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.

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.

C4.4A highly expressed in HER2-positive human breast cancers may indicate a good prognosis.

BACKGROUND: The aim of our study was to investigate the association of C4.4A expression in breast tumors with both patients' clinicopathological characteristics and outcomes in order to clarify the significance of C4.4A in breast cancer. METHODS: Primary breast cancer patients (n = 125, stage I-III) who had undergone breast mastectomy or breast-conserving surgery at our hospital between 2005 and 2011 were recruited for this study. Tumor samples were obtained from surgical specimens and expression status of C4.4A, estrogen receptors, progesterone receptors, human epidermal growth factor receptor 2 (HER2) and Ki67 was analyzed immunohistochemically, while HER2 amplification was examined using fluorescence in situ hybridization. RESULTS: Multivariate analysis showed that HER2 positivity was the only independent predictive factor for C4.4A expression (odds ratio 5.31, 95 % confidence interval 2.04-15.72; P < 0.001). Univariate prognostic analysis of the relationship between C4.4A and disease-free survival showed that survival of patients with C4.4A-positive tumors was longer than that of patients with C4.4A-negative tumors in the HER2-positive subset (P = 0.004) while there was no significant difference in patient outcome according to C4.4A status for total patients (median observation period 37 months, range 1-92 months; P = 0.223). CONCLUSIONS: We established a positive relationship between C4.4A and HER2 status, suggesting that C4.4A expression may be a prognostic factor for HER2-positive breast cancer patients.

Association of body mass index with risk of luminal A but not luminal B estrogen receptor-positive and HER2-negative breast cancer for postmenopausal Japanese women.

BACKGROUND: The impact of body mass index (BMI) on the risk of postmenopausal estrogen receptor (ER)-positive breast cancers has been well documented. However, the mechanism for the impact of BMI on the etiology of luminal A and luminal B subtypes has not yet been identified. METHODS: We analyzed associations between BMI and breast cancers stratified by immunohistochemically defined intrinsic subtypes, and 1,297 Japanese women (615 breast cancer patients and 682 healthy women from a breast cancer screening program) were enrolled in a case-control study. ER-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancers were classified into luminal A and B subtypes according to Ki67 expression levels. RESULTS: Higher BMI was significantly positively associated with postmenopausal breast cancer risk for one-unit increase in BMI (adjusted odds ratio (aOR) 1.09, 95 % confidence interval (CI) 1.04-1.15; P = 0.0008). Analyses of postmenopausal women revealed that BMI was consistently and exclusively associated with luminal A incidence (aOR 1.18, 95 % CI 1.10-1.26; P < 0.0001). When BMI was divided into three categories corresponding to those of controls, among postmenopausal women, the observed positive association was confined to luminal A (high vs low, aOR 2.98, 95 % CI 1.53-5.80; P < 0.005), but not luminal B (aOR 0.95, 95 % CI 0.47-1.91) subtypes. CONCLUSIONS: We observed that BMI was significantly positively associated with increased risk of postmenopausal breast cancer for Japanese women with luminal A, but not with luminal B tumor subtype.

Influence of body mass index on clinicopathological factors including estrogen receptor, progesterone receptor, and Ki67 expression levels in breast cancers.

BACKGROUND: High body mass index (BMI) is associated not only with a higher incidence of breast cancers but also with poorer prognosis. It is speculated that both enhanced production of estrogens and other factors associated with obesity are involved in these associations, but the biological characteristics associated with high BMI have yet to be thoroughly identified. METHODS: We studied 525 breast cancers, focusing on biological differences between tumors associated with high and low BMI and by immunohistochemically defined intrinsic subtype. Ki67 expression levels were used to differentiate luminal A from luminal B estrogen receptor (ER)+/human epidermal growth factor receptor 2 (HER2)-breast cancers. RESULTS: Premenopausal patients with high BMI showed a significantly higher frequency of lymph node metastasis (46.4 % vs. 22.9 %, P = 0.005) and tended to have a larger tumor size (P = 0.05) and higher nuclear grade (P = 0.07) than those with low BMI. These differences were not observed among postmenopausal patients. BMI was not associated with distribution of breast cancer subtypes, and ER, progesterone receptor (PR), and Ki67 expression levels of each subtype showed no differences between high and low BMI among premenopausal patients. CONCLUSION: Higher BMI might influence aggressive tumor characteristics among premenopausal patients, but its influence on ER, PR, and Ki67 expression levels seems to be limited.

Biological characteristics of luminal subtypes in pre- and postmenopausal estrogen receptor-positive and HER2-negative breast cancers.

BACKGROUND: Estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancers can be divided into luminal A and luminal B subtypes based on Ki67 expression levels. However, the biological differences in ER and progesterone receptor (PR) expression levels between these luminal subtypes are not clear. METHODS: We examined immunohistochemical expression levels of ER, PR, and Ki67 in 180 ER-positive/HER2-negative breast cancers while taking menopausal status into account. Breast cancers were divided according to ER and PR levels (H: >50%, L: ≤ 50%), and luminal A and B were classified by the Ki67 labeling index (A: Ki67 <14%, B: Ki67 ≥ 14%). RESULTS: When breast cancers were classified based on ER and PR levels, the distribution of pre- and postmenopausals was significantly different for luminal A (P < 0.0001), but not for luminal B cancers. As for luminal A, ER-H/PR-L cancers were rare among premenopausals (8%), but frequent among postmenopausals (54%). Correlation between ER and PR levels among luminal A cancers was strong in premenopausals but weak in postmenopausals. Since crosstalk with growth factor signaling is unlikely in luminal A, we speculate that intratumoral estrogen insufficiency contributed to the characteristics of postmenopausal ER-H/PR-L cancers. CONCLUSION: We speculate that the biological characteristics of luminal A cancers are influenced by the estrogen environment, but its influence on luminal B cancers may be limited. We believe these considerations constitute useful information for a better understanding of the biology of ER-positive-HER2-negetive breast cancers.