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Journal of Clinical Oncology, Vol 20, Issue 9 (May), 2002: 2319-2326
© 2002 American Society for Clinical Oncology

Assessment of Molecular Markers of Clinical Sensitivity to Single-Agent Taxane Therapy for Metastatic Breast Cancer

By Catherine Van Poznak, Lee Tan, Katherine S. Panageas, Crispinita D. Arroyo, Clifford Hudis, Larry Norton, Andrew D. Seidman

From the Breast Cancer Medicine Service, the Pathology Department, and the Biostatistical Department, Memorial Sloan-Kettering Cancer Center, New York, NY.

Address reprint requests to Catherine Van Poznak, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; email: vanpoznc{at}mskcc.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: The taxanes affect tubulin polymerization and interfere with mitotic transition. A checkpoint blockade at the G1-S boundary would be expected to promote taxane-induced apoptotic cell death through a mechanism that may involve p27. Other proposed determinants of clinical taxane sensitivity/resistance include p53, members of the epidermal growth factor receptor (EGFR) superfamily (eg, HER2, EGFR), and estrogen receptors and progesterone receptors. These molecular markers and their correlation with clinical taxane sensitivity are investigated in this retrospective clinicopathologic study.

PATIENTS AND METHODS: We performed immunohistochemistry (IHC) for estrogen receptors, progesterone receptors, HER2, EGFR, p53, and p27 on 144 breast tumor specimens from patients treated for metastatic breast cancer on a series of clinical trials of single-agent taxane chemotherapy for correlation with clinical response (complete or partial response). Patient characteristics that could influence response (ie, performance status, extent of disease, and prior therapy) were also examined.

RESULTS: In univariate analysis, Karnofsky performance status >= 90% and no prior history of anthracycline therapy correlated with a good clinical response to single-agent taxane (P = .003 and P = .041, respectively). None of the IHC variables tested were predictive of clinical response to taxane therapy, although p27 negativity showed a trend toward significance (P = .075). Concordance between the polyclonal antibody with HercepTest (DAKO, Carpinteria, CA) and the monoclonal antibody CB-11 (BioGenex, San Ramon, CA) was noted (kappa = 0.943); however, neither univariate nor multivariate analysis demonstrated an association between HER2 status and response to taxane chemotherapy.

CONCLUSION: The IHC biomarkers studied were not predictive of response to single-agent taxane chemotherapy in patients with metastatic breast cancer. Identification of molecular correlates of taxane response remains an important goal.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
THE SELECTION OF chemotherapeutic agents and regimens for the treatment of breast cancer is generally derived from large phase III clinical trials, where it is possible to estimate the comparative likelihood of benefit and toxicity for a specific regimen. The taxanes, paclitaxel and docetaxel, play important roles in treating breast cancer1 and large, randomized clinical trials of taxane-containing chemotherapy have demonstrated a survival advantage over previous standard regimens both in the adjuvant setting and in the setting of metastatic disease.2-5 However, these trials are not instructive as to the reason for response or resistance in an individual patient. The identification of patient-specific tumor characteristics that can improve the ability to predict response to therapy would help optimize treatment. This retrospective study was initiated to investigate clinical response in patients with metastatic breast cancer and the correlation with selected biomarkers (HER2, ER, PR, p53, p27, and EGFR) as potential predictors of response to single-agent taxane chemotherapy.

Although there are several molecular markers with prognostic utility in breast cancer, few have been evaluated as predictors of response to treatment. The estrogen receptor (ER) and progesterone receptor (PR) status is used to determine the likelihood of response to endocrine therapy and is a standard prognostic and predictive factor in breast cancer.6,7 Few markers have shown similarly powerful predictive value for response to systemic therapy.

