CORRESPONDENCE

More About: Prognostic Importance of Low c-erbB2 Expression in Breast Tumors

Ruggero Dittadi, Massimo Gion

Affiliation of authors: Regional Center for the Study of the Biological Markers of Malignancy, Regional Hospital, Venice, Italy.

Correspondence to: Ruggero Dittadi, M.S., Centro Regionale Indicatori Biochimici di Tumore, Ospedale Civile, C.po SS. Giovanni e Paolo, 30122 Venice, Italy (e-mail: cnabo{at}provincia.venezia.it).

The Journal recently published correspondence reporting a debate about a particularly low expression of c-erbB2 protein in breast cancer patients, which, as in the case of very high levels of the protein, could indicate a poor prognosis (1,2). That low c-erbB2 protein concentrations may have a different meaning from that of intermediate levels of the protein is not a recent finding. In 1992, by use of an enzyme-linked immunosorbent assay (ELISA) (Oncogene Science, Uniondale, NY) in breast tissue homogenates, our group (3) reported a nonmonotonic relationship of c-erbB2-encoded protein p185 with estrogen and progesterone receptors in breast cancer tissue. In further studies, we found a strong association between both ELISA and western blot analysis with an immunohistochemical method (4,5). However, when we divided breast cancer tissue samples into three groups, both the samples with low levels of p185 and those with high levels were associated with low estrogen and progesterone receptor levels and with a high percentage of lymph node-positive tumors (4,5). These findings were confirmed by other groups [(6) and references in (2)].

In a small number of tissue samples, we found that both low and high p185 concentrations indicate a similar high risk of relapse when compared with tissue samples with intermediate levels of p185 (7). Three further studies [reported in (2)] confirmed similar prognostic behavior, while one did not (1).

All of these papers (17) are, however, only preliminary studies. Although Ferrero-Poüs et al. (1) evaluated more patients than the number reported in previous studies, they performed only an univariate analysis, and the patients whose tissues they examined were not homogeneous with respect to lymph node status and therapies received. It is worth noting that we recently have separately evaluated groups of 100 lymph node-negative and 141 lymph node-positive breast cancer specimens, with a median follow-up of 53 months. By dividing the groups into quartiles, we found that the nonmonotonic prognostic significance (with the first and the fourth quartiles showing the same negative prognostic indication) is restricted to lymph node-positive cases (two-sided P = .001 by the log-rank test). Obviously, these results are also preliminary, and we are planning to enlarge the case series to evaluate separately the prognostic significance in lymph node-positive patients treated with chemotherapy and those treated with hormonal therapy. The study will be carried out by use of modeling that allows for an analysis of the concentration of p185 as a continuous variable, avoiding the need for determination of cut points. Similarly, a longer follow-up is advisable to better evaluate the new data by Koscienly et al. (2), as correctly pointed out by the authors.

We believe that biochemical immunometric methods should be taken into account, at least in the design of clinical studies, for the assessment of p185 expression and its prognostic significance. They allow for quantitative and reproducible results in milligrams of tissue, which are more likely than the microgram samples assessed routinely in immunohistochemical analyses to be truly representative of the tissue. In addition, both analytic standardization and quality control are more feasible.

While the publication of results from pilot studies was certainly necessary to reveal the findings and to stimulate debate, we believe that the next step is to produce more robust studies with a sufficient number of cases in homogeneous groups of patients and possibly validated with an independent set of patients. We believe that additional provisional investigations should be discouraged to avoid the risk of disseminating misinformation about a possibly promising prognostic parameter.

REFERENCES

1 Ferrero-Pous M, Hacene K, Tubiana-Hulin M, Spyratos F. Re: Prognostic importance of low c-erbB2 expression in breast tumors [letter]. J Natl Cancer Inst 1999;91:1584–5.[Free Full Text]

2 Koscielny S, Terrier P, Spielmann M, Delarue JC. Response: re: prognostic importance of low c-erbB2 expression in breast tumors [letter]. J Natl Cancer Inst 1999;91:1585.[Free Full Text]

3 Dittadi R, Donisi PM, Brazzale A, Marconato R, Spina M, Gion M. Immunoenzymatic assay of erbB2 protein in cancer and non-malignant breast tissue. Relationships with clinical and biochemical parameters. Anticancer Res 1992;12:2005–10.[Medline]

4 Dittadi R, Catozzi L, Gion M, Brazzale A, Capitanio G, Gelli MC, et al. Comparison between western blotting, immunohistochemical and ELISA assay for p185neu quantitation in breast cancer specimens. Anticancer Res 1993;13:1821–4.[Medline]

5 Piffanelli A, Dittadi R, Catozzi L, Gion M, Capitanio G, Gelli MC, et al. Determination of ErbB2 protein in breast cancer tissues by different methods. Relationships with other biological parameters. Breast Cancer Res Treat 1996;37:267–76.[Medline]

6 Cuny M, Simony-Lafontaine J, Rouanet P, Grenier J, Valles H, Lavaill R, et al. Quantification of ERBB2 protein expression in breast cancer: three levels of expression defined by their clinico-pathological correlations. Oncol Res 1994;6:169–76.[Medline]

7 Dittadi R, Brazzale A, Pappagallo G, Salbe C, Nascimben O, Rosabian A, et al. ErbB2 assay in breast cancer: possibly improved clinical information using a quantitative method. Anticancer Res 1997;17:1245–7.[Medline]


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