Triple‐negative breast cancer (TNBC) represents 10% of all breast cancers and is a very heterogeneous disease. Globally, women with TNBC have a poor prognosis, and the development of effective ...targeted therapies remains a real challenge. Patient‐derived xenografts (PDX) are clinically relevant models that have emerged as important tools for the analysis of drug activity and predictive biomarker discovery. The purpose of this work was to analyze the molecular heterogeneity of a large panel of TNBC PDX (n = 61) in order to test targeted therapies and identify biomarkers of response. At the gene expression level, TNBC PDX represent all of the various TNBC subtypes identified by the Lehmann classification except for immunomodulatory subtype, which is underrepresented in PDX. NGS and copy number data showed a similar diversity of significantly mutated gene and somatic copy number alteration in PDX and the Cancer Genome Atlas TNBC patients. The genes most commonly altered were TP53 and oncogenes and tumor suppressors of the PI3K/AKT/mTOR and MAPK pathways. PDX showed similar morphology and immunohistochemistry markers to those of the original tumors. Efficacy experiments with PI3K and MAPK inhibitor monotherapy or combination therapy showed an antitumor activity in PDX carrying genomic mutations of PIK3CA and NRAS genes. TNBC PDX reproduce the molecular heterogeneity of TNBC patients. This large collection of PDX is a clinically relevant platform for drug testing, biomarker discovery and translational research.
What's new?
Triple‐negative breast cancer (TNBC) is a highly heterogeneous disease in terms of molecular profile, histological features, clinical behavior, and drug response. Several clinical trials have been conducted for targeted therapies, but only in unselected TNBC patients, with disappointing results. This study shows that patient‐derived xenografts (PDX) reproduce the molecular heterogeneity of TNBC. The presented genomic analysis identifies several interesting targetable drivers, particularly in the PI3K and MAPK pathways. PDX models provide a unique opportunity to test various treatments on individual tumors: already, two specific inhibitors (dual PI3K/mTOR and MEK inhibitor) and their combination are providing encouraging results.
Cancer-related microangiopathic haemolytic anaemia (MAHA) is a rare but life-threatening paraneoplastic syndrome. Only single cases or small series have been reported to date. We set up a ...retrospective multicentre study focusing on breast cancer-related MAHA.
Main inclusion criteria were known diagnosis of breast cancer, presence of schistocytes and either low haptoglobin or cytopenia and absence of any causes of MAHA other than breast cancer, including gemcitabine- or bevacizumab-based treatment. Patient characteristics, treatments and outcome were retrieved from digital medical records.
Individual data from 54 patients with breast cancer-related MAHA were obtained from 7 centres. Twenty-three (44%) patients had a breast tumour with lobular features, and most primary tumours were low grade (grade I/II, N = 39, 75%). ER+/HER2-, HER2+ and triple-negative phenotypes accounted for N = 33 (69%), N = 7 (15%) and N = 8 (17%) cases, respectively. All patients had stage IV cancer at the time of MAHA diagnosis. Median overall survival (OS) was 28 days (range 0-1035; Q1:10, Q3:186). Independent prognostic factors for early death (≤ 28 days) were PS > 2 (OR = 7.0 1.6; 31.8), elevated bilirubin (OR = 6.9 1.1; 42.6), haemoglobin < 8.0 g/dL (OR = 3.7 0.9; 16.7) and prothrombin time < 50% (OR = 9.1 1.2; 50.0). A score to predict early death displayed a sensitivity of 86% (95% CI 0.67; 0.96), a specificity of 73% (95% CI 0.52; 0.88) and an area under the curve of 0.90 (95% CI 0.83; 0.97).
Breast cancer-related MAHA appears to be a new feature of invasive lobular breast carcinoma. Prognostic factors and scores may guide clinical decision-making in this serious but not always fatal condition.
Neuroendocrine breast carcinomas represent a rare subtype of breast cancer. Their definition, prevalence, and prognosis remain controversial in the literature. The 2012 WHO classification of breast ...cancer categorizes neuroendocrine carcinomas into three morphologically distinct subtypes: well-differentiated neuroendocrine tumors, poorly differentiated neuroendocrine carcinomas, and invasive breast carcinomas with neuroendocrine differentiation. We aimed to gain insight into the clinical, morphologic, phenotypic, and molecular features of 47 neuroendocrine breast carcinomas. Targeted next-generation sequencing by an AmpliSeq 22 cancer gene hotspot panel and the Prosigna assay were performed on 42/47 and 35/47 cases, respectively. Average age at diagnosis was 69 years. All tumors were estrogen receptor-positive and the large majority expressed progesterone receptor (89%), GATA3 (98%), FOXA1 (96%), and CK8/18 (98%). There was an almost equal distribution of luminal A (52%) and B (48%) carcinomas. Almost half of the cohort (49%) displayed a high risk of recurrence score with the Prosigna test. Patients with a neuroendocrine carcinoma had a shorter disease-free survival compared with those affected by carcinomas of no special type matched for age, size, grade, and estrogen receptor status. No significant differences were observed in terms of overall survival. Stratification of neuroendocrine carcinomas using the 2012 WHO criteria did not reveal statistically significant differences among the distinct categories (well-differentiated neuroendocrine tumors, poorly differentiated neuroendocrine carcinomas, and invasive breast carcinomas with neuroendocrine differentiation), in terms of either progression-free or overall survival. Our targeted sequencing analysis found three cases (7%) harboring a PIK3CA mutation, and in three other cases (7%) TP53 mutations were detected. This study showed that neuroendocrine breast carcinoma is a distinct subtype of luminal carcinoma with a low rate of PIK3CA mutations and with an aggressive clinical behavior. An accurate identification of neuroendocrine differentiation may be useful to better tailor patient adjuvant therapy within luminal carcinomas.
