A Real-World Application of Liquid Biopsy in Metastatic Colorectal Cancer: The Poseidon Study.

BACKGROUND: First-line decision making is the key to the successful care of mCRC patients and RAS/BRAF status is crucial to select the best targeted agent. In hub centers, a relevant proportion of patients referred from small volume centers may not have standard tissue-based (STB) molecular results available at the time of the first visit (T0). Liquid biopsy (LB) may help circumvent these hurdles. METHODS: A monoinstitutional prospective head-to-head comparison of LB versus (vs.) STB testing was performed in a real-world setting. Selection criteria included: mCRC diagnosis with unknown RAS/BRAF status at T0, tumoral tissue archived in external centers, no previous treatment with anti-EGFR. At T0, patients underwent plasma sampling for LB testing and procedure for tissue recovery. RAS/BRAF genotyping was carried out by droplet digital PCR on circulating-tumoral (ct) DNA. The primary endpoint was the comparison of time to LB (T1) vs. STB (T2) results using the Mann-Whitney U test. Secondary endpoints were the concordance between LB and STB defined as overall percent agreement and the accuracy of LB in terms of specificity, sensitivity, positive and negative predictive value. We also performed an exploratory analysis on urinary (u) ctDNA. RESULTS: A total of 33 mCRC patients were included. Mean T1 and T2 was 7 and 22 days (d), respectively (p < 0.00001). T2 included a mean time for archival tissue recovery of 17 d. The overall percent agreement between LB and STB analysis was 83%. Compared to STB testing, LB specificity and sensitivity were 90% and 80%, respectively, with a positive predictive value of 94% and negative one of 69%. In detail, at STB and LB testing, RAS mutation was found in 45% and 42% of patients, respectively; BRAF mutation in 15%. LB results included one false positive and four false negative. False negative cases showed a significantly lower tumor burden at basal CT scan. Concordance between STB and uctDNA testing was 89%. CONCLUSIONS: Faster turnaround time, high concordance and accuracy are three key points supporting the adoption of LB in routinary mCRC care, in particular when decision on first-line therapy is urgent and tissue recovery from external centers may require a long time. Results should be interpreted with caution in LB wild-type cases with low tumor burden.

Ramucirumab: the long and winding road toward being an option for mCRC treatment.

INTRODUCTION: Colorectal cancer (CRC) is one of the main causes of cancer-related morbidity and mortality worldwide. Mortality is most often attributable to metastatic disease. Despite the progress achieved so far, life expectancy continues to be limited in most patients. Ramucirumab, a most recent antiangiogenic drug, is vying in the race to metastatic CRC (mCRC) treatment since its approval by the Food and Drug Administration (FDA), based on the results of the RAISE study. AREAS COVERED: This article reviews the role of ramucirumab in mCRC, including clinical indication, safety issues, and future perspectives. EXPERT OPINION: The use of Ramucirumab in clinical practice is still limited, probably due to economic burden and the lack of specific biomarkers. Future efforts will be addressed to improve our knowledge in the use of this drug and better guide us in patients' care.

Prognostic Value of Plasma and Urine Glycosaminoglycan Scores in Clear Cell Renal Cell Carcinoma.

BACKGROUND: The prognosis of metastatic clear cell renal cell carcinoma (ccRCC) vastly improved since the introduction of antiangiogenic-targeted therapy. However, it is still unclear which biological processes underlie ccRCC aggressiveness and affect prognosis. Here, we checked whether a recently discovered systems biomarker based on plasmatic or urinary measurements of glycosaminoglycans (GAGs) aggregated into diagnostic scores correlated with ccRCC prognosis. METHODS: Thirty-one patients with a diagnosis of ccRCC (23 metastatic) were prospectively enrolled, and their urine and plasma biomarker scores were correlated to progression-free survival (PFS) and overall survival (OS) as either a dichotomous ("Low" vs. "High") or a continuous variable in a multivariate survival analysis. RESULTS: The survival difference between "High"- vs. "Low"-scored patients was significant in the case of urine scores (2-year PFS rate = 53.3 vs. 100%, p = 3 × 10-4 and 2-year OS rate = 73.3 vs. 100%, p = 0.0078) and in the case of OS for plasma scores (2-year PFS rate = 60 vs. 84%, p = 0.0591 and 2-year OS rate = 66.7 vs. 90%, p = 0.0206). In multivariate analysis, the urine biomarker score as a continuous variable was an independent predictor of PFS [hazard ratio (HR): 4.62, 95% CI: 1.66-12.83, p = 0.003] and OS (HR: 10.13, 95% CI: 1.80-57.04, p = 0.009). CONCLUSION: This is the first report on an association between plasma or urine GAG scores and the prognosis of ccRCC patients. Prospective trials validating the prognostic and predictive role of this novel systems biomarker are warranted.

