Keywords breast cancer - therapy - CDK4/6
Introduction
In 2009, a preclinical trial first noted that cyclin-dependent kinase 4 and 6 inhibitors
(CDK4/6i) could play a special role in the treatment of breast cancer patients with
hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative
(HER2−) disease [1 ]. Since then, the three CDK4/6is ribociclib, palbociclib and abemaciclib have become
part of the standard first-line treatment provided to HR+/HER2− patients with advanced
disease [2 ], [3 ], [4 ]. Two studies have looked at the use of CDK4/6i in the adjuvant setting and reported
a benefit with regards to invasive recurrence-free survival [5 ], [6 ]. Abemaciclib has already been approved for use in the adjuvant setting while ribociclib
is still awaiting approval.
The widespread use of these substances in the treatment algorithms of patients with
breast cancer clearly shows that understanding the modes of action of and resistance
mechanisms to CDK4/6i is an important precondition for developing therapies for this
group of patients.
In this context, both retrospective analyses and prospective studies are investigating
whether and how patient groups can be identified who would particularly benefit from
or be disadvantaged by therapy with CDK4/6i.
Some concepts have focused on the efficacy of the endocrine combination partner by
determining mutations in the estrogen receptor gene (ESR1) . Others are studying the molecular changes which occur during CDK4/6i therapy or
investigating the overall effect of molecular or immunological patterns on their efficacy.
A number of study programs have been set up in recent years which specifically focus
on identifying these mechanisms.
This overview presents the current status of clinical and translational research.
Current national and international study programs investigating the modes of action
of CDK4/6i are also described. In Germany, for example, attention has focused on the
CAPTOR BC trial, which is extensively collecting biomaterials to identify markers
for both efficacy and resistance.
CDK4/6 Inhibitors
High preclinical activity in HR+/HER2− cell lines
The efficacy of treatment with palbociclib was initially investigated in a number
of cell lines [1 ]. A total of 47 cell lines were studied to identify the different molecular subtypes
of breast cancer and the variability between patients. [Fig. 1 ] shows that particularly with HR+, luminal cell lines responded well to treatment
with palbociclib [1 ]. This study and other preclinical studies were followed by early clinical trials
with palbociclib, in particular the PALOMA-1/TRIO-18 trial which led to the approval
of palbociclib for the treatment of metastatic breast cancer [7 ]. During the initial preclinical studies with cell lines [1 ], extensive tests were already being carried out to determine which biomarkers correlated
with response in addition to hormone receptor positivity. Microchip technology was
used for
genome-wide evaluation to determine which genes correlated preclinically with palbociclib
efficacy. Around 450 genes were identified where expression varied between cell lines
which responded to palbociclib and cell lines that did not [1 ]. In sensitive cell lines, the expression of genes which coded for the retinoblastoma
protein (Rb) and cyclin D increased but the expression of CDKN2A decreased [1 ]. These early studies already showed that the mode of action of CDK4/6i therapy depends
on molecular markers. Following this and other studies, large randomized studies of
advanced breast cancer were carried out which led to the approval of CDK4/6i for this
indication.
Fig. 1 Concentrations of palbociclib required to inhibit 50% of cell growth [1 ].
Introduction of CDK4/6 Inhibitors into Clinical Practice
Introduction of CDK4/6 Inhibitors into Clinical Practice
Studies to establish the use of CDK4/6 inhibitors
Studies with the three CDK4/6is palbociclib, ribociclib and abemaciclib were carried
out in different clinical scenarios and with different endocrine combination partners.
The findings of the studies which investigated the use of CDK4/6i as first line-therapy
can be grouped together. These trials mainly included patients in whom the probability
of endocrine resistance was low. The PALOMA-2 (palbociclib), MONALEESA-2 (ribociclib)
and MONARCH-3 (abemaciclib) trials therefore chose an aromatase inhibitor as the combination
partner. But there are also a number of studies which included patients with a high
probability of endocrine resistance. These were usually patients who were receiving
more advanced therapy lines or with rapid progression under an aromatase inhibitor.
Fulvestrant was selected as the combination partner in the PALOMA-3 (palbociclib)
and MONARCH-2 (abemaciclib) trials. Two other studies investigated additional questions.
