Long-term overall survival of patients who undergo breast-conserving therapy or mastectomy for early operable HER2-Positive breast cancer after preoperative systemic therapy: an observational cohort study.

Background: Understanding the survival outcomes associated with breast-conserving therapy (BCT) and mastectomy after preoperative systemic therapy (PST) enables clinicians to provide more personalized treatment recommendations. However, lack of firm survival benefit data limits the breast surgery choices of human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients who receive PST. We sought to determine whether BCT or mastectomy after PST for early operable HER2-positive breast cancer is associated with better long-term survival outcomes and determine the degree to which PST response affects this association. Methods: In this observational cohort study, we compared the long-term survival outcomes of BCT and mastectomy after PST for HER2-positive breast cancer and evaluated the impact of PST response on the relationship between breast surgery performed and survival outcomes. Our cohort included 625 patients with early operable HER2-positive breast cancer who received PST followed by BCT or mastectomy between January 1998 and October 2009. These patients also received standard postoperative radiation, trastuzumab, and endocrine therapy as indicated clinically. We used propensity score matching to assemble mastectomy and BCT cohorts with similar baseline characteristics and used Kaplan-Meier plots and Cox proportional hazards regression to detect associations between surgery types and outcomes. Furthermore, in this study, we analyzed the original data of 625 patients using the inverse probability of treatment weighting (IPTW) method to enhance the reliability of the comparison between the mastectomy and BCT cohorts by addressing potential confounding variables. Findings: Propensity score matching yielded cohorts of 221 patients who received BCT and 221 patients who underwent mastectomy. At the median follow-up time of 9.9 years, compared with BCT, mastectomy was associated with worse overall survival (hazard ratio, 1.66; 95% confidence interval [CI]: 1.08-2.57; P = 0.02). In patients who had axillary lymph node pathological complete response, mastectomy was associated with worse overall survival before matching (hazard ratio, 2.17; 95% CI: 1.22-3.86; P < 0.01) and after matching (hazard ratio, 2.12; 95% CI: 1.15-3.89; P = 0.02). Among patients with pathological complete response in the breast, the survival results did not differ significantly between BCT and mastectomy patients. IPTW method validated that BCT offers better overall survival in patients who had axillary lymph node pathological complete response. Interpretation: People with HER2-positive breast cancer who have already had PST are more likely to survive after BCT, especially if they get a pathological complete response in the axillary lymph nodes. These findings underscore the necessity for further investigation into how responses to PST can inform the choice of surgical intervention and the potential impact on overall survival. Such insights could lead to the development of innovative tools that support personalized surgical strategies in the management of breast cancer. Funding: This work was supported by grants from the Nantong Science and Technology Project (JCZ2022079), Nantong Health Commission Project (QA2021031, MSZ2023040) and National Natural Science Foundation of China (No. 82394430).

Tailoring Neoadjuvant Therapy in Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer: Recent Advances and Strategies.

Neoadjuvant HER2 Therapy: Beyond one-size-fits-all.

Next-Generation HER2-Targeted Antibody-Drug Conjugates in Breast Cancer.

Human epidermal growth factor receptor 2 (HER2) tyrosine kinase is overexpressed in 20% of breast cancers and associated with a less favorable prognosis compared to HER2-negative disease. Patients have traditionally been treated with a combination of chemotherapy and HER2-targeted monoclonal antibodies such as trastuzumab and pertuzumab. The HER2-targeted antibody-drug conjugates (ADCs) trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) represent a novel class of therapeutics in breast cancer. These drugs augment monoclonal antibodies with a cytotoxic payload, which is attached by a linker, forming the basic structure of an ADC. Novel combinations and sequential approaches are under investigation to overcome resistance to T-DM1 and T-DXd. Furthermore, the landscape of HER2-targeted therapy is rapidly advancing with the development of ADCs designed to attack cancer cells with greater precision and reduced toxicity. This review provides an updated summary of the current state of HER2-targeted ADCs as well as a detailed review of investigational agents on the horizon. Clinical trials are crucial in determining the optimal dosing regimens, understanding resistance mechanisms, and identifying patient populations that would derive the most benefit from these treatments. These novel ADCs are at the forefront of a new era in targeted cancer therapy, holding the potential to improve outcomes for patients with HER2-positive and HER2-Low breast cancer.

