Research ArticleClinical Studies

Pretreatment Absolute Lymphocyte Count and Neutrophil-to-lymphocyte Ratio Are Prognostic Factors for Stage III Breast Cancer

KOSHO YAMANOUCHI, SHIGETO MAEDA, DAIKI TAKEI, YOICHI KOGA, MANPEI YAMASHITA, TAKASHI HAMADA, TAKANORI HIRAYAMA, AKIRA YONEDA, TAKAYUKI TOKUNAGA, HIROAKI TAKESHITA and TAMOTSU KUROKI
Anticancer Research July 2021, 41 (7) 3625-3634; DOI: https://doi.org/10.21873/anticanres.15151

Abstract

Background/Aim: Stage III breast cancer comprises a broad spectrum of disease, including the extent of supraclavicular/internal mammary lymph node metastasis. In this study, we evaluated the usefulness of the absolute lymphocyte count (ALC) and neutrophil-to-lymphocyte ratio (NLR) in predicting the prognosis of patients with stage III breast cancer. Patients and Methods: Seventy-five patients with stage III breast cancer who underwent surgery were included. We compared their clinicopathological factors according to the presence or not of supraclavicular/internal mammary lymph node metastasis, and pretreatment ALC or NLR. Results: Patients with metastasis of the studied lymph nodes had a poorer prognosis in comparison to those without metastasis. In patients without these types of lymph node metastasis, both the ALC and NLR were predictive factors for relapse-free and overall survival. Among these patients, those with a low ALC or high NLR had recurrence-free and overall survival comparable to those of patients with supraclavicular/internal mammary lymph node metastasis. Conclusion: Pretreatment ALC and NLR were prognostic factors for patients with stage III breast cancer.

Key Words:

Breast cancer is the most frequent cancer and the second leading cause of cancer death among women in the world (1). In the clinical setting, the prediction of sensitivity to systemic therapy for breast cancer is determined according to a surrogate subtype classification based on the hormone-receptor [estrogen receptor (ER) and progesterone receptor (PgR)], human epidermal growth factor receptor-2 (HER2), and Ki-67 immunohistochemistry (2).

Locally advanced stage III breast cancer, which confers an unfavorable prognosis in comparison to earlier stage breast cancer (3), comprises a broad spectrum of disease, including the extent of lymph node metastasis (4). Stage III breast cancer with metastasis of the supraclavicular or internal mammary (S/I) lymph nodes is known to have an unfavorable prognosis (3, 5). In many cases with stage III breast cancer, multimodal treatment, consisting of not only local therapy, such as surgery and radiotherapy (RT), but also systemic therapy, are selected with curative intent. However, sensitivity to systemic therapy and the clinical outcome are not uniform in breast cancer, even in patients with a similar subtype, tumor grade, and disease progression (6).

The development, progression, and metastasis of solid malignancies seems to be affected by microenvironmental as well as systemic inflammatory and immune responses (7-0). Lymphocytes in both the general circulation and the microenvironment are important for the immune responses to cancer. For instance, infiltration by lymphocytes into a tumor was associated with a good prognosis in patients with triple-negative breast cancer treated with adjuvant chemotherapy (11). On the other hand, neutrophils have been shown to produce cytokines which promote cancer proliferation (12) and to suppress the cytotoxic activity mediated by immune cells such as lymphocytes (13, 14). Recently, various studies have shown a correlation between inflammatory and immune markers and the prognosis of solid malignancies. Among these markers, the absolute lymphocyte count (ALC) and neutrophil-to-lymphocyte ratio (NLR), which are easily obtainable and seem to reflect the immune and inflammatory status, have been widely evaluated due to their efficacy in predicting the prognosis of breast cancer (15-18).

In this study, we evaluated the usefulness of ALC and NLR in predicting the prognosis of patients with stage III breast cancer, with and without involvement of the S/I lymph nodes.

Patients and Methods

We reviewed the clinicopathological data of 75 patients with pathological stage III breast cancer (as defined by the eighth edition of the Union for International Cancer Control TNM Classification of Malignant Tumours) (4), who underwent total or partial mastectomy with radical intent at our hospital between April 2007 and August 2019. This retrospective study was approved by the Institutional Review Board (approval number: 2020079), and the requirement to obtain informed consent was waived.

