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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., (Copyright © 2021 Société FranÇaise du Cancer. Publié par Elsevier Masson SAS. Tous droits réservés.)

HER2 is an important prognostic and predictive biomarker in breast cancer. Its detection makes it possible to define which patients will benefit from a targeted treatment. While assessment of HER2 status by immunohistochemistry in positive vs negative categories is well implemented and reproducible, the introduction of a new "HER2-low" category could raise some concerns about its scoring and reproducibility. We herein described the current HER2 testing methods and the application of innovative machine learning techniques to improve these determinations, as well as the main challenges and opportunities related to the implementation of digital pathology in the up-and-coming AI era., (Copyright © 2021 Société FranÇaise du Cancer. Publié par Elsevier Masson SAS. Tous droits réservés.)

The tumor biopsy remains essential for breast cancer diagnosis and characterization. Indeed, the treatment is decided according to histological subtype, and according to the presence of targetable molecular alterations. Notably, the presence of hormone receptors, ERBB2 hyperexpression or the existence of PIK3CA or ESR1 mutations are among the alterations commonly investigated. But these biological characteristics are determined only partially by tumor biopsy, due to tumor heterogeneity or tumor plasticity that happens spontaneously or under treatment. Liquid biopsy, and in particular circulating tumor DNA and circulating tumor cells, is a non-invasive method to identify and characterize the presence of cancer in the blood. The aim of this review is to determine the value of liquid biopsy to enhance or replace the data provided by a tumor biopsy., (Copyright © 2021 Société FranÇaise du Cancer. Publié par Elsevier Masson SAS. Tous droits réservés.)

