Accelerating Therapeutic Progress in HER2+ and HER2-Low Breast Cancer: State of the Science and Guidance for Individualized Clinical Decisions

Chair and Presenters, Komal Jhaveri, MD, FACP, Javier Cortes, MD, PhD, Prof. Giuseppe Curigliano, MD, PhD, and Ian Krop, MD, PhD, prepared useful Practice Aids pertaining to breast cancer for this CME/MOC/NCPD/AAPA/IPCE activity titled “Accelerating Therapeutic Progress in HER2+ and HER2-Low Breast Cancer: State of the Science and Guidance for Individualized Clinical Decisions.” For the full presentation, downloadable Practice Aids, and complete CME/MOC/NCPD/AAPA/IPCE information, and to apply for credit, please visit us at https://bit.ly/42EzL7g. CME/MOC/NCPD/AAPA/IPCE credit will be available until June 30, 2025.

1. Treatment Recommendations for HER2+
Metastatic Breast Cancer
Full abbreviations, accreditation, and disclosure information available at PeerView.com/SBE40
a
See additional considerations for those receiving systemic HER2-targeted therapy (BINV-Q 4).
b
Assess for germline BRCA1/2 mutations in all patients with recurrent or metastatic breast cancer to identify candidates for PARP inhibitor therapy. While olaparib and talazoparib are
FDA-indicated in HER2-negative disease, the panel supports use in any breast cancer subtype associated with a germline mutation. There is lower-level evidence for HER2-positive tumors, therefore category 2A for this setting.
c
Maintenance trastuzumab/pertuzumab after response
(with concurrent endocrine therapy if ER+ and HER2+ metastatic breast cancer).
d
Fam-trastuzumab deruxtecan-nxki may be considered in the first-line setting as an option for select patients (ie, those with rapid progression within 6 mo of neoadjuvant or adjuvant therapy [12 mo for
pertuzumab-containing regimens]). Fam-trastuzumab deruxtecan-nxki is associated with interstitial lung disease (ILD)/pneumonitis. Regular monitoring for this serious side effect is recommended. For patients with a history of ILD/pneumonitis, there are no data on managing safety or
toxicity of this drug in a trial.
e
Tucatinib + trastuzumab + capecitabine is preferred in patients with both systemic and CNS progression in the third-line setting and beyond, and it may be given in the second-line setting.
f
May be used as an option for third-line and beyond; the optimal
sequence for third-line therapy and beyond is not known. If not a candidate, fam-trastuzumab T-DM1 could be considered in the second-line.
g
Multiple lines of concurrent chemotherapy with anti-HER2 therapy (trastuzumab or a TKI) offer clinical benefit for recurrent unresectable
HER2+ metastatic breast cancer and have been studied in phase 2 or 3 trials. Clinical experience suggests frequent clinical benefit for such treatment. However, there are no meaningful data for use of any of these regimens among patients previously treated with pertuzumab-based
chemotherapy, ado-trastuzumab emtansine, fam-trastuzumab deruxtecan-nxki, or trastuzumab/capecitabine/tucatinib regimens. Thus, the optimal sequence or true benefit of therapy is not known.
h
Trastuzumab given in combination with an anthracycline is associated with significant
cardiac toxicity. Concurrent use of trastuzumab and pertuzumab with an anthracycline should be avoided.
i
Trastuzumab may be safely combined with all nonanthracycline-containing preferred and other single agents listed on BINV-Q 5 for recurrent or metastatic breast cancer.
1. NCCN Clinical Practice Guidelines in Oncology. Breast Cancer. Version 2.2024. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf.
Setting Regimen
HR Positive or HR Negative and HER2 Positive
a,b
NCCN Categoryof Preference Evidence Level
First line
c
Pertuzumab + trastuzumab + docetaxel Preferred regimen 1
Pertuzumab + trastuzumab + paclitaxel Preferred regimen 2A
Second Third line
line
e
Trastuzumab deruxtecan (T-DXd)
d Preferred regimen
Preferred regimen
1
1
Fourth lin e and
beyond
(optimal seque nce
unknown)
g
Trastuzumab + docetaxel or vinorelbine Other recommended regimen
Other recommended regimen
2A
2A
Tucatinib + trastuzumab + capecitabine
e
Trastuzumab emtansine (T-DM1)
f
Trastuzumab + paclitaxel ±carboplatin Other recommended regimen 2A
Capecitabine+ trastuzumab or lapatinib Other recommended regimen
2ATrastuzumab + lapatinib (without cytotoxic therapy) Other recommended regimen
2A
Trastuzumab + other chemotherapy agent s
h,i
Other recommended regimen
Neratinib + capecitabine Other recommended regimen 2A
Additional targeted therapy options (see BINV-Q [6]
of the NCCN guidelines)
Other recommended regimen 2A
Margetuximab + chemotherapy
(capecitabine, eribulin, gemicitabine, or vinorelbine)
Other recommended regimen 2A
2A
Recurrent Unresect able (Local or Regional) or Stage IV (M1) Disease:
Updated Recommendations Based on NCCN Guidelines Version 1.2024
1

