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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.
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OBJECTIVES: Unexpected accumulations of gadolinium in various organs were reported after the administration of gadolinium-based contrast agents, making desirable to reduce the dose while maintaining equivalent diagnostic performance. The aim of this study was to evaluate the contrast enhancement performance of high relaxivity gadopiclenol compared with gadoterate meglumine in abdominal contrast-enhanced magnetic resonance angiography (CE-MRA). MATERIALS AND METHODS: In a first study in healthy rabbits, axial 3D gradient echo sequences were applied at 4.7 T to study arterial enhancement as a function of gadopiclenol dose (0.025, 0.05, 0.075, and 0.1 mmol Gd/kg) or gadoterate meglumine at 0.1 mmol Gd/kg (n = 5-6/group). The increase in signal-to-noise ratio (ΔSNR) in the aorta at the first pass was measured and compared. In a second, crossover study in 6 healthy pigs, abdominal CE-MRA sequences were acquired at 3 T with gadopiclenol at 0.05 mmol Gd/kg or gadoterate meglumine at 0.1 mmol Gd/kg at a 1-week interval. Quantitatively on the maximum intensity projection (MIP) images, the mean MIP SNR within the aorta of both groups was compared. Qualitatively, a blinded comparison of the angiograms was performed by an experienced radiologist to determine the preferred contrast agent. RESULTS: In the rabbit, ∆SNR is linearly correlated with the gadopiclenol dose ( P = 0.0010). Compared with gadoterate meglumine 0.1 mmol Gd/kg, an increase in the ∆SNR is observed after 0.05, 0.075, and 0.1 mmol Gd/kg of gadopiclenol (+63% P = 0.0731, +78% P = 0.0081, and +72% P = 0.0773, respectively), whereas at 0.025 mmol Gd/kg, ∆SNR is in the same range as with gadoterate meglumine 0.1 mmol Gd/kg (+15% P > 0.9999). In pigs, contrast enhancement after gadopiclenol at 0.05 mmol/kg is +22% superior to MIP SNR after gadoterate meglumine at 0.1 mmol Gd/kg ( P = 0.3095). Qualitatively, a preference was shown for gadopiclenol images (3/6) over the gadoterate meglumine examinations (1/6), with no preference being shown for the remainder (2/6). CONCLUSIONS: First-pass CE-MRA is feasible with gadopiclenol at 0.05 mmol Gd/kg with at least the same arterial signal enhancement and image quality as gadoterate meglumine at 0.1 mmol Gd/kg.
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Medios de Contraste , Angiografía por Resonancia Magnética , Compuestos Organometálicos , Animales , Conejos , Angiografía por Resonancia Magnética/métodos , Porcinos , Gadolinio , Aumento de la Imagen/métodos , Meglumina/análogos & derivados , Meglumina/farmacocinética , Meglumina/administración & dosificación , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
PURPOSE: To improve the quality of care for patients with breast cancer, an analysis of the health-care pathway, considering feedback from both health-care practitioners (HCPs) and patients, is needed. METHODS: Between 2020 and 2022, we conducted a survey at French breast cancer centers and analyzed information from questionnaires completed by HCPs and patients. We collected information on center organization, diagnostic processes, treatment decisions and modalities, supportive care, patient advocacy groups, and work issues. RESULTS: Twenty-three breast cancer centers were included and questionnaires completed by 247 HCPs and 249 patients were analyzed. The centers closely followed the legal French framework for cancer treatments, which includes formal diagnostic announcements, multidisciplinary tumor boards, personalized treatment summaries, and supportive care access. HCPs and patients were satisfied with the time to diagnosis (≤ 2 weeks as evaluated by 75% of patients), time to surgery (mean 61 days), time between surgery and chemotherapy (mean 47 days), and time between surgery and radiotherapy (mean 81 days). Fertility preservation counseling for women under 40 years of age was systematically offered by 67% of the HCPs. The majority (67%) of the patients indicated that they had received a personalized treatment summary; the topics discussed included treatments (92%), tumor characteristics (84%), care pathways (79%), supportive care (52%), and breast reconstruction (33%). Among HCPs, 44% stated that reconstructive surgery was offered to all eligible patients and 57% and 45% indicated coordination between centers and primary care physicians for adverse effects management and access to supportive care should be improved, for chemotherapy and radiotherapy, respectively. Regarding patient advocacy groups, 34% of HCPs did not know whether patients had contact and only 23% of patients declared that they had such