Hormone Receptor Status Does Not Affect the Clinical Benefit of Trastuzumab Therapy for Patients with Metastatic Breast Cancer

doi:10.3816/CBC.2005.n.027

Clinical Breast Cancer

Volume 6, Issue 3, August 2005, Pages 247-252

https://doi.org/10.3816/CBC.2005.n.027 Get rights and content

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.

References (52)

VC Jordan et al.
Changing role of the oestrogen receptor in the life and death of breast cancer cells
Breast
(2003)
JC Allegra et al.
Estrogen receptor status: an important variable in predicting response to endocrine therapy in metastatic breast cancer
Eur J Cancer
(1980)
AU Buzdar
The ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial: an update
Clin Breast Cancer
(2004)
S Nicholson et al.
Epidermal growth factor receptor (EGFr) as a marker for poor prognosis in node-negative breast cancer patients: neu and tamoxifen failure
J Steroid Biochem Mol Biol
(1990)
O Stal et al.
ErbB2 status and the benefit from two or five years of adjuvant tamoxifen in postmenopausal early stage breast cancer
Ann Oncol
(2000)
MA Climent et al.
Prognostic value of HER-2/neu and p53 expression in node-positive breast cancer. HER-2/neu effect on adjuvant tamoxifen treatment
Breast
(2001)
A Borg et al.
ERBB2 amplification is associated with tamoxifen resistance in steroid-receptor positive breast cancer
Cancer Lett
(1994)
AE Pinto et al.
C-erbB-2 oncoprotein overexpression identifies a subgroup of estrogen receptor positive (ER+) breast cancer patients with poor prognosis
Ann Oncol
(2001)
AR Bianco et al.
Adjuvant therapy with tamoxifen in operable breast cancer. 10 year results of the Naples (GUN) study
Lancet
(1988)
EL Kaplan et al.
Nonparametric estimation from incomplete observation
J Am Stat Assoc
(1958)

P Klein et al.

Patients with ER+/HER2+ or ER-/HER2 tumors derive similar clinical benefit from trastuzumab (H)-based therapy for metastatic breast cancer

Proc Am Soc Clin Oncol

(2003)

DC Allred et al.

Prognostic and predictive factors in breast cancer by immunohistochemical analysis

Mod Pathol

(1998)

WA Knight et al.

Estrogen receptor as an independent prognostic factor for early recurrence in breast cancer

Cancer Res

(1977)

B Fisher et al.

Tumor nuclear grade, estrogen receptor, and progesterone receptor: their value alone or in combination as indicators of outcome following adjuvant therapy for breast cancer

Breast Cancer Res Treat

(1986)

DJ Slamon et al.

Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer

Science

(1989)

DJ Slamon et al.

Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene

Science

(1987)

RC Bast et al.

2000 update of recommendations for the use of tumor markers in breast and colorectal cancer: clinical practice guidelines of the American Society of Clinical Oncology [published erratum in J Clin Oncol 2001 19:4185-4188. J Clin Oncol 2002; 20:2213]

J Clin Oncol

(2001)

National Comprehensive Cancer Network

Practice Guidelines in Oncology

CC Benz et al.

Estrogen-dependent, tamoxifenresistant tumorigenic growth of MCF-7 cells transfected with HER2/neu

Breast Cancer Res Treat

(1993)

Early Breast Cancer Trialists' Collaborative Group

Tamoxifen for early breast cancer

Cochrane Database Syst Rev

(2001)

C Shih et al.

Transforming genes of carcinomas and neuroblastomas introduced into mouse fibroblasts

Nature

(1981)

MF Press et al.

Evaluation of HER-2/neu gene amplification and overexpression: comparison of frequently used assay methods in a molecularly characterized cohort of breast cancer specimens

J Clin Oncol

(2002)

R Lupu et al.

William L. McGuire Memorial Symposium. The role of erbB2 signal transduction pathways in human breast cancer

Breast Cancer Res Treat

(1993)

M Dowsett

Overexpression of HER-2 as a resistance mechanism to hormonal therapy for breast cancer

Endocr Relat Cancer

(2001)

M Dowsett et al.

HER-2 amplification impedes the antiproliferative effects of hormone therapy in estrogen receptor-positive primary breast cancer

Cancer Res

(2001)

CK Osborne et al.

