Association of stromal tumor-infiltrating lymphocytes with recurrence-free survival in the n9831 adjuvant trial in patients with early-stage HER2-positive breast cancer

Edith A. Perez, Karla V. Ballman, Kathy S. Tenner, E. Aubrey Thompson, Sunil Badve, Helen Bailey, Frederick L. Baehner

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Abstract

Importance: The presence of tumor-infiltrating lymphocytes at diagnosis is reported to be prognostic in triple-negative breast cancer. Objective: To evaluate the association of stromal tumor-infiltrating lymphocytes (STILs) with recurrence-free survival (RFS) in women with human epidermal growth factor receptor 2 (HER2)-positive breast cancer treated with chemotherapy or chemotherapy plus trastuzumab in the N9831 trial. Design, Setting, and Participants: Hematoxylin-eosin-stained tumor slides from patients with early-stage HER2-positive breast cancer in 2 of the 3 arms of the N9831 trial were assessed for STILs at an academic medical center. The amounts of STILs were quantitated in deciles, and a level of at least 60% STILs was used for the prespecified categorical cutoff. The association between STILs and RFS was evaluated with Cox models. Exposure: Standard chemotherapy consisting of doxorubicin-cyclophosphamide followed by weekly paclitaxel (arm A) or doxorubicin-cyclophosphamide followed by weekly paclitaxel plus trastuzumab followed by trastuzumab alone (arm C). Main Outcomes and Measures: Stromal tumor-infiltrating lymphocytes and their association with RFS. Results: A total of 489 patients from arm A and 456 patients from arm C were assessed with a median (range) follow-up of 4.4 (0-13.6) years. The 10-year Kaplan-Meier estimates for RFS in arm A were 90.9%and 64.5%for patients with high and low levels of STILs, respectively (hazard ratio [HR], 0.23 [95%CI, 0.07-0.73]; P = .01). The 10-year estimates for RFS in arm C were 80.0%and 80.1%for patients with high and low levels of STILs, respectively (HR, 1.26 [95%CI, 0.50-3.17]; P = .63). The test for interaction between trastuzumab treatment and STIL status was statistically significant (P = .03). In a multivariable analysis, STIL status remained significantly associated with RFS in arm A and not significantly associated in arm C (HR, 1.01 [95%CI, 0.89-1.15]; interaction P = .04). Conclusions and Relevance: This analysis of participants in the N9831 trial found that the presence of STILs was prognostically associated with RFS in patients treated with chemotherapy alone but not in patients treated with chemotherapy plus trastuzumab. High levels of STILs were associated with lack of trastuzumab therapy benefit, in contrast to a previously reported association between increased levels of STILs and increased trastuzumab benefit in HER2-positive patients.

Original languageEnglish (US)
Pages (from-to)56-64
Number of pages9
JournalJAMA oncology
Volume2
Issue number1
DOIs
StatePublished - Jan 1 2016

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Tumor-Infiltrating Lymphocytes
Breast Neoplasms
Recurrence
Survival
Drug Therapy
Paclitaxel
human ERBB2 protein
Doxorubicin
Cyclophosphamide
Triple Negative Breast Neoplasms
Kaplan-Meier Estimate
Hematoxylin
Eosine Yellowish-(YS)
Trastuzumab
Proportional Hazards Models

ASJC Scopus subject areas

  • Medicine(all)

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Association of stromal tumor-infiltrating lymphocytes with recurrence-free survival in the n9831 adjuvant trial in patients with early-stage HER2-positive breast cancer. / Perez, Edith A.; Ballman, Karla V.; Tenner, Kathy S.; Thompson, E. Aubrey; Badve, Sunil; Bailey, Helen; Baehner, Frederick L.

In: JAMA oncology, Vol. 2, No. 1, 01.01.2016, p. 56-64.

