Retrospective study on the effectiveness of medroxyprogesterone acetate in the treatment of ER-positive/HER2-negative post-menopausal advanced breast cancer: an additional analysis of the JBCRG-C06 Safari study.

BACKGROUND: Only old evidence exists to back up the use of medroxyprogesterone acetate. Therefore, this study aimed to explore the factors that influence the time to treatment failure of medroxyprogesterone acetate in real-world settings as late-line treatment. METHODS: This was a cohort study that used the database of the Safari study on oestrogen receptor-positive post-menopausal advanced breast cancer (UMIN000015168). We created Kaplan-Meier curves for time to treatment failure with medroxyprogesterone acetate. Further, univariate and multivariate analyses were performed using a Cox hazard model of the clinicopathological factors involved in the time to treatment failure of medroxyprogesterone acetate. RESULTS: From the 1031 patients in the Safari study, 279 patients were selected as the population for the analysis of effectiveness of medroxyprogesterone acetate monotherapy. In the analysis of medroxyprogesterone acetate by treatment line, the median time to treatment failure was 3.0 months for third-line treatment and 4.1 months for fourth and subsequent treatment lines. In cases where medroxyprogesterone acetate was used as a third-line or later endocrine treatment, multivariate analysis showed that the length of the disease-free interval was correlated with the length of time to treatment failure of medroxyprogesterone acetate (P = 0.004). With medroxyprogesterone acetate monotherapy as the fourth-line or later treatment, 20% of the patients achieved a time to treatment failure of 12 months or longer. CONCLUSION: In actual clinical practice, patients treated with medroxyprogesterone acetate alone as the fourth or subsequent treatment lines showed a time to treatment failure of 4 months, suggesting that there is merit in using medroxyprogesterone acetate even in late treatment lines, especially in patients with long disease-free interval and those who are difficult to treat using other antineoplastic agents.

A prediction model for early systemic recurrence in breast cancer using a molecular diagnostic analysis of sentinel lymph nodes: A large-scale, multicenter cohort study.

BACKGROUND: The one-step nucleic acid amplification (OSNA) assay can quantify the cytokeratin 19 messenger RNA copy number as a proxy for sentinel lymph node (SN) metastasis in breast cancer. A large-scale, multicenter cohort study was performed to determine the prognostic value of the SN tumor burden based on a molecular readout and to establish a model for the prediction of early systemic recurrence in patients using the OSNA assay. METHODS: SN biopsies from 4757 patients with breast cancer were analyzed with the OSNA assay. The patients were randomly assigned to the training or validation cohort at a ratio of 2:1. On the basis of the training cohort, the threshold SN tumor burden value for stratifying distant recurrence was determined with Youden's index; predictors of distant recurrence were investigated via multivariable analyses. Based on the selected predictors, a model for estimating 5-year distant recurrence-free survival was constructed, and predictive performance was measured with the validation cohort. RESULTS: The prognostic cutoff value for the SN tumor burden was 1100 copies/µL. The following variables were significantly associated with distant recurrence and were used to construct the prediction model: SN tumor burden, age, pT classification, grade, progesterone receptor, adjuvant cytotoxic chemotherapy, and adjuvant anti-human epidermal growth factor receptor 2 therapy. The values for the area under the curve, sensitivity, specificity, and accuracy of the prediction model were 0.83, 63.4%, 81.7%, and 81.1%, respectively. CONCLUSIONS: Using the OSNA assay, the molecular readout-based SN tumor burden is an independent prognostic factor for early breast cancer. This model accurately predicts early systemic recurrence and may facilitate decision-making related to treatment.

Differential prognostic impact of complete blood count-related parameters by prior use of novel androgen receptor pathway inhibitors in docetaxel-treated castration-resistant prostate cancer patients.

