Treating Early Stage Invasive Breast Carcinoma

Breast cancer is detected now in early stages, better than ever, thanks to well developed screening tools like mammogram, ultrasound and self breast examination. With earlier detection, and at lower costs, comes a rise in the number of breast cancer patients.

Through all this, treatment of early breast cancer(as for any cancer) requires a multidisciplinary approach and involves medical, surgical and radiation oncologists. And of late, Early detection and early treatment has lead to improved survival rates, worldwide. Hence, It is recommended that breast cancer is treated in specialized institutions.

Treatment of breast cancer requires proper staging and details on tumor biology.

Even small tumors require clinical findings, imaging and microscopic findings for proper staging and to prevent understaging.

The most important prognostic indicators in early breast cancer are the size, grade, peritumoral vascular invasion , presence of axillary nodes, proliferation markers such as ki67 index, and ER/PR/HER2 status. These factors are crucial in framing the appropriate line of treatment.

While treating breast cancers attention must be given to the age of the patient. If the patient is young, patient must not be overtreated just because she is young, and old patients must not be undertreated.

In younger patients fertility issues must be discussed and guidance to fertility preservation techniques should be provided before starting the treatment.

Which patients fall under the early stage category?

Patients with stage I, IIA and a subset of IIB ( T2 N1 ) disease fall under this category.

Treatment of the Primary

Breast cancer treatment is complex and the patient has to choose from a variety of choices towards their care. Given this, we will use analogies as a simple way to explain regarding the same.

To begin with, treatment can be thought of as two things:

  • Treatment of Primary
  • Treatment of axillary lymph nodes

In ancient days, there used to be tales of the Mahabharata and Ramayana. In modern era, we have Star Wars, and Star Trek.

A common concept in these Epic stories is of a single entity, such as a King or a Large Spaceship and it’s worker drones, the minions.

The primary tumor can be thought of as a large spaceship- destroying surrounding cities and towns, or in a human- normal breast tissue. This spaceship gives rise to many drones that invade other places (other parts of the body) and cause destruction in those places.
In the case of the body, the most commonly affected organs are the axillary lymph nodes.

Image result for alien spaceship destroying
Killer spaceship and its drones

As with any tale, there’s always a single “champion” or “hero” who single handedly attacks the “evil” being.
For the tumor, this treatment of choice is Surgery.

Before going further, there’s another point one has to keep in mind.

Now even though surgery does a very good job at dealing with the main boss, you always need to take care of the minions, and the seedlings who’ve broken off from the main tumor. These cells, which were part of the tumor once upon a time have the capability to rise to the occasional and turn into full blown tumors themselve.

It’s like when you use surgery to kill the (evil) King, one of his soldiers rises to the occasion to avenge his death.
We need to deal with these leftover soldier too, when it comes to cancer treatment.

So, we just can’t perform surgery and leave it at that.


Following Surgery adjuvant therapy has to be added- depending on size, grade, axillary node involvement, hormone receptor expression and HER2 expression to take care of residual tumor cells.

Surgery

Image result for laser army soldiers

A brief review of the different types of surgeries available are discussed below.

Breast Conservation Therapy (BCT)

Breast conservation therapy consists of lumpectomy(removal of the lump) followed by radiation.

A successful breast conservation surgery involves getting a negative surgical margin followed by radiotherapy to get rid of residual disease.

A negative surgical margin implies that the surgeon will just beyond the edges of the tumor lump, including some part of (supposedly) normal tissue so that there’s no tumor cells that get left behind.

We try to resect the tumor to an extent that surgical margins are negative

The main aims of BCT are:

A cosmetically acceptable breast,
and to provide the survival equivalent of mastectomy with low rates of recurrence.

What the surgical team aims to do is to completely remove the tumor, while trying to save the neighbouring normal cells, followed by the radio oncological team that aims to destroy the leftover tumor cells.

Advancements in adjuvant therapy has improved treatment outcomes post BCT and observational studies have shown that BCT has atleast comparable survival to mastectomy.

