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| ORIGINAL ARTICLE |
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| Ahead of print
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Oligometastatic breast cancer: An institutional analysis
Ajay Gogia1, Surya VS Deo2, Daya N Sharma3, Sandeep Mathur4
1 Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India
2 Department of Oncology, All India Institute of Medical Sciences, New Delhi, India
3 Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India
4 Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| Date of Submission | 02-Mar-2020 |
| Date of Decision | 05-Apr-2020 |
| Date of Acceptance | 09-Jun-2020 |
| Date of Web Publication | 22-Jun-2022 |
Correspondence Address:
Ajay Gogia,
Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi
India
 Source of Support: None, Conflict of Interest: None DOI: 10.4103/ijc.IJC_169_20
Introduction: Oligometastatic represents a distinctive subset of metastatic breast cancer (MBC). Incidence has been reported, in 1–5% of all newly diagnosed MBC. Literature is very sparse, especially from India.
Material and Methods: We have ambispectively screened 500 patients of upfront female MBC between the period of January 2013 and August 2018 at Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi and 120 patients of oligometastatic breast cancer (OMBC) were included for analysis. Clinical, pathological, receptor status (ER estrogen receptor, PR progesterone receptor, and HER2/neu human epidermal growth factor), radiological, treatment, and survival details were recorded.
Results: The median age of presentation was 50 (range 22–78) years. One organ was involved in 96 (80%) patients, and two organs were involved in 36 (20%) patients. ER and/or PR was positive in 48 (40.0%), ER/PR, and HER2/neu were positive in 28 (23.3%) cases. Only HER2/neu was positive in 21 (17.5%), and triple negativity was seen in 23 (19.2%) patients. Ninety-four (78.3%) patients received neoadjuvant therapy, and 12 (10%) patients underwent conservative breast surgery. The overall response rate at the metastatic site was 74.1%, and a complete response was seen in 42.5% of patients. Median progression-free survival (PFS) for the cohort was 25.43 months. The estimated PFS at 2 years and, at 5 years, was 54.6% and 21.6%, respectively. The hormone receptor positivity, bone metastasis, and patients with surgery after neoadjuvant chemotherapy (NACT) had a statistically significant better PFS on multivariate analysis. In a subset analysis of HER2/neu receptor-positive patients, who received targeted therapy showed better PFS compared to those who did not receive.
Conclusion: The incidence of OMBC is 24% of the total MBC. The patients with OMBC who have hormone receptor-positive, bone-only metastasis, and surgery after NACT show a better outcome.
Keywords: India, oligometastatic breast cancer, outcome
| » Introduction | |  |
Metastatic breast cancer (MBC) encompasses both primary metastatic breast cancers with distant metastases and those with recurrence on follow-up. Solitary or few detectable metastatic lesions characterize oligometastatic breast cancer (OMBC). It is a distinctive subset of MBC patients who are most likely to gain substantial benefit from an intensified multidisciplinary therapeutic approach.[1],[2],[3] Various studies have been reported the incidence of OMBC; it comprises 1–10% of newly diagnosed metastatic breast cancer patients and around 21.9% of total patients who develop metastasis on follow-up.[2],[3] The objectives of treatment for OMBC is not yet proven in prospective studies. Retrospective studies have documented overall survival (OS) of 185 months and progression-free survival (PFS) of 48 months.[3],[4] There is a lack of data available regarding the clinical-pathological characteristics and outcomes, following therapeutic interventions from India.
| » Material and Methods | | |
We have designed an ambispective cohort study and enrolled patients who were upfront diagnosed with oligometastatic breast cancer in between the period of January 2013 and August 2018 at Institute Rotary Cancer Hospital (IRCH), All India Institute of Medical Sciences (AIIMS), New Delhi. Out of a total of 500 metastatic breast cancer patients, 120 (24%) patients had diagnosed upfront OMBC. None of the patients received any kind of treatment modality before enrolment in this study. Diagnosis and receptor status were confirmed from breast tissue. OMBC was defined as one or two organs involved (apart from the primary lesion), less than five sites of metastasis with less than 5 cm in size.[5] All patients with upfront surgery and surgery after neoadjuvant therapy (NACT) were included in the study. Patients received anthracycline-based and or taxane chemotherapy as per institute protocol.[6],[7] Patients received hormonal treatment and or targeted therapy as per receptor status. All patients underwent evaluation with the complete medical history, physical examination, baseline blood tests, and imaging evaluations bone scintigraphy, computed tomography scan, magnetic resonance imaging (MRI), positron emission tomography (PET-CT), whichever indicated. The effects of the treatment were monitored by clinical examination at every visit and imaging after completion of chemotherapy or early if clinically indicated. Response Evaluation Criteria assess radiological response to treatment in Solid Tumors (RECIST) version 1.1.[8] Responses in bone metastases were evaluated using the methods reported by MD Anderson Cancer Centre (MDACC), with complete response (CR) as clear evidence of complete bone re-calcification with the attainment of near-normal bone architecture or normalization of the scan, and PR as radiological evidence of sclerosis in lytic lesions or marked improvement of bone scan.[9] MRI was performed in patients where clinical suspicion of brain metastasis. The characteristics of the patients with assessable data were compared with the Chi-square test or Wilcoxon rank-sum tests. The OS was defined as the duration from the date of diagnosis to last visit or death. The PFS was calculated from the date of diagnosis of disease to the first date of documented progressive disease or the date of death from breast cancer progression. Survival analysis was done by the Kaplan–Meier method and analyzed using the log-rank test. The univariate and multivariate analysis was performed by Cox regression and included the following variables: age, Performance status (PS), number of involved organs, types of affected organs, liver metastasis, hormone receptor status, HER2 status, administration of local therapy. Differences were considered statistically significant for P less than 0.05. All hormone receptor-positive patients were started on hormonal agents after primary therapy.
