Hormone therapy in breast cancer treatment

What are hormones?

Substances that function as chemical messengers in the body.

They affect the actions of cells and tissues at various locations in the body, often reaching their targets through the bloodstream.

Oestrogen and Progesterone

• produced by the ovaries in premenopausal women and by some tissues in pre and post menopausal women and men

Oestrogen

promotes the development and maintenance of female sex characteristics and the growth of long bone

produced by the ovaries in premenopausal women and by some tissues in pre and post menopausal women and men

Progesterone

plays a role in the menstrual cycle and pregnancy.

produced by the ovaries in premenopausal women and by some tissues in pre and post menopausal women and men

Issues with oestrogen and progesterone

promote growth of some breast cancers that are hormone dependent/hormone sensitive and contain receptors that become activated when hormones bind to them and change expression of genes leading to stimulation of tumour growth

Structure of Oestrogen

Structure of Progesterone

Hormone therapy

slows or stops the growth of hormone-sensitive tumours by blocking the body’s ability to produce hormones or by interfering with effects of hormones on breast cancer cells

ER+ and ER-

oestrogen receptor positive (ER positive), oestrogen sensitive, or oestrogen responsive

oestrogen receptor negative (ER positive), oestrogen insensitive, or oestrogen unresponsive aka they do not use oestrogen to grow → do not respond to hormone therapy

HR+ and HR-

HR+ = tumours that contain oestrogen and/or progesterone receptors

HR- = tumours that lack BOTH oestrogen and progesterone receptor

HRT in HR+ cancer

can promote the growth of the tumour

usually patients asked to stop this therapy or any OC if they are taking it (but EHC can be taken as it is single dose in case of emergency)

HER2

Human Epidermal Growth Factor 2

Triple negative cancer

the cancer does not have receptors for either HER2 or the hormones oestrogen and progesterone

HER2 +ve cancer treatment

herceptin - trastuzumab

What are the main strategies used to treat hormone-sensitive breast cancer?

• blocking ovarian function

• blocking oestrogen production

• blocking oestrogen effects

Blocking ovarian function as a treatment for breast cancer

Known as ovarian ablation

surgically removing the ovaries in a oophorectomy OR treat with radiation

usually permanent

Drugs that block ovarian function

Goserelin - LH-R

ovarian function can be suppressed temporarily by treatment with drugs called gonadotropin-releasing hormone (GnRH) agonists, which are also known as luteinizing hormone-releasing hormone (LH-RH) agonists

Blocking oestrogen production to treat breast cancer

Aromatase inhibitors

block the activity of aromatase which is used in the body to make oestrogen in the ovaries and other tissue

primarily used in post-menopausal women cause in pre-menopausal too much aromatase is made for the inhibitor to be effective

Anastrozole/Letrozole

aromatase inhibitor - temporary

Exemestane

aromatase inhibitor - permanent

Role of aromatase

converts androstenedione to oestrogen/testosterone to oestradiol

makes the hexene ring + carboxyl on the LHS of andro → aromatic ring + OH

Blocking oestrogen effects to treat breast cancer

use SERM - selective oestrogen receptor modulators

• bind to oestrogen receptors and prevent oestrogen from binding

• e.g. tamoxifen and toremifene

Potential issue with SERM

• Potentially not only block estrogen activity (i.e., act as oestrogen antagonists) but also mimic oestrogen effects (i.e., serve as oestrogen agonists).

• SERMs can behave as oestrogen antagonists in some tissues and as oestrogen agonists in other tissues.

• For example, tamoxifen blocks the effects of oestrogen in breast tissue but acts like oestrogen in the uterus and bone.

Tamoxifen

SERMs

to treat HR+ hormone receptor–positive breast cancer.

Fulvestrant

Also blocks oestrogen effects

oestrogen antagonist like SERM BUT no agonist effects

pure antioestrogen

when it binds to ER, it targets the receptor for destruction

Three main ways that hormone therapy is used to treat hormone-sensitive breast cancer

• Adjuvant therapy for early-stage breast cancer

• Treatment of advanced or metastatic breast cancer

• Neoadjuvant treatment of breast cancer

Adjuvant therapy for early-stage breast cancer (tamoxifen)

Women who receive at least 5 years of adjuvant therapy with tamoxifen (after having surgery for early-stage ER-positive breast cancer) have reduced risks of breast cancer recurrence, including a new breast cancer in the other breast, and death (at 15 years).