contact. For one-third of working patients, work issues were not discussed. Twenty-eight percent of patients claimed that they had faced difficulties for supportive care access. Among HCPs, 13% stated that a formal personalized survivorship treatment program was administered to almost all patients and 37% almost never introduced the program to their patients. Compliance to oral treatments was considered very good for 75-100% of patients by 62% of HCPs. CONCLUSIONS: This study provides an updated analysis of breast cancer care pathways in France. Overall, the initial processes of diagnosis, announcement, and treatment were swift and were in agreement with the best care standards. No barriers to accessing care were identified. Based on the study findings, we proposed several strategies to improve the quality of care for patients in supportive care, coordination with primary care physicians, reconstructive surgery, and fertility preservation access.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/terapia , Neoplasias de la Mama/patología , Francia , Adulto , Persona de Mediana Edad , Encuestas y Cuestionarios , Cuidadores/psicología , Satisfacción del Paciente , Anciano , Calidad de la Atención de SaludRESUMEN
A close relationship has been demonstrated between genomic complexity and clinical outcome in uterine smooth muscle tumors. We studied the genomic profiles by array-CGH of 28 fumarate hydratase deficient leiomyomas and 37 leiomyomas with bizarre nuclei (LMBN) from 64 patients. Follow-up was available for 46 patients (from three to 249 months, mean 87.3 months). All patients were alive without evidence of disease. For 51 array-CGH interpretable tumors the mean Genomic Index (GI) was 16.4 (median: 9.8; from 1 to 57.8), significantly lower than the mean GI in LMS (mean GI 51.8, p < 0.001). We described three groups: (1) a group with FH deletion (24/58) with low GI (mean GI: 11 vs. 22,4, p = 0.02), (2) a group with TP53 deletion (17/58) with higher GI (22.4 vs. 11 p = 0.02), and (3) a group without genomic events on FH or TP53 genes (17/58) (mean GI:18.3; from 1 to 57.8). Because none of these tumors recurred and none showed morphological features of LMS we concluded that GI at the cut-off of 10 was not applicable in these subtypes of LM. By integration of all those findings, a GI <10 in LMBN remains a valuable argument for benignity. Conversely, in LMBN a GI >10 or alteration in tumor suppressor genes, should not alone warrant a diagnosis of malignancy. Nine tumors were tested with Nanocind CINSARC® signature and all were classified in low risk of recurrence. We propose, based on our observations, a diagnostic approach of these challenging lesions.
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Leiomioma , Neoplasias Uterinas , Femenino , Humanos , Neoplasias Uterinas/genética , Neoplasias Uterinas/patología , Fumarato Hidratasa/genética , Leiomioma/genética , Leiomioma/patología , Genes p53 , GenómicaRESUMEN
BACKGROUND: The CPS+EG scoring system was initially described in unselected early breast cancer (eBC) patients treated with neoadjuvant chemotherapy (NAC), leading to refined prognostic stratification, and thus helping to select patients for additional post-NAC treatments. It remains unknown whether the performance is the same in new biological breast cancer entities such as the HER2-low subtype. PATIENTS AND METHODS: Outcomes (disease-free (DFS) and overall survival OS)) of 608 patients with HER2-non amplified eBC and treated with NAC were retrospectively analyzed according to CPS-EG score. We compared the prognostic stratification abilities of the CPS+EG in HER2-low and HER2-0 eBC, analyzing ER+ and ER- tumors separately. RESULTS: In ER+ eBC, the CPS+EG scoring system seems to retain a prognostic value, both in HER2-low and HER2-0 tumors, by distinguishing populations with significantly different outcomes (good: score 0-1, poor: score 2-3, and very poor: score 4-5). Using C-indices for DFS and OS, CPS+EG provided the highest prognostic information in ER+ eBC, especially in HER2-0 tumors. In contrast, in ER- eBC, the CPS+EG does not appear to be able to distinguish different outcome groups, either in HER2-low or HER2-0 tumors. In ER- eBC, C-indices for DFS and OS were highest for pathological stage, reflecting the predominant prognostic importance of residual disease in this subtype. CONCLUSIONS: HER2-low status does not influence the prognostic performance of the CPS+EG score. Our results confirm the usefulness of the CPS+EG score in stratifying the prognosis of ER+ eBC after NAC, for both HER2-0 and HER2-low tumors. For ER- eBC, HER2-low status does not influence the performance of the CPS+EG score, which was lower than that of the pathological stage alone.
