

BACKGROUND: Metaplastic breast cancer (MpBC) is a rare histological subtype of breast cancer recognized as a unique pathologic entity in 2000. However, the pathogenesis, optimal therapy, and prognosis of MpBC and the potential effect of systemic treatments on different subtypes of MpBC are not well defined. METHODS: A retrospective population-based study was performed to identify breast cancer patients with MpBC and other triple-negative breast cancers (TNBC) between 2010 and 2014 using the surveillance, Epidemiology, and End Results (SEER) database. Chi-square test was used to analyze characteristics between subgroups. Kaplan-Meier analysis and Multivariate Cox regressions were used to evaluate overall survival (OS) of MpBC, TNBC, and MpBC subgroups. Competing risk analysis and multivariate regression model of competing risk were used to assess breast cancer-specific survival (BCSS) of MpBC and TNBC RESULTS: We identified a study cohort of 22,433 patients (1112 MpBC and 21,321 TNBC). MpBC correlated with older population, larger tumor size and less lymph node involvement, and TNBC phenotype. Patients with MpBC especially with triple-negative subtype (TN-MpBC) had worse survival than the overall TNBC population. However, the prognosis of MpBC without triple-negative subtype (non-TN MpBC) was not different from that of TNBC. In Kaplan-Meier analysis, chemotherapy was not associated with significant difference in OS of TN-MpBC. In non-TN MpBC group, the 3-year OS was 79.8% for patients receiving chemotherapy and 70.5% in patients without chemotherapy, and chemotherapy was associated (P = 0.033) with improved OS. Within the MpBC patients, radiotherapy was significantly (HR 1.544; 95% CI 1.148-2.078; P = 0.004) associated with improved OS and (HR 1.474; 95% CI 1.067-2.040; P = 0.019) BCSS. CONCLUSIONS: Patients with TN-MpBC had worse prognosis than TNBC and chemotherapy was not associated with improved survival. In contrast, non-TN MpBC may derive survival benefit from chemotherapy and radiotherapy.

Correction to: Breast cancer risk in relation to plasma metabolites among Hispanic and African American women.

In the original publication of the article, the sixth author name Krita A. Zanetti was mistakenly included as co-author. The corrected author group is given in the correction article. The original article has been corrected.

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.

RNF11 sequestration of the E3 ligase SMURF2 on membranes antagonizes SMAD7 down-regulation of transforming growth factor ß signaling.

The activity of the E3 ligase, SMURF2, is antagonized by an intramolecular, autoinhibitory interaction between its C2 and Hect domains. Relief of SMURF2 autoinhibition is induced by TGFß and is mediated by the inhibitory SMAD, SMAD7. In a proteomic screen for endomembrane interactants of the RING-domain E3 ligase, RNF11, we identified SMURF2, among a cohort of Hect E3 ligases previously implicated in TGFß signaling. Reconstitution of the SMURF2·RNF11 complex in vitro unexpectedly revealed robust SMURF2 E3 ligase activity, with biochemical properties previously restricted to the SMURF2·SMAD7 complex. Using in vitro binding assays, we find that RNF11 can directly compete with SMAD7 for SMURF2 and that binding is mutually exclusive and dependent on a proline-rich domain. Moreover, we found that co-expression of RNF11 and SMURF2 dramatically reduced SMURF2 ubiquitylation in the cell. This effect is strictly dependent on complex formation and sorting determinants that regulate the association of RNF11 with membranes. RNF11 is overexpressed in certain tumors, and, importantly, we found that depletion of this protein down-regulated gene expression of several TGFß-responsive genes, dampened cell proliferation, and dramatically reduced cell migration in response to TGFß. Our data suggest for the first time that the choice of binding partners for SMURF2 can sustain or repress TGFß signaling, and RNF11 may promote TGFß-induced cell migration.

High turnover of extracellular matrix reflected by specific protein fragments measured in serum is associated with poor outcomes in two metastatic breast cancer cohorts.

