Metronomic chemotherapy preserves quality of life ensuring efficacy in elderly advanced non small cell lung cancer patients

Metastatic non small cell lung cancers (NSCLC) are diseases with poor prognosis and platinum-based doublet chemotherapy still remains their standard cure. Elderly patients often present comorbidities that limit the utilization of this chemotherapy; therefore these patients should have a first-line treatment with low toxicity and capable to preserve the quality of life (QoL) but, at the same time, to ensure the best possible response. Furthermore, a first-line treatment allows patients to be fit for further treatments, prolonging overall survival. At this regard, metronomic chemotherapy can be an optimal choice for elderly, able to improve QoL and to obtain an optimal palliation. We retrospectively studied a cohort of 41 elderly advanced NSCLC patients with different histotypes, treated with metronomic chemotherapy (weekly carbo-paclitaxel or vinorelbine as single agent) as first choice and we analyzed the tolerability, the impact on QoL and the efficacy of these schedules: no toxicity of 3 and 4 grade was observed, together to a clinical benefit of 43%. We administered FACT-L test to evaluate QoL at baseline and after 4 months and found a significant improvement in all FACT-L parameters: physical, social, emotional and functional, confirming a QoL improvement. At a median follow-up of 20.2 months the progression free survival was of 6 months and the overall survival was of 15 months. These results suggest that metronomic chemotherapy can be an effective choice of treatment for elderly NSCLC patients and further trials with more patients are needed to confirm this proposal

Circulating neuregulin-1 and galectin-3 can be prognostic markers in breast cancer

Background: It is important to identify novel plasmatic biomarkers that can contribute to assessing the prognosis and outcome of breast cancer patients. Neuregulin-1 (NRG1) and galectin-3 (Gal-3) are proteins that are involved in breast cancer development and patient survival; therefore, we studied whether the serum concentration of these 2 proteins can be correlated to breast cancer progression. Methods: Plasmatic NRG1 and Gal-3 were evaluated in 25 healthy controls and 50 breast cancer patients at baseline and at 3 and 6 months after treatment with anthracyclines and taxanes, with or without trastuzumab. Results: NRG1 and Gal-3 were significantly more elevated in cancer patients than in healthy controls; further- more, NRG1 and Gal-3 were significantly increased after chemotherapy and were predictive of mortality at 1 year. Conclusions: Circulating NRG1 and Gal-3 can be additional biomarkers indicative of prognosis and outcomes for breast cancer patients

Synchronous primary papillary breast cancer, medullary thyroid carcinoma and neuroendocrine tumor in postmenopausal woman.

Multiple endocrine neoplasia are syndromes involving two or more endocrine tissues, often correlated to RET proto-oncogene mutations. We herein present the first reported case of a 57-years-old woman with three synchronous primary cancers of breast (papillary), thyroid (medullary) and pancreas (neuroendocrine), the latter with liver metastasis. The patient first underwent surgery for papillary breast cancer with axillary lymph nodes metastases. A staging whole body computerized tomography (CT) showed a right lateral cervical lymph node, pancreatic inhomogeneity, peri-pancreatic nodes and a single liver metastasis. The poor response to an antracycline and taxane-based chemotherapy, the good performance status of patient, and associated symptoms, suggested a different origin for pancreatic and hepatic lesions. A careful re-evaluation of clinical history, an octreotide-labeled scan and an immunohistochemical analysis, on both hepatic and pancreatic tissues and on laterocervical lymph node, determined the diagnosis of synchronous papillary breast cancer, pancreatic neuroendocrine tumor (pNET) with liver metastasis and an occult medullary thyroid carcinoma in a patient who had proto-oncogene RET wild type

The kinesin Eg5 inhibitor K858 induces apoptosis but also survivin-related chemoresistance in breast cancer cells

Inhibitors of kinesin spindle protein Eg5 are characterized by pronounced antitumor activity. Our group has recently synthesized and screened a library of 1,3,4-thiadiazoline analogues with the pharmacophoric structure of K858, an Eg5 inhibitor. We herein report the effects of K858 on four different breast cancer cell lines: MCF7 (luminal A), BT474 (luminal B), SKBR3 (HER2 like) and MDA-MB231 (basal like). We demonstrated that K858 displayed anti-proliferative activity on every analyzed breast cancer cell line by inducing apoptosis. However, at the same time, we showed that K858 up-regulated survivin, an anti-apoptotic molecule. We then performed a negative regulation of survivin expression, with the utilization of wortmannin, an AKT inhibitor, and obtained a significant increase of K858-dependent apoptosis. These data demonstrate that K858 is a potent inhibitor of replication and induces apoptosis in breast tumor cells, independently from the tumor phenotype. This anti-proliferative response of tumor cells to K858 can be limited by the contemporaneous over-expression of survivin; consequently, the reduction of survivin levels, obtained with AKT inhibitors, can sensitize tumor cells to K858-induced apoptosis

Are we ready to change clinical practice after the 'soft and text' results?