Objective: The aim of our study was to evaluate the impact of young age on breast cancer presentation and women's prognosis., Methods: We performed a descriptive retrospective study in the university teaching hospital of Tours from January 2007 to December 2013. All women managed for an invasive breast cancer were included. The population was divided in 2 groups according to age: ≤40 years and>40 years. We studied differences in histological, management and outcome characteristics., Results: Two thousand and eighty three women with an invasive breast cancer were included. A hundred and fifty five in the group of women with an age ≤40 years and 1928 in the group of women with an age>40 years. Histological characteristics of breast cancer in younger women were worse than in their older counterparts (with more aggressive features: grade 3, negative hormone receptors, positive Her 2 status, triple negative molecular sub-type). Overall survival was lower in young women than in women age>40 years (P=0.05),as was recurrence free survival (P<0.001), locoregional recurrence free survival (P=0.02) and distant metastasis free survival(P<0.001). Age≤40 years was an independent factor predictive of poor recurrence free survival., Conclusion: In our study we found an impact of age≤40 years on invasive breast cancer presentation and prognosis., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Objectives: The aim of this study was to evaluate the impact of pathological complete response (pCR) on overall survival (OS) and recurrence-free survival (RFS) according to molecular subtypes in women treated for an invasive breast cancer after neoadjuvant chemotherapy (NAC)., Methods: All women (n=225) managed with a neoadjuvant chemotherapy for an invasive breast cancer in our institution between January 2007 and December 2013 were included. The characteristics of patients with pCR (pCR-1), breast pCR and axillary pCR were compared to those without pCR (pCR-0) according to the molecular subtypes: luminal A (n=62), luminal B (n=77), Her-2 (n=31) and triple negative (n=55)., Results: NAC concerned 225 patients of whom 36 (16%) had pCR. Achievement of pCR led to significantly better overall survival in women with Her-2 tumors (35% versus 100%, P=0.035) and also to significantly better locoregional survival in women treated for triple negative tumors (P=0.026). Predictive factors of pCR were a high pathologic grade: OR=2.39, IC 95% (1.19-4.83), P=0.008; Her-2 molecular subtype (P=0.008); positive estrogenic hormonal receptors (P=0.006), a positive Her-2 receptor: OR=2.58, IC 95% (1.20-5.54), P=0.01., Conclusion: Achievement of pCR is an intermediate marker of survival in women managed with NAC for breast cancer., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Introduction: The implementation of an internal quality control is mandatory to guarantee the accuracy of HER2 status in invasive breast cancers., Objectives: To evaluate the impact of our quality control assurance on HER2 status results in invasive breast carcinomas from 2008 to 2014., Methods: HER2 status was determined by immunohistochemistry as the first-line indication, completed by fluorescence in situ hybridization (FISH) for scores 2+ by immunohistochemistry. Internal quality control of HER2 status relied on the standardization of pre-analytical phases, the use of external controls with a known number of HER2 gene copies determined by FISH and continued monitoring of concordance between immunohistochemistry and FISH., Results: The proportion of HER2-positive cases corresponding to scores 3+ by immunohistochemistry and 2+ amplified by FISH varied from 10.6% to 13.8% (median of 11.3%). The proportion of scores 2+ amplified by FISH varied from 13.3% to 32.7% during period of study. The rate of concordance between FISH and immunohistochemistry for score 0/1+ and 3+ cases were≥97%. Eight among 12 discordant cases were false positive resulting from errors in interpretation of immunohistochemistry (score 2+ instead of 3+)., Discussion: Calibration of immunohistochemistry on FISH for HER2 status contributes to limit variability of immunohistochemistry results due to technical issues or interpretation. The implementation of an external control of score 3+ on each slide enables accurate interpretation of score 2+ and 3+ by immunohistochemistry., (Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Triple-negative breast cancer (TN), as defined by the triple negativity in immunohistochemistry: the absence of estrogen receptor, progesterone receptor and the absence of overexpression or amplification of HER2, corresponds to 15 % of invasive breast cancers. This is a very heterogeneous group of tumors both at the genomic and transcriptomic level and at morphological, clinical and prognostic level. Although there are some good prognosis forms, the majority of TN tumors is characterized by a poor prognosis with a greater frequency of visceral metastases and a maximum risk of relapse in the first two years after diagnosis. Systemic adjuvant treatment with chemotherapy is almost always indicated. The surgical treatment and radiotherapy treatment should be comparable to the other subtypes and obey the same rules of oncologic surgery. TN tumors are not associated with a higher risk of locoregional relapse after conservative treatment and adjuvant radiotherapy. Optimization of systemic therapies is currently and for the last decade a challenge. A number of targeted therapies and efficiency biomarkers identification of these targeted therapies is essential to allow significant progress in optimizing systemic therapy for these tumors., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Objectives: In our study, we aimed to assess the pathologic complete response after neo-additive chemotherapy that contains a taxan associated to trastuzumab for patients treated from breast cancer at the institute Jean-Godinot between 2012 and 2014, and to evaluate factors associated to this pathologic complete response., Methods: Retrospective study with clinical, anatomopathologic and radiologic parameters analysis before and after new adjuvant chemotherapy. The statistical analysis was done on logiciel XL-STAT, the Mann-Whitney-Wilcoxon for quantitative variables and Fisher exact tests for qualitative variables, the Spearman rang test., Results: The rate of pathologic complete response is 38.8%. The prognostic factor associated to pathologic complete response is a Ki-67>44%., Conclusion: The pathologic complete response rate corresponds to international lower rate; because of the lack of several data, we found out only one prognostic factor, Ki-67>44%., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Introduction: Phenotype changes between primary tumor and the corresponding brain metastases are recent reported data. Breast cancer, with biological markers predicting prognosis and guiding therapeutic strategy remains an interesting model to observe and evaluate theses changes. The objective of our study was to compare molecular features (estrogen receptor [ER], progesterone receptor [PR], and human epidermal growth factor receptor type 2, [HER2]) between brain metastases and its primary tumor in patients presenting with pathologically confirmed breast cancer., Material and Methods: This retrospective study was based on the immunohistochemical analysis of the brain metastases paraffin embedded samples stored in our institutional tumor bank, after surgical resection. The level of expression of hormonal receptors and HER2 on brain metastases were centrally reviewed and compared to the expression status in primary breast cancer from medical records., Results: Forty-four samples of brain metastases were available for analysis. Hormonal receptor modification status was observed in 11/44 brain metastases (25%) for ER and 6/44 (13.6%) for PR. A modification of HER2 overexpression was observed in brain metastases in 6/44 (13.6%). Molecular subtype modification was shown in 17 cases (38.6%). A significant difference was demonstrated between time to develop brain metastases in cases without status modification (HER2, ER and PR) (med=49.5months [7.8-236.4]) and in cases in which brain metastases status differs from primary tumor (med=27.5months [0-197.3]), (P=0.0244, IC95=3.09-51.62, Mann and Whitney test)., Conclusion: the main interest of this study was to focus on the molecular feature changes between primary tumor and their brain metastases. Time to develop brain metastases was correlated to phenotypic changes in brain metastases., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Breast cancer involves various types of tumors. The objective of this review was to provide a summary of the main methods currently available in clinical practice to characterize breast cancers at a molecular level and to discuss their prognostic and predictive values. Hormonal receptors expression and the HER2 status are prognostic markers and can also predict the response to targeted therapies. Their analysis through immunohistochemistry is systematical. Ki67 is an effective prognostic marker, but its reliability is debated because of its low reproducibility between laboratories and between pathologists. Commercial genomic signatures are all considered valid prognostic tools and may guide physicians to make therapeutic choices. These signatures are costly and should therefore be restricted to situations in which the use of chemotherapy remains equivocal., (Copyright © 2016. Published by Elsevier SAS.)

