HER2-positive Metastatic Breast Cancer Research Articles

Updates in Treatment of HER2-positive Metastatic Breast Cancer

Updates in Treatment of HER2-positive Metastatic Breast Cancer

Efficacy and safety of RC48-ADC in HER2-positive and HER2-low metastatic breast cancer: a multicenter, real-world study

BackgroundA standard treatment recommendation for third-line and subsequent treatments for advanced HER2-positive breast cancer is still missing, especially for low HER2 expression. Nevertheless, there is evidence that these patients might benefits from antibody-drug conjugates (ADCs) treatment. Therefore, this study aimed to evaluate the clinical efficacy, safety, and factors affecting efficacy of Disitamab Vedotin (RC48) for treating HER2-positive and HER2-low metastatic breast cancer (MBC) in the real-world setting.MethodsA retrospective study at five clinical sites was conducted in China, enrolling MBC patients treated with RC48 from July 01, 2021 and May 31, 2023. Patient demographics, treatment patterns, and adverse events (AEs) were recorded and analyzed.ResultsA total of 154 patients were included: 104 (67.53%) patients with HER2-positive and 50 (32.47%) patients with HER2-low MBC. The median progression-free survival (mPFS) was 5.06 months. The objective response rate (ORR) and disease control rate (DCR) were 36.36% and 68.83%, respectively. HER2-positive patients exhibited a mPFS of 5.93 and an ORR of 41.35%. In contrast, patients with low-HER2 had a mPFS of 4.28 months and an ORR of 26.00%. The most common AEs included neutropenia (54.55%), increased AST (53.25%), leukopenia (51.95%), and fatigue (43.51%), mostly graded mild to moderate (grade 1-2).ConclusionsThis extensive study in China demonstrated that RC48 has excellent therapeutic potential for both HER2-positive and HER2-low MBC with a favorable safety profile. The study also suggests that combination therapy significantly boosts efficacy beyond monotherapy, indicating a promising avenue for future ADC development.

Inetetamab for injection in combination with vinorelbine weekly or every three weeks in HER2-positive metastatic breast cancer: A multicenter, randomized, phase II clinical trial

Abstract Objective We aimed to investigate the pharmacokinetics, safety, efficacy, and immunogenicity of different dosing regimens (weekly and every three weeks) of inetetamab in combination with vinorelbine in human epidermal growth factor receptor 2 (HER2)+ patients with metastatic breast cancer who had received one or more chemotherapy regimens. Methods HER2+ patients with metastatic breast cancer who had received one or more chemotherapy regimens were included. Eligible patients received inetetamab administered weekly or every three weeks in combination with vinorelbine injection chemotherapy. Pharmacokinetics, safety, efficacy, and immunogenicity were compared between the groups. Results Sixty HER2+ patients were randomized into a single-week administration group ( n = 29) and a three-week administration group ( n = 31). After the final dose in the single-week administration group and the three-week administration group, the mean Cmax values were 79.773 μg/mL and 146.083 μg/mL; the mean Cmin values were 30.227 μg/mL and 11.926 μg/mL; the mean AUCtau values were 7328.443 μg·h/mL and 22647.101 μg·h/mL; and the mean Cav values were 43.622 μg/ mL and 44.935 μg/mL, respectively. The best overall response (BOR) rates at 24 weeks and unconfirmed BOR rates at 24 weeks were both 40.7% in the single-week dosing group and 40.7% in the three-week dosing group, and the 24-week confirmed disease control rates (DCRs) were 88.9% and 81.5%, respectively. The incidence of adverse events (AEs) was generally consistent across all levels. Conclusion There were slight differences in the mean Cmax, Cmin, AUCtau and Cav between the three-week dosing group and the single-week dosing group, and the mean steady-state concentrations of Cav were comparable; however, there were no differences in efficacy, safety or immunogenicity between the two groups.

