A prospective study on the neurological complications of breast cancer and its treatment: Updated analysis three years after cancer diagnosis

ObjectivesTo quantify the prevalence of neurological complications among breast cancer patients at one and three years after diagnosis, and to identify factors associated with neuropathic pain (NP) and chemotherapy-induced peripheral neuropathy (CIPN).Material and methodsProspective cohort study including 475 patients with newly diagnosed breast cancer, recruited among those proposed for surgical treatment (Portuguese Institute of Oncology, Porto). Patients underwent a neurological evaluation and had their cognitive function assesses with the Montreal Cognitive Assessment, before treatment and at one and three years after enrollment. We estimated the prevalence of each neurological complication, and odds ratios (OR), adjusted for socio-demographic and clinical characteristics, to identify factors associated with NP and CIPN.ResultsMore than half of the patients [54.7%, 95% confidence interval (95%CI): 50.2–59.2] presented at least one neurological complication, at one or at three years after cancer diagnosis. Between the first and the third year of follow-up, there was an increase in the prevalence of NP (from 21.1% to 23.6%), cognitive impairment (from 7.2% to 8.2%), cerebrovascular disease (from 0.6% to 1.5%) and brain metastasis (from 0.0% to 0.6%). The prevalence of CIPN decreased from 14.1% to 12.6%. Axillary lymph node dissection was associated with NP at one year (OR = 2.75, 95%CI: 1.34–5.63) and chemotherapy with NP at three years (OR = 2.10, 95%CI: 1.20–3.67). Taxane-based chemotherapy was strongly associated with prevalence of CIPN at one and three years.ConclusionNeurological complications are frequent even three years after cancer diagnosis and NP remained the major contributor to the burden of these conditions among survivors.     

Bilateral salpingectomy can reduce the risk of ovarian cancer in the general population: A meta-analysis

BackgroundThe results of recent studies have suggested that high-grade serous ovarian cancer predominantly arises within the fallopian tubes. The reduction of ovarian cancer (OC) risk in women with a history of bilateral salpingectomy (BS) has been reported. We performed a meta-analysis to determine the impact of BS in preventing OC in the general population.MethodsWe searched the PubMed, MEDLINE, and EMBASE databases and CENTRAL in the Cochrane Library for all English-language articles published up to January 2015, using the key words ‘ovarian cancer’ and ‘bilateral salpingectomy.’ Odds ratios (ORs) and their 95% confidence intervals (95% CIs) were calculated by standard meta-analysis techniques.ResultsOf the 77 studies retrieved, three were included in this meta-analysis, including one cohort study and two population-based case-control studies with 3509 patients who underwent BS and 5,655,702 controls who did not undergo salpingectomy. Over the combined study period, 29 of the 3509 BS patients developed OC compared with 44,006 of the 5,655,702 without salpingectomy. The meta-analysis results based on the fixed effects model revealed a significant decrease in the risk of OC occurrence in the patients who underwent BS relative to the controls (OR = 0.51, 95% CI 0.35–0.75, I² = 0%). This pattern was also observed in subgroup analysis for the study type.ConclusionsOur results suggest that removal of the fallopian tubes is an effective measure to reduce OC risk in the general population. Therefore, prophylactic bilateral salpingectomy should be considered for women who require hysterectomy with benign indications or sterilisation procedures.     

p53 Reactivation by PRIMA-1Met (APR-246) sensitises V600E/KBRAF melanoma to vemurafenib

Intrinsic and acquired resistance of metastatic melanoma to ^V600E/KBRAF and/or MEK inhibitors, which is often caused by activation of the PI3K/AKT survival pathway, represents a major clinical challenge. Given that p53 is capable of antagonising PI3K/AKT activation we hypothesised that pharmacological restoration of p53 activity may increase the sensitivity of BRAF-mutant melanoma to MAPK-targeted therapy and eventually delay and/or prevent acquisition of drug resistance. To test this possibility we exposed a panel of vemurafenib-sensitive and resistant (innate and acquired) ^V600E/KBRAF melanomas to a ^V600E/KBRAF inhibitor (vemurafenib) alone or in combination with a direct p53 activator (PRIMA-1^Met/APR-246). Strikingly, PRIMA-1^Met synergised with vemurafenib to induce apoptosis and suppress proliferation of ^V600E/KBRAF melanoma cells in vitro and to inhibit tumour growth in vivo. Importantly, this drug combination decreased the viability of both vemurafenib-sensitive and resistant melanoma cells irrespectively of the TP53 status. Notably, p53 reactivation was invariably accompanied by PI3K/AKT pathway inhibition, the activity of which was found as a dominant resistance mechanism to BRAF inhibition in our lines. From all various combinatorial modalities tested, targeting the MAPK and PI3K signalling pathways through p53 reactivation or not, the PRIMA-1^Met/vemurafenib combination was the most cytotoxic. We conclude that PRIMA-1^Met through its ability to directly reactivate p53 regardless of the mechanism causing its deactivation, and thereby dampen PI3K signalling, sensitises ^V600E/KBRAF-positive melanoma to BRAF inhibitors.