Low neutrophil-lymphocyte ratio correlates with extended survival in patients with metastatic breast cancer who achieved clinically complete response following multidisciplinary therapy: A retrospective study

  • Authors:
    • Haruko Takuwa
    • Wakako Tsuji
    • Yoshihiro Yamamoto
    • Masayuki Shintaku
    • Fumiaki Yotsumoto
  • View Affiliations

  • Published online on: March 1, 2018     https://doi.org/10.3892/ol.2018.8145
  • Pages: 6681-6687
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Abstract

The prognosis of patients with metastatic or recurrent breast cancer (MBC) is improving as novel treatments are developed. The present study compared the clinical characteristics of patients with MBC with or without a complete clinical response (cCR) and identified the survival‑associated factors. This was a retrospective study, which included 171 patients treated for MBC between 2011 and 2017 at the Shiga Medical Center for Adults. Neutrophil to lymphocytes ratios (NLRs) were determined in blood samples. The median follow‑up period following diagnosis of MBC was 44 months (range, 0‑217 months). A total of 32 patients (18.7%) achieved a cCR. Compared with the non‑cCR group, the cCR group had significantly fewer metastases or recurrences (P<0.001), significantly fewer visceral metastases (P<0.001), a significantly lower NLR (P<0.001) and were diagnosed with primary breast cancer at a significantly earlier stage (P=0.003). Prognosis was significantly improved in the cCR group compared with the non‑cCR group (P<0.001) and a high NLR (≥19) independently predicted worse survival in a multivariate analysis (P=0.0218; hazard ratio, 1.75; 95% confidence interval, 1.09‑2.85). In conclusion, the present study determined that achieving a cCR and having a low NLR are important for the long‑term survival of patients with MBC.

Introduction

Approximately 20–30% of breast cancers ultimately metastasize or recur. The treatments for metastatic or recurrent breast cancer (MBC) are diverse, and treatment innovations have improved the prognosis and life expectancy of MBC patients (1). More than 20 years ago, only 2–3% of MBC patients achieved a clinical complete response (cCR) and the 10-year survival rate was only about 5% (25), http://ganjoho.jp/reg_stat/). Today, the 10-year survival rate of MBC is 15.6%, and the 5-year survival rate is 32.6%, according to the Research Group of the Japanese National Cancer Research Center (6).

Treatment innovations in the past 10 years include the use of small molecule inhibitors and anti-human epidermal growth factor receptor 2 (HER2) antibodies. In recent clinical trials including anti-HER2 therapy, 10–20% of patients with metastatic breast cancer achieved a cCR (79). However, the factors responsible for a cCR are not known, nor is it known when patients discontinue treatment once a cCR is achieved. Owing to potential adverse events, unnecessary treatments should be avoided.

In recent years, many research groups have investigated the value of anticancer immune responses and the hematological components of the systemic inflammatory response specifically for use in predicting outcome. Some studies have evaluated the prognostic and predictive importance of tumor-infiltrating lymphocytes (TILs) in breast cancer (10,11). And some have reported that the combination of the hematological components of the systemic inflammatory response, as the neutrophil-lymphocyte ratio (NLR) have prognostic value in a variety of cancers (1216).

Therefore, the aim of this study is to analyze the association between cCR and overall survival (OS), and TILs or NLR might be prognositic factor in metastatic breast cancer.

Patients and methods

Patients

A hundred and seventy-one patients with histologically or clinically confirmed MBC who were consecutively treated at the Shiga Medical Center for Adults (Moriyama, Shiga, Japan) between 2011 and 2017 (Table I). Patients had either de novo MBC, a recurrence of a local breast cancer, or distant metastases that appeared after treatment of the primary cancer. Medical records were reviewed in detail. Patients who achieved a cCR were defined as those with no evidence of disease after treatment for MBC (i.e., no evidence of clinical or radiological disease according to the Response Evaluation Criteria in Solid Tumors and as evaluated via computed tomography, magnetic resonance imaging, or positron emission tomography). The frequency and modality of radiographic imaging were at the discretion of the treating physician.

Table I.

Characteristics of patients with metastatic or recurrent breast cancer.

Table I.

Characteristics of patients with metastatic or recurrent breast cancer.

