Background Optimising the selection of HER2-targeted regimens by identifying subsets of HER2-positive breast cancer (BC) patients who need more or less therapy remains challenging. We analysed BC samples before and after treatment with 1 cycle of trastuzumab according to the response to trastuzumab. Methods Gene expression profiles of pre- and post-treatment tumour samples from 17 HER2-positive BC patients were analysed on the Illumina platform. Tumour-associated immune pathways and blood counts were analysed with regard to the response to trastuzumab. HER2-positive murine models with differential responses to trastuzumab were used to reproduce and better characterise these data. Results Patients who responded to single-agent trastuzumab had basal tumour biopsies that were enriched in immune pathways, particularly the MHC-II metagene. One cycle of trastuzumab modulated the expression levels of MHC-II genes, which increased in patients who had a complete response on treatment with trastuzumab and chemotherapy. Trastuzumab increased the MHC-II-positive cell population, primarily macrophages, only in the tumour microenvironment of responsive mice. In patients who benefited from complete trastuzumab therapy and in mice that harboured responsive tumours circulating neutrophil levels declined, but this cell subset rose in nonresponsive tumours. Conclusions Short treatment with trastuzumab induces local and systemic immunomodulation that is associated with clinical outcomes.
While results thus far demonstrate the clinical benefit of trastuzumab, some patients do not respond to this therapy. To identify a molecular predictor of trastuzumab benefit, we conducted whole-transcriptome analysis of primary HER2+ breast carcinomas obtained from patients treated with trastuzumab-containing therapies and correlated the molecular portrait with treatment benefit.The estimated association between gene expression and relapse-free survival allowed development of a trastuzumab risk model (TRAR), with ERBB2 and ESR1 expression as core elements, able to identify patients with high and low risk of relapse. Application of the TRAR model to 24 HER2+ core biopsies from patients treated with neo-adjuvant trastuzumab indicated that it is predictive of trastuzumab response. Examination of TRAR in available whole-transcriptome datasets indicated that this model stratifies patients according to response to trastuzumab-based neo-adjuvant treatment but not to chemotherapy alone. Pathway analysis revealed that TRAR-low tumors expressed genes of the immune response, with higher numbers of CD8-positive cells detected immunohistochemically compared to TRAR-high tumors.The TRAR model identifies tumors that benefit from trastuzumab-based treatment as those most enriched in CD8-positive immune infiltrating cells and with high ERBB2 and low ESR1 mRNA levels, indicating the requirement for both features in achieving trastuzumab response.
The Sertoli cell tumor (SCT) of the testis is a sex cord stromal tumor, usually sporadic, rarely associated with genetic syndromes. Much remains unclear about the molecular genetic changes involved in SCT and its histogenesis. Recently, nuclear β-catenin immunostaining has been reported in a case of bilateral SCT, but the molecular basis of the aberrant nuclear β-catenin expression remains uncertain. In the present study, β-catenin immunohistochemical assay and mutational analysis of exon 3 of the CTNNB1 gene by direct sequencing were performed in 14 SCTs, 2 of which had an unfavorable clinical course. Immunohistochemical study showed that β-catenin was located in the cytoplasm of tumor cells in 4 cases (28.6%) and in both the nuclei and the cytoplasm in the remaining 10 cases (71.4%). β-Catenin mutations were detected in 10 of the 14 patients (71.4%) under evaluation. Ten of 10 mutation-carrying cases showed strong nuclear and diffuse cytoplasmic β-catenin immunoreactivity. Seven of the 8 CTNNB1-mutated tumors tested for cyclin D1 displayed diffuse immunoreactivity in the nuclei of tumor cells. We conclude that CTNNB1 exon 3 mutations are likely to be involved in the pathogenesis of male SCT with nuclear accumulation of β-catenin and affect the expression of cyclin D1.
Teratoma with a malignant somatic component (MSC) is a rare phenomenon recognized when a somatic type malignancy occurs in the context of a germ cell tumor (GCT). The authors present their 29-year experience with 40 patients treated from 1981 to 2009 in their institution. The average age was 31 years. All patients underwent radical orchiectomy, which demonstrated a GCT in 19 with an MSC. The MSC was observed in the other 21 cases in metastatic sites, including lung (13), liver (3), pleura (1), mediastinum (7), supraclavicular lymph nodes (1), and retroperitoneal lymph nodes (9). The most common histologic types were rhabdomyosarcoma (n = 11) and primitive neuroectodermal tumors (n = 10), followed by adenocarcinoma (n = 9), sarcoma, not otherwise specified (n = 5), well-differentiated liposarcoma (n = 2), leiomyosarcoma (n = 2), chondrosarcoma (n = 2), nephroblastoma (Wilms's tumor), carcinoid, malignant peripheral nerve sheath tumor, and a gemistiocytic astrocytoma with choroid plexus tumor (each n = 1). Clinical data were collected through a dedicated database and are available for all 40 cases. After a median follow-up of 37 months, 29/40 (72.5%) were alive and disease-free. Stage-specific survival was 100% for stage I, 87.5% for stage II, and 53% for stage III patients suggesting that patients with MSC confined to the testis have a good prognosis. A lower sensitivity to chemotherapy for a MSC when compared with typical GCT is reported. Surgical excision of the MSC is therefore an essential part of the management.