There are multiple reports on the value of complete blood count (CBC)-related parameters on prognosis in docetaxel-treated castration-resistant prostate cancer (CRPC) patients before the emergence of androgen receptor pathway inhibitors (ARPIs). We investigated the prognostic significance of CBC-related parameters in docetaxel-treated CRPC patients. Patients treated with docetaxel chemotherapy for CRPC between 2008 and 2018 were included. We analyzed the relevance of CBC-related parameters to oncological prognosis in docetaxel chemotherapy, associated with prior use of novel ARPIs. Among 144 Japanese men treated with docetaxel, 49 men (34.0%) had already received ARPI therapy. A high neutrophil-lymphocyte ratio (NLR) was a prognostic factor for poor progression-free survival and overall survival (OS) in both univariate and multivariate analyses. In addition, a low hemoglobin (Hb) level and a high systemic immune-inflammation index (SII) were prognostic factors of poor OS in univariate analysis. Hb level was a prognostic factor of OS in both ARPI-naive and ARPI-treated patients. However, a high NLR and SII were only associated with a poor prognosis in ARPI-naive but not in ARPI-treated patients. Hb, NLR, and SII have been suggested to be prognosticators in docetaxel-treated CRPC patients. The differential prognostic value of NLR and SII between ARPI-naive and ARPI-treated patients may require caution when using these markers in docetaxel-treated CRPC patients.

Factors associated with overall survival after recurrence in patients with ER-positive/HER2-negative postmenopausal breast cancer: an ad hoc analysis of the JBCRG-C06 Safari study.

BACKGROUND: The Safari study (UMIN000015168) was a retrospective, multicenter study in which 1072 consecutive cases of estrogen receptor-positive advanced breast cancer treated using 500 mg fulvestrant were registered. We previously reported the relationship between the patient factors and overall survival after the diagnosis using the same cases and the same factors for the analysis of time to treatment failure in patients with estrogen receptor-positive advanced breast cancer. The current study is an ad hoc analysis that focused on the relationship between the patient factors and overall survival after recurrence by adding factors generally associated with overall survival after recurrence. METHODS: The overall survival after recurrence in patients with estrogen receptor-positive human epidermal growth factor receptor 2 negative recurrent breast cancer was analyzed via univariate and multivariate analyses with a Cox proportional hazards model. RESULTS: A total of 598 cases were used for the analysis of overall survival after recurrence. Multivariate analysis revealed that favorable overall survival (median, 6.4 years) was significantly correlated with long time from recurrence to fulvestrant use (≥3 years), low nuclear or histological grade (G3 vs. G1), long time to treatment failure of initial palliative endocrine therapy (≥12 months) and long time to initial palliative chemotherapy (≥2 years). CONCLUSION: The results of this study indicate that sequential endocrine monotherapy may be a useful treatment option for patients with estrogen receptor-positive/human epidermal growth factor receptor 2 negative recurrent breast cancer who have been successfully treated with initial long-term palliative endocrine therapy.

Adjuvant S-1 plus endocrine therapy for oestrogen receptor-positive, HER2-negative, primary breast cancer: a multicentre, open-label, randomised, controlled, phase 3 trial.

BACKGROUND: Oral fluoropyrimidines, such as S-1, have been shown to have a role in controlling disease progression in metastatic breast cancer. We examined adjuvant treatment with S-1 in patients with oestrogen receptor (ER)-positive and HER2-negative primary breast cancer. METHODS: We did a multicentre, open-label, randomised, controlled, phase 3 trial in 139 sites (137 hospitals and two clinics). Eligible patients were women aged 20-75 years with histologically diagnosed stage I to IIIB invasive breast cancer (intermediate to high risk of recurrence). Patients were temporarily registered at participating institutions and biopsy or surgical samples were collected and sent for central pathological assessment. Patients received 5 years of standard adjuvant endocrine therapy (selective oestrogen receptor modulators with or without ovarian suppression and aromatase inhibitors) with or without 1 year of S-1. Oral S-1 80-120 mg/day was administered twice a day for 14 days with 7 days off. Randomisation (1:1) using the minimisation method was done with six stratification factors (age, axillary lymph node metastasis at surgery or sentinel lymph node biopsy, preoperative or postoperative (neoadjuvant or adjuvant) chemotherapy, preoperative endocrine therapy, proportion of ER-positive cells, and study site). The primary endpoint was invasive disease-free survival, in the full analysis set (all randomly assigned patients, excluding those with significant protocol deviations). The safety analysis set consisted of all patients who received at least one dose of study treatment. Here, we report the results from the interim analysis at the data cutoff date Jan 31, 2019. This trial is registered with Japan Registry of Clinical Trials, jRCTs051180057, and the University hospital Medical Information Network, UMIN000003969. FINDINGS: Between Feb 1, 2012, and Feb 1, 2016, 1930 patients were enrolled in the full analysis set, 957 (50%) received endocrine therapy plus S-1 and 973 (50%) received endocrine therapy alone. Median follow-up was 52·2 months (IQR 42·1-58·9). 155 (16%) patients in the endocrine therapy alone group and in 101 (11%) patients in the endocrine therapy plus S-1 group had invasive disease-free survival events (hazard ratio 0·63, 95% CI 0·49-0·81, p=0·0003). As the primary endpoint was met at interim analysis, the trial was terminated early. The most common grade 3 or worse adverse events were decreased neutrophil count (72 [8%] of 954 patients in the endocrine therapy plus S-1 group vs seven [1%] of 970 patients in the endocrine therapy alone group), diarrhoea (18 [2%] vs none), decreased white blood cells (15 [2%] vs two [<1%]), and fatigue (six [<1%] vs none). Serious adverse events were reported in nine (1%) of 970 patients in the endocrine therapy alone group and 25 (3%) of 954 patients in the endocrine therapy plus S-1 group. There was one (<1%) possible treatment-related death in the endocrine therapy plus S-1 group due to suspected pulmonary artery thrombosis. INTERPRETATION: These data suggest that this combination of S-1 with endocrine therapy could be a potential treatment option for this intermediate and high-risk group of patients with ER-positive, HER2-negative primary breast cancer. FUNDING: Public Health Research Foundation (Japan), Taiho Pharmaceutical.

