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PURPOSE Overexpression of the HER2 protein occurs in 25% to 30% of human breast cancers and leads to a particularly aggressive form of the disease. Efficacy and safety of recombinant humanized anti-HER2 monoclonal antibody as a single agent was evaluated in women with HER2-overexpressing metastatic breast cancer that had progressed after chemotherapy for metastatic disease. PATIENTS AND METHODS Two hundred twenty-two women, with HER2-overexpressing metastatic breast cancer that had progressed after one or two chemotherapy regimens, were enrolled. Patients received a loading dose of 4 mg/kg intravenously, followed by a 2-mg/kg maintenance dose at weekly intervals. RESULTS Study patients had advanced metastatic disease and had received extensive prior therapy. A blinded, independent response evaluation committee identified eight complete and 26 partial responses, for an objective response rate of 15% in the intent-to-treat population (95% confidence interval, 11% to 21%). The median duration of response was 9.1 months; the median duration of survival was 13 months. The most common adverse events, which occurred in approximately 40% of patients, were infusion-associated fever and/or chills that usually occurred only during the first infusion, and were of mild to moderate severity. These symptoms were treated successfully with acetaminophen and/or diphenhydramine. The most clinically significant adverse event was cardiac dysfunction, which occurred in 4.7% of patients. Only 1% of patients discontinued the study because of treatment-related adverse events. CONCLUSION Recombinant humanized anti-HER2 monoclonal antibody, administered as a single agent, produces durable objective responses and is well tolerated by women with HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. Side effects that are commonly observed with chemotherapy, such as alopecia, mucositis, and neutropenia, are rarely seen.

Purpose Angiogenesis is a crucial phenomenon in the development and progression of breast cancer (BC), but the clinical significance of angiogenesis-related proteins in metastatic BC remains unknown. This study investigates the prognostic value of vascular endothelial growth factor receptors 1, 2, 3 (VEGFR1, VEGFR2, VEGFR3) as well as vascular endothelial growth factors A and C (VEGFA and VEGFC) in metastatic BC patients treated with trastuzumab-based regimens.Materials and Methods Two hundred female patients were included. Protein and mRNA expression of the studied angiogenesis-related factors were evaluated by immunohistochemistry and quantitative polymerase chain reaction, respectively.Results High expression of VEGFA, VEGFC, VEGFR1, VEGFR2, and VEGFR3 in the tumor cells was observed in 43.5%, 24.2%, 36%, 29.5%, and 43%, respectively. Stromal elements expressed high levels of VEGFA, VEGFC, VEGFR1, VEGFR2, and VEGFR3 in 78.9%, 93.3%, 90.7%, 90.2%, and 74.8% of tumors with available data. High tumor cell expression of VEGFR1 was a favorable prognosticator for survival among patients with human epidermal growth factor receptor 2 (HER2)–positive tumors (hazard ratio [HR], 0.55; p=0.013). A trend towards longer progression-free survival was detected univariately for patients with HER2-negative tumors and high expression of VEGFR2 (HR, 0.60; p=0.059).Conclusion VEGFR1 and VEGFR2 seem to have significant prognostic value in BC patients with metastatic disease treated with trastuzumab-based regimens.

Background: UJVIRA is the first DCGI approved biosimilar of trastuzumab emtansine (Kadcyla) which may offer an alternative cost-effective treatment option for HER2-positive metastatic breast cancer patients in India. This article summarizes the available clinical evidence supporting the biosimilarity of UJVIRA and Kadcyla with respect to efficacy, pharmacokinetic, safety, and immunogenicity. Methods: A phase 3, randomized, open-label, active-controlled study was conducted at 31 sites across India. A total of 168 patients were enrolled and randomized to receive either UJVIRA or Kadcyla. Of which, only first 50 patients were included in pharmacokinetic assessment. UJVIRA or Kadcyla were administered at a dose of 3.6 mg/kg by intravenous infusion every 3 weeks (21 days) for 8 cycles or until disease progression or unmanageable toxicity, whichever was earlier. The study assessed efficacy (ORR), safety, pharmacokinetics, and immunogenicity. Results: The ORR at the end of Week 24 was 37.76% in the UJVIRA and 33.33% in the Kadcyla group. The risk difference was 4.42% [-12.01, 20.85]. It met non-inferiority margin of -15%. The pharmacokinetic parameters were comparable between groups. No anti-drug antibody was detected in any of the treatment groups. The overall safety profile in terms of TEAEs and laboratory abnormalities was also comparable between the treatment groups. Conclusion: Results demonstrated biosimilarity between UJVIRA and Kadcyla in terms of efficacy, safety, pharmacokinetics, and immunogenicity. Therefore, UJVIRA could prove to be a cost-effective treatment alternative for HER2-positive metastatic breast cancer patients in India.

Aim: To describe real-world treatment patterns/outcomes among patients with HER2+ metastatic breast cancer (MBC). Materials & methods: Real-world treatments and overall survival (OS) were evaluated among adult women diagnosed with HER2+ MBC, with and without brain metastases (BMs), between 1 June 2012 and 31 May 2018 using electronic medical records from the Definitive Oncology Dataset. Results: Among 372 patients, 69% initiated first-line trastuzumab plus pertuzumab-based therapy; many therapy combinations were utilized in the second- to fourth-line. During follow-up (median 24.8 months), 18% of patients died (22% with and 16% without BMs). Mean OS was shortest among patients with BMs at MBC diagnosis in the third- and fourth-line. Conclusion: OS was poor, and no clear standard of care was observed among patients with HER2+ MBC progressing on trastuzumab-based therapies.

Targeted therapies against human epidermal growth factor receptor 2 (HER2) are associated with increased interstitial lung disease (ILD). Trastuzumab, lapatinib, pertuzumab, and trastuzumab emtansine have markedly extended HER2 breast cancer survival but current knowledge on how these HER2-targeted agents induce interstitial lung disease is still poorly defined due to limited cases in the literature. Physicians mostly managed this complication by dose interruption, dose de-escalation, or discontinuation with success. In 2019, the FDA had granted accelerated approval on trastuzumab deruxtecan (T-Dxd) in HER2 breast cancer in the late line setting. Severe ILD incidence rate was over ten percent and led to fatal outcomes in 2.2% of patients in the T-Dxd trial. Searching for biomarkers to detect ILD incidence before it becomes clinically fulminant or for treatment response monitoring is of high clinical value. A Case of life-threatening trastuzumab-induced ILD was encountered in our facility. The ILD was confirmed to be antineutrophil cytoplasmic antibody (ANCA) pulmonary capillaritis. The biomarker of neutrophil extracellular traps (NETs), serum MPO-DNA complex, showed a good correlation with the clinical severity. Soon after B cell depleting agent rituximab usage, the serum MPO-DNA outperformed ANCA autoantibody and maintained its correlation with clinical severity. In addition to the trastuzumab-induced ILD case, a prospective cohort in our facility also confirmed the usefulness of MPO-DNA in monitoring vasculitis activity. We postulated that upfront testing with biomarkers of vasculitis during HER2 targeted treatment with high ILD incidence may be beneficial in the future., Graphical abstract Interaction Between Anti-HER2 Antibody and ANCA-Associated Vasculitis and Neutrophil In lung tissues, only bronchial epithelial cells express human epidermal growth factor 2 (HER2) protein in the cell surfaces. Once trastuzumab binds to the HER2 protein, trastuzumab acts as a stimulus to activate neutrophils to express autoantigen, including leukocyte proteinase 3 (PR3) and myeloperoxidase (MPO). The neutrophils could also directly release PR3 and MPO with cell-free DNA and histone through exocytosis to form a neutrophil extracellular trap (NETs). NETs containing PR3 and MPO could further trigger autoreactive B cells to produce ANCA antibodies, resulting in more neutrophil activation and alveolar-capillary endothelial as well as alveolar epithelial damage, although alveolar epithelial cells do not express HER2. A two-step mechanism explains how all previously reported cases that we identified manifests late with a median time of onset two months after the first trastuzumab exposure.Image 1, Highlights • Drug-induced Interstitial lung disease (DIILD) induced by HER2-targeted therapies, is a well-known adverse drug reaction, but the mechanism is ill-defined and no effective strategy for monitoring and prevention were reported. • We report a Case of trastuzumab-related interstitial lung disease induced by anti-neutrophil cytoplasmic antibody, which was never reported in previous literature. • As neutrophils dominate the inflammatory infiltrate in vasculitis, serum MPO-DNA, a biomarker of neutrophil activity, was performed in this Case and within a prospective vasculitis cohort in our facility and showed promising clinical severity correlation. • Monitoring with vasculitis-related autoantibodies and serum MPO-DNA may be helpful in future HER2-targeted agents since high rates of DIILD were reported due to this group of HER2-targeted agents.

Purpose Gastric cancer with para-aortic node (PAN) metastasis has a chance to be cured with multidisciplinary treatment of D2 and PAN dissection (PAND) following neoadjuvant chemotherapy (NAC), but its prognosis remains unsatisfactory. To establish a better multidisciplinary treatment, a better surrogate endpoint is needed. The present study focused on a pathological complete response at the PANs alone as a new surrogate endpoint and evaluated its prognostic value. Methods The study examined patients who received radical gastrectomy with D2 and PAND after NAC for gastric cancer with PAN metastasis from 2004 to 2015. The study compared five methods of evaluating the response to NAC: RECIST, clinical disappearance of PANs (cPAN), histological response of the primary tumor defined by Japanese Classification of Gastric Carcinoma (JCGC histological criteria) and Becker's criteria, and pathological disappearance of PANs (pPAN). The efficacy of these methods was compared using the hazard ratio (HR) for death between responders and non-responders. Results Thirty-two patients were analyzed. The respective HR and 5-year overall survival rates of responders and non-responders were 1.316 and 49.1% vs. 60.0% by RECIST, 1.106 and 52.9% vs. 52.5% by cPAN, 0.246 and 71.3% vs. 28.6% by JCGC histological criteria, 0.239 and 76.2% vs. 36.8% by Becker's criteria, and 0.074 and 81.0% vs. 0.0% by pPAN. Conclusions A pathological complete response at the PANs had the lowest HR and clearly differentiated the survival, suggesting it might be a good surrogate endpoint for identifying future candidates for NAC in multidisciplinary treatment for gastric cancer with PAN metastasis.

