Oligometastasis of Breast Cancer to the Lung: Prospective Cohort Study of Treatment Strategies (SBP-06)

doi:10.21203/rs.3.rs-1410257/v1

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Oligometastasis of Breast Cancer to the Lung: Prospective Cohort Study of Treatment Strategies (SBP-06)

https://doi.org/10.21203/rs.3.rs-1410257/v1

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Background

Previous study results have suggested that local treatment of isolated lung metastases, may be beneficial and increase overall survival (OS) in highly selected patients. However, these were all retrospective studies. We designed this prospective cohort study to investigate the therapeutic and diagnostic clinical situation of oligometastatic breast cancer in the lung, as well as the prognosis outcomes of patients with this disease.

Methods

We enrolled patients with less than 3 lung nodules which suspected as oligometastases after curative breast cancer surgery. Treatments, including local and systemic therapy, were choice by each physician. The primary outcome was OS of patients with oligometastasis of breast cancer detected in the lung and secondary outcomes were the efficacy and safety of surgery for lung oligometastases. The study was in accordance with the relevant national/institutional guidelines

Results

Between May 2015 and May 2019, 14 patients were enrolled at 5 centers. Resection of lung nodules (metastasectomy) was performed 11 (78.6%) of 14 patients and one was diagnosed with primary lung cancer. Metastasectomy were all performed employing video-assisted thoracic surgery (VATS) and achieved complete resection without perioperative complication. Systemic therapies such as chemotherapy, as well as endocrine and molecular target therapies were administered to all patients except one who declined all treatments offered. The respective 3-year and 5-year OS rates of patients with lung oligometastases were 91.6% and 81.5%. Progression events occurred in 6 patients: 3 (30%) with and 3 (100%) without metastasectomy. Whereas 2 of 10 patients with metastasectomy survived 5 years without progression, progression events occurred all patients without metastasectomy within 1 year.

Conclusion

Lung metastasectomy was worthwhile as a diagnostic evaluation and possibly provide long-term benefit in some patients. Phase 3 trials might be required to provide definitive evidence and to provide criteria for selecting patients.

Trial registration

This study was approved by the Institutional Review Board (IRB No. 960) of the Okayama University Hospital, Okayama, Japan, and was registered in the clinical trials database UMIN (UMIN000016999) on 31 March 2015. Written informed consent was obtained from all enrolled patients.

oigometastasis

breast cancer

lung

metastasectomy

Recently, appropriate use of new drugs, becoming available annually, has allowed long-term control of symptoms due to metastases and has prolonged the lives of patients with metastatic breast cancer. The 3-year overall survival rate was 44% and the 5-year overall survival rate was 28% for patients treated from 1994 to 2000 [1]. However, cure is not possible for these patients, because the cancer cells have spread systemically. Various hypotheses possibly explaining the mechanisms of metastatic disease have been proposed. Fisher suggested the systemic hypothesis, i.e. that clinically apparent cancer is a systemic disease [2]. Hellman advocated the spectrum hypothesis which involves some cancers remaining locoregionally confined, while others are metastatic at presentation, and some progress from locoregional confinement to metastatic disease [3].

Hellman and Weichselbaum proposed the existence of a state of termed oligometastatic disease. Their hypothesis is that certain tumors concentrate their metastases in a single organ or a limited number of organs, such that local therapy might actually be a curative treatment when administered either alone or combined with systemic therapy [4].

Previous study results have suggested that local treatment, either surgical resection or ablative radiotherapy of isolated lung metastases, may be beneficial and increase OS in highly selected patients [5]. However, these were all retrospective studies. As the evidence obtained was insufficient, Clinical Practice Guidelines recommend lung metastasectomy only for diagnostic purposes, i.e., to distinguish primary lung cancer from metastatic breast cancer [6].

We designed this prospective cohort study (SBP-06) to investigate the therapeutic and diagnostic clinical situation of oligometastatic breast cancer in the lung, as well as the outcomes of patients with this disease.

SBP-06 was a prospective cohort study that enrolled patients from 5 centers involved in the Setouchi Breast Project Comprehensive Support Organization. The inclusion criteria were age ≧ 18 years and ≦ 80 years, first and only lung metastasis suspected after curative breast cancer surgery, less than 3 lung nodules detected by CT and/or PET/CT, and confirmed estrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor (HER2) expressions for the primary breast tumor.

