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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 -
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 -
Clinical Breast Cancer Oct 2023Breast cancer represents the most commonly diagnosed neoplasm worldwide and the HER2-positive subtype accounts for nearly 1 in 5 breast cancers. The majority of patients... (Review)
Review
Breast cancer represents the most commonly diagnosed neoplasm worldwide and the HER2-positive subtype accounts for nearly 1 in 5 breast cancers. The majority of patients with breast cancer present with an early-stage disease upon diagnosis, which is thus susceptible to virtually curative treatment strategies. For a stage, I T1a/b N0 HER2-positive disease, upfront surgery followed by adjuvant therapy is the preferred approach. However, there is some uncertainty regarding the appropriate management of stage cT1c cN0, as both the neoadjuvant approach and upfront surgery have been proven to be feasible therapeutic options. The aim of this Delphi consensus was to define the best strategies for the treatment of early HER2-positive breast cancer. This work may help clinicians in the management of early HER2-positive breast cancer.
PubMed: 37543499
DOI: 10.1016/j.clbc.2023.07.006 -
American Journal of Cancer Research 2019Clinical management of anaplastic thyroid cancer (ATC) is very challenging due to its dedifferentiation and aggressiveness. We aim to develop HER2-targeted multimodal...
Clinical management of anaplastic thyroid cancer (ATC) is very challenging due to its dedifferentiation and aggressiveness. We aim to develop HER2-targeted multimodal imaging approaches and assess the diagnostic efficacies of these molecular imaging probes in preclinical ATC models. Flow cytometry was used to detect HER2 expression status in thyroid cancer cell lines. We then developed a HER2-specific immunoPET imaging probe Zr-Df-pertuzumab by radiolabeling a HER-2 specific monoclonal antibody (mAb) pertuzumab with Zr (t=78.4 h) and a fluorescent imaging probe IRDye 800CW-pertuzumab. The diagnostic efficacies of the probes were assessed in subcutaneous and orthotopic ATC models, followed by biodistribution profile and immunofluorescence staining studies. HER2 was highly expressed on the surface of all the four primary thyroid cancer cell lines examined, which included two ATC cell lines (i.e., 8505C and THJ-16T). PET imaging with Zr-Df-pertuzumab clearly visualized all the subcutaneous ATCs with a peak tumor uptake of 20.23±6.44 %ID/g (n=3), whereas the highest tumor uptake of the nonspecific probe Zr-Df-IgG in subcutaneous ATC models was 6.30±0.95 %ID/g (n=3). More importantly, Zr-Df-pertuzumab PET imaging strategy readily delineated all the orthotopic ATCs with a peak tumor uptake of 24.93±8.53 %ID/g (n=3). We also suggested that Cerenkov luminescence imaging (CLI) using Zr-Df-pertuzumab and fluorescence imaging using IRDye 800CW-pertuzumab are useful tools for image-guided removal of ATCs. We demonstrate that HER2 is a promising biomarker for ATC, and multimodal imaging using Zr-Df-pertuzumab and IRDye 800CW-pertuzumab is useful for identifying HER2-postive ATCs.
PubMed: 31815043
DOI: No ID Found -
ACS Medicinal Chemistry Letters Mar 2023Breast cancer (BC) is the primary cause of cancer-related death among women worldwide. The human epidermal growth factor receptor type 2 (HER2)-positive BC accounts for...
Breast cancer (BC) is the primary cause of cancer-related death among women worldwide. The human epidermal growth factor receptor type 2 (HER2)-positive BC accounts for ∼15% of all BCs and a relatively poor prognosis. The disclosure in this patent highlight relates to a combination therapy comprising inavolisib (GDC-0077) and a HER2-targeted therapy such as trastuzumab, pertuzumab, or their combination for the treatment of HER2-overexpressing breast cancer.
PubMed: 36923923
DOI: 10.1021/acsmedchemlett.2c00544 -
Breast Cancer (Dove Medical Press) 2021Human epidermal growth factor receptor type 2 (HER2) is a relevant and effective target in breast cancer. The development of monoclonal antibodies against HER2 has... (Review)
Review
Human epidermal growth factor receptor type 2 (HER2) is a relevant and effective target in breast cancer. The development of monoclonal antibodies against HER2 has revolutionized the treatment of HER2-positive breast cancer. The humanized monoclonal antibody, trastuzumab, was the first in its class to be widely adopted. It was initially studied in the metastatic setting and then in the treatment of early-stage disease, demonstrating significant improvement in overall survival in both settings. The addition of pertuzumab further improved upon results achieved with trastuzumab and chemotherapy, specifically extending overall survival in patients with metastatic disease, lessening the risk of recurrence when used in the adjuvant setting, and improving pathologic complete response rate when utilized in the neoadjuvant setting. In this article, we review the studies that support the use of HER2-directed monoclonal antibodies in early-stage breast cancer both in the adjuvant and neoadjuvant settings and focus on the success of dual HER2-targeted therapy achieved with the combination of trastuzumab and pertuzumab. A newer way to administer these agents, specifically the subcutaneous formulation of pertuzumab and trastuzumab with recombinant human hyaluronidase, will also be discussed.
