Difficulties on the acces to innovative targeted therapies for lung cancer in Spain

Purpose Spanish Lung Cancer Group (SLCG) conducted a review to analyze the barriers to access to innovative targeted therapies for non-small cell lung cancer (NSCLC) in clinical practice in Spain. Methods Review all relevant content published on websites of European Commission, European Medicines Agency, and Spanish Agency of Medicines and Medical Products regarding the authorization and access to oncology treatments. Results More than 20 targeted therapies are available to treat different molecular alterations in patients with NSCLC. European Commission has approved treatments for genomic alterations involving the following genes: ALK, RET, ROS1, EGFR, BRAF, NTRK, KRAS, MET. However, the availability of these therapies in Spain is not complete, as innovative treatments are not reimbursed or funded late, with only five of these alterations currently covered by National Health System. Conclusion SLCG considers imperative to improve the access in Spain to innovative treatments for NSCLC to reduce inequity across European countries

BRCA1, LMO4, and CtIP mRNA Expression in Erlotinib-Treated Non–Small-Cell Lung Cancer Patients with EGFR Mutations

IntroductionLung adenocarcinoma patients harboring EGFR activating mutations attain improved progression-free survival (PFS) with treatment with epidermal growth factor receptor tyrosine kinase inhibitors. However, patients ultimately relapse, indicating that other genetic factors could influence outcome in such patients. We hypothesized that PFS could be influenced by the expression of genes in DNA repair pathways.MethodsWe examined the mRNA expression of C terminus-binding protein–interacting protein and Lin11, Isl-1, and Mec-3 domain only 4 (LMO4) in pretreatment tumor samples from 91 erlotinib-treated advanced non–small-cell lung cancer patients with EGFR mutations in whom breast cancer gene 1 (BRCA1) expression and the concomitant presence of the EGFR T790M mutation had previously been assessed. Gene expression was analyzed by polymerase chain reaction, using β-actin as endogenous gene. Results were correlated with PFS and overall survival.ResultsIn patients with low LMO4 levels, PFS was 13 months, whereas it was not reached for those with high LMO4 levels (p = 0.03). In patients with low levels of both BRCA1 and LMO4, PFS was 19 months whereas it was not reached in those with low BRCA1 and high LMO4 mRNA levels (p = 0.04). In patients with high BRCA1 and low LMO4 levels, PFS was 8 months, whereas it was 18 months in those with high levels of both genes (p = 0.03).ConclusionsLow BRCA1 and high LMO4 levels were associated with longer PFS to erlotinib. Baseline assessment of BRCA1 and LMO4 mRNA expression can help predict outcome to erlotinib

BIM and mTOR expression levels predict outcome to erlotinib in EGFR-mutant non-small-cell lung cancer

Altres ajuts: Fellowship Award of the International Association for the Study of Lung Cancer i grant of the Italian Association for Cancer Research (AIRC My First AIRC Grant n° 14282).Abstract.BIM is a proapoptotic protein that initiates apoptosis triggered by EGFR tyrosine kinase inhibitors (TKI). mTOR negatively regulates apoptosis and may influence response to EGFR TKI. We examined mRNA expression of BIM and MTOR in 57 patients with EGFR-mutant NSCLC from the EURTAC trial. Risk of mortality and disease progression was lower in patients with high BIM compared with low/intermediate BIM mRNA levels. Analysis of MTOR further divided patients with high BIM expression into two groups, with those having both high BIM and MTOR experiencing shorter overall and progression-free survival to erlotinib. Validation of our results was performed in an independent cohort of 19 patients with EGFR-mutant NSCLC treated with EGFR TKIs. In EGFR-mutant lung adenocarcinoma cell lines with high BIM expression, concomitant high mTOR expression increased IC50 of gefitinib for cell proliferation. We next sought to analyse the signalling pattern in cell lines with strong activation of mTOR and its substrate P-S6. We showed that mTOR and phosphodiesterase 4D (PDE4D) strongly correlate in resistant EGFR-mutant cancer cell lines. These data suggest that the combination of EGFR TKI with mTOR or PDE4 inhibitors could be adequate therapy for EGFR-mutant NSCLC patients with high pretreatment levels of BIM and mTOR

Stock Assessment Form Demersal species. Hake GSA7. Reference year: 1998-2015. Reporting year 2016.

