Cisplatin Plus Gemcitabine for Treatment of Breast Cancer Patients with Brain Metastases: a Preferential Option for Triple Negative Patients?

Erten, Çiğdem; Demir, Lutfiye; Somali, İşıl; Alacacıoğlu, Ahmet; Küçükzeybek, Yüksel; Akyol, Murat; Can, Alper; Dirican, Ahmet; Bayoğlu, Vedat; Tarhan, Mustafa Oktay

doi:10.7314/apjcp.2013.14.6.3711

Cited by 23 publications

(17 citation statements)

References 38 publications

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“…ORR for chemotherapy was recorded in 6 (53.3%) patients, and the median OS was 10 months [26]. Similar results were obtained by Erten et al [27]. In this study, 18 BC patients with BM who were treated with cisplatin 30 mg/m 2 (on days 1 and 8) + gemcitabine 1000 mg/m 2 (on days 1 and 8) IV every 21 days.…”

Section: Type Of Palliative Treatment Indicationssupporting

confidence: 75%

“…The overall survival rates of these study patients have not been reported. Median PFS also depended on the type of breast cancer and was greatest in patients with triple-negative breast cancer at 7.4 months (range 2.4-12.3 months); in patients with HER2-type at 5 months, with luminal types at 3.6 and 5.6 months (range 2.6-8.8 months) for all breast cancer molecular types [27].…”

Section: Type Of Palliative Treatment Indicationsmentioning

confidence: 99%

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Management of Brain Metastases from Solid Tumors

Любота¹,

Верещако²,

Anikusko³

et al. 2018

Cancer Management and Therapy

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Brain metastases (BM) are most common intracranial tumors in adults. Recently, significant progress has been shown in diagnosing, prognosis, and treating patients with BM of various malignant tumors. The treatment decisions must be based on the disease prognosis and include radiation therapy, surgery, systemic antitumor therapy, or a combination thereof. Systemic therapy capable of preventing BM or which affects both intracranial and extracranial disease is of paramount importance in the treatment of BM patients. The purpose of this chapter is to consider important prognostic factors that can determine treatment decisions, review the role of blood-brain barrier (BBB), and systemic anticancer treatment to manage BM from solid tumors.

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Section: Type Of Palliative Treatment Indicationssupporting

confidence: 75%

Section: Type Of Palliative Treatment Indicationsmentioning

confidence: 99%

Management of Brain Metastases from Solid Tumors

Любота¹,

Верещако²,

Anikusko³

et al. 2018

Cancer Management and Therapy

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“…Our findings are consistent with similar studies. One retrospective study demonstrated that the median PFS of six mTNBC patients with brain metastasis treated using GP was 7.4 months (95%CI, 2.4–12.3), whereas another study reported that the PFS of 17 mTNBC patients was 5.3 months . The results of the largest phase III trial using Gemcitabine and carboplatin as first‐, second‐ or third‐line treatments for mTNBC ( n = 258) showed that PFS was 4.1 months, OS was 11.1 months and ORR was 30% .…”

Section: Discussionmentioning

confidence: 99%

Cisplatin and gemcitabine as the first line therapy in metastatic triple negative breast cancer

Zhang

Wang

et al. 2014

Int. J. Cancer

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No standard first-line treatment exists for patients with metastatic triple-negative breast cancer (mTNBC). In this single-arm, phase II study (NCT00601159), we evaluated the efficacy and tolerability of cisplatin and gemcitabine (GP) as the first-line therapy in mTNBC. Eligible women were those who had measurable disease with no prior chemotherapy for mTNBC. All patients received 21-day-cycle of cisplatin 25 mg/m 2 on days 1-3 and gemcitabine 1,000 mg/m 2 on days 1 and 8. Treatment was continued until disease progression, unacceptable toxicity or up to 8 cycles. BRCA1/2 mutation status and immunohistochemical basal markers were included in the correlative studies. Sixty-four patients with the median age of 49 years were enrolled. Thirty patients (46.9%) had 1 year from diagnosis to recurrence. The median progression free survival (PFS) was 7.2 months (95%CI, 5.6-8.9 months) and overall survival (OS) was 19.1 months (95%CI, 12.4-25.8 months) with median follow-up 42 months. Patients received treatment for a median of six cycles. The overall response rate was 62.5%. The most common grades 3/4 toxicities were neutropenia (42.2%), thrombocytopenia (29.7%), anemia (18.8%) and nausea/vomiting (15.6%).No specific BRCA1/2 mutation carriers were identified. The efficacy of responses and basal-like subtype were independent favorable factors for PFS and OS, respectively. We conclude that the combination of GP has significant activity and a favorable safety profile as the first-line chemotherapy in mTNBC patients, in particular patients with basal-like subtype. The promising role of this combination as the front-line treatment for mTNBC continued to be evaluated in our ongoing phase III trial (CBCSG006).Triple-negative breast cancer (TNBC), 12-20% of all breast cancers, does not express the estrogen receptor (ER), progesterone receptor and the gene amplification of human epidermal growth factor receptor 2 (HER2).