Role of the estrogen receptor coactivator AIB1 SRC-3) and HER-2/neu in tamoxifen resistance in breast cancer

J Natl Cancer Inst

(2003)

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Approximately 20% of breast cancers have overexpression of the HER2 protein and/or amplification of the HER2 gene and are associated with aggressive tumor behavior and poor disease-free survival and overall survival (OS) rates. Treatment options and outcomes for this disease have been revolutionized with the introduction of targeted HER2 therapies. The pivotal trial showed that the addition of trastuzumab, a monoclonal antibody against HER2, to chemotherapy significantly improved progression-free survival (PFS) and OS compared with chemotherapy alone as first-line therapy for metastatic disease [2]. In the CLEOPATRA trial, the addition of pertuzumab, another monoclonal antibody, to trastuzumab and docetaxel significantly improved the PFS and OS, with a median OS of 56.5 months [19,20]. This combination of dual antibodies and a taxane is considered standard first-line therapy for HER2-positive, advanced breast cancer. Ongoing clinical trials are evaluating novel compounds to further improve upon these results.
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Our data add to existing evidence pointing to a bi-directional cross-talk between the ER and the HER2 pathways [14,15], and to differential treatment effects of anti-HER2 therapy by ER status. For trastuzumab, the relative risk reduction was similar across subgroups defined by hormone receptor status in the adjuvant HERA trial [16] and in three trials in metastatic disease [17]. However, a retrospective analysis of the adjuvant NSABP-B31 study suggested that messenger RNA (mRNA) levels of HER2 and ER might be relevant for the effect of adjuvant trastuzumab, restricting treatment benefit in ER+ tumours to those with higher levels of HER2 mRNA expression [18].
In resource-constrained environments many patients with human epidermal growth factor receptor 2 (HER2)+ early breast cancer are currently not offered adjuvant anti-HER2 therapy. For patients who might be able to receive the tyrosine kinase inhibitor (TKI) lapatinib (e.g. after patent expiration), it is important to identify subgroups of patients for whom anti-HER2 TKI therapy could be beneficial.
To do this, we used data from 2489 patients with centrally confirmed HER2+ disease enrolled in the adjuvant Tykerb Evaluation After Chemotherapy (TEACH) trial, investigating the effect of lapatinib in patients with HER2+ early breast cancer not treated with trastuzumab. We performed subgroup analyses and number-needed-to-treat (NNT) calculations using patient and tumour associated predictors.
Hormone receptor negative (HR−) patients on lapatinib had a significantly prolonged disease-free survival (DFS) compared to HR− patients on placebo (hazard ratio 0.64, P = 0.003). For patients with HR– disease, starting treatment with lapatinib ≤1 year from diagnosis improved DFS by 12.1% [2.1–22.1] at 2 years and 15.7% [4.1–27.2] at 5 years. Depending on lymph node status and time since diagnosis the NNT for recurrence (at 5 years) was between 5.9 (node positive patients <1 year from diagnosis) and 15.9. These numbers are in range with numbers reported for up-front adjuvant trastuzumab for HR unselected patients (e.g. 15.6 for DFS at 4 years in HERA).
In a subgroup analysis of the adjuvant TEACH trial, we show that anti-HER2 monotherapy with a TKI is beneficial as adjuvant therapy in a subgroup of patients. NNT in HER2+ HR– patients are in range with those reported from up-front adjuvant trastuzumab trials.
Effectiveness of targeted therapy in patients with previously untreated metastatic breast cancer: A systematic review and meta-analysis
2015, Clinical Breast Cancer
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Several mechanisms of resistance to endocrine therapy have been proposed, including the activity of HER family receptors.53,54 HER2 overexpression is considered to be a marker of endocrine resistance,53 and approximately 50% of HER2+ breast cancers also express hormone receptors.55,56 In patients with HER2+ disease, there is also a risk of acquiring resistance to trastuzumab.24
Breast cancer is the most common cancer and the most frequent cause of death in women. Targeted therapies offer a possibility of effective and individualized therapy based on the molecular profile of the tumor. The aim of this systematic review was to evaluate the efficacy and safety of targeted agents added to chemotherapy or endocrine therapy in patients with previously untreated metastatic breast cancer (MBC) depending on their human epidermal growth factor receptor 2 (HER2) and hormone receptor (HR) status (positive or negative). The systematic literature search was performed in PubMed, EMBASE, and the Cochrane Library to identify randomized controlled trials (RCTs). Thirteen trials were included. The addition of trastuzumab, pertuzumab, bevacizumab, or lapatinib to chemotherapy significantly (P < .05) improved objective response rate (ORR), time to failure (TTF), and overall survival (OS) in patients with HER2-positive (HER2⁺) disease. Trastuzumab or lapatinib combined with endocrine therapy significantly (P < .05) improved ORR, time to progression (TTP), and progression-free survival (PFS) in patients with HER2⁺ and HR⁺ disease. In patients with HER2-negative (HER2^–) cancer, bevacizumab or lapatinib added to chemotherapy significantly (P < .05), improved ORR but did not prolong PFS and OS (P > .05). In patients with HER2^– and HR^– disease, trastuzumab combined with chemotherapy did not significantly improve (P > .05) ORR or PFS. Targeted therapies also increased the overall risk of adverse events. So far, there is a lack of published results for everolimus and trastuzumab emtansine trials in patients with previously untreated MBC. The addition of targeted therapy to chemotherapy or endocrine therapy using HER2 and HR status significantly improved ORR, PFS, and OS in patients with previously untreated MBC.
