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Hormone Receptor Status Does Not Affect the Clinical Benefit of Trastuzumab Therapy for Patients with Metastatic Breast Cancer
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Hormone Receptor Status Does Not Affect the Clinical Benefit of Trastuzumab Therapy for Patients with Metastatic Breast Cancer Adam Brufsky,1 Barry Lembersky,1 Kathy Schiffman,2 Grazyna Lieberman,2 Virginia E. Paton2 Abstract Background: Hormone receptor (HR) and HER2 signaling pathways are involved in the regulation of breast cancer proliferation. The impact of HR status on the clinical outcome of patients with HER2-overexpressing disease treated with the monoclonal antibody trastuzumab is unknown. Patients and Methods: To evaluate this, we conducted a retrospective analysis of 805 patients with metastatic breast cancer enrolled in 3 clinical trials comparing trastuzumab in combination with chemotherapy versus chemotherapy alone or trastuzumab monotherapy as first-, second-, or third-line treatment. Patients whose tumor samples overexpressed HER2 by fluorescence in situ hybridization (FISH) were stratified based on HR status, and clinical outcomes were compared. Results: Tumor samples from 596 of 805 patients were HER2overexpressing by FISH; 45% of these were HR-positive and 43% were HR-negative (HR status was unknown in 12%). Overall response rate (ORR) and time to progression (TTP) were significantly higher in patients treated with chemotherapy plus trastuzumab than in those treated with chemotherapy alone, irrespective of HR status. Median survival was longer for patients with HR-positive tumors receiving combination therapy compared with those with HR-negative tumors. In the trastuzumab monotherapy trials, ORR and TTP were similar for patients with HR-positive and HR-negative tumors. Median survival was longer for patients with HR-positive tumors compared with those with HR-negative tumors. Conclusion: Hormone receptor status did not affect the clinical benefit of trastuzumab given as a single agent or combined with chemotherapy. The addition of trastuzumab to chemotherapy provides an improved clinical benefit compared with chemotherapy alone, regardless of HR status. Clinical Breast Cancer, Vol. 6, No. 3, 247-252, 2005 Key words: Chemotherapy, Estrogen receptor, HER2, Progesterone receptor
Introduction The estrogen receptor (ER) regulates the expression of genes controlling the development and proliferation of breast tumors.1 Estrogen receptor status has proved clinically useful as a favorable prognostic factor2 and as a predictive factor for selecting patients for antiendocrine therapy in the adjuvant3 and metastatic settings.4 Therapeutic strategies for patients whose tumors express ER include 1Pittsburgh Cancer Institute, Pittsburgh, PA 2Genentech, Inc., South San Francisco, CA
Submitted: Jan 11, 2005; Revised: Mar 2, 2005; Accepted: Mar 3, 2005 Address for correspondence: Virginia E. Paton, PharmD, Genentech Inc, 1 DNA Way, South San Francisco, CA 94080-4990 Fax: 650-225-4538; e-mail: [email protected]
selective ER modification (eg, tamoxifen), aromatase inhibition (eg, anastrozole, letrozole, and exemestane), and administration of “pure” antiestrogens (eg, fulvestrant). Until recently, tamoxifen has been considered the gold standard of therapy for patients with ER-positive breast cancer. Large randomized clinical trials demonstrated improved disease-free survival (DFS) and overall survival (OS) in patients who received tamoxifen for 5 years as adjuvant therapy.5 The efficacy of aromatase inhibitors has also been demonstrated in the adjuvant setting, with improved DFS and longer median time to recurrence compared with tamoxifen.6 Recently, data have been generated to support biologic pathway crosstalk between the HER2 pathway and the ER pathway. The HER2 (c-erbB-2, neu) gene, first identified in
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Clinical Breast Cancer August 2005 • 247
Clinical Benefit with Trastuzumab Regardless of HR Status Table 1 Summary of Clinical Trials Included in the Analysis41-43 Trial
Slamon et al, H0648g41
Cobleigh et al, H0649g42
Vogel et al, H0650g43
Phase
N
Patient Population
Trial Design
III
First-line, standard-dose chemotherapy alone Newly diagnosed, HER2-overexpressing (Doxorubicin/Epirubicin plus Cyclophosphamide 469 MBC previously or Paclitaxel) vs. untreated with chemotherapy plus chemotherapy standard-dose Trastuzumab
II
HER2-overexpressing MBC previously 222 treated with chemotherapy
Second- or third-line monotherapy with standard-dose Trastuzumab
II
HER2-overexpressing MBC previously 114 untreated with chemotherapy
First-line monotherapy with standard or high-dose Trastuzumab