Amplification and overexpression of certain oncogenes have been associated with an aggressive natural history, poor prognosis and, in some situations, chemoresistance, and in other situations, chemosensitivity.8-15 For example, retrospective analysis of HER2 overexpression by Paik et al16 supports the hypothesis that anthracycline-containing adjuvant chemotherapy regimens confer benefit over non–anthracycline-containing regimens. Molecular markers may indicate specific cellular alterations that affect specific targeting mechanisms of a therapeutic treatment. We have speculated that human breast cancers overexpressing HER2 may be significantly more likely to respond to single-agent therapy with paclitaxel or docetaxel. Our prior assessment of tumor HER2 expression through monoclonal antibody (4D5) and the polyclonal antibody (pAb-1) demonstrated that 4D5 positivity was predictive of positive response to taxane monotherapy.17

The taxanes are antimicrotubular agents that promote microtubular assembly from tubulin dimers and stabilize microtubules by preventing depolymerization, thereby interfering with normal mitotic transition. Taxanes causes arrest of cell cycle progression in the mitotic phase of the cell cycle, with accumulation of cells in G2-M interphase.18 The ability of paclitaxel to activate MAP kinase and Raf-1 kinase19 may explain how tubulin active agents (eg, taxanes) could have enhanced cytotoxic effects in HER2 overexpressing cells through downstream perturbation of the signal transduction cascade. Constitutively active epidermal growth factor receptor (EGFR) and HER2 in transfected cell cultures induce paclitaxel resistance and alter expression of beta-tubulin expression.20 EGFR overexpression or altered expression has been reported for a variety of human tumors.

The cell cycle is regulated by a complex system of cyclins, cyclin-dependent kinases, and cyclin-dependent kinase inhibitors that are in turn governed by associated cyclins and by phosphorylation. p27 is a negative regulator implicated in G1-phase arrest. Lower p27 levels in breast cancers assessed by immunohistochemistry (IHC) have been associated with shorter survival.21-23 Increased p27 has been observed in a paclitaxel-resistant breast cancer cell line, compared with its sensitive parental (MDA 435) cells.24 Paclitaxel may be able to induce apoptosis through a non–p53-dependent pathway, possibly involving molecular regulators of apoptosis such as bcl-2, bax, and p27.25

Inactivation of the tumor suppressor gene p53 has been implicated in the development and progression of a number of different cancers.26 Mutants of p53 are present in up to 50% of invasive breast cancers, and loss of its function is associated with high proliferation index and poor clinical outcome. p53 is just one oncogene in a complex pathway that controls both proliferation and apoptosis. Other factors in this pathway include the bax and bcl-2 families. Bax transcription is upregulated by p53, which links the proapoptotic increase in p53 with the bcl-2 family of proteins.27-33

The identification of pretreatment tumor characteristics that are strong predictors of either drug sensitivity or resistance may minimize the proportion of patients who would not derive benefit and maximize the proportion that would benefit. Therefore, we attempted to assess immunohistochemical phenotypes of human cancers that might be associated with poor or favorable clinical responsiveness to single-agent treatment with the taxanes, paclitaxel and docetaxel, for metastatic breast cancer.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Women with metastatic breast cancer treated at Memorial Sloan-Kettering Cancer Center (MSKCC) on nine successive clinical trials between 1991 to 1998 with single-agent taxanes were identified. All patients within these nine trials were candidates for this present study; however, access to sufficient tumor block was limited to those patients who either had their primary surgery at MSKCC or who had their primary surgery elsewhere and had forwarded the tissue block to MSKCC. The specimens evaluated were selected by the availability of adequate quantity of tumor to perform multiple IHC studies. Patients were excluded if there was insufficient accessible material.

Patients
Patients treated with taxane chemotherapy on these nine clinical trials had histologically confirmed, bidimensionally measurable metastatic breast cancer, life expectancy more than 12 weeks, Karnofsky performance status (KPS) >= 60%, and normal organ function (WBC count > 3,500 cells/mL, absolute neutrophil count > 2,000 cells/mL, platelet count > 100,000 cells/mL, creatinine < 2.0 mg/dL, bilirubin < 1.5 mg/dL, and no significant cardiac disease or arrhythmia). Previous chemotherapy and/or hormonal therapy was allowed according to specific eligibility criteria for each individual protocol; no concomitant cytotoxic therapy, hormonal therapy, immunotherapy, or radiotherapy was permitted during protocol therapy with taxane. Exclusion criteria included clinically unstable brain metastases or carcinomatous meningitis, symptomatic lymphangitic pulmonary disease, and history of prior malignancies except completely excised in situ carcinoma of the cervix or nonmelanoma skin cancer. Patient characteristics that can influence response to chemotherapy were extracted from the medical record by chart review. These patient demographic factors are performance status, extent of disease, visceral dominant disease, extent of prior therapy, and prior anthracycline chemotherapy. All patients provided informed consent for protocols approved by the MSKCC Institutional Review Board.

