Tyrosine kinase inhibitors and human epidermal growth factor receptor-2 positive breast cancer

The body of evidence investigating human epidermal growth factor receptor-2(HER2)directed therapy in patients with breast cancer(BC)has been growing within the last decade.Recently,the use of tyrosine kinase inhibitors(TKIs)has been of particular interest in the treatment of human malignancies.This literature commentary is intended to highlight the most recent findings associated with the widely-studied TKI agents and their clinical significance in improving the outcomes of HER2 positive BC.

Efficacy and safety of first‐line regimens for advanced HER2‐positive breast cancer:A Bayesian network meta‐analysis

Background:The current standard of care for advanced human epidermal growth factor receptor 2(HER2)‐positive breast cancer is pertuzumab plus trastuzumab and docetaxel as first‐line therapy.However,with the development of newer treatment regimens,there is a lack of evidence regarding which is the optimal treatment strategy.The aim of this network meta‐analysis was to evaluate the efficacy and safety of first‐line regimens for advanced HER2‐positive breast cancer by indirect comparisons.Methods:A systematic review and Bayesian network meta‐analysis were conducted.The PubMed,EMBASE,and Cochrane Library databases were searched for relevant articles published through to December 2023.The hazard ratio(HR)and 95%credible interval(CrI)were used to compare progressionfree survival(PFS)between treatments,and the odds ratio and 95%CrI were used to compare the objective response rate(ORR)and safety.Results:Twenty randomized clinical trials that included 15 regimens and 7094 patients were analyzed.Compared with the traditional trastuzumab and docetaxel regimen,PFS was longer on the pyrotinib and trastuzumab plus docetaxel regimen(HR:0.41,95%CrI:0.22–0.75)and the pertuzumab and trastuzumab plus docetaxel regimen(HR:0.65,95%CrI:0.43–0.98).Consistent with the results for PFS,the ORR was better on the pyrotinib and trastuzumab plus docetaxel regimen and the pertuzumab and trastuzumab plus docetaxel regimen than on the traditional trastuzumab and docetaxel regimen.The surface under the cumulative ranking curve indicated that the pyrotinib and trastuzumab plus docetaxel regimen was most likely to rank first in achieving the best PFS and ORR.Comparable results were found for grade≥3 AE rates of≥10%.Conclusions:Our results suggest that the pyrotinib and trastuzumab plus docetaxel regimen is most likely to be the optimal first‐line therapy for patients with HER2‐positive breast cancer.

Pre-Operative MRI in HER-2 Receptor Positive and Her-2 Receptor Negative Breast Cancer: A Comparison

Objectives: MRI is the most sensitive modality for local staging of breast cancer. Herceptin receptor over-expression is seen in 15% - 30% of breast tumours, and is associated with increased aggression, poorer prognosis, higher grade at diagnosis and increased lymphatic dissemination. This study aimed at evaluating the role of MRI in Herceptin receptor positive vs negative tumours. Methods: 193 pre-operative MRIs were performed in 2021 for staging of 162 Her-2 negative and 37 Her-2 positive tumours. Recall rates and further biopsies (ipsilateral/contralateral) were assessed in both groups, and MRI largest size was compared to pathological size of invasive cancer and DCIS. Results: 36.4% of Her-2 negative tumours were recalled;further ipsilateral malignancy was identified in 13.6%. Contralateral malignancy was identified in 1.2%. 29.7% of Her-2 positive tumours were recalled;further ipsilateral malignancy was identified in 16.2%. No contralateral malignancy was seen in Her-2 positive tumours. The OR of Her-2 positive tumours having ipsilateral foci of malignancy on MRI is 0.83 (CI 0.3, 2.2). Pathological size concordance with MRI size was seen in 70.3% of Her-2 negative, and 48.6% of Her-2 positive tumours. Discordance in both groups was due to MRI size overestimation (70.8% of Her-2 negative discordance;89.4% of Her-2 positive discordance). Conclusions: Pre-operative MRI did not detect significant increased additional foci in Her-2 positive tumours. Significant concordance with pathological size was not seen in both groups;MRI overestimation was the most frequent cause for discordance in both groups. Advances in Knowledge: This study compares MRI features of Her-2 positive and Her-2 negative tumours. It demonstrates that there is no significant increased multifocality or multicentricity of Her-2 positive tumours, but MRI over-estimates size in 30% of Her-2 negative and 51% of Her-2 positive cancers.

