Association of PD-L1 expression with driver gene mutations and clinicopathological characteristics in non-small cell lung cancer: A real-world study of 10 441 patients.

BACKGROUND: Programmed death ligand-1 (PD-L1) expression is a well-known predictive biomarker of response to immune checkpoint blockade in non-small cell lung cancer (NSCLC). However, there is limited evidence of the relationship between PD-L1 expression, clinicopathological features, and their association with major driver mutations in NSCLC patients in Latin America. METHODS: This retrospective study included patients from Argentina with advanced NSCLC, and centralized evaluation of PD-L1 expression concurrently with genomic alterations in the driver genes EGFR, ALK, ROS1, BRAF, and/or KRAS G12C in FFPE tissue samples. RESULTS: A total of 10 441 patients with advanced NSCLC were analyzed. Adenocarcinoma was the most frequent histological subtype (71.1%). PD-L1 expression was categorized as PD-L1 negative (45.1%), PD-L1 positive low-expression 1%-49% (32.3%), and PD-L1 positive high-expression ≥50% (22.6%). Notably, current smokers and males were more likely to have tumors with PD-L1 tumor proportion score (TPS) ≥50% and ≥ 80% expression, respectively (p < 0.001 and p = 0.013). Tumors with non-adenocarcinoma histology had a significantly higher median PD-L1 expression (p < 0.001). Additionally, PD-L1 in distant nodes was more likely ≥50% (OR 1.60 [95% CI: 1.14-2.25, p < 0.01]). In the multivariate analysis, EGFR-positive tumors were more commonly associated with PD-L1 low expression (OR 0.62 [95% CI: 0.51-0.75], p < 0.01), while ALK-positive tumors had a significant risk of being PD-L1 positive (OR 1.81 [95% CI: 1.30-2.52], p < 0.01). CONCLUSIONS: PD-L1 expression was associated with well-defined clinicopathological and genomic features. These findings provide a comprehensive view of the expression of PD-L1 in patients with advanced NSCLC in a large Latin American cohort.

Overcoming Resistance to Osimertinib by T790M Loss and C797S Acquisition Using Gefitinib in a Patient With EGFR-Mutant NSCLC: A Case Report.

Limited strategies are available at disease progression on osimertinib for patients with EGFR-mutant NSCLC. The emergence of the on-target EGFR C797S mutation has been described as one of the most common mechanisms of resistance. In addition, loss of the EGFR T790M mutation has been mainly investigated as a resistance phenomenon to second-line osimertinib exposure. Remarkably, by studying the molecular profile at progression, it has been reported that the presence of the EGFR-sensitizing mutation, concurrently with the T790M, and C797S resulted in resistance to the current available EGFR tyrosine kinase inhibitors. Here, we report the first clinical evidence of gefitinib efficacy at EGFR exon 19 deletion/C797S mutation/T790M loss-mediated resistance to first-line osimertinib. Our findings highlight that dynamic genetic monitoring is a crucial approach in the evolution of EGFR-mutant NSCLC to understand the acquired molecular mechanisms for driving the best treatment strategy.

Precision medicine in the real-world setting. Clinical activity of talazoparib in a woman with hormone receptor-positive HER2-negative metastatic breast cancer with pathogenic mutation in somatic BRCA2.

Background: Next-generation sequencing (NGS) has proven to be a key implementation to understanding biological pathways involved in cancer. In daily practice, the identification of somatic and germline mutations has allowed physicians to gather relevant information to make therapeutic decisions and benefit patients. Importantly, somatic mutations provide targeted opportunities for treatment and reveal resistance mechanisms to understand patients' tumour evolution. Scanty data in clinical trials and in a real-world setting is available regarding the utility of poly(ADP-ribose) polymerase inhibitors in pathogenic or likely-pathogenic somatic breast cancer gene 1/2 (BRCA1/2) mutations and/or germline or somatic Homologous Recombination-Related Gene mutations in advanced breast cancer (ABC). Case report: Here we report a real-life case of a 47-year-old postmenopausal woman with hormone receptor-positive (HR-positive) Epidermal growth factor receptor 2 (HER2)-negative metastatic BC that had poor response to classic therapeutic strategies for HR+/HER2- ABC. At this point, the possibility of using NGS to guide the treatment was decided in a Molecular Tumour Board (MTB), and the patient had a major response to talazoparib targeting a non-germline BRCA2 mutation. Conclusion: Undoubtedly, more information regarding the cost effectiveness of NGS is needed to develop adequate reimbursement policies for this technology. It should be highlighted that the generalisation of MTBs and the implementation of molecular screening programmes are greatly needed in our region to gain more knowledge of somatic mutations implicated in the Hispanic and Latin-American population with BC diagnosis. Recently presented results of randomised studies may support the evaluation of somatic mutations with NGS to find targeted therapies for ABC patients.

