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Effective biomarkers predictive of the response to treatments are key for precision medicine. This study identifies the staining pattern of the centromeric histone 3 variant, CENP-A, as a predictive biomarker of locoregional disease curability by chemoradiation therapy. We compared by imaging the subnuclear distribution of CENP-A in normal and tumoral tissues, and in a retrospective study in biopsies of 62 locally advanced head and neck squamous cell carcinoma (HNSCC) patients treated by chemoradiation therapy. We looked for predictive factors of locoregional disease control and patient's survival, including CENP-A patterns, Ki67, HPV status and anisokaryosis. In different normal tissues, we reproducibly found a CENP-A subnuclear pattern characterized by CENP-A clusters both localized at the nuclear periphery and regularly spaced. In corresponding tumors, both features are lost. In locally advanced HNSCC, a specific CENP-A pattern identified in pretreatment biopsies predicts definitive locoregional disease control after chemoradiation treatment in 96% (24/25) of patients (OR = 17.6 CI 95% [2.6; 362.8], p = 0.002), independently of anisokaryosis, Ki67 labeling or HPV status. The characteristics of the subnuclear pattern of CENP-A in cell nuclei revealed by immunohistochemistry could provide an easy to use a reliable marker of disease curability by chemoradiation therapy in locally advanced HNSCC patients.

Background: To compare RCB (Residual Cancer Burden) and Neo-Bioscore in terms of prognostic performance and see if adding pathological variables improve these scores., Methods: We analysed 750 female patients with invasive breast cancer (BC) treated with neoadjuvant chemotherapy (NAC) at Institut Curie between 2002 and 2012. Scores were compared in global population and by BC subtype using Akaike information criterion (AIC), C-Index (concordance index), calibration curves and after adding lymphovascular invasion (LVI) and pre-/post-NAC TILs levels., Results: RCB and Neo-Bioscore were significantly associated to disease-free and overall survival in global population and for triple-negative BC. RCB had the lowest AICs in every BC subtype, corresponding to a better prognostic performance. In global population, C-Index values were poor for RCB (0.66; CI [0.61-0.71]) and fair for Neo-Bioscore (0.70; CI [0.65-0.75]). Scores were well calibrated in global population, but RCB yielded better prognostic performances in each BC subtype. Concordance between the two scores was poor. Adding LVI and TILs improved the performance of both scores., Conclusions: Although RCB and Neo-Bioscore had similar prognostic performances, RCB showed better performance in BC subtypes, especially in luminal and TNBC. By generating fewer prognostic categories, RCB enables an easier use in everyday clinical practice.

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., Competing Interests: No competing interests.

A ductal in situ (DCIS) component is often associated with invasive breast carcinoma (BC), and its effect on response to treatment is unknown. We assessed the predictive value of the DCIS component for pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC). We analyzed a cohort of 1148 T1-3NxM0 breast cancer (BC) patients treated by NAC at Institut Curie between 2002 and 2012. The presence of a DCIS component was retrospectively recorded from both the pre-NAC biopsy pathological report and surgical specimens. We included 1148 BC patients treated by NAC for whom pre- and post-NAC data concerning the in situ component were available. DCIS was present before NAC in 19.6% of the population. Overall, 283 patients (19.4%) achieved pCR after NAC. There was no significant association between the presence of DCIS on pre-NAC biopsy and pCR. In a multivariate analysis including subtype, tumor size, grade, mitotic index, and Ki67 index, only BC subtype (luminal/TNBC/ HER2 -positive) and Ki67 were significantly associated with pCR. The presence of a DCIS component on pre-NAC biopsy is not associated with pCR and does not seem to be a critical factor for predicting response to NAC.

