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BACKGROUND: Hereditary diffuse gastric cancer (HDGC) (OMIM# 137215) is an autosomal dominant cancer syndrome associated with CDH1 (OMIM# 192090) mutations. Prophylactic total gastrectomy (PTG) is the most recommended preventive treatment when a pathogenic mutation is found. However, the increasing use of genetic testing has led to the identification of incidental CDH1 mutations in individuals without a family history of gastric cancer. It remains unclear whether these patients should undergo prophylactic total gastrectomy. METHODS: Germline DNA, obtained from peripheral blood, was analysed by NGS. RESULTS: A 47-year-old woman was diagnosed with high-grade serous ovarian carcinoma, FIGO stage IIIC, with a Homologous Recombination Deficiency (HRD) GIS status of 78 (positive, cut-off: 43). She received chemotherapy and niraparib treatment. A multigene panel test revealed no pathogenic mutations in BRCA1 (OMIM# 113705)/BRCA2 (OMIM# 600185) genes, but a de novo deletion of exon 16 in CDH1 was found incidentally. She had no previous family history of gastric or breast cancer. The patient was enrolled in a surveillance program involving periodic endoscopy and was diagnosed with diffuse gastric cancer through biopsies of a pale area in the antrum after 1 year of close endoscopic follow-up. CONCLUSION: This case presents supportive evidence for the pathogenic classification of the loss of the last exon of CDH1.
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Antígenos CD , Cadherinas , Neoplasias Ováricas , Neoplasias Gástricas , Humanos , Femenino , Persona de Mediana Edad , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Antígenos CD/genética , Cadherinas/genética , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Gastrectomía , Mutación de Línea GerminalRESUMEN
BACKGROUND: Immunotherapy-based treatments have demonstrated high efficacy in patients with advanced and locally advanced non-small-cell lung cancer (NSCLC). BRAF mutations affect a small but significant fraction of NSCLC. The efficacy of these therapies in this subgroup of patients is unknown. MATERIALS AND METHODS: Plasma and tissue samples from 116 resectable stage IIIA/B NSCLC patients, included in NADIM and NADIM II clinical trials (NADIM cohort), and from a prospective academic cohort with 84 stage IV NSCLC patients (BLI-O cohort), were analyzed by next-generation sequencing. RESULTS: The p.G464E, p.G466R, p.G466V, p.G469V, p.L597Q, p.T599I, p.V600E (n = 2) BRAF mutations, were identified in four (3.45 %) samples from the NADIM cohort, all of which were cases treated with neoadjuvant chemoimmunotherapy (CH-IO), and four (4.76 %) samples from the BLI-O cohort, corresponding to cases treated with first-line immunotherapy (n = 2) or CH-IO (n = 2). All these patients were alive and had no evidence of disease at data cut-off. Conversely, patients with BRAF wild-type (wt) tumors in the BLI-O cohort had a median progression-free survival (PFS) of 5.49 months and a median overall survival (OS) of 12.00 months (P-LogRank = 0.013 and 0.046, respectively). Likewise, PFS and OS probabilities at 36 months were 60.5 % and 76.1 % for patients with BRAF-wt tumors in the NADIM cohort. The pathological complete response (pCR) rate after neoadjuvant CH-IO in patients with BRAF-positive tumors (n = 4) was 100 %, whereas the pCR rate in the BRAF-wt population was 44.3 % (RR: 2.26; 95 % CI: 1.78-2.85; P < 0.001). CONCLUSION: BRAF mutations may be a good prognostic factor for advanced and locally advanced NSCLC patients undergoing immunotherapy-based treatments.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Mutación , Proteínas Proto-Oncogénicas B-raf , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/terapia , Femenino , Masculino , Persona de Mediana Edad , Anciano , Estadificación de Neoplasias , Pronóstico , Adulto , Estudios Prospectivos , Inmunoterapia/métodos , Biomarcadores de Tumor/genética , Anciano de 80 o más Años , Metástasis de la NeoplasiaRESUMEN
BACKGROUND: Juvenile Polyposis Syndrome (JPS) is a rare autosomal dominant hereditary disorder characterized by the development of multiple hamartomatous gastrointestinal polyps. Here, we present a case of JPS with a mosaic variant in SMAD4. METHODS: Exome sequencing TRIO analysis, using germline DNA from the biological mother and father along with the index case (IC). RESULTS: A 46-year-old male with no family history of cancer presented with chronic iron deficiency anemia and was diagnosed with massive gastric polyposis (≥100 polyps). At the age of 59, he underwent a total gastrectomy, revealing numerous polyps occupying the entire gastric mucosa, including a 5 cm gastric hyperplastic polyp with high-grade dysplasia and focal adenocarcinoma. TRIO analysis identified the c.386A>C p.(Asn129Thr) variant in the SMAD4 gene at an allele frequency (AF) of 22%, suggesting its mosaic origin. Subsequently, the variant was found in heterozygosity in the IC's son, who exhibited two subcentimeter polyps in the colon and seven inflammatory gastric polyps with gastric inflammatory areas and hyperplasia, suggesting that the c.386A>C p.(Asn129Thr) variant in SMAD4 segregated with the phenotype. CONCLUSION: Our study provides evidence supporting the classification of the c.386A>C p.(Asn129Thr) variant in SMAD4 as a likely pathogenic variant. This finding contributes to improved accuracy in the diagnosis and genetic counseling of JPS.