Research output: Contribution to journalArticle

Perez, Edith A. ; Ballman, Karla V. ; Tenner, Kathy S. ; Thompson, E. Aubrey ; Badve, Sunil ; Bailey, Helen ; Baehner, Frederick L. / Association of stromal tumor-infiltrating lymphocytes with recurrence-free survival in the n9831 adjuvant trial in patients with early-stage HER2-positive breast cancer. In: JAMA oncology. 2016 ; Vol. 2, No. 1. pp. 56-64.
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abstract = "Importance: The presence of tumor-infiltrating lymphocytes at diagnosis is reported to be prognostic in triple-negative breast cancer. Objective: To evaluate the association of stromal tumor-infiltrating lymphocytes (STILs) with recurrence-free survival (RFS) in women with human epidermal growth factor receptor 2 (HER2)-positive breast cancer treated with chemotherapy or chemotherapy plus trastuzumab in the N9831 trial. Design, Setting, and Participants: Hematoxylin-eosin-stained tumor slides from patients with early-stage HER2-positive breast cancer in 2 of the 3 arms of the N9831 trial were assessed for STILs at an academic medical center. The amounts of STILs were quantitated in deciles, and a level of at least 60{\%} STILs was used for the prespecified categorical cutoff. The association between STILs and RFS was evaluated with Cox models. Exposure: Standard chemotherapy consisting of doxorubicin-cyclophosphamide followed by weekly paclitaxel (arm A) or doxorubicin-cyclophosphamide followed by weekly paclitaxel plus trastuzumab followed by trastuzumab alone (arm C). Main Outcomes and Measures: Stromal tumor-infiltrating lymphocytes and their association with RFS. Results: A total of 489 patients from arm A and 456 patients from arm C were assessed with a median (range) follow-up of 4.4 (0-13.6) years. The 10-year Kaplan-Meier estimates for RFS in arm A were 90.9{\%}and 64.5{\%}for patients with high and low levels of STILs, respectively (hazard ratio [HR], 0.23 [95{\%}CI, 0.07-0.73]; P = .01). The 10-year estimates for RFS in arm C were 80.0{\%}and 80.1{\%}for patients with high and low levels of STILs, respectively (HR, 1.26 [95{\%}CI, 0.50-3.17]; P = .63). The test for interaction between trastuzumab treatment and STIL status was statistically significant (P = .03). In a multivariable analysis, STIL status remained significantly associated with RFS in arm A and not significantly associated in arm C (HR, 1.01 [95{\%}CI, 0.89-1.15]; interaction P = .04). Conclusions and Relevance: This analysis of participants in the N9831 trial found that the presence of STILs was prognostically associated with RFS in patients treated with chemotherapy alone but not in patients treated with chemotherapy plus trastuzumab. High levels of STILs were associated with lack of trastuzumab therapy benefit, in contrast to a previously reported association between increased levels of STILs and increased trastuzumab benefit in HER2-positive patients.",
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T1 - Association of stromal tumor-infiltrating lymphocytes with recurrence-free survival in the n9831 adjuvant trial in patients with early-stage HER2-positive breast cancer

AU - Perez, Edith A.

AU - Ballman, Karla V.

AU - Tenner, Kathy S.

AU - Thompson, E. Aubrey

AU - Badve, Sunil

AU - Bailey, Helen

AU - Baehner, Frederick L.

