Trastuzumab-related cardiotoxicity in patients with nonlimiting cardiac comorbidity.

BACKGROUND: Significant and symptomatic cardiac comorbidity is a contraindication to adjuvant trastuzumab in breast cancer patients. However, some patients with asymptomatic, nonlimiting cardiac comorbidity and normal baseline left ventricular ejection fraction (LVEF) receive adjuvant trastuzumab in the clinical practice. We sought to describe the tolerability of trastuzumab in these patients. PATIENTS AND METHODS: Retrospective analysis of patients with baseline asymptomatic, nonlimiting cardiac comorbidity receiving adjuvant trastuzumab at six Institutions between July 2007 and January 2016. RESULTS: Thirty-seven patients with HER2-positive, surgery treated breast cancer at high risk of relapse were studied. Median age was 64 years (range 36-82), median baseline LVEF 61% (range 50%-85%). Thirteen patients (35%) received trastuzumab with adjuvant anthracycline and taxane-based regimens, 19 (51%) with taxane-based, three (8%) with off-label vinorelbine and two (5%) with off-label endocrine therapy. Most frequent cardiac comorbidities were ischemic heart disease (35%), valvular disease (30%), atrial fibrillation (19%), and conduction disorders (14%). Nine patients (24.3%) experienced a cardiac event: congestive heart failure (one patient, 3%), asymptomatic LVEF reduction (six patients, 16%), and rhythm disturbances (two patients, 5%). Trastuzumab had to be discontinued either permanently (five patients, 14%) or temporarily (two patients, 5%). At the time of last follow-up visit, all patients showed LVEF within normal limits, except one who had experienced a symptomatic cardiac event (LVEF value at last follow-up 46%). CONCLUSIONS: Caution is needed in patients with significant ongoing cardiovascular risk factors, but when adjuvant trastuzumab is deemed beneficial on breast cancer outcomes, nonlimiting cardiac comorbidity should not preclude treatment.

Response and survival of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy.

BACKGROUND: Predicting treatment benefit and/or outcome before any therapeutic intervention has taken place would be clinically very useful. Herein, we evaluate the ability of the intrinsic subtypes and the risk of relapse score at diagnosis to predict survival and response following neoadjuvant chemotherapy. In addition, we evaluated the ability of the Claudin-low and 7-TNBCtype classifications to predict response within triple-negative breast cancer (TNBC). METHODS: Gene expression and clinical-pathological data were evaluated in a combined dataset of 957 breast cancer patients, including 350 with TNBC, treated with sequential anthracycline and anti-microtubule-based neoadjuvant regimens. Intrinsic subtype, risk of relapse score based on subtype and proliferation (ROR-P), the Claudin-low subtype and the 7-TNBCtype subtype classification were evaluated. Logistic regression models for pathological complete response (pCR) and Cox models for distant relapse-free survival (DRFS) were used. RESULTS: Basal-like, Luminal A, Luminal B, and HER2-enriched subtypes represented 32.7%, 30.6%, 18.2%, and 10.3% of cases, respectively. Intrinsic subtype was independently associated with pCR in all patients, in hormone receptor-positive/HER2-negative disease, in HER2-positive disease, and in TNBC. The pCR rate of Basal-like disease was >35% across all clinical cohorts. Neither the Claudin-low nor the 7-TNBCtype subtype classifications predicted pCR within TNBCs after accounting for intrinsic subtype. Finally, intrinsic subtype and ROR-P provided independent prognostic information beyond clinicopathological variables and type of pathological response. A 5-year DRFS of 97.5% (92.8-100.0%) was observed in these neoadjuvant-treated and clinically node-negative patients predicted to be low risk by ROR-P (i.e. 57.4% of Luminal A tumors with clinically node-negative disease). CONCLUSIONS: Intrinsic subtyping at diagnosis provides prognostic and predictive information for patients receiving neoadjuvant chemotherapy. Although we could not exclude a survival benefit of neoadjuvant chemotherapy in patients with early breast cancer with clinically node-negative and ROR-low disease at diagnosis, the absolute benefit of cytotoxic therapy in this group might be rather small (if any).

