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Keywords:

  • breast neoplasms;
  • HER2;
  • estrogen receptor;
  • trastuzumab;
  • chemotherapy;
  • endocrine therapy

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. CONFLICT OF INTEREST DISCLOSURES
  8. References

BACKGROUND:

The relationship between quantitative immunohistochemical hormone receptor expression and response to the combination of trastuzumab with chemotherapy in HER2-positive advanced breast cancer is currently unknown.

METHODS:

Estrogen receptor (ER) and progesterone receptor expression was studied both as a dichotomous variable (positivity set at ≥1% of positive cells) and as a continuous variable. The effect of hormone receptor expression on overall response rate and progression-free survival in patients receiving trastuzumab-based treatment was studied by univariate and multivariate analysis.

RESULTS:

One hundred eleven of 227 consecutive advanced breast cancer patients treated at 2 Institutions had hormone receptor-positive tumors (49%). High expression of ER (≥30% of tumor cells) predicted reduced probability of tumor response to trastuzumab plus chemotherapy (multivariate odds ratio, 0.422; 95% confidence interval [CI], 0.222-0.803; P = .009). In patients with hormone receptor-positive tumors (≥1% of tumor cells), maintenance endocrine therapy added to trastuzumab upon the completion of chemotherapy was associated with a significant progression-free survival benefit (hazard ratio, 0.521; 95% CI, 0.3325-0.836; P = .007).

CONCLUSIONS:

Our results suggest a predictive role of hormone receptor expression in HER2-positive tumors. Further investigation in this patient subset is warranted to optimize the use of HER2-targeting agents, chemotherapy, and endocrine therapy. Cancer 2012;. © 2011 American Cancer Society.

Estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) are key biological factors in breast cancer. ER activation induces the expression of the progesterone receptor (PGR) and of a series of genes involved in breast cancer development and progression.1 About ⅔ of breast cancers are hormone receptor positive, based on the immunohistochemical expression of either ER, PGR, or both receptors.2 In general, hormone receptor positivity is considered both a favorable prognostic factor and a predictor of the efficacy of endocrine therapy.3

Overexpression and/or amplification of the HER2 receptor occurs in some 15% to 20% of breast cancers in women and denotes a biologically aggressive subset of this disease.4 HER2 positivity is frequently associated with higher histopathological grade, reduced hormone receptor expression, and propensity to metastasize to viscera and to the central nervous system.4-7 Coexpression of HER2 in hormone receptor-positive tumors is associated with reduced efficacy of endocrine therapy.8-10 One of the most credited mechanisms that have been proposed to explain endocrine resistance is cross-talk between the ER and HER family pathways.11-13 Hyperactive HER2 or epidermal growth factor receptor can activate the ER directly, in the absence of its natural ligand. This explains not only resistance to selective estrogen receptor down-modulators, but also to aromatase inhibitors.14

One pivotal phase 3 trial and 1 randomized phase 2 trial demonstrated that the addition of trastuzumab, a therapeutic anti-HER2 monoclonal antibody, to chemotherapy boosted response rate, progression-free survival (PFS), and overall survival, compared with chemotherapy alone, in women with HER2-positive metastatic breast cancer.15, 16 About a half of the patients enrolled in the pivotal trial had coexpression of HER2 and hormone receptor.15 A retrospective analysis of patients enrolled in this trial suggested that the addition of trastuzumab to chemotherapy yielded equal benefits in hormone receptor negative and positive tumors.17 These results added further strength to the paradigm that HER2-positive tumors, because of reduced endocrine-responsiveness, need to be treated with a unified approach of combining chemotherapy with HER2 targeting, regardless of hormone receptor status. One of the main limitations of that analysis was that hormone receptor status was defined as either positive or negative based on the results of local laboratories. Therefore, the potential heterogeneity in clinical behavior according to the degree of hormone receptor expression could not be accounted for.

