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Nature Communications Nov 2021HER2-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...
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.
Topics: Ado-Trastuzumab Emtansine; Adult; Aged; Antibodies, Monoclonal, Humanized; Biomarkers, Tumor; Breast Neoplasms; Humans; Maytansine; Middle Aged; Neoadjuvant Therapy; Paclitaxel; Receptor, ErbB-2; Trastuzumab
PubMed: 34741023
DOI: 10.1038/s41467-021-26019-y -
Signal Transduction and Targeted Therapy 2019Over the past 2 decades, there has been an extraordinary progress in the regimens developed for the treatment of human epidermal growth factor receptor 2 (HER2)-positive... (Review)
Review
Over the past 2 decades, there has been an extraordinary progress in the regimens developed for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Trastuzumab, pertuzumab, lapatinib, and ado-trastuzumab emtansine (T-DM1) are commonly recommended anti-HER2 target agents by the U.S. Food and Drug Administration. This review summarizes the most significant and updated research on clinical scenarios related to HER2-positive breast cancer management in order to revise the guidelines of everyday clinical practices. In this article, we present the data on anti-HER2 clinical research of neoadjuvant, adjuvant, and metastatic studies from the past 2 decades. We also highlight some of the promising strategies that should be critically considered. Lastly, this review lists some of the ongoing clinical trials, findings of which may soon be available.
PubMed: 31637013
DOI: 10.1038/s41392-019-0069-2 -
Archivum Immunologiae Et Therapiae... Jan 2020Clinical progress in the field of HER2-positive breast cancer therapy has been dramatically improved by understanding of the immune regulatory mechanisms of tumor... (Review)
Review
Clinical progress in the field of HER2-positive breast cancer therapy has been dramatically improved by understanding of the immune regulatory mechanisms of tumor microenvironment. Passive immunotherapy utilizing recombinant monoclonal antibodies (mAbs), particularly trastuzumab and pertuzumab has proved to be an effective strategy in HER2-positive breast cancer treatment. However, resistance to mAb therapy and relapse of disease are still considered important challenges in clinical practice. There are increasing reports on the induction of cellular and humoral immune responses in HER2-positive breast cancer patients. More recently, increasing efforts are focused on using HER2-derived peptide vaccines for active immunotherapy. Here, we discuss the development of various HER2-derived vaccines tested in animal models and human clinical trials. Different formulations and strategies to improve immunogenicity of the antigens in animal studies are also discussed. Furthermore, other immunotherapeutic approaches to HER2 breast cancer including, CTLA-4 inhibitors, immune checkpoint inhibitors, anti PD-1/PD-L1 antibodies are presented.
Topics: Animals; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Breast Neoplasms; Cancer Vaccines; Female; Humans; Immunotherapy; Receptor, ErbB-2; Tumor Microenvironment
PubMed: 31915932
DOI: 10.1007/s00005-019-00566-1 -
Cancers Dec 2021The objective of the present study was to review the essential knowledge about the combinations of the most commonly used or under development targeted treatments and... (Review)
Review
BACKGROUND
The objective of the present study was to review the essential knowledge about the combinations of the most commonly used or under development targeted treatments and radiation therapy (RT).
METHODS
Preclinical and clinical studies investigating this combination were extensively reviewed.
RESULTS
Several studies showed that the combination of RT and tamoxifen increased the risk of radiation-induced pulmonary toxicity; therefore, both modalities should not be given concomitantly. The combination of HER2 inhibitors (trastuzumab, pertuzumab) and RT seems to be safe. However, trastuzumab emtansine (T-DM1) should not be administered concurrently with brain RT since this combination could increase the risk of brain radionecrosis. The combination of RT and other new target treatments such as selective estrogen receptor degradants, lapatinib, cell cycle inhibitors, immune checkpoint inhibitors, or molecules acting on DNA damage repair seems feasible but was essentially evaluated on retrospective or prospective studies with a small number of patients. Furthermore, there is considerable heterogeneity among these studies regarding the dose and fractionation of radiation, the dosage of drugs, and the sequence of treatments used.
