Original StudyClinicopathological 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
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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Cited by (27)
Trastuzumab Resistance in Patients With HER2-Positive Advanced Breast Cancer: Results From the SONABRE Registry
2024, Clinical Breast CancerPrognostic role of distant disease-free interval from completion of adjuvant trastuzumab in HER2-positive early breast cancer: Analysis from the ALTTO (BIG 2-06) trial
2020, ESMO OpenCitation Excerpt :With a larger sample size, our analysis shows the important prognostic role of TFI with an almost 11-month absolute median OS advantage (18.4 vs 29.3 months) for patients relapsing >12 months following completion of adjuvant trastuzumab (adjusted HR 0.69; 95% CI 0.54–0.89; p=0.004). In addition, our results provide further evidence on the different behaviour of HER2-positive tumours according to hormone receptor status.13–18 As compared to patients with hormone receptor-positive disease, those with hormone receptor-negative tumours had higher likelihood to relapse within 12 months following completion of adjuvant trastuzumab and had poorer OS irrespective of TFI.
Patterns of Care and Clinical Outcomes of HER2-positive Metastatic Breast Cancer Patients With Newly Diagnosed Stage IV or Recurrent Disease Undergoing First-line Trastuzumab-based Therapy: A Multicenter Retrospective Cohort Study
2017, Clinical Breast CancerCitation Excerpt :Nowadays, these patients are likely to receive several lines of treatments,18,19 with a median OS exceeding 56 months with modern anti-HER2 targeted therapies.4 Furthermore, some of these patients can achieve long-term survival suggesting the possibility of “cure” or at least to obtain long-term disease control in selected cases.11,20,21 Primary breast surgery in patients with de novo HER2-positive MBC was shown to be strongly associated with long-term survival (OR, 2.88; 95% CI, 1.47-5.66).21
Hormone Receptor/Human Epidermal Growth Factor Receptor 2-positive breast cancer: Where we are now and where we are going
2016, Cancer Treatment ReviewsCitation Excerpt :In contrast, a retrospective observational study including 164 women affected by HER2+ tumors treated with trastuzumab-based first line therapy, showed that patients with long-term clinical benefit had a higher likelihood of having HR+ tumors. Anyway, it may be relevant that the subgroup of HR+ patients had received maintenance trastuzumab and/or HT after first-line, which could have positively affected the outcome [40]. In another retrospective study concerning metastatic BC, a cohort of all BC subtypes treated with up to four lines of systemic therapy showed a better PFS, OS and post progression survival (PPS) beyond first line treatment for HER2+ tumors compared to the other BC subtypes (p < 0.0001 for all measures of outcome).
Triple positive breast cancer: A distinct subtype?
2015, Cancer Treatment ReviewsCitation Excerpt :Results have shown that long-term benefit of trastuzumab-based therapy was associated with HR positivity and the absence of previous adjuvant trastuzumab. It is noteworthy that a subgroup of patients with HER-2 positive/HR positive tumors received maintenance trastuzumab and/or endocrine therapy, which may have favorably influenced the outcome [63]. A prospective observational study (registHER) on a cohort of more than 1000 patients with HER-2 positive advanced breast cancer, including 530 patients with HER-2 positive/HR positive tumors, showed that, with or without chemotherapy, outcomes were more favorable for the HR positive subset, since dual targeting of HR and HER-2 pathways was associated with more prolonged PFS and OS compared with HER-2 based therapy alone [64].
Long-Term Non-progression in Metastatic Breast Cancer Beyond 5 Years: Case Series and Review
2021, Current Breast Cancer Reports