Lecture 24 - Breast and Prostate Cancer

Question 1

What is the prostate?

Answer 1

• Encircles the neck of the urinary bladder and urethra
• Primary function is to produce seminal fluid – the liquid in semen that protects, supports and sustains sperm viability and motility
• Devoid of a distinct capsule  increases chance for metastasis
• 4 biologically and anatomically distinct zones or regions

Question 2

What is the structure of the prostate?

Answer 2

Prostate structure
* Peripheral zone (PZ)
* Central zone (CZ)
* Transitional zone (TZ)
* Region of the anterior fibromuscular stroma

Question 3

What is the tissue structure of the prostate?

Answer 3

• Composed of glands which are lined by epithelial cells
• Epithelium is composed of 2 cell layers: basal cuboidal cells below a layer of columnar secretory cells on a basement membrane
• Epithelium exhibits extensive in-folding
• Glands are separated by a fibromuscular stroma (ECM-rich)
  o Stroma generally has less cellularity and has a lot of muscular tissue  this can drive directional movement of cancer cells as they stay away from the stroma

Question 4

What are some pathologic conditions of the prostate?

Answer 4

• Inflammation (prostatitis)
• Benign prostatic hyperplasia (BPH)
• Carcinogenesis

Results in an enlarged prostate and compressed urethra

Question 5

Where do breast cancers arise from?

Answer 5

The terminal duct lobules of the breast

Question 6

What are the cell types of the duct lobules of the breast?

Answer 6

• Basal or myoepithelial cells
  o Contractile cells for milk ejection
  o Estrogen receptor negative
  o Progesterone receptor negative
• Luminal or epithelial cells
  o Responds to hormonal stimulation for milk production
  o Estrogen receptor negative
  o Progesterone receptor negative/positive

Question 7

Why does breast tissue have plasticity and what is the implication of this?

Answer 7

This is due to the presence of stem cells, progenitor cells, and other cells capable of self-renewal and differentiation within the breast tissue.

During normal breast development, stem cells and progenitor cells differentiate into various cell types, including ductal and lobular cells, which are responsible for producing milk.
Implication: making it more susceptible to cancer

Question 8

What is benign prostatic hyperplasia (BPH)?

Answer 8

• Non-cancerous enlargement of the prostate common in men over 50 years
• Pathogenesis
  o Dependent on the action of androgens (mainly testosterone)

Pathology and clinical features of BPH
* Prostate is enlarged, nodular, firm and rubbery
* Weight: 2x more than normal
* Urethra is compressed, deformed and tortuous
* Dysuria (weak stream, incomplete emptying of the urinary bladder)

Question 9

What are the risk factors of prostate cancer?

Answer 9

• Age: men over 50 years old
• Family history: men with a family history are more likely to develop prostate cancer
• Ethnicity (genetics): e.g., European men are more likely
• High levels of testosterone
• Diet: a high fat-diet and obesity increases the risk

Question 10

What are the features and symptoms of prostate cancer?

Answer 10

• By the time symptoms appear, the carcinoma is a palpable inflexible mass, fixed to surrounding tissue
• Symptoms are: similar to BPH with stage-dependent features: in advanced disease – haematuria
  o Bone pain (lower back) due to metastases

Question 11

What is the pathological grading of prostate cancer?

Answer 11

• The Gleason grading/scoring system is used which classified prostate cancer into grades (1-4) based on the glandular pattern and degree of observable (microscopic) differentiation
• Low grade tumours have a relatively good prognosis
• High grade tumours have poorer outcomes
• Grade 4 tumours show least differentiation, i.e. immature cell phenotype (morphology of cell &/or nuclei)
• STAGE 1: found only within the prostate (not outside) & usually slow growth stage – primary site
• STAGE 2: is restricted to but involves more than one part of the prostate, and may grow quickly (due to angiogenesis)
• STAGE 3: has spread to adjacent/surrounding tissues
• STAGE 4: metastasis (to other organs)

Question 12

What is the heterogeneity of prostate cancer

Answer 12

Small malignant glands with enlarged nuclei, prominent nucleoli, and dark cytoplasm, compared with larger benign gland

Question 13

What is the prognosis for patients with prostate cancer?

Answer 13

• Localised low-grade tumours: 95% 10-year survival rate
• High-grade with local metastasis: 50% 5-year survival rate
• High-grade tumours with distant metastasis: poor (2–3-year survival) – outlook is improving with newer experimental therapies

Question 14

What techniques are used to diagnose prostate cancer?

Answer 14

• Rigid/stiff prostate vs rubbery prostate
• Prostate specific antigen (PSA) and/or prostatic acid phosphatase (PAP) useful for screening and monitoring of tumours
• Biopsy: PSA detected by IHC and Gleason scoring
  o Also need to account for the size of the prostate as the levels per volume will be proportional to this
• Ultrasound – assess size
• CT scanning: can assess the extent of spread

Question 15

What are the symptoms, signs and diagnosis of breast cancer?

Answer 15

Symptoms: nipple discharge, palpable mass, pain and lumpiness
Presentations: abnormal mammogram, palpable mass, pain and nipple discharge (lower extent than symptoms)

To diagnose breast cancer, a doctor may perform a clinical breast exam, a mammogram, an ultrasound, or a breast biopsy to confirm the presence of cancer cells.

Question 16

What is the grading scale of breast cancer?

Answer 16

Lower = obvious glandular
Higher = no glands + irregular and mitotic cells

Question 17

What are the genetics of breast cancer?