Relationships between pathological factors and long-term outcomes in patients enrolled in two prospective randomized controlled trials comparing the efficacy of oral tegafur-uracil with CMF (N·SAS-BC 01 trial and CUBC trial).

PURPOSE: To evaluate the efficacies of cyclophosphamide, methotrexate, and fluorouracil (CMF) and tegafur-uracil (UFT) as adjuvant therapy in patients with resected stage I-IIIA breast cancer by immunohistochemistry (IHC)-based subtype and to determine the relationships between clinicopathological factors and long-term outcomes. METHODS: A pooled analysis of the randomized controlled N·SAS-BC 01 and CUBC studies was conducted. Expression of hormone receptors (HRs; estrogen and progesterone receptors), human epidermal growth factor receptor 2 (HER2), and Ki67were assessed by IHC. Tumor-infiltrating lymphocytes (TILs) and nuclear/histological grades were determined by hematoxylin and eosin staining. Relapse-free survival (RFS) and overall survival (OS) were estimated by Kaplan-Meier analysis and hazard ratios were determined by Cox model adjusted for baseline tumor size and nodal status. RESULTS: A total of 689 patients (342 CMF and 347 UFT) were included in the analyses with a median follow-up of 11.1 years. There was no significant difference in RFS or OS between the two cohorts (RFS: 0.96 [95% confidence interval: 0.71-1.30], log-rank test p = 0.80; OS: 0.93 [0.64-1.35], p = 0.70). There was no difference in RFS or OS between the two cohorts for HR+/HER2- and HR+/HER2+ subtypes. RFS was significantly longer in patients treated with UFT compared with CMF in patients with HR-/HER2+ subtype (0.30 [0.10-0.88], p = 0.03). A high TILs level was associated with a better OS compared with low TILs level (p = 0.02). CONCLUSIONS: This long-term follow-up study showed that RFS and OS were similar in patients with luminal-type breast cancer treated with CMF and UFT.

Clinical usefulness of eribulin as first- or second-line chemotherapy for recurrent HER2-negative breast cancer: a randomized phase II study (JBCRG-19).

