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Simple Summary: Breast cancer is a heterogeneous disease with multiple biological, molecular, and histological subtypes. Several metabolomics studies have been performed on breast cancer cells highlighting their metabolic heterogeneity with a potential impact on the efficiency of personalized therapies. In our study, we performed an untargeted metabolomic analysis of breast cancer tumors and identified a metabolic signature for high-grade invasive tumors. AUCs for both the training set and validation set were above 0.88. This result indicates that the model can distinguish high-grade and low-grade tumors with a probability of almost 90%. We also identified several biomarkers of tumor aggressiveness, such as N1,N12-diacetylspermine and tryptophan catabolites, both of which are involved in the inhibition of the immune response. Our study thus provides new insights into the biological mechanisms underlying tumor aggressiveness. Furthermore, the identified biomarkers will enable the development of new strategies for better selection of patients in different immune therapy clinical trials, and thus, for better patient management. All these findings are discussed in relation to the latest publications in the field. 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. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is the most frequently occurring cancer worldwide. With the help of next-generation sequencing, the development of biomedical technologies and the use of bioinformatics, it is now possible to identify specific molecular alterations in tumor cells, such as homologous recombination deficiencies, enabling us to consider using DNA-damaging agents such as platinum salts or PARP inhibitors. In this review, we summarize current knowledge on the clinical utility of genomic tests evaluating homologous recombination repair deficiency for treatment decisions in early and metastatic breast cancer. 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. [ABSTRACT FROM AUTHOR]

Purpose: The vast majority of research studies that have described the links between DNA damage repair or homologous recombination deficiency (HRD) score, and tumor biology, have concerned either triple negative breast cancers or cancers with mutation of BRCA 1/2. We hypothesized that ER + /HER2- early breast tumors without BRCA 1/2 mutation could have high HRD score and aimed to describe their genomic, transcriptomic, and immune landscapes.Patients and Methods: In this study, we reported BRCA 1/2 mutational status, HRD score, and mutational signature 3 (S3) expression, in all early breast cancer (eBC) subtypes from the TCGA database, with a particular focus in ER + /HER2-. In this subtype, bioinformatics analyses of tumor transcriptomic, immune profile, and mutational landscape were performed, according to HRD status. Overall survival (OS), progression free-interval (PFI), and variables associated with outcome were also evaluated.Results: Among the 928 tumor samples analyzed, 46 harbored BRCA 1/2 mutations, and 606 were ER + /HER2- (of which 24 were BRCA 1/2 mutated). We found a subset of BRCA-proficient ER + /HER2- eBC, with high HRD score. These tumors displayed significantly different immune, mutational, and tumor molecular signatures landscapes, compared to BRCA-mutated and BRCA-proficient HRD-low tumors. Outcome did not significantly differ between these 3 groups, but biological factors associated with survival are not the same across the 3 entities.Conclusion: This study highlights possible novel biological differences among ER + /HER2- breast cancer related to HRD status. Our results could have important implications for translational research and/or the design of future clinical trials, but require prospective clinical evaluation. [ABSTRACT FROM AUTHOR]

Determining the status of steroid hormone receptors [oestrogen (ER) and progesterone receptors (PR)] is a crucial part of the breast cancer workup. Thereby, breast cancers can be classified into four subtypes. However, the existence of ER−/PR+ tumours, often reported to be ill‐classified due to technical errors, remains controversial. In order to address this controversy, we reviewed the hormone receptor status of 49 breast tumours previously classified as ER−/PR+ by immunohistochemistry, and compared clinical, pathological and molecular characteristics of confirmed ER−/PR+ tumours with those of ER+ and triple‐negative tumours. We unequivocally confirmed the ER−/PR+ status in 27 of 49 tumours (0.3% of all breast cancers diagnosed in our institution between 2000 and 2014). We found that ER−/PR+ were morphologically and histologically similar to triple‐negative tumours, but very distinct from ER+ tumours, with more aggressive phenotypes and more frequent basal marker expression than the latter. On the molecular level, RNA sequencing revealed different gene expression profiles between the three groups. Of particular interest, several genes controlled by the suppressor of zest 12 (SUZ12) were upregulated in ER−/PR+ tumours. Overall, our results confirm that ER−/PR+ breast cancers are an extremely rare but 'real' tumour subtype that requires careful diagnosis and has distinct features warranting different responsiveness to therapies and different clinical outcomes. Studies on larger cohorts are needed to further characterise these tumours. The likely involvement of SUZ12 in their biology is an interesting finding which may – in a long run – give rise to the development of new therapeutic alternatives. What's new? Expression levels of receptors for estrogen (ER) and progesterone (PR) on breast tumor cells are key determinants of breast cancer classification. In particular, ER/PR status potentially defines four breast cancer subtypes, the existence of one of which, ER‐/PR+ tumors, remains controversial. In this study, the authors compared clinical, pathological, and gene expression characteristics of ER‐/PR+ breast tumors to characteristics of triple‐negative and ER+ tumors. Notably, ER‐/PR+ tumors differed molecularly from triple‐negative and ER+ tumors, in addition to exhibiting more aggressive phenotypes than ER+ tumors. The data indicate that although rare, ER‐/PR+ tumors are an authentic subtype of invasive breast cancer. [ABSTRACT FROM AUTHOR]