VariableAll patients (n=171)cCR (n=32)non-cCR (n=139)P-value
Follow-up period (months) 0.135
  Median446047
  Range0–2711–2470–271
Age at primary breast cancer (y.o.) 0.142
  Median555255
  Range29–8932–7529–89
Age at metastatic breast cancer (y.o.) 0.232
  Median595759
  Range31–9232–8131–92
Disease stage at primary diagnosis, no. (%) 0.003
  Stage 04 (2.3)2 (6.3)2 (1.4)
  Stage I24 (14.0)11 (34.3)13 (9.4)
  Stage II42 (24.6)5 (15.6)37 (26.6)
  Stage III46 (27.0)8 (25.0)38 (27.3)
  Stage IV38 (22.2)4 (12.5)34 (24.5)
  Unknown17 (9.9)2 (6.3)15 (10.8)
Histology, no. (%) 0.619
  Invasive ductal148 (86.4)30 (93.8)118 (84.9)
  Invasive lobular7 (4.1)0 (0.0)7 (5.0)
  Mixed3 (1.8)0 (0.0)3 (2.2)
  Sarcoma1 (0.6)0 (0.0)1 (0.7)
  Other9 (5.3)2 (6.2)7 (5.0)
  Unknown3 (1.8)0 (0.0)3 (2.2)
Receptor status, no. (%) 0.358
  ER+/HER2-93 (54.4)19 (59.4)74 (53.2)
  ER+/HER2+23 (13.5)4 (12.5)19 (13.7)
  ER-/HER2+20 (11.7)6 (18.8)14 (10.1)
  ER-/HER2-28 (16.4)2 (6.3)26 (18.7)
  Unknown7 (4.0)1 (3.0)6 (4.3)
Ki-67 labeling index 0.885
  Median, SD20.3±19.620.5±23.720.9±18.6
  Range1.5–901.5–902–80
Site No. of metastasis/recurrence <0.001
  152 (30.4)25 (78.1)27 (19.4)
  248 (28.1)6 (18.8)42 (30.2)
  ≥371 (41.5)1 (3.1)70 (50.4)
No. of visceral metastasis PgR status <0.001
  051 (29.8)25 (78.1)26 (18.7)
  176 (44.5)6 (18.8)70 (50.4)
  240 (23.4)1 (3.1)39 (28.1)
  34 (2.3)0 (0.0)4 (2.8)
NLR at diagnosis of metastasis/recurrence <0.001
  Median, SD2.44±1.971.46±0.352.66±2.16
  Range0.83–17.500.93–2.770.83–17.50

[i] Bold type indicates a statistically significant difference (P<0.005). cCR, clinical complete response; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; NLR, neutrophil-lymphocyte ratio.

In patients with primary stage IV disease, the abundance of TILs was approximated by examining hematoxylin- and eosin-stained tumor samples under medium power (100×). This examination was limited to patients with stage IV disease because they did not receive prior treatments, which might have affected the TIL score. All samples were reviewed by pathologists. TIL score was defined as the percentage of the tumor and adjacent stroma area infiltrated by lymphocytes; the scores were classified as low (<10%), intermediate (≥10%, 50%>) or high (≥50%) (10,11). Immunohistochemistry was performed to identify the antigens (CD4 and CD8) in the cell membranes of the TILs. Furthermore, neutrophils are easily affected by factors like infection or therapeutic exposure. In order to minimize the effects of treatment or tumor progression, NLRs were determined in blood samples at diagnosis.

The study design was approved by Ethics Review Board of Shiga Medical Center for Adults according to the Declaration of Helsinki.

Statistics

Qualitative data were examined for differences between the cCR and non-cCR groups; both patient and tumor characteristics were examined, and the chi-square test was used. OS was defined as the interval between the date of diagnosis and the date of the last follow-up or death from any cause. OS was calculated using Kaplan-Meier estimates, and differences in OS were evaluated using the log-rank test. A P-value <0.05 was considered significant. A multivariable Cox proportional hazards regression model was used to identify OS-associated factors. To estimate effects of each factor, hazard ratios with 95% confidence intervals were calculated. Data were analyzed using Stat Mate V for Win & Mac Hybrid software (ATMS Co., Ltd, Tokyo, Japan).