Impaired cyclin D3 protein degradation contributes to trastuzumab resistance in HER2 positive breast cancer

As the first anti-HER2 targeted agent approved by FDA in 1998, Trastuzumab has significantly improved the outcome of patients with HER2 positive metastatic breast cancer. Unfortunately, resistance to trastuzumab is a severe obstacle to its therapeutic efficacy in clinical application, and its mechanism has not yet been fully elucidated. In our study, we found that stabilization of cyclin D3 could be one reason for trastuzumab resistance. Trastuzumab could induce G1/G0 phase arrest by downregulating cyclin D3 protein expression. However, the protein expression of cyclin D3 was not affected in trastuzumab-resistant cells, which might be related to aberrant activation of ERK signaling pathway. Furthermore, degradation of cyclin D3 protein by trastuzumab was mainly resulted from ubiquitin-dependent proteasome mechanism instead of transcriptional regulation. In trastuzumab-resistant breast cancer cells, trastuzumab-induced degradation of cyclin D3 protein was abrogated. When the ubiquitin pathway was inhibited, cells would show a predisposition to resistance to trastuzumab. Further, CDK4/6 inhibitor can inhibit the proliferation of trastuzumab-resistant HER-2 positive breast cancer cells. Therefore, combination of CDK4/6 inhibitors and anti-HER2 targeted therapy may be an alternative and promising strategy to overcome trastuzumab resistance in the future.

Pyrotinib combined with metronomic etoposide in heavily pretreated HER2-positive metastatic breast cancer: a single-arm, phase II study

BackgroundExploration of novel combination mode of pyrotinib and chemotherapy for heavily pretreated HER2-positive metastatic breast cancer (MBC) and how to balance survival benefits and compliance are still urgent problems in clinical practice. The current single-arm prospective phase II study aimed to evaluate the efficacy and safety of pyrotinib in combination with metronomic oral etoposide in heavily pretreated HER2-positive MBC.MethodsHER2-positive MBC patients previously treated with trastuzumab were enrolled to receive oral pyrotinib 400 mg per day and metronomic oral etoposide 50 mg per day d1-21 every 28 days, until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). The secondary endpoints were objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), overall survival (OS), and safety.Results22 patients were enrolled with a median of 4 prior treatment regimens for MBC. During the follow-up of 20 evaluable patients, the median PFS was 9.0 months (95% CI, 7.6–10.4 months), and the median OS was 27.0 months (95%CI, 20.9–33.1 months). The ORR was 30% (6/20), the DCR was 80% (16/20), and the CBR was 65% (13/20). The most common grade 3 adverse events (AEs) included nausea (15%), vomiting (15%), diarrhea (5%), anemia (5%), and peripheral neuropathy (5%). No grade 4 or lethal AEs were observed.ConclusionThe combination of pyrotinib with metronomic oral etoposide has achieved promising clinical benefits in heavily pretreated HER2-positive MBC, with acceptable and manageable toxicity.Trial registrationRegistry number: NCT03923179. Registered April 18, 2019.

Impact of trastuzumab emtansine (T-DM1) on spleen volume in patients with HER2-positive metastatic breast cancer.

Trastuzumab emtansine (T-DM1) is a novel therapy for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer, combining the targeted action of trastuzumab with the cytotoxic effects of emtansine. Although T-DM1 has demonstrated greater efficacy and safety compared to traditional therapies, concerns about hepatotoxicity and spleen-related complications have arisen. We conducted a retrospective study of 64 HER2-positive metastatic breast cancer patients treated with T-DM1 at our institution. Patients underwent computed tomography or magnetic resonance imaging at baseline and during treatment cycles. Spleen volume, portal vein diameter, and laboratory values were compared between baseline and 12months after T-DM1 treatment. Median spleen volume significantly increased from 201cm3 (IQR, 157-275) at baseline to 291cm3 (IQR, 215-420) after 12months of T-DM1 treatment (P<0.001). Spleen enlargement was observed in 87.5% of patients, while no significant alteration was detected in portal vein diameter. The change in spleen volume was positively correlated with changes in serum globulin levels, liver enzymes, and bilirubin levels, but did not impact survival outcomes. T-DM1 therapy in HER2-positive metastatic breast cancer leads to significant spleen enlargement and systemic biochemical changes. Future studies should focus on elucidating the long-term implications of these findings and optimizing monitoring strategies for spleen-related complications.

