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Background: Despite the advancement in therapy, breast cancer still remains the most common malignancy in women globally due in part to its heterogeneity. Triple-negative breast cancer (TNBC) represents up to 20% of all breast cancer variants, an aggressive disease with poorer outcomes compared to other breast cancer subtypes. No targeted therapies are currently approved for TNBC, and newer treatment approaches are seriously needed. Androgen receptor (AR), another hormonal receptor, is often expressed in breast cancer, and its role depends on the relative levels of circulating estrogens and androgens. This study aimed to assess the expression of AR in breast cancer in a tertiary hospital in Ghana., Methodology: Immunohistochemical staining for AR was performed on tissue microarray (TMA) blocks, of which estrogen receptor, progesterone receptor, and Her-2/neu had already been done. 197 cases were suitable for the study. Results from the immunostaining were analyzed using the SPSS version 23 for descriptive statistics and correlations (χ2 and Pearson tests)., Results: 197 TMA cases were used. TNBCs constitute 61.9% of the cancers. The majority of these tumors were grade III, ductal carcinoma NST. The mean age was 49.86 ± 14.09, and the modal age group was 40-49 years. Our cases showed 23% AR expression in triple-negative cancers. The study also established that AR is more frequently expressed in low-grade tumors compared to high-grade ones., Conclusion: There is an appreciable level of AR expression in our cases; however, most are quadruple negative. However, AR is more frequently expressed in low-grade tumors than high-grade ones., (Copyright © 2024 Copyright: © 2024 Annals of African Medicine.)

Although patients over 65 years of age represent the majority of breast cancer patients, we have limited data on the safety and efficacy of medical oncology treatments in this population. Their indications are based primarily on expert agreement. This literature review discusses the known data on the safety and efficacy of the main medical treatments for breast cancer: chemotherapy, cytokine-dependent kinase inhibitors 4/6, agents targeting human epidermal growth factor receptor-2, novel antibody conjugates, and immunotherapy., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Thrombotic Microangiopathies (TM) have been described since the 1960s. They are characterized by presence of mechanical haemolytic anemia associated with peripheral thrombocytopenia. TM in cancer can be related to several causes, whose cancer himself: cancer-related microangiopathic haemolytic anaemia (MAHA). Incidence of cancer related MAHA remains unknown. Cancer-related MAHA are mainly observed in mucin-producer adenocarcinomas, such as gastric (half of reported cases) and breast cancer. We conducted a review of all original published cases of TM reported in breast cancer, and we specifically investigated BC-MAHA cases. A Medline search identified 158 MAHA cases including 118 BC-MAHA, and 40 drug-related MAHA. Most of BC-MAHA occur in disseminated cancers, mainly with medullar involvement, and/or bone metastasis. Patients typically suffer from poor general state, bone pain, and/or dyspnea. Laboratory abnormalities such as myelemia or erythromyelemia in peripheral blood are frequently observed. Incidence of coagulation disorders is increased, compared to other MAHA causes. BC-MAHA prognosis is dramatically poor. Treatments classically used in other MAHA causes, such as plasmapheresis or immunoglobulins, are inefficient. Urgent anti-neoplastic therapy may be the only effective treatment, associated to symptomatic therapies (transfusions, blood pressure control)., (Copyright © 2021 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

The HER2 receptor (Human Epidermal Growth Receptor 2) is a transmembrane receptor with tyrosine kinase activity that is over-expressed in 25-30 % of breast carcinomas. Its activation is associated with an exaggeration of cell proliferation with an increase in repair capacity resulting in increased radioresistance. On cardiac tissues, HER2 receptor activation plays a cardio-protective role. Trastuzumab, the first anti-HER2 drug used to treat patients with breast cancer overexpressing HER2 receptor , inhibits the cascade of reactions resulting in the proliferation of tumor cells, thus restoring cellular radiosensitivity. However, the combination of Trastuzumab with radiation therapy also removes HER2 receptor cardio-protective role on myocardial cells which increases the risk of cardiotoxicity. Thus, the concomitant association of these two modalities has long been a subject of controversy. Recent advances in radiation therapy technology and early detection of cardiac injury may limit the cardiotoxicity of this combination. Through this review, we developed the biological basis and the benefit-risk of concomitant combination of radiotherapy and Trastuzumab in adjuvant treatment of breast cancers overexpressing HER2 and we discuss the modalities of its optimization., (Copyright © 2021 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Background and Rationale: Despite improved prognosis of HER2 since the introduction of trastuzumab in the adjuvant setting of early breast cancer, disease recurrences still occur, particularly in certain patient subgroups. The objective of this real-life study conducted in France is to evaluate after 7 years, disease-free survival (DFS) and distant metastatic-free survival (MFS)., Methods: This was a multi-center, retrospective, observational study assessing early HER2+ breast cancer patients diagnosed between January 1st, 2009 and December 31st, 2010 treated with adjuvant trastuzumab. DFS and MFS were evaluated within subgroups according to hormonal and nodal status., Results: Based on 2311 patients documented, according to nodal status, the 7-year DFS rate was significantly higher for N- than for N+ patients [87.2% vs. 66.8%; P<0.001], and the 7-year MFS rate [94.7% for N- vs. 74.9% for N+; P<0.001]. According to hormonal status, the 7-year DFS rate was significantly higher for HR+ than for HR- patients [80.5% vs. 69.2%; P<0.001], and the 7-year MFS rate [88.0% for HR+ vs. 77.7% HR-]., Conclusions: Despite the overall improvement in the prognosis of early HER2+ breast cancers, patients in the N+ and RH- subgroups have a high risk of metastatic recurrence at seven years, justifying the search for more effective treatment alternatives., (Copyright © 2020 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Obesity increases the occurrence of post-menopausal breast cancer and negatively affects prognosis independently of menopausal status. After summarizing the available epidemiological data concerning these associations, we will show that a deleterious crosstalk is established during tumor progression between cancer cells and the surrounding mammary adipose tissue (MAT). In obesity, the chronic sub-inflammatory state of MAT could amplify the negative effect of this crosstalk although other mechanisms also warrant further study. Finally, we will discuss the efficiency of weight loss in both primary prevention and recurrence, a strategy that could be more complex that initially thought., (© 2018 médecine/sciences – Inserm.)