Gene expression profile studies indicate that HER2-positive/hormone receptor-positive and HER2-positive/hormone receptor-negative tumors fall into 2 distinct subtypes.18 These 2 subtypes carry a different prognosis in the absence of HER2 targeting.19 Furthermore, a relationship has been documented between increasing hormone receptor expression and reduced chemoresponsiveness.20, 21

On these premises, we set out to investigate clinical outcomes of trastuzumab plus chemotherapy in patients with HER2-positive advanced breast cancer according to the extent of hormone receptor positivity. The finding of a different clinical outcome related to level of hormone receptor expression might provide a rationale for further studies on the role of endocrine therapy in the treatment of this subset of HER2-positive tumors.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. CONFLICT OF INTEREST DISCLOSURES
  8. References

Patients

Patients were selected from a multi-institutional database containing the clinical data of women with HER2-positive breast cancer receiving trastuzumab-based therapy for metastatic disease and treated at 11 different Institutions in Italy, United Kingdom, and Hungary. For this analysis we considered only patients treated at the European Institute of Oncology in Milan, Italy, and at the Institute for Cancer Research and Treatment in Candiolo, Italy. For all consecutive patients who received at least 1 infusion of trastuzumab for the treatment of HER2-positive metastatic breast cancer, we collected clinical and pathological characteristics, prior treatments for breast cancer, and details of the first trastuzumab-based treatment (drugs and doses, date of progression, and date of death or of last follow-up visit).

HER2 and Hormone-Receptor Assessment

All patients had their specimens reviewed for HER2, ER, and PGR at either 1 of the 2 institutions participating in this study. Whenever possible, assessments were performed on the most recent tumor material, whether it be the primary tumor or a biopsy of metastatic disease. HER2 status was reassessed according to recently published guidelines.22 Positivity was defined as 3+ score by immunohistochemistry (IHC) in >30% of invasive tumor cells using the HercepTest (Dako, Glostrup, Denmark). Equivocal cases at IHC (2+ score or 3+ in ≤30% of invasive tumor cells) were submitted to fluorescence in situ hybridization (FISH) analysis. A ratio of HER2 gene signals to chromosome 17 signals of >2.2 was used as a cutoff to define HER2-gene amplification. The assessment of hormone receptor status was carried out by IHC using the monoclonal antibody (MoAb) to ER (Dako, at 1:100 dilution), and the MoAb to PGR (Dako, 1:800 dilution). Only nuclear reactivity was taken into account for ER and PGR. Positivity was defined as immunostaining in ≥1% of invasive tumor cells.

Statistical Methods

Tumor response was analyzed in patients with measurable disease and reported according to World Health Organization criteria.23 Response rate was defined as the proportion of patients achieving complete remission (CR) or partial remission (PR). For each patient, tumor response was usually planned to be performed every 2 to 3 months during the first year of treatment and every 6 months from the second year onward. For the scope of this analysis, each patient's imaging was reviewed.

PFS was calculated by the Kaplan-Meier method for all patients from the date of the first administration of trastuzumab to the date of tumor progression or death. Living patients were censored at the date of the last follow-up contact.

ER and PGR status was studied both as a dichotomous (positive vs negative) and as a continuous variable.