The MONALEESA-3 trial which included
patients receiving both early and advanced therapy lines also provides results for
ribociclib + fulvestrant as a first-line therapy. The MONALEESA-7 trial provides results
for ribociclib + an aromatase inhibitor in exclusively premenopausal patients.
All studies showed comparable effects with regards to progression-free survival. Median
progression-free survival (PFS) almost doubled in all of the studies. With regards
to overall survival, however, the studies showed clinically relevant differences.
The two palbociclib studies did not achieve a statistically significant prolongation
of overall survival, whereas the remaining studies showed a statistically significant
reduction in the relative mortality risk of around 25%. Although the recent interim
analysis of the MONARCH-3 trial seems to suggest an overall survival benefit, the
final analysis has not yet been published. [Table 1 ] provides an overview of the most important randomized phase III trials with CDK4/6i.
Table 1 Overview of randomized phase III trials with palbociclib, abemaciclib and ribociclib
for the treatment of patients with advanced breast cancer.
N
Therapy
Last patient in
PFS
HR (95% CI)
Median PFS
CDK4/6i | Placebo*
OS
HR (95% CI)
Median OS
CDK4/6i | Placebo*
Percentage with de novo metastasis
Percentage of patients with DFI < 12 months
References
* = interim analysis, ** = not reported, DFI = disease-free interval, HR = hazard
ratio, NA = not applicable, OS = overall survival, PFS = progression-free survival
MONALEESA-2
668
ribociclib ± letrozole
03/2015
0.56 (0.43 – 0.72)
25.3 | 16.0
0.76 (0.63 – 0.93)
53.9 | 51.2
34%
18%
[41 ], [42 ]
MONARCH-3
493
abemaciclib ± NSAI
11/2015
0.54 (0.41 – 0.72)
28.2 | 14.8
0.76 (0.58 – 0.97)
67.1 | 54.1
40%
**
[43 ], [44 ]
PALOMA-2
666
palbociclib ± letrozole
07/2014
0.58 (0.46 – 0.72)
24.8 | 14.5
0.96 (0.78 – 1.18)
63.9 | 51.4
37%
22%
[45 ], [46 ]
MONALEESA-7
672
ribociclib ± ET
08/2016
0.55 (0.44 – 0.69)
23.8 | 13.0
0.71 (0.54 – 0.95)
58.7 | 48.0
19%
4.3%
[47 ], [48 ], [49 ]
MONALEESA-3
726
ribociclib ± fulvestrant
06/2016
0.59 (0.48 – 0.73)
20.5 | 12.8
0.72 (0.57 – 0.92)
53.7 | 41.5
40%
5.4%
[50 ], [51 ], [52 ], [53 ]
MONARCH-2
669
abemaciclib ± fulvestrant
12/2015
0.55 (0.45 – 0.68)
16.9 | 9.3
0.76 (0.61 – 0.95)
46.7 | 37.3
NA
NA
[54 ], [55 ]
PALOMA-3
521
palbociclib ± fulvestrant
08/2014
0.46 (0.36 – 0.59)
9.5 | 4.6
0.81 (0.64 – 1.03)
34.8 | 28.0
NA
NA
[8 ], [56 ], [57 ]
DAWNA-1
361
dalpiciclib* ± fulvestrant
09/2020*
0.42 (0.31 – 0.58)
15.7 | 7.2
not yet reported
not yet reported
NA
NA
[58 ]
The data were so convincing that since the approval of CDK4/6i in 2016 and 2017 in
Germany around 70 – 80% of patients with advanced HR+/HER2− breast cancer receive
first-line therapy with CDK4/6i ([Fig. 2 ]). Understanding the resistance and efficacy mechanisms is particularly important
in this context to establish effective therapy sequences for these patients.
Fig. 2 Use of different therapeutic options as first-line therapy in patients with advanced
HR+/HER2− breast cancer [2 ].