Background Neoadjuvant chemotherapy (NAC) in combination with anti-HER2 treatment is standard of care in patients with early HER2 positive breast cancer. Preoperative radiological evaluation is mandatory for defining the extent of surgery. In this study, we evaluated the correlation between preoperative radiological and postoperative pathological tumor size in early HER2 positive patients after neoadjuvant chemotherapy in combination with trastuzumab and pertuzumab. In a patient population with HER2 positive breast cancer, who received neoadjuvant chemotherapy and anti-HER2 treatment, the correlation between preoperative radiological and postoperative pathological tumor size was performed. Concordance of radiological and pathological tumor size was found in 55.7%, leading to more extensive breast surgery as required in 7 cases and to the underestimation of 6 neoplastic lesions before surgery, respectively. Patients and Methods Seventy early HER2 positive breast cancer patients were included and retrospectively analysed. All preoperative radiological assessments as well as the tumor board decision on surgical extent and pathological evaluation were completed at the Medical University of Vienna. Preoperative radiological assessment of tumor size and lymph node status were compared with final histopathological findings. The correlation between different radiological modalities regarding tumor size was investigated. Results Concordance of radiological and pathological tumor size was found in 55.7 % (50% by sonography and 66.7% by MRI, respectively) of patients with a nonsignificant correlation of r = 0.31 (P = .08). Of the 39 patients with pathologic complete remission (pCR), 16 were also classified as radiological complete response (rCR) while 23 of those showed a radiological stable disease or partial response. In 6 patients, radiological assessment showed a CR but invasive cancer with a tumor size range from 7 to 36 mm was found in histopathological examination. Neither menopausal status (P= .69) nor BMI (P = .60) and age (P = .50) had an impact on the correlation between radiological and histopathological tumor size. Regarding lymph node status, a statistically significant association and clinically relevant correlation between radiological and histopathological evaluation was found (r = 0.66, P Conclusion Concordance between radiology and histopathology was low regarding tumor size after NAC in combination with trastuzumab and pertuzumab, but significant regarding lymph node status.

Background Human epidermal growth factor receptor 2 (HER2)-targeted therapies have not been approved for patients with non-small-cell lung cancer (NSCLC). The efficacy and safety of trastuzumab deruxtecan (formerly DS-8201), a HER2 antibody-drug conjugate, in patients with HER2-mutant NSCLC have not been investigated extensively. Methods We conducted a multicenter, international, phase 2 study in which trastuzumab deruxtecan (6.4 mg per kilogram of body weight) was administered to patients who had metastatic HER2-mutant NSCLC that was refractory to standard treatment. The primary outcome was objective response as assessed by independent central review. Secondary outcomes included the duration of response, progression-free survival, overall survival, and safety. Biomarkers of HER2 alterations were assessed. Results A total of 91 patients were enrolled. The median duration of follow-up was 13.1 months (range, 0.7 to 29.1). Centrally confirmed objective response occurred in 55% of the patients (95% confidence interval [CI], 44 to 65). The median duration of response was 9.3 months (95% CI, 5.7 to 14.7). Median progression-free survival was 8.2 months (95% CI, 6.0 to 11.9), and median overall survival was 17.8 months (95% CI, 13.8 to 22.1). The safety profile was generally consistent with those from previous studies; grade 3 or higher drug-related adverse events occurred in 46% of patients, the most common event being neutropenia (in 19%). Adjudicated drug-related interstitial lung disease occurred in 26% of patients and resulted in death in 2 patients. Responses were observed across different HER2 mutation subtypes, as well as in patients with no detectable HER2 expression or HER2 amplification. Conclusions Trastuzumab deruxtecan showed durable anticancer activity in patients with previously treated HER2-mutant NSCLC. The safety profile included interstitial lung disease that was fatal in two cases. Observed toxic effects were generally consistent with those in previously reported studies. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Lung01 ClinicalTrials.gov number, NCT03505710.).

The current standard of care for many patients with HER2-positive breast cancer is neoadjuvant chemotherapy in combination with anti-HER2 agents, based on HER2 amplification as detected by in situ hybridization (ISH) or protein immunohistochemistry (IHC). However, hematoxylin & eosin (H&E) tumor stains are more commonly available, and accurate prediction of HER2 status and anti-HER2 treatment response from H&E would reduce costs and increase the speed of treatment selection. Computational algorithms for H&E have been effective in predicting a variety of cancer features and clinical outcomes, including moderate success in predicting HER2 status. In this work, we present a novel convolutional neural network (CNN) approach able to predict HER2 status with increased accuracy over prior methods. We trained a CNN classifier on 188 H&E whole slide images (WSIs) manually annotated for tumor Regions of interest (ROIs) by our pathology team. Our classifier achieved an area under the curve (AUC) of 0.90 in cross-validation of slide-level HER2 status and 0.81 on an independent TCGA test set. Within slides, we observed strong agreement between pathologist annotated ROIs and blinded computational predictions of tumor regions / HER2 status. Moreover, we trained our classifier on pre-treatment samples from 187 HER2+ patients that subsequently received trastuzumab therapy. Our classifier achieved an AUC of 0.80 in a five-fold cross validation. Our work provides an H&E-based algorithm that can predict HER2 status and trastuzumab response in breast cancer at an accuracy that may benefit clinical evaluations.

Treatment with trastuzumab, an antihuman epidermal growth factor receptor type 2 humanized monoclonal antibody, has been associated with heart failure in certain patients with cancer; however, the mechanism underlying trastuzumab-induced cardiac dysfunction remains unclear. This study was conducted to clarify the cardiac effects of trastuzumab in cynomolgus monkeys, which are commonly used as cross-reactive species in preclinical safety evaluation. Monkeys were treated with trastuzumab weekly for 1 month (5 doses in total). At first and fifth doses for pressure-volume loop analysis, trastuzumab at 20 mg·kg-1·10 min-1, equivalent to the human therapeutic dose, was administered intravenously to isoflurane-anesthetized animals, followed by 60 mg·kg-1·10 min-1 at a 30-minute interval. The other doses were fixed at 80 mg·kg-1·10 min-1 under unanesthetized conditions. After the first dose, reduced heart rate, decreases in maximal rate of fall of left ventricular pressure, and prolonged time constant for isovolumic relaxation, which are predictors of drug-induced changes in lusitropy, were observed at 20 and 60 mg·kg-1. The changes after the fifth dose were comparable with those after the first dose, indicating trastuzumab did not show exacerbation of cardiac function during the 1-month trial. No significant changes in slope of preload recruitable stroke work, which is a load-independent inotropic parameter, were observed at either dose. In conclusion, trastuzumab-induced little inotropic effect but induced negative chronotropic or lusitropic effects in monkeys, which might be associated with impaired left ventricular diastolic function.

Lay abstract Pegfilgrastim is used to prevent low white blood cell count in patients receiving chemotherapy. Comparable to a generic version of a drug, a biosimilar is a follow-on version of a biologic treatment. We calculated the savings from using biosimilar pegfilgrastim in a hypothetical group of 20,000 patients with breast cancer receiving chemotherapy with AC (doxorubicin/cyclophosphamide). We then computed the number of additional doses of AC chemotherapy that could be purchased with those savings. We did the same for a group of 5000 HER2+ breast cancer patients treated with TCH (docetaxel/carboplatin/trastuzumab). Using biosimilar pegfilgrastim could save $1,083 per patient per cycle. If all patients were treated with biosimilar pegfilgrastim over six cycles, $129.9 million could be saved in the AC group and $32.5 million in the TCH group. This could provide 220,468 additional AC doses and 6981 TCH doses. Biosimilar pegfilgrastim can generate significant savings. These savings can be used to provide additional patients with chemotherapy cost-free.

Aim Anti-human epidermal growth factor receptor 2 (HER2) therapy is an effective treatment for HER2-positive gastric and breast malignancies. However, the efficacy of HER2-targeted therapy in non-small cell lung cancer (NSCLC) patients with HER2 alterations remains controversial. Methods We searched studies on HER2-targeted therapy in NSCLC patients that reported objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS) published from database inception to May 30, 2021. Results A total of 32 trials involving 958 patients were included. The ORRs of HER2-TKIs targeted therapy, humanised monoclonal antibody, trastuzumab-based treatment, and antibody-drug conjugate (ADC) (T-DM1) were 22% (95% CI 11-31), 23% (95% CI 20-65), 26% (95% CI 14-39), and 16% (95% CI -6-37), while that of ADC (DS-8201) was 60% (95% CI 35-85). The DCRs of these groups were 59% (95% CI 49-69), 39% (95% CI -9-88), 63% (95% CI 37-89), 31% (95% CI 4-58), and 87% (95% CI 62-112), respectively. In the subgroup analysis, numerically higher ORRs and DCRs were observed in the poziotinib (38%;75%) and pyrotinib (35%; 83%) groups. The median PFSs of these groups were 5.51 months, 3.09 months, 4.61 months, 2.65 months, and 12.04 months, respectively. Conclusion HER2-targeted therapy can be considered an acceptable treatment strategy for NSCLC patients with HER2 alterations. In particular, ADC (DS-8201), pyrotinib, and poziotinib demonstrated promising anti-tumour activity in HER2-positive NSCLC.

