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Purpose: Although younger age has been negatively associated with persistence to adjuvant endocrine therapy (ET), factors contributing to non-persistence remain poorly understood. We assessed factors associated with non-persistence to ET and described the 5-year trajectories of quality of life (QoL) and symptoms in young women (≤40 years) with hormone receptor-positive breast cancer (BC)., Methods: We retrieved data on clinical characteristics and non-persistence from the medical annual records in the European cohort of the "Helping Ourselves, Helping Others: The Young Women's BC Study" (IBCSG 43-09 HOHO). Women completed surveys at baseline, biannually for three years, and annually for another seven years. Data collection included sociodemographic information, QoL aspects assessed by the Cancer Rehabilitation Evaluation System-Short Form and symptoms assessed by the Breast Cancer Prevention Trial symptom scales. Cox regression models were applied to identify factors associated with non-persistence., Results: The cumulative risk of interrupting ET within 5 years was 27.7 % (95 % CI, 21.5-35.2). The QoL subscale scores remained stable over 5 years, with slight improvements in the physical subscale. Hot flashes decreased (p < 0.001), while vaginal problems intensified (p < 0.001) over time. Being married without children and having difficulties interacting and communicating with the medical team were significantly associated with non-persistence., Conclusions: Discussing the desire to conceive with partnered childless women and establishing a good relationship with the medical team may be important in addressing the non-persistence in young BC survivors. As recent data suggests the safety of pausing ET to conceive, this approach may be a reasonable future option to limit non-persistence., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Eraldo Oreste Bucci reports a relationship with AstraZeneca R&D that includes: consulting or advisory and travel reimbursement. Eraldo Oreste Bucci reports a relationship with Astellas Pharma Europe Ltd that includes: travel reimbursement. Eraldo Oreste Bucci reports a relationship with Bristol Myers Squibb Co that includes: travel reimbursement. Eraldo Oreste Bucci reports a relationship with Eli Lilly and Company that includes: travel reimbursement. Eraldo Oreste Bucci reports a relationship with Merck Serono that includes: travel reimbursement. Eraldo Oreste Bucci reports a relationship with Roche that includes: travel reimbursement. Eraldo Oreste Bucci reports a relationship with Takeda Oncology that includes: travel reimbursement. Lorenzo Gianni reports a relationship with AstraZeneca that includes: consulting or advisory. Lorenzo Gianni reports a relationship with Seagen Inc that includes: consulting or advisory. Lorenzo Gianni reports a relationship with Pfizer and Novartis that includes: travel reimbursement. Alberto Farolfi reports a relationship with from Janssen Oncology, GSK-Tesaro, Astrazeneca, Clovis that includes: paid expert testimony. Rossana Berardi reports a relationship with AZ, BI, Novartis, MSD, Otsuka, Lilly, Roche, Amgen, GSK, EISAI, Seage that includes: consulting or advisory. Anne Patridge reports a relationship with Wolters Kluwer, Novartis that includes: equity or stocks and funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: To provide evidence explaining the poor association between pCR and patients' long-term outcome at trial-level in neoadjuvant RCTs for breast cancer (BC), we performed a systematic-review and meta-analysis of all RCTs testing neoadjuvant treatments for early-BC and reporting the hazard ratio of DFS (HR DFS ) for the intervention versus control arm stratified by pathological response type (i.e., pCR yes versus no)., Methods: The objective was to explore differences of treatment effects on DFS across patients with and without pCR. We calculated the pooled HR DFS in the two strata of pathological response (i.e., pCR yes versus no) using a random-effects model, and assessed the difference between these two estimates using an interaction test., Results: Ten RCTs and 8496 patients were included in the analysis. Patients obtaining pCR in the intervention-arm had a higher, although not statistically significant, risk of DFS-event as compared with patients obtaining pCR in the control-arm: the pooled HR DFS for the experimental versus control arm was 1.23 (95%CI, 0.91-1.65). On the opposite, the risk of