In the therapy recommendations issued by the Breast Commission of the AGO ([Fig. 3 ]), three sequential therapies which are initiated after failure of CDK4/6i therapy
are now based on predictive molecular markers. Poly (ADP-ribose) polymerase inhibitors
(PARPi) are indicated in patients with confirmed BRCA1/2 germline mutation; the phosphatidylinositol 3-kinase inhibitor (PI3Ki) alpelisib
is prescribed to patients with PIK3CA mutation, and the oral selective estrogen receptor degrader (SERD) elacestrant has
been approved in the USA for patients with confirmed mutation in the estrogen receptor
gene ESR1 . Elacestrant has not yet been approved for use in Europe (as at 09/2023), although
the EMA has already issued a positive opinion for elacestrant. The identification
of mutations using plasma-based circulating tumor DNA (ctDNA) is expected to become
increasingly important in this context. Both PIK3CA mutations and
ESR1 mutations can be determined using ctDNA. The scope of ctDNA analysis in clinical
care and research will increase even further in the coming years. [Fig. 4 ] shows the process, influencing factors and possible clinical applications.
Fig. 3 Treatment algorithm of the Breast Commission of the AGO outlining sequential therapies
for patients with HR+/HER2− breast cancer in an advanced therapy setting.
Fig. 4 Possible course and clinical application of ctDNA analysis.
Biomarker Investigations in Large Randomized Studies
Biomarker Investigations in Large Randomized Studies
Initial findings on clonal evolution in the PALOMA-3 trial
Most large randomized studies now also include extensive translational research programs.
These programs have collected important information which can help to predict treatment
efficacy and resistance based on the use of biomarkers.
The PALOMA-3 trial was one of the first studies which extensively investigated the
clonal evolution of disease under CDK4/6i therapy [8 ], [9 ]. Using ctDNA obtained from blood samples, investigations were carried out to determine
which mutations are most commonly found at the end of therapy in potentially relevant
genes compared to the start of therapy. The most common mutations were in the two
genes ESR1 and PIK3CA . Mutations in RB1 occurred more frequently in the palbociclib arm of the study [9 ]. Mutations in PIK3CA (relating to the PI3Ki alpelisib) and probably, in the near future, also mutations
in ESR1 (relating to the SERD elacestrant) are actionable mutations. The PALOMA-3 trial shows
the importance of mutation analysis carried out immediately before the start of therapy
as it provides the basis for treating patients in accordance with their
identified mutation status.
PIK3CA and ESR1 mutations in the MONARCH-2 trial
In the MONARCH-2 trial, patients with endocrine resistance were treated with abemaciclib
and fulvestrant or fulvestrant alone. Samples of ctDNA taken just before starting
therapy were investigated for mutations in PIK3CA and ESR1
[10 ]. A mutation in PIK3CA was found in 44% of patients and an ESR1 mutation was confirmed in 59% of patients. In this trial, however, these biomarkers
had no impact on patientsʼ prognosis [10 ].
Biomarker examinations in the MONALEESA study program
In the MONALEESA trials 2, 3 and 7, extensive pooled analyses of gene expression and
other genomic analyses were carried out in a large group of patients. More than 1150
patients were categorized into their respective intrinsic subtypes using gene expression
analysis with PAM50. Even though these breast cancers are often described as luminal-like,
this clinical assessment is only an estimation. In addition to luminal-A (46.8%) and
luminal-B tumors (24.0%), the pooled MONALEESA-2, 3 and 7 analyses also found tumors
with HER2-enriched (12.6%), normal-like (14.1%) and basal-like (2.4%) intrinsic subtypes.
What was interesting was that the therapeutic effect of ribociclib was found to differ
across the different subgroups. With a hazard ratio (HR) of 0.40 (95% CI: 0.26 – 0.62),
the effect appeared to be greatest in the group with HER2-enriched tumors. This is
probably due to the pronounced endocrine resistance in this group, which became evident
when results were compared to
outcomes with monotherapy. More than one third of patients experienced primary progression
under endocrine monotherapy. The addition of ribociclib probably overcame resistance
in a majority of these patients. Similarly, a majority of patients with basal-like
tumors demonstrated early progression under endocrine monotherapy which was resolved
by the addition of ribociclib (HR = 1.14; 95% CI: 0.46 – 2.83) [11 ].
