Distribution of molecular subtypes of advanced lung adenocarcinoma and clinical outcomes in a center of Argentina.

The prevalence of relevant oncogenic drivers in lung adenocarcinoma varies in our region and data on clinical outcomes is scarce. The objective of the study was to describe the prevalence of KRAS, BRAF and EGFR mutations and ALK translocations in patients with advanced lung adenocarcinoma, and to depict the clinical outcome according to treatment strategies. Patients with adequate tumor biopsy sampling were included. KRAS, BRAF and EGFR mutations were studied by Sanger sequencing. ALK translocations were studied by fluorescent in situ hybridization (FISH) and immunohistochemistry (IH) with antibodies against ALK with clones D5F3 and 5A4. Informed consent was signed by 118 patients and 84 (72%) with complete molecular analysis were included. KRAS mutations were detected in 16 samples (19%), EGFR in 11 (13%), 9 of them conferring sensitivity to EGFR inhibitors, and BRAF mutations in 1 (1%). ALK translocations were detected in 3 samples (4%). Median follow-up was 42.4 [interquartile range (IQR): 27.0-64.2] months. Globally, median overall survival was 10.3 [IQR: 5.6-20.2] months. Median survival was 10.8 [IQR: 6.0-20.3] months in the group of patients without detectable molecular alteration, 9.6 [IQR: 3.7-16.1] months in KRAS mutant population (HR: 1.08; p = 0.82) and 32.5 [IQR: 19.6-38.4] months in patients with ALK translocations or sensitizing EGFR mutated tumors treated with tyrosine kinase inhibitors (HR: 0.27; p = 0.03). In conclusion, the prevalence of molecular alterations and outcomes in our population is similar to that reported in other studies in Western countries.

Correlation between PD-L1 expression (clones 28-8 and SP263) and histopathology in lung adenocarcinoma.

Lung cancer is the leading cause of cancer-related death worldwide. Recent advances in the management of non-small cell carcinoma are focused on the discovery of targeted therapies and novel immunotherapy strategies for patients with advanced disease. Treatment with anti PD-(L)1 immune checkpoint inhibitors requires the development of predictive biomarkers to select those patients that can most benefit from these therapies. Several immunohistochemical biomarkers have been developed in different technological platforms. However, the most useful and accessible for the daily clinical practice need to be selected. The objective of this study was to compare PD-L1 expression by automated immunohistochemistry in lung adenocarcinoma (ADC) FFPE samples with clones 28-8 and SP263 performed with the BenchMark GX automated staining instrument. To further determine interobserver agreement between two pathologists, and to correlate the results with histologic and pathology variables. FFPE tissue from 40 samples obtained from patients with lung ADC were reviewed retrospectively. Among all studied specimens, 53% of samples presented <1% of positive tumor cells with the 28-8 clone and 50% had <1% of PD-L1 expression in tumor cells with the SP263 clone; PD-L1 expression between ≥1 and <5% was observed in 18% and 24%; ≥5 and <50% PD-L1 expression in 18% and 21%; and ≥50% PD-L1 expression in 11% and 5% of samples, respectively. Similar results between antibodies were observed in 84% of cases for each of the four PD-L1 cutoff groups (Pearson's score 0.90, p < 0.00001). The interobserver degree of agreement calculated with Kappa was 0.75 (95%CI: 0.57-0.93), z = 7.08; p < 0.001. Lepidic, acinar and mucinous patterns had predominantly <1% PD-L1 expression, and the solid pattern subtype had high levels of PD-L1 staining using both clones. PD-L1 expression in less than 1% of tumor cells was similar in stages I/II compared to III/IV. No significant differences were observed in PD-L1 staining and quantification pattern between IHC antibodies 28-8 and SP263.

Novel approaches to target HER2-positive breast cancer: trastuzumab emtansine.

The human epidermal growth factor receptor 2 (HER2) is overexpressed in 20% of breast carcinomas. Prior to the development of targeted therapies, HER2-positive breast cancer was associated with more aggressive disease and poor prognosis. Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that results from the combination of trastuzumab and DM1, a derivative of the antimicrotubule agent maytansine. This molecule has the ability to enhance cytotoxic drug delivery to specifically targeted cells that overexpress HER2, therefore, maximizing efficacy while sparing toxicity. In recent years, T-DM1 has shown to improve outcomes in metastatic HER2-positive breast cancer that is resistant to trastuzumab. In addition, T-DM1 is currently being tested in the neoadjuvant and adjuvant settings to identify patients who may benefit from this therapy. This review focuses on the mechanism of action, early and late-phase clinical trials, and ongoing studies of T-DM1 in HER2-positive breast cancer.