Objectives: The 21-gene assay (Oncotype DX(®)) test is used to estimate the risk of recurrence and to predict the benefit of adjuvant chemotherapy at an early stage of endocrine responsive breast cancers, without HER2 overexpression or amplification. This test corresponds to a recurrence score (RS), classifying patients into three groups (low, intermediate or high risk). The objective of this two-center prospective study is to define the impact of Oncotype DX(®) in clinical practice., Methods: Between August 2013 and May 2015, an Oncotype DX(®) test was decided in multidisciplinary meeting, to certain patients with an indication of adjuvant chemotherapy for HR+ and HER2 negative cancers. The therapeutic changes after knowledge of RS were collected. An estimate of the economic impact was performed and a correlation between the RS and usual breast cancer prognostic markers was investigated., Results: Thirty-nine patients had a test, twenty-six (66.7%) of them have finally been no indication retaining chemotherapy. The economy obtained through the use of the test was estimated around 173,000euros. It has not been demonstrated correlation between the RS, the usual decisional and prognostic factors for breast cancer or with adjuvant! Online., Conclusions: The RS has an additional decision value compared to other common decision criteria. Use of Oncotype DX(®) reduced in our experience the indications of adjuvant chemotherapy. The medical and economic impact could be significant., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Objectives: Isolated axillary lymph node metastases is an unusual clinical presentation of breast carcinoma. We studied its different issues., Methods: This study is a follow-up study of 16patients, treated between 1996 and 2012, presenting with axillary metastases with an occult breast carcinoma, which could not be identified by physical examination nor by a conventional imaging or a breast MRI. Clinical characteristics, histological analysis, treatment, monitoring and five-year survival rate were studied., Results: The incidence of this kind of breast cancer was 0.20%. A breast MRI was performed in 75% of the patients. The histology of these tumors showed a rate of hormono-sensibility of 50% and an HER2 overexpression of 44%. Sixty-nine percent of the patients had no breast surgery or radiotherapy; global five-year survival rate for these women was 77.4%±11.5., Conclusion: The survival rates of this study should lead the practitioner to choose a less aggressive breast therapy. Moreover, the histological characteristics explain the high metastatic potential of these tumors, and relate them to the HER2+ subclass of gene expression patterns of breast carcinomas., (Copyright © 2015. Published by Elsevier SAS.)

Trastuzumab improves care of patients with HER2+ breast cancer and allows a major gain in terms of survival. T-DM1 and pertuzumab are two new treatments, which give very encouraging results in metastatic breast cancer. Their place in neo-adjuvant and adjuvant setting still remains to be defined. Bevacizumab have its place in metastatic breast cancer. In adjuvant setting, results are disappointing and in neo-adjuvant setting, we need more studies on subgroups, which can benefit more. Development of the PARP inhibitors was slowed down by recent negative results in metastatic breast cancer but studies continue with more targeted patient's. Finally, everolimus, inhibitor of mTOR, allows to by pass the hormono-resistance in metastatic phase. Its toxicity must be taken into account in particular in adjuvant setting., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

International guidelines on HER2 determination in breast cancer have just been updated by the American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP), on the basis of more than ten-year practice, results of clinical trials and concordance studies. The GEFPICS group, composed of expert pathologists in breast cancer, herein presents these recommendations, adapted to the French routine practice. These guidelines highlight the possible diagnosis difficulties with regards to HER2 status determination, such as intra-tumor heterogeneity, special histological subtypes and biomarker re-evaluation during metastatic relapse. Pre-analytical issues and updated scoring criteria (especially for equivocal cases) are detailed, in order to decrease the occurrence of false negative cases. In the era of personalized medicine, pathologists are more than ever involved in the quality of oncotheranostic biomarker evaluation., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Biomarker assessment of breast cancer tumor samples is part of the routine workflow of pathology laboratories. International guidelines have recently been updated, with special regards to the pre-analytical steps that are critical for the quality of immunohistochemical and in situ hybridization procedures, whatever the biomarker analyzed. Fixation and specimen handling protocols must be standardized, validated and carefully tracked. Cooperation and training of the personnel involved in the specimen workflow (e.g. radiologists, surgeons, nurses, technicians and pathologists) are of paramount importance. The GEFPICS' update of the recommendations herein details and comments the different steps of the pre-analytical process. Application of these guidelines and participation to quality insurance programs are mandatory to ensure the correct evaluation of oncotheranostic biomarkers., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Oncotype DX® has been validated as quantifying the likelihood of distant recurrence at 10 years and overall chemotherapy benefit in patients with estrogen-receptor-positive and HER-2-negative early breast cancer. In 2012, this genomic signature was routinely available for patients in Franche-Comté, France. Patients eligible for Oncotype DX(®) testing had a ER-positive, HER-2-négative early breast cancer with a nodal involvement limited to 0 or 1 positive-node without extracapsular spread; an adjuvant chemotherapy was indicated based on usual prognostic factors. The aim was to assess the economic impact of Oncotype DX(®) testing in a French region. A cost-minimisation analysis from the French Public Healthcare System perspective was performed. The availability of Oncotype DX(®) in Franche-Comté, France, and its use in clinical routine allowed a decrease of 73 % of adjuvant chemotherapy without increase of the cost of the patients' management and with a potential reduction of the cost for the French Public Healthcare System. This strategy was successful and may allow the reimbursement of this test in France for patients with early breast cancer.

Diagnostic strategy of breast cancer has changed enormously during the last thirty years. To classical obligatory morphological data on the macroscopical and microscopical levels are now added imunocytochemistry, which is capable of detecting therapeutic targets such hormonal receptors and HER2 (Human Epidermal growth factor Receptor2), and molecular biology, which yields the molecular profile of tumors and their multigenic properties. By leaning on up-to-date classifications (TNM system and UICC grades), the pathologist is able to evaluate not only diagnostic but also pronostic criteria, leading to personalized and predictive treatments., (© Société de Biologie, 2015.)