DFS-event was higher for control as compared with the intervention-arm in the stratum of patients without pCR: the pooled HR DFS was 0.86 (95%CI, 0.78-0.95). Treatment effect on DFS was significantly different according to pathological response type (interaction test p: 0.014)., Conclusion: We reported new evidence that contributes to explaining the poor surrogacy value of pCR at trial-level in neoadjuvant RCTs for early-BC., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Controversy exists regarding the optimal duration of the extended adjuvant endocrine treatment (ET) in patients with early-stage breast-cancer (eBC). We performed a systematic review and trial-level meta-analysis of all randomized clinical trials (RCTs) comparing a "limited-extended" adjuvant ET (defined as more than 5 but less than 7.5 years of treatment overall) versus a "full-extended" adjuvant ET (defined as more than 7.5 years of treatment overall) in eBC., Methods: To be eligible, RCTs had to i) compare a "limited-extended" adjuvant ET versus a "full-extended" adjuvant ET in patients with eBC; and ii) report disease-free survival (DFS) hazard ratio (HR) according to the disease nodal-status [i.e., nodal-negative (N-ve) versus nodal-positive (N + ve)]. The primary endpoint was to assess the difference in efficacy of full-versus limited-extended ET, measured in terms of the difference in DFS log-HR, according to the disease nodal-status. Secondary endpoint was the difference in efficacy of full-versus limited-extended ET according to tumor size (i.e., pT1 vs pT2/3/4), histological grade (i.e., G1/G2 vs G3), patients' age (i.e., ≤60 vs > 60 years) and previous type of ET (i.e., aromatase inhibitors vs tamoxifen vs switch strategy)., Results: Three phase III RCTs fulfilled the inclusion criteria. A total of 6689 patients were included in the analysis, of which 3506 (53%) had N + ve disease. The full-extended ET provided no DFS-benefit as compared with the limited-extended ET in patients with N-ve disease (pooled DFS-HR = 1.04, 95%CI: 0.89 to 1.22; I 2  = 18%). Conversely, in patients with N + ve disease the full-extended ET significantly improved DFS, with a pooled DFS-HR of 0.85 (95%CI: 0.74 to 0.97; I 2  = 0%). There was a significant interaction between the disease nodal-status and the efficacy of the full-versus limited-extended ET (p-heterogeneity = 0.048). The full-extended ET provided no significant DFS-benefit as compared with the limited-extended ET in all the other subgroups analyzed., Conclusions: Patients with eBC and N + ve disease can obtain a significant DFS-benefit from the full-extended as compared with the limited-extended adjuvant ET., Competing Interests: Declaration of competing interest All other authors declare no conflicts of interest. The lead author (FC) affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained., (Copyright © 2023. Published by Elsevier Ltd.)

Background: We report here for the first time, a comprehensive characterization of biological and clinical features of early-stage triple negative Invasive Lobular Carcinomas(TN-ILCs) METHODS: We analyzed all consecutive patients with early-stage TN-ILC operated at two reference cancer-centers between 1994 and 2012. Primary objective was to assess the invasive disease-free survival(iDFS). Co-primary objective was to assess biological features of TN-ILCs, including molecular intrinsic subtypes based on PAM-50 assay, expression of androgen receptor (AR) and mutational status of ERBB2-gene. Additionally, DNA mutational status of an independent cohort of 45 TN-ILCs from three databases were analyzed, to confirm mutations in ERBB2-gene and to identify other recurrently mutated genes., Results: Among 4152 ILCs, 74(1.8%) were TN and were analyzed. The iDFS at 5 and 10 years of FUP were 50.4%(95%CI,38.0-61.6) and 37.2%(95%CI,25.5-48.8), respectively. The molecular subtype was defined through PAM50-classifier for 31 out of 74 TN-ILCs: 48% were Luminal-A(15/31), 3% luminal-B(1/31), 32% HER2-enriched (10/31), and only 16% basal-like(5/31). Luminal tumors expressed AR more frequently than non-luminal tumors (AR≥1% in 94% of luminal tumors versus 53% in non-luminal tumors; p-value = 0.001). 