QuestionSBA
QuestionChoice
There is no indication for fundoscopy before starting neoadjuvant therapy in a patient with breast cancer
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e
Fundoscopy
QuestionChoice
An ETT may be useful as part of an anaesthetic assessment before surgery; however, the most important investigation before neoadjuvant therapy with trastuzumab is an ECHO
32290
c
Exercise tolerance test (ETT)
QuestionChoice
A DEXA scan is used to assess for osteoporosis. It would not routinely be performed before starting neoadjuvant therapy in breast cancer in a patient without any clear risk factors for osteoporosis
32291
d
Dual-energy X-ray absorptiometry (DEXA) scan
QuestionChoice
There is no clear evidence of decreased lung function with trastuzumab, and pulmonary function testing is not usually indicated
32289
b
Pulmonary function testing
QuestionChoice
Neoadjuvant therapy for a patient with HER2 positive breast cancer is likely to involve the monoclonal antibody trastuzumab (Herceptin). Cardiomyopathy is an important risk of trastuzumab treatment and therefore all patients should have a baseline ECHO before treatment
32288
a
Echocardiogram (ECHO)
QuestionComment
I thought if patient was ER+ve they would go on aromatase inhibitors which could cause osteoporosis, so you would wanna do DEXA scan
12629
QuestionComment
Do we start on both treatments simultanously or ER is the first-line then HER-2 therapy??
22176
User
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Anterior Syndrome
User
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Abigail 
QuestionComment
stupid q why make her positive for both its clearly reasonable to do a DEXA before starting anastrozole so we didnt know which one to pick
26177
User
subscriber
Malignant Benign
QuestionComment
you win some you lose some, this was 3 points dropped. Gutted.
61682
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Gabriel Magalhaes
Concept
Chapter
# Summary


Breast carcinoma is the most prevalent form of cancer among women and the second leading cause of cancer death in the UK. It manifests in various histological subtypes including ductal, lobular, medullary, and phyllodes tumours, each displaying distinct characteristics. Certain genetic mutations, especially BRCA1 and BRCA2, can increase the risk for breast carcinoma. Notable signs and symptoms include unexplained breast mass, nipple discharge, retraction, or skin changes suggestive of breast cancer. Key investigations comprise a triple assessment—clinical examination, radiological examination, and biopsy. Treatment strategies encompass surgical management (wide local excision or mastectomy), radiotherapy, chemotherapy, biological therapy, and hormonal therapy. Risk factors for breast cancer include increased hormone exposure, susceptibility gene mutations, advancing age, and lifestyle factors like obesity, physical inactivity, and alcohol and tobacco use.


# Definition


Breast carcinoma refers to a malignant tumour originating from the cells of the breast tissue. It exhibits different subtypes each with unique cellular properties and clinical implications. The carcinomas can be invasive, indicating they have broken through the basement membrane of the tissue of origin and have the potential to metastasize, or non-invasive (in situ), suggesting they are confined to the initial location.


# Epidemiology


Breast carcinoma is the most common type of cancer in women and accounts for approximately 15% of new cancer cases, representing 50,000 new cases annually. It is the second most common cause of cancer death in the UK.


# Aetiology

Most breast cancers are either ductal (arising from the epithelial lining of the ducts) or lobular (originating from epithelial cells in the terminal ducts of the lobules).


Risk factors for breast carcinoma include:


- Being female
- 99% of breast cancer cases occur in women
- Increased hormone exposure
- Early menarche or late menopause
- Nulliparity or late first pregnancy
- Oral contraceptives or Hormonal Replacement Therapy
- Susceptibility gene mutations
- Most commonly BRCA mutations (BRCA1/BRCA2)
- Advancing age
- Caucasian ethnicity
- Obesity and lack of physical activity
- Alcohol and tobacco use
- History of breast cancer
- Previous radiotherapy treatment