Hake is one of the most important demersal target species for the commercial fisheries in the Gulf of Lions (GSA 7). In this area, hake is exploited by French trawlers, French gillnetters, Spanish trawlers and Spanish longliners. Since 1998, an average of 243 boats are involved in this fishery and, according to official statistics, the total annual catches for the period 1998-2015 have oscillated around an average value of 1961 tons (1139 tons in 2015). In 2009, because of the large decline of small pelagic fish species in the area, the trawlers fishing small pelagic have diverted their effort on demersal species. Between 1998 and 2015, the number of French trawlers operating in the GSA 07 has decreased by 50%. The French trawler fleet is the largest considering catches realized, the proportion of boats and catches are respectively (27% and 73%). The length of hake in the trawler catches ranges between 3 and 92 cm total length (TL), with an average size of 21 cm TL. The second largest fleet is the French gillnetters (41 and 16% respectively, range 13-86 cm TL and average size 39 cm TL), followed by the Spanish trawlers (9 and 10%, respectively, range 5-88 cm TL, and average size 24 cm TL), and the Spanish longliners (4 and 1%, respectively, range 22-96 cm TL and average size 52 cm TL). The hake trawlers exploit a highly diversified species assemblage: Striped red mullet (Mullus surmuletus), red mullet (M. barbatus), angler fish (L. piscatorius), blackbellied angler fish (L. budegassa), european conger (Conger conger), poor-cod (Trisopterus minutus capelanus), fourspotted megrim (Lepidorhombus boscii), soles (Solea spp.), horned octopus (Eledone cirrhosa), squids (Illex coindetii), gilthead seabream (Sparus aurata), European seabass (Dicentrarchus labrax), seabreams (Pagellus spp.), blue whiting (Micromesistius poutassou), tub gurnard (Chelidonichtys lucerna). The stock is in an overexploitation status with a relative low biomass with periodically higher recruitments (1998, 2001-2002 and 2007). Since 2007, the recruitment follows a decreasing trend and is currently at a low level. The recruitment estimated for 2015 is 38152 thousands individuals, which is below the series average (54906 thousands). The spawning stock biomass (SSB) displays a decreasing trend over the analysed period, especially in the very recent year. The exploitation level is currently above the level estimated to be sustainable. The reference point F0.1 (0.15), chosen as proxy of FMSY and as the exploitation reference point consistent with high long term yields is highly lower than current fishing mortality (Fcur=1,92). The exploitation is mainly concentrated on young individuals

Stock Assessment Form Demersal species. Hake - GSA7. Reference year: 1998-2016. Reporting year: 2017

Hake is one of the most important demersal target species for the commercial fisheries in the Gulf of Lions (GSA 7). In this area, hake is exploited by French trawlers, French gillnetters, Spanish trawlers and Spanish longliners. Since 1998, an average of 241 boats are involved in this fishery and, according to official statistics, the total annual catches for the period 1998-2016 have oscillated around an average value of 1914 tons (1057 tons in 2016). In 2009, because of the large decline of small pelagic fish species in the area, the trawlers fishing small pelagic have diverted their effort on demersal species. Between 1998 and 2016, the number of French trawlers operating in the GSA 07 has decreased by 50%. The French trawler fleet is the largest considering catches realized. The proportion of boats and catches are respectively (38% and 74%). The length of hake in the trawler catches ranges between 3 and 92 cm total length (TL), with an average size of 21 cm TL. The second largest fleet is the French gillnetters (46 and 16% respectively. range 13-86 cm TL and average size 39 cm TL), followed by the Spanish trawlers (12 and 11%. respectively. range 5-88 cm TL. and average size 24 cm TL), and the Spanish longliners (4 and 1%. respectively. range 22-96 cm TL and average size 50 cm TL). The hake trawlers exploit a highly diversified species assemblage: Striped red mullet (Mullus surmuletus), red mullet (M. barbatus), angler fish (L. piscatorius), blackbellied angler fish (L. budegassa), european conger (Conger conger), poor-cod (Trisopterus minutus capelanus), fourspotted megrim (Lepidorhombus boscii), soles (Solea spp.), horned octopus (Eledone cirrhosa), squids (Illex coindetii), gilthead seabream (Sparus aurata), European seabass (Dicentrarchus labrax), seabreams (Pagellus spp.), blue whiting (Micromesistius poutassou), tub gurnard (Chelidonichtys lucerna). The stock of European hake in GSA 7 was assessed over the period 1998-2016 applying an XSA analysis (using an R script developed by the Joint Research Center) calibrated with fishery independent survey abundance index (MEDITS). In addition, a yield-per-recruit (Y/R) analysis was carried out, over age classes ranging from 0 to 5+. An a4a analysis was also performed and compared to the XSA classical approach, involving sensitivity analyses on parameters to select the best run. The comparison of the a4a and XSA results displayed a good consistency as the trends for the various variables were found to be similar. Nevertheless, because of the overestimation of the last year estimated recruitment by the a4a model, the WG validated the use of the precautionary XSA approach for this assessment. These methods were applied using the FLR libraries in the statistical software R. Diagnosis of stock status: This stock is in an overexploitation status with a relative low biomass with periodically higher recruitments in 1998, 2001-2002 and 2007. Since 2007, the recruitment has followed a decreasing trend and is currently at a very low level. Since 2010, the fishing mortality has reached the highest levels of the time series. Moreover, spawning stock biomass (SSB) displays a decreasing trend over the analysed period and is at the lowest level of the series without any sign of improvement.The exploitation level is currently above the level estimated to be sustainable. The reference point F0.1 (0.15), chosen as proxy of FMSY and as the exploitation reference point consistent with high long term yields is highly lower than current fishing mortality (Fcur=1,91). The exploitation is mainly concentrated on young individuals

