Distinct Neoadjuvant Chemotherapy Response and 5-Year Outcome in Patients With Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Tumors That Reclassify as Basal-Type by the 80-Gene Signature

Pat W Whitworth, Peter D Beitsch, James V Pellicane, Paul L Baron, Laura A Lee, Carrie L Dul, Mary K Murray, Mark A Gittleman, Raye J Budway, Rakhshanda Layeequr Rahman, Pond R Kelemen, William C Dooley, David T Rock, Kenneth H Cowan, Beth-Ann Lesnikoski, Julie L Barone, Andrew Y Ashikari, Beth B Dupree, Shiyu Wang, Andrea R Menicucci, Erin B Yoder, Christine Finn, Kate Corcoran, Lisa E Blumencranz, William Audeh, NBRST Investigators Group, Pat W Whitworth, Peter D Beitsch, James V Pellicane, Paul L Baron, Laura A Lee, Carrie L Dul, Mary K Murray, Mark A Gittleman, Raye J Budway, Rakhshanda Layeequr Rahman, Pond R Kelemen, William C Dooley, David T Rock, Kenneth H Cowan, Beth-Ann Lesnikoski, Julie L Barone, Andrew Y Ashikari, Beth B Dupree, Shiyu Wang, Andrea R Menicucci, Erin B Yoder, Christine Finn, Kate Corcoran, Lisa E Blumencranz, William Audeh, NBRST Investigators Group

Abstract

Purpose: The 80-gene molecular subtyping signature (80-GS) reclassifies a proportion of immunohistochemistry (IHC)-defined luminal breast cancers (estrogen receptor-positive [ER+], human epidermal growth factor receptor 2-negative [HER2-]) as Basal-Type. We report the association of 80-GS reclassification with neoadjuvant treatment response and 5-year outcome in patients with breast cancer.

Methods: Neoadjuvant Breast Registry Symphony Trial (NBRST; NCT01479101) is an observational, prospective study that included 1,069 patients with early-stage breast cancer age 18-90 years who received neoadjuvant therapy. Pathologic complete response (pCR) and 5-year distant metastasis-free survival (DMFS) and overall survival (OS) were assessed in 477 patients with IHC-defined ER+, HER2- tumors and in a reference group of 229 patients with IHC-defined triple-negative breast cancer (TNBC).

Results: 80-GS reclassified 15% of ER+, HER2- tumors (n = 73) as Basal-Type (ER+/Basal), which had similar pCR compared with TNBC/Basal tumors (34% v 38%; P = .52), and significantly higher pCR than ER+/Luminal A (2%; P < .001) and ER+/Luminal B (6%; P < .001) tumors. The 5-year DMFS (%, [95% CI]) was significantly lower for patients with ER+/Basal tumors (66% [52.6 to 77.3]), compared with those with ER+/Luminal A tumors (92.3% [85.2 to 96.1]) and ER+/Luminal B tumors (73.5% [44.5 to 79.3]). Importantly, patients with ER+/Basal or TNBC/Basal tumors that had a pCR exhibited significantly improved DMFS and OS compared with those with residual disease. By contrast, patients with ER+/Luminal B tumors had comparable 5-year DMFS and OS whether or not they achieved pCR.

Conclusion: Significant differences in chemosensitivity and 5-year outcome suggest patients with ER+/Basal molecular subtype may benefit from neoadjuvant regimens optimized for patients with TNBC/Basal tumors compared with patients with ER+/Luminal subtype. These data highlight the importance of identifying this subset of patients to improve treatment planning and long-term survival.

Conflict of interest statement

Pat W. WhitworthEmployment: Integra LifeSciencesLeadership: Integra LifeSciencesStock and Other Ownership Interests: Targeted Medical Education, Inc, Cerebrotech Medical Systems, Medneon, Integra LifeSciencesHonoraria: 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 James V. PellicaneStock and Other Ownership Interests: PreludeDxHonoraria: Agendia, PreludeDxSpeakers' Bureau: Agendia, PreludeDx Paul L. BaronHonoraria: Myriad GeneticsConsulting or Advisory Role: Myriad GeneticsSpeakers' Bureau: Myriad GeneticsTravel, Accommodations, Expenses: Myriad Genetics William C. DooleyLeadership: Shaga Medical, LLCStock and Other Ownership Interests: Shaga MedicalResearch Funding: Agendia, XoftPatents, Royalties, Other Intellectual Property: Patent pending: microendoscopy system Kenneth H. CowanStock and Other Ownership Interests: United Health GroupConsulting or Advisory Role: MerckResearch Funding: Merck Beth-Ann LesnikoskiEmployment: HCA HealthcareStock and Other Ownership Interests: HCA HealthcareResearch Funding: Agendia (Inst), Seattle Genetics (Inst)Open Payments Link: https://openpaymentsdata.cms.gov/physician/246359 Beth B. DupreeHonoraria: Medtronic Shiyu WangEmployment: AgendiaStock and Other Ownership Interests: Agendia Andrea R. MenicucciEmployment: Agendia Erin B. YoderEmployment: AgendiaStock and Other Ownership Interests: AgendiaTravel, Accommodations, Expenses: Agendia Kate CorcoranEmployment: 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.
FIG 1.
CONSORT diagram. 1,091 patients were assessed for eligibility, of whom 22 were excluded because they did not meet the inclusion criteria, and 45 were excluded because clinical data were unavailable. Patients with IHC-defined HER2+ tumors (n = 290) were excluded. Patients with IHC-defined ER- or TNBC tumors that were classified as BluePrint Luminal- or HER2-Type were excluded. A total of 706 patients were included in the analysis, of whom 477 had ER+, HER2– tumors. The remaining 229 patients had TNBC tumors that were BluePrint Basal-Type and were included as the reference group. ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; TNBC, triple-negative breast cancer.
FIG 2.
FIG 2.
Frequency of grade and distribution of ER% in ER+/Basal tumors. (A) The percentage of each grade (grade 1 = blue, grade 2 = red, grade 3 = teal, grade unknown = orange) is shown for each patient subgroup (ER+/Luminal A, ER+/Luminal B, ER+/Basal, and TNBC/Basal). (B) The distribution of ER expression, shown as percentage, is shown for each patient with an ER+/Basal tumor. BP, BluePrint; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; TNBC, triple-negative breast cancer.
FIG 3.
FIG 3.
pCR rates and 5-year DMFS and OS. (A) pCR rates in each patient subgroup; significance was assessed by using a two-tailed z-test for proportions. (B) DMFS probability and (C) OS probability for each patient subgroup; significance was assessed by using log-rank test (blue = ER+/Luminal A, red = ER+/Luminal B, teal = ER+/Basal, dashed teal lines = TNBC/Basal). BP, BluePrint; DMFS, distant metastasis-free survival; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; OS, overall survival; pCR, pathologic complete response; TNBC, triple-negative breast cancer.
FIG 4.
FIG 4.
Association between pCR and 5-year DMFS and OS. (A) DMFS and (B) OS in patients with ER+/Luminal B tumors (red) and ER+/Basal tumors (blue) that achieved pCR (solid line) or had residual disease (dashed line). (C) DMFS and (D) OS in patients with TNBC/Basal tumors (teal) and ER+/Basal tumors (blue) that achieved pCR (solid line) or had residual disease (dashed line). Significance was assessed by using log-rank test. DMFS, distant metastasis-free survival; ER, estrogen receptor; OS, overall survival; pCR, pathologic complete response; TNBC, triple-negative breast cancer.

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