Primary neuroendocrine breast carcinomas are rare and little-known tumors. Only a limited number of studies on neuroendocrine breast carcinomas have been reported in the literature, and the vast majority of them are small retrospective series or case reports. According to the World Health Organization (WHO), they account for only 2 % to 5 % of breast cancers. Their diagnosis relies on the presence of a neuroendocrine architecture and the expression of neuroendocrine markers (chromogranin A and/or synaptophysin). The revised 2012 WHO classification subdivides them into three categories: (i) well-differentiated neuroendocrine carcinomas, (ii) poorly differentiated neuroendocrine carcinomas or small-cell carcinomas, and (iii) invasive breast carcinomas with neuroendocrine differentiation. Their clinical features and radiological characteristics are not different from those of other types of breast cancer. Because of discordant results, their clinical outcome is still poorly defined. So far, no standard treatment has been established, and most clinicians draw on their experience of invasive ductal cancer. The role of specific treatments like platinum-based chemotherapy, somatostatin analogues, peptide receptor radionucleide therapy or temozolomide remains unclear. A better knowledge of the molecular pathways involved in their carcinogenesis could help to identify new potential therapeutic targets. The efficacy of targeted therapies has to be studied., (Copyright © 2018 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

The development of immune checkpoints inhibitors represents one of the major recent advances in oncology. Monoclonal antibodies directed against the programmed cell death protein 1 (PD-1) or its ligand (PD-L1) provides durable disease control, particularly in melanoma, lung, kidney, bladder and head and neck cancers. The purpose of this review is to synthesize current data on the expression of PD-L1 in breast cancer and on the preliminary clinical results of PD-1/PD-L1 inhibitors in breast cancer patients. In breast cancer, PD-L1 expression is heterogeneous and is generally associated with the presence of tumor-infiltrating lymphocytes as well as the presence of poor-prognosis factors, such as young age, high grade, ER-negativity, PR-negativity, and HER-2 overexpression, high proliferative index, and aggressive molecular subtypes (triple negative, basal-like, HER-2-overexpressing). Its prognostic value remains controversial when assessed with immunohistochemistry, whereas it seems favorable in triple-negative cancers when assessed at the mRNA level. Early clinical trials with PD-1/PD-L1 inhibitors in breast cancer have shown efficacy in terms of tumor response and/or disease control in refractory metastatic breast cancers, notably in the triple-negative subtype. Many trials are currently underway, both in the metastatic and neo-adjuvant setting. A crucial issue is identification of biomarkers predictive of response to PD-1/PD-L1 inhibitors., (Copyright © 2018 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

