Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer Relapsing Post-Adjuvant Trastuzumab: Pattern of Recurrence, Treatment and Outcome

doi:10.1016/j.clbc.2011.03.012

Clinical Breast Cancer

Volume 11, Issue 3, June 2011, Pages 153-160

https://doi.org/10.1016/j.clbc.2011.03.012 Get rights and content

Abstract

Background

The purpose of this study is to evaluate the response to and benefit of first-line metastatic treatment (including re-exposure to trastuzumab) for patients relapsing after exposure to adjuvant trastuzumab (AT).

Patients and Methods

All HER2-positive breast cancer cases relapsing after exposure to AT at our institutions were identified. Clinico-pathologic details, pattern of relapse, and treatment in the metastatic setting were documented. Response to treatment and outcome were assessed.

Results

Twenty-nine relapses were recorded. The median time to relapse was 18.4 months from diagnosis, and 8.7 months from AT initiation. At a median time of observation of 9.9 months, 18 patients had progressed on first-line therapy. The median time-to-progression (TTP) was 8.6 months. Fifteen patients received trastuzumab as first-line treatment, with no statistical difference in TTP between this group and those not re-exposed to trastuzumab. TTP was not statistically different between those relapsing on or after AT. Overall survival was longer for those who relapsed after completion of 1 year of AT as well as those who received further trastuzumab at relapse; however, this did not reach statistical significance.

Conclusion

Overall survival was longer in patients who relapse after completion of AT and who received further trastuzumab at progression.

Introduction

Overexpression or amplification of the human epidermal growth factor receptor 2 (HER2), occurs in approximately 15% of breast cancers,1, 2 and this is associated with a shorter disease-free and overall survival.3, 4, 5 The pivotal phase III trial demonstrated that the addition of trastuzumab to standard chemotherapy regimens significantly increased time to disease progression and overall survival in women who have metastatic breast cancer.⁶ Subsequent adjuvant phase III trials with trastuzumab therapy administered concomitantly with or sequentially to chemotherapy in HER2-positive early breast cancer showed improvements in disease-free and overall survival, and established adjuvant trastuzumab (AT) as a standard of care for HER2-positive breast cancers that require chemotherapy.7, 8, 9, 10 One study has been reported to be negative.¹¹

Although AT has clearly improved the outcome for patients who have HER2-positive early breast cancer, not all benefit and remain disease-free, and some patients relapse despite such adjuvant treatment.7, 8, 9, 10 Currently, no data exists on the relative benefit of subsequent treatment in this AT relapsing group as well as their long-term outcome. Furthermore, it is unclear if there are any differences in outcome for cases in which relapse on AT compared with those who relapse following completion of AT. The purpose of this study was to investigate the pattern of relapse, subsequent treatment, and outcome of HER2-positive breast cancer relapsing on or following AT therapy, as well as the potential benefit of further trastuzumab in the metastatic setting in this patient group.

Section snippets

Identifying Patients Progressing on or During AT

All histopathology reports of invasive breast cancer resected between January 2006 and December 2008 at Imperial College Healthcare NHS Trust (Charing Cross and St Mary's Hospital), West Middlesex Hospital, and Belfast City Hospital were reviewed. Patients presenting with metastatic disease were excluded. The case notes of all HER2-positive patients were identified to detect any patient who had been commenced on AT and who subsequently developed local or distant recurrence.

HER2 Positivity

HER2 was determined

Patient Characteristics and Relapse Data

Two hundren eighty-four patients who had early HER2-positive breast cancer and who had received at least one dose of AT were identified. Twenty-nine (10.2%) relapse events were recorded; however, the relapse date and subsequent treatment data were not available for one patient whose care was transferred to another center. The median time to relapse for the remaining 28 patients was 18.4 months (range, 9.2 to 48.2 months) from initial diagnosis, and 8.7 months (range, 1.4 to 40.0 months) from

Discussion

The introduction of AT has clearly improved the outcome for women who are diagnosed with early HER2-positive breast cancer; however, despite this therapeutic advance, patients still relapse.¹⁴ There is a clear need to understand the natural history and outcomes for HER2- positve breast cancers that are treated with AT, as well as the optimal management for those who develop recurrent disease. Although data exist for long-term risk of recurrence, pattern of recurrence, and risk of death in

