Breast cancer is the most commonly diagnosed cancer (~45k/yr) in women in the UK, also affecting ~300 men every year. Representing almost 1 in 3 malignancies in women, it is the second leading cause of cancer death after lung cancer (1). Despite its rising incidence in developed countries, the survival rates for breast cancer are constantly improving, with 2 out of 3 women now surviving 20 years (2).
Most commonly, women present in general practice with a breast lump (56%). Other common breast changes include a change in the size/shape of their breast, local tenderness and pain (17%), ulceration (16%), nipple changes including inversion or blood stained discharge (11%), skin dimpling (peau d’orange) or tethering, or swelling in the axillary region. Conversely, some women are asymptomatic. Increasing numbers of breast cancer cases are also detected during routine screening owing to the increased uptake and sensitivity of the investigations (3).
On average, a woman will wait 13 months before seeing her GP regarding breast symptoms. However, overall only 3% of women who present with such complaints are actually found to have breast cancer. Hence it is essential not to delay the referral for specialist evaluation, whilst conveying optimism and reassurance about the effectiveness of treatment and survival (4).
Provided below is an overview of NICE referral criteria for patients with suspected breast cancer, with further guidelines available for download from http://egap.evidence.nhs.uk/CG27/section_1#section_1_6.
Histopathologically, breast cancers are divided into those affecting ducts (e.g. ductal carcinomas, comedo, inflammatory), lobules (lobular carcinomas) and the nipple (Paget’s), and can be invasive or in situ. Invasive ductal carcinoma (IDC) is the most common type, accounting for about 80% of invasive breast cancers (3).
Recent findings in breast cancer taxonomy have identified 4 major molecular subgroups of breast cancer: normal-like, luminal (ER-positive), basal-like (mostly ER-negative), or erbb2+ (mostly HER2-amplified). It is now being questioned whether breast cancer should be classified according to its gene expression profile, in order to make more accurate predictions about the outcome of the disease and select the optimal treatment for patients (5).
Breast cancer is a multi-factorial disease, believed to be a result of both genetic and environmental factors. Age, sex, positive past medical history or family history of benign/malignant breast lesions and genetic predisposition seem to be the major contributors to the relative risk of developing breast cancer. In addition, lifetime cumulative exposure to endogenous (age at menarche & menopause, parity, breast feeding) and exogenous (use of COCP, HRT ) hormones, mostly oestrogen, are said to play a significant role. Other lifestyle factors: sedentary lifestyle, poor diet, obesity, smoking, and alcohol intake, have also been implicated (3).
Environmental and lifestyle factors account for most cases of breast cancer, and 8 out of 9 women with the disease develop it sporadically and have no associated family history. However, despite the majority of breast cancers being due to acquired or somatic mutations, approximately 5% of them are due to a known inherited gene. 3 classes of predisposing factors, categorised by their associated risk of breast cancer, are currently known (6):
* High penetrance genes: BRCA1, BRCA2, TP53, which, while extremely uncommon, confer a greater than tenfold risk of breast cancer.
* Genes of unknown penetrance: PTEN, STK11, CDH1, which are associated with specific clinical syndromes such as Cowden, Peutz-Jegherrs, and hereditary diffuse gastric cancer.
* Intermediate penetrance genes: CHEK2, ATM, BRIP1, PALB2, of moderate population frequency, that confer a relative risk of breast cancer of 2-4.
* Low penetrance genes: despite their high population frequency, they are of limited significance to breast cancer risk, when present on their own. However, a substantial component of breast cancer risk might be the combined effect of several low penetrance gene polymorphisms.
These genes code for proteins that ultimately participate in and facilitate a number of cellular processes, including cell division, repair and death. Since cancer develops as a result of ineffective DNA repair, uncontrolled cell division and failure of damaged cells to die by apoptosis, a defect/disturbance to any of these three processes may have disastrous consequences to the cell.
Of the above, homologous recombination repair of double-strand DNA breaks (DSB) plays the major role in breast cancer pathogenesis.
After a double-strand break occurs, sections of DNA around the 5' end of the break are cut away in a process called resection. In the strand invasion step that follows, an overhanging 3' end of the broken DNA molecule then "invades" a similar or identical, but intact, DNA molecule. This is followed by formation of one or two cross-shaped Holliday junctions, connecting the two DNA molecules. Depending on how the two junctions are cleaved by enzymes, the type of homologous recombination that occurs in meiosis results in either chromosomal crossover or non-crossover. Homologous recombination that takes place during DNA repair tends to result in non-crossover products, in effect restoring the damaged DNA molecule as it existed before the double-strand break (5).
