-: Let us learn about management
of patients presenting with advanced breast carcinoma.
This includes women presenting with disease confined
with the breast and regional lymph node basin,
called locally advanced risk carcinoma.
And we use the acronym LABC for this category.
And another group of patients initially presenting
with advanced cancer may actually have already metastasized
to lungs, liver, brain and bone.
And then we use the term metastatic breast carcinoma or MBC.
Breast cancer is now the most common cancer
of the human race.
And it is broadly classified
into three categories, early breast cancer,
locally advanced breast cancer and metastatic breast cancer.
Locally advanced breast cancer constitute around half
of the breast cancer seen in patients presenting in low
and middle income Asian and African countries.
In the west, such as Europe and America,
locally advanced breast cancer comprises less than 5%
of all women presenting with breast cancer due to the fact
that they practice regular self breast examination
and undergo mammographic screening above age group
of 45 to 50 years of age.
In the United Kingdom around 50,200 new cases
of breast cancer are recorded each year.
And this is the data
from United Kingdom between the period 2015 to 2017.
Breast cancer is the most common cancer
in the United Kingdom accounting for 15%
of all new cancer cases.
And this is the data from year 2017.
In Britain, one out of 10 cases are diagnosed
in latest stage.
This is data from England, Scotland from 2014 and 15
and in Northern Ireland.
So it is an uncommon condition in the United Kingdom,
Europe and America.
Locally advanced breast cancer can be defined
as patients presenting with large primary tumor measuring
more than five centimeter what is called T3 tumor
on the TNM classification or chest wall extension
of the tumor label as T4a.
The skin involvement in the form of ulceration,
satellite nodules or peau d'orange
or the skin edema categorized as T4b
on the TNM classification
or inflammatory carcinoma categorize as T4d
on the TNM classification.
Patients presenting with fixed auxiliary lymph nodes
or N2 disease or involvement of infra-clavicular
or supraclavicular nodes labeled as N3 disease
on the TNM AJCC eighth edition classification.
The central concept
in managing locally advanced breast cancer is the fact
that diseases advanced within the breast or chest wall with
or without involvement of regional lymph node basin
but is not yet metastatic.
It has high relapse rate and high risk
of becoming metastatic in the follow up.
So it remains a difficult clinical challenge for management.
The diagnosis and initial workup comprises
a triple assessment but is a combination
of clinical evaluation followed by radiological imaging
and then confirmation of the disease
by appropriate tissue sample.
And the triple assessment achieves clinical diagnosis
with high accuracy and a positive predictive value
of more than 99.9%.
So almost a 100% diagnosis can be asserted
by using the triple assessment.
Metastatic workup is necessary
in women presenting with advanced breast disease
in the form of positron emission tomography
or PET CT scan using isotope fluorine-18 attached
to a molecule form of glucose called deoxy-fluoro-D-glucose
or FDG-F18.
And this employs Warburg effect first described
by Otto Warburg, a German chemist who found
that cancer cells depend exclusively
on glucose for the energy production.
And since cancer cells are rapidly dividing,
they require high amount of glucose.
So if we inject glucose attached to some isotope
like fluorine 18 in this instance, more
of this molecule FDG-F18 will be taken by cancer cells.
And this forms the basis of positive tumour deposits seen
on PET CT scan.
Sometimes it may be difficult to assert involvement
of bones by tumour deposits.
In which case sodium fluoride labeled F-18 is used
to identify boney deposits from primary in the breast.
This is an example of a lady presenting
with advanced breast carcinoma of inflammatory nature
with diffuse enlargement of the mammary gland along
with diffuse skin edema or peau d'orange,
the skin redness involving more than two third
of the breast in this case, along with nipple retraction
and several satellite nodules.
And this patient
had really advanced breast carcinoma presenting
with cancer en cuirasse like picture the entire chest wall.
And even the upper part of the abdominal
had become rock hard like armour of a soldier.
And the disease had spread
to the opposite mammary gland as well
with diffuse skin edema, redness, satellite nodules
and destruction of the nipple-areolar complex
on the ipsilateral side.
Mammography is essential to detect occult lesions
in the same or contralateral breast
and to detect multicentricity.
If breast conservation is preferred, treatment
after initial chemotherapy, then it is essential
to insert a metal clip or a sterile needle
at the site of the tumor.
Or sometimes if this facility of inserting a metal clip
is not available a small piece of silicone catheter
can be placed at the site of the primary before chemotherapy
and then it can be followed after chemotherapy
because then we can ascertain the location
of the primary tumour and then perform a breast conservation
around that metal clip or piece of catheter.