Implementation of a molecular tumour board in LATAM: the impact on treatment decisions for patients evaluated at Instituto Alexander Fleming, Argentina.

BACKGROUND: The role of the molecular tumour board (MTB) is to recommend personalised therapy for patients with cancer beyond standard-of-care treatment. A comprehensive molecular analysis of the tumour in a molecular pathology laboratory is important for all targeted therapies approaches. Here we report the 1-year experience of the Instituto Alexander Fleming Molecular Tumour Board. PATIENTS AND METHODS: The MTB of the Instituto Alexander Fleming was launched in December 2019 in a monthly meeting. In each interactive monthly session, five cases were presented and discussed by the members. These cases were referred by the treating oncologists. The MTB recommendations were sent to each physician individually, and to the rest of the meeting participants. This was discussed with the patients/families by the treating oncologist. The final decision to choose therapy was left to the treating physicians. Of the 32 patients presented at MTB, 28 (87.5%) had potentially actionable alterations and only 4 (12.5%) had no actionable mutation. Six (19%) patients received a local regulatory agency approved drug recommendation, nine (28%) patients received an off-label approval treatment recommendation and three (9%) patients did not receive the treatment due to access and reimbursement of the drug. CONCLUSION: In most of the cases evaluated, the MTB was able to provide treatment recommendations based on targetable genetic alterations. Molecular-guided extended personalised patient care is effective for a small but clinically significant proportion of patients in challenging clinical situations. We believe that the implementation of a MTB is feasible in the Latin America (LATAM) region.

Peripheral changes in immune cell populations and soluble mediators after anti-PD-1 therapy in non-small cell lung cancer and renal cell carcinoma patients.

Patients with non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) have shown benefit from anti-PD-1 therapies. However, not all patients experience tumor shrinkage, durable responses or prolonged survival, demonstrating the need to find response markers. In blood samples from NSCLC and RCC patients obtained before and after anti-PD-1 treatment, we studied leukocytes by complete blood cell count, lymphocyte subsets using flow cytometry and plasma concentration of nine soluble mediators, in order to find predictive biomarkers of response and to study changes produced after anti-PD-1 therapy. In baseline samples, discriminant analysis revealed a combination of four variables that helped differentiate stable disease-response (SD-R) from progressive disease (PD) patients: augmented frequency of central memory CD4+ T cells and leukocyte count was associated with response while increased percentage of PD-L1+ natural killer cells and naïve CD4+ T cells was associated with lack of response. After therapy, differential changes between responders and non-responders were found in leukocytes, T cells and TIM-3+ T cells. Patients with progressive disease showed an increase in the frequency of TIM-3 expressing CD4+ and CD8+ T cells, whereas SD-R patients showed a decrease in these subsets. Our findings indicate that a combination of immune variables from peripheral blood (PB) could be useful to distinguish response groups in NSCLC and RCC patients treated with anti-PD-1 therapy. Frequency of TIM-3+ T cells showed differential changes after treatment in PD vs SD-R patients, suggesting that it may be an interesting marker for monitoring progression during therapy.

