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The HER2-targeted antibody-drug conjugate trastuzumab emtansine (T-DM1) is approved for the treatment of metastatic, HER2-positive breast cancer after prior trastuzumab and taxane therapy, and has also demonstrated efficacy in the adjuvant setting in incomplete responders to neoadjuvant therapy. Despite its objective activity, intrinsic and acquired resistance to T-DM1 remains a major clinical challenge. T-DM1 mediates its activity in a number of ways, encompassing HER2 signalling blockade, Fc-mediated immune response and payload-mediated microtubule poisoning. Resistance mechanisms relating to each of these features have been demonstrated, and we outline the findings of these studies in this review. In our overview of the substantial literature on T-DM1 activity and resistance, we conclude that the T-DM1 resistance mechanisms most strongly supported by the experimental data relate to dysfunctional intracellular metabolism of the construct and subversion of DM1-mediated cell killing. Loss of dependence on signalling initiated by HER2-HER2 homodimers is not substantiated as a resistance mechanism by clinical or experimental studies, and the impact of EGFR expression and tumour immunological status requires further investigation. These findings are instructive with respect to strategies that might overcome T-DM1 resistance, including the use of second-generation anti-HER2 antibody-drug conjugates that deploy alternative linker-payload chemistries. [ABSTRACT FROM AUTHOR]

Background: Clinical trials have shown that trastuzumab, a recombinant monoclonal antibody against HER2 receptor, significantly improves overall survival and disease-free survival in women with HER2-positive early breast cancer, but long-term follow-up data are needed. We report the results of comparing observation with two durations of trastuzumab treatment at a median follow-up of 11 years, for patients enrolled in the HERA (HERceptin Adjuvant) trial.Methods: HERA (BIG 1-01) is an international, multicentre, open-label, phase 3 randomised trial of 5102 women with HER2-positive early breast cancer, who were enrolled from hospitals in 39 countries between Dec 7, 2001, and June 20, 2005. After completion of all primary therapy (including, surgery, chemotherapy, and radiotherapy as indicated), patients were randomly assigned (1:1:1) to receive trastuzumab for 1 year (once at 8 mg/kg of bodyweight intravenously, then 6 mg/kg once every 3 weeks) or for 2 years (with the same dose schedule), or to the observation group. Primary endpoint is disease-free survival, and analyses are in the intention-to-treat population. Hazard ratios (HRs) were estimated from Cox models, and survival curves were estimated by the Kaplan-Meier method. Comparison of 2 years versus 1 year of trastuzumab is based on 366-day landmark analyses. This study is registered with ClinicalTrials.gov (NCT00045032).Findings: Of the 5102 women randomly assigned in the HERA trial, three patients had no evidence of having provided written informed consent to participate. We followed up the intention-to-treat population of 5099 patients (1697 in observation, 1702 in 1-year trastuzumab, and 1700 in 2-years trastuzumab groups). After a median follow-up of 11 years (IQR 10·09-11·53), random assignment to 1 year of trastuzumab significantly reduced the risk of a disease-free survival event (HR 0·76, 95% CI 0·68-0·86) and death (0·74, 0·64-0·86) compared with observation. 2 years of adjuvant trastuzumab did not improve disease free-survival outcomes compared with 1 year of this drug (HR 1·02, 95% CI 0·89-1·17). Estimates of 10-year disease-free survival were 63% for observation, 69% for 1 year of trastuzumab, and 69% for 2 years of trastuzumab. 884 (52%) patients assigned to the observation group selectively crossed over to receive trastuzumab. Cardiac toxicity remained low in all groups and occurred mostly during the treatment phase. The incidence of secondary cardiac endpoints was 122 (7·3%) in the 2-years trastuzumab group, 74 (4·4%) in the 1-year trastuzumab group, and 15 (0·9%) in the observation group.Interpretation: 1 year of adjuvant trastuzumab after chemotherapy for patients with HER2-positive early breast cancer significantly improves long-term disease-free survival, compared with observation. 2 years of trastuzumab had no additional benefit.Funding: F Hoffmann-La Roche (Roche). [ABSTRACT FROM AUTHOR]