2. Detecting and Managing Trastuzumab
Deruxtecan (T-DXd)?Related ILD: The Five ?S? Rules
1

Full abbreviations, accreditation, and disclosure information available at PeerView.com/SBE40 1. Tarantino P, Tolaney SM. JCO Oncol Pract. 2023;19:526-527.
• Careful patient selection
is warranted before
initiating T-DXd to
optimize the monitoring
strategies based on the
baseline risk
• Screening continues
during treatment, with
regular clinical
assessments to exclude
signs/symptoms of ILD
Screen
• The fundamental
diagnostic tools for ILD
remain radiological
scans, with preference
for high-resolution CT
scans of the chest
• A baseline scan is
recommended, with
repeat scans to be
performed every 6-12
weeks
Scan
• Minimizing the risk
of ILD involves
teamwork, which
includes educating
patients and the entire
care team, as well
as multidisciplinary
management once ILD
is suspected
Synergy
• T-DXd should always be
interrupted if ILD is
suspected; it can only
be restarted in the case
of asymptomatic ILD
that fully resolves
Suspend
Treatment
• The mainstay for
treating T-DXd–induced
ILD remains
corticosteroids, with
the dose to be adapted
to the toxicity grade
Steroids

3. Identifying and Categorizing Patients
With HER2+ Breast Cancer
1,2

Full abbreviations, accreditation, and disclosure information available at
PeerView.com/SBE40
a
It is recommended that pathologists use the term ‘faint’ rather than ‘faint/barely perceptible’ for the definition of IHC 0 and IHC 1+, as in the DESTINY-Breast04 trial.
1. Curigliano G et al. ESMO Open. 2024;9:102989. 2. Tarantino P et al. Cancer Discovery. 2022;12:2026-2030. When should
samples be
rescored?
What biopsy
types can
be used?
What assays
can be used?
• Both VENTANA and non-VENTANA assays
can be used to identify HER2-low status
• In the United States, VENTANA 4B5 is approved
as a companion diagnostic for identifying patients
eligible for T-DXd in the HER2-low setting
• In the EU, eligibility for T-DXd is based on
any validated assay
• Primary or metastatic samples can be used
to identify HER2-low breast cancer
• Bone biopsies are not preferred, but may be
considered if no other disease site can be
assessed for HER2
• Surgical excision specimens may be preferable
to core-needle biopsy specimens
When should
biopsies
be repeated?
• After disease progression
How should
HER2 status
be reported?
• Maintain nomenclature consistent with the
ASCO/CAP 2018 algorithm
a
• Include the IHC score (0, 1+, 2+, or 3+) in the
pathology report
• The term ‘HER2-low’ is not preferable in the
pathology report
• Eligible for T-DXd in the HER2-low setting
• No strong rationale to rescore
Any history of IHC 1+ or IHC 2+
History of IHC 0 only
• Consider rescoring with emphasis on differentiating low-end
HER2 expression
• If a primary tumor is scored as IHC 0, evaluate metastatic sample;
if no metastatic sample is available, consider re-evaluating
primary samples
Evolution of HER2 Classification and Current Categories
The availability of novel anti-HER2 treatments is progressively redefining the way HER2 is categorized
Identification of Patients With HER2-Low Breast Cancer
HER2+
HER2-low
HER2-0
