The burden of lung cancer in Latin-America and challenges in the access to genomic profiling, immunotherapy and targeted treatments.

Lung cancer is a public health problem worldwide and Latin America (LATAM) cannot escape this reality. This malignant disease has not only a high prevalence in the region, but is also the main cause of cancer related deaths, and in other emerging countries, the incidence rates are still on the rise. Interestingly in most LATAM countries, lung cancer mortality has been decreasing in men but not in women, reflecting smoking patterns in countries such as Chile, Bolivia, and Brazil. Despite the fact that these issues are well known to government agencies, physicians and patients in the region, current efforts still fall behind those needed in order to face this problem of epidemic proportions. Tobacco control and smoking cessation are the most important interventions against lung cancer, but even with their optimal implementation (which is far from reality at this time) the number of cases in the foreseeable future would still be significant. Beyond tobacco control, advances in our understanding of the molecular component of lung cancer have resulted in new targeted therapies and immune check point inhibitors, which have improved clinical outcomes but at a considerably higher financial cost. LATAM has not widely and speedily adopted these strategies, including new technology and approved novel drugs, due to a number of facts, and therefore only a dismal proportion of LATAMs patient population have benefited from these new advances. A keen focus on a heterogeneous education system for caregivers in lung cancer treatment would likely help standardize care and improve future potential gains from domestic research. In this review we discuss the challenges of treatment implementation, focusing on new technologies.

Gender and outcomes in non-small cell lung cancer: an old prognostic variable comes back for targeted therapy and immunotherapy?

BACKGROUND: There are well-known differences in gender outcome in non-small cell lung cancer (NSCLC) and other cancers. In this work, we evaluated several randomised clinical trials to explore the gender influence in the outcome of patients with NSCLC treated with targeted therapy and immunotherapy. METHODS: We performed a series of meta-analysis to compare the gender outcome in the routine setting for overall survival and progression-free survival (PFS) in phase III randomised clinical trials comparing EGFR inhibitors versus chemotherapy (OPTIMAL, LUX-lung 3, LUX-lung 6, EURTAC, ENSURE and WTJOG); ALK inhibitors versus chemotherapy (ASCEND 4, ASCEND 5, PROFILE 1014 and NCT009323893) and anti-PD1 checkpoint inhibitors versus chemotherapy (CheckMate 017, CheckMate 026, CheckMate 057, KEYNOTE 010 and KEYNOTE 024). RESULTS: Female patients with NSCLC have a reduced risk of death compared with men (HR=0.73; 95% CI 0.67 to 0.79; p<0.00001). Women had a better benefit from EGFR inhibitors than men (HR=0.34; 95% CI 0.28 to 0.40; p<0.00001 vs HR=0.44; 95% CI 0.34 to 0.56; p<0.00001, respectively). The benefit from ALK inhibitors was similar for both genders (HR=0.51; 95% CI 0.42 to 0.61; p<0.00001 vs HR=0.48; 95% CI 0.39 to 0.59; p<0.00001, for women and men, respectively). Anti-PD1 inhibitors significantly improved the PFS in male patients when compared with chemotherapy (HR=0.76; 95% CI 0.68 to 0.86; p<0.00001); in contrast, women showed no benefit in 5/5 randomised trials (HR=1.03; 95% CI 0.89 to 1.20; p=0.69). CONCLUSIONS: In this exploratory study, some targeted treatments were influenced by gender. Despite differences in outcomes that could be attributed to different histology, EGFR and smoking status, gender should be evaluated more deeply as prognostic variable in patients with NSCLC.

Implementation of Computerized Physician Order Entry for Chemotherapy: A Latin American Experience.

