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The Synergistic Effects of SHR6390 Combined With Pyrotinib on HER2+/HR+ Breast Cancer.

ABSTRACT: HER2+/HR+ breast cancer is a special molecular type of breast cancer. Existing treatment methods are prone to resistance; "precision treatment" is necessary. Pyrotinib is a pan-her kinase inhibitor that can be used in HER2-positive tumors, while SHR6390 is a CDK4/6 inhibitor that can inhibit ER+ breast cancer cell cycle progression and cancer cell proliferation. In cancer cells, HER2 and CDK4/6 signaling pathways could be nonredundant; co-inhibition of both pathways by combination of SHR6390 and pyrotinib may have synergistic anticancer activity on HER2+/HR+ breast cancer. In this study, we determined the synergy of the two-drug combination and underlying molecular mechanisms. We showed that the combination of SHR6390 and pyrotinib synergistically inhibited the proliferation, migration, and invasion of HER2+/HR+ breast cancer cells in vitro. The combination of two drugs induced G1/S phase arrest and apoptosis in HER2+/HR+ breast cancer cell lines. The combination of two drugs prolonged the time to tumor recurrence in the xenograft model system. By second-generation RNA sequencing technology and enrichment analysis of the pyrotinib-resistant cell line, we found that FOXM1 was associated with induced resistance to HER2-targeted therapy. In HER2+/HR+ breast cancer cell lines, the combination of the two drugs could further reduce FOXM1 phosphorylation, thereby enhancing the antitumor effect to a certain extent. These findings suggest that SHR6390 combination with pyrotinib suppresses the proliferation, migration, and invasion of HER2+/HR+ breast cancers through regulation of FOXM1.

SUBMITTER: Wang Y

PROVIDER: S-EPMC8716872 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionPyrotinib plus capecitabine has been approved in China for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). Meanwhile, vinorelbine is another important chemotherapy option for MBC available in oral and intravenous forms. Thus, pyrotinib plus vinorelbine may represent a new treatment option, particularly for patients with failed capecitabine treatment. This study reported the first real-world data for pyrotinib plus vinorelbine therapy in HER2+ MBC.MethodsHER2+ MBC patients (n = 97) treated with pyrotinib plus vinorelbine in six institutions across China from May 2018 to June 2020 were enrolled. Progression-free survival (PFS), objective response rate (ORR), overall survival (OS), and toxicity profiles were determined.ResultsSixty-seven percent of patients received more than two lines of systematic therapy. Nearly all patients (97.9%) had received trastuzumab and 50.5% were administered lapatinib. When combined with pyrotinib, 74.2% received oral and 25.8% received intravenous vinorelbine. Median PFS (mPFS) was 7.8 (range, 4.7-10.8) months for all patients. The mPFS in patients administered pyrotinib as second-line therapy and third-or-higher-line therapy were 12.0 and 6.4 months, respectively. Patients who received pyrotinib plus oral or intravenous vinorelbine had similar mPFS (7.8 vs. 6.4 months, p = 0.871). The 23 patients with brain metastases had mPFS of 6.3 (range, 3.4-9.2) months. Lapatinib-naïve patients had significantly longer PFS than lapatinib-treated patients (10.8 months vs. 5.6 months, p = 0.020). Median OS was not achieved. The ORR for 96 patients was 34.3%. Common grade 3 and 4 adverse events were diarrhea (22.7%), neutropenia (7.2%), and leukopenia (4.1%).ConclusionsPyrotinib plus vinorelbine therapy demonstrated promising effects in HER2+ MBC with tolerable toxicity, particularly in patients with second-line treatment and without prior lapatinib treatment, as well as in patients with brain metastases. Oral vinorelbine is a useful alternative to the intravenous form when combined with pyrotinib.Clinical trial registration[ClinicalTrials.gov], identifier [NCT04517305].