Triple positive breast cancer: A distinct subtype?
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A retrospective evaluation on the pivotal and other trastuzumab trials showed efficacy independently on HR status, thus confirming the paradigm of chemotherapy and trastuzumab in all the subsets of HER-2 positive disease. Nevertheless, there are some limitations in the analysis, such as the semplicistic definition of HR status (positive vs negative), which does not take into account the degree of HR expression, and the lack of centralized evaluation [10,11]. Recent data seem to confirm the hypothesis that some heterogeneity exists among HER-2 positive subsets, mostly related to HR expression [12].
Breast cancer is a heterogeneous disease, and within the HER-2 positive subtype this is highly exemplified by the presence of substantial phenotypical and clinical heterogeneity, mostly related to hormonal receptor (HR) expression. It is well known how HER-2 positivity is commonly associated with a more aggressive tumor phenotype and decreased overall survival and, moreover, with a reduced benefit from endocrine treatment. Preclinical studies corroborate the role played by functional crosstalks between HER-2 and estrogen receptor (ER) signaling in endocrine resistance and, more recently, the activation of ER signaling is emerging as a possible mechanism of resistance to HER-2 blocking agents. Indeed, HER-2 positive breast cancer heterogeneity has been suggested to underlie the variability of response not only to endocrine treatments, but also to HER-2 blocking agents. Among HER-2 positive tumors, HR status probably defines two distinct subtypes, with dissimilar clinical behavior and different sensitivity to anticancer agents. The triple positive subtype, namely, ER/PgR/Her-2 positive tumors, could be considered the subset which most closely resembles the HER-2 negative/HR positive tumors, with substantial differences in biology and clinical outcome. We argue on whether in this subgroup the “standard” treatment may be considered, in selected cases, i.e., small tumors, low tumor burden, high expression of both hormonal receptors, an overtreatment. This article review the existing literature on biologic and clinical data concerning the HER-2/ER/PgR positive tumors, in an attempt to better define the HER-2 subtypes and to optimize the use of HER-2 targeted agents, chemotherapy and endocrine treatments in the various subsets.
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Citation Excerpt :
However, subgroup analyses from randomized controlled trials of adjuvant trastuzumab, given sequentially or in combination with chemotherapy, show consistent benefit across hormone receptor-positive and hormone receptor-negative patients.2,4 Although a retrospective cohort study of 227 patients demonstrated a reduced probability of response to trastuzumab plus chemotherapy in ER-positive versus ER-negative MBC (OR: 0.422; 95% CI: 0.22–0.80; p: 0.009)76, analysis of patients enrolled in MBC trials of trastuzumab found no evidence for differential benefit from this agent according to hormone receptor status, whether given as monotherapy or alongside chemotherapy.77 In summary, trastuzumab efficacy in the adjuvant and metastatic setting appears unrelated to hormone receptor status, but there is some evidence that ER/PgR-positivity correlates with lower pCR following administration of trastuzumab-containing neoadjuvant therapy.
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Human epidermal growth factor receptor 2 (HER2), a member of the ErbB family of transmembrane receptor tyrosine kinases, is amplified in 20–30% of invasive breast cancers. HER2 amplification is associated with metastasis and reduced survival. Two HER2-directed therapies have been approved by the United States Food and Drug Administration for the treatment of HER2-overexpressing breast cancer: trastuzumab, a humanized monoclonal antibody against the extracellular portion of HER2; and lapatinib, a dual HER2- and epidermal growth factor receptor-specific tyrosine kinase inhibitor. Despite the improvement in overall survival with the addition of HER2-targeted agents to chemotherapy, many patients do not benefit from these agents because of inherent resistance. In addition, many patients who achieve an initial response eventually acquire drug resistance. Currently, several mechanisms of resistance have been described, including mutations in other signaling pathways, expression of a truncated form of HER2, receptor crosstalk, and autophagy. There are several approaches under study to target these pathways of resistance, including blocking PI3 kinase and mammalian target of rapamycin signaling, blocking neoangiogenesis and the vascular endothelial growth factor axis, using monoclonal antibody targeting of the HER2 dimerization site, and using HER2 monoclonal antibody-drug conjugates. Here we will review the current scientific rationale for these agents and how combinations of these agents may yield additive or synergistic effects and lead to improved outcomes for patients with HER2-amplified breast cancer.