Extensive analysis of tumor mutations and gene amplifications was also carried out
in a pooled patient group (n = 1703) from the MONALEESA-2, 3 and 7 trials [12 ]. At the start of treatment with ribociclib and endocrine therapy, ctDNA was analyzed
with regards to mutations and amplifications of around 550 genes using next generation
sequencing. The most common finding was an alteration in PIK3CA (33%), which in most cases was a mutation. The most commonly amplified genes were
FDF3, FDF4 and FGF19 (8 – 9%). Some genes were identified if a mutation under endocrine monotherapy was
associated with a very short median PFS which was then significantly improved by additonally
administering ribociclib. These genes were FRS2, MDM2, PRKCA, AKT1, BRCA1/2 and ERBB2 . Conversely, no improvement in median PFS following the addition of ribociclib was
found for mutations in CHD4, CDKN2A/B/C and ATM . These
analyses have given rise to a number of hypotheses, but they show that gene mutations
and amplifications play a role in the context of endocrine resistance which has not
yet been scientifically investigated. It is therefore clear that a clinically simple
method (blood sampling and ctDNA analysis) can help to determine predictive markers
which will then be used to direct further therapy ([Fig. 4 ]). This is also being offered to patients with progression in the CAPTOR BC trial
in the context of a scientific subproject ([Fig. 8 ]).
Therapy Monitoring with ctDNA Analysis
Therapy Monitoring with ctDNA Analysis
Monitoring of CDK4/6i therapy with ribociclib – the BioItaLEE trial
The BioItaLEE trial is a potentially pioneering study into the monitoring of ribociclib
plus endocrine therapy using ctDNA. In this study, the amount of tumor-specific ctDNA
was determined prior to the start of therapy and 15 days after starting therapy and
correlated with the median PFS [13 ]. Patients were divided into four groups based on the amount of ctDNA. After a median
follow-up time of 26.9 months, clear prognostic patterns with regards to median PFS
were identified:
no ctDNA at the start of therapy → no ctDNA after 15 days: median PFS not achieved
no ctDNA prior to starting therapy → ctDNA newly present after 15 days: median PFS
15.9 months
ctDNA present before the start of therapy → decrease in ctDNA after 15 days: median
PFS 21.9 months
ctDNA present before the start of therapy → ctDNA present after 15 days: median PFS
12.3 months
The Kaplan-Meier curves are shown in [Fig. 5 ]. Modern tumor-specific biomarkers obtained through ctDNA analysis could allow the
success of therapy to be estimated after just a short treatment period.
Fig. 5 Progression-free survival (PFS) in the BioItaLEE trial depending on changes in ctDNA
between the start of therapy (BL) and 15 days after the start of therapy (D15) [13 ]. Mut = mutated, WT = wildtype.
The BioItaLEE trial also analyzed other biomarkers such as serum thymidine kinase
(sTK), a proliferation marker which correlates with the effect of CDK4/6i [14 ]. Of particular interest were patients where sTK was found to be suppressed under
the limit of detection (LOD) after both 15 days of therapy and 28 days of therapy
([Fig. 6 ], Pattern 1). This group had the best prognosis. With a median follow-up time of
26.9 months, this group did not achieve the median PFS. Patients in whom suppression
of sTK under the LOD was initially achieved after 15 days of therapy but who then
showed an increase again after 28 days of therapy ([Fig. 6 ], Pattern 2) had a median PFS of 22.1 months. Patients who showed no decrease in
sTK under the LOD after 15 days of therapy ([Fig. 6 ], Pattern 3) had the poorest median PFS with just 10.1 months [15 ].
Fig. 6 Progression-free survival in the BioItaLEE trial depending on the changes in serum
thymidine kinase activity under therapy with ribociclib [15 ]. HR = hazard ratio, mPFS = median progression-free survival, sTKa = serum thymidine
kinase activity
Homologous Recombination and Endocrine Resistence
Homologous Recombination and Endocrine Resistence
New molecular patterns associated with endocrine resistence
Data from the MSK-IMPACT cohort on prognosis under CDK4/6i therapy has already been
presented at the 2021 San Antonio Breast Cancer Symposium (SABCS). BRCA2 germline mutation was found to have an unfavorable prognostic effect in patients
under CDK4/6i therapy. Compared to patients with BRCA2 wildtype, patients with BRCA2 mutation had a higher risk of progression (HR = 2.32; 95% CI: 1.38 – 3.91) [16 ].
