Ruigang Cai

Docetaxel–cisplatin might be superior to docetaxel–capecitabine in the first-line treatment of metastatic triple-negative breast cancer

BACKGROUND Triple-negative breast cancer (TNBC) may be more sensitive to platinum. This study was to compare platinum-based regimen with nonplatinum regimen in the first-line treatment of advanced TNBC. PATIENTS AND METHODS Eligible metastatic TNBC (mTNBC) women without prior treatment for advanced disease were randomized (1 : 1) to receive either docetaxel-cisplatin (TP) or docetaxel -capecitabine (TX) q3w for up to 6 cycles, until disease progression or unacceptable toxicity. The primary end point was objective response rate (ORR) and the secondary end points included progression-free survival (PFS) and overall survival (OS). In total 53 patients were enrolled. RESULTS The median follow-up was 24 months. ORR was higher in the TP group than in the TX group (63.0% versus 15.4%, P = 0.001). PFS was more than doubled (10.9 months versus 4.8 months, P < 0.001) and median OS was also greatly improved (32.8 months versus 21.5 months, P = 0.027). Toxic effects were not different except G3/4 vomiting and G2/3 hand-foot syndrome. CONCLUSIONS This study suggested that cisplatin-based chemotherapy was superior to capecitabine-based regimen in the first-line treatment of mTNBC, as measured by ORR, PFS and OS. Further large-scale study should be warranted. These results are not sufficient to change clinical practice.

Circulating miR-19a and miR-205 in Serum May Predict the Sensitivity of Luminal A Subtype of Breast Cancer Patients to Neoadjuvant Chemotherapy with Epirubicin Plus Paclitaxel

Background The luminal A subtype of breast cancer has a good prognosis and is sensitive to endocrine therapy but is less sensitive to chemotherapy. It is necessary to identify biomarkers to predict chemosensitivity and avoid over-treatment. We hypothesized that miRNAs in the serum might be associated with chemosensitivity. Methods Sixty-eight breast cancer patients received neoadjuvant chemotherapy with epirubicin plus paclitaxel. The serum of the patients was collected before chemotherapy and stored at −80°C. The samples were classified into two groups in term of the chemosensitivity. We identified the differential expression patterns of miRNAs between the chemotherapy sensitive and resistant groups using microRNA profiling. Four miRNAs that were differentially expressed between the two groups were further validated in another 56 samples. We created a model fitting formula and a receiver operating characteristics (ROC) curve using logistic regression analysis to evaluate the prediction potency. Results We identified 8 miRNAs differentially expressed between the two groups: 6 miRNAs were up-regulated, and 2 miRNAs were down-regulated in the resistant group compared with the sensitive group. The expression of miR-19a and miR-205 were determined to have significant differences between the two groups (P<0.05). A predictive model of these two miRNAs was created by the logistic regression analysis. The probability of this model was 89.71%. Based on the ROC curve, the specificity was 75.00%, and the sensitivity was 81.25%. Conclusions The combination of miR-19a and miR-205 in the serum may predict the chemosensitivity of luminal A subtype of breast cancer to epirubicin plus paclitaxel neoadjuvant chemotherapy.

Prospective Study of Vinorelbine and Capecitabine Combination Therapy in Chinese Patients with Metastatic Breast Cancer Pretreated with Anthracyclines and Taxanes

Aims: This phase II study prospectively evaluated the feasibility of vinorelbine in combination with capecitabine in Chinese patients with metastatic breast cancer (MBC) pretreated with anthracyclines and taxanes. Methods: Vinorelbine (25 mg/m2 intravenous infusion on days 1 and 8) and capecitabine (1,000 mg/m2 b.i.d., days 1–14) were administered to eligible MBC patients previously treated with anthracyclines and taxanes every 3 weeks for up to 6 cycles, until disease progression or unacceptable toxicity. The primary endpoint was objective response. Results: Seventy-two patients were enrolled. In total, 297 cycles were given (median 4 cycles, range 2–6). The overall response rate was 45.8% (95% CI 34.2–57.4%), including 5 complete (6.9%) and 28 partial responses (38.9%). With median follow-up of 22 months, median time to progression was 7.7 months (95% CI 5.5–10.0) and median survival was 26.1 months (95% CI 19.6–32.6). The response rate was 53.8% in patients resistant to anthracyclines and taxanes combination. The most common hematologic adverse events were leukopenia (81.9%) with grade 3/4 incidence of 41.7%; nausea was the most frequent non-hematologic toxicity (62.5%). Hand-foot syndrome occurred in 12.5% of patients, and diarrhea was rare. Conclusions: Capecitabine 1,000 mg/m2 b.i.d. combined with vinorelbine 25 mg/m2 is an effective and safe treatment for MBC patients, no matter if anthracycline and taxane pretreated or resistant.

Capecitabine combined with docetaxel versus vinorelbine followed by capecitabine maintenance medication for first‐line treatment of patients with advanced breast cancer: Phase 3 randomized trial

In this prospective study, progression‐free survival (PFS) and the safety profiles of docetaxel/capecitabine (TX) and vinorelbine/capecitabine (NX) followed by capecitabine maintenance therapy were compared in patients with metastatic breast cancer.