Summary Background Both innate and adaptive immune responses are important components of anticancer immunity. The CD47–SIRPα interaction could represent an important pathway used by tumour cells to evade immune surveillance. We aimed to evaluate the safety, pharmacokinetics, pharmacodynamics, and anticancer activity of evorpacept (also known as ALX148), a high-affinity CD47-blocking protein with an inactive IgG Fc region in patients with solid tumours. Methods We did a first-in-human, open-label, multicentre, phase 1 dose-escalation and dose-expansion study at nine hospitals and one clinic in the USA and Korea. Eligible patients for the dose-escalation and safety lead-in phases were aged 18 years or older with histological or cytological diagnosis of advanced or metastatic solid tumours with no available standard therapy, measurable or unmeasurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1, and an Eastern Cooperative Oncology Group performance status score of 0 or 1. In the dose-escalation phase, which used a 3 + 3 design, patients received intravenous evorpacept at either 0·3, 1, 3, or 10 mg/kg once per week in 21-day cycles, or 30 mg/kg once every other week in 28-day cycles. In the safety lead-in phase, patients were given the maximum tolerable dose of evorpacept from the dose-escalation phase plus either intravenous pembrolizumab (200 mg administered once every 3 weeks) or intravenous trastuzumab (8 mg/kg loading dose followed by 6 mg/kg once every 3 weeks). In the dose-expansion phase, additional patients aged 18 years or older with second-line or later-line advanced malignancies were enrolled into three parallel cohorts: those with head and neck squamous cell carcinoma (HNSCC) and those with non-small-cell lung cancer (NSCLC) were given the maximum tolerated dose of evorpacept plus intravenous pembrolizumab (200 mg administered once every 3 weeks), and patients with HER2-positive gastric or gastroesophageal junction cancer were given the maximum tolerated dose of evorpacept plus intravenous trastuzumab (8 mg/kg loading dose followed by 6 mg/kg once every 3 weeks) until disease progression, voluntary withdrawal from the study, or unacceptable toxicity. The primary endpoint was the maximum tolerated dose of evorpacept administered as a single agent and in combination with pembrolizumab or trastuzumab, measured by the occurrence of dose-limiting toxicities during the first cycle, and was assessed in all patients who had received at least one dose of evorpacept. Secondary outcomes included the safety, tolerability, and antitumour activity of evorpacept, alone or in combination with pembrolizumab or trastuzumab. The primary outcome, safety, and tolerability were assessed in all patients who had received at least one dose of evorpacept, and antitumour activity was assessed in those who recieved at least one dose of study treatment and underwent at least one post-baseline tumor assessment. This trial is registered with ClinicalTrials.gov , NCT03013218 . Findings Between March 6, 2017, and Feb 21, 2019, 110 patients received single-agent evorpacept (n=28), evorpacept plus pembrolizumab (n=52), or evorpacept plus trastuzumab (n=30), and were included in the safety analysis. Median follow-up was 29·1 months (95% CI not calculable [NC]–NC) in the single-agent cohort, 27·0 months (25·1–28·8) in the evorpacept plus pembrolizumab cohort, and 32·7 months (27·0–32·7) in the evorpacept plus trastuzumab cohort. Two (7%) dose-limiting toxicities in the first cycle were reported in patients who received single-agent evorpacept; neutropenia with an associated infection in one patient with gastroesophageal junction cancer who received 3 mg/kg once per week, and thrombocytopenia with associated bleeding in one patient with pancreatic cancer who received 30 mg/kg once every other week. No maximum tolerated dose was reached; the maximum administered doses were 10 mg/kg once per week or 30 mg/kg once every other week. The 10 mg/kg once per week dose was used in the expansion cohorts in combination with pembrolizumab or trastuzumab. The most common grade 3 or worse treatment-related adverse events were thrombocytopenia with single-agent evorpacept (two [7%] patients) and evorpacept plus pembrolizumab (two [4%]), and thrombocytopenia (two [7%]) and neutropenia (two [7%]) with evorpacept plus trastuzumab. In patients who received single-agent evorpacept, four treatment-related serious adverse events were reported. Five serious treatment-related adverse events related to evorpacept plus pembrolizumab were reported, and one serious adverse event related to evorpacept plus trastuzumab was reported. In response-evaluable patients in the dose-escalation phase (n=15) receiving single-agent evorpacept once per week, four (27%) had a best overall response of stable disease (two received 0·3 mg/kg, one received 3 mg/kg, and one received 10 mg/kg); in the 11 patients who received single-agent evorpacept at the highest dose of 30 mg/kg once every other week, two (18%) had stable disease. In the dose-expansion cohort, overall responses were recorded in four (20·0%; 95% CI 5·7–43·7) of 20 patients with HNSCC who received evorpacept plus pembrolizumab, in one (5·0%; 0·1–24·9) of 20 patients with NSCLC who received evorpacept plus pembrolizumab, and in four (21·1%; 6·1–45·6) of 19 patients with gastric or gastroesophageal junction cancer who received evorpacept plus trastuzumab. Interpretation The safety findings support the use of evorpacept in combination with pembrolizumab or trastuzumab for patients with advanced solid tumours. Preliminary antitumour activity results support future investigation of evorpacept combined with pembrolizumab or trastuzumab in patients with HNSCC, gastric or gastroesophageal junction cancer, and NSCLC. Funding ALX Oncology.

Antibody-drug conjugates (ADCs) are among the most significant advances in clinical cancer treatments, however, they are haunted with fundamental issues like low drug/antibody ratio (DAR), need of large amount of antibody, and complex chemistry. Targeted nanomedicines while offering a promising alternative to ADCs are afflicted with drug leakage and inferior cancer-specificity. Herein, we developed an intelligent cell-selective nanotoxin based on anti-CD44 antibody-polymersome-DM1 conjugates (aCD44-AP-DM1) for potent treatment of solid tumors. DM1 was simultaneously coupled to vesicular membrane via disulfide bonds during self-assembly and anti-CD44 antibody was facilely clicked onto polymersome surface, tailor-making an optimal aCD44-AP-DM1 with a controlled antibody density of 5.0, extraordinary DAR of 275, zero drug leakage and rapid reduction-responsive DM1 release. aCD44-AP-DM1 displayed a high specificity and exceptional cytotoxicity toward MDA-MB-231 triple negative breast cancer, SMMC-7721 hepatocellular carcinoma and A549 non-small cell lung cancer cells with half-maximal inhibitory concentrations (IC50) of 21.4, 3.7 and 64.6 ng/mL, respectively, 3.6–47.2-fold exceeding non-targeted P-DM1. Intriguingly, the systemic administration of aCD44-AP-DM1 significantly suppressed subcutaneous MDA-MB-231 tumor xenografts in nude mice while intratumoral injection achieved complete tumor eradication in four out of five mice, without causing toxicity. This intelligent cell-selective nanotoxin has emerged as a better platform over ADCs for targeted cancer therapy.

The choice of the anti-HER2 agent depends on country-specific availability, the specific, previously administered anti-HER2 therapy and the relapse-free interval, although there is not much published data on the use of lapatinib after progression on pertuzumab and/or T-DM1. The aim of this research is to determine efficacy of lapatinib in this setting. This research included 111 patients with metastatic HER2 positive breast cancer who received lapatinib with capecitabine at The Oncology Institute of Vojvodina. Lapatinib was given to 83 patients after trastuzumab without prior exposure to pertuzumab or T-DM1 while 28 patients received lapatinib after prior exposure to trastuzumab, pertuzumab and/or T-DM1. In order to determine efficacy of lapatinib in both groups, we measured progression free survival (PFS) and overall survival (OS), as well as by subsets: hormonal status (ER-positive and/or PR-positive tumours versus ER-negative and PR-negative tumours), the number of positive axillary lymph nodes (four or more positive axillary lymph nodes versus less than four positive axillary lymph nodes), marker of proliferation (Ki-67 ≥ 30 versus Ki-67 30), disease free interval (metastatic recurrence ≤ 1 year after initial diagnosis versus metastatic recurrence1 year after initial diagnosis or de novo metastatic disease. Median PFS was 5.6 months (95% CI 4.6-6.6) in the group of patients who received lapatinib after prior exposure to trastuzumab, pertuzumab and/or T-DM 1 and 7.4 months (95% CI 6.1-10.2) in the group of patients who received lapatinib after trastuzumab (HR, 0.79; 95% CI 0.61-0.98; P = 0.09). The patients with negative prognostic factors such as hormone receptor negativity, more than four positive axillary lymph nodes, marker of proliferation Ki 67 ≥ 30 and metastatic recurrence ≤ 1 year after initial diagnosis, had a similar PFS, regardless of receiving lapatinib after prior exposure to trastuzumab, pertuzumab and/or T-DM1 or without prior exposure. Median OS was 10.1 months (95% CI 8.6-NR) in the group that received lapatinib after exposure to trastuzumab, pertuzumab and/or T-DM1 and 16.3 months (95% CI 14.4-20.2) in the group of patients who received lapatinib after trastuzumab (HR, 0.76; 95% CI, 0.59-0.94; P = 0.04). Patients with negative prognostic factors such as hormone receptor negativity, more than four positive axillary lymph nodes and marker of proliferation Ki 67 ≥ 30, had no distinctly worse OS, regardless of receiving lapatinib after prior exposure to trastuzumab, pertuzumab and/or T-DM1 or without prior exposure. Lapatinib with capecitabine is an effective therapeutic option, especially in patients with negative prognostic factors, who have received prior chemotherapy, trastuzumab, pertuzumab, T-DM1 and remains an acceptable option for HER2 positive metastatic breast cancer until the novel drugs are approved in developing countries.

