Retreatment with trastuzumab-based therapy after disease progression following lapatinib in HER2-positive metastatic breast cancer.

BACKGROUND: Preclinical data suggest that treatment with lapatinib reinduces sensitivity to trastuzumab in human epidermal growth factor receptor 2(HER2)-positive breast cancer cells. PATIENTS AND METHODS: Between January 2007 and November 2010, 179 HER2-positive metastatic breast cancer patients were treated with lapatinib and capecitabine at nine Italian institutions. We evaluated the clinical outcome of 69 patients (38.5%) retreated with trastuzumab after lapatinib progression. RESULTS: Visceral metastases were identified in 51 (74%) and brain metastases in 16 patients (23%). All patients were pretreated with both trastuzumab- and lapatinib-based therapy. We observed with retreatment with trastuzumab-based therapy: 1 complete remission (2%), 18 partial remission (29%) and 10 stable disease ≥6 months (14%) and 47% of clinical benefit (CB). Median duration of response was 8.1 months [95% confidence interval (CI) 5.5-10.7]. No unexpected toxic effects occurred. At a median follow-up of 13 months, median progression-free survival was 4.9 months (95% CI 4.2-5.6) and overall survival (OS) 19.4 months (95% CI 14.0-25.0). Median OS was longer for patients experiencing CB (not reached versus 13.4 months for patients without CB, P = 0.002). Brain involvement was associated with lower median OS (17.3 versus 23.3 months for patients without brain disease; P = 0.021). CONCLUSION: Retreatment with trastuzumab-based therapy showed CB in 47% of patients progressing during lapatinib-based therapy, leading to a prolonged OS.

Clinical outcome of patients with brain metastases from HER2-positive breast cancer treated with lapatinib and capecitabine.

BACKGROUND: In the present study, we investigated the clinical outcome of patients with brain metastases (BMs) from human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) treated with lapatinib and capecitabine (LC). METHODS: Of 81 HER2+ metastatic BC patients treated with LC at two Italian institutions, 30 patients with BMs eligible for the analysis were identified. All patients were pretreated with trastuzumab for metastatic disease. No patients had received prior lapatinib and/or capecitabine. RESULTS: Median age was 45 years (range 24-75) and 26 of 30 patients (86.7%) had received prior cranial radiotherapy. In the 22 patients with BMs evaluable for response, 7 partial responses (31.8%) and 6 disease stabilizations (27.3%) were observed. Overall, the median brain-specific progression-free survival was 5.6 months (95% confidence interval 4.4-6.8). Patients treated with LC had a median overall survival (from the time of development of BMs) significantly longer compared with 23 patients treated with trastuzumab-based therapies only beyond brain progression (27.9 months versus 16.7 months, respectively, P = 0.01). CONCLUSIONS: LC is active for BMs from HER2+ BC in patients not pretreated with either lapatinib or capecitabine. The introduction of LC after the development of BMs may further improve survival compared with trastuzumab-based therapies only beyond brain progression.

Upfront pembrolizumab as an effective treatment start in patients with PD-L1 ≥ 50% non-oncogene addicted non-small cell lung cancer and asymptomatic brain metastases: an exploratory analysis.

INTRODUCTION: The efficacy of immune checkpoint inhibitors in patients with brain metastases (BMs) from non-oncogene addicted non-small cell lung cancer (NSCLC) is under investigation. Here, we sought to determine the optimal management of NSCLCs with PD-L1 ≥ 50% and asymptomatic BMs who were treated with first-line pembrolizumab. METHODS: Thirty patients from 15 institutions with PD-L1 ≥ 50% NSCLC had asymptomatic BMs, and met inclusion criteria. Patients were classified based on whether they had undergone upfront local radiotherapy for BMs as well as on the type of brain radiotherapy received. RESULTS: Nine patients were treated with upfront pembrolizumab alone, 8 patients with whole-brain radiotherapy (WBRT) followed by pembrolizumab and 13 patients with stereotactic radiosurgery (SRS) followed by pembrolizumab. Patients' characteristics were similar among the three groups of patients except for a higher number of BMs ≥ 3 in the WBRT group. One complete and 4 partial intracranial responses were observed with upfront pembrolizumab alone. The median survival was not reached for the pembrolizumab and WBRT (n = 8) groups, and it was 7.6 months for the SRS (n = 13) group (P = 0.09), with 12-month survival rates being 55.5%, 62.5%, and 23.0%, respectively. Salvage WBRT was delivered in 1 patient in the upfront pembrolizumab group and in 4 patients in the SRS group. CONCLUSIONS: Upfront pembrolizumab showed efficacy in selected patients with PD-L1 ≥ 50% non-oncogene addicted NSCLC and asymptomatic BMs. Prospective studies should address whether pembrolizumab alone, and deferral of radiotherapy, could be pursued in this patient population.

