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Targeted therapies in breast cancer

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There are two well established targets in the treatment of breast cancer. These are the oestrogen receptor and the HER2/neu receptor, a surface glycoprotein. Women with so called “triple negative” breast cancers (TNBC) are hormone receptor and HER2 receptor-negative. Unsurprisingly, this subtype is associated with a poorer prognosis and has more limited treatment options.


Recent advances suggest that the emergence of the Poly-ADP-Ribose-Polymerase (PARP) inhibitors may augment the management of TNBC. To understand how this may be the case, one needs to consider the evolution of targeted therapies in breast cancer to date.

Evolution of hormonal therapy – An historical perspective

In the 1880s, the German surgeon Albert Schinzinger was the first  to propose that a surgical oophorectomy could be used in the  management of locally advanced breast cancer. He also noted that  surgery could result in a reduction in recurrence rates as he noted older women diagnosed with breast cancer tended to fare better than their younger counterparts.

This observation prompted  George Thomas Beatson to perform pioneering surgery, namely  bilateral oophorectomies, in three premenopausal women with  metastatic breast cancer in 1896. Remarkably, one of the women  had a complete response to this approach and survived for a further four years postoperatively, whilst  the other  two  had documented  partial responses.

In 1900, the English surgeon  Stanley Boyd published a review in which he stated that one-third  of breast cancer patients’ disease responded to ovarian ablation.

The discovery of the oestrogen receptor in 1922 led to an increased understanding of the potential of the role of hormonal manipulation in breast  cancer treatment.

The advent of tamoxifen – A practice changing landmark

As knowledge of the mechanisms underlying oestrogen signalling  grew, drugs were developed which targeted the oestrogen receptor. Selective oestrogen receptor modulators (SERMs) comprise the main class of drugs that inhibit ER signalling.

Whilst oestrogens exert a wholly agonistic effect upon the ER, SERMs can either act as an agonist or as an antagonist of the ER, depending on the tissue in question. The most widely used of this  class of drugs is tamoxifen, which works as an oestrogen  antagonist in breast tissue, but as an oestrogen agonist in uterus  and bone. Tamoxifen was first approved for use in the USA by the  FDA in 1973. It was licenced for use in post menopausal women with advanced breast cancer initially.

A large meta-analysis demonstrated that five years of tamoxifen,  compared with no  adjuvant therapy, reduces the annual recurrence rate by 41 per cent, and  the breast cancer mortality rate by 34 per cent amongst women with ER-positive breast cancer.

The benefit is just as effective for  younger as compared to older women, with a similar absolute risk  reduction in the five-year probability of breast cancer recurrence (about 10 per cent). In various adjuvant trials, tamoxifen lowered the incidence of contralateral breast cancer by  almost 50 per cent. From these findings, investigators deduced that  tamoxifen also had potential as a chemopreventative agent.

The emergence of Herceptin and further refinement of targeted therapies

The single most important advance in the evolution of treatment for  breast cancer  in the last decade or so was the development of the humanised monoclonal antibody trastuzumab (Herceptin).

Human epidermal growth factor 2 (HER2/neu) is a growth factor receptor that is amplified in approximately 20-25 per cent of breast cancer, with its related protein product being produced at very elevated levels in malignant cells, and this expression is correlated with more aggressive tumour behaviour.

In 1998, in the wake of studies which showed a significant survival advantage, the FDA approved the use of trastuzumab as a first-line treatment in combination with paclitaxel for women with metastatic HER2/neu positive breast cancer. Subsequent studies have demonstrated that the use of trastuzumab  following surgery was associated with a significant improvement in disease-free survival and overall survival in women with early stage HER2/neu positive breast cancer by  50 per cent.

Although introducing trastuzumab as a standard of care in the management of HER2/neu positive breast cancer has been costly, it is a cost-effective strategy with respect to adjuvant and metastatic HER2/neu amplified breast cancer .
The introduction of trastuzumab into modern breast cancer  chemotherapy protocols has revolutionised the management of HER2/neu positive breast tumours.

Prior to the advent of this agent,  HER2/neu positive breast cancer was associated with significantly poorer outcomes in both the adjuvant and metastatic settings. It has now been demonstrated that  incorporation of trastuzumab into  breast cancer treatment programmes has resulted  in equalising  prognostic outcomes of women with HER2/neu positive disease to  those of women with HER2/neu negative disease, a subtype traditionally associated with a better outcome.

Triple negative breast cancer – A new treatment challenge

Triple negative, or basal-like, breast cancer is an especially “high-risk” subtype and is typically negative for the three targetable proteins – the oestrogen and the progesterone receptor, and the HER2 receptor protein.

This subtype makes up approximately 15 per cent of all breast cancers and typically the overall prognosis is poor with more limited treatment options. Recent data have suggested that this may be set to change  with the advent of PARP (Poly-ADP ribose polymerase) inhibitors.

PARPs are a large family of multifunctional enzymes that have key roles in DNA repair, in particular base excision  repair. BRCA1 and BRCA2 are tumour-suppressor genes, which  code for the DNA repair enzymes that normally repair double-stranded DNA mistakes during cell division, such as those arising  from exposure to chemotherapy (e.g., cisplatin and other alkylating agents such as topoisomerase inhibitors). Mutations in these genes are associated with an increased risk of breast cancer.

Because this is such an important quality-control step during cell division, BRCA1 and BRCA2 have PARP enzymes as backup enzymes in case they are mutated or non-functional. In patients with BRCA1 or BRCA2 mutations, therefore, PARP enzymes are critical to prevent the cell from undergoing apoptosis.

By blocking PARP enzymes, the cancer cell has no ability to repair DNA errors, and is forced to undergo apoptosis. The condition under which a cell can still be viable with a mutation in  either of the repair pathways (BRCA1/BRCA2, or PARP) but dies  when both pathways (or genes) are impaired is known as synthetic  lethality.

Use of therapies that exploit synthetic lethality, such as  PARP inhibition, has become a new direction in cancer-drug  development. Such therapy may be effective for BRCA-mutated and triple negative breast cancers.

In conclusion, the management of breast cancer has been revolutionised by approaches which target the oestrogen and progesterone receptor, as well as the HER2/receptor. Those women whose tumours lack these three targetable proteins have had a much more guarded outlook to date, but it is hoped that new innovative treatments which focus on DNA repair mechanisms will improve the clinical outlook for this patient cohort.

References available on request

Dr Ciara O’Sullivan, SpR and Dr John Kennedy, Consultant Oncologist, Department of Medical Oncology, St James’s Hospital, Dublin 8

 

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