Malignancy: Breast cancer

Question 1

What are the established risk factors for breast cancer? (5)

Answer 1

The causes of breast cancer are complex and there are several risk factors. Established risk factors include age, early onset of menstruation, late menopause, greater age at first completed pregnancy, and a family history.

(The use of oral contraceptives and postmenopausal HRT are also associated with a small excess risk.)

Question 2

What is ductal carcinoma in situ?

Answer 2

Non-invasive breast cancer, also known as ductal carcinoma in situ, is when the cancer remains localised in the ducts. However, in most cases, the cancer is invasive at the time of diagnosis, which means that malignant cells are liable to spread beyond the immediate area of the tumour.

Question 3

For operable breast cancer, primary treatment is surgical using breast-conserving surgery or mastectomy, followed by adjuvant therapy to eradicate the micro-metastases that cause relapses. What is the purpose of radiotherapy following this?

Answer 3

Radiotherapy is recommended after breast conserving surgery, as it reduces local recurrence rates. It is also used after mastectomy if there is a high risk of recurrence.

Question 4

Adjuvant chemotherapy or radiotherapy should be considered for all patients, irrespective of age, and it should be started as soon as clinically possible within How many days before surgery?

Answer 4

Adjuvant chemotherapy or radiotherapy should be considered for all patients, irrespective of age, and it should be started as soon as clinically possible within 31 days of surgery.

Question 5

A high-dose anthracycline-based chemotherapy regimen is usually preferred to a low-dose anthracycline-based regimen or to a non-anthracycline-based regimen.

What is an example of an anthracycline drug?

Answer 5

Doxorubicin.
Blocks topo isomerase 2.
Can turn the urine red.
Higher cumulative doses are associated with cardiomyopathy and it is usual to limit total cumulative doses to 450 mg/m2 because symptomatic and potentially fatal heart failure is common above this dose.

Question 6

What side effects are common with doxorubicin?

Answer 6

Dehyrdration
Diarrhoea
Red colouration of urine.

Question 7

What important side effects are there with doxorubicin?

Answer 7

Higher cumulative doses are associated with cardiomyopathy and it is usual to limit total cumulative doses to 450 mg/m2 beca use symptomatic and potentially fatal heart failure is common above this dose.

Question 8

Adjuvant anthracycline-taxane combination chemotherapy should be considered in patients where the additional benefit outweighs risk. For patients with lymph node-positive breast cancer, what is the taxane of choice?

Answer 8

Adjuvant anthracycline-taxane combination chemotherapy should be considered in patients where the additional benefit outweighs risk.

For patients with lymph node-positive breast cancer, docetaxel can be added as part of an adjuvant chemotherapy regimen; paclitaxel is not recommended.

Question 9

How does docetaxel work?

Answer 9

Docetaxel inhibits mitioic spindle assembly.

Question 10

Following surgery, what agent either alone in combination with chemotherapy can be given to premenopausal women with oestrogen-receptor-positive early invasive breast cancer?

Answer 10

Tamoxifen.

An anti-oestrogen which induces gonadotrophin release by occupying oestrogen receptors in the hypothalamus, therebu interefering with feedback mechanisms; chorionic gonadotrophin is sometimes used as an adjunct in the treatment of female infertility.

Tamoxifen can increase the risk of thromboembolism particularly during and immediately after major surgery or periods of immobility.

Question 11

How does tamoxifen work?

Answer 11

An anti-oestrogen which induces gonadotrophin release by occupying oestrogen receptors in the hypothalamus, therebu interefering with feedback mechanisms; chorionic gonadotrophin is sometimes used as an adjunct in the treatment of female infertility.

It is a selective estrogen-receptor modulator (SERM).

Tamoxifen can increase the risk of thromboembolism particularly during and immediately after major surgery or periods of immobility.

Question 12

What important side effects are there with tamoxifen use?

Answer 12

An anti-oestrogen which induces gonadotrophin release by occupying oestrogen receptors in the hypothalamus, therebu interefering with feedback mechanisms; chorionic gonadotrophin is sometimes used as an adjunct in the treatment of female infertility.

