Association of Circulating Tumor Cells and Tumor Molecular Profile With Clinical Outcomes in Patients With Previously Untreated Metastatic Colorectal Cancer: A Pooled Analysis of the Phase III VISNÚ-1 and Phase II VISNÚ-2 Randomized Trials.

BACKGROUND: The bCTC count is a well-established prognostic biomarker in mCRC, as well as in other tumor types. The aim of this analysis was to evaluate the prognostic/predictive role of the bCTC count (≥3 vs. <3) in previously untreated mCRC. PATIENTS AND METHODS: The study involved 589 untreated mCRC patients included in the intention-to-treat population of 2 randomized clinical trials (phase III VISNU-1 [NCT01640405] and phase II VISNU-2 [NCT01640444] studies). RESULTS: Of the 589 patients, 349 (59.2%) had bCTC≥3 and 240 (40.7%) had bCTC<3. Multivariate analysis showed that the bCTC count is an independent prognostic factor for overall survival (OS) (HR 0.59, 95% CI 0.48-0.72; P = 0.000) and potential for progression-free survival (PFS) (P = 0.0549). Median OS was 32.9 and 19.5 months in patients with bCTC<3 and bCTC≥3 (P <0.001), respectively. This effect was also observed comparing OS in RASwt patients from both studies. Other prognostic factors were: ECOG-PS, primary tumor site, number of metastatic sites and surgery of the primary tumor. Median OS was lower for patients treated with anti-VEGF versus anti-EGFR (22.3 vs. 33.3 months, P <0.0001) while there were no significant differences in PFS according to the targeted treatment received. CONCLUSION: This post-hoc analysis of 2 randomized studies confirms the poor prognosis of patients with bCTC≥3 but this is not associated with other adverse independent prognostic factors such as RAS/BRAF mutations.

Influence of BRAF and PIK3CA mutations on the efficacy of FOLFIRI plus bevacizumab or cetuximab as first-line therapy in patients with RAS wild-type metastatic colorectal carcinoma and <3 baseline circulating tumour cells: the randomised phase II VISNÚ-2 study.

BACKGROUND: We explored the influence of BRAF and PIK3CA mutational status on the efficacy of bevacizumab or cetuximab plus 5-fluorouracil/leucovorin and irinotecan (FOLFIRI) as first-line therapy in patients with RAS wild-type metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: VISNÚ-2 was a multicentre, randomised, phase II study. Patients with RAS wild-type mCRC and <3 circulating tumour cells/7.5 ml blood were stratified by BRAF/PIK3CA status (wild-type versus mutated) and number of affected organs (1 versus >1), and allocated to bevacizumab (5 mg/kg every 2 weeks) or cetuximab (400 mg/m2 then 250 mg/m2 weekly) plus FOLFIRI [irinotecan 180 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil 400 mg/m2 (bolus) then 2400 mg/m2 (46-h continuous infusion) every 2 weeks]. The primary endpoint was progression-free survival (PFS). All analyses were exploratory. RESULTS: Two hundred and forty patients with BRAF/PIK3CA wild-type (n = 196) or BRAF- and/or PIK3CA-mutated tumours (n = 44) were enrolled. Median PFS was 12.7 and 8.8 months in patients with BRAF/PIK3CA wild-type and BRAF/PIK3CA-mutated tumours, respectively [hazard ratio (HR) = 1.22; 95% confidence interval (CI) 0.80-1.85; P = 0.3602]. In the BRAF- and/or PIK3CA-mutated cohort, median PFS was 2.8, 8.8 and 15.0 months in patients with BRAF/PI3KCA-mutated (n = 8), BRAF-mutated/PI3KCA wild-type (n = 16) and BRAF wild-type/PI3KCA-mutated (n = 20) tumours, respectively (P = 0.0002). PFS was similar with bevacizumab plus FOLFIRI versus cetuximab plus FOLFIRI in BRAF/PIK3CA wild-type (HR = 0.99; 95% CI 0.67-1.45; P = 0.9486) and BRAF/PIK3CA-mutated tumours (HR = 1.11; 95% CI 0.53-2.35; P = 0.7820). The most common grade 3/4 treatment-related adverse events were neutropenia, diarrhoea and asthenia in both treatment groups. CONCLUSIONS: BRAF/PIK3CA status influences outcomes in patients with RAS wild-type mCRC but does not appear to assist with the selection of first-line targeted therapy.

