Effectiveness of neoadjuvant trastuzumab and chemotherapy in HER2-overexpressing breast cancer

Purpose

Trastuzumab and chemotherapy is the current standard of care in HER2+ early or locally advanced breast cancer, but there are scanty literature data of its real world effectiveness.

Methods

We retrospectively reviewed 205 patients with HER2+ breast cancer diagnosed in 10 Italian Medical Oncology Units between July 2003 and October 2011. All patients received neoadjuvant systemic therapy (NST) with trastuzumab in association with chemotherapy. Many different chemotherapy regimens were used, even if 90 % of patients received schemes including anthracyclines and 99 % received taxanes. NST was administered for more than 21 weeks (median: 24) in 130/205 (63.4 %) patients, while trastuzumab was given for more than 12 weeks (median: 12 weeks) in 101/205 (49.3 %) patients. pCR/0 was defined as ypT0+ypN0, and pCR/is as ypT0/is+ypN0.

Results

pCR/0 was obtained in 24.8 % and pCR/is in 46.8 % of the patients. At multivariate logistic regression, nonluminal/HER2+ tumors (P < 0.0001) and more than 12 weeks of neoadjuvant trastuzumab treatment (P = 0.03) were independent predictors of pCR/0. Median disease-free survival (DFS) and cancer-specific survival (CSS) have not been reached at the time of analysis. At multivariate analysis, nonluminal/HER2+ subclass (DFS: P = 0.01 and CSS: P = 0.01) and pathological stage II–III at surgery (DFS: P < 0.0001 and CSS: P = 0.001) were the only variables significantly associated with a worse long-term outcome.

Conclusions

Our data set the relevance of molecular subclasses and residual tumor burden after neoadjuvant as the most relevant prognostic factors for survival in this cohort of patients.     

Nine-week trastuzumab treatment versus 52-week trastuzumab treatment for HER2-positive early-stage breast cancer

Purposes

Trastuzumab is known to be effective for early and advanced stages of breast cancer but optimal duration for early-stage breast cancer (EBC) is not well known. We evaluated the efficacy and toxicity of 9- and 52-week trastuzumab therapy for EBC retrospectively.

Methods

In this multicenter study, the medical records of all patients with EBC were analyzed in 8 centers retrospectively. Totally consecutive, 479 female patients who received trastuzumab in the adjuvant treatment were evaluated for disease-free survival (DFS), overall survival (OS), efficacy, and toxicity.

Results

There were 181 (37.8?%) and 298 (62.2?%) patients in the 9- and 52-week trastuzumab groups, respectively. Median follow-up was 30.6?months (5.7–68.9) in the 9-week trastuzumab group and 29.3?months (5.9–59.6) in the 52-week trastuzumab group. Thirty-six month DFS was 90 and 85?% (P?=?0.132) in the 9- and 52-week trastuzumab treatment groups, respectively, and 36-month OS was 96 and 97?% in the 9- and 52-week trastuzumab groups, respectively (P?=?0.779). Symptomatic cardiotoxicity was observed in 1 (0.6?%) patient in the 9-week trastuzumab group and in 4 (1.3?%) patients in the 52-week trastuzumab group.

Conclusions

In this study, similar outcomes were found in the 9- and 52-week trastuzumab treatment groups.     

Combining CD47 blockade with trastuzumab eliminates HER2-positive breast cancer cells and overcomes trastuzumab tolerance

Trastuzumab, a targeted anti-human epidermal-growth-factor receptor-2 (HER2) monoclonal antibody, represents a mainstay in the treatment of HER2-positive (HER2⁺) breast cancer. Although trastuzumab treatment is highly efficacious for early-stage HER2⁺ breast cancer, the majority of advanced-stage HER2⁺ breast cancer patients who initially respond to trastuzumab acquire resistance to treatment and relapse, despite persistence of HER2 gene amplification/overexpression. Here, we sought to leverage HER2 overexpression to engage antibody-dependent cellular phagocytosis (ADCP) through a combination of trastuzumab and anti-CD47 macrophage checkpoint immunotherapy. We have previously shown that blockade of CD47, a surface protein expressed by many malignancies (including HER2⁺ breast cancer), is an effective anticancer therapy. CD47 functions as a “don’t eat me” signal through its interaction with signal regulatory protein-α (SIRPα) on macrophages to inhibit phagocytosis. Hu5F9-G4 (magrolimab), a humanized monoclonal antibody against CD47, blocks CD47’s “don’t eat me” signal, thereby facilitating macrophage-mediated phagocytosis. Preclinical studies have shown that combining Hu5F9-G4 with tumor-targeting antibodies, such as rituximab, further enhances Hu5F9-G4’s anticancer effects via ADCP. Clinical trials have additionally demonstrated that Hu5F9-G4, in combination with rituximab, produced objective responses in patients whose diffuse large B cell lymphomas had developed resistance to rituximab and chemotherapy. These studies led us to hypothesize that combining Hu5F9-G4 with trastuzumab would produce an anticancer effect in antibody-dependent cellular cytotoxicity (ADCC)-tolerant HER2⁺ breast cancer. This combination significantly suppressed the growth of ADCC-tolerant HER2⁺ breast cancers via Fc-dependent ADCP. Our study demonstrates that combining trastuzumab and Hu5F9-G4 represents a potential new treatment option for HER2⁺ breast cancer patients, even for patients whose tumors have progressed after trastuzumab.

