Clinicopathological and molecular pathological characteristics in tamoxifen‑related endometrial cancer
- Authors:
- Published online on: November 9, 2023 https://doi.org/10.3892/ol.2023.14142
- Article Number: 9
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Copyright: © Saeki et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Recently, based on the results of genomic analysis, endometrial cancer (EC) has been classified into four groups molecular-pathologically: polymerase epsilon (POLE)-ultra-mutated, microsatellite instability (MSI)-hypermutated, copy-number-low (CN-L), and copy-number-high (CN-H) groups. POLE-ultra-mutated tumors have the best outcome, while CN-H tumors have the poorest outcome (1). Endometrioid carcinoma has been categorized into the CN-L group, and serous carcinoma and high-grade EC with TP53 mutation are frequently included in CN-H group (1). The MSI-hypermutated tumors appear associated with methylation of the MLH1 promoter, and the prognosis of this type of tumor is moderate, between POLE-ultra-mutated tumors and CN-H tumors (1). We recently reported that the rate of MSI-H in sporadic EC was approximately 10% in Japanese women, apparently lower than that in Western countries (2). Nevertheless, this classification has not been applied in clinical practice, as, to date, there is no immunohistochemistry (IHC) which can substitute for molecular testing.
Patients with hormone receptor (HR)-positive early breast cancer, which accounts for nearly 80% of all breast cancer cases, are recommended to receive adjuvant endocrine therapy after curative surgery (3). Tamoxifen (TAM), a selective ER modulator, is one of the major endocrine therapies along with aromatase inhibitors, but known to sometimes be a cause of EC (TAM-related EC), although infrequently (4–6). The partial agonist action of TAM promotes epithelial proliferation via the ER and might be involved in EC development (7). However, the detailed mechanism has not been fully elucidated, despite this disease having been recognized for a considerable time and numerous studies having been conducted. A study employing the Surveillance Epidemiology and End Results (SEER) data indicated that TAM was not associated with poor-prognosis disease (8), but patients taking TAM have to frequently visit gynecologists for screening and are forced to undergo invasive examinations periodically, such as cytology of the endometrium. Furthermore, based on the results of large clinical trials, the recommended duration of TAM has been extended from five years to 10 years (9). Moreover, recent advances in chemo-regimens have reduced the recurrence rate of breast cancer, thus the number of patients who complete adjuvant TAM treatment has been increasing. It is likely that the number of patients who will develop TAM-related EC will increase, and the establishment of preventative methods will be necessary.
A number of basic investigations have attempted to elucidate the characteristics of TAM-related EC. Employing ChIP-seq, Droog et al (10) identified that cross-talk between forkhead box A1 (FOXA1) and ERα might contribute to the development of TAM-related EC. Several oncogenes, such as PTEN and K-Ras, were also investigated (11), however, due to the relatively low occurrence rate, the nature of TAM-related EC is far from fully understood. Therefore, we conducted copy number variation (CNV) analysis by nCounter and investigated MSI status in TAM-related EC and sporadic EC biopsies to assess the molecular genetic characteristics of TAM-related EC.
Materials and methods
Patients
Among patients with HR-positive invasive breast cancer who received TAM as adjuvant endocrine therapy after curative surgery at our institute between 2013 and 2020, 10 patients developed EC after TAM administration (TAM-related EC). We also analyzed 20 sporadic EC samples randomly selected from 98 patients, whom we investigated in our previous study (2), surgically treated during the same period. The average age of TAM-related EC was 49.6 years, and those with sporadic EC was 60.9 years. None of these patients had been clinically diagnosed as having Lynch Syndrome (LS).