A new paradigm for classifying and treating HER2-positive breast cancer.

BACKGROUND: Because of the phenomenal success of treatment with monoclonal antibodies and antibody-drug conjugates targeting human epidermal growth factor receptor 2 (HER2), most patients with early-stage HER2-positive breast cancer (HER2+ BC) and some with limited metastatic diseases have been cured, and those who have not been cured have achieved significant improvements in overall survival, which has weakened the role of the TNM staging system in the prognosis of HER2+ BC today. Given that the disease is now highly curable, treatment conception, classification, and modalities should differ from those of cancer types with a poor prognosis. It is warranted to build a new paradigm for classifying and treating HER2+ BC. RECENT FINDINGS: In our personal view, we suggest that the classification system should be based not only on traditional anatomy and cancer biology but also on available treatment regimens, their exceptional outcomes, and their toxicities. In this regard, we developed a new concise classification of HER2+ BC based on the TNM staging system, a review of the literature, research results, and our clinical experience, dividing the patients into four distinct groups: curable (lymph-node negative and small (≤3 cm) early breast cancer), do our best to cure (locally advanced or tumors >3 cm early breast cancer), hope for cure (local-regional recurrent, limited metastases, and exceptional responders), and incurable (metastatic breast cancer with poor performance status or non-exceptional responders). CONCLUSION: It will assist clinicians in developing an optimal treatment regimen at the outset, curing more HER2+ BC patients and improving their quality of life.

Safety and impact of dose reductions on efficacy in the randomised MONALEESA-2, -3 and -7 trials in hormone receptor-positive, HER2-negative advanced breast cancer.

BACKGROUND: This pooled analysis of MONALEESA trials evaluated the safety of ribociclib plus endocrine therapy (RIB + ET) with a focus on dose reductions in first-line patients. METHODS: In the dose reduction analysis, data were pooled from MONALEESA-2 (all patients), MONALEESA-3 (patients receiving treatment as first-line ET) and MONALEESA-7 (patients receiving combination therapy with an NSAI as initial ET). Efficacy was analysed by ribociclib relative dose intensity (DI). Safety was analysed in all patients in the trials (except those receiving tamoxifen in MONALEESA-7) and those with/without ≥1 ribociclib dose reduction. RESULTS: Of 818 women who received first-line RIB + ET, 41.8% required ≥1 dose reduction due to AEs (most commonly, neutropenia). Median RIB relative DI in patients without and with dose reductions was 99.3% and 65.6% in MONALEESA-2, 98.4% and 67.8% in MONALEESA-3 and 98·0% and 66·3% in MONALEESA-7. Median PFS was 24.8, 24.9 and 29.6 months for patients who received ≤71% (30th percentile), 72-96% (60th percentile) and 97-100% (90th percentile) RIB relative DI, respectively. No new safety signals emerged in the pooled safety analysis. CONCLUSIONS: This analysis provides reassuring data showing that the clinical benefit of RIB is preserved when dose modifications are undertaken to manage AEs. TRIAL REGISTRATION: MONALEESA-2 (NCT01958021) first posted October 8, 2013; MONALEESA-3 (NCT02422615) first posted April 21, 2015; MONALEESA-7 (NCT02278120) first posted October 29, 2014.

Association of Cardiovascular Disease Risk Factors with Late Cardiotoxicity and Survival in HER2-positive Breast Cancer Survivors.

