C-MYC Alterations and Association With Patient Outcome in Early-Stage HER2-Positive Breast Cancer From the North Central Cancer Treatment Group N9831 Adjuvant Trastuzumab Trial

Abstract

A B S T R A C T PurposeFindings from the human epidermal growth factor receptor 2 (HER2) -positive National Surgical Adjuvant Breast and Bowel Project (NSABP) B31 trial suggested that MYC/HER2 coamplification (Ͼ 5.0 copies/nucleus) was associated with additional benefit from adjuvant trastuzumab in patients with early-stage breast cancer. To further explore this relationship, we investigated associations between MYC amplification and disease-free survival (DFS) in a similar adjuvant trastuzumab HER2-positive breast cancer trial-North Central Cancer Treatment Group (NCCTG) N9831. Patients and MethodsThis analysis included 799 patients randomly assigned to receive chemotherapy alone or with concurrent trastuzumab on N9831. Fluorescence in situ hybridization (FISH) was performed by using a dual-probe mixture for MYC and centromere 8 (MYC:CEP8) on tissue microarrays. MYC amplification was prespecified as MYC:CEP8 ratio Ͼ 2.2 or average MYC copies/nucleus Ͼ 5.0. Exploratory variables included polysomy 8. ResultsIn comparing DFS (median follow-up, 4.0 years) between treatments, patients with MYC:CEP8 ratio Յ 2.2 (n ϭ 618; 77%) and Ͼ 2.2 (n ϭ 181; 23%) had hazard ratios (HRs) of 0.46 (P Ͻ .001) and 0.67 (P ϭ .33), respectively (interaction P ϭ .38). Patients with MYC copies/nucleus Յ 5.0 (n ϭ 534; 67%) and Ͼ 5.0 (n ϭ 265; 33%) had HRs of 0.52 (P ϭ .002) and 0.48 (P ϭ .02), respectively (interaction P ϭ .94). Patients with MYC:CEP8 ratio Ͻ 1.3 with normal chromosome 8 copy number (n ϭ 141; 18%) and Ն 1.3 or Ͻ 1.3 with polysomy 8 (n ϭ 658; 82%) had HRs of 0.66 (P ϭ .28) and 0.44 (P Ͻ .001), respectively (interaction P ϭ .23). Patients with MYC copies/nucleus Ͻ 2.5 (n ϭ 130; 16%) and Ն 2.5 (n ϭ 669; 84%) had HRs of 1.07 (P ϭ .87) and 0.42 (P Ͻ .001), respectively (interaction P ϭ .05). ConclusionWe did not confirm the B31 association between MYC amplification and additional trastuzumab benefit. Exploratory analyses revealed potential associations between alternative MYC/chromosome 8 copy number alterations and differential benefit of adjuvant trastuzumab.

Semi-comprehensive analysis of gene amplification in gastric cancers using multiplex ligation-dependent probe amplification and fluorescence in situ hybridization

“…A similar selective co-amplification of ERBB2 and MYC was found in breast cancer cells and it has been speculated that this co-amplification might be a very favorable prognostic factor when combined with adjuvant therapy by trastuzumab. 26,27 However, this hypothesis was recently refuted. Instead, new data have shown that this coamplification is associated with poor outcome and is associated with the sequence of acquisition of a malignant stem cell-like phenotype that maintains lower growth and therefore may be a key target of new therapy.…”

Breast: Ductal carcinoma

“…However, it was subsequently shown that patients with MYC/HER2 co-amplification in their primary breast tumors benefited significantly more from trastuzumab than did patients with only HER2 amplification. This could, however, not be confirmed in a later study (Perez et al, 2011).…”

Systemic Targeted Therapy for her2-Positive Early Female Breast Cancer: A Systematic Review of the Evidence for the 2014 Cancer Care Ontario Systemic Therapy Guideline

“…That inconsistency could be a result of the small number of patients in each category. In the N9831 study 15,[51][52][53][54][55][56] , 39% of tumours were smaller than 2 cm, with some being 1-2 cm and N0, but data were not reported separately for the latter group. Petrelli and Barni 67 summarized the studies of very-early-stage pT1a/bN0M0 her2-positive breast cancers, including both rcts and retrospective case series.…”

“…Most gave either anthracycline → taxane → trastuzumab or anthracycline → taxane plus trastuzumab. In the N9831 study 15,[51][52][53][54][55][56] , trastuzumab was administered either concurrently or sequentially with taxanes, and a trend toward an increase in the dfs rate was observed for concurrent compared with sequential administration, but the difference was not statistically significant. Ongoing studies are giving trastuzumab and anthracyclines concurrently in the neoadjuvant setting.…”