Pyrotinib and trastuzumab combination treatment synergistically overcomes HER2 dependency in HER2-positive breast cancer: insights from the PHILA trial

The PHILA study suggests that pyrotinib, trastuzumab, and docetaxel significantly improved progression-free survival (PFS) compared with placebo, trastuzumab, and docetaxel in patients with untreated HER2-positive metastatic breast cancer. In this study, we aimed to investigate the synergistic mechanisms of pyrotinib plus trastuzumab and provide further insights for the PHILA trial. The invitro activity of combination treatments was assessed through cell biological and biochemical experiments. The invivo efficacy was evaluated in cell-derived xenografts, a TUBO tumour model, and one clinical case. Next-generation sequencing was performed on circulating tumour DNA (ctDNA) from patients in the PHILA trial. The combination of pyrotinib and trastuzumab more effectively inhibited cell growth than pyrotinib or trastuzumab alone in models of HER2-dependent breast cancer. It potentiated membrane HER2 ubiquitination and downregulation, which resulted in a comprehensive blockade of the HER2 signalling pathway. The pyrotinib-altered membrane HER2 levels had no significant effect on trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity (ADCC). We further validated the synergistic mechanisms in TUBO tumours and one clinical case, rather than models of HCC1954cells harbouring the PIK3CA H1047R mutation. Similarly, in our centre cohort of the PHILA study, patients with genetic alterations in the HER2 signalling cascade had significantly shorter median PFS than individuals with the wild-type pathway. Our findings underscore the robust synergy between pyrotinib and trastuzumab in overcoming HER2 dependency and provide a rationale for pyrotinib, trastuzumab, and docetaxel as one of the optimal choices for patients with untreated HER2-positive metastatic breast cancer, who are dependent on the HER2 signalling cascade. This work was supported by the National Key Research and Development Program of China (2021YFF1201300), the National Natural Science Foundation of China (82172875), the CAMS Innovation Fund for Medical Sciences (CIFMS) (2022-I2M-2-001), and the Joint Innovative Fund of Beijing Natural Science Foundation and Changping District (L234004).

P90-6 Efficacy and safety of neratinib and capecitabine in HER2-positive metastatic breast cancer: a systematic review

P90-6 Efficacy and safety of neratinib and capecitabine in HER2-positive metastatic breast cancer: a systematic review

MO19-4 Trastuzumab deruxtecan, its efficacy in patients with metastatic HER2-positive breast cancer: a systematic review

MO19-4 Trastuzumab deruxtecan, its efficacy in patients with metastatic HER2-positive breast cancer: a systematic review

Health-related quality of life of Canadian patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer.

397 Background: The EuroQol 5 Dimension 5 Level (EQ-5D-5L) is a validated tool that assesses health utility (HU) as a self-reported measure of health-related quality of life (HRQoL). This study aims to generate Canadian-specific HU data for patients with stable, HER2-positive (HER2+) metastatic breast cancer (mBC) receiving standard therapies. Methods: A cross-sectional study was conducted at McGill University Health Centre in Quebec, Canada. Eligibility criteria included: age ≥18 years, de novo or recurrent mBC, stable disease, and active treatment with a Health Canada-approved systemic therapy regimen (any line/time point on treatment). The EQ-5D-5L questionnaire was administered at every visit and each record was treated as a unique singular data point. The HU values were derived using the Canadian algorithm developed by Xie et al., 2016. The EQ-5D-5L measures HRQoL across five domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, and is scored on 5 levels ranging from one “no problems” to five “extreme problems”. A second part of the questionnaire includes a visual analogue scale (VAS) where respondents rank their overall health on scale of 0-100. The primary outcome was mean HU and standard deviation (SD) for HER2+ patients overall. Secondary outcomes included mean HU by hormone receptor (HR) status and describing patient responses to the questionnaire. Results: Between December 2022 and July 2023, a total of 81 HER2+ HU data points were included for analysis, representing 30 patients. For these patients, the mean age was 54.2 years (SD: 10.6). Most patients (58.3%) were on first line and had an Eastern Cooperative Oncology Group Performance Status of 0 (65.5%). The mean HU value was 0.83 (SD: 0.14, n=81). For patients with HR-positive mBC, the mean HU was 0.81 (SD: 0.14, n=44), while for patients with HR-negative mBC, it was 0.85 (SD: 0.13, n=37). The majority of patients reported “no problems” across all domains: mobility (69.1%), self-care (81.5%), usual activities (46.9%), pain/discomfort (35.8%), and anxiety/depression (58%). The mean VAS score was 77.3 (SD: 17.0). Conclusions: This study provides the first Canadian data on contemporary HU values for patients with HER2+ mBC, which reflects current HRQoL amidst a changing treatment landscape.