[Display omitted] • At least half of HER2-positive breast tumors express hormone receptors. • Triple-positive breast cancer has a unique biology. • ER and HER2 pathways are closely related. • ER expression influences response to anti-HER2 therapies. • Combinations of endocrine and anti-HER2 therapies are promising. • Molecular approaches provide the rational for new treatment strategies, including chemo-free. Triple-positive breast tumors overexpress human epidermal growth factor receptor 2 (HER2) and are positive for hormone receptor (HR) expression. Data from real-life and clinical trials show that estrogen receptor (ER) expression affects the response to combinations of anti-HER2 and associated systemic therapies. Despite triple-positive tumors having decreased response rates compared to HR-negative/HER2-positive breast cancers, optimizing anti-HER2 treatment with dual anti-HER2 blockade remains important for optimal disease control. Preclinical data on the cross-talk between ER and growth factor receptor pathways show the efficacy of combinations of endocrine therapy and anti-HER2 drugs, which is confirmed in the clinic. Molecular dissection of triple-positive breast cancer might provide the rational for additional therapeutic strategies and the identification of promising biomarkers. This review summarizes data on systemic treatment efficacy from major clinical trials and perspectives for future clinical research in triple-positive breast cancer. [ABSTRACT FROM AUTHOR]

The implementation of molecular profiling technologies in oncology deepens our knowledge for the molecular landscapes of cancer diagnoses, identifying aberrations that could be linked with specific therapeutic vulnerabilities. In particular, there is an increasing list of molecularly targeted anticancer agents undergoing clinical development that aim to block specific molecular aberrations. This leads to a paradigm shift, with an increasing list of specific aberrations dictating the treatment of patients with cancer. This paradigm shift impacts the field of clinical trials, since the classical approach of having clinico-pathological disease characteristics dictating the patients' enrolment in oncology trials shifts towards the implementation of molecular profiling as prescreening step. In order to facilitate the successful clinical development of these new anticancer drugs within specific molecular niches of cancer diagnoses, there have been developed new, innovative trial designs that could be classified as follows: i) longitudinal cohort studies that implement (or not) "nested" downstream trials, 2) studies that assess the clinical utility of molecular profiling, 3) "master" protocol trials, iv) "basket" trials, v) trials following an adaptive design. In the present article, we review these innovative study designs, providing representative examples from each category and we discuss the challenges that still need to be addressed in this era of new generation oncology trials implementing molecular profiling. Emphasis is put on the field of breast cancer clinical trials. [ABSTRACT FROM AUTHOR]

Abstract: Background: The role of circulating tumor cells (CTCs) in HER2-positive breast cancer patients receiving neoadjuvant therapy is unclear. Patients & methods: We describe the CTC detection rate, HER2 phenotyping and pathological complete response (pCR) in patients enrolled in the NeoALTTO phase III trial. Participation in the CTC sub-study was optional. CTC evaluation was performed centrally using CellSearch® at baseline, week 2 and week 18 (prior to surgery) of neoadjuvant therapy. Results: Samples for CTC analysis were available for 51/455 patients randomized. At baseline, week 2 and week 18, we detected ≥1 CTC/22.5 ml in 5/46 (11%), 4/41 (10%), and 5/31 (16%) patients and ≥1 HER2-positive CTC/22.5 ml in 2/46 (4%), 2/41 (5%), and 3/31 (10%) patients with evaluable samples, respectively. 11/51 patients (21%) had ≥1 CTC/22.5 ml in at least one time point. pCR was observed in 3/11 (27.3%) versus 17/40 (42.5%) patients with detectable and no detectable CTCs, respectively (p = 0.36). No pCR was observed in the three patients with detectable HER2-positive CTCs prior to surgery. Conclusion: Numerically lower pCR rates were observed in patients with detectable CTCs, yet the study remains underpowered. A meta-analysis of CTC studies in this setting is warranted. [Copyright &y& Elsevier]