HER2-
ultralow
HER2+
HER2-negative
ERBB2-amplified
Benefit with the therapeutic
blockade of the HER2
pathway
Targetable with ADCs
under investigation
HER2+
Continuous spectrum of
HER2-low expression
HER2+
HER2-low
HER2-0
For more than two decades,
HER2 has been categorized
in a binary way
(positive vs negative)
It is possible that with the
validation of novel quantitative
HER2 assays the spectrum of
HER2 expression may further
expand to all patients with
HER2-nonamplified tumors,
allowing the dissection of the
granularity of HER2 expression
and informing clinical
decision-making
Additional evolutions may derive
from ongoing trials: The phase III,
randomized DESTINY-Breast06
trial will include a cohort of
patients with ultralow HER2
expression (IHC >0 <1+) and
potentially expand the population
deriving benefit from T-DXd
Results of the DESTINY-
Breast04 trial have confirmed
the benefit of treating
HER2-low (IHC 1+ or
2+/ISH-negative) breast cancer
with T-DXd, highlighting the
need to evolve HER2
categorization in order to
optimally select patients
for treatment with this compound
HER2
expression
IHC/ISH
scores
Traditional
HER2
categories
IHC 0
HER2- HER2+
Currently
targetable
HER2 groups
Potential
future
landscape
HER2-low HER2+
HER2-lowHER2
>0 to
<1+
HER2-
0
HER2+
IHC 1+
IHC 2+/
ISH-
IHC 2+/
ISH+
IHC 3+
Increasing HER2 expression
D
E
S
T
I
N
Y
-
B
r
e
a
s
t
0
4
D
E
S
T
I
N
Y
-
B
r
e
a
s
t
0
6
ERBB2-nonamplified
No benefit with HER2 blockade
Targetable with novel ADCs

4. Breast Cancer Resource Compendium for Patients
Full abbreviations, accreditation, and disclosure information available at PeerView.com/SBE40 GRASP was founded by
Christine Hodgdon and
Julia Maués, advocates
who know firsthand
what it’s like to live
with metastatic
disease.
GRASP
believes in
equity, inclusivity,
and the power of science.
It is committed to fostering
inclusive partnerships and
addressing disparities
that impact cancer
research and access
to treatment.
Recognizing the value
patients bring to research
is a key feature of GRASP.
Clinicians are experts in
treating cancer, researchers
are experts in the science
of cancer, but importantly,
patients are experts
in living with cancer.
GRASP also serves
both cancer scientists
and clinicians, including
oncologists and nurse
professionals who
treat patients and
engage in research.
GRASP serves cancer
advocates and cancer
patients who seek to
better understand the science
behind cancer research,
and effectively bring the
patient perspective
to research
activities.
GRASP is a
patient-led
organization that
connects and
empowers patients,
clinicians, and
researchers to
exchange ideas and
learn from each other.
Programs
GRASP’s bidirectional programs connect
advocates and researchers
Changing the Way We Approach Science,
So We Can Change Lives
GRASP’s patient-led program connects scientists,
clinicians, and patient advocates, empowering them to
exchange ideas and learn from each other. By working
together, we can drive more meaningful and fundable
research and make faster progress to end cancer.
GRASP: Guiding Researchers and Advocates to Scientific Partnerships Programs

