Bisphosphonates (BP) prevent, reduce, and delay cancer-related skeletal complications in patients, and have substantially decreased the prevalence of such events since their introduction. Today, a broad range of BP with differences in potency, efficacy, dosing, and administration as well as approved indications is available. In addition, results of clinical trials investigating the efficacy of BP in cancer treatment-induced bone loss (CTIBL) have been recently published. The purpose of this paper is to review the current evidence on the use of BP in solid tumours and provide clinical recommendations. An interdisciplinary expert panel of clinical oncologists and of specialists in metabolic bone diseases assessed the widespread evidence and information on the efficacy of BP in the metastatic and nonmetastatic setting, as well as ongoing research on the adjuvant use of BP. Based on available evidence, the panel recommends amino-bisphosphonates for patients with metastatic bone disease from breast cancer and zoledronic acid for patients with other solid tumours as primary disease. Dosing of BP should follow approved indications with adjustments if necessary. While i.v. administration is most often preferable, oral administration (clodronate, IBA) may be considered for breast cancer patients who cannot or do not need to attend regular hospital care. Early-stage cancer patients at risk of developing CTIBL should be considered for preventative BP treatment. The strongest evidence in this setting is now available for ZOL. Overall, BP are well-tolerated, and most common adverse events are influenza-like syndrome, arthralgia, and when used orally, gastrointestinal symptoms. The dose of BP may need to be adapted to renal function and initial creatinine clearance calculation is mandatory according to the panel for use of any BP. Subsequent monitoring is recommended for ZOL and PAM, as described by the regulatory authority guidelines. Patients scheduled to receive BP (mainly every 3–4 weeks i.v.) should have a dental examination and be advised on appropriate measures for reducing the risk of jaw osteonecrosis. BP are well established as supportive therapy to reduce the frequency and severity of skeletal complications in patients with bone metastases from different cancers.

Fatty acid synthase (FAS) activity is a potential therapeutic target to treat cancer and obesity. Here, we have identified a molecular link between FAS andHER2(erbB-2) oncogene, a marker for poor prognosis that is overexpressed in 30% of breast and ovarian cancers. Pharmacological FAS inhibitors cerulenin and C75 were found to suppress p185^HER2oncoprotein expression and tyrosine-kinase activity in breast and ovarianHER2overexpressors. Similarly, p185^HER2expression was dramatically down-regulated when FAS gene expression was silenced by using the highly sequence-specific mechanism of RNA interference (RNAi). Pharmacological and RNAi-mediated silencing of FAS specifically down-regulatedHER2mRNA and, concomitantly, caused a prominent up-regulation of PEA3, a transcriptional repressor ofHER2. A cytoplasmic redistribution of p185^HER2was associated with marked morphological changes of FAS RNAi-transfected cells, whereas chemical inhibitors of FAS promoted a striking nuclear accumulation of p185^HER2. The simultaneous targeting of FAS andHER2by chemical FAS inhibitors and the humanized antibody directed against p185^HER2trastuzumab, respectively, was synergistically cytotoxic towardHER2overexpressors. Similarly, concurrent RNAi-mediated silencing of FAS andHER2genes synergistically stimulated apoptotic cell death inHER2overexpressors. p185^HER2was synergistically down-regulated after simultaneous inhibition of FAS andHER2by either pharmacological inhibitors or small interfering RNA. These findings provide evidence of an active role of FAS in cancer evolution by specifically regulating oncogenic proteins closely related to malignant transformation, strongly suggesting thatHER2oncogene may act as the key molecular sensor of energy imbalance after the perturbation of tumor-associated FAS hyperactivity in cancer cells.

Median survival of patients with brain metastases from nonsmall cell lung cancer (NSCLC) is poor and more effective treatments are urgently needed. We have evaluated the efficacy of erlotinib in this setting and its association with activating mutations in the epidermal growth factor receptor (EGFR) gene.We retrospectively identified patients with NSCLC and brain metastases treated with erlotinib.EGFRmutations in exons 19 and 21 were analysed by direct sequencing. Efficacy and tolerability were compared according toEGFRmutational status.69 NSCLC patients with brain metastases were identified, 17 of whom harbouredEGFRmutations. Objective response rate in patients withEGFRmutations was 82.4%; no responses were observed in unselected patients (p<0.001). Median (95% CI) time to progression within the brain for patients harbouringEGFRmutations was 11.7 (7.9–15.5) months, compared to 5.8 (5.2–6.4) months for control patients whoseEGFRmutational status had not been assessed (p<0.05). Overall survival was 12.9 (6.2–19.7) months and 3.1 (2.5–3.9) months (p<0.001), respectively. The toxicity of erlotinib was as expected and no differences between cohorts were observed.Erlotinib is active in brain metastases from NSCLC; this clinical benefit is related to the presence of activating mutations in exons 19 or 21 of theEGFRgene.

Over the past 15 years, therapies directed against human epidermal growth factor receptor 2 (ERBB2 [formerly HER2 or HER2/neu]) have improved overall survival in patients with early-stage^1,2 and metastatic ERBB2-positive breast cancers.^3,4 However, patients with stage IV disease still die on average 2 to 5 years after relapse.^4-6 Metastatic ERBB2-positive breast cancer has a characteristic pattern of spread, with over 75% of patients developing liver metastases,⁷ and approximately half with poor–prognosis central nervous system (CNS) involvement.⁸ Recent studies suggest that small-molecule ERBB2 kinase inhibitors may be effective in patients with ERBB2-positive metastatic breast cancer and CNS metastases.^9,10

The erb B2 oncogene encodes a 185-kilodalton transmembrane protein whose sequence is similar to the epidermal growth factor receptor (EGFR). A 30-kilodalton factor (gp30) secreted from MDA-MB-231 human breast cancer cells was shown to be a ligand for p185 ^{erb B2} . An antibody to EGFR abolished the tyrosine phosphorylation induced by EGF and transforming growth factor-α (TGF-α) but only partially blocked that produced by gp30 in SK-BR-3 breast cancer cells. In two cell lines that overexpress erb B2 but do not express EGFR (MDA-MB-453 breast cancer cells and a Chinese hamster ovary cell line that had been transfected with erb B2), phosphorylation of p185 ^{erb B2} was induced only by gp30. The gp30 specifically inhibited the growth of cells that overexpressed p185 ^{erb B2} . An antibody to EGFR had no effect on the inhibition of SK-BR-3 cell colony formation obtained with gp30. Thus, it appeared that gp30 interacted directly with the EGFR and erb B2. Direct binding of gp30 to p185 ^{erb B2} was confirmed by binding competition experiments, where gp30 was found to displace the p185 ^{erb B2} binding of a specific antibody to p185 ^{erb B2} . The evidence described here suggests that gp30 is a ligand for p185 ^{erb B2} .