Key words advanced breast cancer - chemotherapy - endocrine therapy - antibody drug conjugates
Introduction
The new developments for the treatment of patients in the metastatic treatment situation
have produced some new standard therapies, such as the CDK4/6 inhibitors in the first
advanced line of
therapy in hormone-receptor-positive, HER2-negative breast cancer, the immune
checkpoint inhibitors in triple-negative, PD-L1-positive breast cancer, and the PARP
inhibitors in a
BRCA1/2 germ line mutation. Furthermore, the antibody-drug conjugates (ADCs) sacituzumab
govitecan could become established in subsequent lines of therapy for patients with
triple-negative breast cancer and trastuzumab-deruxtecan in patients with HER2-positive
breast cancer. In particular, new patient groups have recently been identified for
the ADC, in which
these drugs were able to display a high effectiveness despite low expression of
the target molecule.
HER2-low – Biomarker or New Subgroup
HER2-low – Biomarker or New Subgroup
The anti-HER2 ADC trastuzumab deruxtecan (T-DXd) demonstrated high efficacy in patients
with positive HER2 status (HER2 positive according to the criteria of the ASCO/CAP
guidelines [1 ]) in both the single-arm Destiny-B01 study and the Destiny-B03 study. “Positive”
in this context means that the patients either had to have a score of 3+ in
immunohistochemistry or had to have an amplification of the HER2 gene with a gene-to-centromer ratio of ≥ 2.0. This definition identifies patients
who have an extremely poor prognosis
without anti-HER2 treatment because of the activated HER2 pathway. However, the
Destiny-B01 study also included patients who did not have overexpression or amplification
of HER2, but
had some expression of HER2 with an immunohistochemical score of 1+ or 2+ (without
amplification). This population is called “HER2-low”.
“Low Expression” as a therapy concept
The therapy concept that molecules on the cancer surface can be used to direct therapies
there, even if they are not necessarily responsible for a poor prognosis, is not new.
For example,
in clinical studies, anti-HER2 CAR-T cells have already been used for a therapy
with sarcomas [2 ] and anti-HER2 CAR-NK cells for therapy of glioblastomas [3 ]. In both cases, no overexpression or amplification was required for therapy. Another
example is the Di-Sialo ganglioside GD2, which can be found in breast
cancer and other carcinomas [4 ] and which is already relevant for antibody therapy in certain neuroblastomas [5 ]. Although GD2
can be found in about 50% of all breast cancers, it has no influence on the prognosis
and is certainly an interesting target [4 ]. A known, further example is
Trop2, a target which can be addressed by means of ADC sacituzumab govitecan
and is approved for the treatment of patients with previously treated, metastatic
TNBC [6 ].
Thus, the use of therapies against targets that mark the cancer cell, but do not necessarily
have to be responsible for the aggressiveness of a tumor, is not a new concept. With
the new,
highly effective ADCs, these patient groups now seem to be suitable for the establishment
of new therapies. With regard to tumors with low HER2 expression (HER2-low), it was
shown in a
registry study that the degree of expression (score of 1+ or 2+) had no influence
on PFS or OS in HER2-low patients. In the distribution to the molecular subgroups
([Fig. 1 ]), it can be seen that approximately 40% of triple-negative tumors and 53% of HR-positive
HER2-negative tumors have a low expression of HER2 and would
thus be suitable for such a therapy.
Fig. 1 Distribution of the “HER2-low-expressing” tumors in the molecular subtypes in the
metastatic situation (Fig. based on data from [51 ]).
It should be noted that, in the future, new standards will have to be established
in the immunohistochemical assessment of HER2 expression. Until now, low expression
values had no
therapeutic relevance. For a therapy decision, there should be an agreement between
pathologists and therapists.
Trastuzumab deruxtecan in HER2-negative tumors with low HER2 expression
For patients with HER2-negative HR-positive advanced breast cancer, all endocrine
therapy options should first be exhausted [7 ]. However, real-world data show
that even after the introduction of CDK4/6 inhibitors, about 40 – 50% of patients
in the second or third line of therapy are still treated with chemotherapy [8 ], while about 80% of patients are already treated with a CDK4/6 inhibitor [9 ] in the first line of therapy. An improvement in the therapy situation
for these patients would mean a significant progress in therapy. Against this
background, the Destiny-Breast-04 study compared chemotherapy of the physicianʼs choice
(capecitabine, eribulin,
gemcitabine, paclitaxel or Nab-paclitaxel) with ADC trastuzumab deruxtecan [10 ]. Only patients who were considered to have endocrine resistance and who had
already undergone one or two chemotherapies in the advanced treatment situation
could be included.
