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Role of Surgery in Metastatic Breast Cancer: Insights from a Narrative Review

Maha ahmed alamodi alghamdi, syed esam mahmood.

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Correspondence: Syed Esam Mahmood, Abha, 62529, Saudi Arabia, Tel +966550484344, Email [email protected]

Received 2023 Jan 24; Accepted 2023 Apr 27; Collection date 2023.

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/ ). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php ).

Metastatic breast cancer is difficult to cure and has a worse prognosis with higher rates of mortality. Recently, breast surgery is believed to improve the survival rates among these women, but due to limited evidence, definite conclusions cannot be made. Therefore, we undertook this narrative review to synthesize the evidence from existing studies to assess the effectiveness of locoregional surgery and surgery of metastatic sites in improving the outcomes among women diagnosed with metastatic cancer disease along with the summary of current treatment guidelines. We reviewed PubMed and Embase and included both observational studies and randomized controlled trials (RCTs) that were published in English between 2000 and 2021. Outcomes were either survival, quality of life, toxicity related to local treatment assessed by mortality at the end of one month, progression-free survival, and breast cancer-specific survival. The main effect size assessed was hazard ratio with their 95% CIs. After literature search, we found 8 observational studies and 3 RCTs. The findings of the observational studies revealed that breast cancer surgery improves survival from 30% to 50% among women. However, findings from RCTs were mixed for local and distant progression survival. Surgery improved the local progression-free survival but worsened the distant progression-free survival. Besides, there was no effect of breast surgery on quality of life. Regarding the surgery of metastatic site, studies are complex with mixed findings and variation in survival depending upon the type of metastatic site and response to initial systematic therapy and other factors. Based on the existing mixed evidence, it is not possible to make firm and definite conclusions about the effectiveness of breast surgery in improving the survival or quality of life among women with metastatic breast cancer. In future, more RCTs are required with a larger sample size to confirm the findings of observational studies.

Keywords: breast surgery, metastatic breast cancer, women, narrative review

Introduction

Breast cancer is a highly prevalent cancer in women across the world as it contributes to 25% of all diagnosed cancers. 1 It is the second most common cause of cancer-related mortality in the United States. 2 It is estimated that one out of every eight women will be diagnosed with breast cancer in their lifetime and the most commonly affected age group is 55 to 64 years. 3 Each year, approximately 1.67 million cases of breast cancer are identified globally. 4 Of the total breast cancer cases, 20% to 30% end up having metastatic breast cancer, which eventually causes 400, 000 to 50,000 deaths annually across the world. 5 At the time of initial diagnosis, around 3.5% of women with breast cancer had already developed distant metastasis in the United States and this proportion is even higher in resource-poor settings. 6 This implies that annually around 50,000 women will be diagnosed with metastatic breast cancer. 7

While it may be challenging to have a complete cure for metastatic breast cancer, women can now live relatively longer than before due to various treatment modalities. This has increased the survival rate of five years from 10% in 1970 to approximately 40% after 1995. 8 Also, the existing evidence reveals that median survival has improved from 20 to 26 months over the last two decades. 9 However, this increased life expectancy may enhance the risk of symptoms among those women who have not undergone surgical removal of the breast. Although it is necessary to treat breast cancer, sometimes treatment can negatively affect the women’s quality of life. 10 This is perhaps due to fear of developing the disease again, decrease sexuality, and loss of job.

Since metastatic breast cancer is considered an incurable disease with a worse prognosis, usually patients are provided with palliation and systematic therapy. 11 Typically, breast surgery is performed if a woman presents with symptoms. Over the last many decades, it was believed that after metastasis, aggressive local treatment is not beneficial and therefore should not be considered as the treatment of choice. 12 However, evidence from retrospective observational studies and few intervention studies suggest that patients with metastatic breast cancer may benefit from surgery and removal of the breast tumor. 12 This evidence-primarily comes from observational studies, which are subject to confounding and selection bias issues. 13 Therefore, it is important to review the evidence both from observational and interventional studies before making any conclusions about the role of breast surgery in metastatic breast cancer. Further, the evidence generally considers systematic therapy as the main treatment modality in case of metastasis. However, locoregional surgery by removing the breast and axillary tissues along with treating or doing surgery of meta-static site may reduce the symptoms and prevent cancer-related adverse outcomes. To provide up-to-date evidence, we performed a narrative review of both observational and interventional studies carried out to synthesize the findings regarding the efficacy of breast surgery in treating metastatic breast cancer. In addition, we also reviewed the evidence regarding the role of surgery of metastatic sites in preventing cancer-related complications followed by providing a summary of current guidelines in managing metastatic breast cancer.

This narrative review addresses the research question of what is the benefit of breast surgery (mastectomy: removal of the complete breast along with lymph nodes, nipple and areola or lumpectomy: removing breast tissue and tumor but preserving nipple and areola) among women diagnosed with metastatic breast cancer. Any study either observational or intervention study that assessed the effectiveness of breast surgery in improving the survival or quality of life among women with metastatic breast cancer, published in the English language between 2000 and 2021 was included. We searched the databases such as PubMed and Embase by using appropriate search terms such as “Breast surgery” OR” mastectomy” OR “lumpectomy” AND “Metastatic disease” AND “Survival” AND “observational studies” OR” intervention studies” AND “Quality of Life”. The randomized controlled trials that compared breast surgery with systematic therapy including endocrine therapy, chemotherapy, radiotherapy, biologic therapy, and supportive care against only systematic therapy were included. Outcomes were either survival, quality of life, toxicity related to local treatment assessed by mortality at the end of one month, progression-free survival, and breast cancer-specific survival ( Table 1 ).

Methodology Applied for the Development of This Narrative Review

Study Results

Indication of locoregional surgery (breast and axilla) in metastatic breast cancer: evidence from observational studies.

