Subdivision of M1 Stage for De Novo Metastatic Breast Cancer to Better Predict Prognosis and Response to Primary Tumor Surgery

Authors: Caijin Lin MMed1, Jiayi Wu MD1, Shuning Ding MMed1, Chihwan Goh MMed1, Lisa Andriani MMed1, Shuangshuang Lu MD1, Kunwei Shen MD, PhD1, and Li Zhu MD, PhD1
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  • 1 Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China.

Background: Patients with de novo metastatic breast cancer (MBC) constitute a heterogeneous group with different clinicopathologic characteristics and survival outcomes. Despite controversy regarding its prognostic value, primary tumor surgery may improve survival for selected patients. Patients and Methods: Patients with de novo MBC were identified using the SEER database and were then divided randomly into training and validation sets. A Fine-Gray competing risks model was developed to identify the variables associated with increased cancer-specific mortality in the training set. The M1 subdivision system was established based on the independent prognostic factors. Cumulative incidence curves were estimated and compared using Gray’s test. Results: Involvement of brain or liver and number of metastatic sites were identified as independent prognostic factors in multivariate analysis. The M1 category was subdivided into 3 subcategories: M1a, single site involvement except brain and liver; M1b, liver involvement only, or multiple site involvement except brain and liver; and M1c, brain involvement regardless of number of metastatic sites, or liver and other sites involvement except brain (M1b vs M1a: subdistribution hazard ratio [SHR], 1.48; 95% CI, 1.29–1.68; M1c vs M1a: SHR, 2.45; 95% CI, 2.18–2.75). Patients with the M1a subtype benefited most from primary tumor surgery in the adjusted competing risks model (M1a: SHR, 0.57; 95% CI, 0.48–0.67, M1b: SHR, 0.62; 95% CI, 0.47–0.83, and M1c: SHR, 0.59; 95% CI, 0.44–0.80), whereas benefits conferred by treatment with chemotherapy alone increased with the upstaging of metastatic disease (M1a: SHR, 0.72; 95% CI, 0.62–0.83, M1b: SHR, 0.54; 95% CI, 0.44–0.68, and M1c: SHR, 0.53; 95% CI, 0.45–0.61). Conclusions: Subdivision of M1 stage facilitates prognosis prediction and treatment planning for patients with de novo MBC. Treatment offered should be decided in a coordinated multidisciplinary setting. Primary tumor surgery may play an important role in the management of selected patients.

Background

Approximately 5% to 10% of patients with newly diagnosed breast cancer have distant metastases, with 5-year cancer-specific mortality (CSM) ranging from 60% to 74% among different races/ethnicities.1 Median overall survival of patients with de novo metastatic breast cancer (MBC) is reported to be 12 to 32 months, suggesting that these patients constitute a heterogeneous group with a wide range of survival.26 Consequently, it is not appropriate to assign these patients a “catch-all” classification.

Tumor (T), node (N), metastasis (M) classification and staging of malignancy presents the anatomic extent of cancer. Of the 75 types of malignancy described by the TNM staging system, appropriately 20 include further subdivisions of the M1 category, such as prostate and lung cancers.7,8 However, the staging system for breast cancer uses only “M1” to describe metastatic disease. Therefore, all patients with de novo MBC are considered to have the same prognostic stage, regardless of histologic grade and HER2, estrogen receptor (ER), and progesterone receptor (PR) status. Hence, further subdivision of the M1 category for metastatic disease is of clinical importance for accurate prognosis prediction and personalized treatment planning.911

De novo MBC is considered incurable but treatable. Generally, systemic therapy is viewed as the mainstay of treatment.12 Primary tumor surgery is considered in selected patients, mostly in the palliative setting for those with impending complications, such as fungation and skin ulceration.13,14 Considerable controversy remains regarding the prognostic value of nonpalliative surgery for primary tumor. Two randomized trials have suggested caution in selecting patients for locoregional surgery due to little survival gain (ClinicalTrials.gov identifiers: NCT00193778, NCT00941759), whereas a Turkish trial revealed potential benefits, especially in patients with solitary bone metastasis.5 However, the results are not conclusive enough due to inconsistency, and it remains uncertain which subgroup of patients would respond well to either monotherapies or combination therapy. To address this uncertainty, we performed a population-based study and subdivided patients with de novo MBC into different subcategories to stratify prognostication and help treatment planning.

Patients and Methods

Database and Case Selection

Population-based data were obtained from the SEER database, which covers approximately 28% of the US population.16 SEER collects and reports data on patient demographics, primary tumor sites and morphology, tumor stage at diagnosis, first treatment course, and survival outcomes.