The lung immuno-oncology prognostic score (LIPS-3): a prognostic classification of patients receiving first-line pembrolizumab for PD-L1 ≥ 50% advanced non-small-cell lung cancer.

BACKGROUND: To stratify the prognosis of patients with programmed cell death-ligand 1 (PD-L1) ≥ 50% advanced non-small-cell lung cancer (aNSCLC) treated with first-line immunotherapy. METHODS: Baseline clinical prognostic factors, the neutrophil-to-lymphocyte ratio (NLR), PD-L1 tumour cell expression level, lactate dehydrogenase (LDH) and their combination were investigated by a retrospective analysis of 784 patients divided between statistically powered training (n = 201) and validation (n = 583) cohorts. Cut-offs were explored by receiver operating characteristic (ROC) curves and a risk model built with validated independent factors by multivariate analysis. RESULTS: NLR < 4 was a significant prognostic factor in both cohorts (P < 0.001). It represented 53% of patients in the validation cohort, with 1-year overall survival (OS) of 76.6% versus 44.8% with NLR > 4, in the validation series. The addition of PD-L1 ≥ 80% (21% of patients) or LDH < 252 U/l (25%) to NLR < 4 did not result in better 1-year OS (of 72.6% and 74.1%, respectively, in the validation cohort). Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 [P < 0.001, hazard ratio (HR) 2.04], pretreatment steroids (P < 0.001, HR 1.67) and NLR < 4 (P < 0.001, HR 2.29) resulted in independent prognostic factors. A risk model with these three factors, namely, the lung immuno-oncology prognostic score (LIPS)-3, accurately stratified three OS risk-validated categories of patients: favourable (0 risk factors, 40%, 1-year OS of 78.2% in the whole series), intermediate (1 or 2 risk factors, 54%, 1-year OS 53.8%) and poor (>2 risk factors, 5%, 1-year OS 10.7%) prognosis. CONCLUSIONS: We advocate the use of LIPS-3 as an easy-to-assess and inexpensive adjuvant prognostic tool for patients with PD-L1 ≥ 50% aNSCLC.

In situ protein expression of RRM1, ERCC1, and BRCA1 in metastatic breast cancer patients treated with gemcitabine-based chemotherapy.

Ribonucleotide reductase 1 (RRM1) is a determinant of gemcitabine efficacy in non-small-cell lung cancer and pancreatic cancer. We investigated the protein levels of RRM1 and two other DNA repair enzymes, ERCC1 and BRCA1, in 55 metastatic breast cancer (MBC) patients undergoing gemcitabine-based chemotherapy. With automated in situ protein quantification (AQUA v1.6), the average scores for RRM1, ERCC1, and BRCA1 ranged from 245.6-2774.1, 74.0-410.3, and 54.4-1833.1, respectively. They were significantly associated with each other (Spearman's rho > or = .36; p < or = .007). Given their pattern of distribution, RRM1 and BRCA1 are potentially suitable markers for clinical decision making in MBC.

Clinical significance of PTEN and p-Akt co-expression in HER2-positive metastatic breast cancer patients treated with trastuzumab-based therapies.

OBJECTIVE: The phosphatase and tensine homologue gene (PTEN) plays a crucial role in proliferation and survival of cancer cells by antagonizing the function of phosphatidylinositol 3'-kinase (PI3K), which, in turn, results in decreased Akt activity. We investigated the clinical impact of the expression of PTEN, p-Akt and PI3K in HER2-positive metastatic breast cancer (MBC) patients treated with trastuzumab-based therapies. METHODS: Seventy-three patients treated with trastuzumab-based therapies were included and followed prospectively. PTEN, p-Akt and PI3K expression was determined by immunohistochemistry. RESULTS: PTEN, p-Akt and PI3K resulted positive in 48%, 71% and 46.5% of patients, respectively. A significant correlation between PTEN and p-Akt (kappa 0.22, p = 0.03) and p-Akt and PI3K (kappa 0.20, p = 0.05) was observed. PTEN-positive patients had a progression-free survival (PFS) longer than PTEN-negative ones (p = 0.06). When grouped together, patients co-expressing PTEN and p-Akt had a statistically significant longer PFS as compared to the rest of patients (p = 0.01). At the multivariate analysis, PTEN and p-Akt co-expression was an independent predictor of lower risk of progression (hazard ratio 0.53, p = 0.05). CONCLUSION: In HER2-positive MBC, basal co-expression of PTEN and p-Akt might identify those patients who are more likely to benefit from trastuzumab-based therapies.

