Yassir Alaa Muhammed Hassan Shubbar CORRELATION BETWEEN DIFFERENT CLINICOPATHOLOGICAL PARAMETERS AND MOLECULAR SUBTYPES OF FEMALE BREAST CARCINOMA IN SOUTH REGION OF IRAQ.

OBJECTIVE: The aim: To correlate variable clincopathological parameters with molecular subtypes of the breast carcinoma, which affect the prognosis and management of breast malignancy. PATIENTS AND METHODS: Materials and methods: In this study a total of 511 female patients with breast carcinoma were included, ranging from 32 to 85 years of age, with 35.8% premenopausal and 64.1% being post-menopausal. The sample slides were stained immunohistochemically for estrogen receptors (ER), progesterone receptors (PR), ki67 and HER2, the tumors were graded histologically using the Nottingham criteria system. RESULTS: Results: Most tumors (72.8%) ranged between 2 and 5 cm in size; the most common histological type of breast carcinoma (49.7%) was invasive ductal carcinoma of no special type, with grade 2 presented in 51.8% cases; most frequent stage at time of presentation was stage 3A, found in 39.9%; the most frequent molecular subtype was ER and/or PR+, Her2- with low proliferation rate ki67<14% subtype in 48.5%, and those group were more likely (statistically significant) to be older, have stage 3 breast cancer, present with tumor size between 2 and 5 cm and tend to be well differentiated histological grade (grade1), mostly with lymph node positive, and most likely have tumor type of invasive ductal carcinoma of no special type. CONCLUSION: Conclusions: the most common histological type of breast carcinoma in Iraq south was invasive ductal carcinoma of no special type and most cases showed (ER and/or PR+, HER 2-, low ki67) as the most common molecular subtype.

Structural N-glycoproteomics characterization of cell-surface N-glycosylation of MCF-7/ADR cancer stem cells.

Breast cancer is responsible for the highest mortality all over the world. Cancer stem cells (CSCs) along with epithelial mesenchymal transition (EMT) are identified as a driver of cancer which are responsible for cancer metastasis and drug resistance. Several signaling pathways are associated with drug resistance. Additionally, glycosyltransferases regulate different types of glycosylation which are involved in drug resistance. To the end, it is urgent to figure out the knowledge on cell-surface altered N-glycosylation and putative markers. Here, differential cell-surface intact N-glycopeptides in adriamycin (ADR)-resistant michigan breast cancer foundation-7 stem cells (MCF-7/ADR CSCs) relative to ADR-sensitive MCF-7 CSCs were analyzed with site- and structure-specific quantitative N-glycoproteomics. The intact N-glycopeptides and differentially expressed intact N-glycopeptides (DEGPs) were determined and quantified via intact N-glycopeptide search engine GPSeeker. Totally, 4777 intact N-glycopeptides were identified and N-glycan sequence structures among 2764 IDs were distinguished from their isomers by structure-diagnostic fragment ions. Among 1717 quantified intact N-glycopeptides, 104 DEGPs were determined (fold change ≥ 1.5 and p value < 0.05). Annotation of protein-protein interaction and biological processes among others of DEGPs were finally carried out; down-regulated intact N-glycopeptide with bisecting GlcNAc from p38-interacting protein and up-regulated intact N-glycopeptide with ß1,6-branching N-glycan from integrin beta-5 were found.

Multifocal/multicentric breast cancer: Does each focus matter?

BACKGROUND: Multifocal (MF) and multicentric (MC) breast cancer cases have been increasingly diagnosed owing to the extensive use of improved preoperative breast imaging. The current tumor-node-metastasis staging system uses the dimension of the largest tumor and recommends reporting the pathological features of the largest tumor in MF/MC breast cancers. AIM: This study aimed to explore whether the largest or aggregate dimensions of MF and MC breast cancers can better predict tumor behavior. We also attempted to study the histological and biological heterogeneities of separate foci in MF and MC breast cancers to determine whether it was necessary to examine each lesion. METHODS: We retrospectively analyzed 121 patients with MF/MC (103 with MF and 18 with MC) breast cancers and 484 patients with unifocal breast cancer who were treated at the First Affiliated Hospital of Nanjing Medical University. Two methods were used to record the T stage (using the dimensions of the largest lesion and aggregate dimensions of all lesions). The histological grade, immunohistochemical parameters, and molecular subtypes of the largest lesion and other lesions in MF/MC breast cancers were studied to assess intertumoral heterogeneity. RESULTS: The use of aggregate dimensions upstaged 63 patients with MF/MC breast cancers to a more advanced stage and removed the independent effect of cancer multiplicity on lymph node positivity compared with the use of the largest dimension. Mismatches were found in the pathological type (9.9%), histological grade (4.1%), and molecular subtype (8.3%) among different foci. CONCLUSION: The tendency of MF/MC breast tumors to metastasize may be related to tumor load, which can be better predicted by the aggregate dimensions of all foci. The use of the current staging systems may require further evaluation and modification. Intertumoral heterogeneity indicates the necessity for pathological and immunohistochemical assessments of each lesion in patients with MF/MC breast cancers.

