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Mixed neuroendocrine/non-neuroendocrine neoplasms (MiNEN) are rare mixed epithelial neoplasms in which a neuroendocrine component is combined with a non-neuroendocrine component. Here, we provide the clinical, pathologic, and molecular report of a 73-year-old-man presenting with an intestinal MiNEN. The lesion was composed of a well-differentiated G3 neuroendocrine tumor and a colloid adenocarcinoma. The molecular characterization was performed using a multigene next-generation sequencing panel. The neoplasm displayed microsatellite instability due to MLH1 promoter methylation. The extended molecular profile documented the same mutations affecting ARID1A, ASXL1, BLM, and RNF43 genes in both components, indicating a monoclonal origin of the tumor. Regarding component-specific gene mutations, BRCA2 was specifically altered in the neuroendocrine area. It may represent a new actionable target for precision oncology in MiNEN, but the lack of its alteration in the colloid component calls for further considerations on intratumor heterogeneity. The most important finding with potential immediate implications regards the presence of microsatellite instability: it indicates that this molecular alteration should become part of the diagnostic algorithm for these rare neoplasms.

Highlights • There is no uniformly accepted indication to perform the correct management of hibernoma. • Only the complete surgical resection of the known axillary lesion, could be diagnostic and, in most case, curative. • A full multidisciplinary team is essential to focus on all aspects for the management of hibernoma and MEN-1 syndrome., Introduction The present study reports the case of an axillary hibernoma in a patient with lobular homolateral breast cancer and multiple endocrine neoplasia type1 (MEN-1). Hibernoma is a rare benign adipose tissue tumor, and usually manifests as a slowly growing and painless rubbery mass. These tumors can arise in various sites, but mammary hibernomas remain extraordinarily uncommon. Although hibernomas are metabolically active and therefore “glucose-avid” on fluorodeoxyglucose CT-positron emission tomography (FDG CT-PET), imaging alone is inadequate in providing a reliable diagnosis and definitive differential diagnosis from other malignancy. Only complete surgical excision is diagnostic and, in most cases, curative. Presentation of case A 42-years-old woman was followed for MEN-1 syndrome associating with hyperparathyroidism, insulinoma, non-secretory adrenal adenoma and thyroid lump. A FDG CT-PET found high glucid hypermetabolism in thickened elongated area on the front axillary line. Hibernoma was diagnosed after realization of prophylactic left mastectomy, homolateral sentinel lymph node biopsy and exeresis of the known axillary lesion. Discussion Clinical importance lies in distinguishing hibernoma from other benign and malignant breast neoplasms, as well as inflammatory conditions that come into the histologic or radiologic differential. Hibernoma is not currently classified as a non-endocrine tumor related to MEN1, but this association could be not fortuitous for the linkage between modification of Menin protein function and pathogenesis of hibernomas. Conclusion Our case deserves extraordinary attention because, not only it’s a case of MEN1 syndrome associated with hibernoma, but in the context of this lesion there are multiple micro-foci of infiltrating lobular carcinoma.

Pediatric solid neoplasms are rare and very different from those observed in adults. The majority of them are referred to as embryonal because they arise as a result of alterations in the processes of organogenesis or normal growth and are characterized by proliferation of primitive cells, reproducing the corresponding tissue at various stages of embryonic development. This review will focus on embryonal gastrointestinal pediatric neoplasms in adult patients, including pancreatoblastoma, hepatoblastoma, and embryonal sarcoma of the liver. Although they are classically considered pediatric neoplasms, they may (rarely) occur in adult patients. Hepatoblastoma represents the most frequent liver neoplasm in the pediatric population, followed by hepatocellular carcinoma and embryonal sarcoma of the liver; while pancreatoblastoma is the most common malignant pancreatic tumor in childhood. Both in children and adults, the mainstay of treatment is complete surgical resection, either up front or following neoadjuvant chemotherapy. Unresectable and/or metastatic neoplasms may be amenable to complete delayed surgery after neoadjuvant chemotherapy. However, these neoplasms display a more aggressive behavior and overall poorer prognosis in adults than in children, probably because they are diagnosed in later stages of diseases.

