Background

HER2-low breast cancer (BC) is defined by an immunohistochemistry (IHC) assay score 1+ or 2+ with negative in situ hybridization (ISH). Genomic characterization of this subset of BC is still limited. We aimed to compare the genomic alterations found in a subgroup of HER2-low metastatic BC versus HER2-zero tumors (IHC score 0) in order to identify potential biomarkers.

Methods

A retrospective analysis was carried out in a sample of 121 metastatic BC patients from Hospital Universitario 12 de Octubre and HM CIOCC (Madrid, Spain) collected from 2017-2020. Next-generation sequencing (NGS) was performed in formalin-fixed paraffin embedded (FFPE) samples of BC. Biopsies included both primary or metastatic tumor, whichever most recent/accesible was available. Somatic mutations and copy number variations (gains and loss) were gathered from the NGS reports. Two-sided Chi-Square test was used for comparisons of proportions between groups and p values below 0.05 were deemed statistically significant.

Results

We identified a total of 67 HER2-low and 54 HER2-zero breast carcinomas. Both groups were similar in the median age of patients, menopausal status and metastatic pattern. The most frequent phenotype was luminal B for both groups, with a significantly higher prevalence in HER2-low carcinomas (65.7% and 37.0%, p<0.01). The most frequently mutated genes were (Table) PIK3CA (31.3% vs 35.2%, p=0.34) and TP53 (34.3% vs 48.2%, p=0.12) in both HER2-low and HER2-zero categories, respectively. We observed a higher prevalence of FGFR1 amplification (defined as ≥10 copy number gain) in the HER2-low group (12% vs 1.8%, p=0.03) compared to HER2-zero carcinomas. Table: 22P

Only gene alterations with a frequency of ≥5% in any group are shown

Conclusions

In our sample, PIK3CA and TP53 were the most frequently mutated genes in both HER2-low and HER2-zero breast carcinomas. FGFR1 amplification was more prevalent in the HER2-low category compared to HER2-zero tumors. This finding needs to be further confirmed as a potential target in this subset of patients.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

R. Sanchez Bayona: Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: Pfizer. P. Tolosa: Speaker Bureau/Expert testimony: AstraZeneca, Amgen, MSD, Roche and Pfizer. E.M. Ciruelos: Advisory/Consultancy: Pfizer, Eli Lilly, Roche, Novartis, AstraZeneca and MSD; Speaker Bureau/Expert testimony: Roche, Pfizer and Eli Lilly; Travel/Accommodation/Expenses: Roche, Pfizer. All other authors have declared no conflicts of interest.

Background

ALP is an α-specific PI3K-α inhibitor, that has shown to significantly increase the median progression-free survival (PFS) when combined with F in pts with PIK3CA-mutated, HR[+]/HER2[–] ABC who had failed to an aromatase inhibitor (AI) regimen. HG is an on-target effect of the PI3K inhibition, being the most frequent adverse event (AE) of grade (G)3/4 and the most common AE leading to discontinuation of ALP in the randomized, phase III SOLAR-1 study. MF is approved for pts with diabetes mellitus (DM) and represented the preferred option for treating ALP-induced HG in the SOLAR-1 study. METALLICA is evaluating the effect of MF in the prevention of HG in PIK3CA-mutated, HR[+]/HER2[–] ABC pts under treatment with ALP plus F.

Trial design

This is a multicenter, open-label, two-cohort, Simon’s two-stage design, phase II trial. Main selection criteria include: (1) Pts ≥ 18 years diagnosed with AI-resistant, PIK3CA-mutated, HR[+]/HER2[–] ABC; (2) No prior history of type I/II DM requiring anti-diabetic drugs; (3) ≤1 prior line of chemotherapy for ABC and/or no prior treatment with any PI3K inhibitor and/or F. A total of 68 pts will be enrolled into two study cohorts according to the baseline glycaemia status: (A) 48 pts with fasting glycaemia <100 mg/dL and glycosylated hemoglobin (HbA1c) < 5.7%; (B) 20 pts with fasting glycaemia 100–140 mg/dL and/or HbA1c 5.7–6.4%. Pts will receive ALP (300mg, orally, once daily) plus F (500mg, intramuscular injection on days 1, 15 of cycle 1 and on day 1 thereafter) and MF (500mg, twice a day (BID) on days 1–3 and 1000mg BID thereafter). The primary endpoint is the rate of G3/4 HG over the first 2 cycles in both cohorts as per CTCAE v4.03. The secondary endpoints include PFS, overall response rate, time to progression, clinical benefit rate as per RECIST v1.1, and overall safety as per CTCAE 4.03. The stage II will be conducted if G3/4 HG after the first 2 cycles are observed in ≤3 pts of 23 in cohort A and ≤2 pts of 7 in cohort B. The final analysis will be defined as positive if ≤6 pts of 48 in cohort A and ≤4 pts of 20 in cohort B have G3/4 HG. The Simon two-stage design was planned to attain an 80% power at 5% nominal alpha level.

Clinical trial identification

NCT04300790.

Legal entity responsible for the study

MEDSIR.

Funding

Novartis.

Disclosure

A. Llombart Cussac: Leadership role: Eisai, Celgene, Lilly, Pfizer, Roche, Novartis, MSD; Shareholder/Stockholder/Stock options: MedSIR, Initia-Research; Advisory/Consultancy: Lilly, Roche, Pfizer, Novartis, Pierre Fabre, GenomicHealth, GSK; Speaker Bureau/Expert testimony: Lilly, AstraZeneca, MSD; Research grant/Funding (self): Roche, Foundation Medicine, Pierre Fabre, Agendia; Travel/Accommodation/Expenses: Roche, Lilly, Novartis, Pfizer, AstraZeneca. J.M. Pérez-Garcia: Advisory/Consultancy: Roche, Lilly; Travel/Accommodation/Expenses: Roche; Full/Part-time employment: MedSIR. A. Urruticoechea: Travel/Accommodation/Expenses: Roche/Genentech, Pfizer. J.F. Cueva Banuelos: Honoraria (self): Roche, AstraZeneca, Teva, Celgene, Novartis.; Advisory/Consultancy: Roche, AstraZeneca. J. Cortés: Advisory/Consultancy: Roche, Celgene, Cellestia, AstraZeneca, Biothera Pharmaceutical, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Servier, Merck Sharp & Dohme, GSK, Leuko, Bioasis, Clovis Oncology; Honoraria (self): Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp & Dohme, Daiichi Sankyo; Research grant/Funding (institution): Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer Healthcare, Eisai, F. Hoffman-La Roche, Guardanth Health, Merck Sharp & Dohme, Pfizer, Piqur Therapeutics, Puma C, Queen Mary University of London; Licensing/Royalties: MedSIR. All other authors have declared no conflicts of interest.