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Pólipos Adenomatosos , Poliposis Intestinal/congénito , Síndromes Neoplásicos Hereditarios , Neoplasias Gástricas , Masculino , Humanos , Persona de Mediana Edad , Neoplasias Gástricas/genética , Síndromes Neoplásicos Hereditarios/genética , Síndromes Neoplásicos Hereditarios/patología , Proteína Smad4/genéticaRESUMEN
BACKGROUND: Approximately 20% of patients with non-small-cell lung cancer (NSCLC) receive a diagnosis of stage III disease. There is no current consensus regarding the most appropriate treatment for these patients. METHODS: In this open-label, phase 2 trial, we randomly assigned patients with resectable stage IIIA or IIIB NSCLC to receive neoadjuvant nivolumab plus platinum-based chemotherapy (experimental group) or chemotherapy alone (control group), followed by surgery. Patients in the experimental group who had R0 resections received adjuvant treatment with nivolumab for 6 months. The primary end point was a pathological complete response (0% viable tumor in resected lung and lymph nodes). Secondary end points included progression-free survival and overall survival at 24 months and safety. RESULTS: A total of 86 patients underwent randomization; 57 were assigned to the experimental group and 29 were assigned to the control group. A pathological complete response occurred in 37% of the patients in the experimental group and in 7% in the control group (relative risk, 5.34; 95% confidence interval [CI], 1.34 to 21.23; P = 0.02). Surgery was performed in 93% of the patients in the experimental group and in 69% in the control group (relative risk, 1.35; 95% CI, 1.05 to 1.74). Kaplan-Meier estimates of progression-free survival at 24 months were 67.2% in the experimental group and 40.9% in the control group (hazard ratio for disease progression, disease recurrence, or death, 0.47; 95% CI, 0.25 to 0.88). Kaplan-Meier estimates of overall survival at 24 months were 85.0% in the experimental group and 63.6% in the control group (hazard ratio for death, 0.43; 95% CI, 0.19 to 0.98). Grade 3 or 4 adverse events occurred in 11 patients in the experimental group (19%; some patients had events of both grades) and 3 patients in the control group (10%). CONCLUSIONS: In patients with resectable stage IIIA or IIIB NSCLC, perioperative treatment with nivolumab plus chemotherapy resulted in a higher percentage of patients with a pathological complete response and longer survival than chemotherapy alone. (Funded by Bristol Myers Squibb and others; NADIM II ClinicalTrials.gov number, NCT03838159; EudraCT number, 2018-004515-45.).
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Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Nivolumab , Compuestos de Platino , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/cirugía , Recurrencia Local de Neoplasia/tratamiento farmacológico , Estadificación de Neoplasias , Nivolumab/administración & dosificación , Nivolumab/efectos adversos , Nivolumab/uso terapéutico , Compuestos de Platino/administración & dosificación , Compuestos de Platino/efectos adversos , Compuestos de Platino/uso terapéutico , Análisis de Supervivencia , Terapia CombinadaRESUMEN
ALK, ROS1, and RET fusions and MET∆ex14 variant associate with response to targeted therapies in non-small-cell lung cancer (NSCLC). Technologies for fusion testing in tissue must be adapted to liquid biopsies, which are often the only material available. In this study, circulating-free RNA (cfRNA) and extracellular vesicle RNA (EV-RNA) were purified from liquid biopsies. Fusion and MET∆ex14 transcripts were analyzed by nCounter (Nanostring) and digital PCR (dPCR) using the QuantStudio® System (Applied Biosystems). We found that nCounter detected ALK, ROS1, RET, or MET∆ex14 aberrant transcripts in 28/40 cfRNA samples from positive patients and 0/16 of control individuals (70% sensitivity). Regarding dPCR, aberrant transcripts were detected in the cfRNA of 25/40 positive patients. Concordance between the two techniques was 58%. Inferior results were obtained when analyzing EV-RNA, where nCounter often failed due to a low amount of input RNA. Finally, results of dPCR testing in serial liquid biopsies of five patients correlated with response to targeted therapy. We conclude that nCounter can be used for multiplex detection of fusion and MET∆ex14 transcripts in liquid biopsies, showing a performance comparable with next-generation sequencing platforms. dPCR could be employed for disease follow-up in patients with a known alteration. cfRNA should be preferred over EV-RNA for these analyses.