Background: Although 1% is recommended by guidelines as cut-off for estrogen receptor (ER) positivity, the 10% cut-off is often used in clinical practice based on studies showing that breast cancers with ER ≥1% & DFS and OS Hazard Ratios for ER≥1%& Citation Format: Gaia Griguolo, Maria Vittoria Dieci, Michele Bottosso, Vassilena Tsvetkova, Carlo Alberto Giorgi, Silvia Angelini, Giulia Tasca, Enrico Cumerlato, Marcello Lo Mele, PierFranco Conte, Valentina Guarneri. Impact of estrogen receptor levels on outcome in triple negative breast cancer patients treated with (neo)adjuvant chemotherapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-05.

Although 1% is the recommended cut-off to define estrogen receptor (ER) positivity, a 10% cut-off is often used in clinical practice for therapeutic purposes. We here evaluate clinical outcomes according to ER levels in a monoinstitutional cohort of non-metastatic triple-negative breast cancer (BC) patients undergoing (neo)adjuvant chemotherapy. Clinicopathological data of 406 patients with ER

Trastuzumab emtansine (T-DM1) is approved for the treatment of human epidermal growth factor receptor 2 (HER2)-positive (HER2+) metastatic breast cancer (BC) and for residual disease after neoadjuvant therapy, however, not all patients benefit. Here, we hypothesized that the heterogeneity in the response seen in patients is partly explained by the levels of human epidermal growth factor receptor 2 gene (ERBB2) mRNA. We analyzed ERBB2 expression using a clinically applicable assay in formalin-fixed paraffin-embedded (FFPE) tumors (primary or metastatic) from a retrospective series of 77 patients with advanced HER2+ BC treated with T-DM1. The association of ERBB2 levels and response was further validated in 161 baseline tumors from the West German Study (WGS) Group ADAPT phase II trial exploring neoadjuvant T-DM1 and 9 in vitro BC cell lines. Finally, ERBB2 expression was explored in 392 BCs from an in-house dataset, 368 primary BCs from The Cancer Genome Atlas (TCGA) dataset and 10,071 tumors representing 33 cancer types from the PanCancer TCGA dataset. High ERBB2 mRNA was found associated with better response and progression-free survival in the metastatic setting and higher rates of pathological complete response in the neoadjuvant setting. ERBB2 expression also correlated with in vitro response to T-DM1. Finally, our assay identified 0.20&ndash, 8.41% of tumors across 15 cancer types as ERBB2-high, including gastric and esophagus adenocarcinomas, urothelial carcinoma, cervical squamous carcinoma and pancreatic cancer. In particular, we identified high ERBB2 mRNA in a patient with HER2+ advanced gastric cancer who achieved a long-lasting partial response to T-DM1. Our study demonstrates that the heterogeneity in response to T-DM1 is partly explained by ERBB2 levels and provides a clinically applicable assay to be tested in future clinical trials of breast cancer and other cancer types.

Tumour infiltrating lymphocytes (TILs) are an established prognostic biomarker for triple-negative breast cancer (TNBC). We evaluated the role of programmed cell-death ligand-1 (PD-L1), CD8 and FOXP3 expression in refining a prognostic model for non-metastatic TNBC beyond classic factors and TILs.Primary tumour samples from 244 early patients with TNBC, all treated with surgery and chemotherapy, were collected. Stromal TILs were evaluated on haematoxylin-eosin slides according to guidelines. PD-L1, CD8 and FOXP3 were assessed by immunohistochemistry and evaluated by digital pathology.TILs, PD-L1, CD8 and FOXP3 were positively correlated with each other (P 0.001). TILs were confirmed as an independent prognostic factor. When PD-L1, CD8 and FOXP3 were added to multivariable models including classic factors (age, stage, histologic grade) and TILs, PD-L1 provided the largest amount of additional prognostic information: likelihood ratio χBeyond clinicopathological factors and TILs, other immune biomarkers may add prognostic information for early TNBC. The increased PD-L1 expression on residual disease after neoadjuvant chemotherapy strengthens the rationale of testing immune checkpoint inhibitors in the post-neoadjuvant setting.