PURPOSE: Breast cancer and cardiovascular (CV) diseases often share the same risk factors. It is increasingly important to identify risk factors for CV events in patients with high-risk breast cancer and explore optimal treatment regimens. EXPERIMENTAL DESIGN: Early HER2-positive breast cancer patients at our institution between January 1998 and October 2009 were reviewed. Primary outcome was late-severe-CV-event-free survival, and late severe CV events were defined as cardiovascular death, cardiomyopathy, symptomatic heart failure, and myocardial infarction developing 2+ years after breast cancer diagnosis. Kaplan-Meier plots, Cox proportional hazard regressions, and restricted mean survival time were used to evaluate outcomes. RESULTS: We identified 2,448 consecutive eligible patients with a median follow-up time of 111.0 months (interquartile range, 52.0-151.8 months). One hundred and thirty-six patients had late severe CV events and 752 died of any cause [533 (70.9%) died of primary breast cancer; 12 (1.6%) died of cardiovascular disease]. Hypertension [HR, 1.546; 95% confidence interval (95% CI), 1.030-2.320; P = 0.036] and history of coronary artery disease (CAD; HR, 3.333; 95% CI, 1.669-6.656; P < 0.001) were associated with worse late-severe-CV-event-free survival. Anthracycline-containing regimens (HR, 1.536; 95% CI, 0.979-2.411; P = 0.062) was not a significant risk factor for CV events in multivariate analysis. Regimens containing both anthracycline and anti-HER2 therapy were prognostic for better OS (HR, 0.515; 95% CI, 0.412-0.643; P < 0.001). CONCLUSIONS: Hypertension and CAD history were independent prognostic factors for late severe CV events. Adding anti-HER2 agents to anthracycline-containing regimens did not substantially increase the risk for late severe cardiotoxicity and conferred better overall survival.

Whole-genome screen identifies diverse pathways that negatively regulate ciliogenesis.

We performed a high-throughput whole-genome RNAi screen to identify novel inhibitors of ciliogenesis in normal and basal breast cancer cells. Our screen uncovered a previously undisclosed, extensive network of genes linking integrin signaling and cellular adhesion to the extracellular matrix (ECM) with inhibition of ciliation in both normal and cancer cells. Surprisingly, a cohort of genes encoding ECM proteins was also identified. We characterized several ciliation inhibitory genes and showed that their silencing was accompanied by altered cytoskeletal organization and induction of ciliation, which restricts cell growth and migration in normal and breast cancer cells. Conversely, supplying an integrin ligand, vitronectin, to the ECM rescued the enhanced ciliation observed on silencing this gene. Aberrant ciliation could also be suppressed through hyperactivation of the YAP/TAZ pathway, indicating a potential mechanistic basis for our findings. Our findings suggest an unanticipated reciprocal relationship between ciliation and cellular adhesion to the ECM and provide a resource that could vastly expand our understanding of controls involving "outside-in" and "inside-out" signaling that restrain cilium assembly.

Trastuzumab emtansine plus atezolizumab versus trastuzumab emtansine plus placebo in previously treated, HER2-positive advanced breast cancer (KATE2): a phase 2, multicentre, randomised, double-blind trial.

