Breast cancer has been recognized as the most common type of cancer and the leading cause of malignancy-related mortality in women worldwide [
Among various biomarkers, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) play important roles in management and prognosis of patients with breast cancer [
However, in Vietnam, rebiopsy of recurrent lesions has not been routinely performed. The objective of this study is to evaluate the changes of ER, PR, and HER2 status between the primary and recurrent lesions in Vietnamese patients with breast cancer.
This is a retrospective and observational study, conducted at the Vietnam National Cancer Hospital. Convenience sampling method was used to enroll patients during a 4 year period from January 2014 to September 2018. This study was approved by the research committee of the Vietnam National Cancer Institute.
We included patients who were diagnosed with recurrent breast cancer after curative treatment at our institution during the study period. The staging of primary tumor was based on the AJCC Cancer Staging Manual, 7th edition [
The ER, PR, and HER2 status for the primary tumors were obtained from medical chart/pathology report reviews. The rebiopsy tumor tissue samples from recurrent lesions were stained for ER, PR, and HER2 using formalin-fixed and paraffin-embedded (FFPE) sections following Avidin-Biotin Complex (ABC) method, in which tetravalent strept (avidin) and biotinylated antibodies were used. ER, PR, and HER2 classifications were made based on the American Society of Clinical Oncology/College of American Pathologists guideline recommendations for IHC testing of ER, PR, and HER2 in breast cancer [
Representative examples of IHC analysis of the studied biomarkers on a biopsied specimen. ER was markedly expressed (ER score 2+) and PR staining status was negative. The staining score of HER2 was 2+ (FISH test showed that the tumor was HER2-amplified). H&E, hematoxylin and eosin stain; IHC, immunohistochemistry; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2; FISH, Fluorescence in situ hybridization.
The patients were divided into three IHC subtypes based on primary tumor, including HR-positive (ER positive and/or PR positive and HER2 negative), HER2-amplified (HER2 positive/any ER, PR status), and triple-negative (ER negative, PR negative, and HER2 negative).
All data were presented descriptively as a median (interquartile range) or number (percentage). Comparisons between different groups were done using Fisher’s exact test or Chi square test where appropriate.
During the study period, a total of 67 patients were diagnosed with recurrent breast cancer at our institution. The IHC profile of primary tumors was ER/PR-positive in 30 (44.8%) patients, HER2-amplified in 24 (35.8%) patients, and triple-negative in 13 (19.4%) patients.
A summary of patient characteristics is presented in Table
Patient demographics and clinical characteristics.
Characteristics | Number ( |
Percentage |
---|---|---|
|
||
Age (median (IQR)) | 44 | (38–53) |
Menopause status | ||
Pre-menopause | 38 | 56.7% |
Post-menopause | 29 | 43.3% |
Stage at diagnosis | ||
0 | 2 | 3.0% |
I | 11 | 16.4% |
II | 27 | 40.3% |
III | 27 | 30.3% |
Pathological types | ||
Ductal | 54 | 80.6% |
Lobular | 6 | 9.0% |
Other | 7 | 10.4% |
Therapy | ||
Chemotherapy | 53 | 79.1% |
Endocrine therapy | 37 | 55.2% |
Trastuzumab | 5 | 7.5% |
|
||
Duration from primary to recurrent disease | ||
<24 months | 17 | 25.4% |
24–36 months | 8 | 11.9% |
>36–60 months | 28 | 41.8% |
>60 months | 14 | 20.9% |
Locoregional recurrence | 48 | 71.6% |
Chest wall | 17 | 25.4% |
Regional lymph nodes | 36 | 53.7% |
Distant metastasis | ||
Lung | 15 | 22.4% |
Liver | 5 | 7.5% |
Bone | 10 | 14.9% |
Mediastinal lymph node | 9 | 13.4% |
Data: distant metastasis/other | 5 | 7.5% |
Site of biopsy | ||
Locoregional | 45 | 67.2% |
Lung | 8 | 11.9% |
Liver | 4 | 6.0% |
Bone | 2 | 3.0% |
Brain | 1 | 1.5% |
Mediastinal lymph node | 1 | 1.5% |
Others | 6 | 9.0% |
The concordance and discordance of tumor biomarkers between primary and recurrent lesions are shown in Tables
Distribution of ER, PR, and HER2 status between the primary tumor and recurrent lesions (
Biomarkers | Concordance |
Discordance |
Total discordance |
||
---|---|---|---|---|---|
PL (+) | PL (−) | PL (+) | PL (−) | ||
RL (+) | RL (−) | RL (−) | RL (+) | ||
ER | 27 (40.3%) | 22 (32.8%) | 8 (11.9%) | 10 (14.9%) | 18 (26.9%) |
PR | 11 (16.4%) | 30 (44.8%) | 17 (25.4%) | 9 (13.4%) | 26 (38.8%) |
HER2 | 19 (29.7%) | 33 (49.3%) | 5 (7.5%) | 10 (14.9%) | 15 (22.4%) |
PL: Primary lesions; RL: Recurrent lesions.
Conversion rates of receptor status between primary tumor and metastasis.