Background: The integration of Residual Cancer Burden (RCB) and post-treatment Ki67 (Residual Proliferative Cancer Burden [RPCB] index) has been proposed as a stronger predictor of long-term outcome in unselected breast cancer (BC) patients undergoing neoadjuvant chemotherapy (NACT), as compared to RCB. However, no specific analysis in the subgroup of patients with hormone-receptor (HR)-positive/HER2-negative BC is available so far. We investigated the prognostic value of RPCB in an independent cohort of hormone-receptor (HR) positive/HER2 negative BC patients treated with NACT at our Institution. Methods: A cohort of 130 stage II-III, HR+/HER2 negative BC patients who underwent NACT between 2000 and 2014 was included. Archival surgical specimens were evaluated for RCB (Symmans et al. J Clin Oncol 2007). RPCB was calculated by combining RCB and Ki67 as previously described (Sheri et al, Ann Oncol 2015). Patients were categorized in 4 RCB categories (pathological complete response -pCR- and RCB tertiles) and 4 RPCB categories (pCR and RPCB tertiles). Disease-free Survival (DFS) and overall Survival (OS) estimates were determined by Kaplan-Meier analysis and compared using the log-rank test. The c-index was used to compare the performance of the prognostic models. Results: Patients characteristics were: ductal histology 70%, Grade 3 41%, Stage III 54%, PgR negative (≤10%) 35%, median Ki67 at diagnosis 25%. Neoadjuvant chemotherapy included both anthracycline and taxane in 92% of cases. The rate of pCR was 8%. The vast majority of patients received adjuvant endocrine therapy (96%), whereas 30% received further adjuvant chemotherapy. Median follow up was 8.5 years (95% CI 8.0-9.0). RCB was calculated for 105 patients and RPCB was calculated for 85 patients. RPCB was better than RCB in predicting both DFS and OS (5-year DFS and 8-year OS according to RPCB and RCB are reported in the Table). The c-index for DFS prediction was numerically higher for RPCB vs RCB (0.4042316 vs 0.3396437, p=0.08). Similar results were observed for OS prediction: c-index 0.3099490 (RPCB) vs 0.2372449 (RCB), p=0.08. Conclusions: This is the first study evaluating RPCB specifically in HR+/HER2- BC patients treated with NACT. In this independent cohort, after a median follow up of 8.5 years, RPCB was a strong predictor of DFS and OS. The better performance of RPCB vs RCB was in part due to the ability of RPCB to discriminate a subgroup of patients with a particularly worse prognosis after NACT, who may be candidate for clinical trials evaluating novel adjuvant treatments. Five-year DFS and eight-year OS according to RPCB and RCB5-year DFSp-value8-year OSp-valueRPCBpCR100%0.041100% Citation Format: Federica Miglietta, Vassilena Tsvetkova, Maria Vittoria Dieci, Gaia Griguolo, Grazia Vernaci, Alice Menichetti, Cristina Falci, Giovanni Faggioni, Tommaso Giarratano, Simona Frezzini, Eleonora Mioranza, Marcello Lo Mele, PierFranco Conte, Valentina Guarneri. Validation of residual proliferative cancer burden (RPCB) as a predictor of long-term outcome following neoadjuvant chemotherapy in hormone-receptor positive/HER2 negative breast cancer patients [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-06-12.

Background: Tumor infiltrating lymphocytes (TILs) are strong prognostic biomarkers for early TNBC. We evaluated the role of CD8, FOXP3 and PD-L1 expression in refining prognostic models for non-metastatic TNBC in a large cohort of patients treated with standard therapy. Methods: Consecutive patients diagnosed with stage I-III TNBC (ER/PgR 20%) were all significantly associated with improved DFS (HR 0.36 95%CI 0.18-0.72, p=0.004 for CD8; HR 0.48 95%CI 0.28-0.80, p=0.005 for FOXP3; HR 0.52 95%CI 0.28-0.97, p=0.039 for PD-L1). FOXP3 and PD-L1 provided significant additional prognostic information beyond a model containing TILs and stage: likelihood ratio χ2 5.12, p=0.024 for FOXP3; likelihood ratio χ2 5.52, p=0.019 for PD-L1. CD8 did not add relevant prognostic information beyond TILs and stage (likelihood ratio χ2 2.76, p=0.097). Including both FOXP3 and PD-L1 did not add further prognostic information to models already containing TILs, stage and either FOXP3 or PD-L1. Conclusions: FOXP3 and PD-L1 expression evaluated with a software-assisted method were prognostic for stage I-III TNBC pts treated with standard therapy and may contribute to refine the prognostic stratification beyond stage and TILs. This study was supported by a grant from Merck KGaA. Citation Format: Maria Vittoria Dieci, Vassilena Tsvetkova, Gaia Griguolo, Federica Miglietta, Deborah Bacchin, Giulia Tasca, Carlo Alberto Giorgi, Enrico Cumerlato, Enrico Orvieto, Valentina Guarneri, Pierfranco Conte. Integrating CD8, FOXP3 and PD-L1 expression in prognostic models for triple negative breast cancer (TNBC): An analysis of 265 patients treated with standard therapy for stage I-III disease [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-06-14.