PURPOSE: We describe the implementation process of a computerized physician order entry (CPOE) for outpatient chemotherapy at a Latin American hospital, with the intent of providing other institutions with general guidance and insight through our experience. METHODS: In 2012, under the direction of the Department of Medicine of the Instituto Nacional de Enfermedades Neoplásicas, a multidisciplinary team composed of oncologists, nurses, pharmacists, and informatics engineers was formed to develop software for a CPOE for chemotherapy within a preexistent homegrown electronic medical record system in various phases. This included mapping and redesigning processes in an entirely electronic format, integrating the needs of the user for the development of electronic order sets, developing a checkpoint and a warning system to minimize prescription errors, and finally, training all the staff in implementation of the system. RESULTS: A CPOE for outpatient chemotherapy was successfully implemented in 2016. We have successfully standardized 266 chemotherapy orders, including for both solid tumors and hematologic malignancies, on the basis of appropriate guidelines. The software is linked to laboratory results and allows entry of important details for the patient's safety, such as anthropometric information for an automatic dose calculation and ranges for safe prescription. In addition, it is linked to the nursing plan sheets. Finally, it is possible to assess and continuously monitor the complex process of chemotherapy prescription. CONCLUSION: This is the first report of implementation of a CPOE for chemotherapy in our region. The system was designed by a multidisciplinary team with its own resources. Our experience demonstrates the feasibility of computerizing the chemotherapy prescription process, constituting a tangible example for other institutions with potential impact on patient care.

In silico evaluation of DNA Damage Inducible Transcript 4 gene (DDIT4) as prognostic biomarker in several malignancies.

DDIT4 gene encodes a protein whose main action is to inhibit mTOR under stress conditions whilst several in vitro studies indicate that its expression favors cancer progression. We have previously described that DDIT4 expression is an independent prognostic factor for tripe negative breast cancer resistant to neoadjuvant chemotherapy. We herein report that high DDIT4 expression is related to the outcome (recurrence-free survival, time to progression and overall survival) in several cancer types. We performed in silico analysis in online platforms, in pooled datasets from KM Plotter and meta-analysis of individual datasets from SurvExpress. High levels of DDIT4 were significantly associated with a worse prognosis in acute myeloid leukemia, breast cancer, glioblastoma multiforme, colon, skin and lung cancer. Conversely, a high DDIT4 expression was associated with an improved prognostic in gastric cancer. DDIT4 was not associated with the outcome of ovarian cancers. Analysis with data from the Cell Miner Tool in 60 cancer cell lines indicated that although rapamycin activity was correlated with levels of MTOR, it is not influenced by DDIT4 expression. In summary, DDIT4 might serve as a novel prognostic biomarker in several malignancies. DDIT4 activity could be responsible for resistance to mTOR inhibitors and is a potential candidate for the development of targeted therapy.

Challenges in Facing the Lung Cancer Epidemic and Treating Advanced Disease in Latin America.

Lung cancer, the deadliest cancer worldwide, is of particular concern in Latin America. The rising incidence poses a myriad of challenges for the region, which struggles with limited resources to meet the health care needs of its low- and middle-income populations. In this environment, we are concerned that governments are relatively unaware of the pressing need to implement effective strategies for screening, diagnosis, and treatment of lung cancer. The region has also been slow in adopting molecularly-based therapies in the treatment of advanced disease: testing for epidermal growth factor receptor mutations and anaplastic lymphoma kinase rearrangements are not routine, and access to targeted agents such as monoclonal antibodies and tyrosine kinase inhibitors is problematic. In this paper, we review the current situation in the management of lung cancer in Latin America, hoping that this initiative will help physicians, patient associations, industry, governments, and other stakeholders better face this epidemic in the near future.

Repeated observation of immune gene sets enrichment in women with non-small cell lung cancer.

There are different biological and clinical patterns of lung cancer between genders indicating intrinsic differences leading to increased sensitivity to cigarette smoke-induced DNA damage, mutational patterns of KRAS and better clinical outcomes in women while differences between genders at gene-expression levels was not previously reported. Here we show an enrichment of immune genes in NSCLC in women compared to men. We found in a GSEA analysis (by biological processes annotated from Gene Ontology) of six public datasets a repeated observation of immune gene sets enrichment in women. "Immune system process", "immune response", "defense response", "cellular defense response" and "regulation of immune system process" were the gene sets most over-represented while APOBEC3G, APOBEC3F, LAT, CD1D and CCL5 represented the top-five core genes. Characterization of immune cell composition with the platform CIBERSORT showed no differences between genders; however, there were differences when tumor tissues were compared to normal tissues. Our results suggest different immune responses in NSCLC between genders that could be related with the different clinical outcome.