Effects of postmastectomy radiotherapy on prognosis in different tumor stages of breast cancer patients with positive axillary lymph nodes

Objective: To explore the effects of postmastectomy radiotherapy(PMRT) on the locoregional failure-free survival(LRFFS) and overall survival(OS) of breast cancer patients under different tumor stages and with one to three positive axillary lymph nodes(ALNs). Methods: We conducted a retrospective review of 527 patients with one to three positive lymph nodes who underwent modified radical or partial mastectomy and axillary dissection from January 2000 to December 2002. The patients were divided into the T1-T2 N1 and T3-T4 N1 groups. The effects of PMRT on the LRFFS and OS of these two patient groups were analyzed using SPSS 19.0, Pearson's χ2-test, Kaplan-Meier method, and Cox proportional hazard model. Results: For T1-T2 N1 patients, no statistical significance was observed in the effects of PMRT on LRFFS [hazard ratio(HR)=0.726; 95% confidence interval(CI): 0.233-2.265; P=0.582] and OS(HR=0.914; 95% CI: 0.478-1.745; P=0.784) of the general patients. Extracapsular extension(ECE) and high histological grade were the risk factors for LRFFS and OS with statistical significance in multivariate analysis. Stratification analysis showed that PMRT statistically improved the clinical outcomes in high-risk patients [ECE(+), LRFFS: P=0.026, OS: P=0.007; histological grade III, LRFFS: P<0.001, OS: P=0.007] but not in low-risk patients [ECE(–), LRFFS: P=0.987, OS: P=0.502; histological grade I-II, LRFFS: P=0.816, OS: P=0.296]. For T3-T4 N1 patients, PMRT effectively improved the local control(HR=0.089; 95% CI: 0.210-0.378; P=0.001) of the general patients, whereas no statistical effect was observed on OS(HR=1.251; 95% CI: 0.597-2.622; P=0.552). Absence of estrogen receptors and progesterone receptors(ER/PR)(–) was an independent risk factor. Further stratification analysis indicated a statistical difference in LRFFS and OS between the high-risk patients with ER/PR(–) receiving PMRT and not receiving PMRT [ER/PR(–), LRFFS: P=0.046, OS: P=0.039]. However, PMRT had a beneficial effect on the reduction of locoregional recurrence(LRR) but not in total mortality [ER/PR(+), LRFFS: P<0.001, OS: P= 0.695] in T3-T4 N1 patients with ER/PR(+) who received endocrine therapy. Conclusion: PMRT could reduce ECE(+), histological grade III-related LRR, and total mortality of T1-T2 N1 patients. T3-T4 N1 patients with ER/PR(–) could benefit from PMRT by improving LRFFS and OS. However, PMRT could only reduce LRR but failed to improve OS for T3-T4 N1 patients with ER/PR(+) who received endocrine therapy.

Inetetamab combined with sirolimus and chemotherapy for the treatment of HER2‐positive metastatic breast cancer patients with abnormal activation of the PI3K/Akt/mTOR pathway after trastuzumab treatment