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Carcinoma de Pulmón de Células no Pequeñas , Ácidos Nucleicos Libres de Células , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Proteínas Tirosina Quinasas/genética , Neoplasias Pulmonares/patología , Quinasa de Linfoma Anaplásico/genética , ARN/genética , Proteínas Proto-Oncogénicas c-ret/genética , Proteínas Proto-Oncogénicas/genética , Biopsia Líquida , Proteínas de Fusión Oncogénica/genéticaRESUMEN
Importance: Antiangiogenic drug combinations with anti-programmed cell death 1 protein and anti-programmed cell death 1 ligand 1 (PD-L1) agents are a novel treatment option for lung cancer. However, survival remains limited, and the activity of these combinations for tumors with high tumor mutation burden (TMB) is unknown. Objective: To assess the clinical benefits and safety of atezolizumab plus bevacizumab for patients with high-TMB advanced nonsquamous non-small cell lung cancer (NSCLC). Design, Setting, and Participants: This multicenter, single-arm, open-label, phase 2 nonrandomized controlled trial (Atezolizumab Plus Bevacizumab in First-Line NSCLC Patients [TELMA]) included treatment-naive patients aged 18 years or older with confirmed stage IIIB-IV nonsquamous NSCLC with TMB of 10 or more mutations/megabase and no EGFR, ALK, STK11, MDM2, or ROS1 alterations. From May 2019 through January 2021, patients were assessed at 13 sites in Spain, with follow-up until February 28, 2022. Interventions: Participants were given atezolizumab, 1200 mg, plus bevacizumab, 15 mg/kg, on day 1 of each 21-day cycle. Treatment was continued until documented disease progression, unacceptable toxic effects, patient withdrawal, investigator decision, or death. Main Outcomes and Measures: The primary end point was 12-month progression-free survival (PFS) rate (according to Response Evaluation Criteria in Solid Tumours, version 1.1 criteria); PFS was defined as the time from enrollment to disease progression or death. Adverse events were monitored according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Results: A total of 307 patients were assessed for trial eligibility, of whom 266 were ineligible for enrollment. Of the 41 patients enrolled, 3 did not fulfill all inclusion criteria and were excluded. The remaining 38 patients (28 [73.7%] male; mean [SD] age, 63.7 [8.3] years) constituted the per-protocol population. The 12-month PFS rate was 51.3% (95% CI, 34.2%-66.0%), which met the primary end point. The 12-month overall survival (OS) rate was 72.0% (95% CI, 54.1%-83.9%). The median PFS was 13.0 months (95% CI, 7.9-18.0 months), and the median OS was not reached. Of the 38 patients, 16 (42.1%) achieved an objective response and 30 (78.9%) achieved disease control. The median time to response was 2.8 months (IQR, 2.8-3.58 months), with a median duration of response of 11.7 months (range, 3.57-22.4 months; the response was ongoing at cutoff). Of 16 responses, 8 (50.0%) were ongoing. Most adverse events were grade 1 or 2. For atezolizumab, the most common adverse events were fatigue (6 [15.8%]) and pruritus (6 [15.8%]). For bevacizumab, they were hypertension (10 [26.3%]) and proteinuria (4 [10.5%]). Drug discontinuation occurred in 2 patients receiving atezolizumab (5.3%) and 3 patients receiving bevacizumab (7.9%). PD-L1 levels were not associated with response, PFS, or OS. Conclusions and Relevance: These findings suggest that atezolizumab with bevacizumab is a potential treatment for high-TMB nonsquamous NSCLC. Trial Registration: ClinicalTrials.gov Identifier: NCT03836066.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Masculino , Persona de Mediana Edad , Femenino , Bevacizumab/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Antígeno B7-H1/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Proteínas Tirosina Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas/genética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores , Progresión de la Enfermedad , MutaciónRESUMEN
Cancer is conventionally considered an evolutionary disease where tumor cells adapt to the environment and evolve eventually leading to the formation of metastasis through the seeding and growth of metastasis-initiating cells in distant organs. Tumor cell and tumor-stroma communication via soluble factors and extracellular vesicles (EVs) are essential for the success of the metastatic process. As the field of EVs advances, growing data support the role of tumor-derived EVs not only in modifying the microenvironment to facilitate tumor progression but also in inducing changes in cells outside the primary tumor that may lead to a malignant transformation. Thus, an alternative hypothesis has emerged suggesting the conceptualization of cancer as an 'infective' disease. Still, tackling EVs as a possible cancer treatment has not been widely explored. A major understanding is needed to unveil possible additional contributions of EVs in progression and metastasis, which may be essential for the development of novel approaches to treat cancer patients. Here, we review the contribution of EVs to cancer progression and the possible implication of these factors in the oncogenic transformation of indolent cells.