BACKGROUND: HER2-positive metastatic breast cancer is incurable and new treatments are needed. Addition of atezolizumab to trastuzumab emtansine might potentiate anticancer immunity and enhance the HER2-targeted cytotoxic activity of trastuzumab emtansine. We aimed to test this combination in HER2-positive advanced breast cancer that had progressed after previous treatment with trastuzumab and a taxane. METHODS: The KATE2 study is a randomised, double-blind, placebo-controlled, phase 2 study at 68 centres from nine countries across Asia, Australia, North America, and western Europe. Eligible patients were adults (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1 and centrally confirmed, measurable, HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane. Patients were randomly assigned (2:1) either trastuzumab emtansine (3·6 mg/kg of bodyweight) plus atezolizumab (1200 mg) or trastuzumab emtansine plus placebo; all study drugs were administered by intravenous infusion every 3 weeks. Randomisation was done via an interactive voice and web response system using a permuted block scheme (block size of six) and was stratified by PD-L1 status, world region, and liver metastases. Patients, investigators, and study team members were masked to treatment allocation. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02924883, and the study has been completed. FINDINGS: Between Sept 26, 2016, and Aug 7, 2017, 330 patients were screened for the study, of whom 202 were randomly allocated either atezolizumab (n=133) or placebo (n=69). At the recommendation of the independent data monitoring committee, treatment assignment was unmasked on Dec 11, 2017, due to futility and the numerically higher frequency of adverse events among patients assigned atezolizumab. This date was set as the clinical cutoff for the primary analysis. Median follow-up was 8·5 months (IQR 6·1-11·5) for patients assigned atezolizumab and 8·4 months (5·3-11·1) for those assigned placebo. Median progression-free survival was 8·2 months (95% CI 5·8-10·7) for patients assigned atezolizumab versus 6·8 months (4·0-11·1) for those assigned placebo (stratified hazard ratio 0·82, 95% CI 0·55-1·23; p=0·33). The most common grade 3 or worse adverse events were thrombocytopenia (17 [13%] among 132 patients who received atezolizumab vs three [4%] among 68 who received placebo), increased aspartate aminotransferase (11 [8%] vs two [3%]), anaemia (seven [5%] vs 0), neutropenia (six [5%] vs three [4%]), and increased alanine aminotransferase (six [5%] vs two [3%]). Serious adverse events occurred in 43 (33%) of 132 patients who received atezolizumab and 13 (19%) of 68 patients who received placebo. One patient who received atezolizumab died due to a treatment-related adverse event (haemophagocytic syndrome). INTERPRETATION: Addition of atezolizumab to trastuzumab emtansine did not show a clinically meaningful improvement in progression-free survival and was associated with more adverse events. Further study of trastuzumab emtansine plus atezolizumab is warranted in a subpopulation of patients with PD-L1-positive, HER2-positive advanced breast cancer. FUNDING: F Hoffman-La Roche.

Validation of plasma metabolites associated with breast cancer risk among Mexican Americans.

In our previous breast cancer case control study in Hispanics, we found 14 metabolites whose levels differed between cases and controls. To validate the results, we carried out a nested case control study of 100 incident breast cancer and 100 matched healthy women identified from the Mano-A-Mano Mexican American Cohort study. With the adjustment of parity, education, birth place, language acculturation, BMI category, smoking, drinking, physical activity, and sitting time, 4 metabolites were associated with breast cancer risk: 3-hydroxyoctanoate (Odds ratio (OR) = 1.51, 95% confidence interval (CI): 1.10, 3.47), 3-hydroxybutyrate (BHBA) (OR = 1.42, 95%CI: 1.01, 3.72), linoleate (18:2n6) (OR = 1.39, 95% CI: 1.07, 4.04), and bilirubin (OR = 0.54, 95%CI: 0.42, 0.95). Then, we used 3 non-redundant metabolites, namely 3-hydroxyoctanoate, linoleate (18:2n6), and bilirubin, to generate a metabolic risk score. Increased metabolites risk score was associated with a 1.67-fold increased risk of breast cancer (OR = 1.67, 95%CI: 1.32, 3.94). And the significant association was more evident among those who were diagnosed with cancer earlier during the follow-up (≤ 5 years) than their counterparts. In conclusion, we identified four significant metabolites which may help elucidate metabolic pathways that contribute to breast carcinogenesis. Our findings warrant further replication efforts.

Ribociclib plus fulvestrant for advanced breast cancer: Health-related quality-of-life analyses from the MONALEESA-3 study.

