Role of e2, p2 & her2 in cancer breast by Dr. Laxmi Shrikhande

Role of ER,PR,HER2 in Cancer Breast
Dr. Laxmi Shrikhande
Consultant - Shrikhande Hospital, Nagpur
https://facebook.com/laxmi.shrikhande | https://.linkedin.com/in/dr-laxmi-agrawal-shrikhande

Dr. Laxmi Shrikhande - MD; FICOG; FICMU;FICMCH
• Medical Director-Shrikhande Fertility Clinic, Nagpur
• Chairperson Designate Indian College of OB/GY ICOG
• National Corresponding Editor-The Journal of Obstetrics
&Gynecology of India
• Senior Vice President FOGSI 2012
• Patron & President -Vidarbha Chapter ISOPARB
• Received Nagpur Ratan Award at the hands of Union
Minister Shri Nitinji Gadkari
• Received Bharat excellence Award for women’s health
• Received Mehroo Dara Hansotia award for Best
Committee of FOGSI
• National Governing Council member ICOG 2012-2017
• National Governing Council Member ISAR 2014-2019
• National Governing Council Member IAGE for 3 terms
• Chairperson-HIV/AIDS Committee, FOGSI (2007-09)
• President Nagpur OB/GY Society 2005-06
• Immediate Past President Menopause Society, Nagpur
• Associate member of RCOG & ESHRE
• Member of European Society of Human Reproduction
• Visited 96 FOGSI Societies as invited faculty
• Delivered 11 orations and 450 guest lectures
• Publications-Twenty National & eleven International
• Presented Papers in FIGO, AICOG, SAFOG, AICC-RCOG
conferences
• Conducted adolescent health programme for more
than 15,000 adolescent girls
• Conducted health awareness programme for more than
10,000 women

Role of ER,PR,HER2 in
Cancer Breast
DR LAXMI SHRIKHANDE
NAGPUR

Overview
What is the importance of these hormone receptors ?
Classification of breast cancer based on these receptors
Diagnosis of receptor status
Treatment of Receptor + & receptor –ve tumors
Take Home message

INTRODUCTION
Globally, breast cancer is the most frequently diagnosed
cancer and the leading cause of cancer death in females
Breast cancer is a heterogeneous, phenotypically diverse
disease composed of several biologic subtypes that have
distinct behavior.

Classification of breast cancer
Breast cancer is classified into four groups based on IHC profile
ER/PR and Her2/neu expression, positive (+) and/or negative (-). The
groups are:
 ER/PR+,Her2+ = Triple Positive
 ER/PR+,Her2-
 ER/PR-,Her2+
 ER/PR-,Her2- = Triple Negative TNBC
The IHC classification has prognostic and therapeutic implications, is
inexpensive and readily available.

What are estrogen and progesterone
receptors?
Receptors are proteins in or on cells that can attach to certain
substances in the blood.
Normal breast cells and some breast cancer cells have receptors that
attach to the hormones estrogen and progesterone, and depend on
these hormones to grow.
Breast cancer cells taken out during a biopsy or surgery will be
tested for these receptors.

Breast cancer cells may have one, both, or
none of these receptors.
ER-positive: Breast cancers that have estrogen receptors are called
ER-positive (or ER+) cancers.
PR-positive: Breast cancers with progesterone receptors are called
PR-positive (or PR+) cancers.
Hormone receptor-positive: If the cancer cell has one or both of the
receptors above, the term hormone-receptive positive (also called
hormone-positive or HR+) breast cancer may be used.
Hormone receptor-negative: If the cancer cell has neither the
estrogen nor the progesterone receptor, it's called hormone-
receptor negative (also called hormone-negative or HR-).

What is HER2-Positive Breast Cancer?
HER2-positive breast cancer is a type of breast cancer in which
breast cancer cells have a protein receptor called HER2 (human
epidermal growth factor receptor 2).
Normally, this protein helps breast cells grow, divide, and repair
themselves.
But sometimes, something goes wrong in the gene that controls the
HER2 protein and pts body creates too many of these receptors.
As a result, her breast cells grow and divide uncontrollably.

