Association of Depressed Anti-HER2 T-Helper Type 1 Response With Recurrence in Patients With Completely Treated HER2-Positive Breast Cancer: Role for Immune Monitoring | Breast Cancer | JAMA Network
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Figure 1.  Comparison of Disease-Free Patients vs Patients With Recurrence
Comparison of Disease-Free Patients vs Patients With Recurrence

A, Interferon-γ–positive (IFN-γ+) anti-HER2 CD4+ T-cell response variations between human epidermal growth factor receptor 2 (HER2)-positive invasive breast cancer patient cohorts (treatment-naive [n = 22], recurrence [n = 25], and nonrecurrence [n = 48]), stratified by anti-HER2 responsivity, response repertoire (mean number of reactive peptides), and cumulative response (mean total spot-forming cells [SFCs]/106 cells). Bars indicate means in percent; error bars, SEM. One-way analysis of variance P values are shown alongside as calculated by means of post hoc Bonferroni testing. NS indicates nonsignificant. B, Peripheral blood mononuclear cells (PBMCs) from nonrecurrence and recurrence cohorts did not differ significantly in immune competence—measured by IFN-γ production to anti-CD3/anti-CD28 stimulus by enzyme-linked immunospot assay. The horizontal line in the middle of each box indicates the median IFN-γ SFCs/2 x 105 cells, while the top and bottom borders of the box mark the 75th and 25th percentiles, respectively. The whiskers above and below the box mark the 90th and 10th percentiles. C, Relative contributions of Th1 (T-bet+IFN-γ+) vs Th2 (GATA-3+IFN-γ+) phenotypes to HER2 peptide-specific IFN-γ+ cells in nonrecurrence and recurrence cohorts’ PBMCs. Bars indicate means in percent; error bars, SEM. D, Relative proportions of Treg (CD4+CD25+FoxP3+) by flow cytometry. Bars indicate means in percent; error bars, SEM. NS indicates nonsignificant.

Figure 2.  Cox Proportional Hazards Modeling of Disease-Free Survival in Patients With Completely Treated Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast Cancer, Stratified by Anti-HER2 T-Helper Type 1 (Th1) Responsivity.
Cox Proportional Hazards Modeling of Disease-Free Survival in Patients With Completely Treated Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast Cancer, Stratified by Anti-HER2 T-Helper Type 1 (Th1) Responsivity.

Non-Th1–responsive patients demonstrate worse risk-adjusted disease-free survival relative to Th1-responsive patients.

1.
Piccart-Gebhart  MJ, Procter  M, Leyland-Jones  B,  et al; Herceptin Adjuvant (HERA) Trial Study Team.  Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer.  N Engl J Med. 2005;353(16):1659-1672.PubMedGoogle ScholarCrossref
2.
Pohlmann  PR, Mayer  IA, Mernaugh  R.  Resistance to trastuzumab in breast cancer.  Clin Cancer Res. 2009;15(24):7479-7491.PubMedGoogle ScholarCrossref
3.
Datta  J, Rosemblit  C, Berk  E,  et al.  Progressive loss of anti-HER2 CD4+ T-helper type 1 response in breast tumorigenesis and the potential for immune restoration.  Oncoimmunology. 2015;4(10):e1022301.PubMedGoogle ScholarCrossref
4.
Datta  J, Berk  E, Xu  S,  et al.  Anti-HER2 CD4+ T-helper type 1 response is a novel immune correlate to pathologic response following neoadjuvant therapy in HER2-positive breast cancer.  Breast Cancer Res. 2015;17(1):71.PubMedGoogle ScholarCrossref
5.
Disis  ML, Grabstein  KH, Sleath  PR, Cheever  MA.  Generation of immunity to the HER-2/neu oncogenic protein in patients with breast and ovarian cancer using a peptide-based vaccine.  Clin Cancer Res. 1999;5(6):1289-1297.PubMedGoogle Scholar
6.
Koski  GK, Koldovsky  U, Xu  S,  et al.  A novel dendritic cell-based immunization approach for the induction of durable Th1-polarized anti-HER-2/neu responses in women with early breast cancer.  J Immunother. 2012;35(1):54-65.PubMedGoogle ScholarCrossref
7.
Perez  EA, Thompson  EA, Ballman  KV,  et al.  Genomic analysis reveals that immune function genes are strongly linked to clinical outcome in the North Central Cancer Treatment Group n9831 Adjuvant Trastuzumab Trial.  J Clin Oncol. 2015;33(7):701-708.PubMedGoogle ScholarCrossref
8.
Gianni  L, Bianchini  G, Valagussa  P,  et al.  Abstract S6-7: Adaptive immune system and immune checkpoints are associated with response to pertuzumab (P) and trastuzumab (H) in the NeoSphere study.  Cancer Res. 2012;72(24)(suppl):S6-S7.Google Scholar
Brief Report
February 2016