Overexpression of human epidermal-growth-factor receptor-2 (HER2) occurs in ∼16% of breast cancers in the United States (1–3) and has been associated with a number of adverse prognostic factors (summarized in ref. 4). Prior to the advent of HER2-targeted therapeutics, HER2 overexpression was associated with increased risk of recurrence and poor survival rates (1, 2). Trastuzumab is a humanized monoclonal antibody that selectively binds HER2. Clinical use of trastuzumab has dramatically improved the outcomes of patients with HER2⁺ breast cancer and remains the foundational component of modern standard of care treatment regimens for HER2⁺ breast cancer in the neoadjuvant, adjuvant, and metastatic settings (5, 6). Early studies of trastuzumab’s mechanism of action focused on trastuzumab’s inhibition of protumor growth HER2 signaling pathways (7–9). Subsequent research revealed that trastuzumab also coopts a patient’s immune system to promote an antitumor response (7–11). This later body of research initially elucidated trastuzumab’s ability to engage Fc-receptors on natural killer cells (NKs) to promote antibody-dependent cellular cytotoxicity (ADCC) (12, 13). Recent reports have further illuminated trastuzumab’s ability to engage Fc-γ receptors (FcγR) on macrophages and promote antibody-dependent cellular phagocytosis (ADCP) (14).Administering trastuzumab to early-stage HER2⁺ breast cancer patients significantly increases disease-free survival and overall survival rates (15–17). Treating advanced-stage HER2⁺ breast cancer patients with the most efficacious trastuzumab-based regimens, however, produces less hopeful outcomes. For example, the Food and Drug Administration (FDA)-approved regimen studied in the CLEOPATRA clinical trial for HER2⁺ metastatic breast cancer in the first line of treatment utilized trastuzumab in combination with docetaxel and pertuzumab; this regimen resulted in a median progression-free survival of 18.7 mo (18, 19). In the same study, 19.8% of patients did not achieve an objective clinical response to trastuzumab-based treatment (20). And, of the advanced-stage HER2⁺ breast cancer patients who initially responded to trastuzumab, pertuzumab, and docetaxel, the median duration of response was 20.2 mo; thereafter, the majority of patients experienced objective disease-progression, defining acquired clinical resistance to trastuzumab-based therapy (18).A myriad of potential mechanisms of trastuzumab resistance have been reported, such as: 1) perturbation of HER family receptors or binding of therapeutic antibodies to HER2 (e.g., shedding of the HER2 extracellular domain, expression of the Δ16HER2 splice isoform, overexpression of MUC4/MUC1 resulting in steric hindrance to trastuzumab binding to the HER2 extracellular domain, and increased phosphorylation of HER3); 2) parallel receptor pathway activation (e.g., overexpression of other HER family members, up-regulation of IGF1 receptor, erythropoietin receptor, AXL receptor, or MET receptor); and 3) activation of downstream signaling events distal to HER2 receptor (e.g., hyperactivation of the PI3 kinase/Akt pathway by loss of PTEN or PIK3CA mutational activation, cyclin E amplification/overexpression, up-regulation of miR-21, and expression of the estrogen receptor) (21). Impairments in trastuzumab-mediated ADCC may also lead to relative resistance to trastuzumab (22, 23). Interestingly, it has been shown that even after HER2⁺ breast cancers relapse or progress after trastuzumab, resistant cells most often still overexpress HER2 (24). Given the many ways in which trastuzumab resistance develops, there is an urgent clinical need for novel treatment approaches that provide HER2 specificity without eliciting the same mechanisms of trastuzumab resistance that are currently seen in the clinic (25). This led us to hypothesize that engagement of macrophages and activation of ADCP could still be effective even in the face of various resistance mechanisms—as long as the HER2 ectodomain target epitope is present.Our laboratory has previously shown that many different cancers overexpress the CD47 surface protein to convey a “don’t eat me” signal to macrophages (26–29) and to counteract “eat me” signals (30–32), thereby resulting in immune evasion through inhibition of macrophage phagocytosis. This led to the development of a new type of immunotherapy based on macrophage checkpoint inhibition through blockade of CD47. Hu5F9-G4 (magrolimab) is a humanized monoclonal antibody against CD47 that blocks CD47''s interaction with signal regulatory protein-α (SIRPα), thereby diminishing the inhibition of macrophages by cancer cells (33). As a monotherapy, Hu5F9-G4’s anticancer activity works by blocking CD47’s antiphagocytic signaling. The combination of Hu5F9-G4 and tumor-targeting antibodies, moreover, promotes ADCP by increasing the amount of “eat me” signals provided by the interaction of cancer-targeting antibody Fc domains and macrophage Fc-receptors (33–36). We have previously demonstrated this principle of ADCP enhancement in the context of rituximab-resistant CD20-expressing diffuse large B cell non-Hodgkin’s lymphoma. These studies showed that combining Hu5F9-G4 with rituximab (an anti-CD20 tumor-targeting antibody) in human xenograft models produced an anticancer ADCP response (34). In the clinical trials that followed, about half of the patients who are relapsed and refractory to rituximab plus or minus chemotherapy nevertheless responded to magrolimab plus rituximab (35). This clinical study suggested that combining Hu5F9-G4 with rituximab may resensitize refractory lymphoma cells to rituximab via an ADCP mechanism (35, 37).Based on these previous studies, we hypothesized that administering a combination of trastuzumab and Hu5F9-G4 to ADCC-tolerant HER2⁺ breast cancer cells would resensitize these cells to trastuzumab. We found that this combination was more efficacious than either treatment alone. We also found that this combinatorial treatment augments ADCP via Fc-receptor-mediated phagocytosis. Taken together, our study suggests that combining Hu5F9-G4 and trastuzumab may represent an alternative or complementary approach to the current standard of care for advanced HER2⁺ breast cancer that expands trastuzumab’s efficacy through engaging ADCP while preserving and utilizing trastuzumab’s HER2-targeting capabilities.     