Comparisons between patients characteristics were studied by the chi-square or the Fisher exact test (dichotomous variables), and by the Mann-Whitney U test (continuous variables). Survival curves were compared by the log-rank test. Univariate and multivariate logistic regression and Cox-proportional hazards analysis models were studied to identify variables that were independently associated with clinical outcomes of interest. In a first step, we looked for predictors of overall response rate (ORR) and PFS other than receptor status. The list of potential predictors of ORR included: median age at the time of trastuzumab-based therapy, which was dichotomized around the median value of 53 years; disease-free interval from surgery of primary breast cancer to metastasis, which was dichotomized around its median value of 21 months; stage at first diagnosis of HER2-positive breast cancer (I/II vs III vs IV); receipt of prior neoadjuvant or adjuvant chemotherapy; prior exposure to anthracycline, taxanes, and endocrine therapy (any setting); liver involvement; visceral involvement (liver + lung + central nervous system); number of prior lines of chemotherapy for metastatic disease before trastuzumab-based therapy (0 or 1 vs >1); number of sites of metastatic disease (1 or 2 vs >2); and type of chemotherapy added to trastuzumab (taxane-based vs vinorelbine-based vs other regimens). The same list of variables plus response to trastuzumab-based therapy (CR + PR vs stable disease [SD] or progressive disease) and maintenance endocrine therapy was used to identify predictors of PFS. All the variables were entered into the model and then removed by backward stepwise selection. Only variables associated with the outcome of interest at a P value <.05, as determined by the Wald statistic, remained in the model. In a second step, the effect of each definition of hormone receptor positivity on ORR and PFS was individually corrected for the predictors that we identified in the first step. The proportionality of hazards assumption was checked by the log-minus-log survival plot method. All the analyses were conducted by the SPSS 17.0 statistical package (Chicago, Ill).

This study being a retrospective analysis of clinical outcomes, no specific written informed consent was required. However, the process of data collection was conducted in compliance with the ethical requirements of each of the participating institutions.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. CONFLICT OF INTEREST DISCLOSURES
  8. References

A total of 227 patients who had their HER2-status confirmed (HER2 3+ or HER2 amplification by FISH analysis) and received their first trastuzumab-based regimen between June 1999 and November 2008 were eligible for this analysis. Table 1 shows the clinical characteristics of these patients according to hormone receptor status. None of these patients had received trastuzumab in the neoadjuvant or adjuvant setting. Apart from exposure to endocrine therapy before trastuzumab, patients with hormone receptor-positive tumors had a statistically nonsignificant trend toward longer disease-free interval from the diagnosis of primary breast cancer, more frequent skeletal involvement, and less frequent lung metastases. At the time of this analysis, a total of 172 patients had progressed during the initial trastuzumab-based regimen, and 127 patients had died from breast cancer progression. Thirty-six patients in the hormone receptor-positive group received, upon discontinuation of chemotherapy and in the absence of disease progression, an endocrine compound together with trastuzumab (maintenance endocrine therapy). Ten of these patients had never received prior endocrine therapy, and the other 26 had been exposed to endocrine therapy before trastuzumab. Maintenance endocrine therapy consisted of an aromatase inhibitor in all 36 patients. Three of them, who were premenopausal before starting trastuzumab-based therapy, received concomitant pharmacological ovarian function suppression.

Table 1. Patient Characteristics According to HR Status
CharacteristicHR Negative, n = 116HR Positive, n = 111P
  • Abbreviations: CNS, central nervous system; DFS, disease-free interval; ER, estrogen receptor; HR, hormone receptor; IHC, immunohistochemistry; NA, not applicable; NS, nonsignificant at the .05 level; PGR, progesterone receptor.

  • a

    All patients with IHC 2+ positivity were fluorescence in situ hybridization-proven HER2 amplified.

  • b

    One had missing information on stage of disease at initial diagnosis of breast cancer.

  • c

    Either in the neoadjuvant or adjuvant setting and/or in the metastatic setting.

  • d

    From the initial diagnosis of breast cancer to the first occurrence of metastatic disease. For patients with stage IV disease at the onset of breast cancer, DFS was assumed to be equal to 0.

