suggests that they also play an important role in mediating tumor relapse ( Creighton et al . 2009 ). Therefore, this hypothesis provides a plausible explanation for different types of treatment failure, although the mechanisms of resistance and the
Wei Wei and Michael T Lewis
Constanze Hantel, Sara Jung, Thomas Mussack, Martin Reincke, and Felix Beuschlein
, even when diagnosed at an early stage, radical surgery is afflicted by high relapse rates (Terzolo et al . 2007). Thus, overall prognosis in ACC patients is still poor, and innovative treatment options are urgently required ( Abiven et al . 2006
K S Kimbro and J W Simons
of nearby necrosis in the DCISs. HIF-1α appears also associated with VEGF-C expression in invasive ductal carcinomas. In a large retrospective study of 745 patients, high levels of HIF-1α at diagnosis predicted for early relapse and metastatic disease
P J Barrett-Lee
Adjuvant chemotherapy has been shown to provide survival benefits in patients with breast cancer, but some patients still relapse despite this. There is therefore a need for molecular markers present within the primary tumour that can predict for chemotherapy sensitivity or resistance. Until now, no single marker has emerged into routine clinical practice, but several candidate pathways are being extensively investigated. This paper summarises the current status of growth factor singalling and p53 function in this context. The data on human epidermal growth factor receptor-2, topoisomerase II and p53 expression in a variety of breast cancer treatment settings are discussed.
S R D Johnston, G Saccani-Jotti, I E Smith, J Newby, and M Dowsett
Loss of oestrogen-receptor (ER) expression and function may explain the development of tamoxifen resistance in breast cancer. In 72 paired biopsies the immunohistochemical expression of ERs was reduced from 51% before tamoxifen treatment to 29% at progression or relapse, with a reduction in mean H-score from 90 to 61 (P<0.001, paired t-test). However, there was no significant change in progesterone receptor (PgR) or pS2 expression, markers of ER function. Tumours which developed acquired resistance after primary tamoxifen treatment frequently remained ER+ve at relapse (61%) and continued to express PgR or pS2. In contrast, those which progressed with de novo resistance were all ER−ve, although 6 of these tumours expressed high levels of PgR and/or pS2. In tumours which recurred during adjuvant tamoxifen therapy, the frequency and quantitative level both of ERs and of PgR were significantly reduced. These data imply that separate mechanisms of tamoxifen resistance may exist in these clinical subgroups.
Endocrine-Related Cancer (1995) 2 105-110
E L Mazzaferri and N Massoll
The incidence of differentiated thyroid cancer (DTC) has increased in many places around the world over the past three decades, yet this has been associated with a significant decrease in DTC mortality rates in some countries. While the best 10-year DTC survival rates are about 90%, long-term relapse rates remain high, in the order of 20-40%, depending upon the patient's age and tumor stage at the time of initial treatment. About 80% of patients appear to be rendered disease-free by initial treatment, but the others have persistent tumor, sometimes found decades later. Optimal treatment for tumors that are likely to relapse or cause death is total thyroidectomy and ablation by iodine-131 ((131)I), followed by long-term levothyroxine suppression of thyrotropin (TSH). On the basis of regression modeling of 1510 patients without distant metastases at the time of initial treatment and including surgical and (131)I treatment, the likelihood of death from DTC is increased by several factors, including age >45 years, tumor size >1.0 cm, local tumor invasion or regional lymph-node metastases, follicular histology, and delay of treatment >12 months. Cancer mortality is favorably and independently affected by female sex, total or near-total thyroidectomy, (131)I treatment and levothyroxine suppression of TSH. Treatments with (131)I to ablate thyroid remnants and residual disease are independent prognostic variables favorably influencing distant tumor relapse and cancer death rates. Delay in treatment of persistent disease has a profound impact on outcome. Optimal long-term follow-up using serum thyroglobulin (Tg) measurements and diagnostic whole-body scans (DxWBS) require high concentrations of TSH, which until recently were possible to achieve only by withdrawing levothyroxine treatment, producing symptomatic hypothyroidism. New paradigms, however, provide alternative pathways to prepare patients for (131)I treatment and to optimize follow-up. Patients with undetectable or low Tg concentrations and persistent occult disease can now be identified within the first year after initial treatment by recombinant human (rh)TSH-stimulated serum Tg concentrations greater than 2 microg/l, without performing DxWBS. These new follow-up paradigms promptly identify patients with lung metastases that are not evident on routine imaging, but which respond to (131)I treatment. In addition, rhTSH can be given to prepare patients for (131)I remnant ablation or (131)I treatment for metastases, especially those who are unable to withstand hypothyroidism because of concurrent illness or advanced age, or whose hypothyroid TSH fails to increase.
W R Miller, T J Anderson, S White, D Evans, A Krause, and J M Dixon
Neoadjuvant endocrine treatment in which therapy is given while the primary tumour is still in the breast provides a highly useful model system by which to identify mechanisms associated with de novo resistance and signs of early acquired resistance. Most importantly, the model is clinically relevant. It has been confirmed that the absence of tumour oestrogen receptors confers resistance to endocrine therapy. Early changes in tumour cell proliferation following neoadjuvant treatment with the third-generation aromatase inhibitor, letrozole, do not predict accurately for subsequent clinical response. Additionally, changes in proliferation seen at later times can be the consequence of response and may be associated with early resistance. High expression of c-erbB2 does not reduce tumour responses to neoadjuvant treatment with aromatase inhibitors, but is associated with high tumour proliferation before and during treatment. It remains to be determined whether these characteristics confer subsequent resistance to treatment and early relapse in the adjuvant setting.