Many cancers are associated with a signaling pathway called “PI3K/Akt/mTOR” in tumor cells. Under normal circumstances, PI3K can be controlled by the “oncogene PTEN”, which prevents these signaling pathways from functioning.
When the PTEN gene is inactivated for various reasons, its inhibitory effect on PI3K is lost, and the signaling pathway is activated, thus altering the cell cycle and apoptosis, leading to a much higher likelihood of tumor development.
The PI3K inhibitor Buparlisib codenamed BKM120, has been shown in some early studies to exhibit some therapeutic activity against a variety of advanced solid tumors, including breast cancer.
For hormone receptor-positive breast cancer, endocrine therapy is an important tool, yet drug resistance is inevitable as the disease reaches advanced stages.
Theoretical basis of PI3K inhibitor mechanism
Buparlisib is a PI3K inhibitor that acts through the “PI3K/Akt/mTOR signaling pathway.
In breast cancer, the PI3K/Akt/mTOR signaling pathway is abnormally activated in up to 70% of cases. Theoretically, PI3K inhibitors may be able to control breast cancer.
Coping with endocrine therapy resistance and also being alert to adverse effects
BELLE-2 is a phase III clinical study that enrolled 1147 menopausal patients with hormone receptor-positive, HER2-negative breast cancer who were in advanced stages and resistant to conventional endocrine therapy.
Adding Buparlisib to fulvestrant extended patients’ median progression-free survival by 1.9 months (from 5.0 months to 6.9 months), and the risk of tumor progression was reduced by 22%.
In the 372 patients with abnormal PI3K pathway activation, combination therapy extended the survival benefit further, with an extension of progression-free survival by 2.8 months (from 4.0 months to 6.8 months).
This study also exposed Buparlisib s toxicity issues, with a high incidence of moderate adverse reactions in patients, such as elevated transaminases in about 1 in 4 and a 15% incidence of hyperglycemia.
What if even mTOR inhibitors are ineffective in the endocrine treatment of advanced breast cancer?The BELLE-3 study further answered this question by enrolling 432 patients who failed treatment with endocrine drugs combined with mTOR inhibitors.
Adding Buparlisib to fulvestrant prolonged median progression-free survival by 2.1 months (from 1.8 months to 3.9 months) and reduced the risk of tumor progression by 33% in this group of breast cancer patients. However, side effects should not be ignored as well.
From the BELLE-3 results, PI3K inhibitor combined with endocrine therapy is not applicable to all patients with advanced disease. If accompanied by a PIK3CA mutation, then the survival benefit for patients may be greater.
More to explore
Buparlisib in combination with chemotherapy for metastatic breast cancer is an ongoing study, and triple-negative breast cancer is also a pending breakthrough. It is worth looking forward to the fact that Buparlisib has been tried in solid tumors such as advanced breast cancer in China. We will see what the efficacy and safety profile will be.
Summary
For hormone receptor-positive, HER2 -negative advanced breast cancer that is resistant to endocrine therapy, Buparlisib helps fight drug resistance and control tumor progression.
The available evidence suggests that Buparlisib treatment may bring about adverse effects such as elevated transaminases, hyperglycemia, nausea, fatigue, diarrhea, rash, mood abnormalities, and drug toxicity that cannot be ignored. In the future, if it is to go into the clinic, physicians should balance the pros and cons of using the drug.