Treatments, including local and systemic therapy, were selected by each physician. The patients were followed for at least 5 years

The primary outcome was OS of patients with oligometastasis of breast cancer detected in the lung and secondary outcomes were the efficacy and safety of surgery for oligometastastic breast cancer lesions in the lung.

Based on the methods of previous studies, the expected 5y-OS rate and the threshold were assumed to be 50 and 30%, respectively. Based on an α value of 0.05 and a β value of 0.2, the target sample size was defined as 35 patients. Categorical variables were compared using the Chi-square test. All statistical analyses were performed using JMP software (version 10, SAS institute. USA).

Between May 2015 and May 2019, 14 patients were enrolled at 5 centers. Baseline characteristics are listed in Table 1.

Table 1

Baseline characteristics
characteristic	n = 14
Median age, years	59.5(47–75)
Subtype of original tumor
Luminal	8
Luminal HER2	2
HER2	1
Triple Negative	3
Stage of original tumor
Ⅰ	5
ⅡA	4
ⅡB	4
ⅢB	1
Median DFI, months	59(13–220)
Number of lung nodules
1	12
2	2
Size of the largest lung nodule
≦10mm	5
11-20mm	5
no data	4

Eleven (78.6%) of 14 patients received lung nodules resection. Ten patients were pathologically diagnosed as having metastases from breast cancer and one was diagnosed with primary lung cancer. One patient had already been diagnosed as having metastases from breast cancer by biopsy before lung metastasectomy. Two of three patients who did not undergo metastasectomy of the lung were diagnosed by biopsy. ER status changed to positive for one patient and PgR status became negative for another. The discordance rates between metastases and the primary tumor were 8.3%, 10%, and 0% for ER, PgR, and HER2 expressions, respectively. (Table 2)

Table 2

change of receptor status
	Positive conversion	Negative conversion	Discordance rates
ER (n = 12)	1	0	8.3%
PgR (n = 10)	0	1	10%
HER2 (n = 10)	0	0	0%

Operations were all performed employing video-assisted thoracic surgery (VATS) and achieved complete resection. The mean operation time was 87 minutes (27–186 minutes), the mean hospitalization period was 10.2 days (5–14 days), and the median blood loss amount was 5 ml (0-160 ml). No perioperative complications were reported.

Treatments and outcomes were evaluated in 13 patients excluding the one found to have primary lung cancer. Systemic therapies such as chemotherapy, as well as endocrine and HER2 directed therapies were administered to all patients except one who declined all treatments offered, including metastasectomy. (Table 3)

Table 3

treatment of metastases
treatments	n = 13
Lung metastasectomy	10
Systemic therapy	12
None	1
Systemic therapy (1st line)
Hormone therapy	5
Chemotherapy	4
Chemotherapy + HER2 agents	4

The median follow-up was 51 months (10–82 months). The primary outcome event, death from any cause, occurred in 2 (15%) of 13 patients. The respective 3-year and 5-year OS rates of patients with oligometastatic breast cancer lesions in the lung were 91.6% and 81.5%. Median progression free survival (PFS) was 40 months for all patients with oligometastatic breast cancer lesions in the lung. Median PFS was not reached in cases receiving metastasectomy and was 11 months without metastasectomy (P = .0052) (Fig. 1).

Progression events occurred in 6 patients: 3 (30%) with and 3 (100%) without metastasectomy. Whereas 2 of 10 patients with metastasectomy survived 5 years without progression, progression events occurred all patients without metastasectomy within 1 year.

For patients with a first presentation of metastatic disease, pathological examination of an accessible metastatic site should be performed to confirm the diagnosis and re-establish receptor status. When patients underwent surgery for lung metastases of breast cancer, the lung nodules proved to be unrelated to the known cancer, i.e., the lesions were primary lung cancer, benign tumors, or metastases of another origin, in 12–57% of patients [7, 8], as confirmed by our data.

Reevaluation of the receptor status of metastasis did not affect the selection of treatments in this study, however, Kin et al. reported that changes in the subtypes of metastases affected treatment selection in 18% of their patients [9]. Furthermore, gene examination of biopsy tissue may contribute to selecting the optimal approach among the new treatments becoming available.