Platinum-based doublet chemotherapy in pre-treated malignant pleural mesothelioma (MPM) patients: a mono-institutional experience.

BACKGROUND: The major clinical problems of MPM management are the short duration of response and the early relapse. Currently, after the first-line standard pemetrexed/platinum combination there is not a defined regimen for the second line treatment of MPM, and the clinical benefits in fit patients are uncertain. We analyzed the feasibility of gemcitabine/platinum chemotherapy in pretreated MPM patients. METHODS: Eligible patients should have relapsed after first-line chemotherapy with pemetrexed plus cisplatin (24%) or carboplatin (76%); 53% of the patients had previously received trimodality treatment, 18% neoadjuvant chemotherapy followed by pleurectomy/decortication, 29% were inoperable. Patients had to have PS=0-2, adequate organ function, measurable disease. Chemotherapy was gemcitabine 1000 mg/m(2) days 1, 8 associated to the alternative platinum compound respect to 1st line, i.e. cisplatin 75 mg/m(2) or carboplatin AUC 5 day 1 every 3 weeks, for 3-6 cycles. Baseline staging and reassessment after cycles 3 and 6 were performed with CT-scan. RESULTS: Since 2006 17 relapsed MPM patients were referred to our centre. Patients were 12 males and 5 females; median age: 61 years (range 47-74); histology: 12 epithelial, 4 sarcomatoid and 1 biphasic. PS 1-2 (15:2). The combination of gemcitabine with carboplatin/cisplatin was administered as second line treatment in 13 (76%) patients, as third line in 4 (24%) patients. Two patients were lost to follow-up without re-evaluation, therefore radiologic and clinical response was assessable in 15 (88%) patients. Among evaluable patients 10 (67%) showed stable disease and 5 (33%) progressive disease. Symptoms improved in 8 (53%) cases. In the intent-to-treat population median survival was 28 weeks (range 13-168) and median time-to-treatment failure 15 weeks (range 3-75). Toxicity profile showed 2 (13%) grade 4 and 6 (40%) grade 3 thrombocytopenia, 4 (27%) grade 3 leucopenia, 3 (20%) grade 3 anaemia and 6 (40%) of grade 3 neutropenia. Grade 3 non haematological toxicities were nausea (14%) and asthenia (21%). CONCLUSION: Gemcitabine-platinum regimens are able to control symptoms and disease progression with a modest toxicity profile. The present results from a small series of patients should be confirmed by a prospective trial in a larger cohort of patients.

M30 neoepitope expression in epithelial cancer: quantification of apoptosis in circulating tumor cells by CellSearch analysis.

PURPOSE: This study aimed to detect the M30 neoepitope on circulating tumor cells (CTC) as a tool for quantifying apoptotic CTC throughout disease course and treatment. EXPERIMENTAL DESIGN: An automated sample preparation and analysis platform for computing CTC (CellSearch) was integrated with a monoclonal antibody (M30) targeting a neoepitope disclosed by caspase cleavage at cytokeratin 18 (CK18) in early apoptosis. The assay was validated using cell lines and blood samples from healthy volunteers and patients with epithelial cancer. RESULTS: M30-positive CTC could be detected in >70% of CTC-positive carcinoma patients, which were free for both chemotherapy and radiologic treatments. The fraction of M30-positive CTC varied from 50% to 80%, depending on the histotype. To investigate the potential application of the M30 CTC assay for the evaluation of response in early phase trials, CTC and M30-positive CTC were enumerated in a small case series of breast cancer patients during treatment. Results indicate that changes in the balance of M30-negative/positive CTC may be used as a dynamic parameter indicating an active disease, as documented by consistent radiologic findings. CONCLUSIONS: M30 expression on CTC is detectable by immunofluorescence. The M30-integrated test has potential for monitoring dynamic changes in the quote of apoptotic CTC (in addition to CTC count) to evaluate response in clinical trials of molecularly targeted anticancer therapeutics as well as for translational research, in which there is a pressing need for informative circulating biomarkers.