CONCLUSIONS
The combination of RT with most targeted therapies for BC appears to be well-tolerated, but these results need to be confirmed in prospective randomized studies.
PubMed: 34944978
DOI: 10.3390/cancers13246358 -
Frontiers in Oncology 2023Clinical trials have shown a significant increase in pathologic complete response (pCR) with the addition of pertuzumab to neoadjuvant chemotherapy for patients with...
Pathologic response and survival after neoadjuvant chemotherapy with or without pertuzumab in patients with HER2-positive breast cancer: the Neopearl nationwide collaborative study.
PURPOSE
Clinical trials have shown a significant increase in pathologic complete response (pCR) with the addition of pertuzumab to neoadjuvant chemotherapy for patients with early-stage HER-2 positive breast cancer. To date, limited studies have examined comparative outcomes of neoadjuvant pertuzumab in real-world setting. The Neopearl study aimed to assess comparative real-life efficacy and safety of neoadjuvant pertuzumab for these patients.
METHODS
We conducted a nationwide retrospective analysis involving 17 oncology facilities with a certified multidisciplinary breast cancer treatment committee. We identified patients with HER-2 positive stage II-III breast cancer treated with neoadjuvant chemotherapy based on trastuzumab and taxanes with or without pertuzumab. All patients underwent breast surgery and received a comprehensive cardiologic evaluation at baseline and after neoadjuvant treatment. Patients who received the combination of pertuzumab, trastuzumab, and chemotherapy constituted case cohort (PTCT), whereas those treated with trastuzumab and chemotherapy accounted for control cohort (TCT). The pCR rate and 5-year event free survival (EFS) were the primary outcomes. Secondary end-points were rates of conversion from planned modified radical mastectomy (MRM) to breast conservation surgery (BCS) and cardiotoxicities.
RESULTS
From March 2014 to April 2021, we included 271 patients, 134 (49%) and 137 (51%) in TCT and PTCT cohort, respectively. Positive axillary lymph nodes and stage III were more frequent in PTCT cohort. The pCR rate was significantly increased in patients who received pertuzumab (49% vs 62%; OR 1.74, 95%CI 1.04-2.89) and with HER-2 enriched subtypes (16% vs 85%; OR 2.94, 95%CI 1.60-5.41). After a median follow-up of 5 years, the 5-year EFS was significantly prolonged only in patients treated with pertuzumab (81% vs 93%; HR 2.22, 95%CI 1.03-4.79). The same analysis performed on propensity score matched population showed concordant results. On univariate analysis, only patients with positive lymph nodes were found to benefit from pertuzumab for both pCR and 5-year EFS. The rates of conversion from MRM to BCS and cardiologic toxicities did not differ between the cohorts.
CONCLUSION
Our findings support previous data on improved outcomes with the addition of pertuzumab to trastuzumab-based neoadjuvant chemotherapy. This benefit seems to be more significant in patients with clinically positive lymph nodes.
PubMed: 37441419
DOI: 10.3389/fonc.2023.1177681 -
Scientific Reports Aug 2022To evaluate the cardiac safety of anti-HER2-targeted therapy for early breast cancer; to investigate whether trastuzumab combined with pertuzumab increases cardiac...
