Keywords
cyclin-dependent kinase inhibitor proteins - tumor agnostic therapy - squamous cell
carcinoma of head and neck - palbociclib - medical oncology
Introduction
Tumor cells have various molecular characteristics, which, due to their abundance,
end up hindering the effectiveness of traditional cancer treatments, whose approach,
in most cases, is tissue-based rather than molecular. From the moment it became possible
to know the molecular alterations of the cells, and to carry out genetic sequencing
of the tumor, more specific treatments were created, the so-called tumor-agnostic
treatments, aimed at this cellular information, and not dependent on the type of tissue
the cell is part of. Thus, it is necessary to monitor the progression of the tumors
and its molecular alterations throughout treatment, since it ends up being highly
selective to certain specific molecular alterations, so the drugs used in this type
of treatment are active against different subtypes of oncogene-dependent cancers.[1]
[2]
[3]
[4]
[5]
[6]
In head and neck squamous cell carcinoma, there is usually activation of the epidermal
growth factor receptor (EGFR). In human papillomavirus (HPV)-negative head and neck
squamous cell carcinoma (HNSCCs) cases, which show a better response to cyclin inhibitors,
the development pattern is usually based on inactivation of p16INK4A and overexpression
of cyclin D1, resulting in hyperactivation of cyclin-dependent kinase 4 and 6 (CDK4/6).
This is because the loss of p16 functionality allows CDK4/6 to complex with cyclin
D and then phosphorylate and inactivate Rb, releasing E2F and progressing to the G1
phase, after the first checkpoint, and advancing to the S phase of the cell cycle.
Thus, loss of checkpoint regulation leads to uncontrolled cell proliferation, allowing
cancer cells to multiply exacerbatedly.[7]
[8]
[9]
[10]
[11]
[12]
[13]
Increased expression of cyclin or CDKs or decreased levels of endogenous CDK inhibitors,
such as INK4 or CIP/KIP, is found in many cancers, while mutations in genes encoding
CDKs that cause cancer are rare. In this way, CDKs end up becoming targets for cancer
therapies.[14]
[15]
Dual CDK4/6 inhibitors have shown significant efficacy in preclinical and clinical
cancer therapies, especially in breast cancer, as single agents or combined with hormonal
treatments, chemotherapy, radiotherapy, or immunotherapy. It is, therefore, considered
necessary to review the action of these drugs on the cell cycle of cancer cells, to
provide us with therapeutic possibilities[14]
[15]
Although CDK4/6 inhibition results in a decrease in cell multiplication and leads
to an interruption of the cell cycle, it is likely that cell senescence or senescence-like
activity is a crucial mechanism associated with the clinical efficacy of this medication.
Cellular senescence is the phenomenon in which a cell experiences a permanent and
irreversible interruption of its growth in response to cellular stresses, such as
unrepaired DNA damage, which renders it resistant to mitogenic stimulation and oncogenic
challenges.[8]
An example of a CDK4/6 inhibitor is palbociclib, which is currently approved by the
Food and Drug Administration (FDA) only for the treatment of breast cancer, but has
been the subject of several clinical trials in other types of cancer, including head
and neck squamous cell carcinoma.[14]
[16] Palbociclib is a highly effective and selective oral inhibitor of the cyclin-dependent
kinase CDK4/6, with robust preclinical data supporting its effectiveness in tumors
that show retinoblastoma protein expression.[17]
This inhibitor acts on cells in such a way as to decrease phosphorylated Rb, and consequently
restore the function of p16, bringing back the effectiveness of the first G1 checkpoint,
causing cell replication to occur only in healthy cells, and preventing the exacerbated
multiplication of mutant cancer cells. In other words, this drug inhibits the progression
from G1 to S in defective cells, leaving them in what is known as a senescent state,
which allows these cells to respond more effectively to conventional treatments.[8]
[12]
[13]
The present study aims to understand how the genetic composition of head and neck
squamous cell carcinoma cells is affected by CDK4/6 cyclin inhibitors, especially
palbociclib, to understand, based on a comparison between the cellular alterations
that trigger this cancer, how the aforementioned drug, currently used in HER-negative
breast cancers, has been responding in the therapy of cancers of other systems.