# Classification


Breast cancer is not a single disease, but a collection of several subtypes, each with its unique characteristics, prognosis, and treatment options.It can be classified based on its origin cell type such as:


- **Invasive ductal carcinoma (IDC)**: This is the most common type, accounting for about 80% of all breast cancers. It starts in a milk duct, breaks through the wall of the duct, and invades the fatty tissue of the breast.
- **Invasive lobular carcinoma (ILC)**: This type begins in the milk-producing glands (lobules) and can spread to other parts of the body.
- **Ductal carcinoma in situ (DCIS)**: This is a non-invasive or pre-invasive cancer where the cells are confined to the ducts in the breast and have not spread into the surrounding breast tissue.
- **Lobular carcinoma in situ (LCIS)**: This is not a cancer but an area of abnormal cell growth that increases a person's risk of developing invasive breast cancer later.
- **Paget's disease of breast**: Infiltrating carcinoma of nipple epithelium.


It can also be classified based on the hormone receptors present on the surface of the breast cancer:

- **Inflammatory breast cancer (IBC)**: This is a rare but aggressive type of breast cancer that causes the lymph vessels in the skin of the breast to become blocked.

- **Triple-negative breast cancer (TNBC)**: This type lacks estrogen receptors, progesterone receptors, and does not have an excess of the HER2 protein on the cancer cell surfaces. It tends to be more aggressive and has fewer targeted treatments available.

- **HER2-positive breast cancer**: This is a cancer that tests positive for a protein called human epidermal growth factor receptor 2 (HER2), which promotes the growth of cancer cells. It tends to be more aggressive than other types of breast cancer, but it may respond well to targeted therapies that can block HER2.


# Signs and Symptoms


Common clinical manifestations of breast carcinoma include:


- Unexplained breast mass in patients aged 30 and above, with or without pain
- In those aged 50 and older, nipple discharge, retraction/inversion, or other concerning symptoms
- This can also include eczema-type changes surrounding the nipple as seen in Paget's disease of the breast
- Skin changes suggestive of breast cancer
- This includes skin retraction, peau d'orange appearance or ulceration of the skin above an underlying mass.
- Unexplained axillary mass in those aged 30 and above


Approximately 25% of cases are found in routine breast cancer screening (mammography).


# Differential Diagnosis


While an unexplained breast mass is a key indicator of breast carcinoma, it can also represent various other conditions, each characterized by distinct signs and symptoms:


- **Fibroadenoma**: Typically presents as a solitary, painless, and well-circumscribed breast lump in young women
- **Breast Cyst**: Characterized by a round or oval, well-defined, and movable mass. It may be painful and size may vary with the menstrual cycle.
- **Mastitis**: Typically presents in breastfeeding women, characterized by a painful, warm, red breast often accompanied by systemic symptoms like fever.
- **Lipoma**: Presents as a soft, mobile, and painless lump.


# Breast Cancer Screening in the UK


In the United Kingdom, the NHS Breast Screening Programme provides free breast screening services for all women registered with a GP. The programme invites women between the ages of 50 and 70 for breast screening every three years, with the first invitation to screening usually sent to women before they turn 53.


This screening process involves a mammogram, which is an X-ray of the breasts that can help detect breast cancers early, often before they can be felt. The aim of breast cancer screening is to find cancer at an early stage when treatment is most effective.


In 2018, the age range for screening was extended as part of a trial, and some women were invited for screening from the age of 47 up to the age of 73. Women over 70 can still self-refer for screening every three years.


# Investigations

Criteria for 2-week wait:

- Age 30 or more with unexplained breast lump (with or without pain)
- Age 50 or more with nipple discharge, retraction or other changes
- Consider a 2-week wait if a patient is 30 or over with skin changes suggestive of breast cancer or an unexplained lump in the axilla

NB: a non-urgent referral should be considered for patients under the age of 30 with an unexplained breast lump.

