Yolanda Fernández

Mutational analysis of BRCA1 and BRCA2 in hereditary breast and ovarian cancer families from Asturias (Northern Spain)

BackgroundThe prevalence of BRCA1 and BRCA2 mutations in Spain is heterogeneous and varies according to geographical origin of studied families. The contribution of these mutations to hereditary breast and ovarian cancer has not been previously investigated in Asturian populations (Northern Spain).MethodsIn the present work, 256 unrelated high-risk probands with breast and/or ovarian cancer from families living in Asturias were analyzed for the presence of a BRCA1 or BRCA2 gene mutation from October 2007 to May 2012. The entire coding sequences and each intron/exon boundaries of BRCA1/2 genes were screened both by direct sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA).ResultsA total of 59 families (23%) were found to carry a pathogenic germ line mutation, 39 in BRCA1 and 20 in BRCA2. Twenty nine additional families (12%) carried an unknown significance variant. We detected 28 distinct pathogenic mutations (16 in BRCA1 and 12 in BRCA2), of which 3 mutations in BRCA1 (c.1674delA, c.1965C>A and c.2900_2901dupCT) and 5 in BRCA2 (c.262_263delCT, c.2095C>T, c.3263dupC, c.4030_4035delinsC, c.8042_8043delCA) had not been previously described.The novel mutations c.2900_2901dupCT in BRCA1 and c.4030_4035delinsC in BRCA2 occurred in 8 and 6 families respectively and clustered in two separated small geographically isolated areas suggesting a founder effect. These 2 mutations, together with the Galician BRCA1 mutation c.211A>G (9 families), and the common BRCA1 mutation c.3331_3334delCAAG (6 families), account for approximately 50% of all affected families. By contrast, very frequent mutations in other Spanish series such as the BRCA1 Ashkenazi founder mutation c.68_69delAG, was found in only one family.ConclusionsIn this study we report the BRCA1 and BRCA2 spectrum of mutations and their geographical distribution in Asturias, which largely differ from other areas of Spain. Our findings may help design a first step recurrent mutation panel for screening high-risk breast and/or ovarian cancer families from this specific area.

Activity of weekly irinotecan (CPT-11) in patients with advanced non-small cell lung cancer pretreated with platinum and taxanes

Irinotecan (CPT-11), a semisynthetic derivative of camptothecin, is active in the treatment of non-small cell lung cancer (NSCLC). In this report we describe our experience with this drug when used as a single agent in patients with advanced NSCLC refractory to chemotherapy with platinum and taxanes. Nineteen NSCLC patients (thirteen males and six females; 53% adenocarcinoma and 26% squamous cell carcinoma) with a median age of 52 years (range 34–71) and a Karnofsky performance status of 60% (60–80%) were included in the study. At baseline, the patients had a median of two disease sites and had been treated with a median of two prior regimens. Irinotecan was given at a dose of 100 mg/m2 i.v.) weekly for 4 weeks followed by 1 week of rest. A total of 123 weekly infusions were administered, and each patient received a median of 4 weeks of treatment (range 1–32). All patients were evaluated by intention-to-treat analysis for efficacy and safety. Main toxicities reported were grade 3 neutropenia (10% of patients), diarrhea (10% of patients), and grade 4 thrombocytopenia (5% of patients). The overall clinical response rate was 16% (95% CI: 8–24) with three partial responses and 9 (47%) patients with stable disease. The median time to progression and the median survival time were 7 and 15 weeks, respectively. In conclusion, weekly irinotecan showed antitumoral activity and minimum toxicity in NSCLC patients refractory to platinum and taxanes.