Patients with de novo MBC diagnosed in 2010 through 2014 were identified using SEER*Stat software (version 8.3.5; seer.cancer.gov/seerstat). Breast cancer was identified using ICD-O-3 codes (C50.0–C50.6, C50.8, and C50.9). Only patients diagnosed with their first malignancy were included. All patients were >18 years of age. Patients with disease other than stage IV, unknown demographic characteristics and follow-up, or unknown involvement of bone, brain, liver, or lung, and those diagnosed at autopsy or via death certificate were excluded. Eligible patients were divided randomly into the training or validation sets using the basic R function sample().

Statistical Analysis

Pearson chi-square tests were used to analyze categorical variables. The main outcomes were CSM (breast cancer–specific death [BCSD]) and all-cause mortality. CSM was compared by estimating cumulative incidence curves according to Gray’s test.17 A Fine-Gray regression model was developed to estimate subdistribution hazard ratios (SHRs) for CSM.18 Cumulative incidence curves of all-cause mortality were estimated based on the Kaplan-Meier method and compared using the log-rank test. The Cox proportional hazards model using a backward stepwise approach was built to estimate the hazard ratios (HR) for all-cause mortality. Patients in the training set were divided into several groups according to the combination of the independent prognostic factors for CSM. Cumulative incidence rates for CSM in each group were estimated and compared, using a 2-sided P value of <.001 to ensure a significant difference in survival. Groups with significantly different prognosis were divided into different M1 subcategories.

In addition, multiple comparisons based on Gray’s test and a Fine-Gray regression model were performed, with different treatment modalities used as the reference across M1 subcategories. To reduce the bias caused by no adjustment for use of radiotherapy (RT), endocrine therapy, and targeted anti-HER2 therapy, multiple comparisons were repeated in women who did not receive RT and in those with triple-negative breast cancer (TNBC) who did not receive RT.

All tests used 2-sided P values of <.05 suggesting statistical significance unless otherwise stated. Pearson Chi-square test and a Cox proportional hazards model were developed using SPSS Statistics, version 24 (IBM Corp). Kaplan-Meier method, Gray’s test, and a Fine-Gray regression model were performed using R version 3.4.3 (R Foundation for Statistical Computing).

Results

Baseline Characteristics

Of the 312,041 patients diagnosed with breast cancer, 8,582 were identified with de novo MBC, including 4,291 each in the training or validation sets. In both sets, the most frequently involved metastatic sites were bone, lung, liver, and brain, and clinicopathologic characteristics were well-balanced. Detailed baseline characteristics are outlined in Table 1 and supplemental eTables 1, and 2 (available with this article at JNCCN.org).

Table 1.

Baseline Patient Characteristics (N=8,582)

Table 1.

Association Between Characteristics of Distant Metastases and CSM

Univariate analysis showed that involvement of brain, liver, or lung, and of multiple (>1 or >2) metastatic sites was associated with increased CSM. Multivariable analysis showed that involvement of brain (SHR, 2.13; 95% CI, 1.80–2.52; P<.001) and liver (SHR, 1.71; 95% CI, 1.51–1.95; P<.001) were independent prognostic factors. After adjusting for the same parameters, involvement of multiple (>1) metastatic sites remained a significant predictor of CSM (SHR, 1.28; 95% CI, 1.11–1.47; P<.001) (supplemental eTable 3). Additionally, we found that involvement of multiple (>1) metastatic sites was associated with increased CSM in the absence of brain involvement (P<.001) (supplemental eFigure 1A–C). However, no significant difference was observed when brain was involved (P>.05) (supplemental eFigure 1D–F).

Subdivision of M1 Category

Patients in the training set were divided into 5 groups according to the independent prognostic factors (see supplemental eTable 4 for comparisons among the 5 groups). Consequently, patients with de novo MBC were subdivided into 3 categories: M1a, involvement of a single site except brain or liver; M1b, liver involvement only, or involvement of multiple sites except brain or liver; M1c, brain involvement regardless of number of metastatic sites, or involvement of liver and other sites except brain. Both the 3-year CSM and all-cause mortality rates increased across M1 subcategories (Figure 1A, 1D). In the adjusted competing risk model, the association of M1 subcategories with CSM remained significant (M1b vs M1a: SHR, 1.48; 95% CI, 1.29–1.68; P<.001, and M1c vs M1a: SHR, 2.45; 95% CI, 2.18–2.75; P<.001) (Table 2 and supplemental eTable 5). Additionally, the M1 subcategories were also associated with increased all-cause mortality (M1b vs M1a: SHR, 1.47; 95% CI, 1.30–1.66; P<.001, and M1c vs M1a: SHR, 2.38, 95% CI, 2.14–2.65; P<.001) (Table 2 and supplemental eTable 6).

