IntroductionFamilial history of melanoma is a well-known risk factor for the disease, and 7% melanoma patients were reported to have a family history of melanoma. Data relating to the frequency and clinical and pathological characteristics of both familial and non-familial melanoma in Spain have been published, but these only include patients from specific areas of Spain and do not represent the data for the whole of Spain.Patients and methodsAn observational study conducted by the Spanish Group of Melanoma (GEM) analyzed the family history of patients diagnosed with melanoma between 2011 and 2013 in the dermatology and oncology departments.ResultsIn all, 1047 patients were analyzed, and 69 (6.6%) fulfilled criteria for classical familial melanoma (two or more first-degree relatives diagnosed with melanoma). Taking into account other risk factors for familial melanoma, such as multiple melanoma, pancreatic cancer in the family or second-degree relatives with melanoma, the number of patients fulfilling the criteria increased to 165 (15.8%). Using a univariate analysis, we determined that a Breslow index of less than 1 mm, negative mitosis, multiple melanoma, and a history of sunburns in childhood were more frequent in familial melanoma patients, but a multivariate analysis revealed no differences in any pathological or clinical factor between the two groups.ConclusionsSimilar to that observed in other countries, familial melanoma accounts for 6.6% of melanoma diagnoses in Spain. Although no differences in the multivariate analysis were found, some better prognosis factors, such as Breslow index, seem more frequent in familial melanoma, which reflect a better early detection marker and/or a different biological behavior.
Background: Worldwide, colorectal cancer (CRC) has the second highest mortality rate of all malignancies. Sequencing efforts on primary CRC (pCRC) have led to extensive knowledge about its genomic landscape. Because the molecular characteristics change over time and under treatment pressure, tumor characteristics of metastases can differ from those of the primary tumor. Therefore, better insight into the genomic alterations of metastatic CRC (mCRC) is key to improve treatment strategies.Methods: We investigated whole genome sequencing (WGS) data of metastases of 429 CRC patients participating in the CPCT-02 study (NCT01855477). Based on prior treatment data, patients were divided into a group who did and a group who did not receive systemic treatment prior to the moment the biopsy was taken. Our sequencing data was compared to publicly available data from pCRC. In addition, observed molecular patterns were associated with pretreatment regimens and clinical outcome. The potential value of WGS analysis for current clinical practice was explored.Results: Compared to pCRC we found that TP53, ZFP36L2, KRAS, and APC were more frequently mutated in mCRC whereas PIK3CA mutations were less frequent. Clear shifts in the relative contributions of mutational signatures were observed in mCRC compared to pCRC. We identified a subgroup of both pretreated and untreated mCRC samples characterized by signatures rarely found in pCRC (SBS9/39/41). Effects of prior treatment were observed in pretreated patients versus untreated patients on the total number of aberrations, mutational signatures, and CNVs. Based on their molecular landscape, 55% of the patients could qualify for on-or off-label FDAapproved targeted treatments. In addition to KRAS/NRAS and BRAF, mutations in FBXW7 were associated with poor response to EGFR-targeted treatments.Conclusions: Differences in driver genes and mutational signatures were observed between mCRC and pCRC, and genomic effects of prior treatment were observed in pretreated mCRC patients versus untreated patients. In conclusion, this study provides an unprecedentedly comprehensive insight into the molecular landscape of mCRC and identifies clinically useful genomic features for future patient management.Clinical trial identification: NCT01855477.
Background Anti-angiogenic agents are reported to exert clinical activity in patients with epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC). We evaluated the outcomes of the combination of docetaxel plus nintedanib in refractory NSCLC patients harboring EGFR mutations. Methods We retrospectively analyzed 19 patients with advanced EGFR-mutant NSCLC who had progressed to EGFR tyrosine kinase inhibitors (TKI) and platinum-based chemotherapy receiving docetaxel and nintedanib at 14 Spanish institutions from January 2013 to December 2019. Kaplan-Meier and log-rank tests were used to evaluate progression-free survival (PFS) and overall survival (OS). Results Median age was 58.9 years (range 42.8-81), 73.7% were female. All patients were Caucasian, and 73.7% were never or light smokers. The baseline Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 0-1 in 94.7% of patients. All patients had adenocarcinoma. Brain and liver metastases were present in 47.4% and 31.6% of patients, respectively. The most common EGFR mutations were exon 19 deletion (52.6%) and exon 21 L858R mutation (36.8%); 47.4% patients presented the EGFR T790M. 94.8% of the patients had received 2-3 previous treatment lines. Docetaxel was administered at 75 mg/m 2 /3 weeks to 16 patients, at 60 mg/m 2 to 2 patients and at 45 mg/m 2 to one patient. Nintedanib was given until disease progression or unacceptable toxicity at 200 mg twice daily except in 2 patients who received 150 mg twice daily and one patient who received 100 mg/12 h. With a median follow-up of 11.4 months (1-38), the median PFS was 6.1 months [95% confidence interval (CI), 4.9-7.3] and the median OS 10.1 months (95% CI 5.9-14.3). The objective response rate (ORR) was 44.4% (23.7-66.8%) and the disease control rate (DCR) 72.2% (49.4-88.5%). Efficacy tended to be greater in patients with the acquired T790M who had received osimertinib, with a median PFS of 6.3 (95% CI 2.1-10.5) versus (vs.) 4.8 (95% CI 3.5-6.1) and a median OS of 12.3 months (95% CI 8.6-16.0) vs. 6.7 months (95% CI 3.9-9.4), although this tendency was not statistically significant (p = 0.468 and p = 0.159, respectively). Sixteen patients (84.2%) had a total of 34 adverse events (AEs), with a median of two (0-6) AEs per patient. The most frequent AEs were asthenia (20.6%) and diarrhea (20.6%). One treatment-related death due to portal thrombosis was reported. Conclusions Our data indicate that the combination of docetaxel and nintedanib can be considered to be an effective treatment for EGFR TKI-resistant EGFR-mutant NSCLC.
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/m 2 then 250 mg/m 2 weekly) plus FOLFIRI [irinotecan 180 mg/m 2 , leucovorin 400 mg/m 2 , 5-fluorouracil 400 mg/m 2 (bolus) then 2400 mg/m 2 (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 / PIK3C A-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 ...
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