Elsevier

Clinical Breast Cancer

Volume 13, Issue 4, August 2013, Pages 254-263
Clinical Breast Cancer

Original Study
Clinicopathological Features Among Patients With Advanced Human Epidermal Growth Factor–2-Positive Breast Cancer With Prolonged Clinical Benefit to First-Line Trastuzumab-Based Therapy: A Retrospective Cohort Study

https://doi.org/10.1016/j.clbc.2013.02.010Get rights and content

Abstract

Background

The magnitude of benefit of trastuzumab for the treatment of advanced HER2-positive breast cancer varies widely. In this retrospective study, we investigated the clinicopathological features associated with prolonged first-line trastuzumab-based treatment duration.

Patients and Methods

A total of 164 patients diagnosed with advanced HER2-positive breast cancer and treated with first-line trastuzumab-based therapy from 1999 to 2009 were identified. Duration of treatment was classified according to tertiles. Different logistic regression models including age, disease-free interval, number of metastatic sites, visceral disease, hormone receptor, and adjuvant trastuzumab were fitted to investigate associations with benefit of prolonged trastuzumab-based therapies. The predictive value of each model was assessed using C-statistics.

Results

At a median follow-up of 5.8 years (range, 0.7-22.1 years), patients in the short-, intermediate-, and long-term treatment duration groups were given first-line trastuzumab-based therapy for < 7.2 months, 7.2 to 14 months, and > 14 months, respectively. In the multivariate analysis, patients with long-term clinical benefit had a higher likelihood of having hormone receptor-positive tumors (odds ratio [OR]positive vs. negative = 2.39 [95% confidence interval (CI), 1.08-5.31]; P = .032); and a lower likelihood of having received adjuvant trastuzumab (ORadjuvant trastuzumab vs. no adjuvant trastuzumab = 0.30 [95% CI, 0.10-0.96]; P = .043]. C-statistics varied between 0.634 and 0.699.

Conclusion

Long-term benefit of trastuzumab-based therapy is associated with hormone receptor positivity and the absence of previous adjuvant trastuzumab. Nevertheless, clinicopathological features had a low predictive value for prolonged treatment duration. The validation of the current findings and the identification of molecular features associated the magnitude of trastuzumab benefit should be encouraged.

Introduction

Human epidermal growth factor-2 (HER2) protein overexpression or v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian) (ERBB2) gene amplification occurs in approximately 20% of primary breast carcinomas.1 Although traditionally, HER2-positive breast cancers were associated with a poor prognosis, the outcomes of this subtype of breast cancer have changed dramatically with the development and widespread use of trastuzumab. Though HER2-positivity is a predictor of benefit from trastuzumab therapy, there is significant interpatient variability in terms of duration of response, with a large range in median treatment duration across different studies.2, 3, 4, 5 There are reports of cases with prolonged complete response to trastuzumab-based regimens in patients with HER2-positive metastatic breast cancer.6 In contrast, resistance to trastuzumab-based regimens is well recognized in clinical practice.7 This heterogeneity in treatment benefit can make treatment decisions difficult, and information on predictors of prolonged response to anti-HER2 therapies could help to guide clinical decisions.

In gene expression experiments, there is segregation of breast tumors according to hormone receptor (HR) before HER2 segregation, suggesting that HR status is the most important discriminator of breast cancer subtypes.8, 9, 10, 11, 12, 13, 14, 15, 16 Although trastuzumab is effective in HR-positive and HR-negative HER2-positive patients, there are accumulating data that suggest that the behavior of HER2-positive disease is influenced by HR status.17 For example, in an analysis of the National Comprehensive Cancer Network Breast Cancer Outcomes database, patients with HR-negative/HER2-positive disease were less likely to have recurrence in bone, and had a higher risk of death within 5 years of initial diagnosis compared with patients with HR-positive/HER2-positive disease.18

Another area of uncertainty is the effect of adjuvant trastuzumab on the efficacy of HER2-targeted therapies in the metastatic setting. Recent reports suggest that relapse after the use of adjuvant trastuzumab therapy might be associated with a lower rate of clinical benefit of HER2-targeted therapy.19

We aimed to describe the relationship between clinicopathological features and long-term clinical benefit of trastuzumab-based therapies. We hypothesized that patients with HR-positive breast tumors will have a longer duration of advanced first-line trastuzumab-based regimens, and that patients who have received adjuvant trastuzumab will have less benefit from an anti-HER2 regimen in the metastatic setting.

Section snippets

Data Source and Patient Selection

A retrospective consecutive series of 355 HER2-positive advanced breast cancer patients treated at the Dana-Farber Cancer Institute (DFCI) from January 1, 1999 to December 31, 2009 was identified using the DFCI clinical research information system. An end date was chosen to allow a minimum of 30 months of potential follow-up time. Follow-up information was available through July 1, 2012. The Dana-Farber/Harvard Cancer Center institutional review board approved the study and granted a waiver of

Description of the Study Cohort

A total of 164 patients were included in this analysis. The subgroup distribution was: 33% (n = 54) in the short-term treatment duration group, 33% (n = 55) in the intermediate treatment duration group, 33% (n = 55) in the long-term treatment duration group. Median follow-up time since diagnosis was 5.8 years (range, 0.7-22.1 years). The median age at diagnosis was 46.6 years (range, 22.0-83.3 years). Most (86.6%) patients were white (Table 1).

Clinicopathological Characteristics and Patterns of Care

At baseline, most patients (75.6 %) presented with

Discussion

In this cohort of advanced HER2-positive breast cancer patients treated in the first-line setting with a trastuzumab-based regimen, we found significant associations between HR status and adjuvant trastuzumab and clinical benefit of treatment. Patients with HR-positive tumors were more likely to achieve a long-term clinical benefit to a first-line trastuzumab-based regimen. Our results also suggested a lower likelihood of long treatment duration in patients who relapse after adjuvant

Conclusion

Our study supports other observations that suggested that HER2-positive disease is a heterogeneous entity. Although our data suggest that HR is a major driver of the HER2 clinical phenotype, influencing treatment duration, and therefore, clinical benefit of anti-HER2 therapy, and that probably the use of adjuvant trastuzumab also influences clinical benefit of anti–HER2-targeted treatments; they also suggest that classical clinicopathological markers are suboptimal for predicton of long-term

Acknowledgments

I. Vaz-Luis is supported by the Scholars in Clinical Science Program of Harvard Catalyst, The Harvard Clinical and Translational Science Center (Award No. UL1 RR025758) and contributions from Harvard University and its affiliated academic health care centers.

The study was supported by the National Cancer Institute Specialized Program of Research Excellence in Breast Cancer (NIH P50 CA089393), the National Comprehensive Cancer Network, Breast Cancer Research Foundation (to N.U. Lin), Nancy and

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