European Journal of Clinical Investigation,
Год журнала:
2025,
Номер
unknown
Опубликована: Фев. 13, 2025
Abstract
Background
Antibody‐drug
conjugates
are
novel
effective
therapies
for
metastatic
breast
cancer.
Nevertheless,
their
toxicity
profile
can
significantly
affect
patients'
quality
of
life
over
time.
Methods
This
is
a
systematic
review
and
meta‐analysis
randomized
controlled
trials
antibody‐drug
currently
approved
the
treatment
cancer
[trastuzumab‐emtansine
(T‐DM1),
trastuzumab
deruxtecan
(T‐DXd)
sacituzumab‐govitecan
(SG)]
versus
standard
therapy
to
evaluate
risk
adverse
events,
discontinuation
rate
due
toxicity,
impact
on
according
EORTC
QLQ‐C30
scale
subdomains.
Relative
risks
(RR)
hazard
ratios
(HR)
with
95%
CIs
were
calculated
using
random
effects
models.
Results
Nine
total
5753
patients
included.
The
most
common
events
any
grade
T‐DM1
included
thrombocytopenia
(RR
7.14,
CI
4.13–12.36)
increased
alanine‐transaminase
(ALT)
2.04,
1.43–2.91),
T‐DXd
nausea
2.39,
1.90–3.00)
anemia
1.55,
1.27–1.90),
while
SG
neutropenia
1.30,
1.14–1.49),
diarrhea
3.62,
2.97–4.42)
(RR1.90,
1.65–2.19).
Severe
such
as
interstitial
lung
disease
left
ventricular
dysfunction
peculiar
T‐DXd.
delayed
clinical
deterioration
global
health
status
by
(HR
.71,
.59–.86),
physical,
emotional
social
functioning,
pain
fatigue
symptoms.
Conclusions
offers
consolidated
data
associated
life,
emphasizing
differences
based
specific
agent.
These
findings
underscore
critical
need
strategies
prevent,
diagnose
manage
these
toxicities.
Journal of Translational Medicine,
Год журнала:
2024,
Номер
22(1)
Опубликована: Авг. 5, 2024
In
recent
years,
with
advancements
in
medicine,
the
survival
period
of
patients
tumours
has
significantly
increased.
The
adverse
effects
tumour
treatment
on
patients,
especially
cardiac
toxicity,
have
become
increasingly
prominent.
elderly
breast
cancer,
treatment-related
cardiovascular
toxicity
surpassed
cancer
itself
as
leading
cause
death.
Moreover,
an
increasing
number
novel
antitumour
drugs,
such
multitargeted
agents,
antibody‒drug
conjugates
(ADCs),
and
immunotherapies,
been
applied
clinical
practice.
cardiotoxicity
induced
by
these
drugs
more
pronounced,
to
a
complex
diverse
mechanism
damage.
risks
unintended
are
increased
high-dose
anthracyclines,
concurrent
radiation,
addition
traditional
risk
factors
smoking,
hypertension,
diabetes,
hyperlipidaemia,
obesity.
However,
do
not
fully
explain
why
only
subset
individuals
experience
whereas
others
similar
features
not.
Recent
studies
indicate
that
genetics
play
significant
role
susceptibility
development
from
therapies.
These
genes
involved
drug
metabolism,
oxidative
damage,
dysfunction,
other
processes.
emerging
evidence
suggests
epigenetics
also
plays
drug-induced
toxicity.
We
conducted
review
focusing
example
help
oncologists
cardiologists
better
understand
mechanisms
genetic
this
review,
we
specifically
address
relationship
between
alterations
including
chemotherapy-related
changes,
targeted
therapy-related
immune
changes.
discuss
epigenetic
hope
will
improve
stratification
enable
therapeutic
interventions
mitigate
consequences
life-saving
treatments.
Journal of Hematology & Oncology,
Год журнала:
2024,
Номер
17(1)
Опубликована: Дек. 25, 2024
Abstract
Substantial
therapeutic
advancement
has
been
made
in
the
field
of
immunotherapy
breast
cancer.
The
immune
checkpoint
inhibitor
pembrolizumab
combination
with
chemotherapy
received
FDA
approval
for
both
PD-L1
positive
metastatic
and
early-stage
triple-negative
cancer,
while
ongoing
clinical
trials
seek
to
expand
current
treatment
landscape
inhibitors
hormone
receptor
HER2
Antibody
drug
conjugates
are
approved
triple
negative
HER2+
disease,
being
studied
inhibitors.
Vaccines
bispecific
antibodies
areas
active
research.
Studies
cellular
therapies
such
as
tumor
infiltrating
lymphocytes,
chimeric
antigen
receptor-T
cells
T
cell
engineered
promising
ongoing.