1981,7 is overexpressed in approximately 25% of breast cancer tumors.8 HER2 overexpression is an adverse prognostic factor in patients with breast cancer and is associated with reduced time to relapse and poor survival compared with patients who have normal HER2 levels.9,10 Additionally, HER2 overexpression is an important predictive factor used to select patients for treatment with the anti-HER2 monoclonal antibody trastuzumab.11,12 In ER-positive/HER2-overexpressing breast tumors, tamoxifen can act as an agonist, leading to increased proliferation through hormone-independent pathways.13-16 In this scenario, overexpression of HER2 can promote the estrogenic action of tamoxifen through the phosphorylation of coactivators, such as AIB1 (SRC-3) and ER, which can lead to tamoxifen resistance. Osborne et al assessed AIB1 and HER2 levels in 316 breast tumor samples and found that patients whose tumors expressed high levels of AIB1 and HER2 had significantly poorer outcomes with tamoxifen therapy compared with all other patients combined (P = 0.002; log-rank test).17 Responsiveness to tamoxifen is linked to the absolute levels of hormone receptors (HRs) in tumors, which appear to be reduced in patients with HER2 gene overexpression,18 although some earlier studies have failed to find an association.10,19 In vitro studies have shown transfection of various breast cancer cell lines (MCF-7, ZR-75-1, and T-47D) with additional copies of the HER2 gene increased HER2 protein expression and decreased levels of ER and progesterone receptors (PgRs).18,20,21 Furthermore, Konecny et al demonstrated a significant inverse correlation between HER2 overexpression and HR levels in a quantitative analysis of tumor samples from 1559 patients with breast cancer.18 In a cohort of patients with HR-positive tumors, the median ER tumor levels were 44 fmol/mg protein (interquartile range, 13-156 fmol/mg) when HER2 was overexpressed (> 2 gene copies per chromosome 17 centromere detected by fluorescence in situ
248 • Clinical Breast Cancer August 2005
hybridization [FISH]) compared with 92 fmol/mg protein (interquartile range, 35-235 fmol/mg) when HER2 was not overexpressed (P < 0.001). By analyzing HER2 and HR levels as continuous rather than dichotomous variables, the authors were able to show that, as HER2 overexpression increases, the levels of HR decrease correspondingly. The use of dichotomous classifications for HER2 and ER, low cutoff scores to classify a tumor as HER2-overexpressing by immunohistochemistry (IHC), failure to exclude ER-negative tumors,22 and failure to consider ER coactivators17 have all been suggested as explanations for discrepancies among retrospective clinical studies of the influence of HER2 status on response to tamoxifen and other antiendocrine agents in patients with operable or metastatic breast cancer (MBC). Numerous studies have shown that HER2 overexpression predicts decreased benefit from antiendocrine therapy,15,23-35 whereas other studies found no significant difference or a poorer outcome for HER2-overexpressing compared with HER2-negative tumors.22,36,37 On the basis of current evidence, treatment guidelines state that HER2 overexpression does not preclude antiendocrine therapy.12 It is now well established that HER2 gene overexpression strongly predicts response to trastuzumab in patients with MBC.38 Despite the inverse correlation between HER2 and ER levels, approximately half of tumors that demonstrate HER2 overexpression (and are therefore eligible for trastuzumab therapy) will also be ER-positive.18 Although interactions between ER and HER2 have been characterized at the molecular and in vitro levels,39,40 it is not known whether HR status has an effect on clinical response to trastuzumab therapy. This retrospective analysis was performed to evaluate the treatment outcome of patients with HR-positive or HRnegative MBC and concomitant HER2 overexpression who were receiving trastuzumab as a single agent or in combination with chemotherapy.
Patients and Methods Study Design This study describes a retrospective analysis of clinical outcome according to HR status in patients with MBC whose tumors were HER2-overexpressing by FISH and who received trastuzumab in 1 of 3 clinical trials described in Table 1.41-43 Patients were eligible to participate in the trials if they had MBC that was HER2-overexpressing by IHC with a score of 2+ or 3+ using a clinical trial–specific assay (CTA). A subsequent analysis of 784 archived breast cancer specimens from the clinical trial participants was performed to determine HER2 gene overexpression by FISH analysis using the Vysis PathVysionTM HER2 assay.38 Tumors were considered positive for HER2 gene overexpression if the HER2-to-CEP17 ratio was ≥ 2. Only patients with gene overexpression as determined by FISH were included in this analysis. The CTA and FISH analyses on previously unstained specimens were performed at a central laboratory.