### Triple Assessment

Triple assessment is used to investigate suspected breast carcinoma:


1. Clinical examination: of the breast and surrounding lymph nodes
2. Radiological examination:
	- Ultrasound is used for women under the age of 40 or those with higher breast density.
	- A mammogram is commonly used for women over 40 years.
	- If there are concerns of metastatic disease, a CT or PET scan may be done.
3. Biopsy: often a core needle biopsy or fine needle aspirate (FNA)
	- Fine needle aspiration (FNA): Often combined with mammography, however, has a high rate of false negatives.
	- Core needle biopsy: method of choice, can be combined with imaging to aid accuracy.
	- DCIS biopsy will show cellular atypia and hyperchromatic nuclei involving the ducts, but not passing the basement membrane
	- In invasive breast cancer, these abnormal cells will pass the basement membrane
	- In lobular carcinoma, the abnormal cells will be found within the lobular acini

### Further Investigations

Following the triple assessment, further investigations will include:

- Biopsies to determine
- Oestrogen and progesterone receptor status
- Epidermal growth factor receptor status
- Routine blood tests (i.e. LFTs)
- CXR
- MRI is not routinely used. It is used for women with:
- Discrepancy between the extent of disease between clinical examination and imaging
- Dense breast tissue limiting mammography
- Invasive lobular carcinoma to evaluate tumour size when planning breast-conserving surgery
- BRCA1/2 testing is done for women < 50 years with triple-negative breast cancer regardless of family history


### Staging

Staging involves the TNM system considering the size of the tumour (T), the spread to the lymph nodes (N), and the presence of metastases (M). For locally invasive breast cancer, this can include:

- Axilla ultrasound with needle sampling if abnormal lymph nodes are identified

If the cancer is deemed to be advanced, staging investigations should include:

- CT, MRI or bone scintigraphy to determine the presence and extent of visceral and bony metastasis
- PET CT is only used to diagnose metastasis


# Management


The management strategy for breast carcinoma can vary based on several factors including the subtype of carcinoma, stage, hormonal receptor status, and the patient's overall health and preferences.


- Surgical management: Wide local excision (WLE) or mastectomy, with sentinel node biopsies for invasive cancers and possible axillary node clearance for positive nodes. Breast reconstruction can be done concurrently or later.
- Radiotherapy: Adjuvant radiotherapy is commonly offered following WLE to reduce recurrence. It may also be given to patients with higher-stage cancers post-mastectomy.

**Chemotherapy:**

- Suggested for hormone receptor-negative and HER2 over-expressing patients. Neoadjuvant chemotherapy may be given to downstage tumours before surgery. This commonly includes an anthracycline (i.e. doxorubicin) and a taxane (i.e. paclitaxel)
- Biological Therapy:
	- Trastuzumab (Herceptin) should be given to HER2-positive patients with tumour size T1c and above in combination with surgery, chemotherapy and radiotherapy. Patients should have regular cardiac function assessments.
	- Abermaciclib (selective inhibitor of cyclin-dependent kinases 4 and 6) for HER2-negative, hormone receptor-positive breast cancer
	- Pembrolizumab for triple-negative breast cancer
	- Olaparib (PSTP inhibitor) for BRCA positive, HER2 negative high-risk early breast cancer
- **Hormonal Therapy** for oestrogen-positive breast cancer:
	- Anastrozole (aromatase inhibitor) for postmenopausal women
	- Tamoxifen (oestrogen receptor antagonist) for premenopausal patients
	- Bisphosphonates: May be used for reducing occurrence in node-positive cancers.
	- Zoledronic acid has been shown to improve disease-free survival in postmenopausal women with node-positive invasive breast cancer.
	- Bisphosphonates are also advised for treatment-induced menopause in women treated with aromatase inhibitors


# Complications

### Complications of Breast Carcinoma

- Fatigue
- Bone metastases
- Brain metastases
- Psychological difficulties: Anxiety, depression and damage to the individual's self-esteem.
- Recurrence:
	- Local: recurrence in the same breast as the original tumour
	- Regional: recurrence in the axillary or sub-clavicular lymph nodes draining the breast cancer
	- Distant: recurrence once already metastasized to other parts of the body (i.e. liver, lungs, brain, bone)


### Side Effects of Medication Used to Treat Breast Cancer


Treatment for breast cancer often involves medication, including chemotherapy, hormone therapy, and targeted drug therapy. Each of these can have different side effects.