If hormone therapy is a key treatment for hormone receptor positive advanced breast cancers, secondary resistance occurs as a rule. Recently, acquired alterations of the ESR1 gene have been identified as a mechanism of resistance on aromatase inhibitor (AI) treatment. The selective pressure by AI exposure during the metastatic setting triggers the emergence of ESR1 activating mutations. In that context, the "liquid biopsy" concept has been used to detect this molecular resistance before progression. Thus, the ESR1 circulating mutation detection will soon be used in daily practice to help monitoring patients on AI treatment and provide an early change for specific therapies that still have to be determined in prospective clinical trials. This review will present the acquired ESR1 mutations, as well as the methods used for their detection in blood and the potential clinical impact of this approach for hormone receptor positive breast cancer management., (Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Purpose: To compare epidemiological, histological, therapeutic characteristics and prognosis of patients with breast cancer diagnosed during pregnancy with those diagnosed in postpartum period at a national expert center, « Cancer Associé à La Grossesse » network., Methods: Retrospective study of 108 patients with a pregnancy-associated breast cancer (PABC) between 2002 and 2016 comparing 51 patients with PABC during pregnancy and 57 patients with PABC of postpartum., Results: Median gestational age at diagnosis was 16 weeks of gestation (WG). Median size (P=0.92), initial axillary pathology (P=0.29), histological type (P=0.33) and hormone receptor positive (P=0.93), were similar between groups. PABC during pregnancy overexpressed less frequently HER2 (12 % vs 36 %, P=0.003) and were less proliferant (Ki67≥15 %; 64 % vs 75 %, P=0.018) with less radical surgery (45 % vs 70 %, P=0.008). Sentinel lymph node biopsy was performed in 8 patients during pregnancy. Less patients of PABC during pregnancy received trastuzumab 12 % vs 37 %, P=0.003. Median delivery term was 37 WG. Median follow-up 3.2 vs 5.6 years (P=0.002) and recurrence rate for PABC during pregnancy and of postpartum were 3.2 vs 5.6 years (P=0.002) and 12 % vs 32 % (P=0.01), respectively. Our results emphasize histological, surgical and adjuvant treatment differences imposing differentiating PABC during pregnancy from those diagnosed in the postpartum period., (Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Endocrine therapy is a compulsory step in the adjuvant management of early breast cancer expressing the estrogen receptor, by reducing as much as possible serum and tissue levels of estrogens. Tamoxifen is the standard therapy for non-menopausal women. Ovarian function suppression, in addition to exemestane or tamoxifen, could be an alternative option for young women at high risk of recurrence and non menopausal after adjuvant or neo-adjuvant chemotherapy. Recent studies show a trend for improvement of overall survival and disease-free-survival with aromatase inhibitors among postmenopausal women. However, safety of aromatase inhibitors is controversial and adverse events may lead to switch for tamoxifen with no loss of efficacy. Extension therapy by tamoxifen or aromatase inhibitor after five years of tamoxifen and for a total duration of ten years significantly improves overall survival. There is to date no data supporting the extension therapy after five years of aromatase inhibitor., (Copyright © 2015 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Discordances between hormone receptors and HER2 status in primary and metastatic breast cancer have been reported by several studies. In this context, systematic biopsies could be clinically relevant in breast cancer to confirm the biological characteristics of a suspicious lesion. In this article, illustrated by 2 case reports and based on a recent review on this topic, we discuss the clinical significance of receptor discordances and possible diagnosis of a secondary primary tumor. The role of these biopsies for the identification of new therapeutic targets is also envisaged as well as underlying mechanisms for receptors' modification like tumoral heterogeneity, clonal selection and technical artifacts.

Purpose: The aim of the present study was to discuss the epidemiology, clinical and pathologic features, treatment, and prognosis of primary neuroendocrine carcinomas of the breast., Patients and Methods: We report 21 cases diagnosed over a period of 12 years (1995-2011) at the university hospital of Sfax. A review of the clinical data with pathology and immunohistochemistry study was carried out for all the cases., Results: The average age was 62 years (34-86 years). At the time of the diagnosis, tumours were classified T1 and T2 (16 cases), N1 (11 cases) and M1 in two cases. The histological examination has shown 13 cases of solid neuroendocrine carcinoma, six cases of large cell type and two cases of atypical carcinoid. Grade I and II SBR were found in 18 cases. Eighty-one percent of the tumours were reactive for synaptophysin; all tumours were positive for chromogranin. Thirteen (61.9%) tumours were estrogen receptor-positive and 12 (57.5%) progesterone receptor-positive. Nineteen (90.5%) tumours were negative for HER2/neu. Overall five-year survival was 72.7%. All patients had surgical treatment with modified radical mastectomy in 13 cases. Adjuvant treatment was indicated according to histopronostic elements., Conclusion: For primary neuroendocrine carcinoma of the breast, multivariate analysis identified three predictive factors for mortality: disease stage, histological grade and lymph node involvement., (Copyright © 2015 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.)

Luminal breast cancers (i.e. displaying œstrogen receptor expression) account for 70 to 80% of all breast cancers. It encompasses a heterogeneous population of tumors, differing by their clinical course, histopathological characteristics, phenotypes and molecular features. As a continuum of lesions, luminal breast tumors are critically challenged by the recent evolution in treatment decision making. Indeed, whilst about half of luminal breast cancers are associated with a very good prognosis (so-called luminal A tumors with regard to the intrinsic molecular classification), 20% of luminal tumors display a poor clinical outcome (i.e. luminal B tumors), the remaining tumors corresponding to intermediate lesions that are very difficult to accurately classify. Clearly, therapeutic issues are critical, since according to the vast majority of international consensus guidelines luminal A tumors are best treated by endocrine therapy, whilst an additional adjuvant chemotherapy will be proposed to patients harbouring luminal B breast cancer. By providing precise histopathological, phenotypic and molecular characterization of luminal breast tumors, the pathologist is actually the cornerstone of this therapeutic decision. Herein we aim to review the state-of-the-art knowledge on luminal breast carcinomas, with a perspective of routine clinical practice in 2015., (Copyright © 2015 Société Françise du Cancer. Publié par Elsevier Masson SAS. Tous droits réservés. Published by Elsevier Masson SAS. All rights reserved.)