Adam Brufsky et al Table 2 Baseline Characteristics of 805 Patients Enrolled in the 3 Trials According to Hormone Receptor Expression and Treatment41-43 Slamon et al, H0648g41
Characteristic
Trastuzumab plus Chemotherapy (n = 235)
Vogel et al, H0650g43
Chemotherapy Alone (n = 234)
Cobleigh et al, H0649g42
First-Line Trastuzumab Second- or Third-Line Trastuzumab Monotherapy Monotherapy (N = 222) (N = 114)
HRPositive (%)
HRNegative (%)
HRPositive (%)
HRNegative (%)
HRPositive (%)
HRNegative (%)
HRPositive (%)
HRNegative (%)
Karnofsky Performance Status ≤ 80
31
27
34
34
29
24
25
30
≥ 4 Positive Lymph Nodes
39
46
42
50
40
70
49
52
≥ 3 Metastatic Sites
41
29
31
30
33
29
42
30
Previous Adjuvant Chemotherapy
70
82
60
74
63
75
66
79
Previous Adjuvant or Metastatic Hormonal Therapy
71
38
71
33
49
21
74
31
Fluorescence in situ hybridization using previously immunostained tissue sections was performed at the University of Southern California, as previously described.44 Estrogen receptor and PgR status were determined at local laboratories using standard methods. Progesterone receptor–positive tumors and ER-positive tumors respond to hormone therapy in a manner similar, so data from both were pooled and are referred to as HR-positive.45 Clinical outcomes for each trial have been previously described.41-43 In this analysis, overall response rates (ORRs) by intent-to-treat analyses were calculated for FISH-positive/HR-positive and FISH-positive/HR-negative cohorts. Time to progression (TTP) and OS were estimated by Kaplan-Meier analyses.46
Results
spectively, in patients whose tumors were HER2-overexpressing by FISH. In the phase III trial (H0648g),41 the ORR and TTP were similar in the chemotherapy plus trastuzumab arm for patients with HR-positive and HR-negative tumors (ORR, 58% [95% confidence interval {CI}, 46%-69%] vs. 51% [95% CI, 40%-63%]; TTP, 7.6 months [95% CI, 6.99.9 months] vs. 7.3 months [95% CI, 7-10.2 months], respectively). Overall response rates and TTP were increased for patients in the chemotherapy plus trastuzumab arm compared with patients treated with chemotherapy alone for HR-positive and HR-negative tumors. Median OS was longer for patients with HR-positive tumors receiving trastuzumab and chemotherapy (median, 29.4 months; 95% CI, 19.1 months to not reached [NR]) compared with patients with HR-negative tumors (median, 24.1 months; 95% CI, 19.8-31.4 months). Overall, median OS was greater in the combination therapy cohort (29.4 months and 24.1 months) than in the chemotherapy-alone cohort (20.6 months [95% CI, 15.4-30 months] and 21 months [95% CI, 13.2-26.2 months]) for patients with HR-positive and HRnegative tumors, respectively (Figure 3). Previous treatment with hormonal therapy in the adjuvant setting did not impact the efficacy outcome in this study. Hormone receptor status did not influence the response of HER2-overexpressing MBC to first-line single-agent trastuzumab (ORR 33% [95% CI, 20%-50%] vs. 34% [95% CI,
The baseline characteristics for the 805 patients are described in Table 2.41-43 Demographics are similar for the HR-positive and HR-negative cohorts for each trial with the exception of previous treatment with hormonal therapy among patients with HR-positive disease. HER2 overexpression was determined in 765 samples, and 596 specimens (78%) were HER2-overexpressing by FISH. A total of 269 of 596 patients (45%) had HER2-overexpressing/HR-positive tumors, and 255 of 596 patients (43%) had HER2-overexpressing/HR-negative tumors. The HR status of 72 patients (12%) was unknown. Of the 169 patients with HER2-negTable 3 Hormone Receptor Expression and HER2 Status: Combined Results from All Trials41-43* ative tumors by FISH, 100 HR Status HER2 Status (59%) had HER2-negative/ HR-Positive (%) HR-Negative (%) Unknown (%) Total (%) by FISH HR-positive tumors, and 39 Positive 269 (45) 255 (43) 72 (12) 596 (78) (23%) had HER2/HR–negative tumors (Table 3).41-43 Negative 100 (59) 30 (18) 169 (22) 39 (23) Figures 1-3 show the ORR, Total 369 (48) 294 (38) 102 (13) 765 median TTP, and median *HER2 status by FISH was unknown for 40 patients. survival from each study, re-
Clinical Breast Cancer August 2005 • 249
Clinical Benefit with Trastuzumab Regardless of HR Status Figure 1 ORR in Accordance with HR Status and Treatment41-43
Overall Response Rate (%)
70 60
HR-Positive HR-Negative
58 51
50 40
30
30
32
33
34 21
20
18
10 0
Trastuzumab/ Chemotherapy
Chemotherapy Alone
H0648g41
First-Line Trastuzumab
Second/ThirdLine Trastuzumab
H0650g43
H0649g42
months [95% CI, 16.9 to NR] vs. 20.5 months [95% CI, 12.4 to NR], respectively) were slightly longer for patients with HR-positive tumors compared with those with HR-negative tumors in this study, although statistical significance was not achieved (Figures 2 and 3). Patients treated with trastuzumab as second- or third-line monotherapy (trial H0649g)42 had similar clinical outcome regardless of tumor HR status. The ORRs were 21% (95% CI, 13%-31%) and 18% (95% CI, 10%-29%), respectively, for patients with HR-positive versus HR-negative tumors (Figure 1), and TTP was 3.4 months (95% CI, 2.6-3.8 months) versus 3.3 months (95% CI, 2-3.9 months; Figure 2), respectively. The median survival for patients with HR-positive tumors was slightly longer than for patients with HR-negative tumors (15.2 months [95% CI, 12.3-21.6 months] vs. 12.6 months [95% CI, 9.2-16.3 months], respectively; Figure 3).