BCT is not done under the following conditions

  • Pregnancy is a complete contraindication to BCT as it involves radiotherapy that can harm the fetus.
  • Prior radiotherapy to chest
  • Multicentric disease (when the different quadrants of the breast are involved by tumor foci or when distance between two tumor foci is greater than 5 cm)
BCT is avoided in multicentric breast disease
  • Large tumor size in relation to the breast ( Because then Negative margins may not be achievable when tumor size is large in relation to the breast, removal becomes difficult while preserving the beforementioned aims of BCT).
  • Presence of diffuse malignant appearing calcifications on imaging (eg. MRI, mammogram)
  • Persistently positive margins even after re-excision.

Mastectomy

Removal of all breast tissue from a breast to prevent breast cancer.

A mastectomy is done when BCT is contraindicated. Mastectomy also depends on patient preference, incase the patient does not want to go further biopsies, mammograms or postoperative radiation.

In case patients have small breasts the cosmetic outcome may not be that good, even if BCT is performed.

Mastectomy can even be performed as a prophylaxis(preventive measure) in case of BRCA1 AND 2 mutations. This decreases the risk of developing breast cancer by more than 90%. In such cases skin and nipple areola complex can be spared as this results in better cosmetic outcome. Contralateral breast can also be removed, especially in BRCA1 and 2 mutations to minimise the risk of breast cancer.

Types of Mastectomy

1) Simple mastectomy- Wherein entire breast is removed without removal of axillary lymph nodes.

Image result for simple mastectomy

2) Radical mastectomy – The surgeon removes the entire breast, along with level I, II and III along with chest wall muscles. Radical mastectomy is recommended when the cancer has invaded the chest wall muscles. It is now rarely preformed, because in most cases modified radical mastectomy has proven to be just as effective and less disfiguring.

3) Modified Radical mastectomy- Entire breast is removed along with level I and II axillary lymph nodes. The modification to radical being that No muscles are removed from beneath the breast.

Image result for simple mastectomy

4) Partial mastectomy- Partial mastectomy is the removal of the tumor along with normal breast tissue (more tissue than a lumpectomy).

Post mastectomy radiotherapy is given in case the patient is at high risk for local recurrence such as margins are positive and there is axillary node involvement.

Treatment of Axillary lymph nodes

Now that we spoke about how the primary is managed, we will discuss about how lymph nodes are managed.

In breast cancer, management of axilla has become an area of controversy.

In many cases- whether the patient has presented newly or after NeoAdjuvant Chemotherapy, three situations may arise:

  • In case axillary nodes are clinically positive on examination or imaging- surgical dissection of nodes is done.
  • During breast conserving surgery Sentinel biopsy is done. In case sentinel biopsy is negative, the axilla may be left alone.
  • In case sentinel biopsy is positive axillary dissection or axillary Radiotherapy may be considered.

What is sentinel node biopsy?

The first few Lymph nodes into which a tumor drains are called sentinel lymph nodes. These nodes are detected by injecting a dye or radioactive substance near the tumor. The dye travels through the drainage pathway and stains the first lymph nodes it encounters. These nodes are detected and removed for evaluation. The commonly used dyes are isosulphan blue and Pate.

If the sentinel lymph nodes are positive the chances of having positive nodes upstream also are more.

Image result for sentinel node biopsy with blue dye

When do we give radiotherapy?

During Modified radical mastectomy or breast conservation surgery, axillary dissection is done; And if 10 or more nodes are removed and found negative, or there is no extranodal extension, then the axilla is NOT irradiated.

So basically if there is extranodal extension (ENE) present or many nodes are found positive during dissection or if there is inadequate lymph node dissection then the axilla is given radiotherapy.

Recently the AMAROS trial showed that in those patients who have positive sentinel lymph nodes, radiotherapy can be considered a good option and has comparable survival to axillary lymph node dissection. Radiotherapy has proven excellent long term survival, distant metastases free survival and loco-regional control.

Management of axillary lymph nodes is a controversial area in oncology and treatment is decided on a case to case basis by radiation and surgical oncologists.

Neoadjuvant Therapy

Neadjuvant therapy refers to drug treatment given in order to shrink a tumor prior to a definitive course of treatment.

In early stage breast cancer neoadjuvant therapy is given when tumor is large as compared to the breast or when the cosmetic outcome after surgery would be suboptimal.

In patients with HER2 positive and triple negative cancers neoadjuvant therapy is given in the form of chemotherapy (in both cases) and HER2 guided therapy (In HER2 positive tumors) . These subtype of tumors have a very good response to chemotherapy.