Label-Free Plasmon-Enhanced Spectroscopic HER2 Detection for Dynamic Therapeutic Surveillance of Breast Cancer.

The expression of human epidermal growth factor receptor-2 (HER2) has important implications for pathogenesis, progression, and therapeutic efficacy of breast cancer. The detection of its variation during the treatment is crucial for therapeutic decision-making but remains a grand challenge, especially at the cellular level. Here, we develop a machine learning-driven surface-enhanced Raman spectroscopy (SERS)-integrated strategy for label-free detection of cellular HER2. Specifically, our method allows the extraction of cell-rich spectral signatures utilized for identification and classification of cancer cells with distinct HER2 expression with a high accuracy of 99.6%. By combining label-free SERS detection and machine learning-driven chemometric analysis, we are able to perform longitudinal monitoring of therapeutic efficacy at the cellular level during the treatment of HER2+ breast cancer, which aids in the subsequent decision-making and management. This work provides a promising technique capable of performing dynamic label-free spectroscopic detection for therapeutic surveillance of diseases.

Quantitative multiplexed analysis of MMP-11 and CD45 in metastatic breast cancer tissues by immunohistochemistry-assisted LA-ICP-MS.

Breast cancer is the leading cause of cancer death in woman and tremendous efforts are undertaken to limit its dissemination and to provide effective treatment. Various histopathological parameters are routinely assessed in breast cancer biopsies to provide valuable diagnostic and prognostic information. MMP-11 and CD45 are tumor-associated antigens and potentially valuable biomarkers for grading aggressiveness and metastatic probability. This paper presents methods for quantitative and multiplexed imaging of MMP-11 and CD45 in breast cancer tissues and investigates their potential for improved cancer characterization and patient stratification. An immunohistochemistry-assisted laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) method was successfully developed and optimized using lanthanide-tagged monoclonal antibodies as proxies to determine spatial distributions and concentrations of the two breast cancer biomarkers. The labeling degree of antibodies was determined via size exclusion-ICP-tandem mass spectrometry (SEC-ICP-MS/MS) employing online calibration via post-column isotope dilution analysis (IDA). The calibration of spatial distributions of labeled lanthanides in tissues was performed by ablating mold-prepared gelatin standards spiked with element standards. Knowledge of labeling degrees enabled the translation of lanthanide concentrations into biomarkers concentrations. The k-means clustering was used to select tissue areas for statistical analysis and mean concentrations were compared for sets of metastatic, non-metastatic and healthy samples. MMP-11 was expressed in stroma surrounding tumor areas, while CD45 was predominantly found inside tumor areas with high cell density. There was no significant correlation between CD45 and metastasis (P = 0.70); however, MMP-11 was significantly up-regulated (202%) in metastatic samples compared to non-metastatic (P = 0.0077) and healthy tissues (P = 0.0087).

[Updates in hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer in 2021]. / Actualités 2021 sur le cancer du sein localement avancé ou métastatique RH+/HER2−.

Overall, 2021 was marked by the confirmation of the major interest of cell cycle inhibitors for hormone receptor (HR) positive/human epidermal growth factor receptor 2 (HER2) negative advanced breast cancers with very high overall survival data exceeding five years for hormone-sensitive disease. Studies have also confirmed the efficacy and safety of this therapeutic class in the elderly population. New cell cycle inhibitors are under development (SHR6390). New combinations are also being evaluated, notably palbociclib with SAR439859 (a new selective estrogen receptor degrader: SERD). Targeting of the Phosphoinositide 3-kinases (PI3K) pathway by taselisib, in hormone-resistant disease with a Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA) mutation, modestly improves progression-free survival but with a non-negligible toxicity of the treatment.