Overall, the existing evidence from retrospective observational studies reveals a beneficial effect of breast surgery in improving the survival of women ( Table 2 ). For instance, a study by Khan et al in 2002 on 16,023 patients found that breast surgery improved the survival of women by almost 40% (HR: 0.61, 95% CI: 0.58 to 0.65) with statistically significant results. 6 In 2006, Babiera et al conducted a retrospective analysis of 224 patients and 37% of those underwent surgery. 14 The findings of the study demonstrated that breast surgery improved survival by 50% (HR: 0.51, 95% CI: 0.21 to 1.19); however, the results were not statistically significant. 14 These findings were in agreement with a study by Rapiti et al who performed the study in the same year (2006) on 300 patients. 15 Around 42% of the women underwent surgery and authors found surgical treatment reduces the mortality by 40% (HR: 0.60, 95% CI: 0.4 to 1.0) with statistically non-significant results as shown in Table 2 . 15

Summary of Findings Regarding the Effectiveness of Locoregional Breast Surgery in Women Diagnosed with Metastatic Breast Cancer

Likewise, in 2007, Fields et al undertook a study on 409 patients and 46% of women underwent surgery. 16 Authors found that surgery improved survival by almost 50% with statistically significant results (HR: 0.53, 95% CI: 0.42 to 0.67). These findings were analogous to the study by Babiera et al, which provided evidence for the protective effect of breast surgery against mortality. 14 This series of observational studies were followed by subsequent studies from 2006 to 2010 with almost consistent findings for the effect size of the hazard ratio. For instance, in 2007, Gnerlich et al undertook a huge study on 9734 women and 47% of them underwent surgery. 17 Findings revealed that breast surgery reduces mortality by almost 40% with significant and reasonably precise results as indicated by narrow confidence intervals (HR: 0.63, 95% CI: 0.60 to 0.66). 17 In the next year (2008), Blanchard found similar results, however, with wide 95% CIs most likely due to the small sample size of 395 (HR: 0.71, 95% CI: 0.56 to 0.91). 18 These findings were confirmed by Ruiterkam et al and Neuman et al, where surgery was found to reduce mortality by almost 30% to 40%. However, as opposed to Ruiterkam et al (HR: 0.62, 95% CI: 0.51 to 0.76), Neuman et al did not find statistically significant results (HR: 0.71, 95% CI: 0.47 to 1.06). 19 , 20 These results are analogous to subsequent retrospective studies conducted during the same decade, which provide similar conclusions about the role of breast surgery in improving the survival of women diagnosed with metastatic cancer. 21 , 22

Indication of Locoregional Surgery (Breast and Axilla) in Metastatic Breast Cancer: Findings from Interventional Studies

While the observational studies suggest the protective role of surgery in metastatic cancer, these studies are not free of limitations. Due to limitations of internal threats to validity resulting from selection and information bias, and unmeasured confounding, it is crucial to review the evidence from interventional studies before making any firm conclusions. This is because randomized controlled trials (RCTs) control for known and unknown confounders and such designs are considered the ideal and gold standard to address the issues of unmeasured confounding. Recently, only four RCTs are conducted to compare the locoregional surgery plus systematic treatment against only systematic treatment in improving the survival, quality of life, local progression-free survival, distant progression-free survival, breast cancer-specific mortality, and toxicity due to local treatment among women diagnosed with metastatic breast cancer. 23 , 24 If we apply the PICOS framework to such RCTs, the population would be women diagnosed with breast cancer, intervention would be breast surgery plus systematic treatment, the comparison would be systematic treatment, the outcome is the survival or mortality, and setting would be inpatient or outpatient departments. For example, Badwe et al and Soran et al undertook two RCTs on 624 women in 2015 and 2016, respectively, to compare the breast surgery plus systematic treatment with only systematic treatment ( Table 2 ).

Badwe et al conducted a study in India on women who responded to systematic therapy initially, 24 whereas Soran et al carried out a study on women without any previous systematic treatment. 23 Authors found that overall survival at two years improved by almost 20% in the intervention group; however, results were not statistically significant (HR: 0.83, 95% CI: 0.53 to 1.31). 23 , 24 The risk of death was 511 per 1000 in the comparison group, whereas it was 448 per 1000 in the intervention group with a range of 318 to 608 per 1000. 23 , 24 However, the authors did not report the quality of life as an outcome of interest. 23 , 24 Regarding local progression-free survival at two years, findings were statistically significant (HR: 0.22, 95% CI: 0.08 to 0.57), which reveals that breast surgery improved the local progression-free survival by almost 80%. 23 , 24 However, the results were inverse for the distant progression-free survival (HR: 1.42, 95% CI: 1.08 to 1.86), which indicate that surgery may worsen the distant progression-free survival. 24 On the other hand, Radisic et al published an RCT in 2020 to compare the effect of primary surgery on patient-reported quality of life versus no surgery among women with metastatic breast cancer. 25 Authors randomized 90 women to either surgery or a systematic therapy without surgery. 25 The study demonstrated no statistically significant difference in the quality of life as reported by the patients between the intervention and control group. 25 The authors concluded that primary surgery neither improves nor deteriorates the quality of life ( Table 2 ). In 2020, a multi-center trial was conducted on 256 patients diagnosed with stage IV breast cancer who already had undergone systematic therapy for 4 to 8 weeks and were randomized to either systemic therapy or local surgery with or without radiation followed by resuming the systematic therapy. 26 The authors did not find any difference in the three-year survival between the two groups (HR: 1.09, 95% CI: 0.80 to 1.49). Although women receiving only systematic therapy were at a higher risk of locoregional progression, they experienced almost equal or even better quality of life-related outcomes when compared with women receiving local surgery. 26 Another trial by Eastern Cooperative Oncology Group ‐ USA is not completed yet and probably will end by 2025. This trial compares early surgery against standard palliative therapy to treat women with advanced breast cancer. Based on the findings from limited RCTs with inconsistent findings, it is unclear whether breast surgery is effective for metastatic breast cancer until evidence is drawn from more well-designed and well-executed RCTs in the future on the larger sample size.

