Breast cancer is the most common malignancy among Singaporean women, accounting for a third of all female cancers, and affecting some 2000 women yearly. National statistics show a rising trend in the annual incidence of breast cancer over the last 30 years.

International collaborative efforts and translational research have led to incremental gains in our understanding of the biology and clinical course of breast cancer. This has led to important advances in the management of the disease.

Imaging and Screening

Despite the controversies over screening mammography, multiple independent reviews of the literature agree that early detection of breast cancer by this method has been shown to save lives, and hence continues to be the gold standard.

A study of more than 42,000 women found digital mammography to be more sensitive than traditional film mammography in younger women and in women with dense breasts. Compared with traditional mammography, digital mammography was more accurate in detecting breast cancer among women under age 50 (78% vs 51% sensitivity), premenopausal and perimenopausal women (72% vs 51%), and women with dense breasts (70% vs 55%).

Magnetic resonance imaging (MRI) is gaining acceptance as a screening modality of choice for young women at high risk of developing breast cancer based on family history or genetic susceptibility. Randomized trials have shown a higher sensitivity of MRI compared to ultrasound or mammography in this population, although a survival benefit has yet to be proven.

Genomics Based Prognostic Markers in Early Breast Cancer

Gene expression profiling, the measurement of mRNA expression levels of multiple genes simultaneously, can be achieved using microarray (solid-phase assay platform) or quantitative real-time reverse transcription polymerase chain reaction (QRT-PCR). Gene expression profiling has led to the molecular classification of breast cancer subtypes, each with a distinct gene signature and clinical behavior. In addition, various groups have confirmed correlations between relapse risk and the level of expression of specific gene sets in retrospective cohorts. The use of gene profiles to predict relapse risk in women with node negative breast cancer is awaiting validation in multicentre studies and holds the promise of accurately identifying which patients can be spared unnecessary adjuvant chemotherapy.

Adjuvant Therapy

Adjuvant therapy after curative surgery for early stage breast cancer aims to eradicate occult foci of disease, hence reducing the risk of relapse and improving survival.

Paradigm shifts have occurred in adjuvant therapy for two subgroups of women with early stage breast cancer.

The first involves the 20-25% of women whose breast cancers over-express Her-2, a transmembrane protein receptor belonging to the family of epidermal growth factor receptors that predicts an aggressive clinical course with earlier relapse and shortened survival.

Trastuzumab (Herceptin)—which targets and blocks HER-2—has been used since 1998 to treat metastatic breast cancer. Analyses of three large trials showed that trastuzumab could approximately half the risk of relapse when used after or with chemotherapy in postoperative setting. Two of these studies have also shown a survival benefit. The main toxicity observed in trastuzumab is cardiomyopathy, which could be severe in 1-4% of women who received this therapy after an anthracycline . In addition, a portion of the women experienced asymptomatic reductions in cardiac ejection fraction, and the long term consequence of which is unknown.

The second involves postmenopausal women with endocrine responsive breast cancer. Until recently, tamoxifen has been the gold standard. Third generation aromatase inhibitors such as anastrozole, letrozole and exemestane prevent conversion of adrenal androgens to estrogen in postmenopausal women with high potency and specificity, thus leading to a state of profound estrogen deprivation.

Five separate, large, high quality randomized trials have shown superior efficacy of these aromatase inhibitors when used in the adjuvant setting either in place of or after 2 to 5 years of tamoxifen. It has shown relative risk reductions in relapse risk ranging from 17 to 42% when compared to tamoxifen alone. Suggestion of a survival benefit has emerged from a recent meta-analysis of three European trials comparing a sequential strategy involving 2 years of tamoxifen followed by 3 years of anastrozole, to 5 years of tamoxifen. Aromatase inhibitors are linked to fewer thromboembolic complications. On the other hand, the risk of osteoporosis and fractures is higher, which means careful patient selection and monitoring for bone health is required during therapy.

Targeted Therapy in Advanced Breast Cancer

Three targeted agents have been widely used in the management of metastatic breast cancer.

Trastuzumab (Herceptin) has been shown to improve response rate, time to progression and overall survival when given with first line palliative chemotherapy in women with Her-2 overexpressing metastatic breast cancer compared to chemotherapy alone and this is a major advance in the cancer treatment.

Treatment options had until now been limited for women who develop disease progression on trastuzumab based therapy. Many clinicians switch to a different chemotherapy regimen but continue trastuzumab empirically.

Lapatinib is dual inhibitor of epidermal growth factor receptor (EGFR) and Her-2, acting via inhibition of tyrosine kinase activity at the intracellular domain of these receptors. Preliminary results of a multinational randomized trial comparing salvage therapy using the drug capecitabine (Xeloda) plus lapatinib to capecitabine alone in women whose disease has progressed on trastuzumab have recently been released. Patients who received the combination showed a higher response rate and longer time to progression compared to monotherapy with capecitabine.

Continued tumour growth is dependent on angionenesis, a process that is in part driven by vascular endothelial growth factor (VEGF). Bevacizumab (Avastin) is a monoclonal antibody against VEGF. For women with Her-2 non-overexpressing metastatic breast cancer, bevacizumab has been shown to improve response rate and progression free survival when combined with the chemotherapy paclitaxel (Taxol) in the first line setting compared to paclitaxel alone.

The management of breast cancer has entered the molecular era. Genomics may soon replace traditional prognostic and predictive factors that allow accurate patient selection and customised care, thus maximizing treatment efficacy for at-risk individuals, and avoiding unnecessary therapy in others. These are exciting and promising times for researchers, clinician and patients.

Wong Nan Soon
Consultant
Department of Medical Oncology
National Cancer Centre (S)