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
2551 - Efficacy of dose-dense (DD) adjuvant chemotherapy (CT) in hormone receptor positive/HER2-negative early breast cancer (BC) patients (pts) according to immunohistochemically (IHC) defined luminal subtypes: an exploratory analysis of the GIM2 trial.
Presenter: Benedetta Conte
Session: Poster Display session 2
Resources:
Abstract
3426 - High dose Neo-adjuvant chemotherapy in Triple-Negative breast cancer with evidence of homologous recombination deficiency (HRD).
Presenter: Sonja Vliek
Session: Poster Display session 2
Resources:
Abstract
3792 - Risk factors for locoregional recurrence (LRR) after neoadjuvant chemotherapy: pooled analysis of prospective neoadjuvant breast cancer (BC) trials
Presenter: Gustavo Werutsky
Session: Poster Display session 2
Resources:
Abstract
4044 - Estimating radiotherapy-induced cardiovascular mortality in female breast cancer patients.
Presenter: Mark De Ridder
Session: Poster Display session 2
Resources:
Abstract
719 - 3-year follow-up of a phase III trial comparing the efficacy and safety of neoadjuvant and adjuvant trastuzumab and its biosimilar CT-P6 in HER2 positive early breast cancer (EBC)
Presenter: Justin Stebbing
Session: Poster Display session 2
Resources:
Abstract
3595 - Adjuvant chemotherapy in elderly breast cancer patients: pattern of use and impact on overall survival
Presenter: Axel Berthelot
Session: Poster Display session 2
Resources:
Abstract
3992 - Carboplatin-containing neoadjuvant chemotherapy for triple negative breast cancer (TNBC): a propensity score-matched study.
Presenter: Maria Vittoria Dieci
Session: Poster Display session 2
Resources:
Abstract
3477 - Impact of adjuvant trastuzumab emtansine (T-DM1) on incidence of metastatic breast cancer (mBC): an epidemiological model of patients with HER2-positive breast cancer (BC) who did not achieve pathological complete response (pCR) after neoadjuvant treatment (non-pCR)
Presenter: Mellissa Williamson
Session: Poster Display session 2
Resources:
Abstract
3928 - Chemotherapy (CT)-induced anaemia in patients (pts) treated with dose-dense regimen: Results of the prospectively randomised anaemia substudy from the neoadjuvant GeparOcto study
Presenter: Hans Tesch
Session: Poster Display session 2
Resources:
Abstract
2184 - The clinical impact of adjuvant dose-dense sequential chemotherapy (dds-CT) in patients with high-risk operable breast cancer (BC); pooled analysis of 6 clinical trials.
Presenter: Elena Fountzilas
Session: Poster Display session 2
Resources:
Abstract