RESUMEN

PURPOSE: Gallbladder cancer (GBC) is a biliary tract malignancy characterized by its high lethality. Although the incidence of GBC is low in most countries, specific areas such as Chile display a high incidence. Our collaborative study sought to compare clinical and molecular features of GBC cohorts from Chile and the United States with a focus on ERBB2 alterations. METHODS: Patients were accrued at Memorial Sloan Kettering Cancer Center (MSK) or the Pontificia Universidad Católica de Chile (PUC). Clinical information was retrieved from medical records. Genomic analysis was performed by the next-generation sequencing platform MSK-Integrated Mutation Profiling of Actionable Cancer Targets. RESULTS: A total of 260 patients with GBC were included, 237 from MSK and 23 from PUC. There were no significant differences in the clinical characteristics between the patients identified at MSK and at PUC except in terms of lithiasis prevalence which was significantly higher in the PUC cohort (85% v 44%; P = .0003). The prevalence of ERBB2 alterations was comparable between the two cohorts (15% v 9%; P = .42). Overall, ERBB2 alterations were present in 14% of patients (8% with ERBB2 amplification, 4% ERBB2 mutation, 1.5% concurrent amplification and mutation, and 0.4% ERBB2 fusion). Notably, patients with GBC that harbored ERBB2 alterations had better overall survival (OS) versus their ERBB2-wild type counterparts (22.3 months v 11.8 months; P = .024). CONCLUSION: The prevalence of lithiasis seems to be higher in Chilean versus US patients with GBC. A similar prevalence of ERBB2 alterations of overall 14% and better OS suggests that a proportion of them could benefit from human epidermal growth factor receptor type 2-targeted therapies. The smaller cohort of Chile, where the disease prevalence is higher, is a reminder and invitation for the need of more robust next-generation sequencing analyses globally.

Asunto(s)

Neoplasias de la Vesícula Biliar , Receptor ErbB-2 , Humanos , Neoplasias de la Vesícula Biliar/genética , Neoplasias de la Vesícula Biliar/epidemiología , Neoplasias de la Vesícula Biliar/patología , Neoplasias de la Vesícula Biliar/mortalidad , Chile/epidemiología , Receptor ErbB-2/genética , Femenino , Masculino , Persona de Mediana Edad , Anciano , Estados Unidos/epidemiología , Mutación , Estudios de Cohortes , Adulto , Genómica , Anciano de 80 o más Años , Secuenciación de Nucleótidos de Alto Rendimiento

RESUMEN

The mechanisms involved with the pathogenesis of carcinoma ex pleomorphic adenoma (CXPA) seem to be associated with the accumulation of molecular alterations in the pleomorphic adenoma (PA). In this sense, using array-based comparative genomic hybridization (aCGH) a rare series of 27 cases of CXPA and 14 residual PA (rPA) adjacent to the transformation area, we investigated the profile of the copy number alterations (CNAs) comparing benign residual and transformed areas. The main findings were correlated with the histopathological classification by histologic subtype and degree of invasion. The distribution of losses (p = 0.187) and amplifications (p = 0.172) was not statistically different between rPA and CXPA. The number of gains was increased in the transformed areas compared to the benign residual areas (p = 0.005). PLAG1 gain was maintained along the malignant transformation, as it was observed in both residual PA and CXPA samples, likely being an earlier event during transformation. The amplification of GRB7 and ERBB2 may also be an initial step in the malignant transformation of PA to CXPA (salivary duct carcinoma subtype). Furthermore, the amplification of HMGA2 and RPSAP52 were the most prevalent alterations among the studied samples. It was noteworthy that amplified genes in the transformed areas of the tumors were enriched for biological processes related to immune signaling. In conclusion, our results underscored for the first-time crucial CNAs in CXPA, some of them shared with the residual benign area adjacent to the transformation site. These CNAs included PLAG1 gain, as well as amplification of GRB7, ERBB2, HMGA2, and RPSAP52.

