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
4401 - Real-world effectiveness of first-line palbociclib + letrozole for metastatic breast cancer 4 years post approval in the US
Presenter: Jonathan Kish
Session: Poster Display session 2
Resources:
Abstract
5876 - Palbociclib-Fulvestrant (PALBO-FUL) and Everolimus -Exemestane (EVE-EXE) for Second line Hormonal Treatment (HT) of Metastatic Breast Cancer (MBC) with Lobular Histology: a Propensity Score Matched Analysis of a Multicenter ‘Real-World’ Patients (pts) Series.
Presenter: Armando Orlandi
Session: Poster Display session 2
Resources:
Abstract
3587 - Dose-escalation study of G1T48, an oral selective estrogen receptor degrader (SERD), in postmenopausal women with ER+/HER2- locally advanced or metastatic breast cancer (ABC)
Presenter: E Dees
Session: Poster Display session 2
Resources:
Abstract
5696 - Final results of the STEM trial: SFX-01 in the Treatment and Evaluation of ER+ Her2- Metastatic breast cancer (mBC)
Presenter: Sacha Howell
Session: Poster Display session 2
Resources:
Abstract
1475 - Alpelisib (ALP) + Fulvestrant (FUL) in Hormone-Receptor Positive (HR+), Human Epidermal Growth Factor Receptor-2–Negative (HER2–) Advanced Breast Cancer (ABC): Subgroup Analysis by Presence of Visceral Metastasis (VM) in the SOLAR-1 Trial
Presenter: Mario Campone
Session: Poster Display session 2
Resources:
Abstract
2549 - Phase 1 Dose Escalation Study of a Selective Androgen Receptor Modulator RAD140 in Estrogen Receptor Positive (ER+), HER2 Negative (HER2-) Breast Cancer (BC)
Presenter: Erika Hamilton
Session: Poster Display session 2
Resources:
Abstract
3787 - A Phase I study of XZP-3287, a novel oral CDK4/6 Inhibitor, administered on a continuous dosing schedule, in patients with advanced solid tumours
Presenter: Binghe Xu
Session: Poster Display session 2
Resources:
Abstract
4835 - Phase-I dose-escalation and expansion study of the PARP inhibitor, fluzoparib (SHR3162), in patients with advanced solid tumors
Presenter: Huiping Li
Session: Poster Display session 2
Resources:
Abstract
5083 - Phase 2 study of DHP107 (Liporaxel®, oral paclitaxel) in first-line, HER2 negative recurrent/metastatic breast cancer (OPTIMAL study, NCT03315364)
Presenter: Jin-Hee Ahn
Session: Poster Display session 2
Resources:
Abstract
2674 - Multicenter Phase I Trial of Trastuzumab Emtansine (T-DM1) in Combination with Non-Pegylated Liposomal Doxorubicin (NPLD) in HER2[+] Metastatic Breast Cancer (MBC). THELMA Study
Presenter: Elena López-Miranda
Session: Poster Display session 2
Resources:
Abstract