Introduction: The three different breast cancer subtypes (Luminal, HER2- positive, and triple negative (TNBCs) display different natural history and sensitivity to treatment, but little is known about whether residual axillary disease after neoadjuvant chemotherapy (NAC) carries a different prognostic value by BC subtype., Methods: We retrospectively evaluated the axillary involvement (0, 1 to 3 positive nodes, ≥4 positive nodes) on surgical specimens from a cohort of T1-T3NxM0 BC patients treated with NAC between 2002 and 2012. We analyzed the association between nodal involvement (ypN) binned into three classes (0; 1 to 3; 4 or more), relapse-free survival (RFS) and overall survival (OS) among the global population, and according to BC subtypes., Results: 1197 patients were included in the analysis (luminal ( n = 526, 43.9%), TNBCs ( n = 376, 31.4%), HER2 -positive BCs ( n = 295, 24.6%)). After a median follow-up of 110.5 months, ypN was significantly associated with RFS, but this effect was different by BC subtype ( P interaction = 0.004), and this effect was nonlinear. In the luminal subgroup, RFS was impaired in patients with 4 or more nodes involved (HR 2.8; 95% CI [1.93; 4.06], p < 0.001) when compared with ypN0, while it was not in patients with 1 to 3 nodes (HR = 1.24, 95% CI = [0.86; 1.79]). In patients with TNBC, both 1-3N+ and ≥4 N+ classes were associated with a decreased RFS (HR = 3.19, 95% CI = [2.05; 4.98] and HR = 4.83, 95% CI = [3.06; 7.63], respectively versus ypN0, p < 0.001). Similar decreased prognosis were observed among patients with HER2 -positive BC (1-3N +: HR = 2.7, 95% CI = [1.64; 4.43] and ≥4 N +: HR = 2.69, 95% CI = [1.24; 5.8] respectively, p = 0.003)., Conclusion: The prognostic value of residual axillary disease should be considered differently in the 3 BC subtypes to accurately stratify patients with a high risk of recurrence after NAC who should be offered second line therapies.

Introduction: Five to 10% of breast cancers (BCs) occur in a genetic predisposition context (mainly BRCA pathogenic variant). Nevertheless, little is known about immune tumor infiltration, response to neoadjuvant chemotherapy (NAC), pathologic complete response (pCR) and adverse events according to BRCA status., Material and Methods: Out of 1199 invasive BC patients treated with NAC between 2002 and 2012, we identified 267 patients tested for a germline BRCA pathogenic variant. We evaluated pre-NAC and post-NAC immune infiltration (TILs). Response to chemotherapy was assessed by pCR rates. Association of clinical and pathological factors with TILs, pCR and survival was assessed by univariate and multivariate analyses., Results: Among 1199 BC patients: 46 were BRCA -deficient and 221 BRCA- proficient or wild type (WT). At NAC completion, pCR was observed in 84/266 (31%) patients and pCR rates were significantly higher in BRCA- deficient BC ( p = 0.001), and this association remained statistically significant only in the luminal BC subtype ( p = 0.006). The interaction test between BC subtype and BRCA status was nearly significant ( P interaction = 0.056). Pre and post-NAC TILs were not significantly different between BRCA- deficient and BRCA- proficient carriers; however, in the luminal BC group, post-NAC TILs were significantly higher in BRCA- deficient BC. Survival analysis were not different between BRCA- carriers and non-carriers., Conclusions: BRCA mutation status is associated with higher pCR rates and post-NAC TILs in patients with luminal BC. BRCA -carriers with luminal BCs may represent a subset of patients deriving higher benefit from NAC. Second line therapies, including immunotherapy after NAC, could be of interest in non-responders to NAC.

Introduction: Non endometrioid endometrial cancer are infrequent and have poor prognosis. The aim of the study was to evaluate non endometrioid endometrial cancer managment by evaluating endometrial cancer guidelines application., Material and Methods: This multicentric retrospective study enrolled non endometrioid endometrial cancer between January 2009 to December 2019. Analyses adapted at last French guidelines applicated corresponding of year management., Results: Seventy-four non endometrioid endometrial cancer analysed in 10 centers: 34 carcinosarcoma (45,9 %), 29 serous carcinoma (39,2 %), 9 clear cells carcinoma (12,2 %) and 2 undifferentiated carcinoma (2,7 %). For initial management, endometrial cancer guidelines applicated to 45,9 %. First reason of initial guidelines « non-application » was lack of surgical lymph node stadification (57,1 %). For adjuvant management, endometrial cancer guidelines applicated to 38.7 %. First reason of adjuvant guidelines « non-application » was lack lymph node stadification to complete staging when it previously incompletly operated (67,6 %)., Discussion: Non endometrioid endometrial cancer guidelines applicability is difficult. This explicated by high age and comorbidity when surgical lymph node stadification is necessary. Using new staging technic will allow target management and better select lymph node staging indication., (Copyright © 2020 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