Aims: Low‐grade adenosquamous carcinoma of the breast (LGASC) is a rare variant of metaplastic carcinoma characterised by a favourable outcome and histologically composed of glandular and squamous elements in a spindle cell background typically associated with a lymphocytic stromal reaction. Because of its rarity, the immunophenotypic and genetic profile of LGASC has not been sufficiently characterised. The aim of this study was to gain insights into the molecular and phenotypic characteristics of LGASC. Methods and results: We reviewed the clinical and morphological features and detailed the immunohistochemical characteristics of a retrospective series of 13 LGASCs. Targeted sequencing of 50 genes was performed in 10 of 13 cases. Identified mutations were further assessed by Sanger sequencing in a validation series of 11 additional cases. All tumours showed a triple‐negative immunophenotype, expressed ‘basal’ keratins, showed variable levels of epidermal growth factor receptor expression, and did not express androgen receptor. Sequencing analysis of the screening set of LGASCs revealed a high rate (seven of 10 cases) of PIK3CA mutations, whereas no TP53 mutations were found. All PIK3CA mutations were missense mutations located either in exon 20 (n = 6) or in exon 9 (n = 1). The global PIK3CA mutation rate, including the validation series, was 52% (11 of 21 cases). No disease recurrences were observed. [Correction added on 11 June 2018, after first online publication: The percentage of mutation rate was corrected to 52%] Conclusions: Our results indicate that LGASC of the breast is a low‐grade triple‐negative breast cancer that harbours a basal‐like phenotype with no androgen receptor expression, and shows a high rate of PIK3CA mutations but no TP53 mutations. [ABSTRACT FROM AUTHOR]

Context: The molecular subtype of breast tumours plays a major role in cancer prognosis and treatment options. Triple negative tumours (TN) carry the worst prognosis and affects most frequently women of low socioeconomic status (SES). Studies have shown that non-biologic factors, such as the socioeconomic status could have an influence on tumour biology. To this date no study has been done investigating this association in French women. The objective is to study the association between the SES and the molecular tumour subtype of breast cancer patients in the French county of Côte d’Or. This study benefits from the population data from the Côte d’Or breast cancer registry known for its strict quality control policy. Methods: Invasive breast cancer cases between 2003 and 2013 were extracted from the Breast cancer registry database in Côte d’Or. A multivariate analysis was conducted using a hierarchical polytomous regression for the multinomial outcomes for the cancer subtype with HR+/HER2 as reference category. Results: A total of 4553 cases were included in our study. There was no significant association found between SES and tumour subtype in French women at diagnosis. Women older than 75 years were less likely to have a TN and HR+/HER2+ breast cancer (OR = 0.66; CI95% = [0.46–0.94] and OR = 0.51; CI95% = [0.37–0.70] respectively). Women with TN tumour subtype had significantly less lymph node invasion when compared to HR+/HER2- subtype (OR = 0.71; CI95% = [0.54–0.92]). Conclusion: No significant association was found between socioeconomic status and molecular subtype. Further studies are needed to clarify the mechanisms associated with developing each tumour subtype. [ABSTRACT FROM AUTHOR]

