Trastuzumab emtansine with or without pertuzumab versus trastuzumab with taxane for human epidermal growth factor receptor 2-positive advanced breast cancer: Final results from MARIANNE.

BACKGROUND: In the phase 3 MARIANNE trial, trastuzumab emtansine (T-DM1) with or without pertuzumab showed noninferior progression-free survival and better tolerability than trastuzumab plus a taxane (HT) for the first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer. This article reports the final descriptive overall survival (OS) analysis, updated safety data, and additional patient-reported outcomes and biomarker analyses. METHODS: OS was assessed in 1095 patients with HER2-positive breast cancer and no prior therapy for advanced disease who had been randomized to HT, T-DM1 plus a placebo (hereafter T-DM1), or T-DM1 plus pertuzumab (T-DM1+pertuzumab). A post hoc exploratory landmark analysis of OS, baseline patient and disease characteristics, and tumor biomarkers in patients with and without an objective tumor response (OR) according to the Response Evaluation Criteria in Solid Tumors within 6.5 months of randomization was conducted. RESULTS: The median OS was similar across groups (50.9, 53.7, and 51.8 months for the HT, T-DM1, and T-DM1+pertuzumab groups, respectively). Among patients with an OR, the median OS was longer with T-DM1 (64.4 months) and T-DM1+pertuzumab (not reached) versus HT (56.3 months). No baseline characteristics or biomarkers were strongly associated with OR. The incidence of grade 3 or higher adverse events was greater with HT (55.8%) than T-DM1 (47.1%) or T-DM1+pertuzumab (48.6%). The median time to clinically meaningful deterioration (a 3-point or greater change) in neurotoxicity symptoms was shorter with HT (2.1 months) and T-DM1+pertuzumab (4.2 months) than T-DM1 (6.2 months). Fewer patients reported alopecia and diarrhea and were bothered by treatment side effects in the T-DM1 arm. CONCLUSIONS: These results support T-DM1 as a first-line treatment for patients with HER2-positive metastatic breast cancer who are deemed unsuitable for taxane-based therapy.

Correction to: Relationship between tumor biomarkers and efficacy in MARIANNE, a phase III study of trastuzumab emtansine ± pertuzumab versus trastuzumab plus taxane in HER2-positive advanced breast cancer.

Following publication of the original article [1], the authors reported the following errors in the article.

Relationship between tumor biomarkers and efficacy in MARIANNE, a phase III study of trastuzumab emtansine ± pertuzumab versus trastuzumab plus taxane in HER2-positive advanced breast cancer.

BACKGROUND: The phase III EMILIA and TH3RESA trials demonstrated clinical benefits of trastuzumab emtansine (T-DM1) therapy in patients with previously treated HER2-positive metastatic breast cancer (MBC). Data from these and other trials showed that T-DM1-associated survival benefits were observed across biomarker subgroups tested in these trials. Prespecified, exploratory analyses of the phase III MARIANNE study examined the effects of HER2-related biomarkers on PFS in patients administered T-DM1 in the first-line MBC setting. METHODS: In MARIANNE, patients with previously untreated HER2-positive MBC were randomized (1:1:1) to trastuzumab plus taxane, T-DM1 plus placebo, or T-DM1 plus pertuzumab. Biomarker subgroups included HER2 and HER3 mRNA expression levels (≤median vs. >median), HER2 staining intensity (IHC 3+ vs. 2+ vs. 0/1+), PIK3CA status (mutated vs. non-mutated), PTEN H-score (≤median vs. >median), and PTEN protein expression level (0 vs. 1+ vs. 2+ vs. 3+ vs. 4+). PFS was analyzed descriptively for each subgroup using Kaplan-Meier methodology. Additional exploratory post-hoc analyses evaluated the effects of HER2 heterogeneity. Multivariate analyses were also performed. RESULTS: Median PFS was numerically longer for patients with HER2 mRNA levels >median versus ≤median across treatment arms. In general, there were no predictive biomarkers of benefit for either T-DM1 treatment arm; most hazard ratios were close to 1 with wide confidence intervals that included the value 1. Focal HER2 expression (IHC 3+ or IHC 2+) was present in 3.8% of patients and was associated with numerically shorter PFS in the T-DM1-containing treatment arms versus trastuzumab plus taxane. Compared with non-mutated PIK3CA, mutated PIK3CA was associated with numerically shorter median PFS across treatment groups. Post-hoc multivariate analysis showed HER2 mRNA expression and mutated PIK3CA were prognostic for PFS (P ≤ 0.001 for both biomarkers). CONCLUSIONS: In MARIANNE, biomarkers related to the HER2 pathway did not have predictive value for PFS when comparing T-DM1 (with or without pertuzumab) with trastuzumab plus taxane. However, HER2 mRNA level and PIK3CA mutation status showed prognostic value. Evaluation of other potential biomarkers, including immune markers, is ongoing. TRIAL REGISTRATION: Registration number: NCT01120184 . Date of registration: April 28, 2010 (registered prospectively).