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Vesículas Extracelulares , Humanos , Transformación Celular Neoplásica/patología , Línea Celular Tumoral , Microambiente TumoralRESUMEN
Background: Alectinib significantly improves survival of non-small cell lung cancer (NSCLC) patients with anaplastic lymphoma kinase (ALK)-rearrangement. In this study, we analyzed the effects of different ALK rearrangements and co-mutations on the efficacy of alectinib. Methods: Using the electronic medical record system, we reviewed in terms of clinical and pathological features patients with advanced (IIIB/IV stage) ALK-rearranged NSCLC at Shanghai Chest Hospital between January 2018 and December 2021 who were treated with alectinib in first or second line and were assessed for objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). Results: A total of 66 patients were enrolled in the study, and 17 types of ALK rearrangements were detected, of which five types of ALK rearrangements responded well to alectinib. We classified ALK-rearrangements into four main types, namely echinoderm microtubule-associated protein-like 4 (EML4)-ALK (E6:A20), EML4-ALK (E13:A20), EML4-ALK (E20:A20), and others. There was no significant difference in ORR and DCR of these types (ORR: 31.3% vs. 13.0% vs. 18.2% vs. 17.6%, P=0.575; DCR: 93.8% vs. 95.6% vs. 100.0% vs. 88.2%, P=0.627). The 3-year PFS rates were 25.0% (4/16) vs. 13.0% (3/23) vs. 27.3% (3/11) vs. 18.8% (3/16) for EML4-ALK (E6:A20), EML4-ALK (E13:A20), EML4-ALK (E20:A20), and others, respectively (P=0.725). The results of co-mutation analysis showed that the median PFS (mPFS) for patients with tumors harboring TP53 mutations was 30.4 months, significantly shorter than that of patients with tumors without co-mutations and whose mPFS was not mature (P=0.026). TSC1 co-mutation was also identified as a detrimental factor in outcome, with a DCR of 60% vs. 100% (P=0.031), mPFS of 30.4 months vs. not applicable (P=0.160) in patients with vs. those without this co-mutation, respectively. The efficacy of alectinib in patients with brain metastases is comparable to that in patients without distant organ metastases. There were two cases with specific fusion types that also responded to alectinib; namely, double ALK-rearrangements: EML4-ALK (E13:A20) and MSH2-ALK (M7:A20), and with a rare fusion partner, SPECC1L-ALK (S8:A20). Their PFS were 8.7 and 38.0 months, respectively. Conclusions: In this study, the efficacy of alectinib in different types of ALK-rearrangements varied slightly. TP53 and TSC1 co-mutations were identified as detrimental factors affecting efficacy. This study provides references for the response to alectinib in patients with different types of ALK rearrangements and co-mutation.