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Neoplasias de la Mama , Humanos , Femenino , Pronóstico , Neoplasias de la Mama/patología , Terapia Neoadyuvante/métodos , Estudios Retrospectivos , Estadificación de Neoplasias , Receptor ErbB-2 , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia Adyuvante , Supervivencia sin EnfermedadRESUMEN
Artificial intelligence (AI)-assisted diagnosis is an ongoing revolution in pathology. However, a frequent drawback of AI models is their propension to make decisions based rather on bias in training dataset than on concrete biological features, thus weakening pathologists' trust in these tools. Technically, it is well known that microscopic images are altered by tissue processing and staining procedures, being one of the main sources of bias in machine learning for digital pathology. So as to deal with it, many teams have written about color normalization and augmentation methods. However, only a few of them have monitored their effects on bias reduction and model generalizability. In our study, two methods for stain augmentation (AugmentHE) and fast normalization (HEnorm) have been created and their effect on bias reduction has been monitored. Actually, they have also been compared to previously described strategies. To that end, a multicenter dataset created for breast cancer histological grading has been used. Thanks to it, classification models have been trained in a single center before assessing its performance in other centers images. This setting led to extensively monitor bias reduction while providing accurate insight of both augmentation and normalization methods. AugmentHE provided an 81% increase in color dispersion compared to geometric augmentations only. In addition, every classification model that involved AugmentHE presented a significant increase in the area under receiving operator characteristic curve (AUC) over the widely used RGB shift. More precisely, AugmentHE-based models showed at least 0.14 AUC increase over RGB shift-based models. Regarding normalization, HEnorm appeared to be up to 78x faster than conventional methods. It also provided satisfying results in terms of bias reduction. Altogether, our pipeline composed of AugmentHE and HEnorm improved AUC on biased data by up to 21.7% compared to usual augmentations. Conventional normalization methods coupled with AugmentHE yielded similar results while being much slower. In conclusion, we have validated an open-source tool that can be used in any deep learning-based digital pathology project on H&E whole slide images (WSI) that efficiently reduces stain-induced bias and later on might help increase pathologists' confidence when using AI-based products.
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Inteligencia Artificial , Neoplasias de la Mama , Femenino , Humanos , Colorantes , Aprendizaje Automático , Coloración y Etiquetado , Estudios Multicéntricos como AsuntoRESUMEN
The landscape of uterine sarcomas is becoming more complex with the description of new entities associated with recurrent driver molecular alterations. Uterine sarcomas, in analogy with soft tissue sarcomas, are distinguished into complex genomic and simple genomic sarcomas. Leiomyosarcomas and undifferentiated uterine sarcomas belong to complex genomic sarcomas group. Low-grade and high-grade endometrial stromal sarcomas, other rare tumors associated with fusion transcripts (such as NTRK, PDGFB, ALK, RET ROS1) and SMARCA4-deficient uterine sarcoma are considered simple genomic sarcomas. The most common uterine sarcoma are first leiomyosarcoma and secondly endometrial stromal sarcomas. Three different histological subtypes of leiomyosarcoma (fusiform, myxoid, epithelioid) are identified, myxoid and epithelioid leiomyosarcoma being more aggressive than fusiform leiomyosarcoma. The distinction between low-grade and high-grade endometrial stromal sarcoma is primarily morphological and immunohistochemical and the detection of fusion transcripts can help the diagnosis. Uterine PEComa is a rare tumor, which is distinguished into borderline and malignant, according to a risk assessment algorithm. Embryonal rhabdomyosarcoma of the uterine cervix is more common in children but can also occur in adult women. Embryonal rhabdomyosarcoma of the uterine cervix is almost always DICER1 mutated, unlike that of the vagina which is wild-type DICER1, and adenosarcoma which can be DICER1 mutated but with less frequency. Among the emerging entities, sarcomas associated with fusion transcripts involving the NTRK, ALK, PDGFB genes benefit from targeted therapy. The integration of molecular data with histology and clinical data allows better identification of uterine sarcomas in order to better treat them.