Asunto(s)

Adenoma Pleomórfico , Hibridación Genómica Comparativa , Variaciones en el Número de Copia de ADN , Humanos , Adenoma Pleomórfico/genética , Adenoma Pleomórfico/patología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Transformación Celular Neoplásica/genética , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/patología , Adulto , Proteína HMGA2/genética , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Proteínas de Unión al ADN/genética

RESUMEN

Chromosomal instability (CIN), characterized by fluctuations in chromosome number or structure within cells, stands out as a hallmark of cancer, enabling tumors to thrive in hostile conditions. CIN serves as a driver of genetic diversity, giving rise to clonal heterogeneity (CH). Emerging evidence points to a potential correlation between CIN, CH, and the prognosis of breast cancer (BC) patients, especially in tumors exhibiting overexpression of the human epidermal growth factor receptor 2 (HER2+). However, our understanding of the role of CIN in other subtypes of BC is limited. Furthermore, it remains unclear whether CIN levels above a certain threshold in BC tumors could adversely affect tumor growth, or if lower to moderate levels of CIN might be associated with a more favorable prognosis for BC patients compared to elevated levels. Elucidating these relationships could significantly influence risk assessment and the formulation of future therapeutic approaches targeting CIN in BC. This study aimed to assess CIN and CH in tumor tissue samples obtained from Colombian patients diagnosed with luminal A, luminal B, HER2+, or triple-negative BC, and compare them with established clinicopathological parameters. The findings of this study indicate that BC patients exhibit intermediate CIN, high CH, and stable aneuploidy. All these characteristics were found to be related to clinicopathological features. Our results suggest that the identification of CIN, CH, and aneuploidy could improve cancer risk stratification, which could help to clarify the prediction of clinical outcomes and guide personalized therapeutic strategies for patients with different BC subtypes.

Asunto(s)

Neoplasias de la Mama , Inestabilidad Cromosómica , Humanos , Femenino , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Persona de Mediana Edad , Adulto , Anciano , Heterogeneidad Genética , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Pronóstico

RESUMEN

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-low breast cancer has emerged as a new subtype of tumor, for which novel antibody-drug conjugates have shown beneficial effects. Assessment of HER2 requires several immunohistochemistry tests with an additional in situ hybridization test if a case is classified as HER2 2+. Therefore, novel cost-effective methods to speed up the HER2 assessment are highly desirable. METHODS: We used a self-supervised attention-based weakly supervised method to predict HER2-low directly from 1437 histopathological images from 1351 breast cancer patients. We built six distinct models to explore the ability of classifiers to distinguish between the HER2-negative, HER2-low, and HER2-high classes in different scenarios. The attention-based model was used to comprehend the decision-making process aimed at relevant tissue regions. RESULTS: Our results indicate that the effectiveness of classification models hinges on the consistency and dependability of assay-based tests for HER2, as the outcomes from these tests are utilized as the baseline truth for training our models. Through the use of explainable AI, we reveal histologic patterns associated with the HER2 subtypes. CONCLUSION: Our findings offer a demonstration of how deep learning technologies can be applied to identify HER2 subgroup statuses, potentially enriching the toolkit available for clinical decision-making in oncology.

Asunto(s)

Biomarcadores de Tumor , Neoplasias de la Mama , Aprendizaje Profundo , Inmunohistoquímica , Receptor ErbB-2 , Humanos , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/genética , Femenino , Biomarcadores de Tumor/metabolismo , Inmunohistoquímica/métodos , Aprendizaje Automático Supervisado

RESUMEN

Cutaneous squamous cell carcinoma (cSCC) is a neoplasm type often diagnosed in dogs. However, studies focused on further investigating its molecular biology, mainly biomarkers to help implementing new therapies, remain scare in the literature. Thus, immunostaining and the gene expression of epidermal growth factor receptors (HER1 and HER2) in canine cSCC presenting different cell differentiation degrees were herein assessed. Thirty-two (32) canine cSCC were selected, classified based on to their cell differentiation degree and subjected to immunohistochemical study to assess HER1 and HER2 immunostaining intensity and distribution. In addition, HER1 and HER2 gene expression was investigated through real-time PCR. Membranous and cytoplasmic immunostaining were observed in both markers. HER2 prevailed in poorly differentiated cSCC; there was positive protein expression correlation between both markers. Mean HER1 gene expression was higher in moderately differentiated, whereas mean HER2 gene expression was higher in poorly differentiated cSCC. Moreover, there was gene expression correlation between markers, regardless of cell differentiation degree. Thus, HER2 protein immunostaining and gene expression were higher in poorly differentiated canine cSCC and it enabled understanding that increase observed in this epidermal growth factor receptor is proportional to this neoplasm's cell differentiation degree in canine species. Results in the current study helped better understanding canine cSCC's molecular biology; however, it is relevant studying other markers aiming to investigate signaling pathways.