Sites of Metastasis in Breast Cancer and Evidence for the Indication of Surgery of Metastatic Site

There could be various sites where breast cancer can spread such as the brain, eyes, bones, lungs, liver, ovaries, and gastrointestinal tract. Metastasis to these sites is sometimes considered an emergency, leading to making decisions about surgically removing the metastatic site. However, the evidence to perform surgery or provide any other treatment differ by the site of metastasis. For example, for patients with metastasis to the brain, surgical resection, stereotactic radiosurgery, or radiotherapy of the whole brain should be considered regardless of the patient is having symptoms or not. 27 However, this should be done either before or concurrently with systematic treatment. However, there are some exceptions to this for selected patients with restricted intracranial disease due to HER2-positive breast cancer, where only systematic therapy may be considered an option in some cases. Meanwhile, radiation therapy is used for patients with multiple metastatic deposits or extensive leptomeningeal disease. However, for patients with the limited intracranial disease, stereotactic radiosurgery is used whenever possible rather than the radiation of the whole brain to reduce the risk of toxicity. 28

On the other hand, metastasis involving ophthalmic structures ranges from 5% to 38%, with the commonly involved site in metastatic breast cancer being choroid followed by iris, optic nerve, orbital bone, retina, extraocular muscles, vitreous body, ciliary body, an optical disc. 29 , 30 There should be multidisciplinary decisions for local therapy when metastasis involves choroid. 31 In case of metastasis involving ophthalmic structures, a brain CT scan and MRI are also recommended to figure out any concurrent brain metastasis. As far as treatment options for choroidal metastasis are concerned, there are various options. For example, among asymptomatic patients, systematic therapy with careful follow-up and observation is recommended. Whereas, in symptomatic patients, palliative external-beam radiation therapy after sparing the lens and the anterior chamber is considered a safe and effective therapy. For instance, evidence from a prospective study conducted in Germany revealed that visual function improved in 36% of the patients and stabilized in 50% among those who were treated with external-beam radiation therapy (40 Gy) after being diagnosed with choroidal metastasis. 32 On the follow-up of these patients, complete and partial regression was documented in 38% and 44% of the patients, respectively. Likewise, short courses of external-beam radiation therapy may also be useful and improve the visual symptoms and visual acuity as found in one observational study on 123 patients. Other local treatment alternatives could be plaque brachytherapy, proton therapy, or intravitreal injection of anti-vascular endothelial growth factors. 33 However, the data on these therapies are limited and based on case reports or case series. 33

In case of metastasis to bone, indications for local treatment include any bone disease or pathologic fracture, compression of the spinal cord, decreased movement or pain, and disability. Bony metastasis usually responds well to systematic therapy and for asymptomatic patients without evidence of impending fracture, there is no clear evidence and role for resection. However, in the case of painful metastasis, a large body of literature supports the use of the short course, local-fixed external-beam radiation therapy in single or multiple fractions. 34 , 35 Similarly, metastasis to the lungs typically does not need to be intervened locally until patients develop some life-threatening symptoms due to internal or external obstruction to superior vena cava where local treatments may benefit. 36–38 In some cases, pulmonary resection can be done for diagnostic as well as palliative purposes because solitary pulmonary nodules may not be actually breast cancer metastasis. There is no valid and robust data suggestive of resecting the pulmonary tissues in case of metastatic breast cancer except date from case series suggest that it may improve 5-year survival from 30% to 80%, and median survival duration may increase from 40 to 100 months among selective breast cancer patients. 39–42 Findings from a meta-analysis on 2000 patients documented a 5-year survival rate of 46% after resecting isolated metastasis of lung tissue. 43

In case of metastasis to the liver, where more than 50% of the breast cancer can metastasize and most likely present with the disseminated disease with poor prognosis than metastasis to bones or soft tissues with 5% to 10% have isolated involvement of liver. 44 , 45 Usually, local management of liver metastasis is done in case symptoms such as pain, bleeding not treated by medical therapy, or in case of biliary obstruction. However, sometimes local resection is done in symptomless patients, despite the absence of any prospective data comparing systematic treatment with the local treatment. Typically, the local treatment includes hepatic resection and stereotactic body radiation therapy to ablate liver metastasis after evaluating the patient carefully. For peripheral lesions more than 5 cm, surgery can be sometimes useful in preserving the liver function than stereotactic body radiation therapy. However, for central lesions, stereotactic body radiation therapy may work better. Further, the retrospective studies suggest local efficacy of radiofrequency ablation, mainly for hepatic lesions that are solitary and smaller than 3cm, not close to the diaphragm, biliary structure, and major vessels. 46–48 The findings of the systematic review of 19 retrospective studies (n = 535 patients) where hepatectomy was performed for metastatic breast cancer. 49 The results showed that median overall survival was 40 months, five-year survival was 40%, and postoperative mortality was 0% to 6%. 49 However, in a subsequent case-control study of 167 patients, overall survival between those who received surgery and/or ablation was not different from those who were treated medically. The findings indicated that local treatment may offer a significant time of disease-free survival and time from systematic chemotherapy among patients with favorable risk-disease. 50

Lastly, the gastrointestinal tract is usually less likely affected by metastasis, and organs such as the stomach and colon are involved followed by the esophagus and small intestine. 51 The choice of local procedure in case of gastrointestinal tract metastasis should be done with the multidisciplinary approach after reviewing the patient’s symptoms, clinical indications, and ruling out other conditions such as primary tumor of the gastrointestinal tract, lymphoma, or any other benign disease. Similarly, ovaries are also a rare site for breast cancer metastasis. 52 Oophorectomy may provide a beneficial therapeutic effect for premenopausal patients with hormone receptor-positive breast cancer irrespective of metastatic disease to the ovaries is present or not. There are limited data available regarding the local management of ovarian metastasis. In a series of 147 patients with ovarian metastasis, overall median survival was 41 months following ovarian metastasectomy. 53