Other analyses in this cohort investigated the effect of complex mutation patterns
on prognosis under CDK4/6i therapy [17 ]. The differentiation of tumors according to complex mutation patterns (signatures
or profiles) is an attempt to determine different prognostic categories based on these
mutation patterns. During the pathogenesis of tumors, different irritants and circumstances
lead to characteristic mutation profiles. [18 ]. Such mutation profiles can be developed for different types of mutations (single
base pair, doublet base pair, insertion-deletion mutations). The analysis of the MSK-IMPACT
cohort focused on single base pair mutations (SBS) [17 ] for which a recently published work described 96 different signatures [19 ]; these signatures are also available from the Catalogue of Somatic Mutations in
Cancer (COSMIC) [20 ].
Some of these SBS signatures are found more often in breast cancer and can be divided
into the following etiological groups: clock-like signatures, apolipoprotein B mRNA
editing enzyme, catalytic polypeptide (APOBEC) signature, homologous recombination
deficiency (HRD) signature, smoking-related and mismatch repair-related signatures.
The presented clinical data refer to the change in the mutation profile of the primary
tumor when it metastasizes and also to the impact of the mutation profile on the prognosis
of patients treated with CDK4/6i as their first-line therapy. The two mutation profiles
which were found to have increased most during the progression of disease from early-stage
HR+/HER2− breast cancer to metastatic disease were the APOBEC and HRD signatures [17 ]. Significant differences were found with regard to the prognostic importance of
the mutation profiles under first-line therapy with a CDK4/6i. Patients with few mutations
had a median PFS of 17.8 months, patients with an APOBEC signature had a median PFS
of 12.3 months and patients with an HRD signature had a median PFS of only 7.6 months
[17 ].
To what extent this knowledge can be used to determine subsequent therapies or therapy
sequences must be elucidated in future studies. Currently, treatment with a CDK4/6i
is and remains the standard first-line therapy for patients with advanced HR+/HER2−
breast cancer. However, given the short median PFS of patients with an HRD signature,
the question arises whether these patients should not rather be treated with PARPi.
The HRD group consisted of only 10.5% of patients treated with CDK4/6i in the MSK-IMPACT
cohort, representing only a small number of the patients in the study, meaning that
further studies or real-world data are needed for a conclusive assessment.
ESR1 Mutations and Endocrine Combination Partners
ESR1 Mutations and Endocrine Combination Partners
Around 30 – 40% of tumors in patients with advanced endocrine-resistant breast cancer
were found to have a mutation in the estrogen receptor gene ESR1
[21 ], [22 ], [23 ]. These mutations can be determined with a relatively high sensitivity using serum
ctDNA [24 ], [25 ]. It should be easy to determine these mutations over the clinical course of disease.
The mutations in the gene segments of ESR1 coding for the ligand-binding domain were correlated with a poorer clinical outcome
[24 ], [25 ], [26 ], presumably because these mutations lead to changes in protein structure in the
sense of a constitutively active form of the estrogen receptor [27 ], [28 ] ([Fig. 7 ]). Their frequency and the clonal selection of ESR1 mutations under endocrine therapy have focused interest in endocrine resistance on
this mutation.
Fig. 7 Effect of ESR1 mutation on the function of the estrogen receptor (Creative Commons Licence 4.0,
[59 ]). LBD: ligand-binding domain, AF-2: activating factor-2 domain, DBD: DNA-binding
domain, AF-1: activating factor 1 domain, E2: estradiol, SERM: selective estrogen
receptor modulator, SERD: selective estrogen receptor degrader, WT: wildtype, MUT:
mutated (Source: Brett JO, Spring LM, Bardia A et al. ESR1 mutation as an emerging
clinical biomarker in metastatic hormone receptor-positive breast cancer. Breast Cancer
Res 2021; 23: 85. doi:10.1186/s13058-021-01462-3.) © 2021. The Author(s). Licensed under a Creative Commons Attribution 4.0 International
License (http://creativecommons.org/licenses/by/4.0/ ). Changes: Addition of explanations for WT and MUT in the image.
ESR1 mutations and the oral SERD elacestrant
The SERD fulvestrant which is administered intramuscularly has been approved to treat
patients with advanced breast cancer for more than 20 years. With the development
of oral SERDs, research activities into this class of substances have increased significantly.