Figure 1.
Figure 1.

Cumulative incidence curves of (A–C) cancer–specific and (D–F) all-cause mortality for different M1 subcategories in the (A, D) training, (B, E) validation, and (C, F) whole sets. P values were estimated and compared based on Gray’s test (A–C) or log-rank test (D–F).

Abbreviations: BCSD, breast cancer–specific death; LG, log-rank.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 17, 12; 10.6004/jnccn.2019.7332

Table 2.

Multivariate Analysis of Cancer-Specific and All-Cause Mortalitya

Table 2.

Validation of M1 Category Subdivision

Validation of the M1 category subdivision system is described in supplemental eAppendix 1, eFigure 2, and eTables 5–8.

Associations of Treatment Modality and M1 Subcategories With Survival Outcomes

Cumulative incidence curves show the mortality reduction by primary tumor surgery, chemotherapy, or combination therapy across M1 subcategories (Figure 2A–C).

Figure 2.
Figure 2.

Cumulative incidence curves of cancer-specific mortality stratified by treatment modality in patients with (A) M1a, (B) M1b, and (C) M1c disease in the whole set. Patients receiving no treatment were used as the reference category and data are presented as SHR (95% CI).

Abbreviations: BCSD, breast cancer–specific death; chemo, chemotherapy; SHR, subdistribution hazard ratio; surg, surgery.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 17, 12; 10.6004/jnccn.2019.7332

When the monotherapies were compared with no treatment in the whole population, primary tumor surgery remained a favorable prognostic factor in the adjusted competing risk model, especially for patients with M1a disease (M1a: SHR, 0.57; 95% CI, 0.48–0.67; P<.001, M1b: SHR, 0.62; 95% CI, 0.47–0.83; P=.001, and M1c: SHR, 0.59; 95% CI, 0.44–0.80; P<.001) (Table 3). Furthermore, patients with M1a disease benefited less from chemotherapy alone than those with M1b or M1c disease (M1a: SHR, 0.72; 95% CI, 0.62–0.83; P<.001, M1b: SHR, 0.54; 95% CI, 0.44–0.68; P<.001, and M1c: SHR, 0.53; 95% CI, 0.45–0.61; P<.001). Specifically, no significant difference in survival was seen between patients treated with surgery only and those treated with chemotherapy only, with the exception of patients with M1a disease, among whom those receiving chemotherapy only presented a worse prognosis (SHR, 1.27; 95% CI, 1.06–1.51; P=.008). As for the combined therapy, those receiving the combination exhibited the lowest SHR across M1 subcategories (M1a: SHR, 0.39; 95% CI, 0.34–0.46; P<.001, M1b: SHR, 0.46; 95% CI, 0.36–0.58, P<.001, and M1c: SHR, 0.32; 95% CI, 0.26–0.38; P<.001). However, for patients classified as M1b, the combination therapy provided similar benefits to monotherapies (combination vs surgery only: SHR, 0.73; 95% CI, 0.54–1.00; P=.048; combination vs chemotherapy only: SHR, 0.84; 95% CI, 0.68–1.03; P=.094).

Table 3.

Association of Cancer-Specific Mortality With Treatment Modalitya

Table 3.

Similar results were observed in patients with or without TNBC who did not receive RT. Cumulative incidence curves are presented in supplemental eFigure 3. Among patients who did not receive RT (n=5,584), those classified as M1c who received chemotherapy only had a better prognosis than those undergoing surgery only (SHR, 0.69; 95% CI, 0.49–0.97; P=.035) (supplemental eTable 9). In patients with TNBC not receiving RT (n=808), those receiving locoregional surgery presented similar prognosis to treatment-naïve patients (M1a: SHR, 0.94; 95% CI, 0.56–1.59; P=.824, M1b: SHR, 0.78; 95% CI, 0.29–2.12; P=.629, and M1c: SHR, 1.50; 95% CI, 0.75–3.02; P=.251). Compared with surgery, chemotherapy conferred a greater survival benefit across M1 subcategories (M1a: SHR, 0.65, 95% CI, 0.44–0.96; P=.031, M1b: SHR, 0.34; 95% CI, 0.16–0.74; P=.006, and M1c: SHR, 0.32; 95% CI, 0.16–0.64; P=.001).

In addition, comparisons between lumpectomy and mastectomy are presented in supplemental eTable 10. No significant difference in mortality was observed.