PubMed: 34163239
DOI: 10.2147/BCTT.S176514 -
Breast Care (Basel, Switzerland) Dec 2020Trastuzumab significantly improves outcomes in early HER2-positive breast cancer, irrespectively of any prognostic or predictive factors. Unfortunately, about a quarter... (Review)
Review
BACKGROUND
Trastuzumab significantly improves outcomes in early HER2-positive breast cancer, irrespectively of any prognostic or predictive factors. Unfortunately, about a quarter of patients receiving neoadjuvant trastuzumab experience disease recurrence, revealing the unquestionable need for further improvement of treatment outcomes.
SUMMARY
Adding HER2 blockade to adjuvant trastuzumab with pertuzumab and neratinib improves invasive disease-free survival (IDFS), particularly for those at highest risk of recurrence. A shift toward a neoadjuvant strategy for patients with a higher risk of recurrence could result in further treatment optimization. For patients without a pathological complete response (pCR) after the neoadjuvant part of the therapy, a switch to adjuvant trastuzumab emtansine significantly improves IDFS and distant recurrence-free survival and shows a trend towards improved overall survival (OS). On the other hand, for low-risk patients, chemotherapy deescalation should be strongly considered with the use of trastuzumab monotherapy as an anti-HER2 backbone.
KEY MESSAGES
Neoadjuvant therapy should be offered for a significant proportion of HER2-positive early breast cancer patients with a higher risk of recurrence. Postneoadjuvant treatment should be tailored according to the initial stage of disease and the response to neoadjuvant treatment.
PubMed: 33447229
DOI: 10.1159/000511883 -
Scientific Reports Feb 2021Copper-67 (t = 2.58 days) decays by β ([Formula: see text]: 562 keV) and γ-rays (93 keV and 185 keV) rendering it with potential for both radionuclide therapy...
Copper-67 (t = 2.58 days) decays by β ([Formula: see text]: 562 keV) and γ-rays (93 keV and 185 keV) rendering it with potential for both radionuclide therapy and single-photon emission computed tomography (SPECT) imaging. Prompted by the recent breakthrough of Cu production with high specific activity, high radionuclidic purity, and sufficient quantities, the interest in the theranostic potential of Cu has been rekindled. This work addresses the practicability of developing Cu-labeled antibodies with substantially improved quality for cancer radioimmunotheranostics. Proof of concept is demonstrated with pertuzumab, a US-FDA-approved monoclonal antibody for combination therapies of HER2-positive breast cancer. With an average number of 1.9 chelators coupled to each antibody, we achieved a two-order of magnitude increase in radiolabeling efficiency compared to literature reports. In a preclinical therapeutic study, mice (n = 4-7/group) bearing HER2 xenografts exhibited a Cu-dose dependent tumor-growth inhibition from Cu-labeled-Pertuzumab co-administered with trastuzumab. Furthermore, greater tumor size reduction was observed with Cu-labeled-pertuzumab formulations of higher specific activity. The potential of SPECT imaging with Cu radiopharmaceuticals was tested after Cu-labeled-Pertuzumab administration. Impressively, all tumors were clearly visualized by SPECT imaging with Cu-labeled-Pertuzumab even at day 5 post injection. This work demonstrates it is practical to use Cu radioimmunoconjugates for cancer radioimmunotheranostics.
Topics: Animals; Antibodies, Monoclonal, Humanized; Cell Line, Tumor; Copper Radioisotopes; Female; Humans; Immunoconjugates; Immunotherapy; Mice, SCID; Radioimmunotherapy; Receptor, ErbB-2; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; Xenograft Model Antitumor Assays; Mice
PubMed: 33574346
DOI: 10.1038/s41598-021-82812-1 -
Journal of Clinical Oncology : Official... Feb 2022We aimed to improve efficacy and reduce toxicity of high-risk human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC) treatment by replacing... (Comparative Study)
Comparative Study Randomized Controlled Trial
Trastuzumab Emtansine Plus Pertuzumab Versus Taxane Plus Trastuzumab Plus Pertuzumab After Anthracycline for High-Risk Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer: The Phase III KAITLIN Study.