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Background: Kirsten rat sarcoma viral oncogene homolog (KRAS) is one of the most frequently mutated oncogenes in non-small cell lung cancer (NSCLC). The administration of immunotherapy has demonstrated significant efficacy in prolonging the overall survival of patients with KRAS mutation in recent years. However, the efficacy of immunotherapy in KRAS mutant NSCLC is variable. Analysis of T cell receptor (TCR) repertoire may contribute to a better understanding of the mechanisms behind such differential outcomes. Methods: A total of 47 patients with KRAS mutant NSCLC were enrolled in this study. Deep sequencing of the TCR ß chain complementarity-determining regions in tumor tissue and paired peripheral blood specimens was conducted. Comprehensive analysis of TCR repertoire metrics was performed with different KRAS mutation subtypes and concomitant mutations. Moreover, the associations between TCR repertoire metrics and tumor mutation burden (TMB), as well as programmed death-ligand 1 were explored, respectively. Results: TCR repertoire metrics, including Shannon index, Clonality, and Morisita index (MOI), showed no significant differences among different KRAS mutation subtypes. The similar results were observed between patients with tumor protein p53 (TP53) mutation and those with wild-type TP53. In contrast, although no significant differences were found in Shannon index and Clonality, patients with KRAS/serine/threonine kinase 11 (STK11) comutation showed a significantly higher MOI compared to their STK11 wild-type counterparts (P=0.012). In addition, TCR repertoire metrics were neither associated with TMB nor programmed death-ligand 1 expression in KRAS mutant NSCLC. Conclusions: This retrospective study comprehensively described the TCR repertoire in KRAS mutant NSCLC. A higher MOI represented more overlap of the TCR repertoire between tumor tissue and paired peripheral blood, indicating distinctive immunological features in NSCLC with KRAS/STK11 comutation.
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OBJECTIVE: To evaluate the relationship between circulating tumor DNA (ctDNA) presence and tumor features including tumor-infiltrating lymphocyte (TIL) levels in Peruvian breast cancer patients. MATERIALS AND METHODS: This was a prospective study conducted at the Instituto Nacional de Enfemedades Neoplasicas, Peru. We evaluated level of TIL and PIK3CA mutations in ctDNA. Clinical characteristics, including outcome data, were collected from the patient file. Survival was calculated from the date of blood sample drawn to the event time. Data collected were analyzed using SPSS software version 25. RESULTS: We analyzed plasma samples from 183 breast cancer patients. most cases were of Luminal-B (44.8%) phenotype and stage II (41.5%), and median stromal TIL was 30%. PIK3CA mutation in ctDNA was detected in 35% cases (most with E545K) and was associated with lower TIL level (p=0.04). PIK3CA in ctDNA tended to be associated with advanced stages (p=0.09) in the whole series and with higher recurrence rates (p=0.053) in the non-metastatic setting. Patients with presence of PIK3CA in ctDNA tended to have shorter survival (p=0.083). CONCLUSION: Presence of PIK3CA mutation in ctDNA was frequently found in our Peruvian breast cancer series, was associated with lower TIL levels and tended to predict poor outcomes.
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ADN Tumoral Circulante , Neoplasias , Linfocitos Infiltrantes de Tumor/patología , Perú , Estudios Prospectivos , Fosfatidilinositol 3-Quinasa Clase I/genética , ADN Tumoral Circulante/genética , Mutación , Biomarcadores de Tumor/genética , Neoplasias/patologíaRESUMEN
Tumor molecular profiling upon disease progression enables investigations of the tumor evolution. Next-generation sequencing (NGS) of liquid biopsies constitutes a noninvasive readily available source of tumor molecular information. In this study, 124 plasma samples from advanced EGFR-positive NSCLC patients, treated with a first-line EGFR tyrosine kinase inhibitor (EGFR-TKI) were collected upon disease progression. The circulating cell-free DNA (cfDNA) was sequenced using the Oncomine Pan-Cancer Cell-Free Assay™. Excluding EGFR mutations, the most frequently mutated gene was TP53 (57.3%), followed by APC (11.3%), FGFR3 (7.3%), and KRAS (5.6%). Different molecular alterations were observed upon disease progression depending on the location of the original EGFR-sensitizing mutation. Specifically, the detection of the p.T790M mutation was significantly associated with the presence of exon 19 mutations in EGFR (Fisher p-value: 0.028). All KRAS activating mutations (n = 8) were detected in tumors with EGFR mutations in exons 18 and 21 (Fisher p-value < 0.001). Similarly, mutations in NRAS and HRAS were more frequently detected in samples from tumors harboring mutations in exons 18 or 21 (Fisher p-value: 0.050 and Fisher p-value: 0.099, respectively). In conclusion, our data suggest that the mechanisms underlying EGFR-TKI resistance could be dependent on the exon location of the original EGFR-sensitizing mutation.
