Unfavorable prognostic role of tumor-infiltrating lymphocytes in hormone-receptor positive, HER2 negative metastatic breast cancer treated with metronomic chemotherapy

Abstract Background High levels of tumor-infiltrating lymphocytes (TILs) in primary triple negative and HER2-positive breast cancer (BC) have been associated with an improved patients' outcome. The role of TILs in Luminal (hormone receptor positive and HER2 negative) tumors remains to be elucidated. Moreover, the association between TILs and prognosis in the metastatic setting is still unknown. Patients and methods We evaluated the relationship between TILs and time to progression (TTP) in metastatic BC patients enrolled in a prospective phase II trial of metronomic chemotherapy, that used cyclophosphamide 50 mg daily, capecitabine 500 mg thrice daily and vinorelbine 40 mg orally three times a week (VEX combination). Results Of the 108 ER + BC patients enrolled in the VEX trial, 92 (85%) had sufficient tumor tissue and were assessed for TILs in H&E stained slides. TILs were evaluated in 38 primary BC samples and 54 metastatic sites. High (≥10%) TILs levels were significantly correlated with high Ki-67 labeling index. At multivariable analysis, each 10% increase in TILs strongly predicted a worse TTP (HR: 1.27, p = 0.008). VEX trial patients, categorized by a 3 tiers system (0–4%, 5–9% and >10% TILs) showed significantly different progression free survival curves (p = 0.011). Conclusions High TILs levels are significantly associated with a worse TTP in Luminal metastatic BC patients treated by metronomic chemotherapy. Our data confirm the reliability of TILs as a biomarker in the BC metastatic setting. The putative unfavorable prognostic role of TILs in Luminal BC patients might have clinical utility if validated by further studies

The TNM classification of breast cancer: need for change

n/

Continuing trastuzumab beyond disease progression: outcomes analysis in patients with metastatic breast cancer

INTRODUCTION: We performed a retrospective analysis of HER2-overexpressing metastatic breast cancer patients to describe clinical outcomes of those who, despite progression of the disease (PD), maintained trastuzumab for multiple chemotherapy lines. We also compared survival of these patients with that of those who halted trastuzumab at first PD. METHODS: We identified 101 patients treated between July 2000 and January 2007. Nineteen were still receiving the first-line trastuzumab-based treatment without evidence of PD and were not included in this analysis. Of the remaining 82 patients, 59 retained trastuzumab for one or more additional lines of chemotherapy after PD, according to our institution policy. Twenty-three patients who changed treating institution and stopped trastuzumab at first progression were used as a control group. RESULTS: For patients retaining trastuzumab, the median follow-up was 39.6 months. Clinical outcomes showed the typical degradation between first and second lines of therapy which we would expect by halting trastuzumab at first progression. Response rates were 35\% and 16\% and median times to progression were 7.25 and 5.25 months for the first and second lines of trastuzumab therapy, respectively. The median overall survival (OS) rates were 70 months for patients who retained trastuzumab and 56 months for patients who halted the drug (hazard ratio [HR] 0.87, 95\% confidence interval [CI] 0.51 to 1.18; P = 0.52). If we consider OS from the start of trastuzumab therapy, the figures are 53.9 and 34.8 months, respectively (HR 0.78, 95\% CI 0.58 to 1.32; P = 0.2). CONCLUSION: A nonstatistically significant trend of improved survival for patients retaining trastuzumab is observed. This is in line with most retrospective analyses and recent randomized data. Retaining trastuzumab after progression is a reasonable option, but further randomized data are warranted to better define its role in comparison with other available options.

neoadjuvant pegylated liposomal doxorubicin in combination with cisplatin and infusional fluoruracil ccf with and without endocrine therapy in locally advanced primary or recurrent breast cancer

Abstract Purpose To explore the activity of pegylated liposomal doxorubicin (PLD) as neoadjuvant therapy of breast cancer. Methods The combination of PLD with cisplatin and infusional fluorouracil (CCF) for 8 courses was investigated in patients with primary or recurrent T2-T4a-d N0-3 M0 breast cancer. Patients with ER and/or PgR ≥10% tumors also received letrozole (±triptorelin). Results Forty patients entered the study. Four patients had recurrent tumors and 13 had cT4d tumors. Overall, clinical response rate was 77.5% whereas a pathological complete response (pCR) was obtained in 3 patients (7.7%), 4 when considering bilateral tumors. Noticeably 3 pCR were observed among the 10 patients with T4d ER positive tumors (33%). Eleven patients discontinued treatment before completion of the 8 planned courses. Conclusions Our results indicated that CCF yielded an appreciable rate of clinical responses in a series of very locally advanced tumors and an unusually high rate of pCR in T4d ER positive tumors, suggesting an enhanced cutaneous activity of PLD

Pathological features and survival outcomes of very young patients with early breast cancer: How much is "very young"?