Discussion Figure 2 Median TTP in Accordance with HR Status and Treatment41-43 8
7.5
7.3
HR-Positive HR-Negative
Median TTP (Months)
7 6
5.2
5
4.6 4.5 3.7
4
3.4 3.3
3 2 1 0
Trastuzumab/ Chemotherapy
Chemotherapy Alone
H0648g41
First-Line Trastuzumab
Second/ThirdLine Trastuzumab
H0650g43
H0649g42
Figure 3 Median Survival in Accordance with HR Status and Treatment41-43 35
Median Survival (Months)
30 25
HR-Positive HR-Negative
29.4 24.5
24.1 20.6
20
21
20.5 15.2
15
12.6
10 5 0
Trastuzumab/ Chemotherapy
Chemotherapy Alone
H0648g41
First-Line Trastuzumab
Second/ThirdLine Trastuzumab
H0650g43
H0649g42
20.5%-50%] for HR-positive and HR-negative tumors, respectively; trial H0650g; Figure 1).43 The median TTP (5.2 months [95% CI, 3.4-12.4 months] vs. 3.7 months [95% CI, 2.0-7.1 months], respectively) and median survival (24.5
250 • Clinical Breast Cancer August 2005
This retrospective study analyzed the clinical outcome of 596 patients with HER2-overexpressing MBC stratified by HR status and treated with trastuzumab as a single agent or in combination with chemotherapy. This analysis suggests that the treatment of HER2-overexpressing MBC with trastuzumab was associated with increased ORR, TTP, and OS, and patient benefit was not influenced by HR status. Additionally, this analysis confirms the observation that HER2-overexpressing tumors have an equal likelihood of being HR-positive or negative (45% vs. 43%, respectively). Klein et al described 47% and 53% prevalence rates of ERpositive and ER-negative tumors, respectively, in women with HER2-overexpressing disease.47 Similarly, Konecny et al found that 53% of patients with primary breast cancer whose tumors overexpressed HER2 on FISH also had ERpositive tumors.18 On average, 25% of all breast cancers overexpress HER2.8 In this study of patients with HER2-overexpressing tumors, 45% of the tumors were HR-positive and 43% were HR-negative. Extrapolation of these data to the breast cancer population suggests that approximately 11% of breast tumors are HER2-overexpressing/HR-positive, and approximately 11% are HER2-overexpressing/HR-negative. Because of these data, we believe HR status should not preclude testing for HER2 status. Sixty percent of the HER2-negative tumors studied were HR-positive and 23% were HR-negative; therefore, we estimate that approximately 45% of all breast tumors are HER2-negative/HR-positive and approximately 17% are HER2/HR–negative. These data confirm previous observations that HER2-overexpressing tumors are less likely than HER2-negative tumors to be HR-positive.18 Hormonal status for these patients was determined using standard of care methods at the institutions where patients were being treated. These results were not reviewed at a central laboratory for confirmation of HR positivity. Similar to testing for HER2 status, testing for HR status with IHC is associated with some technical issues that may influence the results.48 These testing issues may affect the clinical outcome results presented in this analysis.
Adam Brufsky et al In contrast to the negative predictive effect HER2 status may have on antiendocrine therapy, we found that patients with HER2-overexpressing/HR-positive or HER2-overexpressing/HR-negative tumors derive similar clinical benefit from treatment with trastuzumab (Figures 1-3). Our results suggest that previous antiendocrine therapy for metastatic disease does not appear to influence the overall response to trastuzumab. Outcome was improved with the addition of trastuzumab to chemotherapy as previously described.41 A prospective analysis by Klein et al reported similar findings. The ORRs following trastuzumab and taxane therapy were 56% for HER2-overexpressing/ER-positive tumors and 55% for HER2-overexpressing/ER-negative tumors.47 In this study, median OS of patients with HR-negative tumors was lower than that of patients with HR-positive tumors. Although we did not find evidence that HR status was a predictive factor for benefit from trastuzumab, it does appear that HR status may retain its role as an independent prognostic factor in patients with HER2-overexpressing breast tumors, which is similar to previous reports in earlystage and metastatic disease populations.49-52
Conclusion The HER2-overexpressing tumors identified by FISH have an approximately equal likelihood of being HR-positive or HR-negative, and therefore HR status should not preclude testing for HER2 gene overexpression. Patients with HER2-overexpressing tumors treated with trastuzumab alone or in combination with chemotherapy have similar clinical outcome regardless of HR status, indicating that HR status does not predict clinical benefit obtained from treatment with trastuzumab.
Acknowledgement
11.
12. 13. 14. 15. 16.
17. 18. 19.
20. 21. 22. 23. 24.
25.