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BACKGROUND: Neoadjuvant chemoimmunotherapy for non-small cell lung cancer (NSCLC) has improved pathological responses and survival rates compared with chemotherapy alone, leading to Food and Drug Administration (FDA) approval of nivolumab plus chemotherapy for resectable stage IB-IIIA NSCLC (AJCC 7th edition) without ALK or EGFR alterations. Unfortunately, a considerable percentage of tumors do not completely respond to therapy, which has been associated with early disease progression. So far, it is impossible to predict these events due to lack of knowledge. In this study, we characterized the gene expression profile of tumor samples to identify new biomarkers and mechanisms behind tumor responses to neoadjuvant chemoimmunotherapy and disease recurrence after surgery. METHODS: Tumor bulk RNA sequencing was performed in 16 pretreatment and 36 post-treatment tissue samples from 41 patients with resectable stage IIIA NSCLC treated with neoadjuvant chemoimmunotherapy from NADIM trial. A panel targeting 395 genes related to immunological processes was used. Tumors were classified as complete pathological response (CPR) and non-CPR, based on the total absence of viable tumor cells in tumor bed and lymph nodes tested at surgery. Differential-expressed genes between groups and pathway enrichment analysis were assessed using DESeq2 and gene set enrichment analysis. CIBERSORTx was used to estimate the proportions of immune cell subtypes. RESULTS: CPR tumors had a stronger pre-established immune infiltrate at baseline than non-CPR, characterized by higher levels of IFNG, GZMB, NKG7, and M1 macrophages, all with a significant area under the receiver operating characteristic curve (ROC) >0.9 for CPR prediction. A greater effect of neoadjuvant therapy was also seen in CPR tumors with a reduction of tumor markers and IFNγ signaling after treatment. Additionally, the higher expression of several genes, including AKT1, BST2, OAS3, or CD8B; or higher dendritic cells and neutrophils proportions in post-treatment non-CPR samples, were associated with relapse after surgery. Also, high pretreatment PD-L1 and tumor mutational burden levels influenced the post-treatment immune landscape with the downregulation of proliferation markers and type I interferon signaling molecules in surgery samples. CONCLUSIONS: Our results reinforce the differences between CPR and non-CPR responses, describing possible response and relapse immune mechanisms, opening the possibility of therapy personalization of immunotherapy-based regimens in the neoadjuvant setting of NSCLC.
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Antineoplásicos Inmunológicos , Carcinoma de Pulmón de Células no Pequeñas , Interferón Tipo I , Neoplasias Pulmonares , Antineoplásicos Inmunológicos/uso terapéutico , Antígeno B7-H1/genética , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Progresión de la Enfermedad , Receptores ErbB/genética , Humanos , Inmunoterapia , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Terapia Neoadyuvante , Recurrencia Local de Neoplasia/tratamiento farmacológico , Nivolumab/uso terapéutico , Proteínas Tirosina Quinasas Receptoras , Transcriptoma , Microambiente TumoralRESUMEN
Cancer cells release nucleic acids, freely or associated with other structures such as vesicles into body fluids, including blood. Among these nucleic acids, circulating tumor DNA (ctDNA) has emerged as a minimally invasive biomarker for tumor molecular profiling. However, certain biological characteristics of ctDNA are still unknown. Here, we provide an overview of the current knowledge about ctDNA biological features, including size and structure as well as the mechanisms of ctDNA shedding and clearance, and the physio-pathological factors that determine ctDNA levels. A better understanding of ctDNA biology is essential for the development of new methods that enable the analysis of ctDNA.
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Most cancer-related deaths in breast cancer patients are associated with metastasis, a multistep, intricate process that requires the cooperation of tumour cells, tumour microenvironment and metastasis target tissues. It is accepted that metastasis does not depend on the tumour characteristics but the host's genetic makeup. However, there has been limited success in determining the germline genetic variants that influence metastasis development, mainly because of the limitations of traditional genome-wide association studies to detect the relevant genetic polymorphisms underlying complex phenotypes. In this work, we leveraged the extreme discordant phenotypes approach and the epistasis networks to analyse the genotypes of 97 breast cancer patients. We found that the host's genetic makeup facilitates metastases by the dysregulation of gene expression that can promote the dispersion of metastatic seeds and help establish the metastatic niche-providing a congenial soil for the metastatic seeds.