Beliefs and behavior regarding e-cigarettes in a large cross-sectional survey.

Although e-cigarette use is increasing dramatically, numerous concerns persist regarding toxicity and their role in smoking cessation. We assessed beliefs and behavior regarding e-cigarettes in an adult French population. The 4th French nationwide observational survey, EDIFICE 4, was conducted among representative samples of 1602 laypersons (age, 40-75 years) from 12 June-10 July 2014, using the quota method. Profile, beliefs and behavior were assessed by phone interviews of the participating lay population with no history of cancer (N = 1463). Tobacco use, nicotine dependence (Fagerström test) and e-cigarette use were assessed. E-cigarette users represented 6% of the study lay population. E-cigarette users regarded e-cigarettes as helpful for quitting tobacco smoking and reducing the risk of lung cancer. Current dual users (e-cigarettes + cigarettes) were more likely to attempt to quit than current exclusively cigarette smokers (odds ratio, 3.15 [1.74-5.70]), and to consider themselves at higher risk for lung cancer (OR 3.85 [2.47-5.99]). They also considered e-cigarette vapor to be less toxic than tobacco smoke in terms of both active and passive exposure. Dual users typically consider themselves at higher risk for cancer and intend to quit smoking. Physicians should be made aware of this specific sub-population for whom e-cigarettes may be a useful trigger in the smoking cessation process.

Awareness and Misconceptions of Breast Cancer Risk Factors Among Laypersons and Physicians.

BACKGROUND: Primary prevention of cancer relies on awareness of and consequent identification of risk factors. We investigated knowledge of breast cancer risk factors not only among laywomen but also among female physicians. METHODS: The EDIFICE 4 nationwide observational survey was conducted by phone interviews of a representative female population (737 laywomen and 105 female physicians) aged 40-75 years, using the quota method. This analysis focuses on spontaneous replies to the question "In your opinion, what are the five main risk factors that increase the risk of breast cancer?". RESULTS: Heredity/Family history of breast cancer was the most widely recognized risk factor in both study populations (98.1% physicians vs. 54.2% laywomen; P ≤ 0.01). Smoking (19.0 and 17.5%) and alcohol consumption (3.8 and 5.5%) were among the lifestyle risk factors that were cited by similar proportions of physicians and laywomen, respectively. Other established risk factors were however very rarely cited by either physicians or laywomen, e.g., Exposure to medical radiation (4.8 vs. 0.4%, respectively; P ≤ 0.05) or not cited at all, i.e., Benign mastopathy and Personal history of breast cancer. CONCLUSION: This survey highlights a number of misconceptions relating to behavioral risk factors for breast cancer, including the relative impact of alcohol and tobacco consumption and the importance of menopausal status. The limited awareness of the risk related to Exposure to medical radiation, Benign mastopathy, or Personal history raises concern regarding compliance with national screening recommendations.

Prospective Clinical Utility Study of the Use of the 21-Gene Assay in Adjuvant Clinical Decision Making in Women With Estrogen Receptor-Positive Early Invasive Breast Cancer: Results From the SWITCH Study.

BACKGROUND: The 21-gene Oncotype DX Recurrence Score assay is a validated assay to help decide the appropriate treatment for estrogen receptor-positive (ER+), early-stage breast cancer (EBC) in the adjuvant setting. The choice of adjuvant treatments might vary considerably in different countries according to various treatment guidelines. This prospective multicenter study is the first to assess the impact of the Oncotype DX assay in the French clinical setting. METHODS: A total of 100 patients with ER+, human epidermal growth factor receptor 2-negative EBC, and node-negative (pN0) disease or micrometastases in up to 3 lymph nodes (pN1mi) were enrolled. Treatment recommendations, physicians' confidence before and after knowing the Recurrence Score value, and physicians' perception of the assay were recorded. RESULTS: Of the 100 patients, 95 were evaluable (83 pN0, 12 pN1mi). Treatment recommendations changed in 37% of patients, predominantly from chemoendocrine to endocrine treatment alone. The proportion of patients recommended chemotherapy decreased from 52% pretest to 25% post-test. Of patients originally recommended chemotherapy, 61% were recommended endocrine treatment alone after receiving the Recurrence Score result. For both pN0 and pN1mi patients, post-test recommendations appeared to follow the Recurrence Score result for low and high values. Physicians' confidence improved significantly. CONCLUSION: These are the first prospective data on the impact of the Oncotype DX assay on adjuvant treatment decisions in France. Using the assay was associated with a significant change in treatment decisions and an overall reduction in chemotherapy use. These data are consistent with those presented from European and non-European studies.