In those patients with hormone receptor positive and HER2 negative tumors, neoadjuvant therapy may not show an optimal response but may produce just enough response to perform a BCT instead of a mastectomy. In these patients the decision of whether to give chemotherapy or endocrine therapy depends on patient age, comorbidities, Estrogen receptor expression, Proliferation index and Oncotype Dx score.

Usually Endocrine Therapy is used in those patients who will not be able to tolerate chemotherapy and those who are strongly estrogen receptor positive (allred score of 7 to 8) and patients with low ki67 index (Ki67 is a protein in cells that increase as cells divide. Higher Ki67 levels, indicates quicker division rates).

Sometimes even after a good response to neoadjuvant therapy patient may become unfit for surgery, possibly due to some comorbidity. In this case endocrine therapy can be used. If patient show poor response to endocrine therapy, patient may be considered for radiotherapy.

Adjuvant Therapy

Adjuvant chemotherapy is given to patients after primary treatment, when the doctor thinks there is a high risk the cancer will return. After a primary treatment of surgery or radiation, adjuvant chemotherapy reduces the risk of recurrence. In all lumpectomy patients, node positive cases (irrespective of the number of nodes) and those with positive margins after surgery, radiation to affected breast/chest wall is given. Lymphovascular involvement and perineural invasion are relative indications for radiotherapy and are to be individually decided by the radiation oncologist on a case by case basis.

Depending on tumor characteristics, patient general condition and patient preferences appropriate adjuvant therapy is selected.

If tumor is hormone receptor positive, endocrine therapy is given. If HER2 receptors are present trastuzumab is given.

Adjuvant chemotherapy is added only if the patient has high risk features– tumor size greater than 2 cm, high grade tumor, pathologically involved lymph nodes and high 21 gene recurrence score. In low risk tumors addition of adjuvant chemotherapy has not shown any benefit.

The 21 gene recurrence score (also called oncotype Dx) is used to assess the genes responsible for proliferation and invasion of the tumor. This score also provides information on the risk of distant metastases and the benefit the patient would have from receiving adjuvant chemotherapy.

So in brief- Hormone receptor positive tumor-

If high risk features (size >2cm, high grade)- endocrine therapy + adjuvant chemotherapy

If low risk- endocrine therapy is sufficient

Endocrine therapy is basically used to lower the effect of estrogen on the breast. In premenopausal women Tab Tamoxifen is given in a dose of 20 mg OD for 5 years. This medication blocks the effect of estrogen on breast tissue thus reducing the risk of recurrence and improves survival. In postmenopausal women Tab Anostrozole is given. Anostrozole is an aromatase inhibitor and blocks the conversion of androgens to estrogens in extragonadal tissue.

*If patient is triple negative, adjuvant chemotherapy is considered even if the tumor is greater than 0.5 cm in size as endocrine therapy cannot be given in such patients and chemotherapy is the only option. If tumor is less than 0.5 cm in size there is no need of adjuvant therapy, chemotherapy can be skipped as it has shown no survival advantage in such patients.

In triple negative cases adjuvant chemotherapy is added if tumour is greater than 0.5 cm in size

This is done because triple negative cases does not show much benefit from endocrine therapy.In less than 0.5 cm tumors adjuvant chemotherapy has not shown much benefit

*Patients with a HER2 positive tumor of size greater than 1 cm should receive chemotherapy and HER2 directed therapy.

Patients with HER2 positive tumors receive trastuzumab in the adjuvant setting. Trastuzumab is a monoclonal antibody directed against HER2 receptors reducing proliferation of tumor cells.

In case lymph nodes are positive or in cases where lymph nodes are negative and tumor size is greater than 5 mm, adjuvant chemotherapy plus trastuzumab is recommended in some centres. In some cases adjuvant chemo and trastuzumab are offered even in tumors with size 3-4 mm especially in hormone receptor negative cases.

In HER 2 tumors with lymph node positivity or size greater than 1 cm- adjuvant chemo plus trastuzumab is given.

For 1-2 mm tumor size, adjuvant chemotherapy and trastuzumab is not given.

Trastuzumab is given along with adjuvant chemotherapy and not sequentially, as it is more effective when given along with chemotherapy.

For patients who have received trastuzumab in the neoadjuvant setting the HER2 directed therapy in the adjuvant setting depends on the response to neoadjuvant therapy.