20% of TN-ILCs analyzed(7/35), harbored a pathogenetic and actionable mutation in the ERBB2-gene. Analysis of the independent cohort of 45 TN-ILCs from three different databases, confirmed similar percentage of pathogenetic and actionable mutations in ERBB2-gene(20%; 9/45). Among the top 10 molecular pathways significantly enriched for recurrently mutated genes in TN-ILCs(FDR<0.05), there were ErbB-signaling and DNA-damage-response pathways., Conclusions: TN-ILCs are rare tumors with poor prognosis. Their specific biological features require newly defined targeted therapeutic strategies., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Incomplete response to neoadjuvant chemotherapy (NACT) in triple negative breast cancer (TNBC) patients is correlated to high risk of relapse. This study aimed to evaluate the role of adjuvant chemotherapy in TNBC with residual tumor after NACT., Methods: We retrospectively reviewed the outcome of patients with TNBC with residual tumor at surgery after a neoadjuvant treatment, followed by either adjuvant chemotherapy or observation. Primary endpoints were Disease Free Survival (DFS) and Overall Survival (OS)., Results: Between January 2000 and December 2016, 223 patients with early TNBC operated at the European Institute of Oncology were eligible. A total of 83.4 % of patients received adjuvant chemotherapy after surgery. 90 patients received standard dose infusional regimens, while 96 patients (51.6 %) received oral metronomic chemotherapy. Adjusting the analysis by surgical stage and Ki67 value there was a benefit for DFS and OS in favor of the group that received postoperative chemotherapy (DFS-HR 0.58 p = 0.04; OS-HR 0.54, p = 0.02). At a subgroup analysis according to the different adjuvant treatments received, a benefit for metronomic chemotherapy versus no chemotherapy both for DFS (HR 0.46, p = 0.008) and OS (HR 0.45, p = 0.009) was reported., Conclusion: Our retrospective analysis in a large cohort of TNBC patients with residual disease after NACT confirms the benefit of adding a postoperative treatment to reduce risk of relapse and death. Based on these results, we suggest that the adjuvant therapy based on metronomic cyclophosphamide and methotrexate deserves further investigation in this patients population., Competing Interests: Declaration of interests The authors declared no conflicts of interest. Contributions All authors contributed equally to this paper. All authors made substantial contributions to conception and design, acquisition of data, analysis, and interpretation of data. All authors read and approved the final manuscript., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Triple negative breast cancer encompasses several biological entities with different outcomes and is a priority to identify which patients require more treatment to reduce the risk of recurrence and which patients need less treatment., Patients and Methods: Among the 210 women with first primary invasive apocrine non metastatic breast cancer operated on between January 1998 and December 2016 at the European Institute Oncology, Milan, we identified 24 patients with a pT1-pT2, node-negative, triple negative subtype and Ki-67 ≤ 20% who did not receive adjuvant chemotherapy (CT). We compared the outcome of this cohort with a similar group of 24 patients with ductal tumors who received adjuvant chemotherapy, matched by pathological stage and biological features and also with a similar group of 12 patients with apocrine tumors who received adjuvant chemotherapy., Results: The median age was 64 and 61 years in the apocrine (w/o CT) and ductal group, respectively. The median value of Ki-67 expression was 12% in the apocrine group (w/o CT) and 16% in the ductal group (p < 0.001). After a median follow-up of 7.5 years, no patients in the apocrine group (w/o CT) experienced a breast cancer related event compared with 4 events in the ductal carcinoma group (Gray test p-value = 0.11)., Conclusions: The outcome of selected apocrine triple negative breast cancer patients who did not received adjuvant chemotherapy is excellent and supports a treatment de-escalation. Multicenter projects focusing on the possibility of avoiding adjuvant chemotherapy in selected subtypes of triple negative breast cancers with favorable outcome are warranted., Competing Interests: Declaration of competing interest Emilia Montagna and Giuseppe Cancello received a honorarium for consultant/advisory role from Pierre Fabre. Elisabetta Munzone received a honorarium for consultant/advisory role from Pierre Fabre and Genomic health. Giuseppe Viale has received a honorarium for consultant/advisory role from Dako, Roche, Astellas Pharma, Novartis and he has received funding from Roche, Ventane, Dako. Marco Colleoni has received a honorarium for consultant/advisory role from Novartis, Pierre Fabre, Pfizer, Obi-Pharma, Puba biotechnology, Celldex, Astrazeneca. Eleonora Pagan, Vincenzo Bagnardi, Silvia Dellapasqua, Monica Iorfida, Manueliata Mazza, Giovanni Mazzarol, Paolo Veronesi, Viviana Galimberti, Giorgia Santomauro have no conflict of interest., (Copyright © 2020. Published by Elsevier Ltd.)