IHC Assays
IHC studies were performed on paraffin blocks from tissues fixed in 10% neutral buffered formalin. IHC analysis reported in this study was carried out in a single laboratory (MSKCC). All slides were reviewed by a pathologist (L.T.) without knowledge of the demographic or treatment response information. A hematoxylin and eosin–stained slide was prepared from each block and used for pathologic confirmation of the presence of invasive mammary carcinoma. Interpretation of the results was limited to the invasive portion of the tumor. Reagents used for IHC studies are listed in Table 1. Recognizing the possibility that different epitopes of the HER2 transmembrane protein could potentially have biologic significance regarding chemotherapy sensitivity,17 two different antibodies were used: the polyclonal antibody HercepTest (DAKO, Carpinteria, CA) and the monoclonal antibody CB11 (BioGenex, San Ramon, CA).


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  		Table 1.  Reagents Used for the IHC Studies
 
Tissue sections of 4-µm thickness were prepared, mounted on polylysine-coated slides, deparaffinized, and rehydrated with distilled water. With the exception of CB11 (no treatment, Ventana automated stainer [Ventana Medical Systems, Inc, Tucson, AZ]), the following epitope retrieval was used for the remaining antibodies: microwave on high energy for 5 minutes twice in 0.01 mol/L citrate buffer (pH 6.0) for ER, PR, p53, and p27; 0.1% pepsin at 37°C for 20 minutes for EGFR; and boiling at 95° to 99°C for 40 minutes in diluted epitope retrieval solution (DAKO) for HercepTest. ER and PR were scored as positive when at least 10% of the carcinoma cell nuclei were immunoreactive. For p27 and p53, any percentage of positive nuclei was noted. The intensity of membrane staining of HER2 for both HercepTest and CB11 was evaluated according the criteria set forth by the DAKO HercepTest: score 0 = no or up to 10% membrane staining; score 1+ = partial and/or faint membrane staining in more than 10% of tumor cells; score 2+ = weak to moderate complete membrane staining in more than 10% of tumor cells; and score 3+ = strong complete membrane staining in more than 10% of tumor cells. EGFR was scored as either negative or positive on the basis of the presence of any membrane staining in the tumor cells.

Clinical Response Criteria
A complete response (CR) was defined as disappearance of all measurable and assessable disease, signs, symptoms, and biochemical changes related to the tumor for more than 4 weeks, during which time no new lesion(s) appeared. A partial response was defined as at least a 50% reduction in the sum of the products of the perpendicular diameters of all measurable lesions lasting more than 4 weeks, with no new lesion(s) and no enlargement of existing lesions. Minor response was defined as a reduction of 25% to 49% in the sum of the products of the perpendicular diameters of all measurable lesions lasting more than 4 weeks, with no new lesions and no enlargement of existing lesions. Stable disease was defined as less than a 50% reduction and less than a 25% increase in the sum of the products of two perpendicular diameters of all measurable lesions and lack of appearance of new lesions. Progression of disease was defined as either an increase in the product of the two perpendicular diameters of any measurable lesion by more than 25% over the size at entry or the appearance of new areas of malignant disease. All tumor responses were confirmed and radiographic responses reviewed by a designated reference radiologist. For four of these trials, additional external, independent review of response occurred.

Statistical Analysis
Taxane response was identified as CR, partial response, minor response, stable disease, progression of disease, or inassessable. Statistical analysis was performed on the CR plus partial response subset versus all other tumor response categories combined. Clinical variables were dichotomized as follows: KPS (60% to 80% v 90% to 100%), number of prior treatment regimens (<= two v >= three regimens), prior anthracycline exposure (yes v no), number of organ systems with metastases (<= two v >= three systems), and visceral dominant disease (yes v no). Associations between taxane sensitivity and the clinical characteristics or molecular markers were assessed univariately by {chi}2 analysis. The IHC markers that showed a trend toward statistical significance were analyzed by logistic regression to adjust for clinical characteristics known to be associated with taxane sensitivity.