P91-3 A lower dose of trastuzumab deruxtecan (T-Dxd) is effective in controlling HER2-positive metastatic breast cancer

P91-3 A lower dose of trastuzumab deruxtecan (T-Dxd) is effective in controlling HER2-positive metastatic breast cancer

Prognostic impact of body mass index on metastatic HER2-positive breast cancer survival

Background. The association between body mass index and prognosis in patients with HER2-positive metastatic breast cancer (mBC) is unclear. Purpose – the first purpose of our study was to determine whether BMI is an independent prognostic factor for progression-free survival (PFS) and overall survival (OS) in HER2-positive mBC patients. The second objective was to assess the mutual impact of baseline clinicopathological characteristics on survival outcomes. Materials and Methods. The study group included patients treated at the Sumy Regional Clinical Oncology Center. We considered the underweight patients if their BMI was &lt;18.5 kg/m2, normal weight 18.5–24.9 kg/m2, overweight 25.0–29.9 kg/m2, and obese ≥ 30 kg/m2. The following formula was used for calculations: weight/height2 (kilograms/meter2). Information about the height, weight, and other clinicopathological characteristics of the patient at the time of the start of drug therapy was taken from the primary medical documentation. Pearson’s test and Chi2 test for categorical variables were used to compare baseline clinicopathological characteristics in groups with normal, overweight, and obesity. The Kaplan-Meier method was used to establish the medians of PFS and OS. Cox regression analysis assessed the mutual impact on the survival of various clinicopathological characteristics. The statistical significance threshold was considered P ≤0.05. Results. Seventy-eight patients with HER2-positive mBC were enrolled and categorized according to their BMI in normal weight, overweight, and obese groups. BMI had a different impact on PFS and OS. Median PFS was 14.9, 11.9, and 14.2 months for normal-weight, overweight, and obese patients, respectively. There is no statistically significant difference in PFS between groups (Р = 0.110). Multivariable regression analysis confirmed no impact of BMI on PFS. Nevertheless, metastases in bones and kidneys and the nuclear grade were statistically significant determinants of PFS. Median OS was 26.4, 28.8, and 37.9 months for normal-weight, overweight, and obese patients, respectively. BMI, kidney metastases, and nuclear grade were prognostically significant determinants of OS. Conclusions. BMI is an independent prognostic factor of OS in patients with HER2-positive mBC. Obesity is associated with better OS but does not impact PFS. Metastases in bones and kidneys and the nuclear grade can predict survival outcomes.

Personalized treatment approach for HER2-positive metastatic breast cancer.

Breast cancer (BC) is a leading global concern for women, with 30% being HER2-positive cases linked to poorer outcomes. Targeted therapies like trastuzumab deruxtecan (T-DXd), trastuzumab, pertuzumab, and T-DM1 have revolutionized HER2-positive metastatic breast cancer (MBC) treatment. Although these therapies have improved MBC management and patient outcomes, resistance can develop, reducing effectiveness. Personalized strategies based on tumor characteristics offer hope for better responses and longer outcomes. This review outlines insights into MBC patients responding well to anti-HER2 treatments, even across multiple treatment regimen. Recent immunotherapy, locoregional therapy, and liquid biopsy breakthroughs are covered, suggesting ways to increase long-term responders. Personalized approaches have boosted HER2-positive MBC outcomes, and ongoing research is crucial to uncover new treatments and biomarkers, potentially elevating long-term response rates and prognoses. This may aid in providing new direction to breast cancer clinics.

