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positive signals are sufficient to conclude that a subset of patients benefits from retreatment with a CDK4/6
inhibitor.

Estrogen receptor 1 mutation
In HR-positive breast cancer, a central mechanism of acquired endocrine resistance, particularly to
aromatase inhibitors, is a mutation in the drug target itself, such as a gain-of-function mutation in the
ligand-binding domain of ESR1 [41,42] . ESR1 mutations lead to ligand-independent estrogen receptor (ER)
activity, promoting tumor growth and resistance to endocrine therapy . The prevalence of ESR1 mutations
[43]
depends on the prior duration of endocrine therapy and is detectable in 20%-40% of patients who have
received an AI for metastatic breast cancer [42,44] .

Interestingly, the mutation rate is much lower in the case of recurrent breast cancer and is less than 1% in
endocrine therapy-naive patients, suggesting that ESR1 mutations are acquired mutations during AI
[42]
treatment in the metastatic setting . ESR1 mutations result in estrogen-independent activation of estrogen
receptors and lead to resistance to AIs but not SERDs or SERMs [44-47] . ESR1 mutations usually occur with
[42]
several other genomic alterations and are only partially responsible for the resistance developed .
Nevertheless, molecular testing can be helpful in case of cancer progression during endocrine therapy to
predict resistance to AI therapy in the future.

There are several ways to detect ESR1 mutations. One is the non-invasive detection of circulating tumor
DNA (ctDNA) in the patient’s plasma [48-50] . Analysis of the SoFEA trial showed that patients with ESR1
mutations had significantly better progression-free survival with fulvestrant than exemestane (HR 0.52;
P = 0.02), whereas patients without ESR1 mutation had similar survival rates after receiving either treatment
[46]
(HR 1.07; P = 0.77) . Concordant results were reported by a subgroup analysis of the PALOMA-3 trial [46,51] .
ESR1 mutations were found in the serum of approximately 25% of patients; however, the survival benefit
achieved by adding palbociclib to fulvestrant compared to placebo plus fulvestrant was independent of ESR1
[46]
mutation status .
There is preliminary evidence that ESR1 mutation status helps select further treatment options and monitor
ongoing endocrine therapies. The PADA-1 trial was designed to demonstrate the efficacy of periodic
monitoring of patients treated with palbociclib plus AI for emerging or rising ESR1 mutations in ctDNA to
initiate an early treatment change to palbociclib plus fulvestrant, even before evidence of disease progression
[52]
is apparent . In the first step, 1017 patients were enrolled and treated with palbociclib plus an AI. After a
median of 15.6 months, 172 patients with rising ESR1 mutations were randomized to continue therapy or to
switch the therapy regime to palbociclib plus fulvestrant . Preliminary data showed that the median
[53]
progression-free survival in the palbociclib-AI-arm was 5.7 months vs. 11.9 months in the cohort that
[53]
switched the treatment regime to fulvestrant plus palbociclib . A preliminary analysis of safety outcomes
confirmed the favorable safety profile of palbociclib in combination with any AI with or without a switch to
[54]
fulvestrant . Suppose these findings are confirmed in the final analysis and further studies. In that case,
ESR1 mutation analysis will have clinical implications as an emerging biomarker for endocrine therapy
decision-making in the future or could be used for early modification of therapy regimes to avoid
[52]
expectable tumor progression even before it becomes apparent .

Oral selective ER degraders
Fulvestrant is a SERD that treats advanced HR-positive breast cancer; however, the application is limited to
intramuscular injection. Fulvestrant antagonizes estrogen receptor alpha (ERα) and induces its degradation
by binding the ligand-binding pocket [55,56] . Mutations in the ligand-binding-domain of ESR1 are responsible
for resistance to AIs and reduce the potency of fulvestrant [43,57] . Efforts are currently underway to identify