Tamoxifen can increase the risk of thromboembolism particularly during and immediately after major surgery or periods of immobility.

Question 13

For POSTmenopausal women with oestrogen-receptor positive early invasive breast cancer, not considered to be low risk, what class of drugs (and examples) is first line therapy?

Answer 13

For postmenopausal women with oestrogen-receptor-positive early invasive breast cancer, not considered to be low risk, an aromatase inhibitor, such as anastrozole or letrozole, is first-line therapy.

Question 14

How do aromatase inhibitors such as anastrozole or letrozole work in the treatment of eostrogen-receptor-positive early invasive breast cancer?

Answer 14

The aromatase inhibitors work by inhibiting the action of the enzyme aromatase, which converts androgens into estrogens by a process called aromatization.

As breast tissue is stimulated by estrogens, decreasing their production is a way of suppressing recurrence of the breast cancer tissue.

Letrozole
Anastrozole

Question 15

What is an alternative for postmenopausal women with oestrogen-receptor positive early invasive breast cancer if aromatase inhibitors are contraindicated?

Answer 15

Tamoxifen.

Estrogen receptor blocker.

Question 16

An aromatase inhibitor should be given as initial adjuvant therapy for how many years?

Answer 16

5 years or by switching to an aromatase inhibitor after 2-3 years of tamoxifen for a total of 5 years.

Question 17

There is some evidence that in postmenopausal women with early breast cancer, adjuvant bisphosphonate therapy can prevent what?

Answer 17

Breast cancer recurrence in the bone and improve survival.

IV zoledronic acid or oral sodium clodronate (both unlicensed) are preferred.

Question 18

Adjuvant trastuzumab is recommended as an option in patients with what type of breast cancer?

Answer 18

HER2 positive.

Question 19

Why should trastuzumab not be given concurrently with anthracycline containing regimens?

Answer 19

Because of the risk of congestive heart failure (doxorubicin = cardio), but trastuzumab can be given either concurrently with taxane-based regimens or sequentially.

Question 20

For the majority of patients with oestrogen-receptor-positive advanced breast cancer, endocrine therapy is first-line treatment. Aromatase inhibitors, such as anastrozole, letrozole and exemestane, may be offered to patients with no previous history of endocrine treatment or in those previously treated with tamoxifen.

What is the mechanism of action of exemestane?

Answer 20

Similarily to anastrozole and letrozole it works via inhibiting the aromatase enzyme.

Exemestane works at type I enzyme, letrozole and anastrozole work at type II.

Question 21

Why do the treatment options differ between pre/perimenopausal and postmenopausal women?

Answer 21

The main source of estrogen is the ovaries in premenopausal women, while in post-menopausal women most of the body’s estrogen is produced via the conversion of androgens into estrogen by the aromatase enzyme in the peripheral tissue.

Question 22

What cancer can tamoxifen cause?

Answer 22

Even though tamoxifen is a SERM and is an antagonist in breast tissue, it acts as a partial agonist on the endometrium and has been linked to endometrial cancer in some women.

Question 23

Tamoxifen has been shown to be effective in the treatment of mania in patients with bipolar disorder by blocking what?

Answer 23

Protein kinase C (PKC), an enzyme that regulates neuron activity in the brain.

Question 24

Patients with a variant form of what gene may not recieve the full benefit from tamoxifen because of too slow metabolism of the tamoxifen prodrug into its active metabolites?

Answer 24

CYP2D6.

Question 25

Recent studeis suggest that taking what antidepressant drug class can decrease the effectiveness of tamoxifen?

Why is this?

Answer 25

Recent studies suggest that taking the selective serotonin reuptake inhibitors (SSRIs) antidepressants paroxetine (Paxil), fluoxetine (Prozac), and sertraline (Zoloft) can decrease the effectiveness of tamoxifen, as these drugs compete for the CYP2D6 enzyme which is needed to metabolize tamoxifen into its active forms.

Question 26

Tamoxifen should be considered as first-line treatment for pre- and perimenopausal women with what?

Answer 26

Oestrogen-receptor positive breast cancer who have NOT previously recieved treatment with tamoxifen.