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ARN Helicasas DEAD-box , Neoplasias Endometriales , Neoplasias de los Genitales Femeninos , Leiomiosarcoma , Rabdomiosarcoma Embrionario , Ribonucleasa III , Sarcoma Estromático Endometrial , Neoplasias de los Tejidos Blandos , Neoplasias del Cuello Uterino , Neoplasias Uterinas , Adulto , Niño , Femenino , Humanos , Leiomiosarcoma/diagnóstico , Leiomiosarcoma/genética , Leiomiosarcoma/terapia , Rabdomiosarcoma Embrionario/diagnóstico , Rabdomiosarcoma Embrionario/genética , Rabdomiosarcoma Embrionario/terapia , Sarcoma Estromático Endometrial/diagnóstico , Sarcoma Estromático Endometrial/genética , Sarcoma Estromático Endometrial/terapia , Proteínas Tirosina Quinasas , Proteínas Proto-Oncogénicas , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/genética , Neoplasias Uterinas/terapia , Proteínas Tirosina Quinasas Receptoras , ADN Helicasas , Proteínas Nucleares , Factores de TranscripciónRESUMEN
BACKGROUND: Breast cancers without HER2 amplification but still expressing this membrane protein constitute a new entity called HER2-low tumors. It is important to characterize them in terms of sensitivity to treatment and prognosis. PATIENTS AND METHODS: To investigate chemosensitivity and long-term prognosis of HER2-low early breast cancer (eBC), compared to HER2-0 tumors, we retrospectively retrieved clinicopathological characteristics, response to treatment, and survival data from 511 patients treated for eBC with neoadjuvant chemotherapy (NAC) in a French cancer center between 2007 and 2018. Factors associated with the achievement of pathologic complete response (pCR) and survival were studied among hormone receptor positive (HR+) and negative (HR-) eBC. RESULTS: A total of 280 HR+ (61% HER2-low), and 231 HR- (28% HER2-low) eBC were included. We found classical clinicopathological factors usually associated with chemosensitivity and prognosis, in both HR+ and HR- eBC. By uni- and multivariable analysis, HER2 status (low vs 0) was not independently associated with pCR, either in HR+ or HR- eBC. Relapse free (RFS) and overall survival (OS) were not significantly different between HER2-low and HER2-0 among HR+ tumors. In contrast, among HR- negative tumors, RFS and OS were slightly better in HER2-0 eBC by univariable but not by multivariable analysis. CONCLUSIONS: In eBC patients treated with NAC, taking into account HR expression subtype and other current clinicopathological features, HER2-low tumors did not appear to have different chemosensitivity or prognosis, compared to their HER2-0 counterparts.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/patología , Terapia Neoadyuvante , Estudios Retrospectivos , Receptor ErbB-2/metabolismo , Recurrencia Local de Neoplasia/tratamiento farmacológico , Pronóstico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia AdyuvanteRESUMEN
BACKGROUND: Non-small cell lung cancer is a very poor prognosis disease. Molecular analyses have highlighted several genetic alterations which may be targeted by specific therapies. In clinical practice, progression-free survival on EGFR TKI treatment is between 12 and 14 months. However, some patients progress rapidly in less than 6 months, while others remain free of progression for 16 months or even longer during EGFR TKI treatment. METHODS: We sequenced tumor exomes from 135 lung cancer patients (79 with EGFR-wildtype (WT), 56 with EGFR-mutant tumors) enrolled in the ALCAPONE trial (genomic analysis of lung cancers by next generation sequencing for personalized treatment). RESULTS: Some germline polymorphisms were enriched in the EGFR-mutant subset compared to EGFR-WT tumors or to a reference population. However, the most interesting observation was the negative impact of some germline SNPs in immunity-related genes on survival on EGFR TKI treatment. Indeed, the presence of one of three particular SNPs in the HLA-DRB5 gene was associated with a decreased PFS on EGFR TKI. Moreover, some SNPs in the KIR3DL1 and KIR3DL2 genes were linked to a decrease in both progression-free and overall survival of patients with EGFR-mutant tumors. CONCLUSION: Our data suggest that SNPs in genes expressed by immune cells may influence the response to targeted treatments, such as EGFR TKIs. This indicates that the impact of these cells may not be limited to modulating the response to immunotherapies. Further studies are needed to determine the exact mechanisms underlying this influence and to identify the associated predictive and prognostic markers that would allow to refine treatments and so improve lung cancer patient outcomes. TRIAL REGISTRATION: NCT02281214: NGS Genome Analysis in Personalization of Lung Cancer Treatment (ALCAPONE).