Clinical outcomes to pemetrexed-based versus non-pemetrexed-based platinum doublets in patients with KRAS-mutant advanced non-squamous non-small cell lung cancer.

PURPOSE: KRAS mutation has been associated with enhanced dependency on the folate metabolism in preclinical studies. However, whether KRAS mutation correlates to increased sensitivity to pemetrexed in patients with advanced NSCLC is unknown. METHODS: Patients with advanced non-squamous NSCLC who had a documented EGFR and ALK WT genotype with simultaneous KRAS mutation assessment were evaluated for clinical outcome to pemetrexed- and non-pemetrexed-based first-line platinum doublet according to KRAS mutation status. RESULTS: Of 356 patients identified, 138 harbored a KRAS mutation. Among KRAS-mutant NSCLCs, those treated with platinum/pemetrexed (81/138) had significantly lower ORR (30.9% versus 47.4%, P = 0.05), DCR (51.8% versus 71.9%, P = 0.02) and shorter median progression-free survival [mPFS 4.1 versus 7.1 months, HR 1.48 (95% CI 1.03-2.12), P = 0.03] and median overall survival [mOS 9.7 versus 26.9 months, HR 1.93 (95% CI 1.27-2.94), P = 0.002] compared to those who received a non-pemetrexed-based platinum doublet (57/138). No difference in ORR, DCR, mPFS and mOS was observed between KRAS WT patients who received a pemetrexed-based (124/218) versus non-pemetrexed base platinum doublets (94/218). After adjusting for performance status, age and the presence of brain metastasis at baseline, treatment with pemetrexed-based platinum doublet was associated with an increased risk of death [HR 2.27 (95% CI 1.12-4.63), P = 0.02] among KRAS-mutant patients in multivariate analysis. CONCLUSION: Patients with KRAS-mutant lung adenocarcinoma have a poorer outcome on pemetrexed-based first-line chemotherapy. Whether KRAS-mutant NSCLCs should be excluded from pemetrexed-containing regimens should be assessed prospectively.

Bone of the hands as unusual metastastatic site of renal cell carcinoma.

Metastases to the bones of the hands and feet (acrometastases) represent an uncommon site of recurrence of renal cell carcinoma (RCC). Although challenging, the prompt recognition of solitary acrometastasis from RCC is of crucial importance, since surgical resection of the acrometastasis in the absence of active systemic disease has been reported as beneficial for a subgroup of patients with RCC. Here, we report the case of a patient with RCC metastatic to the left index finger treated with surgical resection of the acrometastasis who shortly thereafter developed progressive disease despite such an aggressive surgical approach.

Inflammatory Markers as Prognostic Factors of Survival in Patients Affected by Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization.

INTRODUCTION: Transarterial chemoembolization (TACE) is a good choice for hepatocellular carcinoma (HCC) treatment when surgery and liver transplantation are not feasible. Few studies reported the value of prognostic factors influencing survival after chemoembolization. In this study, we evaluated whether preoperative inflammatory factors such as neutrophil to lymphocyte ratio and platelet to lymphocyte ratio affected our patient survival when affected by hepatocellular carcinoma. METHODS: We retrospectively evaluated a total of 72 patients with hepatocellular carcinoma that underwent TACE. We enrolled patients with different etiopathogeneses of hepatitis and histologically proven HCC not suitable for surgery. The overall study population was dichotomized in two groups according to the median NLR value and was analyzed also according to other prognostic factors. RESULTS: The global median overall survival (OS) was 28 months. The OS in patients with high NLR was statistically significantly shorter than that in patients with low NLR. The following pretreatment variables were significantly associated with the OS in univariate analyses: age, Child-Pugh score, BCLC stage, INR, and NLR. Pretreated high NLR was an independently unfavorable factor for OS. CONCLUSION: NLR could be considered a good prognostic factor of survival useful to stratify patients that could benefit from TACE treatment.