The natural history of ductal carcinoma in situ (DCIS) is not fully elucidated, but it is recognized that DCIS is the true precursor of invasive carcinoma. Studies could show that DCIS is as heterogeneous as invasive ductal carcinoma, yet, they were unable to predict which DCIS will progress to invasion. Several biomarkers were also demonstrated to have a certain prognostic value. However, except for estrogen receptors and HER2, biomarkers are not yet widely used in clinical practice since their predictive value has not proven to be better than the grade and the classical classifying systems of DCIS. Identifying biomarkers for risk of invasiveness in DCIS could be of great value to help high risk patients through the management of their disease and to avoid overtreatment in low risk patients., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Adenocarcinoma of the stomach, oesophagogastric junction and lower oesophagus remains a major global public health issue. Recently, the introduction of neoadjuvant chemotherapy in the treatment of these cancers has changed the pathological processing of the surgical resection specimens of these patients. The neoadjuvant treatment induces histological changes of the tumour called "tumour response". This tumour response needs to be evaluated, even if at present, there is no adaptation of the adjuvant chemotherapy to the histological tumour response. Several grading systems have been proposed for the different tumour sites (lower oesophagus, oesophagogastric junction and stomach). We will discuss first the macroscopic processing of the surgical resection specimens and then the different ways of assessing the histological response to chemotherapy. A standardized assessment of the histological tumour response is a necessary prerequisite for future studies looking at the adaptation of chemotherapy depending on the histological tumour response., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Vulvar Paget's disease is sub-classified into three types based upon its origin. It might be a primary vulvar disease (type 1) or associated with a non-cutaneous adenocarcinoma-rectal, colonic, cervical (type 2) or linked with an urothelial neoplasia (type 3). Type 1lesions must be considered as potentially invasive. Their immunophenotype is CK7+/CK20-. Classically, in case of depth of invasion below 1mm, nodal metastases are exceptional. We report a case of type 1 Paget's disease in a postmenopausal woman with superficial invasion and multiple inguinal nodal metastases., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Trastuzumab in combination with capecitabine or 5-fluorouracil and cisplatin has been approved by the European Medicines Agency (EMEA) for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive (immunohistochemistry [IHC] 3+ or IHC 2+/ fluorescence in situ hybridization [FISH]-positive or IHC 2+/ silver in situ hybridization [SISH]-positive) metastatic adenocarcinoma of the stomach or gastro-esophageal (GE) junction. HER2 testing in gastric cancer (GC) differs from testing in breast cancer (BC) due to major differences in the tumor biology; as the disease is progressing rapidely, we recommend to test every GC at diagnosis and to offer a rapid testing (less than five days) in the metastatic setting. IHC should be the initial testing methodology and FISH or SISH should be used to retest IHC 2+ samples. As GC more frequently shows incomplete membrane staining and focal staining for HER2, HER2 testing guidelines have been adapted from BC protocols. The scoring system is slightly different in respect to the characteristics of GC. For in situ hybridization, SISH should be used in order to identify heterogeneous staining with a higher accuracy than FISH. Enrollment in training and quality assurance programs is highly recommended. In case of negativity on biopsy, it is recommended to retest for HER2, when possible, on surgical specimens and/or metastasis. This will ensure accurate and consistent HER2 testing results, which will allow the appropriate selection of patients eligible for treatment with trastuzumab., (Copyright © 2011. Published by Elsevier Masson SAS.)

To refine available epidemiological data in early breast cancer, a national and retrospective study analyzed 1,934 cases listed between May and July 2007 by 88 French centers. More than one third of patients had less than 50 years old (26%) or more than 74 (15%). The anatomopathological tumors' characteristics were as following: ≤ 2 cm in 62% of cases, lymphatic invasion in 35% of cases, positive hormone receptors in 85% of cases, and SBR grade III in 18% of cases. The assessment of HER2 status, performed in 1,899 cases (98%), showed at least 12.1% of early stage HER2 positive tumors. HER2 overexpression was higher before 50 years old (15.9 versus 11.5% between 50 and 70 years, and 10.0% if ≥ 70 years old), for the largest tumors (pT2/3/4: 15.9%, ≤ 1 cm: 11.4%, between 1 and 2 cm: 9.0%) or for a high SBR grade (III: 24.7%, II: 12.1%, I: 3.5%). This study allowed to emphasize the prevalence of HER2 overexpression in elderly patients and for small size tumors.