OBJECTIVE To describe the proposed mechanisms of chemotherapy-associated cardiomyopathy (CAC) and potential cardioprotective therapies for CAC including a comprehensive review of existing systematic analyses, guideline recommendations, and ongoing clinical trials. DATA SOURCES A literature search of MEDLINE was performed (from 1990 to June 2020) using the following search terms: anthracycline, trastuzumab, cardiomyopathy, cardiotoxicity, primary prevention, angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), beta blocker, dexrazoxane (DEX) as well as using individual names from select therapeutic categories. STUDY SELECTION AND DATA EXTRACTION Existing English language systematic analyses and guidelines were considered. DATA SYNTHESIS The mechanisms of CAC are multifaceted, but various cardioprotective therapies target many of these pathways. To date, anthracyclines and HER-2 targeted therapies have been the focus of cardioprotective trials to date as they are the most commonly implicated therapies in CAC. While traditional neurohormonal antagonists (ACEIs, ARBs, and beta blockers) and DEX performed favorably in many small clinical trials, the quality of available evidence remains limited. Hence, major guidelines lack consensus on an approach to primary prevention of CAC. Given the uncertain role of preventive therapy, monitoring for a symptomatic or asymptomatic decline in LV function is imperative with prompt evaluation should this occur. Numerous ongoing randomized controlled trials seek to either confirm the findings of these previous studies or identify new therapeutic agents to prevent CAC. Clinical implications are derived from the available literature as well as current guideline recommendations for CAC cardioprotection. CONCLUSION At this time, no single therapy has a clear cardioprotective benefit in preventing CAC nor is any therapy strongly recommended by current guidelines. Additional studies are needed to determine the optimal preventative regimens.

Purpose: There is no research evidence demonstrate which is the better partner strategy, endocrine therapy or chemotherapy, to combine with anti-HER2 therapy as the first-line management of hormone receptor (HR)-positive (HR+) and HER2-positive (HER2+) metastatic breast cancer (MBC). We wished to ascertain if trastuzumab plus endocrine therapy is noninferior to trastuzumab plus chemotherapy. Patients and Methods: We conducted an open-label, noninferiority, phase III, randomized, controlled trial (NCT01950182) at nine hospitals in China. Participants, stratified by previous adjuvant endocrine therapy and disease status (recurrent disease vs. de novo metastasis), were assigned randomly (1:1) to receive trastuzumab plus endocrine therapy (per investigator's choice of oestrogen-receptor modulators or aromatase inhibitor, with/without concurrent ovarian suppression) or chemotherapy (per investigator's choice of taxanes, capecitabine, or vinorelbine). The primary endpoint was progression-free survival (PFS) with a noninferiority upper margin of 1.35 for the HR. The intention-to-treat population was used in primary and safety analyses. Results: A total of 392 patients were enrolled and assigned randomly to receive trastuzumab plus endocrine therapy (ET group, n = 196) or trastuzumab plus chemotherapy (CT group, n = 196). After a median follow-up of 30.2 months [interquartile range (IQR) 15.0–44.7], the median PFS was 19.2 months [95% confidence interval (CI), 16.7–21.7)] in the ET group and 14.8 months (12.8–16.8) in the CT group (hazard ratio, 0.88; 95% CI, 0.71–1.09; Pnoninferiority < 0.0001). A significantly higher prevalence of toxicity was observed in the CT group compared with the ET group. Conclusions: Trastuzumab plus endocrine therapy was noninferior to trastuzumab plus chemotherapy in patients with HR+HER2+ MBC.

Cardiotoxicity (CDT) is the main adverse effect related to trastuzumab (TTZ). The role of the right ventricle (RV) in this context is not clear. We aimed to evaluate the longitudinal changes in RV function during TTZ therapy and to determine RV function changes associated with subclinical CDT. Breast cancer patients underwent echocardiograms at the beginning of TTZ treatment (Exam 1) and every 3 months during the first year (Exams 2, 3, and 4). Subclinical CDT was defined as ≥ 12% relative reduction of left ventricle global longitudinal strain (LV GLS). Twenty-five women (52.1 ± 13.1 y-o) were included. We found a decrease in LV ejection fraction between the first and fourth exams (Ex1: 64.1% ± 4.9 vs Ex4: 60.9% ± 4.9, p = 0.003) and the LV GLS gradually decreased during follow-up (Ex1: - 20.6% ± 2.0; Ex2: - 19.4% ± 2.1; Ex3: - 19.2% ± 1.8; Ex4: - 19.0% ± 2.1, all p < 0.05). RV GLS changed from baseline to 3 month and to 6 month (Ex1: - 23.9% ± 1.6; Ex2: - 22.5% ± 2.1; Ex3: - 22.5% ± 2.3, all p < 0.05), and the RV Fractional Area Change was lower in the third exam (Ex1: 44.3% ± 6.6 vs Ex3: 39.9% ± 6.0, p = 0.004). We found subclinical CDT in 13 patients (52%); worsening in RV parameters did not differ between those with and without subclinical CDT. In this sample, the RV function decreased during TTZ therapy and the decrease was not associated to the observed LV cardiotoxicity.

Aims:Pertuzumab plus trastuzumab and docetaxel is a standard regimen for human epidermal growth factor receptor 2 (HER2)-positive breast cancer in the metastatic, adjuvant, and neoadjuvant settings. Infusion reaction represents one of the common side effects of anti-HER2 agents. There is no standard premedication to prevent infusion reactions, although antihistamines, acetaminophen, and/or corticosteroids are often used for this purpose. This study evaluated the ability of premedication to prevent induction reactions in patients receiving pertuzumab, trastuzumab, and docetaxel. Methods: This retrospective, single-institute study assessed infusion reactions in 72 women with HER2-positive early breast cancer who received pertuzumab, trastuzumab, and docetaxel between November 2018 and April 2021. Thirty-six patients received premedication consisting of oral acetaminophen prior to pertuzumab and trastuzumab administration and dexamethasone and D-chlorpheniramine maleate intravenously prior to docetaxel administration (previous regimen). Thirty-six patients received premedication consisting of acetaminophen, dexamethasone, and D-chlorpheniramine maleate sequentially prior to pertuzumab, trastuzumab, and docetaxel administration (current regimen). Results: The rates of infusion reaction after the initial injection were 55.6 and 16.7% in the previous and current regiment groups, respectively (p = 0.001). Trastuzumab more frequently caused infusion reactions than pertuzumab and docetaxel. Chills, vomiting, and nausea were the major symptoms of infusion reactions. Conclusion: Premedication featuring the upfront use of dexamethasone and D-chlorpheniramine maleate prior to the administration of anti-HER2 targeted agents significantly prevented infusion reactions.

Background: The function of MALAT1, a long non-coding RNAs (lncRNA), in HER2- positive breast cancer remains largely unexplored. Objectives: This study aimed to investigate the effect of MALAT1 on tumor development in HER2-positive breast cancer. Methods: We detected MALAT1 expression in HER2-positive breast cancer cells and tissues, and analyzed the effects of MALAT1 on cell proliferation in HER2-positive breast cancer cells lines (BT-474 and SKBR3). A mouse xenograft model was established for detecting the function of MALAT1 in HER2-positive breast cancer. Results & Discussion: As a result, MALAT1 was remarkably up-regulated in HER2-positive breast cancer both in cells and tissues. In addition, the silencing of MALAT1 inhibited the proliferation of HER2-positive breast cancer cells both in vitro and in vivo. Furthermore, knockdown of MALAT1 by shRNA down-regulated DNMT1, DNMT3a, and DNMT3b, while up-regulated BRCA1 and PTEN in HER2-positive breast cancer both in cell lines and mouse xenograft models. Conclusion: In short, MALAT1 might be a potential biomarker and therapeutic target for HER2- positive breast cancer therapy.

Background We aimed to study the predictive value of early two-dimensional echocardiography (2DE) speckle tracking (ST) for left ventricular ejection fraction (LVEF) changes during trastuzumab treatment for HER2-positive breast cancer. Methods HER2-positive breast cancer patients receiving trastuzumab, with or without anthracycline, underwent 2DE-ST at baseline and after 3 and 6 months (m) trastuzumab. Cardiac magnetic resonance (CMR) imaging (with ST) was performed at baseline and 6 m. We studied the correlation between 2DE-ST- and CMR-derived global longitudinal strain (GLS) and global radial strain (GRS) measured at the same time. Additionally, we associated baseline and 3 m 2DE-ST measurements with later CMR-LVEF, and with cardiotoxicity, defined as CMR-LVEF 10% during trastuzumab. Results Forty-seven patients were included. Median baseline LVEF was 60.4%. GLS measurements based on 2DE-ST and CMR showed weak correlation (Pearson’s r = 0.33; p = 0.041); GRS measurements were uncorrelated (r = 0.09; p = 0.979). 2DE-LVEF at baseline and 3 m, and 2DE-ST-GLS at 3 m were predictive of CMR-LVEF at 6 m. In contrast, the change in 2DE-ST-GLS at 3 m was predictive of the change in CMR-LVEF at 6 m, whereas the change in 2DE-LVEF was not. Importantly, the 11 patients who developed cardiotoxicity (28%) had larger 2DE-ST-GLS change at 3 m than those who did not (median 5.2%-points versus 1.7%-points; odds ratio for 1% difference change 1.81, 95% confidence interval 1.11–2.93; p = 0.016; explained variance 0.34). Conclusions Correlations between 2DE-ST and CMR-derived measurements are weak. Nevertheless, ST-measurements appeared useful to improve the performance of 2DE in predicting LVEF changes after 6 m of trastuzumab treatment.