This study was supported by Genentech, Inc. 26.
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252 • Clinical Breast Cancer August 2005
contribution
Hormone Receptor Status Does Not Affect the Clinical Benefit of Trastuzumab Therapy for Patients with Metastatic Breast Cancer Adam Brufsky,1 Barry Lembersky,1 Kathy Schiffman,2 Grazyna Lieberman,2 Virginia E. Paton2 Abstract Background: Hormone receptor (HR) and HER2 signaling pathways are involved in the regulation of breast cancer proliferation. The impact of HR status on the clinical outcome of patients with HER2-overexpressing disease treated with the monoclonal antibody trastuzumab is unknown. Patients and Methods: To evaluate this, we conducted a retrospective analysis of 805 patients with metastatic breast cancer enrolled in 3 clinical trials comparing trastuzumab in combination with chemotherapy versus chemotherapy alone or trastuzumab monotherapy as first-, second-, or third-line treatment. Patients whose tumor samples overexpressed HER2 by fluorescence in situ hybridization (FISH) were stratified based on HR status, and clinical outcomes were compared. Results: Tumor samples from 596 of 805 patients were HER2overexpressing by FISH; 45% of these were HR-positive and 43% were HR-negative (HR status was unknown in 12%). Overall response rate (ORR) and time to progression (TTP) were significantly higher in patients treated with chemotherapy plus trastuzumab than in those treated with chemotherapy alone, irrespective of HR status. Median survival was longer for patients with HR-positive tumors receiving combination therapy compared with those with HR-negative tumors. In the trastuzumab monotherapy trials, ORR and TTP were similar for patients with HR-positive and HR-negative tumors. Median survival was longer for patients with HR-positive tumors compared with those with HR-negative tumors. Conclusion: Hormone receptor status did not affect the clinical benefit of trastuzumab given as a single agent or combined with chemotherapy. The addition of trastuzumab to chemotherapy provides an improved clinical benefit compared with chemotherapy alone, regardless of HR status. Clinical Breast Cancer, Vol. 6, No. 3, 247-252, 2005 Key words: Chemotherapy, Estrogen receptor, HER2, Progesterone receptor
Introduction The estrogen receptor (ER) regulates the expression of genes controlling the development and proliferation of breast tumors.1 Estrogen receptor status has proved clinically useful as a favorable prognostic factor2 and as a predictive factor for selecting patients for antiendocrine therapy in the adjuvant3 and metastatic settings.4 Therapeutic strategies for patients whose tumors express ER include 1Pittsburgh Cancer Institute, Pittsburgh, PA 2Genentech, Inc., South San Francisco, CA
Submitted: Jan 11, 2005; Revised: Mar 2, 2005; Accepted: Mar 3, 2005 Address for correspondence: Virginia E. Paton, PharmD, Genentech Inc, 1 DNA Way, South San Francisco, CA 94080-4990 Fax: 650-225-4538; e-mail: [email protected]
selective ER modification (eg, tamoxifen), aromatase inhibition (eg, anastrozole, letrozole, and exemestane), and administration of “pure” antiestrogens (eg, fulvestrant). Until recently, tamoxifen has been considered the gold standard of therapy for patients with ER-positive breast cancer. Large randomized clinical trials demonstrated improved disease-free survival (DFS) and overall survival (OS) in patients who received tamoxifen for 5 years as adjuvant therapy.5 The efficacy of aromatase inhibitors has also been demonstrated in the adjuvant setting, with improved DFS and longer median time to recurrence compared with tamoxifen.6 Recently, data have been generated to support biologic pathway crosstalk between the HER2 pathway and the ER pathway. The HER2 (c-erbB-2, neu) gene, first identified in
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Clinical Benefit with Trastuzumab Regardless of HR Status Table 1 Summary of Clinical Trials Included in the Analysis41-43 Trial
Slamon et al, H0648g41
Cobleigh et al, H0649g42
Vogel et al, H0650g43
Phase
N
Patient Population
Trial Design
III
First-line, standard-dose chemotherapy alone Newly diagnosed, HER2-overexpressing (Doxorubicin/Epirubicin plus Cyclophosphamide 469 MBC previously or Paclitaxel) vs. untreated with chemotherapy plus chemotherapy standard-dose Trastuzumab
II
HER2-overexpressing MBC previously 222 treated with chemotherapy
Second- or third-line monotherapy with standard-dose Trastuzumab
II
HER2-overexpressing MBC previously 114 untreated with chemotherapy
First-line monotherapy with standard or high-dose Trastuzumab