HER2 protein overexpression by immunohistochemistry (IHC) and/or erB2 gene amplification by in situ hybridization (ISH) was detected in 4-28% of gastric or gastro-oesophageal junction (GOJ) cancers. Most studies have shown that HER2-overexpressing gastric cancers were worse prognosis. Trastuzumab is a humanized monoclonal antibody directed against HER2 with known efficacy in patients with HER2+ early or metastatic breast cancer. The international randomized trial ToGA study showed the superiority of the combination of trastuzumab with chemotherapy doublet fluoropyrimidine (5-FU or capecitabine) plus cisplatin (FP) every three weeks compared with chemotherapy alone in terms of overall survival : 13.8 versus 11.1 months (HR: 0.74, 95% CI: 0.60-0.91, P = 0.0046) in HER2+ advanced gastric cancers. The benefit was even greater in the subgroup with HER2 overexpression (16% of the screened population) as defined by IHC3+ or IHC2+ confirmed by positive ISH test. Trastuzumab plus FP chemotherapy has become the standard treatment for patients with HER2+ non-pretreated metastatic adenocarcinoma of the stomach or GOJ cancer. All these cancers should be tested for HER2 on paraffin block resection or biopsy specimens of the primary tumour or metastases. Endoscopic gastric biopsies should be multiple. The IHC should be the initial test. The standardized immunohistochemical scoring system differs from that recommended for breast cancer given the heterogeneity of HER2 expression and the frequency of incomplete membranous staining in gastric cancers. Equivocal IHC2+ tumours should be tested by ISH with two tools: fluorescence in situ hybridization (FISH) or bright field in situ hybridization (SISH). The perspectives are the assessment of trastuzumab in the perioperative and adjuvant setting, the development of novel anti-HER2 drugs and research into mechanisms of resistance and predictive molecular markers.

In Europe, patients who may benefit from an HER2 targeted drug are currently selected by immunohistochemistry (IHC). In situ hybridization (ISH) techniques should be used for complementary assessment of ambiguous 2+ IHC cases and for the calibration of the IHC technique. Eligibility to an HER2 target treatment is defined by an HER2 positive status being IHC test 3+ or 2+ amplified. Reliable detection of HER2 status is essential to the appropriate usage of HER2 targeted drugs because its specificity is limited to tumors overexpressing HER2. It is essential that the IHC evaluation of the HER2 status of a mammary carcinoma is optimized and reliable. This GEFPICS' guidelines look over the different steps of the IHC technique, the controls and, the rules for interpretation. Once acquired, this knowledge must be perpetuated by the observation of rules of good technical practice (internal and external controls, quality assurance programs)., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

In western countries, every woman out of eight will develop breast cancer. Over the last two decades, the incidence has considerably increased, but mortality has remained stable and begins to decrease in Europe and the United-States, probably because of new therapy, changes in the use of hormone replacement therapy in postmenopausal women and early diagnosis. Breast cancer is still the first cause of death by cancer in woman under 65. "Triple negative" a breast cancer, a subtype representing 10% of all breast cancers, is characterised by the absence of receptors to oestrogen, progesterone and no histochemical expression of HER-2 growth factor. This subtype carries a poor prognosis and a high incidence of early metastatic recurrence. Furthermore, no target therapy can be defined up to now in this subtype. Thus, identification of new target therapy and prediction of tumoral response to various treatments could help in the global understanding of patients affected by this particularly aggressive type of breast cancer.

CA15-3, a peptide derived from MUC-1, an hormonally-regulated protein, is the most widely used serum marker of breast cancer. CA15-3 level increases at the metastatic phase in 50-80% breast cancer patients. Although rise of CA15-3 precede symptoms of metastasis by a mean time of 2-9 months, current international guidelines do not recommend its routine use for screening for metastases because of moderate sensitivity and absence of clinical impact. We conducted a retrospective study among all patients with metastatic breast cancer seen by three senior breast oncologists during a 4-month period. We evaluated correlation of CA15-3 level at the time of metastatic relapse with ER, PgR and Her2 expressions, tumor type, size and nodal status at initial diagnosis, and sites of metastases. CA15-3 was increased in 168/272 patients (62%) at diagnosis of metastases. ER/PgR positivity was strongly correlated with elevated CA15-3 at this time (P < 0.0001). CA 15-3 was elevated in 69% of the cases of HR+ Her2- primary tumors at time of metastatic relapse. It was elevated in 56% of HR+ Her2+++, 46% of HR- Her2+++ cases and only in 41% of triple-negative cases (P = 0.003). these data confirm that CA 15-3 is very variably elevated at time of metastatic relapse of breast cancer, and this is dependant on HR status.

Breast cancers of basal phenotype have been identified by molecular profiling and are associated with a poor prognosis. This review describes the morphological characteristics of these tumors and focuses on their profiling using immunohistochemistry: absence of detectable hormone receptors and HER2, expression of basal cytokeratins (CK5/6, CK14), myoepithelial markers (p63, smooth muscle actin) and HER1. This phenotype may be encountered in all histological types of breast cancer and is further divided into three subtypes according to prognosis and protein profiling. Pure basal and basal/myoepithelial subtypes have a poor prognosis in contrast to the myoepithelial subtype.