Rol de la biopsia del ganglio centinela en el carcinoma ductal in situ y en el microinvasor: experiencia del Instituto de Oncología Alexander Fleming / Rol of Sentinel Node Biopsy in Ductal Carcinoma In Situ and Microinvasive Breast Cancer: Instituto Alexander Fleming Experience

Determinar la incidencia de ganglio centinela (GC) positivo en pacientes con Carcinoma ductal in situ (CDIS) y microinvasor (T1mic); y describir las características clinicopatológicas de los mismos en relación con el compromiso axilar. Material y método: Se realizó un estudio retrospectivo en 46 pacientes con diagnóstico de CDIS y en 88 pacientes con T1mic a las cuales se les realizó la biopsia del ganglio centinela (BGC), en el período comprendido entre marzo de 1999 y octubre de 2013. Para el análisis estadístico, se utilizó el programa SPSS 17.0. Resultados: Una paciente de 46 (2,1%) con CDIS presentó una micrometástasis en el estudio diferido. No se completó la linfadenectomía axilar (LA). En 4 de las 88 pacientes (4,5%) con T1mic, el GC fue positivo (2 micrometástasis y 2 macrometástasis). A este grupo se le efectuó linfadenetomía axilar (LA); A este grupo se le efectuó linfadenetomía axilar (LA); una paciente presentó un ganglio positivo (micrometástasis) en los ganglios no centinela (GNC). Cuatro pacientes (4,5%) con T1mic presentaron recidiva en la mama y una (1,1%) a distancia. No hubo recurrencias en la paciente con CDIS. En todos estos casos, el GC había sido negativo. Conclusiones: Nuestros resultados son coincidentes con los de la literatura mundial. Actualmente, en el CDIS, no indicamos la BGC, excepto en CDIS extensos, sospecha de invasión en biopsias con aguja gruesa o cuando la paciente debe ser sometida a una mastectomía. A pacientes con T1mic les realizamos la BGC...

Assessment of early response to imatinib 800 mg after 400 mg progression by ¹8F-fluorodeoxyglucose PET in patients with metastatic gastrointestinal stromal tumors.

INTRODUCTION: Imatinib is the standard first-line therapy for advanced gastrointestinal stromal tumor. (18)F-fluorodeoxyglucose PET computed tomography (FDG PET/CT) shows a faster response than computed tomography in nonpretreated patients. PATIENTS & METHODS: After disease progression on imatinib 400 mg, 16 patients were exposed to 800 mg. Tumor response was evaluated by FDG PET/CT on days 7 and 37. Primary objective was to correlate early metabolic response (EMR) with progression-free survival (PFS). RESULTS: EMR by FDG PET/CT scan was not predictive of PFS. Median PFS in these patients was 3 months. Overall survival was influenced by gastric primary site (p = 0.05). CONCLUSION: The assessment of EMR by FDG PET/CT in patients with advanced gastrointestinal stromal tumor exposed to imatinib 800 mg was not predictive of PFS or overall survival.

Tumores carcinoides pulmonares tratados quirúrgicamente valor pronóstico de la 7ª estadificación TNM

Con el objetivo de evaluar el valor pronóstico de la 7a estadificación TNM se analizaron 43 mujeres (61%) y 28 hombres (39%) con diagnóstico de tumor carcinoide tratados quirúrgicamente desde enero/1975 hasta diciembre/2011. Mediana de edad: 38 años (13-67). Presentaron carcinoide típico (CT) 63 (89%) pacientes y 8 (11%) carcinoide atípico (CA). Mediana de seguimiento: 4 años (1 - 24 años). Los estadios correspondientes a CT fueron: IA = 33 (52%), IB = 10 (16%), IIA = 2 (3%), IIB = 2 (3%), IIIA = 12 (19%) y IIIB = 2 (3%); para los CA fueron: IA = 1 (12.5%), IIB = 1 (12.5%), IIIA = 2 (25%) y IIIB = 4 (50%). No hubo diferencia estadísticamente significativa en la supervivencia global a cinco años en el análisis estratificando por estadios (p = 0.689), ni analizando separadamente cada tipo histológico (CT p = 0.547; CA p = 0.592). El intervalo libre de enfermedad fue significativamente menor (CT: 3 años vs CA: 2 años, p = 0.000) y las recaídas más frecuentes en el grupo de carcinoides atípicos (CA: 50% vs CT: 2%, p = 0.000). Los pacientes con CT presentaron buena evolución aun en estadios avanzados, mientras que los que tuvieron CA presentaron menor tiempo de supervivencia e intervalo libre de enfermedad, y mayor frecuencia de recurrencia. El subtipo histológico resultó un factor significativo de pronóstico, mientras que la 7ª estadificación TNM no contribuyó en predecir la supervivencia en los tumores carcinoides.