PURPOSE: In the MONALEESA-3 Phase III trial of patients with hormone receptor-positive human epidermal growth factor receptor-negative advanced breast cancer, ribociclib plus fulvestrant significantly improved progression-free survival (PFS) and overall survival (OS). Here, we present patient-reported outcomes from the trial, including health-related quality of life (HRQOL). METHODS: Patients were randomized (2:1) to receive ribociclib plus fulvestrant or placebo plus fulvestrant. Time to definitive 10% deterioration (TTD) from baseline in HRQOL (global health status [GHS] from the EORTC QLQ-C30 questionnaire) and pain (BPI-SF questionnaire) were assessed using Kaplan-Meier estimates; a stratified Cox regression model was used to estimate the hazard ratio (HR) and 95% CIs. RESULTS: Deterioration ≥10% in the EORTC-QLQ-C30 GHS was observed in 33% of patients in the ribociclib group vs 34% of patients in the placebo (reference) group (HR for TTD ≥ 10% = 0.81 [95% CI, 0.62-1.1]). Similar findings were noted for TTD ≥5% (HR = 0.79 [95% CI, 0.61-1.0]) and TTD ≥15% (HR = 0.81 [95% CI, 0.60-1.08]). TTD ≥10% in emotional functioning (HR = 0.76 [95% CI, 0.57-1.01]) trended in favor of the ribociclib group, whereas results for fatigue and pain were similar between arms. TTD ≥10% in BPI-SF pain severity index score (HR = 0.77 [95% CI, 0.57-1.05]) and worst pain item score (HR = 0.81 [95% CI, 0.58-1.12]) trended in favor of ribociclib vs placebo. CONCLUSIONS: In addition to significantly prolonging PFS and OS compared with placebo plus fulvestrant, adding ribociclib to fulvestrant maintains HRQOL.

Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer.

BACKGROUND: In an earlier analysis of this phase 3 trial, ribociclib plus fulvestrant showed a greater benefit with regard to progression-free survival than fulvestrant alone in postmenopausal patients with hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Here we report the results of a protocol-specified second interim analysis of overall survival. METHODS: Patients were randomly assigned in a 2:1 ratio to receive either ribociclib or placebo in addition to fulvestrant as first-line or second-line treatment. Survival was evaluated by means of a stratified log-rank test and summarized with the use of Kaplan-Meier methods. RESULTS: This analysis was based on 275 deaths: 167 among 484 patients (34.5%) receiving ribociclib and 108 among 242 (44.6%) receiving placebo. Ribociclib plus fulvestrant showed a significant overall survival benefit over placebo plus fulvestrant. The estimated overall survival at 42 months was 57.8% (95% confidence interval [CI], 52.0 to 63.2) in the ribociclib group and 45.9% (95% CI, 36.9 to 54.5) in the placebo group, for a 28% difference in the relative risk of death (hazard ratio, 0.72; 95% CI, 0.57 to 0.92; P = 0.00455). The benefit was consistent across most subgroups. In a descriptive update, median progression-free survival among patients receiving first-line treatment was 33.6 months (95% CI, 27.1 to 41.3) in the ribociclib group and 19.2 months (95% CI, 14.9 to 23.6) in the placebo group. No new safety signals were observed. CONCLUSIONS: Ribociclib plus fulvestrant showed a significant overall survival benefit over placebo plus fulvestrant in patients with hormone-receptor-positive, HER2-negative advanced breast cancer. (Funded by Novartis; MONALEESA-3 ClinicalTrials.gov number, NCT02422615.).

Long-Term Survival Analysis of Adjuvant Chemotherapy with or without Trastuzumab in Patients with T1, Node-Negative HER2-Positive Breast Cancer.

PURPOSE: Adjuvant therapy for small, node-negative HER2-positive breast cancer (HER2+ BC) is controversial. We aimed to identify the subgroup that would benefit most from adjuvant chemotherapy and trastuzumab. EXPERIMENTAL DESIGN: We reviewed records of patients with pT1N0M0 HER2+ BC treated at our institution from January 1, 1998, through October 31, 2009. We compared three groups: A, no adjuvant chemotherapy; B, adjuvant chemotherapy only; and C, adjuvant chemotherapy with trastuzumab. We evaluated disease-free survival (DFS), overall survival (OS), distant recurrence-free survival (DRFS), and breast cancer-specific survival (BCSS) in each group. RESULTS: We reviewed 587 consecutive patients with a median follow-up of 123.0 months. The 10-year DFS rate was 81.0%, 65.4%, and 97.3% in groups A, B, and C, respectively (P < 0.001). The restricted mean survival time ratio did not differ between groups A and B [ratio = 0.982; 95% confidence interval (CI), 0.930-1.036; P = 0.498). Cox regression showed that adjuvant chemotherapy with trastuzumab was associated with better DFS compared with no adjuvant chemotherapy [hazard ratio (HR), 0.071; 95% CI, 0.025-0.204; P < 0.001). Larger tumor size was associated with short DFS (HR, 2.384; 95% CI, 1.549-3.056; P < 0.001); improvements in DFS, OS, DRFS, and BCSS were observed with adjuvant chemotherapy plus trastuzumab in patients with tumors ≥0.8-cm diameter. Receiving adjuvant chemotherapy with trastuzumab was not associated with improved DFS, OS, or DRFS for tumors <0.8 cm. CONCLUSIONS: Adjuvant chemotherapy plus trastuzumab should be recommended for patients with pT1N0M0 HER2+ BC ≥0.8 cm in diameter; adjuvant therapy may not be necessary for tumors <0.8 cm.