Pegylated Liposomal Doxorubicin and Gemcitabine in a Fixed Dose Rate Infusion for the Treatment of Patients With Poor Prognosis of Recurrent Ovarian Cancer: A Phase Ib Study

Introduction Pegylated liposomal doxorubicin (PLD) is currently the reference treatment for platinum-resistant ovarian cancer. The combination of PLD and gemcitabine and the administration of gemcitabine at a fixed dose rate infusion (FDRI) seem to have additive activity in this disease setting. We have launched a phase Ib study with the combination of FDRI gemcitabine followed by PLD in recurrent ovarian cancer with a platinum-free interval of less than 1 year, with parallel pharmacokinetic and pharmacogenetic studies. Methods The starting dose of gemcitabine was 1500 mg/m2, 10 mg/m2 per minute, every 2 weeks (±250 mg gemcitabine titration depending on toxicity), followed by PLD 35 mg/m2 every 4 weeks. Gemcitabine pharmacokinetics and equilibrative nucleoside transporter 1, deoxycytidine kinase, and ribonucleotide reductase M1 gene expression levels were studied. Results Thirty-five patients were treated at 3 different dose levels (DL). Dose level 1 was not tolerated. Nonfrail patients continued to be treated at DL-1 (G 1250 mg/m2 on day 1 and PLD 35 mg/m2 on days 1 and 15). Of 10 evaluable nonfrail patients, 4 displayed dose-limiting toxicity. Frail patients were treated at DL-2 (G 1250 mg/m2 on day 1 and PLD 35 mg/m2 on days 1 and 15). Of the 12 evaluable frail patients, 3 developed dose-limiting toxicity. Neutropenia, palmar-plantar erythrodysesthesia and stomatitis were the most common toxicities. The response rate was 42.8% (95% confidence interval [CI], 34.5%-51.1%), with 17.1% (6/35) complete responses and 25.7% (9/35) partial responses. The median progression-free survival was 7.7 months (95% CI, 2.2-13.1). The median overall survival was 13.9 months (95% CI, 9.4-18.4). The administration of PLD after gemcitabine did not influence gemcitabine pharmacokinetics or its metabolites. The addition of PLD to gemcitabine caused a larger and longer induction of the ribonucleotide reductase M1 gene. Patients with higher baseline levels of deoxycytidine kinase had longer progression-free survival. Conclusion The recommended dose for a phase II study of patients with recurrent ovarian cancer having poor prognosis is PLD, 35 mg/m2 on day 1, and gemcitabine, 1000 mg/m2 on days 1 and 15 delivered at an FDRI of 10 mg/m2 per minute in 28-day cycles.

Impact of the incorporation of tyrosine kinase inhibitor agents on the treatment of patients with a diagnosis of advanced renal cell carcinoma: study based on experience at the Hospital Universitario Central de Asturias.

IntroductionFor nearly the past two decades, cytokines (CKs) have been the only systemic treatment option available for advanced renal cell carcinoma (RCC). In recent years, tyrosine kinase inhibitors (TKIs) have demonstrated clinical activity on this tumour. Our purpose is to describe one centre’s experience with the use of CKs and TKIs in the treatment of patients with advanced RCC.Materials and methodsThis study was designed as a retrospective chart review of RCC patients who were treated with CKs and/or TKIs in our department between July 1996 and June 2008. Efficacy and toxicity were assessed using World Health Organization (WHO) criteria. The Kaplan-Meier method was used to estimate progression-free (PFS) and overall (OS) survival.ResultsNinety-four patients were classified into three groups depending on the modality of treatment administered: 46 were treated with CKs alone and/or chemotherapy (27 with immunotherapy, one with chemotherapy and 18 with both), 28 with TKIs alone (25 with sunitinib and 13 with sorafenib) and 20 with TKIs in second-line treatment following failure with CKs (17 with sunitinib, eight with sorafenib, four with bevacizumab and one with lapatinib). The median age was 60 years in the CK group and 65 and 62, respectively, in TKI in first and second-line treatment groups. Eighty-five percent of patients treated with CKs and 75% in the TKI group in first-line treatment and 80% in second-line treatment were men. Overall, 89% of patients had favourable risk, and 11% had intermediate risk. All patients were considered evaluable for toxicity. The main grade 3–4 (%) toxicity was asthenia for both groups, (ten in TKIs and 15 in CKs). Other grade 1–2 toxicities were mucositis (39), bleeding (8), hypertension (19), skin toxicity (33) and hypothyroidism (12.5) associated with TKIs; and anaemia (33), cough (29), asthenia (39) and emesis (14) associated with CKs. The objective response rate among 80 patients evaluable for activity was 10.6% with CKs and 46.5% and 35%, respectively, with TKIs in first- and second-line treatments. Disease stabilisation with CKs was recorded at 59% of patients and with TKIs 25% and 50% in first- and second-line treatment groups, respectively. The median progression-free survival (PFS) with CKs was 122 days [95% confidence interval (CI) 82–162] and with TKIs 201 days (65–337) in the firstand 346 days (256–436) in second-line treatment groups. The median overall survival (OS) was 229 days (142–316) and 2,074 days (1,152–2,996) for patients treated with CKs and TKIs.ConclusionsOur results are in line with the activity and survival rates previously reported in the literature regarding the use of TKIs for patients with advanced RCC in first- and second-line treatment, which has demonstrated an acceptable toxicity level.