Asunto(s)

Carcinoma de Células Escamosas , Enfermedades de los Perros , Receptores ErbB , Inmunohistoquímica , Receptor ErbB-2 , Neoplasias Cutáneas , Animales , Perros , Enfermedades de los Perros/genética , Enfermedades de los Perros/metabolismo , Carcinoma de Células Escamosas/veterinaria , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Neoplasias Cutáneas/veterinaria , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Inmunohistoquímica/veterinaria , Femenino , Regulación Neoplásica de la Expresión Génica , Masculino , Reacción en Cadena en Tiempo Real de la Polimerasa/veterinaria

RESUMEN

OBJECTIVE: The objective of this study is to assess the clinical pathological attributes of Hepatoid Adenocarcinoma of the Stomach (HAS) and to delineate the differential diagnostic considerations about it. METHOD: The investigation involved analyzing 31 HAS cases using histomorphological assessment, immunohistochemical profiling, and relevant gene detection methodologies. RESULTS: Among the 31 HAS cases, 9 (29.0%) were of trabecular hepatoid adenocarcinoma of the stomach, 7 (22.6%) were of glandular hepatoid adenocarcinoma of the stomach, 4 (12.9%) were of nesting hepatoid adenocarcinoma of the stomach, 3 (9.7%) were of clear cell hepatoid adenocarcinoma of the stomach, and 8 (25.8%) were of diverse hepatoid adenocarcinoma of the stomach. Of these 31 cases, 24 were male, accounting for 77.4% of the cases. Serum alpha-fetoprotein (AFP) levels were notably elevated, with radioimmunoassay results reaching 1240 ng/ml; 28 out of 31 cases had AFP levels below 25 µg/l, accounting for 90.3%. Related genes: HER2 protein indicated positive expression on the cell membrane in 35.5% (11/31) of the cases; HER2 gene amplification detected by the FISH technique was 12.9% (4/31). Tumoral stromal lymphocytes exhibited a PD-1 positive expression rate of 58.1% (18/31). In gastric cancer tissues, the PD-L1 positive rate was 45.1% (14/31). CONCLUSION: HAS represents a distinctive subtype of gastric cancer with a propensity for mimicking other forms of tumors, underscoring the significance of discerning its unique histopathological attributes for accurate differential diagnosis and tailored therapeutic interventions.

Asunto(s)

Adenocarcinoma , Neoplasias Gástricas , alfa-Fetoproteínas , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Neoplasias Gástricas/metabolismo , Masculino , Adenocarcinoma/genética , Adenocarcinoma/patología , Femenino , Persona de Mediana Edad , Anciano , alfa-Fetoproteínas/metabolismo , alfa-Fetoproteínas/análisis , Anciano de 80 o más Años , Adulto , Biomarcadores de Tumor/genética , Diagnóstico Diferencial , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética

RESUMEN

PURPOSE: HER2 overexpression in breast cancer correlates with poor outcomes. The incorporation of Trastuzumab into the treatment regimen has notably improved patient prognoses. However, cardiotoxicity emerges in approximately 20% of patients treated with the drug. This study aims to investigate the association between the HER2 655 A > G polymorphism, Trastuzumab-induced cardiotoxicity, and patient survival. METHODS: The study involved 88 patients treated with Trastuzumab. Cardiotoxicity, defined as a reduction in left ventricular ejection fraction (LVEF) from baseline or the emergence of clinical signs of congestive heart failure, was identified during treatment follow-up. Genotyping of HER2 655 A > G employed TaqMan SNP technology. RESULTS: Genotype frequencies of HER2/neu 655 (53 AA, 32 AG, and 3 GG) were consistent with Hardy-Weinberg equilibrium. No significant differences were observed in mean baseline LVEF between patients who developed cardiotoxicity and those who did not. Within these groups, neither AA nor AG genotypes showed an association with changes in mean baseline or reduced LVEF levels. Logistic regression analysis, adjusted for hormonal status and anthracycline treatment, revealed that AG genotype carriers face a significantly higher risk of cardiotoxicity compared to AA carriers (OR = 4.42; p = 0.037). No association was found between the HER2/neu 655 A > G polymorphism and disease-free or overall survival, regardless of whether the data was adjusted for stage or not. CONCLUSION: HER2 655 A > G polymorphism is significantly linked to an increased risk of Trastuzumab-induced cardiotoxicity but does not correlate with variations in disease-free survival or overall survival rates.