The detection of specific alterations by genetic analyses has been included in the diagnostic criterions of the World Health Organization's classification of soft tissues tumors since 2013. The presence of a SS18 rearrangement is pathognomonic of synovial sarcoma (SS). MDM2 amplification is strongly correlated to well-differentiated or dedifferentiated liposarcoma (DDLPS) in the context of sarcoma. We identified one case of poorly differentiated sarcoma harboring both SS18-SSX2 fusion and MDM2 amplification. The review of the literature showed high discrepancies, concerning the incidence of MDM2 amplification in SS: from 1.4% up to 40%. Our goal was to precisely determine the specific clinico-pathological features of this case and to estimate the frequency and characteristics of the association of SS18-SSX fusion/MDM2 amplification in sarcomas. We performed a retrospective and prospective study in 96 sarcomas, (56 SS and 40 DDLPS), using FISH and/or array-CGH to detect MDM2 amplification and SS18 rearrangement. None of the 96 cases presented both genetic alterations. Among the SS, only the index case (1/57: 1.7 %) presented the double anomaly. We concluded that MDM2 amplification in SS is a very rare event. The final diagnosis of the index case was a SS with SS18-SSX2 and MDM2 amplification as a secondary alteration. If the detection of MDM2 amplification is performed first in a poorly differentiated sarcoma, that may lead to not search other anomalies such as SS18 rearrangement and therefore to an erroneous diagnosis. This observation emphasizes the strong complementarity between histomorphology, immunohistochemistry and molecular studies in sarcoma diagnosis., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Adventitious bursitis of the plantar fat pad is a common cause of forefoot pain. It may develop at sites where subcutaneous tissue is exposed to friction and high pressure. In the forefoot, adventitious bursitis is usually adjacent to bony prominences of the metatarsal heads. Diagnosis and management of adventitious bursitis usually do not require imaging studies. However, the condition occasionally presents as a solid pseudotumoral mass requiring imaging. Magnetic resonance imaging (MRI) may demonstrate a heterogeneous mass with a solid component exhibiting intermediate to high signal intensity on T2-weighted images and thick nodular enhancement suggesting a neoplastic lesion. We report three cases of adventitious bursitis in patients who complained of a painful palpable mass on the forefoot, with a partially solid and enhancing component seen on MRI. In the first case, a biopsy was performed for the diagnosis of adventitious bursitis. The two other cases exhibited a solid component on MRI. However, a diagnosis of adventitious bursitis was suspected, and it was felt that a biopsy could be postponed. The spontaneous regression of the mass with relative discharge of the forefoot pressure confirmed the diagnosis. With these three cases, we illustrate the MR findings that could suggest adventitious bursitis despite the presence of a solid component and that may obviate the need for pathologic proof., (Copyright Journal of Radiology Case Reports.)

Immunosurveillance plays an important role in breast cancer (BC) prognosis and progression, and can be geared by immunogenic chemotherapy. In a cohort of 1023 BC patients treated with neoadjuvant chemotherapy (NAC), 40% of the individuals took comedications mostly linked to aging and comorbidities. We systematically analyzed the off-target effects of 1178 concurrent comedications (classified according to the Anatomical Therapeutic Chemical (ATC) Classification System) on the density of tumor-infiltrating lymphocytes (TILs) and pathological complete responses (pCR). At level 1 of the ATC system, the main anatomical classes of drugs were those targeting the nervous system (class N, 39.1%), cardiovascular disorders (class C, 26.6%), alimentary and metabolism (class A, 16.9%), or hormonal preparations (class H, 6.5%). At level 2, the most frequent therapeutic classes were psycholeptics (N05), analgesics (N02), and psychoanaleptics (N06). Pre-NAC TIL density in triple-negative BC (TNBC) was influenced by medications from class H, N, and A, while TIL density in HER2 + BC was associated with the use of class C. Psycholeptics (N05) and agents acting on the renin-angiotensin system (C09) were independently associated with pCR in the whole population of BC or TNBC, and in HER2 -positive BC, respectively. Importantly, level 3 hypnotics (N05C) alone were able to reduce tumor growth in BC bearing mice and increased the anti-cancer activity of cyclophosphamide in a T cell-dependent manner. These findings prompt for further exploration of drugs interactions in cancer, and for prospective drug-repositioning strategies to improve the efficacy of NAC in BC., (© 2019 The Author(s). Published with license by Taylor & Francis Group, LLC.)