Discussion

This study focused on the association between anatomic extent of metastatic disease and CSM in patients with de novo MBC. We found that involvement of liver and brain and of multiple metastatic sites were independently associated with CSM. We also further subdivided patients with significantly different prognoses into M1a, M1b, or M1c subcategories, and found that cumulative incidence rates of both CSM and all-cause mortality were significantly different across M1 subcategories. Our findings indicate that selected patients might benefit from aggressive locoregional treatment and that subdivision of M1 stage may guide individualized treatment planning.

Consistent with previous research,19 we found that brain and liver involvement were each independently associated with an unfavorable prognosis for patients with de novo MBC. In our study, the number of sites involved proved to be an independent predictor for CSM, which was accordant with the findings of many previous studies, which reported HRs ranging from 1.45 (95% CI, 1.35–1.55) to 1.56 (95% CI, 1.02–2.40).4,5,20,21 The results of both the previous study and the present study indicated that metastatic sites and the number of sites involved might be key parameters for risk stratification. In autopsy studies, patients with brain metastases were reported as more likely to have multiple sites involved.22 Interestingly, no significant difference in survival was observed between patients with single and multiple metastatic sites in the presence of brain involvement in our study. Hence, we established an M1 subdivision system and divided patients with bone-only or lung-only metastases into the M1a category due to relatively favorable prognosis. Those with brain involvement were categorized as M1c. In our study, patients with M1b disease had an approximately 40% increased mortality risk, and those with M1c disease exhibited greater than 2-fold higher risk of mortality compared with those with M1a disease. Similar directions of the association were observed across different molecular subtypes.

Palliative systemic therapy is usually considered the therapeutic backbone for patients with metastatic breast cancer.12,14 Despite this, studies have reported that approximately 40% of women receive locoregional surgery and some patients desire a complete excision of primary tumor for psychosocial reasons,2325 and many other reports reached an entirely different conclusion regarding primary tumor surgery versus systemic therapy. A Turkish study (MF07-01) reported a 34% higher overall survival for patients receiving locoregional surgery combined with chemotherapy compared with those receiving chemotherapy alone (HR, 0.66; 95% CI, 0.49–0.88; P=.005), especially in those with more indolent disease, such as HoR+/HER2– subtype and single-bone involvement.15 Similarly, our data revealed that for patients with bone metastases (mainly classified as M1a), primary tumor surgery might provide a favorable prognosis. In addition, numerous retrospective studies and meta-analyses had reaffirmed the survival benefit associated with locoregional surgery with or without chemotherapy for advanced disease.23,24,26,27 On the contrary, an Indian trial reported a significant decrease in distant progression-free survival (HR, 1.42; 95% CI, 1.08–1.85; P=.012) in patients receiving locoregional treatment compared with chemotherapy only.28 Cautious interpretation was suggested because of the insufficient use of subsequent systemic therapy and targeted anti-HER2 therapy. In addition, the lack of stratification factors might lead to unbalanced inclusion.

In our study, we attempted to account for margin status, which was not accessible in the SEER database, and divided the whole population into patients receiving no surgery, lumpectomy, or mastectomy. We hypothesized that patients undergoing mastectomy may be more likely to receive a negative margin, and thus surgery types might be an alternative indicator for margin status to some extent.29 Many previous works reported no survival gain from surgery with positive margins in metastatic setting.25,30,31 However, our study presented no survival difference between women receiving mastectomy or lumpectomy, and therefore it could be speculated that many patients may obtain clear margins after lumpectomy. Similarly, Lane et al25 reported a positive margin rate of <20% for patients receiving lumpectomy or mastectomy based on a national database. However, we cannot determine whether more aggressive surgery (simple of modified mastectomy) can provide additional benefits.

We also found that surgical resection did not improve survival for women with TNBC across M1 subcategories. Similarly, Neuman et al32 reported that survival gain was observed among women with ER/PR-positive and/or HER2-amplified disease, although not in those with TNBC, indicating that less benefit might be obtained from primary surgery of metastatic disease with aggressive tumor biology.

Our findings may have some implications for clinical practice. For patients with M1a disease, the combination of surgery and chemotherapy is preferred due to the approximately 50% reduction in mortality risk. It is reasonable to assume that these patients present better performance status and more favorable prognosis and that they can tolerate and benefit from the aggressive combination. For the M1b subcategory, which consists of patients with different metastatic burden, combined treatment has no clinical necessity because only statistically borderline survival improvement is observed between monotherapies and combination therapy; both surgery alone and chemotherapy alone may benefit specific subgroups of patients. Further investigation is required. As for patients with M1c disease, systemic chemotherapy alone may be considered after considering the surgical difficulty, potential decline in quality of life, possible visceral crisis, and palliation of symptoms. Among women who did not receive RT, those receiving chemotherapy alone experienced a 30% (70% in those with TNBC) reduction in mortality risk compared with those receiving surgery only. The fact that the lowest SHRs were associated with combined therapy may be attributed to selection bias, and we believe that this bias increases with upstaging of the metastatic disease. Women with M1c disease tend to present with organ failure and short life expectancy26; however, those receiving locoregional surgery may have better general well-being, thus leading to the lowest SHRs observed.

