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.

Liquid biopsy for KRAS, NRAS and BRAF mutation testing in advanced colorectal cancer patients: the Argentinean experience.

Objective: To analyze the frequency of KRAS, NRAS and BRAF hotspot mutations in circulating tumor DNA (ctDNA) from patients with metastatic colorectal cancer (mCRC). Methods: Observational, descriptive and retrospective study in mCRC patients with available ctDNA-based genotype of KRAS, NRAS and BRAF. Results: The frequencies of plasma mutations for KRAS, NRAS and BRAF were 34% (± 7), 4% (± 3) and 4% (± 3), respectively. Median overall survival of plasma-tested RAS/BRAF-mutated patients was 26.6 months (95% CI: 14.4-not estimable [NE]), while RAS/BRAF wild-type patients did not reach the median survival during follow-up. Median progression-free survival for RAS/BRAF wild-type and RAS/BRAF-mutated patients was 12 (95% CI: 7-NE) and 4 months (95% CI: 4-NE), respectively. Conclusion: Our work supports the utility of KRAS, NRAS and BRAF analysis in liquid biopsy from mCRC patients.

A clinical and molecular portrait of non-metastatic anal squamous cell carcinoma.

Anal squamous cell carcinoma (ASCC) is a rare gastrointestinal malignancy associated with high-risk Human papillomavirus (HPV) infection. Despite improved outcomes in non-metastatic ASCC, definitive chemoradiotherapy constitutes the standard treatment for localized disease. Evidences for predictive and prognostic biomarkers are limited. Here, we performed a viral, immune, and mutational characterization of 79 non-metastatic ASCC patients with complete definitive chemoradiotherapy. HPV-16 was detected in 91% of positive cases in single infections (78%) or in coinfections with multiple genotypes (22%). Fifty-four percent of non-metastatic ASCC cases displayed mutations affecting cancer driver genes such as PIK3CA (21% of cases), TP53 (15%), FBXW7 (9%), and APC (6%). PD-L1 expression was detected in 57% of non-metastatic ASCC. Increased PD-L1 positive cases (67%) were detected in patients with complete response compared with non-complete response to treatment (37%) (p = 0.021). Furthermore, patients with PD-L1 positive tumors were significantly associated with better disease-free survival (DFS) and overall survival (OS) compared with patients with PD-L1 negative tumors (p = 0.006 and p = 0.002, respectively). PD-L1 expression strongly impacts CR rate and survival of non-metastatic ASCC patients after standard definitive chemoradiotherapy. PD-L1 expression could be used to stratify good versus poor responders avoiding the associated morbidity with abdominal perineal resection.

Prognostic Impact of An Integrative Landscape of Clinical, Immune, and Molecular Features in Non-Metastatic Rectal Cancer.

Rectal Cancer (RC) is a complex disease that involves highly variable treatment responses. Currently, there is a lack of reliable markers beyond TNM to deliver a personalized treatment in a cancer setting where the goal is a curative treatment. Here, we performed an integrated characterization of the predictive and prognostic role of clinical features, mismatch-repair deficiency markers, HER2, CDX2, PD-L1 expression, and CD3-CD8+ tumor-infiltrating lymphocytes (TILs) coupled with targeted DNA sequencing of 76 non-metastatic RC patients assigned to total mesorectal excision upfront (TME; n = 15) or neoadjuvant chemo-radiotherapy treatment (nCRT; n = 61) followed by TME. Eighty-two percent of RC cases displayed mutations affecting cancer driver genes such as TP53, APC, KRAS, ATM, and PIK3CA. Good response to nCRT treatment was observed in approximately 40% of the RC cases, and poor pathological tumor regression was significantly associated with worse disease-free survival (DFS, HR = 3.45; 95%CI = 1.14-10.4; p = 0.028). High neutrophils-platelets score (NPS) (OR = 10.52; 95%CI=1.34-82.6; p = 0.025) and KRAS mutated cases (OR = 5.49; 95%CI = 1.06-28.4; p = 0.042) were identified as independent predictive factors of poor response to nCRT treatment in a multivariate analysis. Furthermore, a Cox proportional-hazard model showed that the KRAS mutational status was an independent prognostic factor associated with higher risk of local recurrence (HR = 9.68; 95%CI = 1.01-93.2; p <0.05) and shorter DFS (HR = 2.55; 95%CI = 1.05-6.21; p <0.05), while high CEA serum levels were associated with poor DFS (HR = 2.63; 95%CI = 1.01-6.85; p <0.05). Integrated clinical and molecular-based unsupervised analysis allowed us to identify two RC prognostic groups (cluster 1 and cluster 2) associated with disease-specific OS (HR = 20.64; 95%CI = 2.63-162.2; p <0.0001), metastasis-free survival (HR = 3.67; 95%CI = 1.22-11; p = 0.012), local recurrence-free survival (HR = 3.34; 95%CI = 0.96-11.6; p = 0.043) and worse DFS (HR = 2.68; 95%CI = 1.18-6.06; p = 0.012). The worst prognosis cluster 2 was enriched by stage III high-risk clinical tumors, poor responders to nCRT, with low TILs density and high frequency of KRAS and TP53 mutated cases compared with the best prognosis cluster 1 (p <0.05). Overall, this study provides a comprehensive and integrated characterization of non-metastatic RC cases as a new insight to deliver a personalized therapeutic approach.

