Risk factors for joint symptoms in postmenopausal Japanese breast cancer patients treated with anastrozole: a prospective multicenter cohort study of patient-reported outcomes.

BACKGROUND: Endocrine treatment-related adverse events have a strong impact on patients' quality of life and sometimes result in treatment discontinuation. Since joint symptoms are the most frequently recognized side effect of aromatase inhibitors, evaluation of associated risk factors may yield significant findings. PATIENTS AND METHODS: A total of 391 postmenopausal Japanese women with estrogen receptor-positive breast cancer and treated with adjuvant anastrozole were enrolled from 28 centers for assessment of patient-reported outcomes (PROs) in this prospective cohort study (SAVS-JP, UMIN000002455). Patients completed the self-report questionnaire at baseline and after 3, 6, 9, and 12 months of treatment for evaluation of frequency of treatment-related joint symptoms (arthralgia, decrease in range of joint motion, and joint stiffness). RESULTS: We obtained PROs from 362 patients (92.6 %) at baseline and at one or more subsequent points. New or worsening from baseline of joint symptoms were reported by 260 patients (71.8 %). More than 90 % of the symptoms were mild or moderate and nearly 80 % had occurred by 6 months. Multivariate analysis showed that a short time span after menopause [odds ratio (OR) 0.95, 95 % confidence interval (CI) 0.90-0.99; P = 0.02] and adjuvant chemotherapy (OR 2.29, 95 % CI 1.06-4.95; P = 0.03) were significant independent risk factors for joint symptoms. No significant relationships between body mass index (BMI) and joint symptoms were identified. Eighteen patients discontinued treatment during the 1st year and eight of them reported joint symptoms. CONCLUSION: Taking into consideration that PROs may yield higher prevalence rates than physician ratings for symptoms published in pivotal clinical trials, we found that a short time span after menopause and use of adjuvant chemotherapy, but not high BMI, were significantly associated with joint symptoms. These findings might prove useful for counseling before initiating treatment with adjuvant aromatase inhibitors in postmenopausal Japanese women.

Phase II trial in Japan of sequential administration of weekly paclitaxel followed by FEC as neoadjuvant chemotherapy for locally advanced breast cancer [KBCSG0206 trial: Kinki Breast Cancer Study Group (KBCSG)].

OBJECTIVE: We conducted a phase II trial in Japan to evaluate the efficacy and tolerability of weekly paclitaxel followed by fluorouracil, epirubicin, and cyclophosphamide (FEC) as neoadjuvant chemotherapy (NAC) for locally advanced breast cancer (LABC). METHODS: Patients with clinical stage IIIA-IIIB breast cancer received NAC consisting of 12 once-a-week cycles of paclitaxel followed by 4 once-every-third-week cycles of FEC. RESULTS: Fifty patients with LABC were enrolled, 47 of whom were administered paclitaxel followed by FEC as NAC. The clinical response rate for all chemotherapies was 85.1%, and the pathological complete response rate was 27.7%. Regarding toxicity, grade 3-4 neutropenia was observed in 10% of patients. No serious toxicities requiring the discontinuation of treatment were encountered. The rate of breast conservation surgery was 31.9%, median survival had not been reached at the time of conclusion of this study, and the 3-year survival rate was 85.1%. Median disease-free survival was 40.2 months, and the 3-year disease-free survival rate was 62.1%. CONCLUSIONS: Weekly paclitaxel followed by FEC demonstrated efficacy and tolerable toxicity in a neoadjuvant setting for LABC.

Erratum to immediate breast volume replacement using a free dermal fat graft after breast cancer surgery: multi-institutional joint research of short-term outcomes in 262 Japanese patients.

[This corrects the article on p. 179 in vol. 4, PMID: 26005649.].

Body mass index and menopausal disorders during menopause affect vasomotor symptoms of postmenopausal Japanese breast cancer patients treated with anastrozole: a prospective multicenter cohort study of patient-reported outcomes.