We analyzed 43 women (61%) and 28 men (39%) surgically treated for carcinoid tumors from Jan/1975 to Dec/2011. Median age: 38 years (13-67). Typical carcinoid (TC) appeared in 63 (89%) patients, 8 (11%) suffered from atypical carcinoid (AC). Median follow-up: 4 years (1-24). TC stages were: IA = 33 (52%), IB = 10 (16%), IIA = 2 (3%), IIB = 2 (3%), IIIA = 12 (19%) and IIIB = 2 (3%); AC stages were: IA = 1 (12.5%), IIB = 1 (12.5%), IIIA = 2 (25%) and IIIB = 4 (50%). TNM classification did not show significant differences on 5-years survival period by stage (p = 0.689), even according to histological type (TC: p = 0.547; AC: p = 0.592). The disease-free survival rate was significantly lower (TC: 3 years vs. AC: 2 years, p = 0.000) and relapses were more frequent in AC (AC: 50% vs. TC: 2%, p = 0.000). The 7th TNM staging was not influential in estimating survival from carcinoid tumours in our population. The histological subtype was a better prognostic factor.

[Surgically treated bronchopulmonary carcinoid tumours. Prognostic value of TNM staging 7a edition]. / Tumores carcinoides pulmonares tratados quirúrgicamente. Valor pronóstico de la 7a estadificación TNM.

We analyzed 43 women (61%) and 28 men (39%) surgically treated for carcinoid tumors from Jan/1975 to Dec/2011. Median age: 38 years (13-67). Typical carcinoid (TC) appeared in 63 (89%) patients, 8 (11%) suffered from atypical carcinoid (AC). Median follow-up: 4 years (1-24). TC stages were: IA = 33 (52%), IB = 10 (16%), IIA = 2 (3%), IIB = 2 (3%), IIIA = 12 (19%) and IIIB = 2 (3%); AC stages were: IA = 1 (12.5%), IIB = 1 (12.5%), IIIA = 2 (25%) and IIIB = 4 (50%). TNM classification did not show significant differences on 5-years survival period by stage (p = 0.689), even according to histological type (TC: p = 0.547; AC: p = 0.592). The disease-free survival rate was significantly lower (TC: 3 years vs. AC: 2 years, p = 0.000) and relapses were more frequent in AC (AC: 50% vs. TC: 2%, p = 0.000). The 7th TNM staging was not influential in estimating survival from carcinoid tumours in our population. The histological subtype was a better prognostic factor.

Utilidad del cisplatino intrapericárdico en el tratamiento del derrame pericárdico maligno / Usefulness of Intrapericardial Cisplatin for the Management of Malignant Pericardial Effusion

Introducción El derrame pericárdico maligno recidiva en hasta el 62% de los pacientes luego de una pericardiocentesis. Debido a ello, se ha intentado completar el tratamiento con la instilación intrapericárdica de drogas luego del drenaje de la cavidad. El cisplatino ha demostrado que es útil y seguro para ese propósito. Objetivo Presentar la experiencia en nuestra institución del uso del cisplatino intrapericárdico en el tratamiento del derrame pericárdico maligno. Material y métodos Se incluyeron los pacientes ingresados en el Instituto Alexander Fleming entre enero de 2005 y mayo de 2009 con diagnóstico de taponamiento cardíaco o de derrame pericárdico grave tratados con drenaje percutáneo e instilación de cisplatino intrapericárdico (10 mg en 20 ml de solución fisiológica por 5 días). Se requirió: a) confirmación citológica de malignidad o b) hallazgo ecocardiográfico de lesiones compatibles con invasión neoplásica del saco pericárdico y c) poca expectativa de respuesta a un tratamiento sistémico. Resultados Se incluyeron 9 pacientes (6 hombres y 3 mujeres), edad media 60 años (51-69). El tumor primario fue pulmonar (n = 4), de mama (n = 1), de vejiga (n =1), de esófago (n = 1), de riñón (n = 1) y de próstata (n = 1). La citología fue positiva en 6 casos. El tiempo de permanencia del catéter fue de 7 días. Hubo efectos adversos en tres casos: dolor, fiebre y fibrilación auricular. Un solo paciente tuvo recidiva del derrame al mes. Ocho pacientes fallecieron [tiempo medio a la muerte: 50 días (7-83)] y uno vive. Conclusiones El cisplatino intrapericárdico resulta factible de realizar, se tolera bien y se observa un porcentaje bajo de recidivas, lo cual cumple con el objetivo del tratamiento.