Purpose: Breast mucinous carcinoma is a particular histological form characterized by the extracellular production of mucus. The pure form is rarely reported and its prognostic is better than the other types of the breast cancer. The aim of the present study was to discuss the various anatomoclinical, therapeutic aspects and the prognostic factors of the pure mucinous carcinoma of the breast., Patients and Methods: We report seven cases diagnosed over a period of 11 years (1993-2003) in the laboratory of anatomy and pathological cytology of the university hospital of Sfax. A review of the clinical files with immunohistochemistry study (hormonal receptor, synaptophysine, chromogranine, Bcl2, Ki67, P53 and Her-2/neu (C-erbB-2)) were carried out for all the cases., Results: pure colloid carcinoma of the breast accounted for 0,5% of the whole of the breast cancers. The average age of patients was 69 years. At the time of the diagnosis, four tumours were classified T4, one T3, two T2, two N1 and one N3; no patient had presented metastasis (M0) according to pTNM classification. The echomammography showed regular contours mass in four cases. The anatomopathological study showed that the neuroendocrine differentiation was found in two cases, all the tumours had presented positivity for the hormonal receptors (oestrogen and progesterone) and negativity for the other antibodies, two cases exhibited the Bcl2 positivity and negativity for the other antibodies. An adjuvant radiotherapy was carried out for all the patients. The average duration of follow-up was of 33 months; the evolution was marked by the occurrence of metastases in two cases., Conclusion: The pure colloid carcinoma of the breast constitutes a particular morphological entity which deserves to be individualized; neuroendocrine differentiation of these tumours must be required. Their forecast is relatively favourable.

Main Objective: determine the profile of the hormonal receptors and HER2 in order to optimize the patient's treatment by hormonotherapy and to propose targeted therapeutic to the few patients can procure themselves, when the indication is put., Secondary Objectives: show the feasibility of these exams in sub-Saharan Africa and also the necessity to improve the technical tray permitting to do these exams in routine thus., Patients and Methods: Preliminary results of a prospective, descriptive study, on 10 months, achieved to the Cancerology service of Treichville CHU in Abidjan (Ivory Coast). Our results were about 22 patients., Results: The middle age of our patients was of 42.7 years. The stages to the diagnosis were advanced (86%) with nodes metastasis (77%), 8 patients out of 20 were RH+ of which only one postmenopausal patient, 8 patients out of 20 were HER2+ of which 2 to 2++ and 6 to 3+++. The FISH test has been achieved for the 2 positive patients to 2 ++ by IHC and came back positive. One of patients HER2+ could have adjuvant Herceptin., Conclusion: Breast cancer is bad prognosis affection in our developing countries because of the patient's young age, of the advanced stages to the diagnosis. The knowledge of the status of the hormonal receptors and the HER2 over expression is necessary, as well the importance to pursue this survey and to set up an immunohistochemy unit in Ivory Coast. It will permit the realization in routine of these exams and, then, the improvement of the breast cancer patient's treatment.

The principal mission of the Breast International Group (Big), Transbig, and the Breast European Adjuvant Study Team (Breast), all located at the Jules Bordet Institute in Brussels, is to accelerate and facilitate the initiation and conduct of large and difficult breast cancer clinical trials. This is made possible through the excellent network of research groups, scientists, physicians and many other collaborators deeply committed to academic clinical and translational research. A clear example of this collaboration is the HERA trial (Herceptin Adjuvant trastuzumab in HER2 positive early breast cancer) that contributed to a change of clinical practice and improved the prognosis for this particular patient population. In addition, there is an important new generation of adjuvant trials, for example, Mindact, which is evaluating the use of microarray technology in treatment decision making, and the Altto and Neo-Altto studies, which have just started and are evaluating lapatinib, a small tyrosine kinase molecule given either adjuvantly or neo-adjuvantly, alone, sequentially or in combination with trastuzumab, in patients with HER2 positive early breast cancer. The latter studies, with their strong translational research component, aim to determine which tumour profiles will best benefit from lapatinib as opposed to treatment with trastuzumab alone.

HER-2 and potentially topoisomerase II alpha are clinically useful parameters in breast cancer. The gene status and protein expression are, for both markers, used as predictive markers in research or clinical practice. New guidelines for HER-2 testing from ASCO and CAP have been recently published and new definition for HER-2 gene amplification will probably decrease the impact of polysomy 17 on HER-2 FISH status evaluation. Different forms of HER-2 receptor (p95HER-2, p185HER-2) could be considered as prognostic or predictive markers in the future if preliminary results are confirmed. The topoisomerase II alpha case is more complex as the results of preclinical and clinical studies seem to be contradictory. The results of the clinical studies are so far, encouraging but need to be confirmed. Moreover studies should be designed to define which one of the protein or the gene or both should be evaluate as predictive markers of response to anthracyclines chemotherapy. More studies are needed today to consider this marker for daily practice.

Introduction: Mucoepidermoid carcinoma is one of the most frequent malignant lesions of salivary glands. The treatment is based on clinical, paraclinical and histological data. Several studies on the prognostic value of molecular markers for these cancers were made with contradictory results. The aim of this retrospective study was to analyze the prognostic value of molecular markers of salivary gland mucoepidermoid carcinoma., Material and Methods: Sixteen patients were treated for mucoepidermoid carcinoma of principal and/or accessory salivary glands between 1994 and 2003. An immunohistochemical study of archive specimen was performed. Nine markers were specifically studied: 4 proteins/oncoproteins (p53, bcl2, c-erb-B2 and cd117), 2 markers of proliferation (PCNA and Ki67), 1 growing factor receptor (EGFR), 1 epithelial adhesion molecule (E-cadherin), and 1 angiogenic cytokine (PDGF)., Results: Nine men and 7 women were included, with a mean age of 43.7 years (14-80). The mean diameter of tumors was 3.1 mm (1-14), and the parotid gland was the most frequent location. The mean global survival rate was 57.3 months with a median of 55 months. The 2 to 5 years survival expectation rate were 82.5% and 46.4% respectively. The mean survival rate for women was superior to that of men (P=0.043). The expression of p53 and the high expression rate of EFGR were bad prognostic factors (respectively P=0.049 and P=0.012). The expression of PCNA was linked to the location (mainly the salivary gland) and to the diameter of the tumor (respectively P=0.037 and P=0.029). The degree of EFGR positivity and the histological grade were linked (P=0.027)., Discussion: The strong expression of EGFR was statistically linked to the histological tumor grade. The degree of PCNA positivity seemed to be associated to the preferential location in the main salivary glands and to the diameter of the tumor. The strong expression of p53 and EGFR were bad prognostic factors. These retrospective results need to be confirmed by prospective randomized and larger studies. EGFR and p53 were significant negative prognostic factors. EGFR was highly correlated to the histological grade, making it an interesting target for further investigation.