Phase I Study and Biomarker Analysis of Pyrotinib, a Novel Irreversible Pan-ErbB Receptor Tyrosine Kinase Inhibitor, in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer

Purpose This phase I study assessed the safety, tolerability, pharmacokinetics, antitumor activity, and predictive biomarkers of pyrotinib, an irreversible pan-ErbB inhibitor, in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. Patients and Methods Pyrotinib was administered continuously, orally, once per day to patients who did not have prior exposure to tyrosine kinase inhibitors of HER2. Planned dose escalation was 80, 160, 240, 320, 400, and 480 mg. For pharmacokinetic analysis, timed blood samples were collected on day 1 and day 28. Next-generation sequencing was performed on circulating tumor DNA and genomic DNA from tumor samples. Results Thirty-eight patients were enrolled. The dose-limiting toxicity was grade 3 diarrhea, which occurred in two patients administered 480 mg of pyrotinib; thus, the maximum tolerated dose was 400 mg. Common pyrotinib-related adverse events included diarrhea (44.7% [17 of 38]), nausea (13.2% [five of 38]), oral ulceration (13.2% [five of 38]), asthenia (10.5% [four of 38]), and leukopenia (10.5% [four of 38]). The only grade 3 adverse event was diarrhea. Pharmacokinetic analyses indicated that pyrotinib exposure was dose dependent. The overall response rate was 50.0% (18 of 36), and the clinical benefit rate (complete response + partial response + stable disease ≥ 24 weeks) was 61.1% (22 of 36). The median progression-free survival was 35.4 weeks (95% CI, 23.3 to 40.0 weeks). The overall response rate was 83.3% (10 of 12) in trastuzumab-naive patients and 33.3% (eight of 24) in trastuzumab-pretreated patients. Preliminary results suggest that PIK3CA and TP53 mutations in circulating tumor DNA ( P = .013) rather than in archival tumor tissues ( P = .474) may predict the efficacy of pyrotinib. Conclusion Continuous once-per-day pyrotinib was well tolerated and demonstrated promising antitumor activity in HER2-positive patients with metastatic breast cancer. The maximum tolerated dose was established as 400 mg. Diarrhea was the dose-limiting toxicity. The promising antitumor activity and acceptable tolerability of pyrotinib warrant its further evaluation in a phase II study.

HER2 as a predictive factor for successful neoadjuvant anthracycline chemotherapy of locally advanced and early breast cancer

Objective The aim of this study was to look for predictive and prognostic factors in anthracycline-based neoadjuvant chemotherapy. Methods Three hundred and nine patients with early-stage or locally advanced breast cancer were enrolled in this study and preoperatively treated with neoadjuvant chemotherapies in intense dose-dense (cyclophosphamide + epirubicin) or conventional (paclitaxel + epirubicin) regimens. Outcome parameters included overall objective response rate, as well as factors for determining pathological features influencing the efficacy of chemotherapy, such as estrogen receptor, progesterone receptor, and HER2 status, Eastern Cooperative Oncology Group (ECOG) score, tumor size, tumor inflammation, and lymph node metastasis. Results The overall pathological complete response (pCR) rate was 14.3%, and the main factor affecting the efficacy of chemotherapy was HER2 expression. The pCR rate was significantly higher for patients with HER2 overexpression, compared with patients with low HER2 expression (27.5% vs. 9.6%, p<0.001). The recurrence risk for patients with pCR decreased 1.12-fold compared with patients without pCR (5-year disease-free survival [DFS]: 81.8% vs. 65.7%, p=0.038). Patients in the HER2 overexpression subgroup benefited more from pCR than those in the HER2 low expression group (5-year DFS: 86.4% vs. 62.1%, p=0.049). Conclusion HER2 overexpression in primary tumors might be a predictive marker for good efficacy of anthracycline-based neoadjuvant chemotherapy. The pCR is a suitable prognostic factor, even for patients with HER2 overexpression.

Phase I safety and pharmacokinetic study of cipatinib, an original dual tyrosine kinase inhibitor: Phase I clinical trial of cipatinib

Cipatinib is a novel tyrosine kinase inhibitor against both EGFR and HER2/neu. This phase I trial was conducted to assess the safety, dose‐limiting toxicities (DLTs), and maximum‐tolerated dose of cipatinib in HER2‐positive patients with advanced breast cancer.

Toremifene, rather than tamoxifen, might be a better option for the adjuvant endocrine therapy in CYP2D6*10T/T genotype breast cancer patients in China: Toremifene is a better option for the adjuvant endocrine therapy

Toremifene (TOR) is a valid and safe alternative to tamoxifen (TAM) for adjuvant endocrine therapy in breast cancer patients with a metabolic pathway that differs from that of TAM. TOR might have a therapeutic advantage in certain subgroups of patients, such as Chinese women with the CYP2D6 *10 (c.100C > T) T/T genotype, who would get less benefit when receiving adjuvant TAM treatment. A total of 230 breast cancer patients who received adjuvant TAM (n = 115) or TOR (n = 115) at the National Cancer Center were analyzed. The CYP2D6 *10 genotype was not significantly associated with DFS in patients who received TOR (p = 0.737). Patients treated with TOR had a higher 5‐year disease‐free survival (DFS) rate than those treated with TAM (89.6% vs. 80.9%, p = 0.009). TOR treatment remained an independent prognostic marker of DFS in multivariate analysis compared with TAM (hazard ratio = 0.51; p = 0.014). For all of the 50 CYP2D6 *10 T/T genotype patients, TOR treatment group had a significantly higher 5‐year DFS rate than TAM group (90.9% vs. 67.9%, p = 0.031). For the remaining 170 CYP2D6 *10 C/C or C/T genotype patients, there was no significant difference between the 5‐year DFS rates of the TOR and TAM groups (89.2% vs. 85.1%, p = 0.188). The advantage of adjuvant TOR over TAM in Chinese breast cancer patients might be caused by the significant benefit obtained by the CYP2D6 *10 T/T patients, who accounted for one‐fifth of the overall population. TOR might be a good option for adjuvant endocrine therapy in this subgroup of patients in China.

Timing of paclitaxel treatment in pre-operative or post-operative does not affect survival in breast cancer patients

Two epirubicin and paclitaxel‐based neoadjuvant chemotherapy regimens were compared in breast cancer patients.