BACKGROUND: Anthracycline (A) or taxane T-based regimens are the standard early-line chemotherapy for metastatic breast cancer (BC). A previous study has shown a survival benefit of eribulin in heavily pretreated advanced/recurrent BC patients. The present study aimed to compare the benefit of eribulin with treatment of physician's choice (TPC) as first- or second-line chemotherapy for recurrent HER2-negative BC. METHODS: Patients with recurrent HER2-negative BC previously receiving anthracycline and taxane AT-based chemotherapy in the adjuvant or first-line setting were eligible for this open-label, randomized, parallel-group study. Patients were randomized 1:1 by the minimization method to receive either eribulin (1.4 mg/m2 on day one and eight of each 21-day cycle) or TPC (paclitaxel, docetaxel, nab-paclitaxel or vinorelbine) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included time to treatment failure (TTF), overall response rate (ORR), duration of response, and safety (UMIN000009886). RESULTS: Between May 2013 and January 2017, 58 patients were randomized, 57 of whom (26 eribulin and 31 TPC) were analyzed for efficacy. The median PFS was 6.6 months with eribulin versus 4.2 months with TPC (hazard ratio: 0.72 [95% confidence interval (CI), 0.40-1.30], p = 0.276). Median TTF was 6.0 months with eribulin versus 3.6 months with TPC (hazard ratio: 0.66 [95% CI, 0.39-1.14], p = 0.136). Other endpoints were also similar between groups. The most common grade ≥ 3 adverse event was neutropenia (22.2% with eribulin versus 16.1% with TPC). CONCLUSIONS: Eribulin seemed to improve PFS or TTF compared with TPC without statistical significance. Further validation studies are needed.

Plasma Sphingosine-1-Phosphate Levels Are Associated with Progression of Estrogen Receptor-Positive Breast Cancer.

Although numerous experiments revealed an essential role of a lipid mediator, sphingosine-1-phosphate (S1P), in breast cancer (BC) progression, the clinical significance of S1P remains unclear due to the difficulty of measuring lipids in patients. The aim of this study was to determine the plasma concentration of S1P in estrogen receptor (ER)-positive BC patients, as well as to investigate its clinical significance. We further explored the possibility of a treatment strategy targeting S1P in ER-positive BC patients by examining the effect of FTY720, a functional antagonist of S1P receptors, on hormone therapy-resistant cells. Plasma S1P levels were significantly higher in patients negative for progesterone receptor (PgR) expression than in those positive for expression (p = 0.003). Plasma S1P levels were also significantly higher in patients with larger tumor size (p = 0.012), lymph node metastasis (p = 0.014), and advanced cancer stage (p = 0.003), suggesting that higher levels of plasma S1P are associated with cancer progression. FTY720 suppressed the viability of not only wildtype MCF-7 cells, but also hormone therapy-resistant MCF-7 cells. Targeting S1P signaling in ER-positive BC appears to be a possible new treatment strategy, even for hormone therapy-resistant patients.

A randomized study comparing docetaxel/cyclophosphamide (TC), 5-fluorouracil/epirubicin/cyclophosphamide (FEC) followed by TC, and TC followed by FEC for patients with hormone receptor-positive HER2-negative primary breast cancer.

PURPOSE: Our primary objective was to determine the benefit/risk of anthracycline-free regimens by comparing docetaxel + cyclophosphamide (TC) alone, fluorouracil + epirubicin + cyclophosphamide (FEC) followed by TC, or TC followed by FEC as a primary treatment for patients with HR-positive, HER2-negative BC. METHODS: We randomized patients with stage I-III HR-positive HER2-negative, operable BC to receive either six cycles of TC (TC6), three cycles of FEC followed by three cycles of TC (FEC-TC), or three cycles of TC followed by three cycles of FEC (TC-FEC). The primary endpoint was the pathological response. Secondary endpoints included clinical response, type of surgical procedure, recurrence, death, and adverse events (by NCI-Common Terminology Criteria for Adverse Events v.3.0). We conducted all statistical analyses using SAS Version 9.2. RESULTS: We enrolled 195 patients and analyzed data from 193 as the intention-to-treat population. Pathological complete response rates were numerically higher in the TC6 group than in the other groups (p = 0.321). The breast conservation rate was significantly higher in the TC6 group (73%) than in the other groups (FEC-TC 51%, TC-FEC 45%, p = 0.007). Adverse events with grade > 3 were not common in the treatment groups (p = 0.569). The overall and distant disease-free survivals were similar among the groups with median follow-up of 5.80 years. CONCLUSIONS: Despite similar long-term efficacy and safety profile, the higher breast conservation rate in the TC6 group suggests that preoperative chemotherapy without an anthracycline may benefit patients with HR-positive HER2-negative BC. TRIAL REGISTRATION: UMIN000003283 https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000003873.

Effect of Smoking on Oncological Outcome among Prostate Cancer Patients after Radical Prostatectomy with Neoadjuvant Hormonal Therapy.

