Metastatic breast cancer, specifically HER2-positive subtype, represents an advanced stage of breast cancer characterized by the presence of human epidermal growth factor receptor 2 (HER2) overexpression. HER2-positive breast cancer tends to be more aggressive, but advancements in treatment options have significantly improved outcomes. Targeted therapies play a crucial role in managing metastatic HER2-positive breast cancer. Trastuzumab (Herceptin) and pertuzumab are monoclonal antibodies that specifically target the HER2 protein, inhibiting its activity and impeding cancer cell growth. These drugs are often used in combination with chemotherapy to enhance their effectiveness. In addition to trastuzumab and pertuzumab, other HER2-targeted therapies such as ado-trastuzumab emtansine (Kadcyla) and lapatinib may be employed in certain cases. Ado-trastuzumab emtansine is an antibody-drug conjugate that delivers chemotherapy directly to HER2-positive cancer cells, minimizing damage to healthy cells. Lapatinib, on the other hand, is a small molecule inhibitor that blocks HER2 and other related receptors. Given the chronic nature of metastatic breast cancer, treatment plans are often individualized based on the patient's overall health, specific characteristics of the cancer, and prior treatments. Hormone therapy may also be considered if the cancer is hormone receptor-positive. Clinical trials and ongoing research continue to explore novel treatment options, providing hope for further advancements in managing HER2-positive metastatic breast cancer. Patients are encouraged to work closely with their healthcare team to determine the most appropriate and effective treatment plan tailored to their unique circumstances.

1. Systemic treatment for HER2-positive
metastatic breast cancer
Reprint from UpToDate
DR SUMIT KUMAR
Assistant professor
NEIGRIHMS, Shillong

2. INTRODUCTION
Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer- related death
among females worldwide.
In the united states, up to 5 percent of women diagnosed with breast cancer have metastatic disease at
the time of first presentation.
Up to 30 percent of women with early-stage, non- metastatic breast cancer at diagnosis will develop
distant metastatic disease.
Although metastatic breast cancer is unlikely to be cured, meaningful improvements in survival have been
seen, coincident with the introduction of newer systemic therapies.
Hormone receptor positive (estrogen and/or progesterone receptor positive)
And /or human epidermal growth factor receptor 2 (HER2) is
overexpression(ie, HER2 positive).
Available treatment
options vary based on

3. AGENDA FOR THIS PRESENTATION
The treatment of HER2-
positive metastatic
breast cancer

4. RATIONALE FOR HER2-DIRECTED THERAPY AND AVAILABLE AGENTS
Approximately 20 percent of breast cancers overexpress human epidermal growth factor
receptor 2 (HER2)
Overexpression of receptor associated with an increased risk of disease recurrence and an
overall worse prognosis.
•Either 3+ staining by immunohistochemistry for
the HER2 protein or
•Evidence of HER2 gene amplification by
fluorescence in situ hybridization (FISH ratio ≥2.0
or HER2 copy number ≥6.0)
A high level of
HER2
overexpression,
as determined by

5. RATIONALE FOR HER2-DIRECTED THERAPY AND AVAILABLE AGENTS
Patients without HER2 overexpression do not appear to benefit from HER2 Targeted drugs.
Recommendation for HER2 status is to asses from biopsy from metastatic site due discordance
between the primary tumor and metastases
Recommend that patients receive HER2-directed therapy as first- and later-line treatment.
• improved overall survival.
• extended time to death by between five and eight
months.
• also increased the risk of congestive heart failure),
cardiotoxicity was reversible with holding
treatment.
In a meta-analysis of
seven randomized trials,
involving 1497 patients
with HER2-positive
metastatic breast cancer,
the addition of
trastuzumab to treatment

6. RATIONALE FOR HER2-DIRECTED THERAPY AND AVAILABLE AGENTS
Trastuzumab
monoclonal antibody that binds
the extracellular domain of HER2
Pertuzumab
a monoclonal antibody that binds the
extracellular dimerization domain of HER2
and prevents it from binding to itself or to
other members of the EGFR family.
Ado-trastuzumab emtansine (T-DM1)
an antibody-drug conjugate
composed of trastuzumab, a thioether
linker, and the antimicrotubule agent
DM1.
1
2
3
Fam-trastuzumab deruxtecan (T-DXd)
an antibody-drug conjugate composed of
trastuzumab, a thioether linker, and the
antimicrotubule agent DM1
Tucatinib
an oral tyrosine kinase inhibitor that is
selective for the kinase domain of
HER2, with minimal inhibition of
EGFR.
Lapatinib
tyrosine kinase inhibitor against EGFR1
and HER2 that results in inhibition of
signaling pathways downstream of HER2,.
4
5
6
Neratinib
An irreversible pan-HER inhibitor.
Margetuximab
Fc-engineered anti-HER2-receptor
monoclonal antibody.
7
8