Fifteen per cent of metastatic breast cancer will develop symptomatic leptomeningeal metastases. The introduction of trastuzumab (Herceptin) therapy has improved the response rates of survival of patients with metastatic breast cancer overexpressing HER2. Although previous studies are retrospective and of limited number, involving small study groups and different types of patient management, several authors have reported a 30% incidence of leptomeningeal metastases in patients with metastatic breast cancer overexpressing HER2 who were treated with trastuzumab, while 70 to 80% of cases of the disease were controlled systemically. In order to improve control of the disease at the level of the central nervous system (CNS), routine detection of leptomeningeal metastases in high-risk patients could be offered. CA 15-3 in cerebrospinal fluid (CSF) detection might be useful in helping to diagnose CNS metastases, particularly where cytology results are negative--which applies to 30% of cases--because tumor markers are more sensitive in detecting the tumor process. Our study validate CA 15-3 measurement in CSF and reference values were given.

HER2-positive status is the sole criterion for identifying patients with breast cancer for Herceptin (trastuzumab) therapy. Accurate assessment of HER2 status is essential to ensure that all patients who may benefit from Herceptin are correctly identified. There are several assays available to determine HER2 status: the most common in routine clinical practice are immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). The pros and cons of those two tests and the other upcoming methods for assessing HER2 status (with a focus on chromogenic in situ hybridization CISH recently approved by European Commission) are described in this manuscript. The importance of adhesion to quality assurance programs is underlined. Finally, the different national testing guidelines are discussed.

Inflammatory Breast Carcinoma (IBC) is a rare but aggressive form of breast carcinoma. Characteristic clinical and pathological features are well documented. Pathological response to chemotherapy is currently the only identified prognostic factor. This high-grade tumor exhibits phenotypical features of an aggressive tumor: absence of hormonal receptors in 56 to 83% of cases, high proliferating index, p53 expressed in 30 to 69%, Immunohistochemistry (IHC) detection of HER2 over expression in 38 to 60%. Current work on IBC points out specific molecular mechanisms: adhesion molecules such as E-Cadherin, apomucin MUC1 and angiogenesis processes contribute to the IBC phenotype. So does a gene named WISP3. This gene has been recently cloned and sequenced. It has been shown to be lost in IBC and could control tumor growth, invasion, and angiogenesis. This paper summarizes current knowledge on IBC and describes a new basis for a molecular definition of IBC.

The development of targeted antitumor agent aiming the HER family of tyrosine kinase transmembrane receptors, focused on the issue of target detection. For HER2, the techniques used to detect an overexpression are well established and none has, to date, shown its superiority. These are immunohistochemistry (protein) and in situ fluorescent hybridization (DNA). For EGFR, the diversity of the activation means (amplification, mutation, enhanced transcription, ligands...) leads to technical caveats. Immunohistochemistry appears to be the most appropriate test for clinical use but standardized assays and scoring systems are mandatory. The EGFR levels of expression are very high in some normal tissues such as oral mucosae. In tumors, EGFR levels are variable. The highest expression is found in head and neck epithelial tumors. EGFR expression is also elevated in oral and lung dysplasia. EGFR testing may be required before targeted treatment. An exciting endpoint would be the functional and dynamic evaluation of EGFR and downstream proteins for patients, before and during treatment.

In Europe, patients who may benefit from Herceptin((R)) (an HER2 targeted drug) are currently selected by immunohistochemistry (IHC). Reliable detection of HER2 status is essential to the appropriate usage of Herceptin(R), because its specificity is limited to tumours overexpressing HER2. It is essential that the IHC evaluation of the HER2 status of a mammary carcinoma be optimized and reliable. This technical paper reviews the different steps of the IHC technique, the controls and, the rules for interpretation. The sensitivity of the IHC technique must be adjusted so as not to produce false negatives or false positives. As opposed to other methods, it can be carried out whatever the fixation conditions of the tissues. The interpretation of the immunostains also requires training; it is fraught with problems for intermediate positivities. The ideal score to evaluate HER2 status has not yet been defined. It will thus be necessary to report the percentage of stained cells, the intensity of the staining, and, in respect to Herceptin((R)) treatment, the HercepTest scoring system (recommended in the package insert). Once acquired, this knowledge must be perpetuated by the observation of rules of good technical practice (internal and external controls, quality assurance programs). FISH should be used for complementary assessment of 2+ cases (on condition that they have not been fixed in Bouin's liquid) and for the calibration of the IHC technique.