Median age, y [range]54 [30-80]51 [27-79]NS
HER2 status, No. (%)a   
 IHC 3+105 (90)99 (89)NS
 IHC 2+11 (10)12 (11) 
HR subclass, No. (%)   
 ER+ and PGR+78 (70)NA
 ER+ and PGR29 (26) 
 ER and PGR+ 4 (4) 
 ER and PGR116 (100)0 
Initial disease stage, No. (%)b   
 I/II54 (47)54 (49)NS
 III33 (28)33 (30) 
 IV29 (25)23 (21) 
Prior adjuvant/neoadjuvant chemotherapy, No. (%)72 (62)75 (68)NS
Prior exposure to anthracyclines, No. (%)c74 (64)66 (59)NS
Prior exposure to taxanes, No. (%)c24 (21)21 (19)NS
Prior endocrine therapy, No. (%)   
 None101 (87)34 (31) 
 Adjuvant only15 (13)55 (50)NA
 For metastatic disease only0 (0)5 (4) 
 Both adjuvant and for metastatic disease0 (0)17 (15) 
Median DFS in months [range]d17 [0-124]24 [0-146].076
Sites of metastatic disease, No. (%)   
 Liver45 (39)50 (45)NS
 Lung43 (37)27 (24).038
 Bone44 (38)63 (57).007
 Soft tissue/nodes80 (69)68 (61)NS
 Central nervous system5 (4)1 (1)NS
Visceral involvement, lung + liver + CNS, No. (%)75 (65)65 (59)NS
Number of metastatic sites, No. (%)   
 142 (36)42 (38)NS
 231 (27)31 (28) 
 ≥343 (37)38 (34) 
Number of prior chemotherapies for metastatic disease, No. (%)
 092 (79)96 (86)NS
 111 (10)7 (6) 
 ≥213 (11)8 (7) 
Type of chemotherapy with trastuzumab, No. (%)   
 Taxane based72 (62)55 (50)NS
 Vinorelbine based40 (34)49 (44) 
 Other regimens4 (3)7 (6) 
Received maintenance endocrine therapy, No. (%)0 (0)36 (32)<.001

The overall response rate to the first trastuzumab-based regimen, calculated in 212 patients with measurable disease, was 63% (95% confidence interval [CI], 56%-69%). In all patients, median PFS and median survival were 13 months (95% CI, 10-16 months) and 40 months (95% CI, 36-44 months), respectively. The status of ER and PGR, defined as positive versus negative at a cutoff of ≥1% stained cells, failed to show any significant impact on ORR and PFS neither when the 2 receptors were considered individually, nor when analyzed in any other possible combination (not shown). Considering only patients with hormone receptor-positive tumors, the median percentage of positive cells was 62% (range, 1%-100%) for ER and 20% (range, 1%-95%) for PGR. When considered as continuous variables, ER expression was significantly associated with reduced response rate (hazard ratio [HR], 0.990; 95% CI, 0.982-0.998; P = .018), and PGR expression was significantly associated with reduced risk of progression (HR, 0.991; 95% CI, 0.984-0.999; P = .026). Plots of odds ratio for response and hormone receptor for PFS by extent of ER and PGR immunoreactivity suggested a nonlinear relationship between these variables. To find a cutoff for ER and PGR positivity, we created multiple dichotomous variables using 10-percentage point intervals of immunohistochemical positivity (ie, <9% vs ≥10%, <19% vs ≥20%, etc). Each newly created variable was then studied by univariate logistic regression and Cox proportional regression analysis with tumor response and tumor progression, respectively, as dependent variables. A value of 30% for the ER was the lowest percentage of positivity that resulted in a statistically significant difference in response rate (Table 2). A difference of borderline statistical significance was observed for PGR at a cutoff of 50%, but 15 (88%) of 17 of these tumors had concomitant ER expression in ≥30% of tumor cells. We therefore decided to consider only ER expression for further analyses of response rate. Expression of ER (HR, 0.724; P = .050), PGR (HR, 0.607; P = .026), or both receptors (HR, 0.710; P = .033) in ≥30% of tumor cells was significantly associated with an improvement in PFS compared with lower or null expression (Figs. 1-3).

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Figure 1. Progression-free survival (PFS) according to estrogen receptor (ER) expression at a cutoff of 30% is shown. ER ≥30%, solid line; ER <30%, dashed line. Median PFS was 16 versus 11 months (log-rank test, P = .049) for ER ≥30% and ER <30%, respectively. (Hazard ratio, 0.724; 95% confidence interval, 0.524-1.000; P = .050.)