Hormone-receptor expression and activity of trastuzumab with chemotherapy in HER2-positive advanced breast cancer patients.

BACKGROUND: The relationship between quantitative immunohistochemical hormone receptor expression and response to the combination of trastuzumab with chemotherapy in HER2-positive advanced breast cancer is currently unknown. METHODS: Estrogen receptor (ER) and progesterone receptor expression was studied both as a dichotomous variable (positivity set at ≥ 1% of positive cells) and as a continuous variable. The effect of hormone receptor expression on overall response rate and progression-free survival in patients receiving trastuzumab-based treatment was studied by univariate and multivariate analysis. RESULTS: One hundred eleven of 227 consecutive advanced breast cancer patients treated at 2 Institutions had hormone receptor-positive tumors (49%). High expression of ER (≥ 30% of tumor cells) predicted reduced probability of tumor response to trastuzumab plus chemotherapy (multivariate odds ratio, 0.422; 95% confidence interval [CI], 0.222-0.803; P = .009). In patients with hormone receptor-positive tumors (≥ 1% of tumor cells), maintenance endocrine therapy added to trastuzumab upon the completion of chemotherapy was associated with a significant progression-free survival benefit (hazard ratio, 0.521; 95% CI, 0.3325-0.836; P = .007). CONCLUSIONS: Our results suggest a predictive role of hormone receptor expression in HER2-positive tumors. Further investigation in this patient subset is warranted to optimize the use of HER2-targeting agents, chemotherapy, and endocrine therapy.

Moderate immunohistochemical expression of HER-2 (2+) without HER-2 gene amplification is a negative prognostic factor in early breast cancer.

BACKGROUND: Human epidermal growth factor receptor (HER)-2 testing in patients with operable breast cancer is aimed at identifying candidates for adjuvant anti-HER-2 treatment. However, commonly defined "HER-2(-)" tumors express variable levels of the HER-2 protein, which can influence prognosis. We compared the clinical outcomes of operable breast cancer patients stratified according to a common HER-2 testing algorithm. METHODS: We studied 1,150 women (median age, 58 years; range, 22-94 years) undergoing surgery for early breast cancer at our institution. HER-2 status was determined using the HercepTest™ (Dako, Glostrup, Denmark) and, when needed, by fluorescence in situ hybridization (FISH). Patients receiving adjuvant trastuzumab were excluded. The impact of HER-2 status on the disease-free survival (DFS) time was studied using multivariate Cox proportional regression analysis. RESULTS: Four hundred-fifty seven (40%), 454 (39%), 116 (10%), and 123 (11%) patients were considered HER-2 0+, HER-2 1+, HER-2 2+/HER-2(-) by FISH, and HER-2(+) (3+ or HER-2(+) by FISH), respectively. Compared with a HER-2 0 or 1+ status, a HER-2 2+/HER-2(-) by FISH status was associated with a worse DFS outcome on multivariate analysis. Compared with a HER-2(+) status, a HER-2 2+/HER-2(-) status showed a time-dependent effect on the DFS probability, with an initial advantage that worsened every year by a factor of 1.649. CONCLUSION: A HER-2 2+/HER-2(-) status is an adverse prognostic factor in patients with operable breast cancer. Because of suggestions from randomized trials that the benefits of adjuvant trastuzumab may not be limited to patients with HER-2(+) tumors, patients with a HER-2 2+/HER-2(-) status are ideal candidates for studies testing this hypothesis.

Underuse of anthracyclines in women with HER-2+ advanced breast cancer.

