Randomized phase III trial of a neoadjuvant regimen of four cycles of adriamycin plus cyclophosphamide followed by four cycles of docetaxel (AC4-D4) versus a shorter treatment of three cycles of FEC followed by three cycles of docetaxel (FEC3-D3) in node-positive breast cancer (Neo-shorter; NCT02001506).

PURPOSE: To determine whether six cycles of FEC3-D3 has a comparable efficacy to eight of AC4-D4. METHODS: The enrolled patients (pts) were clinically diagnosed with stage II or III breast cancer. The primary endpoint was a pathologic complete response (pCR), and the secondary endpoints were 3 year disease-free survival (3Y DFS), toxicities, and health-related quality of life (HRQoL). We calculated that 252 pts were needed in each treatment group to enable the detection of non-inferiority (non-inferiority margin of 10%). RESULTS: In terms of ITT analysis, 248 pts were finally enrolled. The 218 pts who completed the surgery were included in the current analysis. The baseline characteristics of these subjects were well balanced between the two arms. By ITT analysis, pCR was achieved in 15/121 (12.4%) pts in the FEC3-D3 arm and 18/126 (14.3%) in the AC4-D4 arm. With a median follow up of 64.1 months, the 3Y DFS was comparable between the two arms (75.8% in FEC3-D3 vs. 75.6% in AC4-D4). The most common adverse event (AE) was Grade 3/4 neutropenia, which arose in 27/126 (21.4%) AC4-D4 arm pts vs 23/121 (19.0%) FEC3-D3 arm cases. The primary HRQoL domains were similar between the two groups (FACT-B scores at baseline, P = 0.35; at the midpoint of NACT, P = 0.20; at the completion of NACT, P = 0.44). CONCLUSION: Six cycles of FEC3-D3 could be an alternative to eight of AC4-D4. Trial registration ClinicalTrials.gov NCT02001506. Registered December 5,2013. https://clinicaltrials.gov/ct2/show/NCT02001506.

Changes in bone mineral density during 5 years of adjuvant treatment in premenopausal breast cancer patients.

PURPOSE: Adjuvant treatment for breast cancer in postmenopausal women is a risk factor for bone loss. However, the association between bone mineral density (BMD) changes in premenopausal breast cancer patients and various adjuvant treatment regimens is not well characterized. In this study, we evaluated the changes in BMD according to adjuvant treatment in premenopausal women with breast cancer. METHODS: Between 2006 and 2010, BMD data of 910 premenopausal women with breast cancer before operation and 1, 2, 3.5, and 5 years post-operation were retrospectively analyzed. The patients were divided according to the type of treatment: observation (O), tamoxifen (T), chemotherapy (C), C followed by T (C → T), and gonadotropin-releasing hormone (GnRH) agonist with T (G + T). RESULTS: After 5 years of follow-up, BMD changes were similar between the T and O groups (all p > 0.05). Within 1 year of treatment, the C group showed the most significant BMD loss. The C → T and G + T groups showed more significant BMD loss in the lumbar spine and femur than the O and T groups (both p < 0.001, both). After 1 year of treatment, BMD loss in the lumbar spine was significantly greater in the C → T and G + T groups than in the T group; this tendency was maintained for 5 years of treatment (all p < 0.005). CONCLUSION: Premenopausal women who received adjuvant treatment which induced menopause showed significant bone loss which lasted for 5 years. Although no significant difference was observed between the O and T groups, tamoxifen treatment during chemotherapy or GnRH agonist treatment might prevent bone loss.

Cancer panel analysis of circulating tumor cells in patients with breast cancer.

Liquid biopsy using circulating tumor cells (CTCs) is a noninvasive and repeatable procedure, and is therefore useful for molecular assays. However, the rarity of CTCs remains a challenge. To overcome this issue, our group developed a novel technology for the isolation of CTCs on the basis of cell size difference. The present study isolated CTCs from patients with breast cancer using this method, and then used these cells for cancer gene panel analysis. Blood samples from eight patients with breast cancer were collected, and CTCs were enriched using size-based filtration. Enriched CTCs were counted using immunofluorescent staining with an epithelial cell adhesion molecule (EpCAM) and CD45 antibodies. CTC genomic DNA was extracted, amplified, and screened for mutations in 400 genes using the Ion AmpliSeq Comprehensive Cancer Panel. White blood cells (WBCs) from the same patient served as a negative control, and mutations in CTCs and WBCs were compared. EpCAM+ cells were detected in seven out of eight patients, and the average number of EpCAM+ cells was 8.6. The average amount of amplified DNA was 32.7 µg, and the percentage of reads mapped to any targeted region relative to all reads mapped to the reference was 98.6%. The detection rate of CTC-specific mutations was 62.5%. The CTC-specific mutations were enhancer of zeste polycomb repressive complex 2 subunit, notch 1, AT-rich interaction domain 1A, serine/threonine kinase 11, fms related tyrosine kinase 3, MYCN proto-oncogene, bHLH transcription factor, APC, WNT signaling pathway regulator, and phosphatase and tensin homolog. The technique used by the present study was demonstrated to be effective at isolating CTCs at a sufficiently high purity for genomic analysis, and supported the use of comprehensive cancer panel analysis as a potential application for precision medicine.

Changes in serum hydroxyvitamin D levels of breast cancer patients during tamoxifen treatment or chemotherapy in premenopausal breast cancer patients.

BACKGROUND: We investigated the effect of breast cancer adjuvant treatment on vitamin D status, as measured by serum hydroxyvitamin D (25OHD). METHODS: Premenopausal patients (n=483) diagnosed with non-metastatic breast cancer in 2009 at Asan Medical Center had serum 25OHD levels prospectively analysed at diagnosis and 6 and 12months after surgery. We excluded patients who took vitamin D supplements or received neoadjuvant chemotherapy. Vitamin D sufficiency was defined as a serum level of ⩾30ng/ml, insufficiency as 20-29ng/ml and deficiency as <20ng/ml. RESULTS: Compared with baseline serum 25OHD, patients who received chemotherapy had decreased serum 25OHD levels at 6months (-5.52ng/ml, p=0.003) and 12months (-1.24ng/ml, p=0.517) and patients who received anti-hormone therapy had significantly increased serum 25OHD levels at 6months (+3.00ng/ml, p=0.681) and 12months (+6.47ng/ml, p=0.002, respectively). Among patients who received chemotherapy, 49.5% were vitamin D sufficient at diagnosis but only 26.9% were sufficient 6months after finishing chemotherapy and this percentage increased to 45.2% at 12months. CONCLUSIONS: Vitamin D levels decrease during chemotherapy but recover after treatment ends. Anti-hormone therapy with tamoxifen causes serum vitamin D levels to increase. Whether the increased serum vitamin D affects the antitumour effect of the tamoxifen has yet to be determined.