Pre-Existing Tumoral B Cell Infiltration and Impaired Genome Maintenance Correlate with Response to Chemoradiotherapy in Locally Advanced Rectal Cancer.

Locally advanced rectal cancer (LARC) remains a medical challenge. Reliable biomarkers to predict which patients will significantly respond to neoadjuvant chemoradiotherapy (nCRT) have not been identified. We evaluated baseline genomic and transcriptomic features to detect differences that may help predict response to nCRT. Eligible LARC patients received nCRT (3D-LCRT 50.4 Gy plus capecitabine 825 mg/m2/bid), preceded by three cycles of CAPOX in high systemic-relapse risk tumors, and subsequent surgery. Frozen tumor biopsies at diagnosis were sequenced using a colorectal cancer panel. Transcriptomic data was used for pathway and cell deconvolution inferential algorithms, coupled with immunohistochemical validation. Clinical and molecular data were analyzed according to nCRT outcome. Pathways related to DNA repair and proliferation (p < 0.005), and co-occurrence of RAS and TP53 mutations (p = 0.001) were associated with poor response. Enrichment of expression signatures related to enhanced immune response, particularly B cells and interferon signaling (p < 0.005), was detected in good responders. Immunohistochemical analysis of CD20+ cells validated the association of good response with B cell infiltration (p = 0.047). Findings indicate that the presence of B cells is associated with successful tumor regression following nCRT in LARC. The prevalence of simultaneous RAS and TP53 mutations along with a proficient DNA repair system that may counteract chemoradio-induced DNA damage was associated with poor response.

Eficacia de los inhibidores de ALK en dos casos con evaluación positiva por inmunohistoquímica y negativa por FISH / Efficacy of ALK inhibitors in two cases with positive evaluation by immunohistochemistry and negative by FISH

En el carcinoma de pulmón de células no pequeñas (CPCNP), la activación de ALK se produce por la formación de genes de fusión. El perfil clínico donde ocurre con más frecuencia corresponde a pacientes jóvenes, mayormente mujeres, no fumadores, histología de adenocarcinoma y ausencia de mutaciones de EGFR y KRAS. Su presencia se describe en el 3-10% de los CPCNP. La importancia de la determinación de ALK radica en que identifica un subgrupo de pacientes con un comportamiento biológico diferente, en los cuales el tratamiento con inhibidores específicos, como el crizotinib, ceritinib o alectinib, es más eficaz que los convencionales. Las alteraciones moleculares de ALK pueden identificarse por hibridación in situ (ISH), por inmunohistoquímica (IHQ) y por RT-PCR, aunque el FISH es el procedimiento diagnóstico de referencia a nivel clínico. Se examinaron 308 casos de CPCNP y se compararon los resultados por FISH e IHQ. De los 8 (3%) identificados con expresión positiva, sólo 6 presentaron el rearreglo de ALK. Se presentan dos casos clínicos con ALK positivo por IHC y FISH negativo, uno presentó respuesta al tratamiento dirigido y otro no. A pesar de que el FISH es el gold standard, se acepta el uso de IHQ ya sea para definir conducta como único test o para screening y ulterior confirmación por FISH en los casos positivos. Estos dos casos con distinta respuesta al tratamiento con IHQ positiva pero FISH negativo, indican la ausencia de pautas, requiriendo de más conocimiento en el futuro para optimizar las conductas médicas (AU)

In non-small cell lung cancer, ALK activation is produced by gene fusion. The clinical scenario where this type of tumor appears more frequently is in young, female patients, without smoking history, adenocarcinoma histology and with no EGFR or KRAS mutation. It is described as 3 to 10% of non- small cell lung cancer cases. The importance of ALK determinations lies in the identification of a subgroup of patients with a different biological behavior and sensible tumor to target therapy with ALK inhibitors. Molecular alterations of ALK can be determined by in situ hybridization, immunohistochemistry (IHC) and RT-PCR, FISH is the reference diagnostic procedure in clinical applications. Were evaluated 308 cases of non-small cell lung cancer, and FISH and IHC results were compared. Eight (3%) cases presented positive expression, but only 6 of them presented ALK rearrangements. These two clinical cases of patients with IHC positive but FISH negative for ALK are presented, observing good clinical response in only one of them. Although FISH is considered the gold standard technique, IHC use is accepted for treatment decisions as a lone procedure or as screening with FISH confirmation in positive cases. These two particular cases express the absence of guidelines in this infrequent scenario, needing more knowledge in the future in order to take better medical decisions (AU)