New initiatives in the treatment of breast cancer

Better targeted therapies will reduce the burden of treatment, while improving the outcomes

With the 5-year survival for women diagnosed with breast cancer at 90%, the thrust of new initiatives is to discover whether that outcome can be either improved or achieved with less or better targeted therapy. Breast cancer was one of the first tumours to be successfully treated with a targeted therapy: trastuzumab improved outcomes for women with HER2-positive breast cancer, initially when treating metastatic disease, and then in the adjuvant therapy setting.1

New targets, new treatments

Among the new agents that target HER2-positive breast cancer are lapatanib, pertuzumab and trastuzumab emtansine (TDM-1), which can be used alone or combined with other agents to treat metastatic breast cancer.1 Newer targets for therapeutic agents include poly(ADP-ribose) polymerase (PARP), an enzyme involved in DNA repair. Therapy with PARP inhibitors such as olaparib are emerging treatments for patients with mutations in the BRCA1 or BRCA2 genes.1

As many as 40% of women with breast cancer will become resistant to currently available treatments, and alternative agents are needed. The cyclin-dependent kinases, particularly CDK4 and CDK6, are important for cell cycle phase progression, and inhibitors such as palbociclib are being trialled as drugs for treating metastatic breast cancer.2 However, there are so many possibilities for targeted drugs that we need to develop new strategies for identifying which should be investigated. One promising approach is to look for correlations between gene mutations that are upregulated in some breast cancers and bioactive compounds that downregulate these genes, thereby identifying potentially useful new therapies.3

An alternative approach to treatment is immunotherapy. This includes increasing the activity of a patient’s T cells and then re-infusing them, or conjugating drugs with antibodies to better target cancerous cells; vaccines that enable an immune response to tumour-associated antigens; and checkpoint inhibitor drugs, such as pembrolizumab, which block molecules that inhibit the immune response.1 Monitoring the cancer and predicting the treatment response is vital, and detecting circulating tumour cells is being investigated for this purpose.4

In the adjuvant setting, only some patients will need additional therapy. Studies are examining whether adding genetic signatures to clinico-pathological information can better predict those whose survival will not require adjuvant chemotherapy.5

Radiation therapy

Accelerated partial breast irradiation (APBI) has been investigated as a parallel strategy for reducing the toxicity of radiation therapy as part of breast conservation after lumpectomy.6 APBI delivers radiotherapy to a 1–2 cm area around the site where the lump was removed, rather than to the whole breast. Delivering higher doses per fraction allows radiation treatment to be completed in a few days rather than over 5 or 6 weeks. Several techniques are used — including brachytherapy with multiple implanted wires or radioactive seeds, balloon catheter brachytherapy, and intra-operative radiation therapy combined with targeted external beam radiotherapy using 3-dimensional conformal radiotherapy or proton beams — each of which spares normal tissue around the target. The relative roles of each technique are yet to be clarified, and the selection criteria for patients most suitable for each approach need refining.

The efficacy of radiation to the breast may be further improved by concomitant immunotherapy.7

Surgery

The extent of surgery required for curing breast cancer has been decreasing. Building upon previous findings that, in many cases, lumpectomy and radiotherapy could replace mastectomy, trials have shown that sentinel lymph node biopsy can be used to avoid axillary dissection in T1 (less than 2 cm in diameter) and T2 cancers (less than 5 cm in diameter) if the sentinel lymph node is negative, as well as in selected patients with limited sentinel node involvement,8 according to the pathology of the primary tumour and the sentinel node. Moreover, if a patient requires chemotherapy, providing it prior to surgery does not compromise survival, and is associated with a higher rate of breast conservation surgery.9 Neo-adjuvant therapy also provides more time for the results of genetic tests, which may determine the extent of surgery, to become available, and yields information about the chemo-sensitivity of the tumour. Oncoplastic surgery techniques that combine adequate cancer surgery with reconstruction techniques are being developed that will improve the cosmetic outcomes of surgery.9

Prevention

In addition to better treatments, new research is providing more information about preventing breast cancer. For example, a recent study by the Women’s Health Initiative has shown that longer duration of obesity is linked with an increased risk of post-menopausal breast cancer.10 This should stimulate trials that investigate which interventions reduce this risk. Data on chemo-prevention with tamoxifen are being supplemented by trials of aromatase inhibitors, and trastuzumab is being trialled in patients with HER2-positive ductal carcinoma in situ (DCIS) to assess whether invasive disease can be prevented.11

Finally, several studies are focused on improving the quality of life of the increasing number of survivors of breast cancer.