About a half of breast cancers traditionally classified as HER2-negative show a low HER2 expression (IHC 1+ or IHC 2+ and ISH negative) that can be targeted by new antibody-drug conjugates. There is no data on the evolution of HER2-low status from primary tumor to relapse.
Patients with matched primary and relapsed breast cancer samples from two Institutions (IOV-IRCCS Padova and Treviso Hospital) were included. HER2 was evaluated according to ASCO/CAP recommendations in place at the time of diagnosis. Cases diagnosed between 2007 and 2013 were reviewed by IHC to comply with the cut-off of >10% cells staining for HER2 positivity. Moreover, 100 random samples were reviewed by a blinded pathologist: agreement with the original report was 80%. HER2-neg cases were sub-classified as HER2-low (IHC 1+, or IHC 2+ and ISH not amplified), or HER2-0 (IHC 0).
575 patients were included. Primary tumor phenotype was: 59% luminal-like (HR+/HER2-neg), 25% HER2-pos, 16% triple-negative. The proportion of HER2-low cases was 34% on the primary tumor and 38% on the relapse samples. Among HER2-neg cases, HER2-low status was more frequent in Luminal-like vs triple-negative tumors (47% vs 41% on primary tumor samples, p=0.268; 54% vs 40% on relapse samples, p=0.006). The overall rate of HER2 discordance was 38% (Table), mostly represented by HER2-0 switching to HER2-low (15%) and HER2-low switching to HER2-0 (14%). A minority (9%) of cases lost or acquired HER2-positivity. Among patients with a primary HER2-neg tumor, the rate of HER2 discordance was higher in luminal-like vs triple-negative cases (45% vs 35% p=0.080). This difference was mostly driven by cases switching from HER2-0 to HER2-low: 40% of luminal-like/HER2-0 vs 24% of triple-negative/HER2-0 patients (p=0.088).
Relapse HER2-0 HER2-low HER2-positive Total Primary tumour n % n % n % n % HER2-0 134 23% 85 15% 13 2% 232 40% HER2-low 78 14% 109 19% 9 2% 196 34% HER2-positive 6 1% 23 4% 118 20% 147 26% Total 217 38% 218 38% 140 24% 575 100%
HER2-low expression is highly unstable during disease evolution. Relapse biopsy in case of a primary HER2-0 tumor may open new opportunities for treatment in a relevant proportion of patients.
The authors.
Has not received any funding.
M. Fassan: Advisory/Consultancy, Research grant/Funding (institution), outside the submitted work: Astellas Pharma; Advisory/Consultancy, outside the submitted work: Diaceutics; Advisory/Consultancy, outside the submitted work: Tesaro; Research grant/Funding (institution), outside the submitted work: QED Therapeutics. P.F. Conte: Research grant/Funding (institution), outside the submitted work: Merck; Honoraria (self), Research grant/Funding (institution), outside the submitted work: Roche; Honoraria (self), outside the submitted work: Novartis; Honoraria (self), outside the submitted work: Lilly. V. Guarneri: Honoraria (self), Research grant/Funding (institution), outside the submitted work: Roche; Honoraria (self), outside the submitted work: Novartis; Honoraria (self), outside the submitted work: Eli Lilly. M.V. Dieci: Honoraria (self), outside the submitted work: Genomic Health; Honoraria (self), outside the submitted work: Eli Lilly; Honoraria (self), outside the submitted work: Celgene. All other authors have declared no conflicts of interest.