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BACKGROUND: Perivascular epithelioid cell neoplasms (PEComas) encompass a heterogeneous family of mesenchymal tumors. Previously described clinicopathologic features aimed at distinguishing benign from malignant variants but lacked prognostic value. METHODS: This retrospective analysis examined clinicopathologic data from patients who had localized PEComa across French Sarcoma Network centers. The authors analyzed 12 clinicopathologic features in a Cox proportional hazard framework to derive a multivariate prognostic risk model for event-free survival (EFS). They built the PEComa prognostic score (PEC-PRO), in which scores ranged from 0 to 5, based on the coefficients of the multivariate model. Three groups were identified: low risk (score = 0), intermediate risk (score = 1), and high risk (score ≥ 2). RESULTS: Analyzing 87 patients who had a median 46-month follow-up (interquartile range, 20-74 months), the median EFS was 96.5 months (95% confidence interval [CI], 47.1 months to not applicable), with 2-year and 5-year EFS rates of 64.7% and 58%, respectively. The median overall survival was unreached, with 2-year and 5-year overall survival rates of 82.3% and 69.3%, respectively. The simplified Folpe classification did not correlate with EFS. Multivariate analysis identified three factors affecting EFS: positive surgical margins (hazard ratio [HR], 5.17; 95% CI, 1.65-16.24; p = .008), necrosis (HR, 3.94; 95% CI, 1.16-13.43; p = .030), and male sex (HR, 3.13; 95% CI, 1.19-8.27; p = 0.023). Four variables were retained in the prognostic model. Patients with low-risk PEC-PRO scores had a 2-year EFS rate of 93.7% (95% CI, 83.8%-100.0%), those with intermediate-risk PEC-PRO scores had a 2-year EFS rate of 67.4% (95% CI, 53.9%-80.9%), and those with high-risk PEC-PRO scores had a 2-year EFS rate of 2.3% (95% CI, 0.0%-18.3%). CONCLUSIONS: The PEC-PRO score reliably predicts the risk of postoperative recurrence in patients with localized PEComa. It has the potential to improve follow-up strategies but requires validation in a prospective trial.
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Neoplasias de Células Epitelioides Perivasculares , Humanos , Masculino , Femenino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Adulto , Neoplasias de Células Epitelioides Perivasculares/patología , Neoplasias de Células Epitelioides Perivasculares/terapia , Neoplasias de Células Epitelioides Perivasculares/mortalidad , Neoplasias de Células Epitelioides Perivasculares/cirugía , Anciano , Adulto Joven , Adolescente , Modelos de Riesgos Proporcionales , Tasa de SupervivenciaRESUMEN
BACKGROUND: HER2 expression is often negative or low in primary breast cancers (BCs) but its changes with disease progression remain poorly known. We aimed to estimate them between primary and recurrent tumours, and identify predictive factors. METHODS: We compared the HER2 status, and clinical and pathological characteristics by its evolution category (stable or changed), between all primary BCs and matched recurrences registered in our database in 2000-2020 (n = 512). RESULTS: HER2-low tumours were the most prevalent at diagnosis (44.9%), followed by HER2-negative tumours (39.3%). HER2 status significantly changed in 37.3% of recurrences, mainly of HER2-negative and HER2-low tumours. HER2-negative tumours which relapsed as HER2-low significantly more frequently expressed oestrogen receptors (ER) and recurred later than stably HER2-negative tumours. Changed HER2 status in distant metastases correlated with lower proliferation rates and higher ER expression in primary tumours, and among metastases of hormone receptor-positive (HR+) tumours-with weak progesterone receptor (PR) expression in primary tumours. CONCLUSIONS: HER2 status changes with BC progression, with enrichment of HER2-low tumours in advanced stages. The ER+/PR- status, low proliferation index and time to late recurrence correlated with these changes. These findings highlight the need of retesting recurrences, especially of HR + primary tumours, to identify candidates for new anti-HER2 therapies.
