Abstract
Background/Aim: Despite advances in the treatment of breast cancer, metastatic breast cancer (MBC) remains difficult to cure, and few MBC patients survive 10 years after receiving a breast cancer metastasis diagnosis. We collected the cases of patients with MBC who survived >10 years post-metastasis diagnosis and assessed the patients’ characteristics. Patients and Methods: We retrospectively analyzed the cases of 245 consecutive patients diagnosed with MBC between January 2005 and December 2012 at our institution. Among them, 167 patients with confirmed survival of >10 years (i.e., long-term survival) or confirmed death at ≤10 years post-metastasis diagnosis were enrolled. Results: There were 22 patients with MBC who survived >10 years. Regarding the cancer subtypes, 11 patients (50%) with long-term survival were HER2-positive. Seven of the 11 patients with HER2-positive MBC have been without recurrence although anti-HER2 therapy was discontinued. Triple-negative breast cancer (TNBC) was most common in the patients who survived ≤5 years but was not present in the >10-year survival group. In the HER2-negative cases, more cases in the long-term survival group were treated with local therapy (34.4% in the <5-year survival group, 43.8% in the 5-10-year group, and 72.7% in the >10-year group). Conclusion: MBC patients who survive >10 years after being diagnosed with metastasis are more likely to be HER2-positive and treated with local therapy. This suggests the efficacy of anti-HER2 therapy, and, conversely, clarifies unmet needs in TNBC and luminal-type MBC. The usefulness of local therapy was also supported by our findings.
Breast cancer is the most common malignancy in women worldwide (1). It has a relatively good prognosis, and advances in the treatment of breast cancer have improved the survival rate of patients with recurrent or metastatic breast cancer (2, 3). The American Cancer Society reported that the average 10-year survival rate for women with non-metastatic invasive breast cancer is 84%, but, only ~13% of patients with metastatic breast cancer survive for 10 years or more after their diagnosis (4). A recent observative cohort study of newly diagnosed metastatic breast cancer (MBC) in the Epidemio-Strategy-Medical-Economical (ESME)-MBC cohort revealed that the median overall survival (OS) of patients with MBC was 37.22 months (slightly over 3 years) (3). Despite advances in treatment for breast cancer, recurrent and metastatic breast cancer remain difficult to cure, and there are still few patients who survive 10 years. In this study, we collected the cases of MBC patients treated at our institution who achieved long-term survival (>10 years), and we examined their characteristics in an effort to identify factors that may contribute to the long-term survival of MBC patients.
Patients and Methods
We retrospectively analyzed the cases of 245 consecutive patients diagnosed with recurrent or metastatic breast cancer at Gunma University Hospital between January 2005 and December 2012, which assures a follow-up period of >10 years. Patients with incomplete clinical information and MBC patients who are currently alive and whose survival time is ≤10 years since being diagnosed with metastasis were excluded. Among them, 167 patients with confirmed survival of >10 years or confirmed death ≤10 years were enrolled in the study, which was approved by our clinical ethics committee.
This study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Clinical Ethics Committee of Gunma University. Informed consent was taken from the participants of the study. Written consent was obtained from all patients for the use of their tissue samples, their records and imaging in future studies.
The parameters extracted from the hospital’s database included age at diagnosis of metastasis, breast cancer subtype, the presence of de novo stage IV or recurrent disease, the presence/absence of organ metastasis, time to metastasis [i.e., disease-free interval (DFI)] for recurrent cases, sites of metastasis at the diagnosis of metastasis, number of treatment regimens for metastatic disease, use or non-use of local therapy (radiotherapy, surgery, etc.) and overall survival (OS).
Breast cancer subtypes were defined based on the patient’s estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2) status of the primary or metastatic tumor as follows: luminal-type breast cancer (ER- or PgR-positive, HER2-negative), luminal-HER2 type (ER- or PgR-positive and HER2-positive), HER2 type (ER- and PgR-negative and HER2-positive), and triple-negative breast cancer (TNBC) (ER- and PgR-negative and HER2-negative) (5). The ER and PgR statuses were assessed by using an Allred score ≥3 as indicating ER and PgR positivity (5). HER2 over-expression was determined by an immunohistochemistry (IHC) analysis and a fluorescence in-situ hybridization (FISH) analysis with IHC 3+ or IHC 2+/FISH+ indicating HER2 positivity (5).
Statistical analyses. We divided the metastatic breast cancer cases into three groups according to the patients’ survival: those who died ≤5 years after receiving a metastasis diagnosis, those who died between 5 and 10 years after the diagnosis of metastasis, and those who survived for >10 years after a metastasis diagnosis. We conducted a univariate statistical analysis using Fisher’s exact test or the χ2 test with Yates’ correction. Differences were considered significant when p<0.05.
Results
There were 22 patients with MBC who survived >10 years after receiving a metastasis diagnosis during the period examined. The median age of the long-term survivors was 59 years (range=40-76 years). Table I summarizes the characteristics of the patients in the three groups according to survival and presents the results of the univariate analysis conducted to determine the characteristics of the patients who survived for >10 years. In regard to subtypes, 11 (50%) of the long-term survival patients were HER2-positive (HER2 type, n=5; luminal-HER2 type, n=6). TNBC was most common in the patients who survived ≤5 years, and there were no TNB cases among the patients who survived >10 years.
The characteristics of metastatic breast cancer patients who died ≤5 years of a metastasis diagnosis, those who died 5-10 years after a metastasis diagnosis, and those who survived for >10 years.