Background: Human epidermal growth factor receptor 2 (HER2) overexpressing malignancies, including breast and gastro-esophageal, are associated with a poor prognosis. The cardiotoxicity of trastuzumab, a HER2-targeting monoclonal antibody, is well established. However, the cardiotoxic effect of pertuzumab, another HER2-directed therapy, is less well documented. The objective of this systematic review and meta-analysis was to determine the risk of cardiac events in patients with HER2-positive cancer who are receiving pertuzumab. Methods: We performed a systematic review of phase 2 and 3 randomized controlled trials in which the addition of pertuzumab to other standard therapies in patients with stage I-IV HER2-positive cancer was evaluated, and cardiac adverse effects reported. We searched MEDLINE (1946-2020), Embase (1974-2020), and CENTRAL. Two independent reviewers assessed the risk of bias and extracted the data. Risk ratios (RRs) with 95% confidence intervals (CIs) were calculated from the pooled data using the inverse variance method and random-effects models. Results: Eight randomized controlled trials (8420 patients) were included: 1 was gastro-esophageal; 7 were breast cancer trials. Participants’ median age ranged from 49 to 61.5 years. All participants received trastuzumab and chemotherapy in addition to pertuzumab or placebo. Compared with placebo, pertuzumab increased the risk of clinical heart failure (HF; RR [95% CI]: 1.97 [1.05-3.70]; I2 = 0%). However, pertuzumab had no demonstrable effect on asymptomatic/minimally symptomatic left ventricular systolic dysfunction (RR [95% CI]: 1.19 [0.89-1.61]; I2 = 19%). Conclusions: Pertuzumab increases the risk of clinical HF, but not asymptomatic/minimally symptomatic left ventricular systolic dysfunction, in HER2-positive cancer patients. Further research into the mechanisms underlying pertuzumab-related HF is needed to understand its clinical spectrum of cardiotoxicity. Résumé: Introduction: Les tumeurs malignes qui surexpriment le récepteur 2 du facteur de croissance épidermique humain (HER2, de l’anglais Human epidermal growth factor receptor 2), notamment le cancer du sein et le cancer de la jonction gastro-œsophagienne, sont associées à un mauvais pronostic. La cardiotoxicité du trastuzumab, un anticorps monoclonal qui vise le HER2, est bien établie. Toutefois, les effets cardiotoxiques du pertuzumab, un autre traitement qui vise le HER2, sont moins bien démontrés. L’objectif de cette revue systématique et de cette méta-analyse était de déterminer le risque d’événements cardiaques chez les patients atteints d’un cancer HER2 positif qui prennent du pertuzumab. Méthodes: Nous avons réalisé une revue systématique d’essais comparatifs à répartition aléatoire de phase 2 et de phase 3 lors desquels nous avons évalué l’ajout du pertuzumab à d’autres traitements standards chez les patients atteints d’un cancer HER2 positif de stades I-IV, et signalé les effets indésirables sur le cœur. Nous avons fait des recherches dans MEDLINE (1946-2020), Embase (1974-2020) et CENTRAL. Deux examinateurs indépendants ont évalué le risque de biais et extrait les données. Les données groupées ont permis de calculer les intervalles de confiance (IC) à 95 % des risques relatifs (RR) au moyen de la méthode de la variance inverse et des modèles à effets aléatoires. Résultats: Nous avons inclus huit essais contrôlés randomisés (8420 patients), soit un qui portait sur le cancer de la jonction gastro-œsophagienne, et sept sur le cancer du sein. L’âge médian des participants se situait entre 49 à 61,5 ans. Tous les participants ont pris le trastuzumab et ont suivi une chimiothérapie en plus de la prise du pertuzumab ou du placebo. Comparativement au placebo, le pertuzumab a fait augmenter le risque de manifestations cliniques de l’insuffisance cardiaque (IC) (RR [IC à 95 %] : 1,97 [1,05-3,70]; I2 = 0 %). Toutefois, le pertuzumab n’a démontré aucun effet sur la dysfonction systolique du ventricule gauche asymptomatique/minimalement symptomatique (RR [IC à 95 %] : 1,19 [0,89-1,61]; I2 = 19 %). Conclusions: Le pertuzumab fait augmenter le risque de manifestations cliniques de l’IC, mais pais la dysfonction systolique du ventricule gauche asymptomatique/minimalement symptomatique, chez les patients atteints d’un cancer HER2 positif. Des recherches plus approfondies sur les mécanismes sous-jacents à l’IC liée au pertuzumab sont nécessaires pour comprendre son spectre de manifestations cliniques de cardiotoxicité.

Background Trastuzumab emtansine (T-DM1) is indicated as second-line treatment for human epidermal growth factor receptor 2 (HER2)-positive metastatic or unresectable locally advanced breast cancer, after progression on trastuzumab and a taxane-based chemotherapy. We wished to determine if the line of treatment in which T-DM1 is administered has an impact on progression-free survival (PFS) and in particular, if prior treatment with capecitabine/lapatinib or pertuzumab modifies PFS of further treatment with T-DM1. Patients and methods We performed a multicenter retrospective study in 3 Belgian institutions. We evaluated PFS with T-DM1 in patients treated for HER2 positive metastatic or locally advanced unresectable breast cancer between January 1, 2009 and December 31, 2016. Results We included 51 patients. The median PFS was 9.01 months. The line of treatment in which T-DM1 (1st line, 2nd line, 3rd line or 4+ lines) was administered had no influence on PFS (hazard ratio 0.979, CI95: 0.835–1.143). There was no significant difference in PFS whether or not patients had received prior treatment with capecitabine/lapatinib (9.17 vs 5.56 months, p-value 0.875). But, patients who received pertuzumab before T-DM1 tended to exhibit a shorter PFS (3.55 months for T-DM1 after pertuzumab vs 9.50 months for T-DM1 without pretreatment with pertuzumab), even if this difference was not statistically significant (p-value 0.144). Conclusion Unlike with conventional chemotherapy, the line of treatment in which T-DM1 is administered does not influence PFS in our cohort of patients with advanced HER2-positive breast cancer.

HER2 is a predictive biomarker for HER2-targeted therapeutics. For antibody–drug conjugates (ADCs; e.g., trastuzumab emtansine (T-DM1)), HER2 is utilized as a transport gate for cytotoxic agents into the cell. ADC biomarkers may therefore be more complex, also reflecting the intracellular drug transport. Here we report on a positive correlation between the early endosome marker RAB5A and T-DM1 sensitivity in five HER2-positive cell lines. Correlation between RAB5A expression and T-DM1 sensitivity is confirmed in breast cancer patients treated with trastuzumab emtansine/pertuzumab in the I-SPY2 trial (NCT01042379), but not in the trastuzumab/paclitaxel control arm. The clinical correlation is further verified in patients from the KAMILLA trial (NCT01702571). In conclusion, our results suggest RAB5A as a predictive biomarker for T-DM1 response and outline proteins involved in endocytic trafficking as predictive biomarkers for ADCs., Antibody Drug Conjugates (ADCs) are emerging in the field of precision cancer medicine. Here, the authors suggest using endocytosis as a predictive biomarker for response

Background and Aim: IGF1R and HER2 are both members of the growth factor receptor family which is known to play a different role in breast cancer. However, correlation between IGF1R and HER2 has created a controversial situation that need to be fully delineated in development of Herceptin resistance. The aim of this study was to investigate the mechanism of Herceptin resistance through the IGF1R pathway in HER2 positive breast cancer. Materials and Methods: Clinical data were obtained from TCGA database and archived documents from The First Affiliated Hospital of Bengbu Medical College. Western blot and immunohistochemistry were used to detect proteins and their phosphorylation. Cell transfection were constructed using shRNA lentivirus vectors. RNAs were analyzed by RT-qPCR. Proteins in serum were analyzed by ELISA assay. Cell proliferation was analyzed by MTS method. Luciferase report experiment was conducted to verify RNA’s inter-reaction. Results: Western blot showed IGF2 protein was significantly increased in Herceptin resistant SKBR3-R cells (P

HER2-targeted therapy dramatically improves outcomes in early breast cancer. Here we report the results of two HER2-targeted combinations in the neoadjuvant I-SPY2 phase 2 adaptive platform trial for early breast cancer at high risk of recurrence: ado-trastuzumab emtansine plus pertuzumab (T-DM1/P) and paclitaxel, trastuzumab and pertuzumab (THP). Eligible women have >2.5 cm clinical stage II/III HER2+ breast cancer, adaptively randomized to T-DM1/P, THP, or a common control arm of paclitaxel/trastuzumab (TH), followed by doxorubicin/cyclophosphamide, then surgery. Both T-DM1/P and THP arms ‘graduate’ in all subtypes: predicted pCR rates are 63%, 72% and 33% for T-DM1/P (n = 52), THP (n = 45) and TH (n = 31) respectively. Toxicity burden is similar between arms. Degree of HER2 pathway signaling and phosphorylation in pretreatment biopsy specimens are associated with response to both T-DM1/P and THP and can further identify highly responsive HER2+ tumors to HER2-directed therapy. This may help identify patients who can safely de-escalate cytotoxic chemotherapy without compromising excellent outcome., HER2-targeted therapy improves patient’s outcome in early breast cancer. Here, the authors present the efficacy and biomarker analysis of two HER2-targeted combinations (ado-trastuzumab emtansine plus pertuzumab and paclitaxel, trastuzumab and pertuzumab) in the context of the neoadjuvant I-SPY2 phase 2 adaptive platform trial for early breast cancer at high risk of recurrence.