The recurrence rate of malignant pericardial effusion after pericardiocentesis is 62%. For this reason, intrapericardial instillation of therapeutic agents is performed after pericardial evacuation to improve the treatment. Cisplatin has proved to be a useful and safe agent. Objective To present our experience with intrapericardial instillation of cisplatin for the management of malignant pericardial disease. Material and Methods We included patients admitted to the Instituto Alexander Fleming between January 2005 and May 2009 with cardiac tamponade or severe pericardial effusion treated with pericardial drainage and instillation of cisplatin (10 mg in 20 ml of physiological solution for 5 days). Malignant pericardial effusion had to be confirmed by cytological examination or by echocardiographic evidence of malignant disease involving the pericardial space. Low treatment expectation was another requirement for inclusion. Results A total of 9 patients (6 men and 3 women) were included; mean age was 60 years (51-69). The primary tumors were lung cancer (n=4); breast cancer (n=1); bladder cancer (n=1); esophageal cancer (n=1), and prostate cancer (n=1). The cytological examination was positive in 6 cases. The catheter was removed after 7 days. Three patients presented adverse events: pain, fever and atrial fibrillation. One patient had a recurrence one month later. Eight patients died [mean time to death: 50 days (7-83)] and one is alive. Conclusion Intrapericardial instillation of cisplatin is a feasible and welltolerated procedure. The incidence of recurrences is low.

High-risk human papilloma virus infection, tumor pathophenotypes, and BRCA1/2 and TP53 status in juvenile breast cancer.

Juvenile breast cancer is rare and poorly known. We studied a series of five breast cancer patients diagnosed within 25 years of age that included two adolescents, 12- and 15-years-old, and 3 young women, 21-, 21-, and 25-years-old, respectively. All cases were scanned for germline mutations along the entire BRCA1/2 coding sequences and TP53 exons 4-10, using protein truncation test, denaturing high performance liquid chromatography and direct sequencing. Paraffin-embedded primary tumors (available for 4/5 cases), and a distant metastasis (from the 15-years-old) were characterized for histological and molecular tumor subtype, human papilloma virus (HPV) types 16/18 E6 sequences and tumor-associated mutations in TP53 exons 5-8. A BRCA2 germline mutation (p.Ile2490Thr), previously reported in breast cancer and, as compound heterozygote, in Fanconi anemia, was identified in the 21-year-old patient diagnosed after pregnancy, negative for cancer family history. The tumor was not available for study. Only germline polymorphisms in BRCA1/2 and/or TP53 were detected in the other cases. The tumors of the 15- and 12-years-old were, respectively, classified as glycogen-rich carcinoma with triple negative subtype and as secretory carcinoma with basal subtype. The tumors of the 25-year-old and of the other 21-year-old were, respectively, diagnosed as infiltrating ductal carcinoma with luminal A subtype and as lobular carcinoma with luminal B subtype. No somatic TP53 mutations were found, but tumor-associated HPV 16 E6 sequences were retrieved from the 12- and 25-year-old, while both HPV 16 and HPV 18 E6 sequences were found in the tumor of the 15-year-old and in its associated metastasis. Blood from the 15- and 25-year-old, diagnosed with high-stage disease, resulted positive for HPV 16 E6. All the HPV-positive cases were homozygous for arginine at TP53 codon 72, a genotype associated with HPV-related cancer risk, and the tumors showed p16(INK4A) immunostaining, a marker of HPV-associated cancers. Notably menarche at 11 years was reported for the two adolescents, while the 25-year-old was diagnosed after pregnancy and breast-feeding. Our data suggest that high-risk HPV infection is involved in a subset of histopathologically heterogeneous juvenile breast carcinomas associated with menarche or pregnancy and breast-feeding. Furthermore we implicate BRCA2 in a juvenile breast carcinoma diagnosed at 21 years of age, 4 years after an early full-term pregnancy, in absence of cancer family history.