Breast cancer

Breast cancer (BC) is the most common malignancy in women and it’s the second most common cause of cancer mortality. The condition is related to increased oestrogen. When we talk about breast cancer we can mean either non-invasive or invasive carcinoma. These tumors develop from different parts of the terminal duct lobular unit (TDLU). They most frequently affect the upper outer quadrant of the breast.

Breast cancer is most common in older, post-menopausal women. Cancers in younger women are commonly hereditary rather than sporadic. 90% of cases are sporadic and 10% are familial. Breast cancer in men is very rare but it does occur.

The lifetime risk of developing breast cancer in an American woman is 1 in 8 (12.5%), which is really high compared to other cancers. 2/3 of cases occur in women 55 or older.

Etiology

• Female gender
• Risk increases continuously after age 30
• Living in western countries
• Positive family history (women with 2 or more first-degree relatives with breast or ovarian cancer have more than 50% risk of developing BC)
• Increased oestrogen exposure
  • Nulliparity
  • Early menarche
  • Oestrogen-containing contraceptives
• Obesity
• Germ-line mutations in BRCA1 or BRCA2
• Atypical hyperplasia in benign breast disease
• Physical inactivity, smoking, drinking alcohol

Pathology

Increased oestrogen exposure is highly associated with breast cancer. Many of the risk factors like obesity, early menarche and nulliparity cause increased oestrogen/progesterone ratio. Oestrogens stimulate the production of growth factors which may promote tumor development. Factors which reduce unopposed oestrogen exposure, like late menarche and breast feeding are protective.

Histologically cancers can be distinguished from benign conditions based on the absence of myoepithelial cells, which are absent in cancers.

Invasive ductal carcinoma

Invasive ductal carcinoma accounts for 80% of invasive carcinomas. It originates from a milk duct in the breast and occurs when DCIS invades past the basement membrane of the ducts. Histologically the tumor consists of duct-like structures embedded in a desmoplastic (fibrous) stroma. It is this desmoplastic stroma that causes the tumor to be hard and firm and visible on mammography. 2/3 express estrogen or progesterone receptors, while 1/3 express HER2/NEU.

Invasive lobular carcinoma

Invasive lobular carcinoma accounts for 5 – 10% of invasive carcinoma. It originates from a breast lobule. It occurs when LCIS invades past the basement membrane of the lobules. As these cells lack E-cadherin the tumor cells don’t form structures. The tumor cells often forms single rows with each other. Signet ring cells may be present. Almost all express hormone receptors, very few express HER2/NEU.

Other types of breast cancer

Other types of breast cancer include tubular, mucinous, and medullary carcinoma; these account for 10% of BC cases.

Tubular carcinoma is characterised by the presence of well-formed tubular or glandular structures infiltrating the stroma. This type has a favourable prognosis.

Mucinous carcinoma accounts for 1 – 2% of invasive carcinoma. It is characterised by tumor cells that have lost their orientation. Instead of secreting mucus into a lumen they secrete mucus outward. This causes the tumor cells to be surrounded by “pools of mucus”, as can be seen in the histo slide. This type has a favourable prognosis.

Medullary carcinoma is characterised by high grade tumor cells with inflammatory infiltrate. It’s more frequent in women with BRCA1 mutations. These cancers consist of sheets of large anaplastic cells with well circumscribed pushing borders. Clinically they can be mistaken for fibroadenomas. They lack hormone receptors and do not overexpress HER2/NEU –> Triple- negative.

Inflammatory breast carcinoma (mastitis carcinomatosa) is a rare and aggressive form of breast cancer. It is characterised by an inflamed breast, with erythema and oedema. This inflammation is sterile and occurs because tumors cells have filled the lymphatic vessels of the breast, similar to lymphangitis carcinomatosa. What’s important for this subtype is that mastectomy is not performed; chemotherapy and irradiation are performed instead. This condition should be considered in women with mastitis that doesn’t resolve with antibiotics.

Non-invasive breast cancer

Breast cancer that has not (yet) invaded past the basement membrane. There are two types, DCIS and LCIS.