Combination of Docetaxel, Epirubicin and Vinorelbine Administered Every 2 Weeks as First-line Therapy in Patients with Metastatic Breast Cancer: A Dose-finding Study

AbstractAims. To assess efficacy and optimum combination dosage of intravenous docetaxel (T), epirubicin (E) and vinorelbine (N) administered every 2 weeks and without colony stimulating factor (CSF) support in patients with metastatic breast cancer (MBC). Patients and method. Patients (n = 51) with MBC were consecutively assigned to four different dose levels (DL) to receive (in mg/m2): Level I = T35 + E30 + N25; Level II = T30 + E30 + N25; Level III = T30 + E25 + N25; and Level IV = T25 + E25 + N25. Consecutive cycles were delayed if absolute neutrophil and/or platelet counts fell below 1.5 × 109 and 100 × 109l−1, respectively. Treatment at a given dose level was suspended if 33% or more of patients included in a given cohort had unacceptable toxicity. Results. The patients evaluable for toxicity (n = 48) received 448 cycles (median 9; range 1–23). There was neutropenia G 3–4 in 30 patients (63%) with fever in 3 (6%). The G 2–3 non-hematological toxicities were alopecia in 39 patients (81%), mucositis in 11 (23%), and nausea/vomiting in 8 (17%). There were no toxic deaths. Treatment delay or dose reduction after first cycle occurred in ≥30% of patients treated in all DLs, except the fourth. Objective response was achieved in 29 of the 47 evaluable patients (58%; 95% CI: 50–66). The median duration of response, time-to-progression and overall survival were 13, 11 (range 8–14) and 20 (range 16–24) months, respectively. Conclusion. The combination of docetaxel, epirubicin and vinorelbine without CSF support ought not to exceed 25 mg/m2 every 2 weeks. The efficacy is no greater than other existing regimens for first-line treatment of MBC.

Tratamiento adyuvante en pacientes diagnosticados de carcinoma no microcítico de pulmón: estado de la evidencia científica

Surgery is the current treatment of choice in patients with early-stage non-small cell lung cancer. Based on the high rates of recurrence, additional local and systemic treatments have been developed, aimed at improving the cure rates. The comparative studies about the benefits of post-operative adjuvant chemotherapy and/or radiotherapy, and the meta-analysis studies made during the last decades, reviewed in some articles appeared in 95 and 97, did not confirm a significant improvement of the overall survival. Since then, new comparative trials carried out with a higher number of patients and with more active and standard chemotherapy seem to show a benefit of the administration of platinum-based chemotherapy, although it has not gained general acceptance. More recently, a new meta-analysis, that included the previous studies, has confirmed an overall increase of 4 % in survival of patients treated by surgery and adjuvant chemotherapy, especially in stages II-III patients receiving schedules of cisplatin and vinorelbine. Further studies are needed to determine the real therapeutic value of other agents, as uracil-tegafur and radiotherapy.