Are Biosimilars the Future of Oncology and Haematology?

Biological drugs are vital but often high-cost components of cancer treatment. Several biosimilar versions of these drugs have been approved in Europe and/or the USA, with many more in development. However, there is some disconnect between the biosimilars that are approved for use and those accessible in clinical practice, with availability impacted by factors including patent litigation and complex healthcare insurance policies, particularly in the USA. Provided the barriers to widespread uptake can be overcome, biosimilars offer potential benefits including cost savings and improved patient access versus the reference product (RP). This article provides an up-to-date and focused perspective on the development and use of biosimilars in the haemato-oncology setting. European and US regulatory pathways governing biosimilar licensing demand that there are no clinically meaningful differences between a biosimilar and its RP. Pathways are rigorously enforced and involve comprehensive non-clinical evaluations and clinical trials in selected indications to establish the equivalence or non-inferiority of efficacy, and the comparability of safety, of the biosimilar versus its RP. 'Indication extrapolation' is only permitted if scientifically justifiable considering mechanism(s) of action, pharmacokinetics, immunogenicity and safety in relevant patient populations. Switching treatment from RP to biosimilar is supported by most available data, predominantly from indications other than cancer, and post-marketing pharmacovigilance programmes are warranted. Notably, the potential benefits of biosimilar cancer treatment may extend beyond direct cost savings: for example, the availability of biosimilars of common regimen components may help incentivise the evaluation and/or clinical use of new treatment approaches and novel drugs.

Clinical development of CT-P6 in HER2 positive breast cancer.

Introduction: CT-P6 (trastuzumab-pkrb, Herzuma) is a trastuzumab biosimilar approved for use in HER2 positive breast cancer and HER2 positive gastric cancer. CT-P6 has been shown to exhibit similar safety and efficacy profiles to its reference product, trastuzumab. Preclinical and clinical studies have been performed to prove equivalence between CT-P6 and the trastuzumab originator. Areas Covered: In this review, we examine the evidence comparing CT-P6 with its reference product, trastuzumab. Both monoclonal antibodies function to target cells that overexpress HER2 on the cell surface. Preclinical pharmacologic modeling of CT-P6 shows a similar mechanism of action to trastuzumab, similar pharmacologic properties and a phase I trial in healthy volunteers showed similar pharmacokinetics. A multicenter phase III randomized clinical trial in patients with early breast cancer showed equivalent safety and efficacy between CT-P6 and trastuzumab. One-year follow-up of patients showed identical rates of cardiotoxicity. Expert Opinion: Preclinical and clinical studies showed CT-P6 pharmacologic profile, safety and efficacy are equivalent to trastuzumab. As such, it is a safe and effective alternative for use in patients with HER2 positive breast cancer and gastric cancer. Its implementation into clinical practice can potentially increase patient access and help financially alleviate overburdened health-care systems.

Efficacy and Safety of Ribociclib With Letrozole in US Patients Enrolled in the MONALEESA-2 Study.

