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

Pat W Whitworth, Peter D Beitsch, Mary K Murray, Paul D Richards, Angela Mislowsky, Carrie L Dul, James V Pellicane, Paul L Baron, Rakhshanda Layeequr Rahman, Laura A Lee, Beth B Dupree, Pond R Kelemen, Andrew Y Ashikari, Raye J Budway, Cristina Lopez-Penalver, William Dooley, Shiyu Wang, Patricia Dauer, Andrea R Menicucci, Erin B Yoder, Christine Finn, Lisa E Blumencranz, William Audeh, Pat W Whitworth, Peter D Beitsch, Mary K Murray, Paul D Richards, Angela Mislowsky, Carrie L Dul, James V Pellicane, Paul L Baron, Rakhshanda Layeequr Rahman, Laura A Lee, Beth B Dupree, Pond R Kelemen, Andrew Y Ashikari, Raye J Budway, Cristina Lopez-Penalver, William Dooley, Shiyu Wang, Patricia Dauer, Andrea R Menicucci, Erin B Yoder, Christine Finn, Lisa E Blumencranz, William Audeh

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.

Conflict of interest statement

Pat W. WhitworthEmployment: Integra LifeSciences (I)Leadership: Integra LifeSciences (I)Stock and Other Ownership Interests: Targeted Medical Education Inc, Integra LifeSciences (I)Honoraria: Puma BiotechnologyConsulting or Advisory Role: ImpediMed, Prelude Therapeutics, Becton DickinsonResearch Funding: Prelude Therapeutics, Agendia, MedneonTravel, Accommodations, Expenses: Targeted Medical Education Inc Peter D. BeitschEmployment: InvitaeLeadership: Targeted Medical Education IncStock and Other Ownership Interests: Targeted Medical Education Inc, InvitaeResearch Funding: InvitaeExpert Testimony: Dune Medical Devices, ImpediMedUncompensated Relationships: Medneon Paul D. RichardsStock and Other Ownership Interests: NanoViricidesResearch Funding: Carrick Therapeutics (Inst) James V. PellicaneStock and Other Ownership Interests: PreludeDxHonoraria: Agendia, PreludeDxSpeakers' Bureau: Agendia, PreludeDx Beth B. DupreeLeadership: Caliber MedicalStock and Other Ownership Interests: Videra SurgicalHonoraria: Medtronic, Perimeter Medical William DooleyLeadership: Shaga Medical LLCStock and Other Ownership Interests: Shaga MedicalResearch Funding: Agendia, XoftPatents, Royalties, Other Intellectual Property: patent pending—microendoscopy system Shiyu WangEmployment: Agendia Patricia DauerEmployment: AgendiaStock and Other Ownership Interests: AgendiaTravel, Accommodations, Expenses: Agendia Andrea R. MenicucciEmployment: Agendia Erin B. YoderEmployment: AgendiaStock and Other Ownership Interests: AgendiaTravel, Accommodations, Expenses: Agendia Lisa E. BlumencranzEmployment: Agendia William AudehEmployment: AgendiaLeadership: AgendiaStock and Other Ownership Interests: AgendiaConsulting or Advisory Role: Celanese, Private HealthResearch Funding: AgendiaTravel, Accommodations, Expenses: AgendiaNo other potential conflicts of interest were reported.

Figures

**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.

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Source: PubMed

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

Abstract

Conflict of interest statement

Figures

References

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