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Neoplasias de la Mama , Receptor ErbB-2 , Humanos , Femenino , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/terapia , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Progresión de la Enfermedad , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismoRESUMEN
INTRODUCTION: Soft tissue sarcomas (STSs) are a rare and heterogenous group of tumors, with poor prognostic, judging from their frequency to relapse. Few drugs are available after the conventional first-line regimen. Since 2007, trabectedin got approval after failure of anthracyclines and ifosfamide, for advanced or metastatic STS. This led to a FDA approval in 2015, but real-world evidence is still required, complementary to the pivotal phase II and III trials. METHODS: One hundred twenty-six patients with STS, treated by trabectedin between 2002 and 2019, were analyzed in this retrospective study, in two French centers. The effects of trabectedin on survival, response, and toxicity were described. All patients were tested for toxicities, and efficacy was assessed in patients exposed to at least 2 cycles of trabectedin. RESULTS: Three median cycles were administered per patient (1-79). Among the 113 patients analyzed for efficacy, the median progression-free survival was 3.0 months (95% CI: 2.3-4.8), with an overall survival of 12.3 months (95% CI: 10.2-16.9). The rate of disease control was 46% at the end of treatment. Myxoid liposarcoma (n = 11) was the histology subtype that benefited most from this chemotherapy with median progression-free survival and overall survival of 13.3 months (95% CI: 2.3-18.7) and 27.8 months (95% CI: 3.2-64.7), respectively. Adverse events were manageable. DISCUSSION AND CONCLUSION: Efficacy of trabectedin is confirmed in terms of clinical benefit and low toxicity, especially for myxoid liposarcoma. Combinatory regimens are under clinical trials to optimize the place of this chemotherapy.
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Leiomiosarcoma , Liposarcoma Mixoide , Sarcoma , Neoplasias de los Tejidos Blandos , Tetrahidroisoquinolinas , Humanos , Adulto , Trabectedina/efectos adversos , Estudios Retrospectivos , Liposarcoma Mixoide/tratamiento farmacológico , Tetrahidroisoquinolinas/efectos adversos , Dioxoles/efectos adversos , Leiomiosarcoma/patología , Antineoplásicos Alquilantes/efectos adversos , Supervivencia sin Enfermedad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias de los Tejidos Blandos/tratamiento farmacológicoRESUMEN
Determining the status of steroid hormone receptors [oestrogen (ER) and progesterone receptors (PR)] is a crucial part of the breast cancer workup. Thereby, breast cancers can be classified into four subtypes. However, the existence of ER-/PR+ tumours, often reported to be ill-classified due to technical errors, remains controversial. In order to address this controversy, we reviewed the hormone receptor status of 49 breast tumours previously classified as ER-/PR+ by immunohistochemistry, and compared clinical, pathological and molecular characteristics of confirmed ER-/PR+ tumours with those of ER+ and triple-negative tumours. We unequivocally confirmed the ER-/PR+ status in 27 of 49 tumours (0.3% of all breast cancers diagnosed in our institution between 2000 and 2014). We found that ER-/PR+ were morphologically and histologically similar to triple-negative tumours, but very distinct from ER+ tumours, with more aggressive phenotypes and more frequent basal marker expression than the latter. On the molecular level, RNA sequencing revealed different gene expression profiles between the three groups. Of particular interest, several genes controlled by the suppressor of zest 12 (SUZ12) were upregulated in ER-/PR+ tumours. Overall, our results confirm that ER-/PR+ breast cancers are an extremely rare but 'real' tumour subtype that requires careful diagnosis and has distinct features warranting different responsiveness to therapies and different clinical outcomes. Studies on larger cohorts are needed to further characterise these tumours. The likely involvement of SUZ12 in their biology is an interesting finding which may - in a long run - give rise to the development of new therapeutic alternatives.
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Biomarcadores de Tumor/genética , Carcinoma Ductal de Mama/patología , Carcinoma Lobular/patología , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Anciano , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/metabolismo , Carcinoma Lobular/genética , Carcinoma Lobular/metabolismo , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Pronóstico , Receptor ErbB-2/metabolismo , Neoplasias de la Mama Triple Negativas/clasificación , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/metabolismoRESUMEN
Primary triple-negative invasive lobular breast carcinomas (TN-ILCs), which do not express hormone receptors and HER2 at diagnosis, are rare and poorly known. In this study, we analyzed the largest TN-ILC series ever reported in the literature, in comparison to phenotypically similar breast tumor subtypes: triple-negative invasive ductal carcinoma (TN-IDC) and hormone receptor-positive invasive lobular carcinoma (HR + ILC). All primary TN-ILCs registered in our database between 2000 and 2018 (n = 38) were compared to tumors from control groups, matched by stage and Elston/Ellis grade, with regard to clinical, pathologic, and immunohistochemical characteristics. A comparative molecular analysis (whole-exome and RNA sequencing using next-generation technology) was also performed. We found that TN-ILC patients were older than those with HR + ILC (P = 0.002) or TN-IDC (P < 0.001). Morphologically, TN-ILCs had aggressive phenotypes, with more pleomorphism (P = 0.003) and higher nuclear grades than HR + ILCs (P = 0.009). Immunohistochemistry showed that TN-ILCs less frequently expressed basal markers (CK5/6, EGFR and SOX10) than TN-IDCs (P < 0.001), while androgen receptor (AR) positivity was more prevalent (P < 0.001). Survival curves analysis did not show differences between TN-ILC and TN-IDC patients, while overall and distant metastasis-free survival were significantly worse compared to those with HR + ILCs (P = 0.047 and P = 0.039, respectively). At a molecular level, we found that TN-ILCs had particular transcriptomic profiles, characterized by increased AR signaling, and associated with frequent alterations in the PI3K network and ERBB2. Interestingly, whole-exome analysis also identified three specific recurrent ESRRA hotspot mutations in these tumors, which have never been described in breast cancer to date and which were absent in the other two tumor subtypes. Our findings highlight that TN-ILC is a unique aggressive breast cancer associated with elderly age, which belong to the luminal androgen receptor subtype as determined by immunohistochemistry and transcriptomic profiling. Moreover, it harbors specific molecular alterations (PI3K, ERBB2 and ESRRA) which may pave the way for new targeted therapeutic strategies.
