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Anti-HER2 CD4(+) T-helper type 1 response is a novel immune correlate to pathologic response following neoadjuvant therapy in HER2-positive breast cancer.

Datta J, Berk E, Xu S, Fitzpatrick E, Rosemblit C, Lowenfeld L, Goodman N, Lewis DA, Zhang PJ, Fisher C, Roses RE, DeMichele A, Czerniecki BJ - Breast Cancer Res. (2015)

Bottom Line: Pathologic complete response (pCR) following neoadjuvant trastuzumab and chemotherapy (T + C) is associated with decreased recurrence and improved prognosis.After controlling for potential confounders, anti-HER2 Th1 responsivity remained independently associated with pathologic response (odds ratio 8.82, p = 0.016).In recruited non-pCR patients, anti-HER2 Th1 repertoire (3.7 vs. 0.5, p = 0.014) and cumulative response (192.3 vs. 33.9 SFC/10(6), p = 0.014) improved significantly following HER2-pulsed DC1 vaccination.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, University of Pennsylvania Perelman School of Medicine, Rena Rowen Breast Center, 3400 Civic Center Drive, Philadelphia, PA, 19104, USA. Jashodeep.datta@uphs.upenn.edu.

ABSTRACT

Introduction: A progressive loss of circulating anti-human epidermal growth factor receptor-2/neu (HER2) CD4(+) T-helper type 1 (Th1) immune responses is observed in HER2(pos)-invasive breast cancer (IBC) patients relative to healthy controls. Pathologic complete response (pCR) following neoadjuvant trastuzumab and chemotherapy (T + C) is associated with decreased recurrence and improved prognosis. We examined differences in anti-HER2 Th1 responses between pCR and non-pCR patients to identify modifiable immune correlates to pathologic response following neoadjuvant T + C.

Methods: Anti-HER2 Th1 responses in 87 HER2(pos)-IBC patients were examined using peripheral blood mononuclear cells pulsed with 6 HER2-derived class II peptides via IFN-γ ELISPOT. Th1 response metrics were anti-HER2 responsivity, repertoire (number of reactive peptides), and cumulative response across 6 peptides (spot-forming cells [SFC]/10(6) cells). Anti-HER2 Th1 responses of non-pCR patients (n = 4) receiving adjuvant HER2-pulsed type 1-polarized dendritic cell (DC1) vaccination were analyzed pre- and post-immunization.

Results: Depressed anti-HER2 Th1 responses observed in treatment-naïve HER2(pos)-IBC patients (n = 22) did not improve globally in T + C-treated HER2(pos)-IBC patients (n = 65). Compared with adjuvant T + C receipt, neoadjuvant T + C - utilized in 61.5 % - was associated with higher anti-HER2 Th1 repertoire (p = 0.048). While pCR (n = 16) and non-pCR (n = 24) patients did not differ substantially in demographic/clinical characteristics, pCR patients demonstrated dramatically higher anti-HER2 Th1 responsivity (94 % vs. 33 %, p = 0.0002), repertoire (3.3 vs. 0.3 peptides, p < 0.0001), and cumulative response (148.2 vs. 22.4 SFC/10(6), p < 0.0001) versus non-pCR patients. After controlling for potential confounders, anti-HER2 Th1 responsivity remained independently associated with pathologic response (odds ratio 8.82, p = 0.016). This IFN-γ(+) immune disparity was mediated by anti-HER2 CD4(+)T-bet(+)IFN-γ(+) (i.e., Th1) - not CD4(+)GATA-3(+)IFN-γ(+) (i.e., Th2) - phenotypes, and not attributable to non-pCR patients' immune incompetence, host-level T-cell anergy, or increased immunosuppressive populations. In recruited non-pCR patients, anti-HER2 Th1 repertoire (3.7 vs. 0.5, p = 0.014) and cumulative response (192.3 vs. 33.9 SFC/10(6), p = 0.014) improved significantly following HER2-pulsed DC1 vaccination.

Conclusions: Anti-HER2 CD4(+) Th1 response is a novel immune correlate to pathologic response following neoadjuvant T + C. In non-pCR patients, depressed Th1 responses are not immunologically "fixed" and can be restored with HER2-directed Th1 immune interventions. In such high-risk patients, combining HER2-targeted therapies with strategies to boost anti-HER2 Th1 immunity may improve outcomes and mitigate recurrence.

No MeSH data available.