Prognostic Value of Tumor Infiltrating Lymphocytes in Locally Advanced HER2 Enriched Breast Cancer.

PURPOSE: We aim to study the association between stromal tumor infiltrating lymphocytes (TILs) level and disease free survival (DFS) in a group of ER and PR negative, HER2+ locally advanced breast cancer patients who underwent curative intent surgery. METHODS: This is a retrospective cohort study including 66 locally advanced hormone receptor-negative; HER2+ breast cancer patients presented between 2013 and 2015 at NCI-Cairo, Egypt. Enrolled patients had at least clinically T3 and/or node positive disease either clinically or radiologically. Metastatic workup included CT and bone scans or PET-CT. Patients with hormone receptor positive, HER2 negative, inadequate paraffin block and who lost follow up before or immediately after curative surgery were excluded. Patients were followed from breast surgery till relapse date for a minimum of 36 months. TILs and CD8 antigen were assessed on paraffin-embedded blocks using immunohistochemistry. RESULTS: Patients with a median age of 52 years presented with clinical T3 stage (53%) and N1 stage (61%). Modified radical mastectomy was performed in 79%. Only 41% received neoadjuvant chemotherapy and 56% received trastuzumab. TILs were 50, 17 and 33% for absent, intermediate and extensive groups and CD8+ lymphocytes were present in 80% of cases. At the end of follow-up period, 23 patients (35%) were found to have disease recurrence either loco-regional (22%) or distant (78%). TILs were 14, 4 and 5% for absent, intermediate and extensive respectively; while CD8+ lymphocytes were absent in 6% and present (≥1%) in 17%. Higher DFS was recorded for patients with extensive TILs level only who received trastuzumab. CONCLUSION: High TILs is good prognosis in HER2 enriched breast cancer provided that patients received HER2 directed therapy. Moreover, CD8+ lymphocytes are highly representative and maybe used as an alternative for TILs. We recommend considering TILs and specifically CD8+ as one of the risk factors that predict prognosis of HER2+ breast cancer.

New Insights in the Interaction of FGF/FGFR and Steroid Receptor Signaling in Breast Cancer.

Luminal breast cancer (BrCa) has a favorable prognosis compared with other tumor subtypes. However, with time, tumors may evolve and lead to disease progression; thus, there is a great interest in unraveling the mechanisms that drive tumor metastasis and endocrine resistance. In this review, we focus on one of the many pathways that have been involved in tumor progression, the fibroblast growth factor/fibroblast growth factor receptor (FGFR) axis. We emphasize in data obtained from in vivo experimental models that we believe that in luminal BrCa, tumor growth relies in a crosstalk with the stromal tissue. We revisited the studies that illustrate the interaction between hormone receptors and FGFR. We also highlight the most frequent alterations found in BrCa cell lines and provide a short review on the trials that use FGFR inhibitors in combination with endocrine therapies. Analysis of these data suggests there are many players involved in this pathway that might be also targeted to decrease FGF signaling, in addition to specific FGFR inhibitors that may be exploited to increase their efficacy.

Apolipoprotein B mRNA-Editing Catalytic Polypeptide-Like-Induced Protein Changes in Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer Throughout Disease Progression.

PURPOSE: Apolipoprotein B mRNA-Editing Catalytic Polypeptide-like (APOBEC) enzymes are mutagenic factors contributing to tumor progression and therapy resistance. However, the effects of APOBEC-induced protein changes have not been systematically assessed. Here, we describe the effects of APOBEC on the coding sequence in primary and metastatic estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer (BC). METHODS: We determined the enrichment of amino acid (AA) changes resulting from APOBEC mutagenesis in 323 primary BC tumors and 424 metastatic breast cancer (mBC) lesions via comparison with a simulated mutational genomic landscape not under selection pressure. We subsequently explored genes with recurrent APOBEC-associated AA changes and investigated the clonality of individual APOBEC-associated mutations. Using public sequencing data from an independent primary BC and mBC cohort, we further confirm our findings by reporting genes having these enriched AA changes in an APOBEC context. RESULTS: Our analysis demonstrated that several APOBEC-derived AA changes are significantly enriched compared with a simulated AA change distribution drawn at random. Among the enriched AA changes, Glutamate(E)>Lysine(K) and Glutamate(E)>Glutamine(Q) were mostly found at hotspots in oncogenes, whereas termination codons (Glutamine[Q]>STOP[X] and Serine[S]>STOP[X]) occurred in tumor suppressor genes and, mostly, not at hotspot locations. These mutations are found in genes contributing to BC initiation, eg, introduction of termination codons in TP53, MAP3K1, and CDH1 (in lobular BC) and two oncogenic hotspots in PIK3CA (p.E542K and p.E545K). In endocrine-resistant BC, we observed APOBEC-induced termination codons at ER-modulating genes, KMT2C, ARID1A, NF1, and ZFHX3. Finally, in mBC, compared with single PIK3CA mutations, dual PIK3CA mutations occurred more frequently in an APOBEC context (Fisher's exact P < .001). CONCLUSION: Our results show that APOBEC mutagenesis recurrently targets various known drivers of BC initiation, progression, and endocrine resistance.