Anthracyclines are among the most active drugs in breast cancer. Because of excessive cardiotoxicity, their use in combination with trastuzumab has been discouraged in patients with human epidermal growth factor receptor (HER)-2(+) metastatic breast cancer. We sought to describe how this treatment paradigm influenced the use of anthracyclines in this patient setting. We analyzed a multi-institutional database containing the treatment history of 450 patients who received at least one trastuzumab-based regimen for HER-2(+) metastatic breast cancer. Patients were considered eligible for anthracyclines for metastatic disease if they were never exposed (NE) or had been previously exposed (PE) to an anthracycline in the neoadjuvant or adjuvant setting and had relapsed after 12 months from the last dose. We then assessed the use of anthracycline-based therapy after failure with the first trastuzumab-based regimen in eligible patients. Three-hundred twenty-one patients were considered eligible for anthracyclines. In total, 190 eligible patients developing disease progression during the initial trastuzumab-based therapy were analyzed. An anthracycline was administered as first salvage treatment in 14 NE and two PE patients. Another 15 NE and nine PE patients received an anthracycline as a further line of therapy. Of 119 eligible patients who died from breast cancer, only 30 received an anthracycline for metastatic disease. In conclusion, despite the fact that two thirds of the patients receiving trastuzumab-based therapy for HER-2 metastatic breast cancer are eligible for anthracyclines, these drugs are infrequently used nowadays to treat trastuzumab-refractory disease. A role for these compounds should be redefined in this patient subset.

Trastuzumab with either docetaxel or vinorelbine as first-line treatment for patients with HER2-positive advanced breast cancer: a retrospective comparison.

BACKGROUND: Combinations of trastuzumab with either docetaxel or vinorelbine are considered valuable treatment options for HER2-positive metastatic breast cancer patients. We performed a retrospective comparison of the clinical outcomes associated with either one of these combinations. METHODS: From a multi-institutional database we retrieved 179 patients treated with either docetaxel or vinorelbine plus trastuzumab as first-line therapy for HER2-positive advanced breast cancer. RESULTS: Docetaxel-trastuzumab was superior to vinorelbine-trastuzumab in terms of response rate (RR: 77 vs 57%, p = 0.01) and median overall survival (OS: 35 vs 23 months, p = 0.04), but not in median time to progression (TTP: 12 vs 10 months, p = 0.53). At multivariate analysis, type of treatment was not associated with TTP but was an independent predictor of OS, with a significant reduction in the risk of death in favor of docetaxel-trastuzumab (HR 0.474, 95% IC 0,303-0.742, p < 0.01). CONCLUSION: Docetaxel or vinorelbine, when combined with trastuzumab, provide excellent rates of tumor control in patients with previously untreated HER2-positive advanced breast cancer. Docetaxel may offer some advantage in terms of response rate and resulted in a significantly prolonged overall survival, which, because of the retrospective design of our study, deserves further investigation in prospective trials.

Treatment with Beta-Blockers and ACE-Inhibitors in Breast Cancer Patients Receiving Adjuvant Trastuzumab-Based Therapy and Developing Mild Cardiac Toxicity: A Prospective Study.

BACKGROUND: Angiotensin Converting Enzyme inhibitors (ACEis) and beta-blockers (BB) are suggested to prevent and treat trastuzumab-related cardiac toxicity. We performed a prospective clinical trial in women experiencing mild cardiac toxicity (MCT) while on adjuvant treatment with trastuzumab. METHODS: MCT was defined as an asymptomatic absolute decrease in LVEF of ≥ 10 percentage units to >50%. Treatment consisted of enalapril 2.5 mg bid and carvedilol 3.75 mg bid, which were up-titrated to 10 mg bid for the enalapril and 6,25 mg bid of carvedilol. In patients receiving study drug, the primary study end-point was LVEF recovery, which was defined as a post-trastuzumab LVEF returning to no less than -5 percentage points of the baseline value. RESULTS: 103 patients were enrolled, 100 started trastuzumab, and 98 completed the planned treatment. Sixteen patients (16%) had MCT and received study drugs until trastuzumab completion. None of these patients achieved a post-trastuzumab LVEF recovery. Nevertheless, treated patients had significantly higher median LVEF recovery from nadir to post-trastuzumab LVEF in (8% points vs. 4% points, respectively, p = 0.004), resulting in no difference in post-treatment LVEF values compared to patients without MCT. CONCLUSION: Treatment of MCT with ACEis and BB allows faster LVEF recovery from nadir values and should be further studied in this setting.