Pathological assessment and immunohistochemistry
Pathological assessment for EC and breast cancer was carried out at Juntendo University Hospital by two experienced pathologists (HS and AA) based on the WHO Classification. The histological subtype of all ECs was endometrioid carcinoma. Tissue sections of 4 µm were prepared from formalin-fixed paraffin-embedded blocks of EC surgical specimens and IHC was performed. IHC staining for mismatch repair (MMR) proteins was performed using primary monoclonal antibodies against MLH1 (clone ES05; Dako, Carpinteria, CA), MSH2 (clone FE11; Dako), PMS2 (clone EP51; Dako) and MSH6 (clone EP49; Dako). The staining procedures were previously described in detail (12). All MMR proteins (MLH1, MSH2, PMS2 and MSH6) were assessed for positive staining in the nuclei of cells. IHC for MMR proteins was also performed for breast cancer and endometrial hyperplasia specimens as precursor lesions for EC where available. Protein expression for the products of genes identified as amplified by CNV analysis were also assessed by IHC using the following antibodies: vascular endothelial growth factor receptor 2 (VEGFR2; clone 55B11; Cell Signaling Technology, Danvers, MA), tropomyosin receptor kinase (Trk) C (clone C44H5; Cell Signaling Technology), platelet-derived growth factor receptor β (PDGFRB; clone 28E1; Cell Signaling Technology), Notch1 (polyclonal, Santa Cruz Biotechnology, Dallas TX) and TrkA (clone 12G8; Cell Signaling Technology). Antigen retrieval was performed by heating in tris-ethylenediamine tetraacetic acid buffer (pH 9.0) for VEGFR2 and PDGFRB and in citrate buffer (pH 6.0) for TrkA, TrkC and Notch1.
Nucleic acid extraction
Genomic DNA was extracted from TAM-related EC surgical specimens as follows: 10 µm tissue sections were cut and DNA was extracted using a QIAamp DNA Formalin-Fixed Paraffin-Embedded Tissue kit (Qiagen Inc., Hilden, Germany). EC lesions and non-neoplastic endometrium or simultaneously resected ovary was separately dissected under a microscope for each case. Nontumorous tissue from each patient was used as a control. As nontumorous tissue, ovary and non-neoplastic endometrium were employed for TAM-related EC and sporadic EC cases, respectively.
Copy number variation and microsatellite instability assessment
A total of 30 samples, including 10 TAM-related ECs and 20 sporadic ECs, underwent CNV analysis using the NanoString nCounter gene expression system (NanoString Technologies, Seattle, WA). A customized panel including 28 genes encoding receptor tyrosine kinases which we previously established (13) was employed. The copy number for these genes for each EC lesion compared to the nonneoplastic lesion were determined in nSolver according to the manufacturer's instructions. Each copy number ratio was calculated with the score of nonneoplastic lesion being 2. MSI status was assessed in all 10 TAM-related EC, including 10 surgical and one endometrial curettage specimens. MSI testing was outsourced to the Takara Bio Inc. (Shiga, Japan) and the Fasmac Co. Ltd. (Kanagawa, Japan) as previously described (14). Using a Promega MSI Multiplex System, five loci from the DNA sequence for microsatellite markers (BAT-25, BAT-26, NR-21, NR-24, and MONO-27) were amplified. MSI-high (MSI-H) was determined if instability was detected at two or more markers, as recommended by the revised Bethesda Guidelines (15). Tumors with one or no unstable marker were classified as low levels of microsatellite instability (MSI-L) or microsatellite stable (MSS), respectively.
Methylation assay
Promoter-region methylation status of MLH1 was analyzed in two cases in which MLH1 protein expression was lost by IHC. The detailed procedure has been described (16). The primers for methylated and unmethylated alleles were designed as done by House et al (17).
Ethical approval and informed consent
This study was carried out with approval from the Ethics Committee of Juntendo University (No. 2020281) and complies with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. All participants were informed that the research policy was available on the homepage of the hospital and that they had the opportunity to opt-out of the study at any time later on, which was approved by the Ethics Committee. The Ethics Committee approved of the opt-out method for the use of specimens and clinical data under the condition that all data were anonymized. Authors had access to information that could identify individual participants during or after data collection. Only those participants who had not opted-out from the study were included in the data analysis.
Statistical analysis
Mann-Whitney U tests and unpaired t tests were performed to analyze CNV data between TAM-related ECs and sporadic ECs. In addition, the Fisher's exact test and unpaired t-test was performed to compare clinicopathological data between TAM-related ECs and sporadic ECs, and between the MSI-H and MSI-L/MSS groups in TAM-related ECs. These data were evaluated using a two-tailed test and P<0.05 was considered to indicate a statistically significant difference.
Results
Clinicopathological findings
Table I shows the clinicopathological characteristics of TAM-related ECs and sporadic ECs. Age was significantly younger in patients with TAM-related EC than those with sporadic EC (P=0.004). There was no significant difference in pathological stage based on the FIGO 2008 classification.