Objectives: Tumor-associated antigens (TAAs) are frequently overexpressed in several cancer types. The aim of this study was to investigate the expression of TAAs in breast cancer., Material and Methods: A total of 250 selected invasive breast cancers including 50 estrogen receptor (ER)-positive (Luminal B like), 50 triple-negative (TN), 50 ER-positive lobular type, 50 ER- and progesterone receptor (PgR)-positive (Luminal A like) and 50 cerbB2-positive breast cancers, were assessed for New York esophageal squamous cell carcinoma-1 (NY-ESO-1), Wilms tumor antigen (WT-1) and PReferentially expressed Antigen of MElanoma (PRAME) antigen expression by immunohistochemistry (IHC)., Results: A significantly higher expression of cancer testis (CT)-antigens NY-ESO-1 and WT-1 antigen was detected in TN breast cancers compared with ER-positive tumors. NY-ESO-1 overexpression (score 2 + and 3+) assessed by monoclonal and polyclonal antibodies was detected in 9 (18%) TN cancers as compared to 2 (4%) ER-positive tumors (p = 0.002). WT1 over-expression (score 2 + and 3+) was confirmed in 27 (54%) TN tumor samples as compared to 6 (12%) ER-positive (p < 0.0001). PRAME over-expression (score 2 + and 3+) was detected in 8 (16%) HER2 positive tumor samples as compared to no TN and ER-positive cancers (p = 0.0021)., Conclusions: NY-ESO-1 and WT1 antigens are overexpressed in TN breast cancers. Because of the limited therapeutic options for this patient subgroup, CT antigen-based vaccines might prove to be useful for patients with this phenotype of breast cancer., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Most research addressing needs and concerns of young patients with breast cancer (≤40 years) is retrospective. The HOHO European protocol is a prospective multicenter cohort study of young women with newly diagnosed breast cancer, about fertility, psychosocial and quality of life concerns. Here we report the baseline data and focus on predictors of fertility concerns., Materials and Methods: Patient surveys and medical record review were used. The baseline survey included sociodemographic, medical and treatment data as well as questions on fertility concerns and preservation strategies. Subscales from the CAncer Rehabilitation Evaluation System-Short Form (CARES-SF) were administered to measure specific quality of life aspects. Uni- and multivariable modeling were used to investigate predictors of greater fertility concern., Results: Among 297 eligible respondents, 67% discussed fertility issues before starting therapy, 64% were concerned about becoming infertile after treatment, and 15% decided not to follow prescribed therapies. Fifty-four percent of women wished future children before diagnosis; of these, 71% still desired biologic children afterwards. In multivariable analysis, not having children was the only patient characteristic significantly associated with fertility concerns at diagnosis. Twenty-seven percent used fertility preservation strategies. Women who received chemotherapy reported greater physical (p = 0.021) and sexual difficulties (p = 0.039) than women who did not. Women who were married or had a partner reported less psychosocial problems than single women (p = 0.039)., Conclusions: Young women with newly diagnosed breast cancer have several concerns, including, but not limited to, fertility. The HOHO European study provides valuable information to develop targeted interventions., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objectives: To assess efficacy of bevacizumab in combination with oral chemotherapy in patients with breast cancer with lymphangitic spread to the chest wall (LBC). To identify surrogate biomarkers of response to bevacizumab., Patients and Methods: We randomly assigned patients to receive bevacizumab plus either sequential or concurrent oral vinorelbine and capecitabine every 3 weeks. The primary endpoint was time to ultimate progression (TTP); the response rate and overall survival (OS) were secondary endpoints. We performed gene expression profiling on baseline tissue samples collected from triple negative LBC. We assessed circulating