Ductal carcinoma in situ

Ductal carcinoma in situ (DCIS) is the most common non-invasive carcinoma. The tumor cells originate from the cells of the terminal duct lobular unit and fill ducts of the breast. The name is a bit misleading as it doesn’t always develop from the ducts.

At this stage the tumor cells do not invade past the basement membrane of the ducts. If the tumor cells start to invade past the basement membrane the tumor becomes an invasive carcinoma.

Cells in the centre of the ducts die by necrosis as they don’t receive enough nutrients and oxygen. This forms calcifications that are visible on mammography. High grade DCIS is called the comedo type is characterised by severe atypia and extensive central necrosis and calcification.

DCIS rarely causes a palpable mass and is often discovered during routine mammography. Treatment by surgery and irradiation is curative in almost 100% of cases.

DCIS can also be present simultaneously as an invasive carcinoma, as seen in the invasive ductal carcinoma slide.

Lobular carcinoma in situ

Lobular carcinoma in situ (LCIS) also originates from the the cells of the terminal duct lobular unit. This name is also a bit misleading, suggesting that it only develops in the lobule, but this is false. However, they are more frequently present in the lobules.

Like for DCIS the tumor cells don’t invade past the basement membrane of the lobules; when they do the condition is called invasive lobular carcinoma. The most important difference between LCIS and DCIS is that LCIS very rarely produces calcifications or masses, so they’re often discovered incidentally.

Unlike DCIS, LCIS is often multifocal and occurs in both breasts simultaneously. They’re not removed surgically but rather treated with chemotherapy and regular follow-up.

The tumor cells in LCIS have lost an intercellular adhesion molecule called E-cadherin, which causes them to be disconnected from each other.

Molecular subtypes

Overexpression of HER2/NEU proto oncogene is present in 20-30% of invasive breast cancer. HER2 positivity indicates a more aggressive cancer, but because we have targeted therapy against HER2 the prognosis of HER2 positive cancers is the same as HER2 negative.

Many breast cancers express oestrogen receptors (ER) and/or progesterone receptors (PR) as well. ER and/or PR positivity indicates better prognosis as hormonal therapy can be used.

Cancers which express none of the three (HER2/NEU, oestrogen receptor or progesterone receptor) are known as triple negative cancers, and they have a poor prognosis.

Of the familial cases, mutations in BRCA1 and BRCA2 are most common. Germ-line mutations in BRCA1 or BRCA2 is found in one third of cases with hereditary breast cancer. They’re rarely mutated in sporadic cases of cancer. These proteins are tumor suppressors involved in DNA repair.

Metastasis

Breast cancer most commonly metastasizes to the lungs, skeleton and liver.

Clinical features

Breast cancers are usually detected during routine mammography screening of postmenopausal women, or in women with self-palpated breast lump. Thanks to mammography screening, presentation by a palpable mass is becoming more and more rare. Encouraging women to perform breast self examination regularly is also important for screening.

The breasts are usually asymmetric as the breast with the tumor changes size or shape. Cancers are usually hard, painless, have irregular surface, cause skin or areola dimpling, and may cause nipple discharge. If the tumour is fixed to skin or the chest wall, it may be advanced. Eczematous lesion on the nipple or areola may be suggestive of Paget’s disease of the nipple. DCIS and LCIS rarely cause symptoms and are mostly discovered during screening.

Diagnosis and evaluation

Patients presenting with a lump or positive findings should undergo thorough history and physical examination, imaging (mammography and/or ultrasound), as well as tissue diagnosis. Histology is mandatory for diagnosis and can be accomplished with FNAB or core biopsy.

After diagnosis, we must determine the histological subtype and molecular characteristics. Biopsy should be taken of any suspicious lymph nodes. CT of the chest, abdomen, and pelvis should be performed.

Mammography can detect calcifications, which occurs in most breast cancers. Calcifications can also be present in benign conditions like fat necrosis and sclerosing adenosis.

Breast cancers should be examined immunopathologically for whether it expresses HER2, progesterone receptor, or oestrogen receptor, as specific treatments exist for each of them, thereby improving the prognosis.