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Original ContributionHormone Receptor Status Does Not Affect the Clinical Benefit of Trastuzumab Therapy for Patients with Metastatic Breast Cancer

Abstract

Background

Patients and Methods

Results

Conclusion

Breast

Eur J Cancer

Clin Breast Cancer

J Steroid Biochem Mol Biol

Ann Oncol

Breast

Cancer Lett

Ann Oncol

Adjuvant therapy with tamoxifen in operable breast cancer. 10 year results of the Naples (GUN) study

Lancet

Nonparametric estimation from incomplete observation

J Am Stat Assoc

Patients with ER+/HER2+ or ER-/HER2 tumors derive similar clinical benefit from trastuzumab (H)-based therapy for metastatic breast cancer

Proc Am Soc Clin Oncol

Prognostic and predictive factors in breast cancer by immunohistochemical analysis

Mod Pathol

Estrogen receptor as an independent prognostic factor for early recurrence in breast cancer

Cancer Res

Tumor nuclear grade, estrogen receptor, and progesterone receptor: their value alone or in combination as indicators of outcome following adjuvant therapy for breast cancer

Breast Cancer Res Treat

Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer

Science

Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene

Science

2000 update of recommendations for the use of tumor markers in breast and colorectal cancer: clinical practice guidelines of the American Society of Clinical Oncology [published erratum in J Clin Oncol 2001 19:4185-4188. J Clin Oncol 2002; 20:2213]

J Clin Oncol

Practice Guidelines in Oncology

Estrogen-dependent, tamoxifenresistant tumorigenic growth of MCF-7 cells transfected with HER2/neu

Breast Cancer Res Treat

Tamoxifen for early breast cancer

Cochrane Database Syst Rev

Transforming genes of carcinomas and neuroblastomas introduced into mouse fibroblasts

Nature

Evaluation of HER-2/neu gene amplification and overexpression: comparison of frequently used assay methods in a molecularly characterized cohort of breast cancer specimens

J Clin Oncol

William L. McGuire Memorial Symposium. The role of erbB2 signal transduction pathways in human breast cancer

Breast Cancer Res Treat

Overexpression of HER-2 as a resistance mechanism to hormonal therapy for breast cancer

Endocr Relat Cancer

HER-2 amplification impedes the antiproliferative effects of hormone therapy in estrogen receptor-positive primary breast cancer

Cancer Res

Role of the estrogen receptor coactivator AIB1 SRC-3) and HER-2/neu in tamoxifen resistance in breast cancer

J Natl Cancer Inst

Original Contribution
Hormone Receptor Status Does Not Affect the Clinical Benefit of Trastuzumab Therapy for Patients with Metastatic Breast Cancer