Related in: MedlinePlus

Consolidated Standards of Reporting Trials (CONSORT) diagram of the study population. In this study, 87 patients with human epidermal growth factor receptor 2-positive (HER2pos) breast cancer were enrolled; all tumors were histologically confirmed as invasive breast cancer (IBC) with HER2 overexpression (3+ or 2+/fluorescence in situ hybridization (FISH)-positive). Cohorts are labeled (a–g) for ease of comparison (of immune responses), and are referred to in Results. Time points at which blood was drawn are indicated (red callout boxes). Median follow up in the cohort treated with trastuzumab and chemotherapy (T + C) was 26 (IQR 16.5–31.0) months. pCR pathologic complete response, DCI type 1-polarized dendritic cell, Adj adjuvant, mo months
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Fig1: Consolidated Standards of Reporting Trials (CONSORT) diagram of the study population. In this study, 87 patients with human epidermal growth factor receptor 2-positive (HER2pos) breast cancer were enrolled; all tumors were histologically confirmed as invasive breast cancer (IBC) with HER2 overexpression (3+ or 2+/fluorescence in situ hybridization (FISH)-positive). Cohorts are labeled (a–g) for ease of comparison (of immune responses), and are referred to in Results. Time points at which blood was drawn are indicated (red callout boxes). Median follow up in the cohort treated with trastuzumab and chemotherapy (T + C) was 26 (IQR 16.5–31.0) months. pCR pathologic complete response, DCI type 1-polarized dendritic cell, Adj adjuvant, mo months

Mentions: After approval by the Institutional Review Board of the University of Pennsylvania, 87 patients with HER2pos IBC were enrolled in a non-biased fashion (Table 1). Eligible patients had histologically confirmed IBC, HER2/neu overexpression (i.e., immunochemistry (IHC) 3+ or 2+/fluorescence in situ hybridization (FISH)-positive) confirmed at our institution, no evidence of distant metastasis, and were not receiving immunosuppressive medications. Informed consent was obtained from all participants. Anti-HER2 CD4+ Th1 responses of recruited subjects were analyzed prospectively. Anti-HER2 Th1 responses in treatment-naïve (i.e., not receiving definitive therapy at enrollment) stage I–III HER2pos IBC patients (n = 22) were established as an immunologic "baseline", and were compared with Th1 responses in stage I–III HER2pos IBC patients who had completed T + C treatment (n = 65; i.e., either neoadjuvant or adjuvant T + C plus definitive surgery). In patients treated with T + C, analyses were stratified by sequence of chemotherapy (i.e., neoadjuvant versus adjuvant), and further sub-stratified by pCR and non-pCR status within the neoadjuvant cohort (Fig. 1). pCR was defined as absence of residual invasive cancer on pathologic examination of resected breast specimen(s) and sampled lymph nodes (i.e., ypT0/Tis ypN0).Table 1


Anti-HER2 CD4(+) T-helper type 1 response is a novel immune correlate to pathologic response following neoadjuvant therapy in HER2-positive breast cancer.

Datta J, Berk E, Xu S, Fitzpatrick E, Rosemblit C, Lowenfeld L, Goodman N, Lewis DA, Zhang PJ, Fisher C, Roses RE, DeMichele A, Czerniecki BJ - Breast Cancer Res. (2015)

Consolidated Standards of Reporting Trials (CONSORT) diagram of the study population. In this study, 87 patients with human epidermal growth factor receptor 2-positive (HER2pos) breast cancer were enrolled; all tumors were histologically confirmed as invasive breast cancer (IBC) with HER2 overexpression (3+ or 2+/fluorescence in situ hybridization (FISH)-positive). Cohorts are labeled (a–g) for ease of comparison (of immune responses), and are referred to in Results. Time points at which blood was drawn are indicated (red callout boxes). Median follow up in the cohort treated with trastuzumab and chemotherapy (T + C) was 26 (IQR 16.5–31.0) months. pCR pathologic complete response, DCI type 1-polarized dendritic cell, Adj adjuvant, mo months
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4488128&req=5

Fig1: Consolidated Standards of Reporting Trials (CONSORT) diagram of the study population. In this study, 87 patients with human epidermal growth factor receptor 2-positive (HER2pos) breast cancer were enrolled; all tumors were histologically confirmed as invasive breast cancer (IBC) with HER2 overexpression (3+ or 2+/fluorescence in situ hybridization (FISH)-positive). Cohorts are labeled (a–g) for ease of comparison (of immune responses), and are referred to in Results. Time points at which blood was drawn are indicated (red callout boxes). Median follow up in the cohort treated with trastuzumab and chemotherapy (T + C) was 26 (IQR 16.5–31.0) months. pCR pathologic complete response, DCI type 1-polarized dendritic cell, Adj adjuvant, mo months
Mentions: After approval by the Institutional Review Board of the University of Pennsylvania, 87 patients with HER2pos IBC were enrolled in a non-biased fashion (Table 1). Eligible patients had histologically confirmed IBC, HER2/neu overexpression (i.e., immunochemistry (IHC) 3+ or 2+/fluorescence in situ hybridization (FISH)-positive) confirmed at our institution, no evidence of distant metastasis, and were not receiving immunosuppressive medications. Informed consent was obtained from all participants. Anti-HER2 CD4+ Th1 responses of recruited subjects were analyzed prospectively. Anti-HER2 Th1 responses in treatment-naïve (i.e., not receiving definitive therapy at enrollment) stage I–III HER2pos IBC patients (n = 22) were established as an immunologic "baseline", and were compared with Th1 responses in stage I–III HER2pos IBC patients who had completed T + C treatment (n = 65; i.e., either neoadjuvant or adjuvant T + C plus definitive surgery). In patients treated with T + C, analyses were stratified by sequence of chemotherapy (i.e., neoadjuvant versus adjuvant), and further sub-stratified by pCR and non-pCR status within the neoadjuvant cohort (Fig. 1). pCR was defined as absence of residual invasive cancer on pathologic examination of resected breast specimen(s) and sampled lymph nodes (i.e., ypT0/Tis ypN0).Table 1

