scholarly journals Modelling hypersensitivity to trastuzumab defines biomarkers of response in HER2 positive breast cancer

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Laura Díaz-Gil ◽  
Fara Brasó-Maristany ◽  
Claudriana Locatelli ◽  
Ariana Centa ◽  
Balász Győrffy ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Surface ◽  
Therapeutic Option ◽  
Cell Counting ◽  
Her2 Overexpression ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Cellular Models ◽  
Her2 Breast Cancer

Abstract Background Trastuzumab-based therapies are the therapeutic option for HER2 positive (HER2+) breast cancer. HER2 amplification is the only biomarker validated for trastuzumab-based therapies. However, a proportion of tumors become refractory during treatment course. For this reason, the finding of new biomarkers beyond HER2 overexpression to identify patients who would benefit most from trastuzumab regimens is of outstanding importance. Methods Models of trastuzumab-resistant or hypersensitive cells were generated by exposure to trastuzumab. Cell surface, total HER2, and analyses of proteins involved in cell cycle or apoptosis were analyzed by western blotting. Cell proliferation was analyzed by cell counting, cell cycle and apoptosis was evaluated by FACS. Transcriptomic characterization of the cellular models was performed using bioinformatic online tools, and clinico-genomic analyses were performed using the PAMELA clinical trial data. Results Besides differing in sensitivities to trastuzumab, the different cellular models also showed distinct response to other anti-HER2 drugs (lapatinib, neratinib, pertuzumab and T-DM1) used in the clinic. That differential effect was not due to changes in cell surface, total or activated HER2. Trastuzumab caused important induction of cell death in hypersensitive cells but not in parental or resistant cells. Transcriptomic analyses of these cellular models together with querying of online databases allowed the identification of individual genes and gene signatures that predicted prognosis and trastuzumab response in HER2+ breast cancer patients. Conclusion The identification of trastuzumab response biomarkers may be used to select patients particularly sensitive to facilitate the use of trastuzumab-based therapies and refine follow-up guidelines in patients with HER2+ tumors.

Outcomes of HER2-positive nonmetastatic breast cancer patients with or without deleterious BRCA mutations after trastuzumab treatment.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e12550-e12550
Author(s):  
Aimaz Afrough ◽  
Heather Lin ◽  
Angelica M. Gutierrez-Barrera ◽  
Jennifer Keating Litton ◽  
Vicente Valero ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Brca Mutation ◽  
Disease Free Survival ◽  
Metastatic Breast ◽  
Her2 Overexpression ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Brca Mutations ◽  
Her2 Breast Cancer

e12550 Background: Human epidermal growth factor receptor (HER2) overexpression or amplification occurs in 20–25% of all breast cancers and is associated with an aggressive form of the disease with reduced disease-free survival (DFS) and overall survival (OS). However, the outcome of patients with HER2+ tumor and BRCA mutation is poorly described. The purpose of this analysis was to analyze the clinical and pathological features and outcomes of patients with HER2+ breast cancer regards to their BRCA status. Methods: Patients who were referred for genetic counseling between 2004-2012 and who had a HER2+ breast cancer treated with trastuzumab were included in our analysis. Patients were considered Her2+ if immunohistochemistry was 3+ or had a ratio of ≥2 by FISH. Patients with metastatic breast cancer at diagnosis were excluded. Clinical and pathological and outcome data was extracted from a prospectively maintained research data base after IRB approval was obtained. Results: Ninety-four patients were identified. The median age at diagnosis was 39 years (range 21 – 58). The majority of the patients were White (76%). Tumors were invasive ductal carcinoma in 89% and had nuclear grading of 3 in 76% of patients. Hormone receptors were positive in 66% and BRCA 1 or 2 mutations were positive in 16% (N=15). The majority of the patients were treated with a combination of Anthracyclines plus Taxanes (76%). All patients received trastuzumab in the neoadjuvant or adjuvant setting. After a median follow-up of 4.4 years, OS and DFS in all patients were 97% and 88%, respectively. Three HER2-positive breast cancer patients had died (3.2 %). Recurrence had occurred in 11 patients; all of these patients were BRCA negative. OS and DFS of patients with BRCA mutations were then compared with OS and DFS of patients without BRCA mutation (both 100% vs. 96% and 81.9%, respectively). There was no statistically significant survival difference in BRCA mutation carriers compared with non-carriers (p=0.362). Conclusions: The presence of a BRCA mutation does not seem to offer prognostic information in this population. Further investigation with larger cohort are needed for confirmation.