This
review
provides
an
update
recent
major
cancer
discusses
future
directions
Current Oncology,
Год журнала:
2025,
Номер
32(2), С. 81 - 81
Опубликована: Янв. 31, 2025
Leptomeningeal
metastasis
(LM)
is
a
rare
and
challenging
manifestation
of
advanced
breast
cancer
(ABC)
with
severe
morbidity
mortality.
Patients
LM
may
be
asymptomatic,
or
present
non-specific
neurologic
deficits,
thereby
possibly
delaying
diagnosis.
Treatment
typically
requires
multimodal
approach
for
effective
management,
symptom
relief,
quality-of-life
improvement.
Trastuzumab-deruxtecan
(T-DXd),
humanized
monoclonal
antibody
drug
conjugate,
demonstrated
efficacy
across
diverse
subtypes
expressing
variable
levels
HER2
proteins.
Currently,
T-DXd
the
standard
care
patients
advanced,
pretreated,
low
cancer.
There
limited
evidence
response
brain
metastases
(BM)
leptomeningeal
to
in
HER2-low
patients,
most
data
extrapolated
from
HER2-positive
studies.
This
case
report
presents
first
documented
instance
patient
debilitating,
symptomatic,
untreated
hydrocephalus
demonstrating
rapid
dramatic
clinical
T-DXd.
finding
holds
crucial
relevance,
highlighting
potential
benefit
initiating
systemic
therapy
early
treatment
address
both
central
nervous
system
(CNS)
non-CNS
disease
burden,
rather
than
until
after
radiation
therapy.
Signal Transduction and Targeted Therapy,
Год журнала:
2025,
Номер
10(1)
Опубликована: Фев. 14, 2025
Abstract
Aberrant
RNA
alternative
splicing
in
cancer
generates
varied
novel
isoforms
and
protein
variants
that
facilitate
progression.
Here,
we
employed
the
advanced
long-read
full-length
transcriptome
sequencing
on
gallbladder
normal
tissues,
tumors,
cell
lines
to
establish
a
comprehensive
transcriptomic
atlas.
It
is
of
note
receptor
tyrosine
kinases
were
one
most
dynamic
components
with
highly
variable
transcript,
Erb-B2
kinase
2
(ERBB2)
as
prime
representative.
A
designated
ERBB2
i14e,
was
identified
for
encoding
functional
protein,
its
expression
elevated
strongly
associated
worse
prognosis.
With
regulation
factors
ESRP1/2,
i14e
alternatively
spliced
from
intron
14
encoded
peptide
proved
interaction
ERBB3
downstream
signaling
activation
AKT.
inducible
attenuated
anti-ERBB2
treatment
efficacy
tumor
xenografts.
Further
studies
patient
derived
xenografts
models
validated
blockage
antisense
oligonucleotide
enhanced
sensitivity
trastuzumab
drug
conjugates.
Overall,
this
study
provides
specific
profile
discovers
mechanism
resistance,
thus
ultimately
devising
strategies
improve
therapy.
Immunology and Cell Biology,
Год журнала:
2025,
Номер
unknown
Опубликована: Март 10, 2025
In
this
article
for
the
"Highlights
of
2024"
series,
we
discuss
antibody–drug
conjugates
(ADCs),
which
are
an
emerging
class
targeted
cancer
therapies
that
harness
specificity
monoclonal
antibodies
to
deliver
cytotoxic
agents
directly
tumor
cells.
ADCs
bind
tumor-associated
antigens,
undergo
internalization
via
receptor-mediated
endocytosis,
and
release
their
payload
intracellularly,
reducing
systemic
toxicity.
This
highly
selective
mechanism
has
led
significant
advancements
in
oncology,
improving
treatment
efficacy
while
minimizing
adverse
effects.
Antibody–drug
(ADCs)
transforming
management
a
range
cancers
have
potential
also
be
practise-changing
other
malignancies.
These
drugs
bridge
contemporary
immunology
oncology
by
integrating
enriched
epitopes,
with
potency
drugs.
By
selectively
delivering
potent
payloads
cells,
enhance
therapeutic
toxicity
associated
conventional
chemotherapy
radiotherapy
approaches.1
The
development
stems
from
combination
decades
research,
been
instrumental
refining
antibody
generation
understanding
how
immune
system
recognizes
targets
deepening
knowledge
about
mode
action
cytotoxins
used
as
most
effectively
link
these
tumor-targeting
antibodies.
Here,
highlight
key
translation
bench-to-bedside,
focusing
on
clinical
trials
across
various
types.