Results

The median follow-up time for the 171 patients with MBC in our study was 44 months (range, 0–271 months). Thirty-two (18.7%) patients, including 10 patients with HER2+-disease (5.8%), had a cCR, with no evidence of disease or a secondary recurrence for 40 months (range, 0–200 months); no patient died during 40 months. All cCR patient terminated treatment after the first or second line of MBC therapy. Most of them had multiple metastatic sites, limited to median 2 organs (range, 1–3 organs). The median time to achieve a cCR was 20 months (range, 0–85 months). Although patients who had achieved cCR included patients who had undergone metastatic site resection without systemic therapy, usually their main therapy was systemic therapy. Compared with non-cCR patients, cCR patients had fewer sites of metastases or recurrences (P<0.001), fewer visceral metastases (P<0.001), and a lower NLR (P<0.001) and were diagnosed with primary breast cancer at an earlier stage (P=0.003).

Among the 120 (70.2%) patients with visceral metastases, 7 patients (5.8%) achieved a cCR: 5 patients received systemic therapy without surgery, and 2 patients underwent resection for brain and lung metastases, respectively. In patients with visceral metastases, the NLR at diagnosis was significantly lower in the cCR (n=7) than the non-cCR group (n=25, P<0.001). The characteristics of patients with visceral metastasis are summarized in Table II.

Table II.

Characteristics of patients with visceral metastases.

Table II.

Characteristics of patients with visceral metastases.

VariablesAll patients (n=120)cCR (n=7)non-cCR (n=113)P-value
Follow-up period (months) 0.153
  Median449840
  Range0–24713–2470–171
Age at primary breast cancer (y.o.) 0.222
  Median554955
  Range29–8932–6129–89
Age at metastatic breast cancer (y.o.) 0.077
  Median595059
  Range31–8932–6131–89
Disease stage at primary diagnosis, no. (%) 0.942
  Stage 02 (1.7)0 (0.0)2 (1.8)
  Stage I10 (8.3)1 (14.2)9 (8.0)
  Stage II33 (27.5)2 (28.6)31 (27.4)
  Stage III33 (27.5)2 (28.6)31 (27.4)
  Stage IV30 (25.0)2 (28.6)28 (24.8)
  Unknown12 (10.0)0 (0.0)12 (10.6)
Histology, no. (%) 0.964
  Invasive ductal106 (88.4)7 (100.0)99 (87.6)
  Invasive lobular4 (3.3)0 (0.0)4 (3.5)
  Mixed1 (0.8)0 (0.0)1 (0.9)
  Sarcoma1 (0.8)0 (0.0)1 (0.9)
  Other6 (5.0)0 (6.2)6 (5.3)
  Unknown2 (1.7)0 (0.0)2 (1.8)
Receptor status, no. (%) 0.983
  ER+/HER2-65 (54.2)4 (57.1)61 (54.0)
  ER+/HER2+15 (12.5)1 (14.3)14 (12.4)
  ER-/HER2+14 (11.7)1 (14.3)13 (11.5)
  ER-/HER2-22 (18.3)1 (14.3)21 (18.6)
  Unknown4 (3.3)0 (0.0)4 (3.5)
Ki-67 labeling index 0.352
  Median ± SD22.3±19.613.3±20.623.2±18.9
  Range1.5–801.5–502–80
Site no. of metastasis/recurrence 0.006
  117 (14.2)3 (42.9)14 (12.4)
  236 (30.0)4 (57.1)32 (28.3)
  ≥367 (55.8)0 (0.0)67 (59.3)
NLR at diagnosis of metastasis/recurrence <0.001
  Median ± SD2.84±2.311.29±0.102.92±2.34
  Range0.83–17.501.21–1.400.83–17.50

[i] Bold type indicates a statistically significant difference (P<0.01). cCR, clinical complete response; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; NLR, neutrophil-lymphocyte ratio.

Median OS were longer in cCR group than non-cCR group (P<0.001; Fig. 1). OS was also longer in patients with a low NLR (<1.9) than in those with a high NLR (≥1.9) at the time of MBC diagnosis (33 vs. 79 months, P=0.004; Fig. 2). In the multivariate analysis, a high NLR was associated with worse OS (P=0.0218; hazard ratio, 1.75; 95% confidence interval, 1.09–2.85; Table III). Three patients with a high NLR achieved a cCR, none of three had visceral metastases, and all of them received multidisciplinary therapy consisting of systemic therapy and local resection.

Table III.

Multivariate analysis of factors associated with overall survival.

Table III.

Multivariate analysis of factors associated with overall survival.