Association of Depressed Anti-HER2 T-Helper Type 1 Response With Recurrence in Patients With Completely Treated HER2-Positive Breast Cancer: Role for Immune Monitoring

Author Affiliations
  • 1Division of Endocrine and Oncologic Surgery, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia
  • 2Division of Medical Oncology, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia
  • 3Department of Epidemiology and Biostatistics, Hospital of the University of Pennsylvania, Philadelphia
  • 4Rena Rowen Breast Center, Hospital of the University of Pennsylvania, Philadelphia
JAMA Oncol. 2016;2(2):242-246. doi:10.1001/jamaoncol.2015.5482
Abstract

Importance  There is a paucity of immune signatures identifying patients with human epidermal growth factor receptor 2 (HER2)-positive invasive breast cancer (IBC) at risk for treatment failure following trastuzumab and chemotherapy.

Objective  To determine whether circulating anti-HER2 CD4-positive (CD4+) T-helper type 1 (Th1) immunity correlates with recurrence in patients with completely treated HER2-positive IBC.

Design, Setting, and Participants  Hypothesis-generating exploratory translational analysis at a tertiary care referral center of patients with completely treated HER2-positive IBC with median (interquartile range) follow-up of 44 (31) months. Anti-HER2 Th1 responses were examined using peripheral blood mononuclear cells pulsed with 6 HER2-derived class II–promiscuous peptides via interferon-γ (IFN-γ) enzyme-linked immunospot assay.

Main Outcomes and Measures  T-helper type 1 response metrics were anti-HER2 responsivity, repertoire (number of reactive peptides), and cumulative response across 6 peptides (spot-forming cells [SFCs]/106 cells). Anti-HER2 Th1 responses in treatment-naive patients (used as an immunologic baseline) were compared with those in patients completing trastuzumab and chemotherapy; in the latter group, analyses were stratified by recurrence status. Recurrence was defined as any locoregional or distant breast event, or both. Cox regression analysis estimated the instantaneous hazard of recurrence (ie, disease-free survival [DFS]) stratified by anti-HER2 Th1 responsivity.

Results  In 95 women with HER2-positive IBC (median [range] age, 49 [24-85] years; 22 treatment-naive, 73 treated with trastuzumab and chemotherapy), depressed anti-HER2 Th1 responsivity (recurrence, 2 of 25 [8%], vs nonrecurrence, 40 of 48 [83%]; P < .001), mean (SD) repertoire (0.1 [0.1] vs 1.5 [0.2]; P < .001), and mean (SD) cumulative response (14.8 [2.0] vs 80.2 [11.0] SFCs/106 cells; P < .001) were observed in patients incurring recurrence (n = 25) compared with patients without recurrence (n = 48). After controlling for confounding, anti-HER2 Th1 responsivity remained independently associated with recurrence (P < .001). This immune disparity was mediated by anti-HER2 CD4+T-bet+IFN-γ+ (Th1)—not CD4+GATA-3+IFN-γ+ (Th2) or CD4+CD25+FoxP3+ (Treg)—phenotypes, and not attributable to immune incompetence. When stratifying trastuzumab plus chemotherapy-treated patients by Th1 responsivity, Th1-nonresponsive patients demonstrated a worse DFS (median, 47 vs 113 months; P < .001) compared with Th1-responsive patients (hazard ratio, 16.9 [95% CI, 3.9-71.4]; P < .001).

Conclusions and Relevance  Depressed anti-HER2 Th1 response is a novel immune correlate to recurrence in patients with completely treated HER2-positive IBC. These data underscore a role for immune monitoring in patients with HER2-positive IBC to identify vulnerable populations at risk of treatment failure.