This narrative review provides insights into the role of breast surgery in metastatic breast cancer by synthesizing findings from both observational and interventional studies. The findings from the review of observational studies the beneficial effects of breast surgery in improving the survival of women diagnosed with metastatic breast cancer. These findings are consistent across all retrospective studies included in the narrative review with variation in statistical significance, which may be due to differences in the sample size. Despite the consistent evidence from observational studies, critics consider this as low quality of evidence because of substantial bias associated with observational studies. Regardless of this criticism, a possible explanation for such findings or mechanism by which breast surgery may work is because the primary breast tumor is perhaps a reservoir of tumor cells and can be a source of more cells that can grow and dislodge to other tissues. 54 Therefore, removal of primary breast tumor may reduce the probability of generating new metastasis, thereby improving survival. Besides, the tumor cells may produce growth factors, which can trigger signals that may help the growth of metastatic sites. 55 The evidence from animal studies suggests that resection of the primary tumor may result in a decline in the growth of metastatic tumors. 56

Contrary to this, the evidence from very few RCTs is limited and inconclusive. The findings of the RCTs reveal that breast surgery may improve the two-year survival, local progression-free survival but may not improve the distant progression-free survival and quality of life. Thus, without robust evidence drawn from several RCTs, it is hard to make definite conclusions on the benefits and risks of breast cancer surgery for metastatic breast cancer. Also, the existing evidence is clueless about the breast-specific survival and evidence for toxicity from local treatment does not differ across two groups that only comes from one RCT. Further, women diagnosed with metastatic breast cancer are not a homogenous group of patients rather they differ from each other based on prognoses. It is possible that women with minimal metastasis may have better survival than women whose multiple organs are affected by metastasis. 24 This suggests that RCTs need to be conducted from different countries rather than relying on data from one or a few countries. This is because women in developed countries may be diagnosed at an earlier stage with minimal metastasis, whereas women from developing countries may be diagnosed with multiple organ metastasis. This may affect the results of surgery in two groups of women, therefore, generalizing findings from a few RCTs to all women may not be warranted.

Summary of the Current Guidelines (National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO) in Metastatic Breast Cancer

Survival of patients diagnosed with metastatic breast cancer is increasing as a result of new treatment modalities; therefore, patients should be given optimal treatment to control their symptoms and provide spiritual and psychological support. 57 Typically, such patients are treated with systematic therapy, but this can be given along with locoregional surgery after evaluating the disease status of the patients. Generally, the guidelines recommend taking a multidisciplinary approach for the adequate management of metastatic breast cancer. According to ESMO clinical practice guidelines, treatment decisions of these patients should not depend upon the patient’s age; however, patients’ comorbid, and preferences need to be taken into account by taking a joint multidisciplinary approach. 58 Besides, supportive care should be considered in the overall treatment plan of ABC along with palliative care to control the symptoms of patients. 58 Therapeutic decisions need to be made in a multidisciplinary context for patients who are newly diagnosed with stage IV breast cancer with intact primary tumor. In the absence of symptomatic local disease, locoregional treatment of the primary tumor is not beneficial to improve overall survival and therefore is not recommended in routine. 58 Among patients experiencing local symptoms due to primary tumor or metastasis, there is a need to evaluate the use of local treatment approaches. 58 The resection of the primary tumor may be considered for those patients who are diagnosed with metastasis to bones only, HER2-negative tumors, patients younger than 55 years of age, patients who are diagnosed with HR-positive tumors, patients with oligometastatic disease, and those who respond well to initial systematic therapy. 58 Further, for patients diagnosed with advanced breast cancer (ABC), this includes both inoperable locally advanced breast cancer and metastatic breast cancer. 59 The ABC guidelines, jointly developed by ESMO and The European School of Oncology (ESO), are endorsed by multiple international organizations and have been recently updated with the details of treatment modalities after assessing the symptoms, pathology reports, and other workups of the patient. 59 These guidelines are based on the principle of equal access to multidisciplinary and specialized care including anticancer care, palliative and end-of-life care with full implementation of guidelines tailored to the needs of the patients. 59

Conclusion and Implications for Future Research

The observational studies suggest the beneficial effect of breast surgery in metastatic breast cancer; however, the evidence from RCTs is very limited and inconclusive. Without having firm evidence from RCTs, it is hard to make any conclusions about the benefits of breast surgery because observational studies are usually affected by issues of selection bias and unmeasured confounding. Until the data from large ongoing RCTs is obtained, the decision to perform surgery on a woman diagnosed with metastatic breast cancer should be individualized. Both patient and physician need to decide together about the treatment keeping the risks, benefits, and costs of each intervention in mind. Due to a dearth of robust evidence, future RCTs with larger sample sizes should be carried out both in developing and developed countries, and these RCTs should separately analyze the group of women who are symptomatic versus non-symptomatic or they are provided with systematic therapy or not before the surgery. Also, one needs to consider HER2-positive breast cancer with metastasis and compare the outcomes separately for those who either did or did not obtain anti-HER2 treatment.

Funding Statement

The authors extend their appreciation to the Deanship of Scientific Research at King Khalid University for funding this work through large group Research Project under grant number RGP2/263/44.

Institutional Review Board Statement

Ethical review and approval were waived for this study due to it not directly involving human subjects (secondary research study).

Informed Consent Statement

The study itself was a review article and did not involve human subjects and hence patient consent was waived.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

The authors declare no conflicts of interest in this work.

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Intensity of metastasis screening and survival outcomes in patients with breast cancer

Jong-ho cheun, jigwang jung, eun-shin lee, jiyoung rhu, han-byoel lee, kyung-hun lee, tae-yong kim, wonshink han, seock-ah im, dong-young noh, hyeong-gon moon.

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Corresponding author.

Contributed equally.

Received 2020 Jun 2; Accepted 2021 Jan 11; Collection date 2021.

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ .

Previous randomized trials, performed decades ago, showed no survival benefit of intensive screening for distant metastasis in breast cancer. However, recent improvements in targeted therapies and diagnostic accuracy of imaging have again raised the question of the clinical benefit of screening for distant metastasis. Therefore, we investigated the association between the use of modern imaging and survival of patients with breast cancer who eventually developed distant metastasis. We retrospectively reviewed data of 398 patients who developed distant metastasis after their initial curative treatment between January 2000 and December 2015. Patients in the less-intensive surveillance group (LSG) had significantly longer relapse-free survival than did patients in the intensive surveillance group (ISG) (8.7 vs. 22.8 months; p = 0.002). While the ISG showed worse overall survival than the LSG did (50.2 vs. 59.9 months; p = 0.015), the difference was insignificant after adjusting for other prognostic factors. Among the 225 asymptomatic patients whose metastases were detected on imaging, the intensity of screening did not affect overall survival. A small subgroup of patients showed poor survival outcomes when they underwent intensive screening. Patients with HR-/HER2 + tumors and patients who developed lung metastasis in the LSG had better overall survival than those in the ISG did. Highly intensive screening for distant metastasis in disease-free patients with breast cancer was not associated with significant survival benefits, despite the recent improvements in therapeutic options and diagnostic techniques.

Subject terms: Breast cancer, Metastasis

Introduction

Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer-related death among women 1 . Despite improved overall survival among patients with breast cancer 2 , a significant number of patients eventually develop distant metastasis after initial treatment 3 . The diagnosis of distant metastasis in patients with breast cancer is clinically and psychologically important because the presence of metastasis results in a shift of disease-free status into incurable stage IV status.

Current major guidelines recommend against the use of routine imaging to detect distant metastasis in asymptomatic patients with breast cancer 4 , 5 . These recommendations are based on the findings of randomized trials that showed no survival or quality-of-life benefits on routine intensive imaging studies for breast cancer 6 – 8 . A recently updated systematic review of the randomized trials showed that regular physical examination and yearly mammograms are as effective as highly intensive imaging considering overall survival 9 . Thus, intensive screening for distant metastasis does not provide survival benefit but rather increases the risk of extending the duration of toxic treatment, as intensive screening might result in the earlier detection of metastatic lesions 6 , 7 .

However, the above-mentioned randomized trials were conducted nearly three decades ago when treatment strategies for resectable breast cancer were substantially different from those used currently. Moreover, the survival of patients with metastatic breast cancer has significantly improved over the last three decades 10 – 12 . Furthermore, a subset of patients with metastatic breast cancer experience durable clinical remission when they are treated with intensive multidisciplinary approaches for oligometastatic lesions 13 , 14 . Finally, there has been a significant improvement in the diagnostic accuracy of various imaging techniques. Thus, the clinical benefit of intensive screening for distant metastasis should be reevaluated.

Retrospective analysis of the benefit of intensive screening for patients with breast cancer has major drawbacks: patients at a higher risk of developing distant metastasis may undergo imaging tests more frequently, resulting in selection bias 15 , 16 . Moreover, patients who undergo intensive screening may show improved post-relapse survival, as the metastatic lesions might be detected earlier, resulting in lead-time bias, and the lesions can be biologically indolent, causing length bias 17 . Accordingly, in the present study of 398 patients with breast cancer with distant metastasis, we tried to minimize selection bias by excluding all patients without distant metastasis and aimed to negate lead-time bias by defining survival as the duration between the date of initial treatment and the date of death.

Patients and methods

We obtained the baseline clinical data and reviewed the detailed information of patients with breast cancer who were diagnosed between January 2000 and July 2015 from our institutional database of patients with breast cancer. We included patients who developed distant metastasis after the initial recurrence-free survival (RFS) treatment. We excluded patients with synchronous or metachronous malignancies in other organs, bilateral breast cancer, male breast cancer, and recurrent breast cancer. We identified 398 patients who were initially diagnosed with non-metastatic, resectable breast cancer, received follow-up care in our institution, and eventually developed distant metastasis. From the database, we obtained the baseline characteristics and clinicopathologic information. Initial breast cancer was pathologically staged according to the 7th AJCC criteria. Hormone receptor (i.e., HR, including estrogen and/or progesterone receptors) data were collected according to immunohistochemistry findings, with positivity defined as > 1%. Human epidermal growth factor receptor type 2 (HER2) status was evaluated with anti-HER2 antibodies and/or fluorescence in situ hybridization. We also collected the data regarding the use of various imaging studies including chest radiography, bone scintigraphy, computed tomography (CT), ultrasonography (USG), magnetic resonance imaging (MRI), and fludeoxyglucose-positron emission tomography ( 18 F-FDG/PET).

Distant metastasis and screening intensity

Distant metastasis was defined as any recurrences at any sites outside the breast and regional lymph nodes. The metastatic sites included the bones, lungs, pleura, liver, brain, and distant lymph nodes; they were classified into bone, visceral (lung, pleura, liver, brain, and distant lymph node), and mixed metastases (bone and visceral) for comparison. When metastases were observed in multiple organs within 2 months of treatment, they were defined as multiple site metastases. The clinical diagnosis of distant metastasis was made after histologic confirmation of metastasis or imaging findings compatible with metastasis when biopsy was not feasible. We also reviewed the presence of symptoms associated with metastases using each patient’s medical records. Ambiguous cases such as the perception of symptoms after knowing the presence of metastasis or symptoms not associated with the site of metastases were considered asymptomatic.

To assess the intensity of distant metastasis screening, we calculated the time interval between the date of clinical diagnosis of distant metastasis and the date of previous imaging examinations that targeted the organ where the metastasis developed. For example, if a patient developed bone metastasis, the screening intensity was determined considering the date of the previous bone scintigraphy or  18 F-FDG/PET. For lung and liver metastases, the dates of chest radiography, chest CT, and 18F-FDG/PET and the dates of abdominal USG, abdominal CT, and  18 F-FDG/PET were considered, respectively (Fig.  1 ). Additionally, we performed same analysis using a different definition of surveillance intensity by calculating total number of exams between the time of operation and diagnosis of distant metastasis dividing with RFS for each patient. Moreover, only tests that were conducted within 2 years before the occurrence of metastasis were analyzed separately.