Both HER2 IHC (HercepTest and CB-11) results were considered negative if scored 0 or 1 and positive if scored 2 or 3. The kappa statistic was used to assess concordance between (HercepTest and CB-11). Additional HER2 statistical analysis was performed using 0 to 2+ staining as a negative result and 3+ as positive. A cut-point analysis was performed by the maximum {chi}2 with P value adjustment method to determine positive values for p27 and p53. This analysis revealed p27-negative as 0% staining and any staining as p27-positive and p53-negative as less than 10% staining and 10% staining as positive.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The database consists of patients treated at MSKCC on nine different clinical trials (1991 to 1998) using single-agent taxane (paclitaxel, eight trials; docetaxel, one trial) chemotherapy for metastatic breast cancer. The treatment regimens used are listed in Table 2. Dose adjustments were directed by toxicities and protocol. The single-agent taxane protocol database contains 340 patients. Not all patients had accessible and/or sufficient tissue for investigational immunohistochemical studies. Many patients had been referred to MSKCC and had only stained pathology slides submitted for confirmation of disease before protocol enrollment. The tumor blocks of 188 patients were available, and the medical records of these 188 patients were reviewed for clinical data. The clinical characteristics of these patients are listed in Table 3.


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  		Table 2.  Taxane Monotherapy Regimens (N = 188)
 

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  		Table 3.  Demographic Variables
 
Of the 188 patients whose paraffin-embedded tumor block was accessible, 144 had adequate quantity of material with evidence of invasive breast cancer for planned IHC studies. Of the patients with available tissue, 61 of 144 (42%) experienced a CR or partial response with single-agent taxane therapy (listed in Table 3 as a subset of the 188 patients). One hundred four tumor blocks assessed were from the primary breast cancers; 40 tumor blocks were from metastatic sites. The results of the IHC assays are listed in Table 4. Most patients had hormone receptor–negative disease, with ER-negative disease in 66% and PR-negative disease in 81.9%. Consistent with prior reports, the HER2 assays revealed that approximately one quarter of patients had tumors overexpressing HER2 2+/3+ by IHC. The results of both the polyclonal HercepTest and the monoclonal assay CB-11 are listed in Table 4. Concordance between the HercepTest and CB-11 was high (kappa = .943; 95% confidence interval, 0.877 to 1.0).


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  		Table 4.  Immunohistochemistry
 
Univariate analysis, {chi}2 analysis, and multivariate analysis performed to assess both the clinical and IHC results for predictive value of response to taxane therapy revealed that only better KPS and lack of prior exposure to anthracycline chemotherapy were predictive of response to single-agent taxane chemotherapy. Univariate analysis is shown in Table 5 and multivariate analysis in Table 6. None of the biomarkers assessed by IHC (ER, PR, EGFR, HER2, p27, and p53) showed a statistically significant association with clinical response to taxane therapy. Univariate and multivariate analysis of HER2 score 0 to 2+ v 3+, and analyses using cutoff 0 to 1+ v 2 to 3+, showed no association with clinical taxane response by either HercepTest or CB11. Multivariate analysis of p27, KPS, and prior exposure to doxorubicin by logistic regression demonstrated persistence of a trend for p27 negativity and clinical taxane response. Our analysis used the cut point of any p27 staining as positive. The assessment of p27 by quartile categories 0% to 25%, 26% to 50%, 51% to 75%, and 76% to 100% yielded no correlation with response of taxane chemotherapy (data not shown). Analysis by individual protocol for a relationship between the individual biomarkers and response to taxane regimen did not reveal a correlation (data not shown). Although serial biopsy assessment was not performed, the results of IHC interpatient results from primary breast cancer tissue versus tissue from metastatic sites revealed a significant difference only for PR status, where more primary tissues were found to be PR-positive (P = .041). Interestingly, ER and PR status were not predictive of taxane response in either univariate or multivariate analysis.