Over
past
30
years
emergence
approaches
manipulate
seen
gradual
new
targeting
immunotherapies
capable
avoiding
often
toxicities
surgeries,
chemotherapies
radiotherapies.2
For
example,
dawn
"humanization",
pioneered
Nobel
Laureate
Professor
Greg
Winter
1980s,3
transformed
into
effective
therapeutics
against
cancer,
leading
efficacious
personalized
such
cetuximab
EGFR+
colorectal
head
neck
cancers,
trastuzumab
pertuzumab
HER2+
breast
checkpoint
inhibitors
anti-PD-1
melanoma,
more
recently
precision-targeted
therapy
particular
ado-trastuzumab
emtansine
(T-DM1)
fam-trastuzumab
deruxtecan
(T-DXd)
cancers.2,
4
composed
component
conjugated
agent
linker
is
otherwise
stable
until
located
surface
malignant
cells
resulting
preferential
cytotoxin
at
site.5
function
through
combines
immunological
precision
effects
small-molecule
involves
binding
specific
target
antigen
minimal
expression
healthy
tissues.6
Effective
exhibit
both
high
rapid
internalization,
ensuring
efficient
intracellular
drug
delivery.7
Once
bound,
ADC–antigen
complex
undergoes
endocytosis
then
trafficking
lysosomes,
where
is,
payload.8
depends
type
linker.9
Cleavable
linkers
designed
break
down
response
conditions
low
pH,
glutathione
levels
or
enzymatic
cleavage
proteases.
contrast,
non-cleavable
require
full
degradation
within
lysosome
before
can
released,
exerts
its
effect
disrupting
essential
cellular
processes,
cell
death.10
typically
employ
two
main
classes
agents:
microtubule
inhibitors,
monomethyl
auristatin
E,
interfere
tubulin
polymerization
disrupt
mitosis,
DNA-damaging
agents,
calicheamicin,
cause
lethal
DNA
strand
breaks
prevent
replication.
Depending
ADC
design,
killing
include
antibody-dependent
cytotoxicity
bystander
activating
tumoricidal
functions
natural
killer
cells.5
A
schematic
outlining
illustrated
Figure
1.
Through
mechanism,
revolutionizing
several
combining
payloads,
significantly
outcomes
off-target
Currently,
US
Food
Drug
Administration
(FDA)
granted
regulatory
approval
13
use,
occurring
decade,
despite
first
dating
back
2000,
gemtuzumab
ozogamicin
(Mylotarg®)
acute
myeloid
leukemia.
While
no
received
FDA
approvals
use
2024,
January
2025
datopotamab
deruxtecan,
TROP2-targeting
ADC,
metastatic
signaling
continued
progress
field.11
year
than
100
developed,
many
ongoing
efforts
expand
applications
multiple
types
notable
examples
summarized
Table
last
few
T-DXd
emerged
superior
HER2-targeting
compared
T-DM1,
demonstrated
Phase
3
DESTINY-Breast03
trial.12
was
FDA-approved
2013
HER2-positive
demonstrate
efficacy.
However,
T-DXd,
higher
drug-to-antibody
ratio
T-DM1
(~8
vs.
~3–4)
topoisomerase
I
inhibitor
instead
inhibitor,
emtansine,
offered
advantages,
including
enhanced
penetration
effect.
properties
not
only
increase
but
improve
tumors
heterogeneous
HER2
expression,
potentially
overcoming
resistance.
Additionally,
optimized
improves
stability
release,
contributing
activity.
patients
who
had
taxanes
trastuzumab,
improved
progression-free
survival
7.2
29
months
extended
overall
42.7
52.6
months.
there
were
drug-related
treatment-emergent
events
serious
one
being
interstitial
lung
disease.
It
worth
noting
evaluated
continues
further
investigations.13
major
outcome
FDA's
accelerated
any
HER2-expressing
solid
previously
undergone
therapy,
making
it
tumor-agnostic
ADCs.
Beyond
disitamab
vedotin
(DV)
shown
promise
urothelial
carcinoma,
uses
E
payload.14
2
study
evaluates
locally
advanced,
refractory
around
50%
objective
displaying
promising
outcomes.
results
particularly
given
aggressive
subtype
limited
options,
especially
progressed
after
inhibitors.15
trial
highlighted
DV
patient
subgroups,
those
liver
metastases
treated
inhibitors.14
remains
concern,
neuropathy
neutropenia
common
events,
reflecting
related
profile.
currently
approved
National
Medical
Products
China
gastric
success
suggests
broader
tumors.
Another
2024
SHR-A1811,
1/2
HER2-mutant
non-small
(NSCLC).16
Unlike
HER2-amplified
mutations
NSCLC
resistance
traditional
HER2-targeted
therapies,
treatments
crucial
population.
contains
(SHR169265),
assessed
platinum-based
chemotherapy,
group
options.
rate
41.9%,
responses
lasting
over
some
patients.
nearly
half
experiencing
Grade
events.