PURPOSE
We aimed to improve efficacy and reduce toxicity of high-risk human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC) treatment by replacing taxanes and trastuzumab with trastuzumab emtansine (T-DM1).
METHODS
The phase III KAITLIN study (NCT01966471) included adults with excised HER2-positive EBC (node-positive or node-negative, hormone receptor-negative, and tumor > 2.0 cm). Postsurgery, patients were randomly assigned 1:1 to anthracycline-based chemotherapy (three-four cycles) and then 18 cycles of T-DM1 plus pertuzumab (AC-KP) or taxane (three-four cycles) plus trastuzumab plus pertuzumab (AC-THP). Adjuvant radiotherapy/endocrine therapy was permitted. Coprimary end points were invasive disease-free survival (IDFS) in the intention-to-treat node-positive and overall populations with hierarchical testing.
RESULTS
The median follow-up was 57.1 months (interquartile range, 52.1-60.1 months) for AC-THP (n = 918) and 57.0 months (interquartile range, 52.1-59.8 months) for AC-KP (n = 928). There was no significant IDFS difference between arms in the node-positive (n = 1,658; stratified hazard ratio [HR], 0.97; 95% CI, 0.71 to 1.32) or overall population (n = 1846; stratified HR, 0.98; 95% CI, 0.72 to 1.32). In the overall population, the three-year IDFS was 94.2% (95% CI, 92.7 to 95.8) for AC-THP and 93.1% (95% CI, 91.4 to 94.7) for AC-KP. Treatment completion rates (ie, 18 cycles) were 88.4% for AC-THP and 65.0% for AC-KP (difference driven by T-DM1 discontinuation because of laboratory abnormalities [12.5%]). Similar rates of grade ≥ 3 (55.4% 51.8%) and serious adverse events (23.3% 21.4%) occurred with AC-THP and AC-KP, respectively. KP decreased clinically meaningful deterioration in global health status versus THP (stratified HR, 0.71; 95% CI, 0.62 to 0.80).
CONCLUSION
The primary end point was not met. Both arms achieved favorable IDFS. Trastuzumab plus pertuzumab plus chemotherapy remains the standard of care for high-risk HER2-positive EBC.
Topics: Ado-Trastuzumab Emtansine; Adult; Aged; Anthracyclines; Antibiotics, Antineoplastic; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Humans; Middle Aged; Receptor, ErbB-2; Time Factors; Trastuzumab
PubMed: 34890214
DOI: 10.1200/JCO.21.00896 -
MAbs 2020Given the increasing use of combination therapy with multiple monoclonal antibodies (mAbs), there is a clinical need for multiplexing assays. For the frequently...
Given the increasing use of combination therapy with multiple monoclonal antibodies (mAbs), there is a clinical need for multiplexing assays. For the frequently co-administered anti-human epidermal growth factor receptor 2 (HER2) mAbs trastuzumab and pertuzumab, we developed a high-throughput and robust hybrid ligand-binding liquid chromatography-mass spectrometry (LC-MS)/MS quantitative assay. Nanomolar concentrations of trastuzumab and pertuzumab were determined in 10 µL serum samples after extraction by affinity purification through protein A beads, followed by on-bead reduction, alkylation, and trypsin digestion. After electrospray ionization, quantification was obtained by multiple reaction monitoring LC-MS/MS using SILuMab as an internal standard. The method was validated according to the current guidelines from the US Food and Drug Administration and the European Medicines Agency. Assay linearity was established in the ranges 0.250-250 μg/mL for trastuzumab and 0.500-500 μg/mL for pertuzumab. The method was accurate and selective for the simultaneous determination of trastuzumab and pertuzumab in clinical samples, thereby overcoming the limitation of ligand binding assays that cannot quantify mAbs targeting the same receptor. Furthermore, this method requires a small blood volume, which reduces blood collection time and stress for patients. The assay robustness was verified in a clinical trial where trastuzumab and pertuzumab concentrations were determined in 670 serum samples. As we used commercially available reagents and standards, the described generic bioanalytical strategy can easily be adapted to multiplex quantifications of other mAb combinations in non-clinical and clinical samples.
Topics: Antibodies, Monoclonal, Humanized; Female; Humans; Male; Tandem Mass Spectrometry; Trastuzumab
PubMed: 32744170
DOI: 10.1080/19420862.2020.1795492