Introduction

Although human epidermal growth factor receptor 2 (HER2)-targeted therapies, in combination with chemotherapy, have dramatically improved survival in HER2-positive breast cancer (BC),1 a substantial proportion of these patients develop resistance and ultimately experience recurrence.2 Immune signatures identifying patients at risk for such treatment failure are lacking. We recently demonstrated a progressive loss in anti-HER2 CD4-positive (CD4+) T-helper type 1 (Th1) immunity across a tumorigenesis continuum in HER2-positive BC, extending from healthy donors, through patients with HER2-positive ductal carcinoma in situ, and ultimately patients with HER2-positive invasive BC (IBC).3 Additionally, anti-HER2 Th1 response emerged as a novel immune correlate to pathologic response following neoadjuvant trastuzumab plus chemotherapy in HER2-positive BC.4 In light of these observations, we hypothesized that anti-HER2 Th1 immunity may be associated with disease recurrence. In an exploratory cohort, we examined differences in circulating anti-HER2 Th1 immunity between recurrent and disease-free HER2-positive IBC patients in order to identify immune correlates to recurrence.

Box Section Ref ID

At a Glance

  • We investigated whether circulating anti–human epidermal growth factor receptor 2 (HER2) CD4+ T-helper type 1 (Th1) immunity correlates with disease recurrence (locoregional, distant, or both) in HER2-positive breast cancer patients who have completed HER2-targeted (ie, trastuzumab) therapy.

  • Anti-HER2 T-cell responses were depressed in patients incurring recurrence compared with disease-free patients (P < .001).

  • HER2 Th1 responsivity remained independently associated with recurrence (P < .001), and Th1-nonresponsive patients demonstrated a worse disease-free survival (median, 47 vs 113 months; P < .001) vs Th1-responsive patients.

  • Immune monitoring in completely treated HER2-positive patients may identify populations at risk of clinicopathologic failure.

Methods
Study Design

On approval by the institutional review board of the University of Pennsylvania, 95 patients with HER2-positive BC were recruited prospectively in a nonbiased fashion after written informed consent was obtained. Eligible patients had histologically confirmed IBC, ERBB2 (formerly HER2 or HER2/neu) overexpression (3+ [n = 82] or 2+/fluorescence in situ hybridization positive [n = 13]), and were not receiving immunosuppressive medications. Anti-HER2 Th1 responses in treatment-naive (no definitive therapy at enrollment) patients with stage I to III HER2-positive IBC (n = 22) were compared with Th1 responses in patients with stage I to IV HER2-positive IBC (n = 73) who had completed trastuzumab plus chemotherapy treatment—either neoadjuvant (n = 37; immune responses from this cohort have been reported previously4) or adjuvant trastuzumab plus chemotherapy (n = 36) plus definitive surgery (schedules and dosing of trastuzumab plus chemotherapy regimens are presented in the eMethods in the Supplement). In trastuzumab plus chemotherapy–treated patients, analyses were stratified by recurrence status. Although recurrence status was known at study enrollment, evaluation and analysis of anti-HER2 Th1 responses was blinded to this information.

Human epidermal growth factor receptor 2–positive–confirmed recurrences were defined as any locoregional or distant breast event. Patients incurring recurrence were enrolled prior to initiation of second-line chemotherapy, HER2-targeted therapy, or experimental (eg, HER2–pulsed dendritic cell vaccination) protocols. Patients without recurrence were eligible for analysis only if disease-free interval was 24 months at minimum (eFigure 1 in the Supplement).

Immune Response Detection

Anti-HER2 responses were examined in unexpanded peripheral blood mononuclear cells (PBMCs) pulsed ex vivo with 6 validated HER2-derived major histocompatibility complex class II–promiscuous peptides,5 by measuring interferon-γ (IFN-γ), interleukin-4 (IL-4), or IL-10 production via enzyme-linked immunospot assay, as previously described (eMethods in the Supplement).3,4,6 Specifically, PBMCs were incubated with either HER2 peptides (4 µg; Genscript), media alone (unstimulated control), or positive control (anti–human CD3/CD28 antibodies [0.5 µg/mL; BD Pharmingen]) at 37°C for 36 to 48 hours.