Prevalence
About 1 of 5 of breast cancers are HER2-positive.
Of cancers that are HER2+, around 50 % are also ER +
Roughly 70 % of breast cancers are estrogen-receptor-positive, most
of these being progesterone-receptor-positive as well.
Overall 10 % of tumors are triple-positive

Why is knowing hormone receptor status
important?
It helps in prognostication and planning treatment.
Hormone therapy drugs can be used to either lower estrogen levels
or stop estrogen from acting on breast cancer cells.
This kind of treatment is helpful for hormone receptor-positive
breast cancers, but it doesn’t work on tumors that are hormone
receptor-negative (both ER- and PR-negative).

How to Diagnose hormone receptor status?
A test called an immunohistochemistry (IHC) is used most often to
find out if cancer cells have estrogen and progesterone receptors
A tumor is hormone receptor-positive if at least 1% of the cells
tested have estrogen and/or progesterone receptors.
Otherwise the test will say the tumor is hormone receptor-negative.

Diagnosis of HER2-Positive Breast Cancer
The IHC test uses certain antibodies that identify the HER2
protein in a sample of breast cancer tissue.
The FISH test uses fluorescent pieces of DNA that stick to
the HER2 gene in cells, which can then be counted under a
microscope.
The Inform Dual ISH test uses stains that color HER2 genes
in a tissue sample so they can be counted under a
microscope.

Diagnosis of HER2-Positive Breast Cancer
It is not clear if one test is more accurate than the other, but FISH is
more expensive and takes longer to get the results. Often the IHC
test is done first.
If the IHC result is 0 or 1+, the cancer is considered HER2-negative.
These cancers do not respond to treatment with drugs that target
HER2.
If the IHC result is 3+, the cancer is HER2-positive. These cancers are
usually treated with drugs that target HER2.
If the IHC result is 2+, the HER2 status of the tumor is not clear and
is called "equivocal." This means that the HER2 status needs to be
tested with FISH to clarify the result.

False positive/ Negative
It has been shown that some hormone status (ER, PR, and HER2)
test results may sometimes be wrong(false positive or false
negative).
This is probably because different laboratories have different
regulations for classifying positive and negative test results.

Prognosis based on ER & PR + status
Hormone receptor-positive cancers tend to grow more slowly than
those that are hormone receptor-negative.
Women with hormone receptor-positive cancers tend to have a
better outlook in the short-term, but these cancers can sometimes
come back many years after treatment.

Prognosis for Hormone receptor-negative
These cancers tend to grow faster than hormone receptor-
positive cancers.
If they come back after treatment, it’s often in the first few
years.
Hormone receptor-negative cancers are more common in
women who have not yet gone through menopause.

Prognosis for HER2-Positive Breast Cancer
around 20% are HER2-positive.
The outlook for this type of cancer depends on treatment received
by the women and the stage of cancer. But new treatments like
chemotherapy plus trastuzumab have boosted survival rates:
7-year disease-free: Around 93%
10-year disease-free: About 70%-75%
Overall: 80%-85%

Triple-Positive vs. Triple-Negative
At first glance, it would seem triple-positive breast cancer would
offer the best prognosis, followed by tumors that are estrogen-
receptor-positive or HER2-positive, and triple-negative tumors
having the worst outcomes.
However, that doesn't appear to be the case. While some triple-
positive tumors act more like ER+ tumors, some of these tumors
bare similarities to triple-negative tumors in that they are more
aggressive, occur in younger people, have higher tumor grades at
diagnosis, and pose a greater likelihood to recur both locally,
regionally, and metastatically.

