Carboplatin plus taxanes are non-inferior to epirubicin plus cyclophosphamide followed by taxanes as adjuvant chemotherapy for early triple-negative breast cancer

Du, Feng; Wang, Wenmiao; Wang, Yongsheng; Li, Ming; Zhu, Anjie; Wang, Jiayu; Cai, Rong; Ma, Fei; Fan, Ying; Li, Qing; Zhang, Pin; Todorović, Vladimir; Yuan, Peng; Xu, Binghe

doi:10.1007/s10549-020-05648-9

Cited by 30 publications

(26 citation statements)

References 34 publications

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“…In conclusion, we show that low dose prexasertib can sensitize carboplatin-resistant TNBC to carboplatin. We believe that this combination could potentially bring the remarkable benefits of responders to carboplatin 8,47,48 , to the majority of basal-like TNBC, providing more options to these otherwise difficult-totreat tumors.…”

Section: Discussionmentioning

confidence: 99%

The mitotic checkpoint is a targetable vulnerability of carboplatin-resistant triple negative breast cancers

Moens

Zhao

Baietti

et al. 2021

Sci Rep

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Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, lacking effective therapy. Many TNBCs show remarkable response to carboplatin-based chemotherapy, but often develop resistance over time. With increasing use of carboplatin in the clinic, there is a pressing need to identify vulnerabilities of carboplatin-resistant tumors. In this study, we generated carboplatin-resistant TNBC MDA-MB-468 cell line and patient derived TNBC xenograft models. Mass spectrometry-based proteome profiling demonstrated that carboplatin resistance in TNBC is linked to drastic metabolism rewiring and upregulation of anti-oxidative response that supports cell replication by maintaining low levels of DNA damage in the presence of carboplatin. Carboplatin-resistant cells also exhibited dysregulation of the mitotic checkpoint. A kinome shRNA screen revealed that carboplatin-resistant cells are vulnerable to the depletion of the mitotic checkpoint regulators, whereas the checkpoint kinases CHEK1 and WEE1 are indispensable for the survival of carboplatin-resistant cells in the presence of carboplatin. We confirmed that pharmacological inhibition of CHEK1 by prexasertib in the presence of carboplatin is well tolerated by mice and suppresses the growth of carboplatin-resistant TNBC xenografts. Thus, abrogation of the mitotic checkpoint by CHEK1 inhibition re-sensitizes carboplatin-resistant TNBCs to carboplatin and represents a potential strategy for the treatment of carboplatin-resistant TNBCs.

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Section: Discussionmentioning

confidence: 99%

The mitotic checkpoint is a targetable vulnerability of carboplatin-resistant triple negative breast cancers

Moens

Zhao

Baietti

et al. 2021

Sci Rep

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“…PATTERN trial reported that 6 cycles of “TPt” regimen(paclitaxel plus carboplatin) gained a better survival in eTNBC, compared with a standard-dose regimen of 3FEC (fluorouracil, epirubicin, and cyclophosphamide) -3T (docetaxel) 21 . Similarly, Du et al demonstrated that six cycles of TPt regimen was non-inferior to a standard 4EC-4T regimen 22 . With increasing and conflicting results reported by different trials, we conducted the present meta-analysis of RCTs to evaluate the controversial value on the survival of eTNBC for Pt-based regimens.…”

Section: Introductionmentioning

confidence: 95%

Survival benefit of platinum-based regimen in early stage triple negative breast cancer: A meta-analysis of randomized controlled trials

Bian

Wen

et al. 2021

npj Breast Cancer

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Platinum (Pt)-based chemo-regimens have been proved effective in neoadjuvant and salvage chemotherapy of triple negative breast cancer (TNBC). However, the survival benefit of Pt-based regimens in early stage TNBC(eTNBC) treatment has remained unclear. We conducted a meta-analysis to explore its role in improving the clinical outcomes of eTNBC. We carried out a comprehensive literature search on 15 March 2021 for randomized controlled trials (RCTs) comparing ajuvant/neoadjuvant Pt-based and Pt-free chemo-regimens in eTNBC patients, according to PRISMA 2020. We extracted the survival data and utilized the STATA software to calculate the summarized hazard ratios (HRs) and 95% confidence interval (95% CI) for overall survival (OS) and disease-free survival (DFS). Seven eligible RCTs enrolling a total of 2,027 eTNBC patients were identified in this meta-analysis, with 1,007 receiving Pt-free regimens, and the other 1,020 patients receiving Pt-based regimens, respectively. Patients in Pt-based regimens arm were associated with significant improved DFS (HR = 0.70, 95% CI: 0.58–0.84), and OS (HR = 0.78, 95% CI: 0.61–1.00). The survival benefits of DFS remained consistent in both the two strategies of Pt usage, either adding Pt to standard anthracyclines&taxanes based regimens (A&T + Pt), or combination of Pt and taxanes alone (TPt). The survival benefits also remained consistent in either neoadjuvant or adjuvant use of Pt. The present meta-analysis of RCTs revealed that Pt-based chemo-regimens could significantly improve both DFS and OS for eTNBC patients. Based on efficiency and toxicity, we recommend Pt-based regimens for eTNBC, especially the “A&T + Pt” mode if the toxicities are tolerable, which may lead TNBC therapy into a new era.

