Basal Type Breast Adenocarcinoma Eva Desmond DT204/2 C

Introduction In this presentation I will discuss: The prevalence of breast cancer and basal type breast adenocarcinoma Triple Negative breast cancers The aetiology of basal type breast adenocarcinoma Screening Clinical presentation Diagnosis Clinical Trials

The Epidemiology of Breast Cancer The most commonly diagnosed non- cutaneous cancer in women Accounts for 28% of all cancers in women Accounts 14% of all female deaths due to cancer In 2012 the highest incidence was in Belgium (147.5 per 100,000) In Ireland patients per 100,000 were diagnosed in 2012 Your text here Fig. 1: Incidence of breast cancer in Europe in 2012

Basal-type Breast Adenocarcinoma Also called basal-like breast cancer It is a malignant tumour originating in the ducts or lobules of the breast in which the tumour cells resemble basal or myoepithelial cells The cells in this type of malignancy express markers that are usually present on basal cells in other parts of the body It is one of five subtypes of Triple Negative Breast cancer (TNBC) It is a very aggressive form of cancer with a poor prognosis Fig 2: Basal and ductal carcinomas of the breast

Triple Negative Breast Cancer TNBC is a cancer in which the tumour cells do not express oestrogen or progesterone receptors and do not show overexpression of Human Epidermal growth factor Receptor 2 (HER2) Approximately 10-17% of all breast cancers are Triple Negative Breast Cancers Each subtype has a different prognosis This type of cancer is associated with a poor prognosis due to the limited treatment options More than 90% of TNBCs are of the basal-like subtype

Aetiology Not a lot is known about the aetiology of basal-like breast cancer Increased risk associated with: Use of oral contraceptives for ≥1 year Women aged ≤ 40 (i.e. premenopausal women) Women of African origin Family history of basal-like breast cancer BRCA1 mutations Women with multiple children who did not breastfeed Use of lactation suppressing drugs High waist-hip ratio Breast feeding for longer durations has been shown to be preventative

Screening Screening for breast cancer is done by mammography This has been shown to reduce mortality and morbidity rates in breast cancer The aim is to detect tumours in early stages while treatment is easier and before metastasis However, it is not always effective Following mammographies that show abnormalities, Fine-needle Aspirations and occasionally core biopsies are taken for tumour analysis Fig. 3: Mammograms showing Triple Negative primary tumours

Clinical Presentation Most basal-like breast tumours present as large, high grade tumours at diagnosis Patients may be asymptomatic Mammograms of TNBC normally show large tumours with pushing boarders They are not usually associated with microcalcifications Central necrosis or fibrosis are often seen They often present as interval tumours They have high proliferative rates and are usually ductal tumours Fig. 4: Invasive basal type ductal carcinoma of the breast showing central necrosis [16]

Diagnosis Basal-like breast cancer is diagnosed using an immunohistochemical panel of biomarkers The tumour cells stain positively for the expression of cytokeratin 5/6 They stain negatively for the expression of oestrogen and progesterone receptors and for the overexpression of HER2 Other markers used include; vimentin, laminin, c-KIT, p63, nestin, osteonectin, caveolin, and NFGR. The BCRA1 mutation is very commonly associated with triple negative breast cancers There is a high level of recurrence in the first 3 years after diagnosis and a relatively low 5 year survival rate

Molecular Methods Microarray expression patterns are used to measure levels of expression of certain genes in tumours They can be analysed to detect overepression of genes such as the HER2 gene The Polymerase Chain Reaction (PCR) can be used to detect the presence of oncogenes or genetic mutations The BCRA1 mutation is detected by this method Immunohistochemical methods are more frequently used in the typing of breast cancers than molecular methods Molecular methods are mainly used in research

Treatment Therapy for basal type breast adenocarcinoma and other TNBCs is very limited Most therapies used to treat other breast cancers are not suitable due to a lack of hormone receptors Chemotherapy is the main treatment used However, there is a high rate of recurrance within 2-3 years associated with this treatment Patients who have advanced stage basal type breast adenocarcinoma generally do not respond very well to this treatment and tend to have a poor prognosis

Treatment Radiation therapy or neoadjuvant chemotherapy are often used to shrink tumours before a lumpectomy is performed Lumpectomy may not be suitable in metastatic setting or where tumours are >5 cm in diameter In these cases mastectomy is performed Postoperative radiotherapy may given depending on lymph node status Postoperative radiotherapy has been shown to reduce recurrance rates Fig. 5: Lumpectomy

Clinical Trials There are currently no targeted therapies used in the treatment of basal-type breast carcinoma or other Triple-Negative breast cancers There are several markers on basal-like tumours which are being tested as potential targets Epidermal Growth Factor Receptor (EGFR) is expressed in more than 60% of basal type breast tumours It has been successfully targeted using antibodies, inhibitors and phosphorylation in other tumour types c-KIT is a growth factor receptor that has also been targeted in other tumour types

Clinical Trials DNA-repair defects are seen in tumours with BCRA1 mutations This results in sensitivity to systemic agents such as platinum agents which are currently being tested as a possible form of chemotherapy Poly (ADP-ribose) polymerase (PARP) proteins are enzymes involved in many cell processes PARP inhibitors may be used to treat breast malignancies with dysfunctional BRCA pathways

Clinical Trials Animal models with basal type tumours are currently used in the development of targeted therapies Mouse models with BCRA1 mutations are commonly used in the testing of therapies against malignancies with the BCRA1 mutation Stem cells are not currently a major area of research for basal type breast adenocarcinoma A large amount of research is being done to improve treatment for patients with Basal Type Breast Adenocarcinoma and other Triple Negative Breast Cancers

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