Current status of PI3K-mTOR inhibition in hormone-receptor positive, HER2-negative breast cancer

Breast cancer (BC) is the most common cancer in women and second only to lung cancer in terms of mortality. Among the three different BC subtypes, the oestrogen receptor positive represents nearly 70% of all cases and it is usually treated with anti-oestrogen drugs. However, the majority of hormone receptor positive metastatic BC patients develop resistance to anti-oestrogen treatments.The need for more down-stream therapies brought to the development of therapeutic strategies inhibiting the phosphatidylinositol 3-kinase-mammalian target of rapamycin (mTOR) pathway. Inhibitors of the mTOR have been tested in different clinical trials; everolimus has been Food and Drug Administration approved for the treatment of oestrogen receptor positive/human epidermal growth factor receptor 2 negative BC patients in combination with exemestane in patients who have progressed to anastrozole or letrozole after the encouraging results coming from BOLERO-2 trial. Similar results were obtained by the TAMRAD investigatory study testing tamoxifen in combination with everolimus in advanced BC. This editorial focuses on the results from BOLERO-2, BOLERO 4 and BOLERO-6, which tested the clinical importance of mTOR inhibition. We comment also on the role of phosphatidylinositol 3-kinase-mTOR inhibition as reported in the BELLE-2 and BELLE-3 trials and the future directions for the inhibition of this tumour metabolic axis.

Navigating breast cancer brain metastasis:Risk factors,prognostic indicators,and treatment perspectives

In this editorial,we comment on the article by Chen et al.We specifically focus on the risk factors,prognostic factors,and management of brain metastasis(BM)in breast cancer(BC).BC is the second most common cancer to have BM after lung cancer.Independent risk factors for BM in BC are:HER-2 positive BC,triplenegative BC,and germline BRCA mutation.Other factors associated with BM are lung metastasis,age less than 40 years,and African and American ancestry.Even though risk factors associated with BM in BC are elucidated,there is a lack of data on predictive models for BM in BC.Few studies have been made to formulate predictive models or nomograms to address this issue,where age,grade of tumor,HER-2 receptor status,and number of metastatic sites(1 vs>1)were predictive of BM in metastatic BC.However,none have been used in clinical practice.National Comprehensive Cancer Network recommends screening of BM in advanced BC only when the patient is symptomatic or suspicious of central nervous system symptoms;routine screening for BM in BC is not recommended in the guidelines.BM decreases the quality of life and will have a significant psychological impact.Further studies are required for designing validated nomograms or predictive models for BM in BC;these models can be used in the future to develop treatment approaches to prevent BM,which improves the quality of life and overall survival.

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.

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.

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.