We analyzed the association between smoking and oncological outcome after radical prostatectomy with neoadjuvant hormonal therapy. This study included men who had undergone radical prostatectomy with neoadjuvant hormonal therapy between 2003 and 2016. We evaluated the association between clinicopathological factors and smoking status as well as the prognostic significance of smoking status in biochemical recurrence. The patients' backgrounds were comparable between smokers and nonsmokers. Smoking status were identified as significant risk factors of biochemical recurrence. Smoking was a risk factor of biochemical recurrence, suggesting that smoking may promote cancer recurrence after surgical treatment combined with hormonal therapy.

Multicenter study of primary systemic therapy with docetaxel, cyclophosphamide and trastuzumab for HER2-positive operable breast cancer: the JBCRG-10 study.

BACKGROUND: The original aim of this study was to evaluate the treatment sequence and anthracycline requirement in docetaxel, cyclophosphamide and trastuzumab therapy. After one death in the anthracycline-containing arm, the protocol was amended to terminate the randomization. The single-docetaxel, cyclophosphamide and trastuzumab arm was continued to examine the efficacy and safety of the anthracycline-free regimen. METHODS: Women with human epidermal growth factor receptor-2-positive, operable and primary breast cancer were randomized to receive 5-fluorouracil, epirubicin and cyclophosphamide (four cycles) followed by docetaxel, cyclophosphamide and trastuzumab (four cycles), or docetaxel, cyclophosphamide and trastuzumab followed by 5-fluorouracil, epirubicin and cyclophosphamide, or docetaxel, cyclophosphamide and trastuzumab (six cycles). After the protocol amendment, patients were allocated to the docetaxel, cyclophosphamide and trastuzumab arm alone. The primary endpoint was a pathological complete response. RESULTS: In total, 103 patients were enrolled between September 2009 and September 2011: 21, 22 and 24 patients in the 5-fluorouracil, epirubicin and cyclophosphamide followed by docetaxel, cyclophosphamide and trastuzumab; docetaxel, cyclophosphamide and trastuzumab followed by 5-fluorouracil, epirubicin and cyclophosphamide and docetaxel, cyclophosphamide and trastuzumab arms, respectively, and 36 patients in the docetaxel, cyclophosphamide and trastuzumab arm after the protocol amendment. In total, 60 patients were allocated to the docetaxel, cyclophosphamide and trastuzumab arm, in which the pathological complete response rate was 45.8%, and disease-free survival at 3 years was 96.6%. Patients with stage I or IIA in the docetaxel, cyclophosphamide and trastuzumab arm showed good disease-free survival (100% at 3 years). The comparison of efficacy among the three arms was statistically underpowered. Left ventricular ejection fraction decreased significantly after 5-fluorouracil, epirubicin and cyclophosphamide followed by docetaxel-docetaxel, cyclophosphamide and trastuzumab (P = 0.017), but not after docetaxel, cyclophosphamide and trastuzumab followed by 5-fluorouracil, epirubicin and cyclophosphamide or docetaxel, cyclophosphamide and trastuzumab. CONCLUSIONS: The pathological complete response rate for docetaxel, cyclophosphamide and trastuzumab was similar to previous reports of anthracycline-containing regimens. Docetaxel, cyclophosphamide and trastuzumab might be an option for primary systemic therapy in human epidermal growth factor receptor-2-positive early breast cancer. A larger confirmatory study is necessary.

Novel Osteogenic Behaviors around Hydrophilic and Radical-Free 4-META/MMA-TBB: Implications of an Osseointegrating Bone Cement.