Ultrasound scan of the mammary gland is useful to measure
the exact tumor size especially in dense breasts
and in delineating the axillary supra
or infra clavicular lymph nodes.
It also aids in taking a core biopsy
from the breast primary, as well as from the lymph nodes.
And it helps the radiologist
in taking the tissue biopsy from a specific solid part
of the tumor avoiding any cystic degeneration
and avoiding any blood vessels in and around the tumor
which may lead to hematoma
or bruising around the biopsy site.
Axillary ultrasound is helpful
in identifying suspicious axillary lymph nodes
and helps in taking biopsy or aspiration cytology
from these suspicious lymph nodes in the axilla.
MRI may be indicated in certain situations
where breast is radio dense on mammography
or there is discordance between the clinical finding
and the imaging.
In patients where a biopsy report such as lobular histology,
MRI should be carried out to a certain multicentricity
and bilateral involvement.
Wherever there is doubt of multicentricity or multifocality,
MRI comes to our rescue.
During follow up of patients following initial treatment
especially with breast conservation.
MRI helps in detecting recurrence
in their residual remaining breast.
And in ladies where a silicone implant has been inserted.
Complications of the silicone implant such as gel bleed
or early capsular contracture can be ascertained very nicely
by magnetic resonance imaging with contrast.
A large needle core biopsy is carried
out following breast imaging using a 14 gauge needle,
preferably under ultrasound guidance.
It provides adequate amount of tissue for ascertaining
the diagnosis as well as the presence of steroid receptors
like estrogen receptor, progesterone receptor,
Her 2 neu status and nuclear rating along
with ascertainment of markers like P53 and ki67.
Sometimes it is helpful in identifying S-phase fraction
or thymidine labeling index measuring
a special protein called LIBC, a protein which is lost
in inflammatory breast carcinoma can be helpful
in some specified cases.
The management of locally advanced breast cancer requires
a combined modality approach incorporating surgery,
radiotherapy, systemic therapy, including chemotherapy,
hormone therapy and targeted therapy.
A multidisciplinary approach is essential
for initial treatment planning comprising experts
from breast surgery, radiation and medical oncology,
plastic surgeons, radiologists, pathologists
breast care nurses and breast support groups
along with patients, advocates and relatives.
Prognostic factors
for locally advanced breast cancer include
axillary nodule status, patients where survival
has been found to drop from 73% within five years
if no axillary lymph node is involved compared
to only 46% if patient has N2 disease.
The tumour size also has a strong influence
on affecting the survival.
Patients with hormone receptor positivity
in general enjoy longer disease free survival compared
to those women where there is absence of hormone receptors
or in women with triple negative disease.
Other factors, which are sometimes used
are higher thymidine labeling index, a predictor
of poor prognosis, Her2 neu status, nuclear grade,
presence of p53, all point towards
a shorter overall survival and disease free survival.
Presence of physiological subtypes also influence prognosis
such as triple negative disease, HER 2 neu rich disease,
hormone poor or hormone absent disease
and patients who have inflammatory type of breast cancer.
The all carry poor prognosis.
The management comprises initial start
of primary chemotherapy also called pre-operative
or induction chemotherapy.
The rationale behind starting neo-adjuvant chemotherapy
is the fact that there is a high burden
of micrometastasis in these patients.
And hence we have to commence systemic therapy
at the earliest.
The advantages of early start of neo-adjuvant chemotherapy
are listed on this slide.
It allows delivery of the drugs
through an intact vasculature, which is disturbed
if we have performed surgery
or given radiotherapy prior to chemotherapy.
Neo-adjuvant chemotherapy allows an in-vivo assessment
or tailoring of the response to chemotherapy
because we have the opportunity to measure
the tumor successively during follow up.
There is increased chance
of breast conservation in women
who receive neo-adjuvant chemotherapy compared
to those where surgery is offered as the initial treatment.
In some studies, it has been shown that after surgery
there is a growth spurt of the remaining tumour cells.
And this can be suppressed by early start of chemotherapy.
Neo-adjuvant chemotherapy also enables the oncologist
to evaluate the biological effect of chemotherapy
if we take serial biopsy during neo-adjuvant chemotherapy.
Downsizing the primary tumour and lymph node metastasis,
facilitates a less radical local regional approach.