Asunto(s)

Antineoplásicos Inmunológicos , Neoplasias de la Mama , Cardiotoxicidad , Polimorfismo de Nucleótido Simple , Receptor ErbB-2 , Trastuzumab , Humanos , Trastuzumab/efectos adversos , Trastuzumab/uso terapéutico , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/mortalidad , Persona de Mediana Edad , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Cardiotoxicidad/etiología , Cardiotoxicidad/genética , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico , Adulto , Anciano , Genotipo , Tasa de Supervivencia , Pronóstico

RESUMEN

PURPOSE: The advent of circulating tumor DNA (ctDNA) technology has provided a convenient and noninvasive means to continuously monitor cancer genomic data, facilitating personalized cancer treatment. This study aimed to evaluate the supplementary benefits of plasma ctDNA alongside traditional tissue-based next-generation sequencing (NGS) in identifying targetable mutations and tumor mutational burden (TMB) in colorectal cancers (CRC). METHODS: Our study involved 76 CRC patients, collecting both tissue and plasma samples for NGS. We assessed the concordance of gene mutational status between ctDNA and tissue, focusing on actionable genes such as KRAS, NRAS, PIK3CA, BRAF, and ERBB2. Logistic regression analysis was used to explore variables associated with discordance and positive mutation rates. RESULTS: In total, 26 cancer-related genes were identified. The most common variants in tumor tissues and plasma samples were in APC (57.9% vs 19.7%), TP53 (55.3% vs 22.4%) and KRAS (47.4% vs 43.4%). Tissue and ctDNA showed an overall concordance of 73.53% in detecting actionable gene mutations. Notably, plasma ctDNA improved detection for certain genes and gene pools. Variables significantly associated with discordance included gender and peritoneal metastases. TMB analysis revealed a higher detection rate in tissues compared to plasma, but combining both increased detection. CONCLUSIONS: Our study highlights the importance of analyzing both tissue and plasma for detecting actionable mutations in CRC, with plasma ctDNA offering added value. Discordance is associated with gender and peritoneal metastases, and TMB analysis can benefit from a combination of tissue and plasma data. This approach provides valuable insights for personalized CRC treatment.

Asunto(s)

ADN Tumoral Circulante , Neoplasias Colorrectales , Secuenciación de Nucleótidos de Alto Rendimiento , Mutación , Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/patología , Masculino , Femenino , ADN Tumoral Circulante/sangre , ADN Tumoral Circulante/genética , Persona de Mediana Edad , Anciano , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Proteínas Proto-Oncogénicas B-raf/genética , GTP Fosfohidrolasas/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Fosfatidilinositol 3-Quinasa Clase I/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/sangre , Adulto , Anciano de 80 o más Años , Proteína p53 Supresora de Tumor/genética , Receptor ErbB-2/genética , Proteína de la Poliposis Adenomatosa del Colon/genética , Proteínas de la Membrana/genética , Proteínas de la Membrana/sangre

RESUMEN

Chromosomal instability (CIN), defined by variations in the number or structure of chromosomes from cell to cell, is recognized as a distinctive characteristic of cancer associated with the ability of tumors to adapt to challenging environments. CIN has been recognized as a source of genetic variation that leads to clonal heterogeneity (CH). Recent findings suggest a potential association between CIN and CH with the prognosis of BC patients, particularly in tumors expressing the epidermal growth factor receptor 2 (HER2+). In fact, information on the role of CIN in other BC subtypes, including luminal B BC, is limited. Additionally, it remains unknown whether CIN in luminal B BC tumors, above a specific threshold, could have a detrimental effect on the growth of human tumors or whether low or intermediate CIN levels could be linked to a more favorable BC patient prognosis when contrasted with elevated levels. Clarifying these relationships could have a substantial impact on risk stratification and the development of future therapeutic strategies aimed at targeting CIN in BC. This study aimed to assess CIN and CH in tumor tissue samples from ten patients with luminal B BC and compare them with established clinicopathological parameters. The results of this study reveal that luminal B BC patients exhibit intermediate CIN and stable aneuploidy, both of which correlate with lymphovascular invasion. Our results also provide valuable preliminary data that could contribute to the understanding of the implications of CIN and CH in risk stratification and the development of future therapeutic strategies in BC.