Self-evaluation of duration of adjuvant chemotherapy side effects in breast cancer patients: A prospective study.

BACKGROUND: We recently reported that self-evaluation of the incidence and severity of treatment-related side effects (TSEs) using a National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0-based questionnaire was feasible and more informative than doctor reports in patients undergoing standard adjuvant chemotherapy for operable breast cancer. Here, we compare self- and doctor-evaluated day of onset and duration of TSEs in the same population. PATIENTS AND METHODS: Six hundred and four patients were enrolled at 11 sites in Italy. CTCAE v4.0 definitions of grade of severity of nausea, vomiting, constipation, anorexia, dysgeusia, diarrhea, fatigue, pain, paresthesia, and dyspnea were translated into Italian and rephrased. Questionnaires were administered after the first and third chemotherapy cycles. At each time-point, information on TSEs was extracted from the medical charts and compared to patient questionnaires. RESULTS: A total of 594 and 573 paired patient and doctor questionnaires were collected after cycles one and three, respectively. TSE duration was significantly longer when reported by patients compared to doctors for six and seven of ten items after cycles one and three, respectively. Due to the combined effect of doctor underreporting of TSE incidence and duration, the mean percentages of cycle days with TSEs were significantly higher for all ten items when based on patient reports. Day of onset could not be evaluated because of insufficient numbers of complete records. CONCLUSIONS: Self-reporting TSE duration is feasible using a CTCAE-derived questionnaire. As doctors tend to underestimate TSE incidence and duration, patient-reported outcomes should be incorporated into clinical practice, perhaps using eHealth technologies, to harness their potential to better estimate total TSE burden.

Breast cancer in BRCA mutation carriers: medical treatment.

About 10% of breast cancers are associated with the inheritance of autosomal dominant breast cancer susceptibility alleles BRCA1 and BRCA2. Until recently, the medical management of BRCA mutation-associated breast cancer has not differed from that of the sporadic breast cancer counterpart. However, there is mounting evidence that this molecular alteration confers sensitivity or resistance to systemic therapies that can be exploited in terms of medical management. For example, studies support the use of platinum salts chemotherapy in BRCA mutated cancers. Moreover, a number of targeted therapies are showing activity in BRCA mutation carriers. Above all, BRCA defective tumor cells are particularly sensitive to Poly(ADP-ribose) polymerase (PARP) inhibitors. This review will summarize the state of the art of the medical treatment of breast cancer in BRCA mutation carriers, with a particular focus on chemotherapies and targeted therapies.

Investigational ErbB-2 tyrosine kinase inhibitors for the treatment of breast cancer.

INTRODUCTION: ErbB2 overexpression and/or gene amplification is present in 20% of all breast cancers and characterizes an aggressive form of this disease. Despite the availability of several active drugs that have yielded substantial survival improvements, most patients with ErbB2-positive metastatic disease will develop tumor progression, either because of primary or acquired resistance. Therefore, research has focused on drugs that can more efficiently interfere with ErbB2 and with other members of the epidermal growth factor receptor family. AREAS COVERED: This review focuses on those investigational drugs that inhibit ErbB2 tyrosine kinase activity (TKIs) for treating breast cancer. EXPERT OPINION: ErbB-targeting TKIs show encouraging activity in patients with ErbB-positive tumors that are resistant to conventional ErbB-therapies (mostly trastuzumab), confirming pre-clinical observations. Efficient interference with the ErbB-network signaling implies also a potential use in ErbB2-normal tumors, where the phenotype is sustained by ErbB-aberrant signaling. Finally, early data suggests that ErbB-targeting TKIs could be active in treating patients with activating ErbB2 mutations. Ongoing and future research efforts should elucidate what is, according to the peculiarities of these compounds, their positioning in the treatment of women with breast cancer.

