Breast Cancer

• Breast cancer is the most frequently diagnosed cancer in women

worldwide (2.6 million new cases in 2020)
• The leading cause of cancer death in women worldwide
• The countries in Asia and Africa shared 63% of total deaths in 2020
• Breast cancer incidence is expected to increase in low- and medium-
income countries
• Most women in high-income country will survive more
 This is Breast Cancer Epidemiology in The
World
• These two pie-charts show that breast cancer is leading in the
number of incicence and mortality worldwide
What about Breast Cancer Epidemiology in Indonesia?
As GLOBOCAN reported
in 2020, breast cancer is
still the highest in
number of new cases
But the mortality comes
as 2nd rank after lung
cancer
 The Five Years of Survival will Depend on
The Stage of Breast Cancer
Survival of breast cancer drops from 99% to 30 % only, as the cancer
advancing to higher stage
 Characteristics of Breast Cancer Patients by
Stage in Indonesia
Data from collegues in Gajah Mada Univ-Indonesia in 2019 shows that
63% of patients come in stages III and IV
 TNBC Distribution by Stage, Dharmais
Cancer Hospital 2020
Similar to data presented from Dharmais Cancer Hospital (Samuel et
al), in TNBC which he observed on, the result is 60% of patients came
in stages III and IV
 Breast Cancer Case Distribution Trends by Age Group
in Dharmais National Cancer Center Hospital, 2020
Still from Dharmais Center Hospital, data shows that the peak
incidence belongs to the age group of 40 up to 50 years old.
 Breast Cancer Distribution by Histopatology Subtypes
in Dharmais National Cancer Hospital, 2020
And from cancer registry data we can see that generally, 39% of
patients came in more aggressive subtypes, which are HER2+ and
TNBC
How is the survival rate of breast cancer
patients in reality?
In the past only 25%
of breast cancer
patient survived.
Nowadays, we can
achieve up to 50% of
survival
And in the future, we
hope that it may
advance to 75%
 Breast Cancer Subtypes
Subtypes Therapy Note
Luminal A Endocrine therapy Frequency of 50% Systemic
• ER +++ Histological grade: I & II
• PR +++ (low grade) Treatment of
• HER2 negative breast cancer
• Ki67 <14%
• Good prognosis depends on
breast cancer
Luminal B Chemotherapy and Frequency of 15% subtypes
• ER ++ endocrine therapy Histological grade : II &
• PR +/- III (intermediate-high
• HER2 negative grade)
• Ki67 14-30% BRCA2 mutation
• Intermediate
prognosis
Breast Cancer Subtypes
Subtypes Therapy Note

HER2 Luminal Endocrine therapy + Frequency of 20%

• ER ++ chemotherapy + anti-HER2 Histological grade: III (high
• PR +/- grade)
• HER2 +++
• Ki67 >14%
• Intermediate prognosis

HER2 enrichated Chemotherapy + anti-HER2 Frequency of 20%

• ER negatif Histological grade : III (high
• PR negatif grade)
• HER2 +++ p53 mutation
• Ki67 high
• Poor prognosis
Breast Cancer Subtypes
Subtypes Therapy Note

Triple negative basal like Chemotherapy Frequency of 15%

• ER negative Histological grade: III (high
• PR negative grade)
• HER2 negative P53, BRCA1 mutations
• Ki67 high
• Poor prognosis
Cytotovic Drugs : How Do They Work?
There are many types of chemotherapy and each of them works on a
specific phase. Although some of them can work on the whole phase
(phase non-specific).
One chemotherapy regimen consists of two or three drugs that work
on different phases, thus increasing the treatment offectiveness
Cytotoxic mechanism of chemotherapy of
drugs
Most cytotoxic drugs are against DNA replication to interfere with
abundant cell proliferation.

Not only DNA replication, some of them also interfere during the
translation into RNA and protein expression. And the final result is
apoptosis of the cancer cell.
2. Treatment for HR + Breast Cancer
• SERM (has been using since 1977)  blocking the esterogen
receptors sites
• Aromatase inhibitor (since 1992)  aromatase enzyme (blocking the
hormone synthesis)
• SERD (since 2010)  destroying the esterogen receptors
Is there any Resistance to Endocrine
Therapy?
• 15-20% patients have intrinsic resistance to endocrine therapy
(primary)
• 30-40% patients have resistance after a few years of treatment
(secondary)
• Most of the ER+ breast cancer patients initially respond to endocrine
therapy  has better prognosis  however it is associated with
relapse within 10 years after diagnosis.