Poly(methyl methacrylate) (PMMA)-based bone cement, which is widely used to affix orthopedic metallic implants, is considered bio-tolerant but lacks osteoconductivity and is cytotoxic. Implant loosening and toxic complications are significant and recognized problems. Here we devised two strategies to improve PMMA-based bone cement: (1) adding 4-methacryloyloxylethyl trimellitate anhydride (4-META) to MMA monomer to render it hydrophilic; and (2) using tri-n-butyl borane (TBB) as a polymerization initiator instead of benzoyl peroxide (BPO) to reduce free radical production. Rat bone marrow-derived osteoblasts were cultured on PMMA-BPO, common bone cement ingredients, and 4-META/MMA-TBB, newly formulated ingredients. After 24 h of incubation, more cells survived on 4-META/MMA-TBB than on PMMA-BPO. The mineralized area was 20-times greater on 4-META/MMA-TBB than PMMA-BPO at the later culture stage and was accompanied by upregulated osteogenic gene expression. The strength of bone-to-cement integration in rat femurs was 4- and 7-times greater for 4-META/MMA-TBB than PMMA-BPO during early- and late-stage healing, respectively. MicroCT and histomorphometric analyses revealed contact osteogenesis exclusively around 4-META/MMA-TBB, with minimal soft tissue interposition. Hydrophilicity of 4-META/MMA-TBB was sustained for 24 h, particularly under wet conditions, whereas PMMA-BPO was hydrophobic immediately after mixing and was unaffected by time or condition. Electron spin resonance (ESR) spectroscopy revealed that the free radical production for 4-META/MMA-TBB was 1/10 to 1/20 that of PMMA-BPO within 24 h, and the substantial difference persisted for at least 10 days. The compromised ability of PMMA-BPO in recruiting cells was substantially alleviated by adding free radical-scavenging amino-acid N-acetyl cysteine (NAC) into the material, whereas adding NAC did not affect the ability of 4-META/MMA-TBB. These results suggest that 4-META/MMA-TBB shows significantly reduced cytotoxicity compared to PMMA-BPO and induces osteoconductivity due to uniquely created hydrophilic and radical-free interface. Further pre-clinical and clinical validations are warranted.

The Impending Epidemic of Cardiovascular Diseases in Patients With Cancer in Japan.

Onco-cardiology, a new academic field, aims to improve the quality of life and prognosis of cancer patients and survivors with cardiovascular diseases (CVD). With the aging of the population, an epidemic of cancer with CVD is emerging in developed countries. Cancer and CVD share risk factors, pathophysiology, treatments, and preventive and rehabilitative measures. A multidisciplinary team-based approach is needed to support cancer treatment to maximize its effectiveness and minimize its cardiotoxic potential. Basic and clinical onco-cardiology are already being practiced harmoniously. However, systematization in academia and clinical practice and accumulation of evidence have just started. In this review, we present the epidemiology, common risk factors between cancer and CVD, future epidemic of CVD in patients with cancer, and the necessity for an onco-cardiological approach to managing the burden of CVD in cancer patients and survivors.

Burden of cardiovascular disease in Japanese cancer patients and survivors: a single cancer-center study in Niigata City.

BACKGROUND: Cardiovascular disease (CVD) and cancer are major causes of death in Japan. As most CVDs are chronic and often aggravate, long-term follow-up is necessary. Although some cancer patients and survivors have CVD, its prognostic significance and prevalence are unknown. Therefore, we conducted a retrospective study at our center to determine the prevalence of cancer patients with CVD. METHODS: In 2015, our 10-year (2005-2014) cancer registry was summarized. Comorbidities including left ventricular dysfunction, atrial fibrillation (AF), ischemic heart disease, aortic stenosis, venous thromboembolism (VTE), and elevation of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) were examined. RESULTS: In total, 26,235 de novo cancer patients were registered and 16,130 survived until January 1, 2015. The 5-year survival rate was 64.0% for all cancer patients and 44.2% for cancer patients with CVD. Cox proportional hazards analysis adjusting for age, cancer stage, and body mass index revealed that AF [hazard ratio (HR) 1.219, male; P = 0.038], VTE (HR 1.517, male; P = 0.003 and HR 2.089, female; P < 0.001), and NT-proBNP elevation (HR 1.861, female; P = 0.002) were significantly associated with death. The CVD prevalence among cancer survivors in 2015 was 8.7% vs 3.5% for males vs females. AF was the most common CVD (prevalence: male, 4.0%; female, 1.0%). The prevalence of most CVD in adults increased progressively with age, with male predominance (12.1% for male and 7.5% for female patients in the 80 s age group). CONCLUSIONS: One in 10 elderly cancer survivors has serious CVD. AF, VTE, and heart failure were critical comorbidities. Cardiologists and cancer-care providers should recognize CVD presence and monitor patients closely, providing medications or interventions concurrently with cancer therapy.

Future projection of cancer patients with cardiovascular disease in Japan by the year 2039: a pilot study.