To evaluate the cardiac safety of anti-HER2-targeted therapy for early breast cancer; to investigate whether trastuzumab combined with pertuzumab increases cardiac toxicity compared with trastuzumab; to evaluate the predictive value of high-sensitivity Troponin (hs-TnI) and QTc for the cardiotoxicity associated with anti-HER2 targeted therapy in early breast cancer. A total of 420 patients with early-stage HER2-positive breast cancer who received trastuzumab or trastuzumab combined with pertuzumab for more than half a year in Tianjin Medical University Cancer Hospital from January 2018 to February 2021 were included. Left ventricle ejection fraction (LVEF), hs-TnI values, and QTc were measured at baseline and 3, 6, 9, 12 months. Cardiotoxicity was defined as a decrease in LVEF of at least 10 percentage points from baseline on follow-up echocardiography. Cardiotoxicity developed in 67 of the 420 patients (15.9%) and all patients had LVEF above 50% before and after treatment. The incidence of cardiotoxicity in trastuzumab and trastuzumab combined with pertuzumab was 14.3% and 17.9%, respectively (P > 0.05). Logistic regression analysis showed that age, coronary heart disease, left chest wall radiotherapy, and anthracyclines sequential therapy were independent risk factors for cardiotoxicity (P < 0.05). The value of hs-TnI and QTc at the end of treatment (12th month) were selected for ROC curve prediction analysis and the area under the ROC curve was 0.724 and 0.713, respectively, which was significantly different from the area of 0.5 (P < 0.05). The decrease of LVEF in the study was mostly asymptomatic, from the heart safety point of view, the anti-HER2 targeted therapy for early breast cancer was well tolerated. Trastuzumab combined with pertuzumab did not significantly increase cardiotoxicity. However, subgroup analysis suggests that in the presence of coronary artery disease (CAD) and sequential treatment with anthracene, trastuzumab and pertuzumab may increase the cardiac burden compared with trastuzumab. Hs-TnI and QTc may be useful in monitoring and predicting cardiotoxicity associated with anti-HER2 targeted therapy for early breast cancer.
Topics: Breast Neoplasms; Cardiotoxicity; Female; Heart; Humans; Receptor, ErbB-2; Trastuzumab
PubMed: 35995984
DOI: 10.1038/s41598-022-18342-1 -
American Journal of Cancer Research 2020Human Epidermal Growth Factor Receptor 2-positive breast cancer (HER2+ BC) is defined by increased amplification of the oncogene and/or overexpression of its associated... (Review)
Review
Human Epidermal Growth Factor Receptor 2-positive breast cancer (HER2+ BC) is defined by increased amplification of the oncogene and/or overexpression of its associated HER2 transmembrane receptor protein. HER2+ BC represents approximately 15-20% of breast cancer, and it is independently associated with a higher grade, more aggressive phenotype, and worse prognosis. With the advent of trastuzumab, the prognostic landscape for HER2+ BC patients has considerably improved. However, both and acquired resistance to trastuzumab remain a significant obstacle for many patients, requiring novel therapies for further clinical benefit. Over the last two decades, there has been extraordinary progress in the development of HER2+ BC treatment regimens, with extensions into -amplified gastroesophageal junction cancer via the NCI-MATCH precision medicine trial program (NCT02465060). Trastuzumab, pertuzumab, T-DM1, and lapatinib are commonly recommended as a single agent (along with chemotherapy) or in combinations of anti-HER2 agents in neoadjuvant, adjuvant and metastatic settings according to National Comprehensive Cancer Network (NCCN) guidelines. Currently, the combination of trastuzumab, pertuzumab, and taxane chemotherapy are first-line for HER2+/HR- metastatic breast cancer with potential breakthrough therapies such as trastuzumab-deruxtecan (DS-8201a), margetuximab and tucatinib (ONT-380) on the horizon. Furthermore, recent clinical trials have demonstrated the potential utility of hormone receptor status, PAM-50 luminal intrinsic subtype, PD-L1, and TIL as predictive biomarkers for response to HER2+ therapies. We briefly introduce the origin of HER2, the invention of trastuzumab, and the classification of HER2+ BC. Each HER2-targeted therapy is then presented by indication, mechanism of action, and relevant clinical trials with subsequent elaboration and contextualization within clinical settings with an epilogue of potential future biomarkers for clinical use in HER2+ BC. We summarize the most significant and updated research in clinical practice relevant to HER2+ BC management and highlight the clinical status of upcoming anti-HER2 agents as well as immunotherapy drugs in combination with anti-HER2 agents.