In the Destiny-Breast-04 study, 65% of hormone receptor-positive patients had received
preliminary therapy with a CDK4/6 inhibitor and around 60% had received chemotherapy
in the metastatic
situation. 58% had a HER2 IHC score of 1+ and 42% had a score of 2+ in the absence
of amplification of the HER2 gene [10 ].
Median progression-free survival was improved from 4.8 months to 9.9 months (HR = 0.50;
95% CI: 0.40 – 0.63; p < 0.0001). This was true for both hormone receptor-positive
and
hormone-receptor-negative patients (HR = 0.51; 95% CI 0.40 – 0.64 for HR-positive
and HR = 0.46; 95% CI: 0.24 – 0.89 for TNBC).
Median overall survival was also improved. In the overall population, the HR was 0.64
(95% CI: 0.49 – 0.84). Again, the effect was significant in both the HR-positive population
(HR = 0.64;
95% CI: 0.48 – 0.86; [Fig. 2 ]) and in the TNBC population (HR = 0.48; 95% CI: 0.24 – 0.95).
Fig. 2 Overall survival in the Destiny-Breast-04 study. Data extracted from Modi et al.
[10 ] using the method according to Guyot et al. [52 ]. With this method in a 2 : 1 randomization, the number of death events is estimated
to be 123 patients in the T-Dxd arm and 72 in the TPC arm.
However, it should be noted that with 58 TNBC patients, the analysis was only of an
exploratory nature. Also, with a median follow-up period of 18.4 months, it must be
noted that no
statement can be made about the overall survival during a longer follow-up period.
Nevertheless, the statement that over a period of 1.5 years, approximately 35% fewer
deaths occur if
therapy with T-DXd is carried out instead of chemotherapy, has statistical significance
and will most likely influence the therapy decisions.
Unlike in the Destiny-B03 study, the Destiny-B04 study again reported 3 deaths associated
with interstitial lung disease as a result of T-DXd therapy. The possibility of these
rare but
dangerous side effects should be known to the practitioner, and diagnostic (low
dose, high resolution CT) and therapeutic (cortisone therapy) measures should always
be initiated immediately
in case of respiratory symptoms or suspicion of interstitial lung disease.
New Data on the Therapy of the PI3K/AKT/PTEN Signaling Pathway
New Data on the Therapy of the PI3K/AKT/PTEN Signaling Pathway
The PIK3CA pathway as a central component of signal transduction
There are few therapies for which there are clear predictive biomarkers. The presence
of hormone receptors predicts the effect of endocrine therapies and HER2 status predicts
the
effectiveness of anti-HER2 therapies. Another predictive factor is the presence
of PIK3CA tumor mutations for the efficacy of PI3K inhibitors. This was demonstrated for both
buparlisib in the BELLE-2 study and alpelisib in the SOLAR-1 study. In the BELLE-2
study, the hazard ratio in favor of fulvestrant + buparlisib therapy in a group with
PIK3CA mutation
was 0.58 (95% CI: 0.41 – 0.82) and 1.02 in the group without PIK3CA mutation (95% CI: 0.79 – 1.30) [11 ]. In the SOLAR-1 study, the HR in the
PIK3CA mutated group was 0.65 (95% CI: 0.50 – 0.85) and 0.85 in the wild-type group (95%
CI: 0.58 – 1.25) [12 ]. Thus, this principle could be
confirmed in 2 studies. In fact, the PI3K/AKT signaling pathway is a central
mechanism of signal transduction with an extraordinary significance for many physiological
and pathophysiological
processes [13 ], [14 ].
While the PI3 kinase interacts with the transmembrane receptors at the beginning of
the signal cascade, the AKT kinase downstream of PIK3 and PTEN is responsible for
the further signal
transduction. Activation of this signaling pathway occurs in patients with hormone
receptor-positive disease in approx. 55% of all cases [15 ]. A review of
these signal transduction pathways is shown in [Fig. 3 ].