For patients with residual disease after neoadjuvant HER2 directed therapy, medication is switched to Ado-trastuzumab emtansine. This drug is a conjugate of trastuzumab and emtansine (DM1) a microtubule inhibitor which prevents cell division. It is administered for 14 cycles. No chemotherapy is administered with or after Ado-trastuzumab emtansine.

In case after neoadjuvant therapy the residual lesion still remains- HER2 directed therapy is switched to Ado-trastuzumab emtansine.

This drug has side effects such as deranged liver function tests (raised liver enzymes, raised bilirubin), decreased platelet count, decreased ejection fraction and peripheral neuropathy which leads to discontinuation of the drug.

In the Indian setup the patient is usually continued on trastuzumab because of the exorbitant costs of Ado-trastuzumab emtansine.

For patients with no residual diseases trastuzumab is continued to complete a year of HER2 directed therapy.

Follow up after treatment

Patients after completion of treatment need to be checked atleast once in awhile.

When should you Follow-Up?

It is recommended that patients follow up every 3-6 monthly during the first three years, 6-12 monthly for the next 2 years, and annually thereafter.

What should you expect at each FollowUp visit?

During every follow up, a detailed history of current complains and treatment given should be taken. Any change in the course of treatment prior to the follow up visit must be noted.

Patient should be asked for weight loss, anorexia and fatigue.

Local examination should be carried out:

On examination the affected breast or chest wall must be examined as well as the contralateral breast. Both axillae must be carefully examined.

Breasts are examined for nodules, skin changes, lumps especially at the site of incision. Axillary site is examined for lumps, ulceration. Post Radiotherapy fibrosis may be present which may be mistaken for recurrent lesion.

System wise history and examination must be done.

Skeletal system– Patient may present with swelling of the ipsilateral arm due to lymphedema after lymph node removal. Patient can present with weakness in upper limb due to brachial plexus damage.

Nervous system examination– Nervous system related complains and signs are looked for in follow up patients. Chemotherapy given during breast cancer can result in peripheral neuropathy. Breast cancer is a common cause of brain metastases. Motor, sensory and gait needs to be assessed.

Gastrointestinal symptoms– Gastrointestinal signs and symptoms must be assessed. Right upper quadrant must be examined for tenderness and hepatomegaly.

Cardiac examination– Anthracycline based chemotherapy used in breast cancer can cause cardiomyopathy.

Pulmonary examination– Sympoms such as cough, difficulty in breathing, hemoptysis must be looked for. Breath sounds must be assessed.

Gynaecologic examination– complains of bleeding per vaginal and pain should be asked for. Tamoxifen has proliferative effects on the endometrium and can cause endometrial cancer.

On Radiological Imaging:

Mammography– Studies have shown that surveillance mammography after BCT or mastectomy resulted in improved survival than in those patients who did not.

Mammography is used to detect signs of recurrence in ipsilateral breast as well as surveillance of contralateral breast.

MRI– should be done in women with high risk such as BRCA mutation and close family history.

Genetic counselling

Breast cancer patients who have not under gone genetic testing should undergo these tests especially in case of men and women diagnosed with breast cancer under the age of 50 or with a strong family history. BRCA mutation analysis may be considered.

In triple negative or ER negative breast cancers or cancers with HER2 overexpression in women under 60, mutation analysis should be considered.

Once a patient with genetic mutation is detected, testing for genetic mutation in other family members can be done. Testing for mutations in affected individuals initially and then testing for family members is much more easier and gives than testing for family members initially since there are high chances of these turning out to be inconclusive.

Lab tests and extensive imaging during follow up has not shown much benefit in improving overall survival. A 2005 metanalysis comparing mammography and clinical examination with radiological and lab tests have not shown difference in survival between the two arms.

These additional imaging and lab tests lead to an increasing number of false positives. False negative results maybe misleading to the patient. Early diagnosis of such patients only lead to earlier interventions and increasing toxicities.

Liver function tests– these are elevated in 80% patients even in those without metastases.

Liver function tests, chest imaging, bone scan, PET scan, Abdominal CT or ultrasound need not be performed during a follow up as they have not proven to be of much benefit and to be of much help in changing the course of the disease. These should be reserved for those patients who are symptomatic or those who show signs of progression or recurrence.

Leave a Reply