Project description:BACKGROUND:Patients with breast cancer experience a variety of disease symptoms and treatment-related side effects that can adversely affect functioning. The breast cancer experience may differ across disease stages and biomarker subtypes. This study identified relevant disease symptoms, treatment-related side effects, and physical functioning impacts in women with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. METHODS:One-on-one concept elicitation interviews were conducted with 15 patients with HR+/HER2- advanced breast cancer. Open-ended questions about patient experience with breast cancer and its treatment were drawn from a semi-structured interview guide. All interviews were audio-recorded and transcribed verbatim, and codes were used to document and organize patient descriptions of their experiences. Coded concepts were defined, supported by exemplary patient quotes, and analyzed for frequency of mention and saturation. Five interviews with experienced oncologists were conducted to supplement the concept elicitation interviews. RESULTS:The average age of the patients was 66?years. Most (53%) self-identified as White/Caucasian; 40%, as Black/African American. Patients were reported to have metastases to bone (87%), liver (20%), lung (13%), skin (7%), and lymph nodes (7%). The most frequently reported disease-related concepts were fatigue and lump in breast (47% each) and pain (40%), while the most frequently reported treatment-related side effects were hair loss (67%), fatigue/tiredness (47%), and nausea (40%). Patients identified 10 concepts associated with both breast cancer and its treatment, including fatigue/tiredness, shortness of breath, weakness, and nausea. The most frequently reported impacts on physical function included working around home (73%), walking (73%), and cooking (53%). The most frequently reported symptoms and side effects from the expert perspective included fatigue, pain, and hot flashes (n?=?5 each, 100%), while the ability to work (n?=?5, 100%) and walk (n?=?3, 60%) were reported impacts, aligning with those concepts reported by patients. The resulting concepts were organized into a patient-based conceptual model. CONCLUSIONS:Patients have varied experiences due to HR+/HER2- advanced breast cancer and its treatment, and commonly experience fatigue/tiredness, hair loss, general pain, lump in breast, and nausea, as well as impacts to physical functioning (specifically, activities of daily living and mobility).

Project description:At present, local therapy, such as surgery and radiotherapy, is the mainstay treatment for brain metastasis and anti-human epidermal growth factor receptor type 2 (HER2)-targeted therapy has been shown to be efficacious for HER2+ breast cancer (BC) patients with brain metastasis. However, Clinical studies comparing the combined effects of the two treatments are lacking. This study sought to investigate the efficacy and safety of pyrotinib and radiotherapy versus pyrotinib-based therapy in treating HER2+ BC patients with brain metastasis. This retrospective, observational study collected data from 79 HER2+ BC patients with brain metastasis who received pyrotinib-based therapy from May 2018 to December 2021. Among these patients, 35 received pyrotinib-based therapy concurrently with, or within 3 months before or after, brain radiotherapy (Group A), and 44 received pyrotinib-based therapy as the primary regimen (with no restriction as to whether they had received brain radiotherapy previously or not, the interval between receiving radiotherapy and receiving pyrotinib was >3 months) (Group B). Patient information was collected by the Electronic Medical Records System. The primary endpoints were progression-free survival (PFS) and overall survival (OS). The secondary endpoints were the objective response rate (ORR), the clinical benefit rate (CBR), and safety. The assessment of adverse effects was based on CTCAE5.0. The intracranial ORRs were 48.6% in Group A and 20.5% (9/44) in Group B (P=0.015). The intracranial CBRs were 80.0% in Group A and 65.9% in Group B. The median intracranial PFS times (IC-PFS) were 15.0 months and 9.0 months in Group A and Group B, respectively (P=0.385). There was no statistically significant difference in OS between the 2 groups (95.0 vs. 98.0 months, P=0.872). The subgroup analysis showed that patients with active brain metastasis who received pyrotinib and radiotherapy had a longer IC-PFS time than those who received pyrotinib-based therapy(P=0.056). No serious adverse reactions (e.g., acute brain edema, cognitive dysfunction, or treatment-related death events) were observed. Pyrotinib combined with radiotherapy is recommended for HER2+ breast cancer active brain metastasis patients who can tolerate radiotherapy and pyrotinib. Pyrotinib-based therapy may be considered for patients who cannot tolerate radiotherapy and pyrotinib.

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The Synergistic Effects of SHR6390 Combined With Pyrotinib on HER2+/HR+ Breast Cancer.

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