Fig. 3 The PI3K/AKT/PTEN signaling pathway [53 ].
The FAKTION study is one of the first studies to investigate the effects of the selective
AKT inhibitor capivasertib [16 ]. The study, which had recruited
patients from 2016 to 2018, included patients with resistance to an aromatase
inhibitor. Furthermore, one chemotherapy line and up to 3 previous endocrine therapies
were permitted as long as
they did not contain fulvestrant or a PI3K/AKT/mTOR inhibitor. A total of 140
patients were randomized 1 : 1 to treatment with fulvestrant or fulvestrant + capivasertib.
Data on significant
improvement in progression-free survival have already been published [15 ]. Overall survival data, extended data on PFS and extensive biomarker data have now
been presented. The PFS difference was consolidated with the longer follow-up
and, with an HR of 0.56 (95% CI: 0.38 – 0.81), is consistent with the initial report.
At 4.8 months and 10.3
months, the median PFS times were the same as in the initial report. This PFS
benefit was also translated into a statistically significant overall survival benefit
with an HR of 0.66 (95%
CI: 0.45 – 0.97). Median overall survival improved from 23.4 months to 29.3 months
[16 ].
The biomarker data are of particular interest for this study. For the recently presented
analysis, new state-of-the-art analysis methods were used to divide the patients into
two groups:
“PI3K/AKT/PTEN signaling pathway activated” vs. “not activated”. This was done
by means of mutation tests for PIK3CA, AKT1, PTEN and immunohistochemical examinations for PTEN loss.
Thus, 76 patients could be assigned to the group with altered signaling pathway
and 64 to the group with non-altered signaling pathway. The results confirmed the
efficacy of capivasertib
therapy in patients whose signaling pathway was altered and the lack of efficacy
in patients whose signaling pathway was not altered ([Table 1 ]).
Table 1 Results of the analysis of the FAKTION study according to biomarker status for the
PI3K/AKT/PTEN pathway.
Total population
PIK3/AKT/PTEN altered
PIK3/AKT/PTEN altered
N
140
76
64
Median PFS fulvestrant
4.8 months
4.6 months
4.9 months
Median PFS fulvestrant + capivasertib
10.3 months
12.8 months
7.7 months
Hazard ratio PFS (fulvestrant + capivasertib vs. fulvestrant)
0.56 (95% CI: 0.38 – 0.81)
0.44 (95% CI: 0.26 – 0.72)
0.70 (95% CI: 0.40 – 1.25)
Median OS fulvestrant
23.4 months
20.0 months
25.2 months
Median OS fulvestrant + capivasertib
29.3 months
38.9 months
26.0 months
Hazard ratio OS (fulvestrant + capivasertib vs. fulvestrant)
0.66 (95% CI: 0.45 – 0.97)
0.46 (95% CI: 0.27 – 0.79)
0.86 (95% CI: 0.49 – 1.52)
This underscores the principle that molecular testing can identify patients for whom
therapy, in this case with capivasertib, makes sense. The adverse reaction profile
showed a higher rate
in capivasertib patients for the following side effects: Diarrhea, rash, hyperglycemia,
vomiting, infections and oral mucositis.
Since the FAKTION study was conducted at a time when treatment with CDK4/6 inhibitor
was not yet standard, this preliminary treatment is missing in this study. Against
this background, the
results of the CAPItello-291 study will provide insights into a population in
which a CDK4/6 inhibitor was also approved as a preliminary therapy [17 ].
Combination therapy with CDK4/6 inhibition, as tested in the CAPItello-292 study
[18 ], is also of interest.
Data from the Large, Randomized CDK4/6 Inhibitor Studies are Almost Complete
Data from the Large, Randomized CDK4/6 Inhibitor Studies are Almost Complete
Data overview for the phase III CDK4/6 inhibitor studies is almost complete
For the three CDK4/6 inhibitors palbociclib, ribociclib and abemaciclib, a total of
seven large randomized studies have been conducted ([Table 2 ]). Because
of the improved prognosis, the data from the studies in the first line of therapy
in relation to overall survival have only recently been published.
Table 2 Overview of the large, randomized phase III CDK4/6 inhibitor studies.