Resisitance to Relapse and

endocrine Therapy metastase
How about the Treatment after Resistance?
• PI3K Inhibitor  blocking the PI3K pathway
• Mtor inhibitor  blocking the Mtor pathway
• CDK4/6 inhibitor  blocking the cell cycle: Palbociclib , Ribociclib and
Abemaciclib
3. HER2 Positive Breast Cancer
• Approximately 15-20% of all breast cancer.
• Associated with aggressive phenotype, higher rate of recurrence, and
inferior survival.
Trastuzumab plus chemotherapy improved PFS and OS significantly
in patients with HER2 (+) early and advanced breast cancer

22-25%
HER2 (+) metastatic breast
cancer patients have primary or
secondary resistance to
Trastuzumab-based regimen becomes standard of care for HER2 (+) trastuzumab
breast cancer patients
The first and second anti-HER2 theraphies are Trastuzumab (since 1998)
and Pertuzumab (since 2012). Then they are continued with several
other drugs.
Neratinib
• Beside intravenous Trastuzumab and Partuzumab, there is an oral
pan-HER2 inhibitor.
• Approved by US FDA in 2017 (brand name: Nerlynx)
• Indicated for extended adjuvant therapy for HER2
overexpression/amplified after trastuzumab-based adjuvant therapy
Pyrotinib
• Oral irreversible pan HER-2 inhibitor.
• Developed by Shanghai Hengrui pharmaceutical, approved in China in
August 2018.
• Indicated for patient with HER2+ metastatic or advanced breast
cancer previously treated with anthracycline or taxane (in
combination with capecitabine)
Tucatinib
• Potent and HER2 selective small molecule TKI, reversible
• Approved by US FDA in 2020.
• Indicated for HER2+ unresectable,metastatic,advanced breast cancer
including CNS metastatic, previously treated with 1 or more anti-
HER2-based regimen in metastatic setting.
Margetuximab
• Approved by US FDA in December 2020
• Indicated for HER2 (+) metastatic breast cancer previously treated
with ≥ 2 anti-HER2, at least for 1 metastatic disease.
• Higher rate of infusion reaction.
Trastuzumab Emtansine
• Since 2013, T-DM1 has three components : Trastuzumab, DM1 and a
non-reducible thioether link set, designed to be stable in the
circulation before entering HER2-overexpressing cells.
• DM1 derived from maytansine  24-270x more potent than
paclitaxel.
Trastuzumab Deruxtecan
• Consists of HER2 monoclonal antibody (trastuzumab), cleavable
tetrapeptide- based linker, and cytotoxic payload (deruxtecan)
• Approved by US FDA in 2019.
• Side effect : lung interstitial disease/pneumonitis and moderately
emetogenic.
Olaparib
• A poly (ADP-ribose) polymerase (PARP) inhibitor
• The first treatment approved specifically for BRCA mutation carriers
with HER2-negative metastatic breast cancer and previous treatment
with chemotherapy in the neoadjuvant, adjuvant, pr metastatic
setting
• A targeted treatment alternative to cytotoxic chemotherapy
4. Immunotherapy
Pembrolizumab and Atezolizumab are immunotherapy drugs that has been approved
by FDA for breast cancer since 2021.

Can be used with chemotherapy to treat triple-negative breast cancer :

1. Before and after surgery for stage 2 or 3 cancers

2. Inoperable local recurrence
3. Metastatic

Administration : intravenous (IV) infusion, typically every 3 or 6 weeks. (American

Cancer Society)
Combine Immunotherapy and conventional
cytotoxic drugs
The combination will be better because conventional chemotherapy
can activate anticancer immune responses through different
mechanisms :
1. The inhibition of tumor-induced-suppressive mechanisms
2. The direct stimulation of T and B cell responses
3. The enhancement tumor immunovisibility by cytotoxic cell subsets
or phagocytes
We still in empirical medicine : one treatment for all
The Different of One Treatment for all and
Personalized Treatment
Main pathways implicated in tumor growth
and progression of breast cancer
This figure shows that numerous pathways are doing the crosstalk
which not only contributes to breast cancer growth and progression
but also gives potential targeted treatment strategies
WHAT CAN WE DO?
• Perform Cancer Biomarkers
• To make a personalized therapy
• Each person has different size, means different mutation
Since 1990s treatments are given empirically, which are the same for
every patient.
But since 2000s, as the targeted therapies were invited, treatments
become more specific.
And these targeted therapies are strengthened by immunotherapy
which is given only to particular patients with specific indications.
Since the invention of molecular genomics, it is hoped that the
treatments are getting more specific
Future Breast Cncer Management
Question that can be answered by cancer
biomarkers
As the figure shows, breast cancer genomic testing has been
recommended since 2021.
Which level to test? How will you do it?
What is The importance of biomarkers?
• Characteristic that is measured as an indicator of risk of cancer,
occurrence of cancer, or patient outcome (Sarhadi et al, 2022)
• The materials which we can examine are :
o miRNAs, DNA, proteins, cellular metabolites, exosomes, organic materials.
Etc.
Personalized Medicine in Breast Cancer
As cancer grows, mutation found is no longer single-mutation, but
multiple mutations.
Liquid Biopsy for Breast Cancer
• Several types of tumor material that can be assessed by liquid
biopsies :
• Circulating tumor cells (CTCs)
• Cell-free circulating tumor DNA (ctDNA)
• Extracellular vesicles (Evs)