Question 27

In patients with advanced breast cancer that is imminently life-threatening or with visceral organ involvement, which requires early relief of symptoms, what chemotherapy regimen is the preferred treatment?

Answer 27

In patients with advanced breast cancer that is imminently life-threatening or with visceral organ involvement, which requires early relief of symptoms, an anthracycline-based chemotherapy regimen is the preferred treatment.

Question 28

Gemcitabine in combination with paclitaxel is recommended for the treatment of metastatic breast cancer only when docetaxel monotherapy or docetaxel with capecitabine are also considered appropriate.

How does gemcitabine work?
How does capecitabine work?

Answer 28

Gemcitaibine can masquerade as cytidine and is incorporated into new DNA strands being synthesised as the cell replicates.

It is a synthetic pyrimidine nucleoside prodrug - a nucleoside analog.

Capecitabine is metabolised to 5-FU which in turn is a TS inhibitor, hence inhibiting the synthesis of thymidine monophosphate, the active form of thymidine which is required for the de novo synthesis of DNA.

Question 29

What side effects are associated with Gemcitabine?

Answer 29

Renal impairment, tumour lysis syndrome, influenza like symptoms.

Question 30

How does capecitabine work?

Answer 30

Capecitabine is metabolised to 5-FU which in turn is a TS inhibitor, hence inhibiting the synthesis of thymidine monophosphate, the active form of thymidine which is required for the de novo synthesis of DNA.

Question 31

What gonadorelin analogue is licensed for advanced breast cancer in pre- and perimenopausal women suitable for hormone manipulation?

Answer 31

Goserelin.

Question 32

What progestogen preparation are licensed for the treatment of breast cancer? (3)

Answer 32

1. Medroxyprogesterone acetate.
2. Norethisterone.
3. Megestrol acetate

Question 33

Chemoprevention of breast cancer should be offered to all women identified as high risk.

What is the recommended treatment for premenopausal women who do not have a history or increased risk of thromboembolic disease or endometrial cancer?

Answer 33

Tamoxifen (unlicensed) due to risk of thrombo events.

Should be continued for 5 years .

Question 34

Chemoprevention of breast cancer should be offered to all women identified as high risk.

Anastrozole can be offered to post-menopausal women who do not have what condition?

Answer 34

Severe osteoporosis.

Question 35

Chemoprevention of breast cancer should be offered to all women identified as high risk.

What are the options for post-menopausal women who have severe osteoporosis or who do not wish to take anastrozole?

Answer 35

Tamoxifen provided there is no history or risk of thromboembolic disease or endometrial cancer.

Both of which tamoxifen is associated with.

[Alternatively: raloxifen hydrochloride in post-menopausal women with a uterus and no risk factors]

Question 36

Hormone replacement therapy for the treatment of menopausal symptoms should be discontinued in all women who are diagnosed with breast cancer.

Paroxetine or fluoxetine (unlicensed) can be offered to women with breast cancer for relieving menopausal symptoms only if they are not taking what medication?

Answer 36

Tamoxifen: risk of interaction due to competition to bind at CYP2D6.

Question 37

Hormone replacement therapy for the treatment of menopausal symptoms should be discontinued in all women who are diagnosed with breast cancer.

What are the other options for relieving their symptoms?

Answer 37

Paroxetine or fluoxetine [unlicensed indications] may be offered to women with breast cancer for relieving menopausal symptoms, particularly hot flushes, but not to those taking tamoxifen—risk of interactions.

Clonidine hydrochloride, venlafaxine [unlicensed indication] and gabapentin [unlicensed indication] should only be offered to treat hot flushes in women with breast cancer after they have been fully informed of the significant side effects.

Question 38

Breast cancer in men is rare. Although, not fully understood, risk factors may be associated with what?

Answer 38

Breast cancer in men is rare. Although, not fully understood, risk factors may be associated with sex hormone metabolism, including those acquired through liver disease or testicular trauma, environmental risk factors such as industrial exposure to heat, and genetic predisposition. Treatment is similar to that for women involving surgery, radiotherapy, drug therapy, or a combination of these.