N
Therapy
Last patient in
PFS
HR (95% CI)
Median PFS
CDK4/6 | Placebo*
OS
HR (95% CI)
Median OS
CDK arm | Placebo*
Proportion of de novo metastatic patients
Proportion of patients with DFI < 12 months
References
* Based on the respective publication with the longest follow-up.
** Presumably similar to MONALEESA-2 and MONALEESA-7, as the following inclusion criterion
applied: “Endocrine therapy in the neoadjuvant or adjuvant setting was permitted if
the
patient had a disease-free interval. 12 months from the completion of endocrine
therapy.”
*** This study reported treatment-free interval (not DFI). Not comparable with other
DFI percentages.
NA: Not applicable since preliminary therapies were a prerequisite for participation
in the advanced setting; ET: endocrine therapy
MONALEESA-2
668
Ribociclib + letrozole
03/2015
0.56 (0.43 – 0.72)
25.3 | 16.0
0.76 (0.63 – 0.93)
63.9 | 51.4
34%
2.1%
[20 ], [34 ]
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%
**
[35 ], [36 ]
PALOMA-2
666
Palbociclib + letrozole
07/2014
0.58 (0.46 – 0.72)
24.8 | 14.5
0.96 (0.78 – 1.18)
53.9 | 51.2
37%
22%***
[21 ], [37 ]
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%
[38 ], [39 ], [40 ]
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%
[41 ], [42 ], [43 ], [44 ]
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
[45 ], [46 ]
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
[47 ], [48 ], [49 ]
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
[50 ]
Subgroup analysis of the MONALEESA-3 study reports median overall survival for the
first line of therapy
The MONALEESA-3 study is the only study that included patients with both tumors sensitive
to hormone therapy and resistant to hormone therapy, defined by the time between discontinuation
of
adjuvant anti-hormonal therapy (first line) or progression under antihormone
therapy in first-line therapy. In this context, the evaluation of these subgroups
is of particular interest. The
subgroups evaluated independently were those with de novo metastases and those
who had a therapy-free interval from the end of adjuvant therapy of more than 12 months.
This population is
called first-line population in MONALEESA-3. Patients with a treatment-free interval
of less than 12 months (even if they had been treated in the first line of therapy)
and patients with
endocrine preliminary therapy were treated as patients of the second-line therapy.
In the patients sensitive to hormone therapy (MONALEESA-3 first-line population),
a very clear difference
between the treatment arms could be seen with a hazard ratio of 0.67 (95% CI:
00.50 – 0.90) [19 ]. The median overall survival in this population was 51.8
months for fulvestrant monotherapy and 67.6 months for ribociclib-fulvestrant
therapy. In the hormone-resistant group (MONALEESA-3 second-line population), the
difference was not so clear
(HR = 0.80; 95% CI: 0.61 – 1.05) with median overall survival times of 33.7 and
39.7 months [19 ].
Negative overall survival data from the PALOMA-2 study is difficult to interpret
The MONALEESA-2 study was the first study in the first line of therapy in combination
with aromatase inhibitors to report a statistically significant overall survival benefit
[20 ] ([Table 2 ]). The PALOMA-2 study had similar inclusion and exclusion criteria as the MONALEESA-2
study. In addition to the
MONALEESA-2 population, patients who had a disease-free interval of less than
12 months from the end of adjuvant endocrine therapy were also included. This group
accounted for 22% of the
PALOMA-2 patients ([Table 2 ]). In all, the analysis of the overall survival data from the PALOMA-2 study did
not show that adding palbociclib to letrozole
could improve overall survival [21 ]. The hazard ratio for the entire patient population was 0.96 (95% CI: 0.78 – 1.18).
The median overall survival was 51.2
months for the letrozole arm and 53.9 months for the palbociclib + letrozole
arm. Overall, however, the study is difficult to interpret due to a follow-up bias.
In the palbociclib arm, 13%
of patients were not censored for death by month 84, and 21% in the endocrine
monotherapy arm. These differences were sometimes even greater in the subgroup analyses
and more balanced in
others, so that the interpretation of the subgroups is also rather difficult.
