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Molecular Oncology, Markers, Clinical Correlates |
Medical Oncology Division, Hospital 12 de Octubre, 28041 Madrid [R. C., S. M., H. C-F.]; Hematology and Medical Oncology Division, Hospital Clínic, 46010 Valencia [A. L.]; Medical Oncology Division, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona [B. O.]; Medical Oncology Division, Hospital Germans Trias i Pujol, 08916 Barcelona [A. B.]; Medical Oncology Division, Hospital Clínico, 28040 Madrid [A. C.]; Medical Oncology Division, Hospital General, 03010 Alicante [B. M.]; Pathology Department, Institut Català d’Oncologia, 08907 Barcelona [B. L.], Spain
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The adverse prognostic effect of HER2 overexpression may be related to the resistance to chemotherapy (7) . Two neoadjuvant (preoperative) chemotherapy studies (using mitoxantrone plus methotrexate and CAF/cyclophosphamide-epirubicin-5-fluorouracil, respectively) have found a negative association of HER2 expression with response (8 , 9) . Furthermore, in metastatic breast carcinoma, two retrospective studies have found an inverse relationship between HER2 expression in primary tumor tissue (10) or serum (11) and the response to single agent mitoxantrone or cyclophosphamide-Novantrone-fluorouracil, respectively. In the adjuvant setting, the predictive value of HER2 is controversial (7) . Four studies using CMF or CMF-like adjuvant chemotherapy (International Breast Cancer Study Group study V, Intergroup 0011, Guy’s/Manchester, and Stockholm Breast Cancer Group) have shown that tumors that overexpress HER2 have shorter disease-free survival times than those with normal amounts of HER2 gene product (12, 13, 14, 15) . No such lack of benefit was noted, however, when conventional doses of adjuvant CAF (CALGB 8541, and its ancillary study 8869; Ref. 16 ), PAF (National Surgical Adjuvant Breast and Bowel Project study B-11; Ref. 17 ), or a single cycle of perioperative CAF (European Organization for Research and Treatment of Cancer study 10854; Ref. 18 ) were used.
The study that we performed is the first prospective assessment of the predictive value of HER2 ECD expression in metastatic breast carcinoma. We report the clinical outcome of 58 patients with advanced breast cancer treated with a first-line chemotherapy combination of paclitaxel and doxorubicin and analyzed for the expression of HER2 in the serum and primary tumor tissue. We show that the efficacy of treatment (measured as the response rate and the duration of response) is significantly impaired in patients who express elevated levels of circulating HER2 ECD.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The clinical variables that were recorded were as follows: menopausal status, estrogen receptor status, stage at first diagnosis (relapsing versus initially metastatic), previous adjuvant chemotherapy, number of metastatic sites, dominant site of metastases, and the tumor marker CA 15-3, which previously had been associated with metastatic breast cancer burden (19) . When possible, paraffin blocks from the primary breast carcinomas were collected, and immunohistochemical analysis was performed.
Seventy-seven patients participated in the Phase II clinical trial. Fifty-eight had serum samples evaluable for circulating HER2. In 40 cases, HER2 expression was determined in primary tumor tissue.
Chemotherapy.
The chemotherapy regimen used was a combination of doxorubicin (50
mg/m2), followed by a 3-h infusion of paclitaxel
(175 mg/m2), administered every 21 days for six
to nine cycles (Spanish Ministry of Health protocol no. 94/20).
Treatment efficacy was evaluated by each of the investigators, and
responses were confirmed by an independent panel of experts (two
radiologists and one medical oncologist). No local treatments were
allowed in the target lesions. Efficacy parameters used for this
analysis were objective response rate, as defined by WHO criteria, and
duration of response, defined as the time elapsed from the achievement
of an objective response until disease progression. The results of the
Phase II trial will be reported
elsewhere.4
Median
follow-up at the time of the analysis was 23 months. Twenty-seven
patients had received previous adjuvant tamoxifen, and 27 patients had
received tamoxifen for metastatic disease.
HER2 Measurements.
The levels of circulating HER2 were measured using a sandwich enzyme
immunoassay, according to the manufacturer’s instructions (Human neu
quantitative ELISA; Calbiochem; Ref. 20
). The HER2 ECD
values are expressed in fmol/ml.
Immunostaining for HER2 in primary carcinomas was performed using the anti-c-HER2 antibody CB11 (Biogenex) at a dilution of 1:80, and a streptavidin-biotin detection system (kit LSAB2; DAKO). Development was performed with diaminobenzidine, using Harris’ hematoxylin counterstain. Membrane HER2 staining was quantified in percentages (0–100%). Cases were considered positive when 10% or more of tumor cells had intense membrane staining.