Prevalence and management of HER2/neu-positive early breast cancer in a single institution following availability of adjuvant trastuzumab

Aim: To ascertain the prevalence of HER2/neu‐positive early breast cancer (EBC), utilisation of adjuvant trastuzumab and incidence of cardiac toxicity in a community private hospital setting. Methods: Prospective data collected by breast oncologist and surgeons in all women diagnosed with EBC at the Mount Hospital (MH) were reviewed. Women with HER2/neu‐positive disease diagnosed between 1 October 2006 and 31 March 2009 were included in this analysis. Results: In total, 1128 women with invasive EBC were seen in the 30‐month period. All tumours underwent HER2/neu testing by immunohistochemistry, with 61% being evaluated by in situ hybridisation. Time to definitive HER2/neu result improved over time from median of 17 to 14 days. The prevalence of HER2 positivity (by in situ hybridisation) in this cohort was 12%. Uptake of trastuzumab‐based treatment was 100% in those patients receiving their treatment at the MH, compared to 52% of the 25 patients treated elsewhere. Ninety‐eight per cent of MH patients completed the planned 12 months of therapy, with one patient developing recurrent disease and two patients experiencing significant cardiac toxicity. Chemotherapy relative dose intensity was 98% in HER2/neu‐positive and negative patients. At a median of 25 months follow up, actuarial disease‐free and overall survival in the HER2/neu‐positive cohort is 99% and 100% respectively. Conclusion: In a community private hospital setting, adjuvant trastuzumab and chemotherapy was delivered optimally, in line with national and international guidelines. Early efficacy and safety results in a non‐clinical trial setting underscore the significant benefits achieved with this targeted therapy in HER2/neu‐positive EBC.     

Cardiotoxicity in HER2-positive breast cancer patients

Heart Failure Reviews - Due to the recent advances in diagnosis and management of patients with HER2-positive breast cancer, especially through novel HER2-targeted agents, cardiotoxicity becomes an...     