The response to chemotherapy can be ascertained
by (indistinct) criteria, pathological complete response
that is complete disappearance of the tumour
both on clinical as well as pathological evaluation
of the breast tissue after surgery is associated
with very long-term disease free survival.
PCR has been shown to occur in 30 to 40% patients
where a combination of anthracycline drugs
like Adriamycin or epirubicin is used along
with taxane and other drugs.
Several studies have now confirmed
that PCR achievers enjoy a longer disease free life
both in terms of overall survival
as well as disease free survival.
Most oncologists use a combination
of anthrocycline based drugs along
with taxanes for four to six cycles.
Addition of docetaxel or paclitaxel
has increased the pathological and clinical response rate
in most studies.
Some oncologists have used a platinum based drug
such as paclitaxel, along with epirubicin to increase
the pathological response further.
In most studies, however, taxanes and anthrocyclines appear
to do the job successfully.
Neo-adjuvant trastuzumab has been found to be effective
in women presenting with HER2 rich or HER2 positive disease
because it can improve the survival.
Its potential use has been found both
in the adjuvant setup as well as a neo-adjuvant setting.
And it has generated considerable interest
among the oncologists.
As high as 75% of clinical response can be achieved
if we use a combination of paclitaxel along
with trastuzumab in locally advanced setting.
Hormone therapy in the neo-adjuvant setup
has also been used.
It is quite safe and effective alternative
to post-menopausal women where chemotherapy is not
an option due to comorbidity like severe heart
or renal or other systemic diseases.
Various drugs like Tamoxifen, LHRH analogs,
aromatase inhibitors they all have been used
and found to be effective as neoadjuvant hormone therapy.
Now we come to local therapy.
The definitive local therapy has been traditionally
in the form of a modified radical mastectomy used
as the standard of care for most women presenting
with locally advanced breast cancer.
However, several studies have now confirmed that the safety
of breast conservation in many women
with locally advanced breast cancer
if they achieved significant regression
of the tumour with neo-adjuvant chemotherapy.
The criteria for breast conservation
following neo-adjuvant chemotherapy are listed
on this slide.
Patient's desire for breast conservation
of course is offered most importance.
There should be absence of multicentric disease
in the remaining breast.
There should be absence of diffuse microcalcification
on mammogram and a skin involvement
or inflammatory cancer should be absent.
The residual breast mass after neo-adjuvant chemotherapy
should be less than four centimeter
so that we can perform risk conservation
by a lumpectomy and achieve safe negative margin.
Factors determining the local regional recurrence are listed
on this slide.
Patients presenting with fixed axillary nodes or involvement
of the infra or supra clavicular nodes that is N3 disease
in general have high local regional recurrence.
Patient in whom after surgery and initial chemotherapy
there is still a residual disease seen
on the pathological assessment measuring more
than two centimeter, presence of multifocal disease
in the residual breast tissue is again appointed
towards poor prognosis.
And presence of lymphovascular invasion
in the residual specimen is also appointed
towards poor outcome in the form
of high local regional recurrence.
Radiotherapy has been used to reduce the risk
of local regional recurrence after mastectomy
by as high as two third proportion.
And therefore it is used in most patients presenting
with locally advanced best cancer following chemotherapy
and surgery.
Radiotherapy has been found to reduce the mortality odds
by as high as 20%.
The early breast cancer trial is collaborative group
or EBCTCG from Oxford University has documented
an overall survival advantage
of post mastectomy, radiotherapy
in women who have no positive disease.
The guideline for postmastectomy radiotherapy
are listed here.
They include women who have positive axillary lymph nodes,
skin involvement, presence of lymphovascular emboli
or tumour measuring more than five centimeter
in the largest diameter.
Adjuvant hormone therapy has been used following surgery
in women who have positive estrogen
or progesterone receptors.
And they reduce the hazard of death by as much as 25%.
Selective estrogen receptor modulators
or SERM like Tamoxifen, Raloxifene have been used.
They are validated studies from America
in the form of National Surgical Adjuvant Breast
and Bowel Project or NSABP-14 and 24 trials.
They have documented reduction in recurrence
in the both operated breast as well as
in the contralateral breast.
Aromatase inhibitors, such as Letrazole and Anastrazole
have achieved reversible non-steroidal block
in the production of estrogen from extragonadal site
outside the ovaries.
The AI or aromatase inhibitors are currently recommended
for patients in the post menopausal age group.
After initial systemic neo-adjuvant chemotherapy
we assess the response.