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Carcinoma de Pulmón de Células no Pequeñas , Carcinoma , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Células Germinativas , Pulmón , Receptores ErbB/genéticaRESUMEN
Gynecologic carcinosarcomas (CS) are biphasic neoplasms composed of carcinomatous (C) and sarcomatous (S) malignant components. Because of their rarity and histologic complexity, genetic and functional studies on CS are scarce and the mechanisms of initiation and development remain largely unknown. Whole-genome analysis of the C and S components reveals shared genomic alterations, thus emphasizing the clonal evolution of CS. Reconstructions of the evolutionary history of each tumor further reveal that C and S samples are composed of both ancestral cell populations and component-specific subclones, supporting a common origin followed by distinct evolutionary trajectories. However, while we do not find any recurrent genomic features associated with phenotypic divergence, transcriptomic and methylome analyses identify a common mechanism across the cohort, the epithelial-to-mesenchymal transition (EMT), suggesting a role for nongenetic factors in inflicting changes to cellular fate. Altogether, these data accredit the hypothesis that CS tumors are driven by both clonal evolution and transcriptomic reprogramming, essential for susceptibility to transdifferentiation upon encountering environmental cues, thus linking CS heterogeneity to genetic, transcriptomic, and epigenetic influences. Significance: We have provided a detailed characterization of the genomic landscape of CS and identified EMT as a common mechanism associated with phenotypic divergence, linking CS heterogeneity to genetic, transcriptomic, and epigenetic influences.
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Carcinosarcoma , Neoplasias Ováricas , Sarcoma , Humanos , Femenino , Carcinosarcoma/genética , Neoplasias Ováricas/genéticaRESUMEN
INTRODUCTION: Intracystic papillary carcinoma is defined as papillary carcinoma located in a dilated or cystic duct. There is no consensus regarding the management of this lesion. The aim of our study is to evaluate the frequency of associated invasive lesions and the need to perform an axillary staging during surgery. MATERIAL AND METHODS: This is a retrospective study concerning intracystic papillary carcinomas diagnosed at the Georges-François Leclerc Cancer Center between January 2010 and December 2021. Inclusion criteria were an age superior to 18 years and a histologic diagnosis confirmed at biopsy. RESULTS: Fifty-nine patients were included in this study. All but one patient underwent surgery: 39 patients (67.2%) underwent lumpectomy, and 18 patients (31.1%) underwent total mastectomy. An axillary staging was performed in 51 patients (86.4%). On final histologic analysis, 31 patients (52.5%) had pure intracystic papillary carcinoma and/or associated with in situ and 27 patients (45.8%) had invasive and/or microinvasive lesions. After univariate analysis, the only variable significantly associated with the presence of invasive lesions on final histologic analysis was the palpation of the lesion with a P-value of 0.09. DISCUSSION: Through this study, it appears necessary to discuss the realization of an axillary staging by conducting an axillary sentinel node procedure because of the high frequency of invasive lesions associated with intracystic papillary carcinoma.