New and developing chemical pharmacotherapy for treating hormone receptor-positive/HER2-negative breast cancer.

INTRODUCTION: Endocrine therapy is the mainstay of treatment for a substantial proportion of hormone receptor positive (HR+) breast cancer (BC). Indeed, patients with metastatic disease not immediately life threatening may experience long disease control across several lines of endocrine therapy. The major limitation of this therapeutic approach is primary or acquired resistance. A better understanding of endocrine resistance has resulted in newer targeted agents to be added to endocrine therapy. Areas covered: This review highlights new findings in the treatment of HR+/HER2- BC, with a particular focus on new drugs from phase 3 development onwards. Expert opinion: Combining endocrine therapy with agents targeting putative mechanisms of endocrine resistance is a newer treatment paradigm in HR+ BC. Adding a biologically targeted agent to endocrine therapy results in improved response rate, and clinical benefit rate, and prolonged progression-free survival. A clear advantage in overall survival has not yet been reported. Combination therapy allows to delay chemotherapy but increases toxicities and costs, which are critical factors in decision making in the clinical practice. Moreover, identification and validation of biomarkers of response are needed. Ongoing and future trials should elucidate the role of these compounds in the treatment of HR+/HER2- BC.

Self-evaluation of Adjuvant Chemotherapy-Related Adverse Effects by Patients With Breast Cancer.

IMPORTANCE: Patient perspective on chemotherapy-related adverse effects is being increasingly acknowledged both in experimental clinical trials and in clinical practice. OBJECTIVE: To evaluate a 10-item, paper questionnaire derived from the US National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 for patient-reported chemotherapy-related adverse effects. DESIGN, SETTING, AND PARTICIPANTS: Prospective, single-arm study of 604 women with breast cancer receiving standard adjuvant chemotherapy conducted at 11 outpatient oncology clinics at academic and nonacademic Italian hospitals between January 2011 and October 2013. The CTCAE version 4.0 definitions of grade of severity for nausea, vomiting, constipation, anorexia, dysgeusia, diarrhea, fatigue, pain, paresthesia, and dyspnea were translated into Italian and rephrased. Questionnaires were administered after the first and third cycle of chemotherapy. Adverse effect information was also extracted from the medical records to compare with patient-reported data. MAIN OUTCOMES AND MEASURES: Differences in adverse effect-reporting between paired questionnaires and agreement between patient and physician adverse effect-reporting (grade 0 vs grade ≥1) were studied. Linear regression was used to study the effect of the number of patients enrolled at each institution on the magnitude of discrepancy in adverse effect-reporting between patients and physicians. RESULTS: A total of 604 women (median age, 53.4 years; interquartile range, 45.0-62.7 years) were enrolled. The number of patients enrolled at each site varied between 6 and 236. Three patients withdrew consent prior to starting the first cycle of adjuvant chemotherapy. After cycle 1 of adjuvant chemotherapy, 596 patient questionnaires were collected, and 581 patient questionnaires were collected after cycle 3. Of the questionnaires collected, 594 and 573 had corresponding questionnaire results extracted from medical records at the same time point. The median (interquartile range) percentage of completed questionnaire fields was 82% (80%-88%) for both the first and third cycle questionnaires, and the results of the 2 patient questionnaires showed a reduction in vomiting (severity), diarrhea (both incidence and severity), and pain (both incidence and severity), as well as a statistically significant increase in dysgeusia (both incidence and severity) and dyspnea (both incidence and severity) in the second patient-completed questionnaire. The frequency and severity of chemotherapy-related adverse effects were consistently greater in patient-reported data than physician-reported data. As a result, interrater agreement was low for most adverse effects, ranging from 0.10 for anorexia to 0.54 for vomiting (Cohen κ statistic). There was a strong and significant positive correlation between the magnitude of the discrepancy in the frequency of reporting adverse effects and the number of patients enrolled at each site. CONCLUSIONS AND RELEVANCE: Adherence to reporting adjuvant chemotherapy-related adverse effects using the CTCAE system is high in women undergoing adjuvant chemotherapy for breast cancer. Workload may contribute to agreement discrepancies by limiting the physician-patient relationship.