Background: Polarity defects are a hallmark of most carcinomas. Cells from invasive micropapillary carcinomas (IMPCs) of the breast are characterized by a striking cell polarity inversion and represent an interesting model for the analysis of polarity abnormalities.Methods: In-depth investigation of polarity proteins in 24 IMPCs and a gene expression profiling, comparing IMPC (n = 73) with invasive carcinomas of no special type (ICNST) (n = 51) have been performed.Results: IMPCs showed a profound disorganization of the investigated polarity proteins and revealed major abnormalities in their subcellular localization. Gene expression profiling experiments highlighted a number of deregulated genes in the IMPCs that have a role in apico-basal polarity, adhesion and migration. LIN7A, a Crumbs-complex polarity gene, was one of the most differentially over-expressed genes in the IMPCs. Upon LIN7A over-expression, we observed hyperproliferation, invasion and a complete absence of lumen formation, revealing strong polarity defects.Conclusion: This study therefore shows that LIN7A has a crucial role in the polarity abnormalities associated with breast carcinogenesis. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the value of F-fluorodeoxyglucose positron emission tomography (F-FDG PET/CT) to predict a pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) in women with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Material and methods: Fifty-seven consecutive women with HER2-positive breast cancer, treated with trastuzumab plus taxane-based NAC, were prospectively included. Maximum Standardized Uptake Value of the primary tumor and axillary nodes were measured at baseline (PET.SUV) and after the first course of NAC (PET.SUV). Tumor metabolic volumes were assessed to determine Total Lesion Glycolysis (TLG). The tumor metabolic response (ΔSUV and ΔTLG) was calculated. Results: In univariate analysis, negative hormonal receptor status ( p = 0.04), high tumor grade ( p = 0.03), and low tumor PET.SUV ( p = 0.001) were predictive of pCR. Tumor ΔSUV correlated with pCR ( p = 0.03), provided that tumors with low metabolic activity at baseline were excluded. ΔTLG did not correlate with pCR. In multivariate analysis, tumor PET.SUV < 2.1 was the best independent predictive factor (Odds ratio =14.3; p = 0.004) with both negative and positive predictive values of 76 %. Although the metabolic features of the primary tumor did not depend on hormonal receptor status, both the baseline metabolism and early response of axillary nodes were higher if estrogen receptors were not expressed ( p = 0.01 and p = 0.03, respectively). Conclusion: In HER2-positive breast cancer, very low tumor residual metabolism after the first cycle of NAC (SUV < 2.1) was the main predictor of pCR. These results should be further explored in multicenter studies and incorporated into the design of clinical trials. [ABSTRACT FROM AUTHOR]

Aims HER2 instant-quality fluorescence in-situ hybridization ( IQFISH) is a new fluorescence in-situ hybridization ( FISH) assay developed with a non-toxic buffer that reduces the hybridization time to 1-2 h, enabling a turnaround time of 3 h 30 min from dewax to counting. The aim of this study was to compare assessment of HER2 status using IQFISH and assessment using standard FISH. Methods and results We selected 160 breast cancer samples according to their HER2 status as determined by immunohistochemistry ( IHC) in a retrospective multicentre cohort (40 cases in each scoring category, i.e. 0/1+/2+/3+). Each participating site ( n = 5) constructed its tissue microarray ( TMA) of 32 archival cases and sent it to the central site (site 1). HER2 IHC, HER2 FISH and HER2 IQFISH were performed blindly at site 1. IQFISH provided excellent quality signals without any background staining, thus allowing excellent reading conditions even on TMA. Statistical analysis showed almost perfect agreement between IQFISH and FISH (99.3%, κ = 0.98). The only discordant case was an equivocal one with an HER2/ CEP17 ratio near the ASCO/ CAP cut-off. Conclusions The highly concordant data support IQFISH as a useful alternative to FISH, allowing reliable assessment of HER2 status. Use of this method could lead to reporting of HER status to the oncologist within a day. [ABSTRACT FROM AUTHOR]

Abstract: Purpose of the research: HER2-positive and triple-negative breast cancer (TNBC) still have a poor prognosis. Pathological complete response (pCR) is usually considered a surrogate marker for outcome. The aim of this study was to reconsider these parameters on a large population after a long follow-up. 348 patients with unilateral breast cancer who received neoadjuvant treatment at our institution over 30 years were included. Results: Patients were classified according to hormonal receptors (HR) and HER2. Median follow-up was 7 years. pCR was significantly lower in HR+/HER2− tumors (P < 0.0001). The 7-year OS rates were 76.1% (HR+/HER2−), 60.1% (TNBC), 72.4% (HR+/HER2+), and 49.9% (HR−/HER2+). Disease-free survival (DFS) and OS differed significantly according to pCR. Among HER2+ patients, pCR rate, DFS and OS were greater with trastuzumab. Conclusions: TNBC and HR−/HER2+ tumors have the worst outcome. pCR remains a significant prognostic factor. Trastuzumab strongly improves pCR and survival in HER2+ tumors. [Copyright &y& Elsevier]

Du fait du dépistage du cancer du sein généralisé en France depuis 2004, les cancers du sein in situ représentent 15 à 20 % des nouveaux cancers du sein. Ces recommandations élaborées par l’Institut national du cancer et la Société française de sénologie et pathologie mammaire définissent les meilleures stratégies de prise enchargede ces lésions. La mammographie et l’échographie bilatérale sont les examens d’imagerie de référence. Les indications de l’IRM mammaire sont limitées. Letraitement de référence des cancers canalaires in situ, quand il est réalisable, comporte une tumorectomie et une radiothérapie. Les marges saines doivent être au minimum de 2 mm. Le curage ganglionnaire n’a pas d’indication, et la place du ganglion sentinelle est précisée. Pour les cancers lobulaires in situ, les recommandations s’appuient sur la classification LIN (OMS 2003). La surveillance recommandée des cancers du sein in situ traités comporte au minimum un examen clinique et une mammographie annuels complétés le plus souvent d’une échographie. [ABSTRACT FROM AUTHOR]