BACKGROUND: In the Mammary Oncology Assessment of LEE011's (Ribociclib's) Efficacy and Safety (MONALEESA-2) study, combination treatment with the selective inhibitor of cyclin-dependent kinases 4/6 ribociclib with letrozole significantly improved progression-free survival (PFS) versus letrozole alone in postmenopausal women with hormone receptor-positive HR+/HER2- advanced breast cancer (ABC). Herein we present results from the subset of US patients enrolled in MONALEESA-2. PATIENTS AND METHODS: Postmenopausal women with HR+/HER2- ABC without previous treatment for advanced disease were randomized (1:1) to ribociclib 600 mg/d (3 weeks on/1 week off) with letrozole 2.5 mg/d (continuous) or placebo with letrozole. The primary end point was locally assessed PFS. RESULTS: Overall, 213 US patients were enrolled in MONALEESA-2 (ribociclib, n = 100; placebo, n = 113). Baseline characteristics were similar between treatment groups and consistent with the global population. With a median follow-up of 27 months, 38 (38%) and 29 (26%) patients in the ribociclib and placebo groups, respectively, had continued to receive treatment. Median PFS was 27.6 months with ribociclib and 15.0 months with placebo (hazard ratio, 0.53). The most common all-cause adverse events were neutropenia (ribociclib, 72.0% [n = 72]; placebo, 4.6% [n = 5]), nausea (ribociclib, 69.0% [n = 69]; placebo, 44.0% [n = 48]), and fatigue (ribociclib, 60.0% [n = 60]; placebo, 50.5% [n = 55]). Two patients (ribociclib, 2.0%; placebo, 0%) experienced febrile neutropenia. CONCLUSION: In the US subset of MONALEESA-2, ribociclib with letrozole showed superior efficacy versus letrozole alone. These findings are consistent with the global population and support first-line use of ribociclib with letrozole in patients with HR+/HER2- ABC.

Correction to: Breast cancer risk in relation to plasma metabolites among Hispanic and African American women.

In the original publication of the article, the sixth author name Krita A. Zanetti was mistakenly included as co-author. The corrected author group is given in the correction article. The original article has been corrected.

Immunotherapy and targeted therapy combinations in metastatic breast cancer.

Immunotherapy is emerging as a new treatment modality in breast cancer. After long-standing use of endocrine therapy and targeted biological therapy, improved understanding of immune evasion by cancer cells and the discovery of selective immune checkpoint inhibitors have created novel opportunities for treatment. Single-drug therapies with monoclonal antibodies against programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) have shown little efficacy in patients with metastatic breast cancer, in part because of the low number of tumour-infiltrating lymphocytes in most breast cancers. There is growing interest in the development of combinations of immunotherapy and molecularly targeted therapies for metastatic breast cancer. In this Personal View, we review the available data and ongoing efforts to establish the safety and efficacy of immunotherapeutic approaches in combination with HER2-targeted therapy, inhibitors of cyclin-dependent kinases 4 and 6, angiogenesis inhibitors, poly(ADP-ribose) polymerase inhibitors, as well as chemotherapy and radiotherapy.

Breast cancer risk in relation to plasma metabolites among Hispanic and African American women.

PURPOSE: The metabolic etiology of breast cancer has been explored in the past several years using metabolomics. However, most of these studies only included non-Hispanic White individuals. METHODS: To fill this gap, we performed a two-step (discovery and validation) metabolomics profiling in plasma samples from 358 breast cancer patients and 138 healthy controls. All study subjects were either Hispanics or non-Hispanic African Americans. RESULTS: A panel of 14 identified metabolites significantly differed between breast cancer cases and healthy controls in both the discovery and validation sets. Most of these identified metabolites were lipids. In the pathway analysis, citrate cycle (TCA cycle), arginine and proline metabolism, and linoleic acid metabolism pathways were observed, and they significantly differed between breast cancer cases and healthy controls in both sets. From those 14 metabolites, we selected 9 non-correlated metabolites to generate a metabolic risk score. Increased metabolites risk score was associated with a 1.87- and 1.63-fold increased risk of breast cancer in the discovery and validation sets, respectively (Odds ratio (OR) 1.87, 95% Confidence interval (CI) 1.50, 2.32; OR 1.63, 95% CI 1.36, 1.95). CONCLUSIONS: In summary, our study identified metabolic profiles and pathways that significantly differed between breast cancer cases and healthy controls in Hispanic or non-Hispanic African American women. The results from our study might provide new insights on the metabolic etiology of breast cancer.