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Neoplasias de la Mama , Carcinoma Ductal de Mama , Carcinoma Papilar , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Carcinoma Papilar/patología , Carcinoma Papilar/cirugía , Metástasis Linfática , Mastectomía Radical , Mastectomía Segmentaria , Invasividad Neoplásica , Ganglio Linfático Centinela/patología , Carcinoma Ductal de Mama/patología , Carcinoma Ductal de Mama/cirugíaRESUMEN
PURPOSE: To retrospectively assess the rate of pathologic complete response in the axilla according to breast cancer biologic subtypes, and to study the impact of nodal response on survival. METHODS: Inclusion criteria were all T-stage breast cancers with initial lymph node involvement, non-metastatic, treated with neoadjuvant chemotherapy followed by surgery with axillary lymph node dissection, managed at the George-François Leclerc Cancer Center in Dijon, France, between 2000 and 2018. RESULTS: Among 437 patients included, the rate of complete nodal response rate varied according to tumor subtypes: 69.4% in Hormone Receptors (HR)-/HER2-positive, 47.4% in HR-/HER2-negative, 46.7% in HR+/HER2-positive, 8.5% in HR+/HER2-negative. By multivariate analysis, the factors significantly associated with complete nodal response were HER2-positive profile (OR 4.48 [2.14-9.65], P<0.001 if HR+; OR 8.02 [3.54-18.74], P<0.001 if HR-), triple negative tumors (OR 3.01 [1.40-6.58], P=0.005), SBRIII grade (OR 6.85 [2.28-29.58], P=0.002) and breast complete response (OR 18.69 [9.67-38.53], P<0.001). Five-year recurrence rates were 15.7% in ypN0, 23% in ypN1, 41.2% in ypN2, 50% in ypN3 patients (P<0.001). Five-year overall survival rates were 92.2% in ypN0, 85.7% in ypN1, 72.2% in ypN2, 65.4% in ypN3 patients (P<0.001). CONCLUSION: The impact of nodal response on survival was significant. Pathologic complete response in the axilla appears to be a good surrogate marker of long-term outcome in patients treated for these cancers.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/cirugía , Neoplasias de la Mama/patología , Terapia Neoadyuvante , Axila/patología , Estudios Retrospectivos , Ganglios Linfáticos/patología , Escisión del Ganglio Linfático , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Receptor ErbB-2/uso terapéuticoRESUMEN
PURPOSE: Identification of metabolomic biomarkers of high SBR grade in non-metastatic breast cancer. METHODS: This retrospective bicentric metabolomic analysis included a training set (n = 51) and a validation set (n = 49) of breast cancer tumors, all classified as high-grade (grade III) or low-grade (grade I-II). Metabolomes of tissue samples were studied by liquid chromatography coupled with mass spectrometry. RESULTS: A molecular signature of the top 12 metabolites was identified from a database of 602 frequently predicted metabolites. Partial least squares discriminant analyses showed that accuracies were 0.81 and 0.82, the R2 scores were 0.57 and 0.55, and the Q2 scores were 0.44431 and 0.40147 for the training set and validation set, respectively; areas under the curve for the Receiver Operating Characteristic Curve were 0.882 and 0.886. The most relevant metabolite was diacetylspermine. Metabolite set enrichment analyses and metabolic pathway analyses highlighted the tryptophan metabolism pathway, but the concentration of individual metabolites varied between tumor samples. CONCLUSIONS: This study indicates that high-grade invasive tumors are related to diacetylspermine and tryptophan metabolism, both involved in the inhibition of the immune response. Targeting these pathways could restore anti-tumor immunity and have a synergistic effect with immunotherapy. Recent studies could not demonstrate the effectiveness of this strategy, but the use of theragnostic metabolomic signatures should allow better selection of patients.
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The detection of tumour gene mutations by DNA or RNA sequencing is crucial for the prescription of effective targeted therapies. Recent developments showed promising results for tumoral mutational status prediction using new deep learning based methods on histopathological images. However, it is still unknown whether these methods can be useful aside from sequencing methods for efficient population diagnosis. In this retrospective study, we use a standard prediction pipeline based on a convolutional neural network for the detection of cancer driver genomic alterations in The Cancer Genome Atlas (TCGA) breast (BRCA, n = 719), lung (LUAD, n = 541) and colon (COAD, n = 459) cancer datasets. We propose 3 diagnostic strategies using deep learning methods as first-line diagnostic tools. Focusing on cancer driver genes such as KRAS, EGFR or TP53, we show that these methods help reduce DNA sequencing by up to 49.9% with a high sensitivity (95%). In a context of limited resources, these methods increase sensitivity up to 69.8% at a 30% capacity of DNA sequencing tests, up to 85.1% at a 50% capacity, and up to 91.8% at a 70% capacity. These methods can also be used to prioritize patients with a positive predictive value up to 90.6% in the 10% patient most at risk of being mutated. Limitations of this study include the lack of external validation on non-TCGA data, dependence on prevalence of mutations in datasets, and use of a standard DL method on a limited dataset. Future studies using state-of-the-art methods and larger datasets are needed for better evaluation and clinical implementation.