| » Results | | |
Baseline characteristics of patients are given in [Table 1]. The median age of presentation was 50 (range 22–78) years. The median duration of symptoms before the diagnosis of OMBC was 5.5 (range 3–12) months. The number of patients with performance status 1 was 106 (88.3%). The number of organs involved with metastatic lesions was 1 in 96 (80%) patients and 2 in 36 (20%) of patients. The most common site of metastasis was bone, followed by visceral (lung and liver) and non-regional lymph node. A small proportion of patients had the brain, adrenal, and ovarian metastasis. In receptor analysis, 48 (40.0%), 28 (23.3%), 21 (17.5%), and 23 (19.2) patients were positive for only hormone receptor (ER and/or PR), hormone, and HER2/neu receptor, only HER2/neu receptor, and Triple negative breast cancer (TNBC). | Table 1: Patient disease and treatment characteristics (upfront oligometastatic disease)
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One hundred two (85%) patients recived combination chemotherapy. Seventy-nine (65.8%) patients received anthracycline-taxane-based chemotherapy, 15 (12.5%) received taxane-platinum-based chemotherapy, 18 (15%) patients received single-agent chemotherapy/hormonal agent/hormonal agent with targeted therapy. Twenty-six (21.7%) patients were operated upfront, 58 (48.3%) patients were operated after neoadjuvant therapy, and 36 (30%) patients were not operated. Breast conservation surgery (BCS) was done in 12 (10%), and modified radical mastectomy (MRM) was done in 72 (60%) patients. Out of 49 patients who were positive for HER2/neu, only 24 (49.3%) patients received targeted agents due to financial constraints. Median PFS for the cohort was 25.43 (95% Confidence Interval [CI] : 18.6 - 32.23) months. Estimated PFS at 2 and 5 years was 54.6% and 21.6% respectively. Estimated OS at 2 and 5 years was 91.1% and 67.5% respectively. On univariate analysis [Table 2], hormone receptor-positive, bone metastasis, absence of liver metastasis, and patients who underwent surgery after NACT showed significantly better PFS.
Median PFS of patients with hormone receptor-positive was 29.5 months, and hormone receptor-negative was 21 months (P = 0.02). Median PFS of patients with bone metastasis was 38.43 (CI 22.7-46.43) months and 20.28 (CI 13.3-29.2) months, without bone metastasis. Median PFS of patients without liver, metastasis was 26.9 (CI 21.8–47.4) months, and with liver metastasis was 13.3 (CI 9.6–38.4) months, P = 0.03. Median PFS of patients with surgery after neoadjuvant chemotherapy was 47.43 (CI 21.1-46.4) months, whereas the median PFS of other patients was 21.8 (CI 14.8-29.5) months [hazard ratio of 0.55 (CI 0.32–0.96), P = 0.03]. HER2/neu receptor-positive patients who received targeted therapy showed better PFS compared to those who did not receive it. Median PFS of patients who received targeted therapy was 30.1 (CI 14–46.19) months, whereas median PFS of patients without targeted therapy was 20.8 (CI 10.6–30.9) months. [Figure 1], [Figure 2], [Figure 3] have shown significant variables with the outcome. On multivariate analysis patients with hormone receptor-positive [HR 0.46 (CI 0.14–0.87), P = 0.017], only bone metastasis [HR 0.54 (0.2920.99), P = 0.05] and surgery after NACT [HR 0.47 (CI 0.26–0.85), P = 0.013] have better clinical outcome. | Figure 1: Kaplan-Meier Curve: Progression-free survival (in months) of patients with (upper one) and without bone metastasis (lower one)
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 | Figure 2: Kaplan-Meier Curve: Progression-free survival (in months) of patients with (upper one) and without Surgery after NACT (lower one)
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 | Figure 3: Kaplan-Meier Curve: Progression-free survival (in months) of patients with HER2/neu receptor positive breast cancer treated with targeted agents (upper one) and without targeted therapy (lower one)
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| » Discussion | | |
MBC is a heterogeneous disease, and its clinical presentation varies from solitary metastasis to diffuse and multiorgan involvement. OS of patients with MBC is slowly improving, and the risk of death is decreasing by 1–2% each year.[10] This improvement can be attributed to the widespread availability of new systemic therapies and the availability of newer diagnostic modalities.[11]
There is always a difference in opinion regarding surgery in OMBC. Surgery has been performed either BCS or MRM after NACT in most of the cases in this study. Two different approaches have explored the role of surgery in MBC: resection of the primary tumor and resection of the metastatic site.[12] One preclinical study using the orthotopic breast cancer mouse model has shown the reduction in tumor burden via primary tumor resection halted metastatic progression.[13] However, this data has not been implicated in human breast cancer. Prospective and retrospective studies evaluating the effect of surgical resection of the primary lesion in MBC have yielded somewhat mixed results.[14],[15],[16],[17],[18]