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“…Both regimens were repeated every 3 weeks. The above study indicated non-inferiority of carboplatin plus taxanes to epirubicin plus cyclophosphamide followed by taxanes (TP vs. EC-T, 5-year DFS = 84.4 vs. 85.8%; absolute difference: 1.4%, 95% CI −5.3–8.1%; p = 0.034) as adjuvant chemotherapy for early TNBC ( Du et al, 2020 ).…”

Section: Progress Of Adjuvant Research On Pt Derivatives In Combination With Taxanesmentioning

confidence: 79%

“…In a phase II trial, a subset of randomly assigned chemotherapy-naïve patients with TNBC after surgery received six cycles of taxane and platinum (TP) regimen (docetaxel: 75 mg/m 2 or paclitaxel 175 mg/m 2 ; carboplatin AUC = 5, day 1) or epirubicin, cyclophosphamide, and taxane (EC-T) regimen (4 cycles of epirubicin: 90 mg/m 2 ; cyclophosphamide: 600 mg/m 2 , day 1 accompanied with four cycles of docetaxel 75 mg/m 2 or paclitaxel 175 mg/m 2 , day 1) ( Du et al, 2020 ). Both regimens were repeated every 3 weeks.…”

Section: Progress Of Adjuvant Research On Pt Derivatives In Combination With Taxanesmentioning

confidence: 99%

Platinum and Taxane Based Adjuvant and Neoadjuvant Chemotherapy in Early Triple-Negative Breast Cancer: A Narrative Review

Tian

Tan

et al. 2021

Front. Pharmacol.

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Platinum (Pt) derivatives such as cisplatin and carboplatin are the class of drugs with proven activity against triple-negative breast cancer (TNBC). This is due to the ability of Pt compounds to interfere with the DNA repair mechanisms of the neoplastic cells. Taxanes have been efficacious against estrogen receptor-negative tumors and act by disruption of microtubule function. Due to their distinct mechanisms of action and routes of metabolism, the combination of the Pt agents and taxanes results in reduced systemic toxicity, which is ideal for treating TNBC. Also, the sensitivity of BRCA1-mutated cells to taxanes remains unsolved as in vitro evidence indicates resistance against taxanes due to BRCA1 mutations. Recent evidence suggests that the combination of carboplatin and paclitaxel resulted in better pathological complete response (pCR) in patients with TNBC, both in neoadjuvant and adjuvant settings. In vitro studies showed sequential dependency and optimal time scheduling of Pt- and taxane-based chemotherapy. Also, combining carboplatin with docetaxel in the NAC regimen yields an excellent pCR in patients with BRCA-associated and wild-type TNBC. TNBC is a therapeutic challenge that can be tackled by identifying new therapeutic sub-targets and specific cross-sections that can be benefitted from the addition of Pt- and taxane-based chemotherapy. This review summarizes the merits as well as the mechanism of Pt- and taxane-based adjuvant and neoadjuvant chemotherapies in early TNBC from the available and ongoing clinical studies.

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Carboplatin plus taxanes are non-inferior to epirubicin plus cyclophosphamide followed by taxanes as adjuvant chemotherapy for early triple-negative breast cancer

Cited by 30 publications

References 34 publications

The mitotic checkpoint is a targetable vulnerability of carboplatin-resistant triple negative breast cancers

The mitotic checkpoint is a targetable vulnerability of carboplatin-resistant triple negative breast cancers

Survival benefit of platinum-based regimen in early stage triple negative breast cancer: A meta-analysis of randomized controlled trials

Platinum and Taxane Based Adjuvant and Neoadjuvant Chemotherapy in Early Triple-Negative Breast Cancer: A Narrative Review

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