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Carcinoma Lobular/patología , Receptores Androgénicos/metabolismo , Receptores de Estrógenos/genética , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Lobular/genética , Carcinoma Lobular/metabolismo , Análisis Mutacional de ADN , Femenino , Humanos , Persona de Mediana Edad , Mutación , Fosfatidilinositol 3-Quinasas/genética , Receptor ErbB-2/genética , Receptores Androgénicos/genética , Neoplasias de la Mama Triple Negativas/metabolismo , Receptor Relacionado con Estrógeno ERRalfaRESUMEN
AIMS: Superficial CD34-positive fibroblastic tumor (SCD34FT) and PRDM10-rearranged soft tissue tumor (PRDM10-STT) are rare mesenchymal tumors. These lesions have clinicopathological similarities, but their relationship remains controversial. This study aimed to characterise a series of cases of SCD34FT and PRDM10-STT. METHODS AND RESULTS: Ten lesions each of SCD34FT and PRDM10-STT were studied using immunohistochemistry, array-comparative genomic hybridisation (aCGH), RNA sequencing and exome sequencing. Tumors mainly occurred in young adults, were generally small (< 5 cm) and arose predominantly in the superficial soft tissues of the lower extremities. Follow-up data were available in 15 cases (SCD34FT, n = 7, median 16 months; PRDM10-STT, n = 8, median 14 months), local recurrences occurred in four cases (SCD34FT, two of 10; PRDM10-STT, two of 10), while no distant spread was documented. Morphologically, tumors were relatively well-circumscribed and composed of sheets and fascicles of spindle and pleomorphic cells showing low mitotic activity (< 1/mm²) without necrosis. Other findings included: granular cell change, lipoblast-like cells, ectatic blood vessels with fibrinous material, myxoid stromal changes, metaplastic bone and increased mitotic activity (> 1/mm²). All tumors diffusely expressed CD34, while pan-keratin and desmin were commonly seen focally. SynCAM3 was diffusely expressed in 12 cases (SCD34FT, n = 5; PRDM10-STT, n = 7), independently of fusion status. aCGH profiles were 'flat' (PRDM10-STT, n = 4; SCD34FT, n = 2) and exome sequencing showed no recurrent pathogenic mutations (PRDM10-STT, n = 2; SCD34FT, n = 4). Overall, the only morphological features seen exclusively in PRDM10-STT were myxoid stromal changes (three of 10) and metaplastic bone (two of 10). CONCLUSION: We expand the current knowledge on PRDM10-STT and SCD34FT and provide additional evidence for considering them as overlapping entities.