endothelial cells (CEC), circulating endothelial progenitors (CEP) and circulating pericyte progenitors (CPP)., Results: A total of 66 patients were enrolled. There was no difference in TTP (median TTP 5.3 vs. 4.8 months, p = 0.21) and in OS (median OS 15.8 vs 11.9 months; p = 0.25) when comparing concurrent vs sequential treatment, respectively. Response rate was 25% vs 28% in the concurrent vs sequential arm (p = 1.00), respectively. A set of 16 genes predictive of response to bevacizumab was identified. The counts of CEPs and viable CECs below the median value were associated with an improved overall survival: 26.6 vs 9.5 months for CEPs and 22.6 vs 11.0 months for viable CECs, respectively (p = 0.02)., Conclusions: Oral chemotherapy and bevacizumab (BEVIX) is an active regimen in patients with LBC. We support the importance of using LBC as a biological model for investigating angiogenesis inhibitors. CECs and CEPs biomarkers have been identified as predictive markers of outcome and warrant further investigation., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: The indication of adjuvant chemotherapy for patients with highly proliferative estrogen receptor-positive breast cancer is controversial. We analyzed the predictive value of Ki67 for the efficacy of adjuvant chemotherapy in patients with estrogen receptor-positive, node-positive breast cancer., Patients and Methods: We identified 1241 patients with Luminal B early stage breast cancer with 1-3 axillary positive nodes who underwent surgery between 1995 and 2005 at the European Institute of Oncology and received adjuvant hormonotherapy and/or chemotherapy. Differences in the distribution of characteristics according to treatment were evaluated by the Chi-square test. To evaluate the effect of adding chemotherapy to hormonotherapy, the propensity score method was used to match patients' characteristics minimizing bias related to the non-random assignment of treatment., Results: The probability of receiving chemotherapy was significantly associated with age, tumor grade, degree of hormone responsiveness, tumor size and peripheral vascular invasion. The propensity score distribution was statistically different between the two treatment groups (p < 0.0001). The 5-year OS percentages were 95.8% (95% CI, 93.5-97.2) in the hormonotherapy group and 96.2% (95%CI, 94.4-97.4%) in the hormonotherapy/chemotherapy group (log-rank test p-value 0.663). The 5-year DFS percentages were 84.6% (95% CI, 81.0-87.6%) in the hormonotherapy group and 84.2% (95% CI, 81.3-86.7%) in the hormonotherapy/chemotherapy group (log-rank test p-value 0.388). However, when analyzing the 5-year DFS by Ki-67 distribution, Subpopulation Treatment Effect Pattern Plot (STEPP) analysis showed a beneficial effect of chemotherapy in patients with highly proliferative tumor (Ki-67 ≥ 32%). The interaction between Ki-67 and treatment was statistically significant (p = 0.027)., Conclusions: Ki67 expression identifies a subset of patients with Luminal B and node-positive breast cancer who could benefit from addition of adjuvant chemotherapy to hormonotherapy. Dichotomy was observed for Ki67 at 32% level., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Purpose: To develop a Risk Score (RS) to predict distant recurrence among premenopausal women with node-negative endocrine-responsive early breast cancer., Methods: The Cox model was used to develop the RS using clinical and histopathological features from 378 women participating in the IBCSG Trial VIII who received endocrine therapy alone or following chemotherapy. The performance of the resulting model was validated on a cohort of 1005 patients from a single institution who received endocrine therapy alone., Results: In a multivariable analysis, the risk of distant recurrence was associated with tumor size, ER, Ki-67 and peritumoral vascular invasion. In the validation cohort, patients with high RS were at greater risk of distant recurrence compared to patients with low RS (HR, 17.41; 95% CI, 5.72-52.95)., Conclusion: In premenopausal women with node-negative endocrine-responsive early breast cancer, the RS identifies patients at higher risk of distant recurrence., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Biopsy of metastatic site of disease can influence treatment decisions, but its impact on survival remains uncertain., Patients and Methods: One-hundred patients with first metachronous liver metastases (LM) from breast cancer (BC) who underwent liver biopsy