PY - 2016/1/1

Y1 - 2016/1/1

N2 - Importance: The presence of tumor-infiltrating lymphocytes at diagnosis is reported to be prognostic in triple-negative breast cancer. Objective: To evaluate the association of stromal tumor-infiltrating lymphocytes (STILs) with recurrence-free survival (RFS) in women with human epidermal growth factor receptor 2 (HER2)-positive breast cancer treated with chemotherapy or chemotherapy plus trastuzumab in the N9831 trial. Design, Setting, and Participants: Hematoxylin-eosin-stained tumor slides from patients with early-stage HER2-positive breast cancer in 2 of the 3 arms of the N9831 trial were assessed for STILs at an academic medical center. The amounts of STILs were quantitated in deciles, and a level of at least 60% STILs was used for the prespecified categorical cutoff. The association between STILs and RFS was evaluated with Cox models. Exposure: Standard chemotherapy consisting of doxorubicin-cyclophosphamide followed by weekly paclitaxel (arm A) or doxorubicin-cyclophosphamide followed by weekly paclitaxel plus trastuzumab followed by trastuzumab alone (arm C). Main Outcomes and Measures: Stromal tumor-infiltrating lymphocytes and their association with RFS. Results: A total of 489 patients from arm A and 456 patients from arm C were assessed with a median (range) follow-up of 4.4 (0-13.6) years. The 10-year Kaplan-Meier estimates for RFS in arm A were 90.9%and 64.5%for patients with high and low levels of STILs, respectively (hazard ratio [HR], 0.23 [95%CI, 0.07-0.73]; P = .01). The 10-year estimates for RFS in arm C were 80.0%and 80.1%for patients with high and low levels of STILs, respectively (HR, 1.26 [95%CI, 0.50-3.17]; P = .63). The test for interaction between trastuzumab treatment and STIL status was statistically significant (P = .03). In a multivariable analysis, STIL status remained significantly associated with RFS in arm A and not significantly associated in arm C (HR, 1.01 [95%CI, 0.89-1.15]; interaction P = .04). Conclusions and Relevance: This analysis of participants in the N9831 trial found that the presence of STILs was prognostically associated with RFS in patients treated with chemotherapy alone but not in patients treated with chemotherapy plus trastuzumab. High levels of STILs were associated with lack of trastuzumab therapy benefit, in contrast to a previously reported association between increased levels of STILs and increased trastuzumab benefit in HER2-positive patients.

AB - Importance: The presence of tumor-infiltrating lymphocytes at diagnosis is reported to be prognostic in triple-negative breast cancer. Objective: To evaluate the association of stromal tumor-infiltrating lymphocytes (STILs) with recurrence-free survival (RFS) in women with human epidermal growth factor receptor 2 (HER2)-positive breast cancer treated with chemotherapy or chemotherapy plus trastuzumab in the N9831 trial. Design, Setting, and Participants: Hematoxylin-eosin-stained tumor slides from patients with early-stage HER2-positive breast cancer in 2 of the 3 arms of the N9831 trial were assessed for STILs at an academic medical center. The amounts of STILs were quantitated in deciles, and a level of at least 60% STILs was used for the prespecified categorical cutoff. The association between STILs and RFS was evaluated with Cox models. Exposure: Standard chemotherapy consisting of doxorubicin-cyclophosphamide followed by weekly paclitaxel (arm A) or doxorubicin-cyclophosphamide followed by weekly paclitaxel plus trastuzumab followed by trastuzumab alone (arm C). Main Outcomes and Measures: Stromal tumor-infiltrating lymphocytes and their association with RFS. Results: A total of 489 patients from arm A and 456 patients from arm C were assessed with a median (range) follow-up of 4.4 (0-13.6) years. The 10-year Kaplan-Meier estimates for RFS in arm A were 90.9%and 64.5%for patients with high and low levels of STILs, respectively (hazard ratio [HR], 0.23 [95%CI, 0.07-0.73]; P = .01). The 10-year estimates for RFS in arm C were 80.0%and 80.1%for patients with high and low levels of STILs, respectively (HR, 1.26 [95%CI, 0.50-3.17]; P = .63). The test for interaction between trastuzumab treatment and STIL status was statistically significant (P = .03). In a multivariable analysis, STIL status remained significantly associated with RFS in arm A and not significantly associated in arm C (HR, 1.01 [95%CI, 0.89-1.15]; interaction P = .04). Conclusions and Relevance: This analysis of participants in the N9831 trial found that the presence of STILs was prognostically associated with RFS in patients treated with chemotherapy alone but not in patients treated with chemotherapy plus trastuzumab. High levels of STILs were associated with lack of trastuzumab therapy benefit, in contrast to a previously reported association between increased levels of STILs and increased trastuzumab benefit in HER2-positive patients.

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