Development of gemcitabine in non-small cell lung cancer: the Italian contribution.

Gemcitabine, a pyrimidine nucleoside antimetabolite, is one of the most promising new cytotoxic agents. The drug has shown activity in a variety of solid tumors, but appears to be most active in the treatment of non-small cell lung cancer. In this disease, several Italian investigators have evaluated gemcitabine in phase II and III clinical trials. Due to preclinical synergism with cisplatin, the Italian Lung Cancer Project played an important role to assess the efficacy and activity of the gemcitabine-cisplatin combination along with the best doses and schedule to adopt, thus leading to gemcitabine approval for first line treatment of advanced non-small cell lung cancer. Several Italian studies have also investigated gemcitabine non-platinum based combinations, gemcitabine in third generation platinum-based triplets and gemcitabine as second line therapy, but all these studies led to conflicting and inconclusive results. The low toxicity profile makes the drug a valid option for unfit and elderly patients. The Multicenter Italian Lung Cancer in the Elderly Study was a phase III randomized trial conducted in elderly patients with advanced non-small cell lung cancer that showed that single agent gemcitabine is at least as effective as either single agent vinorelbine or the combination of gemcitabine and vinorelbine. In the neoadjuvant treatment of stage III disease, a number of phase II studies with third generation platinum-based doublets or triplets have been conducted by Italian investigators with encouraging results. Current clinical trials are addressing the role of gemcitabine in combination with new targeted therapies. Future studies should be designed in order to identify subgroups of patients who are more likely to benefit from gemcitabine chemotherapy.

Activity and safety of bevacizumab plus fotemustine for recurrent malignant gliomas.

BACKGROUND: No established chemotherapeutic regimen exists for the treatment of recurrent malignant gliomas (rMGs). Herein, we report the activity and safety results of the bevacizumab (B) plus fotemustine (FTM) combination for the treatment of rMGs. PATIENTS AND METHODS: An induction phase consisted of B 10 mg/kg days 1, 15 plus FTM 65 mg/m(2) days 1, 8, and 15. Nonprogressive patients entered the maintenance phase with B 10 mg/kg plus FTM 75 mg/m(2) every 3 weeks. The primary endpoint was response rate; secondary endpoints included safety, progression free survival (PFS), and overall survival (OS). RESULTS: Twenty-six patients affected by recurrent MGs (50% glioblastoma) were enrolled. Eight partial responses (31%) were observed. Median PFS and OS were 4 (95% C.I.: 2.8-5.1) and 6 months (95% C.I.: 4.2-7.8), respectively. Responses were significantly associated with both improved PFS and OS (P = 0.002 and P = 0.001, resp.). Treatment adverse events were mostly mild to moderate in intensity. Bevacizumab-related adverse events included grade 3 venous thromboembolic event (8%), grade 2 epistaxis (4%), hypertension (8%), and gastrointestinal perforation (4%). CONCLUSIONS: Bevacizumab plus FTM showed activity and good tolerability in pretreated MGs. Further investigations are needed in order to verify the benefits deriving from the addition of B to a cytotoxic in this clinical setting of patients.

New target therapies for brain metastases from breast cancer.

Central nervous system (CNS) metastases from breast cancer (BC) represent an important cause of disease-related morbidity and mortality. For BC patients who develop CNS metastases, local control measures (both surgery and radiation) are essentially palliative and usually poorly effective, with systemic therapies often failing to achieve optimal control mainly due to the presence of the blood-brain barrier which hampers adequate penetration of therapeutic agents into the brain. However, recent evidence suggests that the status of the human epidermal growth factor receptor-2 (HER2) strongly influences the incidence of CNS metastases and the survival of BC patients from the time of development of CNS metastases, with HER2-positive (HER2+) patients generally experiencing higher rates of CNS metastases and prolonged overall survival compared to patients with HER2-negative disease. This phenomenon likely reflects the difficult CNS drug-penetration and improved control of extra-CNS disease following the clinical use of the anti-HER2 monoclonal antibody trastuzumab. Importantly, this HER2-based survival difference has important implications when planning the optimal treatment of BC patients with CNS metastases. To date, although no systemic therapy has been specifically approved for the treatment of CNS metastases from BC, several targeted agents are being clinically developed for this purpose. In the present review we will discuss the targeted therapies that are under investigation for the treatment of CNS metastases from BC, highlighting the different implications based on whether a given agent is being developed to target CNS metastases from HER2+ or HER2-negative breast cancer.