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thumbnail image

Figure 2. Progression-free survival (PFS) according to progesterone receptor (PGR) expression at a cutoff of 30% is shown. PGR ≥30%, solid line; PGR <30%, dashed line. Median progression-free survival was 21 versus 12 months (log-rank test, P = .024) for PGR ≥30% and PgR <30%, respectively. (Hazard ratio, 0.607; 95% CI, 0.390-0.942; P = .026.)

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thumbnail image

Figure 3. Progression-free survival (PFS) according to combined estrogen receptor (ER) and progesterone receptor (PGR) expression at a cutoff of 30% is shown. Either or both ER and PGR ≥30%, solid line; both ER and PGR <30%, dashed line. Median PFS was 16 versus 11 months (log-rank test, P = .032) hormone receptor positive and negative, respectively. (HR 0.710; 95% CI, 0.518-0.973; P = .033.)

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Table 2. Effect of ER (Cutoff 30%) and PGR (Cutoff 50%) Expression on Tumor Response
Receptor PositivityaNo. (%)CR + PR, No. (%)SD + PD, No. (%)Pb
  • Abbreviations: ER, estrogen receptor; PD, progressive disease; PGR, progesterone receptor; PR, partial remission; SD, stable disease.

  • Analysis was conducted in a total of 212 patients who could be evaluated for tumor response.

  • a

    Each single receptor.

  • b

    Two-tailed chi-square test.

ER    
 0%-29%140 (66)95 (68)45 (32).032
 30%-100%72 (34)38 (53)34 (47) 
PGR    
 0%-49%195 (92)126 (65)69 (35).055
 50%-100%17 (8)7 (41)10 (59) 

Multivariate Analysis

Liver involvement, number of prior chemotherapies for metastatic disease before trastuzumab, and type of chemotherapy associated with trastuzumab were independent predictors of ORR on multivariate analysis (Table 3). The effect of each definition of hormone receptor positivity on ORR was then individually corrected by these predictors (Table 4). Expression of the ER in ≥30% of tumor cells was significantly associated with reduced probability of response to chemotherapy and trastuzumab.

Table 3. Predictors of Tumor Response (Multivariate Analysis)
VariableOR95% CIP
  1. Abbreviations: CI, confidence interval; OR, odds ratio.

Liver metastases2.0951.122-3.912.020
Type of chemotherapy   
 Taxane based1  
 Vinorelbine based0.4920.268-0.906.023
 Other regimens0.0510.006-0.449.007
Prior chemotherapy for metastatic disease
 0 or 1 prior regimen1  
 2 or more prior regimens0.2260.079-0.647.006
Table 4. Effect of Each Definition of Hormone Receptor Status on Overall Response Rate Individually Corrected for Other Significant Predictors
VariableNo. (%)OR95% CIP
  1. Abbreviations: OR, odds ratio; ER, estrogen receptor; PGR, progesterone receptor.

  2. Each OR has been generated by correcting each definition of hormone receptor positivity by liver involvement, number of prior treatments for metastatic disease, and type of chemotherapy associated with trastuzumab.

ER ≥1%98 (46)0.7970.433-1.467.466
PGR ≥ 1%75 (35)0.9930.980-1.005.260
ER and/or PGR ≥1%103 (49)0.8330.453-1.534.558
ER ≥30%72 (34)0.4220.222-0.803.009