However, these subgroups would have been of particular interest because a certain
endocrine resistance had to be
assumed in the PALOMA-2 study in a total of 22% of patients, since in these patients
the interval from the end of adjuvant endocrine therapy to relapse had been less than
12 months. If we
look at the population of patients in whom this interval had been more than 12
months, we find a hazard ratio (0.73; 95% CI: 0.53 – 1.01), which was very similar
to that of MONALEESA-2 and
MONARCH-3. However, the beneficial effect of palbociclib was not seen in the
de novo metastatic group (HR = 1.19; 95%: 0.84 – 1.7), whereas a clear therapeutic
effect was seen in this group
in the MONALEESA-2 study. This subgroup of de novo metastatic patients again
had a clear follow-up bias in the PALOMA-2 study. This example shows how difficult
it is to interpret the data
from the PALOMA-2 study.
There are still no direct comparisons between the CDK4/6 inhibitors, so that no statement
can be made about varying clinical efficacy. In the clinical decision, however, the
existing data
situation must not be disregarded, because therapy alternatives are available
for each choice of a substance.
The final overall survival analysis of the MONARCH-3 study is still pending. In an
interim analysis, we find a hazard ratio of 0.76 (95% CI: 0.58 – 0.97), which had
not yet achieved
statistical significance due to the study design with interim analysis.
Should CDK4/6 inhibitor therapy be continued with progress?
After progress under a CDK4/6 inhibitor, the question arises as to how to proceed
further. This treatment situation was investigated in the maintain study. Patients
with progress under
CDK4/6 inhibitor therapy were randomized 1 : 1 to either ribociclib + modified
ET therapy (continuation of CDK4/6 inhibitor therapy under ribociclib or switch to
ribociclib) and to therapy
with a modified ET alone. In patients receiving an aromatase inhibitor, therapy
with fulvestrant was initiated, and in patients receiving fulvestrant, a change to
exemestane was permitted
later in the course of the study. A total of 119 patients were randomized. The
majority of patients enrolled (n = 103) were on palbociclib therapy at the time of
enrollment in the study, 14
were on ribociclib therapy and 2 on abemaciclib therapy. It has been shown that
discontinuation of CDK4/6 therapy and continuation of treatment with endocrine monotherapy
has not been
beneficial for patients. Prolonged median progression-free survival (5.3 months)
was seen with continued CDK4/6 inhibitor therapy compared to the monotherapy arm (2.8
months). The
corresponding hazard ratio was 0.57 (95% CI: 0.39 – 0.95). This effect appeared
to be present both in the case of a switch from fulvestrant to exemestane (n = 20)
and in the case of a switch
from aromatase inhibitor to fulvestrant (n = 99), although it must be noted that
the subgroup of exemestane patients was very small. The hypothesis that the switch
to fulvestrant was most
likely going to eventuate in a therapeutic benefit due to an accumulation of
somatic ESR1 mutations could not be confirmed. In a total of 78 patients there was a mutation
status of
ESR1 . No treatment benefit for the continuation of CDK4/6 inhibitor therapy was observed
in the group of patients with an ESR1 mutation (HR = 1.22; 95% CI: 0.59 – 1.49),
while the benefit in the group of patients without mutation recorded a hazard
ratio of 0.30 (95% CI: 0.15 – 0.62).
This study underscores the importance of a better understanding of the progression
mechanisms among CDK4/6 inhibitors. The PADA-1 study investigated another question
in this context. In
early detection of ESR1 mutations in the blood without clinical progression, a benefit could be seen in the
PADA-1 study in the switch from aromatase inhibitors to fulvestrant [22 ]. The change in clinical progression in the MAINTAIN study in the group of ESR1- mutated patients had shown no effect. The reasons can only be presumed,
but can possibly be explained by high fulvestrant activity. This shows that progression
mechanisms may be more complicated than previously assumed and further studies are
necessary to enable
better sequence planning. Studies such as MINERVA [23 ] and the CAPTOR-BC study [23 ], which are currently starting to recruit,
address these questions.