Increased extracellular matrix (ECM) formation and matrix metalloprotease (MMP)-mediated ECM degradation are parts of tumorgenesis and generates collagen fragments that are released into circulation. We evaluated the association of specific collagen fragments measured in serum with outcomes in two independent metastatic breast cancer (MBC) cohorts. ELISAs were used to measure C1M (MMP-generated type I collagen fragment), C3M (MMP-generated type III collagen fragment), C4M (MMP-generated type IV collagen fragment), and PRO-C3 (pro-peptide of type III collagen) in pretreatment serum from a phase 3 randomized clinical trial of second-line hormone therapy (HR+, n = 148), and a first-line trastuzumab-treated cohort (HER2+, n = 55). All sites of metastases were included. The collagen fragments were evaluated by Cox-regression analysis for their association with time-to-progression (TTP) and overall survival (OS). In the HR+ cohort, higher C1M and C3M levels (75th percentile cut-off) were associated with shorter TTP; all fragments were associated with shorter OS. In the HER2+ cohort, higher levels of all fragments were associated with shorter TTP; higher PRO-C3 was associated with shorter OS. In multivariate analysis of the HR+ trial for OS, higher levels of all fragments were significant for reduced OS when added separately (C1M HR = 2.1, p < 0.001; C3M HR = 1.8, p = 0.028; C4M HR = 1.8, p = 0.018; PRO-C3 HR = 1.8, p = 0.017); none other clinical covariates were significant. In conclusion, collagen fragments quantified in pretreatment serum was associated with shorter TTP and OS in two independent MBC cohorts receiving systemic therapy. If validated, quantification of ECM remodeling in serum has potential as prognostic and/or predictive biomarkers in MBC.

First-line ribociclib plus letrozole in postmenopausal women with HR+ , HER2- advanced breast cancer: Tumor response and pain reduction in the phase 3 MONALEESA-2 trial.

PURPOSE: The phase 3 MONALEESA-2 study demonstrated that addition of ribociclib (RIB) to letrozole (LET) significantly improved progression-free survival (PFS) in patients (pts) with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC). Here, we evaluated duration of response (DoR), tumor shrinkage, PFS by treatment-free interval (TFI), and health-related quality of life (HRQoL). METHODS: Postmenopausal women (N = 668) with HR+ , HER2- ABC and no prior systemic therapy for ABC were randomized to RIB (600 mg/day; 3 weeks on/1 week off) plus LET (2.5 mg/day; continuous) or placebo (PBO) plus LET. Primary end point was PFS; HRQoL was the secondary end point; DoR was exploratory end point and PFS by TFI was post hoc analysis. RESULTS: Of 501 pts with measurable disease and confirmed complete or partial response, median DoR was 26.7 months (95% CI, 24.0-NR) in the RIB arm versus 18.6 months (95% CI, 14.8-23.1) in the PBO arm. At 8 weeks, more pts in the RIB arm (32%) versus the PBO arm (17%) experienced best percentage change ≥ 60%. The average pain reduction was greater in the RIB arm (26%) versus the PBO arm (15%). PFS benefit was seen with RIB vs PBO, irrespective of TFI. CONCLUSION: RIB plus LET versus PBO plus LET is associated with earlier and more durable tumor response, greater degree of tumor shrinkage and pain reduction, and PFS benefit irrespective of TFI. These data further support RIB plus LET as a first-line treatment option for postmenopausal women with HR+ , HER2- ABC.

A phase II study of imatinib mesylate and letrozole in patients with hormone receptor-positive metastatic breast cancer expressing c-kit or PDGFR-ß.

Background Imatinib mesylate is a potent inhibitor of the Abl, KIT and platelet derived growth factor (PDGF) receptor tyrosine kinases. Preclinical data suggest that combining imatinib mesylate with anti-estrogen therapy may be synergistic in hormone receptor-positive breast cancer. We report results of the first phase II trial evaluating the efficacy of the novel combination of imatinib mesylate and letrozole in the treatment of postmenopausal women with metastatic breast cancer. Patients and Methods 45 postmenopausal women with hormone receptor-positive metastatic breast cancer whose tumors demonstrated c-kit and/or PDGFR-ß positivity were treated with imatinib mesylate 400 mg PO twice daily and letrozole 2.5 mg PO once daily until disease progression or unacceptable toxicity. Results There were no complete responses and five partial responses for an objective response rate of 11%. An additional 16 patients had stable disease lasting at least 24 weeks for a clinical benefit rate of 46.7%. The median progression-free and overall survival was 8.7 months (95% confidence interval: 3.8-11.4 months) and 44.3 months (95% confidence interval: 34.0-55.3 months), respectively. The most common grade 3 or higher treatment related adverse events were fatigue and diarrhea, occurring in 9 (20%) and 7 patients (16%), respectively. Conclusion The combination of imatinib mesylate and letrozole is well tolerated but appears to have limited efficacy in the treatment of hormone receptor-positive metastatic breast cancer.