To evaluate, in breast cancer patients treated by neoadjuvant chemotherapy, the predictive value of reduction in FDG uptake with regard to complete pathological response (pCR). Forty-seven women with non-metastatic, non-inflammatory, large or locally advanced breast cancer were included. Tumour uptake of FDG was evaluated before and after the first course of neoadjuvant chemotherapy. Four indices were used: maximal and average SUV without or with correction by body surface area and glycaemia (SUVmax, SUVavg, SUVmax-BSA-G and SUVavg-BSA-G, respectively). The predictive value of reduction in FDG uptake with respect to pCR was studied by logistic regression analysis. Relationships between baseline [18F]FDG uptake and prognostic parameters were assessed. The relative decrease in FDG uptake (ΔSUV) after the first course of neoadjuvant chemotherapy was significantly greater in the pCR group than in the non-pCR group ( p < 0.000066). The four FDG uptake indices were all strongly correlated with each other. A decrease in SUVmax-BSA-G of 85.4% ± 21.9% was found in pCR patients, versus 22.6% ± 36.6% in non-pCR patients. ΔSUVmax-BSA-G <−60% predicted the pCR with an accuracy of 87% and ΔSUVs were found to be only factors predictive of the pCR at multivariate analysis. An elevated baseline SUV was associated with high mitotic activity ( p < 0.0016), tumour grading ( p < 0.004), high nuclear pleomorphism score ( p < 0.03) and negative hormonal receptor status ( p < 0.005). In breast cancer patients, after only one course of neoadjuvant chemotherapy the reduction in FDG uptake is an early and powerful predictor of pCR. [ABSTRACT FROM AUTHOR]

Hypothesis: The cause of breast cancer is linked to many macroscopic events, including benign breast disease. In this study we asked whether molecular changes could discriminate fibroadenoma, which is one of the most common benign breast disease lesions associated or not with breast cancer. Design: Retrospective cohort study. Setting: Anticancer medical center. Subjects: Archival tissues in 32 cases of fibroadenoma, diagnosed in the same breast as a breast carcinoma, are compared with a control group of 26 cases of fibroadenomas unaffected by breast cancer. Main Outcome Measures: Histological features are characterized in all samples. The epithelial and stromal components are analyzed for a loss of heterozygosity and a microsatellite instability using a polymerase chain reaction–based method with 11 polymorphic microsatellite markers at 7 chromosomal regions frequently altered in breast cancer. The p53 gene mutations were also determined at exons 5 to 9. Results: The frequency of complex fibroadenomas was similar in both groups (P = .42). Only in the case group did we observe proliferative lesions confined in fibroadenomas, including atypical ductal hyperplasia (2 cases), lobular neoplasia (3 cases), or low-grade ductal carcinoma in situ (2 cases). There is no significant morphological difference between the 2 groups. Neither microsatellite alterations nor p53 gene mutations are present in the fibroadenoma components. Loss of heterozygosity is found only in the epithelial component of the 2 ductal carcinomas in situ confined in fibroadenomas. Conclusions: Genetic alterations, which are most frequently involved in malignant breast carcinomas, are not present in fibroadenomas, regardless of their association with breast cancer or their histological complexity. These findings suggest that fibroadenomas are not associated with breast carcinogenesis. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. • HER2-low status does not influence the prognostic performance of the CPS+EG score. • For ER+ eBC, the CPS+EG score properly stratifies both HER2-0 and HER2-low tumors. • For ER- eBC, the performance of the CPS+EG score is lower than that of the PS alone. [ABSTRACT FROM AUTHOR]

Abstract: The accurate determination of HER-2 in invasive breast cancer has become a critical issue, particularly in the context of the results of recent trastuzumab (Herceptin®) adjuvant trials. This multicentre study evaluated inter-observer reproducibility in interpretation of HER-2 immunostains performed in different laboratories according to their in-house technique. A total of 74 HER-2 immunostains were evaluated by 16 pathologists and by a central review committee. As determined by central review, the HER-2 score was 0 in 33 cases (44%), 1+ in 10 cases (13%), 2+ in 9 cases (12%) and 3+ in 23 cases (31%). The overall kappa value was good (kappa=0.75). Agreement was excellent for the 0/1+ group (kappa=0.85) and for the 3+ group (kappa=0.82). As expected, the score 2+ group showed poor agreement (kappa=0.38). A quality assurance process showed that ring studies and adherence to national guidelines greatly improve inter-observer reproducibility. [Copyright &y& Elsevier]