What is the Current Role of Immunotherapy for Colon Cancer?

Colon cancer is a leading cause of cancer related mortality. Until very recently the only existing options that medical oncologists had to treat metastatic colon cancer were a combination of chemotherapy, anti-EGFR and anti-angiogenic agents. We currently have the first proof that immune therapies could be an effective approach to battle colorectal cancers that carry a mismatch repair machinery deficient phenotype. It is expected that as our knowledge of the different mechanisms of immune-resistance grows, this therapeutic modality might soon be applicable to all patients. However, due to the continuous increase in the cost of oncological drugs, some treatment overheads may soon become prohibitive for many. In this review we will examine the current evidence related to this topic with the objective to provide the reader with concise but practical information about the potential role of immunotherapy in CRC.

Immunotherapy for Non-Small Cell Lung Cancer - Finally a Hint of Hope.

Lung cancer is a major public health problem worldwide and the leading cause of cancerrelated mortality in developed countries. Significant advances have been made especially with the discovery of targeted agents. However, only a small proportion of patients carry activating mutations; until recently conventional chemotherapy and angiogenesis inhibitors were the preferred treatment for the vast majority of patients. Now, the successful experience of anti-PD-1 agents may have opened the door to a novel and previously unexplored dimension in the treatment of lung cancer: immunotherapy. In this mini-review we will discuss the current applications and future consequences related this topic, paying special attention to the clinical studies that constitute the scientific evidence to supports its use.

Anti-Hormonal Therapies for Premenopausal Patients--What did we Learn from the TEXT/SOFT Trials?

Between 20-25% of all breast cancers are diagnosed in patients younger than 50 years of age, most of whom are still premenopausal. Currently, tamoxifen is considered the standard of care for adjuvant treatment in these cases. However, in postmenopausal women, aromatase inhibitors (AIs) are a better choice. Given the superiority of AIs over tamoxifen in postmenopausal women, multiple investigators explored the potential role of AIs in premenopausal patients receiving ovarian suppression. Until very recently, available data derived from the ABCSG-12 clinical trial argued against the combination of AIs and ovarian suppression. This idea, however, may have changed with the release of the combined analysis of two clinical trials: SOFT and TEXT which evaluated the use of ovarian suppression in combination therapy. Clinicians will soon reconsider the possibility of using this strategy for premenopausal patients. Given the availability of this new data this review will analyze the consequences derived from this study, contextualize this new information within the vast available literature of anti-hormonal therapy, and discuss potential arguments in favor of and against the use of this approach.

Recent treatment advances and novel therapies in pancreas cancer: a review.

PURPOSE: Over the last couple of years, we have witnessed the availability of a wide variety of different therapeutic agents and the identification of effective combinations of existing ones that have transformed the way we approach and treat pancreatic cancer. Proof of this are the recent validations that combinations of conventional chemotherapy drugs, the FOLFIRINOX regimen and gemcitabine plus nab-paclitaxel, significantly improves clinical outcomes in patients with metastatic disease. However, deeper and more sophisticated understanding of the biology of this cancer as well as the ability to develop better and perhaps more precise drugs predict that the landscape may be changing even more. METHODOLOGY AND RESULTS: In this review, we will summarize the most recent treatment advances including FOLFIRINOX, gemcitabine plus nab-paclitaxel and discuss novel approaches such as immune-mediated therapies, drugs that disrupt the tumor-stromal compartment, PARP inhibitors for BRCA pathway-deficient pancreatic cancer and new generations of conventional chemotherapeutics, which are in early phases of clinical development and have shown promising early results. We will also discuss some examples of drugs that failed, despite very good preliminary data, in order to appraise the lessons learned from these negative clinical trials. Lastly, we will comment on ongoing adjuvant and neoadjuvant trials. CONCLUSION: We hope that at least some of these will result in positive trials and add to our armamentarium for treating this challenging malignancy.

Therapeutic options for HER-2 positive breast cancer: Perspectives and future directions.

During the last 15 years we have witnessed an unprecedented expansion in the drugs developed to target human epidermal growth factor receptor-2 (HER-2) positive breast cancer. Trastuzumab, pertuzumab, ado-trastuzumab emtansine and lapatinib are currently food and drug administration (FDA)-approved for the treatment of breast cancer patients with HER-2 over-expressed. However, given the amount of information gathered from years of uninterrupted clinical research, it is essential to have periodic updates that succinctly recapitulate what we have learnt over these last years and help us to apply that information in our daily practice. This review will pursue that objective. We will summarize the most relevant and updated information related to the state of the art management of HER-2 positive breast cancer in all the clinical scenarios including the adjuvant, neoadjuvant and metastatic settings. But we will also critically appraise that literature in order to highlight some key clinical concepts that should not be overlooked. Lastly, this review will also point out some of the most promising strategies that are currently being tested and may soon become available.