VariableHR95% CIP-value
Non-cCR2.270.87–5.940.0955
Primary stage IV1.140.64–2.030.6495
Metastatic sites no. ≥31.790.95–3.360.0714
Visceral sites no. ≥21.070.62–1.860.7968
NLR≥1.901.751.09–2.850.0218

[i] Bold type indicates a statistically significant difference (P<0.05). HR, hazard ratio; CI, confidence interval; cCR, clinical complete response; NLR, neutrophil-lymphocyte ratio.

Core needle biopsy samples were obtained from 26 stage IV MBC patients before treatment (Table IV). Two patients had synchronous bilateral breast cancers. Lymphocyte infiltration was scored as high [≥50%; (Fig. 3A), intermediate (≥10%, 50%>), and low (<10%; (Fig. 3B)]. Focusing on 4 patients with triple-negative disease, all of them belonged to low TILs and resulted in non-cCR.

Table IV.

Clinicopathological implications of TILs for patients with primary stage IV disease.

Table IV.

Clinicopathological implications of TILs for patients with primary stage IV disease.

No.AgeER/HER2Ki-67 (%)Metastatic siteTILsOutcomef/u (months)Other information
166+/−20Bone, lung, LNLowPD16
267+/− (rt.)2LungLowSD19Bilateral
+/− (lt.)2LungLowSD19
365+/−20LungLowSD50
485+/−50LungLowPR11
559+/−7.5Bone, lung, LNIntermediateSD15
668+/−20BoneLowcCR29
759+/−5Bone, liver, LNLowDeceased10ILC
889+/−10Bone, lungLowDeceased10ILC
980+/−10BoneLowPD57
1056+/−4Contralateral breast, bone, pleura, LN, peritoneumIntermediateDeceased7ILC
1158+/−/Bone, pleura, lungLowDeceased43IMPC
1261+/−40Bone, liverLowDeceased4
1361+/−1.5LungLowcCR69
1466+/−/Bone, lung, liver, LNLowDeceased66
1554+/−/Bone, pleura, pericardiac membraneIntermediateDeceased62
1644+/− (rt.)2BoneIntermediatePD14Bilateral
44+/+ (lt.)3BoneIntermediatePD14
1764+/+10Bone, liverLowPR3
1836+/+30Bone, lungLowPR19
1962−/+50Lung, liverIntermediateSD48
2056−/+90Contralateral LNLowcCR14Fig. 3B
2132−/+50Lung, LNHighcCR38Fig. 3A
2257−/+40Bone, pleura, LN, contralateral breast, localIntermediatePD37
2375−/−5Bone, lung, liver, muscleLowDeceased4
2487−/−7.5BoneLowSD2
2560−/−/Pleura, localLowDeceased67
2685−/−/Lung, peritoneum, LNLowSD1

[i] TILs, tumor infiltrating lymphocytes; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; rt., right; lt., left; LN, lymph nodes; cCR, clinical complete response; PR, partial response; SD, stable disease; PD, progressive disease; BC, breast cancer; f/u, follow up; ILC, invasive lobular carcinoma; IMPC, invasive micropapillary carcinoma.

Discussion

MBC accounts for most breast cancer-associated deaths. However, some patients with MBC achieve a cCR and survive for a long time after multidisciplinary treatment. Owing to new agents and therapies, the prognosis for MBC has been improving (1).

In the present study, patients who achieved a cCR survived for a longer period of time than those who did not (Fig. 1). Compared with patients in the non-cCR group, those in the cCR group were diagnosed with primary breast cancer at an earlier stage and had fewer number of recurrent or metastatic sites, and a lower NLR (Table I). Over half of the patients in cCR group acquired NED status after local resection of lymph node metastases or oligometastases. Thus, volume reduction is an instrumental in achieving a cCR, irrespective of phenotype or Ki-67 status. Most important strategy is appropriate primary disease control. Table II shows that the cCR group tended to have a small number of metastatic sites and a low NLR, even if visceral metastases were present. Seven patients who had a cCR had visceral metastases, 5 of 7 received systemic therapy without surgery. Although the number of patients with visceral metastases who achieved a cCR is small, these patients are expected to increase along with new drugs development. Since trastuzumab was developed in the 1990's, improvement of anti-HER2 therapy has been remarkable. An increase of the patients who achieve a cCR, especially HER2+ patients, is expected in the future.