Despite the possible benefits from surgery, systemic therapy is still the preferred choice for MBC.12,14 In our study, the M1a subcategory contains more ER/PR-positive disease, which can be well-controlled by some state-of-the-art therapies, such as the combination of CDK4/6 inhibitors with endocrine therapies. Nonetheless, it is of great interest and necessity to study whether and when to perform primary tumor surgery for selected patients with long-term disease control by CDK4/6 inhibitors.

This work has several limitations. First, some variables were not available in SEER, such as the number and size of metastatic lesions and other metastatic sites. Therefore, involvement of contralateral axillary lymph nodes, pleura, and other sites was not included for further subdivision of M1 category. The variable “number of metastatic sites,” which was the total number of sites involved in the bone, brain, liver, or lung, might cause potential bias. Second, SEER did not provide detailed information on locoregional treatment, making it impossible to adjust for margin status, surgery of the axilla and metastatic disease, and use of RT. Neither could we account for the systemic therapy in terms of use, timing of initiation, and patient response, preventing adjustment for the sequence of surgery and systemic therapy and other potential confounders. Third, other confounders such as Charlson comorbidity score were not adjusted for, and the possibly unbalanced distribution of comorbidity might be another source of selection bias, resulting in the observed benefit from surgery. Finally, each M1 subcategory consists of a heterogeneous group of patients; therefore, the treatment advice based on M1 subcategory may not apply to each individual in that subcategory. We acknowledge that the M1 category subdivisions and the observed relationship between M1 subcategories and treatment modality should be prospectively validated. As treatment moves toward precision and personalization, multigene assays and biologic subtypes in addition to cancer staging may also play an increasingly important role in clinical decision-making.

Conclusions

The subdivision of M1 category reported herein, taking into account the metastatic sites and number of sites involved, may provide both patients with de novo MBC and oncologists with critical information for informing prognosis and help facilitate treatment choice. Treatment offered to women with metastatic disease should be determined by a coordinated, multidisciplinary team. As the prolongation of survival resulted from systemic therapy, primary tumor surgery may further benefit selected patients who respond well to systemic therapy. Although results of several related randomized trials are awaited, patients with de novo MBC should be provided with the currently available evidence when determining treatment approach.

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Submitted November 3, 2018; accepted for publication June 18, 2019.

Author contributions: Study concept and design: Lin, Wu, Zhu. Data acquisition: Lin, Ding, Goh. Data analysis and interpretation: Lin, Wu, Ding, Andriani, Lu, Shen. Manuscript preparation: All authors. Final approval: Zhu.

Disclosures: The authors have disclosed that they have not received any financial considerations from any person or organization to support the preparation, analysis, results, or discussion of this article.

Correspondence: Li Zhu, MD, PhD, Comprehensive Breast Health Center, Ruijin Hospital, 197 Ruijin Er Road, Huangpu District, Shanghai 200025, China. Email: zhuli8@yeah.net

Supplementary Materials

  • View in gallery

    Cumulative incidence curves of (A–C) cancer–specific and (D–F) all-cause mortality for different M1 subcategories in the (A, D) training, (B, E) validation, and (C, F) whole sets. P values were estimated and compared based on Gray’s test (A–C) or log-rank test (D–F).

    Abbreviations: BCSD, breast cancer–specific death; LG, log-rank.

  • View in gallery

    Cumulative incidence curves of cancer-specific mortality stratified by treatment modality in patients with (A) M1a, (B) M1b, and (C) M1c disease in the whole set. Patients receiving no treatment were used as the reference category and data are presented as SHR (95% CI).

    Abbreviations: BCSD, breast cancer–specific death; chemo, chemotherapy; SHR, subdistribution hazard ratio; surg, surgery.

  • 1.

    DeSantis CE, Ma J, Goding Sauer A, et al. . Breast cancer statistics, 2017, racial disparity in mortality by state. CA Cancer J Clin 2017;67:439448.

  • 2.

    Mariotto AB, Etzioni R, Hurlbert M, et al. . Estimation of the number of women living with metastatic breast cancer in the United States. Cancer Epidemiol Biomarkers Prev 2017;26:809815.

    • Crossref
    • PubMed
    • Search Google Scholar
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