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.
Table 1: Drugs that target the hormonal pathway in breast cancer
Leuprolide (Lucrin) or Goserelin (Zoladex)
Megestrol acetate (Megace)
*These are aromatase inhibitors
Currently, for ER-positive breast cancer or hormone responsive breast cancer, the use of anti-oestrogen treatment with these drugs are important and has saved many lives worldwide. Women with early stage endocrine receptor positive breast cancer would now take at least 5 years of adjuvant hormonal therapy to reduce recurrence and improve survival. Recent data even suggests that longer durations of adjuvant endocrine therapy (such as the ATLAS trial using tamoxifen for 10 versus 5 years) will benefit women as some of these ER positive cancers do relapse later than the typical 5 years that is mentioned and tracked in studies.
Recent technology using gene expression profiling has helped us understand the various subtypes of breast cancer. The development of this classification is based on the genes expressed in the tumour cells. These were then analysed by an algorithm for patterns of gene expression. There are four main intrinsic molecular subtypes: human epidermal growth factor receptor 2 –enriched (HER2 enriched), basal-like, luminal A, and luminal B subtypes. This categorisation does affect how doctors regard breast cancers in contrast to the standard way using immunohistochemistry or staining pattern of the tumour using antibodies. There might then be some differences in the way breast tumour is grouped based on these genetic technologies or by immunostains.
In general, the hormone positive breast cancers belong to the luminal A and luminal B subtypes. There are specific features of luminal B compared to luminal A breast cancers:
Lower expression of hormone or oestrogen receptors
Luminal B is more likely oestrogen receptor (ER) positive, progesterone receptor (PR) negative and can be Her2 positive (ER+,PR-, Her2+)
Higher cell proliferation or turnover based on cell markers such as Ki67. This may imply the tumour cells are more active, at least under microscopy
Higher histologic grade when examined under the microscope (higher histologic grade means it appears more “aggressive” or disorganised under microscopy)
Luminal B breast cancers seem to have a worse outcome compared to luminal A breast cancers
The pattern of tumour spread may involve the bone and to a lesser degree the lung for luminal B breast cancers whereas luminal A breast cancers tend to involve the bone primarily. Luminal B pattern of metastasis may be more similar to basal-like and HER2-enriched breast cancers.
Luminal B hormone positive breast cancers may have a lower percentage of hormone receptors staining on pathology. They would then benefit from both chemotherapy and hormonal therapy.
In summary, breast cancer classification and treatment is undergoing many changes. What we understand as hormone responsive or oestrogen receptor positive breast cancer has been shown by next generation sequencing (NGS) and other technologies to comprise at least 2 subtypes of breast cancer. Luminal A and luminal B breast cancers are distinct in several important features. The growth of such tumours are driven by different oncogenic mechanisms. Understanding them will be the beginning of designing treatments suitable for these patients to improve outcomes.
“Expert knowledge means better care for cancer”
Dr Peter Ang
MMed (Int Med)
FAMS (Medical Oncology)