Our study verified the prognostic value of NLR in MBC, as reported by others (1216). Additionally, patients with a high NLR achieved a cCR by multidisciplinary therapy combined with, local resection and systemic therapy. Neutrophils play an important role in the metastatic microenvironment (1719). It is generally believed that neutrophils dynamically regulate cancer progression and metastasis. Resection of metastatic sites where the immune system does not target cancer cells is a reasonable strategy.

To assess the relationship between the tumor microenvironment and therapeutic effects, we focused on TILs because a high serous NLR might reflect local lymphocyte invasion. We examined lymphocyte infiltration in patients with stage IV disease (Table IV); because they were treatment-naïve, and their TIL scores were treatment-unrelated. Twenty-eight specimens from 26 patients were available for review. Assessment of the 4 patients (3 low TILs; 1 high TILs) who achieved a cCR [estrogen receptor (ER)+/HER2, 2 patients; ER/HER2+, 2 patients] showed that the TIL score had no prognostic value in MBC. According to previous reports, the TIL score is a prognostic marker in HER2+ breast cancers (20), as well as triple-negative breast cancers (TNBC) in the both neoadjuvant and adjuvant settings (11,21,22). Because all TNBC patients in this study showed low TILs, the relationship between prognosis of TNBC patients and high TILs could not be evaluated.

We did not evaluate the biopsy samples from all metastatic sites. This would be of interest because metastatic cancer cells have different characteristics from primary cancer cells (23). Additionally, TILs review was performed in core needle biopsy samples histologically. Strictly, core needle biopsy was not standard approarch for TILs evaluation (10).

In our study, 43 of the 137 patients with primary stage I–III breast cancer experienced recurrence during adjuvant therapy; the phenotypes of tumors were ER+/HER2 (29 patients), ER+/HER2+ (9 patients), ER/HER2+ (1 patient), and ER/HER2 (4 patients). In these patients, recurrence is thought to be mainly from tumor-related factors (e.g., resistance to systemic therapy) rather than host-related factors. Because recent whole-exosome and transcriptome analysis revealed that one of the most important mechanism in acquired drug resistance in breast cancer therapy is mutation in cancer cells, not in host normal cells (24,25). Host-related factors such as individual adherence to therapy, ability of drug metabolism, activity of drug degrading enzyme are also important. However, appropriate adjuvant systemic therapy is especially needed regarding the high mutation activity of tumor related to drug-resistance.

In conclusion our study showed cCR and low NLRs associate with extended survival times in patients with MBC.

Acknowledgements

Not applicable.

Funding

No funding was received.

Availability of data and materials

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

Authors' contributions

HT, WT and FY designed the study. MS and YY contributed to the evaluation of TIL scoring and the immunohistochemistry analysis of CD4 and CD8. HT performed survival analysis and multivariate analysis of the other data.

Ethics approval and consent to participate

The present study was approved by the Ethics Review board of the Shiga Medical Center for Adults.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Glossary

Abbreviations

Abbreviations:

cCR

clinical complete response

ER

estrogen receptor

HER2

human epithelial growth factor receptor 2

MBC

metastatic breast or recurrent breast cancer

NLR

neutrophil-lymphocyte ratio

OS

overall survival

TIL

tumor-infiltrating lymphocyte

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APA
Takuwa, H., Tsuji, W., Yamamoto, Y., Shintaku, M., & Yotsumoto, F. (2018). Low neutrophil-lymphocyte ratio correlates with extended survival in patients with metastatic breast cancer who achieved clinically complete response following multidisciplinary therapy: A retrospective study. Oncology Letters, 15, 6681-6687. https://doi.org/10.3892/ol.2018.8145
MLA
Takuwa, H., Tsuji, W., Yamamoto, Y., Shintaku, M., Yotsumoto, F."Low neutrophil-lymphocyte ratio correlates with extended survival in patients with metastatic breast cancer who achieved clinically complete response following multidisciplinary therapy: A retrospective study". Oncology Letters 15.5 (2018): 6681-6687.
Chicago
Takuwa, H., Tsuji, W., Yamamoto, Y., Shintaku, M., Yotsumoto, F."Low neutrophil-lymphocyte ratio correlates with extended survival in patients with metastatic breast cancer who achieved clinically complete response following multidisciplinary therapy: A retrospective study". Oncology Letters 15, no. 5 (2018): 6681-6687. https://doi.org/10.3892/ol.2018.8145