Acknowledgments

Carlo Palmieri acknowledges the grant support he receives from Cancer Reasearch UK. Ondrej Gojis is partly funded by a grant awarded by the Ministry of Education of the Czech Republic (Project “Oncology” MSM 0021620808) and is also a recipient of Translational Research Fellowship from the European Society of Medical Oncology. The Department of Oncology at Imperial College London/Imperial College HealthCare NHS Trust is an Experimental Cancer Medicine Centre (ECMC) which is supported by funds

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Cited by (16)

Prognostic 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 Open
Citation Excerpt :
However, a small number of patients included in these trials were enrolled after failure of (neo)adjuvant anti-HER2 therapy.4 5 Limited evidence, derived mostly from small retrospective studies, is currently available on the performance of first-line anti-HER2 therapy in patients relapsing after prior exposure to targeted agents in the early setting.8 12 19–25 Based on these studies, it cannot be excluded that patients exposed to anti-HER2 targeted treatment in the early setting may experience a smaller benefit with first-line therapy.
In HER2-positive breast cancer, time elapsed between completion of (neo)adjuvant trastuzumab and diagnosis of metastatic disease (‘trastuzumab-free interval’, TFI) is crucial to choose the optimal first-line treatment. Nevertheless, there is no clear evidence to support its possible prognostic role.
In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) trial, patients with HER2-positive early breast cancer were randomised to 1 year of either trastuzumab alone, lapatinib alone, their sequence or their combination. This exploratory analysis included only patients in the trastuzumab alone or trastuzumab plus lapatinib arms who developed a distant disease-free survival (DDFS) event. Overall survival (OS) was defined as time between date of DDFS event and death; age at diagnosis, tumour size and hormone receptor status were the variables included in the multivariate models.
Out of 8381 patients included in ALTTO, 404 patients in the trastuzumab alone and trastuzumab plus lapatinib arms developed a DDFS event, of which 201 occurred <12 months (group A) and 203 >12 months (group B) after completion of adjuvant trastuzumab. No significant difference in location of first DDFS event was observed (p=0.073); a numerically higher number of patients in group A than in group B developed brain metastasis (26% vs 15%). Choice of first-line therapy differed between the two groups (p=0.022): in group A, more patients received lapatinib (25% vs 11%) and less pertuzumab (8% vs 17%). Median OS was 29.3 and 18.4 months in groups B and A, respectively (adjusted HR 0.69; 95% CI 0.54–0.89; p=0.004). The longer OS for patients in group B was observed across the analysed subgroups without interaction according to hormone receptor status (p=0.814) nor type of administered adjuvant anti-HER2 treatment (p=0.233).
TFI has prognostic value in patients with HER2-positive early breast cancer treated with adjuvant trastuzumab-based therapy. TFI is a valid tool to better individualise clinical recommendations and to design future first-line treatment trials for metastatic patients.
Clinical outcomes of patients with breast cancer relapsing after (neo)adjuvant trastuzumab and receiving trastuzumab rechallenge or lapatinib-based therapy: a multicentre retrospective cohort study
2020, ESMO Open
Citation Excerpt :
These factors have likely influenced the preference towards a drug with a different mechanism of action (tyrosine-kinase inhibitor) and with documented activity in brain metastasis like lapatinib. So far, there is paucity of data regarding the clinical outcome of patients relapsing after (neo)adjuvant trastuzumab.24 26–29 International guidelines3 11 recommend the use of pertuzumab in patients relapsing more than 12 months following the completion of adjuvant anti-HER2 therapy and T-DM1 for those developing disease relapse within 12 months based on the results of the EMILIA trial.12 However, patients relapsing between 6 and 12 months from adjuvant trastuzumab were excluded from EMILIA trial; therefore, we lack clear data on anti-HER2 treatment performance in this subgroup of patients.
In the prepertuzumab era, we evaluated the clinical outcomes of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer who underwent first-line trastuzumab-based or lapatinib-based therapy according to prior exposure to (neo)adjuvant trastuzumab.
In this multicentre retrospective cohort study conducted in 14 Italian centres of the Gruppo Italiano Mammella, consecutive patients undergoing first-line trastuzumab or lapatinib-based therapy were included. Analyses were performed according to the type of first-line therapy for metastatic disease (trastuzumab or lapatinib). Dichotomous clinical outcomes were analysed using logistic regression and time-to-event outcomes using Cox proportional hazard models controlling for relevant demographic, clinicopathological and therapy characteristics.
Out of 450 patients included in the study, 416 (92%) received trastuzumab and 34 (7.5%) lapatinib. As compared with the trastuzumab cohort, more patients in the lapatinib cohort had a trastuzumab-free interval <1 month (37% vs 13.9%; p=0.017) and brain metastasis as first site of relapse (38.2% vs 9.4%; p<0.001). Among the 128 patients who relapsed after prior (neo)adjuvant trastuzumab, 101 (78.9%) received first-line trastuzumab and 27 (21.1%) first-line lapatinib. The following outcomes were observed with first-line lapatinib or trastuzumab, respectively: overall response rate 45.5% vs 61.3% (p=0.184), clinical benefit rate 68.2% vs 72.5% (p=0.691), median progression-free survival (PFS) 11.4 vs 12.0 months (p=0.814) and median overall survival (OS) 34.7 vs 48.2 months (p=0.722). In patients with brain metastasis as first site of relapse, median PFS was 12.2 vs 9.9 months (p=0.093) and median OS 33.7 vs 28.5 months (p=0.280), respectively.
