Breast cancer biology and the future of tailored therapies (2013)

Breast cancer is the globally most common malignancy amongst women. The incidence has increased dramatically over the last decades, particularly in the developing world. In 1980, 600 000 women were diagnosed with breast cancer, whereas 1.6 million received the same diagnosis in 2010 1. On the basis of these figures, it is obvious that preventive measurements are needed, combined with novel therapy strategies based on tumour biological characteristics. The mortality from breast cancer has decreased by around 30–40% since 1980s due to the use of adjuvant therapies and early detection. Targeted therapies such as trastuzumab (a monoclonal antibody that blocks HER2/neu receptor functions) and other anti-HER2-based drugs like lapatinib, pertuzumab and TDM-1 have lately been in focus. These drugs, in particular if used in combination together with chemotherapy, improve outcome in the metastatic setting. There is hope that improved use of these and other similar drugs may ultimately result in cure. The curative potential has already been demonstrated in the adjuvant and neoadjuvant settings. In the latter, histopathological remission is obtained in more than 50% of the cases when used in combination with chemotherapy. At the June 2012 Nobel conference ‘Breast cancer; progress and challenges in prevention, risk prediction, tumour biology and treatment’, world-leading experts gathered to discuss recent findings related to breast cancer biology and treatment. In addition to major support from the Nobel Assembly at Karolinska Institutet, the meeting was also sponsored by the Swedish Research Council, the Swedish Cancer Society, Journal of Internal Medicine (JIM) and the Karolinska Institutet-funded BRECT breast cancer research network. Some of the major and important topics are discussed in five review papers of this JIM issue. In this introductory paper, we address and introduce each of them. It is increasingly recognized that the tumour microenvironment exerts important regulatory functions that influence tumour growth and metastasis. Two reviews in this JIM issue address the complex roles of hypoxia and the importance of activation of stromal cells at metastatic sites 2, 3. The review by Rundqvist and Johnson describes how hypoxia induces functional alterations in various cells of the tumour microenvironment, including macrophages, vascular cells and fibroblasts 2. These responses affect metastasis through multiple mechanisms, including alterations in the paracrine signalling to malignant cells and changes in the functional characteristics of the vasculature or immune cells. The classical ‘seed-and-soil’ hypothesis of cancer metastasis emphasizes the importance of host cell–tumour cell interactions in metastasis. These ideas receive new support through a series of findings outlining the importance of host cell activation in metastatic seeding 3. A number of recent experimental studies suggest that the activation of such ‘pre-metastatic niches’ includes both recruitment of bone marrow–derived cells and activation of resident cells including fibroblast. Obviously, targeting of these processes is a highly interesting strategy for adjuvant cancer therapy. Important progress in the characterization of normal tissue stem cells, and their progenitors, has been made over the recent past. This is relevant because the phenotype of breast cancer cells is influenced both by the tumour cell of origin and the presence of specific somatic genetic alterations, including activation of oncogenes or inactivation of tumour suppressor genes. Moreover, the maintenance and spread of breast tumours is proposed to rely on a population(s) of tumour cells with self-renewal capacity and presenting several similarities to normal tissue stem cells. Martinez and Huelsken review in this JIM issue the present knowledge on the metastatic process and its dependency on cancer stem cells 4. Special emphasis is put on the understanding of which cancer cells are endowed with metastatic potential and the key role exerted by extracellular matrix (ECM) components in establishing cellular niches supporting the growth of metastatic cancer cells. Targeting such ECM proteins provides a new and interesting alternative therapeutic strategy to curb metastatic disease. Future breast cancer therapies will include improved selection of drugs, dosage and scheduling, based on a better understanding of breast cancer biology. Tumour heterogeneity is likely one of the most important factors limiting the efficacy of present therapies as described by Hayes and Paoletti 5. Another emerging issue is the clinically relevant disconcordance in marker expression between primary tumours and metastatic lesions. Endocrine therapies are cornerstones both in the early management of breast cancer as well as for recurrent disease 6. More recently, new targets have been identified including ‘mammalian target of rapamycin’ (mTOR). Inhibitors of this target together with endocrine therapies have demonstrated added value. Endocrine therapies can also be combined with anti-HER2-based therapies for the subgroup of oestrogen receptor–positive disease which also display alteration of the HER2 pathway. The effect so far is inferior to that obtained with the combined use of cytotoxic agents and anti-HER2-based therapies. During the metastatic spread, further genetic changes occur and act together with the tumour stroma. Monitoring the biology of metastatic disease is required for optimal treatment. Present procedures include different types of radiological investigations, including advanced functional imaging techniques. The additional need of biopsies of metastatic disease is becoming recognized, but the practical limitations are sometimes a problem. Circulation tumour cells and cell-free tumour DNA are emerging as highly interesting alternative sources of prognostic and response-predictive information 5. Targeted therapies have improved breast cancer patient survival, but still 5–20% of all breast cancer patients die from the disease within 10 years of initial diagnosis. At the same time, there is a large number of systemically treated women who are in no need of postsurgical adjuvant therapy. These women thus only experience the acute and late adverse health effects of systemic therapy. It is therefore of outmost importance to identify better prognostic markers and therapy predictors with the potential of reducing under- and overtreatment. From the reviews in this issue of JIM, we learn that tumour heterogeneity induces therapy resistance but that circulating tumour cells could be a novel way to monitor carcinogenic evolution. It is also recognized that to identify tumours that form metastasis, appropriate functional assessment of the primary disease is needed, that the microenvironment of the metastatic cells is of outmost important and that hypoxia influences the metastatic potential. Lastly, we learn that novel combinations of drugs, including endocrine drugs and drugs targeting mammalian target of rapamycin (mTOR) inhibitors, can be a way to increase therapeutic efficacy. These reviews all point at the complexity of carcinogenesis and the need of translational research efforts to identify markers of prognosis, therapy response and resistance. Bergh's research groups has received research grants from Astra-Zeneca (KI-AZ collaboration), Amgen,Bayer, Roche and Sanofi-Aventis for clinical studies including biopsy, gene expression and PET studies to the Karolinska Institutet and Karolinska University hospital, but no personal payments.