In the USA, the oral SERD elacestrant has already been approved to treat patients
with hormone therapy-resistant advanced breast cancer if ESR1 mutations are confirmed in the patientʼs ctDNA. In the EMERALD approval study [29 ], patients with ESR1 mutation who received elacestrant had a longer median PFS than patients who received
standard endocrine therapy (HR 0.55; 95% CI: 0.39 – 0.77). Elacestrant did not improve
median PFS in patients without ESR1 mutation (HR 0.86; 95% CI: 0.63 – 1.19) [29 ].
ESR1 mutations and fulvestrant as first-line therapy
In addition to the approval studies, studies have also focused on biomarkers. The
PADA-1 trial is particularly important in this context. In this study, ctDNA was used
to determine whether patients who were receiving first-line therapy with an aromatase
inhibitor and palbociclib had an ESR1 mutation. If the presence of ESR1 mutation in serum was confirmed and the patient showed no clinical progression, patients
were randomized into groups: in one group the endocrine combination partner of the
aromatase inhibitor was switched to fulvestrant while the other group continued to
receive treatment with an aromatase inhibitor and palbociclib. 172 patients were randomized.
The median PFS under continuation of the aromatase inhibitor therapy was 5.7 months;
the median PFS if therapy was switched to fulvestrant was 11.9 months (HR 0.61; 95%
CI: 0.43 – 0.86) [30 ].
The CAPTOR Study Program
CAPTOR BC study design
The CAPTOR BC study is a phase IV trial which investigates resistance and the mechanisms
of action for combination therapy with ribociclib and endocrine therapy. The study
is also investigating several new research concepts to find new genes and pathways
which could identify a priori patients for whom ribociclib would be effective as well
as those for whom ribociclib will not be effective. This could provide additional
information on which therapy sequences will be most appropriate. The CAPTOR BC trial
also records all subsequent therapies initiated after the end of therapy with ribociclib.
As the study is hoping to include large numbers of patients, the aim has been to simplify
the practical implementation of the study while simultaneously achieving the extensive
study goals ([Fig. 8 ]).
Fig. 8 Study design of the CAPTOR BC trial and planned molecular analyses. ET = endocrine
therapy, FFPE = formalin-fixed, paraffin-embedded tissues, HR = homologous recombination,
OS = overall survival, PFS = progression-free survival, SNP = single-nucleotide polymorphism
Patients are included if routine clinical examination finds that ribociclib is indicated
as part of their first-line therapy. Patients will be followed up until death, for
a maximum period of 4 years, or until the end of the overall study (November 2027).
Blood samples are taken on inclusion in the study and each patient is requested to
provide the study with paraffinized tumor samples. Up to 7 more blood samples are
taken over the course of the study ([Fig. 8 ]). The patientʼs quality of life is also recorded using patient-reported outcome
tools and a paper-based questionnaire or app.
This means that extensive information and biomaterials can be obtained with a relatively
simple study design. Some of the scientific objectives of the CAPTOR BC trial are
described in more detail below.
Detection of agnostic biomarkers in the CAPTOR BC trial
Despite numerous studies which have already investigated the mechanisms of action
of CDK4/6i-based therapies, many methods have not yet been exhausted. Up to now, the
use of agnostic approaches was largely ruled out, purely because of the rather small
case numbers in the studies carried out to date. Modern methods of analysis are being
used to carry out genome-wide identifications of gene expression, genetic mutations
and gene copy alterations in a short space of time. If the case numbers are sufficiently
high, new genes and signalling pathways which were not previously taken into consideration
will be identified. A good example of this was the discovery of more than 300 gene
loci which explain more than 40% of familial breast cancer risks [31 ], [32 ], [33 ], [34 ], [35 ], [36 ], [37 ], [38 ]. The first big association studies were able to discover and validate the breadth
of the genetic basis of the risk of breast cancer. Other examples are the immunomodulatory
genes identified using a similar approach in the context of the SUCCESS trial which
correlate with neutropenia and prognosis [39 ]. The large number of patients (n = 2000) in the CAPTOR BC study paves the way to
carry out several such genome-wide analyses.
ctDNA in scientific and healthcare research in the CAPTOR BC trial
Just how varied the options for ctDNA analysis are has been described. A number of
scientific and healthcare applications are conceivable, both in the context of therapy
monitoring and for the molecular characterization of diseases. Serial blood sampling
is being carried out as part of the CAPTOR BC trial, and the samples are prepared
and processed in accordance with the latest state of knowledge of ctDNA analysis.