Correction to: Persistent major alopecia following adjuvant docetaxel for breast cancer: incidence, characteristics, and prevention with scalp cooling.

In the original publication of the article, Table 1 was published with incorrect caption and values. The Table 1 with corrected caption and values is given in this Correction.

Persistent major alopecia following adjuvant docetaxel for breast cancer: incidence, characteristics, and prevention with scalp cooling.

BACKGROUND: Persistent alopecia (PA) after docetaxel has been recently described. The aim of our study is to establish the incidence and characteristics of PA following adjuvant docetaxel for breast cancer (BC) and to test the ability of scalp cooling in prevention. PATIENTS AND METHODS: BC patients receiving adjuvant chemotherapy followed or not by endocrine therapy (and a control group receiving only endocrine therapy) were interviewed in a single institution at 1.5 to 5 years following primary diagnosis searching for PA. A confirmatory prevalence study was later performed in other two institutions. Finally, a prevention study using prophylactic scalp cooling (PSC) with ELASTO-GEL hypothermia caps in patients receiving adjuvant docetaxel was performed. RESULTS: In the initial prevalence study (492 patients), minor forms of PA (grade 1) were recorded with all chemotherapy regimens and aromatase inhibitors. Patients receiving docetaxel regimens at cumulative dose (CD) ≥ 400 mmg/m2 presented a significantly higher prevalence of grades 1 PA (33-52%) and 2 PA (5-12%). Prevalence of grade 2 PA with docetaxel CD ≥ 400 mmg/m2 was confirmed in two other institutions. Overall, grade 2 PA was seen in 10.06% (95% CI 7.36-13.61) of 358 patients with docetaxel regimens reaching CD ≥ 400 mmg/m2, but not in patients with lower docetaxel CD, other chemotherapy regimens, or endocrine therapy alone. In prevention trial, no grade 2 PA occurred among 116 patients receiving adjuvant docetaxel (≥ 400 mmg/m2) and PSC followed-up after a 96 months median time. PSC was well tolerated. No scalp relapses were seen among 30 patients (22% of all inclusions) having disease relapse. CONCLUSION: Adjuvant treatment with docetaxel (CD ≥ 400 mmg/m2) is associated with a significant rate of grade 2 PA, leading to wearing a wig, in around 10% of patients. This toxicity was completely prevented with scalp cooling. Clinical Trial Reference: NCT00515762.

Prognostic significance of tumor regression in lymph nodes after neoadjuvant therapy for rectal carcinoma.

Neoadjuvant therapy (NAT) is mainly indicated for locally advanced rectal carcinoma. Many reports have shown that regression of the primary tumor is a prognostic factor. However, few reports to date have analyzed the potential prognostic significance of lymph node regression in rectal carcinoma. The aim of the present study is to describe the pattern of tumor regression in lymph nodes after NAT for rectal carcinoma and its potential prognostic significance. We have retrospectively reviewed 106 cases of rectal carcinoma treated at a single institution. We have retrieved data from the patients and reviewed the histopathological slides to evaluate tumor regression both of the primary tumor and of LN metastases. Prognosis has been defined both in terms of disease-free survival (DFS) and disease-specific survival (DSS). Of the patients, 16% showed complete response of the primary tumor, while 24% showed poor response, according to the CAP regression grading system. Absence of lymph node involvement after therapy was found in 80% of the patients (ypN0 cases), while 20% were ypN+. We reviewed 639 LN; 85 were involved by tumor, and 170 showed histological signs of tumor regression. The main pattern of tumor regression in lymph nodes was fibrosis (66.3%), followed by hystiocytosis (29.1%) and mucin pools (4.6%). We found histological signs of regression in 57% of ypN0 cases and 76% of ypN+ cases. We found a significant association between regression grade of the primary tumor and of lymph node metastases. For ypN0 patients with persistence of the primary tumor after NAT, the median DFS was significantly shorter in patients showing tumor regression in the LN. In a Cox multivariate survival model for DFS, this prognostic influence was independent of the regression grade of the primary tumor and also of the ypTNM stage. We found no significant association between any factor and DSS. The pattern of tumor regression in lymph nodes was not significantly associated with prognosis. Tumor regression in lymph nodes is an important prognostic factor in rectal carcinoma after NAT and should be specifically looked for and included in pathology reports.

