Dossier: Breast cancers
“Tumour marker guided” salvage treatment prolongs survival of breast cancer patients: final report of a 7-year study

https://doi.org/10.1016/j.biopha.2003.09.004Get rights and content

Abstract

Objectives. – Randomised trials on breast cancer showed no significant benefit from post-operative follow-up with clinical and/or conventional radiological means. We hypothesised that carcinoembryonic antigen (CEA), tissue polipeptyde antigen (TPA), breast cancer associated antigen 115 D8/DF3 (CA15.3) tumour marker panel is sensitive enough for significantly anticipating salvage treatment and prolonging survival of relapsing breast cancer patients.

Methods. – From October 1981 to May 1999, 68 (62%) of 109 patients with distant metastases were recruited. Thirty-six (53%) received salvage treatment at the time of significant increase in one or more components of CEA–TPA–CA15.3 tumour marker panel and negative instrumental examinations (“tumour marker guided” treatment) and 32 (47%) were treated only after radiological confirmation of metastases (conventional treatment). The prognostic factors of the two groups did not show any statistically significant difference.

Results. – The time from one or more tumour marker increase to clear clinical and/or radiological signs of distant metastases (lead time) was significantly prolonged in the 36 patients with “tumour marker guided” treatment (17.3 ± 13.1 vs. 2.9 ± 2.9 months, P < 0.001, Wilcoxon test) as well as the survival curves from salvage therapy and from mastectomy (the proportion of survivors was: at 36 months from salvage therapy 28% vs. 9%, P = 0.0094; at 84 months from mastectomy 42% vs. 19%, P = 0.0017). The multivariate Cox analysis showed that time from mastectomy to tumour marker increase and “tumour marker guided” salvage treatment were the only significantly different variables (P = 0.00001 and 0.005, respectively).

Conclusion. – These data point out that “tumour marker guided” salvage treatment significantly prolongs disease-free and overall survivals of relapsing responsive patients.

Introduction

Retrospective and prospective randomised trials on breast cancer patients have showed no significant benefit from a post-operative follow-up based on clinical and/or conventional radiological means (bone scanning, chest radiography, liver echography). In most retrospective studies, no significant difference in relapse-free time and in the overall survival was found when relapses were discovered by the patients themselves or at a follow-up visit [1], [2], [3], [4], [5], [6], [7]. In two prospective randomised trials, the intensive clinical and instrumental follow-up detected distant and local recurrences earlier than the only clinical follow-up. Nevertheless, this earlier diagnosis obtained by intensive use of conventional and radiological means did not demonstrate significant prolongation of the overall survival [8], [9].

Breast cancer metastasises to bone with high frequency and incidence also because tumour cells find the hematopoietic bone marrow of the axial skeleton especially idoneous to their survival and growth thanks to the interaction with the local cytokine network that controls bone remodelling [10], [11]. However, studies on breast cancer metastasis have been limited for many reasons and in particular because the earliest detection of bone metastases is too insensitive or too laborious for routine, large-scale studies or for studying the first steps of bone colonisation [10].

Following the hypothesis that clinical signs and conventional radiological means are not sensitive enough for early disclosing of distant metastases, we have being using since 1984 carcinoembryonic antigen (CEA), tissue polipeptyde antigen (TPA), breast cancer associated antigen 115 D8/DF3 (CA15.3) tumour marker panel to post-operatively follow-up breast cancer patients [12]. We established precise criteria for defining tumour marker concentration values for suspecting or for excluding distant metastases [12], [13]. In our experience, the CEA–TPA–CA15.3 tumour marker panel proved to anticipate by 2 or more months the clinical and/or instrumental signs of relapse [15] in more than half of the patients eventually developing distant metastases. Therefore, we started a study where the survival of relapsed patients treated at the time of elevated serum CEA and/or TPA and/or CA15.3 values and negative radiological findings was compared with that of relapsed patients treated conventionally at the time of definite positive radiological and/or clinical findings. Following the preliminary publication of data [14], [12], [13], we now report in this paper the final results of this study.

Section snippets

Patients and follow-up study

All studied patients after mastectomy were monitored clinically, biochemically and instrumentally, according to the previously reported schedule [12], [13], [14]. In particular, the post-operative follow-up visits were carried out every 6 or 4 months depending on whether they were N– or N+ at pathological examination. ER– and PR– patients were allocated to the shorter interval for follow-up. Initially, the serum CEA–TPA–CA15.3 panel determination, routine blood tests (ESR, glucose, calcium,

Tumour markers, instrumental examinations, hormone receptors

Serum TPA, CEA and CA15.3 concentrations were measured by commercial kits. From 1981 to 1995, TPA was measured by an IRMA (Sangtec Medical, Bromma, Sweden) commercial kit. Serum levels initially >60 mU ml–1 and subsequently >85 mU ml–1 were considered to be elevated. Serum CA15.3 concentrations were determined by IRMA (Cis International) using a commercial kit and 32 mU ml–1 was taken as the cut-off level. CEA was measured initially by Lepetit Lysophase RIA (Milano, Italy) and subsequently by

Patient accrual

From October 1981 to May 1999, 109 patients with distant metastases came to our observation in the Department of Internal Medicine of Pisa University. Forty-one patients were excluded because of the following reasons: 14 were metastatic at the time they entered into the follow-up, 19 withdrew from the follow-up during the treatment, and eight because of rapidly progressive metastasisation that did not permit the evaluation of any treatment. Sixty-eight metastatic patients were evaluated (Fig. 1

Discussion

Since 1978, we have been using tumour markers in suspected metastatic breast cancer post-operatively. Since 1984, we selected CEA–TPA–CA15.3 tumour marker panel and developed criteria to increase sensitivity and specificity of this tool [13], [14], [15].

The precise criteria for interpreting tumour marker levels together with history and routine laboratory examinations at each follow-up visit, allowed us to greatly reduce the number of falsely suspected distant metastases as well as the number

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