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Page 10 of 22 Droste et al. J Cancer Metastasis Treat 2023;9:2 https://dx.doi.org/10.20517/2394-4722.2022.94

PI3K/AKT/mTOR pathway [37,69] . This pathway plays an essential role in developing endocrine resistances by
stabilizing the CDK4/6 complex and reversing the effect of CDK4/6 inhibition [5,69,70] . Several interactions
[69]
exist between the PI3K/AKT/mTOR pathway and the ER pathway . Some of the interactions and
therapeutic targets are shown in Figure 2. Targeting the PI3K/AKT/mTOR pathway is a promising
approach to overcoming endocrine resistance and has been investigated by numerous studies, some of
[69]
which have already shown a significant impact on survival rates . Some selected studies are reviewed in
more detail below.

mTOR inhibition
The most clinically relevant substance targeting the PI3K/AKT/mTOR pathway is everolimus, an mTOR
complex 1 (mTORC1) inhibitor. The combination of everolimus and exemestane was used in clinical
practice before CDK4/6 inhibitors emerged and remaines a mainstay in treating HR-positive breast
cancer [71-76] . In the phase III BOLERO-2 trial, exemestane plus everolimus was compared to exemestane plus
placebo in patients with HR-positive advanced breast cancer who had recurrence or progression during
prior therapy with a NSAI . The addition of everolimus to exemestane resulted in a clinically significant
[71]
improvement in progression-free survival in the overall population and all subgroup analyses, including
patients with visceral metastases [71-73] . In terms of median overall survival, the addition of everolimus did not
result in statistically significant improvement (31.0 months for everolimus plus exemestane vs. 26.6 months
[74]
for placebo plus exemestane; HR 0.89; log-rank P = 0.14) . The most common grade 3 and 4 adverse events
were stomatitis, anemia, hyperglycemia, fatigue, and pneumonitis, which occurred more frequently with
everolimus than with placebo .
[71]
For confirmation, Im et al. initiated the EVEREXES trial involving 235 patients, including 199 from Asia .
[75]
The study investigated the efficacy of everolimus in combination with exemestane in postmenopausal
women with HR-positive, HER2-negative advanced breast cancer previously treated with a NSAI . Median
[75]
progression-free survival in the Asian subgroup was similar to the survival in the overall population
(9.3 months in both groups), with an overall response rate of 19.6% . The reported data were consistent
[75]
with previously published results of the BOLERO-2 trial, and no new safety signals were identified [72,75] . As
CDK4/6 inhibitors had not been used when the study was conducted, subsequent studies have now
examined the use of everolimus plus exemestane in patients previously treated with a CDK4/6 inhibitor.

Mo et al. reported a smaller progression-free survival benefit from treatment with everolimus plus
exemestane in patients previously treated with a CDK4/6 inhibitor compared to patients who were not
[77]
(3.8 months vs. 5.4 months) . There was no significant difference in overall survival between the two
groups . In contrast, Cook et al. showed no influence of prior treatment with a CDK4/6 inhibitor on
[77]
progression-free survival for patients treated with everolimus plus exemestane compared to patients without
prior exposure (3.6 months vs. 4.2 months) . In addition, they reported a numerical improvement in
[78]
overall survival (15.6 months vs. 11.3 months) for patients previously treated with a CDK4/6 inhibitor .
[78]
The discussion of the efficacy of everolimus plus exemestane after treatment with a CDK4/6 inhibitor is
accompanied by the discussion of the optimal treatment sequence. Jeong et al. investigated the efficacy and
clinical outcome in dependence on the treatment sequence of everolimus and CDK4/6 inhibitors in a
retrospective analysis . The sequence of CDK4/6 inhibition plus endocrine therapy followed by everolimus
[79]
plus exemestane was associated with a non-significant but numerical benefit in median progression-free
and overall survival compared with the study arm that received everolimus plus exemestane followed by a
CDK4/6 inhibitor plus endocrine therapy . Considering tumor response rates, time to initiation of
[79]
chemotherapy, and rates of treatment discontinuation, the study results showed a trend in favor of the
sequence of CDK4/6 inhibition plus endocrine therapy, followed by everolimus plus exemestane . In
[79]