One of the scientific objectives is to learn as much as possible about the course
of disease progression under CDK4/6i therapy. The basis for this will be the analysis
of ctDNA obtained at the time of progression. As part of the CAPTOR BC study, patients
who have received treatment with a CDK4/6i and for whom marker-guided therapy is now
indicated will be offered a ctDNA analysis under study conditions at the time of progression.
Research is currently focused on investigating whether there are other molecular genomic
markers in addition to the genes PIK3CA,
ESR1 and BRCA1/2 that could help to identify appropriate subsequent therapies. One of the programs
in this field of study is the multicenter program “Comprehensive Assessment of clinical
feaTures and biomarkers to identify patients with advanced or metastatic breast Cancer
for marker-driven trials in Humans” (CATCH) of the National Center for Tumor Diseases
(NCT).
New Therapeutic Approaches in Clinical Studies
New Therapeutic Approaches in Clinical Studies
The CATCH study program
The speed of drug development processes has increased significantly in recent years.
As the understanding of how the human genome functions and the importance of relevant
mechanisms on the development of breast cancer has increased, more targeted drugs
have been approved, i.e., drugs which address a target partly determined by molecular
testing. Examples include CDK4/6i (palbociclib, ribociclib, abemaciclib), the PIK3CAi
alpelisib, PARPi (olaparib, talazoparib), immune checkpoint inhibitors (ICIs) (atezolizumab,
pembrolizumab), antibody-drug conjugates (ADCs) (sacituzumab-govitecan, trastuzumab-deruxtecan),
the AKT inhibitor capivasertib, the oral SERD elacestrant and others.
As drug developments have occurred in parallel, the current therapy standard is usually
not reflected in study populations. One example of this is alpelisib and the SOLAR-1
trial. This study included almost no patients who had received pretreatment with CDK4/6i,
even though treatment with CDK4/6i is now the standard first-line therapy. This makes
it clear how important it is to carry out therapies and, specifically, sequential
therapies in molecularly informed trials.
The multicenter CATCH program is a platform which aims to provide a basis to test
the efficacy of individualized cancer drugs (precision oncology), specificially drugs
for metastatic breast cancer, and to provide comprehensive access to controlled evidence-based
precision oncology structures.
To do this, the individual genetic makeup of therapy-resistant metastasis in breast
cancer patients is analyzed using modern molecular biological procedures to identify
molecular points of attack ([Fig. 9 ]). Based on specific molecular changes, patients will be offered targeted therapies
in further clinical studies, either in the context of approval studies or as off-label
therapies ([Fig. 10 ]). These drugs should delay disease progression while maintaining patientsʼ quality
of life. The pilot phase of the trial showed that it was possible to delay disease
progression for longer in around one third of patients than is currently possible
with standard therapies, and that a positive impact on disease progression could be
expected even for patients who had received many prior therapies [40 ]. The information obtained in this study will be used over the longer term in subsequent
studies to develop innovative targeted effective substances and modern diagnostic
processes which will be transferred to standard care. The CATCH program is independent
of the CAPTOR BC trial, but for patients, both study concepts may be closely connected.
After disease progress is identified in the CAPTOR BC trial and the relevant molecular
characterization is carried out, studies such as CATCH will be used to offer new and
innovative therapies to patients based on their molecular characteristics.
Fig. 9 Technical procedure used for molecular characterization in the CATCH program.
Fig. 10 Therapy allocation based on molecular characteristics in the CATCH program.
Outlook
The large number and the quality of analyses of molecular biomarkers show ever more
clearly that molecular characterization of breast cancer offers benefits to patients.
The use of some markers is already standard when determining the indications for approved
therapies. Large study programs such as the CAPTOR BC and CATCH studies, which include
high numbers of patients, provide the basis for the creation of future treatment concepts
which will expand this body of knowledge for the benefit of patients.