Stock Assessment Form Demersal species. Red mullet GSA7. Reference year: 2004-2014. Reporting year: 2015.

In the Gulf of Lions (GSA 7), red mullet is exploited by both French and Spanish trawlers. Information on French gillnetters is only available for 2011, 2013 and 2014, but although it is suspected that they have been fishing red mullet in the past, no data is available to quantify their catches. According to official statistics, during this period the total annual landings have oscillated around an average value of 216 tons and the French trawlers have been dominating the fishery, as they represent 82% of the catches (177 tons) on the period. After 2009, because of the large decline of small pelagic fish species in the area, the trawlers fishing small pelagic have diverted their effort on demersal species, this can explain the high levels of catches since 2010. Between 2004 and 2014, the number of French trawlers operating in the GSA 07 has decreased by 52%. From a maximum number of 121 trawlers in 2004, the French fleet catching red mullet is nowadays composed by 57 units. This follows management measures to reduce the number of boats. The mean modal lengths in the catches of the French and Spanish trawlers are 13.7 and 15 cm, respectively and the length at first capture is about 5 cm. Catch is mainly composed by individuals of age 0, 1 and 2 (Figure 6.1.3-2), while the oldest age class (4+ group) is poorly represented. In GSA 07, the trawl fishery is a multi-specific fishery. In addition to M. barbatus, the following species can be considered important by-catches: Merluccius merluccius, Lophius sp., Pagellus sp., Trachurus sp., Mullus surmuletus, Octopus vulgaris, Eledone sp., Scyliorhinus canicula, G. melastomus, Trachinus sp., Triglidae, Scorpaena sp

Stock Assessment Form Demersal species. Red mullet GSA7. Reference year: 2004-2015. Reporting year: 2016

In the Gulf of Lions (GSA 7), red mullet is exploited by both French and Spanish trawlers. Information on French gillnetters is only available for 2011, 2013, 2014 and 2015, but although it is suspected that they have been fishing red mullet in the past, no data is available to quantify their catches. According to official statistics, during this period the total annual landings have oscillated around an average value of 228 tons (351 tons in 2015) and the French trawlers have been dominating the fishery, as they represent 83% of the catches (189 tons) on the period. After 2009, because of the large decline of small pelagic fish species in the area, the French trawlers fishing small pelagic have diverted their effort on demersal species, this can explain the high levels of catches since 2010. Between 2004 and 2014, the number of French trawlers operating in the GSA 07 has decreased by 50%. From a maximum number of 121 trawlers in 2004, the French fleet catching red mullet is nowadays composed by 58 units. This follows management measures to reduce the number of boats. The mean modal lengths in the catches of the French and Spanish trawlers are 14 and 16 cm, respectively and the minimum length caught is about 5 cm. Catch is mainly composed by individuals of age 0, 1 and 2, while the oldest age class (3+ group) is poorly represented. In GSA 07, the trawl fishery is a multi-specific fishery. In addition to M. barbatus, the following species can represent important catches: Merluccius merluccius, Lophius sp., Pagellus sp., Trachurus sp., Mullus surmuletus, Octopus vulgaris, Eledone sp., Scyliorhinus canicula, G. melastomus, Trachinus sp., Triglidae, Scorpaena sp., Raja sp. The stock is in a High overfishing status with a relative high biomass and punctually higher recruitments (2006, 2007, 2010, 2013 and 2015). The exploitation level is currently above the level estimated to be sustainable since the referent point F0.1 is equal to 0.35 and current fishing mortality (Fcurrent) to 1.13. The current fishing mortality is the lowest of the series and the spawning stock biomass currently follows an upward trend with signs of stabilization in 2014-2015. The exploitation is mainly concentrated on young individuals (age 0-2). Moreover 75% of the recruitment is mature. The current biomass (2015) is above the 66th percentile, however computed over a relatively short time-period (2004-2015)