In patients with HER2-positive breast cancer relapsing after prior (neo)adjuvant trastuzumab, first-line treatment with trastuzumab or lapatinib was not associated with a significant difference in the clinical outcomes. A non-significant trend favouring the use of lapatinib was observed in patients with brain metastasis as the first site of relapse.
HER2-positive metastatic breast cancer: A changing scenario
2015, Critical Reviews in Oncology/Hematology
Citation Excerpt :
Several observational studies, carried out in different countries, were published in the last few years [29–34]. First of all, 13% of Pts did not receive AT and a further 8.2% discontinues AT after start, mainly for toxicity-related reasons [34] and this is consistent with the interruption rate in HERA Trial (10%) [24,25], much lower than in the Joint US Trials (31%) [22,27] and confirms other observational studies in Germany [30] and Italy [35], while in UK 38% of patients did not receive AT, 42% of them for early stage, 21% for age considered too advanced [33,36]. Reported relapse rate, at different observation time after AT is ranging from 3.3% to 14% (Table 2).
Adjuvant trastuzumab (AT) dramatically improved HER2-positive breast cancer prognosis. Relapsed disease after AT has different patterns and information is available from observational studies. In this Review Chemotherapy regimens combined to anti-HER2 blockade are discussed, focusing in particular the role of anthracyclines, taxanes and capecitabine. The use of trastuzumab beyond progression and the role of other anti-HER2 agents like lapatinib, pertuzumab and T-DM1 are explored, as also dual blockade and in trastuzumab resistant Patients. Metastatic “de novo” HER2 Luminal (co-expression of HER2 and hormone receptors) Patients are eligible for anastrozole and trastuzumab but if pretreated with trastuzumab they are also eligible for lapatinib and letrozole. In any case endocrine treatment plays a complementary role to chemotherapy which remains pivotal. The last topic explored is treatment options for patients with brain metastases where both trastuzumab given concurrent with radiotherapy or lapatinib and capecitabine appear as potentially active.
Trastuzumab retreatment after relapse on adjuvant trastuzumab therapy for human epidermal growth factor receptor 2-positive breast cancer: Final results of the retreatment after herceptin adjuvant trial
2014, Clinical Oncology
Citation Excerpt :
To our knowledge, RHEA is the only prospective trial carried out to exclusively address this question worldwide. Krell and colleagues [30] reported results from an exploratory study involving 29 patients who had relapsed after receiving at least one dose of trastuzumab as adjuvant treatment. Of these patients, those who received trastuzumab with chemotherapy (docetaxel; 5-fluorouracil, epirubicin and cyclophosphamide followed by docetaxel [FEC-D]; or vinorelbine) in the first-line metastatic setting had an ORR of 26.7% versus 18.2% for those who received chemotherapy alone; the median time-to-progression was 7.2 versus 8.6 months.
Trastuzumab, in combination with chemotherapy, is the standard of care for patients with early and metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The Retreatment after HErceptin Adjuvant trial assessed the efficacy and safety of trastuzumab plus a taxane as first-line treatment for patients with metastatic breast cancer (MBC) who had relapsed after adjuvant trastuzumab for HER2-positive early breast cancer.
In total, 43 patients with HER2-positive MBC who had received previous adjuvant trastuzumab for ≥10 months, with a relapse-free interval of ≥6 months after the last adjuvant trastuzumab dose, were recruited. Eligible patients (n = 41) were assigned to receive trastuzumab, either weekly or every 3 weeks, in combination with docetaxel or paclitaxel until disease progression.
At the final analysis, with a median follow-up time of 40 months, a positive response was observed in 25/41 patients (61%; 95% confidence interval: 48.7–80.4%), stable disease in 7/41 (17.1%) and progressive disease in 6/41 (14.6%). Three patients had missing response assessments (one had no measurable lesions at baseline and two had no post-baseline tumour assessments). The median progression-free survival (PFS) was 8.0 months (95% confidence interval: 6–11 months) and the median overall survival was 25.0 months (16–33 months). No correlation was found between response rate, PFS or overall survival and the duration of adjuvant trastuzumab treatment, trastuzumab-free interval, relapse-free interval, hormone receptor status or type of pre-metastatic treatment. The most common adverse events (all grades) were alopecia (32%) and diarrhoea (32%). Six patients (14.6%) developed at least one serious adverse event. No congestive heart failure or any unexpected adverse events were reported.
Trastuzumab, in combination with a taxane, is an effective and well-tolerated first-line treatment for MBC in patients who relapse after trastuzumab-based adjuvant therapy.
Survival Outcomes of Retreatment with Trastuzumab and Cytotoxic Chemotherapy for HER2-Positive Recurrent Patients With Breast Cancer Who Had Been Treated with Neo/adjuvant Trastuzumab Plus Multidrug Chemotherapy: A Japanese Multicenter Observational Study
2018, Breast Cancer: Basic and Clinical Research
Cost-effectiveness of pertuzumab combined with trastuzumab and docetaxel as a first-line treatment for HER-2 positive metastatic breast cancer
2018, Expert Review of Pharmacoeconomics and Outcomes Research