Background:We explored the efficacy and safety of inetetamab combined with sirolimus and chemotherapy for the treatment of human epidermal factor receptor 2(HER2)‐positive metastatic breast cancer patients with abnormal activation of the PI3K/Akt/mTOR(PAM)pathway after trastuzumab treatment.Methods:For this prospective multicenter clinical study,HER2‐positive metastatic breast cancer patients with PAM pathway mutations confirmed by histology or peripheral blood genetic testing were enrolled from July 2021 to September 2022.Patients were randomly assigned to a trial or control group.The patients in the trial group received inetetamab combined with sirolimus and chemotherapy,while the control group patients received pyrotinib and chemotherapy.The RECIST v1.1 standard was used to evaluate efficacy.Descriptive statistics were used to summarize the clinicopathological features,and the Kaplan–Meier method was used to generate survival curves.The log‐rank test was used to compare progression‐free survival(PFS)between the two groups.Results:A total of 59 HER2‐positive metastatic breast cancer patients with abnormal activation of the PAM pathway were included,of which 37 received inetetamab combined with sirolimus and chemotherapy treatment and 22 received pyrotinib and chemotherapy treatment.The median PFS was 4.64 months in the inetetamab group and 5.69 months in the pyrotinib group,with no statistically significant difference(p=0.507).The objective response rates were 27.3%for the inetetamab group and 29.4%for the pyrotinib group.The safety assessment indicated that the adverse event(AE)incidences were 86.1%(31/36)in the inetetamab group and 78.9(15/19)in the pyrotinib group,with 9(25%)and four(21.1%)Grade 3/4 AEs in the inetetamab and pyrotinib groups,respectively.Conclusions:For metastatic HER2‐positive breast cancer patients with abnormal PAM pathway activation and previous trastuzumab treatment,the combination of inetetamab with sirolimus and chemotherapy is equivalent to the combination of pyrotinib and chemotherapy.Therefore,this regimen could be a treatment option for PAM pathway‐activated metastatic HER2‐positive breast cancer patients.

HER-2/EGFR, the major targets for anti-metastasis effect of tetraarsenic oxide on SKBR3 breast cancer cells

Breast cancer is one of the most common female malignant tumors in the world. Although many therapeutic methods for HER-2 positive breast cancer have been developed, the drug resistance and distant metastasis still remain. Tetraarsenic oxide（As_4O_6） has been demonstrated with an anticancer effect on squamous cell carcinoma and cervical cancer. However, there is no report about the relationship between As_4O_6 and HER-2 positive breast cancer. In the present study, we detected the inhibitory efficacy and mechanism of As_4O_6 on the migration and invasion of SKBR3 breast cancer cells using molecular biological methods. The wound-healing assay, matrigel migration assay, transwell invasion assay and cell adhesion assay were used to assess the migration, invasion and adhesion of SKBR3 cells intervened by As_4O_6. Meanwhile, the reverse transcription-PCR and western blotting were performed to investigate the mechanism of As_4O_6 on the migration and invasion of SKBR3 breast cancer cells. The results demonstrated that As_4O_6 could efficiently inhibit the migration and invasion of SKBR3 cells, the HER-2 positive breast cancer cells, and the adhesion of SKBR3 cells was decreased after As_4O_6 treatment. The mechanism revealed that As_4O_6 anticancer efficacy was related to HER-2/EGFR pathways. As_4O_6 exerted its inhibitory effects on migration and invasion in HER-2 positive breast cancer cells by regulating the factors（EGFR, HER-2, Akt, MMP-9） in HER2/ EGFR signaling pathway and other key molecules. In conclusion, the present study indicated that As_4O_6 inhibited the invasion and migration process of HER-2 positive breast cancer SKBR3 cells by negatively regulating the HER-2/EGFR-mediated signaling pathway. These data provided evidence that As_4O_6 might serve as potential anti-metastasis drug for clinical treatment of breast cancer.

Anti-HER-2 therapy following severe trastuzumab-induced cardiac toxicity

The human epidermal growth factor receptor 2(HER2)is overexpressed in 25%e30%of breast cancer patients.Anti-HER2 therapies have changed the aggressive course of HER2t breast cancer.In spite of the therapeutic benefits,their cardiotoxicities are major concerns,especially when used concurrently with anthracyclines.Here we present an elderly patient with relapsed HER2t breast cancer.Her presentation for relapsed disease was unusual for the physical finding as well as the history of trastuzumabinduced severe cardiotoxicity while requiring additional anti-HER2 therapy.She received neoadjuvant anti-HER2 treatment for stage III breast caner.Due to severe reduction of cardiac ejection fraction(EF),she only received five doses of adjuvant transtuzumab.Unfortunately her disease relapsed one year later with chest wall lesions and a persistent low EF.We treated the patient with lapatinib combined with capecitabine which resulted rapid resolution of her chest wall lesion.More importantly,the patient had one year of disease control without deterioration in her ejection fraction.We discussed the management of recurrent HER2t breast cancer with chest wall disease and the choice of anti-HER2 therapy in patients with a history of transtuzumab-induced cardiac dysfunction.