Despite improvements in early detection, surgery and systemic therapy, metastatic breast cancer remains a major cause of death. Luminal type breast cancers expressing hormone estrogen receptor (ER) or progesterone (PR) and without HER2 overexpression are generally sensitive to endocrine therapy, but raise the issue of the occurrence of resistance to treatment, particularly at metastatic stage. A better understanding of hormone resistance may guide the development of new therapeutics. New strategies aim at enhancing and prolonging of endocrine sensitivity, by optimizing existing schemes, or by combining an endocrine therapy with a targeted therapies specific to hormone resistance pathways: ER signaling, PI3K/AKT/mTOR and Cyclin Dependent Kinase (CDK). Key corners of 2014 include confirmation of benefit of high dose fulvestrant, and commercialization of everolimus as the first mTOR inhibitor in this indication. Other strategies are being tested dealing with new endocrine therapies or new molecular targets such as PI3K inhibitors, insulin-like growth factor receptor (IGF-R) and histone deacetylase (HDAC) inhibitors. Coming years may be fruitful and might radically change our way to treat these patients., (Copyright © 2015 Société Françise du Cancer. Publié par Elsevier Masson SAS. Tous droits réservés. Published by Elsevier Masson SAS. All rights reserved.)

Hormone-dependent breast cancer is the first example of cancer treated by targeted therapy for more than 30 years. Blocking estrogen pathway was the first therapeutical strategy for this subtype of breast cancer, and remains the principle of current standard treatment. Despite the efficacy of drugs used in endocrine therapy, hormone resistance is a major problem for the management of patients with hormone-dependent breast cancer. In this review, we will discuss the development of strategies targeting the PI3K/Akt/mTOR pathway, CDK4/6 (Cyclin Dependent Kinase 4/6) and FGFR (Fibroblast Growth Factor Receptor) in hormone-dependent metastatic breast cancer (ER+). Recent results of clinical trials showed that combination of endocrine therapy with such pharmacological inhibitors is a promising strategy to overcome endocrine resistance. Mutated forms and isoforms of ERα have been recently discovered and its targeting could represent an therapeutic alternative. Future progress will focus on the identification of new compounds and combinations with other targeted therapies to improve the efficacy of such inhibitors in clinical practice., (Copyright © 2015 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

HER2 (human epidermal growth factor receptor 2) is overexpressed in 15 to 20% of breast cancer. Anti-HER2 targeted therapies, notably trastuzumab, have transformed the natural history of this disease. Trastuzumab emtansine, consisting of trastuzumab coupled to a cytotoxic agent, emtansine (DM1), by a stable linker, has been approved in November 2013 by the European Medicine Agency. Trastuzumab emtansine targets and inhibits HER2 signaling, but also allows emtansine to be directly delivered inside HER2-positive cancer cells. It is indicated as single-agent in taxane and trastuzumab-pretreated HER2-positive breast cancer patients with metastatic and locally recurrent unresecable disease or relapsing within 6 months of the end of adjuvant therapy. This indication is based on the results of the EMILIA study, an open label phase III randomized trial comparing trastuzumab emtansine to lapatinib-capecitabine. The two primary endpoints were reached. The progression-free survival was 6.4 months in the lapatinib-capecitabine arm versus 9.6 months for the trastuzumab emtansine arm (HR=0.65; 95% CI=0.55-0.77, P<0.001). Overall survival at the second interim analysis was 25.1 months in the lapatinib-capecitabine arm versus 30.9 months in the trastuzumab emtansine arm (HR=0.68; 95% CI=0.55-0.85, P<0.001). Moreover, adverse events were more frequent in the lapatinib-capecitabine arm., (Copyright © 2015 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Hormone receptors are expressed in more than 75% of breast cancer. Therefore, two prescription modalities of endocrine therapy could be proposed: either sequential or concomitant to breast cancer irradiation. If combined to radiotherapy, is endocrine therapy a radiosensitizer? Does endocrine therapy enhance the risk factor of radio-induced toxicity? Here, we will distinguish the interaction of ionizing radiation combined with therapies targeting oestrogen receptor (REα) from the interaction of ionizing radiation with oestrogen. This review aims at making clear all these items.

Purpose: Recent improvements in the detection of breast cancer at an early stage have resulted in a rising incidence of breast ductal carcinoma in situ with microinvasion. So far, there is no consensus regarding its optimal management. We hereby report on our 10-year single institutional experience in breast ductal carcinoma in situ with microinvasion including pathological reviewing., Patients and Methods: All consecutive patients treated for a ductal carcinoma in situ with microinvasion at the Institut Claudius-Regaud (Toulouse, France) over a 10-year period were included in this study. We reviewed all available histological materials., Results: Sixty-three patients were eligible for this study. Two patients presented with a lymph node invasion at diagnosis. Each patient benefited from initial surgical management, which consisted either in mastectomy (n=25) or conservative resection (n=37). Axillary exploration was performed in 52 patients (82%). After a median follow-up of 61.3 months [46.9;69], the 5-year overall survival and disease free survival were 98.2 (95% CI=[88.2;99.7]) and 89.5% (95% CI=[76.3;95.6]) respectively. Two delayed invasive relapses occurred leading to one specific death. The pathological review highlighted a trend towards a loss of HR and HER2 expression (9%) in the microinvasive component in comparison with its surrounded in situ carcinoma., Conclusion: The risk of initial lymph node involvement and delayed invasive local relapse deserve an optimal locoregional management including lymph node evaluation. The non-negligible discrepancy's rate between in situ and microinvasive components justifies HR status and HER2 expression assessment on the microinvasive component., (Copyright © 2014 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.)

Phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is commonly deregulated in breast cancer and has been involved in resistance to endocrine therapy. In the BOLERO-2 study, the addition of everolimus, a selective inhibitor of mTOR protein, to exemestane was associated with a significant improvement in progression-free survival, compared to exemestane plus placebo, in patients with hormone receptor-positive, HER2-negative metastatic breast cancer, and resistant to non-steroidal aromatase inhibitor therapy. However, adverse events and treatment stops were more often observed with the combination therapy, suggesting the need for a careful benefit/risk evaluation before initiating this new combination. This review aims at synthesizing the biological basis of the everolimus-exemestane association, presenting the main validated and ongoing therapeutic trials, interests and limits, as well as the multiple potential therapeutic perspectives.

Osteogenesis imperfecta is an unusual disease also called Lobstein disease. Characterized by abnormalities of collagen biosynthesis, a possible mutation on 17th chromosome is described. On the other hand, 29% of breast cancers present a mutation on the same chromosome. Nevertheless, the association of osteogenesis imperfecta and breast cancer is at the moment unknown. Therapeutic management is very difficult because of a loss in dihydropyrimidine dehydrogenase for patients having osteogenesis imperfecta, generating some toxicity by default in catabolism of 5-fluorouracil. We report the case of a 49-year-old woman with a breast cancer in the context of osteogenesis imperfecta. Dosimetric considerations permitting to reduce chess dose level have been performed for this patient. With a follow-up of 6 months, no imaging fracture has been revealed after radiotherapy. No evident conclusion about radiation injury from a case report could be described in case of osteogenesis imperfecta. To our knowledge, this is the first case which take into account potential radiation induced toxicities., (Copyright © 2014. Published by Elsevier SAS.)

Breast cancer is now considered as a large collection of distinct biological entities, the management of which is increasingly personalized. Personalized medicine - defined as a medicine, which uses molecular profiles, notably genetic profiles, from patients and/or tumors to tailor therapeutic decisions - is now introduced in the management of breast cancer at any stages: screening and prevention of hereditary forms, prognostic and predictive evaluation of early breast cancer, and, more recently, novel clinical trials in advanced breast cancer, where genetic characterization of tumor tissue based on genomics, including next-generation sequencing tools, is used to drive specific therapeutic targeting.

Incidence of centimetric or infracentimetric node negative (pT1a-b, N0) breast cancer is increasing due to screening procedures. Although considered as having an overall favorable prognosis, several retrospective studies have suggested a higher risk of relapse when HER2 is overexpressed. Since randomized studies evaluating trastuzumab in the adjuvant setting did not include T1a-bN0, there is no level I evidence supporting the administration of a trastuzumab-based post-operative chemotherapy in these cases. However, some recent retrospective data suggest a benefit for such a strategy and current guidelines recommend to consider adjuvant chemotherapy plus trastuzumab in pT1bN0. The final decision, as well as the nature of cytotoxics to be administered in combination with trastuzumab, require a careful evaluation of the benefit/risk ratio in order to minimize the risk of toxic events, notably at the cardiac level.

More than one million new cases of breast cancer are diagnosed each year worldwide and more than 400,000 deaths occur due to this pathology. Obesity is a risk factor for postmenopausal breast cancer and the place held by the adipose tissue and secretions (i.e. adipokines) begins to be recognized. Indeed, firstly, plasma adipokine levels, modulated in obesity situation, could have effects "remotely" on mammary carcinogenesis and, secondly, breast cancer cells are surrounded by adipocyte microenvironment, which is probably more important in the case of obesity, and may be locally influenced by it. In this context, leptin appears to be strongly involved in mammary carcinogenesis and may contribute to the angiogenesis process and local pro-inflammatory mechanisms, especially in obese patients for whom increased metastatic potential and risk of mortality are described., (Copyright © 2013. Published by Elsevier Masson SAS.)

Triple-negative breast cancer (TNBC), as defined by the absence of estrogen and progesterone receptor expression, as well as the lack of HER2 overexpression/amplification, corresponds to 15% of breast cancer and represents an aggressive form of the disease. TNBC are frequently confounded with basal subtype in the molecular classification of breast cancer and also share some similarities with BRCA1-mutated tumors. Epidemiological and clinical characteristics are distinct from other subtypes, including a younger age at diagnosis, a higher risk of relapse in spite of increased chemosensitivity, and a higher incidence of lung and brain metastatic relapses. Conventional cytotoxics remain the mainstay of current systemic management but recent evaluation of more targeted therapeutics, including specific cytotoxics (such as the use of platinum salts), PARP and EGFR inhibition, and antiangiogenics have been performed, providing contrasted but rather disappointing results. Recent data indicate that TNBC represent a heterogeneous entity composed of multiple and distinct molecular subtypes, which should deserve specific targeted therapeutics.