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Antígenos CD34/metabolismo , Proteínas de Unión al ADN , Fibroblastos/patología , Neoplasias de los Tejidos Blandos , Factores de Transcripción , Adolescente , Adulto , Biomarcadores de Tumor , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Femenino , Reordenamiento Génico , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/metabolismo , Neoplasias de los Tejidos Blandos/patología , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Adulto JovenRESUMEN
Post-radiation sarcomas are rare secondary cancers arising from radiation therapies. To date, few genetic specificities have been described for such malignancies and the oncogenesis of sarcomas with complex genetics (both sporadic and post-radiation) remains largely misunderstood. We performed genomic and transcriptomic analyses on 77 post-radiation sarcomas using DNA-array and RNA sequencing. Consequently, we were able to investigate changes in copy number variations, transcriptome profiling, fusion gene expression, and mutational landscapes. We compare these data to a reference cohort of 93 sporadic sarcomas. At genomic level, similar chromosomal complexity was observed both in post-radiation and sporadic sarcomas with complex genetics. We found more frequent CDKN2A and CDKN2B (coding for p14/p16 and p15 proteins, respectively; at 9p21.3) losses in post-radiation (71%) than in sporadic tumors (39%; P = 6.92e-3). Among all detected fusion genes and punctual variations, few specificities were observed between these groups and such alterations are not able to drive a strong and specific oncogenesis. Recurrent MYC amplifications (96%) and KDR variants (8%) were detected in post-radiation angiosarcomas, in agreement with the literature. Transcriptomic analysis of such angiosarcomas revealed two distinct groups harboring different genomic imbalances (in particular gains of 17q24.2-17qter) with different clinical courses according to patient's vital status. Differential gene expression analysis permitted to focus on the immune response as a potential actor to tumor aggressiveness. Histochemistry validated a lower inflammation and lower immune infiltrate at tumor periphery for highly aggressive angiosarcomas. Our results provide new genomic and transcriptomic information about post-radiation sarcomas. The techniques we used (RNA-seq and DNA-arrays) did not highlight major differences in sarcomas with complex genetics depending on the radiation context, revealing similar patterns of transcriptomic profiles and chromosomal copy number variations. Additional characterizations, particularly whole genome sequencing, could measure changes in DNA following radiation therapy in such malignancies and may precise their oncogenesis.
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Neoplasias Inducidas por Radiación/genética , Sarcoma/etiología , Sarcoma/genética , Anciano , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , TranscriptomaRESUMEN
BACKGROUND: In luminal androgen receptor (AR) tumours, FOXA1 may direct AR to sites occupied by ER in luminal tumours, thus stimulating proliferation. METHODS: AR and FOXA1 expression were evaluated by immunohistochemistry in 333 non-metastatic triple-negative breast cancers (TNBC). Positivity threshold was set at ≥ 1% staining. Lymphocytic infiltration, PD-L1expression, PIK3CA mutations, PTEN defects and BRCA1 promoter methylation were assessed. RESULTS: AR + /FOXA1 + tumours (42.4%) were more frequently: found in older patients, lobular, of lower nuclear grade, with more frequently PIK3CA mutations; exhibited less frequently BRCA1 promoter methylation, defects of PTEN and PD-L1 expression than others. Recurrence-free and overall survivals were significantly lower for AR + /FOXA1 + TNBC (median follow-up: 7.8 years). CONCLUSIONS: AR + /FOXA1 + expression defines a luminal-like TNBC subgroup affected with a worse outcome compared to other TNBC and a higher risk of late recurrences. This subgroup appears enriched in PIK3CA mutations, suggesting a role for PI3K inhibitors in this subgroup.
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Fosfatidilinositol 3-Quinasa Clase I/genética , Factor Nuclear 3-alfa del Hepatocito/genética , Recurrencia Local de Neoplasia/genética , Receptores Androgénicos/genética , Neoplasias de la Mama Triple Negativas/genética , Anciano , Antígeno B7-H1/genética , Proteína BRCA1/genética , Biomarcadores de Tumor/genética , Supervivencia sin Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Persona de Mediana Edad , Mutación/genética , Recurrencia Local de Neoplasia/clasificación , Recurrencia Local de Neoplasia/patología , Pronóstico , Factores de Riesgo , Neoplasias de la Mama Triple Negativas/clasificación , Neoplasias de la Mama Triple Negativas/patologíaAsunto(s)
Calcinosis/diagnóstico , Hemangioendotelioma Epitelioide/diagnóstico , Neoplasias Hepáticas/diagnóstico , Hígado/patología , Neoplasias Pulmonares/diagnóstico , Adulto , Biopsia , Calcinosis/patología , Proteínas de Unión al Calcio/análisis , Femenino , Hemangioendotelioma Epitelioide/patología , Hemangioendotelioma Epitelioide/secundario , Humanos , Hígado/diagnóstico por imagen , Neoplasias Hepáticas/patología , Pulmón/diagnóstico por imagen , Neoplasias Pulmonares/secundario , Tomografía Computarizada por Rayos X , Transactivadores/análisis , UltrasonografíaRESUMEN
AIM: Microarray studies identified a subgroup of molecular apocrine tumors (estrogen receptor [ER] negative/androgen receptor [AR] positive) that express luminal genes including FOXA1. FOXA1 may direct AR to sites normally occupied by ER in luminal tumors, inducing an estrogen-like gene program that stimulated proliferation. MATERIALS & METHODS: Expression of AR and FOXA1 was evaluated by immunohistochemistry in 592 patients with nonmetastatic triple-negative breast cancer (TNBC). RESULTS: Coexpression of AR and FOXA1 was found in 15.2% of patients. These tumors were more frequently lobular, found in older patients and exhibited a lower nuclear grade and a greater degree of node involvement. They less often exhibited lymphocytic infiltrate, pushing margins, syncytial architecture, central fibrosis or necrosis. CONCLUSION: TNBC with coexpression of AR and FOXA1 seems to behave like luminal tumors with a morphological profile distinct from other TNBC. These biomarkers could be useful to identify a subgroup of TNBC and could have future therapeutic implications.