For PFS, we proceeded in the same way. In a first step, we found that disease-free interval, prior exposure to taxanes, visceral involvement, number of sites of metastatic disease, response to trastuzumab-based therapy, and maintenance endocrine therapy were independently associated with PFS (Table 5). The effect of each definition of hormone receptor positivity on PFS was then individually corrected by these predictors (second step, Table 6). Although trends toward reduced risk of progression were seen for ER, PGR, or their combined expression at a cutoff of 30% of positive cells, no statistically significant effect was seen. We hypothesized that maintenance endocrine therapy could have acted as a confounding factor in this analysis. Therefore, we created 2 new variables combining the use of maintenance endocrine therapy and hormone receptor expression at both the 1% and the 30% cutoff. Hormone receptor positivity and high hormone receptor expression were defined as ER and/or PGR positivity in ≥1% and ≥30% of invasive tumor cells, respectively. Hormone receptor negativity and low or low/absent hormone receptor expression were defined as both ER and PGR positivity in <1% and <30% of invasive tumor cells, respectively. Results of the multivariate analysis including these newly created variables are shown in Table 7. In the absence of maintenance endocrine therapy, no difference in PFS was seen between patients with hormone receptor-positive and hormone receptor-negative tumors. Conversely, the administration of maintenance endocrine therapy to women with hormone receptor-positive tumors was associated with a proportional reduction in the risk of progression of about 48% compared with the reference group (HR, 0.521; P = .007). A similar effect of maintenance endocrine therapy on PFS was observed in women whose tumors showed high hormone receptor expression, whose risk of disease progression was halved (HR, 0.502; P = .004). Interestingly, high HR expression was associated with a nonsignificant trend toward reduced risk of progression also in patients not receiving maintenance endocrine therapy (HR, 0.747; P = .122). All patients receiving maintenance endocrine therapy had achieved at least disease stabilization during trastuzumab-based therapy. To account for this potential bias, we performed a sensitivity analysis including only patients with SD or an objective response, but results did not change (not shown).

Table 5. Predictors of Progression-Free Survival (Multivariate Analysis)
VariableHR95% CIP
  1. Abbreviations: CI, confidence interval; CR, complete remission; HR, hazard ratio; PR, partial remission.

Disease free interval <21 months1.6111.186-2.187.002
Prior exposure to a taxane1.4581.017-2.091.040
Visceral metastases1.8801.315-2.687.001
Three or more of sites of metastatic disease1.7951.287-2.504.001
CR or PR to trastuzumab-based therapy0.4590.335-0.631<.001
Maintenance endocrine therapy0.5220.328-0.830.006
Table 6. Effect of Each Definition of Hormone Receptor Status on Progression-Free Survival Individually Corrected for Other Significant Predictors
VariableNo. (%)HR95% CIP
  1. Abbreviations: CI, confidence interval; ER, estrogen receptor; HR, hazard ratio; PGR, progesterone receptor.

  2. Each HR has been generated by correcting each definition of hormone receptor positivity by prior exposure to taxanes, visceral involvement, number of sites of metastatic disease, response to trastuzumab-based therapy, and receipt of maintenance endocrine therapy.

ER ≥1%106 (47)0.8900.634-1.251.503
PGR ≥1%82 (36)0.8650.612-1.223.413
ER and/or PGR ≥1%111 (49)0.9140.654-1.279.601
ER ≥30%78 (34)0.7750.543-1.107.161
PGR ≥30%37 (16)0.7560.469-1.219.251
ER≥30% and/or PGR≥30%86 (38)0.7720.537-1.110.162
Table 7. Association of Maintenance Endocrine Therapy and PFS (Multivariate Analysis)
Maintenance HT According to Receptor PositivityaNo. (%)HR95% CIP
  • Abbreviations: CI, confidence interval; ER, estrogen receptor; HR, hazard ratio; HT, hormonotherapy; PGR, progesterone receptor.

  • HRs of the effects of hormone receptor positivity and maintenance endocrine therapy on progression-free survival corrected by prior exposure to taxanes, visceral involvement, number of sites of metastatic disease, and response to trastuzumab-based therapy.

  • a

    Hormone receptor positivity is defined as ER and/or PGR ≥1%, whereas hormone receptor negativity is defined as both ER and PGR <1%.

  • 2Extent of hormone receptor positivity is defined as high (ER ≥30% and/or PGR ≥30%) or low/absent (ER <30% and PGR <30%).

  • 3Only 2 patients in this group received maintenance endocrine therapy.