BACKGROUND: The number of cancer patients in Japan is estimated to rise to 3.5 million by 2025. The disease burden may be further complicated by comorbidities caused by cardiovascular disease (CVD). Predicting the number of cancer patients with CVD can help anticipate future resource needs. METHODS: We used statistics derived from the Niigata Cancer Center CVD Study (2015) as well as population estimates from the National Cancer Center's Cancer Registry and Statistics survey of 2017 for convenience. We simply multiplied the projected number of cancer patients through the year 2039 by the CVD prevalence in 2015, with patients classified by sex, age, and cancer type to estimate the number of cancer patients with CVD. RESULTS: The total number of Japanese cancer patients with CVD was 253,000 in 2015 and is predicted to increase rapidly by 30,000 in 2020 and peak at 313,000 in 2030-2034. Men will dominate the CVD population at 2.5-fold the number of women. The growth rate of the population with both cancer and CVD will be greater than that of the cancer-only population (1.23 vs 1.18, P < 0.001), and will comprise notably high proportions of patients with prostatic, breast, and uterine cancers (1.80, 1.57, and 1.66, P < 0.001, respectively). CONCLUSION: Future cancer patients will be older and more likely to have CVD. Although men will continue to dominate this population, the increase in the number of women will be pronounced. Cancer care providers should be trained to recognize CVD and provide any necessary interventions concurrently with cancer therapy.

Correction to: Future projection of cancer patients with cardiovascular disease in Japan by the year 2039: a pilot study.

n the original publication, in a title of Table 2.

Palbociclib in combination with letrozole in patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: PALOMA-2 subgroup analysis of Japanese patients.

BACKGROUND: In PALOMA-2, palbociclib-letrozole significantly improved progression-free survival (PFS) vs placebo-letrozole in women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) advanced breast cancer (ABC) in the first-line setting. We evaluated the efficacy, safety, and pharmacokinetics of palbociclib in Japanese women in PALOMA-2. METHODS: In this phase 3 study, 666 postmenopausal women with ER+/HER2- ABC were randomized 2:1 to palbociclib (125 mg/day [3 weeks on/1 week off]) plus letrozole (2.5 mg daily) or placebo plus letrozole. A prespecified, exploratory, subgroup analysis of Japanese patients (n = 46) was conducted to compare results with those of the overall population. RESULTS: At the February 26, 2016 cutoff, median PFS among the 46 Japanese patients was 22.2 months (95%CI, 13.6‒not estimable) with palbociclib-letrozole vs 13.8 months (5.6‒22.2) with placebo-letrozole (hazard ratio, 0.59 [95%CI, 0.26-1.34]). The most common adverse events (AEs) were hematologic and more frequent among Japanese patients than the overall population (neutropenia: 93.8% [87.5% grade 3/4] vs 79.5% [66.4%]; leukopenia: 62.5% [43.8%] vs 39.0% [24.8%]); no Japanese patients had febrile neutropenia. Palbociclib dose reductions due to toxicity (mainly neutropenia) were more common in Japanese patients (62.5% vs 36.0%); few permanently discontinued due to AEs. Although mean palbociclib trough concentration was higher in Japanese patients vs non-Asians (95.4 vs 61.7 ng/mL), the range of individual values of the Japanese patients was within that of non-Asians. CONCLUSIONS: These results from PALOMA-2 suggest that palbociclib-letrozole merits consideration as a first-line treatment option for postmenopausal Japanese patients with ER+/HER2‒ ABC. ClinicalTrials.gov: NCT01740427.

Disproportionate Effect of Sub-Micron Topography on Osteoconductive Capability of Titanium.

Titanium micro-scale topography offers excellent osteoconductivity and bone-implant integration. However, the biological effects of sub-micron topography are unknown. We compared osteoblastic phenotypes and in vivo bone and implant integration abilities between titanium surfaces with micro- (1-5 µm) and sub-micro-scale (0.1-0.5 µm) compartmental structures and machined titanium. The calculated average roughness was 12.5 ± 0.65, 123 ± 6.15, and 24 ± 1.2 nm for machined, micro-rough, and sub-micro-rough surfaces, respectively. In culture studies using bone marrow-derived osteoblasts, the micro-rough surface showed the lowest proliferation and fewest cells attaching during the initial stage. Calcium deposition and expression of osteoblastic genes were highest on the sub-micro-rough surface. The bone-implant integration in the Sprague-Dawley male rat femur model was the strongest on the micro-rough surface. Thus, the biological effects of titanium surfaces are not necessarily proportional to the degree of roughness in osteoblastic cultures or in vivo. Sub-micro-rough titanium ameliorates the disadvantage of micro-rough titanium by restoring cell attachment and proliferation. However, bone integration and the ability to retain cells are compromised due to its lower interfacial mechanical locking. This is the first report on sub-micron topography on a titanium surface promoting osteoblast function with minimal osseointegration.

