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© 2000 American Society for Clinical Oncology
Predictors of Response to ChemotherapySt Bartholomew’s Hospital London, United Kingdom To the Editor:We read with interest the article by Chang et al1 in the October 1999 issue of the Journal of Clinical Oncology in which the authors observed that estrogen receptor (ER) expression, lack of c-erbB-2 expression, and a decrease in Ki67 expression were significant predictors of good clinical response (GCR). These parameters have been investigated by several authors with conflicting results.2-4 The inconsistency regarding the role of p53, Ki67, c-erbB-2, and bcl-2 in predicting tumor response to neoadjuvant therapy may be related to sampling error, as the expression of immunohistochemical markers is known not to be uniform throughout tumors. The authors did not provide details regarding percentage change in Ki67 expression, nor did they present the correlation coefficient, to show the strength of the association between Ki67 change and GCR.5 Table 5 in their article shows that an increase in bcl-2 expression was associated with a 40% reduction in GCR at 3 months (P = .005); the authors then go on to state in the text that increases in bcl-2 are associated with a nonsignificant trend toward increased likelihood of GCR at 3 months. This discrepancy requires clarification, since the role of bcl-2 expression in predicting clinical response remains controversial. Furthermore, bcl-2 expression is usually associated with ER expression, and the results shown in Table 4 are inconsistent with this established association.3 Finally, we would like to suggest that telomerase activity in fine-needle aspiration specimens may provide a more reliable in vivo marker of chemosensitivity in women undergoing neoadjuvant systemic therapy for breast cancer. This hypothesis is currently under investigation at our institution.6 REFERENCES
1.
Chang J, Powles TJ, Allred DC, et al: Biologic markers as predictors of clinical outcome from systemic therapy for primary operable breast cancer. J Clin Oncol, 17:3058-3063, 1999 2. Cree IA, Kurbacher CM: Individualizing chemotherapy for solid tumors: Is there any alternative? Anticancer Drugs 8:541-548, 1997[Medline] 3. Bozzetti C, Nizzoli R, Naldi N, et al: Bcl-2 expression on fine-needle aspirates from primary breast carcinoma: Correlation with other biologic factors. Cancer 87:224-230, 1999[Medline] 4. Rudolph P, Olsson H, Bonatz G, et al: Correlation between p53, c-erbB-2, and topoisomerase II alpha expression, DNA ploidy, hormonal receptor status and proliferation in 356 node-negative breast carcinomas: Prognostic implications. J Pathol 187:207-216, 1999[Medline] 5. Billgren AM, Rutqvist LE, Tani E, et al: Proliferating fraction during neoadjuvant chemotherapy of primary breast cancer in relation to objective local response and relapse-free survival. Acta Oncol 38:597-601, 1999[Medline] 6. Mokbel K: The role of telomerase in breast cancer. Eur J Surg Oncol (in press)
ResponseBaylor College of Medicine Houston, TX In Reply:Immunocytochemical analysis of biologic markers on samples obtained by fine-needle aspiration (FNA) has shown high correlation with results from paraffin sections and biochemical assays.1,2 We have previously validated the assays used in this study3 by demonstrating a high concordance between measurements obtained by FNAs and histologic paraffin sections.4 We have also reported no significant change in the level of expression of hormone receptors, Ki67, S-phase fraction, or ploidy from FNA cytology taken 2 weeks apart in a study involving 20 control patients who had not received any systemic therapy.5 Hence, the measurements of changes in biologic markers by repeat FNA before and after exposure to treatment may be used as additional predictive markers of response to therapy. Inconsistencies in the literature on the role of these biologic markers are more likely to reflect different chemotherapy regimens, timing of repeat biopsies, and different technical approaches to detecting a single biologic feature (eg, hormone receptors measured by ligand binding assays or immunohistochemistry). Assessing changes in Ki67 as a continuous variable would be problematic, especially since percentage change scores cannot be calculated if pretreatment values are zero. Moreover, good clinical response (GCR) was assessed as a dichotomous variable in this study3; hence, evaluation of correlation coefficient with change in Ki67 expression would be inappropriate. The relative likelihood from the logistic regression analysis in this study would provide the measure of association between change in Ki67 and GCR. There are several studies evaluating the relationship between bcl-2 expression and response to therapy. Expression of bcl-2 is positively correlated with estrogen receptor (ER) expression in a number of studies, and together with ER predicts for tamoxifen responsiveness.6 Conversely, other studies have shown that bcl-2 expression may be associated with resistance to chemotherapy.7 In this study,3 the majority of patients received chemoendocrine treatment, and this may explain the lack of predictive value of bcl-2 expression and response. Increased bcl-2 expression was associated with a 2.2-fold increased likelihood of clinical response (defined as complete and partial response), but there was no significant association with GCR. Moreover, there is increasing evidence that bcl-XL rather than bcl-2 may be a more important determinant of chemotherapy-induced apoptosis.8 Finally, the National Institutes of Health consensus statement defined useful predictive factors for breast cancer as those with independent and significant predictive value and therapeutic implications that have been validated by clinical testing. Their determination should be feasible, reproducible, and readily interpreted by the clinician.9 Measurements of new predictive and prognostic variables should be standardized and validated by clinical outcome in large patient populations without selection bias.10 We note the comments regarding telomerase activity, which should be evaluated according to these guidelines. REFERENCES 1. Frigo B, Pilotti S, Zurrida S, et al: Analysis of estrogen and progesterone receptors on preoperative fine-needle aspirates. Breast Cancer Res Treat 33:179-184, 1995[Medline] 2. Bozzetti C, Nizzoli R, Naldi N, et al: Fine-needle aspiration technique for the concurrent immunocytochemical evaluation of multiple biologic parameters in primary breast carcinoma. Treat 32:221-228, 1994 3. Chang J, Powles TJ, Allred DC, et al: Biologic markers as predictors of clinical outcome from systemic therapy for primary operable breast cancer. J Clin Oncol 17:3058-3063, 1999 4. Makris A, Allred DC, Powles TJ, et al: Cytological evaluation of biological prognostic markers from primary breast carcinomas. Breast Cancer Res Treat 44:65-74, 1997[Medline] 5. Makris A, Powles TJ, Allred DC, et al: Quantitative changes in cytological molecular markers during primary medical treatment of breast cancer: A pilot study. Breast Cancer Res Treat 53:51-59, 1999[Medline]
6.
Elledge RM, Green S, Howes L, et al: bcl-2, p53, and response to tamoxifen in estrogen receptor-positive metastatic breast cancer: A Southwest Oncology Group study. J Clin Oncol 15:1916-1922, 1997
7.
Bonetti A, Zaninelli M, Leone R, et al: bcl-2 but not p53 expression is associated with resistance to chemotherapy in advanced breast cancer. Clin Cancer Res 4:2331-2336, 1998 8. Liu JR, Fletcher B, Page C, et al: Bcl-xL is expressed in ovarian carcinoma and modulates chemotherapy-induced apoptosis. Gynecol Oncol 70:398-403, 1998[Medline] 9. NIH consensus conference: Treatment of early-stage breast cancer. JAMA 265:391-397, 1991
10.
McGuire WL: Breast cancer prognostic factors: Evaluation guidelines. J Natl Cancer Inst 83:154-155, 1991
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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