Treatment of Hormone-Positive Metastatic Breast Cancer

Just as each organ can have more than one type of cancer, breast cancer also has many subtypes. The most common is the hormone receptor-positive, HER2 (CerbB2)-negative group. Hormone receptors refer to estrogen (ER) and progesterone (PR) receptors on the tumor cell surface. Metastatic (stage 4) breast cancer patients have hormone receptor positivity in %75 of cases.

Below, you can see breast cancer types according to their biological characteristics:

For a patient with hormone receptor-positive, HER2 -negative metastatic breast cancer, endocrine (hormonal) treatment is given first if there are no life-threatening metastases.

Drugs used in endocrine (hormonal) treatment can be considered in 4 classes as follows:

• Selective estrogen receptor modulator: tamoxifen,
• LHRH agonists for ovarian suppression: goserelin, leuprolide
• Selective estrogen downregulator: fulvestrant 
• Aromatase inhibitors: anastrozole, letrozole, exemestane

Endocrine treatment for breast cancer began in 1977 with tamoxifen (see the discovery of tamoxifen). After 1995, LHRH agonists providing ovarian suppression (suppression of female ovarian function) and aromatase inhibitors for postmenopausal patients entered treatment. In 2002, fulvestrant began to be used. For a long time, these treatments were used sequentially on their own, moving to the next endocrine treatment when progression (cancer advancement) occurred.

Let us look at developments in hormone-positive breast cancer treatment from tamoxifen to the present:

TAMOXIFEN: The United States Food and Drug Administration (FDA) approved it in 1977 for use in metastatic (advanced) breast cancer. A few years later it also received approval in adjuvant treatment. Tamoxifen has been the most widely used endocrine treatment for years and remains important. It is estimated that more than 500.000 women are alive today as a result of tamoxifen treatment. In metastatic disease, its clinical benefit rate was calculated as %54 and objective response rate as %34.

AROMATASE INHIBITORS: Their use began after FDA approval in 1995 of a drug containing anastrozole . Clinical studies and meta-analyses showed that it was more effective than tamoxifen in postmenopausal metastatic breast cancer patients.

FULVESTRANT: It was approved by the FDA in 2002. In 2010, the 500mg dose was found more effective than the 250mg dose, and the use of 250mg was abandoned in practice.

FULVESTRANT + ANASTROZOLE: The FACT and SWOG S0226 studies showed that combination treatment was superior to anastrozole alone.

Resistance to hormonal therapy and new-generation targeted treatments in breast cancer

Unfortunately, responses to endocrine treatments started alone were observed to decline after 1 year, with resistance to hormonal therapy developing. To overcome this endocrine resistance and prolong response duration, combinations with targeted therapies called CDK inhibitors were tried, with very successful results. Breast cancer treatment guidelines therefore now recommend endocrine and targeted treatment combinations for metastatic disease in the 1st-line setting with a higher level of evidence.

CDK INHIBITORS: Although these new-generation agents do not act directly on female hormones, they act against hormone-positive breast cancer through the cell cycle . The first approved drug in this class, a CDK 4/6 inhibitor, was approved in 2015: palbociclib (Ibrance). CDK inhibitors have brought a breath of fresh air to hormone-positive breast cancer treatment.

Comparison of FIRST-line endocrine treatment combinations in advanced hormone-positive breast cancer in terms of progression-free survival

Comparison of SECOND-line endocrine treatment combinations in advanced hormone-positive breast cancer in terms of progression-free survival

Side effects of CDK inhibitors

The most common side effects of this drug group are nausea, diarrhea and other gastrointestinal (stomach and bowel) complaints; leukopenia-neutropenia and other low blood counts; infections; fatigue, alopecia (hair loss) and ECG changes.