The DFI for the recurrent cases was shortest in the <5-year survival group but did not differ much between the 5-10-year and >10-year survival groups. The number of treatment regimens for recurrence tended to be higher in the 5-10-year survival group compared to the <5-year survival group and was lower in the >10-year survival group, in which more HER2-positive patients were receiving treatment.
The evaluation of metastatic sites showed that no patients with brain metastasis survived >5 years. In the HER2-negative patients, liver metastases were more common in the 5-year survival group (25.8%), and the rates were 9.4% in the 5-10-year group and 0% in the >10-year group. There were no significant differences among the three groups regarding the presence or absence of local therapy such as radiation. The analysis of the HER2-negative cases revealed that more cases in the long-term survival group were treated with local therapy (34.4% in the <5-year group, 43.8% in the 5-10-year group, and 72.7% in the >10-year group).
Discussion
Metastatic breast cancer is difficult to cure and survival beyond 10 years is not common, but advances in treatment have certainly extended the prognosis (2, 3). In this study, we were able to examine 22 patients with recurrent MBC who survived >10 years. The results of our analyses confirmed a high proportion of HER2-positive cases in the group of patients who survived for >10 years. This may be due to advances in the treatment of HER2-positive breast cancer. The overall survival of MBC patients has improved somewhat in recent years, and this extended prognosis effect has been confined to HER2-positive cases (3). The most remarkable advancement in breast cancer therapy has been the discovery of highly effective agents that can be used in anti-HER2 therapy, such as trastuzumab, pertuzumab, lapatinib, neratinib, ado-trastuzumab emtansine (T-DM1), and trastuzumab deruxtecan (6-9).
In the present study, the DFI of the recurrent cases was shorter and the number of treatment regimens for recurrence tended to be lower in the >10-year survival group. A possible explanation for the shorter DFI to metastasis and fewer treatment regimens for metastasis in the long-term survivors may be that these patients are more sensitive to treatment for MBC, including anti-HER2 therapy. We also observed that 7 of the 11 patients with HER2-positive MBC have been without recurrence as of this writing, although their anti-HER2 therapy was discontinued. These data may indicate that anti-HER2 therapy could be curative for some patients with HER2-positive MBC, which is considered to be difficult to cure (10).
None of the present patients with TNBC survived >10 years, confirming the unmet need in TNBC treatment. Immune checkpoint inhibitors have been clinically applied to TNBC and are expected to improve the prognosis in the near future (11-13). However, the further development of treatment methods for TNBC is necessary.
For the luminal types of breast cancer, CDK4/6 inhibitors and PI3K inhibitors are now in clinical application (14-16), and a further improvement in prognosis is expected in the near future. Our present cohort included 11 MBC patients with luminal-type cancer who survived for >10 years. An interesting finding of our analyses is that many of the patients who achieved long-term survival were treated with local therapies such as radiation and surgery. The efficacy of local therapy for oligo-metastases has been reported and studied in recent years, and it is possible that local therapy may be useful for MBC patients as well (17-19). The usefulness of local therapy should be evaluated carefully, because there may be a potential bias in that many long-term survivors are included in this study in which local therapy can be considered. We also note that local therapy with irradiation has been attempted in cases of brain metastases, with poor prognoses. Further research is needed to determine the usefulness of local therapy for MBC.
Regarding metastatic sites, patients with brain metastases from breast cancer have a high mortality rate and poor prognosis (20). Our patient cohort had no patient with brain metastasis who survived >5 years. Local treatment such as surgical resection and radiation therapy remains the major treatment for brain metastases, but the possibility of systemic therapy to control brain metastases (especially in HER2-positive cases) has been reported, and future developments are promising, as is local treatment (21, 22). Poor prognosis has also been reported for liver metastases in patients with breast cancer metastases (23). In the present HER2-negative patients, liver metastases were more common in the 5-year survival group, and there were no liver metastases in the >10-year survival group, which is consistent with a previous report (23). However, even with liver metastases, the present study’s HER2-positive patients survived for a long period of time, suggesting the possibility of long-term disease control.
This study has several potential limitations, including its retrospective design and the relatively small number of patients. The choice of treatment is likely to be made by the treating physicians and is thus not constant. However, our findings are valuable as there is apparently no published prior examination of cases of MBC patients surviving beyond 10 years. Our results are also thought-provoking as they suggest the efficacy of anti-HER2 therapy and, conversely, clarify unmet needs in TNBC and luminal-type MBC. The usefulness of local therapy is also supported by our findings.
In conclusion, the survival of patients with metastatic breast cancer has been prolonged, and further improvement is expected. Our analyses revealed that metastatic breast cancer patients who survive >10 years are more likely to be HER2-positive and more likely to have a luminal type of MBC that was treated with local therapy. In light of our findings, the sensitivity of HER2-positive breast cancer should be examined. Long-term survival may be expected for cases in which local therapy can be considered, and further investigations of the efficacy of local therapy are merited.
Acknowledgements
The Authors would like to thank Ms. Fumie Takada and Ms. Harumi Kanai for their secretarial assistance. FT and HK belong to the Department of General Surgical Science, Gunma University Graduate School of Medicine. Maebashi, Gunma, Japan.
Footnotes
Authors’ Contributions
MK and TF analyzed data and wrote the initial draft of the manuscript. MK, TF, CH, KT, YN, MO and SO collected data and were involved in the initial study conception and design. TF and MK interpreted the results and were involved in drafting the work and revising it critically for important intellectual content. KS approved the final version to be published. All Authors have read and approved the final manuscript.
Conflicts of Interest
The Authors have no competing interests as defined by BMC, or other interests that might be perceived to influence the results and/or discussion reported in this paper.
- Received November 3, 2022.
- Revision received November 14, 2022.
- Accepted November 15, 2022.
- Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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