Neratinib in HER2-Positive Breast Cancer Patients

2019 ◽  
Vol 53 (6) ◽  
pp. 612-620 ◽  
Author(s):  
Rutugandha Paranjpe ◽  
Dima Basatneh ◽  
Gabriel Tao ◽  
Carmine De Angelis ◽  
Sobia Noormohammed ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Disease Free Survival ◽  
Common Adverse Effect ◽  
Stage I ◽  
Phase Iii ◽  
Therapeutic Window ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Safety And Efficacy ◽  
Her2 Breast Cancer

Objective:To review the chemistry, pharmacology, pharmacokinetics, safety, and efficacy of neratinib in human epidermal growth factor receptor (HER2)+ breast cancer (BC). Data Sources: A PubMed search was performed using the term neratinib between September 12, 2018, and November 21, 2018. References of published articles and reviews were also assessed for additional information. Study Selection and Data Extraction: English-language preclinical and clinical studies on the chemistry, pharmacology, pharmacokinetics, safety, and efficacy of neratinib were evaluated. Data Synthesis: Neratinib, an irreversible inhibitor of HER1, HER2, and HER4, is Food and Drug Administration approved for the extended adjuvant treatment of stage I-III HER2+ BC to follow trastuzumab-based therapy. A phase III study has demonstrated statistically significant improvement in 5-year disease-free survival rate (90.2 vs 87.7; hazard ratio = 0.73, 95% CI = 0.57-0.92, P = 0.0083). Its most common adverse effect is diarrhea, observed in more than 90% of patients. The incidence of grade 3/4 diarrhea (~40%) is reduced by half with loperamide prophylaxis, which is recommended for the first 8 weeks of neratinib therapy. Other common adverse reactions are nausea and fatigue. The patients need to be monitored for liver function tests and drug interactions with acid-reducing agents, CYP3A4 inhibitors/inducers, and P-glycoprotein substrates with narrow therapeutic window. Relevance to Patient Care and Clinical Practice: American Society of Clinical Oncology and National Comprehensive Cancer Network clinical guidelines suggest the use of neratinib for extended adjuvant therapy following 1-year trastuzumab in stage I to III HER2+ BC. Diarrhea remains a clinically significant but manageable adverse event. Conclusion: Neratinib significantly improves treatment outcomes and has manageable toxicity in stage I to III HER2+ BC patients.

scholarly journals Somatic Mutations in HER2 and Implications for Current Treatment Paradigms in HER2-Positive Breast Cancer

2020 ◽  
Vol 2020 ◽  
pp. 1-13 ◽  
Author(s):  
Maria Gaibar ◽  
Laura Beltrán ◽  
Alicia Romero-Lorca ◽  
Ana Fernández-Santander ◽  
Apolonia Novillo
Keyword(s):  
Breast Cancer ◽  
Somatic Mutations ◽  
Tyrosine Kinase Domain ◽  
Her2 Overexpression ◽  
Breast Cancer Patients ◽  
Trastuzumab Resistance ◽  
Her2 Gene ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

In one of every four or five cases of breast cancer, the human epidermal growth factor receptor-2 (HER2) gene is overexpressed. These carcinomas are known as HER2-positive. HER2 overexpression is linked to an aggressive phenotype and a lower rate of disease-free and overall survival. Drugs such as trastuzumab, pertuzumab, lapatinib, neratinib, and the more recent afatinib target the deregulation of HER2 expression. Some authors have attributed somatic mutations in HER2, a role in resistance to anti-HER2 therapy as differential regulation of HER2 has been observed among patients. Recently, studies in metastatic ER + tumors suggest that some HER2 mutations emerge as a mechanism of acquired resistance to endocrine therapy. In an effort to identify possible biomarkers of the efficacy of anti-HER2 therapy, we here review the known single-nucleotide polymorphisms (SNPs) of the HER2 gene found in HER2-positive breast cancer patients and their relationship with clinical outcomes. Information was recompiled on 11 somatic HER2 SNPs. Seven polymorphisms are located in the tyrosine kinase domain region of the gene contrasting with the low number of mutations found in extracellular and transmembrane areas. HER2-positive patients carrying S310F, S310Y, R678Q, D769H, or I767M mutations seem good candidates for anti-HER2 therapy as they show favorable outcomes and a good response to current pharmacological treatments. Carrying the L755S or D769Y mutation could also confer benefits when receiving neratinib or afatinib. By contrast, patients with mutations L755S, V842I, K753I, or D769Y do not seem to benefit from trastuzumab. Resistance to lapatinib has been reported in patients with L755S, V842I, and K753I. These data suggest that exploring HER2 SNPs in each patient could help individualize anti-HER2 therapies. Advances in our understanding of the genetics of the HER2 gene and its relations with the efficacy of anti-HER2 treatments are needed to improve the outcomes of patients with this aggressive breast cancer.