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Aprendizaje Profundo , Humanos , Estudios Retrospectivos , Redes Neurales de la Computación , Mutación , OncogenesRESUMEN
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
There is little data concerning the implications of PIK3CA mutations outside of the known hotspots described in ER+/HER2- metastatic breast cancer (mBC). Similarly, PIK3R1 mutations could also lead to activation of PI3K pathway, but are poorly described. We determined the incidence and type of all somatic PIK3CA and PIK3R1 mutations by whole exome sequencing (WES) in a pan-cancer cohort of 1200 patients. Activation of the PI3K pathway was studied using phospho-AKT immunohistochemistry. Associations between PIK3CA/PIK3R1 mutations and response to chemotherapy were studied in mBC cases. We found 141 patients (11.8%) with a PIK3CA and/or PIK3R1 mutation across 20 different cancer types. The main cancer subtype was mBC (45.4%). Eighty-four mutations (62.2%) occurred in the three described hotspots; 51 mutations occurred outside of these hotspots. In total, 78.4% were considered activating or probably activating. Among PIK3R1 mutations, 20% were loss of function mutations, leading to a constitutional activation of the pathway. Phospho-AKT quantification in tumor samples was in favor of activation of the PI3K pathway in the majority of mutated tumors, regardless of mutation type. In ER+/HER2- mBC, first line chemotherapy efficacy was similar for PIK3CA-mutated and PIK3CA-WT tumors, whereas in triple negative mBC, chemotherapy appeared to be more effective in PIK3CA-WT tumors. In this large, real-life pan-cancer patient cohort, our results indicate that PIK3CA/PIK3R1 mutations are widely spread, and plead in favour of evaluating the efficacy of PI3K inhibitors outside of ER+/HER2- mBC and outside of hotspot mutations.
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Neoplasias de la Mama , Neoplasias de la Mama Triple Negativas , Humanos , Femenino , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasa Clase I/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Resultado del Tratamiento , Factores de Transcripción/genética , Mutación , Fosfatidilinositol 3-Quinasa Clase Ia/genéticaRESUMEN
Breast cancer is the most frequently occurring cancer worldwide. With its increasing incidence, it is a major public health problem, with many therapeutic challenges such as precision medicine for personalized treatment. Thanks to next-generation sequencing (NGS), progress in biomedical technologies, and the use of bioinformatics, it is now possible to identify specific molecular alterations in tumor cells-such as homologous recombination deficiencies (HRD)-enabling us to consider using DNA-damaging agents such as platinum salts or PARP inhibitors. Different approaches currently exist to analyze impairment of the homologous recombination pathway, e.g., the search for specific mutations in homologous recombination repair (HRR) genes, such as BRCA1/2; the use of genomic scars or mutational signatures; or the development of functional tests. Nevertheless, the role and value of these different tests in breast cancer treatment decisions remains to be clarified. In this review, we summarize current knowledge on the clinical utility of genomic tests, evaluating HRR deficiency for treatment decisions in early and metastatic breast cancer.