Pyrotinib plus capecitabine for patients with HER2-positive metastatic breast cancer and brain metastases (PERMEATE trial): overall survival results from a multicenter, single-arm, two-cohort, phase 2 trial

The phase 2 PERMEATE study has shown the antitumor activity and safety of pyrotinib plus capecitabine in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer and brain metastases. In this report, survival results were updated with extended follow-up. Between January 29, 2019 and July 10, 2020, adult patients with HER2-positive metastatic breast cancer who had radiotherapy-naïve brain metastases (cohort A, n=59) or progressive disease after radiotherapy (cohort B, n=19) were enrolled and received pyrotinib (400mg once daily) and capecitabine (1000mg/m2 twice daily on days 1-14 of each 21-day cycle) until disease progression or unacceptable toxicity. Secondary endpoints progression-free survival (PFS) and overall survival (OS) were updated, and post-hoc central nervous system (CNS)-PFS was analyzed. This study is registered with ClinicalTrials.gov (NCT03691051). As of February 2, 2023, the median follow-up duration was 30.9 months (interquartile range, 16.1-39.8). Median PFS was 10.9 months (95% confidence interval [CI], 7.6-14.6) in cohort A and 5.7 months (95% CI, 3.4-11.5) in cohort B. Median OS was 35.9 months (95% CI, 24.4-not reached) in cohort A and 30.6 months (95% CI, 12.6-33.3) in cohort B. Median CNS-PFS was 13.6 months (95% CI, 9.0-15.8) in cohort A and 5.7 months (95% CI, 3.4-11.5) in cohort B. Median OS was 34.1 months (95% CI, 21.7-not reached) for 14 patients with intracranial progression only in cohort A who restarted pyrotinib plus capecitabine after local radiotherapy. These data support further validation in a randomized controlled trial for the assessment of pyrotinib in combination with capecitabine as systemic therapy for patients with HER2-positive breast cancer and brain metastases. National Cancer Center Climbing Foundation Key Project of China, Jiangsu Hengrui Pharmaceuticals.

Safety profile of trastuzumab originator vs biosimilars: a systematic review and meta-analysis of randomized clinical trials.

In the last decade trastuzumab biosimilars became more and more frequent. Among their uses, from several years, they have been available in Europe for the treatment of HER2-positive metastatic breast cancer, as an alternative to Herceptin®. This meta-analysis aimed to analyze the available literature with particular focus on phase 3 randomized clinical trials (RCTs) comparing adverse events between trastuzumab biosimilar and originator. A systematic review was conducted in Pubmed and Scopus to include all phase 3 RCTs related to trastuzumab in patients with HER2-positive breast cancer and published up to July 31, 2023. Of the 508 records identified, 14 articles were meta-analyzed for safety information, including serious treatment emergent adverse events, death-related adverse events, neutropenia, leukopenia, infections, increased ALT, increased AST, anti-drug antibody, and neutralizing antibody. Included patients had an early breast cancer (N=2,877) or a metastatic breast cancer (N=2,603). No significant difference in death-related adverse events was found for trastuzumab biosimilar and originator when evaluated for an early breast cancer in the neoadjuvant phase (Risk Ratio [RR], 1.30; 95% confidence interval [CI], 0.47-3.59; I2 = 0%; p = 0.57) and overall (RR, 0.43; 95%CI, 0.11-1.66; I2 = 20%; p = 0.26), and for metastatic breast cancer (RR, 0.61; 95%CI, 0.30-1.26; I2 = 0%; p = 0.85). No difference was also observed for all other safety outcomes as in accordance with clinical studies necessary for the registration and approval of a biosimilar at a European level.

Effectiveness of trastuzumab deruxtecan rechallenge in a patient with HER2-positive metastatic breast cancer: a case report.