1981,7 is overexpressed in approximately 25% of breast cancer tumors.8 HER2 overexpression is an adverse prognostic factor in patients with breast cancer and is associated with reduced time to relapse and poor survival compared with patients who have normal HER2 levels.9,10 Additionally, HER2 overexpression is an important predictive factor used to select patients for treatment with the anti-HER2 monoclonal antibody trastuzumab.11,12 In ER-positive/HER2-overexpressing breast tumors, tamoxifen can act as an agonist, leading to increased proliferation through hormone-independent pathways.13-16 In this scenario, overexpression of HER2 can promote the estrogenic action of tamoxifen through the phosphorylation of coactivators, such as AIB1 (SRC-3) and ER, which can lead to tamoxifen resistance. Osborne et al assessed AIB1 and HER2 levels in 316 breast tumor samples and found that patients whose tumors expressed high levels of AIB1 and HER2 had significantly poorer outcomes with tamoxifen therapy compared with all other patients combined (P = 0.002; log-rank test).17 Responsiveness to tamoxifen is linked to the absolute levels of hormone receptors (HRs) in tumors, which appear to be reduced in patients with HER2 gene overexpression,18 although some earlier studies have failed to find an association.10,19 In vitro studies have shown transfection of various breast cancer cell lines (MCF-7, ZR-75-1, and T-47D) with additional copies of the HER2 gene increased HER2 protein expression and decreased levels of ER and progesterone receptors (PgRs).18,20,21 Furthermore, Konecny et al demonstrated a significant inverse correlation between HER2 overexpression and HR levels in a quantitative analysis of tumor samples from 1559 patients with breast cancer.18 In a cohort of patients with HR-positive tumors, the median ER tumor levels were 44 fmol/mg protein (interquartile range, 13-156 fmol/mg) when HER2 was overexpressed (> 2 gene copies per chromosome 17 centromere detected by fluorescence in situ
248 • Clinical Breast Cancer August 2005
hybridization [FISH]) compared with 92 fmol/mg protein (interquartile range, 35-235 fmol/mg) when HER2 was not overexpressed (P < 0.001). By analyzing HER2 and HR levels as continuous rather than dichotomous variables, the authors were able to show that, as HER2 overexpression increases, the levels of HR decrease correspondingly. The use of dichotomous classifications for HER2 and ER, low cutoff scores to classify a tumor as HER2-overexpressing by immunohistochemistry (IHC), failure to exclude ER-negative tumors,22 and failure to consider ER coactivators17 have all been suggested as explanations for discrepancies among retrospective clinical studies of the influence of HER2 status on response to tamoxifen and other antiendocrine agents in patients with operable or metastatic breast cancer (MBC). Numerous studies have shown that HER2 overexpression predicts decreased benefit from antiendocrine therapy,15,23-35 whereas other studies found no significant difference or a poorer outcome for HER2-overexpressing compared with HER2-negative tumors.22,36,37 On the basis of current evidence, treatment guidelines state that HER2 overexpression does not preclude antiendocrine therapy.12 It is now well established that HER2 gene overexpression strongly predicts response to trastuzumab in patients with MBC.38 Despite the inverse correlation between HER2 and ER levels, approximately half of tumors that demonstrate HER2 overexpression (and are therefore eligible for trastuzumab therapy) will also be ER-positive.18 Although interactions between ER and HER2 have been characterized at the molecular and in vitro levels,39,40 it is not known whether HR status has an effect on clinical response to trastuzumab therapy. This retrospective analysis was performed to evaluate the treatment outcome of patients with HR-positive or HRnegative MBC and concomitant HER2 overexpression who were receiving trastuzumab as a single agent or in combination with chemotherapy.
Patients and Methods Study Design This study describes a retrospective analysis of clinical outcome according to HR status in patients with MBC whose tumors were HER2-overexpressing by FISH and who received trastuzumab in 1 of 3 clinical trials described in Table 1.41-43 Patients were eligible to participate in the trials if they had MBC that was HER2-overexpressing by IHC with a score of 2+ or 3+ using a clinical trial–specific assay (CTA). A subsequent analysis of 784 archived breast cancer specimens from the clinical trial participants was performed to determine HER2 gene overexpression by FISH analysis using the Vysis PathVysionTM HER2 assay.38 Tumors were considered positive for HER2 gene overexpression if the HER2-to-CEP17 ratio was ≥ 2. Only patients with gene overexpression as determined by FISH were included in this analysis. The CTA and FISH analyses on previously unstained specimens were performed at a central laboratory.