RESUMEN
INTRODUCTION: Early-stage ovarian cancer represents 20 to 33% of all ovarian cancers and is thus quite rare in France, with around 1200 new cases per year. No study to date has convincingly demonstrated the utility of lymphadenectomy in early-stage ovarian cancer. We sought to evaluate the impact on overall survival of complete surgical staging in patients management for FIGO stage I and II ovarian cancer. METHODS: We performed a retrospective observational study using data from the Cote d'Or Registry of Gynecological Cancers. We included patients with invasive early stage epithelial ovarian cancer (FIGO stages I and II), diagnosed between 1 January 1998 and 31 December 2015. RESULTS: A total of 179 patients were included in the study. Patients who had lymphadenectomy were younger on average (P<0.001) and had fewer comorbidities (P=0.03). Lymphadenectomy was performed during the first surgery in 59.2% of cases (58 patients) and during a second, re-staging surgery in 40.8% (n=40). When complete surgical staging was performed, the rate of up-staging (to at least FIGO stage III) was 11.2% (11/98). The median follow-up was 8.4 years. At the study, 31.6% patients with complete surgical staging had died and 48.4% patients also died in the group without lymphadenectomy, HR 0.59 CI [0.36-0.97] P<0.04. CONCLUSION: In patients with early-stage ovarian cancer, complete surgical staging appears to yield a benefit in terms of overall survival. In 10 to 15% of cases, it leads to upstaging, with the resultant indication for maintenance therapy, which has also shown a survival benefit.
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Neoplasias Ováricas , Humanos , Femenino , Estadificación de Neoplasias , Neoplasias Ováricas/patología , Carcinoma Epitelial de Ovario/cirugía , Escisión del Ganglio Linfático , Estudios Retrospectivos , Sistema de RegistrosRESUMEN
BACKGROUND: HER2-positive (HER2 +) invasive lobular breast cancer (ILC) is rare and poorly characterised. In particular, patient outcomes compared to those associated with HER2 + invasive ductal cancer (IDC) and HER2-negative (HER2 -) ILC, as well as the benefits of anti-HER2 therapy, are not well established. METHODS: We analysed the data from the Côte d'Or Registry of Breast and Gynaecological Cancers (France) for all patients diagnosed with early-stage HER2 + ILC (62 cases), HER2 + IDC (833 cases) and HER2 - ILC (685 cases) between 1998 and 2015 to compare overall and disease-free survival (OS and DFS) between these groups in correlation with anti-HER2 therapy. RESULTS: ILCs were associated with older age, larger tumours, lower histological grades, higher hormonal receptor positivity rates and multifocality, and more common endocrine therapy. OS and DFS between the three groups did not differ. We found that anti-HER2 therapy was associated with a survival benefit in patients with HER2 + IDC. In contrast, the survival of HER2 + ILC patients was not improved by anti-HER2 treatment, remaining close to that of HER2 - ILC patients. CONCLUSION: HER2 + ILC seems not to be associated with better outcomes than HER2 + IDC but may not differ from HER2 - ILC in terms of survival.
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Neoplasias de la Mama , Carcinoma Ductal de Mama , Carcinoma Lobular , Humanos , Femenino , Neoplasias de la Mama/patología , Resultado del Tratamiento , Supervivencia sin EnfermedadRESUMEN
PURPOSE: The prognosis of local invasive recurrence (LIR) after prior carcinoma in situ (CIS) of the breast has not been widely studied and existing data are conflicting, especially considering the specific prognosis of this entity, compared to de novo invasive breast cancer (de novo IBC) and with LIR after primary IBC. METHODS: We designed a retrospective study using data from the specialized Côte d'Or Breast and Gynecological cancer registry, between 1998 and 2015, to compare outcomes between 3 matched groups of patients with localized IBC: patients with LIR following CIS (CIS-LIR), patients with de novo IBC (de novo IBC), and patients with LIR following a first IBC (IBC-LIR). Distant relapse-free (D-RFS), overall survival (OS), clinical, and treatment features between the 3 groups were studied. RESULTS: Among 8186 women initially diagnosed with IBC during our study period, we retrieved and matched 49 CIS-LIR to 49 IBC, and 46 IBC-LIR patients. At diagnosis, IBC/LIR in the 3 groups were mainly stage I, grade II, estrogen receptor-positive, and HER2 negative. Metastatic diseases at diagnosis were higher in CIS-LIR group. A majority of patients received adjuvant systemic treatment, with no statistically significant differences between the 3 groups. There was no significant difference between the 3 groups in terms of OS or D-RFS. CONCLUSION: LIR after CIS does not appear to impact per se on survival of IBC.