Interstitial
disease
notable,
fatal
case
reported.
1
advanced
biliary
tract
almost
60%
patients.17
development,
another
gaining
traction
due
nature
large
B-cell
lymphoma.
reported
1b/2
investigated
mosunetuzumab,
CD20xCD3
bispecific
T-cell
engager,
polatuzumab
vedotin,
CD79B-targeting
ADC.18
proven
single
agent,
mosunetuzumab
enhances
T-cell-mediated
cytotoxicity.
59.2%,
complete
50%,
demonstrating
durable
heavily
pretreated
showed
manageable
safety
profile,
fatigue
grade
combined
loncastuximab
tesirine
rituximab
relapsed
follicular
lymphoma,19
following
previous
(ClinicalTrials.gov
Identifier:
NCT02702141).
Follicular
lymphoma
difficult
treat,
relapse
early
first-line
therapy.
tesirine,
anti-CD19
pyrrolobenzodiazepine
payload,
rituximab,
CD20-targeting
antibody.19
ADC-mediated
damage
rituximab-induced
activation.
67%
months,
strong
anti-tumor
activity
Despite
efficacy,
lymphopenia
common,
although
infrequent.
advancement
treatment,
offering
precise
approach
five
expanding
role
hematologic
malignancies,
innovations
selection,
strategies
encouragingly
rates
durability,
exhausted
therapies.
toxicities,
neuropathy,
myelosuppression
disease,
remain
challenges,
emphasizing
need
careful
selection
management.
critical
strength
lies
component,
allows
underscores
growing
biomarker-driven
marking
shift
toward
tailored
molecular
rather
same
reflects
effort
optimize
design.
Furthermore,
combine
immune-based
(anti-PD-1,
anti-CTLA-4),
represents
frontier
treatment.
leveraging
simultaneously
enhancing
blockade,
future
could
overcome
mechanisms.
With
innovation
set
become
cornerstone
modern
hope
Funding
Guimaraes's
Laboratory
partially
provided
Research
Future
Fund,
Australia
(with
support
Queensland
Children's
Hospital
Foundation,
Microba
Life
Sciences,
Richie's
Rainbow
Translational
Institute
University
Queensland,
Australia)
under
award
number
2019485;
funding
Cooper
Rice-Brading
Australia,
Tie
Dye
Project,
Bricks
&
Smiles,
Kids
Cancer
Tour
de
Cure,
PA
Breast
Foundation
(award
2023/IIRS0063).
JJ
supported
Australian
Government
Training
Program
Scholarship.
content
solely
responsibility
authors
does
necessarily
represent
official
views
organizations
agencies.
Jiya
Jose:
Conceptualization;
investigation;
writing
–
original
draft.
John
D
Hooper:
supervision;
review
editing.
Fernando
Souza-Fonseca-Guimaraes:
acquisition;
project
administration;
draft;
FSFG
Board
Member
Cure
member
Scientific
Advisory
Committee
ANZSA.
Sciences
sponsors
research
laboratory
FSFG.
Other
commercial,
proprietary
financial
interest
study.
Nature Communications,
Год журнала:
2025,
Номер
16(1)
Опубликована: Апрель 2, 2025
Trastuzumab
deruxtecan
(T-DXd)
is
an
antibody-drug
conjugate
(ADC)
targeting
HER2,
exhibiting
significant
clinical
efficacy
in
breast
cancer
(BC)
with
varying
HER2
expression,
including
HER2-low
and
HER2-ultralow.
However,
the
precise
mechanism
underlying
its
contribution
of
immune
activation
these
settings
remain
unclear.
Here,
we
demonstrate
that
T-DXd
HER2-negative
BC
independent
engagement
ADC
internalization.
Instead,
activity
relies
on
extracellular
proteases,
such
as
cathepsin
L
(CTSL),
within
tumor
microenvironment.
Irrespective
their
status,
stromal
compartments
invasive
abundantly
express
CTSL,
which
efficiently
cleaves
specialized
linker
T-DXd,
facilitating
payload
release
inducing
cytotoxicity
against
HER2-low/negative
tumors.
In
HER2-positive
BC,
antibody
backbone
engages
Fcγ-receptors
drives
antibody-dependent
cellular
phagocytosis
(ADCP).
Concurrently,
cytotoxic
(DXd)
induces
immunogenic
cell
death,
further
activating
myeloid
cells
via
TLR4
STING
pathways
to
enhance
antigen
presentation
CD8+
T
cells.
Notably,
also
upregulates
CD47
dampening
activation.
Combining
checkpoint
blockade
significantly
enhances
anti-tumor
responses
a
HER2-transgenic
mouse
model,
while
durable
memory
prevent
recurrence
after
therapy
cessation.