Breast cancer represents a major public health problem. Approximately one woman in ten is likely to develop a malignant tumor of the breast in their lifetime. The frequency of breast cancer is rising steadily for 20 years and the practical benefits in the diagnosis, prognosis and treatment of this disease are still too limited. Actually, there is no tumor marker with a specificity and sensitivity sufficient to have an utility in clinical and early diagnosis of breast cancer, although, carcinoembryonic antigen (CEA), MUC-1 and CA 15-3 were reported to be useful as markers for monitoring this disease. Thus, proteomics approaches are needed for the discovery and the identification of new protein biomarkers that may allow a better understanding of biological mechanisms of breast tumor development and serve as potential therapeutic targets. This article reviews advances in this field, as well as, the major contribution of these markers in breast pathology, with a focus on their biological characteristics and their clinical and therapeutic involvement.

The Ras/Raf/Mek/Erk pathway is a key component of tumor progression and modulates proliferation, survival, differentiation and angiogenesis. Hyperactivation of this pathway is highly implicated in tumorigenesis especially by gain of function mutation of Kras or Braf. Mek position at the end of the pathway seems to be a promising new therapeutic target in the Kras or Braf mutated cancers. In this review, we aimed at describing the Ras/Raf/Mek/Erk pathway, the new therapeutic approaches in solid tumors and their toxicities. However, there seems to be predictives factors of tumor responses to these new agents and mechanisms of resistance that we will tend to analyse.

Iron plays a fundamental role in biology and its concentration in living organisms is regulated very precisely. Many molecules of storage and transportation are used to maintain the intracellular homeostasis. Cancer cells have alterations in this balance. Recent studies have shown that breast cancer cells present abnormal expression of several proteins such as hepcidin and ferroportin. A prognostic impact of these alterations has been reported in patients with breast cancer. Regulatory molecules of iron metabolism could become therapeutic targets. This is an innovative approach that has emerged for treating a cancer which, despite advances in treatment and the emergence of targeted therapies, remains the leading cause of cancer death in women.

Breast cancer (BC) has the highest incidence rate in women in industrialized countries. Statistically, it is estimated that one out of 10 women will develop BC during her life. Evidence is accumulating for the role of ion channels in the development of cancer. Most studied ion channels in BC are K(+) channels, which are involved in cell proliferation, cell cycle progression and cell migration, and Na(+) channels, which correlate with invasiveness. Emerging studies demonstrated the role of Ca(2+) signaling in cancer cell proliferation, survival and migration. Recent findings demonstrated that the expression and/or activity of the transient receptor potential (TRP) channels are altered in several cancers. Among the TRP families, TRPC (canonical or classical), TRPM (melastatin) and TRPV (vanilloid) are related to malignant growth and cancer progression. Although these channels are frequently and abundantly expressed in many tumors, their specific expression, activity and roles in BC are still poorly understood. The expression of TRP channels has also been proposed as a tool for diagnosis, prognosis and/or therapeutic issues of several diseases. In cancer, TRPV6 and TRPM8 have been proposed as tumor progression markers of prostate cancer outcome and TRPC6 as a novel therapeutic target for esophageal carcinoma. Interestingly high levels of TRPC3 expression correlate with a favorable prognosis in patients with lung adenocarcinoma. Our team has recently reported the expression and role of TRPC1, TRPC6, TRPM7, TRPM8 and TRPV6 in BC cell lines and primary cultures. We have also investigated TRP expression and their clinical significance in human breast adenocarcinoma and we suggest that TRP channels are new potential BC markers. Indeed TRPC1 and TRPM8 may be considered as good prognosis markers of well-differentiated tumors, TRPM7 as a proliferative marker of poorly differentiated tumors and TRPV6 as a prognosis marker of aggressive cancers. In this review, we summarize the data reported to date regarding the changes in TRP expression associated with BC. We also discuss the importance of TRP channels in BC cells proliferation and migration and their interest as new BC markers.

Twenty years have passed between the discovery of oncogene HER2, the description of its implication in mammary carcinogenesis, and the development of specific targeted therapies. To date, trastuzumab and lapatinib are the two anti-HER2 targeted therapies commonly used, demonstrating therapeutic effects. Although their clinical efficacy seems to be exclusively related to the amplification of the HER2 gene or to the overexpression of the protein, these factors are not sufficient since tumors can develop resistance. Because of a better knowledge in those mechanisms of resistance, novel therapeutic agents could help to bypass them. How should these be used with respect to current anti-HER2 targeted therapies? Recent notions such as oncogene addiction, tumor cell dormancy and residual disease led us to propose a new entity that we named the "sedimentation strategy", in which distinct targeted approaches are summed during the treatment of metastatic breast cancer patients.

The Renal Insufficiency and Anticancer Medications (IRMA) study is a French national, observational study, which demonstrated the high prevalence of abnormal renal function in a population of 4,684 solid tumour patients, treated in 15 cancer centers. Among them, 7.2% had a SCR level ≥ 110 mmol/L. In the 1,898 patients with breast cancer, only 31 patients (1.63%) had a SCR level ≥ 110 mmol/L. Nevertheless, respectively 51.8 and 50.8% had a creatinine clearance estimated with the Cockcroft-Gault and aMDRD formulae, below 90 mL/min. Even if the most used medications (anthracyclins, taxanes, trastuzumab, hormone therapies) are not nephrotoxic, these results are important because bevacizumab modifies the need for renal management. In case of renal insufficiency, some other treatments such biphosphonates IV, capecitabin and platin salts need drug dosage adjustment or interruption.