Asunto(s)

Neoplasias de la Mama , Inestabilidad Cromosómica , Humanos , Femenino , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Proyectos Piloto , Persona de Mediana Edad , Anciano , Adulto , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , Pronóstico , Aneuploidia , Heterogeneidad Genética

RESUMEN

PURPOSE: Although pharmaceutical companies conduct clinical trials of novel human epidermal growth factor receptor 2 (HER2)-low-directed drugs, diagnosing HER2-low cancer by immunohistochemistry (IHC) and in situ hybridization (ISH) remains challenging. This study investigates the performance of first-in-kind computerized intelligence to classify samples across gene expression levels and differentiate HER2-low tumors. MATERIALS AND METHODS: We classified 251 samples: 142 primary invasive breast cancers (IBCs), 75 ductal carcinomas in situ (DCIS), and 34 mammaplasties (reference) using mRNA expression data from the QuantiGene Plex 2.0 assay. We used g3mclass probabilistic software to assess the number of classes in the assay data, the mean and the variance in each class, diagnostic cutoffs, and the prevalence of each class in the study population. RESULTS: HER2-low (IHC score of 1+ or 2+/ISH-) accounted for 31% of IBC. First, we discovered that HER2-low tumors were represented by cases with normal ERBB2 transcript levels that were expected to produce physiologic levels of HER2 (70%) and cases with abnormally upregulated unamplified ERBB2 (30%). We termed the latter cancers ERBB2-up as they do not meet the standard definitions for ERBB2 overexpression and amplification. Second, HER2-low IBC classified as ERBB2-up had not only abnormally increased luminal growth and adhesion markers (ERBB2, ESR1, PGR, IGF1R, VAV2, VAV3, KRT8, CDH1) but also downregulated myoepithelial marker (KRT5). The vascularization (RAP1 and C3G), immune cell infiltration (VAV1), and mesenchymal transition (CDH2) markers were dysregulated. Finally, in the independent cohort of DCIS, 40% of HER2-low DCIS shared similar traits with HER2-low IBC except for rare downregulation of KRT5 and no change in C3G, VAV1, and CDH2. CONCLUSION: We demonstrated how innovative bioinformatic tools could help diagnose cancer across the spectrum of ERBB2 expression to aid decision making for HER2-low.

Asunto(s)

Neoplasias de la Mama , Carcinoma Intraductal no Infiltrante , Humanos , Femenino , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Receptor ErbB-2/genética , Biología Computacional

RESUMEN

HER2-enriched tumors are responsible for 20% of breast tumors and have high rates of immune infiltrates in the tumor stroma that respond favorably to neoadjuvant chemotherapy. In the context of tumors, telomeres control cell death and prevent tumor cells from replicating discontinuously, leading to their immortalization. This study aimed to evaluate the presence of tumor-infiltrating lymphocytes, hTERT expression, hTERT promoter mutation, and leukocyte telomere length in HER2-enriched breast tumors. A total of 103 cases were evaluated, 19 with pathologic complete response. The TILs percentage was above ≥10 in 44 cases (43%) and significantly present in patients ≥50 years of age. hTERT staining positivity was mostly nuclear, significantly present in the non-pCR group, and associated with a lower survival rate. Leukocyte telomeres were elongated for HER2-enriched tumors, and in multivariate analysis, shortening was associated with an increased risk of death. Overall, our results show that the nuclear and cytoplasmic presence of hTERT may indicate a worse prognosis and that leukocyte telomere elongation is a protective factor.

Asunto(s)

Neoplasias de la Mama , Femenino , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos Infiltrantes de Tumor/patología , Terapia Neoadyuvante/métodos , Pronóstico , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo

RESUMEN

Breast cancer is a heterogeneous disease with distinct clinical and molecular characteristics. Scientific advances in molecular subtype differentiation support the understanding of cellular signaling, crosstalk, proliferation, survival, migration, and invasion mechanisms, allowing the development of new molecular drug targets. The breast cancer subtype with super expression and/or amplification of human growth factor receptor 2 (HER2) is clinically aggressive, but prognosis significantly shifted with the advent of anti-HER2 targeted therapy. Zoledronic-acid (ZOL) combined with a neoadjuvant Trastuzumab-containing chemotherapy regimen (Doxorubicin, Cyclophosphamide followed by Docetaxel, Trastuzumab) increased the pCR rate in a RH-positive/ HER2-positive subgroup, according to the phase II Zo-NAnTax trial. To verify genes that could be related to this response, a microarray assay was performed finding 164 differentially expressed genes. Silico analysis of these genes showed signaling pathways related to growth factors, apoptosis, invasion, and metabolism, as well as differentially expressed genes related to estrogen response. In addition, the RAC3 gene was found to interact with the MVD gene, a member of the mevalonate pathway. Taken together, these results indicate that RH-positive/ HER2-positive patients present gene alterations before treatment, and these could be related to the improvement of pCR.