Plasma HER2 amplification in cell-free DNA during neoadjuvant chemotherapy in breast cancer

Purpose

Measurement of human epidermal growth factor receptor 2 (HER2) gene amplification in cell-free DNA (cfDNA) is an evolving technique in breast cancer, enabling liquid biopsies and treatment monitoring. The present study investigated the dynamics of plasma HER2 gene copy number and amplification in cfDNA during neoadjuvant chemotherapy.

Patients and methods

The study included 50 patients from a prospective cohort analyzed during neoadjuvant chemotherapy. Fifty healthy women with no history of cancer served as control group and 15 patients with metastatic breast cancer were used to validate the assay. Total cfDNA and HER2 gene amplification were measured by quantitative real-time polymerase chain reaction.

Results

Plasma HER2 gene copy number (p = 0.794), HER2 gene amplification (p = 0.127) and total cfDNA (p = 0.440) did not differ significantly from the levels in the control group. Eighteen patients (36 %) obtained pathological complete response (pCR). HER2 gene copy number before the operation was significantly higher than the baseline level (p < 0.0001), but there was no difference between patients with and without pCR (p = 0.569). Likewise, there was no difference in plasma HER2 gene amplification between tissue HER2-positive and -negative patients (p = 0.754).

Conclusions

The results indicate that neither total cfDNA nor HER2 gene copy number is elevated in primary breast cancer patients compared to healthy controls. The level of both parameters increased during neoadjuvant chemotherapy, but without any relation to treatment effect. There was no indication of plasma HER2 gene amplification in the HER2-positive patients in the neoadjuvant setting.     

Clinical therapeutic effects of trastuzumab in HER2-positive breast cancer patients: A protocol for systematic review and meta-analysis

Background:Despite the developments in diagnosis and treatment of HER2-positive metastatic breast cancer, there is a high likelihood in the development of resistance to trastuzumab. In general, HER2-positive patients with deteriorated health face negative clinical outcomes. The present study is conducted to systematically explore the medicinal properties of trastuzumab in HER2-positive breast cancer patients.Methods:Randomized controlled trials investigating the clinical properties of including trastuzumab to treat HER2-positive breast cancer cases will be sourced by exploring these online-based databases: MEDLINE, BIOSIS, China National Knowledge Infrastructure (CNKI), Cochrane Library, EMBASE, Central Register of Controlled Trials, and WanFang. Two independent authors will screen the literature, gather data, and assess the quality of selected studies. The significance of the relationship between the medical properties of trastuzumab when incorporated to treat HER2-positive breast cancer cases will be evaluated according to the relative risk, mean differences or standardized mean differences, and 95% confidence interval.Results:The outcomes from this review shall be issued in a journal that will be reviewed by peers.Conclusion:The conclusions presented in this review will serve as a reference for clinical practitioners and scholars to determine whether trastuzumab is an effective and safety intervention for treating HER2-positive breast cancer patients.Ethics and dissemination:Since this study is a systematic review of published studies, an ethical approval is not needed.Systematic review registration number:March 31, 2021.osf.io/wvqkf (https://osf.io/wvqkf/).     

HER2 overexpression and activation, and tamoxifen efficacy in receptor-positive early breast cancer

Objectives  Tamoxifen is a partial ER antagonist that is highly effective in the treatment of receptor positive breast cancer. It significantly reduces recurrence and improves survival in both pre- and postmenopausal women. Unfortunately, many ER+ positive tumors progress despite tamoxifen treatment and until now, no possibility exists to prospectively identify tamoxifen-resistant tumors. It has been suggested that that in HER2 over-expressing tumors, cross-talk via activated HER2 receptors is a key mechanisms by which tumors become tamoxifen-resistant. Methods  We have therefore used immunohistochemistry to analyze the expression of HER2 and activated ptyr-1248 HER2 in 408 women of ER+, early breast cancer who had received at least 2 years of adjuvant tamoxifen. We then analyzed possible associations between HER2 and pHER2 expression, and prognostic parameters, and evaluated the effect of HER2 expression and survival. Results  With HER2 being positive in 12 of 208 (2.9%) of ER+ positive tumors, HER2 overexpression was found to be considerably less common in ER+ tumors than what has been thought previously. The majority of HER2 overexpressing tumors, however, also expressed the activated receptor form (r = 0.664; P < 0.0001). Both HER2 and pHER2 are moderately correlated with Grading (r = 0.138; P = 0.0052 and r = 0.118; P = 0.0241, respectively) and nodal involvement (r = 0.163; P = 0.0018 and r = 0.134; P = 0.016, respectively), but neither HER2 nor its activated form are significant predictors of RFS, DFS, or OS. Conclusions  Taken together, we have demonstrated that in ER+ breast cancer, the HER2 receptor is commonly activated, but its low prevalence in ER+ tumors does not render it a useful prognostic parameter in tamoxifen-treated patients.     