Background Cardiorespiratory fitness (CRF) is reduced in cancer survivors and predicts cardiovascular disease (CVD)–related and all-cause mortality. However, routine measurement of CRF is not always feasible. Objectives The purpose of this study was to identify clinical, cardiac biomarker, and imaging measures associated with reduced peak oxygen consumption (VO2peak) (measure of CRF) early post–breast cancer therapy to help inform CVD risk. Methods Consecutive women with early-stage HER2+ breast cancer receiving anthracyclines and trastuzumab were recruited prospectively. Within 6 ± 2 weeks of trastuzumab completion, we collected clinical information, systolic/diastolic echocardiographic measures, high-sensitivity troponin I, B-type natriuretic peptide, and VO2peak using a cycle ergometer. Regression models were used to examine the association between VO2peak and clinical, imaging, and cardiac biomarkers individually and in combination. Results Among 147 patients (age 52.2 ± 9.3 years), the mean VO2peak was 19.1 ± 5.0 mL O2·kg−1·min−1 (84.2% ± 18.7% of predicted); 44% had a VO2peak below threshold for functional independence (, Central Illustration

Antibody–drug conjugate (ADC) was novel type of anticancer drugs. Trastuzumab deruxtecan (T-DXd), a human epidermal growth factor receptor 2 (HER2) targeting ADC, can be a novel treatment option for HER2 alternation (mutation, expression, amplification) advanced-stage non-small-cell lung cancer (NSCLC) from DESTINY-Lung01 result. Herein, we report a successful treatment with T-DXd for NSCLC harboring HER2 exon 20 insertion mutation in a patient with poor performance status (PS). We presented a case of a 52-year-old heavily pretreated female patient diagnosed with lung adenocarcinoma (cT1bN3M0, stage IIIB). After fifth-line pretreatment of systemic chemotherapy, primary tumor recurrence, pleural effusion, and miliary lung metastases were observed. The patient presented with hypoxia requiring oxygen therapy via nasal cannula at a flow rate of 4 L per minute, cancer pain, and cachexia requiring opioid treatment. Her Eastern Cooperative Oncology Group PS score was assessed 3. Comprehensive genomic profiling revealed HER2 exon 20 insertion mutation. After treatment with T-DXd was approved by the ethical review committee of Nippon Medical School Hospital, treatment was started. The tumor size decreased significantly, and her PS score decreased from 3 to 1, with improvement of hypoxia, cancer pain, and cachexia. The patient is still receiving treatment, without disease progression 6 months after starting treatment with T-DXd. Despite cases of poor PS, NGS should be performed and target therapy including ADCs should be considered.

Aim: A systematic literature review and network meta-analysis of randomized controlled trials in patients receiving therapy for HER2+ unresectable/metastatic breast cancer after ≥1 HER2-directed therapy was conducted to compare progression-free survival (PFS) and overall survival (OS). Methods: Hazard ratios (HRs) and relative differences from fractional polynomials (FPs) for PFS and OS were assessed by Bayesian network meta-analyses. Results: For PFS, surface under the cumulative rankogram (SUCRA) ranked tucatinib plus trastuzumab with capecitabine as highest in both HR and FP analyses, followed by T-DM1 monotherapy and neratinib plus capecitabine. For OS, SUCRA ranked tucatinib plus trastuzumab with capecitabine as highest in both HR and FP analyses, followed by pertuzumab plus trastuzumab with capecitabine and T-DM1 monotherapy, with similar scores. Conclusion: Tucatinib plus trastuzumab with capecitabine, and T-DM1 monotherapy, consistently showed improved PFS and OS versus lapatinib/trastuzumab plus capecitabine and non-targeted treatments.

Background: Nowadays breast cancer (BC) is the most common cancer in women. More than 1.5 million cases are detected yearly. Survival of patients is dependent on several factors. Metastasis and cancer recurrence of different types and in different locations have various outcome. Methods: This is a retrospective cohort study to describe survival of patients after diagnosis of breast cancer based on receptor subtypes and sites of metastasis among Iranian population. A total number of 2051 females with breast cancer were evaluated and among these, 138 patients with recurrent BC were investigated. Results: The 1-year survival of local, bone, visceral and brain metastasis were 64.99%, 63%, 32.83%, and 21.57%, respectively. Based on sites of metastasis, bone and local metastasis showed the best survival while brain and visceral metastasis had the worst survival and prognosis. Conclusion: Our study showed that Her2 enriched positive BCs had the worst survival and triple negative receptor BC showed the best survival. This may be due to the discovery of Herceptin drugs for Her 2 enriched receptor breast cancers which ameliorates their prognosis and survival. Also, drugs related to luminal A and B which are used to improve their survival and hormonal therapy could be associated with their better prognosis in comparison to triple negative receptor subtype. Since our patients have not consumed Herceptin drugs over the last 17 years, the difference between our findings and those of other studies could be related to the release of this category of drugs.

Her2 overexpression is associated with an aggressive form of breast cancer and malignant transformation. We demonstrate in this work that nanolipoprotein particles (NLPs) synthesized in a cell-free manner can be used to transfer Her2 protein into the membrane of nonmalignant cells in 3D culture in a nontoxic and facile manner. With NLP-mediated Her2 protein delivery, we observed an increased probability of nonmalignant cells forming apolar nongrowth-arrested tumor-like structures. The NLP delivery system alone or Her2-NLPs plus the Her2 inhibitor trastuzumab showed no effect on the acinar organization rate, indicating that Her2 signaling is key to this process. Transcriptomics revealed essentially no effect of empty NLPs compared to untreated cells, whereas Her2-NLPs versus either untreated or empty-NLP-treated cells revealed upregulation of several factors associated with breast cancer. Pathway analysis also suggested that known nodes downstream of Her2 were activated in response to Her2-NLP treatment. This demonstrates that Her2 protein delivery with NLPs is sufficient for the malignant transformation of nonmalignant cells. Thus, this system offers a new model for studying cell surface receptor signaling without genomic modification or transformation techniques.

HER2-positive (HER2+) breast cancer (BC) is a heterogenous and multifaceted disease, with interesting therapeutic implications. First, all intrinsic molecular subtypes can be identified in HER2+ tumors, with the HER2-enriched being the most frequent. Such subtypes do not differ much from their counterparts in HER2-negative disease, apart for the high expression of genes in/near the HER2 amplicon on chromosome 17. Intrinsic subtyping, along with the quantification of ERBB2 mRNA levels, is associated with higher rates of pathologic complete response across neoadjuvant trials of dual HER2 blockade and might help select patients for de-escalation and escalation treatment strategies. Secondly, HER2+ tumors have a broad range of DNA alterations. ERBB2 mutations and alterations in the PI3K/Akt/mTOR pathway are among the most frequent and might predict benefit from potent pan-HER, PI3K and mTOR inhibitors. Moreover, HER2+ tumors are usually infiltrated by lymphocytes. These tumor infiltrating-lymphocytes (TILs) predict response to neoadjuvant anti-HER2-based treatment and exert a prognostic role. PD-L1, detected in ∼42 % of HER2+ BC, might also be useful to define patients responding to novel anti-PD1/PD-L1 immunotherapies. New multiparametric clinicopathologic and genomic tools accounting for this complexity, such as HER2DX, are under development to define more tailored treatment approaches. Finally, HER2-targeted antibody-drug conjugates (ADC) such as trastuzumab deruxtecan might be active in tumors with low expression of HER2. Overall, there is a need to molecularly characterize and develop novel targeted therapies for HER2+ disease., Highlights • Almost 50 % of HER2+ breast cancer (BC) are molecularly HER2-Enriched (HER2-E). • Most relevant mutations are found in ERBB2 (∼4 %) and PI3K/AKT/mTOR pathway (>30 %). • Tumor infiltrating lymphocytes are frequent, predictive and prognostic in HER2+ BC. • HER2 heterogeneity and HER2 low status are gaining therapeutic relevance. • New treatments need to consider HER2+ molecular and microenvironmental complexity.

The previous studies had demonstrated the promising effectiveness and acceptable safety of pyrotinib in patients with HER2‐positive metastatic breast cancer. We aimed to investigate the real‐world data of pyrotinib in complex clinical practice and complement the findings of clinical trials. Two hundred and eighteen patients were included for effectiveness analysis. A total of 62.0% had received two or more lines of systematic therapy, and 95.4% had been exposed to prior anti‐HER2 therapy, with 95.4% receiving trastuzumab, 5.0% receiving pertuzumab, and 40.8% receiving lapatinib. The median progression‐free survival (PFS) was 9.3 months and the objective response rate (ORR) was 44.0%. Patients treated with pyrotinib‐based therapy as first, second, or later line had a median PFS of 15.0, 10.3, and 6.8 months, respectively. Patients treated with pyrotinib and trastuzumab received significant benefit in terms of median PFS compared with pyrotinib alone (10.7 (9.1–12.3) vs. 8.8 (8.1–9.5), p = 0.016). Patients pretreated with lapatinib had a median PFS of 6.9 months. The median PFS time was 7.0 months in patients with brain metastasis. Multivariate Cox regression analyses showed that lines of pyrotinib‐based therapy (1 vs. 2 vs. ≥3), prior treatment with lapatinib, and combination treatments with trastuzumab proved to be independent predictors of PFS. Two hundred and forty‐eight patients were included in the safety analysis, and the results showed that the toxicity of pyrotinib was tolerable, with the most common grade 3/4 adverse event being diarrhea (19.8%). Pyrotinib‐based therapy demonstrated promising efficacy and tolerable toxicity in first‐, second‐, and later‐line treatments and in lapatinib‐treated patients. The combination of pyrotinib and trastuzumab showed advantages in PFS, even for patients resisting trastuzumab. Pyrotinib‐based therapy could be the preferred choice for brain metastasis patients, especially when combined with brain radiotherapy., Pyrotinib‐based therapy demonstrated promising efficacy and tolerable toxicity in first‐, second‐, and later‐line treatments and in lapatinib‐treated patients. Dual anti‐HER2 therapy with pyrotinib and trastuzumab showed advantages in PFS, even for patients resisting trastuzumab. Pyrotinib‐based therapy could be the preferred choice for brain metastasis patients, especially when combined with brain radiotherapy.

