Cancer 12: Cancer as a disease - Breast cancer

Question 1

What type of cancer is breast cancer?

Answer 1

Carcinoma (malignant cancer of the epithelial cells)

Question 2

Describe the progression of normal to malignant breast?

Answer 2

See slide 11

1) Normal
2) Benign carcinoma (benign proliferation of luminal cells)
3) Lobular carcinoma (tumour cell with tubular arrangement with no epithelial cells), Medullary carcinoma (tumour cells with endocrine vessels), carcinoma (most common type - no real structure)

Question 3

Why is the mortality rate of breast cancer falling?

Answer 3

Because the of early diagnosis, chemo/radiotherapy and hormonal therapy

Question 4

Describe the cellular organisation of the mammary gland?

Answer 4

A layer of myoepithelial cells (contract to squeeze the ducts), some of which are slightly vacuolated around
the luminal epithelial cells (main causes of breast cancer), making contact with the basement membrane. see slide 10/11

Question 5

What are ER-positive breast cancers?

Answer 5

Breast cancers that grow in response to oestrogen - 80% of all breast cancers are oestrogen receptor positive.

See slide 12

Question 6

What is breast cancer growth mainly mediated by?

Answer 6

Oestrogen

Question 7

Describe the eostrogen receptor

Answer 7

Oestrogen is a steroid hormone - they bind to ER which is a transcription factor. (activates it).
ER dissociates from hdp90 and dimerises.

Question 8

What genes goes oestrogen regulate?

Answer 8

Cyclin D1 - regulator of cell cycle
c-myc - regulation of cell survival
TGF-alpha - causes cell growth
progesterone receptor - clear link between oestrogen. You stain for PR when diagnosing breast cancer.

Question 9

What are the treatment methods for breast cancer?

Answer 9

• surgery (mastectomy or lumpectomy)
• radiation therapy
• chemotherapy
• endocrine therapy

Question 10

What is also done during a mastectomy?

Answer 10

During either type of surgery, one or more nearby lymph nodes are also removed to see if cancer cells have spread to the lymphatic system. When a woman has breast-conserving surgery, primary therapy almost always includes radiation therapy (randomized prospective trials that have investigated radiation use provide conclusive evidence that radiation reduces ipsilateral breast cancer recurrences

Question 11

Endocrine therapy

Answer 11

18

Question 12

What is done in endocrine therapy?

Answer 12

• Ovarian suppression
• Blocking oestrogen production by enzymatic inhibition
• Inhibiting oestrogen responses

Question 13

Describe the hormonal control of target tissues in terms of breast cancer?

Answer 13

see slide 20

Question 14

What is ovarian ablation?

Answer 14

The ovary is the major source of estrogen biosynthesis in pre-menopausal women.

Ovarian Ablation aims to eliminate this source. This can be carried out by;

• surgical oophorectomy
• ovarian irradiation

Question 15

What are the problems on ovarian ablation?

Answer 15

The major problems associated with these procedures are morbidity and irreversibility (they may want to have children.

To overcome these issues treatments to produce medical ovarian ablation have been developed.

Question 16

What is medical ovarian ablation?

Answer 16

Reversible and reliable medical ovarian ablation can be achieved using Luteinising Hormone Releasing Hormone (LHRH) agonsists.

Because of the high levels of LHRH the receptor for LHRH on the pituitary gland is overstimulated so the receptor is down regulated.

This leads to suppression of LH release and inhibition of ovarian function, including estrogen production.

Question 17

List some LHRH agonists?

Answer 17

Goserelin, Buserelin, Leuprolide and Triptorelin

Administered in high doses to be effective.

Question 18

How do you inhibit oestrogen action?

Answer 18

Tamoxifen and ICI 182,780 are molecules which look like oestrogen - high affinity but no efficacy to the ER.

These are anti-oestrogens - negate the stimulatory effects of estrogen by blocking the ER, causing the cell to be held at the G1 phase of the cell cycle.

Question 19

Describe tamoxifen?

Answer 19

It is a competitive inhibitor of the oestrogen to the ER.

Tamoxifen is the endocrine treatment of choice for metastatic disease in postmenopausal patients (approximatley 1/3 patients respond).

It is a selective oestrogen receptor modulators (SERMs)

• has oestrogenic effects in bone
• has oestrogenic effecs in the CVS

Few side effects - hot flushes, thromboembolic episodes and endometrial thickening, hyperplasia, and fibroids following several years of therapy.

Tamoxifen reduces the incidence of contralateral breast cancer by a third

Question 20

What is problem with anti-oestrogens?

Answer 20

• Osteoporosis - oestrogen is important to maintain bone in premenopausal women. However tamoxifen has oestrogenic effects in the bone.
• Atherosclerosis - oestrogen lowers LDLs and raises HDLs. However tamoxifen has oestrogenic effects in the CVS.

Question 21

In postmenopausal women what is the major source of oestrogen?

Answer 21

Not he ovaries but from the conversion of adrenal hormones (androstenedione/testosterone) to oestrogen.

Conversion is catalysed by aromatase enzyme complex in the liver, muscle and FAT (extra-adrenal)

Question 22

Describe aromatase

Answer 22

?

Question 23

What are atomatase inhibitors?

Answer 23

Irreversible - slide 40/41
Reversible -

Very few side effects and very effective. Replace tamoxifen as the first line treatment

Question 24

Describes progestins in breast cancers

Answer 24

used in the endocrine treatement - slide 43

Question 25

What is the problem with patients with metastatic disease?

Answer 25

They are resistant to endocrine therapies.

However, most cases continue to demonstrate estrogen responses and contain estrogen receptor

Question 26

What are the risks and causes of breast cancer?

Answer 26

Risk factor - life time exposure to oestrogen?

• Early age of onset of menarche
• Late age to menopause
• Age at first full-term pregnancy
• Some forms of the contraceptive pill
• Hormone Replacement
• Therapy
• Obesity
• Diet, physical activity, height, medication (Aspirin)

Question 27

Screening

Answer 27

People detect themselves… slide 50