Trastuzumab administered in combination with various chemotherapy regimens has led to outstanding improvements in both disease-free survival and overall survival. So far, thousands of patients have been treated in this way which has proven to be reasonably safe, with cardiac events being the predominant recognisable toxicity requiring surveillance. Notwithstanding the large cumulative experience of the oncology community in treating early HER2/neu-positive breast cancer with trastuzumab, some uncertainties remain, with key issues being the ideal time of chemotherapy administration and the optimal duration of trastuzumab therapy. This paper discusses these issues in the light of the recent updates of some of the pivotal clinical trials in the adjuvant context. © 2013 S. Karger GmbH, Freiburg [ABSTRACT FROM AUTHOR]

Purpose. This study measured the time taken for setting up the different facets of Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO), an international phase III study being conducted in 44 participating countries. Methods. Time to regulatory authority (RA) approval, time to ethics committee/institutional review board (EC/IRB) approval, time from study approval by EC/IRB to first randomized patient, and time from first to last randomized patient were prospectively collected in the ALTTO study. Analyses were conducted by grouping countries into either geographic regions or economic classes as per the World Bank's criteria. Results. South America had a significantly longer time to RA approval (median: 236 days, range: 21-257 days) than Europe (median: 52 days, range: 0 -151 days), North America (median: 26days, range:22-30days),and Asia-Pacific (median:62 days, range: 37-75 days). Upper-middle economies had longer times to RA approval (median: 123 days, range: 21-257 days) than high-income (median: 47 days, range: 0-112 days) and lower-middle income economies (median: 57 days, range: 37-62 days). No significant difference was observed for time to EC/IRB approval across the studied regions (median: 59 days, range 0-174 days). Overall, the median time from EC/IRB approval to first recruited patient was 169 days (range: 26-412 days). Conclusion. This study highlights the long time intervals required to activate a global phase III trial. Collaborative research groups, pharmaceutical industry sponsors, and regulatory authorities should analyze the current system and enter into dialogue for optimizing local policies. This would enable faster access of patients to innovative therapies and enhance the efficiency of clinical research. [ABSTRACT FROM AUTHOR]

Abstract: Background: The MINDACT (Microarray In Node-negative and 1–3 node positive Disease may Avoid ChemoTherapy) trial investigates the clinical utility of the 70-gene profile (MammaPrint) for the selection of breast cancer patients for adjuvant chemotherapy (CT) together with standard clinicopathological criteria. We present the results of the pilot phase consisting of first 800 patients included. Methods: MINDACT has enrolled 6600 patients, classified into high or low risk by MammaPrint and clinicopathological risk through Adjuvant! Online. Patients with both clinical (C) and genomic (G) high risks are offered adjuvant CT; those with both C and G low risks do not receive CT; patients with discordant risk are randomised for the decision of adjuvant CT based on C or G risk. CT randomisation of anthracycline-based versus docetaxel/capecitabine and endocrine therapy randomisation between letrozole and tamoxifen→letrozole are offered. Results: During the pilot phase 46% of screened patients were enrolled. Main reasons for non-enrolment were node positivity before trial amendment, sample quality problems and failure to meet logistic settings. Among the 800 patients, 386 (48%) were C-low/G-low, 198 (24.8%) as C-high/G-high, 75 (9.4%) as C-low/G-high and 141 (17.6%) as C-high/G-low. In total 216 (27%) cases were discordant. The difference between patients with C-high (42%) and G-high risk (34%) is 8.25% (95% confidence interval (CI), 4.7–11.8%; P <.0001). Compliance with the treatment decision was high (>92%). Conclusions: The logistically complex MINDACT trial is feasible in a multinational setting. The proportion of discordant patients, the potential reduction in CT by using the genomic signature and compliance to treatment assignment are in accordance with the trial hypotheses. [Copyright &y& Elsevier]

The article focuses on the systemic therapy for advanced breast cancer. It states that the Early Breast Cancer Trialists' Collaborative Group's compilation of breast cancer management and clinical trials have paved way for the development of adjuvant treatments for cancer. However, advances in systemic therapy for metatistic disease have been more difficult to recognize. The important historical perspective and framework for interpreting future advances in breast cancer therapy are presented.