Two of the major proteins implicated in homologous recombination are encoded by the high-penetrance genes, BRCA1 and BRCA2, and boast multiple functions that, in turn, are intertwined to control genomic stability in a cell. Inherited mutations in these genes therefore predispose to breast and ovarian cancers in women, and prostate cancer in men.
The general approach to evaluation of suspected breast cancer has become standardised with the triple assessment, involving clinical examination, imaging and biopsy. Wide ranges of imaging modalities are available, including mammography, ultrasonography, MRI and PET scanning. Of these, mammography is most commonly used in breast cancer screening. However, in females under 35 years of age ultrasound scanning is considered more appropriate, mainly to avoid false positive results due to high mammary tissue density in this age group (7). Tissue samples are essential for definite histological diagnoses and these are obtained via fine needle aspiration or core biopsy. Triple assessment is considered a ‘gold standard’, with sensitivity of 97-100%, and specificity of 98-100% for detection of breast cancer.
Other laboratory tests carried out on the sampled tissue include determination of receptor status (ER, PR, HER2/neu) and genetic screening for susceptibility genes. These results help in deciding upon the most appropriate treatment regime for an individual patient, as well as establishing the likely prognosis. For instance, while positivity for HER2/neu (8) confers poor prognosis with rapid cancer progression, presence of ER/PR receptors on the tumour cells implies their sensitivity to anti-hormonal treatment.
Clinical and pathological staging provide further support for the diagnosis, prognosis and the most appropriate choice of treatment. Nonetheless, the single most important predictive factor is the presence/absence of lymph node involvement in the axillary specimen (9). Women with locally advanced breast cancer have a considerably poorer outlook than those diagnosed early. Sporadically, patients have evident spread of cancer on first presentation, but more frequently metastatic disease is an indication of recurrence.
The sentinel lymph node (SLN) is the first lymph node, or set of nodes, to which cancer is likely to spread from the primary tumour - indeed, cancer cells may appear in the SLN before spreading anywhere else. SLN biopsy is a procedure in which the sentinel lymph node is excised and examined under a microscope to determine whether cancer cells are present. SLN biopsy is based on the idea that cancer cells metastasise in an orderly way from the primary tumor to the sentinel lymph node(s), then to other nearby lymph nodes.
While a negative SLN biopsy result suggests that cancer has not spread to the lymph nodes, a positive result indicates that cancer is present in the SLN and may be present in other regional lymph nodes, thus aiding the staging of disease and development of most suitable treatment plan.
Recent recognition of the heterogeneous nature of breast cancer has prompted introduction of individual treatment plans. While the management algorithms still follow the recommendations set by SIGN (10), i.e. local (surgical) options, radiotherapy and systemic (11) treatments (chemotherapy, hormonal, biological), these are now tailored to the characteristics of the tumour. Broadly speaking, patients’ options include:
First line treatment with anthracycline-based chemotherapy (epirubicin, doxorubicin) is standard and may be followed by a taxane (docetaxel, paclitaxel). Depending on the response to the primary chemotherapy, a range of other treatments may be available including breast conserving surgery or definitive local therapy, total mastectomy and axillary nodal clearance, followed by radiotherapy to the chest wall and to the regional lymph nodes. Subsequent systemic treatment may include further chemotherapy, endocrine therapy (if ER positive), or Trastuzumab (if HER2 positive). (12)
Recently in 2006, the UK has approved treatment of patients with Her2 overexpression, with Trastuzumab (Herceptin). Trastuzumab is a humanised monoclonal IgG antibody, which, upon blocking of the Her2 receptor (EGFR), reduces downstream MAPK or P13K pathways signalling and ultimately arrests the cell in the G1 phase of the cell cycle; thus inhibiting cell proliferation and tumour cell survival respectively. When used in conjunction with chemotherapy, it vastly improves survival rate. Trastuzumab is usually well tolerated, with cardiotoxicity being its only serious side effect.
Treatment for patients with metastatic breast cancer is palliative in nature, and the prognosis is better for women with soft tissue (e.g. bone) rather than visceral (e.g. liver) metastases. The choice of therapy for stage IV disease is driven by two factors: the possible toxicity and side effects of the treatment versus the improvement in QoL and the potential of prolonging disease-free survival, with the aim is to control rather than cure the disease (9).
Breast cancer remains an area of research that continues to attract considerable interest from the scientific and medical elites, pharmaceutical industry giants, as well as breast cancer sufferers and their families (13). Current research focuses on several areas (14,15):
* Targeting of the signalling pathways implicated in breast cancer pathogenesis, namely ErbB family of receptor tyrosine kinases and Ras proteins of small GTPases family:
Result of this approach is new promising research into anti-EGF receptor strategies, as well as farnesyl transferase inhibitors. PARP inhibitors are another class of drugs in active development but with exciting early results in treatment of triple-negative breast cancer.
