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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 15 of 22

[120]
discontinuation rate due to toxic effects . Meanwhile, another study also demonstrated an overall survival
[121]
benefit with olaparib monotherapy in patients receiving olaparib as first-line therapy . Similar positive
results were reported by the EMBRACA trial, which investigated the efficacy of talazoparib, another PARP
inhibitor . Talazoparib provided a significant benefit over standard chemotherapy in terms of
[122]
progression-free survival (8.6 months vs. 5.6 months; P < 0.001) and patient-reported outcomes .
[122]
One of the selection criteria of the described studies was a proven germline mutation. However,
monotherapy with olaparib also showed positive effects in the presence of a somatic BRCA mutation in a
phase II trial by Tung et al. . The same study investigated the effect of olaparib in patients with metastatic
[124]
breast cancer and mutations in homologous recombination-related genes other than BRCA 1/2. However, it
confirmed an improvement in progression-free survival only in patients with germline “partner and
[124]
localizer of BRCA 2” (PALB2) mutation . These results may indicate that the population of breast cancer
patients who could benefit from PARP inhibition could be expanded through further studies.

A recently published, retrospective real-world study by Bruno et al. investigated the impact of an existing
germline pathogenic variant in a DNA repair-related gene on the therapeutic efficacy of a CDK4/6
[125]
inhibitor . Reported pathogenic variants were germline mutations in the BRCA 1/2, Ataxia Telangiectasia
Mutated, and Checkpoint kinase 2 genes . A proven germline mutation was associated with a shorter
[125]
median progression-free survival (10.2 months) compared with patients without these mutations
(15.6 months) or nontested patients (17.6 months) . The multivariable analysis revealed that mutation
[125]
status was an independent prognostic factor associated with shorter progression-free and overall survival in
patients receiving CDK4/6 inhibitors . This highlights the need for genetic testing to better select the
[125]
therapy strategy for specific patient populations.

Histone deacetylase inhibition - an example of an epigenetic approach
Unlike genetic mutations, epigenetic alterations are not due to mutations in the primary DNA sequence but
cause changes in gene expression. The role of epigenetics in tumor progression and the development of
endocrine resistance in HR-positive breast cancer is an emerging field of clinical investigation . There are
[126]
first promising approaches to reverse to effects of epigenetic alterations by epigenetic modifiers, such as
histone deacetylase (HDAC) inhibitors . Entinostat is an orally administered HDAC inhibitor currently
[127]
[128]
under investigation as it has shown potential antiproliferative activity in breast cancer cells . On the
pharmacological level, it functions by inhibiting the enzyme histone deacetylase, which is thought to play an
essential role in regulating gene expression through epigenetic modifications . HDAC inhibition leads to
[127]
the downregulation of estrogen-independent signaling pathways and causes a normalization of ER
levels [129,130] . Available data show controversial results regarding the impact of entinostat on survival
rates [127,131,132] . A phase II study investigated the influence of the addition of entinostat vs. placebo once a
week to the daily application of exemestane in postmenopausal women with HR-positive advanced breast
cancer who had tumor progression on a NSAI . The addition of entinostat improved median progression-
[133]
free survival to 4.3 months vs. 2.3 months with placebo (HR 0.73; one-sided P = 0.055; two-sided P = 0.11)
and median overall survival to 28.1 months vs. 19.8 months with placebo (HR 0.59; P = 0.036) . Entinostat
[133]
[133]
was generally well tolerated, with leading adverse events of grade 3 or 4 being fatigue and neutropenia . A
phase III trial with a Chinese patient cohort with advanced HR-positive breast cancer also reported a
[132]
positive impact of entinostat . Analysis of 354 enrolled patients showed an improved progression-free
survival of 6.32 months in the exemestane-entinostat-arm compared to 3.72 months in the exemestane-
[132]
placebo-arm (HR 0.74; P < 0.001) . Reported adverse events included neutropenia, thrombocytopenia,
and leucopenia, all of them significantly more often in patients treated with entinostat . In contrast,
[132]
another randomized phase III trial with similar inclusion criteria reported no improvement in progression-
free (3.3 vs. 3.1 months; HR 0.87; P = 0.03) or overall survival (23.4 vs. 21.7 months; HR 0.99; P = 0.94),