Clinical utility of exemestane in the treatment of breast cancer.

Breast cancer is the most prevalent cancer in women, causing a significant mortality worldwide. Different endocrine strategies are available for the treatment of hormone-sensitive breast cancer, including antiestrogen tamoxifen and fulvestrant, as well as third-generation aromatase inhibitors (AIs), such as letrozole, anastrozole, and exemestane. In this review, we will focus on exemestane, its clinical use, and its side effects. Exemestane is a steroidal third-generation AI now used in all treatment settings for breast cancer. In the metastatic disease, it has been extensively investigated as the first-, second-, and further-line treatment and it is now registered for the treatment of postmenopausal women with advanced estrogen-receptor-positive breast cancer whose disease has progressed following antiestrogen therapy. A potential lack of cross-resistance with nonsteroidal AIs has been described, giving additional therapeutic opportunities in sequences of endocrine agents. Exemestane is also approved for the adjuvant treatment of postmenopausal early breast cancer, either as upfront monotherapy for 5 years, as a switch following 2-3 years of tamoxifen, or as extended therapy beyond 5 years of adjuvant treatment. New promising data also showed a beneficial effect in young premenopausal early breast cancer patients, when administered together with ovarian suppression. Interesting results have also emerged when exemestane has been investigated as neodjuvant treatment as well as preventive agent in healthy women at high risk for breast cancer. Exemestane is generally well tolerated, with a side effect profile similar to that of other AIs, including menopausal symptoms, arthralgia, and bone loss. In conclusion, exemestane can be considered an effective and well-tolerated endocrine treatment option for all stages of breast cancer.

Buparlisib , an oral pan-PI3K inhibitor for the treatment of breast cancer.

INTRODUCTION: Deregulation of the phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) intracellular signaling pathway is common in breast cancer (BC) and has been found to be potentially implicated in resistance to endocrine and anti-HER2 therapies. Targeting the PI3K/Akt/mTOR pathway may remove this inhibition and restore sensitivity to these compounds. Buparlisib (BKM120) is a potent oral pan-class I PI3K inhibitor that is being extensively evaluated in multiple tumor types. AREAS COVERED: This review briefly summarizes the pharmacodynamics and pharmacokinetics of buparlisib, focusing on preclinical and clinical data in BC and on ongoing randomized trials. EXPERT OPINION: Overall, buparlisib is a safe and tolerable drug and, despite its peculiar toxicity profile, it is suitable for studies in combination with other anticancer agents in BC. Early-phase clinical trials in BC have provided evidence of antitumor activity. Several trials are being conducted in all the biological subsets of BC, including combinations with endocrine therapy, anti-HER2 agents, PARP-inhibitors and chemotherapy. While clinical results are eagerly awaited, biological material suitable for both genomic and non-genomic analyses is being collected. The authors expect an intense investigation of the potential biomarkers that explain response or resistance to buparlisib and inspire strategies to rationally explore the therapeutic potential of this drug.

Linifanib: current status and future potential in cancer therapy.

Angiogenesis is one of the major mechanisms controlling tumor proliferation and metastatic spreading. Targeting of pro-angiogenic factors and their downstream effectors represents an appealing therapeutic option in the treatment of different cancer types. Linifanib (ABT-869) is a novel tyrosine-kinase inhibitor (TKI) inhibitor and its anti-angiogenic activity has been explored in numerous clinical trials. Here, we review preclinical development of linifanib focusing on its pharmacodynamic and pharmacokinetic characteristics and briefly summarize its evaluation in clinical trials. Linifanib selectively targets VEGFR and PDGFR and has low off-target inhibitory activity. Preclinical and early-phase trials have been showing promising efficacy results However, although signals of anti-tumor activity have been proven in some malignancies, linifanib late-phase development has been facing some challenges due to limited efficacy and increased toxicities. New strategies aimed at finding biomarkers of response and minimizing toxicities are needed to allow the further development of a promising compound.