Protocol and evaluations. All patients underwent total or partial mastectomy according to the size of the tumor and patient’s preference. In principle, sentinel lymph node biopsy was performed for patients without clinical axillary lymph node metastasis. Axillary lymph node dissection was performed for patients with clinical axillary lymph node metastasis or a positive sentinel lymph node. We did not perform dissection or biopsy of either the S/I lymph nodes in any patients. Adjuvant RT was performed for patients with partial mastectomy and those with lymph node metastasis. Systemic adjuvant therapy was selected according to the subtype, age, extent of disease, and patient’s preference.

ER and PgR were regarded as positive when their nuclear expression was found to be ≥1% by immunohistochemistry. HER2 expression was scored according to the American Society of Clinical Oncology/College of American Pathologists guidelines (19). HER2 scores by immunohistochemistry of 0 and 1 were defined as negative, while a score of 3 was defined as positive. In HER2 2+ samples, in situ hybridization analysis was carried out. Luminal disease was defined as ER-/PgR-positive and HER2-negative, HER2-positive disease was defined as HER2-positive irrespective of the ER/PgR expression, and triple-negative was defined as negativity for ER, PgR and HER2.

After radical surgery for breast cancer, we followed-up patients every 3 to 6 months until 5 years, and then every 1 year until 10 years. All patients underwent a physical examination at each visit and mammography and the measurement of the carcinoembryonic antigen level once per year. Additionally, some patients underwent blood tests, including the measurement of liver function markers with/without cancer-associated antigen 15-3 (CA15-3) and periodic imaging, such as computed tomography, at each physician’s discretion. If the patient showed some symptoms or findings that suggested recurrence of breast cancer, further examinations were performed. The therapeutic strategy after the diagnosis of recurrence was developed based on age, disease-free interval, hormone-receptor status, HER2 status, extent of disease, and the patient’s preference. For instance, for patients with non-life-threatening hormone receptor-positive and HER2-negative disease, especially those who had no symptoms, hormone therapy was the initial treatment of choice and sequential hormonal therapies were continued for as long as possible. For patients with HER2-positive disease, an anti-HER2 agent and chemotherapy or hormone therapy was administered.

The ALC and NLR were assessed at baseline (i.e., within 4 weeks before perioperative systemic therapy). The NLR was defined as the absolute neutrophil count in the peripheral blood divided by the ALC.

Relapse-free survival (RFS) was defined as the period from the date of surgery to the date of the last follow-up examination, first recurrence, or death. Overall survival (OS) was defined as the time from the pathological diagnosis of breast cancer to the date of the last follow-up or death.

Statistical analysis. We compared the clinicopathological factors in patients with (S/I+) and without (S/I‒) supraclavicular or internal mammary lymph node metastasis. The data are presented as the median (range) unless otherwise stated. The Mann–Whitney U-test or t-test was used for comparisons of continuous variables between two groups. Fisher’s exact probability test was used for the comparison of categorical variables. RFS and OS were assessed using the Kaplan–Meier approach, with differences between groups tested using a log-rank test. p-Values of less than 0.05 were considered to indicate statistical significance. All statistical analyses were conducted using EZR (Saitama Medical Center, Jichi Medical University, Japan).

Results

Patient background characteristics. The median follow-up period was 50 months (4-133 months). Eleven patients with S/I lymph node metastasis were classified into the S/I+ group and 64 patients without such lymph node metastasis were classified into the S/I‒ group. The background characteristics of the patients in each group are shown in Table I. The median age of the patients at diagnosis of breast cancer was 52 (35-5) years in the S/I+ group and 57 (27-86) years in the S/I‒ group (p=0.38). The proportions of the breast cancer subtypes did not differ between the groups (p=0.42). The median number of axillary lymph nodes with metastasis in the S/I+ group was more than twice than that of the S/I‒ group (p<0.05). The proportions of patients who underwent total mastectomy, axillary lymph node dissection, perioperative chemotherapy, and postoperative RT did not differ between the groups. The baseline ALC and NLR were similar for both groups. The sites of initial recurrence, including the bone, liver, lung, local site, lymph node, and central nervous system also did not differ between the two groups.