Hormonal dependence of breast cancer has been known for a long time, yet about half of breast cancers with estrogen receptor will not respond to antihormonal therapy. Now, we know that this resistance may be related to a dysfunction of the estrogen pathway, or that of growth factors and particularly the pathway of cell activation PI3K/Akt/mTOR. Prevention of these different mechanisms of resistance could involve combination therapies such as anti-estrogens (SERMs, aromatase inhibitors) with inhibitors of the activity of growth factors that are particularly temsirolimus and everolimus for the activation pathway cell PI3K/Akt/mTOR.

Fifteen percent of breast cancers overexpress Her2, a tyrosin-kinase receptor. Because of its prognosis and its incidence, several efforts have been done in the last years to better understand mechanisms of Her2 action. This led to the development of targeted therapies such as trastuzumab, monoclonal antibody directed against the Her2 extra-cellular domain. Trastuzumab provides significant clinical benefit in women with Her2-positive breast cancers. However, many women will either not respond or progress despite this treatment. The aim of this article is to summarize mechanisms of action of Her2 and of trastuzumab, and to better understand pathways activated in resistant tumors in order to identify ways to overcome them.

Breast cancer remains a major public health problem. Even if there is an increase in this cancer curability, metastatic breast cancer remains a lethal disease in the vast majority of cases. Therapeutic advances in the chemotherapeutic and targeted therapies fields induced an increase in survival, however the proportion of long survivors remains low. Phenotypic instability, an early process initiated during tumour progression, and continued on the metastatic stage of the disease, can be one of the putative hypotheses explaining these results. An increasing amount of scientific data are pledging for a reanalysis of the phenotypic profile regarding hormone receptors and HER-2 status of metastatic lesions in order to identify drugable targets and allow individualisation of the treatment of these metastatic breast cancer patients. Phenotypic changes between the primary tumour and the paired metastatic lymph nodes are a challenging pitfall, raising the question of which site has to be assessed in the adjuvant treatment decision process. This article presents a comprehensive analysis of the frequency of theses phenotypic changes altogether with new modalities to evaluate this phenotypic status.

Bone homeostasis is maintained by the remodelling of bone which depends on a balance between osteoclast-mediated bone resorption and osteoblast-mediated bone formation. Malignant bone lesions are very common in patients with cancer; whether they result from a tumor in bone (giant cell tumour of bone, osteosarcoma, multiple myeloma...) or they are bony metastases from advanced cancers of which the most osteotropic are breast and prostate cancer. Malignant cells within the bone disrupt the normal bone remodelling process, leading to increased bone destruction and occurence of pathological fractures. Receptor activator of NF-kB (RANK) and its ligand (RANKL) play a pivotal role in the regulation of bone remodelling; by binding to RANK, RANKL stimulates osteoclastogenesis and bone resorption, whereas its cognate decoy receptor osteoprotegerin (OPG) blocks this process by interacting with RANKL. Tumour cells produce different factors that manipulate the RANK/RANKL/OPG pathway in order to stimulate bone destruction. Furthermore, pending on the tumour type, RANKL plays a role in the migration, invasion and proliferation of malignant cells within the bone, while OPG increases survival of tumour cells. Inhibition of RANK/RANKL system may therefore offer new therapeutic perspectives for the treatment of primitive and secondary bone cancers.

Breast cancer is a widely spread women's disease. In spite of progress in the field of surgery and adjuvant therapies, the risk of breast cancer metastatic relapses remains high especially in those overexpressing HER2. Different studies have shown cellular and/or humoral immune responses against HER2 in patients with HER2-overexpressing tumors. This immune response is associated with a lower tumor development at early stages of the disease. These observations, associated with the efficiency today demonstrated by a trastuzumab-based anti-HER2 immunotherapy, allowed to envisage various vaccinal strategies against HER2. These findings have so led to the hypothesis that the generation of an anti-HER2 immune response should protect patients from HER2-overexpressing tumor growth, and induction of a stable and strong immunity by cancer vaccines is expected to lead to establishment of immune memory, thereby preventing tumor recurrence. However, an immunological tolerance against HER2 antigen exists representing a barrier to effective vaccination against this oncoprotein. As a consequence, the current challenge for vaccines is to find the best conditions to break this immunological tolerance. In this review, we will discuss the different anti-HER2 vaccine strategies currently developed; considering the strategies having reached the clinical phases as well as those still in preclinical development. The used antigen can be composed of tumoral allogenic cells or autologous cells or be specific of HER2. It can be delivered by denditric cells or in a DNA, peptidic or proteic form. Another area of the research concerns the use of anti-idiotypic antibodies mimicking HER2., (Copyright © 2009 Elsevier Masson SAS. All rights reserved.)