Definition of time intervals. We calculated the interval between the date of clinical diagnosis of metastasis and the date of previous imaging studies of target organs. For instance, for a patient with lung metastasis, as shown in this figure, the time interval (X 2 ) was defined as the date between chest CT at diagnosis of metastasis and previous chest radiography, not including abdominal USG and abdominal CT. 18 F-FDG-PET was allowed regardless of metastasis sites. The time intervals for patients with bone metastasis (X 1 ) and those with liver metastasis (X 3 ) were calculated with the same principles. USG, ultrasonography; CT, computed tomography; 18 F-FDG-PET, fludeoxyglucose-positron emission tomography.

Statistical analyses

Overall survival was the time between the date of initial diagnosis and the date of death. Recurrence-free survival was the time from the date of initial diagnosis to the date of first clinical diagnosis of distant metastasis. The date of death was obtained from the Office for National Statistics of Korea. Survival analyses were performed with the Kaplan–Meier method. The log-rank test and Gehan-Breslow-Wilcoxon test were used to compare survival curves. The Cox proportional hazards regression model was used for multivariate survival analysis. Variables that showed a  P -value < 0.05 on the log-rank or Breslow test were included in multivariate analysis. All analyses were performed using SPSS (version 22.0; SPSS, Inc.). The statistical significance was set at  P  < 0.05.

Ethics approval and consent to participate

This study was approved by the institutional review board (IRB) of Seoul National University Hospital (SNUH; IRB No. H-1905-047-1031), and the study followed the Declaration of Helsinki and good clinical practice guidelines. All patients gave informed consent.

Patient characteristics

We identified 398 patients with breast cancer who developed distant metastasis and who met the inclusion criteria. The mean age at the time of initial treatment was 47.6 ± 11.0 years. Almost half of the patients had stage III breast cancer initially (45.8%), and two-thirds of the patients underwent mastectomy (68.6%). The clinical characteristics of the included patients are listed in Table 1 . The interval between the detection of metastatic lesions and the date of previous imaging studies for the particular organ for each individual patient is shown in Fig.  1 . The median interval between the previous imaging study and the detection of metastasis was 10.5 ± 9.8 months. Our patients were classified into two groups: the intensive screening group (ISG, n = 199) and the less-intensive screening group (LSG, n = 199), with median intervals of 4.5 ± 1.6 and 16.4 ± 11.0 months, respectively. The ISG had a significantly higher incidence of neoadjuvant chemotherapy, postoperative radiotherapy, stage III disease, and previous history of locoregional recurrence, and was more likely to be diagnosed in more recent years (Table 1 ).

Demographic and clinical characteristics of patients.

Data are number of patients and percent (%) or mean ± standard deviation.

ISG intensive surveillance group, LSG less-intensive surveillance group, BMI body mass index, BCS breast-conserving surgery, HER2 human epidermal growth factor receptor 2, TNBC triple-negative breast cancer.

a Stratified according to the American Joint Committee on Cancer (AJCC) 7 th TNM stage.

Survival outcomes and screening intensity

The distant-metastasis free survival of the 398 patients with breast cancer according to the frequency of imaging studies is shown in Fig.  2 a. Patients in the ISG had a significantly shorter distant-metastasis free survival especially in the early phase of follow-up than in the LSG (log rank p = 0.083, Breslow p = 0.002). The LSG had a significantly higher overall survival (log rank p = 0.046, Breslow p = 0.015, Fig.  2 b). However, after adjusting for other prognostic factors, multivariate Cox regression analysis revealed no significant difference in overall survival between the two groups (hazard ratio [HR] = 1.21, 95% confidence interval [CI]: 0.95–1.54; p = 0.124; Table 2 ). The initial N stage, hormone receptor status, Ki-67 expression level, history of previous locoregional recurrence, presence of symptoms at the diagnosis of distant metastasis, and metastatic site remained independent factors predicting overall survival. Additionally, we used different definition of surveillance intensity based on the number of all exams during the RFS. The survival analysis showed similar results including that of the Cox-regression analysis (Supplementary Fig.  1 ). To further minimize the effect of the confounding variables, we conducted propensity score matching incorporating initial N stage, hormone receptor status, Ki-67 expression level, history of previous locoregional recurrence, presence of symptoms and metastatic sites. Based on propensity score matching, a total of 159 pairs of patients was included in the survival analysis. There was no difference in overall survival between matched LSG and ISG groups (log rank p = 0.264, Breslow p = 0.129, Supplementary Fig.  2 a).

Kaplan–Meier curves showing recurrence-free survival and overall survival of all patients. The Kaplan–Meier curves show recurrence-free survival (a) and overall survival (b–f) . The survival curves for all 398 patients (b) and for patients stratified according to the hormone receptor and HER2-overexpression status (c–f) are shown. Among all, 13 patients were unable to obtain the data of subtypes. P-values were calculated by using the log-rank test along with Gehan–Breslow–Wilcoxon tests (in the parenthesis). ISG intensive surveillance group, LSG less-intensive surveillance group, HR hormone receptor, HER2 human epidermal growth factor receptor type 2.

Clinicopathologic features affecting post-operative overall survival.

HR hazard ratio, CI confidence interval, BMI body mass index, HER2 human epidermal growth factor receptor 2, Ref. reference.

*The p values are derived from the Log-rank test and the p values from the Breslow test are shown in the parenthesis.