View this table:
Table I.

Patient background characteristic according to presence (S/I+) or not (S/I‒) of supraclavicular/internal mammary lymph nodal metastasis.

Factors that affected survival in patients with stage III breast cancer. We compared survival in patients with stage III breast cancer. According to the subtype of breast cancer, patients with triple-negative disease had worse RFS than those with luminal disease (5-year luminal vs. triple-negative: 65.3 vs. 32.5%, p<0.05) and tended to have poor RFS in comparison to those with HER2-positive disease (5-year HER2 vs. triple-negative: 70.8 vs. 32.5%, p=0.10) (Figure 1A). Patients with triple-negative also had significantly worse OS than those with luminal (5-year: luminal vs. triple-negative: 87.8 vs. 49.2%, p<0.05) (Figure 1B). The 5-year RFS rate was 35.8% for the S/I+ group and 63.5% for the S/I‒ group (p=0.05) (Figure 2A). The OS of the patients in the S/I+ group was significantly worse than that of the S/I‒ group (5-year 50.8 vs. 82.4%, p<0.01) (Figure 2B).

Figure 1.
Figure 1.

Comparison of relapse-free (A) and overall (B) survival according to the breast cancer subtype. HER2: Human epidermal growth factor receptor 2. Log-rank p-values are given.

Figure 2.
Figure 2.

Comparison of relapse-free (A) and overall (B) survival between patients with (S/I+) and without (S/I‒) metastasis of the supraclavicular/internal mammary lymph nodes. Log-rank p-values are given.

We evaluated the efficacy of perioperative chemotherapy based on survival. Perioperative chemotherapy did not affect survival of patients with stage III breast cancer as a whole (with vs. without chemotherapy, 5-year RFS: 57.1 vs. 62.5%, p=0.99; 5-year OS; 79.2 vs. 82.4%, p=0.81) (Figure 3A). In the subgroup analysis, although chemotherapy did not significantly affect either type of survival for the S/I‒ group (Figure 3B), it tended to improve RFS of the S/I+ group (5-year RFS; 43.8 vs. 33.3%, p=0.08) (Figure 3C). Postoperative RT did not significantly affect survival in the overall population nor in the subgroup analysis (data not shown).

Figure 3.
Figure 3.

Comparison of relapse-free (upper panels) and overall (lower panels) survival according to chemotherapy (CTx). A: Whole study cohort. B: Patients without metastasis of the supraclavicular/internal mammary lymph nodes (S/I‒). C: Patients with such metastasis (S/I+). Log-rank p-values are given.

Correlation of the ALC and NLR with survival in stage III breast cancer. Figure 4 shows the correlation between baseline ALC and survival. The median values were used as cut-off values. In all the cases, the patients with a high ALC (n=35) tended to have better RFS than those with a low ALC (n=36) (cut-off value 1,500 n/μl, 5-year RFS; 75.0 vs. 45.2%, p=0.06) (Figure 4A). There were no differences in the proportions of patients who received chemotherapy, the presence of S/I lymph node metastasis, or the number of metastatic axillary lymph nodes between the patients with a high ALC and those with a low ALC (data not shown). In patients of the S/I‒ group, those with a high ALC (n=29) had significantly better RFS (cut-off value 1,500 n/μl, 5-year: 80.9 vs. 45.9%, p<0.05) and OS (5-year OS; 95.0 vs. 69.5%, p<0.05) (Figure 4B) in comparison to the patients with a low ALC (n=33). For the patients in the S/I+ group, RFS and OS did not differ to a statistically significant extent (p=0.55 and p=0.64, respectively) (Figure 4C). The patients with a low ALC in the S/I‒ group had similar RFS (p=0.40) and OS (p=0.25) to those of the S/I+ group (Figure 5A). In a subgroup analysis according to the subtype of breast cancer, the patients with HER2+ breast cancer with a high ALC had longer OS in comparison to those with a low ALC considering the population overall and in the S/I‒ group (p<0.05 each) (data not shown).

Figure 4.
Figure 4.

