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Droste et al. J Cancer Metastasis Treat 2023;9:2 https://dx.doi.org/10.20517/2394-4722.2022.94 Page 11 of 22

[69]
Figure 2. Targeting the PI3K/AKT/mTOR pathway; Modified from Du Rusquec et al., 2020 . E: Estrogen; ER: estrogen receptor; GFR:
growth factor receptor; PI3K: phosphatidylinositol-3 kinase; PI3Ki: phosphatidylinositol-3 kinase inhibitor; AKT: protein kinase B; AKTi:
AKT kinase inhibitor; PTEN: phosphatase and tensin homolog; mTORC1/2: mammalian target of rapamycin complex 1/2; mTORC1/2i:
mammalian target of rapamycin complex 1/2 inhibitor.

conclusion, the authors suggested considering CDK4/6 inhibitor-based treatment regimes as an earlier
[79]
treatment line as survival rates tend to favor the sequence of CDK4/6 inhibitor followed by everolimus .
Nevertheless, the results showed that subsequent therapy with everolimus plus exemestane after disease
progression on a CDK4/6 inhibitor is justifiable, even if the additional benefit on survival rates is moderate.

There have been approaches with other mTOR inhibitors. Temsirolimus is an mTOR inhibitor that is
selective for mTORC1. The HORIZON trial was designed to evaluate the clinical outcome and safety of
adding temsirolimus to letrozole in AI-naive patients . The study included 1112 postmenopausal patients
[80]
with AI-naive, HR-positive advanced breast cancer . Data analysis showed no improvement in
[80]
progression-free survival in the temsirolimus-letrozole group compared to adding a placebo to letrozole .
[80]
On the other hand, significantly more adverse events, such as hyperglycemia, diarrhea, and stomatitis, were
reported with temsirolimus . Based on these results, it was speculated that the lack of improvement in
[80]
survival was due to cancer cells in the metastatic setting not being exposed to endocrine therapy earlier. The
cancer cells might not have depended on the PI3K/mTOR pathway and were thus insensitive to mTOR
[81]
inhibition .
Another approach was taken with sapanisertib, a selective mTOR inhibitor with dual specificity against
mTORC1 and mTOR complex 2 [82,83] . Preclinical studies supported the theory that dual inhibition of both
protein complexes might significantly suppress cancer cell proliferation [84,85] . Based on this assumption,
García-Sáenz et al. hypothesized that dual inhibition with sapanisertib may restore the sensitivity of the
cancer cell to endocrine therapies in patients with HR-positive breast cancer . The phase II trial compared
[86]
the daily or weekly application of sapanisertib plus fulvestrant with fulvestrant alone in postmenopausal
women whose tumors had progressed during therapy with an AI . Median progression-free survival was
[86]
numerically longer in patients treated with sapanisertib plus fulvestrant (daily use: 7.2 months; weekly use:
5.6 months) than with fulvestrant alone (3.5 months), with the most significant improvement in patients
who had previously received a CDK4/6 inhibitor . However, there was no statistical significance for daily
[86]
or weekly application, and the rates of reported adverse events were higher in either arm of combination
therapy (32% and 36%) compared with fulvestrant alone (4%) . Based on these results, the authors did not
[86]