Abstract: With the reporting of five studies with different and complementary designs, but all demonstrating a similar and striking benefit from the targeted drug trastuzumab in HER2-overexpressing breast cancer, the year 2005 has profoundly marked the history of randomised adjuvant breast cancer trials. In view of the halving in recurrence risk, obtained at the real but small risk of cardiotoxicity, these results are generating hope in women affected with this aggressive form of the disease. But at the same time these results pose real challenges to healthcare authorities faced with the high cost of the anti-HER2 monoclonal antibody. These results also leave oncologists and patients to deal with a complex treatment tailoring process that needs to take into account risk of an early relapse as well as the benefit versus risk of trastuzumab according to the different patterns of administration used in the clinical trials. [Copyright &y& Elsevier]

The editorial comments on the use of anthracyclines in the adjuvant treatment of early breast cancer. Anthracycline-based chemotherapy was studied in the National Institute of Canada Clinical Trials Group Mammary.5 and found to reduce mortality and increase the absolute survival rate. The cyclophosphamide-epirubicin-fluorouracil combination costs more than the cyclophosphamide, methotexate and fluorouracil regimen and has more side effects. A study by Pritchard and colleagues found that CEF treatment was more effective against tumors associated with HER2 overexpression or amplification. The effectiveness of trastuzumab is mentioned.

Background Epirubicin-based chemotherapy improves the outcome of early breast cancer (BC) patients. However, cardiotoxicity remains an important side effect. Methods We re-consented node-positive BC patients enrolled in a phase III trial between 1988 and 1996 which compared six cycles of oral cyclophosphamide, methotrexate, fluorouracil (CMF) versus two epirubicin–cyclophosphamide regimens differing by the anthracycline cumulative dose [standard-dose epirubicin and cyclophosphamide (SDE) (8 × 60 mg/m 2 ) and higher-dose epirubicin and cyclophosphamide (HDE) (8 × 100 mg/m 2 )]. Eligible patients were those who were alive and free of disease and had no contra-indications to the proposed tests (cardiac evaluation). Cardiotoxicity was defined as asymptomatic systolic dysfunction (left ventricular ejection fraction (LVEF) < 50%, New York Heart Association (NYHA) Class I) or symptomatic heart failure (NYHA Class II–IV). Differences in cardiotoxicity between CMF and SDE/HDE were assessed using chi-square and Fisher Exact tests for binary variables and t -test and Wilcoxon test for continuous variables. Results Among the 777 patients, 20 cases of CHF were reported (CMF = 1, SDE = 5, HDE = 14; p < 0.001). Between September 2010 and June 2013, 82 patients (30%) out of 269 eligible patients accepted to participate in this substudy. Median follow-up was 18 years (range 15–24). Epirubicin-treated patients had significantly higher heart rate, more abnormal echocardiograms and LVEF by magnetic resonance imaging (MRI) compared to CMF-treated ones. A trend towards higher BNP was also observed in the SDE/HDE group ( P = 0.08). No differences were observed in LVEF assessed by echocardiogram or troponin T levels. Conclusions Participation rate in this substudy was lower than expected highlighting the complexity of re-calling patients several years after the initial BC diagnosis. After 18 years, epirubicin-treated patients had a lower LVEF by MRI, more abnormal echocardiograms, higher heart rates compared to patients treated with CMF. However, no major delayed cardiotoxicity was observed. [ABSTRACT FROM AUTHOR]