In evaluable patients, Th1 responses to 1:100-diluted recall stimuli Candida albicans (Allermed Laboratories) and tetanus toxoid (Santa Cruz Biotechnology) whole proteins were examined.3 Anti-HER2 Th1 reactivity was determined using empirical methodology as described previously.3,4 Positive/reactive response to a HER2 peptide was defined as at least 20 spot-forming cells (SFCs)/2 × 105 PBMCs in experimental wells after subtraction of unstimulated background. Three metrics of immune response were measured: (1) responsivity (proportion of patients responding to ≥1 of 6 peptides), (2) repertoire (mean number of reactive peptides), and (3) cumulative response across 6 peptides (SFCs/106 cells).

Flow cytometry, the functional contribution of Th1 vs Th2 subtypes, and statistical analysis are described in the eMethods in the Supplement.

Statistical Analysis

Descriptive statistics summarized distributions of patient characteristics and immune response variables. Comparisons between nonrecurrent and recurrent HER2-positive IBC cohorts were performed as indicated: (1) 2-group/univariate testing: unpaired t test (parametric continuous), Wilcoxon rank-sum test (nonparametric continuous), and χ2 tests (categorical); (2) more than 2–group testing: 1-way analysis of variance with post hoc Bonferroni testing. Variables with P < .10 on univariate testing were entered into a forward, stepwise multivariable logistic regression model (P < .05 for entry) to determine independent correlates to recurrence (binary outcome yes/no). Missing data for postneoadjuvant pathologic response status (n = 36) and lymphovascular invasion (n = 12) were imputed using the Markov chain Monte Carlo method. Five imputation data sets were created and 5 sets of analyses were combined per the formula of Rubin.

Univariate DFS estimates were examined by Kaplan-Meier methodology, stratifying by anti-HER2 Th1 responsivity and other covariates. Observations of patients without recurrence (minimum 24 month follow-up) were censored at last known follow-up. To analyze the instantaneous hazard of all variables and control for varied follow-up, Cox proportional hazards modeling was performed. The assumptions of the Cox model were assessed, including interactions and proportionality of hazards over time. P < .05 was considered statistically significant. All tests were 2 sided. Analyses were performed using SPSS, version 22 (IBM Corp).

Results
Patient Characteristics

Demographic and tumor-related characteristics of the overall cohort (n = 95, all female) are detailed in eTable 1 in the Supplement. In trastuzumab plus chemotherapy–treated patients (n = 73), median (range) age was 49 (24-85) years; a majority of patients had estrogen receptor–positive/progesterone receptor–positive tumors (43 [59%]) and presented with locally advanced/node-positive disease (clinical stage I, 7 [10%]; stage II, 35 [48%]; stage III, 31 [42%]). Neoadjuvant trastuzumab plus chemotherapy was administered in 37 (51%) patients, and doxorubicin-cyclophosphamide-paclitaxel-trastuzumab was the commonly used regimen (49 [67%]) (eMethods in the Supplement). Simple or modified radical mastectomy was performed most frequently (39 [53%]).

Twenty-five of 73 (34%) patients incurred either locoregional recurrence, distant recurrence, or both (eTable 2 in the Supplement); Th1 responses in a majority (21 [84%]) of these patients were determined at the time of diagnosis of recurrence.

Depression of Anti-HER2 Th1 Responses in Patients With HER2-Positive IBC Incurring Recurrence

Anti-HER2 Th1 responsivity, repertoire, and cumulative responses were compared between treatment-naive (n = 22), trastuzumab plus chemotherapy–treated nonrecurrent (n = 48), and trastuzumab plus chemotherapy–treated patients with recurrent disease (n = 25). Using anti-HER2 Th1 responses from treatment-naive patients as an immunologic “baseline,” significantly depressed anti-HER2 Th1 responsivity (treatment-naive, 8 [36%], vs recurrence, 2 [8%], vs nonrecurrence, 40 [83%]; P < .001), mean (SD) repertoire (0.6 [0.2] vs 0.1 [0.1] vs 1.5 [0.2]; P < .001), and mean (SD) cumulative response (32.8 [4.7] vs 14.8 [2.0] vs 80.2 [11.0] SFCs/106 cells; P < .001) were observed in patients incurring recurrence compared with disease-free patients (Figure 1A).

