Effects of Age and Immune Landscape on Outcome in HER2-Positive Breast Cancer in the NCCTG N9831 (Alliance) and NSABP B-31 (NRG) Trials

Abstract

Purpose: Young age has been shown to be an independent predictor of poor outcome in breast cancer. In HER2-positive breast cancer, the effects of aging remain largely unknown.

Experimental design: A total of 4,547 patients were included [3,132 from North Central Cancer Treatment Group (NCCTG) N9831 and 1,415 from National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31]. Pathologic stromal tumor-infiltrating lymphocyte (sTIL) and molecular tumor infiltrating lymphocyte (mTIL) signatures were evaluated.

Results: In NCCTG N9831, comparable benefit of trastuzumab was observed in all patients [age ≤ 40; HR, 0.43; 95% confidence interval (CI), 0.28-0.66; P < 0.001; and age > 40; HR, 0.56; 95% CI, 0.45-0.69; P < 0.001]. Similar results were observed in NSABP B-31 (age ≤ 40; HR, 0.45; 95% CI, 0.29-0.68; P < 0.001; and age > 40; HR, 0.42; 95% CI, 0.33-0.54; P < 0.001). Among patients who received chemotherapy alone, younger age was associated with poor outcome in the hormone receptor-positive subset, but not the hormone receptor-negative subset, in both trials. Although there was no association between sTILs and age, a small, but significant increase in mTIL CD45 and some immune subset signatures were observed. Among patients who received chemotherapy alone, patients over 40 years of age with lymphocyte-predominant breast cancer had excellent outcome, with 95% remaining recurrence free at 15 years.

Conclusions: Among patients treated with trastuzumab, there was no significant difference in outcome related to age. Our study suggests that trastuzumab can negate the poor prognosis associated with young age.

Trial registration: ClinicalTrials.gov NCT00005970 NCT00004067.

Conflict of interest statement

Conflict of interest: There is no relevant conflict of interest for Dr. Chumsri, Mr. Serie, Drs. Pogue-Geile, Soyano-Muller, Lou, Colon-Otero, Knutson, Moreno-Aspitia, and Thompson. Dr. Perez worked at Genentech, Inc. Mr. Mashadi-Hossein and Dr. Warren worked at NanoString Technologies, Inc.

©2019 American Association for Cancer Research.

Figures

Figure 1.

Kaplan-Meier Curves of Recurrence-Free Survival Comparing Chemotherapy Alone and Concurrent Trastuzumab Arms. A, NCCTG N9831 patients ≤ 40 years old; B, NCCTG N9831 patients > 40 years old; C, NSABP B-31 patients ≤ 40 years old; D, NSABP B-31 patients > 40 years old. AC-T indicates adjuvant chemotherapy followed by paclitaxel; AC-TH, adjuvant chemotherapy followed by paclitaxel with concurrent trastuzumab; NCCTG, North Central Cancer Treatment Group; NSABP, National Surgical Adjuvant Breast and Bowel Project.

Figure 2.

Kaplan-Meier Curves of Recurrence-Free Survival Stratified by Age ≤ 40 Versus > 40 Years Old in Separate Analysis. A, NCCTG N9831 patients with lymph node involvement (N = 2,716): i, HR+ subgroup in chemotherapy alone arm; ii, HR− subgroup in chemotherapy alone arm; iii, HR+ in concurrent trastuzumab arm; and iv, HR− in concurrent trastuzumab arm. B, NSABP B-31 patients with lymph node involvement (N = 1,415): i, HR+ subgroup in chemotherapy alone arm; ii, HR− in chemotherapy alone arm; iii, HR+ subgroup in concurrent trastuzumab arm; and iv, HR− in concurrent trastuzumab arm. AC-T indicates adjuvant chemotherapy followed by paclitaxel; AC-TH, adjuvant chemotherapy followed by paclitaxel with concurrent trastuzumab; HR+, hormone receptor-positive; HR−, hormone receptor-negative; NCCTG, North Central Cancer Treatment Group; and NSABP, National Surgical Adjuvant Breast and Bowel Project.

Figure 3.

A, Pathologic quantification of stromal TIL in deciles and age. B, Molecular TIL and age. ER/PR indicates estrogen receptor/progesterone receptor; TIL, tumor infiltrating lymphocytes.

Figure 4.

Kaplan-Meier Curves of Recurrence-Free Survival (RFS) and Overall Survival (OS) Stratified by Age ≤ 40 versus > 40 Years Old and LPBC in NCCTG N9831. A, RFS in chemotherapy alone arm. B, RFS in concurrent trastuzumab arm. C, OS in chemotherapy alone arm. D, OS in concurrent trastuzumab arm. AC-T indicates adjuvant chemotherapy followed by paclitaxel; AC-TH, adjuvant chemotherapy followed by paclitaxel with concurrent trastuzumab; LPBC, lymphocyte-predominant breast cancer; NCCTG, North Central Cancer Treatment Group; NSABP, National Surgical Adjuvant Breast and Bowel Project.