2013 San Antonio Breast Cancer Symposium.

The San Antonio Breast Cancer Symposium is considered by researchers and physicians involved in breast cancer management as one of the most important international events on the subject. A dense program of plenary presentations of novel findings, main lectures, poster discussions and displays, it encompasses all the aspects of the rapidly evolving field of breast cancer research and treatment. This article briefly summarises some of the presentations that are expected to have an impact on the medical treatment of breast cancer.

Clinical outcome in women with HER2-positive de novo or recurring stage IV breast cancer receiving trastuzumab-based therapy.

BACKGROUND: Five to 10% of women with newly diagnosed breast cancer have synchronous metastases (de novo stage IV). A further 20% will develop metastases during follow-up (recurring stage IV). We compared the clinical outcomes of women with HER2-positive metastatic breast cancer (MBC) receiving first-line trastuzumab-based therapy according to type of metastatic presentation. PATIENTS AND METHODS: Retrospective analysis of 331 MBC patients receiving first-line trastuzumab-based treatment. Response rates (RR) were compared by the chi-square test. Time-to progression (TTP) and overall survival (OS) curves were compared by the log-rank test. Cox-proportional hazards models were used to study predictors of PFS and OS, including the type of metastatic presentation. RESULTS: Seventy-seven patients (23%) had de novo stage IV disease. Forty-six of these patients underwent surgery of the primary ("de novo/surgery"). Response rates to first-line trastuzumab-based therapy and median progression-free survival did not differ in patients with "recurring", "de novo/surgery" and "de novo" without surgery ("de novo/no surgery) stage IV breast cancer. However, women with "de novo/surgery" stage IV breast cancer had the longest median OS (60 months), and those with "de novo/no surgery" stage IV breast cancer the shortest (26 months). For women with recurring metastatic breast cancer median OS was 40 months (overall log-rank test, p < 0.01). Multivariate analysis confirmed these findings. CONCLUSION: Our analysis shows that response rates and PFS to first-line trastuzumab-based therapy do not differ significantly between de novo and recurring stage IV, HER2 positive breast cancer. The observed difference in OS favoring women with de novo stage IV disease submitted to surgery of the primary tumor could be the result of a selection bias.

Current status and future perspectives in the endocrine treatment of postmenopausal, hormone receptor-positive metastatic breast cancer.

INTRODUCTION: Endocrine therapy is a fundamental component of the therapeutic repertoire for treatment of metastatic, hormone receptor-positive breast cancer. Inevitably, however, tumors develop resistance to these compounds, and overcoming this phenomenon is a key motivator of research in this field. AREAS COVERED: This review summarizes the current status of endocrine therapy for the treatment of metastatic disease, with a main focus on postmenopausal patients. Furthermore, strategies that could potentially sustain endocrine resistance and future perspectives in this direction are also to be described. Relevant references were identified by PubMed searches and from the abstract books of the annual meetings of The European Society of Clinical Oncology (ESMO), The American Society of Clinical Oncology (ASCO) and from the San Antonio Breast Cancer Symposia. EXPERT OPINION: Combinations of endocrine therapy with HER2 targeting agents, as well as with compounds that can interfere with PI3K/Akt/mTOR signaling, are two promising strategies for delaying or overcoming endocrine resistance, mediated by these relevant biological pathways. Due to increased costs and the burden of toxicity associated with these combination therapies, compared to endocrine therapy alone, it is imperative to concentrate efforts on establishing biomarkers that can predict efficacy.