In women who achieve good partial or complete response,
we complete all six cycles of chemotherapy
and this is followed by either breast conservation
or mastectomy as decided in the multidisciplinary team.
In women who do not have significant response
of the tumor that is less than 30% regression
in the largest diameter
they will be offered either alternate systemic chemotherapy
or a mastectomy with or without use of a myocutaneous flap
to close the large skin defect.
Following this surgical approach
we offer external radiotherapy to the chest wall, along
with the local regional nodal basin covering
the internal mammary chain, the supra clavicular chain
and the axilla.
If patient is hormone receptor positive, ER/PR positive
we offer hormone therapy in the post menopausal group
in the form of aromatase inhibitors and Tamoxifen
in patients who have not attained menopause yet.
Tamoxifen can be added with
or without bilateral salpingo-oophorectomy
to increase the response.
Routine follow up of the patients is carried out
to detect recurrence.
Initially patient is evaluated every three monthly
in the clinic for a period of two years
followed by six monthly evaluation
till five years of initial treatment.
And if they remain disease free for full five years
then they are called at yearly interval subsequently
or they can be discharged back
to their general practitioner.
Mammogram is arranged every year
for the contralateral breast in women
who had breast conservation,
even the treated breast is assessed by mammogram.
And in doubtful cases, we can arrange MRI
to ascertain doubtful recurrence in the residual breast.
Ladies who are taking Tamoxifen, it is useful to assess
the influence of Tamoxifen on the endometrium in the form
of a sonographic evaluation by trans vaginal ultrasonography
and a gynecological checkup every year to ascertain
any chance of endometrial carcinoma
or significant endometrial hyperplasia or dysplasia.
Patients receiving aromatase inhibitors should have
their bone density or DEXA scan evaluated every six monthly
along with proper supplement of calcium and vitamin D.
With bisphosphonate bone strengthening agents.
The patients presenting with local regional recurrence
should have a biopsy of the recurrent site
because sometimes the receptor status change
after the initial treatment.
So a patient who was initially ER/PR positive
may actually develop ER/PR negative disease.
So biopsy must be carried out
and receptor status must be reevaluated
in all patients with recurrent disease.
A PET CT for metastatic workup is well in order
because these patients may have a high incidence
of multiple metastases elsewhere in the body
besides local recurrence within the breast.
Surgery can be performed to remove the local recurrence
if possible after initial systemic therapy and radiotherapy
should be given if it was not given
in the previous treatment.
If a prior lumpectomy was carried out and there
is a recurrence we can offer full completion, mastectomy.
Chemotherapy, hormone therapy, trastuzumab and other forms
of targeted therapies with or without second dose
of radiation can be arranged based on evaluation
of the multi-disciplinary team.
Survival in these patients using a multi-modality approach
with current drugs and targeted therapies
has improved considerably up to 65 to 89%
within five year local region recurrence varying
from five to 20%.
Patients with negative axilla
after neo-adjuvant chemotherapy have obtained
in some studies up to 80%, five year survival rate.
Patients on the other hand with heavy nodal burden
in the axilla with 10 or more positive nodes
have rather poor and dismal prognosis only having less
than 10% chance surviving for five years.
And this bar diagram shows the survival pattern
in different stages of locally advanced breast cancer.
The take home message from this presentation is
that locally advanced breast cancer is defined as bulky T3
and T4 tumour associated with matted axillary lymph nodes
or presence of supra
or infra clavicular lymph nodes, N3 disease.
Outcome of these patients
have improved considerably following
a multi-modality approach,
using currently available systemic chemotherapy
and targeted therapies.
Breast conservation is feasible, especially in women
who achieve significant reduction
of the tumour size following neo-adjuvant chemotherapy.
Treatment with neo-adjuvant chemotherapy
can (indistinct) patients with poor prognosis based
on their pathological complete response or PCR.
PCR achievers in most (indistinct) have been shown
to enjoy longer disease free life.
There are some issues in management
of locally advanced breast cancer in women living
in low and middle income countries of Asia and Africa.
They often present late
with large fungating ulcerated bleeding tumours.
About half of them may harbour metastasis and may succumb
to disease within four to five years.
There are comorbidities in the form of anaemia,
local infection, pain in the chest wall or the arm
due to involvement of (indistinct).
There can be problem of large skin defect following surgery,
requiring a large myocutaneous
of flap or free tissue transfer.
In general these women have poor long-term outcome.
Only about half of them will live for five years.
Hence there is a need for public education screening
for detecting disease in earlier stages where it is curable.
Thank you.