Luminal breast cancer is the most common subtype among molecular subgroups of breast cancer identified by gene profiling, and it accounts for more than half of all breast cancer cases around the world [1]. These cancers are characterized by hormonal receptors and low proliferative activity; in particular Luminal A (high rate of estrogen and progesterone receptors, low proliferative index, low grading) is the breast cancer type with the best prognosis, while Luminal B can be further subclassified into two phenotypes, depending of the expression of HER2 (Luminal B HER2 positive or Luminal B HER2 negative). Luminal B is characterized by low rate of estrogen and progesterone receptors and high proliferative index. The breast cancer incidence has increased in the last years, especially among younger women. The treatment of premenopausal women involves all the problems correlated to fertility preservation, an important issue for every woman affected by cancer [2]. The gold standard treatment for premenopausal women with hormone receptors positive early breast cancer is tamoxifen for 5 years, with or without ovarian suppression, which has demonstrated a significant effect on overall survival and in the reduction of relapses [3]. However, the association of ovarian suppression with aromatase inhibitors has emerged as a valid alternative in the adjuvant setting for premenopausal patients. The Phase III Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT) trials conducted by the International Breast Cancer Study Group (IBCSG) in collaboration with the Breast International Group (BIG) and the North American Breast Cancer Group (NABCG), involved 4690 patients in 27 countries across 6 continents [4]. These researches demonstrated, for the first time, the superiority of exemestane in combination with the gonadotropin-releasing hormone analogue (GnRH-A) triptorelin, over tamoxifen plus ovarian suppression in the prevention of recurrence in young premenopausal women with hormone-sensitive early-stage breast cancer [4]. Exemestane and triptorelin treatment determined a decrease of 28% in the relative risk of developing a recurrence, with a disease-free survival at 5 years of 91.1%, compared with 87.3% in the tamoxifen group [4]. Despite the significant improvement in disease-free survival (DFS), an improvement in overall survival (OS) has not been demonstrated in the exemestane arm at a median follow-up of 5.7 years (68 months). The BIG1.98, ATAC and IES trials had previously confirmed the efficacy of aromatase inhibitors compared with tamoxifen in the adjuvant treatment of postmenopausal women in terms of risk of recurrence (range 15-25%) and distant metastases (around 27%) [5-7] and increased DFS, although no significant change in the OS and a small increase in cardiovascular risk were evidenced [5]

Are pharmacogenomic biomarkers an effective tool to predict taxane toxicity and outcome in breast cancer patients? Literature review

Purpose Breast cancer is a heterogeneous disease, char- acterized by various molecular phenotypes that correlate with different prognosis and response to treatments. Taxa- nes are some of the most active chemotherapeutic agents for breast cancer; however, their utilization is limited, due to hematologic and cumulative neurotoxicity on treated patients. To understand why only some patients experi- ence severe adverse effects and why patients respond and develop resistance with different rates to taxane therapy, the metabolic pathways of these drugs should be completely unraveled. The variant forms of several genes, related to taxane pharmacokinetics, can be indicative markers of clin- ical parameters, such as toxicity or outcome. Methods The search of the data has been conducted through PubMed database, presenting clinical data, clinical trials and basic research restricted to English language until June 2015. Results We studied the literature in order to find any pos- sible association between the major pharmacogenomic variants and specific taxane-related toxicity and patient outcome. We found that the data of these studies are * Susanna Scarpa [email protected] Francesca De Iuliis [email protected] Gerardo Salerno [email protected] Ludovica Taglieri [email protected] 1 Experimental Medicine Department, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy sometimes discordant, due to both the small number of enrolled patients and the heterogeneity of the examined population. Conclusions Among all analyzed genes, only CYP1B1 and ABCB1 resulted the strongest candidates to become biomarkers of clinical response to taxane therapy in breast cancer, although their utilization still remains an experi- mental procedure. In the future, greater studies on genetic polymorphisms should be performed in order to identify differentiating signatures for patients with higher toxic- ity and with resistant or responsive outcome, before the administration of taxanes

Taxane induced neuropathy in patients affected by breast cancer: literature review

Taxane induced neuropathy (TIN) is the most limiting side effect of taxane based chemotherapy, relative to the majority of breast cancer patients undergoing therapy with both docetaxel and paclitaxel. The symptoms begin symmetrically from the toes, because the tips of the longest nerves are affected for first. The patients report sensory symptoms such as paresthesia, dysesthesia, numbness, electric shock-like sensation, motor impairment and neuropathic pain. There is a great inter-individual variability among breast cancer women treated with taxanes, in fact 20-30% of them don't develop neurotoxicity. Actually, there is no standard therapy for TIN, although many medications, antioxidants and natural substances have been tested in vitro and in vivo. We will summarize all most recent literature data on TIN prevention and treatment, in order to reach an improvement in TIN management. Further studies are needed to evaluate new therapies that restore neuronal function and improve life quality of patients

On and off metronomic oral vinorelbine in elderly women with advanced breast cancer

background: Elderly patients with metastatic breast cancer (MBC) have more problems receiving chemotherapy than younger patients, especially with the presence of multiple comorbidities, adverse drug events and function- al decline. Low-dose oral administration of cytotoxic agents such as vinorelbine, a semisynthetic vinca alkaloid that interferes with microtubule assembly, leading to arrest of cell division, is usually effective and well tolerated. Methods: From February 2010 to February 2014, 32 patients with MBC, median age 76 years (range 69-83) were treated with oral vinorelbine 30 mg (total dose), one day on and one day off, until disease progression or unac- ceptable toxicity levels were reported. Toxicity, quality of life and clinical benefit were evaluated. Matched t-tests were conducted to discern whether quality-of-life indicator (p<0.05 was considered significant) differed before and 6 months after treatment. Statistical analysis was performed using Graph Pad Prism 5.0 (GraphPad Software Inc., San Diego, CA, USA). Results: No grade 3 and 4 adverse events were reported. A clinical benefit of 50% was found in our cohort. On and off metronomic vinorelbine oral administration resulted in good tolerability and safe profile in our selected elderly population, and improved patient adherence to therapy. conclusions: The present study demonstrated that metronomic vinorelbine might be a potential treatment in elderly patients by reducing adverse effects and increasing quality of life, setting the stage for future extensive clinical trials