Ossifying fibromyxoid tumor (OFT) is a very rare soft tissue tumor which is characterized by incomplete peripheral mature bone shell. To date, cytological features of OFT have been poorly studied ...with only seven case reports. In this study, an additional case of OFT investigated by fine‐needle aspiration is presented. A 75‐year‐old man with advanced nasopharyngeal carcinoma presented with peripherally calcified right breast mass. Smears were hypercellular and stroma‐rich. Tumor cells were mainly dispersed, with epithelioid morphology and eccentrically located nuclei. In the background, there was abundant eosinophilic myxoid secretion. No necrosis, atypia, or mitotic activity was found. The tumor showed diffuse S‐100, CD10, STAT6 expression and focal desmin, estrogen receptor (ER), and progesteron receptor (PgR) expression. Fluorescence in situ hybridization study revealed PHF1 rearrangement in 9% of cells. Cytological characteristic of OFT is quite distinctive and precise diagnosis can be made, especially when it is coupled with compatible radiological findings.
Luminal androgen receptor (LAR) breast cancer accounts for 10% of all triple-negative breast cancers (TNBC). Anti-androgen therapy for this subtype is in development, but yields only partial clinical ...benefits. In this study, we aimed to characterize the genomic alterations of LAR TNBC, to analyze activation of the PI3K signaling pathway and to compare the response to PI3K pathway inhibitors with that to anti-androgen therapy in patient-derived xenografts (PDX) of LAR TNBC.
: Four LAR PDX models were identified, on the basis of their transcriptomic profiles, in a cohort of 57 PDX models of TNBC. The expression of
-related genes, basal and luminal cytokeratins and EMT genes was analyzed by RT-PCR and IHC.
and
mutations were identified by targeted NGS, and activation of the PI3K pathway was analyzed with a reverse-phase protein array. Three LAR PDXs with a
or
mutation were treated with the AR inhibitor enzalutamide, a PI3K inhibitor, a
PI3K-mTOR inhibitor and a mTORC1-mTORC2 inhibitor. Finally, we screened a clinical cohort of 329 TNBC for
and
hotspot mutations.
: LAR TNBC PDXs were significantly enriched in
and
mutations, and had higher levels of luminal-androgen-like gene expression and a higher PI3K pathway protein activation score than other TNBC subtypes. Immunohistochemistry analysis revealed strong expression of the luminal cytokeratin CK18 and AR in three LAR PDX models. We found that mTOR and PI3K inhibitors had marked antitumor activity
in PDX harboring genomic alterations of
and
genes that did not respond to the AR antagonist enzalutamide.
mutations were detected in more than one third of AR+ TNBC from patients (38%), and only 10% of AR-negative TNBC.
: Our results for PDX models of LAR TNBC resistant to enzalutamide indicate that
and
are potential therapeutic targets.
BackgroundHigh throughput molecular screening techniques allow the identification of multiple molecular alterations, some of which are actionable and can be targeted by molecularly targeted agents ...(MTA). We aimed at evaluating the relevance of using this approach in the frame of Institut Curie Molecular Tumor Board (MTB) to guide patients with cancer to clinical trials with MTAs.Patients and methodsWe included all patients presented at Institut Curie MTB from 4 October 2014 to 31 October 2017. The following information was extracted from the chart: decision to perform tumour profiling, types of molecular analyses, samples used, molecular alterations identified and those which are actionable, and inclusion in a clinical trial with matched MTA.Results736 patients were presented at the MTB. Molecular analyses were performed in 442 patients (60%). Techniques used included next-generation sequencing, comparative genomic hybridisation array and/or other techniques including immunohistochemistry in 78%, 51% and 58% of patients, respectively. Analyses were performed on a fresh frozen biopsy in 91 patients (21%), on archival tissue (fixed or frozen) in 326 patients (74%) and on both archival and fresh frozen biopsy in 25 patients (6%). At least one molecular alteration was identified in 280 analysed patients (63%). An actionable molecular alteration was identified in 207 analysed patients (47%). Forty-five analysed patients (10%) were enrolled in a clinical trial with matched MTA and 29 additional patients were oriented and included in a clinical trial based on a molecular alteration identified prior to the MTB analysis. Median time between date of specimen reception and molecular results was 28 days (range: 5–168).ConclusionsThe implementation of an MTB at Institut Curie enabled the inclusion of 10% of patients into a clinical trial with matched therapy.
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