The CDKN2B-AS1 gene, also called ANRIL , is located at the human CDKN2A/B locus at 9p21.3 and transcribed by RNA polymerase II into a long non-coding RNA of 3834 bp. The CDKN2B-AS1 gene overlaps a critical region of 125 kb covering the CDKN2B gene. The CDKN2A/B locus encompasses three major tumor suppressors juxtaposed and joined into a p16-CDKN2A/p15-CDKN2B/p14-ARF gene cluster. CDKN2A encodes splice variants p16-CDKN2A and p14-ARF, and CDKN2B encodes p15-CDKN2B. ANRIL shares a bidirectional promoter with the p14-ARF gene and is transcribed from the opposite strand to the cluster. We performed an analysis of the expression level of ANRIL and tumor suppressor p16-CDKN2A, p15-CDKN2B , and p14-ARF genes using quantitative RT-PCR in a multitumor panel. We observed the overexpression of the four genes ANRIL , p16-CDKN2A, p15-CDKN2B , and p14-ARF in the great majority of the 17 different cancer types. ANRIL was upregulated in 13/17 tumors compared to normal tissues, ranging from 5% (prostate cancer) to 91% (cervix cancer), with variable expression of p16-CDKN2A, p15-CDKN2B , and p14-ARF genes. A high positive correlation was identified between levels of expression of ANRIL and the three tumor suppressors. The strongest positive association was observed with p14-ARF ( p < 0.001) in all but one (lung squamous cell carcinoma) of the examined tumor types. This correlation suggests coordinated deregulated mechanisms in all cancer types through aberrant activation of a bidirectional p14-ARF/ANRIL promoter. Furthermore, significant positive correlation was unexpectedly established in prostatic carcinomas, in contradiction with previous data.

The advent of digital pathology provides us with the challenging opportunity to automatically analyze whole slides of diseased tissue in order to derive quantitative profiles that can be used for diagnosis and prognosis tasks. In particular, for the development of interpretable models, the detection and segmentation of cell nuclei is of the utmost importance. In this paper, we describe a new method to automatically segment nuclei from Haematoxylin and Eosin (H&E) stained histopathology data with fully convolutional networks. In particular, we address the problem of segmenting touching nuclei by formulating the segmentation problem as a regression task of the distance map. We demonstrate superior performance of this approach as compared to other approaches using Convolutional Neural Networks.

Background: Pregnancy-associated breast cancer (PABC) refers to breast cancers (BC) diagnosed during pregnancy or shortly after birth. Although the inflammatory environment of post-partum PABC cases (designed as PP-PABC) may be deleterious, so far PP-PABC have scarcely been distinguished from breast cancers diagnosed during pregnancy. Furthermore, whether PP-PABC cases have an enhanced immune infiltration remains unknown. We investigated chemosensitivity, immune infiltration and survival of PP-PABC patients treated by neoadjuvant chemotherapy (NAC) compared to non-PABC matched BC patients., Materials and Methods: We identified PP-PABC cases among a cohort of 1199 invasive BC treated with NAC between 2002 and 2012. Each PP-PABC case was matched with 3 non-PABC controls, according to age and pathological breast cancer subtype. Microbiopsy specimens and paired surgical samples were evaluated for stromal lymphocyte infiltration. Association of clinical and pathological factors with pathological complete response (pCR) and disease-free survival (DFS) was assessed by univariate and multivariate analyses., Results: Our final population study was composed of 116 patients (29 PP-PABC and 87 non-PABC). Median follow-up was of 49.0 and 29.3 months, respectively. After NAC, pCR rates (p = 0.64), post-NAC immune infiltration (stromal TILs: p = 0.67; intratumoral TILs: p = 0.14), and DFS rates (p = 0.17) were comparable between PP-PABC and non-PABC patients in global population. Similar results were found after stratification by pathological subtype., Conclusion: We observed similar patterns between postpartum PABC and control tumors in terms of chemosensitivity, immune infiltration, and prognostic. Our results enhance the idea that PP-PABC should receive the same standard of care treatment as other patients, including neoadjuvant chemotherapy., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: Triple-negative breast cancer (TNBC) patients with residual disease after neoadjuvant chemotherapy have a poor outcome. We developed patient-derived xenografts (PDX) from residual tumors to identify efficient chemotherapies and predictive biomarkers in a context of resistance to anthracyclines- and taxanes-based treatments. Experimental Design: PDX were established from residual tumors of primary breast cancer patients treated in neoadjuvant setting. TNBC PDX were treated by anthracyclines, taxanes, platins, and capecitabine. Predictive biomarkers were identified by transcriptomic and immunohistologic analysis. Downregulation of RB1 was performed by siRNA in a cell line established from a PDX. Results: Residual TNBC PDX were characterized by a high tumor take, a short latency, and a poor prognosis of the corresponding patients. With the exception of BRCA1/2-mutated models, residual PDX were resistant to anthracyclines, taxanes, and platins. Capecitabine, the oral prodrug of 5-FU, was highly efficient in 60% of PDX, with two models showing complete responses. Prior treatment of a responder PDX with 5-FU increased expression of thymidylate synthase and decreased efficacy of capecitabine. Transcriptomic and IHC analyses of 32 TNBC PDX, including both residual tumors and treatment-naïve derived tumors, identified RB1 and TYMP proteins as predictive biomarkers for capecitabine response. Finally, RB1 knockdown in a cell line established from a capecitabine-responder PDX decreased sensitivity to 5-FU treatment. Conclusions: We identified capecitabine as efficient chemotherapy in TNBC PDX models established from residual disease and resistant to anthracyclines, taxanes, and platins. RB1 positivity and high expression of TYMP were significantly associated with capecitabine response. Clin Cancer Res; 24(11); 2605-15. ©2018 AACR ., (©2018 American Association for Cancer Research.)

