Abstract P4-14-05: Genomic parameters affecting the outcome of patients with advanced breast cancer treated with trastuzumab
Authors: Gogas H , Kotoula V , Alexopoulou Z , Christodoulou C , Kostopoulos I , Bobos M , Raptou G , Charalambous E , Tsolaki E , Xanthakis I , Pentheroudakis G , Koutras A , Bafaloukos D , Papakostas P , Aravantinos G , Psyrri A , Petraki K , Kalogeras KT , Fountzilas G , Pectasides D 
Published: May 2016

Abstract
Background-Aim: There is an unmet need for de-selecting HER2-positive patients with advanced breast cancer (ABC), since only some of those patients benefit from the addition of anti-HER2 agents to chemotherapy. The aim of this study was to investigate candidate biomarkers, including MYC and MET, in parallel with an extended array of biomarkers previously associated with trastuzumab (T) resistance.
Patients and Methods: Two hundred and twenty-nine ABC patients treated with T and chemotherapy over a period of 13 years were included in the study. Paraffin tumors were retrospectively centrally assessed with immunohistochemistry (IHC) for breast cancer subtypes; fluorescence in situ hybridization (FISH) for HER2, TOP2A and centromere (CEN) 17, MYC and CEN8, MET and CEN7; qPCR for MYC and MET copy number (CN); and, for PI3K activation (PIK3CA mutations, PTEN and phospho-mTOR IHC). Patterns of CEN CN aberrations corresponding to chromosome "polysomy" were also evaluated, with cut-offs based on normal tissue. Time to progression (TTP) and survival were evaluated from the initiation of T as first-line treatment.
Results: Median follow-up was 70 months. Of the 229 patients treated with T as HER2-positive, central analysis identified 90 cases being HER2-negative, as per current guidelines (39.3% of the total cohort). HER2-positive patients showed a trend for survival benefit over HER2-negative patients (median 50.7 vs. 38.1 months, respectively, p=0.118). HER2-positive tumors were subtyped as Luminal-HER2 (n=77) and HER2-enriched (n=53); 156 patients presented with ABC and 65 with disease initially diagnosed at stage IV (de novo ABC). MET and MYC CN gains (≥2.5 copies) were found in 40 (25%) and 15 (9%) cases with qPCR, while MET and MYC amplification with FISH was present in 4 (2.5%) and 31 (18%) cases, respectively. Concordance between FISH and qPCR was low for MYC (kappa value 0.46) and absent for MET. Polysomy was collectively observed in 70 cases, in 54 of them (32% of all tumors) concerning any 1 of the 3 examined chromosomes. This condition, called restricted polysomy, interacted with ABC presentation, conferring decreased survival to patients with ABC (HR=2.32, 95% CI 1.43-3.76, Wald's p=0.001) but not to those with de novo ABC (interaction p=0.077). MYC CN gain was the only marker significantly associated with increased risk for progression (HR=3.22, 95% CI 1.66-6.24, p&lt;0.001) and death (HR=5.45, 95% CI 2.89-10.28, p&lt;0.001) at univariate analysis. Adjustment of all tested markers with standard clinicopathological parameters revealed that along with poor patient performance status that was associated with poor prognosis, MYC CN gain was an independent adverse prognosticator for both TTP and survival (all p-values &lt;0.001). The HER2-enriched subtype was independently associated with T benefit for TTP (p=0.001) and survival (p=0.051). The interaction between restricted polysomy and disease presentation was also independently significant for survival (p=0.041).
Conclusions: MYC CN gain is a strong unfavorable prognosticator in T-treated ABC patients. Distinguishing between HER2-positive subtypes seems important for identifing T benefit in ABC. Chromosomal polysomy may distinctly affect T benefit in patients with pre-treated and de novo ABC.
Citation Format: Gogas H, Kotoula V, Alexopoulou Z, Christodoulou C, Kostopoulos I, Bobos M, Raptou G, Charalambous E, Tsolaki E, Xanthakis I, Pentheroudakis G, Koutras A, Bafaloukos D, Papakostas P, Aravantinos G, Psyrri A, Petraki K, Kalogeras KT, Fountzilas G, Pectasides D. Genomic parameters affecting the outcome of patients with advanced breast cancer treated with trastuzumab. [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 P4-14-05.