Sacituzumab Govitecan in Patients with HER2-negative HR-positive Breast Cancer
Sacituzumab Govitecan in Patients with HER2-negative HR-positive Breast Cancer
Trop-2 is an antigen which is overexpressed in some cancers such as breast cancer,
some thyroid carcinomas, pancreatic carcinoma, colon carcinoma, urothelial carcinoma
and other tumors [24 ] – [26 ]. Even if participations in signaling pathways are postulated, which play a role
in the development of cancer or
progression, it has not yet been possible to prove that Trop-2 is a prognosis
marker for patients with breast cancer [27 ]. However, as already described above,
the activity of the addressed signaling pathway does not necessarily appear to
be of great importance for an efficacy of some ADCs, but rather the pure presence
of the target molecule, in the
case of Trop-2. Already in the ASCENT study, it was shown that even with low Trop-2
expression, an effect of sacituzumab govitecan could still be demonstrated [28 ].
Against this background, the results of the TROPiCS-02 study have now been presented.
The TROPiCS-02 study included hormone receptor-positive, HER2-negative patients who
had to have completed
some preliminary therapies. These included at least endocrine therapy, taxane
therapy and therapy with a CDK4/6 inhibitor. At least 2 and no more than 4 chemotherapy
lines for metastatic
disease had to be completed. Thus, only HR-positive/HER2-negative patients who
had clearly completed preliminary therapies were included in this study [29 ].
Patients were randomized 1 : 1 to treatment with sacituzumab govitecan or to chemotherapy
at the physicianʼs choice (capecitabine, vinorelin, gemcitabine, eribulin). The aim
of such a study
should be to improve the prognosis with a more favorable side effect profile.
The study was positive with regard to the primary study objective PFS. The median
PFS was extended from 4.0 months to 5.5 months. The hazard ratio was 0.66 (95% CI:
0.53 – 0.83; p = 0.0003).
With these results, the study was able to fairly accurately demonstrate the effect
that had been planned and assumed in advance. Overall survival was not statistically
significantly different
in this interim analysis. Median overall survival was improved from 12.3 to 13.9
months. This corresponded to an HR of 0.84 (95% CI: 0.67 – 1.06; p = 0.14) [29 ].
It is questionable whether a difference in median PFS of 1.5 months is clinically
relevant, in particular because the side effect profile in terms of hematological,
gastrointestinal side
effects and alopecia was less favorable in the sacituzumab-govitecan arm than
in the chemotherapy arm [29 ]. However, this adverse reaction profile did not
appear to affect the quality of life. The quality of life measured by the EORTC-QLQ-C30
questionnaire was maintained longer (time to deterioration) with sacituzumab govitecan
than with
chemotherapy [29 ].
It is known from real-world data that patients still receive a large proportion of
chemotherapy in the second and third lines of therapy after CDK4/6 inhibitor therapy
[8 ]. Against this background, the data from the TROPiCS-02 study are certainly promising
and it is desirable that this drug is investigated in earlier lines of
therapy with the intention of checking whether a larger, absolute improvement
in the prognosis can also be achieved in a collective with a generally better prognosis.
Outlook
For patients with advanced, hormone receptor-positive, HER2-negative breast cancer,
new findings have been published with the PALOMA-2 study, the Destiny-Breast-04 study
and the TROPiCS-02
study, which have a high relevance for clinical practice. With an overall survival
benefit and an acceptable side effect profile, trastuzumab deruxtecan could establish
itself after an
approval extension for patients with an MBC and the property HER2-low. The Destiny-Breast-06
study [30 ], which examines the substance in patients with
metastatic breast cancer and HER2-low expression in previous lines of therapy,
is currently still recruiting.
The lack of evidence of an overall survival benefit presents both doctors and patients
with the challenge of meaningfully interpreting the data. Experience from clinical
practice will show
whether the different data situation ([Table 1 ]) will result in different prescribing behavior. With the CDK4/6 inhibitors as standard
of care and the
different study data, the need to better understand the mechanisms of action and
resistance in order to better plan treatment sequencing or further combination therapies
is growing. Clinical
studies, for example, pursue the approach of switching the therapy to a SERD in
the case of an ESR1 mutation under therapy with a CDK4/6 inhibitor and aromatase inhibitor [31 ]. Furthermore, the CAPTOR-BC study [32 ] and the MINERVA study [23 ] mark the launch of two
translational research programs in Germany, which also investigate the molecular
mechanisms of resistance and mode of action of the CDK4/6 inhibitors ribociclib and
abemaciclib.