Copy number variation and immunohistochemistry between tamoxifen-related endometrial cancer and sporadic endometrial cancer
A summary of the results of CNV analysis is shown in Fig. 1. In total, five genes, KDR, NTRK3, PDGFRB, NOTCH1 and NTRK1, appeared as frequently amplified genes in TAM-related EC, compared with sporadic EC (KDR, P=0.039; NTRK3, P=0.006; PDGFRB, P=0.035; NOTCH1, P<0.001; NTRK1, P=0.011) by either Mann-Whitney U test or unpaired t-test.
Next, IHC for the five proteins encoded by these genes was performed (Table SI). Representative images are shown in Fig. S1. One TAM-related EC case was diffusely and strongly positive for VEGFR2 and weakly positive for PDGFRB. Two sporadic EC cases were focally and weakly positive for TrkC and one sporadic EC case was focally and weakly positive for PDGFRB. Notch1 was positive for all cases and various intensity was seen from 1+ (weakly positive) to 3+ (strongly positive). Overall, intensity of IHC did not correlate with the ratio of copy number.
Microsatellite instability status in tamoxifen-related endometrial cancers
Next, we investigated MSI status in all 10 TAM-related ECs. Of the 10 TAM-related EC cases, four were MSI-H (40%) and six cases were MSS (60%). The clinicopathological findings according to MSI status are shown in Table II. There were no differences in age, pathological stage, EC tumor grade, or the length of time after initiating TAM administration, according to MSI status.
Immunohistochemistry for mismatch repair proteins
Since we observed some MSI-H cases in TAM-related EC, we next conducted IHC for MMR proteins. As shown in Table III, four cases lost some MMR proteins and these corresponded to the MSI-H cases. All of MSI-H cases were endometrioid carcinoma, Grade 1 and one case was classified as FIGO Stage II due to an invasion to cervical stroma. Representative images of one case (Case #1) are shown in Fig. 2. Among the 10 patients with TAM-related EC, surgical specimens of primary breast cancer were available for IHC in six cases. All six breast cancer specimens retained MMR protein expression, including one MSH-H tumor (Case #2).
 | Table III.MSI status and MMR protein expression based on immunohistochemistry in tamoxifen-related endometrial cancer. |
Microsatellite instability status and mismatch repair protein expressions in previous benign biopsy specimens
Among MSI-H cases of TAM-related ECs, Case #2 patient underwent histological examinations of the endometrium several times before developing EC and was diagnosed with endometrial hyperplasia without atypia. Hence, we also examined MSI status and MMR protein expressions in this biopsy specimen of hyperplasia. The benign lesion was MSI-H, and MLH1 and PMS2 expressions were deficient, similar to the surgical specimen of subsequent EC.
Methylation assay for MLH1 promoter region in MLH1 protein-deficient tumors
For two cases in which MLH1 protein was lost by IHC, we further conducted MLH1 methylation-specific polymerase chain reaction. Methylation of the MLH1 promoter region was detected in both cases (Fig. 3).
Discussion
Our CNV analysis revealed that the amplification of five receptor tyrosine kinase genes, KDR, NOTCH1, NTRK1, NTRK3 and PDGFRB, were more frequently detected in TAM-related EC, compared with sporadic EC. Meanwhile, the expression of corresponding proteins for these genes, assessed by IHC, did not reflect the results of the CNV analysis. This discrepancy might be caused by some deficiency or modification in the process of transcription. Yet, the biological significance of these genes for TAM-related EC cannot be ruled out and may merit further investigation.
According to the cBioPortal for Cancer Genomics across TCGA pan cancer atlas (18), the frequency of amplification for each gene in endometrioid carcinoma or mixed carcinoma of EC is low (KDR none, NOTCH1 1.04–4.76%, NTRK1 1.83–19.05%, NTRK3 0.26% and PDGFRB none). Our cases might show the characteristics of TAM-related EC different from sporadic EC. The frequency of MSI-H in TAM-related EC was 40%, higher than what we previously reported in sporadic EC in Japanese patients (2). There have been a few reports on MSI status in TAM-related EC and their results differed to the current study, as the frequency of MSI-H in TAM-related EC was not different from (19) or, rather, was lower than that in sporadic EC (11). However, these studies employed relatively older methods (e.g., with less microsatellite markers) while we followed the revised Bethesda Guidelines. It is unclear whether TAM promotes MSI or not. In the current study, we were unable to perform a functional analysis. Further investigations employing cell lines to assess changes in MSI status with TAM treatment and analysis of endometrial tissue over time before developing TAM-related EC are also warranted.
