Background
During the past decade, advanced human epidermal growth factor receptor 2 (HER2)-targeted therapies have significantly improved outcomes for patients with HER2-positive advanced breast cancer (ABC) [
1]. Clinical evaluations of pertuzumab and trastuzumab (PT) in combination with different chemotherapy regimens in the CLEOPATRA trial and our previous study have highlighted clinical benefits [
2,
3].
Pertuzumab and trastuzumab are humanized monoclonal anti-HER2 antibodies with complementary proposed mechanisms of action. Both antibodies work through the disruption of HER2 dimerization with HER3 and other epidermal growth factor receptors (EGFRs), leading to the inhibition of HER2 signaling [
4]. Anti-HER2 antibodies are thought to mediate tumor regression not only by interrupting oncogenic signaling, but also by inducing antibody-dependent cell-mediated cytotoxicity (ADCC) [
4]. ADCC can induce innate immune system responses via Fcγ receptors. These responses are sustained by natural killer (NK) cells; concomitantly, adaptive immunity involving tumor-infiltrating lymphocytes (TILs) develops in response to a specific antigen, which is sustained by T and B lymphocytes [
5]. The association of TILs with clinical outcomes suggests a significant role for antitumor immunity in HER2-positive ABC [
6].
Immune responses against cancer cells might involve a balance between tumor inhibitory mechanisms induced by intrinsic immunity and the ability of tumor cells to evade immune surveillance [
7]. During cancer immunoediting phases (i.e., elimination, equilibrium, and escape), activated effector cytotoxic T lymphocytes can migrate to the tumor and infiltrate the tumor microenvironment [
7,
8]. It has been reported that circulating peripheral lymphocytes and neutrophils can migrate towards a tumor site in a directed manner along the humoral factors, such as a chemoattractant [
9]. A recent study demonstrated that circulating tumor-specific T lymphocytes related to neoantigens can be isolated from the peripheral blood of patients with melanoma [
10]. These data may indicate that blood-based parameters (PBBPs) reflect a local immune reaction against cancer cells. In line with such a mechanism, the absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) are reported to be immune-related prognostic factors for patients with malignancy [
11,
12]. In addition, relationships between low levels of NLR and improved response to neoadjuvant chemotherapy have been reported for patients with breast cancer [
13‐
15]. Therefore, PBBPs seem to affect treatment efficacy for ABC treated with chemotherapy and anti-HER2 therapy; however, this topic has yet to be fully studied.
In the present study, we aimed to explore whether PBBPs are related to improved progression-free survival (PFS) in patients with HER2-positive ABC treated with HER2-targeted PT combined with eribulin (ERI) or nab-paclitaxel (Nab-PTX).
Discussion
In this prospective-retrospective evaluation of PBBPs in baseline clinical data, we identified ALC as a predictive factor for PFS in patients with HER2-positive ABC. Additionally, high ALC at baseline was significantly associated with improved PFS in HER2-positive ABC treated with either ERI or Nab-PTX in combination with PT. To the best of our knowledge, this study is the first to analyze predictive factors associated with ALC in HER2-positive ABC. For treatment of ABC, predictive factors related to systemic immune response are yet to be considered in clinical practice.
Usually, somatic mutations in cancer cells lead to the production of altered proteins that are recognized as antigens by the innate immune system via major histocompatibility complex class I; consequently, TILs inhibit tumor progression [
17]. Anti-HER2 antibodies also mediate anticancer effects in part via the induction of ADCC by opsonizing cancer cells that are recognized by the innate immune system [
18]. Anti-HER2 antibodies not only neutralize the trophic function of HER2, but they also elicit an initial NK-mediated ADCC response that is presumably followed by a cytotoxic T lymphocyte-dependent adaptive immune repose directed against breast cancer associated antigens [
18]. The effect of pertuzumab in antitumor immunity is still unknown. In a subgroup analysis of the CLEOPATRA trial, patients with a high abundance of TILs (> 20%) had better PFS than those with low TILs (≤20%) in the PT group, but not in the trastuzumab group [
6]. These data might indicate that preexisting immune responses enhance treatment efficacy, which could be boosted by combination therapy with conventional chemotherapy and PT [
19]. Although prognostic markers including NLR and PLR have been evaluated in several malignant diseases [
12], our study demonstrated that ALC is superior to NLR and PLR for predicting improved PFS in ABC patients treated with conventional chemotherapy combined with PT. High ALC may indicate enhanced immunity in tumors; alternatively, ALC may be a potential biomarker of host immunity. Although the detailed underlying mechanism of prolonged PFS in patients with ALC ≥1500/μL is currently unknown, it is likely that these results reflect the synergistic activity of PT acting alongside the host immune response.
Our results showed that the favorable PFS in patients with ALC ≥1500/μL was prominent in the ER- and PgR- subgroups. It is well established that TILs are not frequently observed in ER+/HER2- breast cancers [
20]; thus, the prognostic significance of TILs is not recognized in these cases [
20]. Even among HER2+ breast cancers, the frequency of TILs was significantly lower in ER+ cases compared with ER- cases [
6]. These data indicate that anticancer immunity is not dominant in ER+ cases. Thus, ALC may be a less effective predictor in ER+ and PgR+ cases compared to ER- and PgR- cases.
Both ERI and Nab-PTX could be classified as microtubule inhibitors with differential mechanisms of action [
21]. Both drugs can cause G2/M cell cycle arrest due to disruption of mitotic spindles, resulting in apoptotic cell death after prolonged mitotic blockage [
22]. In the current study, a favorable PFS in patients with ALC ≥1500/μL was observed, irrespective of a combination treatment with ERI or Nab-PTX. Because chemotherapies differ with regard to immunogenicity (e.g., immunogenic [doxorubicin or cyclophosphamide] or non-immunogenic [dacarbazine] [
21]), it is unclear whether relationships exist between PFS and ALC in patients treated with PT in combination with other chemotherapies or endocrine therapies.
This study has several limitations. First, we used a retrospective design from two single prospective phase 2 studies with relatively small sample sizes. Second, prior chemotherapies may affect baseline levels of PBBPs. However, because a positive association between ALC levels and PFS was consistently recognized in patients with and without prior chemotherapy, the influence of prior chemotherapy appears to be limited. There was no significant difference for any PBBP during the course of treatment (data not shown), but the prognostic significance of PBBPs during the treatment course is currently unknown. Considering these limitations, prospective studies that include a large number of patients are needed to further elucidate the results of the present study.