Prognostic Value of Intracellular Transcription of Factors HIF-1α and p53 and Their Relation to Estradiol and TNM Parameters of Breast Cancer Tissues in Women with Invasive Ductal Carcinoma in Thi-Qar Province, Iraq.

Breast cancer is the most common malignancy affecting women's health, with an increasing incidence worldwide. This study aimed to measure the intracellular concentration of the hypoxia-inducible factor 1 α (HIF-1α), tumor suppression protein p53, and estradiol (E2) in tumor tissues of adult females with breast cancer and their relation to tumor grade, tumor size, and lymph node metastases (LNM). The study was conducted on 65 adult female participants with breast mass admitted to the operating theater in Al-Hussein Teaching Hospital and Al-Habboby Teaching Hospital in Nasiriyah, Iraq, from January to November 2021. Fresh breast tumor tissues were collated and homogenized for intracellular biochemical analysis using the enzyme-linked immunosorbent assay method. In total, 44 (58%) out of 65 patients, in the age range of 18-42 years and the mean±SD age of 32.55±6.40 years, had fibroadenomas, and other 21 (42%) cases, in the age range of 32-80 years and the mean±SD age of 56±14.4 years had invasive ductal carcinoma (IDC) breast cancer. Intracellular levels of HIF-1α, p53, and E2 were elevated significantly (P<0.001) in IDC cases compared to the benign group. The most malignant tumors of IDC cases were in grade III and sizes T2 and T3. The tissue concentrations of HIF-1α, P53, and E2 were significantly elevated in patients with tumor stage T3 compared to T2 and T1. A significant elevation was found in the levels of HIF-1α, p53, and E2 in the positive LNM subgroup compared to the negative LNM group. Based on the obtained results, the prognostic value of the intracellular HIF-1α is considered to be a useful prognostic factor in Iraqi women with ICD and the combination of a HIF-1α protein with the nonfunctional p53 and E2 tends to indicate the proliferation, invasiveness, and metastases of the breast tumors.

Artificial Intelligence-Aided Multiple Tumor Detection Method Based on Immunohistochemistry-Enhanced Dark-Field Imaging.

The immunohistochemical method serves as one of the most practical tools in clinical cancer detection and thus has great application value to overcome the existing limits of the conventional method and further improve the detecting efficiency and sensitivity. This study employed 3,3'-diaminobenzidine (DAB), a conventional color indicator for immunohistochemistry, as a novel high-sensitive scattering reagent to provide a multidimensional image signal varying with the overexpression rate of tumor markers. Based on the scattering properties of DAB aggregates, an efficient and robust artificial intelligence-aided immunohistochemical method based on dark-field imaging has been established, with improvement in both the imaging quality and interpretation efficiency in comparison with the conventional manual-operated immunohistochemical method. Referencing the diagnosis from three independent pathologists, this method succeeded in detecting HER2 overexpressed breast tumors with a sensitivity of 95.2% and a specificity of 100.0%; meanwhile, it was found to be applicable for non-small-cell lung tumors and malignant lymphoma as well. As demonstrated, this study provided an effective and reliable means for making diagnostic suggestions, which exhibited great potential in multiple tumor pathological detection at low cost.

Upregulated expression of DDX5 predicts recurrence and poor prognosis in breast cancer.