BACKGROUND: Adverse events related to endocrine therapies have a major impact not only on patients' quality of life but also on treatment discontinuation. Although vasomotor symptoms induced by aromatase inhibitors are frequently recognized, risk factors, especially for Japanese women, are not well reported. To identify risk factors for vasomotor symptoms of Japanese breast cancer patients treated with adjuvant anastrozole, we conducted a prospective cohort study based on patient-reported outcomes (PROs). PATIENTS AND METHODS: For this prospective cohort study (SAVS-JP, UMIN000002455), 391 postmenopausal Japanese estrogen receptor-positive breast cancer patients who were treated with adjuvant anastrozole were recruited from 28 centers. The PRO assessment was obtained from a self-reported questionnaire at baseline, 3, 6, 9 and 12 months between August 2009 and April 2012. Vasomotor symptoms, comprising hot flashes, night sweats, and cold sweats, were categorized into four grades (none, Grade 1: mild, Grade 2: moderate, Grade 3: severe). Pre-existing symptoms were only included if they had become worse than at baseline. RESULTS: Hot flashes, night sweats, and cold sweats at baseline were reported by 20.5, 15.1, and 8.2 % of the patients, respectively, and new appearance or worsening of symptoms in comparison with baseline by 38.4, 29.3, and 28.7 %, respectively. About 80 % of newly occurring symptoms were Grade 1, and less than 5 % were Grade 3. Vasomotor symptoms were reported by 201 out of 362 patients (55.5 %) during the first year and the mean time to onset was 5.6 months. Patients with vasomotor symptoms were significantly younger (mean 62.8 years, range 38-86 vs 64.7 years, range 37-84; p = 0.02), had higher body mass index (BMI) (23.4 kg/m2, range 15.8-39.9 vs 22.4 kg/m2, range 15.8-34.9; p = 0.01), had vasomotor symptoms sooner after menopause (12.4 years, range 0-51 vs 15.1 years, range 1-37; p = 0.002), and had more menopausal disorders during menopause (63.3 vs 36.7 %; p = 0.002). Multivariate analysis showed that BMI [odds ratio (OR) 1.09 per unit of increase, 95 % confidence interval (CI) 1.02-1.16; p = 0.009] and experiencing menopausal disorders (OR 2.11, 95 % CI 1.35-3.30; p = 0.001) were significantly associated with vasomotor symptoms. CONCLUSION: High BMI and experiencing menopausal disorders at menopause were found to be significantly associated with the occurrence of vasomotor symptoms. These findings are expected to prove useful for the management of postmenopausal Japanese women treated with aromatase inhibitors.

[Clinical study of ambulatory patient cancer chemotherapy for advanced colorectal cancer].

To evaluate ambulatory patient cancer chemotherapy, the clinical response, toxicities and survival time were analysed among 19 patients with non-curative or recurrent colorectal cancer who were treated by Uracil/Tegafur (UFT) plus oral Leucovorin (UZEL) for the past 2 years. The patients were administered UFT (300 mg/m2/day) and UZEL (75 mg/body/day) for 28 days with a one-week interval every 35 days as one course.A partial response (PR) was observed in 6 patients (31.6%) and stable disease (SD) in 8. The median survival time was 16 months. Although nausea/vomiting, diarrhea and leucopenia were noted, no severe side effects were observed. These results suggested that UFT plus Leucovorin therapy might be a useful cancer chemotherapy for ambulatory patients with advanced colorectal cancer.

Immediate breast volume replacement using a free dermal fat graft after breast cancer surgery: multi-institutional joint research of short-term outcomes in 262 Japanese patients.

BACKGROUND: Immediate volume replacement using a free dermal fat graft (FDFG) has been proven safe with early postoperative benefits. The aims of the present study were to clarify adequate indications and risk factors associated with operative morbidity. PATIENTS AND METHODS: A multi-institutional analysis of partial mastectomy with immediate volume replacement with FDFG was undertaken in 14 hospitals specializing in breast cancer treatment. Clinical and oncological variables were analyzed to identify factors associated with postoperative complications. RESULTS: A total of 262 cases were analyzed. Considering the observation period and overlap of patients, 13 (5.4%) out of 242 patients had complications within 1 month of surgery while 7 (4.6%) out of 151 patients developed complications 1-12 months after surgery. Two hundred and eleven out of 242 patients were statistically examined using a multivariate analysis, which revealed that the weight of resected breast tissue, size of implanted FDFG (cranio-caudal length), and weight of implanted FDFG were associated with a higher likelihood of postoperative complications. CONCLUSIONS: Immediate breast volume replacement using a FDFG after breast cancer surgery should be done for selected patients with breast cancer to avoid postoperative complications. The prospective and larger investigations are warranted for the establishment of appropriate guidelines.

Expression of a novel splicing variant deleting exons 4 and 6 of the progesterone receptor gene is a rare event in breast cancer.