What is cross talk ?
Cancers that are triple-positive may behave differently than would
be expected based on HER2 or estrogen receptor positivity alone
and may be affected by the relationship between these receptors.
This interaction between the receptors is referred to by researchers
as "crosstalk.“
The crosstalk between HER2 and ER may work to signal hormonal
resistance. In other words, communication between the receptors
(say HER2 and ER) may result in anti-estrogen therapy being less
effective in triple positive tumors.

What is cross talk ?
In a similar fashion, activation of estrogen receptor signaling (related
to being ER+) may result in resistance to HER2-targeted therapies.
This could explain some of the variability in HER2-positive tumors,
some of which respond much better than others to HER2-blocking
drugs.
It may be this "crosstalk" that explains why responses to hormonal
therapy or HER2-targeted therapy aren't always what one may
expect.
Further research is needed to look for answers, as well as ways to
reduce the crosstalk that leads to resistance.

ER and PR + treatment
Premenopausal women
Tamoxifen for five years.
After five years assess, menopausal status. If not yet menopausal, consider
continuing on tamoxifen for five more years. If menopausal, consider staying on
tamoxifen or switching to an aromatase inhibitor.
Postmenopausal women
Tamoxifen for 10 years or
An aromatase inhibitor for five years or
Tamoxifen for five years followed by an aromatase inhibitor for up to five years or
Tamoxifen for two to three years followed by an AI for up to five years (Note:
There is insufficient evidence to recommend taking an AI for greater than five yrs.)

Her2 + treatment
Patients with HER2-positive non-metastatic breast cancer
generally warrant adjuvant or neoadjuvant treatment with
chemotherapy and trastuzumab, though other HER2-
directed agents also may play a role in management
Benefits of adjuvant chemotherapy in early breast cancer
have been demonstrated in a large meta-analysis

Her2 + treatment
Trastuzumab should be administered concomitantly with the non-
anthracycline components of chemotherapy, rather than
sequentially after chemotherapy. Although administration of
trastuzumab sequentially after completion of all chemotherapy has
demonstrated activity, it appears to be less effective than when
given concurrently.
Other HER2-directed agents are under investigation.

Her2 + treatment
Residual disease — For those with residual disease after
neoadjuvant HER2-directed therapy, switch to ado-trastuzumab
emtansine (T-DM1) in the adjuvant setting and continue for 14
cycles. No further chemotherapy is administered with or after T-
DM1.
No residual disease — For those with pathologic complete response
following HER2-directed therapy, continue adjuvant trastuzumab,
with or without pertuzumab, to complete a year of HER2-directed
therapy. (Grade 2B).

Her2 + treatment
Patients who have not received neoadjuvant therapy — Many
patients with HER2-positive disease will be treated with neoadjuvant
therapy. However, for those with smaller, node-negative tumors,
initial surgical treatment may be appropriate, followed by adjuvant
therapy. In such patients with tumors that are <2 cm and node
negative, offer adjuvant therapy with paclitaxel plus trastuzumab for
12 weeks, followed by trastuzumab alone to complete a year of
treatment.
Other adjuvant chemotherapy regimens, with or without
pertuzumab, are available for those with larger tumors who were not
treated neoadjuvants

Her2 + treatment- How to prescribe
Trastuzumab
It is administered with a loading dose (weekly schedule: 4 mg/kg;
three-weekly schedule: 8 mg/kg) prior to the usual dose (weekly
schedule: 2 mg/kg; three-weekly schedule: 6 mg/kg).
Adjuvant treatment is typically started within 4-6 wks after surgery.
Earlier treatment is not necessarily better, but a delay of more than
12 weeks may be detrimental .
 In addition, for women who are of reproductive potential, the FDA
recommends the use of effective contraception during treatment
and for at least seven months after receiving the last dose of
trastuzumab.