Study Type – Therapy (case series) Level of Evidence 4 OBJECTIVE • To investigate the optimal management and prognostic factors of patients with malignant transformation (MT) in germ‐cell tumour (GCT) by re‐evaluating Institutional series. PATIENTS AND METHODS • Patients with an MT within GCT have been identified from the institutional database and all slides have been reviewed by the referral pathologist. RESULTS • From June 1982 to October 2009, 48 patients and 13 somatic histologies have been identified. Twelve patients presented with stage I, 12 with stage II and 24 with stage III disease. All stage I patients are alive and disease‐free after a median follow up of 88 months (interquartile range 38–103). • Of the 36 metastatic cases, 11 underwent GCT‐oriented chemotherapy plus surgery and seven of them are currently disease‐free. Three patients underwent MT‐chemotherapy, one relapsed and is still under treatment. Overall, 17 patients relapsed (35%) and three of them have been rescued by GCT‐chemotherapy. Five‐year overall survival was 100% for stage I, 80% (95% CI 40–94) for stage II and 44% (95% CI 19–67) for stage III patients. Stage III disease at MT, incomplete surgical removal and primitive neuroectodermal tumours plus adenocarcinoma histologies were significant adverse prognostic factors for survival. CONCLUSIONS • New insights emerged into the impact of histology and chemotherapy on MT. The development of an adenocarcinoma component as well as the possible efficacy of a GCT‐tailored chemotherapy in a multimodal strategy are addressed for the first time, while disease extent at transformation and extent of radical surgery are confirmed as significant prognosticators. • An international web database for registration of all cases of MT worldwide is presented.
Background:Breast cancer clinical outcome is affected by tumor molecular features, and the identification of subtype-specific prognostic biomarkers is relevant for breast cancer translational research. Gene expression signatures proved to be able to complement prognostic information provided by classical clinico-pathological features. Recently, microRNAs (miRNAs) have been causally linked to tumorigenesis and cancer progression and have been associated with patient outcome, also in breast cancer.Methods:MicroRNAs associated with the development of distant metastasis were identified in a cohort of 92 ESR1+/ERBB2− lymph node-negative breast cancers from patients not receiving adjuvant treatment. Results were confirmed and further investigated in a total of 1246 miRNA and gene expression profiles of the Molecular Taxonomy of Breast Cancer International Consortium data set. Moderated t-test, univariable and multivariable Cox regression models were used for statistical analyses.Results:miR-30e* was identified as independent protective prognostic factor in lymph node-negative untreated patients with ESR1+/ERBB2− tumours and retained a significant association with a good prognosis in treated patients with the same tumor subtype as well as in the ERBB2+ subtype, but not in ESR1−/ERBB2− tumours.Conclusions:We highlighted a relevant and subtype-specific role in breast cancer for miR-30e* and demonstrated that adding miRNA markers to gene signatures and clinico-pathological features can help for a better prognostication.
SummaryA‐lamins, encoded by the LMNA gene, are major structural components of the nuclear lamina coordinating essential cellular processes. Mutations in the LMNA gene and/or alterations in its expression levels have been linked to a distinct subset of human disorders, collectively known as laminopathies, and to cancer. Mechanisms regulating A‐lamins are mostly obscure. Here, we identified E3 ubiquitin ligase Smurf2 as a physiological regulator of lamin A and its disease‐associated mutant form progerin (LAΔ50), whose expression underlies the development of Hutchinson‐Gilford progeria syndrome (HGPS), a devastating premature aging syndrome. We show that Smurf2 directly binds, ubiquitinates, and negatively regulates the expression of lamin A and progerin in Smurf2 dose‐ and E3 ligase‐dependent manners. Overexpression of catalytically active Smurf2 promotes the autophagic–lysosomal breakdown of lamin A and progerin, whereas Smurf2 depletion increases lamin A levels. Remarkably, acute overexpression of Smurf2 in progeria fibroblasts was able to significantly reduce the nuclear deformability. Furthermore, we demonstrate that the reciprocal relationship between Smurf2 and A‐lamins is preserved in different types of mouse and human normal and cancer tissues. These findings establish Smurf2 as an essential regulator of lamin A and progerin and lay a foundation for evaluating the efficiency of progerin clearance by Smurf2 in HGPS, and targeting of the Smurf2–lamin A axis in age‐related diseases such as cancer.
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