Advances and new perspectives in the treatment of metastatic colon cancer.

During the last decade we have witnessed an unprecedented outburst of new treatment approaches for the management of metastatic colon cancer. Anti-angiogenic drugs, epidermal growth factor receptor blockers and multi-kinase inhibitors have all resulted in small but consistent improvement in clinical outcomes. However, this progress has paradoxically leaded us into new challenges. In many cases the clinical development was done in parallel and the lack of head-to-head comparison evolved into circumstances where several valid new "standards of care" are available. Even though desirable in essence, the availability of many options as well as different possible combinations frequently leaves the busy clinician in the difficult situation of having to choose between one or the other, sometimes without solid evidence to support each decision. In addition, progress never stops and new agents are continuously tested. For these reason this review will try to summarize all the clinical trials that constitute the theoretical framework that support our daily practice but will also procure the reader with rational answers to common clinical dilemmas by critically appraising the current literature. Lastly, we will provide with a compilation of promising new agents that may soon become our next line of defense against this deadly disease.

Distribution of molecular subtypes of advanced lung adenocarcinoma and clinical outcomes in a center of Argentina

The prevalence of relevant oncogenic drivers in lung adenocarcinoma varies in our region and data on clinical outcomes is scarce. The objective of the study was to describe the prevalence of KRAS, BRAF and EGFR mutations and ALK translocations in patients with advanced lung adenocarcinoma, and to depict the clinical outcome according to treatment strategies. Patients with adequate tumor biopsy sampling were included. KRAS, BRAF and EGFR mutations were studied by Sanger sequencing. ALK translocations were studied by fluorescent in situ hybridization (FISH) and immunohistochemistry (IH) with antibodies against ALK with clones D5F3 and 5A4. Informed consent was signed by 118 patients and 84 (72%) with complete molecular analysis were included. KRAS mutations were detected in 16 samples (19%), EGFR in 11 (13%), 9 of them conferring sensitivity to EGFR inhibitors, and BRAF mutations in 1 (1%). ALK translocations were detected in 3 samples (4%). Median follow-up was 42.4 [interquartile range (IQR): 27.0-64.2] months. Globally, median overall survival was 10.3 [IQR: 5.6-20.2] months. Median survival was 10.8 [IQR: 6.0-20.3] months in the group of patients without detectable molecular alteration, 9.6 [IQR: 3.7-16.1] months in KRAS mutant population (HR: 1.08; p = 0.82) and 32.5 [IQR: 19.6-38.4] months in patients with ALK translocations or sensitizing EGFR mutated tumors treated with tyrosine kinase inhibitors (HR: 0.27; p = 0.03). In conclusion, the prevalence of molecular alterations and outcomes in our population is similar to that reported in other studies in Western countries.

La prevalencia de alteraciones en oncogenes en adenocarcinoma de pulmón varía en nuestra región. El objetivo fue describir la prevalencia de mutaciones en KRAS, BRAF y EGFR y las translocaciones de ALK en pacientes con adenocarcinoma de pulmón y estudiar la supervivencia de acuerdo a subtipos moleculares. Se incluyeron pacientes con biopsias adecuadas para el estudio. Se evaluó el estado mutacional de KRAS, BRAF y EGFR por secuenciación con la técnica de Sanger. Las translocaciones de ALK se estudiaron por hibridación in situ por fluorescencia (FISH) e inmunohistoquimica (IHQ) contra ALK (clones D5F3 y 5A4). De 118 pacientes evaluados, se incluyeron 84 (72%) con análisis molecular completo. Se detectaron mutaciones de KRAS en 16 muestras (19%), EGFR en 11 (13%), y BRAF en 1 muestra (1%). Se detectaron rearreglos de ALK en 3 muestras (4%). La mediana de seguimiento de los pacientes fue de 42.4 [rango intercuatilo (RIC): 27.0-64.2] meses. Globalmente, la mediana de supervivencia en la población fue 10.3 [RIC: 5.6-20.2] meses y fue de 10.8 [RIC: 6.0 20.3] meses en pacientes sin alteraciones moleculares detectables. La mediana de supervivencia de los pacientes con mutación en KRAS fue de 9.6 [RIC: 3.7-16.1] meses (HR: 1.08; p = 0.82) y 32.5 [RIC: 19.6-38.4] meses en el grupo con rearreglos de ALK o mutaciones en EGFR tratados con inhibidores de tirosina quinasa (HR: 0.27; p = 0.03). En conclusión, la prevalencia de alteraciones moleculares en nuestra población fue similar a otros países occidentales.