Asunto(s)

Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Ácido Zoledrónico/uso terapéutico , Terapia Neoadyuvante , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Trastuzumab/uso terapéutico , Ciclofosfamida/uso terapéutico , Resultado del Tratamiento

RESUMEN

Gastroesophageal cancer (GEC) is an aggressive disease characterized by a high frequency of metastasis and poor overall survival rates. GEC presents HER2 overexpression in 5 to 25% of tumors eligible for HER2-targeted therapy. HER2 evaluation requires protein levels and copy number alteration analyses by immunohistochemistry (IHC) and in situ hybridization (FISH or SISH), respectively. These are semiquantitative methodologies that need an expert and well-trained pathologist. Therefore, the use of new surrogate methods for HER2 evaluation in cancer, such as gene expression analysis, might improve GEC HER2 classification. We evaluated HER2 positivity in GEC through conventional IHC and SISH analyses and investigated the potential application of HER2 mRNA expression by quantitative PCR to categorize GEC samples as HER2-positive or HER2-negative. Among 270 GEC samples, 10.9% were HER2-positive by IHC and SISH analyses. HER2 mRNA was overexpressed in HER2-positive GEC samples and presented high accuracy in distinguishing those tumors from HER2-negative GEC. Nevertheless, HER2 mRNA analysis was not capable of classifying HER2-equivocal GEC samples into HER2-positive or -negative according to SISH data. Quantitative PCR analysis showed HER2 overexpression in HER2-positive GEC samples. Nevertheless, HER2 mRNA analysis failed to classify HER2-equivocal GEC according to SISH data.

Asunto(s)

Neoplasias Esofágicas , Neoplasias Gástricas , Humanos , Receptor ErbB-2/genética , Neoplasias Gástricas/metabolismo , Hibridación in Situ , Neoplasias Esofágicas/genética , ARN Mensajero

RESUMEN

PURPOSE: The TAPUR Study is a pragmatic phase II basket trial evaluating antitumor activity of commercially available targeted agents in patients with advanced cancers harboring potentially actionable genomic alterations. Data from two cohorts of patients with colorectal cancer (CRC) with either ERBB2 amplifications or ERBB2 or ERBB3 (ERBB2/3) mutations treated with pertuzumab plus trastuzumab (P + T) are reported. METHODS: Eligible patients with measurable CRC were selected for treatment with P + T according to protocol-specified genomic matching rules. Patients had no remaining standard treatment options, Eastern Cooperative Oncology Group performance status 0-2, and adequate organ function. Simon's two-stage design was used with a primary study end point of disease control (DC; objective response [OR] or stable disease of at least 16 weeks duration [SD16+]). Secondary end points include safety, response duration, progression-free survival (PFS), and overall survival (OS). RESULTS: Thirty-eight patients with CRC with ERBB2 amplification (N = 28) or ERBB2/3 mutations (N = 10) were treated with P + T. For the ERBB2 amplification cohort, DC and OR were observed in 54% and 25% of patients, respectively; the median PFS and median OS (95% CIs) were 17.2 (11.1 to 27.4) weeks and 60.0 (32.1 to 102.3) weeks, respectively. For the ERBB2/3 mutation cohort, DC and OR were observed in 10% and 0% of patients, respectively; the median PFS and median OS were 9.6 (5.1 to 16.0) weeks and 28.8 (7.6 to 146.3) weeks, respectively. Four of 38 patients experienced grade 3 adverse events or serious adverse events including anemia, infusion reaction, diarrhea, left ventricular systolic dysfunction, and decreased lymphocyte count. CONCLUSION: Although P + T treatment does not appear to have antitumor activity in CRC with ERBB2/3 mutations, this combination has antitumor activity in patients with CRC with ERBB2 amplification and warrants further study.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Colorrectales , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Mutación , Receptor ErbB-2/genética , Trastuzumab/uso terapéutico