This corrects the article DOI: 10.1038/bjc.2017.85.

Background: The objective of this study was to describe characteristics at diagnosis and outcomes of adults with soft tissue sarcoma., Methods: The authors conducted a retrospective multicenter study of 12,262 patients who were treated between January 1980 and 31 December 2013 in French Sarcoma Group centers and enrolled in the "Conticabase." Diagnoses were systematically reviewed by expert pathologists, and entities were classified according to the 2013 World Health Organization classification. Diagnostic characteristics, treatments, and outcomes are described for the entire cohort, for the subgroup of patients with translocation-related sarcomas, and for 9 different histologic subtypes., Results: The results stressed the magnitude of heterogeneity among adult sarcomas. For example, compared with other sarcomas, translocation-related sarcomas (2143 tumors; 20.8%) were associated with a younger age at presentation (40.6 vs 60.0 years; P < .0001), a low rate of predisposing conditions (0.01% vs 22.3%; P < .0001), a higher rate of lymph node involvement (4.7% vs 1.3%; P < .0001), and a higher rate of synchronous metastasis (11.9% vs 6.7%; P < .001); and complete (R0) resection (41.6% vs 31.9%; P < .0001), receipt of (neo)adjuvant radiation therapy (62.6% vs 42.2%; P < .0001), and receipt of (neo)adjuvant chemotherapy (36.6% vs 22.3%; P < .0001) were significantly more frequent. Overall, translocation-related sarcomas were associated with a lower rate of local relapse (18.1% vs 26.0%; P < .0001) but a higher rate of metastatic relapse (42.0% vs 30.7%; P < .0001)., Conclusions: Collaborative efforts are urgently needed to better assess the natural history and management options for every histologic subtype of sarcoma. Cancer 2018;124:1179-87. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

In the original version of this Article, financial support and contributions in manuscript preparation were not fully acknowledged. The PDF and HTML versions of the Article have now been corrected to include the following:'M.P. and P.O. would like to thank Prof. Roderick Y.H. Lim for advice during manuscript preparation and for providing the laboratory and microscopy infrastructure.… [We also thank] the NanoteraProject, awarded to the PATLiSciII Consortium (M.P and P.O)…'.

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.