Background This meta-analysis aimed to test the hypothesis that the HER2-positive metastatic breast cancer (mBC) patients treated with anti-HER2 antibodies in trial intervention arms have a greater prolongation of overall survival (OS) than of progression-free survival (PFS) and this extra-prolongation of median survival time in OS relates specifically to the anti-HER2 antibody. Methods The NCBI/Pubmed and Cochrane databases were searched systematically for HER2-positive or mBC trials published in English during January 1999–November 2017. Treatment arms with shorter PFS were considered as the “control” arm, whereas those with longer PFS as the “test” arm. The between-treatment drug differences were grouped into nine categories. Groups with or without anti-HER2 antibodies were pooled respectively for comparisons. The interrelationships between PFS and OS hazard ratios (HRs) and median survival time differences were investigated by conducting fixed-effects and mixed-effects linear meta-regression analyses. Results Twenty-eight trials (10,928 patients) from 438 articles were collected, and four with missing data were excluded in meta-regression analysis. Overall median PFS (HR = 0.73, 95% CI: 0.68–0.78) and median OS (HR = 0.82, 95% CI: 0.77–0.87) weakly favored the longer PFS arm with a weak correlation between the PFS and OS HRs. However, the between-treatment drug difference was anti-HER2 antibody, the absolute increment in median OS time was double that of median PFS time (p, Highlights • Our study dissected the overall survival benefit over progression-free survival in HER-2 positive metastatic breast cancer treated with anti-HER2 antibody by meta-analysis. • Use of anti-HER2 antibodies, but not other anticancer drugs, to treat HER2-positive metastatic breast cancer independently predicted the OS compared with PFS. • The design of future clinical trials should consider anti-HER2 antibodies carefully in the treatment armamentarium for HER2-positive metastatic breast cancer.

Human epidermal growth factor receptor 2 (HER2) is a proto-oncogene that, when mutated or overexpressed, plays an important role in oncogenesis. The landscape of HER2-positive breast cancer has changed dramatically over the past 2 decades with the FDA approval of a growing number of agents (antibodies, tyrosine kinase inhibitors, and antibody-drug conjugates) targeting the HER2 receptor. HER2 inhibition has also been approved for HER2-positive gastric cancer. HER2 is amplified in 9% and mutated in 3% of lung cancer. Historically, HER2-targeted therapy for lung cancer with trastuzumab, pertuzumab, and trastuzumab emtansine has failed to demonstrate a survival benefit. Trastuzumab deruxtecan (T-DXd) is a novel antibody-drug conjugate with a tetrapeptide linker, which delivers a topoisomerase I inhibitor with a drug-to-antibody ratio of 7~8. The potency of the active payload, as well as its significant bystander effect, resulted in significant anti-tumor activity. The DESTINY-Lung01 trial evaluated T-DXd in HER2-positive non-squamous non-small cell lung cancer (NSCLC) and reported a progression-free survival of 14 months in HER2-mutated NSCLC, earning its breakthrough designation by the FDA. In this review, we will discuss the structural characteristics, pharmacodynamics, and pharmacokinetics of T-DXd. We will also shed light on the preclinical and ongoing clinical trials of T-DXd along with future directions in the management of HER2 positive lung cancer.

Human epidermal growth factor receptor 2 (HER2) is overexpressed and/or amplified in approximately 20% of breast cancers, conferring an aggressive tumor behavior but also an opportunity for targeted therapies. In the advanced setting, the prognosis of patients suffering from this disease has greatly improved after the introduction of new anti-HER2 drugs beyond trastuzumab. For most patients, a taxane combined with trastuzumab and pertuzumab in the first-line setting, followed by trastuzumab-emtansine in second line, should be considered the standard of care today. However, chemo-free anti-HER2 strategies in hormone receptor-positive, HER2-positive breast cancer could also be considered in selected patients. In the third-line setting and beyond, several emerging anti-HER2 therapies are becoming available, including tucatinib, fam-trastuzumab deruxtecan-nxki (DS-8201a), neratinib, and margetuximab-cmkb. In addition, new compounds and combinations are showing promising results in the late-line setting. The treatment landscape of HER2-positive advanced disease is evolving constantly, active drugs such as pertuzumab and trastuzumab-emtansine are moving to early-stage, many biomarkers, including quantification of HER2 itself, are being explored to improve patient selection, and patient populations with specific needs are emerging, such as those with brain metastasis. Here, we provide an overview of the current and future management of HER2-positive advanced breast cancer.

In breast cancer, the currently approved anti‐receptor tyrosine‐protein kinase erbB‐2 (HER2) therapies do not fully meet the expected clinical goals due to therapy resistance. Identifying alternative HER2‐related therapeutic targets could offer a means to overcome these resistance mechanisms. We have previously demonstrated that an endosomal sorting protein, sortilin‐related receptor (SorLA), regulates the traffic and signaling of HER2 and HER3, thus promoting resistance to HER2‐targeted therapy in breast cancer. This study aims to assess the feasibility of targeting SorLA using a monoclonal antibody. Our results demonstrate that anti‐SorLA antibody (SorLA ab) alters the resistance of breast cancer cells to HER2 monoclonal antibody trastuzumab in vitro and in ovo. We found that SorLA ab and trastuzumab combination therapy also inhibits tumor cell proliferation and tumor cell density in a mouse xenograft model of HER2‐positive breast cancer. In addition, SorLA ab inhibits the proliferation of breast cancer patient‐derived explant three‐dimensional cultures. These results provide, for the first time, proof of principle that SorLA is a druggable target in breast cancer., SorLA interacts with HER2 and HER3 and positively regulates their oncogenic signaling. Here, we report that SorLA‐targeting antibody synergizes with trastuzumab to inhibit proliferation of HER2‐amplified, trastuzumab‐resistant breast cancer cells. In addition, SorLA ab monotherapy inhibits proliferation of breast cancer patient‐derived explant cultures. These results provide proof of principle that SorLA is a druggable target in breast cancer.

Although various new drugs have been developed, the prognosis of therapeutic advances for metastatic gastric cancer is insufficient. Trastuzumab deruxtecan (T-DXd), a new human epidermal growth factor receptor 2 (HER2)-targeting antibody-drug conjugate (ADC), has demonstrated promising results in clinical trials.In this article, we review the history of anti-HER2 ADCs and focus on the efficacy and safety of T-DXd and describe the development of new anti-HER2 drugs.So far, no other anti-HER2 ADCs have demonstrated efficacy in patients with HER2-positive advanced gastric cancer with two or more previous lines of chemotherapy, including trastuzumab. However, a new drug, T-DXd, has shown a significantly higher objective response rate and a longer overall survival and, thus, was approved in Japan. In the future, new anti-HER2 drugs and/or treatment strategies including T-DXd along with cytotoxic chemotherapy or immune checkpoint inhibitors will be developed.

The standard first-line treatment for human epidermal growth factor receptor type 2 (HER2)-positive advanced gastric cancer (AGC) is trastuzumab in combination with cisplatin and fluoropyrimidines. We evaluated the efficacy and safety of S-1 and oxaliplatin (100 mg/m2) (SOX100) combined with trastuzumab, a monoclonal antibody against HER2 for HER2-positive AGC. In this single-arm, multicenter phase II study, patients with HER2-positive AGC received S-1 (80–120 mg per day) orally on days 1–14, oxaliplatin (100 mg/m2) intravenously on day 1, and trastuzumab (8 mg/kg on day 1 of the first cycle, followed by 6 mg/kg every 3 weeks) intravenously. The primary end point was 1-year survival rate. The secondary end points included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and safety. A total of 25 patients from six centers were enrolled from December 2015 to March 2020. In the 25 patients evaluable for analysis, the 1-year survival rate was 70.8% [90% confidence interval (CI) = 55.5–86.1%], whereas the median OS, PFS, and ORR were 17.8 (95% CI 10.5–22.9) months, 7.6 (95% CI 5.0–10.9) months, and 75.0% (95% CI 53.3–90.2), respectively. Major grade 3/4 adverse events included anorexia (20%), anemia (16%), peripheral sensory neuropathy (16%), and diarrhea (15%). SOX100 combined with trastuzumab was effective with a favorable safety profile in patients with HER2-positive AGC.