Materials and Methods
The current systematic review, conducted without a meta-analysis, is registered in
the International Prospective Register of Systematic Reviews (PROSPERO) under registration
number CRD42024539528.
Sources of Information
A systematic search was performed in the PubMed and LILACS databases from 2013 to
2024. In addition, clinical trial registries, including ClinicalTrials.gov, were searched.
The articles included were in Portuguese and English. In addition, the bibliography
of articles and reviews from the present study was manually selected for additional
study eligibility.
Eligibility Criteria
The study characteristics are expressed in the population, intervention, control group,
outcome format (PICO):
Population: Patients diagnosed with HPV-negative head and neck squamous cell carcinoma.
Intervention: To evaluate the effectiveness of palbociclib's response in head and
neck squamous cell carcinoma, taking into account the drug's effect on the tumor's
cell cycle.
Control: Cells with a regular cell cycle, without defects or overexpression of the
factors involved, and cells with alterations in the factors involved resulting in
head and neck squamous cell carcinoma.
Outcome: To understand how palbociclib acts, and how it can help in the regression
of head and neck squamous cell carcinoma.
In addition, only articles that met the inclusion criteria and did not include the
exclusion criteria were eligible.
Inclusion criteria: Articles in Portuguese or English with the keywords squamous cell carcinoma of the head and neck, palbociclib/palbociclib, CDK4/6
inhibitors, or tumor-agnostic/tumor agnostic in their title or abstract.
Exclusion criteria: Articles outside the periodicity of 2013 to 2024, or that present
studies on HPV-positive head and neck squamous cell carcinoma, or that bring any drug
association other than palbociclib associated with cetuximab.
Data Collection Process
A total of 37 articles of interest to the research were obtained from the LILACS and
PubMed databases. During screening, 24 articles were obtained, 13 of which were excluded
due to duplication between the databases. All texts were actively searched and reviewed
by two reviewers. If there was no agreement, the conflict was resolved by discussion
and consensus. In the event of disagreement over the inclusion of a citation, the
article was independently assessed and revised by another reviewer. If disagreement
persisted, a fourth reviewer decided whether or not to include the article. The article
selection process is outlined in [Fig. 1], describing the reasons that led to the exclusion of some of the articles.
Fig. 1 Flowchart of the systematic review process.
As for the eligibility criteria, 14 articles were excluded due to incompatible study
design, 4 were excluded due to incompatible population, and in 4, the study medication
was not compatible. Of the remaining 4 articles, 2 were included for study analysis,
and the other 2 were excluded due to incompatible drug combinations.
Risk of Bias between Studies
The methodological quality of the study was assessed using the Joanna Briggs Institute
(JBI) tool, so that the two studies included in this article underwent a thorough
assessment, following the criteria instructed by the tool in question. They were then
placed in the Risk-Of-Bias VISualization (Robvis) system, thus generating [Fig. 2], which shows results related to:
Fig. 2 Bias risk analysis using the Risk-Of-Bias VISualization (robvis) platform.
Bias due to the randomization process, which presented a low risk of bias in both
articles.
Bias due to deviations from the intended interventions, which showed high bias in
both studies, since the deviations were not very well elucidated in the studies, which
could lead to an ambiguous interpretation of the results.
Bias due to lack of outcome data was low in the study by Adkins et al (2019) and worrying
in the study by Michel et al (2016), since the latter did not provide results for
the partial response criterion.
Finally, measurement and selection bias were low in both studies, leading to an overall
study bias considered to be low.
For both studies, palbociclib was administered at a dose of 125 mg/day orally, taken
on days 1 to 21 of each 28-day cycle. Cetuximab was administered at a dose of 400 mg/m2 intravenously on the first cycle day 1 and then once a week at a dose of 250 mg/m2.
Results
The study by Michel et al. (2016)7 shows that of the 9 patients included in the study, 6 were resistant to Cetuximab,
and 4 were resistant to platinum, with 1 of the 9 being resistant to both medications.