Efficacy and safety of the combination of metformin, everolimus and exemestane in overweight and obese postmenopausal patients with metastatic, hormone receptor-positive, HER2-negative breast cancer: a phase II study.

Background Increased adiposity is thought to result in worse clinical outcomes in patients with breast cancer through increased estrogen production, hyperinsulinemia, insulin resistance, and activation of the phosphatidylinositol-3-kinase/AKT/mammalian target of rapamycin (mTOR) pathway. Thus, we hypothesized that the addition of metformin to everolimus and exemestane, could lead to better outcomes in overweight and obese patients with metastatic, hormone receptor-positive, HER2-negative breast cancer. We conducted a phase II trial to evaluate the efficacy and safety of the combination of metformin, everolimus and exemestane in overweight and obese postmenopausal women with metastatic, hormone receptor-positive, HER2-negative breast cancer. Methods Twenty-two patients with a body mass index ≥25 kg/m2 were treated with metformin 1000 mg twice daily, everolimus 10 mg daily and exemestane 25 mg daily. Median progression-free (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Results Median PFS and OS were 6.3 months (95% confidence interval [CI]: 3.8-11.3 months) and 28.8 months (95% CI: 17.5-59.7 months), respectively. Five patients had a partial response and 7 had stable disease for ≥24 weeks yielding a clinical benefit rate of 54.5%. Compared with overweight patients, obese patients had an improved PFS on univariable (p = 0.015) but not multivariable analysis (p = 0.215). Thirty-two percent of patients experienced a grade 3 treatment-related adverse event (TRAE). There were no grade 4 TRAEs and 7 patients experienced a grade 3 TRAE. Conclusion The combination of metformin, everolimus and exemestane was safe and had moderate clinical benefit in overweight and obese with patients metastatic, hormone receptor-positive, HER2-negative breast cancer.

Prognosis in different subtypes of metaplastic breast cancer: a population-based analysis.

BACKGROUND: Metaplastic breast cancer (MpBC) is a rare histological subtype of breast cancer recognized as a unique pathologic entity in 2000. However, the pathogenesis, optimal therapy, and prognosis of MpBC and the potential effect of systemic treatments on different subtypes of MpBC are not well defined. METHODS: A retrospective population-based study was performed to identify breast cancer patients with MpBC and other triple-negative breast cancers (TNBC) between 2010 and 2014 using the surveillance, Epidemiology, and End Results (SEER) database. Chi-square test was used to analyze characteristics between subgroups. Kaplan-Meier analysis and Multivariate Cox regressions were used to evaluate overall survival (OS) of MpBC, TNBC, and MpBC subgroups. Competing risk analysis and multivariate regression model of competing risk were used to assess breast cancer-specific survival (BCSS) of MpBC and TNBC RESULTS: We identified a study cohort of 22,433 patients (1112 MpBC and 21,321 TNBC). MpBC correlated with older population, larger tumor size and less lymph node involvement, and TNBC phenotype. Patients with MpBC especially with triple-negative subtype (TN-MpBC) had worse survival than the overall TNBC population. However, the prognosis of MpBC without triple-negative subtype (non-TN MpBC) was not different from that of TNBC. In Kaplan-Meier analysis, chemotherapy was not associated with significant difference in OS of TN-MpBC. In non-TN MpBC group, the 3-year OS was 79.8% for patients receiving chemotherapy and 70.5% in patients without chemotherapy, and chemotherapy was associated (P = 0.033) with improved OS. Within the MpBC patients, radiotherapy was significantly (HR 1.544; 95% CI 1.148-2.078; P = 0.004) associated with improved OS and (HR 1.474; 95% CI 1.067-2.040; P = 0.019) BCSS. CONCLUSIONS: Patients with TN-MpBC had worse prognosis than TNBC and chemotherapy was not associated with improved survival. In contrast, non-TN MpBC may derive survival benefit from chemotherapy and radiotherapy.