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Expresión Génica , Factor Nuclear 3-alfa del Hepatocito/genética , Receptores Androgénicos/genética , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Factor Nuclear 3-alfa del Hepatocito/metabolismo , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Oportunidad Relativa , Receptores Androgénicos/metabolismo , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Carga TumoralRESUMEN
Type 1 auto-immune pancreatitis (type 1 AIP) is the pancreatic manifestation of IgG4-related systemic disease (IgG4-RD). This disease has recently been individualized and is characterized by elevated serum IgG4 levels and extrapancreatic lesions with common histologic characteristic: dense infiltration of lymphocytes, IgG4-positive plasma cells and storiforme fibrosis. Obliterative phlebitis is frequently detected. The pancreas is frequently involved in this disease. As approach to the pancreas for histological examination is generally difficult, AIP is diagnosed using a combination of clinical, serological, morphological and histopathological features. In pseudotumoral cases, AIP can be misdiagnosed as pancreatic cancer. Since AIP responds dramatically to steroid therapy, accurate diagnosis of AIP can avoid unnecessary laparotomy or pancreatic resection. We report here a case of a patient who underwent surgery for presumed pancreatic cancer. The final diagnosis was type 1 AIP.
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Adenocarcinoma/diagnóstico , Enfermedades Autoinmunes/diagnóstico , Errores Diagnósticos , Hipergammaglobulinemia/complicaciones , Inmunoglobulina G/análisis , Neoplasias Pancreáticas/diagnóstico , Pancreatitis/diagnóstico , Anciano , Enfermedades Autoinmunes/etiología , Enfermedades Autoinmunes/patología , Enfermedades Autoinmunes/cirugía , Biopsia , Humanos , Ictericia Obstructiva/etiología , Laparotomía , Masculino , Pancreaticoduodenectomía , Pancreatitis/etiología , Pancreatitis/patología , Pancreatitis/cirugía , Pérdida de PesoRESUMEN
PURPOSE: The objective of this study was to evaluate, in the luminal human epidermal growth factor receptor 2 (HER2)-negative breast cancer subtype, the prognostic value of tumour glucose metabolism at baseline and of its early changes during neoadjuvant chemotherapy (NAC). METHODS: This prospective study included 61 women with hormone-sensitive HER2-negative breast cancer treated with NAC. (18)F-Fluorodeoxyglucose (FDG) positron emission tomography (PET) was performed at baseline. Hepatic activity was used as a reference to distinguish between low metabolic and hypermetabolic tumours. In hypermetabolic tumours, a PET exam was repeated after the first course of NAC. The relative change in the maximum standardized uptake value of the tumour (∆SUV) was calculated. RESULTS: Nineteen women had low metabolic luminal breast cancers at baseline, correlated with low proliferation indexes. Forty-two women had hypermetabolic tumours, corresponding to more proliferative breast cancers with higher Ki-67 expression (p = 0.017) and higher grade (p = 0.04). The median follow-up period was 64.2 months (range 11.5-93.2). Thirteen women developed recurrent disease, nine of whom died. Worse overall survival was associated with larger tumour size [>5 cm, hazard ratio (HR) = 6.52, p = 0.009] and with hypermetabolic tumours achieving a low metabolic response after one cycle of NAC (ΔSUV < 16%, HR = 10.63, p = 0.004). Five-year overall survival in these poor responder patients was 49.2%. Overall survival in women with low metabolic tumours or hypermetabolic/good response tumours was 100 and 96.15%, respectively. CONCLUSION: In luminal HER2-negative breast tumours, tumour metabolism at baseline and changes after the first course of NAC are early surrogate markers of patients' survival. A subgroup of women with hypermetabolic/poorly responding tumours, correlated with poor prognosis at 5 years, can be identified early. These results may guide future studies by tailoring the NAC regimen to the metabolic response.