Abstract We collected information on 497 consecutive breast cancer patients aged less than 35 years operated at the European Institute of Oncology. The main aim of the study is to compare biological and clinical features dividing the population by age: Patients aged p = 0.79) and overall survival ( p = 0.99) between the three age groups. This latter findings was confirmed using age as a continuous variable assuming a linear association between age and the outcomes considered, too. In conclusion, our data indicate that the group of patients with breast cancer below 35 years is essentially a homogenous group when classical clinical and immunohistochemical features were considered

increased mean corpuscular volume of red blood cells predicts response to metronomic capecitabine and cyclophosphamide in combination with bevacizumab

Abstract Background There is an urgent need for the identification of commonly assessable predictive factors in the treatment of patients with metastatic breast cancer. Methods During the course of a treatment including low dose metronomic oral cyclophosphamide and capecitabine plus i.v. bevacizumab (plus erlotinib in one third of the patients) for metastatic breast cancer, we observed that a relevant number of patients developed repeatedly elevated levels of mean corpuscular volume (MCV) of red blood cells without a significant fall in hemoglobin levels. We conducted a retrospective analysis on these 69 patients to evaluate if the increase in MCV could be associated to tumor response. Results During the course of treatment 42 out of 69 patients (61%) developed macrocytosis. Using Cox proportional hazards modeling that incorporated macrocytosis (MCV≥100 fl) as a time-dependent covariate, macrocytosis resulted in a halved risk of disease progression (HR 0.45; 95% CI, 0.22–0.92, p-value 0.028). In a landmark analysis limited to patients with no sign of progression after 24 weeks of treatment, median time to progression was 72 weeks (48 weeks after landmark) in patients who had developed macrocytosis, and 43 weeks (19 weeks after landmark) in patients who had not (p = 0.023). Conclusion Macrocytosis inversely related to risk of disease progression in patients treated with metronomic capecitabine plus cyclophosphamide and bevacizumab for metastatic breast cancer. This finding may be explained through thymidylate synthase inhibition by capecitabine. Whether bevacizumab has a role in determining macrocytosis, similarly to what happens with sunitinib, has to be further investigated. If other studies will confirm our findings, macrocytosis might be used as an early marker of response during metronomic treatment with capecitabine and cyclophosphamide with or without bevacizumab

Acute toxicity and esterase response to carbaryl exposure in two different populations of amphipods Hyalella curvispina

During the last years, a carbaryl insecticide was extensively applied in the valley of Río Negro and Neuquén, North Patagonia Argentina, to manage codling moths (Cydia pomonella), the main pest of pear and apple trees. In this study carbaryl susceptibility and B-esterase activity from both insecticide-exposed and non-exposed field populations of amphipods Hyalella curvispina were studied. Two subpopulations, one susceptible to carbaryl (LC50 = 213 ± 7.5 μg/L carbaryl) and one resistant to it (LC50 = 14,663 ± 2379 μg/L carbaryl), were found in the agricultural area selected in this study. Both populations were, in turn, more resistant to carbaryl than the population from a pristine area (LC50 = 11.31 ± 2.27 μg/L carbaryl). The in vivo 48h-IC50 values for cholinesterase (ChE) were close to the corresponding 48h-LC50 values as determined for the non-exposed population (IC50 = 7.16 ± 0.86 μg/L carbaryl) and for the susceptible subpopulation from the insecticide-exposed site (IC50 = 193 ± 99 μg/L carbaryl). Carbaryl exposure of the amphipods from the agricultural area mentioned above produced a significant decrease of carboxylesterase (CabE) activity, at a sublethal concentration (10 μg/L) that was not able to significantly inhibit ChE, thereby showing a protective role of CabE and its usefulness as early biomarker. However, at lethal concentrations the inhibition of ChE activity was higher than that of CabE. On the other hand, CabE of amphipods from the pristine site was less sensitive to carbaryl than ChE, suggesting a different participation of CabE in ChE protection in the susceptible population of H. curvispina. Pulse exposure to carbaryl for 2 h caused a significant inhibition of ChE in amphipods from both populations, with a fast recovery as expected for a carbamate insecticide. In conclusion, we proved that amphipods from the said agricultural area have developed resistance to carbaryl and showed the presence of two subpopulations with a different response to the insecticide. Moreover, these results reinforce the use of ChE together with CabE inhibition as indicators of carbamate exposure in H. curvispina.Fil: Anguiano, Olga Liliana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Instituto de Investigación y Desarrollo en Ingeniería de Procesos, Biotecnología y Energías Alternativas. Universidad Nacional del Comahue. Instituto de Investigación y Desarrollo en Ingeniería de Procesos, Biotecnología y Energías Alternativas; Argentina. Universidad Nacional del Comahue. Facultad de Ingeniería; ArgentinaFil: Vacca, Melina. Universidad Nacional del Comahue. Facultad de Ciencias del Ambiente y la Salud; ArgentinaFil: Rodriguez Araujo, María Emilia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional del Comahue. Facultad de Ciencias del Ambiente y la Salud; ArgentinaFil: Montagna, Mónica. Universidad Nacional del Comahue. Facultad de Ciencias del Ambiente y la Salud; Argentina. Centro de Investigaciones en Toxicología Ambiental y Agrobiotecnología del Comahue; ArgentinaFil: Venturino, Andres. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Centro de Investigaciones en Toxicología Ambiental y Agrobiotecnología del Comahue; ArgentinaFil: Ferrari, Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Instituto de Investigación y Desarrollo en Ingeniería de Procesos, Biotecnología y Energías Alternativas. Universidad Nacional del Comahue. Instituto de Investigación y Desarrollo en Ingeniería de Procesos, Biotecnología y Energías Alternativas; Argentin