Abstract GS1-02: NSABP B-47 (NRG oncology): Phase III randomized trial comparing adjuvant chemotherapy with adriamycin (A) and cyclophosphamide (C) → weekly paclitaxel (WP), or docetaxel (T) and C with or without a year of trastuzumab (H) in women with node-positive or high-risk node-negative invasive breast cancer (IBC) expressing HER2 staining intensity of IHC 1+ or 2+ with negative FISH (HER2-Low IBC)

Abstract

Background: Adjuvant trastuzumab (H) reduces cancer recurrence and improves survival in patients (pts) with HER2-amplified or overexpressing (IHC 3+ staining intensity) IBC. Two of the landmark trials that demonstrated the efficacy of H-based eligibility on HER2 testing performed at local site laboratories were found to contain a cohort of pts without amplification or IHC overexpression on tissue submitted for central testing. These HER2-low cohorts appeared to benefit from the addition of H, and efforts at external HER2 testing validation and laboratory explorations did not negate these findings. NSABP B-47 was performed to determine if these findings would be confirmed in a large prospective randomized trial. The primary aim was to determine whether the addition of H to chemotherapy (CT) regimens of AC→WP or TC (choice per investigator discretion) would improve invasive disease-free survival (IDFS). Methods: From 2/8/2011 to 2/10/2015, 3270 women were enrolled with 1630 pts randomly assigned to Arm 1 [TC: docetaxel 75mg/m2, cyclophosphamide 600 mg/m2 every 3 weeks x 6 cycles; or AC→WP: doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 2 or 3 weeks x 4 cycles followed by paclitaxel 80 mg/m2 every week x 12], and 1640 pts to Arm 2 [same CT regimens + 12 months of H]. Pts were stratified by IHC score (1+ vs 2+), number of positive nodes (0-3, 4-9, ≥10), hormone receptor status (ER or PgR positive vs both negative), and CT (TC vs AC→WP). Overall 58.5% were ≥50 years, 57% had tumors with IHC 1+, 17.3% were ER- and PgR-, 19.9% were node negative, and 27.4% had ≥4 positive nodes. TC was the intended CT regimen for 44.2%. Results: As of 7/31/2017, the median follow-up time was 46.1 months. We observed 264 IDFS events, which triggered the definitive analysis for the primary endpoint. The addition of H to CT showed a 5-year IDFS of 89.6% compared to 89.2% for CT alone (HR 0.98; 95%CI 0.77-1.26; P=0.90). The findings did not differ by level of HER2 IHC expression, level of lymph node involvement, or hormone receptor status. 5-year point estimates for RFI were 92.0% for CT+H compared to 92.2% for CT alone (HR 0.995; 95%CI 0.75-1.32; P=0.97). 5-year estimates for DRFI were 92.7% for CT+H and 93.5% for CT alone (HR 1.10; 95%CI 0.81-1.49; P=0.55). The addition of H did not change OS significantly with 5-year point estimates of 94.8% in CT+H vs 96.2% in CT alone (HR 1.33; 95%CI 0.91-1.94; P=0.14). 4.3% of women in the CT arm experienced Grade 4 or 5 toxicities compared to 5.0% in CT+H. Conclusion: The addition of H to CT did not demonstrate a reduction in IDFS, RFI, or DRFI in women with non-overexpressing but IHC measurable HER2 IBC. This prospective study did not confirm the retrospective findings in NSABP B-31 or N9831. The threshold of HER2 expression or genetic amplification for H benefit remains unchanged. Support: NCI U10-180868, -180822, -44066, UG1-189867, and Genentech, Inc. Citation Format: Fehrenbacher L, Cecchini RS, Geyer CE, Rastogi P, Costantino JP, Atkins JN, Polikoff J, Boileau J-F, Provencher L, Stokoe C, Moore TD, Robidoux A, Borges V, Albain KS, Swain SM, Paik S, Mamounas EP, Wolmark N. NSABP B-47 (NRG oncology): Phase III randomized trial comparing adjuvant chemotherapy with adriamycin (A) and cyclophosphamide (C) → weekly paclitaxel (WP), or docetaxel (T) and C with or without a year of trastuzumab (H) in women with node-positive or high-risk node-negative invasive breast cancer (IBC) expressing HER2 staining intensity of IHC 1+ or 2+ with negative FISH (HER2-Low IBC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS1-02.

Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update

“…5 Data from NRG trial B-47 (ClinicalTrials.gov identifier: NCT01275677) confirmed the lack of benefit from adjuvant trastuzumab for patients whose tumors lack gene amplification and are immunohistochemistry (IHC) 1þ or 2þ. 6 Consequently, HER2 gene amplification assessed by in situ hybridization (ISH) or protein overexpression assessed by IHC remains the primary predictor of responsiveness to HER2-targeted therapies in breast cancer.…”

“…The HER2 testing algorithm for breast cancer is updated to address the recommended workup for less common clinical scenarios (approximately 5% of cases) observed when using a dual-probe ISH assay. These scenarios are described as ISH group 2 (HER2/ chromosome enumeration probe 17 [CEP17] ratio 2.0; average HER2 copy number ,4.0 signals per cell), ISH group 3 (HER2/CEP17 ratio ,2.0; average HER2 copy number 6.0 signals per cell), and ISH group 4 (HER2/ CEP17 ratio ,2.0; average HER2 copy number 4.0 and , 6.0 signals per cell). The diagnostic approach includes more rigorous interpretation criteria for ISH and requires concomitant IHC review for dual-probe ISH groups 2 to 4 to arrive at the most accurate HER2 status designation (positive or negative) based on combined interpretation of the ISH and IHC assays.…”

Promises and Pitfalls of Using Liquid Biopsy for Precision Medicine

“…The trial was terminated by an independent data monitoring committee after 63 patients had been randomized because it demonstrated that trastuzumab could not eliminate CTCs in this setting. In line with the Treat CTC trial results, the NSABP B47 phase III trial including more than 3,000 patients demonstrated that 1 year of adjuvant trastuzumab did not improve invasive disease-free survival when added to standard chemotherapy in HER2-negative breast cancer (68). More examples such as the Treat CTC/NSABP B47 example are needed to provide evidence that CTCs or ctDNA elimination after short drug exposure can provide relevant information that can be used in addition to data from the activity of the drug in the metastatic and neoadjuvant setting in order to make more informed decisions before testing this drug in a large phase III adjuvant trial.…”

HER2 Directed Antibody-Drug-Conjugates beyond T-DM1 in Breast Cancer

“…These HER2low cohorts seemed to benefit from trastuzumab in a retrospective unplanned subgroup analysis [11,12]. The efficacy of an adjuvant trastuzumab treatment in HER2-low (immunohistochemistry [IHC] 1+ or 2+ but not HER2 amplified) breast cancer patients was prospectively investigated in the phase III trial NSABP B-47 [13]. In this trial, 3,270 patients were randomized 1:1 to standard adjuvant chemotherapy with or without one year of trastuzumab.…”