Statistical Methods.
The association of HER2 with clinical parameters was evaluated with the
2 test, using the Mantel-Haenszel test to
evaluate linear associations. Multivariate analysis of categorical
variables was performed using logistic regression. Correlations were
performed using the Spearman test. The Mann-Whitney U test
was used to test differences between mean values of subgroups. To
evaluate the duration of response, the Kaplan-Meier estimation was
used, and comparisons were made with the log-rank test. For
multivariate analysis of time-dependent variables, the Cox proportional
hazards regression model was used.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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To test the specificity of circulating HER2 ECD in advanced breast
cancer, we determined the expression of HER2 in 40 of the primary
breast carcinomas. As can be seen in Table 1
, 73% of cases expressing HER2 in the
primary tumor had elevated circulating HER2 ECD at relapse, and 66% of
the cases negative in the primary tumor were also negative when they
developed metastasis. Therefore, HER2 expression in the serum and in
tumor tissue were significantly associated (P = 0.032).
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. Menopausal
status, estrogen receptor status, stage at diagnosis (relapsing
versus initially metastatic), previous adjuvant
chemotherapy, dominant site of metastases, and the number of metastatic
sites did not correlate with HER2. However, elevated circulating HER2
ECD levels were associated significantly with positivity for the tumor
marker CA 15-3 (P = 0.002), indicating that the
expression of HER2 in the serum is associated with metastatic tumor
burden in patients with advanced breast carcinoma. To corroborate the association between circulating HER2 ECD and tumor burden, we performed a correlation analysis between the logarithmically transformed values of HER2 and CA 15-3. We observed a moderate correlation between HER2 ECD and CA 15-3, which was statistically significant (r = 0.5; P < 0.001). In addition, patients with elevated circulating HER2 had higher CA 15-3 values compared with patients with nonelevated HER2 (23.5 versus 34.7 units/ml; P = 0.011). This confirms the association between the levels of circulating HER2 ECD and the extent of metastatic breast cancer.
Finally, we assessed the relative importance of the clinical variables and tissue HER2 on the elevation of circulating HER2 ECD. A logistic regression analysis showed that only tissue HER2 (P = 0.016) and CA 15-3 (P = 0.019) were independent variables associated with elevated serum HER2 ECD.
Correlation of Circulating HER2 ECD and Treatment Efficacy.
Treatment efficacy was evaluable in 55 of the cases with circulating
HER2 measurement. Three patients were not evaluable for response: one
patient had a lung embolism after the first cycle; one patient had a
hypersensitivity adverse event after the second treatment; and one
patient had only nonmeasurable bone lesions.
Table 2
shows that 0% of the patients
with elevated HER2 had a complete response (95% CI, 0–13%), whereas
26% of patients with nonelevated HER2 had a complete clinical response
(95% CI, 12–45%). In addition, almost twice the proportion of cases
with elevated HER2 did not respond to therapy when compared with the
cases with nonelevated HER2 (37 versus 23%; 95% CI,
19–59% and 10–41%, respectively). Therefore, there was a
statistically significant inverse relationship between the levels of
circulating HER2 and the clinical response (P = 0.021).
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illustrates that elevated circulating
HER2 ECD levels are associated with a shorter response duration. We
also performed a Cox analysis of the response duration using HER2 ECD
as a continuous variable. This analysis showed that HER2 ECD had a
borderline statistical significance (P = 0.06).
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Correlation of Treatment Efficacy with Tissue HER2 and CA 15-3.
Although this was not an objective in our study, we explored the
correlation between the efficacy of chemotherapy in our cases and both
the primary tissue expression of HER2 and the levels of CA 15-3. Table 2
shows that there was a trend for tissue HER2 expression to correlate
inversely with the response to treatment. However, in this case the
association was not significant.
On the other hand, CA 15-3 levels in patients with advanced breast
carcinoma showed a significant inverse correlation with the response to
chemotherapy. As can be seen in Table 2
, positive CA 15-3 levels were
associated with a lower probability of obtaining a complete response.
CA 15-3 levels, however, did not correlate with a higher
probability of not responding.
Multivariate Analysis of Treatment Efficacy.