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  		Table 5.  {chi}2 Univariate Analysis*
 

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  		Table 6.  Multivariate Analysis: Logistic Regression*
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We performed a retrospective clinicopathologic correlative science study to evaluate potential molecular correlates of clinical responsiveness to single-agent taxane chemotherapy for metastatic breast cancer. Because the database was created while investigating the optimal dosing and schedule of taxane therapy, there is heterogeneity in the regimens within nine different clinical therapeutic protocols. The clinical factors of KPS >= 90% (P = .003) and no prior anthracycline exposure (P = .041) were predictive of a positive response to taxane therapy by both univariate and multivariate analyses. None of the biomarkers assessed by IHC (ER, PR, EGFR, HER2, p53, and p27) showed a statistically significant ability to act as predictors of clinical response to taxane therapy, although p27 negativity showed a trend toward significance by both univariate and multivariate analyses when adjusted for KPS and prior anthracycline exposure. Because demographic data correlated with clinical response to taxane monotherapy for metastatic breast cancer, we felt it appropriate to include the full clinical data sample (n = 188) and not to limit our presentation to include only those patients whose tissue was available (n = 144). These observations await independent, prospective confirmation and remain hypothesis generating.

Although well characterized for their prognostic and predictive power for hormonal therapies, ER and PR status was not predictive of response to single-agent taxane chemotherapy in either univariate or multivariate analysis within our study population. Of note, the majority of patients within our study were ER-negative and/or PR-negative (66% and 82%, respectively). The predominance of hormone receptor–negative patients within our study may reflect the patient referral pattern to the phase II clinical trials of single-agent taxane chemotherapy for metastatic breast cancer at MSKCC during the years 1991 to 1998. This finding could be important in light of the fact that no benefit was observed for the addition of paclitaxel to doxorubicin and cyclophosphamide in the ER-positive subset of patients treated in Cancer and Leukemia Group B study 9344.34

Approximately one quarter of tumor samples tested positive for overexpression of HER2 (2 to 3+) as would be expected. Our results are noteworthy for the lack of correlation between HER2 status as assessed by either HercepTest or CB-11 and response to single-agent taxane therapy. These findings are partly in contrast to our earlier analysis.17 In this earlier analysis of fewer cases, HER2 status as assessed by the monoclonal antibody 4D5 was predictive of positive response to taxane monotherapy, whereas HER2 assessment with the polyclonal antibody pAb-1, was not. In the present study, we demonstrated strong concordance between the two IHC methods of evaluating HER2 status (HercepTest and CB-11), which was not observed between 4D5 and pAb-1. Evaluating HER2 status by IHC assesses protein overexpression, whereas an alternative means of studying HER2 status, fluorescent in situ hybridization (FISH), measures gene amplification. The molecular analysis of amplification offers a more quantitative approach, and there appears to be a close correlation between amplification reflected in increased copy number and the ability to detect HER2 immunohistochemically.35-37 A retrospective analysis of patients with metastatic breast cancer randomized to either paclitaxel and epirubicin or cyclophosphamide and epirubicin demonstrated that the patients in the paclitaxel and epirubicin arm whose tumors had HER2 gene amplification by FISH experienced a statistically significant improvement in response rate and progression-free survival and a borderline significant improvement in overall survival.38 Although FISH may become the preferred method of defining HER2 status, a functional assay (eg, PN2A, an antibody that is more specific for the activated, phosphorylated HER2 receptor) may also be relevant for prediction of therapeutic benefit.39

In virtually all reports to date, loss of p27 in epithelial cancers has been shown to correlate significantly with high-grade, poorly differentiated tumors showing significantly lower p27 protein expression than their well-differentiated counterparts. A potential taxane-induced mechanism of p53-independent apoptosis by induction of p27 has been reported.40 In this study, both univariate and multivariate analyses demonstrated a trend toward statistical significance with p27 negativity and response to single-agent taxane chemotherapy. Although most studies21-23,41 have scored cases as 0% to 25%, 25% to 50%, 50% to 75%, and more than 75% or using the cutoff of high (> 50% of cells staining) versus low staining,42,43 our statistical analysis has shown no effect in separating these groups when assessing for clinical response to taxane therapy.