We then examined the association between the screening intensity for distant metastasis and survival considering different subtypes of breast cancer. There was no significant interaction between variables including subtypes and sites of metastasis and intensity of surveillance (p > 0.05, data not shown). As shown in Fig.  2 c–f and supplementary Fig.  3 , the screening intensity did not affect the survival outcomes considering HR + /HER2-, HR + /HER2 + , and HR-/HER2- subtypes. However, the LSG group had significantly better overall survival than the ISG group did when the tumors were HR-/HER2 + . Nevertheless, the prognostic importance of screening intensity did not remain significant in this subgroup after adjusting for other prognostic factors by using a Cox regression model (HR = 1.47, 95% CI: 0.80–2.73; p = 0.217, Supplement Table 1 ).

Sites of metastasis, presence of symptoms, and effects of screening intensity

Among the 398 patients with distant metastasis, 220 developed distant metastasis in a single organ: 100 patients had bone metastasis, 85 had lung metastasis, and 35 had liver metastasis. The remaining 178 patients developed metastases in multiple organs. The intensity of screening did not affect the overall survival of patients who developed metastasis in the bones, liver, or multiple organs. However, the overall survival of patients whose first site of metastasis was the lungs was significantly low (Fig.  3 ). The screening intensity remained an independent prognostic factor of overall survival in patients with lung metastasis after adjusting for other prognostic factors (HR = 2.10, 95% CI: 1.06–4.17; p = 0.034, Supplement Table 2 ). However, the patients with lung metastasis in the ISG showed higher incidence of symptoms (43.9% vs. 19.5%, p = 0.018) and previous history of local recurrences (41.5% vs. 14.6%, p = 0.007).

Kaplan–Meier curves showing overall survival depending on initial metastases sites. The survival curves for patients with bone (a) , liver (b) and multiple metastases (d) showed no significant differences between the two groups. However, the intensive surveillance group showed a significantly low overall survival among patients with lung metastasis (c) . ISG intensive surveillance group, LSG less-intensive surveillance group.

As the presence of symptoms at the time of diagnosis might lead to the performance of imaging studies earlier than the pre-scheduled dates, patients who develop symptomatic, rapidly progressing distant metastasis are more likely to have a shorter time interval between the previous imaging studies and the diagnosis of distant metastasis. To overcome this issue, we identified 225 patients whose distant metastases were asymptomatic and who were diagnosed using screening imaging studies. As shown in Fig.  4 a, we observed similar associations between the screening intensity and the survival outcomes of patients with asymptomatic distant metastasis. Also, the propensity score matching analysis for asymptomatic patients using 96 pairs of patients showed the same result (Supplementary Fig.  2 b). Patients in the LSG had significantly higher overall survival when the patients had HR-/HER2 + tumors and when the first site of metastasis was the lungs (Fig.  4 b–h, Supplementary Fig.  3 ). Among these 225 asymptomatic patients, we also observed that the screening intensity showed borderline prognostic significance in HR−/HER2− subtype (Fig.  4 e). However, the interaction assessment among asymptomatic patients revealed significant interaction between both hormone receptor status (p = 0.001) and the metastasis site (p = 0.022) and the intensity of surveillance.

Kaplan–Meier curves showing overall survival of asymptomatic patients and subgroups. The Kaplan–Meier curves show the overall survival of 225 asymptomatic patients. Overall survival was analyzed after dividing the patients into the intensive surveillance group and less-intensive surveillance group (a) . Further subgroup analysis was performed according to subtypes (b–e) and sites of metastases (f–h) . Among asymptomatic patients, 3 patients were unable to obtain the data of subtypes. ISG intensive surveillance group, LSG less-intensive surveillance group, HR hormone receptor, HER2 human epidermal growth factor receptor type 2.

In the current study, we showed that intensive imaging during the post-treatment follow-up period was not associated with survival benefit in patients with breast cancer. We also observed that in a subset of patients, i.e., patients with lung metastasis, highly intensive screening for distant metastasis was associated with poor survival outcomes. Our data indicate that, despite the recent development in targeted therapy for patients with stage IV breast cancer, earlier detection of distant metastasis does not result in survival benefit for patients with breast cancer who developed distant metastasis.

Two randomized controlled trials have evaluated the efficacy of intensity of surveillance in patients with breast cancer. In 1994, the Interdisciplinary Group for Cancer Care Evaluation (GIVIO) 7 randomized 1320 patients with breast cancer into intensive or clinical surveillance; they reported that treatment outcomes and quality of life were not significantly different between the groups after follow-up for 71 months. Similarly, Del Turco et al. and Palli et al. 6 , 18 enrolled 1,243 patients, and showed significantly higher recurrence free survival for clinical groups, but failed to show significant difference on overall mortality at 5- and 10-years of follow-ups. The data showed the lack of survival benefit of intensive surveillance for distant metastasis; these are the basis of the current guidelines that recommend against routine imaging studies—except mammography—for asymptomatic disease-free patients with breast cancer 4 , 5 , 19 . However, these trials were conducted before the era of targeted therapies such as trastuzumab ( NCT00829166 ) or CDK inhibitors ( NCT01740427 ), which have significantly improved the survival of patients with stage IV breast cancer 20 , 21 . Moreover, the diagnostic accuracy of modern imaging studies has substantially improved since these clinical trials 22 – 24 . Therefore, our study included patients who were diagnosed between 2000 and 2015, and the results show that intensive surveillance still lacks any survival benefit.

Although current guidelines 4 , 5 , 19  and systematic review 9 , 25 do not recommend routine imaging for patients with breast cancer, real-word practices often involve the use of advanced imaging studies owing to the belief that earlier detection of distant metastasis may lead to improved survival  15 , 16 , 26 , 27 . Moreover, diagnostic studies for distant metastasis may provide emotional support and reassurance to both the physician and patient  6 , 28 – 30 . However, frequent visits may elevate the anxiety of breast cancer survivors  31 , and intensive surveillance may increase false-positive results for distant metastasis that may further increase the psychological burden  32 , 33 . Furthermore, Meyer et al. 34 reported a significant association between intensive surveillance and the risk of secondary cancer or radiation-induced malignancy in the patient’s lifetime. Therefore, the decision regarding optimal surveillance after the initial treatment for breast cancer must be well-balanced after considering the advantages and disadvantages.

