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

Probody® therapeutics (Pb-Tx) are masked antibodies designed to be conditionally activated in the tumor microenvironment by tumor-associated proteases. This allows Pb-Tx to address previously undruggable targets (eg, CD166) that are highly expressed in both tumor and normal tissue. CX-2009 is a Probody drug conjugate of a masked anti-CD166 monoclonal antibody conjugated to DM4. A phase I CX-2009 monotherapy study showed safety and durable clinical activity (clinical benefit rate at 24 weeks [CBR24] 35%) in patients (pts) with mHR+/HER2− BC or mTNBC. Pacmilimab, a Probody PD-L1 inhibitor, showed acceptable safety in a recent phase I study.

Trial design

This phase II, open-label study with 3 parallel arms (n≈40/arm) will evaluate CX-2009 monotherapy (7 mg/kg Q3W) in pts with mHR+/HER2− BC or mTNBC, and CX-2009 (7 mg/kg Q3W) combined with pacmilimab (1200 mg Q3W) in pts with mTNBC. Adult pts with an ECOG PS of 0–1, measurable disease, and willingness to receive ocular prophylaxis for DM4-related toxicities will be enrolled. Key eligibility criteria for the mHR+/HER2− BC cohort include 2–4 metastatic prior regimens (excluding single-agent hormonal therapy). HR+/HER2− BC cohorts will enroll without screening for CD166. Pts with mTNBC must be CD166+ by IHC and have received 1–3 prior metastatic regimens. For mTNBC pts who receive the doublet, key exclusion criteria include known PD-L1–negative tumor status, history of or active autoimmune disease, and progression within 120 days of 1^st dose of an immuno-oncology agent. Pts with corneal disorders will be excluded. The primary endpoint is overall response rate (ORR) assessed by an independent radiology committee per RECIST v1.1. Secondary endpoints include ORR by investigator, duration of response, CBR16 & 24, progression-free survival, and overall survival. This study will also evaluate safety and tolerability, pharmacokinetics, and antidrug antibodies with CX-2009 as monotherapy and in combination with pacmilimab. This trial is enrolling (NCT04596150).

Clinical trial identification

NCT04596150.

Editorial acknowledgement

Mark Phillips, PharmD, MBA, CMPP of Phillips Gilmore Oncology Communications, Inc., Philadelphia, PA, USA provided medical editing assistance, which was funded by CytomX.

Legal entity responsible for the study

CytomX Therapeutics, Inc., South San Francisco, CA, USA.

Funding

CytomX Therapeutics, Inc., South San Francisco, CA, USA.

Disclosure

K.D. Miller: Research grant/Funding (institution): CytomX. L.A. Emens: Licensing/Royalties: Aduro; Licensing/Royalties: IND; Honoraria (self), Advisory/Consultancy: AbbVie; Honoraria (self), Advisory/Consultancy: Amgen; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Bayer; Advisory/Consultancy, Travel/Accommodation/Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy: Celgene; Honoraria (self), Advisory/Consultancy: Chugai; Advisory/Consultancy, no compensation: CytomX; Advisory/Consultancy, no compensation: eTHeRNA; Advisory/Consultancy, Travel/Accommodation/Expenses: Genentech; Honoraria (self), Advisory/Consultancy: Gritstone; Honoraria (self), Advisory/Consultancy: MedImmune; Honoraria (self), Advisory/Consultancy: Molecuvax; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Macrogenics; Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Honoraria (self), Advisory/Consultancy: Peregrine; Honoraria (institution), Advisory/Consultancy, Travel/Accommodation/Expenses: Replimune; Advisory/Consultancy, Travel/Accommodation/Expenses: Roche. S.M. Tolaney: Research grant/Funding (institution): CytomX; Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy: Eli Lilly; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Merck; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Nektar; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Genentech/Roche; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Immunomedics; Research grant/Funding (institution): Exelixis; Honoraria (self), Research grant/Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Eisai; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): NanoString; Honoraria (self): Puma; Research grant/Funding (institution): Cyclacel; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Sanofi; Honoraria (self), Advisory/Consultancy: Celldex; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Odonate; Honoraria (self), Advisory/Consultancy: Seattle Genetics; Honoraria (self), Advisory/Consultancy: Silverback Therapeutics. S.A. Hurvitz: Research grant/Funding (institution): Ambrx; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Arvinas; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Daiichi Sankyo; Research grant/Funding (institution): Genentech/Roche; Research grant/Funding (institution): GSK; Research grant/Funding (institution): Immunomedics; Research grant/Funding (institution): Lilly; Research grant/Funding (institution): Macrogenics; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): OBI Pharma; Research grant/Funding (institution): Pieris; Research grant/Funding (institution): PUMA; Research grant/Funding (institution): Radius; Research grant/Funding (institution): Sanofi; Research grant/Funding (institution): Seattle Genetics; Research grant/Funding (institution): Dignitana; Advisory/Consultancy, Shareholder/Stockholder/Stock options: NKMax. E. Hamilton: Research grant/Funding (institution): Seattle Genetics; Research grant/Funding (institution): Puma; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): CytomX; Research grant/Funding (institution): Hutchinson; Research grant/Funding (institution): MediPharma; Research grant/Funding (institution): OncoMed; Research grant/Funding (institution): MedImmune; Research grant/Funding (institution): StemCentrx; Research grant/Funding (institution): Genentech/Roche; Research grant/Funding (institution): Curis; Research grant/Funding (institution): Verastem; Research grant/Funding (institution): Zymeworks; Research grant/Funding (institution): Syndax; Research grant/Funding (institution): Lycera; Research grant/Funding (institution): Rgenix; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Mersana; Research grant/Funding (institution): Millenium; Research grant/Funding (institution): TapImmune. V. Paton, A.L. Hannah: Full/Part-time employment: CytomX. V. Boni: Research grant/Funding (institution): Loxo; Research grant/Funding (institution): Lilly; Research grant/Funding (institution): Sanofi; Research grant/Funding (institution): Roche/Genentech; Research grant/Funding (institution): Zenith Therapeutics; Research grant/Funding (institution): Tesaro; Research grant/Funding (institution): CytomX; Research grant/Funding (institution): Puma; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Menarini; Research grant/Funding (institution): Seattle Genetics; Research grant/Funding (institution): Daiichi Sankyo; Honoraria (self), Advisory/Consultancy: Guidepoint; Honoraria (self), Advisory/Consultancy: Oncoart.