• (This data can strengthened the result of radiodiagnostic)

The MDT working together can decrease
delays and optimized patient outcomes

Preventive Early
Diagnostic Treatment Palliative
screening diagnostic
Symptoms Imaging Special Diagnostic Multimodality Recist 2nd/3rd line
No symptoms First detect lesion ist biopsy personalized treatment
Physician consul treatment Staging
contact Initial clinical tation Final evaluation Clinical trial
radiographic Histopatologic Comorbidity Palliative end
stage stage management Rebiopsy of life care
established

Biomolecular status
Liquid Biopsy for Breast Cancer
Extracellular vesicles
• Extracellular vesicles (Evs)  secreted by cells
• Are reservoirs of active molecules, including proteins, lipids, miRNA,
ncRNAs, and DNA
Evs for liquid Biopsy of Breast Cancer
Evs celluler function
• Besides diagnostics predictive and monitoring, Exosomes can also act
as treatment.
• EV may dock at the plasma membrane of the target cell and activate
intracellular signaling
• Or, Exosomes may be endocytosed by phagocytosis and releasing
their content into cytoplasm of the recipient
Evs cellular function
The ability to modify the EV content makes them a promising tool for
cancer therapy

Research for Mesnchymal stem cell (MSCs)-Evs could be utilize for

antitumor therapy.
 mSCs-Evs for breast cancer therapy

Wharton jelly’s MSCs-EVs (WJ-EV) could stimulate breast cancer cells

(BCC) to produce Wbcc (WJ-EV-incorporated BCC), Wbcc and their derived
EV decreased cancer progression.
MSCs-Evs for breast cancer therapy
Wbbc-EV Wbbc and their derived EV attenuated cancer progression by
reducing the proliferation and metastasis of the original BCC, the
angiogenic abilities.
Prerequisites for precision oncology : Tumor
Molecular Board
After tumor progression/new patients, the doctor make a biopsy, and
perform NGS.
The results must be reported to ,molecular tumor board, and the TMB
give drugs based on molecular profiling.
The result must also reported to breast cancer database

This data belongs to Prof. Jee Hyun Kim from Korea which I took, to show
that molecular tumor board (for all solid tumor) is already established in
Korea and it has been really helping to determine cancer patients
medication
 Who involve in Molecular Tumor Board?
Fascilitates interpretation of complex genomic profiling
TMB will give
and implementation pf experimental approaches for advice with Inter-
rare mutations that are beyond the standard-of-care Professional
May include regional boards for determining workflow
Decision
and approaches for institutional boards

Includes bioinformaticians and molecular Multidisiplin Team

biologists/pathologists who can evaluate complex
alteralions. Including mechanisms of scaulred resistance must do since the
begining
Access to complex testing, such as whole-exome
sequencing or more complex NGS panels
The higher TMB is, the
more mutations in
genome found.
Following transcription
and translation, we can get
more peptide antigens
which result to higher
expression of surface
receptors.
And this is the candidate
of new targeted drugs.
Liquid biopsy already available
in US Market since 2020, and
has been growing up to now.
It is predicted to raise fast each
year as the need also growing.
Liquid biopsy is mostly used for
treatment selection, and also for
diagnosis and monitoring.
Surprisingly, it’s also used for
early detection/screening.
Indonesia is fastes growing market for liquid biopsy
And according to
www.grandviewresearch.com,
Indonesia is the fastes growing
market for liquid biopsy.
That means this is our
opportunity to begin with
precision medicine to
determine our patients
precisely, and give the
appropriate drugs to each
patients.
Summary
• Biomarkers discovery is a necessary factor for the development of
breast cancer treatment in the future
• Several potential molecules have been discovered to be utilize in
breast cancer management, by Liquid Biopsi.
• Extracellular vesicles-based treatmenr is a promisingmethod that
could I,prove the quality and effectivity of breast cancer management
in the future.
• Molecular Tumor Board is necessary dor each country to make a
better outcome for patients.