Hypoxia in breast cancer: pathogenesis, characterization and biological/therapeutic implications.

Nearly 50% of locally advanced breast cancers exhibit hypoxic and/or anoxic tissue areas that are heterogeneously distributed within the tumour mass. Hypoxia is predominantly caused by structural and functional abnormalities of the newly formed tumour vessels arising from neovascularization, by a disturbed microcirculation, by enlarged diffusion distances, and by tumour-associated or therapy-induced anaemia. The extent of pretherapeutically measured hypoxic tissue areas is independent of clinical tumour size and stage, and histological type and grade. Anaemia can substantially worsen tumour O2 depletion. Hypoxia is known to directly or indirectly confer resistance to irradiation and some chemotherapeutic drugs leading to treatment failure. Sustained tumour hypoxia also gives rise to a more malignant phenotype (malignant progression). Due to this association between tumour hypoxia, malignant progression and treatment failure, tumour oxygenation has proven to be an independent, powerful prognostic factor for local control, overall and disease-free survival. Pretreatment assessment of tumour hypoxia is therefore needed to allow the selection of patients for more aggressive treatment within clinical trials or for individualization of therapy, and to identify patients who could benefit from hypoxiatargeting treatment measures. Due to a relatively high risk of relapse, patients with hypoxic tumours should undergo close surveillance. Anaemia in cancer patients should be prevented/corrected in order to improve radio-/chemosensitivity and thus to increase cancer cure rates.