Trastuzumab deruxtecan (T-DXd), a high-payload antibody drug conjugate, has been reported to exert potent antitumor effects and has recently shown promising efficacy against human epidermal growth factor receptor 2 (HER2)-positive adenocarcinoma. Despite its high efficacy, interstitial lung disease (ILD) is a severe adverse event (AE) associated with T-DXd. This report describes a patient who was successfully treated with a dose-reduced T-DXd challenge after recovery from ILD. Little disease progression was observed during the treatment interruption period; thus, the effect of T-DXd was considered to have been maintained. T-DXd may induce ILD, and re-administration under careful observation is considered an important option for treating patients with HER2-positive breast cancer.

A pooled analysis of trastuzumab deruxtecan in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer with brain metastases

This exploratory pooled analysis investigated the efficacy and safety of trastuzumab deruxtecan (T-DXd) versus comparator treatment in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) with brain metastases (BMs) at baseline, categorized according to previous local treatment. T-DXd data were pooled from DESTINY-Breast01/-02/-03. Comparator data, from patients receiving physician's choice therapy and trastuzumab emtansine, were pooled from DESTINY-Breast02 and -03, respectively. Baseline BM status was assessed according to US Food and Drug Administration criteria. The endpoints included intracranial objective response rate (ORR; complete or partial response in the brain) per blinded independent central review (BICR) by RECIST version 1.1, time to intracranial response, intracranial duration of response (DoR), central nervous system progression-free survival (CNS-PFS) by BICR, overall survival (OS), and safety. A total of 148 patients who received T-DXd and 83 patients who received comparator treatment had BMs at baseline. In those treated with T-DXd, the intracranial ORR of patients with treated/stable and untreated/active BMs was 45.2% and 45.5%, respectively. The median (range) time to intracranial response was 2.8 months (1.1-13.9 months) and 1.5 months (1.2-13.7 months) in patients with treated/stable and untreated/active BMs, respectively. For those with treated/stable BMs, the median intracranial DoR was 12.3 [95% confidence interval (CI) 9.1-17.9] months, and for those with untreated/active BMs, it was 17.5 months (95% CI 13.6-31.6 months). The median CNS-PFS and OS were 12.3 months (95% CI 11.1-13.8 months) and not reached (95% CI 22.1 months-not estimable) in those with treated/stable BMs, and 18.5 months (95% CI 13.6-23.3 months) and 30.2 months (95% CI 21.3 months-not estimable) in those with untreated/active BMs, respectively. Drug-related treatment-emergent adverse events grade ≥3 were experienced by 43.2% of patients with BMs and 46.4% without BMs with T-DXd. T-DXd demonstrated meaningful intracranial efficacy and clinical benefit in OS, with an acceptable and manageable safety profile in patients with HER2-positive mBC with treated/stable and untreated/active BMs.

Trastuzumab-Deruxtecan: Redefining HER2 as a Tumor Agnostic Biomarker.

Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) targeting HER2-positive malignancies across various tumor types. Through its unique composition, T-DXd achieves selective payload delivery, inducing cell death and halting tumor progression. Clinical trials initially investigated T-DXd's efficacy in HER2-positive advanced or metastatic breast, gastric, lung, and colorectal cancers; however, recent results from the DESTINY-PanTumor02 trial further underscore T-DXd's versatility, prompting T-DXd's US FDA approval for HER2-positive (immunohistochemistry [IHC] 3+) solid tumors. Moreover, in addition to T-DXd's efficacy against brain metastasis, T-DXd is showing promising results in HER2-low and HER2-ultra-low metastatic breast cancer, indicating a broader population of patients who may benefit.

438TiP Trastuzumab deruxtecan with pyrotinib in first-line HER2-positive unresectable or metastatic breast cancer: An exploratory, multi-center, single-arm, phase II study (TROPHY, trial in progress)

438TiP Trastuzumab deruxtecan with pyrotinib in first-line HER2-positive unresectable or metastatic breast cancer: An exploratory, multi-center, single-arm, phase II study (TROPHY, trial in progress)

378P Updated data on real-world efficacy and safety of inetetamab-based therapy in HER2-positive metastatic breast cancer patients with prior exposure to trastuzumab

378P Updated data on real-world efficacy and safety of inetetamab-based therapy in HER2-positive metastatic breast cancer patients with prior exposure to trastuzumab