Tamoxifen is approved for adjuvant hormone treatment of premenopausal and postmenopausal women with ER-positive early-stage breast cancer, and the aromatase inhibitors anastrozole and letrozole are approved for this use in postmenopausal women.

Exemestane

Aromatase inhibitor approved for adjuvant treatment of early-stage breast cancer in postmenopausal women who have received tamoxifen previously.

Treatment of advanced or metastatic breast cancer using hormone therap

Many types of HT are approved for treatment of metastatic/recurrent hormone-sensitive breast cancer including:

• tamoxifen/toremifene to treat metastatic breast cancer

• fulvestrant for postmenopausal women with metastatic ER-positive breast cancer that has spread after treatment with antioestrogen (could also be used in premenopausal women who have had an ovarian ablation)

• aromatase inhibitors for post menopausal women with metastatic/locally advanced hormone-sensitive breast cancer but only as INITIAL therapy

• Aromatase inhibitors (including Exemestane) may also be used to treat postmenopausal women who’s disease has advanced after treatment with tamoxifen

Lapatinib

tyrosine kinase inhibitor

targeted therapy drug used in combination with aromatase inhibitor to treat HER-positive metasatic breast cancer in postmenopausal women

Locoregional recurrence

ER-positive breast cancer that has come back in the breast, chest wall, or nearby lymph nodes after treatment

Palbociclib use

targeted therapy used in combination with letrozole as initial therapy for the treatment of hormone receptor–positive, HER2-negative advanced breast cancer in postmenopausal women.

also approved to be used in combination with fulvestrant for the treatment of women with hormone receptor–positive, HER2-negative advanced or metastatic breast cancer whose cancer has gotten worse after treatment with another hormone therapy

CDK 4/6

Cyclin dependent kinase that promote the growth of hormone receptor positive cancer cells

Palbociclib

CDK4/6 inhibitor

Neoadjuvant treatment of breast cancer using hormone therapy

The goal of neoadjuvant (before surgery) therapy is to reduce the size of a breast tumour to allow breast-conserving surgery.

Neoadjuvant hormone therapy (in particular, with aromatase inhibitors) can be effective in reducing the size of breast tumours in postmenopausal women.

The results in premenopausal women are less clear because only a few small trials involving relatively few premenopausal women have been conducted thus far.

How can Tamoxifen reduce the risk of developing breast cancer?

Tamoxifen if taken for 5 years can reduce the risk of developing invasive breast cancer by about 50% in post menopausal women who were at increased risk and long term it reduces the incidence of breast cancer for at least 20 years

Raloxifene if taken for 5 years reduces breast cancer risk in such women by about 38%

How can Raloxifene reduce the risk of developing breast cancer?

Raloxifene if taken for 5 years reduces breast cancer risk in such women by about 38% in post menopausal women who were at increased risk and long term it reduces the incidence of breast cancer for at least 20 years

Can aromatase inhibitors reduce risk of breast cancer?

Yes, it has been found to reduce the risk of breast cancer in postmenopausal women at increased risk of the disease.

Women who took exemestane were 65% less likely than those who took a placebo to develop breast cancer after three years.

After 7 years of follow-up women who took anastrozole were 50% less likely than those who took placebo to develop breast cancer.

Common side effects of hormone therapy

hot flashes

night sweats

vaginal dryness

disruption of menstrual cycle

Side effects of Tamoxifen

Risk of blood clots, especially in the lungs and legs

Stroke

Cataracts

Endometrial and uterine cancers

Bone loss in premenopausal women

Mood swings, depression, and loss of libido

Side effects of Raloxifene

Risk of blood clots, especially in the lungs and legs

Stroke in certain subgroups

Side effects of Aromatase inhibitors

Risk of heart attack, angina, heart failure, and hypercholesterolemia

Bone loss

Joint pain

Mood swings and depression

Side effects of Ovarian suppression drugs

Bone loss

Mood swings, depression, and loss of libido

Side effects of Fulvestrant

Gastrointestinal symptoms

Loss of strength

Pain

Antidepressants + Tamoxifen

SSRIs can inhibit CYP2D6 which is responsible for metabolising the Tamoxifen into it’s more active metbaolite

inhibiting the CYP2D6 enzyme can slow the metabolism of tamoxifen and reduce it’s effectiveness → need patients to consider switch to a weaker inhibitor (e.g. sertraline) or one that isn’t an inhibitor at all (e.g. citalopram/venlafaxine

if postmenopausal then suggest aromatase inhibitor instead?