Receptor negative116 (51)1  
Receptor positive no maintenance75 (33)0.9140.654-1.279.601
Receptor positive + maintenance36 (16)0.5210.325-0.836.007
Maintenance HT according to extent of hormone receptor positivityb    
Low or absent expression (±maintenance)c139 (61)1  
High expression, no maintenance54 (24)0.7470.516-1.081.122
High expression with maintenance34 (15)0.5020.313-0.807.004

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. CONFLICT OF INTEREST DISCLOSURES
  8. References

In this retrospective analysis, we found significant associations between hormone receptor status and clinical outcomes in patients with HER2-positive advanced breast cancer receiving trastuzumab with chemotherapy. The probability of achieving an objective tumor response was more than halved in patients whose tumors showed high expression of ER (≥30% of the cells). We also found that adding maintenance endocrine therapy to trastuzumab upon the completion of chemotherapy yielded a significant PFS benefit in patients with ≥1% of cells staining positively for ER and/or PGR. Finally, we observed a nonsignificant trend toward an improvement in PFS in patients whose tumors expressed high levels of ER and/or PGR in the absence of maintenance endocrine therapy.

The independent value of different definitions of hormone receptor positivity was corrected for a list of significant predictors of ORR and PFS that were obtained by multivariate analysis. Most of these clinical variables—for example, prior exposure to chemotherapy for metastatic disease, short disease-free interval from surgery, high tumor burden, or visceral involvement—are known to be associated with clinical outcome in metastatic breast cancer patients. In addition, we found that patients receiving trastuzumab combined with chemotherapeutic agents other than taxanes had a reduced likelihood of response. In particular, those receiving trastuzumab and vinorelbine, which is a popular trastuzumab-based regimen, had their probability of response halved with respect to those receiving trastuzumab with a taxane. In the light of the recent results of a prospective randomized trial showing equivalence between docetaxel or vinorelbine combined with trastuzumab in the first-line setting,24 our finding is likely the result of a bias caused by the retrospective nature of our analysis. For this reason, it should be considered only an explanatory variable in our dataset. Similarly, we believe that our finding that prior exposure to taxanes before receiving trastuzumab-based therapy had a negative impact on PFS should be considered with caution. In an effort to explain this association, we conducted exploratory analyses on the characteristics of this group of 45 patients. Compared with taxane-naive patients, those who had received a taxane before their first trastuzumab-based regimen had been exposed more frequently to neoadjuvant or adjuvant chemotherapy (89% vs 59%; P < .001) and to anthracyclines (100% vs 52%; P < .001). Furthermore, they had more frequently received trastuzumab-based therapy as second or further line of treatment for metastatic disease (31% vs 13%; P = .010) and had more frequently received trastuzumab with chemotherapy other than taxanes (62% vs 40%; P = .002). All together, these features suggest that prior exposure to taxanes might not be directly associated with worse PFS. It rather identifies in this dataset a population of patients with a sum of factors that can negatively affect PFS. However, a negative association of prior exposure to taxanes with PFS in patients receiving trastuzumab-based therapy for metastatic disease is worthy of further investigation. At the present time, a substantial proportion of HER2-positive patients recurring after adjuvant chemotherapy are likely to have been exposed to this class of drugs.

Before discussing the plausibility of our findings, we shall highlight some limitations of our study. First, it was a retrospective study of patients treated over a relatively long period of time with different trastuzumab-based regimens. Second, maintenance endocrine therapy was administered to 32% of patients with positive hormone receptor status at the discretion of the treating physician. From the medical charts and patient characteristics, we could only ascertain that it was administered in patients achieving disease stabilization or objective response after a certain number of cycles of chemotherapy. A sensitivity analysis considering only patients achieving disease stabilization or objective response to trastuzumab plus chemotherapy confirmed the findings obtained in the entire dataset. However, we could not exclude that other factors that influenced the prescription of endocrine therapy could also be correlated with better outcome. In an effort to minimize the limitations of the retrospective design, we selected from a large database only patients who were treated at 2 institutions with longstanding experience in the treatment of breast cancer. Furthermore, tumor response evaluations were carried out at the diagnostic unit of the 2 participating institutions, and imaging was reviewed for the scope of this analysis.

