Trastuzumab in Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer: Results of a Prospective, Noninterventional Study on Routine Treatment Between 2006 and 2012 in Germany.

PURPOSE: Trastuzumab is part of the standard treatment in patients with human epidermal growth factor receptor 2-positive early breast cancer in addition to (neo)adjuvant chemotherapy. This German prospective noninterventional study, which included major patient cohorts underrepresented in the pivotal randomized studies, examined the generalizability of the results of those studies. PATIENTS AND METHODS: Between 2006 and 2012, 4,027 patients were enrolled and treated with trastuzumab; they were unselected regarding age or concomitant/sequential adjuvant chemotherapy. Long-term outcome data were obtained in yearly intervals. All analyses were descriptive in nature. RESULTS: Among 3,940 evaluable patients, 26% were elderly (older than 65 years of age). More than half of the population had pN0 tumor stage. Ninety-four percent received chemotherapy: 78% as adjuvant treatment and 14% as neoadjuvant treatment, 2% both. Anthracyclines were administered in 87% and taxanes in 66%. Trastuzumab was stopped prematurely in 9% (because of cardiotoxicity in 3.5%). Recurrence-free survival was 90.0% (95% confidence interval [CI], 88.9%-91.1%) and 82.8% (95% CI, 81.2%-84.4%) after 3 and 5 years, respectively. The corresponding figures for overall survival were 96.8% (95% CI, 96.1%-97.6%) and 90.0% (95% CI, 88.6%-91.4%). Pathological primary tumor size, lymph node involvement, and hormone receptor status had the greatest independent effect on recurrence risk. Cardiac function toxicity of National Cancer Institute common toxicity criteria grade ≥2 and ≥3 was observed in 2.5% and less than 1% of patients, respectively. CONCLUSION: The maturing follow-up data seem to confirm the beneficial results of trastuzumab treatment for early breast cancer from the randomized studies. Moreover, these findings support use of trastuzumab-based therapy in patients groups less commonly included in the phase III trials (e.g., elderly patients and those with stage I disease). The Oncologist 2017;22:131-138Implications for Practice: On the basis of the results of large pivotal phase III studies, the inclusion of trastuzumab in adjuvant treatment regimens for human epidermal growth factor receptor 2-positive breast cancer is standard of care. However, in these trials, elderly patients, those with comorbidities, and/or those with contraindications or refusal of cytotoxic chemotherapy are typically underrepresented. This study provides data on observed treatment options, outcomes, and risks in a wider, unselected patient population (including more than 1,000 patients with stage I disease), treated routinely in several institutions of varying size and location across Germany.

Primary metastatic breast cancer in the era of targeted therapy - Prognostic impact and the role of breast tumour surgery.

BACKGROUND: Except for meeting the individual palliative need, the benefit of breast surgery in primary metastatic breast cancer (PMBC), also known as de novo metastatic breast cancer, on long-term outcomes remains controversial. Twenty-four hundred and one patients with metastatic breast cancer, enrolled between 2000 and 2011 in two prospective non-interventional studies on targeted therapy, were screened with respect to this question. METHODS: One study investigated trastuzumab therapy for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer in addition to mainly first-line chemotherapy. The other observed bevacizumab added to chemotherapy as first-line treatment for mostly HER2-negative disease. RESULTS: Five-hundred and seventy (24%) patients presented with PMBC, and valid information on resection of the primary tumour was available for 568 women. Out of these, 426 (75%) underwent local resection. The latter group was characterised by less overall metastatic burden and a lower proportion of T4 tumours. No major differences were observed with respect to age, hormone receptor and HER2 status, visceral disease and performance status. Numerically, the surgery group showed a slightly favourable progression-free survival (PFS, medians: 13.6 versus 11.8 months; P = 0.18) and overall survival (OS, 34.1 versus 31.7; P = 0.23). However, in multivariable analysis, including all other univariably significant parameters, no trend for better outcome after surgery remained detectable, neither for PFS (hazard ratio 0.99; P = 0.92) nor for OS (0.95; P = 0.71). CONCLUSIONS: Our findings suggest no major survival benefit for local resection in the overall PMBC population treated with modern targeted therapies. However, further analyses are warranted to define specific risk groups, which may benefit from surgical removal of the primary.

Early molecular changes in Alzheimer disease: can we catch the disease in its presymptomatic phase?