7. APPROACH IN HER-2 POSITIVE PATIENTS
Previously
Untreated Patient
Treated Patient
Neo(adjuvant)
Preferred
option
Alternative
THP;-Docetaxel,transtuzumaband
Pertuzumab
• T-DM 1
• Single agent transtuzumab
• Transtuzumab plus pertuzumab
Special consideration for HR positive:-
Premenopausal- ovarian suppression or
ablation followed by AI with HER2 directed therapy
Postmenopausal :-HER2 directed therapy plus AI
Treatment –free interval of six months or
longer
Treatment free interval of less than six
months

8. then randomly assigned
to treatment with
TRASTUZUMAB PLUS PERTUZUMAB PLUS A TAXANE EVIDENCE
At a median follow-up of 19 months
Improvement in ORR (80 versus 69%)
Improvement in PFS (median, 19 versus 12
months)
At over eight years of follow-up:-
Improvement in OS (median, 57 versus 41
months)
Eight-year survival rates of 37 versus 23 percent
Toxicity included higher rates of
Diarrhea (67 versus 46 %),
Neutropenia (53 versus 50 %),
Rash (34 versus 24 %),
Mucosal inflammation (27 versus 20 %),
Dry skin (10 versus 4 %),
And serious (grade 3/4) febrile neutropenia (14 versus
CLEOPATRA trial
phase III(808 women with HER2-positive metastatic breast cancer)
Trastuzumab (8 mg/kg loading dose
then 6 mg/kg and docetaxel (75
mg/m2)
every three weeks and continued until disease progression or intolerable side effects
Pertuzumab (840 mg loading dose then 420
mg)
Placebo

9. TRASTUZUMAB PLUS PERTUZUMAB PLUS A TAXANE EVIDENCE
PERUSE study
1436 patients with advanced HER2-positive breast
cancer
Trastuzumab
and Pertuzumab
Docetaxel or
Paclitaxel or
Nabpaclitaxel
Median PFS was comparable between docetaxel, paclitaxel, and nabpaclitaxel; 20, 23, and
18 months, respectively)
Compared with docetaxel-containing therapy, paclitaxel- containing therapy was associated
with more neuropathy (31 versus 16 percent), but less febrile neutropenia (1 versus 11
percent) and mucositis (14 versus 25 percent).
COMBINE WITH EITHER

10. Ado-trastuzumab emtansine (T-DM1) evidence
MARIANNE trial
phase III(1000 women with progressive or recurrent locally advanced breast cancer or
previously untreated metastatic breast cancer )
ARM 1
docetaxel or paclitaxel,
ARM 2
T-DM1 plus placebo
ARM 3
T-DM1 plus pertuzumab.
The median PFS for 3 arms
was 13.7, 14.1, and 15.2
months, respectively
There was no significant difference in PFS
in
•arm 2 compared with arm 1
•arm 3 compared with arm 1
•or between arm 3 and arm 2
The ORR in the three arms
was 68, 60, and 64 percent,
respectively.
•Neutropenia, Neuropathy
and Peripheral Edema less
with nontaxane arms.
In particular, alopecia was numerically
much less with nontaxane arms
•Liver function test
abnormalities and
thrombocytopenia more with T-
DM1 arms.

11. ENDOCRINE THERAPY EVIDENCE
PERTAIN Study
phase II(258 postmenopausal women previously untreated metastatic breast cancer )
ARM 1
Pertuzumab plus Transtuzumab and AI,
ARM 2
Transtuzumab plus AI
Improved median PFS for 3-drug combination (18.9 versus 15.8 months)
•Grade 3 or higher adverse events were observed in 50 percent of patients receiving trastuzumab and
pertuzumab versus 39 percent of those receiving trastuzumab alone.
 noted that one-half of women received induction therapy with a taxane for 18 to 24 weeks prior to the initiation
of endocrine therapy
Randomly
assigned into

