Abstract 4776
Background
Breast cancer is the second most diagnosed cancer globally accounting for over 2 million new worldwide cases of the disease in 2017. Chemotherapy (including cyclophosphamide and anthracyclines) is the mainstay for triple-negative breast cancer (TNBC) treatment. Despite high rates of responses to neoadjuvant chemotherapy, TNBC patients experience high rates of distant recurrence and less than 30% of patients with metastatic disease treated with chemotherapy will survive 5 years. These poor cancer patient outcomes highlight the need for novel companion diagnostics and therapies to identify the patients who will derive benefit and improve the response to therapy. Herein, we have identified ‘cell division cycle associated protein 3’ (CDCA3) as a novel protein that may prove useful to enhance chemotherapy response in TNBC.
Methods
Bioinformatics, Western blot, immunohistochemistry, siRNA depletion of CDCA3, CRISPR-Cas9 knockout, dose response, cell viability.
Results
CDCA3 transcripts are elevated across increasing grades of breast cancer, TNBC versus non-TNBC and in basal-like (BLIA and BLIS) versus luminal-AR and mesenchymal TNBC subtypes (METABRIC datasets). Elevated CDCA3 levels were strongly prognostic for patient outcome in high grade breast cancer and TNBC. Tissue microarray (TMA) immunohistochemistry analysis of over 300 breast cancers indicated heterogeneous CDCA3 staining is strongly prognostic in Ki67+ and TNBC cases of disease. CDCA3 staining correlated with markers of poor prognosis (nuclear grade, mitotic score, nuclear pleomorphism) and was associated with a poor prognosis. In vitro, we identified that, consistent with clinical data, CDCA3 levels were elevated in TNBC versus non-TNBC cell lines. In 10 TNBC cell lines, endogenous CDCA3 expression correlated with sensitivity to both cisplatin and doxorubicin, with CDCA3high levels having higher IC50 values and thereby being associated with a poor prognosis. Consistently, depleting these cells of CDCA3 markedly enhanced sensitivity to both cisplatin and doxorubicin.
Conclusions
Our data highlight CDCA3 as a novel prognostic factor in TNBC that modulates sensitivity to chemotherapy. These findings point to the therapeutic potential of targeting CDCA3 in TNBC.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
5793 - Real world treatment sequencing patterns in secondary breast cancer (SBC): Pathway visualisation using national datasets.
Presenter: Ashley Horne
Session: Poster Display session 2
Resources:
Abstract
3185 - Utilization Pattern of Bone Targeting Agents in Patients with Solid Tumor in Taiwan, Hong Kong and Korea
Presenter: Shi Jie Lai
Session: Poster Display session 2
Resources:
Abstract
3705 - Clinico-pathological Features and Prognosis of Patients with Pregnancy Associated Breast Cancer – A Matched Case Control Study
Presenter: Ruyan Zhang
Session: Poster Display session 2
Resources:
Abstract
1421 - TRYbeCA-2: A Randomized Phase 2/3 Study of Eryaspase in Combination with Gemcitabine and Carboplatin Chemotherapy versus Chemotherapy Alone As First-Line Treatment in Patients with Metastatic or Locally Recurrent Triple-Negative Breast Cancer
Presenter: Ahmad Awada
Session: Poster Display session 2
Resources:
Abstract
4119 - CONTESSA TRIO: A Multinational, Multicenter, Phase 2 Study of Tesetaxel plus 3 Different PD-(L)1 Inhibitors in Patients with Metastatic Triple-Negative Breast Cancer (TNBC) and Tesetaxel Monotherapy in Elderly Patients with HER2- Metastatic Breast Cancer (MBC)
Presenter: Sara Tolaney
Session: Poster Display session 2
Resources:
Abstract
4545 - Bintrafusp alfa (M7824) and Eribulin Mesylate in Treating Patients With Metastatic Triple Negative Breast Cancer (TNBC)(NCT03579472)
Presenter: Jennifer Litton
Session: Poster Display session 2
Resources:
Abstract
3340 - Effectiveness of Olaparib Plus Trastuzumab in HER2[+], BRCA–mutated (BRCAm) or Homologous Recombination Deficient (HRD) Advanced Breast Cancer (ABC) patients (pts). The OPHELIA Study
Presenter: José Enrique Alés-Martínez
Session: Poster Display session 2
Resources:
Abstract
1113 - RIBOB : A Study on the efficacy and safety of Ribociclib in combination with letrozole in Older women (≥70 years) with hormone receptor-positive (HR+) HER2-negative (HER2-) advanced Breast cancer (aBC) with no prior systemic therapy for advanced disease
Presenter: Cindy Kenis
Session: Poster Display session 2
Resources:
Abstract
4025 - RIbociclib plus Goserelin with Hormonal Therapy versus physician Choice chemotherapy in premenopausal or perimenopausal patients with HR+, HER2– inoperable locally advanced or metastatic breast cancer – RIGHT Choice study
Presenter: Nagi El Saghir
Session: Poster Display session 2
Resources:
Abstract
3516 - Palbociclib Rechallenge in Hormone Receptor (HR)[+]/HER2[-] Advanced Breast Cancer (ABC). PALMIRA Trial
Presenter: Antonio Llombart Cussac
Session: Poster Display session 2
Resources:
Abstract