Answer 17

Some cases of breast cancer have been linked to inherited genetic mutations, such as mutations in the BRCA1 and BRCA2 genes.
Other genes associated with an increased risk of breast cancer include PALB2, ATM, CHEK2, PTEN, TP53, and STK11.

Question 18

What are the sub-types of breast cancer?

Answer 18

Breast cancer can be broadly classified based on the expression of estrogen receptor (ER) into two subtypes: ER-positive breast cancer and ER-negative breast cancer. The ER-positive subtype is the most common, accounting for about 70% of all breast cancers. ER-negative breast cancer accounts for the remaining 30% of cases.

Question 19

What is the ER positive subtype of breast cancer?

Answer 19

The ER-positive subtype is characterized by the presence of functional ER, which promotes the growth and survival of cancer cells in response to estrogen. In this subtype, estrogen binds to ER on the surface of cancer cells, which triggers a cascade of downstream signaling events that activate genes involved in cell growth, proliferation, and survival. The ER-positive subtype can be further divided based on the expression of other receptors, such as progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2).

Question 20

What is the ER negative subtype of breast cancer?

Answer 20

The ER-negative subtype is characterized by the absence of functional ER, which means that estrogen does not promote cancer cell growth and survival. This subtype is often more aggressive and less responsive to hormonal therapy, which is the mainstay of treatment for ER-positive breast cancer. ER-negative breast cancer is often associated with mutations in genes such as TP53, BRCA1, and BRCA2, which are involved in DNA repair and tumor suppression.

Question 21

What are the molecular subtypes of breast cancer?

Answer 21

Luminal A: This subtype accounts for about 50-60% of all breast cancers and is characterized by the presence of estrogen receptor (ER) and/or progesterone receptor (PR), as well as low levels of the proliferation marker Ki-67. Luminal A tumors tend to grow slowly and have a good prognosis.

Luminal B: This subtype also expresses ER and/or PR, but has higher levels of Ki-67, indicating higher proliferation. Luminal B tumors tend to grow faster than Luminal A tumors and have a worse prognosis.

HER2-positive: This subtype accounts for about 15-20% of all breast cancers and is characterized by overexpression of the human epidermal growth factor receptor 2 (HER2) protein. HER2-positive tumors tend to be aggressive and have a poor prognosis, but can be treated with targeted therapies such as trastuzumab.

Triple-negative/basal-like: This subtype accounts for about 10-15% of all breast cancers and is characterized by the absence of ER, PR, and HER2. Triple-negative/basal-like tumors tend to be aggressive and have a poor prognosis, and currently there are no targeted therapies available for this subtype.

Normal-like: This subtype is rare and has gene expression patterns similar to those of normal breast tissue. Normal-like tumors tend to have a good prognosis.

Question 22

Why is it important to determine the subtype of breast cancer?

Answer 22

Treatment decisions and prognosis determination

Question 23

What is the prognosis for certain breast cancer molecular subtypes?

Answer 23

In general, breast cancers that are hormone receptor-positive (ER+/PR+) tend to have a better prognosis than hormone receptor-negative (ER-/PR-) breast cancers.
Triple-negative breast cancer (ER-/PR-/HER2-) tends to have a poorer prognosis because it lacks the expression of an oestrogen receptor, progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). As a result, TNBC cannot be targeted by hormonal or HER2-targeted therapies.

Question 24

How does androgen signalling occur in the prostate?

Answer 24

Via the hypothalamic-pituitary-adrenal/gonadal-prostate axis
Gonadotropin-releasing hormone (GnRH) stimulates the secretion of gonadotropic hormone (Gn) from the anterior pituitary, & Gn in turn stimulates production of testosterone
Circulating testosterone acts in a negative feedback loop to down-regulate the expression of GnRH
Adrenocorticotropic hormone (ACTH), also made by the pituitary, stimulates androgen synthesis in the adrenal gland
Testosterone (T) and dihydrotestosterone (DHT) bind to the androgen receptor (AR), causing increased expression of androgen-responsive genes which promote cell proliferation
Steroid receptors are within the cell cytoplasm and bound to proteins (HSP) which keep them inactive. However, ligand DHT binds to androgen receptors and bumps off the proteins HSP, higher affinity to DHT, and allows the androgen receptor to travel from the cytoplasm to the nucleus. Therefore, the androgen receptor acts as a transcription factor (but can only do so in the nucleus).

Question 25

How are androgen dependent prostate cancer cells targeted?

Answer 25

Androgen receptor antagonists (drugs that resemble the androgen receptor) and can bind to the testosterone binding site, compete with testosterone and block the transcriptional activation.

Question 26

How do prostate cancer cells adapt to become androgen-independent?

Answer 26

Tumour cells become insensitive to androgen at later stages of the disease – PROBLEM
Normal prostate and early-stage prostate cancers rely on androgens for growth and survival, so anti-androgen therapy is effective in cancer
If not completely removed, cancer cells eventually become androgen-independent, androgen therapy resistant
Note that the androgen receptor (AR) can also be activated via MAPK & PI3K pathways – this mechanism is active in androgen resistant disease
This means that the androgen antagonists won’t work any longer!

Question 27

What are some prostate cancer therapies?

Answer 27

Next-generation androgen receptor (AR) targeting agents
* Molecular characterisation of patients: through next-generation sequencing or transcriptome analysis, will help to dissect mechanisms of resistance and to identify biomarkers allowing the selection of patients for specific treatment
* The improved understanding of the intra-patient molecular heterogeneity and of the multiple, redundant and compensatory signalling networks in cancer supports a role of rational combined targeted therapy
Robotic surgery of prostate