Erhan Gokmen

Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

BACKGROUND Neratinib, an irreversible tyrosine-kinase inhibitor of HER1, HER2, and HER4, has clinical activity in patients with HER2-positive metastatic breast cancer. We aimed to investigate the efficacy and safety of 12 months of neratinib after trastuzumab-based adjuvant therapy in patients with early-stage HER2-positive breast cancer. METHODS We did this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 495 centres in Europe, Asia, Australia, New Zealand, and North and South America. Eligible women (aged ≥18 years, or ≥20 years in Japan) had stage 1-3 HER2-positive breast cancer and had completed neoadjuvant and adjuvant trastuzumab therapy up to 2 years before randomisation. Inclusion criteria were amended on Feb 25, 2010, to include patients with stage 2-3 HER2-positive breast cancer who had completed trastuzumab therapy up to 1 year previously. Patients were randomly assigned (1:1) to receive oral neratinib 240 mg per day or matching placebo. The randomisation sequence was generated with permuted blocks stratified by hormone receptor status (hormone receptor-positive [oestrogen or progesterone receptor-positive or both] vs hormone receptor-negative [oestrogen and progesterone receptor-negative]), nodal status (0, 1-3, or ≥4), and trastuzumab adjuvant regimen (sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system. Patients, investigators, and trial sponsors were masked to treatment allocation. The primary outcome was invasive disease-free survival, as defined in the original protocol, at 2 years after randomisation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00878709. FINDINGS Between July 9, 2009, and Oct 24, 2011, we randomly assigned 2840 women to receive neratinib (n=1420) or placebo (n=1420). Median follow-up time was 24 months (IQR 20-25) in the neratinib group and 24 months (22-25) in the placebo group. At 2 year follow-up, 70 invasive disease-free survival events had occurred in patients in the neratinib group versus 109 events in those in the placebo group (stratified hazard ratio 0·67, 95% CI 0·50-0·91; p=0·0091). The 2-year invasive disease-free survival rate was 93·9% (95% CI 92·4-95·2) in the neratinib group and 91·6% (90·0-93·0) in the placebo group. The most common grade 3-4 adverse events in patients in the neratinib group were diarrhoea (grade 3, n=561 [40%] and grade 4, n=1 [<1%] vs grade 3, n=23 [2%] in the placebo group), vomiting (grade 3, n=47 [3%] vs n=5 [<1%]), and nausea (grade 3, n=26 [2%] vs n=2 [<1%]). QT prolongation occurred in 49 (3%) patients given neratinib and 93 (7%) patients given placebo, and decreases in left ventricular ejection fraction (≥grade 2) in 19 (1%) and 15 (1%) patients, respectively. We recorded serious adverse events in 103 (7%) patients in the neratinib group and 85 (6%) patients in the placebo group. Seven (<1%) deaths (four patients in the neratinib group and three patients in the placebo group) unrelated to disease progression occurred after study drug discontinuation. The causes of death in the neratinib group were unknown (n=2), a second primary brain tumour (n=1), and acute myeloid leukaemia (n=1), and in the placebo group were a brain haemorrhage (n=1), myocardial infarction (n=1), and gastric cancer (n=1). None of the deaths were attributed to study treatment in either group. INTERPRETATION Neratinib for 12 months significantly improved 2-year invasive disease-free survival when given after chemotherapy and trastuzumab-based adjuvant therapy to women with HER2-positive breast cancer. Longer follow-up is needed to ensure that the improvement in breast cancer outcome is maintained. FUNDING Wyeth, Pfizer, Puma Biotechnology.

Risk factors for central nervous system metastasis in patients with metastatic breast cancer

AimsPatients with metastatic breast cancer (MBC) and central nervous system (CNS) involvement have an impaired survival and quality of life. In this study, we investigated the risk factors for CNS metastasis among patients with MBC.MethodsThe risk factors for development of CNS metastasis were analyzed in 154 patients with MBC. Expression of c-erbB-2, Ki-67, p53, and hormone receptors was examined by immunohistochemistry (IHC) in breast cancer tissue samples from the 154 patients. Kaplan-Meier and log-rank tests were used for the analysis of overall survival (OS). Chi-square test was used for univariate analysis.ResultsMedian OS was significantly poorer for patients with CNS metastasis as compared with patients with no CNS metastasis (OS, 23 mo vs 30 mo, respectively;p = 0.03). Ki-67 and p53 overexpressions by IHC, and lung metastasis as the first site of relapse, were associated with a higher risk of developing CNS metastasis in the univariate analysis (p ≤ 0.05). The presence of lung metastasis (odds ratio [OR]= 2.82, 95% confidence interval [CI]: 1.13-7.00,p = 0.02) and p53 overexpression (OR = 2.44, 95% CI: 0.99-6.00,p = 0.05) were the two predictive factors associated with occurrence of CNS metastasis in the multivariate analysis.ConclusionsIn this study, the presences of lung metastasis as the first site of relapse and p53 overexpression were predictive for the occurrence of CNS metastasis in patients with MBC. Life expectancy of patients with CNS metastasis is significantly shorter than those without CNS metastasis. These results may have clinical significance in counseling MBC patients with regard to their prognosis.