Antibody-drug conjugates in triple negative breast cancer.

Triple negative breast cancer (TNBC) is a heterogeneous disease that comprises 15-20% of all breast cancers and is more frequently seen in younger women, African-Americans, and BRCA1 expression. Advanced TNBC carries aggressive features and is associated with overall poor outcomes. Unfortunately, there are no targeted therapies available for non-BRCA associated TNBC, which remains a high unmet therapeutic need. One emerging treatment modality includes antibody-drug conjugates which are highly selective monoclonal antibodies conjugated to cytotoxic agents, designed to deliver cytotoxic drugs to antigen-expressing tumor cells. This review will highlight three antibody-drug conjugates currently being evaluated in TNBC (CDX-011, SGN-LIV1a, IMMU-132), including one that has been given Breakthrough Therapy designation from the US FDA.

Efficacy and safety of the trastuzumab biosimilar candidate CT-P6.

Trastuzumab is an anti-HER2 monoclonal antibody indicated for the treatment of HER2-overexpressing breast and gastric cancers. Despite its clinical efficacy, access to the biological drug can be limited due to its relatively high price, especially in low-income countries. CT-P6 (Herzuma®) is a biosimilar candidate of originator or 'reference' trastuzumab, which may offer an alternative, more cost-effective treatment option. This article reviews the unmet needs of patients eligible to receive reference trastuzumab and the potential place of a trastuzumab biosimilar within the market. The review also summarizes the available clinical evidence supporting the biosimilarity of CT-P6 and reference trastuzumab with respect to pharmacokinetics, efficacy, safety and immunogenicity.

CT-P6 compared with reference trastuzumab for HER2-positive breast cancer: a randomised, double-blind, active-controlled, phase 3 equivalence trial.

BACKGROUND: CT-P6 is a proposed biosimilar to reference trastuzumab. In this study, we aimed to establish equivalence of CT-P6 to reference trastuzumab in neoadjuvant treatment of HER2-positive early-stage breast cancer. METHODS: In this randomised, double-blind, active-controlled, phase 3 equivalence trial, we recruited women aged 18 years or older with stage I-IIIa operable HER2-positive breast cancer from 112 centres in 23 countries. Inclusion criteria were an Eastern Cooperative Oncology Group performance status score of 0 or 1; a normal left ventricular ejection fraction of at least 55%; adequate bone marrow, hepatic, and renal function; at least one measureable lesion; and known oestrogen and progesterone receptor status. Exclusion criteria included bilateral breast cancer, previous breast cancer treatment, previous anthracycline treatment, and pregnancy or lactation. We randomly allocated patients 1:1 to receive neoadjuvant CT-P6 or reference trastuzumab intravenously (eight cycles, each lasting 3 weeks, for 24 weeks; 8 mg/kg on day 1 of cycle 1 and 6 mg/kg on day 1 of cycles 2-8) in conjunction with neoadjuvant docetaxel (75 mg/m2 on day 1 of cycles 1-4) and FEC (fluorouracil [500 mg/m2], epirubicin [75 mg/m2], and cyclophosphamide [500 mg/m2]; day 1 of cycles 5-8) therapy. We stratified randomisation by clinical stage, receptor status, and country and used permuted blocks. We did surgery within 3-6 weeks of the final neoadjuvant study drug dose, followed by an adjuvant treatment period of up to 1 year. We monitored long-term safety and efficacy for 3 years after the last patient was enrolled. Participants and investigators were masked to treatment until study completion. The primary efficacy endpoint, analysed in the per-protocol population, was pathological complete response, assessed via specimens obtained during surgery, analysed by masked central review of local histopathology reports. The equivalence margin was -0·15 to 0·15. This trial is registered with ClinicalTrials.gov, number NCT02162667, and is ongoing, but no longer recruiting. FINDINGS: Between Aug 7, 2014, and May 6, 2016, we randomly allocated 549 patients (271 [49%] to CT-P6 vs 278 [51%] to reference trastuzumab). A similar proportion of patients achieved pathological complete response with CT-P6 (116 [46·8%; 95% CI 40·4-53·2] of 248 patients) and reference trastuzumab (129 [50·4%; 44·1-56·7] of 256 patients). The 95% CI of the estimated treatment outcome difference (-0·04% [95% CI -0·12 to 0·05]) was within the equivalence margin. 19 (7%) of 271 patients in the CT-P6 group reported serious treatment-emergent adverse events versus 22 (8%) of 278 in the reference trastuzumab group; frequent (occurring in more than one patient) serious adverse events were febrile neutropenia (four [1%] vs one [<1%]) and neutropenia (one [<1%] vs two [1%]). Grade 3 or worse treatment-related adverse events occurred in 17 (6%) of 271 patients in the CT-P6 group versus 23 (8%) of 278 in the reference trastuzumab group; the most frequently reported adverse event was neutropenia in ten (4%) versus 14 (5%). INTERPRETATION: CT-P6 showed equivalent efficacy to reference trastuzumab and adverse events were similar. Availability of trastuzumab biosimilars could increase access to this targeted therapy for HER2-positive early-stage cancer. FUNDING: Celltrion Inc.