The high frequency of MSI-H in TAM-related ECs indicates that the prognosis of these tumors may be better than that of sporadic ECs. However, one report suggests a worse prognosis among LS patients with EC occurring in the group taking TAM (20). Considering the recent trend of extension of TAM duration after breast cancer surgery, we believe that it is necessary to continue to investigate the characteristics of this tumor in more detail.
In our study, patients in the TAM-related EC group were significantly younger than those in the sporadic EC group, while the risk of EC due to TAM is known to be higher in older patients (4,21). The main reason for the lower age in our cohort is possibly due to the low frequency of TAM administration in postmenopausal women. Compared to a few decades ago, aromatase inhibitors rather than TAM are now given to most postmenopausal patients as adjuvant endocrine therapy for breast cancer in Japan. Thus, the number of postmenopausal breast cancer patients taking TAM has decreased. Unfortunately, we were unable to collect detailed data on the type and duration of endocrine therapy for all of the patients who underwent curative surgery for breast cancer. Therefore, it was not possible to assess the exact frequency of TAM-related EC development.
We could not completely exclude the possibility that patients with TAM-related EC had a background of LS. For instance, Case #2 developed urinary tract cancer after breast cancer and EC but had no relevant family history. Case #3 had a family history as her mother suffered colon cancer and father experienced urinary tract and liver cancers. Only one primary breast cancer sample was available among the MSI-H cases, and the expression of MMR proteins were retained. However, some reports indicate that breast cancer in patients with LS is not necessarily MSI-H (22,23), hence LS cannot be determined by MMR protein expressions in breast cancer. Nevertheless, no patients in our cohort had undergone genetic testing for LS diagnosis.
Our data indicate that TAM-related ECs are frequently MSI-high. If further study confirms our finding, gynecological routine screening during TAM medication may be less critical than expected because MSI-high EC is known to have a relatively favorable prognosis (1). As such, unnecessary testing may be reduced in the future in clinical practice. Furthermore, for treatment of TAM-related EC, MSI status should be actively tested for to determine the optimal individualized postoperative treatment.
A major limitation of this study is, as with other studies, the small sample size. Another difficulty of analyzing this disease is that presumably not all TAM-related EC develop due to TAM. Considering the low occurrence rate of TAM-associated EC, there is even the possibility that it only arises from biologically altered-endometrium by TAM, but that TAM does not ‘promote’ the development of cancer per se. Given the timing of TAM administration, i.e., duration of the treatment and time after completion of treatment, we believe that it is also necessary to continue to accumulate more patients over a longer period.
In our study, we investigated the molecular characteristics of TAM-related ECs and revealed several genes with specific changes in TAM-related ECs. Furthermore, the frequency of MSI was higher in TAM-related EC. Our findings may lead to a reduction of unnecessary gynecologic testing in clinical practice, and also encourage the testing of MSI status for optimal individualized treatment. We believe that researchers need to continue to analyze TAM-related ECs from a variety of perspectives.
Supplementary Material
Supporting Data
Supporting Data
Acknowledgements
The authors would like to thank Ms. Tomomi Ikeda and Ms. Takako Ikegami (Laboratory of Molecular and Biochemical Research, Biomedical Research Core Facilities, Juntendo University Graduate School of Medicine, Tokyo, Japan) for the technical assistance with microsatellite instability analysis, and Dr Hidetaka Eguchi (Intractable Disease Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan) for technical assistance with the NanoString nCounter gene expression system for copy number variation analysis.
Funding
The present study was supported through grants from the Grant-in-Aid of the Japan Society for the Promotion of Science KAKENHI (grant nos. 20K17594 and 21K15409) and a grant from the Institute for Environmental & Gender-specific Medicine, Juntendo University (grant no. E2011).
Availability of data and materials
All data generated or analyzed during this study are included in this published article.
Authors' contributions
HS, YH and TS designed the study. HS, YH, MTH, YM, LR, YI, TU, EY and YT conducted data acquisition. YH, YI, TU, EY and YT treated patients. HS, YH, AA and TY performed pathological assessment and histological analysis. HS, YH, YM and TS conducted data analysis and statistical analysis. HS and YH drafted the original manuscript and TS and TY substantially revised it. HS and YH confirm the authenticity of all the raw data. All authors have read and approved the final manuscript.
Ethics approval and consent to participate
All procedures performed in studies involving human participants were in accordance with the ethical standards of the Ethics Committee of Juntendo University (approval no. 2020281; Tokyo, Japan) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The requirement for informed consent was waived by the Ethics Committee of Juntendo University.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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