Tratamiento anti-hormonal adyuvante en mujeres post-menopáusicas con diagnóstico de carcinoma de mama

Over the recent decades, tamoxifen has been considered the standard adjuvant treatment of postme-nopausal women with hormone-receptor positive breast cancer based on its capacity to reduce the annual breast cancer death. More recently, several major randomized controlled trials carried out with three different new aromatase inhibitors used either from the time of primary surgery or after 2-3 or 5 years of adjuvant tamoxifen therapy have shown a significant improvement in disease-free survival with respect to tamoxifen therapy. The described treatment-related side effects suggest different profiles of toxicity. Musculoskeletal disorders and cardiovascular events are the most serious side effects associated with the use of aromatase inhibitors, as well as the thromboembolic events and endometrial abnormalities are associated with tamoxifen therapy. An optimal treatment strategy for aromatase inhibitors administration, interventions to prevent or alleviate treatment-related side effects and identification of women at higher risk having more benefit with aromatase inhibitors need to be addressed.

Activity of carboplatin in patients with advanced non-small cell lung cancer pre-treated with a non-platinum combination

SummaryTo assess the efficacy of carboplatin when used as a single agent in patients with advanced non small cell lung cancer (NSCLC) and who are refractory to chemotherapy with a non-platinum combination, we recruited patients (n = 40) NSCLC patients, 36 of whom were males, with an overall median age of 59 years (range 39–79) and Karnofsky Performance Status of 70% (range 60–90%). At baseline, the patients had a median of one disease site (range 1–3) and had received a median of one prior regimen (range 1–2). Carboplatin was administered (i.v.; AUC = 6) every 3 weeks until disease progression or non-acceptable toxicity was reached. In total 169 cycles were administered (median 4 cycles/patient; range 1–8). Main toxicities were grade 2–3 anemia and grade 4 thrombocytopenia (22.5% of patients). Overall clinical response rate was 10% (4 partial responses); 26 patients (65%) had stable disease and 8 (20%) had disease progression. Median time to progression and median survival time were 90 and 187 days, respectively. One year survival rate was 13%.We conclude that carboplatin shows minimal toxicity with a discrete anti-tumor activity in patients with NSCLC and who are refractory to non-platinum combinations.

Cisplatin plus gemcitabine with or without vinorelbine as neo-adjuvant therapy for radically treatable stage III non-small cell lung cancer. Results of a randomised study of the Grupo Oncologico del Norte de Espana

7121 The combinations of cisplatin (C) with gemcitabine (G) and/or vinorelbine (V) have shown to be effective and safe regimens in the first line treatment of NSCLC. This study has been designed to detect a 25% increase in objective response measured by CT scan with the triplet combination (CGV) with respect to cisplatin/gemcitabine combination (CG) administered as neo-adjuvant therapy in patients with radically-treatable stage III NSCLC. With 80% of power and one-sided 5% significant level, the simple size required to confirm this hypothesis is 75 evaluable patients in each arm of treatment. Patients (pts) ≤ 75 years old, Karnofsky index ≥ 70% and adequate haematological, renal and hepatic function are stratified by stage (IIIA versus IIIB) and randomly assigned to: C 50 mg/m2 i.v. and G 1250 mg/m2 i.v. d1 and d8 alone (CG) or in combination with V 25 mg/m 2 i.v. d1 and d8 (CGV) both regimens every 3 weeks for 3 consecutive cycles followed by definitive local treatment (LT). From December 1999 to December 2005, a hundred and forty-nine pts have been randomised (CG/CGV); median age 58/58; median Karnofsky index 80/80; stage IIIA 24/26; stage IIIB 51/48; squamous 37/39; adenocarcinoma 31/32; anaplastic 7/3. Major haematological toxicities grade 3-4 were (CG/CGV; %); Anaemia (5/5) neutropenia (31/34); thrombocytopenia (4/5). Two pts in CG (2.7%) and 4 in CGV arm (5.5%) developed neutropenic fever. Major non-haematological toxicities grade 2-3 were: N/Vomiting (31/32) and fatigue (12/20). Global recurrences have been registered in 57% and 54% of pts treated with CG and CGV arm respectively. Exclusive local/ distant failure (%) has been 16/23 in CG and 23/18 in CGV arm. Preliminary results show similar high efficacy associated with moderate toxicity in both groups of treatment. The study is continuing. [Table: see text] No significant financial relationships to disclose.