RESUMEN

ERBB2 exon 20 insertions may impact the clinical management of lung cancer patients. However, the frequency of ERBB2 exon 20 insertions in lung cancer patients in Brazil is scarce. Here, we analyzed 722 Brazilian non-small cell lung cancer (NSCLC) patients from Barretos Cancer Hospital that were indicated to require routine lung cancer molecular testing. ERBB2 exon 20 insertions were evaluated by a targeted panel using next-generation sequencing (NGS). Clinicopathological and molecular data were collected from patient medical records. Among the 722 NSCLC patients, 85.2% had lung adenocarcinomas, 53.9% were male, 66.8% were quitter or current smokers, and 63.2% were diagnosed at an advanced stage of the disease. We identified 0.8% (6/722) of patients who harbored the insertion p.(Tyr772_Ala775dup) at exon 20 of the ERBB2 gene. All ERBB2 mutated patients were diagnosed with lung adenocarcinoma, were never smokers, and wild-type for EGFR, KRAS, and ALK hotspot alterations. Less than 1% of Brazilian NSCLC patients harbor ERBB2 exon 20 insertions, yet they could benefit in future from the new drugs in development.

Asunto(s)

Adenocarcinoma del Pulmón , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Masculino , Femenino , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Brasil , Mutación , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Exones , Receptor ErbB-2/genética

Asunto(s)

Neoplasias Colorrectales , Biomarcadores de Tumor , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/terapia , Humanos , Receptor ErbB-2/genética

RESUMEN

BACKGROUND: Breast cancer incidence in the United States is lower in Hispanic/Latina (H/L) compared with African American/Black or Non-Hispanic White women. An Indigenous American breast cancer-protective germline variant (rs140068132) has been reported near the estrogen receptor 1 gene. This study tests the association of rs140068132 and other polymorphisms in the 6q25 region with subtype-specific breast cancer risk in H/Ls of high Indigenous American ancestry. METHODS: Genotypes were obtained for 5,094 Peruvian women with (1,755) and without (3,337) breast cancer. Associations between genotype and overall and subtype-specific risk for the protective variant were tested using logistic regression models and conditional analyses, including other risk-associated polymorphisms in the region. RESULTS: We replicated the reported association between rs140068132 and breast cancer risk overall [odds ratio (OR), 0.53; 95% confidence interval (CI), 0.47-0.59], as well as the lower odds of developing hormone receptor negative (HR-) versus HR+ disease (OR, 0.77; 95% CI, 0.61-0.97). Models, including HER2, showed further heterogeneity with reduced odds for HR+HER2+ (OR, 0.68; 95% CI, 0.51-0.92), HR-HER2+ (OR, 0.63; 95% CI, 0.44-0.90) and HR-HER2- (OR, 0.77; 95% CI, 0.56-1.05) compared with HR+HER2-. Inclusion of other risk-associated variants did not change these observations. CONCLUSIONS: The rs140068132 polymorphism is associated with decreased risk of breast cancer in Peruvians and is more protective against HR- and HER2+ diseases independently of other breast cancer-associated variants in the 6q25 region. IMPACT: These results could inform functional analyses to understand the mechanism by which rs140068132-G reduces risk of breast cancer development in a subtype-specific manner. They also illustrate the importance of including diverse individuals in genetic studies.

Asunto(s)

Neoplasias de la Mama , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/etnología , Neoplasias de la Mama/genética , Cromosomas Humanos Par 6 , Femenino , Hispánicos o Latinos , Humanos , Modelos Logísticos , Perú/epidemiología , Receptor ErbB-2/genética , Receptores de Estrógenos/genética , Receptores de Progesterona/genética

RESUMEN

PURPOSE: About 10% of breast cancer (BC) is diagnosed in stage IV. This study sought to identify factors associated with time to progression (TTP) and overall survival (OS) in a cohort of patients diagnosed with de novo metastatic breast cancer (MBC), from a single cancer center in Colombia, given that information on this aspect is limited. METHODOLOGY: An observational, analytical, and retrospective cohort study was carried out. Time to progression and OS rates were estimated using the Kaplan-Meier survival functions. Cox models were developed to assess association between time to progression and time to death, using a group of fixed variables. RESULTS: Overall, 175 patients were included in the study; 33.7% of patients had luminal B HER2-negative tumors, 49.7% had bone involvement, and 83.4% had multiple metastatic sites. Tumor biology and primary tumor surgery were the variables associated with TTP and OS. Patients with luminal A tumors had the lowest progression and mortality rates (10 per 100 patients/year (95% CI: 5.0-20.0) and 12.6 per 100 patients/year (95% CI: 6.9-22.7), respectively), and patients with triple-negative tumors had the highest progression and mortality rates (40 per 100 patients/year (95% CI: 23.2-68.8) and 44.1 per 100 patients/year (95% CI: 28.1-69.1), respectively). Across the cohort, the median TTP was 2.1 years (95% CI: 1.6; the upper limit cannot be reached) and the median OS was 2.4 years (95% CI: 2-4.3). CONCLUSIONS: In this cohort, patients with luminal A tumors and those who underwent tumor surgery given that they presented clinical benefit (CB) after initial systemic treatment, had the lowest progression and mortality rates. Overall, OS was inferior to other series due to high tumor burden and difficulties in accessing and continuing oncological treatments.