Bottom Line: Pathologic complete response (pCR) following neoadjuvant trastuzumab and chemotherapy (T + C) is associated with decreased recurrence and improved prognosis.After controlling for potential confounders, anti-HER2 Th1 responsivity remained independently associated with pathologic response (odds ratio 8.82, p = 0.016).In recruited non-pCR patients, anti-HER2 Th1 repertoire (3.7 vs. 0.5, p = 0.014) and cumulative response (192.3 vs. 33.9 SFC/10(6), p = 0.014) improved significantly following HER2-pulsed DC1 vaccination.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, University of Pennsylvania Perelman School of Medicine, Rena Rowen Breast Center, 3400 Civic Center Drive, Philadelphia, PA, 19104, USA. Jashodeep.datta@uphs.upenn.edu.

ABSTRACT

Introduction: A progressive loss of circulating anti-human epidermal growth factor receptor-2/neu (HER2) CD4(+) T-helper type 1 (Th1) immune responses is observed in HER2(pos)-invasive breast cancer (IBC) patients relative to healthy controls. Pathologic complete response (pCR) following neoadjuvant trastuzumab and chemotherapy (T + C) is associated with decreased recurrence and improved prognosis. We examined differences in anti-HER2 Th1 responses between pCR and non-pCR patients to identify modifiable immune correlates to pathologic response following neoadjuvant T + C.

Methods: Anti-HER2 Th1 responses in 87 HER2(pos)-IBC patients were examined using peripheral blood mononuclear cells pulsed with 6 HER2-derived class II peptides via IFN-γ ELISPOT. Th1 response metrics were anti-HER2 responsivity, repertoire (number of reactive peptides), and cumulative response across 6 peptides (spot-forming cells [SFC]/10(6) cells). Anti-HER2 Th1 responses of non-pCR patients (n = 4) receiving adjuvant HER2-pulsed type 1-polarized dendritic cell (DC1) vaccination were analyzed pre- and post-immunization.

Results: Depressed anti-HER2 Th1 responses observed in treatment-naïve HER2(pos)-IBC patients (n = 22) did not improve globally in T + C-treated HER2(pos)-IBC patients (n = 65). Compared with adjuvant T + C receipt, neoadjuvant T + C - utilized in 61.5 % - was associated with higher anti-HER2 Th1 repertoire (p = 0.048). While pCR (n = 16) and non-pCR (n = 24) patients did not differ substantially in demographic/clinical characteristics, pCR patients demonstrated dramatically higher anti-HER2 Th1 responsivity (94 % vs. 33 %, p = 0.0002), repertoire (3.3 vs. 0.3 peptides, p < 0.0001), and cumulative response (148.2 vs. 22.4 SFC/10(6), p < 0.0001) versus non-pCR patients. After controlling for potential confounders, anti-HER2 Th1 responsivity remained independently associated with pathologic response (odds ratio 8.82, p = 0.016). This IFN-γ(+) immune disparity was mediated by anti-HER2 CD4(+)T-bet(+)IFN-γ(+) (i.e., Th1) - not CD4(+)GATA-3(+)IFN-γ(+) (i.e., Th2) - phenotypes, and not attributable to non-pCR patients' immune incompetence, host-level T-cell anergy, or increased immunosuppressive populations. In recruited non-pCR patients, anti-HER2 Th1 repertoire (3.7 vs. 0.5, p = 0.014) and cumulative response (192.3 vs. 33.9 SFC/10(6), p = 0.014) improved significantly following HER2-pulsed DC1 vaccination.

Conclusions: Anti-HER2 CD4(+) Th1 response is a novel immune correlate to pathologic response following neoadjuvant T + C. In non-pCR patients, depressed Th1 responses are not immunologically "fixed" and can be restored with HER2-directed Th1 immune interventions. In such high-risk patients, combining HER2-targeted therapies with strategies to boost anti-HER2 Th1 immunity may improve outcomes and mitigate recurrence.

No MeSH data available.


Related in: MedlinePlus