Myocardial HER2 expression with 111In-DTPA-trastuzmab scan in patients shortly after anthracycline treatment

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3057-3057
Author(s):  
P. J. Perik ◽  
M. N. Lub-De Hooge ◽  
P. L. Jager ◽  
M. A. De Korte ◽  
J. A. Gietema ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Xenograft Model ◽  
Metastatic Breast ◽  
Optimal Timing ◽  
Her2 Overexpression ◽  
Compensatory Mechanism ◽  
Her2 Expression ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Adjuvant Trastuzumab

3057 Background: The monoclonal antibody trastuzumab, apart from antitumor effect, can induce cardiotoxicity, particularly when combined with anthracyclines. Myocardial HER2 upregulation may serve, transiently, as a compensatory mechanism induced by cardiac stress. Previously we showed in a xenograft model that 111In-DTPA-trastuzumab scintigraphy can detect HER2 positive lesions (Br J Pharmacol 2004;143:99–106) but that myocardial 111In-DTPA-trastuzumab uptake was found in only 1 of 17 anthracycline-pretreated HER2-positive metastatic breast cancer patients (ESMO 2004#50). This low number may be related to the long interval between anthracycline administration (median 11 months) and performed scan in these patients. To evaluate whether myocardial HER2 expression is induced by anthracyclines, we performed 111In-DTPA-trastuzumab scans in patients shortly after anthracycline treatment. Methods: Patients who completed 4–6 cycles of anthracycline-based chemotherapy (< 3 weeks after last dose) underwent gammacamera imaging 48 and 96 h after iv administration of 150 MBq 111In-DTPA-trastuzumab (5mg). Results: 10 anthracycline-treated patients, 8 as adjuvant breast cancer treatment and 2 for metastatic sarcoma have been enrolled. Myocardial 111In-DTPA-trastuzumab uptake was observed in 5/10 anthracycline-treated patients who all were without symptomatic cardiac dysfunction. Conclusions: Shortly after completion of anthracycline treatment myocardial HER2 overexpression was detectable in 50% of the patients. This may be a transient phenomenon. 111In-DTPA-trastuzumab scan after anthracycline treatment prior to adjuvant trastuzumab may identify patients more susceptible for trastuzumab-induced cardiotoxicity. This important observation may add to optimal timing of trastuzumab therapy i.e. when HER2/neu expression in the heart is negative (again). [Table: see text]

Estrogen receptor in HER2-positive early breast cancer: Two different diseases?

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 642-642 ◽  
Author(s):  
Eva Maria Ciruelos Gil ◽  
Ismael Ghanem ◽  
Luis Manso ◽  
Sergio Hoyos ◽  
Carlos Castañeda ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Study Groups ◽  
Her2 Overexpression ◽  
Her2 Positive ◽  
Ki 67 ◽  
Luminal B ◽  
Her2 Breast Cancer ◽  
Group A ◽  
Long Term Prognosis ◽  
Group B

642 Background: HER2+ breast cancer (BC) is a well characterized subtype of BC, due to the predictive value of HER2 overexpression for anti-HER2 targeted therapies. Nevertheless, around 50% of HER2+ BC are ER+ and clasiffied as luminal B/HER2+, but their biological and clinical behaviour may be different from HER2+/ER- tumors. Methods: We retrospectively reviewed 347 HER2+ (Herceptest +++ or FISH+) early BC patients (see Table) diagnosed at our institution in 1997-2007, and were divided into two study groups: HER2+/ER+ (group A) and HER2+/ER- (group B). ER+ was defined if expressed in > 10% tumor cells. Results: See table below. Mean age: 54.7 y (44.6 – 65). Mean Ki 67 was higher in B (37,2 vs 22,4%, p<0.0001). At the current FU, n¼ of events were insufficient to reach median DFS/OS. Mean DFS was 6.9 y (3.5 – 10.2); recurrent disease was higher (p 0.003) for B (54 pts, 43%) vs A (62 pts, 28%). 5-year DFS estimates: 78.4 % (95% CI 72.3 – 83.3) and 62.3 % (95% CI 53 – 70.27) for A and B, and 10-year DFS was 73.4% (95% CI 66.6 – 79) and 52.5% (95% CI 42.4 – 61.6) for A and B, respectively (p 0.0006). Most common recurrent sites were local (18) and bone (9) for HER2+/ER+ and liver (8) and lung (8) for HER2+/ER-. Mean OS was 8.03y (5.4 – 10.8); 28 (12,6%) pts died in A, vs 26 (21%) in B (p 0.043). 5-year OS estimates: 93.9 % (95% CI 89.7 – 96.4) and 87.6 % (95% CI 80.3 – 92.3) for A and B, and 10-year DFS was 84.2% (95% CI 77.5 – 89.0) and 74.1% (95% CI 63.4 – 82.2) for A and B, respectively (p 0.01). Conclusions: ER expression in HER2+ early BC defines two clinically distinct diseases with different long-term prognosis. These data may help to better individualize adjuvant therapies and future clinical trial designs. [Table: see text]