Asunto(s)

Neoplasias de la Mama , Neoplasias de la Mama/patología , Estudios de Cohortes , Colombia/epidemiología , Femenino , Humanos , Estadificación de Neoplasias , Receptor ErbB-2/genética , Receptor ErbB-2/uso terapéutico , Estudios Retrospectivos , Resultado del Tratamiento

RESUMEN

Breast cancer (BC) is a heterogeneous disease composed of multiple subtypes with different molecular characteristics and clinical outcomes. The metastatic process in BC depends on the transcription factors (TFs) related to epithelial-mesenchymal transition (EMT), including the master regulator Twist1. However, its role beyond EMT in BC subtypes remains unclear. Our study aimed to investigate the role of Twist1, beyond EMT, in the molecular subtypes of BC. In patients, we observed the overexpression of TWIST1 in the HER2+ group. The silencing of TWIST1 in HER2+ BC cells resulted in the upregulation of 138 genes and the downregulation of 174 genes compared to control cells in a microarray assay. In silico analysis revealed correlations between Twist1 and important biological processes such as the Th17-mediated immune response, suggesting that Twist1 could be relevant for IL-17 signaling in HER2+ BC. IL-17 signaling was then examined, and it was shown that TWIST1 knockdown caused the downregulation of leading members of IL-17 signaling pathway. Taken together, our findings suggest that Twist1 plays a role on IL-17 signaling in HER2+ BC.

Asunto(s)

Neoplasias de la Mama/inmunología , Regulación Neoplásica de la Expresión Génica/inmunología , Interleucina-17/inmunología , Proteínas Nucleares/inmunología , Receptor ErbB-2/inmunología , Transducción de Señal/inmunología , Proteína 1 Relacionada con Twist/inmunología , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Femenino , Humanos , Interleucina-17/genética , Proteínas Nucleares/genética , Receptor ErbB-2/genética , Transducción de Señal/genética , Proteína 1 Relacionada con Twist/genética

RESUMEN

The reported rates of HER2 positivity in cervical cancer (CC) range from 0% to 87%. The importance of HER2 as an actionable target in CC would depend on HER2 positivity prevalence. Our aim was to provide precise estimates of HER2 overexpression and amplification in CC, globally and by relevant subgroups. We conducted a PRISMA compliant meta-analytic systematic review. We searched Medline, EMBASE, Cochrane database, and grey literature for articles reporting the proportion of HER2 positivity in CC. Studies assessing HER2 status by immunohistochemistry or in situ hybridization in invasive disease were eligible. We performed descriptive analyses of all 65 included studies. Out of these, we selected 26 studies that used standardized American Society of Clinical Oncology / College of American Pathologists (ASCO/CAP) Guidelines compliant methodology. We conducted several meta-analyses of proportions to estimate the pooled prevalence of HER2 positivity and subgroup analyses using geographic region, histology, tumor stage, primary antibody brand, study size, and publication year as moderators. The estimated pooled prevalence of HER2 overexpression was 5.7% (CI 95%: 1.5% to 11.7%) I2 = 87% in ASCO/CAP compliant studies and 27.0%, (CI 95%: 19.9% to 34.8%) I2 = 96% in ASCO/CAP non-compliant ones, p < 0.001. The estimated pooled prevalence of HER2 amplification was 1.2% (CI 95%: 0.0% to 5.8%) I2 = 0% and 24.9% (CI 95%: 12.6% to 39.6%) I2 = 86%, respectively, p = 0.004. No other factor was significantly associated with HER2 positivity rates. Our results suggest that a small, but still meaningful proportion of CC is expected to be HER2-positive. High heterogeneity was the main limitation of the study. Variations in previously reported HER2 positivity rates are mainly related to methodological issues.

Asunto(s)

Amplificación de Genes , Regulación Neoplásica de la Expresión Génica , Receptor ErbB-2/genética , Neoplasias del Cuello Uterino/genética , Femenino , Humanos , Neoplasias del Cuello Uterino/patología