Bone health in breast cancer patients: A comprehensive statement by CECOG/SAKK Intergroup

Bone is the most common site of distant metastases in breast cancer that can cause severe and debilitating skeletal related events (SRE) including hypercalcemia of malignancy, pathologic fracture, spinal cord compression and the need for palliative radiation therapy or surgery to the bone. SRE are associated with substantial pain and morbidity leading to frequent hospitalization, impaired quality of life and poor prognosis. The past 25 years of research on the pathophysiology of bone metastases led to the development of highly effective treatment options to delay or prevent osseous metastases and SRE. Management of bone metastases has become an integral part of cancer treatment requiring expertise of multidisciplinary teams of medical and radiation oncologists, surgeons and radiologists in order to find an optimal treatment for each individual patient. A group of international breast cancer experts attended a Skeletal Care Academy Meeting in November 2012 in Istanbul and discussed current preventive measures and treatment options of SRE, which are summarized in this evidence-based consensus for qualified decision- making in clinical practice.

p53 protein accumulation and presence of visceral metastasis are independent prognostic factors for survival in patients with metastatic inflammatory breast carcinoma.

Objective: The aim of this study was to determine the markers of prognosis in metastatic inflammatory breast cancer (IBC). Subjects and Methods: The prognostic value of patients’ clinical characteristics and expression of c-erbB-2, p53, Ki-67, ER and PgR were assessed in the 45 patients with IBC who had developed distant metastasis. Immunohistochemical methods were used to detect the expression of c-erbB-2, p53, Ki-67, ER and PgR in surgical resection specimens of the patients’ primary tumor. Results: The median overall survival (OS) measured from the diagnosis of metastatic disease was 23 months. In the univariate analysis, p53 protein accumulation and the presence of visceral metastasis were predictive of poor survival (p = 0.01 and 0.003, respectively). In the multivariate analysis, accumulation of p53 protein and the presence of visceral metastasis correlated with OS (p = 0.02 and 0.008, respectively). Conclusion: In metastatic IBC, accumulation of p53 protein and presence of visceral metastasis are independent prognostic factors for OS. Established prognostic factors in non-IBC patients such as patient age, histologic grade, hormone receptor status and c-erbB-2 status did not have independent significance in IBC in this study.

Comparison of HER2 status determination methods in HER2 (2 +) patients: Manual fluorescent in situ hybridization (FISH) vs. dual silver enhanced in situ hybridization (SISH)

HER2 amplification has been demonstrated in 15-25% of invasive breast carcinomas and can be assessed using immunohistochemical and in situ hybridization methods. Here, we compared the accuracy of dual SISH to manual FISH in HER2 (2+) breast carcinoma and evaluated the feasibility of dual SISH method in routine practice. Sixty HER2 (2+) consecutive tumor samples diagnosed between January 2009 and February 2013 were selected. Demographic, histological and immunohistochemical features and FISH results were recruited from patient records and compared to dual SISH results. Nine (15%) of the 60 tumor samples were excluded from statistical analysis due to lack of interpretable SISH signals. HER2 staining percentages by immunohistochemistry differed between 20 and 80%. HER2 amplification was shown in 7 (13.7%) and 8 (15.7%) patients by FISH and SISH, respectively. Very good agreement was observed between FISH and SISH methods (kappa value: 0.92). Significant correlation was found between HER2 staining percentage and FISH positivity, in contrast to SISH positivity (p=0.012 vs. p=0.069). Our results are consistent with previously reported literature, indicating SISH can be used to determine HER2 status. However, preanalytical and analytical problems may cause inadequate or uncountable signals, making interpretation impossible for the pathologist and highlighting the importance of standardization and quality control programs.

Correlations Between Oncotype DX Recurrence Score and Classic Risk Factors in Early Breast Cancer: Results of A Prospective Multicenter Study in Turkey

OBJECTIVE Breast cancer is the most common malignancy among Turkish women and the rate of early stage disease is increasing. The Oncotype DX 21-gene assay is predictive of distant recurrence in ER-positive, HER2-negative early breast cancer. We aimed to evaluate the correlations between Recurrence Score (RS) and routine risk factors. MATERIALS AND METHODS Ten academic centers across Turkey participated in this prospective trial. Consecutive patients with breast cancer who had pT1-3, pN0-N1mic, ER-positive, and HER2-negative tumors were identified at tumor conferences. Both pre- and post-RS treatment decisions and physician perceptions were recorded on questionnaire forms. Correlations between RS and classic risk factors were evaluated using univariate and multivariate analyses. RESULTS Ten centers enrolled a total of 165 patients. The median tumor size was 2 cm. Of the 165 patients, 57% had low RS, 35% had intermediate RS, and 8% had high RS, respectively. Multivariate analysis indicated that progesterone receptor (PR) and Ki67 scores were significantly related to RS. CONCLUSION Oncotype DX Recurrence Score does not seem to have a significant correlation with the majority of classic risk factors, but it may have a correlation with PR score and Ki67 score.