Comparison of relapse-free (upper panels) and overall (lower panels) survival according to absolute lymphocyte count (ALN). A: Whole study cohort. B: Patients without metastasis of the supraclavicular/internal mammary lymph nodes (S/I‒). C: Patients with such metastasis (S/I+). Log-rank p-values are given.

Figure 5.
Figure 5.

Comparison of relapse-free (upper panels) and overall (lower panels) survival according to supraclavicular/internal mammary lymph nodal metastasis (S/I) combined with absolute lymphocyte count (ALC) and with neutrophil-to-lymphocyte ratio (NLR). Significantly different versus S/I+ at *p<0.05 and **p<0.01.

With regard to the correlation between the baseline NLR (cut-off value 2.57), and survival, the patients of the S/I‒ group with a low NLR (n=31) had significantly better RFS than those with a high NLR (n=31) (5-year: 76.1 vs. 47.3%, p<0.05) and tended to have better OS (5-year: 87.1 vs. 76.2%, p=0.09) (Figure 6B). In the subgroup analysis according to the breast cancer subtype, patients with luminal breast cancer with a low NLR had longer RFS than those in the overall population with a high NLR and in the S/I‒ group (p<0.05 each) (data not shown). In patients of the S/I+ group, there were no significant differences in RFS (p=0.48) or OS (p=0.85) according to NLR using a cut-off value of 2.35 (Figure 6C). The patients of the S/I‒ group with a high NLR had similar RFS (p=0.50) and OS (p=0.24) to patients of the S/I+ group (Figure 5B).

Figure 6.
Figure 6.

Comparison of relapse-free (upper panels) and overall (lower panels) survival according to neutrophil-to-lymphocyte ratio (NLR). A: Whole study cohort. B: Patients without metastasis of the supraclavicular/internal mammary lymph nodes (S/I‒). C: Patients with such metastasis (S/I+). Log-rank p-values are given.

Discussion

In this evaluation, we found that patients with S/I lymph node metastasis had worse survival than those without, as previously reported (3, 5). Furthermore, in patients with S/I lymph node metastasis, perioperative chemotherapy tended to increase RFS. At our Institute, dissection or biopsy of S/I lymph nodes was not performed. In the retrospective evaluation of local therapy for supraclavicular lymph node metastasis, dissection of these lymph nodes plus RT did not improve survival in comparison to RT alone (20, 21). With regard to internal mammary lymph nodes, accurate staging by biopsy may benefit some patients, by identifying patients who may benefit from more intensive chemotherapy and RT (22, 23). The Japanese guidelines for breast cancer, however, report that the efficacy of internal mammary lymph node biopsy was inconclusive (24). Because most studies on dissection or biopsy of the S/I lymph nodes have been retrospective, prospective studies with large study populations are needed to confirm the efficacy of surgical dissection for these regions. In a retrospective one-arm evaluation, multimodal treatment, including neoadjuvant chemotherapy, breast surgery, and RT, achieved acceptable local control and survival in patients with internal mammary (25) and S/I lymph node metastasis (26). Furthermore, an evaluation of the National Cancer Database revealed that patients with cN3c breast cancer (supraclavicular lymph node involvement) who received multimodal therapy showed improved OS in comparison to patients who did not receive standard therapy (27). In a phase III study, RT targeting the medial supraclavicular lymph nodes improved 15-year breast cancer mortality and breast cancer recurrence but not OS (28). The guidelines for breast cancer recommend RT targeting the S/I regions in patients with axillary lymph node metastasis (24, 29). In our study, perioperative chemotherapy and postoperative RT were administered to 72.2% and 54.5% of the S/I+ patients. Currently, combined aggressive treatment approaches with curative intent, which include chemotherapy, breast surgery, RT, endocrine therapy and molecular targeted therapy, have been proposed for these patients (26, 30, 31).