Preoperative concomitant chemo-radiotherapy in superior sulcus tumour: A mono-institutional experience.

UNLABELLED: Superior sulcus tumour (SST) is an uncommon neoplasia whose optimal treatment remains controversial. Usually resected after induction RT or treated with definitive chemo-radiotherapy, it has recently aroused more interest because of preoperative chemo-radiotherapy. Treatment consisted of a platinum-based chemotherapy: carboplatin AUC 5 on days 1 and 22, combined with mitomycin-C 8 mg/m(2) on days 1 and 22, and vinblastine 4 mg/m(2) on days 1, 8, 22 and 29 (MVC) from 1994 to 1999, or combined with navelbine 25mg/m(2) on days 1, 8, 22 and 29 (NC), from 2000 to 2007. Radiotherapy was administered 5 days/week, 30 Gy in 10 fractions on days 22-35 (from 1994 to 1996), or 44 Gy in 22 fractions on days 22-52 (from 1997 to 2007). SURGERY was planned after 2-3 weeks since the completion of radiotherapy. Since 1994, 37 pts were treated with induction chemo-radiotherapy, 1 with induction radiotherapy only. Induction chemotherapy: 16 pts had MVC (43%) and 21 NC (57%); induction radiotherapy: 7 patients treated with MVC had 30 Gy/10F, 9 had 44 Gy/22F; all the patients treated with NC had 44 Gy/22F, but 2 of them did not complete radiotherapy because of early death (after 16 Gy/8F) and toxicity (after 38 Gy/19F). Grade 3-4 haematological toxicity of induction chemo-radiotherapy was found in 13 patients (35%); the most frequent non-haematological toxicities were constipation and oesophagitis. One complete, 18 partial and 8 minimal responses/stable disease were observed. Moreover, 1 progression disease and 1 early death occurred. SURGERY: 30 upper lobectomies (17 right, 13 left) and 4 segmentectomies, with chest wall resections, were performed (89% resection rate); 4 pts were not operated. Radical resections were achieved in 74% of the patients, with 5 pathologic complete remissions at resection. Twenty-seven patients (71%) had improvement of shoulder/arm pain. Median progression-free survival was 64 weeks and median survival was 148 weeks. The 5-year overall and progression-free survivals were 40% and 29%, respectively. In the multimodality treatment of SST, concurrent carboplatin-based chemotherapy plus radiotherapy were active and feasible without major toxicities. This resulted in high resectability rate and favourable progression-free and overall survival rates.

Second and third line treatment in advanced non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. About 50% of the patients present locally advanced or metastatic disease at the time of diagnosis. First line therapy usually consists of a combination of cisplatin or carboplatin with a third-generation agent (paclitaxel, docetaxel, gemcitabine, or vinorelbine) that results in less than 5% 5-year survival (Goldstraw et al., 2007). Recently a different approach based on histological subtype has been introduced in the first line treatment of NSCLC: in the non-squamous histotypes, cisplatin plus pemetrexed, compared to the cisplatin plus gemcitabine combination, showed a better outcome, leading to its introduction in the first line treatment setting. In recent years advances in the second and third line treatments have led to a prognostic improvement. Two cytotoxic agents, docetaxel and pemetrexed, are approved as NSCLC second line treatment, and a new class of drugs against specific molecular targets -- tyrosine Kinase inhibitors (TKI) -- has emerged as an alternative to conventional treatment. Many trials are ongoing to assess the activity of new drugs, alone or in combination with other agents, or new combinations of third-generation chemotherapeutic agents.

Second and third line treatment in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide, and the advances in second and third line treatment have led to prognostic improvements in the latest years. Besides the two cytotoxic agents, docetaxel and pemetrexed, approved in NSCLC second line treatment, a new class of drugs against specific molecular targets seems to be an alternative to conventional treatment. Many trials are ongoing to assess the activity of new drugs, alone or in association, and new combinations of third-generation chemotherapeutic agents.

Overprotective caregivers of elderly cancer patients: a case report.

The essential role of the caregiver in the management of elderly cancer patients is still poorly documented. This case report concerns a woman with metastatic lung carcinoma who was sincerely informed and successfully treated with chemotherapy and gefitinib only after gaining the trust of her overprotective daughter. Devoting time to the relatives represents a key element to create a communicative and efficient relationship with older cancer patients.