A phase I trial of ganetespib in combination with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer.

BACKGROUND: Targeted therapies in HER2-positive metastatic breast cancer significantly improve outcomes but efficacy is limited by therapeutic resistance. HER2 is an acutely sensitive Heat Shock Protein 90 (HSP90) client and HSP90 inhibition can overcome trastuzumab resistance. Preclinical data suggest that HSP90 inhibition is synergistic with taxanes with the potential for significant clinical activity. We therefore tested ganetespib, a HSP90 inhibitor, in combination with paclitaxel and trastuzumab in patients with trastuzumab-refractory HER2-positive metastatic breast cancer. METHODS: In this phase I dose-escalation study, patients with trastuzumab-resistant HER2-positive metastatic breast cancer received weekly trastuzumab (2 mg/kg) and paclitaxel (80 mg/m2) on days 1, 8, 15, and 22 of a 28-day cycle with escalating doses of ganetespib (100 mg/m2, 150 mg/m2, and a third cohort of 125 mg/m2 if needed) on days 1, 8, and 15. Therapy was continued until disease progression or toxicity. The primary objective was to establish the safety and maximum tolerated dose and/or recommended phase II dose (RP2D) of this therapy. The secondary objectives included evaluation of the effects of ganetespib on the pharmacokinetics of paclitaxel, and to make a preliminary assessment of the efficacy of the combination therapy. RESULTS: Dose escalation was completed for the two main cohorts without any observed dose-limiting toxicities. Nine patients received treatment. The median prior lines of anti-HER2 therapy numbered three (range 2-4), including prior pertuzumab in 9/9 patients and ado-trastuzumab emtansine (T-DM1) in 8/9 patients. The most common grade 1/2 adverse events (AEs) were diarrhea, fatigue, anemia, and rash. There were no grade 4 AEs related to ganetespib. The overall response rate was 22% (2/9 patients had partial response) and stable disease was seen in 56% (5/9 patients). The clinical benefit rate was 44% (4/9 patients). The median progression-free survival was 20 weeks (range 8-55). CONCLUSION: The RP2D of ganetespib is 150 mg/m2 in combination with weekly paclitaxel plus trastuzumab. The combination was safe and well tolerated. Despite prior taxanes, pertuzumab, and T-DM1, clinical activity of this triplet regimen in this heavily pretreated cohort is promising and warrants further study in HER2-positive metastatic breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov NCT02060253 . Registered 30 January 2014.

Clinical nomogram to predict bone-only metastasis in patients with early breast carcinoma.