6 versus 12 months of adjuvant trastuzumab in HER2+ early breast cancer: A systematic review and meta-analysis

Background:Adjuvant trastuzumab improves survival outcomes of human epidermal receptor 2 positive early breast cancer patients. Currently, administration of 12 months adjuvant trastuzumab is the standard therapy. However, whether 6 months treatment is non-inferior to the standard 12 months treatment remains controversial.Methods:Relevant records were searched in PubMed, Cochrane Library, Web of Science, and EMBASE through Jan 14, 2020. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) for disease-free survival (DFS) and overall survival (OS) were meta-analyzed. The primary endpoint was DFS with a non-inferiority hazard margin of 1.2 and the second was OS with 1.43.Results:Three randomized clinical studies met the inclusion criteria, including 3974 patients in 6 months group and 3976 in 12 months group. HR for DFS was 1.18 (95% CI 0.97–1.44, P = .09), with the non-inferiority margin comprised in the 95% CI. HR for OS was 1.14 (95% CI 0.98–1.32, P= .08), whereas the upper limit of 95% CI did not exceed the non-inferiority hazard margin.Conclusion:Our analysis failed to show that 6 months treatment was non-inferior to 12 months treatment in improving the DFS. Although the non-inferiority of the 6-month adjuvant trastuzumab treatment was found for OS, considering that breast cancer patients should receive additional systematic therapies when disease progression or relapse happens, we suggest that 12 months adjuvant trastuzumab treatment should remain the standard therapeutic strategy for patients with early human epidermal receptor 2 positive breast cancer.     

Combined detection of Her2/neu gene amplification and protein overexpression in effusions from patients with breast and ovarian cancer

Purpose  

Her2/neu protein overexpression and gene amplification is found in 20–30% of breast cancer patients and correlates with poor clinical outcome. Patients who profit from anti-Her2/neu- therapy are routinely selected by examination of tumour specimens using immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH) separately. Many studies found a good correlation between both methods for score 1+ samples and for score 3+ samples, but not for score 2+ samples. In this study, we examined pleural and ascitic effusions with a combined approach using IHC and FISH on the same cells, under the following aspects: (1) frequency of Her2/neu protein expression and gene amplification in effusions; (2) correlation between score of protein expression and gene amplification; (3) impact of chromosome 17 polyploidy on Her2/neu protein expression.     

HER2 overexpression as a prognostic factor in metastatic breast cancer patients treated with high-dose chemotherapy and autologous stem cell support

We retrospectively evaluated the predictive and prognostic role of HER2 expression in 44 metastatic breast cancer (MBC) patients treated with high-dose consolidation chemotherapy (HDCT) and autologous stem cell support after induction chemotherapy (IC) with six courses of epirubicin+paclitaxel (22 patients) or gemcitabine+epirubicin+paclitaxel (22 patients). HER2 expression was evaluated by an immunohistochemical method (Herceptest, Dako). A total of 13 patients (29.5%) showed a HER2 overexpression (score 3+). After IC, nine patients were in complete response (CR), 30 in partial response (PR), and five in stable disease (SD); after HDCT, 20 (45.5%) obtained a CR, and 23 were in PR, for a conversion rate of 48.5%. Conversion rate for HER2-positive patients was 87.5 vs 37% for HER2-negative patients (P=0.018). The median progression-free (PFS) and overall survivals (OS) were 17.6 (95% CI 13.2-22.0) and 44 (95% CI 25.9-62.3) months, respectively. Patients with HER2 overexpression experienced a significantly (P=0.0042) shorter median PFS (15.3 months, 95% CI 11.1-19.5) compared to HER2-negative patients (21.3 months, 95% CI 14.3-28.4). The median OS was 27.6 months (95% CI 4.5-50.7) in HER2-positive patients and 50.3 months (95% CI 38.7-62.0) in HER2-negative patients (P=0.345). These results indicate that HER2 overexpression predicts a worse outcome for patients with MBC treated with HDCT, despite the high CR rate obtained in this subset of patients.     