Histopathological evaluation of breast cancers implies currently not only the assessment of the classical diagnostic and prognostic criteria, but also that of biological parameters. The importance in medical practice of some of these parameters (oestrogen receptors, proliferation index) is widely accepted, whereas the significance of others (p53, c-erb B-2, tumoral angiogenesis) is still controversial. Immunohistochemistry is both a reliable and simple method for the evaluation of these parameters in so far the indications of this analysis are accurate and the technical procedures well defined.

Two new immunoenzymatic assays for c-erbB-2 oncoprotein and epidermal growth factor receptor (EGF-R) (Oncogene Science) in human breast cancer were validated. Correlations between these assays and some clinical and biological parameters were also studied. The repeatability and reproducibility of standard curves for the two methods gave a coefficient of variation (CV) of less than 4% and about 10% respectively. The accuracy of c-erbB-2 oncoprotein and EGF-R assays was examined by using dilution and recovery tests throughout the standard curves. The linear relations between theoretical and measured values, for these tests, had slopes close to 1 and an intercept near 0. The median value for EGF-R, measured on solubilized membranes of 290 primary tumors, was 0.12 fmol/micrograms protein, the mean value was 0.37 (range 0 to 35.7). For c-erbB-2 oncoprotein, the median value, measured using the same population, was 2.75 human neu unit/micrograms protein, the mean value was 7.85 (range 1 to 125). There was an inverse relationship between EGF-R values and those for the estrogen receptor (ER), progesterone receptor and pS2 protein as well as menopausal status. C-erbB-2 oncoprotein concentrations were positively correlated with ER, pS2 protein and cathepsin D. Furthermore, a significant positive correlation was observed between EGF-R levels and c-erbB-2 oncoprotein levels. In conclusion, immunoenzymatic assays of EGF-R and c-erbB-2 oncoprotein are easy to use, sensitive and reliable. The accurate standardisation of immunoenzymatic assays could contribute to the clinical use of EGF-R and c-erbB-2 oncoprotein as prognostic factors in breast cancer.

The present study was performed on 45 mammary biopsies submitted to the Pathology Department, Hôtel-Dieu de France Hospital, for evaluation of hormonal receptor. Histological typing and grading did not reveal any difference with the literature, but the mean size of tumor at clinical presentation was 4 cm (+/- 1.6) and 83% of patients with known lymph node status, had metastases. Immunohistochemical assay for hormonal receptors on frozen sections disclosed positivity for estrogen and progesterone receptors in 18 cases (43%), similar to other studies. pS2, intracytoplasmic estrogen-induced protein, is positive in 19 out of 32 studied cases (59%), similar to what is reported by others. The latter does not appear to bring more information than hormone receptors considering therapy and prognosis. Oncoprotein C-erb B2 membrane over-expression is noted in 65% with no significant correlation to histological grade, size of tumor or node status. Antigen Ki-67 marker demonstrates high proliferation rates in 19 tumors (48.7%). The markers studied do not seem to be more conclusive than the hormone receptors. The major fact disclosed by the study of this small series is the advanced stage at clinical presentation, urging an adequate medical education of the Lebanese population, and prompting to appropriate self-screening. Nevertheless, new tumor markers are continuously presented in the literature. In this era of marker extravaganza, a "wait-and-see" attitude would be a wise alternative.

An overexpression of the c-erbB-2 oncoprotein has been demonstrated in the breast cancer and has been associated with a poor prognosis. Our study involved 23 cases of mammary Paget's disease which was found to be associated with the intraductal carcinomas in 13 cases, the intraductal carcinomas supposed micro-invasive in 2 cases, the infiltrating ductal carcinomas with predominant intraductal component in 6 cases and the infiltrating ductal carcinomas in 2 cases. The presence of c-erbB-2 oncoprotein has been determined immunohistochemically with 3 different antibodies: rabbit anti-human c-erbB-2 oncoprotein A485 (Dako), c-erbB-2 oncoprotein (internal domain) mouse monoclonal antibody NCL-CB11 (Novocastra), and c-erbB-2 oncoprotein (external domain) mouse monoclonal antibody NCL-CBE1 (Novocastra). An overexpression of the c-erbB-2 oncoprotein has been observed in 21 of the 23 studied cases. We noted an intense membrane staining in the intraepidermal or intraglandular tumour cells of mammary Paget's disease. Any staining has been observed in 2 cases with glandular component of pure intraductal type. These results are identical whatever the antibody used. In a previous study concerning mammary Paget's disease, it has been noted a correlation between this overexpression and presence of large malignant cells. We also have found this notion in mammary Paget's disease where the c-erbB-2 positive neoplastic cells in the different tumour components were large with prominent cytoplasm. The obtained results argue strongly for adenocarcinomatous origin for mammary Paget's disease and exhibit that the overexpression of c-erbB-2 oncoprotein was not constantly in correlation with a poor prognosis.