BACKGROUND: Bone is one of the most common sites of distant metastasis in breast cancer. The purpose of this study was to combine selected clinical and pathologic variables to develop a nomogram that can predict the likelihood of bone-only metastasis (BOM) as the first site of recurrence in patients with early breast cancer. METHODS: Medical records of patients with non-metastatic breast cancer were retrospectively collected. On the basis of the analysis of patient and tumour characteristics using the Cox proportional hazards regression model, a nomogram to predict BOM was constructed for a 4175-patient-training cohort. The nomogram was validated in an independent cohort of 579 patients. RESULTS: Among 4175 patients with non-metastatic breast cancer, 314 developed subsequent BOM. Age, T classification, lymph node status, lymphovascular space invasion, and hormone receptor status were significantly and independently associated with subsequent BOM. The nomogram had a concordance index of 0.69 in the training set and 0.73 in the validation set. CONCLUSIONS: We have developed a clinical nomogram to predict subsequent BOM in patients with non-metastatic breast cancer. Selection of a patient population at high risk for BOM could facilitate research of more specific staging approaches or the selective use of bone-targeted therapy.

CD44 expression contributes to trastuzumab resistance in HER2-positive breast cancer cells.

Resistance to HER2-targeted therapies remains a major obstacle in the treatment of HER2-overexpressing breast cancer. CD44, a putative breast cancer stem cell (CSC) marker, is overexpressed in trastuzumab-resistant breast cancer cells. While CSC-related genes may play a role in the development of trastuzumab resistance, conflicting results have been published about CSC response to trastuzumab. We hypothesized that CD44 contributes to trastuzumab resistance independently of its role as a CSC marker. We used trastuzumab-sensitive breast cancer cell lines and their trastuzumab-resistant isogenic counterparts to evaluate the role of CD44 in response to trastuzumab. miRNA and mRNA expression were analyzed using microarray chips. A gene set enrichment analysis was created and matched with response to trastuzumab in cells and patient samples. The proportions of CSC in trastuzumab-resistant cells were similar to or lower than in the trastuzumab-sensitive cells. However, CD44 expression levels were significantly higher in both trastuzumab-resistant cell lines and its knockdown led to an increased response to trastuzumab. The invasiveness and anchorage-independent growth of trastuzumab-resistant cells were higher and blocked by downregulation of CD44. Results also showed that CD44-related resistance to trastuzumab is regulated by miRNAs. We identified a CD44-related gene expression profile that correlated with response to trastuzumab in cell lines and breast cancer patients. CD44 mediates trastuzumab resistance in HER2-positive breast cancer cells independently of its role as a CSC marker and that this role of CD44 is partly regulated by miRNA.

Systemic Therapy for HER2-Positive Central Nervous System Disease: Where We Are and Where Do We Go From Here?

Patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer are at an increased risk of developing brain metastases. The incidence and prevalence of central nervous system (CNS) disease are increasing due to improved survival, which can be attributed to better systemic therapies for extracranial disease. The current standard of care for brain metastases includes a combination of surgery and/or radiation. Systemic therapies are typically reserved for patients with intracranial progression following radiation, due to their limited ability to cross the blood-brain barrier. None of the available anti-HER2 agents (trastuzumab, lapatinib, pertuzumab, and ado-trastuzumab emtansine (T-DM1)) are currently approved for the treatment of brain metastases. Research is underway evaluating novel anti-HER2 agents, which have demonstrated CNS activity. This article discusses the current data on using anti-HER2 therapies to treat CNS disease as well as the newer anti-HER2 agents, which may overcome the current challenges faced in treating brain metastases in the HER2-positive patient population.

Genomic Signatures in Breast Cancer: Limitations of Available Predictive Data and the Importance of Prognosis.

Several biomarkers and gene mutations in breast cancer have been shown to be predictive, in that they determine which treatments a patient should receive. Ideally, predictive markers would be available that could determine the most appropriate treatment plan based on a patient's biology. This goal is becoming a reality in some treatment settings and cancer types, with the increasing use of targeted therapies directed against specific molecular abnormalities. Immunohistochemistry (IHC) testing is in standard use for guiding breast cancer therapy. Testing for the estrogen receptor (ER) and progesterone receptor (PR) guides the use of endocrine therapy, and human epidermal growth factor receptor 2 (HER2) testing guides the use of HER2-targeted therapies. Although IHC provides some discrimination among breast cancer subsets and helps identify appropriate therapy, more information can be gained through gene expression analyses. Contemporary multianalyte assays have demonstrated greater precision and reproducibility than seen with IHC-based assays. The most important contribution of multigene assays is the identification of women with ER/PR-positive, HER2-negative, early-stage breast cancer who are at low risk of recurrence and therefore will likely do well with endocrine therapy alone. These patients can be safely spared from the cytotoxic effects of chemotherapy.