* Prevention of tumour cell division, as utilised by epothilones, which, like chemotherapeutic taxanes, interfere with microtubular system (protein tubulin) thus preventing cell division, yet, are far less toxic, better tolerated, and have the potential to escape the known mechanisms of taxane resistance.
* Addressing the tumour environment, as employed by anti-angiogenic agents, which disrupt the initial signal in the angiogenic cascade thus interfering with tumour growth.
* Development of techniques that allow maximisation of effectiveness of known treatments while minimising the potential side effects:
In case of nab-paclitaxel, the reformulation of paclitaxel with albumin circumvents solvent-associated toxicity and utilizes the natural carrier role of albumin in the human circulation. Another radiotherapeutic technique, in which magnets are used to pull chemotherapy drugs into tumours, is currently under investigation.
* Tumour vaccines, current favourite of the press, aim to induce anti-tumour immunity and have a number of targets, including tumour-specific antigens, particular oncogenes, or the proteins they code for. These, however, are still highly experimental and require more research.
* Epigenetics is a fast-developing and promising area of research:
DNA methylation is of particular interest to researchers as changes to the methylation status of CpG islands in the promoter regions affect transcription of important genes. Also, changes in gene methylation or histone acetylation may serve as biomarkers of cancer risk, assist in cancer detection, provide molecular staging, or predict prognosis or response to treatment.
Considerable advances have been made in breast cancer detection, diagnosis and therapy, granting its sufferers one of the highest treatment success rates and best survival prognoses of all cancers. However, it goes without saying that more research is needed.
With breast cancer now recognised to be both a clinically and pathologically assorted disease rather than a single entity, its future focus is likely to be on further individualisation of patient care, and without further doubt, is an area to keep an eye on.
(1) Office for National Statistics (2008) Cancer statistics registrations: registrations of cancer diagnosed in 2005, England. Series MB1 number 36. London: Office for National Statistics.
(2) Jemal A, Siegel R, Ward E, et al. (2009) Cancer statistics, 2009. CA Cancer J Clin; 59: 225-49.
(3) Timothy et al. (2001) Epidemiology of breast cancer. The Lancet Oncology; Vol 2, 3: 133-140
(4) National Institute for Clinical Excellence,CG80 Early and locally advanced breast cancer: NICE guideline. February 2009.
(5) Li SX, et al. (2010) DNA Repair and Personalized Breast Cancer Therapy. Environmental and Molecular Mutagenesis, 51: 897-908
(6) Turnbull C, Rahman N. (2008) Genetic predisposition to breast cancer: past, present, and future. Annual Reviews of Genomics and Human Genetics; 9: 321-345
(7) Boyd NF, et al. (2010) Breast Tissue Composition and Susceptibility to Breast Cancer. J Natl Cancer Institute; 102: 1224-1237
(8) Macrinici V, Romond E. (2010) Clinical Updates on EGFR/HER–Targeted Agents in Early-Stage Breast Cancer Clinical Breast Cancer, Vol. 10, Supplement 1, 38-46
(9) Hudis CA. (2003) Current status and future directions in breast cancer therapy. Clinical Breast Cancer, Vol. 4, Suppl. 2, 70-75.
(10) SIGN. Scottish Intercollegiate Guidelines Network, Management of breast cancer in women. A national clinical guideline. 2005.
(11) Widakowich C, et al. (2007) Molecular targeted therapies in breast cancer: Where are we now? The International Journal of Biochemistry & Cell Biology; 39: 1375–1387
(12) Saurel CA, et al. (2010) Changes to Adjuvant Systemic Therapy in Breast Cancer: A Decade in Review. Clinical Breast Cancer, Vol. 10, No. 3, 196-208
(13) Chu D, Lu J. (2008) Novel therapies in breast cancer: what is new from ASCO 2008. Journal of Hematology & Oncology, 1:16
(14) Normanno N, et al. (2009) Target-based therapies in breast cancer: current status and future perspectives Endocrine-Related Cancer; 16: 675–702
(15) Carey LA. (2010) Through a Glass Darkly: Advances in Understanding Breast Cancer Biology, 2000-2010. Clinical Breast Cancer, Vol. 10, No. 3, 188-195
Image 1: Early symptoms/signs of breast cancer; www.womenshealth.gov
Image 2: Sentinel lymph node biopsy; www.melanomawa.org.au/conventional.html