12. MONITORING THERAPY AND DEFINITION OF TREATMENT FAILURE
•patient preferences,
•disease-related factors (sites of disease, evaluability of disease by imaging or
tumor markers, pace of disease progression),
•and clinical factors (renal function, iodinated contrast dye allergy, presence of
uncontrolled diabetes).
The continuous evaluation of
patients during therapy (including
timing of imaging and the selection
of imaging modality) should be
individualized according to
•serial clinical examination,
•repeat laboratory evaluation (including tumor markers when initially elevated),
•and radiographic imaging.
Careful assessment for response to
treatment requires
•recommendations every three months for the first year of therapy, and if there
has been no evidence of cardiac toxicity after a year of treatment,then every six
months for patients remaining on treatment.
Patients on HER2-directed therapy
require regular monitoring of cardiac
function with echocardiogram or
multigated acquisition scan.

13. OPTIMAL TREATMENT DURATION OF CHEMOTHERAPY
Although the optimal duration of trastuzumab treatment is
also unknown.
With THP Regimen, Complete Response in 5-10% as Ist line for MBC
After achievement of best response to treatment (usually after 6 to 12 months of combined
therapy): discontinue cytotoxic chemotherapy and continue trastuzumab (with or without
pertuzumab therapy),
In patients whose tumors are also hormone receptor positive:- add endocrine therapy to
HER2-directed therapy following discontinuation of chemotherapy.

14. Optimal treatment duration of a HER2-directed agent —
decision
Discontinue or continue her-2 directed agent design individualized as no prospective data
available as such.
 For those who experience progression at any point, move to next-line therapy.
Continuation may cause:-
• increase the risk of cumulative
toxicity (especially cardiotoxicity),
• increase healthcare costs, and
• may be inconvenient,
Discontinuation may lead
to:- early disease
progression

15. PATIENTS WHO REQUIRE SECOND- OR LATER-LINE TREATMENT
Reaso
n
1
Disease
progression
2
Toxicity
Cardiomyopathy:
transtuzumab or pertuzumab
ILD/Pneumonitis: TDM-1 or
fam-transtuzumab
deruxtecan

16. Fam-trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate composed of an anti-
HER2 antibody,a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor
Earlier line options
DESTINY-Breast03
trial
phase III(524 patients with HER2-positive metastatic breast cancer
with progression on a trastuzumab- and taxane-containing
regimen)
T-DXd versus T-DM1
 Median PFS:-28.8 V/S 6.8 months
 Improved OS compared (median OS not reached in
either group),
 Grade ≥3 adverse events :-56% V/S 52%
 Interstitial lung disease:-15% V/S 3%
(DESTINY-
Breast02)
patients who have already received T-DM1,
T-DXd V/S clinician's choice
(capecitabine with either trastuzumab or
lapatinib)
 PFS; 17.8 versus 6.9 months)
 OS; 39.2 versus 26.5 months

17. ADO-TRASTUZUMAB EMTANSINE (ALTERNATIVE) —T-DM1 is an
alternative to fam-trastuzumab deruxtecan, provided they have not received it previously.
Result :-
• improved PFS (median, 6.2 versus 3.3 months.
• improved OS (median, 22.7 versus 15.8 months).
• T-DM1 was not associated with an increased incidence of serious (grade 3/4) adverse
events
Earlier line options
TH3RESA trial
602 patients with unresectable, locally advanced, recurrent, or metastatic breast cancer
randomly assigned in a 2:1 ratio to treatment with
T-DM1 or clinician's choice therapy (majority
received trastuzumab plus chemotherapy (68
percent)
All patients had progressed on at least two HER2-directed
regimens (with progression on both trastuzumab- and
lapatinib-containing regimens).
 This improvement in PFS was seen in those patients treated with and in those treated without
trastuzumab in the clinician's choice arm

18. Earlier line options
showed improved survival with T-DM1, even in the presence of crossover treatment.
ADO-TRASTUZUMAB EMTANSINE (ALTERNATIVE) —T-DM1 is an alternative
to fam-trastuzumab deruxtecan, provided they have not received it previously.
EMILIA trial
978 patients with with HER2-positive breast cancer previously treated with trastuzumab and a taxane
ARM 1
T-DM1(3.6mg/kg IV),
ARM 2
capecitabine (1000 mg/m2 orally twice a day, days 1 to 14) plus lapatinib
(1250 mg orally daily)
Randomly
assigned into
every three weeks and continued until disease progression or intolerable side effects
At a median follow-up of 19 months, , T-DM1
resulted in
Improvement in ORR (44versus 31%)
Improvement in PFS (median, 10 versus 6
months)
improvement in OS (median, 31 versus 25
months
Toxicity included lower rates with T-DM1 :-
Grade 3/4 toxicity overall (41 versus 57 percent
Diarrhea (2 versus 21 %),
palmar plantar erythrodysesthesia (0 versus 16
percent)
vomiting (0.8 versus 5 percent).
Toxicity included higher rates with T-DM1 :-
• Thrombocytopenia (13 versus 0.2 percent
• Overall higher rate of bleeding (30 versus 16
percent)
• ALT; 7 versus 2 percent