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Neoplasias de la Mama/diagnóstico por imagen , Carcinoma/diagnóstico por imagen , Fluorodesoxiglucosa F18 , Terapia Neoadyuvante , Tomografía de Emisión de Positrones , Radiofármacos , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/terapia , Carcinoma/tratamiento farmacológico , Femenino , Humanos , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Resultado del TratamientoRESUMEN
BACKGROUND: With the development of some new antibody-drug conjugates, the HER2 classification of breast carcinomas now includes the HER2-low (H2L) category: IHC 1+, 2+ non-amplified by ISH, and double-equivocal carcinomas, mostly luminal, expressing hormone receptors (HR+). METHODS: We analyzed mutational status and transcriptomic activities of three HER2 effector pathways: PI3K-AKT, MAPK, and JAK-STAT, in association with clinicopathologic features, in 62 H2L carcinomas compared to 43 HER2-positive and 20 HER2-negative carcinomas, all HR+. RESULTS: H2L carcinomas had significantly lower histoprognostic grades and mitotic and Ki67 proliferation indexes than HER2-positive carcinomas. Their PIK3CA mutation rates were close to those of HER2-negative and significantly higher than in HER2-positive carcinomas, contrary to TP53 mutations. At the transcriptomic level, we identified three distinct groups which did not reflect the new HER2 classification. H2L and HER2-negative carcinomas shared most of clinicopathological and molecular characteristics, except HER2 membrane expression (mRNA levels). The presence of a mutation in a signaling pathway had a strong pathway activation effect. PIK3CA mutations were more prevalent in H2L carcinomas, leading to a strong activation of the PI3K-AKT signaling pathway even in the absence of HER2 overexpression/amplification. CONCLUSION: PIK3CA mutations may explain the failure of conventional anti-HER2 treatments, suggesting that new antibody-drug conjugates may be more effective.
RESUMEN
A patient with a PD-L1-negative, TMB-low, KEAP1/STK11 co-mutated metastatic non-small cell lung cancer (NSCLC) experienced a multisite radiological progression at 3 months after initiation of chemoimmunotherapy as first-line treatment for metastatic disease. After the radiological progression, while she was not undergoing treatment, the patient had spontaneous lesions shrinkage and further achieved a prolonged complete response. Genomic and transcriptomic data collected at baseline and at the time of pseudoprogression allowed us to biologically characterize this rare response pattern. We observed the presence of a tumor-specific T-cell response against tumor-specific neoantigens (TNAs). Endogenous retroviruses (ERVs) expression following chemoimmunotherapy was also observed, concurrent with biological features of an anti-viral-like innate immune response with type I IFN signaling and production of CXCR3-associated chemokines. This is the first biological characterization of a NSCLC pseudoprogression under chemoimmunotherapy followed by a prolonged complete response in a PD-L1-negative, TMB-low, KEAP1/STK11 co-mutated NSCLC. These clinical and biological data underline that even patients with multiple factors of resistance to immune checkpoint inhibitors could trigger a tumor-specific immune response to tumor neoantigen, leading to complete eradication of the tumor and probably a vaccinal immune response.
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Antígeno B7-H1 , Carcinoma de Pulmón de Células no Pequeñas , Progresión de la Enfermedad , Proteína 1 Asociada A ECH Tipo Kelch , Neoplasias Pulmonares , Mutación , Humanos , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Proteína 1 Asociada A ECH Tipo Kelch/genética , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Antígeno B7-H1/genética , Femenino , Persona de Mediana Edad , Biomarcadores de TumorRESUMEN
PURPOSE: To evaluate the outcomes of adult patients with spermatic cord sarcoma (SCS). METHODS: All consecutive patients with SCS managed by the French Sarcoma Group from 1980 to 2017 were analysed retrospectively. Multivariate analysis (MVA) was used to identify independent correlates of overall survival (OS), metastasis-free survival (MFS), and local relapse-free survival (LRFS). RESULTS: A total of 224 patients were recorded. The median age was 65.1 years. Forty-one (20.1%) SCSs were discovered unexpectedly during inguinal hernia surgery. The most common subtypes were liposarcoma (LPS) (73%) and leiomyosarcoma (LMS) (12.5%). The initial treatment was surgery for 218 (97.3%) patients. Forty-two patients (18.8%) received radiotherapy, 17 patients (7.6%) received chemotherapy. The median follow-up was 5.1 years. The median OS was 13.9 years. In MVA, OS decreased significantly with histology (HR, well-differentiated LPS versus others = 0.096; p = 0.0224), high grade (HR, 3 versus 1-2 = 2.7; p = 0.0111), previous cancer and metastasis at diagnosis (HR = 6.8; p = 0.0006). The five-year MFS was 85.9% [95% CI: 79.3-90.6]. In MVA, significant factors associated with MFS were LMS subtype (HR = 4.517; p < 10-4) and grade 3 (HR = 3.664; p < 10-3). The five-year LRFS survival rate was 67.9% [95% CI: 59.6-74.9]. In MVA, significant factors associated with local relapse were margins and wide reresection (WRR) after incomplete resection. OS was not significantly different between patients with initial R0/R1 resection and R2 patients who underwent WRR. CONCLUSIONS: Unplanned surgery affected 20.1% of SCSs. A nonreducible painless inguinal lump should suggest a sarcoma. WRR with R0 resection achieved similar OS to patients with correct surgery upfront.