Interferon-γ+ responses to anti-CD3/anti-CD28 stimulation (P = .57) (Figure 1B) or tetanus (P = .41) and Candida (P = .74) (eFigure 2 in the Supplement) did not differ significantly between the nonrecurrence and recurrence cohorts, suggesting that the observed anti-HER2 Th1 disparity is not attributable to immune incompetence or host-level T-cell anergy in patients with recurrent disease. Decreased mean (SEM) proportions of HER2-specific CD4+T-bet+IFN-γ+ (0.25 [0.1%] vs 0.02 [0.01%]; P = .04), but not CD4+GATA-3+IFN-γ+ or CD4+GATA-3+IFN-γ-, phenotypes were observed in the recurrence compared with nonrecurrence cohort, respectively (Figure 1C).

Neither HER2-stimulated IL-4+ measures of Th2 function (eFigure 3A in the Supplement), HER2-stimulated IL-10+ measures of Treg function (eFigure 3B in the Supplement), nor relative proportions of circulating Treg (ie, CD4+CD25+Foxp3+) phenotypes (Figure 1D) differed between nonrecurrence and recurrence cohorts.

Association of Anti-HER2 Th1 Responsivity With Disease-Free Survival

Next, independence of the association between anti-HER2 Th1 response and recurrence was examined. On univariate testing, recurrence and nonrecurrence cohorts did not differ by age, menopausal status, race, body mass index, comorbidity, stage, estrogen receptor–positive/progesterone receptor–positive status, lymphovascular invasion, nuclear grade, or need for mastectomy. However, recurrence was more frequent among patients receiving adjuvant trastuzumab plus chemotherapy (P = .02) and those with residual disease following neoadjuvant therapy (P = .006). When controlling for these variables via multivariable regression, anti-HER2 Th1 responsivity (P < .001), but not trastuzumab plus chemotherapy sequence (P = .14) or pathologic response (P = .76), remained independently associated with recurrence (eTable 3 in the Supplement).

Stratifying the analytic cohort by anti-HER2 Th1 responsivity at a median (interquartile range) follow-up of 44 (28-59) months, Th1-nonresponsive patients demonstrated a significantly worse disease-free survival (median, 47 vs 113 months; P < .001) compared with Th1-responsive patients; this association was corroborated by Cox modeling (hazard ratio for Th1 nonresponsive cohort, 16.9 [95% CI, 3.9-71.4]; P < .001) (Figure 2).

Discussion

In this hypothesis-generating exploratory analysis, circulating anti-HER2 CD4+ Th1 response emerges as a novel immune correlate to breast cancer recurrence in patients with completely treated HER2-positive IBC. While not attributable to immune incompetence, depressed anti-HER2 T-cell responses in patients with recurrent disease were driven predominantly by Th1 phenotypes. When relevant clinicopathologic factors were controlled for, anti-HER2 Th1 responsivity was independently associated with recurrence; on risk-adjusted analysis, Th1-nonresponsive patients demonstrated worse disease-free survival compared with Th1-responsive patients. To our knowledge, this is the first demonstration of an association between disease recurrence and a host-level immune correlate specific to an oncodriver in breast tumorigenesis.

These data are intriguing in the light of evidence suggesting that benefit from trastuzumab therapy—both in the adjuvant7 and neoadjuvant8 setting—may be restricted to immune-enriched tumors, with Th1 genes IFN-γ and tumor necrosis factor imparting a particularly dominant role.7 Altogether, it appears that absent tumor-level Th1 gene expression, as well as deficient circulating anti-HER2 Th1 immunity, may presage failure of HER2-targeted therapy. Monitoring patients with completely treated HER2-positive BC for real-time fluctuations in anti-HER2 Th1 immunity may reveal vulnerable populations at risk of relapse and identify critical opportunities for therapeutic intervention, such as anti-HER2 Th1-directed immune interventions.4

Since immune responses were examined at the time of recurrence, it remains unclear whether anti-HER2 Th1 immunity in these patients remained suppressed following completion of index trastuzumab therapy or declined contemporaneously with development of recurrence; longitudinal surveillance of anti-HER2 Th1 responses is required. Other limitations warrant emphasis. These findings should be interpreted as hypothesis generating and warrant large-scale validation; this study did not address other HER2-targeted agents (eg, lapatinib, pertuzumab); the relative preponderance of patients with locally advanced disease in our cohort may diminish applicability in early-stage disease; and finally, while the case for anti-HER2 Th1 immune monitoring is compelling, our study is unable to establish numerical thresholds for such monitoring or correlations between the depth of immune depression and recrudescent tumor burden.

