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

PATRICIA phase II trial showed that Palbociclib in combination with trastuzumab is safe and exhibits promising survival outcomes in trastuzumab pretreated HER2+/HR+ advanced breast cancer with a PAM50 Luminal A or B subtype (Ciruelos E. et al, CCR 2020). Based on these results, PATRICIA II was designed to include only patients with HER2+/HR+, PAM50 Luminal A/B tumors to receive palbociclib, trastuzumab and ET versus treatment of physician’s choice (TPC).

Trial design

PATRICIA II is a randomized open-label, adaptive design, phase II study. Patients must have centrally confirmed HER2+/HR+ and PAM50 Luminal A or B tumors and have received at least 1 (and no more than 4) prior lines of anti-HER2 regimens for locally advanced or metastatic BC. Patients are randomized 1:1 to receive trastuzumab plus palbociclib at a standard dose of 125 mg/day orally 3 weeks on/ 1 week off and ET (Cohort C1) or TPC (cohort C2). ET options in cohort 1 are either an aromatase inhibitor, fulvestrant or tamoxifen +/- ovarian suppression. TPC options in cohort C2 are T-DM1 or chemotherapy (gemcitabine, vinorelbine, capecitabine, eribulin, paclitaxel or docetaxel) plus trastuzumab. Stratification factors include number of previous regimens for advanced or metastatic BC (1-2 vs 3-4) and the presence of visceral disease (yes vs no). Primary endpoint is to compare the progression-free survival between two arms. The study has an 80% power with two-sided alpha=0.05 to detect a HR of 0.62 in favor of the palbociclib cohort. Secondary endpoints include response rate, overall survival, safety, and quality of life. Tumor tissue and blood samples will be collected for biomarker analyses. An estimated total of 516 patients will be screened to include 232 patients with HER2+/HR+ PAM50 Luminal A or B tumors. The recruitment is ongoing in 20 sites in Spain and as of February 3^rd, 2021, 107 patients were screened and 30 were enrolled in the trial.

Clinical trial identification

NCT02448420.

Legal entity responsible for the study

SOLTI.

Funding

Pfizer.

Disclosure

E.M. Ciruelos: Advisory/Consultancy, Non-remunerated activity/ies: Pfizer; Advisory/Consultancy: Roche; Advisory/Consultancy: Lilly; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Novartis; Advisory/Consultancy: MSD. S. Pernas Simon: Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: Polyphor; Advisory/Consultancy: Seattle Genetics; Advisory/Consultancy: Roche. M. Oliveira: Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Philips Healthcare; Advisory/Consultancy, Research grant/Funding (institution): Genentech; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Research grant/Funding (institution): Immunomedics; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Seattle Genetics; Advisory/Consultancy, Research grant/Funding (institution): GSK; Research grant/Funding (institution): Boehringer Ingelheim; Research grant/Funding (institution): Puma Biotechnology; Research grant/Funding (institution): Zenith Epigenetics; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy: Puma Biotechnology; Travel/Accommodation/Expenses: Pierre Fabre; Travel/Accommodation/Expenses: Eisai. B. Bermejo De Las Heras: Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy: Palex; Advisory/Consultancy: MSD; Advisory/Consultancy: Novartis; Advisory/Consultancy: Pfizer. X. González-Farré: Advisory/Consultancy: SOLTI Breast Cancer Group; Advisory/Consultancy, Non-remunerated activity/ies: Roche; Advisory/Consultancy: Eisai. P. Villagrasa: Honoraria (self): NanoString. A. Prat: Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Roche; Honoraria (self), Advisory/Consultancy: MSD Oncology; Honoraria (self), Advisory/Consultancy: Lilly; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Daiichi Sankyo; Advisory/Consultancy, Research grant/Funding (self): NanoString Technologies; Advisory/Consultancy: Oncolytics Biotech; Advisory/Consultancy: Amgen; Advisory/Consultancy: Puma. All other authors have declared no conflicts of interest.