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Leiomiosarcoma , Liposarcoma , Sarcoma , Neoplasias de los Tejidos Blandos , Cordón Espermático , Masculino , Adulto , Humanos , Anciano , Pronóstico , Cordón Espermático/patología , Estudios Retrospectivos , Lipopolisacáridos , Recurrencia Local de Neoplasia/patología , Sarcoma/cirugía , Liposarcoma/cirugía , Liposarcoma/diagnóstico , Leiomiosarcoma/patologíaRESUMEN
Molecular testing is extremely important in cancer care, starting as early as at diagnosis. In order to address the challenge of providing reliable results within the timeframe adapted to patient management and suitable to guide clinical decisions, a capturebased nextgeneration sequencing (NGS) panel focusing on ten genes known to harbor genetic variations which may be targeted by approved drugs in patients with cancer was designed and validated. Very favorable analytical performances were obtained for both solid and liquid biopsies. For solid biopsies, a low read depth (80X per nucleotide) led to the genotype detection accuracy of 100%. The read of raw data for liquid biopsies resulted in the 91.19% result concordance between paired solid and liquid samples. The present method met all the requirements for the ISO15189 certification. During our threeyear experience of routinely using this panel, almost 2,300 samples from lung and colorectal cancers, melanomas and gastrointestinal stromal tumors have been analyzed. It was found that our panel detected slightly more gainoffunction variants than described in the literature. Surprisingly, lossoffunction variants were also detected in certain of the analyzed genes. Finally, liquid biopsy data revealed statistically different mutated allele frequencies between tumor types, but also between mutated genes and variants themselves. In conclusion, the use of our capturebased NGS panel is perfectly adapted to perform relevant molecular diagnosis in a time frame compatible with patient care.
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Secuenciación de Nucleótidos de Alto Rendimiento , Neoplasias , Biopsia , Frecuencia de los Genes , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Mutación/genética , Neoplasias/diagnóstico , Neoplasias/genéticaRESUMEN
PURPOSE: EORTC-1506-STBSG was a prospective, multicentric, randomised, open-label phase 2 trial to assess the efficacy and safety of second-line nintedanib versus ifosfamide in patients with advanced, inoperable metastatic soft tissue sarcoma (STS). The primary end-point was progression-free survival. PATIENTS/METHODS: Patients with a variety of STS subtypes were randomised 1:1 to nintedanib (200 mg b.i.d. p.o. until disease progression) or ifosfamide (3 g/m2 i.v. days 1-3, every 21 days for ≤6 cycles). A Korn design was applied aiming to detect an improvement in median progression-free survival (mPFS) from 3 to 4.5 months (HR = 0.667). An interim look was incorporated to stop the trial for futility if <19 of the first 36 patients treated with nintedanib were progression-free at week 12. RESULTS: At the interim analysis, among the first 36 eligible and evaluable patients randomised for nintedanib, only 13 (36%) were progression-free at week 12. The trial was closed for further accrual as per protocol. In total, 80 patients were randomised (40 per treatment group). The mPFS was 2.5 months (95% CI: 1.5-3.4) for nintedanib and 4.4 months (95% CI: 2.9-6.7) on ifosfamide (adjusted HR = 1.56 [80% CI: 1.14-2.13], p = 0.070). The median overall survival was 13.7 months (95% CI: 9.4-23.4) on nintedanib and 24.1 months (95% CI: 10.9-NE) on ifosfamide (adjusted HR = 1.65 [95%CI:0.89-3.06], p = 0.111). The clinical benefit rate for nintedanib and ifosfamide was 50% versus 62.5% (p = 0.368), respectively. Common treatment-related adverse events (all grades) were diarrhoea (35.9% of patients), fatigue (25.6%) and nausea (20.5%) for nintedanib; and fatigue (52.6%), nausea (44.7%) and vomiting, anorexia and alopecia (28.9% each) for ifosfamide. CONCLUSION: The trial was stopped for futility. The activity of nintedanib did not warrant further exploration in non-selected, advanced STSs.