Effectiveness of neo-adjuvant systemic therapy with trastuzumab for basal HER2 type breast cancer: results from retrospective cohort study of Japan Breast Cancer Research Group (JBCRG)-C03.

PURPOSE: While human epidermal growth factor receptor 2 (HER2) target therapies have significantly improved the prognosis of patients with HER2-enriched breast cancer, differing clinical benefits and gene expression analyses suggest a divergent HER2 subgroup. We aimed to investigate whether the basal HER2 subtype of breast cancer has distinguished characteristics. METHODS: We performed a substudy by using data from a retrospective multi-institutional cohort of JBCRG-C03. Between 2001 and 2011, we identified 184 eligible patients who received concurrent neo-adjuvant chemotherapy (NAC) with trastuzumab for hormone receptor-negative and HER2-positive breast cancer. We defined basal HER2 subtype breast cancer as HER2-positive, ER/PgR-negative, and basal markers (EGFR, CK14 or CK5/6) positive by immunohistochemistrical evaluation. The pathologic complete response (pCR) and disease-free survival (DFS) rates were compared between the two subtypes. RESULTS: A total of 127 (69.0%) patients achieved pCR after NAC and 29 (15.8%) patients experienced events of DFS within a 42 month median follow-up period (interquartile range 26-58 months). Although the basal HER2 subtype was related with poor DFS (3 year DFS: non-basal HER2, 95.0%; basal HER2, 86.9%; adjusted HR 3.4; 95% CI 1.2-14.5), neither the subtype (pCR: non-basal HER2, 75%; basal HER2, 66.7%; adjusted OR 0.60; 95% CI 0.27-1.28) nor the degree of expression of basal markers was significantly related with the pCR rate. CONCLUSION: Basal HER2 phenotype showed poor DFS, but equivalent pCR rate after concurrent neo-adjuvant chemotherapy with trastuzumab. A different treatment approach to basal-HER2 type is needed even for cases that achieved adequate clinical response after NAC.

Intraoperative Nomograms, Based on One-Step Nucleic Acid Amplification, for Prediction of Non-sentinel Node Metastasis and Four or More Axillary Node Metastases in Breast Cancer Patients with Sentinel Node Metastasis.

BACKGROUND: One-step nucleic acid amplification (OSNA) for cytokeratin 19 messenger RNA is an intraoperative diagnostic procedure for the detection of lymph node metastasis. OBJECTIVE: This study aimed to construct intraoperative nomograms using OSNA for the prediction of non-sentinel lymph node (NSLN) metastasis and four or more axillary lymph node (ALN) metastases. METHODS: Of the 4736 breast cancer patients (T1-3, N0) who underwent sentinel lymph node (SLN) biopsy and had SLNs examined intraoperatively with OSNA, 623 with SLN metastasis treated with completion ALN dissection (cALND) were retrospectively analyzed, and were randomly divided into training (n = 312) and validation (n = 311) sets. RESULTS: Of the clinicopathological parameters available preoperatively and intraoperatively, the multivariate analysis of the training set revealed that clinical tumor size and total tumor load (TTL) determined by OSNA were significantly associated with NSLN metastasis, and that clinical tumor size, number of macrometastatic SLNs, and TTL were significantly associated with four or more ALN metastases. Nomograms for NSLN metastasis and four or more ALN metastases were constructed using these parameters, and their area under the receiver operating characteristic curve (AUC) of the validation set were both 0.70, with a diagnostic accuracy similar to that of previously reported postoperative nomograms. CONCLUSIONS: We constructed intraoperative nomograms using OSNA for the prediction of NSLN metastasis and four or more ALN metastases. These nomograms are as accurate as the conventional postoperative nomograms and might be helpful for decision making regarding the indication for cALND or the choice of adjuvant chemotherapeutic regimens and radiation field.