It is worth noting that most of the patients had a history of smoking. As for the
response to the combination treatment of palbociclib and cetuximab, the best tumor
response was seen in two patients, and there was no description of the patients who
had a partial response. Stable disease was seen in 6 patients and disease progression
was observed in only 1 patient. In the present study, the average duration of response
was 112 days.
The study by Adkins et al. (2019)9 assessed 62 patients diagnosed with HNSCC, most commonly in the larynx and oral cavity.
They were divided into 2 groups, the 1st with 30 patients with HPV-negative HNSCC
without previous use of cetuximab, but resistant to platinum, 2 of whom died early.
Of the 28 evaluated in this group, 3 showed the best response and 8 showed a partial
response, 14 maintained stable disease, and 3 progressed. The median duration of response
for this group was 4 months.
In the 2nd group, 32 patients were selected who were resistant to the use of cetuximab
in monotherapy; of these, 5 were not evaluable. Of the remaining 27, 1 showed a better
response and 4 a partial response, 13 showed disease stability, and the other 9 progressed.
The median duration of response for this group was 6 months. The groups were followed
up for an average of 5.4 months, making it possible to extract the results described.
[Table 1].
Table 1
Results of selected articles relevant to the study
|
Author (year)
|
Title
|
Study country
|
Number of patients
|
Number of platinum-resistant patients
|
Number of patients resistant to cetuximab
|
Number of evaluable patients
|
Best response (n = patients)
|
Partial response (n = patients)
|
Stable disease (n = patients)
|
Disease progression (n = patients)
|
|
Michel, L., Ley, J., Wildes, T. M., Schaffer, A., Robinson, A., Chun, S. E., Lee,
W. et al. (2016)7
|
Phase I trial of palbociclib, a selective cyclin dependent kinase 4/6 inhibitor, in
combination with cetuximab in patients with recurrent/metastatic head and neck squamous
cell carcinoma.
|
USA
|
9
|
3
|
6
|
9
|
2
|
–
|
6
|
1
|
|
Adkins, D., Ley, J., Neupane, P., Worden, F., Sacco, A. G., Palka, K. et al. (2019)9
|
Palbociclib and cetuximab in platinum-resistant and in cetuximab-resistant human papillomavirus-unrelated
head and neck cancer: a multicenter, multigroup, phase 2 trial.
|
USA
|
62
|
30
|
32
|
55
|
4
|
12
|
27
|
12
|
Discussion
The present systematic review shows that the use of a CDK4/6 cyclin inhibitor, palbociclib,
is capable of bringing a cancer cell to a state of senescence, regulating cell proliferation,
which is out of control, and restoring the function of the G1 to S checkpoint of the
cell cycle, which was lost during the mutation that turned the cell into a cancer.[8]
The drug in question is part of the treatment protocol for HR+ breast cancer only
and is not approved by the FDA for any other type of tumor. However, clinical trials
show relative evidence of this drug in other cancers, including HPV-negative HNSCC,
which was the focus of the current study.
Looking at other systematic reviews, the similarities between the most common defects
found in the cell cycle of head and neck squamous cell carcinoma and HR+ breast cancer
are clear. Van Caloen et al. (2019)[10] shows that HNSCC is driven by inactivation of the p16-INK4a and TP53 proteins, as
well as amplification of the CCND1 protooncogenes and inactivation of the CDKN2A tumor
suppressor gene. Similarly, Clark et al. (2016)[17] found that palbociclib showed greater antiproliferative effects in HR+ breast cancer
cells through the loss of p16 or the increase in CCND1, and, thus, after completing
the 3 phases of the Palbociclib: Ongoing Trials in the Management of Breast Cancer
(PALOMA) study, was included as a therapeutic option for this type of tumor, in association
with antiestrogens, including letrozole and fulvestrant.
This similarity gives rise to the guiding question of this systematic review, which
asks how palbociclib, approved only for HR+ breast cancer, can also be effective in
head and neck squamous cell carcinoma. There are no studies in the literature that
clearly demonstrate this mechanism, but some describe results that allow us to think
about a future inclusion of palbociclib, in association with an EGF2 inhibitor, cetuximab,
to prolong the prognosis of HNSCC.