Correlation of quantitative p95HER2, HER2, and HER3 protein expression with pathologic complete response (pCR) in HER2-positive breast cancer patients (pts) treated with neoadjuvant chemotherapy and trastuzumab.

2012 ◽  
Vol 30 (27_suppl) ◽  
pp. 137-137 ◽  
Author(s):  
Jose Caetano Villasboas ◽  
Judith Hurley ◽  
Jodi Marie Weidler ◽  
Agnes Paquet ◽  
Carmen Gomez Fernandez ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Pathologic Complete Response ◽  
Metastatic Breast ◽  
Complete Response ◽  
Invasive Disease ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Additional Information ◽  
Her2 Breast Cancer ◽  
Poor Outcomes

137 Background: Elevated p95HER2 [HER2-M611-CTF (carboxy-terminal-fragment) also known as p95] expression has been correlated with poor outcomes in HER2+ pts with metastatic breast cancer treated with trastuzumab (T); however, limited data is available on the correlation between p95 and pCR to T in the neoadjuvant (NEO) setting, where p95 was measured by immunohistochemistry. The current study aims to determine whether quantitative p95, HER3 and HER2 expression correlated with pCR in pts treated with T + chemotherapy in the NEO setting. Methods: pCR data and quantitative HER2 (H2T), p95, and HER3 (H3T) results by HERmark/VeraTag assays were available in 45 patient cases with pre-therapy, formalin-fixed, paraffin-embedded breast tumors. pCR was defined as the absence of invasive disease in the breast. Quantitative biomarker data were correlated with pCR according to previously published or presented biomarker cutoffs. Results: The overall pCR rate was 46.7% (ER+: 14.3% vs. ER-: 75%; p<0.0001) and was significantly associated with higher H2T levels (p=0.02) and lower H3T levels (p=0.04). In ER- subjects (N=24), no difference in H2T levels was observed between pCR vs non-pCR groups (median H2T=111.5 vs 150.5, respectively; p=0.721). However, within the ER+ group (N=21), H2T levels were significantly higher in the pCR group vs non-pCR group (median H2T=254 vs 37.3; p=0.024). Using multivariate logistic regression, increasing log(H2T) (p = 0.012), ER-negativity (p = 0.027) and low p95 (p = 0.074) were found to correlate or trend with pCR. Conclusions: pCR was significantly associated with high H2T, particularly in ER+ HER2+ breast cancer pts who received NEO therapy with T + chemotherapy. Lower H3T was also associated with pCR. A trend towards pCR was seen in tumors with low p95. These data suggest that quantitative H2T, H3T and p95 may provide additional information on response to T-based regimens in breast cancer stratified by ER status. Additional investigation into the relationship between quantitative H2T, p95 and H3T expression and T response in the NEO setting in larger cohorts is warranted.

Rate of use of NCCN “preferred” chemotherapy regimens for the treatment of HER2 positive breast cancer.

2017 ◽  
Vol 35 (8_suppl) ◽  
pp. 163-163
Author(s):  
Eric J. Gratias ◽  
Margaret Rausa ◽  
Lee N. Newcomer ◽  
Kurt Andrews ◽  
Nick Andrews ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Adjuvant Chemotherapy ◽  
Neoadjuvant Chemotherapy ◽  
Cancer Patients ◽  
Treatment Options ◽  
Management Program ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Nccn Guidelines ◽  
Her2 Breast Cancer