The current study has several limitations. This was a retrospective study from a single, high-volume institution. The retrospective nature inherently raises the possibility of selection bias. To eliminate the effect of selection bias that high-risk patients with breast cancer may undergo very intensive screening, we limited our analysis to patients who eventually developed distant metastasis. Despite our efforts of excluding patients who did not develop distant metastasis, patients with more aggressive features within the study population were more likely to undergo intensive surveillance, as indicated in our results. This selection bias may have masked the potential protective effect of intensive surveillance, because the high-risk features—such as triple-negative subtype or advanced stage at diagnosis—are associated with shorter time to death after the development of distant metastasis 12 . Therefore, our current findings require further validation by using data from a multi-institutional database or a nationwide registry. However, obtaining detailed clinical information about the type of metastasis and the use of imaging studies remain a major hurdle for such validation studies. In addition, we could not adjust for the complex information regarding the use of adjuvant systemic therapies and the response to palliative systemic treatment. Moreover, our study population included a substantial proportion of patients whose disease severity was determined by using the clinical TNM staging because they underwent neoadjuvant therapy. The potential discrepancy between the clinical stage and anatomic stage of breast cancer might have made our results more complex 35 . Finally, it is unclear why intensive surveillance was associated with worse overall survival in patients with HR−/HER2 + tumors or patients who developed lung metastasis in our study. It is possible that small number of patients in each subgroup or unknown confounding factors may have resulted this observation. Additionally, unadjusted confounding factors may have contributed to this observation. Cox-regression analysis also showed significant interaction between both hormone receptor status or metastasis sites and intensive surveillance. Unfortunately, we were not able to perform additional propensity score matching analysis due to the small number of patients in this subgroup. Alternatively, we cannot also exclude the possibility that higher anxiety caused by intensive screening may have affected the survival outcomes, because stress and anxiety promoted tumor progression in mouse models of various solid tumors including breast tumors 36 – 38 .

The results of this retrospective study suggest the lack of any association between intensive surveillance for distant metastasis and survival benefit in asymptomatic, disease-free patients with breast cancer after their initial treatments.

Supplementary Information

Author contributions.

Study concepts and design was done by J.-H.C., J.J. and H.-G.M. Collection and assembly of data were performed by J.-H.C., J.J., E.-S.L. and J.R. Data analysis and interpretation were performed by J.-H.C., J.J., H.-B.L., W.H. and H.-G.M. Statistical analysis was done by J.-H.C., J.J. and H.-G.M. Manuscript preparation and editing was performed by J.-H.C., J.J., and H.-G.M. Manuscript review was done by K.-H.L., T.-Y.K., H.-B.L., W.H., S.-A.I. and D.-Y.N. Final approval of manuscript was performed by all authors.

This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HA15C0011). This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Ministry of Science and ICT, Republic of Korea (MSIT) (No NRF-2019R1A2C2005277).

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare no competing interests.

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

These authors contributed equally: Jong-Ho Cheun and Jigwang Jung.

The online version contains supplementary material available at 10.1038/s41598-021-82485-w.

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Epigenetic regulation of breast cancer metastasis

• Published: 19 October 2023
• Volume 43 , pages 597–619, ( 2024 )

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• Chitra Thakur 1 ,
• Yiran Qiu 1 ,
• Aashna Pawar 1 &
• Fei Chen 1  

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Breast cancer is the most frequently diagnosed malignancy and the second leading cause of cancer-related mortality among women worldwide. Recurrent metastasis is associated with poor patient outcomes and poses a significant challenge in breast cancer therapies. Cancer cells adapting to a new tissue microenvironment is the key event in distant metastasis development, where the disseminating tumor cells are likely to acquire genetic and epigenetic alterations during the process of metastatic colonization. Despite several decades of research in this field, the exact mechanisms governing metastasis are not fully understood. However, emerging body of evidence indicates that in addition to genetic changes, epigenetic reprogramming of cancer cells and the metastatic niche are paramount toward successful metastasis. Here, we review and discuss the latest knowledge about the salient attributes of metastasis and epigenetic regulation in breast cancer and crucial research domains that need further investigation.

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Epigenetic Mechanisms of Cancer Metastasis

Tumor Microenvironment and Epigenetic Implications in Breast Cancer Progression

A three layered histone epigenetics in breast cancer metastasis

Data availability, abbreviations.

epidermal growth factor receptor 2

estrogen receptor

progesterone receptor

breast cancer

triple-negative breast cancer

disseminated tumor cells

extracellular matrix

epithelial-mesenchymal transition

mesenchymal-epithelial transition

pre-metastatic niche

extracellular vesicles

vascular endothelial growth factor

matrix metalloproteinases

circulating tumor cells

cancer stem cells

breast cancer stem cells

transcription factors

enhancer of zeste homolog 2

programmed death ligand 1

lysyl oxidase

manganese superoxide dismutase

proline dehydrogenase

cytosine-phosphate-guanine

ADAM metallopeptidase domain 12

urokinase-type plasminogen activator

circulating tumor

histone acetyltransferases

histone methyltransferases

histone deacetylases

histone demethylases

protein arginine methyltransferases

suberanilohydroxamic acid

poly(ADP-ribose) polymerase

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The research projects in FC’s laboratory are supported by the National Institutes of Health (NIH) grants R01 ES031822, R01 ES028335, and R01 ES028263 and the Research Start-up fund of Stony Brook University.

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Chitra Thakur, Yiran Qiu, Aashna Pawar & Fei Chen

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Thakur, C., Qiu, Y., Pawar, A. et al. Epigenetic regulation of breast cancer metastasis. Cancer Metastasis Rev 43 , 597–619 (2024). https://doi.org/10.1007/s10555-023-10146-7

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Received : 22 July 2023

Accepted : 02 October 2023

Published : 19 October 2023

Issue Date : June 2024

DOI : https://doi.org/10.1007/s10555-023-10146-7

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