To assess the relative importance of circulating HER2 on treatment
efficacy in comparison with other variables, we performed multivariate
analyses (Table 3)
. Tissue HER2 was not
introduced in the models because it compromised the number of cases. We
first performed a logistic regression analysis, using objective
response (response versus no response) as the dependent
variable. The circulating HER2 level was the only variable that showed
a significant association in the multivariate analysis
(P = 0.03). Second, we performed a Cox regression
analysis of the duration of response. This showed that of the variables
entered in the model, only circulating HER2 ECD retained statistical
significance in the multivariate analysis (P = 0.04).
Therefore, circulating HER2 ECD is a significant predictor of treatment
efficacy that is independent of other clinical variables.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In the present study, the distribution of HER2 levels in the serum of patients with advanced breast cancer is similar to the distribution we found in a previous study in which the same assay was used (21) . We categorized the levels of circulating HER2 ECD using 450 fmol/ml as a cutoff. The proportion of cases with elevated HER2 in our study was identical to the positivity rate that has been reported by other authors in patients with metastatic breast cancer using the same or similar ELISAs (43, 45, and 34%, respectively; Refs. 22, 23, 24 ).
Our results showing a relationship of HER2 ECD expression and resistance to chemotherapy are consistent with several reports in the adjuvant and neoadjuvant settings. Retrospective analysis of adjuvant chemotherapy in node-negative patients, such as the International Breast Cancer Study Group study V (12) and the Intergroup study 0011 (13) , and in node-positive patients, such as the Guy’s/Manchester (14) , have showed that adjuvant CMF chemotherapy has reduced efficacy in the subset of HER2-positive patients. A study by Fehm et al. (6) in node-positive breast carcinoma found that HER2 ECD-positive patients had a worse outcome than HER2-negative patients when treated with either adjuvant CMF or cyclophosphamide-Novantrone-fluorouracil. Two recent prospective studies have evaluated the efficacy of preoperative chemotherapy in relation with HER2 status (8 , 9) . In the study by Makris et al. (8) , the response rate was significantly lower in HER2-positive than in HER2-negative cases (57 versus 93%; P = 0.007), and in the report by Vargas-Roig et al. (9) , 89% of HER2-positive patients developed distant metastases, whereas only 38% of the HER2-negative cases did (P = 0.006). The results of the present study are further supported by a subsequent study of HER2 ECD that we have carried out in 43 patients with metastatic breast cancer treated with a biweekly combination of paclitaxel and gemcitabine. In this study, which used the same HER2 ECD test and cutoff, the response rate to paclitaxel-gemcitabine was 85% in HER2 ECD-positive patients and 40% in the HER2-negative cases (P = 0.003), and the duration of response was 6 and 10.5 months, respectively (P = 0.06; Ref. 25 ).
Other studies, in contrast, have not found an association between HER2 expression and resistance to chemotherapy. The CALGB study 8869 (16) evaluated three doses of adjuvant CAF chemotherapy (standard, low, or very low) in 396 cases with node-positive breast cancer. They found that standard CAF was more active than the lower doses and that this was especially true in the HER2-positive cases. The National Surgical Adjuvant Breast and Bowel Project study B-11 showed that PAF adjuvant treatment in ER-negative, node-positive patients was superior to L-phenylalanine mustard-5-fluorouracil. An evaluation of HER2 expression in this study (17) observed that the benefit of PAF is restricted to HER2-positive patients. Because some of the drugs in the CMF and L-phenylalanine mustard-5-fluorouracil regimens are identical to those in CAF or PAF, it has been hypothesized that doxorubicin, the drug that is not common in the comparative regimens, may be more active in HER2-positive cases. A recent update of CALGB study 8541/8869, however, although validating the results in the 396 cases of the first report, has not able to replicate the results in an additional cohort of 595 patients (26) . Two published retrospective studies, one in primary breast cancer (27) and another in advanced breast cancer (28) , have not found a correlation between treatment response to CAF and HER2 tumor tissue expression. The retrospective design of all of these studies and the limitations of immunohistochemical analysis in archival samples (29 , 30) may explain some of the discrepancies observed and make the point for prospectively designed trials when evaluating biological endpoints.