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Mutación de Línea Germinal , Metástasis de la Neoplasia , Neoplasias de la Mama/genética , Estudio de Asociación del Genoma Completo , Humanos , Microambiente TumoralRESUMEN
The treatment scenario for patients with resectable non-small cell lung cancer has changed dramatically with the incorporation of immunotherapy. The introduction of immunotherapy into treatment algorithms has yielded improved clinical outcomes in several phase II and III trials in both adjuvant (Impower010 and PEARLS) and neoadjuvant settings (JHU/MSK, LCMC3, NEOSTAR, Columbia/MGH, NADIM, and CheckMate-816), leading to new U.S. Food and Drug Administration approvals in this sense. Different treatment options are now available for patients, making the optimal treatment scenario a matter of intense debate. In this review, we summarize the main results concerning treatment sequencing in resectable non-small cell lung cancer from the past 30 years in the preimmunotherapy era, focusing on recent advances after incorporation of immunotherapy. Finally, the utility of several parameters (PD-L1, tumor mutational burden, radiomics, circulating tumor DNA, T-cell receptor, and immune populations) as predictive biomarkers for therapy personalization is discussed.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/terapia , Humanos , Inmunoterapia/métodos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/terapia , Terapia NeoadyuvanteRESUMEN
PURPOSE: Neoadjuvant chemotherapy plus nivolumab has been shown to be effective in resectable non-small-cell lung cancer (NSCLC) in the NADIM trial (ClinicalTrials.gov identifier: NCT03081689). The 3-year overall survival (OS) and circulating tumor DNA (ctDNA) analysis have not been reported. METHODS: This was an open-label, multicenter, single-arm, phase II trial in which patients with stage IIIA NSCLC, who were deemed to be surgically resectable, were treated with neoadjuvant paclitaxel (200 mg/m2 once a day) and carboplatin (area under curve 6) plus nivolumab (360 mg) once on day 1 of each 21-day cycle, for three cycles, followed by adjuvant nivolumab monotherapy for 1 year (240 mg once every 2 weeks for 4 months, followed by 480 mg once every 4 weeks for 8 months). The 3-year OS and ctDNA analysis were secondary objectives of the trial. RESULTS: OS at 36 months was 81.9% (95% CI, 66.8 to 90.6) in the intention-to-treat population, rising to 91.0% (95% CI, 74.2 to 97.0) in the per-protocol population. Neither tumor mutation burden nor programmed cell death ligand-1 staining was predictive of survival. Conversely, low pretreatment levels of ctDNA were significantly associated with improved progression-free survival and OS (hazard ratio [HR], 0.20; 95% CI, 0.06 to 0.63, and HR, 0.07; 95% CI, 0.01 to 0.39, respectively). Clinical responses according to RECIST v1.1 criteria did not predict survival outcomes. However, undetectable ctDNA levels after neoadjuvant treatment were significantly associated with progression-free survival and OS (HR, 0.26; 95% CI, 0.07 to 0.93, and HR, 0.04; 95% CI, 0.00 to 0.55, respectively). The C-index to predict OS for ctDNA levels after neoadjuvant treatment (0.82) was superior to that of RECIST criteria (0.72). CONCLUSION: The efficacy of neoadjuvant chemotherapy plus nivolumab in resectable NSCLC is supported by 3-year OS. ctDNA levels were significantly associated with OS and outperformed radiologic assessments in the prediction of survival.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Terapia Neoadyuvante/métodos , Nivolumab/uso terapéuticoRESUMEN
Background: There is currently a lack of effective biomarkers to evaluate efficacy of neoadjuvant therapy (NAT) for resectable non-small cell lung cancer (NSCLC) patients. Circulating tumor DNA (ctDNA) has been investigated as a non-invasive tool for the assessment of tumor burden and minimal residual disease (MRD). The utility of ctDNA profiling in reflecting NAT efficacy, however, has not been confirmed. This study explored the association of ctDNA change with treatment response to NAT and recurrence-free survival (RFS) after surgery. Methods: Eligible patients with stage IB-IIIA NSCLC were retrospectively included if they had received neoadjuvant immunotherapy combined with chemotherapy (IO+Chemo), dual immunotherapy (IO+IO), or chemotherapy alone (Chemo). We conducted ctDNA profiling before and after NAT, after surgery, and during follow-ups using an ultra-deep lung cancer-specific MRD (LC-MRD) sequencing panel. Results: A total of 22 patients who received NAT followed by surgery between August 2018 and July 2019 were included in this study. The major pathological response (MPR) rates were 58.33% (7/12) in the IO+Chemo group, 25.00% (1/4) in the IO+IO group, and 16.67% (1/6) in the Chemo group. The ctDNA dynamics during NAT were highly concordant with pathologic response, demonstrating 100% sensitivity and 83.33% specificity, for an overall accuracy of 91.67%. Pre-surgery detectable ctDNA (after NAT) trended to correlate with inferior RFS [hazard ratio (HR), 7.41; 95% confidence interval (CI): 0.91-60.22, log-rank P=0.03]. At 3-8 days after surgery, ctDNA was detectable in 31.8% of patients and was an independent risk factor for recurrence (HR, 5.37; 95% CI: 1.27-22.67; log-rank P=0.01). The presence of ctDNA at 3 months after surgery showed 83% sensitivity and 90% specificity for predicting relapse (C-index, 0.79; 95% CI: 0.62-0.95). During disease monitoring after surgery, molecular recurrence by means of ctDNA preceded radiographic relapse, with a median time of 6.83 months. Conclusions: This study investigated the potential of ctDNA in evaluating NAT efficacy in NSCLC, implying the high concordance between ctDNA and pathological response. We also set out the prognostic value of perioperative ctDNA in predicting recurrence.