Upfront pembrolizumab as an effective treatment start in patients with PD-L1 ≥ 50% non-oncogene addicted non-small cell lung cancer and asymptomatic brain metastases: an exploratory analysis

Introduction The efficacy of immune checkpoint inhibitors in patients with brain metastases (BMs) from non-oncogene addicted non-small cell lung cancer (NSCLC) is under investigation. Here, we sought to determine the optimal management of NSCLCs with PD-L1 ≥ 50% and asymptomatic BMs who were treated with first-line pembrolizumab. Methods Thirty patients from 15 institutions with PD-L1 ≥ 50% NSCLC had asymptomatic BMs, and met inclusion criteria. Patients were classified based on whether they had undergone upfront local radiotherapy for BMs as well as on the type of brain radiotherapy received. Results Nine patients were treated with upfront pembrolizumab alone, 8 patients with whole-brain radiotherapy (WBRT) followed by pembrolizumab and 13 patients with stereotactic radiosurgery (SRS) followed by pembrolizumab. Patients’ characteristics were similar among the three groups of patients except for a higher number of BMs ≥ 3 in the WBRT group. One complete and 4 partial intracranial responses were observed with upfront pembrolizumab alone. The median survival was not reached for the pembrolizumab and WBRT (n = 8) groups, and it was 7.6 months for the SRS (n = 13) group (P = 0.09), with 12-month survival rates being 55.5%, 62.5%, and 23.0%, respectively. Salvage WBRT was delivered in 1 patient in the upfront pembrolizumab group and in 4 patients in the SRS group. Conclusions Upfront pembrolizumab showed efficacy in selected patients with PD-L1 ≥ 50% non-oncogene addicted NSCLC and asymptomatic BMs. Prospective studies should address whether pembrolizumab alone, and deferral of radiotherapy, could be pursued in this patient population (AU)

Treatment of advanced non-small cell lung cancer.

In the last decade the treatment of advanced-metastatic non-small cell lung cancer has substantially improved. If in the early 90s there was still concern about the real efficacy of chemotherapy over best suppotive care alone in the advanced setting, constant developments in clinical research have demonstrated the survival advantage of active anti-cancer drugs not only in the first-line setting, but, lately, even in patients with recurrent disease after failure of two previous chemotherapy lines. With the premises of high throughput technologies, translational research is aiming to characterize patients and tumors on a molecular basis. With pharmacogenomics it would then be possible to accurately predict patient outcome and tailor the treatment strategy according to the geno-phenotype of single patients.

Insulin-like growth factor receptor 1 (IGFR-1) is significantly associated with longer survival in non-small-cell lung cancer patients treated with gefitinib.

BACKGROUND: The aim of the study was to assess whether loss of PTEN and expression of insulin-like growth factor receptor 1 (IGFR-1) could be responsible for intrinsic resistance to the tyrosine kinase inhibitor (TKI) gefitinib. PATIENTS AND METHODS: One hundred and twenty-four gefitinib-treated patients with advanced non-small-cell lung cancer (NSCLC) were analyzed for PTEN and IGFR-1 expression by immunohistochemistry. RESULTS: IGFR-1 was evaluated in 77 patients and resulted positive in 30 (39.0%). IGFR-1 expression was not significantly associated with clinical or biological characteristics. No difference in response to gefitinib treatment (16.7% versus 12.8%, P = 0.74) and time to progression (2.6 versus 3.06 months, P = 0.83) was observed between IGFR-1+ and IGFR-1-. Median survival was significantly longer in IGFR-1+ patients (17.8 versus 7.3 months, P = 0.013). PTEN expression was successfully evaluated in 93 cases. Loss of PTEN was detected in 19 tumors (20.4%) and was not associated with any clinical or biological characteristic. No difference in terms of response, time to progression and survival was observed between PTEN+ and PTEN- patients. In multivariable analysis IGFR-1 negative status was significantly associated with higher risk of death (hazard ratio 2.21, P = 0.012). CONCLUSIONS: IGFR-1 expression and loss of PTEN are not associated with intrinsic resistance to gefitinib. Clinical relevance of these two biomarkers as determinant for acquired resistance, and the prognostic role of IGFR-1 expression in patients not exposed to TKIs should be evaluated further.