between 1999 and 2009 were identified. One-hundred matched control patients with LM from BC and no biopsy were selected., Results: Liver biopsy had no statistically significant impact on survival when comparing biopsied patients to controls [HR 0.82 (95% CI 0.58-1.16)]. Patients with early metastasis (within 3 years) undergoing liver biopsy had a better survival [HR 0.60 (95% CI 0.38-0.97)] compared to those who did not. Liver biopsy had no statistically significant impact on survival in patients with late LM (after 3 years) [HR 1.09 (95% CI 0.69-1.74)]. We observed that 18 out of 100 biopsied patients (18.0%) had a conversion of predictive factors which allowed adjusting for therapy, specifically new expression of ER (n=5), overexpression of HER2 (n=12) or both (n=1). Fourteen out of 18 (77.8%) received anti-HER2 treatment for the first time at the time of metastasis and 3 others (16.7%) received hormone therapy. Those 18 patients showed a better survival compared to the other 82 biopsied patients [HR 0.55 (95% CI 0.28-1.10)] and compared to the 13 biopsied patients with disappearance of features which predicted responsiveness to a given treatment [HR 0.19 (95% CI 0.06-0.62)]., Conclusions: Liver biopsy can impact survival of patients with early metastases from BC. Discordance between primary and distant lesions can offer the patients new treatment options., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: There is an urgent need for the identification of commonly assessable predictive factors in the treatment of patients with metastatic breast cancer., Methods: During the course of a treatment including low dose metronomic oral cyclophosphamide and capecitabine plus i.v. bevacizumab (plus erlotinib in one third of the patients) for metastatic breast cancer, we observed that a relevant number of patients developed repeatedly elevated levels of mean corpuscular volume (MCV) of red blood cells without a significant fall in hemoglobin levels. We conducted a retrospective analysis on these 69 patients to evaluate if the increase in MCV could be associated to tumor response., Results: During the course of treatment 42 out of 69 patients (61%) developed macrocytosis. Using Cox proportional hazards modeling that incorporated macrocytosis (MCV ≥ 100 fl) as a time-dependent covariate, macrocytosis resulted in a halved risk of disease progression (HR 0.45; 95% CI, 0.22-0.92, p-value 0.028). In a landmark analysis limited to patients with no sign of progression after 24 weeks of treatment, median time to progression was 72 weeks (48 weeks after landmark) in patients who had developed macrocytosis, and 43 weeks (19 weeks after landmark) in patients who had not (p=0.023)., Conclusion: Macrocytosis inversely related to risk of disease progression in patients treated with metronomic capecitabine plus cyclophosphamide and bevacizumab for metastatic breast cancer. This finding may be explained through thymidylate synthase inhibition by capecitabine. Whether bevacizumab has a role in determining macrocytosis, similarly to what happens with sunitinib, has to be further investigated. If other studies will confirm our findings, macrocytosis might be used as an early marker of response during metronomic treatment with capecitabine and cyclophosphamide with or without bevacizumab., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Combined trastuzumab and intravenous vinorelbine yielded high clinical activity as preoperative treatment in patients (pts) with HER 2/neu positive breast cancer., Patients and Methods: We tested a preoperative combination of trastuzumab with oral vinorelbine (oV) in pts with locally advanced (T2-T4 N0-3 M0) HER2-positive breast cancer. Trastuzumab was administered i.v q 3 wks and oV was administered at the dose of 55 mg/sqm on days 1 and 3 q 3 wks, for 8 courses. Pts with ER > or = 10% tumors received endocrine therapy with letrozole 2.5 mg/day, plus monthly triptorelin if premenopausal., Results: Forty-five pts entered the study. The overall response rate (CR + PR) was 76% (95% CI: 60%-87%). pCR was observed in 4 pts (10%). Among ER-positive tumors 21/25 pts obtained a clinical response (84%) and two pts obtained a pCR (8%)., Conclusions: The combination of trastuzumab and oral vinorelbine demonstrated encouraging activity in patients with HER 2 positive ER-positive tumors. Alternative strategies should be investigated in patients with endocrine non responsive disease., (Copyright 2010 Elsevier Ltd. All rights reserved.)