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Cancer Topics

Hormonal Therapy in Advanced Breast Cancer and Newer Agents to Overcome Resistance
Hormonal Therapy in Advanced Breast Cancer and Newer Agents to Overcome Resistance

Because resistance to hormonal therapies can happen in up to a quarter of cases, newer therapeutic strategies have been developed to attempt to overcome this. There are several oral medications such as palbociclib, ribociclib or everolimus which when combined with pre-existing hormonal therapies have improved disease outcomes.

Both palbociclib (Ibrance) and ribociclib (Kisqali) belong to a group of drugs known as CDK4/5 inhibitors which block proteins in the cell called cyclin-dependent kinases (CDKs), in particular CDK4 and CDK6. This interferes with cell division and thus stops cancer growth.  Palbociclib (Ibrance) and Ribociclib (Kisqali) are both approved for the treatment of hormone-receptor positive metastatic breast cancer in postmenopausal women. The use of Palbociclib (Ibrance) has been studied in combination with hormonal therapies such as letrozole (Femara) and fulvestrant (Faslodex) and Ribociclib (Kisqali) has been has been studied in combination with letrozole (Femara) and these new drug combinations have shown improved disease outcomes. There are numerous ongoing trials evaluating these group of drugs in both advanced and early stage breast cancers.

Introduction 

There has been much publicity about using targeted therapy for cancer treatment. What is the first “targeted” therapy for breast cancer? Well, actually, it should be hormonal or endocrine therapy. The development of treatments using medication that target the oestrogen (or estrogen) receptor expressing breast cancers is one of the great advances for oncology. More than a century ago, it was found that ablating or removing the hormonal function of the ovaries, pituitary or adrenals was a way to treat some advanced breast cancer patients. It was not until about 50 years ago that there were steroid hormone receptors, known as oestrogen receptors (ER) and progesterone receptors (PR), that the tumour expressed that mediated this benefit.  The ER expressing or ER positive breast cancer is then the target for anti-oestrogen therapies. Drugs were subsequently developed to act on the oestrogen receptor pathway. Some of these drugs include SERMs (Selective Estrogen Receptor Modulators), and aromatase inhibitors.

Cancer is heterogeneous, which means that different cancer cells have been observed to have distinct features, gene expression, metabolism, metastatic potential. These differences exist and may not always be clear to observers initially. For example, on a chicken farm, the chickens would look quite the same but there are still differences between them to the careful observer. The differences in the tumour cells can occur between tumours (inter-tumour heterogeneity) or within tumours (intra-tumour heterogeneity). This has implications for treatment because we categorise our therapeutic strategies. This also explains why in patients with large volume or amount of tumour cells (particularly in metastatic setting), we have difficulty eliminating all the tumour cells.

In breast cancer, based on molecular profiling, tumours have been classified according to expression of oestrogen receptor (ER),  progesterone receptor (PR) and human epidermal growth factor 2  (HER2, also known as HER2/neu) receptor status into several clinical subtypes :

1. Treated as hormone-positive (or endocrine positive) breast cancer

    ER positive, PR positive, HER2 negative

    ER positive, PR negative, HER2 negative

    ER negative, PR positive, HER2 negative (uncommon)

2. Treated as HER2-positive (or HER 2 neu positive) breast cancer

    ER negative, PR negative, HER2 positive

    ER positive, PR positive, HER2 positive

    ER positive, PR negative, HER2 positive

    ER negative, PR positive, HER2 positive (uncommon)

3. Treated as triple negative breast cancer (TNBC)

    ER negative, PR negative, HER2 negative

Treatment of ER positive breast cancer

Oestrogen receptor (or estrogen receptor) is expressed in about 70% of all breast cancers and endocrine therapies are the mainstay of treatment for these tumours. There are various endocrine options available . Hormonal therapies can be used as part of the overall treatment for your breast cancer, the optimal strategy of which will be determined by your oncologist.

Year Drug Mechanism
1896

1977

1990s

2000s

Ovarian ablation/suppression

Surgical (removal of both ovaries aka oophorectomy)

Radiotherapy

Medical (GnRH analogues)

SERMS Tamoxifen

Aromatase Inhibitors

Exemestane (Aromasin)

Letrozole (Femara)

Estrogen receptor downregulators

Fulvestrant (Faslodex)

Estrogen deprivation in premenopausal women

Antagonizes estrogen receptors in breast tissue

Antagonizes conversion of androstendione and to estradiol in peripheral tissues (fat, liver, muscle, brain)

Impairs ER dimerization, increases ER degradation, and disrupts nuclear localisation of ER

 

“Expert knowledge means better care for cancer”

Written by:

Dr Tan Sing Huang Dr Peter Ang
MBBS (Singapore)  MBBS (Singapore)
M.Med (Singapore) MMed (Int Med)
MRCP (UK)  MRCP (UK)
FAMS (Medical Oncology)  FAMS (Medical Oncology)