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Ifosfamida/administración & dosificación , Indoles/administración & dosificación , Inutilidad Médica , Sarcoma/tratamiento farmacológico , Adulto , Anciano , Femenino , Humanos , Ifosfamida/efectos adversos , Indoles/efectos adversos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Supervivencia sin Progresión , Estudios Prospectivos , Criterios de Evaluación de Respuesta en Tumores Sólidos , Sarcoma/diagnóstico , Sarcoma/mortalidad , Sarcoma/patologíaRESUMEN
BACKGROUND: Since 2010, nationwide networks of reference centers for sarcomas (RREPS/NETSARC/RESOS) collected and prospectively reviewed all cases of sarcomas and connective tumors of intermediate malignancy (TIM) in France. METHODS: The nationwide incidence of sarcoma or TIM (2013-2016) was measured using the 2013 WHO classification and confirmed by a second independent review by expert pathologists. Simple clinical characteristics, yearly variations and correlation of incidence with published clinical trials are presented and analyzed. RESULTS: Over 150 different histological subtypes are reported from the 25172 patients with sarcomas (n = 18712, 74,3%) or TIM (n = 6460, 25.7%), with n = 5838, n = 6153, n = 6654, and n = 6527 yearly cases from 2013 to 2016. Over these 4 years, the yearly incidence of sarcomas and TIM was therefore 70.7 and 24.4 respectively, with a combined incidence of 95.1/106/year, higher than previously reported. GIST, liposarcoma, leiomyosarcomas, undifferentiated sarcomas represented 13%, 13%, 11% and 11% of tumors. Only GIST, as a single entity had a yearly incidence above 10/106/year. There were respectively 30, 64 and 66 different histological subtypes of sarcomas or TIM with an incidence ranging from 10 to 1/106, 1-0.1/106, or < 0.1/106/year respectively. The 2 latter incidence groups represented 21% of the patients with 130 histotypes. Published phase III and phase II clinical trials (p<10-6) are significantly higher with sarcomas subtypes with an incidence above 1/106 per. CONCLUSIONS: This nationwide registry of sarcoma patients, with exhaustive histology review by sarcoma experts, shows that the incidence of sarcoma and TIM is higher than reported, and that tumors with a very low incidence (1<106/year) are less likely to be included in clinical trials.
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Sarcoma/epidemiología , Sarcoma/patología , Adolescente , Adulto , Anciano , Femenino , Francia/epidemiología , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estudios Prospectivos , Sarcoma/clasificación , Sarcoma/diagnóstico , Organización Mundial de la Salud , Adulto JovenRESUMEN
In locally advanced rectal cancer, radiotherapy (RT) followed by surgery have improved locoregional control, but distant recurrences remain frequent. Although checkpoint inhibitors have demonstrated objective response in several cancers, the clinical benefit of PD-1/PD-L1 blockade remains uncertain in rectal cancer. We collected data from biopsies and surgical specimens in 74 patients. The main objective was to evaluate the impact of neoadjuvant RT and fractionation on PD-L1 expression. Secondary objectives were to study the relation between PD-L1 expression and tumor regression grade (TRG), progression-free survival (PFS), overall survival (OS), and CD8 TILs infiltration. Median rates of cells expressing PD-L1 pre- and post-RT were 0.15 (range, 0-17) and 0.5 (range, 0-27.5), respectively (p = 0.0005). There was no effect of RT fractionation on PD-L1+ cell rates. We found no relation between CD8+ TILs infiltration and PD-L1 expression and no difference between high-PD-L1 or low-PD-L1 expression and TRG. High-to-high PD-L1 expression profile had none significant higher OS and PFS compared to all other groups (p = 0.06). Median OS and PFS were higher in biopsies with >0.08 PD-L1+ cells. High-to-high PD-L1 profile and ypT0-2 were significantly associated with higher OS and PFS. This study did not show the differential induction of PD-L1 expression according to fractionation.
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Adenocarcinoma , Antígeno B7-H1/metabolismo , Neoplasias del Recto , Adenocarcinoma/metabolismo , Adenocarcinoma/radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Neoplasias del Recto/metabolismo , Neoplasias del Recto/radioterapia , Estudios RetrospectivosRESUMEN
Metaplastic breast carcinoma is a rare subtype of breast cancer. This subtype is mostly found in association with poorly differentiated ductal breast carcinomas and rarely with other breast carcinoma types. We report the case of a 69-year-old woman with an exceptional invasive lobular breast carcinoma associated with metaplastic squamous cell bone metastasis occurring 2 years after the initial breast cancer diagnosis. Whole-exome sequencing and subsequent immunohistochemistry of the lesions were used to link the squamous cell bone metastasis of unknown origin to the primary breast carcinoma initially diagnosed. Searching for primary carcinoma when metastatic lesions of unknown origin occur can be complex. Current molecular biology techniques may help pathologists in associating metastasis with the primary carcinoma by identifying shared specific gene mutations, even when different morphological and immunohistochemical profiles are observed between the tumours.