Billard-Sandu et al. (2020)[12] point out that HPV-negative HNSCC generally has a poor prognosis, which encourages
the search for new treatment strategies. Given that EGFR inhibitors show a satisfactory
response in the treatment of this cancer, the pattern of genetic alterations found
in the pathology in question has the potential to cause a decrease in the effectiveness
of EGFR inhibitors, corroborating with the lower survival of patients.
For this reason, new medications are being studied to improve the prognosis of HNSCC,
including palbociclib, which allows for slower disease progression, possibly explained
by its action at a different stage of the cell cycle of these cells, when compared
with cetuximab in monotherapy. The CDK4/6 cyclin inhibitor decreases phosphorylated
Rb and, consequently, restores the function of p16, bringing back the effectiveness
of the first G1 checkpoint, causing cell replication to occur only in healthy cells,
and preventing the exacerbated multiplication of mutant cancer cells. In other words,
this drug inhibits the progression from G1 to S in defective cells, leaving them in
what is known as a senescent state, which allows these cells to respond more effectively
to conventional treatments, including cetuximab.[8]
[12]
To confirm the hypothesis discussed in this paper, clinical trials were analyzed that
studied the clinical response of several patients with HPV-negative HNSCC, using palbociclib
associated with cetuximab. Analyzing the results of Adkins et al. (2019),[9] we see that of the 62 patients studied, only 12 showed disease progression, the
others showed a complete or partial response, or kept the disease stable, bringing
a favorable result, in relation to disease progression, when compared with the isolated
use of drugs or even in relation to patients who underwent chemotherapy with platinum
derivatives.
In this same study, it was shown that the duration of response, although satisfactory,
was shorter with the use of the combination of palbociclib and cetuximab than with
PD-1 inhibitors, but progression-free survival was higher in patients who used the
combination compared with those who used monotherapy.
Looking at the results of the clinical trial by Michel et al. (2016),[7] of the 9 patients evaluated, only one showed disease progression, with the others
showing a complete response or stabilization of the disease. Thus, it is argued that
both the rate of disease control and the duration of response were superior in relation
to the same parameters in monotherapy.
Finally, this systematic review presents important aspects, showing a clear correlation
between the genetic alterations found in HNSCC and HR+ breast cancer, allowing the
same CDK4/6 cyclin inhibitor to be used in both pathologies in association with the
conventional medications already known for each of them. Therefore, the effectiveness
of palbociclib in HNSCC is not clearly described, due to the lack of studies in the
area, but the few that were found show that there is a possibility of including this
medication in the therapeutic regimen for this cancer, requiring further clinical
studies to strengthen this hypothesis.
Conclusion
The present systematic review indicates that the CDK4/6 inhibitor palbociclib has
promising potential to induce senescence in tumor cells and modulate cell proliferation
and is currently approved only for the treatment of HR+ and HER2- breast cancer. The
preliminary studies discussed in this review suggest a possible applicability in other
types of cancer, such as HPV-negative HNSCC, given the similarity in the mechanisms
of cell cycle deregulation.
The clinical studies analyzed report that the combination of palbociclib with cetuximab
demonstrated relevant antitumor activity, especially in cases resistant to platinum
and to cetuximab itself, with superior results to monotherapy in terms of progression-free
survival. However, the exact mechanisms by which palbociclib acts in this context
are not yet fully elucidated. Furthermore, the scarcity of studies on this subject
in the literature limits the strength of the conclusions, reinforcing the need for
further clinical and preclinical investigations to validate the role of palbociclib
in this therapeutic scenario.
Bibliographical Record
Maria Eduarda Bertolazzi Teixeira, João Pedro Fabrini da Silva, Ana Cristina da Silva
do Amaral Herrera. The action of Palbociclib on the Cell Cycle of Head and Neck Squamous
Cell Carcinoma: A Systematic Review. Brazilian Journal of Oncology 2025; 21: s00451811626.
DOI: 10.1055/s-0045-1811626