The observation of prolonged disease-free survival for patients with HER2 overexpressing primary tumors receiving more dose-intense anthracycline-based chemotherapy suggests that the presence of a marker of more malignant phenotype might allow identification of a subset of patients who would optimally benefit from a specific therapeutic strategy.44 The assessment of two or more coexpressed genes may further increase the predictive power of biologic markers. The clinical trial Cancer and Leukemia Group B 8541 examined three different dose-intensity regimens of adjuvant cyclophosphamide, doxorubicin, and fluorouracil in women with stage II breast cancer. Retrospective analysis of HER2 and p53 expression in a subset of these patients demonstrated that HER2 positivity and p53 negativity showed an improved survival with high-dose cyclophosphamide, doxorubicin, and fluorouracil.45

Approximately one quarter of the tissue samples that underwent biopsy in our study were obtained from a metastatic site. As serial biopsies (comparing primary with metastatic biopsy specimens within the same patient) were not part of this study, we cannot draw conclusions on the effects of the site of biopsy on our results. However, other investigators have performed IHC assays for bcl-2 and p53 on serial biopsy specimens in breast cancer patients and have demonstrated consistent results within individual patients.46 Assessment of both primary and metastatic lesions for HER2 and p53 in breast cancer patients demonstrated consistent results between the primary tumor and the metastatic lesion for both markers.47

Serial biopsy in the neoadjuvant setting for locally advanced breast cancer may offer a more optimal scenario for correlative studies of molecular predictors of chemosensitivity. Marcus et al48 reported analysis on 19 breast cancer patients with locally advanced breast cancer who had sequential tumor assessment for HER2, p53, cyclin D1, and p27. The biopsy specimens were obtained at diagnosis, after two cycles of doxorubicin and docetaxel, and at mastectomy after six cycles of doxorubicin and docetaxel. Although pretreatment tumor specimens strongly expressing HER2 or p53 predicted response to doxorubicin and docetaxel in this small study, cyclin D1, bcl-2, and p27 did not. Although this small study suggests markers possibly predictive of response to combination chemotherapy, extrapolation to either single-agent doxorubicin or taxane chemotherapy is not possible. HER2, p53, and bcl-2 have been investigated as predictors of response to doxorubicin and paclitaxel as single-agent therapy for metastatic breast cancer.49 However, these markers did not demonstrate a correlation between expression of these markers and clinical response to either agent. Similarly, the present study evaluating, ER, PR, HER2, EGFR, p53, and p27 did not show the ability to predict clinical response to single-agent taxane therapy for metastatic breast cancer.

The taxanes are among the most active agents in the treatment of breast cancer, with response proportions in the range of 30% to 60% noted in single-agent trials of these agents in patients with minimal or no prior therapy and 20% to 45% in patients with extensive prior chemotherapy.1 This activity, coupled with an understanding of their unique property of shifting the dynamic equilibrium of microtubular assembly toward stabilized tubulin polymers, has led to the widespread use of these agents in the treatment of breast cancer. Investigation of tubulin isotype expression and relationship to taxane resistance is ongoing.20 Measurements of parameters that can assist in the identification of patients likely to benefit from specific therapeutic agents and strategies will undoubtedly yield improved treatment planning. The development of gene microarray analysis for molecular characterization of breast tumor tissue promises to be the basis for an improved molecular taxonomy of breast cancer50,51 and to allow for the selection of therapeutic agents tailored to the individual patient’s tumoral genetic profile. In fact, it is conceivable that IHC correlative studies such as this may become obsolete in the not-too-distant future if the success of this technology is realized. The identification of clinically significant biomarker correlates of response to chemotherapy, and taxanes in particular, remains an important goal.


   ACKNOWLEDGMENTS
 
Supported by U.S. Army Medical Research and Materiel Command grant no. DAMD17-94-J-4329.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
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Submitted August 21, 2001; accepted January 31, 2002.




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