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BACKGROUND: ALK rearrangements are present in 5% of nonsmall cell lung cancer (NSCLC) tumors and identify patients who can benefit from ALK inhibitors. ALK fusions testing using liquid biopsies, although challenging, can expand the therapeutic options for ALK-positive NSCLC patients considerably. RNA inside extracellular vesicles (EVs) is protected from RNases and other environmental factors, constituting a promising source for noninvasive fusion transcript detection. METHODS: EVs from H3122 and H2228 cell lines, harboring EML4-ALK variant 1 (E13; A20) and variant 3 (E6a/b; A20), respectively, were successfully isolated by sequential centrifugation of cell culture supernatants. EVs were also isolated from plasma samples of 16 ALK-positive NSCLC patients collected before treatment initiation. RESULTS: Purified EVs from cell cultures were characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and flow cytometry. Western blot and confocal microscopy confirmed the expression of EV-specific markers as well as the expression of EML4-ALK-fusion proteins in EV fractions from H3122 and H2228 cell lines. In addition, RNA from EV fractions derived from cell culture was analyzed by digital PCR (dPCR) and ALK-fusion transcripts were clearly detected. Similarly, plasma-derived EVs were characterized by NTA, flow cytometry, and the ExoView platform, the last showing that EV-specific markers captured EV populations containing ALK-fusion protein. Finally, ALK fusions were identified in 50% (8/16) of plasma EV-enriched fractions by dPCR, confirming the presence of fusion transcripts in EV fractions. CONCLUSIONS: ALK-fusion transcripts can be detected in EV-enriched fractions. These results set the stage for the development of EV-based noninvasive ALK testing.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Vesículas Extracelulares , Neoplasias Pulmonares , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular , Vesículas Extracelulares/metabolismo , Humanos , Neoplasias Pulmonares/patología , Proteínas de Fusión Oncogénica/genética , ARN , Proteínas Tirosina Quinasas Receptoras/genéticaRESUMEN
BACKGROUND: Extracellular vesicles (EVs), released by most cell types, provide an excellent source of biomarkers in biological fluids. However, in order to perform validation studies and screenings of patient samples, it is still necessary to develop general techniques permitting rapid handling of small amounts of biological samples from large numbers of donors. RESULTS: Here we describe a method that, using just a few microliters of patient's plasma, identifies tumour markers exposed on EVs. Studying physico-chemical properties of EVs in solution, we demonstrate that they behave as stable colloidal suspensions and therefore, in immunocapture assays, many of them are unable to interact with a stationary functionalised surface. Using flocculation methods, like those used to destabilize colloids, we demonstrate that cationic polymers increase EV ζ-potential, diameter, and sedimentation coefficient and thus, allow a more efficient capture on antibody-coated surfaces by both ELISA and bead-assisted flow cytometry. These findings led to optimization of a protocol in microtiter plates allowing effective immunocapture of EVs, directly in plasma without previous ultracentrifugation or other EV enrichment. The method, easily adaptable to any laboratory, has been validated using plasma from lung cancer patients in which the epithelial cell marker EpCAM has been detected on EVs. CONCLUSIONS: This optimized high throughput, easy to automate, technology allows screening of large numbers of patients to phenotype tumour markers in circulating EVs, breaking barriers for the validation of proposed EV biomarkers and the discovery of new ones.