Abstract
The Oxford Overview of adjuvant endocrine trials [1] indicates that 5 years of adjuvant tamoxifen reduces recurrence by 41% and deaths by 34% in women with oestrogen receptor (ER)-positive breast cancers. At 5 years, in all patients studied, the recurrence rate was 25.8% in controls but 13.9% on tamoxifen. There was a substantial 'carry over' effect of tamoxifen such that even after 15 years of follow up mortality was about 30% less in tamoxifen-treated patients. The effect of tamoxifen was greater in patients with ER-positive, PR-positive as compared with ER-positive PR-negative tumours. These data indicate a substantial effect of tamoxifen but it is clear that approximately half of patients are resistant to tamoxifen de novo (early relapses) or acquire resistance if we assume that women who relapsed later had an initial response to tamoxifen. The potential reasons for resistance include activated growth factor pathways overriding the inhibitory effects of the drug either via nuclear or membrane ER. Of ER-positive PR-negative tumours, 30% are HER1/2-positive, as compared with about 10% of ER-positive PR-positive tumours, and this difference may account for their lower activity of tamoxifen in PR-negative tumours. Modern aromatase inhibitors (AIs) are more effective in reducing relapse compared with tamoxifen whether AI treatment is initiated after surgery (ATAC and BIG1-98 trials) or after 2–3 years of tamoxifen (ITA, ARNO/ABCSG). At present, it is difficult to distinguish any differences in effectiveness between the three agents used in these trials (anastrozole, letrozole and exemestane) but small differences in toxicity patterns are beginning to emerge. The reason for the greater effectiveness of AIs is not clear. In randomized studies of neoadjuvant endocrine therapy [2] and in the anastrozole adjuvant trials (ATAC and ARNO/ABCSG) [3], the AIs used were particularly more active than tamoxifen in the ER-positive PR-negative subgroup of tumours, but this was not seen in the BIG1-98 and IES trials. Studies on letrozole resistant human mammary tumour cell lines show that growth factor pathways such as MAPK (mitogen-activated protein kinase) are activated, and sensitivity to the AI can be restored by growth factor pathway inhibitors [4]. Also, AI resistance can be reduced by combined treatment with fulvestrant in animal models. These data suggest mechanisms whereby AI resistance may be circumvented in patients and point to new approaches to adjuvant treatment.
Highlights
Prognostic and predictive factors play important roles in profiling predicts clinical outcome of breast cancer
Genetic tests derived from gene expression profiling studies are likely to become useful as prognostic and predictive tests to guide clinical decision making in the treatment of primary breast cancer
The 76-gene profile was strongly predictive of those patients who will develop a distant metastasis within 5 years or will remain recurrence free during that period and in multivariate analysis when corrected for traditional prognostic factors including grade (HR 5.55; P < 0.00003)
Summary
Prognostic and predictive factors play important roles in profiling predicts clinical outcome of breast cancer. Results Between August 1993 and July 1999, 885 patients with primary breast cancer and four or more tumor-positive lymph nodes were randomized in 10 Dutch centers in a study of high-dose chemotherapy. We conducted a phase II trial to define the safety, the efficacy, the pathological response rate and survival associated with four cycles DXR–GMZ administered every 3 weeks followed by surgery, four cycles of FAC50 as a primary therapy in MBC. Method Fifty-four patients with invasive breast cancer treated in 2004 underwent axillary ultrasound and cytological puncture with fine needle of suspicious nodes before surgery Suspicious nodes were those with at least one of the following signs: long-to-short axis ratio less than 1.5, absence of hilius and cortical disruption. BrdU and MTT exhibited inhibition of DNA synthesis and metabolic activity of treated MBC cells compared with untreated controls
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