DEAD-box helicase 5 (DDX5) has been shown to promote tumorigenesis and cancer progression. However, the relationship between DDX5 and recurrence in breast cancer (BC) patients remains unknown. The objective of the present study was to evaluate the correlation of DDX5 with recurrence-free survival (RFS) and breast cancer-specific survival (BCSS) in patients with BC. The expression of DDX5 was examined by immunohistochemical analysis. RFS was calculated by Kaplan-Meier survival analysis. Univariate and multivariable associations were assessed by Cox proportional hazards models. In the present study, a total of 868 BC patients were analysed, and we found that DDX5 protein was significantly overexpressed in BC tissues compared to adjacent normal tissues. Elevated DDX5 was associated with an aggressive phenotype in BC patients. Moreover, DDX5 protein was upregulated in recurrent patients compared with nonrecurrent patients, and DDX5 protein levels were positively associated with worse RFS and BCSS in BC patients. High DDX5 expressing BC patients with age more than 50 year, advanced clinical stage or histological grade had a significantly increased risk of recurrence and shorter survival. Our findings highlight the significance of DDX5 in the recurrence and clinical outcome of BC patients and suggest that DDX5 may be a potential predictive biomarker for patients with BC.

Comparison of the Modified Immunohistochemical Marker Score and 21-Gene Recurrence Score Assay in Patients with Estrogen Receptor-Positive Breast Cancer.

INTRODUCTION: Not only the 21-gene recurrence score (RS) assay but also online prognostic tools and immunohistochemical prognostic models predict chemotherapy benefits for women with early breast cancer (BC). Multigene assays, including Oncotype DX, are expensive and not covered by insurance in some countries Methods: In this study, we retrospectively analyzed a series of 155 patients with estrogen receptor-positive primary BC for whom an Oncotype DX assay was performed between January 2016 and August 2021. The patients' modified immunohistochemical marker (mIHC4) scores were calculated on the basis of their pathological reports. The correlations of the RS with the online tool PREDICT and mIHC4 scores were evaluated. RESULTS: Of the patients, 43.9% were premenopausal, 147 (94.8%) had T1 or T2 tumor, and 55.5% had no positive lymph nodes. Low (0-10), intermediate (11-25), and high RSs (26-100) were obtained in 16.1%, 61.9%, and 21.9% of the patients, respectively. The RS showed no correlation with the PREDICT score (r = 0.2720) but correlated with the mIHC4 score (r = 0.6356). In addition, a stronger correlation was observed in the patients with no node involvement and in the postmenopausal patients (r = 0.6609 and r = 0.7277, respectively). CONCLUSIONS: A relatively strong correlation was observed between the RS and the mIHC4 score. The mIHC4 score is a potentially easy and useful tool to guide adjuvant chemotherapy decision making, especially for postmenopausal patients with no node involvement if a genomic test could not be performed for some reason.

Predicting axillary response to neoadjuvant chemotherapy: the role of diffusion weighted imaging.

OBJECTIVE: The aim of this study is to investigate whether the primary tumour response to neoadjuvant chemotherapy (NAC), based on the increase in the ADC-values (apparent diffusion coefficient) within the breast lesion, could help to predict axillary complete response. METHODS: We retrospectively included 74 patients who were treated with NAC followed by surgery at Lucus Augusti Hospital between January 2015 and September 2020. Simple logistic regression was used to evaluate the factors associated with axillary pathological complete response, including the changes in breast tumour ADC-values due to the treatment. RESULTS: Axillary complete response was correlated with negative oestrogen receptor status, Her2 positivity and response of primary tumour. It was achieved in 31% of the patients. In addition, the increase in the tumour ADC-values with NAC was higher for responders. Among the tumours that demonstrated an increase in ADC-value >0.92 ×10-3 mm2/s, 42.8% (15/35) showed axillary complete response. Eight (20.5%) breast cancers with an increase in ADC below the cut-off value were found to have no metastatic nodes after treatment (p = 0.038). CONCLUSION: Our results suggest that the performance of models predicting axillary response to NAC can be improved by adding the tumour response determined also using diffusion-weighted imaging. ADVANCES IN KNOWLEDGE: For the fist time, we investigate the relation between tumour response to NAC, assessed using diffusion-weighted imaging, and axillary pathologic complete response.

Trastuzumab deruxtecan for HER2+ advanced breast cancer.

