Qiao Li

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.

ctDNA dynamics: a novel indicator to track resistance in metastatic breast cancer treated with anti-HER2 therapy

Background Most studies utilizing circulating tumor DNA (ctDNA) to monitor disease interrogated only one or a few genes and failed to develop workable criteria to inform clinical practice. We evaluated the feasibility of detecting resistance to anti-HER2 therapy by serial gene-panel ctDNA sequencing. Results Primary therapeutic resistance was identified in 6 out of 14 patients with events of progressive disease. For this subset comparison of pre- and post-treatment ctDNA assay results revealed that HER2 amplification concurred with disease progression (4/6, 66.7%). Mutations in TP53 (3/6, 50.0%) and genes implicated in the PI3K/mTOR pathway (3/6, 50.0%) were also dominant markers of resistance. Together, resistance to HER2 blockade should be indicated during treatment if any of the following situations applies: 1) recurrence or persistence of HER2 amplification in the blood; 2) emergence or ≥20% increase in the fraction of mutations in any of these resistance-related genes including TP53/PIK3CA/MTOR/PTEN. Compared with CT scans, dynamic ctDNA profiling utilizing pre-defined criteria was sensitive in identifying drug resistance (sensitivity 85.7%, specificity 55.0%), with a concordance rate up to 82.1%. Besides, the ctDNA criteria had a discriminating role in the prognosis of HER2-positive metastatic breast cancer. Methods 52 plasma samples were prospectively collected from 18 patients with HER2-positive metastatic breast cancer who were treated with an oral anti-HER1/HER2 tyrosine kinase inhibitor (ClinicalTrials.gov NCT01937689). ctDNA was assayed by gene-panel target-capture next-generation sequencing. Conclusions Longitudinal gene-panel ctDNA sequencing could be exploited to determine resistance and guide the precise administration of anti-HER2 targeted therapy in the metastatic setting.

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.

Young breast cancer patients who develop distant metastasis after surgery have better survival outcomes compared with elderly counterparts

To investigate the recurrence pattern and subsequent survival outcomes in young breast cancer population, 483 young patients (≤ 35) and 739 elderly patients (≥ 65), who received mastectomy or breast-conserving surgery from 2008 to 2012, were included in this study. The young population presented with a higher rate of pathologic tumor stage (P < 0.001), positive pathologic lymph node (P < 0.001), grade III tumors (P < 0.001), and lymphovascular invasion (P < 0.001). With a median follow-up of 56.5 months, young patients had a significantly lower 5-year disease-free survival (73.7% vs 83.4%, P = 0.001), while no difference in 5-year overall survival was observed (91.7% vs 91.7%, P = 0.721). The 5-year cumulative incidences of locoregional relapse (8.9% vs 4.3%, P = 0.009) and distant metastasis (18.8% vs 9.5%, P < 0.001) were significantly higher in the young population. However, for patients with distant metastasis, the survival outcomes were significantly better in the young patients (5-year overall survival since diagnosis: 60.0% vs 47.3%, P = 0.025; 5-year overall survival after recurrence: 31.0% vs 24.3%, P = 0.001). Young breast cancer patients present with more aggressive clinicopathological features and have poor prognosis compared with elderly. But young patients with distant metastasis might have better survival outcomes.

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.

TNM stage at diagnosis is more predictive of prognosis than pathological complete response in young breast cancer treated with neoadjuvant chemotherapy

This study was carried out to investigate chemotherapy response and its relation with prognosis in young breast cancer patients who were treated with neoadjuvant chemotherapy (NCT). A total of 74 patients aged 35 years or less and 67 patients aged 60 years or more, who received NCT from January 2003 to December 2013, were included. Young patients presented a tendency to have a tumor size of more than 5 cm (P=0.085) and to have lymphovascular invasion (P= 0.007) compared with older counterparts. Pathological complete response (pCR) rates were similar between the young group and the old cohort (12.2 vs. 13.4%, P= 0.821). Patients in the younger group showed significantly lower 5-year disease-free survival compared with the old subset (62.2 vs. 77.8%, P= 0.037), but no significant difference in the 5-year overall survival was observed (84.0 vs. 94.8%, P= 0.212). In the group of young patients, pCR was not a significant predictor for diseasefree survival (P= 0.408), whereas significant differences were observed with respect to the ascending TNM (tumor–node–metastasis) stage at diagnosis (P= 0.001). Young breast cancer patients treated with NCTpresent more aggressive clinicopathological features and worse prognosis compared with their elderly counterparts. TNM stage at diagnosis may be more predictive of prognosis than pCR in young breast cancer patients treated with NCT. Anti-Cancer Drugs 29:176–183 Copyright