Redundant cyclin overexpression and gene amplification in breast cancer cells.

Cyclins are prime cell cycle regulators and are central to the control of major check points in eukaryotic cells. The aberrant expressions of two cyclins (i.e., cyclins A and D1) have been observed in some cancers, suggesting they may be involved in loss of growth control. However, in spite of these occasional changes involving only two cyclins, there are no clear connections between general derangements of other cyclins or their dependent kinases in a single tumor type. We detected general cyclin overexpression in 3 of 3 breast tumor tissue samples. In addition, using proliferating normal vs. human tumor breast cells as a model system, we observed a number of alterations in cyclin expression: (i) an 8-fold amplification of cyclin E gene in one tumor line, a 64-fold overexpression of its mRNA, and altered expression of its protein; (ii) deranged expression of cyclin E protein in all (10 of 10) tumor cell lines studied; (iii) increased cyclin mRNA stability, resulting in (iv) general overexpression of RNAs and proteins for cyclins A and B and CDC2 in 9 of 10 tumor lines and (v) deranged order of appearance of cyclins in synchronized tumor vs. normal cells, with mitotic cyclins appearing prior to G1 cyclins. These multiple general derangements in cyclin expression in human breast cancer cells provide evidence linking aberrant cyclin expression to tumorigenesis.     

The efficacy of trastuzumab in Her-2/neu-overexpressing metastatic breast cancer is independent of p53 status

Purpose: Her-2/neu and p53-mediated signalling have been shown to interact at various cellular levels. However, the clinical relevance of p53 alterations in patients receiving trastuzumab for Her-2/neu-overexpressing metastatic breast cancer (MBC) remains unknown. The present study was performed to corroborate previous in vitro findings from our laboratory showing that trastuzumab induces growth arrest and apoptosis in a p53-independent manner.Method: Retrospective immunohistochemical (IHC) analysis for p53 protein expression was carried out on tumour specimens from 104 patients receiving trastuzumab-based treatment for Her-2/neu-overexpressing MBC at a single institution. p53 status was correlated with response (R) and clinical benefit (CB), median progression-free survival (PFS) time and overall survival (OAS) time in univariate and multivariate analyses.Results: Characteristics were similar between p53-negative and p53-positive tumours (all P>0.05). In univariate analyses, R (39% vs 26%, P=0.208), CB (70% vs 57%, P=0.218), PFS (6.2 months vs 4.2 months, P=0.186) and OAS (23.8 months vs 23.2 months, P=0.650) were similar for p53-positive tumours and p53-negative tumours, respectively. In multivariate analyses, p53 status was not a significant predictor of R, CB, PFS or OAS (all P>0.05).Conclusions: p53 status, as determined by IHC, is not a predictor of the clinical efficacy of trastuzumab-based treatment in patients with Her-2/neu-overexpressing MBC.     

Cardiac toxicity of trastuzumab in elderly patients with breast cancer

Breast cancer (BC) is diagnosed in ≥ 65 year old women in about half of cases. Experts currently recommend that systemic therapy is offered to elderly patients with BC, if, based on their overall conditions and life expectancy, it can be reasonably anticipated that the benefits will outweigh the risks of treatment. Like for young subjects, the monoclonal antibody against human epidermal growth factor receptor-2 (HER-2), trastuzumab, represents a valid therapeutic option when BC over-expresses this receptor. Unfortunately, administration of trastuzumab is associated with the occurrence of left ventricular dysfunction and chronic heart failure (CHF), possibly because of interference with the homeostatic functions of HER-2 in the heart. Registry-based, retrospective analyses have reported an incidence of CHF around 25% in elderly women receiving trastuzumab compared with 10%–15% in those not given any therapy for BC, and the risk of CHF has been estimated to be two-fold higher in > 60–65 year old trastuzumab users vs. non-users. Extremely advanced age and preexisting cardiac disease have been shown to predispose to trastuzumab cardiotoxicity. Therefore, selection of older patients for treatment with trastuzumab should be primarily based on their general status and the presence of comorbidities; previous chemotherapy, especially with anthracyclines, should be also taken into account. Once therapy has started, efforts should be made to ensure regular cardiac surveillance. The role of selected biomarkers, such as cardiac troponin, or new imaging techniques (three-dimension, tissue Doppler echocardiography, magnetic resonance imaging) is promising, but must be further investigated especially in the elderly. Moreover, additional studies are needed in order to better understand the mechanisms by which trastuzumab affects the old heart.