Trastuzumab deruxtecan (T-DXd, DS-8201), an anti-HER2 antibody-drug conjugate, has shown significant clinical benefits in HER2+ metastatic breast cancer patients. In the phase 2 DESTINY-Breast01 trial, T-DXd demonstrated an objective response of 60.9% and median progression-free survival of 16.4 months, laying the foundation for accelerated approval in HER2+ metastatic breast cancer patients who have received two or more prior anti-HER2-based regimens in the metastatic setting. Moreover, T-DXd exhibited promising antitumor efficacy against HER2-low-expressing metastatic breast cancer. Its distinctive side effect was pneumonitis, with a 13.6% incidence. It is approved in the US with boxed warnings for interstitial lung disease and embryo-fetal toxicity. This review focuses on preclinical, pharmacokinetic and pharmacodynamic data on T-DXd and clinical evidence of its antitumor activity (both as monotherapy and in combination) and tolerability in metastatic breast cancer.

Lay abstract Breast cancer can be grouped based on its HR and HER2 status. For patients with HER2+ breast cancer, treatments that fight HER2 portion are adopted. Trastuzumab deruxtecan (DS-8201) is a new drug that consists of two parts: a cytotoxic drug and anti-HER2 antibody. It can selectively target HER2-expressing tumor cells. In a recent clinical trial, trastuzumab deruxtecan demonstrated tumor shrinkage in six of ten patients. The time to increase in tumor size or death was 16 months. Its antitumor effect was also demonstrated in low-HER2-expressing breast cancer. Approximately 13% of patients experience lung inflammation following trastuzumab deruxtecan treatment. In these cases, the drug should be promptly halted and the doctor can start steroid therapy.

GC-MS Analysis, Molecular Docking and Pharmacokinetic Properties of Phytocompounds from Solanum torvum Unripe Fruits and Its Effect on Breast Cancer Target Protein.

This study was designed to identify phytocompounds from the aqueous extract of Solanum torvum unripe fruits using GC-MS analysis against breast cancer. For this, the identified phytocompounds were subjected to perform molecular docking studies to find the effects on breast cancer target protein. Pharmacokinetic properties were also tested for the identified phytocompounds to evaluate the ADMET properties. Molecular docking studies were done using docking software PyRx, and pharmacokinetic properties of phytocompounds were evaluated using SwissADME. From the results, ten best compounds were identified from GC-MS analysis against breast cancer target protein. Of which, three compounds showed very good binding affinity with breast cancer target protein. They are ergost-25-ene-3,6-dione,5,12-dihydroxy-,(5.alpha.,12.beta.) (- 7.3 kcal/mol), aspidospermidin-17-ol,1-acetyl-16-methoxy (- 6.7 kcal/mol) and 2-(3,4-dichlorophenyl)-4-[[2-[1-methyl-2-pyrrolidinyl]ethyl amino]-6-[trichloromethyl]-s-triazine (- 6.7 kcal/mol). Further, docking study was performed for the synthetic drug doxorubicin to compare the efficiency of phytocompounds. The binding affinity of ergost-25-ene-3,6-dione,5,12-dihydroxy-,(5.alpha.,12.beta.) is higher than the synthetic drug doxorubicin (- 7.2 kcal/mol), and the binding affinity of other compounds is also very near to the drug. Hence, the present study concludes that the phytocompounds from the aqueous extract of Solanum torvum unripe fruits have the potential ability to treat breast cancer.

Bridging Endocrine Therapy for HR+/HER2- Resectable Breast Cancer: Is it Safe?

BACKGROUND: The COVID-19 pandemic has required new treatment paradigms to limit exposures and optimize hospital resources, including the use of neoadjuvant endocrine therapy (NAET) as bridging therapy for HR+/HER2-invasive tumors and DCIS. While this approach has been used in locally advanced disease, it is unclear how it may affect outcomes in resectable HR+/HER2- tumors. METHODS: Women ≥18 years diagnosed with in situ (Tis) or non-metastatic HR+/HER2- breast cancer from March-May 2019 and 2020 were included. Fisher's exact test and two-sample t test were used to compare baseline characteristics and surgical outcomes between strata. Sub-analysis was performed between patients who received primary surgery vs a bridging NAET approach. RESULTS: Despite similar clinical characteristics, patients in 2019 were more likely to have a surgery-first approach (75% vs 42%, P-value = .0007), receive surgery sooner (22 vs 29 days, P-value < .001), and within 60 days from diagnosis date (100% vs 85%, P-value = .0301). Neoadjuvant endocrine therapy was a more prevalent approach in 2020 (48% vs 7%, P-value < .0001). Rates of clinical to pathologic up-staging remained consistent across primary surgery vs bridging NAET subgroups (P-value = .9253). DISCUSSION: Pandemic-driven treatment protocols provide a unique opportunity to assess the utility of bridging endocrine therapy for resectable HR+/HER2- tumors. Differences in clinical and pathologic staging were similar across groups and did not appear to be affected by receipt of NAET. Our limited cohort demonstrates this strategic therapeutic avenue can optimize health care utilization and may be a reasonable approach when delaying surgery is preferred.