To our knowledge, only 1 study has evaluated the antitumor activity of trastuzumab with chemotherapy in HER2-positive advanced breast according to hormone receptor expression.17 Brufsky et al retrospectively analyzed patients enrolled in clinical trials of trastuzumab alone or with chemotherapy including the Pivotal trial.15 The authors found that patients with hormone receptor-positive and hormone receptor-negative tumors achieved similar benefits from trastuzumab with chemotherapy, compared with chemotherapy alone. Furthermore, in patients receiving chemotherapy and trastuzumab, response rate and time to progression did not differ according to hormone receptor status. It must be noted, however, that the hormone receptor status was defined as either positive or negative by local laboratories, and the extent of hormone receptor positivity was not analyzed. By using the same criteria, considering that thresholds for hormone receptor positivity have changed over the years from 1% to 10%, our findings confirm Brufsky's observation in part. Below the threshold of 30% of immunopositive cells, we could not find a significant difference in clinical outcomes according to hormone receptor status. On the contrary, when the extent of hormone receptor positivity and the effect of the addition of maintenance endocrine therapy were accounted for, we found significant associations between hormone receptor status and clinical outcomes. Despite the limitations because of the retrospective design, our observation strongly suggests that hormone receptor coexpression identifies 2 subgroups within the HER2-positive subset that differ not only in prognosis,25 but also in response to current anti-HER2 therapeutic strategies. Estrogen receptor expression has been found to be an independent predictor of reduced response to chemotherapy20, 26; other factors can explain reduced responsiveness to anti-HER2 therapy in hormone receptor-coexpressing tumor cells. An inverse relationship between HER2 and hormone receptor expression has been previously described by Konecny et al.7 Current methods to evaluate patients' eligibility for anti-HER2 therapy are not sensitive to variations in the amount of HER2 protein that may affect response to HER2 inhibition. Indeed, studies using total HER2 and HER2 homodimer quantification could identify, within what is commonly defined as HER2-positive status, a direct relationship between protein levels and responsiveness to anti-HER2 therapy.27, 28 In addition, interplay between HER2 and ER may provide a way to escape HER2 inhibition.29 This interplay, which is bidirectional because HER positivity confers resistance to endocrine therapy in tumors that coexpress hormone receptor,8 suggests that simultaneous HER2 and hormone receptor targeting may be required for optimal disease control in this subset of patients. Recently, 2 studies evaluated the combination of an aromatase inhibitor with anti-HER2 therapy consisting of trastuzumab or lapatinib.30, 31 In both studies, combined treatment improved response rate and PFS, compared with endocrine therapy alone. These 2 studies provide an important proof of principle, and in our opinion, a platform for future development in patients with HER2-positive/hormone receptor-positive tumors.

In summary, we observed that HER2-positive tumors also expressing high levels of hormone receptor may be less responsive to the addition chemotherapy plus trastuzumab, a finding that is consistent with 2 recently presented international randomized neoadjuvant trials. The PFS prolongation seen in patients adding endocrine therapy to trastuzumab upon the completion of chemotherapy suggests that these tumors retain endocrine responsiveness. If confirmed in independent datasets, this predictive role of hormone receptor expression would have therapeutic implications. Further research is warranted to optimize the use of HER2-targeting agents, chemotherapy, and endocrine therapy in patients whose tumors coexpress both HER2 and hormone receptor.

FUNDING SOURCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. CONFLICT OF INTEREST DISCLOSURES
  8. References

Partially supported by Ricerca Sanitaria Finalizzata 2009, Piedmont Region.

CONFLICT OF INTEREST DISCLOSURES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. CONFLICT OF INTEREST DISCLOSURES
  8. References

Filippo Montemurro has received speakers honoraria from GlaxoSmithKline S.P.A. The other authors of this paper do not have any potential conflicts of interest to disclose.

References

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. FUNDING SOURCES
  7. CONFLICT OF INTEREST DISCLOSURES
  8. References
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