Analysis of overall survival from a phase III study of ixabepilone plus capecitabine versus capecitabine in patients with MBC resistant to anthracyclines and taxanes.

Limited proven treatment options exist for patients with metastatic breast cancer (MBC) resistant to anthracycline and taxane treatment. Ixabepilone, a novel semisynthetic analog of epothilone B, has demonstrated single-agent activity in MBC resistant to anthracyclines and taxanes. In combination with capecitabine in a phase III trial (CA163-046) in this setting, ixabepilone prolonged progression-free survival and increased objective response rate relative to capecitabine (Thomas et al. J Clin Oncol 25:5210-5217, 2007). Here, we report the results of overall survival (OS), a secondary efficacy endpoint from the CA163-046 trial. Seven hundred fifty-two patients with MBC resistant to anthracyclines and taxanes were randomized to ixabepilone (40 mg/m(2) intravenously on day 1 of a 21-day cycle) plus capecitabine (2,000 mg/m(2) orally on days 1 through 14 of a 21-day cycle) or capecitabine alone (2,500 mg/m(2) on the same schedule). Patients receiving ixabepilone plus capecitabine treatment had a median survival of 12.9 months compared to 11.1 months for patients receiving capecitabine alone (HR = 0.9; 95%CI: 077-1.05; P = 0.19). This observed increase in median OS favored the combination; however, the difference was not statistically significant. Predefined subset analyses showed a clinically meaningful increase in OS in KPS 70-80 patients receiving ixabepilone plus capecitabine (HR = 0.75; 95% CI: 0.58-0.98). Ixabepilone plus capecitabine did not show a significant improvement in survival compared to capecitabine alone in patients with MBC resistant to anthracyclines and taxanes. The observed differences in survival favored the combination arm. A clinical benefit was also seen in patients in the KPS 70-80 subgroup.

Activity of ixabepilone in oestrogen receptor-negative and oestrogen receptor-progesterone receptor-human epidermal growth factor receptor 2-negative metastatic breast cancer.

Oestrogen receptor (ER)-negative breast cancer, including oestrogen receptor-, progesterone receptor- and human epidermal growth factor receptor 2-negative (ER/PR/HER2-negative) breast cancer, is more aggressive than ER-positive disease. A major limitation in the treatment of ER-negative disease subtypes is the inherent insensitivity to hormonal agents (tamoxifen, aromatase inhibitors) that are widely used in the treatment of breast cancer. Thus, therapeutic options for poor prognosis patients with ER-negative breast cancer are limited to a handful of chemotherapeutic agents, and new agents are needed to improve the treatment of this disease. Ixabepilone, a novel epothilone B analogue with low susceptibility to cellular mechanisms that confer resistance to taxanes and other chemotherapeutic agents, has demonstrated potent preclinical antitumour activity in multiple models, including those with primary or acquired drug resistance. This review summarises the results of a prospective subset analysis from a phase III clinical trial evaluating ixabepilone for the treatment of metastatic breast cancer (MBC), in which efficacy and safety were evaluated in patients with ER-negative and ER/PR/HER2-negative disease.

Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment.

PURPOSE: Effective treatment options for patients with metastatic breast cancer resistant to anthracyclines and taxanes are limited. Ixabepilone has single-agent activity in these patients and has demonstrated synergy with capecitabine in this setting. This study was designed to compare ixabepilone plus capecitabine versus capecitabine alone in anthracycline-pretreated or -resistant and taxane-resistant locally advanced or metastatic breast cancer. PATIENTS AND METHODS: Seven hundred fifty-two patients were randomly assigned to ixabepilone 40 mg/m(2) intravenously on day 1 of a 21-day cycle plus capecitabine 2,000 mg/m(2) orally on days 1 through 14 of a 21-day cycle, or capecitabine alone 2,500 mg/m(2) on the same schedule, in this international phase III study. The primary end point was progression-free survival evaluated by blinded independent review. RESULTS: Ixabepilone plus capecitabine prolonged progression-free survival relative to capecitabine (median, 5.8 v 4.2 months), with a 25% reduction in the estimated risk of disease progression (hazard ratio, 0.75; 95% CI, 0.64 to 0.88; P = .0003). Objective response rate was also increased (35% v 14%; P < .0001). Grade 3/4 treatment-related sensory neuropathy (21% v 0%), fatigue (9% v 3%), and neutropenia (68% v 11%) were more frequent with combination therapy, as was the rate of death as a result of toxicity (3% v 1%, with patients with liver dysfunction [>/= grade 2 liver function tests] at greater risk). Capecitabine-related toxicities were similar for both treatment groups. CONCLUSION: Ixabepilone plus capecitabine demonstrates superior efficacy to capecitabine alone in patients with metastatic breast cancer pretreated or resistant to anthracyclines and resistant to taxanes.