Conclusions

Depressed anti-HER2 Th1 response is a novel immune correlate to recurrence in patients with completely treated HER2-positive IBC. These data underscore a role for immune monitoring in patients with HER2-positive IBC to identify vulnerable populations at risk of treatment failure.

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Article Information

Accepted for Publication: October 30, 2015

Corresponding Author: Brian J. Czerniecki, MD, PhD, Department of Surgery, University of Pennsylvania Perelman School of Medicine, Rena Rowen Breast Center, 3400 Civic Center Dr, Philadelphia, PA 19104 (brian.czerniecki@uphs.upenn.edu).

Published Online: December 30, 2015. doi:10.1001/jamaoncol.2015.5482.

Author Contributions: Drs Datta and Czerniecki had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Datta, McMillan, Goodman, DeMichele, Czerniecki.

Acquisition, analysis, or interpretation of data: Datta, Fracol, McMillan, Berk, Xu, Lewis, DeMichele, Czerniecki.

Drafting of the manuscript: Datta, McMillan, Goodman, Czerniecki.

Critical revision of the manuscript for important intellectual content: Datta, Fracol, McMillan, Berk, Xu, Lewis, DeMichele, Czerniecki.

Statistical analysis: Datta, Fracol, McMillan, Lewis.

Obtained funding: Datta, Czerniecki.

Administrative, technical, or material support: Datta, Fracol, Berk, Xu, Goodman, Lewis, DeMichele, Czerniecki.

Study supervision: DeMichele, Czerniecki.

Conflict of Interest Disclosures: None reported.

Funding/Support: This work was supported by National Institutes of Health grant R01 CA096997, Pennies in Action (http://www.penniesinaction.org), and a University of Pennsylvania Abramson Cancer Center Breast Translational Center of Excellence grant.

Role of the Funder/Sponsor: The funding agencies had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

References
1.
Piccart-Gebhart  MJ, Procter  M, Leyland-Jones  B,  et al; Herceptin Adjuvant (HERA) Trial Study Team.  Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer.  N Engl J Med. 2005;353(16):1659-1672.PubMedGoogle ScholarCrossref
2.
Pohlmann  PR, Mayer  IA, Mernaugh  R.  Resistance to trastuzumab in breast cancer.  Clin Cancer Res. 2009;15(24):7479-7491.PubMedGoogle ScholarCrossref
3.
Datta  J, Rosemblit  C, Berk  E,  et al.  Progressive loss of anti-HER2 CD4+ T-helper type 1 response in breast tumorigenesis and the potential for immune restoration.  Oncoimmunology. 2015;4(10):e1022301.PubMedGoogle ScholarCrossref
4.
Datta  J, Berk  E, Xu  S,  et al.  Anti-HER2 CD4+ T-helper type 1 response is a novel immune correlate to pathologic response following neoadjuvant therapy in HER2-positive breast cancer.  Breast Cancer Res. 2015;17(1):71.PubMedGoogle ScholarCrossref
5.
Disis  ML, Grabstein  KH, Sleath  PR, Cheever  MA.  Generation of immunity to the HER-2/neu oncogenic protein in patients with breast and ovarian cancer using a peptide-based vaccine.  Clin Cancer Res. 1999;5(6):1289-1297.PubMedGoogle Scholar
6.
Koski  GK, Koldovsky  U, Xu  S,  et al.  A novel dendritic cell-based immunization approach for the induction of durable Th1-polarized anti-HER-2/neu responses in women with early breast cancer.  J Immunother. 2012;35(1):54-65.PubMedGoogle ScholarCrossref
7.
Perez  EA, Thompson  EA, Ballman  KV,  et al.  Genomic analysis reveals that immune function genes are strongly linked to clinical outcome in the North Central Cancer Treatment Group n9831 Adjuvant Trastuzumab Trial.  J Clin Oncol. 2015;33(7):701-708.PubMedGoogle ScholarCrossref
8.
Gianni  L, Bianchini  G, Valagussa  P,  et al.  Abstract S6-7: Adaptive immune system and immune checkpoints are associated with response to pertuzumab (P) and trastuzumab (H) in the NeoSphere study.  Cancer Res. 2012;72(24)(suppl):S6-S7.Google Scholar
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