Genomic Classification of HER2-Positive Patients With 80-Gene and 70-Gene Signatures Identifies Diversity in Clinical Outcomes With HER2-Targeted Neoadjuvant Therapy

Abstract

Purpose: The prospective Neoadjuvant Breast Registry Symphony Trial compared the 80-gene molecular subtyping signature with clinical assessment by immunohistochemistry and/or fluorescence in situ hybridization in predicting pathologic complete response (pCR) and 5-year outcomes in patients with early-stage breast cancer.

Methods: Standard-of-care neoadjuvant chemotherapy combined with trastuzumab or trastuzumab plus pertuzumab was given to patients with human epidermal growth factor receptor 2 (HER2)-positive tumors (n = 295). pCR was the primary end point, with secondary end points of distant metastasis-free survival and overall survival at 5 years.

Results: Among clinically defined HER2-positive (cHER2) tumors, the 80-gene assay identified 29.5% (87 of 295) as Luminal-Type (cHER2/gLuminal), 14.9% (44 of 295) as Basal-Type (cHER2/gBasal), and 55.6% (164 of 295) as HER2-Type (cHER2/genomically classified as HER2 [gHER2]). Patients with cHER2/gHER2 tumors had a higher pCR rate (61.6%) compared with non-gHER2 tumors (26.7%; P < .001). Dual targeting for cHER2/gHER2 tumors yielded a higher pCR rate (75%) compared with those treated with single HER2-targeted therapy (54%; P = .006). For cHER2/gBasal tumors, the 42.9% pCR rate observed with dual targeting was not different from that with trastuzumab alone (46.4%; P = .830). Among those with cHER2/gBasal tumors, 5-year distant metastasis-free survival (68.6%; 95% CI, 49.1 to 81.9) was significantly worse than in patients with cHER2/gLuminal tumors (88.9%; 95% CI, 78.0 to 94.6) and cHER2/gHER2 tumors (87.4%; 95% CI, 80.2 to 92.2; P = .010), with similar corresponding overall survival differences.

Conclusion: The 80-gene assay identified meaningful genomic diversity in patients with cHER2 disease. Patients with cHER2/gHER2 tumors, who benefitted most from dual HER2-targeted therapy, accounted for approximately half of the cHER2 cohort. Genomically Luminal tumors had low pCR rates but good 5-year outcomes. cHER2/gBasal tumors derived no benefit from dual therapy and had significantly worse 5-year prognosis; these patients merit special consideration in future trials.

Trial registration: ClinicalTrials.gov NCT01479101.

FIG 1.

Further classification of IHC-/FISH-defined HER2+ patients with BluePrint. Sankey diagram depicting (Left) 295 IHC-/FISH-defined HER2+ patients sorted by (Right) genomic subtype using BluePrint into HER2-Type (cHER2/gHER2) or further classified as Luminal-Type (cHER2/gLuminal) or Basal-Type (cHER2/gBasal). cHER2, clinically defined HER2+; FISH, fluorescence in situ hybridization; gHER2, genomically classified as HER2; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; IHC, immunohistochemistry.

FIG 2.

Therapeutic response and 5-year outcomes by BluePrint. (A) The pCR rate of all 295 cHER2 patients (^adark gray bar) compared with pCR rates when stratified by BluePrint. The pCR rates of each BluePrint molecular subtype are shown (blue, cHER2/gLuminal; red, cHER2/gHER2; teal, cHER2/gBasal) with the remaining proportion of immunohistochemistry-/fluorescence in situ hybridization–defined HER2+ patients shown for each comparison in light gray bars: ^bcHER2/gHER2 and cHER2/gBasal, ^ccHER2/gLuminal and cHER2/gBasal, and ^dcHER2/gLuminal and cHER2/gHER2. Significance was evaluated using a two-tailed proportional z-test. Five-year probabilities of (B) DMFS and (C) OS for each BluePrint subgroup were assessed by the log-rank test. cHER2, clinically defined HER2+; DMFS, distant metastasis-free survival; gBasal, genomically defined Basal-Type; gHER2, genomically defined HER2-Type; gLuminal, genomically defined Luminal-Type; OS, overall survival; pCR, pathologic complete response.

FIG 3.

Association between therapeutic response and the 5-year outcome. Five-year probabilities of (A, C, and E) DMFS and (B, D, and F) OS stratified by pCR were assessed by the log-rank test for each BluePrint subtype: (A and B) cHER2/gLuminal, (C and D) cHER2/gHER2, and (E and F) cHER2/gBasal. cHER2, clinically defined HER2+; DMFS, distant metastasis-free survival; gBasal, genomically defined Basal-Type; gHER2, genomically defined HER2-Type; gLuminal, genomically defined Luminal-Type; HER2, human epidermal growth factor receptor 2; OS, overall survival; pCR, pathologic complete response.

FIG 4.

Therapeutic response and 5-year outcome by treatment arm. (A) The proportion of each BluePrint molecular subtype (cHER2/gLuminal, cHER2/gHER2, and cHER2/gBasal) treated with single HER2-targeted therapy (H; blue bars) versus dual HER2-targeted therapy (H + P; red bars). The pCR rate of (B) all immunohistochemistry-/fluorescence in situ hybridization–defined HER2+ patients and (C) BluePrint molecular subtypes (blue, cHER2/gLuminal; orange, cHER2/gHER2; and red, cHER2/gBasal), treated with H versus H + P. Significance was evaluated using a two-tailed proportional z-test. Five-year probabilities of (D and E) DMFS and (F and G) OS stratified by BluePrint molecular subtype and (D and F) treatment with H or (E and G) treatment with H + P. cHER2, clinically defined HER2+; DMFS, distant metastasis-free survival; gBasal, genomically defined Basal-Type; gHER2, genomically defined HER2-Type; gLuminal, genomically defined Luminal-Type; H, trastuzumab; HER2, human epidermal growth factor receptor 2; OS, overall survival; P, pertuzumab; pCR, pathologic complete response.