The IKKε kinase, an atypical member of the IKK family of kinases, was recently identified as an oncogene overexpressed in over 30% of breast cancers. Besides its role in the regulation of the NF-κB transcription factor, which is well recognized for its implication in the development of breast cancers, IKKε was shown to phosphorylate numerous targets. Analysis of the phosphorylation of some of these substrates in the context of breast cancer highlighted new oncogenic signaling pathways that constitute potential targets for new therapies. Interestingly, IKKε is involved in the development of resistance to Tamoxifène. Thus, IKKε is a promising therapeutic target for newly developed breast cancer treatment., (© 2011 médecine/sciences - Inserm / SRMS.)

The breast pathology includes a large array of entities for which macroscopic and microscopic analysis remains fundamental. Tissue and cell morphology allows in most cases the distinction between benign or malignant tumours and therefore provides the clinicians with essential information for the therapeutic strategy. In the Pathology laboratory, immunohistochemistry and molecular biology have improved the specificity of the diagnosis and have introduced new prognostic and predictive markers for tumour management. The last edition of the WHO classification, released in 2003, distinguishes 21 varieties of invasive carcinoma and 2 categories of intraepithelial neoplasia based on the morphology and immunohistochemical profile. Other diseases can affect the breast, although much less frequently, such as Paget's disease of the nipple, phyllode tumours, sarcomas, lymphomas... These diseases will not be reviewed here.

Breast cancer mortality is decreasing, partly due to better adjuvant treatments with new drugs and new schedules. In Belgium, the overall survival is 76%. Chemotherapy is still an important treatment option. We need to better select patients who really will benefit from treatment in order to decrease toxicity and improve long term outcome.Targeting the specific population is now a priority. Prognostic and predictive factors will enable us to better define the sub-population of patients most benefiting from treatment. We will also discuss the knowledge of systemic treatment. When we have to decide wether chemotherapy is indicated, we need to well balance the treatment risks and benefits because gain in survival is important but reducing short and long term toxicity is also a challenge.

The incidence of brain metastases is particularly high in HER2-overexpressing (HER2+) breast cancer. Several hypotheses have been raised trying to explain this peculiar phenomenon, including a better control of extra-cerebral metastases with HER2-targeting agents, but also the own effect of HER2+ tumor cells that may have a marked brain tropism. In this context, the development of prevention strategies is highly relevant. After a brief description of the natural history of HER2+ breast cancer, three different prevention strategies are discussed in this article, including a secondary prevention strategy by systematic screening of brain metastases, and two primary prevention strategies with prophylactic cerebral irradiation and the optimisation of the adjuvant treatment. None of these strategies has been validated to date. A prolonged follow-up is crucial in order to detail the natural history of HER2+ breast cancers and to evaluate the impact of new treatments on the incidence of brain metastases.

Brain metastases are prevalent in solid tumours and lymphomas. They are associated with poor survival. The brain is regarded as a sanctuary site for metastatic tumour cells where they exist partially protected from drugs by the blood brain barrier. Amongst the different molecular sub-types of breast cancer, HER2 positive tumours and triple negative tumours exhibit the highest incidence of brain metastasis. Specific strategies are needed to fight brain metastatic disease. Preclinical models for brain metastasis have been developed, yielding mechanistic molecular knowledge and new therapeutic approaches.

This review focuses on new aspects in growth hormone (GH) biology and pathophysiology presented at the Endocrine Society's meeting, in San Diego, in June 2010. First, we will describe recent advances in the understanding of cytokine hormone signaling via STAT5 in mammary gland development, highlighting the primary role of miR193b for differentiation of mammary stem cells into alveolar progenitor cells. We will examine the potential implication of endocrine and autocrine GH for mammary gland carcinogenesis. Three novel murine models bearing tissue-specific inactivation of GH receptor or JAK2 bring new insights into the large spectrum of GH effects on energy homeostasis. We will also report new data supporting a paracrine regulation of GH secretion in women by estrogen's action in the brain. Thereafter we will question the reasons for GH abuse for doping by assessing the hormonal impact on body composition and physical performance in recreational athletes. Finally, we will discuss the controversial issue of GH replacement in acromegalic patients presenting GH deficiency after treatment of acromegaly., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

During the past decade, molecular signatures allowed a better classification of breast carcinoma and a better evaluation of their prognosis. However, we still need predictive factors of treatment and /or prognosis factors specific of each patient. Regarding hormonal therapy, expression of hormone receptors is essential, but not sufficient to accurately predict response to treatment for all patients. To date, numerous data have identified different pathways of resistance to hormonal treatment, associated with heterogeneity in response to long term treatment. The challenge remains to identify and to anticipate these changes for each patient.

Regulation of the proteome by post-translational modifications (PTM) emerges as a major contributing factor to the functional diversity in biology regulating cellular processes. Because PTM are key to the physiologic functions of the proteins involved, it is imperative that we understand the << coding >> that these modifications impart to regulate diverse activities. As estrogen signalling mediates a plethora of PTM not only on the receptors themselves but also on their coregulators, we investigate to << crack >> the ER code. Besides the long-known phosphorylation, other covalent additions such as acetylation, ubiquitination, sumoylation and methylation have been described for estrogen receptors in recent years. These modifications affect receptor stability and activity, and provide potential mechanisms for cell- or-gene-specific regulation. A better understanding of the impact of these PTMs on estrogen receptor should help in the identification of new drugs for breast cancer treatments.