Background Breast cancer (BC) is largely prevalent worldwide. HER2-positive BC account for roughly 20–25% of all BC cases and has an overall survival lower than other BC. Innovation on BC therapeutics is a constant, but novel therapies have higher costs. Therefore, cost-effectiveness research is essential to provide healthcare decision-makers with solid foundations for a resource allocation. This study aims to estimate the average direct medical costs/patient and cost-effectiveness of adding pertuzumab in neoadjuvant treatment (NeoT) for HER2-positive breast cancer (BC). Methods Two retrospective real-world consecutive cohorts of ≥18yo female patients diagnosed with HER2-positive BC treated with NeoT at the Breast Clinic of IPO-Porto were studied. The AC-DH regimen (2012–2015) comprised 8 cycles of neoadjuvant therapy (4 cycles of doxorubicin + cyclosphosphamide followed by 4 cycles ofdocetaxel + trastuzumab), while the AC-DHP regimen (2015–2017) included also pertuzumab as NeoT. NeoT was followed by surgery and adjuvant trastuzumab. Micro-costing technique and a bottom-up approach was used comprising all medical direct costs from the hospital perspective. Unit costs were obtained from government official prices or from IPO-Porto costing system. Costs were adjusted to 2017 and are expressed in euros. Multivariable logistic regression models were used for effectiveness assessment, while generalized linear models with gamma distribution were used for costs. ICER was calculated using the pathological complete response (pCR) as the preferential measure of effectiveness. Sensitivity analysis was also performed. Results AC-DHP (n = 40) and AC-DH (n = 54) cohorts had heterogenous patient profiles (median age 43y/53y; 67.5%/59.3% positive HR; 60.0%/27.8% operable; 25.0%/24.1% inflammatory, respectively). The AC-DHP average total cost/patient was 56,375€, with pertuzumab accounting for 13,978€ (24.79%) and increasing in 15,982€ the average cost/patient (p, Highlights i.The results obtained in the AC-DHP cohort, which included Pertuzumab as a NeoT, suggest better clinical outcomes compared to the AC-DH group, a confirmation based on real-world data.ii.Some patient profiles seem to be more promising concerning the overall costs for pathological complete response, but the present data does not include a long-term follow-up period, which suggests that interpretations should be performed with caution.iii.Pertuzumab cost estimated represented a great proportion of overall total costs per patient, but further research (including the costs of the whole episode of care) and continuously monitoring (additional RWE) is needed for a more robust cost-effectiveness analysis. Supplementary Information The online version contains supplementary material available at 10.1186/s13561-021-00332-0.

Even though gene amplification or protein overexpression occurs in approximately one-fifth of all breast cancers, the discovery of HER2 has, nevertheless, had profound implications for the disease. Indeed, the characterization of the receptor resulted in a number of significant advances. Structurally, unique features provided avenues for the development of numerous compounds with target-specificity; molecularly, biological constructs revealed a highly complex, internal signal transduction pathway with regulatory effects on tumor proliferation, survival, and perhaps, even resistance; and clinically, disease outcomes manifested its predictive and prognostic value. Yet despite the receptor’s utility, the beneficial effects are diminished by tumor recurrence after neo- or adjuvant therapy as well as losses resulting from the inability to cure patients with metastatic disease. What these observations suggest is that while tumor response may be partially linked to uncoupling cell surface message reception and nuclear gene expression, as well as recruitment of the innate immune system, disease progression and/or resistance may involve a reprogrammable signaling mainframe that elicits alternative growth and survival signals. This review attempts to meld current perceptions related to HER2-positive metastatic breast cancer with particular attention to current biological insights and therapeutic challenges.

Breast cancer is a very frequent type of cancer and much attention is paid to therapy with considerable efforts both in the pharmacological and clinical fields.The present work aims to create a non-linear dynamic model of action of the drug Trastuzumab against HER-2 + breast cancer, mainly considering its action of ADCP (antibody-dependent phagocytosis) killing of cancer cells. The model, while also considering the other therapeutic effects induced by Trastuzumab, shows how the action of this monoclonal antibody in the induction of ADCP through the action of macrophages, is strictly connected to the formation of a multi-complex “Trastuzumab -HER-2 - macrophage” that shows a prolonged action over time, responsible for the increase in the Overall Survivor (OS) parameter reported in various. The model shows the correlation between the various therapeutic effects and the killing action of cancer cells through the variation of the dynamic fluctuation of the representative ”c” parameter.

Aims: Preclinical comparative similarity studies of trastuzumab-dkst, a Herceptin® biosimilar, are reported. Materials & methods: Primary sequence and higher order structure and pharmacological mechanisms of action were compared using multiple techniques. Pharmacokinetics and repeat-dose toxicity were assessed in cynomolgus monkeys. Results: Primary structures were identical; secondary and tertiary structures were highly similar. Non-significant differences were observed for charge heterogeneity. Twelve of 13 glycan species were highly similar, with slightly higher total mannose levels in trastuzumab-dkst. FcγR and FcRn binding activity was highly similar. Each drug equally inhibited HER2+ cell proliferation, demonstrating equivalent relative potency in mediating HER2+ cell cytolysis by antibody-dependent cellular cytotoxicity. Pharmacokinetic and toxicological profiles in cynomolgus monkeys were similar. Conclusion: Trastuzumab-dkst, US-licensed trastuzumab and EU-approved trastuzumab demonstrate high structural and functional similarity.

Purpose Assessment of HER2 overexpression using immunohistochemistry (IHC) and/or in situ hybridisation (ISH) for the detection of HER2 amplifications is standard to identify patients for established HER2-directed treatments. Patients with lower HER2 expression levels have recently also become candidates for novel therapies targeting HER2. This study aimed to assess tumour and patient characteristics and prognosis in patients with advanced breast cancer (aBC), relative to low HER2 expression levels. Methods PRAEGNANT is a prospective aBC registry (NCT02338167), focusing on molecular biomarkers. Patients in all therapy lines receiving any kind of treatment are eligible. This analysis includes patients with conventionally HER2-negative aBC. Clinical outcome was compared in the groups with no (IHC score 0) or with low HER2 expression (IHC 1+, or IHC 2+/ISH negative). Results Low HER2 expression levels in triple-negative aBC patients did not influence progression-free survival. Overall survival appeared poorer in patients with IHC 2+ compared with patients with no HER2 expression in the unadjusted analysis (hazard ratio 2.24, 95% confidence interval 0.1.12–4.47). However, this effect was not maintained in the adjusted analysis. In HER2-negative, hormone receptor–positive patients, low HER2 expression appeared to have no effect on prognosis, neither progression-free survival nor overall survival. Conclusions We could not demonstrate that HER2 expression at a low level and assessed in clinical routine can differentiate patients into prognostic groups. However, the prevalence of patients with a low expression makes this population interesting for clinical trials with potentially active treatments using HER2 as a target.

Gastric cancer inflicts significant health issues globally despite its declining incidence. The disease is known to be diagnosed at its advanced stages also corresponding with a poor prognosis for patients. The integral therapeutic choices to cure advanced gastric cancer have progressed swiftly in modern days. The preface of molecularly targeted therapeutic techniques would potentiate the personalized approach depending on patient-specific and tumor-specific features, exasperating the advantages of chemotherapy. Here we have reviewed the modern therapeutics such as immune therapy, chemotherapy, m-RNA based therapeutics, alongside evaluating the influence of age, sex and comorbidities-like factors on the occurrence of gastric cancer. Gastric cancer therapy consolidated target agents comprising inhibitors of programmed death-1(PD-1), human epidermal growth factor receptor 2 (HER2), mRNA, and epidermal growth factor receptor (EPGF). A combination of trastuzumab to platinum-mediated chemotherapy evolved has a typical front-line therapy in advanced gastric cancer. An attempt has been made to epitomize the contemporary-modern research on targeted therapy for advanced gastric cancer.

This is a summary of the article discussing the results of the DESTINY-Breast01 study originally published in the New England Journal of Medicine. The DESTINY-Breast01 study is a clinical study in participants with a type of breast cancer called HER2-positive breast cancer. The participants in the study received a treatment called trastuzumab deruxtecan, also known as T-DXd. The purpose of this summary is to help you understand the results of the DESTINY-Breast01 study. T-DXd is currently available as a treatment for adults with HER2-positive breast cancer that cannot be removed by surgery, also called unresectable, or that has spread, also called metastatic. In the DESTINY-Breast01 study, all the participants had HER2-positive breast cancer that was metastatic or unresectable. All participants were required to have had previous treatment for their HER2-positive breast cancer with another treatment, called trastuzumab emtansine or T-DM1. All the participants received T-DXd every 3 weeks. Part 1 was done to learn how T-DXd acted in the body, and to choose a dose to give to all the participants in Part 2. In Part 2, 184 participants received T-DXd at 5.4 mg/kg and the results showed that T-DXd reduced tumor growth. Up to 60.9% of the participants had their tumors shrink or disappear, with a treatment response that lasted for nearly 15 months on average. The participants lived with their cancer for around 16 months before it got worse. During the study, 183 out of 184 participants had side effects, known as adverse events. The most common adverse event was nausea. There were 42 participants (22.8%) who had serious adverse events, including lung toxicity. These results suggest that T-DXd could be a treatment option for people with metastatic HER2-positive breast cancer who have already been treated with T-DM1. Additional studies will provide more information and results about T-DXd. ClinicalTrials.gov NCT number: NCT03248492. To read the full Plain Language Summary of this article, click on the View Article button above and download the PDF. Link to original article here .

Advances in human epidermal growth factor receptor 2 (HER2)-directed therapies have revolutionised the care of patients with HER2-positive breast cancer. While adjuvant trastuzumab in combination with chemotherapy has dramatically improved the prognosis for patients with early-stage disease, up to a quarter of patients will develop recurrent disease. The standard-of-care treatment paradigm has evolved with the introduction of newer HER2-directed therapies and increasing use of neoadjuvant systemic therapy, the latter providing us with important functional data to HER2-directed therapies and impacting subsequent adjuvant therapy decisions. However, these new strategies come at a cost of increased toxicity and economic burden, and only a subset of patients benefit from such approaches. Thus, ongoing work is required to identify predictive biomarkers of response, to de-escalate treatment in patients who may do just as well with less therapy, and new therapeutic approaches for patients who do not respond to currently used therapies. In this review, we will examine the current therapeutic landscape, summarise the latest evidence, and list the current treatment algorithms for early stage HER2-positive breast cancer.