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Original studyHuman Epidermal Growth Factor Receptor 2–Positive Breast Cancer Relapsing Post-Adjuvant Trastuzumab: Pattern of Recurrence, Treatment and Outcome

Abstract

Background

Patients and Methods

Results

Conclusion

Introduction

Section snippets

Identifying Patients Progressing on or During AT

HER2 Positivity

Patient Characteristics and Relapse Data

Discussion

Acknowledgments

Ann Oncol

Eur J Cancer

Lancet

Prognostic markers in breast cancer: the reliability of HER2/neu status in core needle biopsy of 325 patients with primary breast cancer

Wien Klin Wochenschr

Human breast cancer: correlation of relapse and survival with amplification of the HER2-2/neu oncogene

Science

ERBB2 amplification in breast cancer analyzed by fluorescence in situ hybridization

Proc Natl Acad Sci USA

Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2

N Engl J Med

Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab with docetaxel, carboplatin and trastuzumab in HER2 positive early breast cancer patients: BCIRG 006 study

Breast Cancer Res Treat

Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer

N Engl J Med

Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer

N Engl J Med

Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer

N Engl J Med

Trastuzumab for patients with axillary-node-positive breast cancer: results of the FNCLCC-PACS 04 trial

J Clin Oncol

Effect of preoperative chemotherapy on the outcome of women with operable breast cancer

J Clin Oncol

Original study
Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer Relapsing Post-Adjuvant Trastuzumab: Pattern of Recurrence, Treatment and Outcome