PubMed: 32368385
DOI: No ID Found -
Cell Reports. Medicine Oct 2023Patients with early-stage HER2-overexpressing breast cancer struggle with treatment resistance in 20%-40% of cases. More information is needed to predict HER2 therapy...
Patients with early-stage HER2-overexpressing breast cancer struggle with treatment resistance in 20%-40% of cases. More information is needed to predict HER2 therapy response and resistance in vivo. In this study, we perform (phospho)proteomics analysis of pre-treatment HER2 needle biopsies of early-stage invasive breast cancer to identify molecular signatures predictive of treatment response to trastuzumab, pertuzumab, and chemotherapy. Our data show that accurate quantification of the estrogen receptor (ER) and HER2 biomarkers, combined with the assessment of associated biological features, has the potential to enable better treatment outcome prediction. In addition, we identify cellular mechanisms that potentially precondition tumors to resist therapy. We find proteins with expression changes that correlate with resistance and constitute to a strong predictive signature for treatment success in our patient cohort. Our results highlight the multifactorial nature of drug resistance in vivo and demonstrate the necessity of deep tumor profiling.
Topics: Humans; Female; Breast Neoplasms; Receptor, ErbB-2; Proteomics; Biomarkers, Tumor; Neoadjuvant Therapy; Biopsy, Needle
PubMed: 37794585
DOI: 10.1016/j.xcrm.2023.101203 -
CJC Open Nov 2021Human epidermal growth factor receptor 2 (HER2) overexpressing malignancies, including breast and gastro-esophageal, are associated with a poor prognosis. The... (Review)
Review
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]; I = 0%). However, pertuzumab had no demonstrable effect on asymptomatic/minimally symptomatic left ventricular systolic dysfunction (RR [95% CI]: 1.19 [0.89-1.61]; I = 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.
PubMed: 34901806
DOI: 10.1016/j.cjco.2021.06.019 -
Breast (Edinburgh, Scotland) Dec 2022The identification of the HER2 alteration as an actionable oncogenic driver in breast cancer has propelled the development of HER-targeting monoclonal antibodies (mAb)... (Review)
Review
The identification of the HER2 alteration as an actionable oncogenic driver in breast cancer has propelled the development of HER-targeting monoclonal antibodies (mAb) such as trastuzumab and pertuzumab, which led to dramatic improvements in survival outcomes. Lately, the great strides made toward developing antibody-conjugation methods have led to the development of a new class of compelling compounds, the antibody-drug conjugates (ADCs) targeting HER2 which have profoundly transformed the treatment landscape of breast cancer. HER2-targeting ADCs, trastuzumab-emtansine and trastuzumab-deruxtecan, have improved the overall survival in the second and third-line settings with manageable adverse events. Other HER2-targeting ADCs using novel technological advances in the antibody, linker and/or payload conception have shown promising activity in preclinical and clinical studies and some of them are now being evaluated in larger clinical trials. Multiple challenges still impede the success of ADCs in breast cancer namely the lack of a comprehensive understanding of resistance mechanisms as well as the mechanisms of action of ADCs in special subgroups of patients such as those with low or ultra-low HER2 expression and patients with brain or leptomeningeal metastases (BM). In this framework, we review the approved indications and ongoing trials for HER2-targeting ADCs, across patient subgroups, including those with BM and discuss the associated potential mechanisms of action and resistance. Last, we provide an overview of the future perspectives involving HER2-targeting ADCs in breast cancer.
Topics: Humans; Female; Breast Neoplasms; Receptor, ErbB-2; Trastuzumab; Ado-Trastuzumab Emtansine; Immunoconjugates
PubMed: 36334569
DOI: 10.1016/j.breast.2022.10.016