The diagnosis of malignant peripheral nerve sheath tumor remains challenging, especially in the sporadic setting. Malignant peripheral nerve sheath tumor is a rare malignancy, and owing to the lack of specific histological criteria, immunohistochemical and molecular diagnostic markers, several differential diagnoses must be considered, in particular melanoma. Recently, inactivation of the polycomb repressive complex 2 (PRC2), induced by inactivating mutations in two of its critical constituents SUZ12 and EED, was reported in a large subset of malignant peripheral nerve sheath tumors. Homozygous PRC2 inactivation induces complete loss of trimethylation at lysine 27 of histone 3 (H3K27me3). Recent studies suggest that complete loss of H3K27me3 is highly specific for malignant peripheral nerve sheath tumor and may be a useful immunohistochemical diagnostic marker. Therefore, to determine the specificity of the complete loss of H3K27me3 expression in the context of the differential diagnosis of malignant peripheral nerve sheath tumor from melanoma (its major potential mimic), we performed H3K27me3 immunohistochemistry in a pathologically and genetically well-characterized cohort of primary (neurofibromatosis type 1 (NF1), radiation-associated and sporadic context) malignant peripheral nerve sheath tumors (n=122) and in a cohort or primary (desmoplastic) and metastatic melanomas (n=265). In total, 88 (72%) malignant peripheral nerve sheath tumors, including 46 (71%) NF1-associated, 4 (100%) radiation-associated, and 38 (72%) sporadic tumors, showed complete loss of H3K27me3. We observed increased loss of H3K27me3 with increasing histological grade. Interestingly, we found complete loss of H3K27me3 in 37% (n=98) of all melanomas, including 25% (n=9) of primary desmoplastic melanomas. Moreover, partial loss ('mosaic' pattern) was observed in 23 (19%) of all malignant peripheral nerve sheath tumors and in 136 (51%) of all melanomas. Complete loss of H3K27me3 detected by immunohistochemistry is not specific for malignant peripheral nerve sheath tumor and cannot be used safely when distinguishing malignant peripheral nerve sheath tumor from melanoma.

At the stage of carcinoma in situ, the basement membrane (BM) segregates tumor cells from the stroma. This barrier must be breached to allow dissemination of the tumor cells to adjacent tissues. Cancer cells can perforate the BM using proteolysis; however, whether stromal cells play a role in this process remains unknown. Here we show that an abundant stromal cell population, cancer-associated fibroblasts (CAFs), promote cancer cell invasion through the BM. CAFs facilitate the breaching of the BM in a matrix metalloproteinase-independent manner. Instead, CAFs pull, stretch, and soften the BM leading to the formation of gaps through which cancer cells can migrate. By exerting contractile forces, CAFs alter the organization and the physical properties of the BM, making it permissive for cancer cell invasion. Blocking the ability of stromal cells to exert mechanical forces on the BM could therefore represent a new therapeutic strategy against aggressive tumors.Stromal cells play various roles in tumor establishment and metastasis. Here the authors, using an ex-vivo model, show that cancer-associated fibroblasts facilitate colon cancer cells invasion in a matrix metalloproteinase-independent manner, likely by pulling and stretching the basement membrane to form gaps.

Introduction: HER2-positive breast cancer (BC) is a heterogeneous group of aggressive breast cancers, the prognosis of which has greatly improved since the introduction of treatments targeting HER2. However, these tumors may display intrinsic or acquired resistance to treatment, and classifiers of HER2-positive tumors are required to improve the prediction of prognosis and to develop novel therapeutic interventions., Methods: We analyzed 2893 primary human breast cancer samples from 21 publicly available datasets and developed a six-metagene signature on a training set of 448 HER2-positive BC. We then used external public datasets to assess the ability of these metagenes to predict the response to chemotherapy (Ignatiadis dataset), and prognosis (METABRIC dataset)., Results: We identified a six-metagene signature (138 genes) containing metagenes enriched in different gene ontologies. The gene clusters were named as follows: Immunity, Tumor suppressors/proliferation, Interferon, Signal transduction, Hormone/survival and Matrix clusters. In all datasets, the Immunity metagene was less strongly expressed in ER-positive than in ER-negative tumors, and was inversely correlated with the Hormonal/survival metagene. Within the signature, multivariate analyses showed that strong expression of the "Immunity" metagene was associated with higher pCR rates after NAC (OR = 3.71[1.28-11.91], p = 0.019) than weak expression, and with a better prognosis in HER2-positive/ER-negative breast cancers (HR = 0.58 [0.36-0.94], p = 0.026). Immunity metagene expression was associated with the presence of tumor-infiltrating lymphocytes (TILs)., Conclusion: The identification of a predictive and prognostic immune module in HER2-positive BC confirms the need for clinical testing for immune checkpoint modulators and vaccines for this specific subtype. The inverse correlation between Immunity and hormone pathways opens research perspectives and deserves further investigation., Competing Interests: The authors have declared that no competing interests exist.