Summary: Background: Several randomised trials have confirmed the benefit of adjuvant trastuzumab for patients with HER2-positive early breast cancer. However, concern has been expressed that adjuvant trastuzumab might be associated with an increased frequency of CNS relapses. We assessed the frequency and course of CNS relapses, either as first event or at any time, using data from the HERA trial. Methods: We estimated the cumulative incidence of first disease-free survival (DFS) events in the CNS versus other sites by competing risks analysis in patients with HER2-positive early breast cancer who had been randomly assigned to receive 1 year of trastuzumab or to observation in the HERA trial after a median follow-up of 4 years (IQR 3·5–4·8). To obtain further information about CNS relapse at any time before death, we circulated a data collection form to investigators to obtain standardised information about CNS events that occurred in all patients who had died before July, 2009. We estimated the cumulative incidence of CNS relapse at any time with a competing risks analysis. Results: Of 3401 patients who had been assigned to receive 1 year of trastuzumab or to observation, 69 (2%) had a CNS relapse as first DFS event and 747 (22%) had a first DFS event not in the CNS. The frequency of CNS relapses as first DFS event did not differ between the group given 1 year of trastuzumab (37 [2%] of 1703 patients) and the observation group (32 [2%] of 1698; p=0·55 [Gray''s test]). 481 data collection forms were distributed, of which 413 (86%) were returned. The proportion of patients who had died and experienced a CNS relapse was numerically higher in the observation group (129 [57%] of 227) than in the group given trastuzumab for 1 year (88 [47%] of 186; p=0·06 [Gray''s test]). Most CNS relapses were symptomatic (189 [87%] of 217). Conclusion: Adjuvant trastuzumab does not increase the risk of CNS relapse in patients with HER2-positive early breast cancer. Funding: None. [Copyright &y& Elsevier]

Abstract: Aim: The safety, pharmacokinetics and efficacy of sorafenib plus docetaxel in patients with advanced refractory cancer were investigated in a Phase I, dose-escalation trial. Methods: Twenty-seven patients in four Cohorts received docetaxel on Day 1 (Cohorts 1 and 4: 75mg/m2; Cohorts 2 and 3: 100mg/m2) plus sorafenib on Days 2–19 (Cohorts 1 and 2: 200mg twice-daily (bid); Cohorts 3 and 4: 400mg bid) in 21-day cycles. Results: Most common adverse events (AEs) (Grade 3–5) included neutropenia (89%), leucopaenia (81%), hand–foot skin reaction (30%) and fatigue (30%). The most common drug-related AEs leading to dose reduction/interruption or permanent discontinuation were dermatologic (41%), gastrointestinal (26%) and constitutional (22%). Coadministration of sorafenib altered the pharmacokinetics of docetaxel. On average, docetaxel area under the concentration–time curve (AUC)0–24 increased by 5% (Cohort 1), 54% (Cohort 2), 36% (Cohort 3) and 80% (Cohort 4) with docetaxel plus sorafenib, while C max increased by 16–32%, independent of sorafenib/docetaxel doses. Three of 25 evaluable patients (11%) had partial responses; 14 (52%) had stable disease. Conclusion: Dose-limiting dermatologic AEs were more common than expected for either therapy alone. A starting dose of docetaxel 75mg/m2 plus sorafenib 400mg bid (with dose reductions for dermatological toxicities) is proposed for Phase II. [Copyright &y& Elsevier]

Background. Randomized studies have shown different magnitude of bevacizumab benefit in the treatment of advanced breast cancer. Regulatory agencies have modified bevacizumab treatment indications across different regions. In this study, we perform a meta-analysis of phase III studies aiming to interrogate themagnitude of bevacizumab benefit for the treatment of first-line HER2- negative metastatic breast cancer (MBC). Methods. Data from studies E2100, AVADO and RIBBON-1 were used to calculate the benefit of bevacizumab in terms of tumor overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and toxicities. Combined statistical estimates of hazard ratios (HR) and odds ratios were calculated using fixed-effects or random effects models. Results. A total of 2,695 patients were evaluated. Combining bevacizumab with different chemotherapy backbones resulted in a 30% risk reduction of PFS events (HR = 0.70; 95% confidence interval [CI], 0.57-0.86) and increased ORR (odds ratio 1.81; 95% CI, 1.53-2.14). No OS benefit could be demonstrated (HR = 0.95; 95% CI, 0.85-1.06). Bevacizumab significantly increased the incidence of adverse events such as proteinuria, hypertension and cardiovascular events. Conclusions. Bevacizumab combined with chemotherapy in the first-line treatment of MBC significantly improved ORR and PFS, but also increased grade 3-4 toxicities. No significant OS advantage was observed. [ABSTRACT FROM AUTHOR]

The article reflects on progress made with respect to bench-to-bedside research in breast cancer. The advent of molecular oncology has led researchers to realize that breast cancer is a heterogeneous disease, for which a one size fits all approach to patient treatment is no longer optimal, which contributed to a change of thinking on clinical trial design .