According to Surveillance, Epidemiology, and End Results (SEER) data of 29,916 MBC patients, half of who underwent primary tumor resection, showed an association with increased overall survival compared with no surgery.[14] An analysis of a prospective trial of de novo MBC patients who underwent surgery of the primary tumor showed no difference in PFS and OS compared with nonsurgical intervention both in HER2-positive and negative MBC.[16] In a randomized control trial by Soran et al., 274 women with de novo MBC were randomly assigned to local management (mastectomy or BCS with radiation) followed by systemic therapy versus systemic therapy only.[17] Patients treated with local management experienced an improvement in 5-year survival (46.4% versus 26.4%; HR 0.66, 95% CI 0.49–0.88). By contrast, in another randomized control trial by Badwe R et al., 350 women with de novo MBC who achieved a partial or complete response to anthracycline-based chemotherapy were randomly assigned to surgery and standard postoperative radiation versus no locoregional treatment.[18] There was no difference between the two groups in regards to median OS (19.2 versus 20.5 months in the control group, HR 1.04, 95% CI 0.81–1.34). [Table 3] have shown different studies on OMBC.
The second approach is to target metastatic sites if the primary disease is in remission. Resection of the isolated focal metastatic lesion to the liver has been shown to improve outcomes in colon cancer.[19],[20] However, there have been no prospective randomized trials to inform the benefit of such an approach to breast cancer, but several cohorts, case series, and systemic reviews have been published.[21],[22],[23],[24] Because this review was limited by extreme heterogeneity inpatient population, various treatments, and study designs, we interpret this analysis with some caution. A meta-analysis of 14 studies evaluated the efficacy of Radio frequency ablation (RFA) compared with hepatic resection and found the latter group to be more efficacious (combined OR for 5 years OS 0.38, P < 0.001).[25],[26] None of our patients have opted for the options of local treatment.
We have observed that patients with HR-positive had statistically significant PFS. This observation can be explained by the fact that all the patients who were positive for HR received hormonal agents. It helped them to control breast cancer for a longer time compared to those who were HR negative. We did not find any difference in patients on PFS in patients with HER2/neu receptor-positive and HER2/neu receptor-negative, due to only 50% of patients received targeted therapy in patients who were positive for HER2/neu receptor positive. In a subset of patients who were positive for the HER2/neu receptor, those who received targeted therapy had statistically significant PFS. Despite the development of newer therapies, many patients cannot afford targeted agents in our institute. There is an unmet need for a patient assistance program in developing countries so that these patients can receive expensive therapies. There is no difference in TNBC patients, which states that this has the worst tumor biology and carries a poor prognosis. We found that the absence of liver metastasis and bone, only metastasis had a statistically significant poor outcome. We did not find any difference in patients with age, lung, lymph node metastasis; these results were similar to the previous study by Kobayashi et al.[3] We had also observed that type of chemotherapy, single or two organ metastasis did not show any significant statistical PFS, reported in the study by Trovo et al.[27] This can be explained by ethnic and geographic variability in the population. All the given retrospective studies have suggested a multidisciplinary treatment approach to OMBC for curative intent, but prospective data are lacking. There have been various studies from India on metastatic breast cancer, but data regarding OMBC is sparse.[28],[29] To the best of our knowledge, this is the first study from a developing country as a multidisciplinary approach to metastatic breast cancer. The strength of our study is that part of the study is documented prospectively, and we have taken those cases where all clinical details are available.
| » Conclusion | | |
The incidence of OMBC is 24% of the total MBC. The patients with OMBC who have hormone receptor-positive, bone-only metastasis, and surgery after NACT show a better outcome. Patients with HER2/neu receptor-positive should receive targeted agents, and there is an unmet need for a patient assistance program for making these costly medications in the affordable limit of the general population.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]
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