Alzheimer disease (AD) is the most common form of dementia and characterized by deposition of amyloid-ß (Aß) plaques, neurofibrillary tangles consisting of hyperphosphorylated tau, atrophy, and progressive neurodegeneration. While the familial, early onset form of AD is known to be caused by specific mutations in genes encoding presenilin 1, presenilin 2, or amyloid-ß protein precursor, the underlying mechanisms leading to the development of sporadic AD are still not known. The major risk factors are, however, aging and APOE ε4. Here we review the latest evidence for the involvement of malfunctioning insulin signaling, dysfunction of mitochondria-associated membranes, cerebrovascular changes, increased oxidative stress and free radical formation, DNA damage, disturbed energy metabolism, and synaptic dysfunction in early stages of AD. We focus on whether the changes in these processes precede or succeed the earliest symptoms in AD patients, i.e., minimal cognitive impairment. Since changes in Aß processing are probably a key event in AD we also highlight the relationship of the above mentioned processes with the formation, secretion, aggregation, and toxicity of Aß. Based on our literature findings we propose a model in which insulin dysfunction, pathological cerebrovascular changes, dysfunction of mitochondria-associated membranes, and/or synaptic changes are likely to interact with each other, thereby initiating and facilitating the development of AD pathology by accelerating the production and deposition of Aß. Increased oxidative stress and free radical formation, DNA damage, disturbed energy metabolism, and synaptic loss follow these events, but still occur very early in AD.

Prevention of age-related changes in hippocampal levels of 5-methylcytidine by caloric restriction.

Aberrant DNA methylation patterns have been linked to molecular and cellular alterations in the aging brain. Caloric restriction (CR) and upregulation of antioxidants have been proposed as interventions to prevent or delay age-related brain pathology. Previously, we have shown in large cohorts of aging mice, that age-related increases in DNA methyltransferase 3a (Dnmt3a) immunoreactivity in the mouse hippocampus were attenuated by CR, but not by overexpression of superoxide dismutase 1 (SOD1). Here, we investigated age-related alterations of 5-methylcytidine (5-mC), a marker of DNA methylation levels, in a hippocampal subregion-specific manner. Examination of 5-mC immunoreactivity in 12- and 24-month-old wild type (WT) mice on control diet, mice overexpressing SOD1 on control diet, wild type mice on CR, and SOD1 mice on CR, indicated an age-related increase in 5-mC immunoreactivity in the hippocampal dentate gyrus, CA3, and CA1-2 regions, which was prevented by CR but not by SOD1 overexpression. Moreover, positive correlations between 5-mC and Dnmt3a immunoreactivity were observed in the CA3 and CA1-2. These findings suggest a crucial role for DNA methylation in hippocampal aging and in the mediation of the beneficial effects of CR on aging.

Age-related increase in levels of 5-hydroxymethylcytosine in mouse hippocampus is prevented by caloric restriction.

Aberrations in epigenetic marks have been associated with aging of the brain while caloric restriction (CR) and upregulation of endogenous antioxidants have been suggested as tools to attenuate the aging process. We have recently observed age-related increases in levels of 5-methylcytidine (5-mC) and DNA methyltransferase 3a (Dnmt3a) in the mouse hippocampus. Most of those age-related changes in these epigenetically relevant markers were prevented by CR but not by transgenic overexpression of the endogenous antioxidant superoxide dismutase 1 (SOD1). As recent work has suggested a distinct role for hydroxymethylation in epigenetic regulation of gene expression in the brain, the current study investigated age-related changes of 5-hydroxymethylcytosine (5-hmC) in the mouse hippocampus, and furthermore tested whether CR and transgenic upregulation of SOD1 affected any age-related changes in 5-hmC. Immunohistochemical analyses of 5-hmC in 12- and 24-month-old wild-type and transgenic mice overexpressing SOD1, which were kept under either a control or a calorie restricted diet, revealed an increase of 5-hmC immunoreactivity occurring with aging in the hippocampal dentate gyrus, CA3 and CA1-2 regions. Moreover, CR, but not overexpression of SOD1, prevented the age-related increase in the CA3 region. These findings indicate that the aging process in mice is connected with changes in epigenetic machinery in the hippocampus and suggest that CR acts by influencing epigenetic regulation.