We identified a novel alternatively spliced isoform of PR mRNA in breast cancer tissues. The deleted transcript was characterized by an out-of-frame deletion of 437 bp, corresponding to the complete loss of exons 4 and 6 (PR delta4+6 ASV). PR delta4+6 ASV will result in a partial defect in the region of the ligand-binding domain of hormone receptors, suggesting that the conserved residues are missing from the core of the protein. In the limited number of samples studied, a novel PR delta4+6 mRNA was detected in 1 of 45 (2.2%) non-cancerous tissues of patients with breast cancer, in 5 of 45 (11.1%) cancerous tissues of patients with breast cancer. Loss of both exons 4 and 6 will be induced by incomplete splicing and/or repair mechanism. Further studies are necessary to establish the biological significance of this alternative splicing. The expressions of ASVs that induced the mimic PR transcripts need to be considered when designing strategies for regulation analysis of the PR gene.

Low dose capecitabine plus weekly paclitaxel in patients with metastatic breast cancer: a multicenter phase II study KBCSG-0609.

PURPOSE: The combination of capecitabine and paclitaxel (XP) has demonstrated synergistic antitumor activity in preclinical models. The purpose of this phase II study was to evaluate the efficacy and safety of a monthly XP regimen in patients with metastatic breast cancer (MBC). METHODS: Eligible patients had received one or fewer prior chemotherapy regimens for MBC. Patients received oral capecitabine of low dose (828 mg/m(2) twice daily, days 1-21) plus paclitaxel (80 mg/m(2), i.v., over 60 min, days 1, 8 and 15) every 28 days until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR). Progression-free survival (PFS), overall survival (OS) and safety were secondary endpoints. An exploratory analysis of efficacy according to hormone receptor (HR) status was performed. RESULTS: Forty-four patients were enrolled, and 43 patients were evaluable. ORR was 46.5%. PFS and OS were 8.3 and 22.9 months, respectively. ORR was 45.5% in patients with HR-positive tumors and 50% in HR-negative cases. The most frequently observed grade 3/4 adverse events were neutropenia (27.9%), leukopenia (11.6%), hand-foot syndrome (HFS, 9.3%) and fatigue (7.0%). There were no discontinuations due to HFS. CONCLUSIONS: Monthly XP was an effective and well-tolerated regimen for the first- or second-line treatment for MBC.

ARHI/NOEY2 inactivation may be important in breast tumor pathogenesis.

Allelic loss frequently occurs on the short arm of chromosome 1 in human breast carcinoma, suggesting that the ARHI/NOEY2 gene, an imprinted putative tumor suppressor gene, is involved in the pathogenesis of the tumor entity. To clarify the clinical importance of ARHI/NOEY2 mRNA in breast cancer, we studied whether ARHI/NOEY2 inactivation might contribute to tumors arising in the breast. An ARHI/NOEY2 message was detected by real-time PCR analysis in all noncancerous breast tissues, but was not detected in 2 of 26 breast cancer tissue samples. In 10 of 26 breast cancer tissue samples ARHI/NOEY2 mRNA was substantially reduced. ARHI/NOEY2 expression was lost or markedly reduced in 12 of 26 (46.15%) breast cancer tissue samples. In summary, we conclude that decreased ARHI/NOEY2 mRNA expression may play an important role in the pathogenesis of breast cancer.

Novel alternatively spliced variant with a deletion of 52 BP in exon 6 of the progesterone receptor gene is observed frequently in breast cancer tissues.

The human progesterone receptor (PR) is a ligand-activated nuclear transcription factor that mediates progesterone action in target tissues. We found a novel alternatively spliced variant (ASV) of the PR mRNA in breast cancer tissues. The deleted transcript was characterized by an out-of-frame deletion of 52 bp in exon 6 (PR delta6/2 ASV). The PR delta6/2 ASV mRNA results in a partial defect in the region of the ligand-binding domain of the hormone receptor, where conserved residues are missing from the core of the protein. To clarify the clinical significance of the PR delta6/2 ASV, we investigated the expression of this ASV in noncancerous and cancerous tissues from patients with breast cancer using RT-PCR. The novel PR delta6/2 mRNA was detected in 24 of 39 (61.5%) cancerous tissues and in 3 of 39 (7.7%) noncancerous tissues from patients with breast cancer. PR delta6/2 ASV mRNA was expressed more frequently in breast cancer tissues than in noncancerous tissues (p < 0.0001), which suggests a possible relationship between the expression of PR delta6/2 and breast cancer. Our observations may provide a novel strategy for the genetic diagnosis of breast cancer.