Among the inflammatory and immune markers that have been reported to predict the prognosis associated with solid malignancies, we focused on the ALC and NLR, both of which are easily obtainable. ALC has been found to be a predictor of local and systemic recurrence in patients with breast cancer patients (15, 16). Moreover, ALC has been reported to be associated with the prognosis, in that, an ALC of ≥1,500/μl was a good predictive factor for progression-free survival in patients with stage IV HER2-positive breast cancer (17). While the ALC may reflect a potential immune reaction to cancer, the NLR additionally reflects systemic inflammation, in that an elevated NLR can facilitate cancer progression via pro-inflammatory and angiogenic cytokines. A relationship between the pretreatment NLR and outcome (disease-free survival and OS) was reported in elderly patients with breast cancer (18). With regard to factors predicting the therapeutic responsiveness, a lower pretreatment NLR was reported to be likely to lead to a pathological complete response in patients who received neoadjuvant chemotherapy (32). Longitudinal inflammatory markers, including the NLR, were also reported to be associated with frailty in patients with breast cancer receiving chemotherapy (33). Considering the subtype of breast cancer, the NLR was associated with survival in patients with triple-negative disease (34, 35) or HER2-positive disease (cases without trastuzumab administration) (36).

Our evaluation showed that a low ALC and high NLR potentially predicted a poor prognosis in patients with S/I‒ stage III breast cancer and that these patients had RFS and OS similar to S/I+ patients. Although ALC and NLR have been demonstrated to predict the efficacy of treatment, the validity of the treatment choice (i.e., escalation or de-escalation) based on these markers has not been elucidated. A recent study reported a relationship between inflammatory and immune markers, including the ALC or NLR, and the number of tumor-infiltrating lymphocytes in breast cancer (37). The NLR was reported to be related to the clinical response to programmed death 1 and programmed death-ligand 1 inhibitors in advanced non-small cell lung cancer (38). These findings indicate systemic ALC and NLR are directly related to microenvironmental immunity and future basic and clinical studies might elucidate the efficacy and validity of immunotherapy for cancer according to inflammatory and immune marker levels.

Are inflammatory and immune marker values, including the ALC and NLR, the cause of or consequence of aggressiveness or the progression of cancer? Interestingly, an elevated NLR was reported to be associated with an increased risk of occurrence of breast cancer (39). Furthermore, a higher ALC was reported to predict lower mortality from early-stage triple-negative breast cancer (35). Thus, the individual intrinsic values of these markers might reflect the status of the host immune system and be factors that partially determine the occurrence, progression, and prognosis of cancer.

The present study was associated with some limitations. Firstly, it was a retrospective study and the follow-up strategies for outpatients, including the frequency of imaging examinations, was not uniform and depended on each physician. Thus, RFS would be less reliable in comparison with OS. Secondly, the number of patients was not sufficient. In particular, the numbers of patients with triple-negative disease or metastasis of the S/I lymph nodes were too small for a reliable subgroup analysis.

In conclusion, among patients with stage III breast cancer, those with metastasis of the S/I lymph nodes had a poorer prognosis in comparison to those without metastasis. Both the baseline ALC and NLR were prognostic factors and patients with stage III S/I‒ breast cancer with a low ALC or high NLR had RFS and OS comparable to patients with stage III S/I+ breast cancer. Since inflammatory and immune markers, including the ALC and NLR, have been reported possibly reflect microenvironmental immunity, they may be helpful for deciding appropriate cancer therapies.

Footnotes

  • Authors’ Contributions

    All Authors contributed to the study design, commented on previous versions of the article, read and approved the final article. Material preparation, data collection and analysis were performed by KY and SM. The first draft of the article was written by KY.

  • Conflicts of Interest

    The Authors declare that they have no conflicts of interest.

  • Received May 24, 2021.
  • Revision received June 11, 2021.
  • Accepted June 15, 2021.

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Pretreatment Absolute Lymphocyte Count and Neutrophil-to-lymphocyte Ratio Are Prognostic Factors for Stage III Breast Cancer
KOSHO YAMANOUCHI, SHIGETO MAEDA, DAIKI TAKEI, YOICHI KOGA, MANPEI YAMASHITA, TAKASHI HAMADA, TAKANORI HIRAYAMA, AKIRA YONEDA, TAKAYUKI TOKUNAGA, HIROAKI TAKESHITA, TAMOTSU KUROKI
Anticancer Research Jul 2021, 41 (7) 3625-3634; DOI: 10.21873/anticanres.15151
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