In our study, we used a combination of doxorubicin and paclitaxel, two drugs that have been suggested to be more active in HER2-positive breast cancer (16 , 17 , 31) . The design of our single-arm study does not allow a conclusion about the interaction between HER2 expression and the individual efficacy of doxorubicin or paclitaxel. HER2-associated chemoresistance has been reported to be independent of the multidrug resistance gene mdr-1 (32) , and recent animal experiments using cells transfected with HER2 have suggested that the lack of response to chemotherapy of HER2-positive tumors is related to the rapid proliferation of the tumor cells that survive the chemotherapy and not to an intrinsic resistance to chemotherapy (33) . In agreement with these observations, a recent investigation in which the apoptotic index was measured in primary breast carcinomas before and 24 h after doxorubicin-containing chemotherapy showed that HER2-positive tumors have a markedly reduced apoptotic response to chemotherapy (34) . Therefore, the expression of HER2 may not indicate a pleiotropic resistance to chemotherapy, but rather it represents a cellular growth advantage that allows the regrowth of tumor cells after treatment. This is consistent with the shorter duration of responses that we observed in the cases with elevated circulating HER2 ECD.
In our study, we observed a significant association of circulating HER2 ECD levels in the serum with the expression of HER2 in the primary tumor, although the assay reagents used for the detection of HER2 in the serum and in the tumor were not the same. Our results agree with the concordance indices for HER2 of 70–80% that have been reported with variations in the diagnostic HER2 antibodies (30) . In our series, circulating HER2 ECD levels also correlated with an indicator of tumor burden, the marker CA 15-3, reflecting that HER2 ECD levels in the serum depend on the amount of metastatic tumor cells. This is in agreement with the results of Krainer et al. (35) , who found a very similar correlation coefficient between serum HER2 ECD and CA 15-3 in patients with metastatic breast cancer. The detection of elevated HER2 ECD levels in the absence of HER2 overexpression in the primary tumor tissue reflects the different timeframes in the collection of samples. Whereas HER2 was determined at the time of primary surgery, HER2 ECD was determined much later in the disease course, when distant metastases were present. It has been suggested that HER2 amplification may be involved in the progression of breast cancer from a hormone-dependent to a hormone-independent phenotype. A study of multiple biopsies of patients with advanced breast cancer undergoing hormonal treatment showed that HER2 amplification appeared (9–31 months after the initiation of therapy) in 6 of 34 HER2-negative cases (36) .
Our data suggest that circulating HER2 ECD levels may be a better indicator of resistance to chemotherapy than the expression of HER2 in the primary tumor. However, the small number of cases in which we could determine tissue HER2 and the different methods of tumor tissue processing that were used in each of the centers participating in the study do not allow a definitive conclusion. An advantage for the use of serum samples over archival tissue in patients with advanced breast carcinoma is that, in general, serum samples may be obtained more easily after relapse. Therefore, the measurement of circulating HER2 in the serum may be more reliable and reproducible than the measurement of HER2 in archival paraffin blocks. Our study cannot distinguish whether HER2 ECD predicts for resistance to paclitaxel or to doxorubicin because we used the drugs in combination. The Eastern Cooperative Oncology Group study 1193 measured circulating HER2 in patients with advanced breast cancer that received paclitaxel, doxorubicin, or the combination paclitaxel-doxorubicin. The results from this study will provide important information on this issue when they are published. Our clinical trial did not include an untreated control arm, an instance difficult to justify in the management of advanced breast carcinoma. Therefore, the value of circulating HER2 ECD as either a pure predictive factor (related only to chemotherapy) or a mixed predictive/prognostic factor (related to chemotherapy and also to intrinsic disease characteristics) cannot be fully established from our results (37) .
With the evidence provided in our study, a recommendation for selecting conventional chemotherapy regimens in advanced breast cancer based on HER2 status is not justified. In contrast, we suggest that the poor response rate that is associated with HER2 expression might be reversed with anti-HER2-specific therapies, an approach that has been effective in the laboratory (38 , 39) and in randomized clinical trials (40) with monoclonal antibodies.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This study was supported in part by
Bristol-Myers Squibb. 
2 To whom requests for reprints should be
addressed, at Servicio de Oncología Médica, Hospital 12
de Octubre, 28041 Madrid, Spain. E-mail: rcolomer{at}hdoc.insalud.es
3 The abbreviations used are: ECD, extracellular
domain; CAF, cyclophosphamide-Adriamycin-5-fluorouracil; CMF,
cyclophosphamide-methotrexate-5-fluorouracil; CALGB, Cancer and
Leukemia Group B; PAF, L-phenylalanine
mustard-5-fluorouracil-doxorubicin; CI, confidence interval.
4 A. Lluch et al., Doxorubicin and
paclitaxel in advanced breast cancer: importance of prior adjuvant
anthracycline therapy, submitted for publication.
Received 1/27/00; revised 3/29/00; accepted 3/29/00.
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