Pathological studies are on occasion performed employing a bronchoscopic approach or CT-guided transthoracic needle biopsy, but the accuracies of diagnosis for lung nodules less than 1cm are reportedly 44% [10] and 70% [11], respectively. Lung metastasectomy is more invasive than either the bronchoscopic approach or CT-guided transthoracic needle biopsy, while VATS has increasingly been performed in recent years because it is less invasive than thoracotomy with fewer intraoperative complications, and in many cases complete resection of the parenchymal metastases can be achieved [12].

As complete lung metastasectomy was performed employing VATS all in cases and there were no perioperative complications in this study, our experience indicates lung metastasectomy to be a reasonable approach.

In general, the role of local management of metastatic breast cancer is palliation of symptomatic sites. However, some studies have raised the possibility of prolonging survival in highly selected patients with good performance status, a long disease-free interval, and/or oligometastatic disease. Local therapy for lung oligometastases from breast cancer has been shown to result in long-term disease control in a retrospective study and meta-analyses [13, 14, 15]. In the largest dataset on lung metastasectomy in 467 breast cancer patients, reported by Friedel et al., the median survival was 37 months (5-year OS was 38% and the 10-year OS was 22%) [16]. This present prospective cohort study also suggested the survival benefit of lung metastasectomy. The outcomes of patients with lung oligometastasis in our study were much better than those reported previously, possibly due to the development of more effective drug treatments in recent years. The lung metastasectomy procedures were performed between 1960 and 1994 in the study reported by Friedel [16]. Another factor explaining improved survival might be advancements in imaging studies allowing early detection of metastasis.

A randomized phase 3 trial might be required to provide definitive evidence of survival benefit. NRG-BR002 (NCT 02364557) is an ongoing phase 3 trial designed to determine whether ablation (through stereotactic body radiotherapy and/or surgical resection of all known metastases) in oligometastatic breast cancer patients improves OS.

Prognostic factors impacting local therapy include the number of metastases, long disease-free interval, and the completeness of resection [13, 16, 17]. Progression events occurred in all 3 patients with a disease-free interval (DFI) < 36 months in our study.

Whether local therapy for metastases with systemic agents prolongs survival may depend on how extensive micrometastases are. At present, the number of detectable metastases or the DFI can serve as prognostic markers for the severity of micrometastases. New biomarkers such as circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) have been shown to predict poor outcomes [18, 19]. ctDNA will be evaluated as a translational primary endpoint in NRG-BR002 and the results obtained might contribute to the selection of patients who would benefit from local therapy for metastases.

Ablative radiotherapy is an alternative to surgical resection as a local treatment strategy for metastasis and reportedly improves OS [20]. However, surgical resection has the advantage of allowing histopathologic examination and ablative radiotherapy is invasive with a treatment-related death rate of 4.5% [20]. Nonetheless, ablative radiotherapy may be useful for treating metastases that are difficult to resect such as central lung metastases or metastatic lesions in unresectable organs.

This prospective cohort study showed that lung metastasectomy by VATS was a reasonable approach to determining the pathological diagnosis and reevaluating receptor status with acceptable safety and invasiveness. Some patients who underwent lung metastasectomy survived 5 years or more without progression events, raising the possibility of achieving long-term benefits of the local therapy for metastases. Phase 3 trials might be required to provide definitive evidence and to provide criteria for selecting patients most likely to benefit from this strategy as well as determining the optimal timing of local therapy.

Overall survival

Estrogen receptor

PgR

Progesterone receptor

HER2

Human epidermal growth factor receptor

VATS

Video-assisted thoracic surgery

PFS

Progression free survival

DFI

Disease-free interval

CTCs

Circulating tumor cells

ctDNA

circulating tumor DNA

Ethics approval and consent to participate

Consent for publication

Not applicable

Availability of data and materials

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

Competing interests

The authors declare that they have no competing interests.

Funding

The authors thank the patients who participated in the Setouch Breast Project (SBP06) clinical trial. This study was supported by the Setouch Breast Comprehensive Support Project, which is a non-profit organization in Okayama, Japan.

Authors' contributions

TS, SO, and HD were involved in the design of the study. RM and TS were involved in the analysis, interpretation of data and revision of the manuscript. All authors were involved in interpretation of data, and read and approved the final manuscript.

Acknowledgements

Not applicable

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No competing interests reported.

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Oligometastasis of Breast Cancer to the Lung: Prospective Cohort Study of Treatment Strategies (SBP-06)

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Background

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Discussion

Conclusion

Abbreviations

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