Her2 + treatment
A subcutaneous form has received approval by the FDA based on
similar pathologic complete response rates as the IV form when used
with chemotherapy in the neoadjuvant setting .
However, the intravenous (IV) formulation of trastuzumab was used
in all canonical trials of therapy for both early- and late-stage, HER2-
positive breast cancer.
Although pending further data, IV is preferred over the
subcutaneous formulation (particularly in the adjuvant/neoadjuvant
setting)
Biosimilars for trastuzumab have also been approved by the FDA

Her2 + treatment
Treatment duration — Although various durations of treatment have
been examined, the standard course of adjuvant trastuzumab is one
year .
Results from randomized trials demonstrate no improvement with
extension to two years .

Highlights of Triple + Breast ca
Triple positive (TP) tumours exhibit a unique clinical and biological
behavior.
TP breast cancer behavior might also be driven by HR status.
TP tumors with low disease burden and high HR expression resemble
luminal tumours.
The identification and characterization of this subset may avoid
overtreatment.

Triple-negative
breast cancer cells don’t have estrogen or progesterone receptors and also
don’t make too much of the protein called HER2.
These cancers tend to be more common in women younger than 40 years of
age, who are African-American, or who have a mutation in the BRCA 1 gene.
Triple-negative breast cancers grow and spread faster than most other types of
breast cancer.
Because the cancer cells don’t have hormone receptors, hormone therapy is not
helpful in treating these cancers.
And because they don’t have too much HER2, drugs that target HER2 aren’t
helpful, either

Triple –ve and BRCA testing
Up to 20 percent of patients with TNBC harbor a breast cancer susceptibility
gene (BRCA) mutation, particularly in BRCA1 .
By contrast, less than 6% of all breast cancers are associated with a BRCA
mutation.
any patient with triple-negative disease should be offered BRCA testing.
Moreover, any patient age 60 years or younger with TNBC should undergo BRCA
germline testing.
For those with metastatic disease, results of BRCA testing have therapeutic
implications.

Recommendations for TNBC Treatment
The principles that apply to the surgical treatment and use of
radiation therapy in breast cancer, and the systemic treatment
approach in both the neoadjuvant and adjuvant settings, are similar
in TNBC and other HER2-negative subtypes.
Neoadjuvant or adjuvant chemotherapy is typically administered for
women with TNBC ≥0.5 cm or node-positive TNBC (regardless of
tumor size). These patients have a higher risk of relapse compared
with other breast cancer phenotypes and are not candidates for
other forms of adjuvant therapy (ie, HER2-directed treatment or
endocrine therapy)

Despite a higher risk of relapse compared with other breast cancer
subtypes, there are no specific post-treatment surveillance
guidelines for patients with TNBC
In the metastatic setting, combination chemotherapy may be
appropriate for those with extensive or rapidly progressive visceral
disease, in whom the higher chance of response is thought to
outweigh the higher risks of toxicity. However, there are no
prospective data that show combination chemotherapy improves
overall survival compared with single-agent sequential cytotoxic
chemotherapy.
Recommendations for TNBC Treatment

Role of Repeat biopsy in metastatic TNBC
In patients with metastatic breast cancer, a confirmatory
biopsy of a suspected lesion should be obtained when
possible with reassessment of ER, PR, and HER2 because
there is a possible discordance of these markers between
primary and metastatic disease

Special considerations during the covid-19 pandemic
COVID-19 pandemic has increased the complexity of cancer care.
Important issues include
 balancing the risk from treatment delay versus harm from COVID-
19,
ways to minimize negative impacts of social distancing during care
delivery, and
appropriately and fairly allocating limited health care resources

Take Home Message
ER ,PR and HER2 should be tested on surgical specimen
It helps in prognostication and planning appropriate therapy for
women.
Triple + has better prognosis than triple –ve
All Triple + don’t behave in an identical fashion because of cross talk
Refer the women to Oncologist for Treatment of Ca breast

The Art of Living
Anything that
helps you to
become
unconditionally
happy and loving
is what is called
spirituality.
H. H. Sri Sri Ravishakar

Role of e2, p2 & her2 in cancer breast by Dr. Laxmi Shrikhande

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