Background Tumor-infiltrating lymphocytes (TILs) evaluated in primary breast cancer (BC) convey prognostic information. Limited data in the metastatic setting are available. Methods Secondary lesions from 94 BC patients, 43 triple-negative (TN) and 51 HER2-positive, were evaluated for TILs and expression of CD8, FOXP3, and PD-L1 by immunohistochemistry. Results TILs levels on metastasis were generally low (median 5%) and did not differ between TN and HER2+ tumors. Younger patients showed significantly lower TILs (p = 0.002). In HER2+ patients, TILs were higher in lung metastases as compared to other sites (p = 0.038). TILs composition was different across metastatic sites: skin metastases presented higher FOXP3 (p = 0.002) and lower CD8/FOXP3 ratio (p = 0.032). Patients treated for metastatic BC prior to biopsy had lower CD8 (overall: p = 0.005, HER2+: p = 0.011, TN: p = 0.075). In TN patients, median overall survival (OS) was 11.8 and 62.9 months for patients with low and high TILs, respectively (HR 0.29, 95%CI 0.11–0.76, log-rank p = 0.008). CD8/FOXP3 ratio was also prognostic in TN patients (median OS 8.0, 13.2, and 54.0 months in 1st, 2nd and 3th tertile, log-rank p = 0.019). Both TILs and CD8/FOXP3 ratio were independent factors at multivariate analysis. Counterintuitively, in HER2+ BC, low TILs tumors showed better prognosis (median OS 53.7 vs 39.9 months in TILs low and TILs high, not statistically significant). Conclusions Our findings indicate the relevance of TILs as prognostic biomarker for TNBC even in the advanced setting and provide novel hypothesis-generating data on potential sources of immune heterogeneity of metastatic BC. Electronic supplementary material The online version of this article (10.1186/s13058-018-1003-1) contains supplementary material, which is available to authorized users.

Breast cancer (BC) is a heterogeneous disease including multiple histological subtypes with different biological behavior and clinical outcome for the patient. Due to its heterogeneity, BC is classified into different groups, providing possibilities for target therapies and improving the outcome – histological, TNM classification, molecular classification. The molecular classification, proposed at the beginning by Perou et al in 2000, divides BC into 5 subtypes - Luminal A, Luminal B, HER 2 enriched, claudin-low and basal like. More attention should be paid to the further classification of basal like BC. This is also a heterogeneous disease including triple negative breast cancers (TNBC). They show no expression of ER, PrR or HER2 and are considered difficult to treat. Despite the bad prognosis, some of these patients demonstrate great benefit from the traditional neoadjuvant chemotherapy. Lehman et al. identified 6 molecular subtypes of TNBC, using gene expression profiling – basal like 1 (BL1), basal like 2 (BL2), mesenchymal (M), mesenchymal stem-like (MSL), immunomodulatory (IM) and luminal androgen receptor (LAR). However, after histopathological quantification and laser-capture microdissection they refined their classification and in 2016 the new molecular classification of TNBC excluding the IM and MSL types was published. The working group has concluded that the characteristics of the tumors in these two groups were due to tumor-infiltrating lymphocytes and tumor-associated stromal cells and not to the tumor cells. The refinement of the classification of TNBC provides a better distribution of the patients into the different groups and better response to the applied therapy.

Introduction Low-grade adenosquamous breast cancer (ASBC) is a rare histological subtype of metaplastic breast cancer. Even tough it is a triple negative cancer, it is characterised by a good prognosis, low probability of distant metastases and higher risk of local relapses. Clinical Case This is a clinical case of a 65-year-old woman with a retroareolar nodule on the left breast. After histological examination a diagnosis of low-grade adenosquamous breast cancer was established. Further examination of lymph nodes showed regional metastasis of ASBC. Discussion Due to its specific growth patterns the diagnosis could easily be mistaken, mostly on core biopsy samples. Vast differential diagnosis is required. The definitive diagnosis could be given on histological examination of surgical sample. Therefore, the recommended treatment is surgical removal of the lesion until more follow-up data is available in literature.