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“…It is used in combination with other drugs for the treatment of locally advanced or metastatic non-small-cell lung cancer, bladder cancer, and ovarian cancer, and as a single agent for the treatment of adenocarcinoma of the pancreas 4. Clinical studies have also demonstrated its extensive activity against breast carcinomas, including male breast cancer,5 metastatic breast cancer, and triple-negative breast cancer 6,7. In recent years, gemcitabine resistance has emerged and has become a serious concern in clinical practice; however, the exact mechanism of gemcitabine resistance in breast cancer is still unknown.…”

Section: Introductionmentioning

confidence: 99%

Gemcitabine resistance in breast cancer cells regulated by PI3K/AKT-mediated cellular proliferation exerts negative feedback via the MEK/MAPK and mTOR pathways

Yang¹,

Lin²,

Guo³

et al. 2014

OTT

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Chemoresistance is a major cause of cancer treatment failure and leads to a reduction in the survival rate of cancer patients. Phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) and mitogen-activated protein kinase (MAPK) pathways are aberrantly activated in many malignant tumors, including breast cancer, which may indicate an association with breast cancer chemoresistance. In this study, we generated a chemoresistant human breast cancer cell line, MDA-MB-231/gemcitabine (simplified hereafter as “231/Gem”), from MDA-MB-231 human breast cancer cells. Flow cytometry studies revealed that with the same treatment concentration of gemcitabine, 231/Gem cells displayed more robust resistance to gemcitabine, which was reflected by fewer apoptotic cells and enhanced percentage of S-phase cells. Through the use of inverted microscopy, Cell Counting Kit-8, and Transwell assays, we found that compared with parental 231 cells, 231/Gem cells displayed more morphologic projections, enhanced cell proliferative ability, and improved cell migration and invasion. Mechanistic studies revealed that the PI3K/AKT/mTOR and mitogen-activated protein kinase kinase (MEK)/MAPK signaling pathways were activated through elevated expression of phosphorylated (p)-extracellular signal-regulated kinase (ERK), p-AKT, mTOR, p-mTOR, p-P70S6K, and reduced expression of p-P38 and LC3-II (the marker of autophagy) in 231/Gem in comparison to control cells. However, there was no change in the expression of Cyclin D1 and p-adenosine monophosphate-activated protein kinase (AMPK). In culture, inhibitors of PI3K/AKT and mTOR, but not of MEK/MAPK, could reverse the enhanced proliferative ability of 231/Gem cells. Western blot analysis showed that treatment with a PI3K/AKT inhibitor decreased the expression levels of p-AKT, p-MEK, p-mTOR, and p-P70S6K; however, treatments with either MEK/MAPK or mTOR inhibitor significantly increased p-AKT expression. Thus, our data suggest that gemcitabine resistance in breast cancer cells is mainly mediated by activation of the PI3K/AKT signaling pathway. This occurs through elevated expression of p-AKT protein to promote cell proliferation and is negatively regulated by the MEK/MAPK and mTOR pathways.

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Cisplatin Plus Gemcitabine for Treatment of Breast Cancer Patients with Brain Metastases: a Preferential Option for Triple Negative Patients?

Cited by 23 publications

References 38 publications

Management of Brain Metastases from Solid Tumors

Management of Brain Metastases from Solid Tumors

Cisplatin and gemcitabine as the first line therapy in metastatic triple negative breast cancer

Gemcitabine resistance in breast cancer cells regulated by PI3K/AKT-mediated cellular proliferation exerts negative feedback via the MEK/MAPK and mTOR pathways

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