Novel targeted agents for the treatment of advanced breast cancer.

The discovery of the molecular processes involved in cancer development has led to the design of an array of targeted agents. These agents, directed to specific proteins in the machinery of cancer cells, interfere with vital cascades involved in cell invasion, metastasis, apoptosis, cell-cycle control and angiogenesis. In breast cancer, the main pathways studied and targeted by drugs are the HER2 pathway, EGFR, VEGF, PI3K/Akt/mammalian target of rapamycin (PI3K-M-Tor), IGF/IGFR, poly(ADP ribose) polymerase 1, HDAC and many others. In this review, we present the most promising studies of these new targeted therapies and novel combination of targeted therapies with cytotoxic agents for the treatment of breast cancer patients.

Trastuzumab subcutaneo en el tratamiento del cancer de mama HER2 positivo / Subcutaneous trastuzumab in breastcancer treatment of her2 positive

La sobreexpresión o amplificación del receptor HER2 seobserva en el 20% de pacientes con cáncer de mama y seasocia con un pronóstico adverso. El agente anti HER2más ampliamente utilizado en la clínica es el trastuzumab,anticuerpo monoclonal. El tratamiento adyuvante tieneuna duración de 12 meses y en cáncer de mama metastásicose continúa más allá de la progresión. La mayoría delos pacientes recibirá trastuzumab durante 1 año, muchosrecibirán 2 a 3 años, y algunos han recibido/recibirán más de8 años. Surge así un interés creciente por la vía subcutánea(SC) de administración: menos invasiva, menos costosay más cómoda. El estudio HannaH, ensayo de fase III,abierto y aleatorizado, utilizó una dosis fija subcutánea de600 mg de trastuzumab en combinación con quimioterapianeoadyuvante y la comparó con la vía de administraciónendovenosa (EV) aprobada. Se incluyeron pacientes concáncer de mama HER2 (+) operable, localmente avanzado einflamatorio. Los objetivos primarios fueron: concentraciónsérica mínima predosis del ciclo 8 y respuesta patológicacompleta. Se aleatorizaron 299 pacientes a trastuzumab EVy 297 a trastuzumab SC. La concentración sérica mínimamedia fue 57.8 μ/ml en el grupo EV y 78.7 en el grupo SC.El 40.7% de los pacientes en el grupo EV y el 45.4% en elgrupo SC logró respuesta patológica completa. TrastuzumabSC resultó no inferior para ambos objetivos primarios.La incidencia de eventos adversos grados 3 a 5 fue similar enambos grupos. La demostración de no-inferioridad sugiereque el trastuzumab SC ofrece una válida y más convenientealternativa al trastuzumab EV.

Overexpression or amplification of HER2 is found in 20%of patients with breast cancer and is associated with anunfavourable prognosis. Trastuzumab is the anti HER2agent most widely used in clinical practice. Adjuvanttreatment should be given during 12 months, and in themetastatic setting treatment should continue beyond progression.Most patients will receive treatment during oneyear, many will be treated during 2 to 3 years, and somepatients will remain in treatment for more than 8 years.In this context, a subcutaneous route of administrationbecomes an attractive option: less invasive, less costly,and more comfortable for patients. The HannaH study is a phase III, open, randomized clinical trial that used a fixedsubcutaneous dose of 600 mg of trastuzumab in combinationwith neoadjuvant chemotherapy and compared it tothe approved intravenous (IV) route of administration.Patients with HER2 (+) operable, locally advanced andinflammatory breast cancer were included in the study.Primary endpoints included: serum trough concentrationpre-dose cycle 8 and pathologic complete response. Twohundred and ninety-nine patients were randomized to IVtrastuzumab and 297 to SC trastuzumab. Mean serumtrough concentration was 57.8 μ/ml in the IV group and78.7 in the SC group. In the IV group 40.7% of patientsachieved pathologic complete response, and 45.4% in the SCgroup. The SC formulation resulted non-inferior for bothprimary objectives. Incidence of grade 3-5 adverse eventswas similar in both groups. The non-inferior results suggestthat SC trastuzumab is a valid and more convenientalternative to IV trastuzumab.