Stock Assessment Form Demersal species. Red mullet - GSA7. Reference year: 1998-2016. Reporting year: 2017

In the Gulf of Lions (GSA 7), red mullet is exploited by both French and Spanish trawlers. Information on French gillnetters is only available for 2011 and 2013-2016, but although it is suspected that they have been fishing red mullet in the past, no data is available to quantify their catches. According to official statistics, during the first part of this period (2004-2012), the total annual landings have oscillated around an average value of 190 tons; since 2012, landings have shown a clear increasing trend. French trawlers dominate the fishery, as they represent 88% of the catches (average 201 tons) for the entire period. After 2009, because of the large decline of small pelagic fish species in the area, the trawlers fishing small pelagic have diverted their effort on demersal species, which may partially explain the high levels of catches since 2010. Between 2004 and 2014, the number of French trawlers operating in the GSA 07 has decreased by 50%: From a maximum number of 121 trawlers in 2004, the French fleet catching red mullet is nowadays composed by 57 units. This follows management measures to reduce the number of boats. The mean modal lengths in the catches of the French and Spanish trawlers are 14 and 15 cm, respectively and the length at first capture is about 5 cm. Catch is mainly composed by individuals of age 0, 1 and 2 (Figure 6.1.3-2), while the oldest age class (3+ group) is poorly represented. In GSA 07, the trawl fishery is a multi-specific fishery. In addition to M. barbatus, the following species can represent important catches: Merluccius merluccius, Lophius sp., Pagellus sp., Trachurus sp., Mullus surmuletus, Octopus vulgaris, Eledone sp., Scyliorhinus canicula, G. melastomus, Trachinus sp., Triglidae, Scorpaena sp. and Raja sp. The assessment was carried out by means of Extended Survivor Analysis (XSA) over the period 2004-2016, calibrated with fishery independent survey abundance index (MEDITS). In addition, a yield-per-recruit (Y/R) analysis was carried out, over age classes ranging from 0 to 3+. These methods were applied using the FLR libraries in the statistical software R. The residuals, retrospective analyses and other sensitivity analysis performed confirm the stability of the assessment using XSA model. The stock is in a High overfishing status with a relative high biomass and an increasing trend in the recruitment. The exploitation level is currently above the level estimated to be sustainable since the referent point F0.1 is equal to 0.35 and current fishing mortality (Fcurrent) to 1.18 (average 2014-2016). The current fishing mortality follows fluctuations without clear trend and the spawning stock biomass currently follows an upward trend. The exploitation is mainly concentrated on young individuals (age 0-2). Moreover 75% of the recruitment is mature. The current biomass is above the 66th percentile, however computed over a relatively short time-period (2004-2016)

Stock Assessment Form Demersal species. Hake GSA7. Reference year: 1998-2014. Reporting year 2015

Hake is one of the most important demersal target species for the commercial fisheries in the Gulf of Lions (GSA 7). In this area, hake is exploited by French trawlers, French gillnetters, Spanish trawlers and Spanish longliners. Since 1998, an average of 243 boats are involved in this fishery and, according to official statistics, the total annual catches for the period 1998-2014 have oscillated around an average value of 2012 tons (1983 tons in 2014). In 2009, because of the large decline of small pelagic fish species in the area, the trawlers fishing small pelagic have diverted their effort on demersal species. Between 1998 and 2014, the number of French trawlers operating in the GSA 07 has decreased by 50%. The French trawler fleet is the largest considering catches realized, proportion of boats and catches are respectively (27% and 73%). The length of hake in the trawler catches ranges between 3 and 92 cm total length (TL), with an average size of 21 cm TL. The second largest fleet is the French gillnetters (41 and 16% respectively, range 13-86 cm TL and average size 39 cm TL), followed by the Spanish trawlers (9 and 10%, respectively, range 5-88 cm TL, and average size 24 cm TL), and the Spanish longliners (4 and 1%, respectively, range 22-96 cm TL and average size 52 cm TL). The hake trawlers exploit a highly diversified species assemblage: Striped red mullet (Mullus surmuletus), red mullet (M. barbatus), angler fish (L. piscatorius), blackbellied angler fish (L. budegassa), european conger (Conger conger), poor-cod (Trisopterus minutus capelanus), fourspotted megrim (Lepidorhombus boscii), soles (Solea spp.), horned octopus (Eledone cirrhosa), squids (Illex coindetii), gilthead seabream (Sparus aurata), European seabass (Dicentrarchus labrax), seabreams (Pagellus spp.), blue whiting (Micromesistius poutassou), tub gurnard (Chelidonichtys lucerna)