Adam Brufsky et al Table 2 Baseline Characteristics of 805 Patients Enrolled in the 3 Trials According to Hormone Receptor Expression and Treatment41-43 Slamon et al, H0648g41
Characteristic
Trastuzumab plus Chemotherapy (n = 235)
Vogel et al, H0650g43
Chemotherapy Alone (n = 234)
Cobleigh et al, H0649g42
First-Line Trastuzumab Second- or Third-Line Trastuzumab Monotherapy Monotherapy (N = 222) (N = 114)
HRPositive (%)
HRNegative (%)
HRPositive (%)
HRNegative (%)
HRPositive (%)
HRNegative (%)
HRPositive (%)
HRNegative (%)
Karnofsky Performance Status ≤ 80
31
27
34
34
29
24
25
30
≥ 4 Positive Lymph Nodes
39
46
42
50
40
70
49
52
≥ 3 Metastatic Sites
41
29
31
30
33
29
42
30
Previous Adjuvant Chemotherapy
70
82
60
74
63
75
66
79
Previous Adjuvant or Metastatic Hormonal Therapy
71
38
71
33
49
21
74
31
Fluorescence in situ hybridization using previously immunostained tissue sections was performed at the University of Southern California, as previously described.44 Estrogen receptor and PgR status were determined at local laboratories using standard methods. Progesterone receptor–positive tumors and ER-positive tumors respond to hormone therapy in a manner similar, so data from both were pooled and are referred to as HR-positive.45 Clinical outcomes for each trial have been previously described.41-43 In this analysis, overall response rates (ORRs) by intent-to-treat analyses were calculated for FISH-positive/HR-positive and FISH-positive/HR-negative cohorts. Time to progression (TTP) and OS were estimated by Kaplan-Meier analyses.46
Results
spectively, in patients whose tumors were HER2-overexpressing by FISH. In the phase III trial (H0648g),41 the ORR and TTP were similar in the chemotherapy plus trastuzumab arm for patients with HR-positive and HR-negative tumors (ORR, 58% [95% confidence interval {CI}, 46%-69%] vs. 51% [95% CI, 40%-63%]; TTP, 7.6 months [95% CI, 6.99.9 months] vs. 7.3 months [95% CI, 7-10.2 months], respectively). Overall response rates and TTP were increased for patients in the chemotherapy plus trastuzumab arm compared with patients treated with chemotherapy alone for HR-positive and HR-negative tumors. Median OS was longer for patients with HR-positive tumors receiving trastuzumab and chemotherapy (median, 29.4 months; 95% CI, 19.1 months to not reached [NR]) compared with patients with HR-negative tumors (median, 24.1 months; 95% CI, 19.8-31.4 months). Overall, median OS was greater in the combination therapy cohort (29.4 months and 24.1 months) than in the chemotherapy-alone cohort (20.6 months [95% CI, 15.4-30 months] and 21 months [95% CI, 13.2-26.2 months]) for patients with HR-positive and HRnegative tumors, respectively (Figure 3). Previous treatment with hormonal therapy in the adjuvant setting did not impact the efficacy outcome in this study. Hormone receptor status did not influence the response of HER2-overexpressing MBC to first-line single-agent trastuzumab (ORR 33% [95% CI, 20%-50%] vs. 34% [95% CI,
The baseline characteristics for the 805 patients are described in Table 2.41-43 Demographics are similar for the HR-positive and HR-negative cohorts for each trial with the exception of previous treatment with hormonal therapy among patients with HR-positive disease. HER2 overexpression was determined in 765 samples, and 596 specimens (78%) were HER2-overexpressing by FISH. A total of 269 of 596 patients (45%) had HER2-overexpressing/HR-positive tumors, and 255 of 596 patients (43%) had HER2-overexpressing/HR-negative tumors. The HR status of 72 patients (12%) was unknown. Of the 169 patients with HER2-negTable 3 Hormone Receptor Expression and HER2 Status: Combined Results from All Trials41-43* ative tumors by FISH, 100 HR Status HER2 Status (59%) had HER2-negative/ HR-Positive (%) HR-Negative (%) Unknown (%) Total (%) by FISH HR-positive tumors, and 39 Positive 269 (45) 255 (43) 72 (12) 596 (78) (23%) had HER2/HR–negative tumors (Table 3).41-43 Negative 100 (59) 30 (18) 169 (22) 39 (23) Figures 1-3 show the ORR, Total 369 (48) 294 (38) 102 (13) 765 median TTP, and median *HER2 status by FISH was unknown for 40 patients. survival from each study, re-
Clinical Breast Cancer August 2005 • 249
Clinical Benefit with Trastuzumab Regardless of HR Status Figure 1 ORR in Accordance with HR Status and Treatment41-43
Overall Response Rate (%)
70 60
HR-Positive HR-Negative
58 51
50 40
30
30
32
33
34 21
20
18
10 0
Trastuzumab/ Chemotherapy
Chemotherapy Alone
H0648g41
First-Line Trastuzumab
Second/ThirdLine Trastuzumab
H0650g43
H0649g42
months [95% CI, 16.9 to NR] vs. 20.5 months [95% CI, 12.4 to NR], respectively) were slightly longer for patients with HR-positive tumors compared with those with HR-negative tumors in this study, although statistical significance was not achieved (Figures 2 and 3). Patients treated with trastuzumab as second- or third-line monotherapy (trial H0649g)42 had similar clinical outcome regardless of tumor HR status. The ORRs were 21% (95% CI, 13%-31%) and 18% (95% CI, 10%-29%), respectively, for patients with HR-positive versus HR-negative tumors (Figure 1), and TTP was 3.4 months (95% CI, 2.6-3.8 months) versus 3.3 months (95% CI, 2-3.9 months; Figure 2), respectively. The median survival for patients with HR-positive tumors was slightly longer than for patients with HR-negative tumors (15.2 months [95% CI, 12.3-21.6 months] vs. 12.6 months [95% CI, 9.2-16.3 months], respectively; Figure 3).