« HER2-faible ¼, un nouveau concept dans la prise en charge des cancers du sein: HER2-low breast cancer: a new concept in breast cancer treatment strategy.

HER2, a human epidermal growth factor, being activated by amplification, is a negative prognostic factor in breast cancer. HER2 is the target of anti-HER2 antibodies (Trastuzumab, Pertuzumab…). For more than 10 years, breast cancers have been classified into HER2 positive and HER2 negative. However, the advent of new cytotoxic drugs combined with anti-HER2 antibodies, such as TDM1 or trastuzumab déruxtécan, have shown very promising therapeutic activity in patients with low HER2 expression breast cancer. These new therapeutic perspectives encourage a better identification of low HER2 tumours in order to identify patients who could benefit from them. Thus, the classification of breast tumours evolves to individualize HER2-negative tumours (score 0), HER2-positive tumours (score 3+ and 2+ amplified) and HER2-low tumours (scores 1+ and 2+ not-amplified). HER2-low tumours are common and represent more than half of all breast cancers. To identify these HER2-low tumours, pathology laboratories should not change their usual technique calibrated according to ASCO/CAP and GEFPICS recommendations. Until more clinical data about response to these new treatment strategies are available, GEFPICS does not require pathologists to identify this HER2-low category. Nevertheless, this designation will allow clinicians to identify patients whose tumours fall into this category in the very short term and offer them new treatment options.

Cancer du sein HER2-low : comment un concept biologique s'immisce-t-il dans la décision thérapeutique ?: HER2-low breast cancer: how does a biological concept interfere in therapeutic decision?

The emergence of a new tumor entity called HER2-low breast cancer leads us to reconsider therapeutic indications in patients whose tumors were usually considered as luminal or triple negative. The development of antibody-drug conjugates (ADCs) allows using HER2 as a vector of a cytoxic drug with significant clinical efficacy in breast cancer with low HER2 expression. Trastuzumab deruxtecan monotherapy is currently evaluated in phase III trials in HER2-low patients, but also in combination in earlier phase studies. Many ADCs are in development, with highly anticipated results. The toxicities of these various ADCs seem manageable and compatible with prolonged administration. Her2-low breast cancer subtype may benefit from dedicated therapeutic strategies in the next few years.

Aspects cliniques : Cancers HER2 et atteinte du système nerveux central, que faire en 2021 ?: Central nervous system metastases from HER2 positive breast cancers: what to do in 2021?

Metastatic breast cancer is the second most common cause of brain metastasis (BM), and this problem is particularly marked for the amplified HER2 subtype (HER2+), with a cumulative incidence reaching up to 49 % in the ER-/HER2+ subgroup. Literature review shows that therapeutic progress has been major since the marketing of systemic anti-HER2+ treatments, with life expectancies now relatively unaffected by brain development. The recommended treatments are, on the one hand, specific treatment for brain development and, on the other hand, appropriate systemic treatment. Regarding local treatments, we will always favor surgery when possible, especially for large metastases, and stereotaxic radiotherapy, possibly iterative. One should be wary of whole brain irradiation which has never been shown to improve overall survival, but which is clearly associated with more cognitive toxicities. All the systemic anti-HER2 treatments currently on the market have shown efficacy on BM from HER2+ breast cancer and must therefore be chosen above all on the basis of their potential activity on the systemic disease at the time of cerebral evolution. If BM evolution happen without concomitant systemic progression, and local treatment can control it, it is not recommended to change the current medical treatment. Finally, randomized clinical studies opened to patients with active brain disease are starting to be published. The first of them showed the benefit of the triple combination tucatinib-trastuzumab-capecitabine in this context.