Abstract P3-07-04: Intrinsic subtype and therapeutic response among early stage HER2-positive breast tumors from the North Central cancer treatment group (Alliance) N9831 trial
Authors: Perez EA , Ballman KV , Mashadi-Hossein A , Tenner KS , Kachergus JM , Norton N , Necela BM , Carr JM , Ferree S , Perou CM , Cheang MCU , Thompson EA 
Published: May 2016

Importance: 20-25% of patients with early stage HER2-positive breast cancer develop tumor relapse after adjuvant trastuzumab. Identification of such patients is a key goal for clinical management decisions.

Objective: To assess molecular heterogeneity among early stage HER2-positive patients using the Prosigna™ algorithm, to define intrinsic subtypes, and to determine the clinical significance of such heterogeneity.

Design: The NanoString® platform was used to measure the abundance of the PAM50 subtype signature transcripts. Samples from the NCCTG (Alliance) N9831 trial were analyzed using the Prosigna™ algorithm to define intrinsic subtype and risk scores. Subtypes were evaluated for recurrence-free survival following chemotherapy with or without trastuzumab.

Setting: Samples were obtained from a multi-center randomized phase III trial of chemotherapy versus chemotherapy plus trastuzumab.

Participants: All tumors were centrally evaluated for HER2 positivity, defined as IHC 3+ and/or FISH &gt;2.0; 1392 patients were evaluated for molecular subtype.

Intervention(s): Patients received adjuvant chemotherapy (doxorubicin plus cyclophosphamide followed by paclitaxel) (n=484) or chemotherapy plus trastuzumab (n=908).

Main Outcome Measure(s): The primary outcome was recurrence-free survival as a function of subtype and treatment.

Results: Patients with HER2-positive tumors with HER2-enriched features comprised about 70% of the sample cohort, and these individuals received significant benefit from adjuvant trastuzumab (HR=0.68, 95%CI: 0.52, 0.89, p=0.005), as did the relatively fewer patients (291/1392) with Luminal-type tumors (HR=0.52, 95%CI: 0.32, 0.85, p=0.01). The sample cohort contained a small number of patients with tumors having Basal-like features (97/1392), and the data suggest that these individuals may have received less benefit from trastuzumab, beyond that received from chemotherapy alone (HR=1.06, 95%CI:0.53,2.13, p=0.87).

Conclusions: The majority of HER2-positive tumors are classified as HER2-enriched or Luminal using the Prosigna algorithm, and patients with such tumors benefit from adjuvant trastuzumab. About 10% of HER2-positive tumors exhibit Basal-like genomic features, and such tumors appear to recur at fairly similar frequency irrespective of treatment with chemotherapy or chemotherapy plus trastuzumab. Patients with HER2-positive/Basal-like tumors may represent a cohort that should be considered for enrollment in trials to evaluate emerging novel HER2-targeted agents, other targeted therapies, or combinations of both approaches.

Support provided in part by CA129949 and CA15083.

Citation Format: Perez EA, Ballman KV, Mashadi-Hossein A, Tenner KS, Kachergus JM, Norton N, Necela BM, Carr JM, Ferree S, Perou CM, Cheang MCU, Thompson EA. Intrinsic subtype and therapeutic response among early stage HER2-positive breast tumors from the North Central cancer treatment group (Alliance) N9831 trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-04.