We distinguish early and advanced breast cancer. Early breast cancer is non-invasive or has not spread beyond nearby lymph nodes. Advanced breast cancer has spread beyond nearby lymph nodes or metastasized to other organs.

Sentinel lymph node biopsy

Many cases present with spread to the axillary lymph nodes, so biopsy of this lymph node is very important in determining stage and prognosis.

The procedure where axillary lymph nodes are biopsied is called sentinel lymph node biopsy. During this procedure the breast is injected with radioactive material. This material will then drain to the sentinel (first-in-line) lymph node, which is then removed and examined. If not for this method, we would have to remove all axillary lymph nodes and examine them all. This causes lymphoedema of the arm of the patient, which should be avoided.

Screening

Mammography screening is a part of most countries’ cancer screening programmes. In Hungary, it’s recommended annually for ages between 40 and 65, and has reduced mortality by 21%. In Norway, it’s recommended every second year for ages 50 – 69 and has reduced mortality by 20 – 30%.

The rationale behind mammography screening is that some cancers (both invasive and non-invasive) which are too small to be palpated are visible with mammography as calcifications, masses, or asymmetries. Two views are obtained, craniocaudal (CC) and mediolateral oblique (MLO) view. Screening may detect both cancer and precancerous lesions.

Ultrasound is not used for screening but may be used to supplement it if mammography findings are suspicious.

Healthy women who are suspected to have BRCA mutation should be genetically tested for this. BRCA positive healthy women should be offered prophylactic mastectomy.

Treatment

The main treatment is surgical (some form of surgery is performed in all cases which are operable), however oncological therapies are also important. DCIS is managed like breast cancer. Treatment based on stage:

• For early breast cancer (stage 0 – 2)
  • Without BRCA mutation
    • Breast-conserving surgery + adjuvant radiotherapy
  • With BRCA mutation
    • Mastectomy
    • Prophylactic contralateral mastectomy
    • Prophylactic bilateral salpingo-oopherectomy
• For locally advanced breast cancer (stage 3)
  • Neoadjuvant systemic therapy + surgical resection + adjuvant systemic therapy
• For metastatic breast cancer (stage 4)
  • The cancer is generally not curable, but it can be treated palliatively
  • Neoadjuvant systemic therapy + surgical resection and/or radiotherapy
  • With BRCA mutation – PARP inhibitors

Surgical therapy

Surgical therapy may be breast-conserving surgery or mastectomy. Breast-conserving surgery removes the mass and as little of the breast as possible and preserves the rest of the breast. Breast-conserving surgery should always be followed up by radiation therapy. Staging of axillary lymph nodes must always be performed during surgery. Breast reconstruction may be performed later for cosmetic purposes. LCIS requires no surgery if histology determines that it’s of the “classic” type. Nonclassic LCIS requires surgery.

Chemotherapy

Chemotherapy usually involves anthracyclines and taxanes.

Radiotherapy

The standard is to deliver whole-breast radiation and the radiation must be planned by CT to minimize radiation injury to the heart and lungs.

Hormonal therapy

If the cancer is hormone positive, hormonal therapy is indicated, often with tamoxifen, aromatase inhibitors, or fulvestrant.

Targeted therapy

If the cancer is HER2-positive, anti-HER2 therapy (trastuzumab) is indicated. PARP inhibitors may be used for BRCA-positive advanced BC.

Immunotherapy

A PD-L1 inhibitor (atezolizumab) may be used for triple-negative BC.

Prognosis

The prognosis of breast cancer depends on its TNM stage. Distant metastasis (M1) equals a very poor prognosis but is uncommon. The subtypes of breast cancer arranged from worst prognosis to best prognosis are: Inflammatory carcinoma > invasive ductal carcinoma > the rest. Medullary carcinoma is always triple negative.

Complications

Paget disease of the breast is the condition where tumor cells originating from DCIS or invasive carcinoma extend into and replace the epithelial cells of the epidermis of the nipple. This causes the nipple to become firm, ulcerated, hyperkeratotic and inflamed.