5. Breast Cancer Resource Compendium
for Healthcare Providers and Patients
Full abbreviations, accreditation, and disclosure information available at
PeerView.com/SBE40 Resources for healthcare providers
• Online hub with quick access to resources, videos, downloads, and more
• Print publications for your patients
• Free webinars, frequently with CEs
• Sexual Health Toolkit
• Survivorship Series training program for oncology nurse navigators
• Monthly e-newsletter with resources, updates, and events
• Volunteer opportunities as speakers, advisors, or bloggers
We have resources for Young, Black, Metastatic, and LGTBQ+ patients
Contact us today to learn how we can support you and your team
[phone] | [email protected]
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For over 30 years, Living Beyond Breast Cancer has offered
emotional, practical, and evidence-based information to help
people diagnosed with breast cancer and those who care for
them make informed decisions with confidence.
Resources for your breast cancer patients
• Easy-to-use website
• Video library and award-winning blog
• Free downloadable publications
• Conferences, events, and programs
• Peer-to-peer support: Breast Cancer
Helpline and private Facebook groups
• Financial assistance: The Living
Beyond Breast Cancer Fund
• Free books for kids and families:
Reading for Reassurance
• Advocacy trainings and volunteer
opportunities
View HCP Resources
lbbc.org/hcp

6. Breast Cancer Resource Compendium
for Healthcare Providers and Patients
Full abbreviations, accreditation, and disclosure information available at
PeerView.com/SBE40 What are HER2-positive and
HER2-low breast cancer?
Not all breast cancers are the same. In HER2-positive breast cancer,
changes in a gene called HER2 trigger breast cancer growth.
A normal HER2 gene makes HER2 proteins that help cells grow,
multiply, or repair damage in a healthy way. When the gene makes
too many copies of itself, which tells the breast cells to make too
many HER2 receptors (HER2 protein overexpression), it leads
to breast cancer. Knowing if a cancer is driven by HER2 helps
determine treatment, because HER2-targeted therapies can treat
HER2-positive and HER2-low breast cancers.
HOW IS HER2 STATUS CONFIRMED?
After biopsy, a tissue sample is tested using an immunohistochemistry (IHC)
test, a fluorescence in situ hybridization (FISH) test, or both. These two
biomarker tests show how many HER2 proteins (receptors) are on the surface
of breast cancer cells. Usually, an IHC test is performed first because it gives a
numeric score. If the IHC score falls in a certain range, a FISH test is performed.
FISH results are positive or negative.
WHAT TREATMENTS ARE AVAILABLE FOR HER2-POSITIVE BREAST CANCER?
HER2-positive breast cancers are treated with targeted therapies tailored to the
HER2 receptor. Treatment can also include chemotherapy, surgery, and radiation
therapy. If the cancer is also hormone receptor-positive, patients may also take
endocrine therapy.
Anti-HER2 biosimilars—drugs that are structurally and functionally similar to
anti-HER2 biologic medicines—are also available.
WHAT TREATMENTS ARE AVAILABLE FOR HER2-LOW BREAST CANCER?
Only one HER2-targeted therapy is FDA approved to treat HER2-low breast cancer:
trastuzumab deruxtecan. If the cancer is also hormone receptor-positive, it can also
be treated with endocrine therapy. If it tests hormone receptor-negative, treatments
may include chemotherapy.
Fifteen to 20% of all breast
cancers are HER2-positive.
Another 50-60% test positive
for small amounts of HER2,
but not enough to be HER2-
positive. These breast cancers
are considered HER2-low.
Possible results include:
•HER2-positive: an IHC score of 3+
• HER2-low: an IHC score of 1+ or 2+,
followed by a negative FISH test
•HER2-negative: an IHC score of 0
Drug class Cancer stage
Monoclonal antibodies
Margetuximab Metastatic
Pertuzumab All stages
Trastuzumab All stages
Tyrosine kinase inhibitors
Lapatinib
Advanced or
metastatic
Neratinib All stages
Tucatinib Metastatic
Antibody-drug conjugates
Ado-trastuzumab emtansineAll stages
Trastuzumab deruxtecanMetastatic
To learn more, visit lbbc.org/her2