**Chemotherapy** drugs are powerful medications that aim to destroy rapidly dividing cells, such as cancer cells. However, they can also affect healthy cells, leading to a range of side effects, including fatigue, hair loss, easy bruising and bleeding, infection, anaemia, nausea and vomiting, appetite changes, peripheral neuropathy, and problems with concentration or memory.

Chemotherapy agents can have specific side effects such as:

- Doxorubicin is associated with cardiac toxicity (e.g. cardiac arrhythmias, myopericarditis)
- Paclitaxel is associated with lung fibrosis.


**Hormone therapy** drugs, such as tamoxifen and aromatase inhibitors, are used to treat hormone receptor-positive breast cancers. Common side effects include hot flushes, vaginal dryness or discharge, menstrual changes, fatigue, mood changes, and osteoporosis. In rare cases, tamoxifen can increase the risk of serious conditions like endometrial cancer and blood clots.


**Targeted drug therapies** such as trastuzumab (Herceptin), pertuzumab (Perjeta), and ado-trastuzumab emtansine (Kadcyla), are designed to interfere with specific proteins or processes that contribute to cancer growth.

Side effects include:

- Infections
- Bruising and easy bleeding
- Anaemia
- Cardiac (i.e. arrhythmias)
- Insomnia
- GI side effects (i.e. diarrhoea, vomiting, constipation, appetite loss, weight loss)
- Runny nose
- Conjunctivitis
- Hair loss
- Nail changes
- Hand foot syndrome: the palms and plantar surfaces become sore, peel, crack and blister.
- Hepatotoxicity



### Surgical Complications

Key surgical complications include:

- Venous thromboembolism
- Lymphoedema
- Pain


### Breast Cancer in Pregnancy

Breast cancer is the most common malignancy to occur during pregnancy. Radiotherapy and chemotherapy are most commonly delayed until completion of pregnancy, but surgical intervention can be considered.

# Prognosis

The prognosis for individuals with breast cancer has vastly improved, almost doubling over the past 50 years. The ten-year survival for breast cancer in England is 75.9%

A poorer prognosis is associated with:

- Advancing age
- Being male
- Stage III or IV
- Tumour size
- Tumour grade
- Hormone receptor-negative tumours (oestrogen or progesterone receptor-negative)
- HER 2 positive tumours


# NICE Guidelines

[NICE Guidelines on Early and Locally Advanced Breast Cancer](https://www.nice.org.uk/guidance/ng101)

[NICE Guidelines on Advanced Breast Cancer](https://www.nice.org.uk/guidance/cg81)

# References

[Patient Info Breast Cancer](https://www.nice.org.uk/guidance/cg81)

[BMJ Best Practice Breast Cancer](https://bestpractice.bmj.com/topics/en-gb/718?q=Metastatic%20breast%20cancer&c=suggested)

[NHS Breast Cancer in Women](https://www.nhs.uk/conditions/breast-cancer-in-women/)

[Cancer Research UK Breast Cancer](https://www.cancerresearchuk.org/about-cancer/breast-cancer/survival)
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Baseline echocardiogram is essential before initiating neoadjuvant therapy in HER2 positive breast cancer to assess the risk of trastuzumab-induced cardiomyopathy.
A 56-year-old woman is diagnosed with HER2 (human epidermal growth factor receptor 2) positive breast cancer. Her case is discussed at the breast cancer multidisciplinary team (MDT) meeting, and it is decided that she would benefit from neoadjuvant therapy before surgery.

Which of the following is the most important investigation to perform before starting treatment?
a