163 Background: The National Comprehensive Cancer Network (NCCN) Guidelines represent a well-established standard of care for the treatment of HER2+ breast cancer patients. eviCore healthcare is a licensee of NCCN that uses the NCCN guidelines to support its proprietary chemotherapy management program. All regimens assigned NCCN Category of Evidence 1, 2A, or 2B are adherent treatments in the eviCore program. NCCN recommends many systemic treatment options for HER2+ breast cancer, and a limited group is designated by NCCN as “preferred” based on superior efficacy and/or safety. This study evaluated the frequency of NCCN-preferred regimen use by practicing oncologists in HER2+ breast cancer patients. Methods: Chemotherapy authorizations for all HER2+ breast cancer patients with ≥ 1 injectable drug from 4/1/2015-9/30/2016 for multiple payers were included; > 90% of authorizations occurred in United HealthCare members. Cases with incomplete data were excluded. 3685 fully evaluable cases were stratified by stage, ER/PR status, and NCCN-preferred vs. NCCN-recommended status. The frequency of NCCN-preferred regimen selection was calculated for each subgroup. Results: There were 2883 HER2+/ER+ and/or PR+ cases and 802 HER2+/ER-/PR- cases. The highest frequency of NCCN-preferred regimen use occurred in neoadjuvant chemotherapy for patients with Stage III HER2+/ER+ and/or PR+ disease, where 88% of 289 patients used an NCCN-preferred regimen. Metastatic HER2+ patients had a markedly lower rate of NCCN-preferred regimen use at 62% of 557 cases. Only 48% of 1096 patients with Stage I/II HER2+/ER+ and/or PR+ disease received NCCN-preferred regimens. Conclusions: Patients receiving neoadjuvant chemotherapy for HER2+ breast cancer receive NCCN-preferred regimens at significantly higher rates than patients receiving adjuvant chemotherapy or metastatic treatment. Less than half of patients receiving adjuvant chemotherapy are receiving NCCN-preferred regimens. Further study is needed to determine the reasons for low preferred regimen use and ways to optimize preferred regimen use in HER2+ breast cancer.

Phase II study of preoperative chemotherapy versus standard postoperative chemotherapy in HR-negative HER2-positive breast cancer patients.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e12118-e12118
Author(s):  
Meng Xiu ◽  
Pin Zhang
Keyword(s):  
Breast Cancer ◽  
Preoperative Chemotherapy ◽  
Postoperative Chemotherapy ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Her2 Breast Cancer ◽  
Kaplan Meier ◽  
Significant Difference ◽  
Risk Patients

e12118 Background: HR-/HER2+ breast cancer is a subtype with aggressive characteristic and poor survival. More clinical evidence are needed for choice of therapeutic strategies. Methods: Patients with T1-3N0-3M0 received preoperative chemotherapy (PTX 175 mg/m2, CBP AUC 4, q2w*6) combined with trastuzumab (2mg/kg qw) or standard postoperative chemotherapy such as ddAC-PH, AC-PH, TCH. The primary endpoint was RFS. Results: 86 patients were enrolled, 43 received preoperative chemotherapy (pre arm) and the other 43 received postoperative chemotherapy (post arm). There was no significant difference in baseline between the two arms. 22.1% of patients were stage IIA, 25.6% IIB, 34.9% IIIA, and 18.6% IIIC. At a median follow-up of 33.4 months, 16 patients had relapsed (pre arm 8, post arm 8). The median time from diagnosis to relapse was 22.8 months (7.1-49.2) and 23.8 months (11.4-37.4) in pre and post arm. Kaplan-Meier survival analysis estimated that the 3-year RFS were similar (pre vs post: 73.4% vs 75.4%, p= 0.631). Only 1 death occurred in post arm. Table showed that in subgroups, there was no statistical difference in risk of recurrence between pre and post arms. In pre arm, ORR was 97.7% clinically, and pCR (ypT0/TisN0) was 39.0%. No patients achieved pCR relapsed, and the residual invasive lesions indicated poor prognosis. Table showed that Neo-Bioscore 4-5 was related to recurrence event significantly ( p= 0.021). The rate of breast-conserving in pre arm was higher (19.5% vs 9.3%), and PCb regiments every 2 weeks had similar adverse effects with standard chemotherapy, and less patients had dose reductions (18.6% vs 25.6%). Conclusions: Preoperative chemotherapy versus standard postoperative chemotherapy results in similar RFS among HR-/HER2+ patients. Preoperative chemotherapy can identify prognosis of patients early by Neo-Bioscore and adjuvant therapy should be strengthened for high-risk patients. PCb every 2 weeks combined with trastuzumab can be an option of preoperative therapy for HER2+ breast cancer. Clinical trial information: NCT02934828. [Table: see text]

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

2021 ◽  
Vol 118 (29) ◽  
pp. e2026849118
Author(s):  
Rosalynd Upton ◽  
Allison Banuelos ◽  
Dongdong Feng ◽  
Tanuka Biswas ◽  
Kevin Kao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Monoclonal Antibody ◽  
Cancer Patients ◽  
Early Stage ◽  
Regulatory Protein ◽  
Her2 Overexpression ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Her2 Gene ◽  
Her2 Positive

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

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