Markers | Total | HR-positive |
HER2 amplified |
Triple-negative |
---|---|---|---|---|
|
||||
No conversion | 49 | 23 (76.7%) | 18 (75.0%) | 8 (61.5%) |
From (+) to (−) | 8 | 6 (20.0%) | 2 (8.3%) | 0 |
From (−) to (+) | 10 | 1 (3.3%) | 4 (16.7%) | 5 (38.5%) |
Total | 67 | 30 (100%) | 24 (100%) | 13 (100%) |
|
||||
No conversion | 41 | 12 (40.0%) | 20 (83.3%) | 9 (69.2%) |
From (+) to (−) | 17 | 14 (46.7%) | 3 (12.5%) | 0 |
From (−) to (+) | 9 | 4 (13.3%) | 1 (4.2%) | 4 (30.8%) |
Total | 67 | 30 (100%) | 24 (100%) | 13 (100%) |
|
||||
No conversion | 52 | 24 (80.0%) | 19 (79.2%) | 9 (69.2%) |
From (+) to (−) | 5 | 0 | 5 (20.8%) | 0 |
From (−) to (+) | 10 | 6 (20.0%) | 0 | 4 (30.8%) |
Total | 67 | 30 (100%) | 24 (100%) | 13 (100%) |
In terms of HER2, the conversion rate was 22.4% (95% CI: 12.1%–32.6%), including 5 (7.5%) patients from positive to negative and 10 (14.9%) patients in the reverse. HER2 gain proportions were 20% (6/30) and 30.8% (4/13) in HR-positive and triple-negative groups, respectively.
With the above conversion of receptor status, the IHC subtype was changed in 25/67 (37.3%) patients. Changing from HR-positive to HER2 amplified and to Triple-negative had the highest frequency (6/67 patients in each change, 9.0%). Meanwhile, changes from HER2 amplified to HR-positive, from triple-negative to HR-positive and to HER2 amplified occurred in 4 patients (6.0%) each. Only 1 patient (1.5%) switched from HER2 amplified to triple-negative. In contrast, a change to positive of either ER, PR, or HER2 was observed in 8/13 triple-negative patients (61.5%).
Regarding the biopsy of recurrent lesions, changes in ER, PR, and HER2 status of locoregional recurrences were recorded in 26.7%, 40.0%, and 20.0%, respectively. Among distant metastasis biopsies, discordance rate was also highest in PR status (36.4%), followed by ER and HER2 (27.3% each) (Table
Distribution of ER, PR, and HER2 status according to biopsied site.
Sites of biopsy | Total | Change in ER | Change in PR | Change in HER2 status | |||
---|---|---|---|---|---|---|---|
Discordant |
Concordant |
Discordant |
Concordant |
Discordant |
Concordant |
||
Locoregional lesions | 45 | 12 (26.7%) | 33 (73.3%) | 18 (40.0%) | 27 (60.0%) | 9 (20.0%) | 36 (80.0%) |
Metastasis lesions | 22 | 6 (27.3%) | 16 (72.7%) | 8 (36.4%) | 14 (63.6%) | 6 (27.3%) | 16 (72.7%) |
Lung | 8 | 3 (37.5%) | 5 (62.5%) | 2 (25.0%) | 6 (75.0%) | 2 (25.0%) | 6 (75.0%) |
Liver | 4 | 0 | 4 (100%) | 0 | 4 (100%) | 1 (25.0%) | 3 (75.0%) |
Bone | 2 | 1 (50%) | 1 (50%) | 1 (50%) | 1 (50%) | 0 | 2 (100%) |
MLN | 1 | 0 | 1 (100%) | 1 (100%) | 0 | 1 (100%) | 0 |
Others | 7 | 2 (28.6%) | 5 (71.4%) | 4 (57.1%) | 3 (42.9%) | 2 (28.6%) | 5 (71.4%) |
MLN: Mediastinal lymph nodes.
The proportions of receptor discordance were similar between locoregional and distant metastatic sites, which was presented in all three IHC subtype groups (
Our study included 67 cases of recurrent breast cancer after curative treatment. RL biopsies with IHC showed considerable rates of receptor status conversions, including 26.9% in ER, 38.8% in PR, and 22.4% in HER2. There were no statistical differences in conversion rates in regard to different sites and times of recurrence. Eight out of 13 triple-negative patients (61.5%) had a change to positive of either ER, PR, or HER2 status compared to the primary tumors. To our knowledge, this is one of the few reports in Vietnam as well as in other developing countries [
Biopsy of metastatic and recurrent lesions in breast cancer plays an important role, not only to achieve a final diagnosis, but also to re-evaluate ER, PR, and HER2 status. Evidence has shown that the conversion of these markers between primary and RL could be useful in the clinical management of patients with breast cancer [
There are several possible mechanisms for the conversion in ER, PR, and HER-2 expression. Firstly, technical artifacts and the variability in the accuracy of IHC tests may contribute to the difference of biomarker status between primary and recurrent tumors [
Discordances of receptor status between primary tumor and recurrent lesions may lead to difficulty in determining tumor status and planning treatment accordingly [
Our results, consistent with previous studies, did not observe any associations between receptor conversion and the duration from primary tumor diagnosis to recurrence, sites of recurrence, or tumor molecular subtypes [
There is a substantial conversion rate of receptor status between primary and recurrent tumors in breast cancer. Rebiopsy could help confirm the recurrence and may play an important role in clinical management. The conversion from receptor-negative to positive may provide new therapeutic opportunities for patients with recurrent breast cancer, including endocrine and targeted therapies for those who were previously not indicated.
The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.
This study was approved by the ethics committee of the Vietnam National Cancer Institute. Informed consent was waived due to the retrospective nature of this study.
The authors declare that they have no conflicts of interest.
Nguyen Thi Hoa and Phung Thi Huyen are equal contributors and co-primary authors.
We gratefully acknowledge the Department of Pathology and Molecular Biology, Vietnam National Cancer Hospital and other staffs at Vietnam National Cancer Hospital for their valuable assistance during our study.