Stock Assessment Form Demersal species. Reference year: 2004-2013. Reporting year: 2014. Red mullet of the Gulf of Lions (GSA 07)

Fishery: In the Gulf of Lions (GSA 7), red mullet is exploited by both French and Spanish trawlers. Information on French gillnetters is only available for 2011 and 2013, but although it is suspected that they have been fishing red mullet in the past, no data is available to quantify their catches. Between 2004 and 2013, around 100 boats have been involved in the fishery. According to official statistics, during this period the total annual landings have oscillated around an average value of 200 tons and the French trawlers have been dominating the fishery, as they represent 73% of the catches (165 tons) on the period. After 2009, because of the large decline of small pelagic fish species in the area, the trawlers fishing small pelagic have diverted their effort on demersal species, this can explain the high catches of 2010. Between 1998 and 2013, the number of French trawlers operating in the GSA 07 has decreased by 39%, while it decreased by more than 30% between 2010 and 2013. From a maximum number of 123 trawlers in 2004, the French fleet catching red mullet is nowadays composed by 61 units. This follows management measures to reduce the number of boats. The mean modal lengths in the catches of the French and Spanish trawlers were 13.9 and 14.9 cm, respectively and the length at first capture is about 6 cm. Catch is mainly composed by individuals of age 0, 1 and 2 (Figure 3.1.2.), while the oldest age class (4+ group) is poorly represented. In GSA 07, the trawl fishery is a multi-specific fishery. In addition to M. barbatus, the following species can be considered important by-catches: Merluccius merluccius, Lophius sp., Pagellus sp., Trachurus sp., Mullus surmuletus, Octopus vulgaris, Eledone sp., Scyliorhinus canicula, G. melastomus, Trachinus sp., Triglidae, Scorpaena sp. Data and parameters: The information used for the assessment of the stock consisted in annual size composition of catches (estimated from monthly or quarterly sampling in the main landing ports), official landings and biological parameters estimated from data collected in the GSA 7 (2004-2013) by IFREMER for the DCF. These parameters are length-weight relationship, sex-ratio and maturity ogive. They were computed using inbio (R scripts developed by IEO). From 2004 to 2012, the length-weight relationship was used to compute the mean weight at age. For 2013 we used the weight estimates produced by COST tools. The mean weights at age were computed as the average of males and females abundance weighted by the catch numbers and the weights were adjusted by sop correction. Size compositions were converted from number at length to number at age by knife edge slicing (deriving the growth from DCF data) from 2004 to 2012, whereas in 2012 and 2013 age-length key from otolith readings were used. Natural mortality was estimated using PROBIOM (Abella et al., 1997). Assessment method: The assessment was carried out by means of Extended Survivor Analysis (XSA) over the period 2004-2013, and calibrated with indices from the scientific survey MEDITS, and yield-per-recruit (Y/R) for the period 2011-2013. These methods were applied using the FLR libraries in the statistical software R. Model performance: No concern was raised about that issue. Results: Fcurrent (average last 3 years, ages 0-3) 0.45 F0.1 (estimated in 2012) 0.14 Flim Fpa Biomass current (tons) 2011-2013 1022 Biomass (33th) 597 Biomass (66th) 690 Blim Bpa Bmsy Current Recruitment (Thousands) 2011-2013 35077 Fcurrent/F0.1 3.21 Diagnosis of stock status: The stock is in an overexploitation status with a relative high abundance and punctually higher recruitments (2005, 2006 and 2013). This diagnostic is based upon analytical results based on fishing mortality. The exploitation level is currently above the level estimated to be sustainable since the referent point F0.1 is equal to 0.14 and current fishing mortality (Fcurrent 2011-2013) is equal to 0.45. The current fishing mortality is the lowest of the series and the spawning stock biomass currently follows an upward trend. The exploitation is mainly concentrated on young individuals (age 0-2), moreover 60% of the recruitment (age 0) is mature. The current biomass (2011-2013) is above the 66th percentile. However computed over a relatively short time-period (2004-2013), the increase in spawning stock biomass and the decrease in fishing mortality have to be noticed. The important decrease in numbers of French trawler fleet since 1998, reducing the number of boats by 39%, is likely to start to have a positive effect on the stock. Advices and recommendation: Reduce fishing mortality -Improve the fishing pattern of the trawlers so that the minimum length of catches is consistent with the minimum legal landing size -Freezing of the effort in the Fishery Restricted Area It is important to notice that some management measures have been taken since 2011 (reduction from 2010 to 2013 by more than 30% of the number of trawlers). This measure was over at the end of 2013