BRCA2 gene: a candidate for clinical testing in familial colorectal cancer type X.

Familial colorectal cancer type X (FCCX) encompasses a group of families with dominant inheritance pattern of colorectal cancer (CRC) but no alteration in any known CRC susceptibility gene. Therefore, the explanation of their susceptibility is a priority to offer an accurate genetic counseling. We screened the 27 coding exons and exon-intron boundaries of BRCA2 in 48 FCCX probands. We identified 29 variants including a frameshift mutation. Deleterious variant c.3847_3848delGT p.(Val1283Lysfs*2) showed cosegregation with disease as well as loss of heterozygosity (LOH) in CRC tumor DNA. This is the first evidence of germline BRCA2 pathogenic mutation associated with CRC risk. Furthermore, missense variants c.502C>A p.(Pro168Thr), c.5744C>T p.(Thr1915Met) and c.7759C>T p.(Leu2587Phe) were proposed as candidate risk alleles based on cosegregation, LOH tumor analysis and in silico testing.

Adjuvant chemotherapy for early-stage non-small-cell lung cancer. Single-centre experience and literature review

BACKGROUND: In recent years platinum-based chemotherapy has become the standard of care for patients with good performance status after complete resection in stages IB-IIIA non-small-cell lung cancer (NSCLC), although the benefit is mainly in stages II and IIIA. PATIENTS AND METHODS: In a retrospective trial we evaluate the clinical efficacy and toxicity profile of a platinum- and taxanes-based adjuvant chemotherapy in completely resected IB-IIIA NSCLC. The primary end point was relapse- free survival (RFS); principal secondary end points were overall survival (OS) and safety of the regimen. Potential predictive factors of efficacy and clinical patterns of relapse were also analysed. RESULTS: From January 2003 to December 2006, 41 patients met the inclusion criteria and were evaluable. Median age at diagnosis was 68.1 years (CI 95% 54-72; range 45-78). Most patients were males (87.7%) and had an Eastern Cooperative Oncology Group performance status score (PS) of 0-1 (87.8%), and 53.6% had adenocarcinomas. Pathological stages were as follow: 48.7% stage IB, 24.3% stage II and 26.8% stage IIIA. 75.6% of patients underwent a lobectomy and mediastinal lymphadenectomy and were treated with a combination of carboplatin AUC6 and paclitaxel 200 mg/m2 (85.36%) for 3 or 4 cycles. With a median follow-up of 18.2 months (range 5.1-46.5), 26 patients (63%) were free of disease and 32 of them were alive (78%). Median RFS was 12.1 months (CI 95% 9.8-14.9) and median OS had not been reached at the time of analysis. Patients with PS< or =1 at diagnosis had a higher RFS [p=0.051 (CI 95% 0.90-0.96)]. Toxicity was generally mild and haematologic events were the most frequent. Non-haematologic toxic effects of chemotherapy were asthenia/ anorexia (12.2%), nausea/vomiting (12.2%) and peripheral neuropathy (17%), but severe toxic effects (grade 3 or greater) were uncommon (<10%). We did not observe treatment-related deaths. CONCLUSIONS: Platinum-taxane-based adjuvant chemotherapy in IB-IIIA NSCLC following complete resection is feasible, well tolerated and can be delivered in most patients in the adjuvant setting. Ongoing molecular studies may have value in determining which patients will benefit from adjuvant chemotherapy (AU)

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