Discussion Figure 2 Median TTP in Accordance with HR Status and Treatment41-43 8
7.5
7.3
HR-Positive HR-Negative
Median TTP (Months)
7 6
5.2
5
4.6 4.5 3.7
4
3.4 3.3
3 2 1 0
Trastuzumab/ Chemotherapy
Chemotherapy Alone
H0648g41
First-Line Trastuzumab
Second/ThirdLine Trastuzumab
H0650g43
H0649g42
Figure 3 Median Survival in Accordance with HR Status and Treatment41-43 35
Median Survival (Months)
30 25
HR-Positive HR-Negative
29.4 24.5
24.1 20.6
20
21
20.5 15.2
15
12.6
10 5 0
Trastuzumab/ Chemotherapy
Chemotherapy Alone
H0648g41
First-Line Trastuzumab
Second/ThirdLine Trastuzumab
H0650g43
H0649g42
20.5%-50%] for HR-positive and HR-negative tumors, respectively; trial H0650g; Figure 1).43 The median TTP (5.2 months [95% CI, 3.4-12.4 months] vs. 3.7 months [95% CI, 2.0-7.1 months], respectively) and median survival (24.5
250 • Clinical Breast Cancer August 2005
This retrospective study analyzed the clinical outcome of 596 patients with HER2-overexpressing MBC stratified by HR status and treated with trastuzumab as a single agent or in combination with chemotherapy. This analysis suggests that the treatment of HER2-overexpressing MBC with trastuzumab was associated with increased ORR, TTP, and OS, and patient benefit was not influenced by HR status. Additionally, this analysis confirms the observation that HER2-overexpressing tumors have an equal likelihood of being HR-positive or negative (45% vs. 43%, respectively). Klein et al described 47% and 53% prevalence rates of ERpositive and ER-negative tumors, respectively, in women with HER2-overexpressing disease.47 Similarly, Konecny et al found that 53% of patients with primary breast cancer whose tumors overexpressed HER2 on FISH also had ERpositive tumors.18 On average, 25% of all breast cancers overexpress HER2.8 In this study of patients with HER2-overexpressing tumors, 45% of the tumors were HR-positive and 43% were HR-negative. Extrapolation of these data to the breast cancer population suggests that approximately 11% of breast tumors are HER2-overexpressing/HR-positive, and approximately 11% are HER2-overexpressing/HR-negative. Because of these data, we believe HR status should not preclude testing for HER2 status. Sixty percent of the HER2-negative tumors studied were HR-positive and 23% were HR-negative; therefore, we estimate that approximately 45% of all breast tumors are HER2-negative/HR-positive and approximately 17% are HER2/HR–negative. These data confirm previous observations that HER2-overexpressing tumors are less likely than HER2-negative tumors to be HR-positive.18 Hormonal status for these patients was determined using standard of care methods at the institutions where patients were being treated. These results were not reviewed at a central laboratory for confirmation of HR positivity. Similar to testing for HER2 status, testing for HR status with IHC is associated with some technical issues that may influence the results.48 These testing issues may affect the clinical outcome results presented in this analysis.
Adam Brufsky et al In contrast to the negative predictive effect HER2 status may have on antiendocrine therapy, we found that patients with HER2-overexpressing/HR-positive or HER2-overexpressing/HR-negative tumors derive similar clinical benefit from treatment with trastuzumab (Figures 1-3). Our results suggest that previous antiendocrine therapy for metastatic disease does not appear to influence the overall response to trastuzumab. Outcome was improved with the addition of trastuzumab to chemotherapy as previously described.41 A prospective analysis by Klein et al reported similar findings. The ORRs following trastuzumab and taxane therapy were 56% for HER2-overexpressing/ER-positive tumors and 55% for HER2-overexpressing/ER-negative tumors.47 In this study, median OS of patients with HR-negative tumors was lower than that of patients with HR-positive tumors. Although we did not find evidence that HR status was a predictive factor for benefit from trastuzumab, it does appear that HR status may retain its role as an independent prognostic factor in patients with HER2-overexpressing breast tumors, which is similar to previous reports in earlystage and metastatic disease populations.49-52
Conclusion The HER2-overexpressing tumors identified by FISH have an approximately equal likelihood of being HR-positive or HR-negative, and therefore HR status should not preclude testing for HER2 gene overexpression. Patients with HER2-overexpressing tumors treated with trastuzumab alone or in combination with chemotherapy have similar clinical outcome regardless of HR status, indicating that HR status does not predict clinical benefit obtained from treatment with trastuzumab.
Acknowledgement
11.
12. 13. 14. 15. 16.
17. 18. 19.
20. 21. 22. 23. 24.
25.
This study was supported by Genentech, Inc. 26.
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252 • Clinical Breast Cancer August 2005