19. Later line options/ alternative
TUCATINIB, CAPECITABINE, AND TRASTUZUMAB — Tucatinib is an oral tyrosine
kinase inhibitor that is selective for the kinase domain of HER2, with minimal inhibition of epidermal
growth factor receptor. It is approved by the FDA for use in combination.
Randomised trial
480 heavily pretreated patients with HER2-positive metastatic breast cancer (median of four prior lines of
therapy),
ARM 1
tucatinib-capecitabine-trastuzumab,
ARM 2
capecitabine-trastuzumab plus placebo
Randomly
assigned into
Tucatinib combination versus placeo combination
gp
One-year PFS rate :-33 versus 12 percent
Median duration of PFS :-7.8 and 5.6 months
OS at two years :-45 versus 27 percent
Grade 3Toxicity in tucatinib combination gp
Diarrhea (13 versus 9 %),
palmar-plantar erythrodysesthesia syndrome (13
versus 9 percent),
elevations in ALT and AST levels (approximately 5
versus 0.5 percent for each)
fatigue (5 versus 4 percent).

20. MARGETUXIMAB — Margetuximab is an fc-engineered anti-her2-receptor monoclonal
antibody that is FDA approved
Serious adverse events were comparable between the two groups.
Later line options/ alternative
SOPHIA trial
the phase III , 536 patients with disease progression after at least two lines of anti-HER2 therapy
ARM 1
Margetuximab and chemotherapy
ARM 2
Transtuzumab and chemotherapy
assigned into
Margetuximab combination versus transtuzumab combination
gp
Median duration of PFS :-5.8 and 4.9 months
OS :-21.6 versus 21.9 percent

21. Later line options/ alternative
Trastuzumab with cytotoxic agents
Retreatment with a trastuzumab-based regimen
ORR of 31 percent
median duration of response of eight months.
median PFS and OS :5 and 15 months, respectively
Neratinib and capecitabine
NALA phase III trial, improved mean PFS relative to
lapatinib with capecitabine (8.8 versus 6.6 months,
respectively; although OS results were similar (mean OS
of 24 versus 22 months, respectively;
Lapatinib plus capecitabine)
Compared with capecitabine, the combination of lapatinib
plus capecitabine resulted in:
• A significant benefit in time to tumor progression (median,
six versus four months).
• A trend towards an improvement in OS (median, 75
versus 65 weeks), which was not
statistically significant.
1
2
3
Trastuzumab in combination with multiagent
chemotherapy)
with trastuzumab plus either a combination regimen (paclitaxel
and carboplatin) or single-agent paclitaxel. Combination
chemotherapy plus trastuzumab resulted in:
A higher incidence of grade 3 and 4 hematologic toxicity.
A higher objective response rate compared with trastuzumab plus
paclitaxel (52 versus 36 percent).
Longer PFS (median, 10.7 versus 7.1 months) but no statistically
significant improvement in OS (median, 36 versus 32 months).
4

22. SUMMARY AND RECOMMENDATIONS
Approximately 20 percent of breast cancers overexpress human
epidermal growth factor receptor 2 (HER2)
For newly diagnosed metastatic HER2 positive breast cancer,
transtuzumab, pertuzumab plus taxane regimen treatment of choice.
For patients with hormone receptor- and her2-positive metastatic breast
cancer,her2-directed therapy in combination with endocrine therapy is an
acceptable alternative.

23. Patients on her2-directed therapy require regular monitoring of cardiac
function with echocardiogram or multigated acquisition scan.
For patients who progress six months or longer after the completion of
adjuvant therapy, trastuzumab plus pertuzumab in combination with a
taxane (docetaxel or paclitaxel).
For patients who progress during or within six months of
adjuvant treatment, fam-trastuzumab deruxtecan (t-dxd) rather
than trastuzumab-emtansine.
SUMMARY AND RECOMMENDATIONS
SUMMARY AND RECOMMENDATIONS

24. Thank you