Patient survey on cancer genomic medicine in Japan under the national health insurance system.

In Japan, comprehensive genomic profiling (CGP) tests have been reimbursed under the national health care system for solid cancer patients who have finished standard treatment. More than 50,000 patients have taken the test since June 2019. We performed a nation-wide questionnaire survey between March 2021 and July 2022. Questionnaires were sent to 80 designated Cancer Genomic Medicine Hospitals. Of the 933 responses received, 370 (39.7%) were web based and 563 (60.3%) were paper based. Most patients (784, 84%) first learned about CGP tests from healthcare professionals, and 775 (83.1%) gave informed consent to their treating physician. At the time of informed consent, they were most worried about test results not leading to novel treatment (536, 57.4%). On a scale of 0-10, 702 respondents (75.2%) felt that the explanations of the test result were easy to understand (7 or higher). Ninety-one patients (9.8%) started their recommended treatment. Many patients could not receive recommended treatment because no approved drugs or clinical trials were available (102/177, 57.6%). Ninety-eight patients (10.5%) did not wish their findings to be disclosed. Overall satisfaction with the CGP test process was high, with 602 respondents (64.5%) giving a score of 7-10. The major reason for choosing 0-6 was that the CGP test result did not lead to new treatment (217/277, 78.3%). In conclusion, satisfaction with the CGP test process was high. Patients and family members need better access to information. More patients need to be treated with genomically matched therapy.

Comprehensive genomic profiling from C-CAT database unveiled over 80% presence of oncogenic drivers in anaplastic thyroid carcinoma including BRAF, RAS family, NF1, and FGFR1.

OBJECTIVE: Anaplastic thyroid carcinoma (ATC) is considered a very aggressive carcinoma and has been difficult to treat with therapeutic strategies. This study examines the landscape of genomic alteration in ATC, including the BRAF V600E mutation, and its clinical implications. DESIGN, PATIENTS AND MESUREMENT: A retrospective observational study was conducted using collected at the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) in Japan, utilizing comprehensive genomic profiling data from 102 ATC cases. Additionally, AACR-GENIE data from 267 cases were analysed for validation. Statistical methods, including the conditional Kendall tau statistic and χ2 tests, were employed for survival analysis and gene mutation comparisons. RESULTS: Among 102 ATCs, BRAF, RAS, and other driver mutations were found in 83 cases (81.2%). The prevalence of BRAF V600E mutations was as high as 60%. Co-mutation analysis identified different genomic profiles in the BRAF, RAS, and wild-type groups. Despite the diverse molecular backgrounds, no significant differences in clinical variables and overall survival were observed. The analysis considering left-side amputation suggested that RAS mutations had a poorer prognosis. In the BRAF/RAS wild-type group, FGFR1 and NF1 were identified as driver mutations, with an accumulation of copy number variations and less TERT promoter mutations. This molecular subgrouping was also supported by the AACR-GENIE data. CONCLUSIONS: Comprehensive genomic analysis of ATC in Japan revealed distinct molecular subgroups, highlighting the importance of BRAF V600E mutations, particularly V600E, as potential therapeutic targets and suggest the relevance of tailor-made therapeutic strategies based on genomic profiling.

Human resources for administrative work to carry out a comprehensive genomic profiling test in Japan.

Comprehensive genomic profiling (CGP) tests have been nationally reimbursed in Japan since June 2019 under strict restrictions, and over 46,000 patients have taken the test. Core Hospitals and Designated Hospitals host molecular tumor boards, which is more time-consuming than simply participating in them. We sent a questionnaire to government-designated Cancer Genomic Medicine Hospitals, including all 12 Core Hospitals, all 33 Designated Hospitals, and 117 of 188 Cooperative Hospitals. The questionnaire asked how much time physicians and nonphysicians spent on administrative work for cancer genomic medicine. For every CGP test, 7.6 h of administrative work was needed. Physicians spent 2.7 h/patient, while nonphysicians spent 4.9 h/patient. Time spent preparing for molecular tumor boards, called Expert Panels, was the longest, followed by time spent participating in Expert Panels. Assuming an hourly wage of ¥24,000/h for physicians and ¥2800/h for nonphysicians, mean labor cost was ¥78,071/patient. On a monthly basis, more time was spent on administrative work at Core Hospitals compared with Designated Hospitals and Cooperative Hospitals (385 vs. 166 vs. 51 h/month, respectively, p < 0.001). Consequently, labor cost per month was higher at Core Hospitals than at Designated Hospitals and Cooperative Hospitals (¥3,951,854 vs. ¥1,687,167 vs. ¥487,279/month, respectively, p < 0.001). Completing a CGP test for a cancer patient in Japan is associated with significant labor at each hospital, especially at Core Hospitals. Streamlining the exchange of information and simplifying Expert Panels will likely alleviate this burden.

Clinical utility of Todai OncoPanel in the setting of approved comprehensive cancer genomic profiling tests in Japan.

Comprehensive cancer genome profiling (CGP) has been nationally reimbursed in Japan since June 2019. Less than 10% of the patients have been reported to undergo recommended treatment. Todai OncoPanel (TOP) is a dual DNA-RNA panel as well as a paired tumor-normal matched test. Two hundred patients underwent TOP as part of Advanced Medical Care B with approval from the Ministry of Health, Labour and Welfare between September 2018 and December 2019. Tests were carried out in patients with cancers without standard treatment or when patients had already undergone standard treatment. Data from DNA and RNA panels were analyzed in 198 and 191 patients, respectively. The percentage of patients who were given therapeutic or diagnostic recommendations was 61% (120/198). One hundred and four samples (53%) harbored gene alterations that were detected with the DNA panel and had potential treatment implications, and 14 samples (7%) had a high tumor mutational burden. Twenty-two samples (11.1%) harbored 30 fusion transcripts or MET exon 14 skipping that were detected by the RNA panel. Of those 30 transcripts, 6 had treatment implications and 4 had diagnostic implications. Thirteen patients (7%) were found to have pathogenic or likely pathogenic germline variants and genetic counseling was recommended. Overall, 12 patients (6%) received recommended treatment. In summary, patients benefited from both TOP DNA and RNA panels while following the same indication as the approved CGP tests. (UMIN000033647).

Long-Term Risk of Being Bedridden in Elderly Patients Who Underwent Oncologic Surgery: A Retrospective Study Using a Japanese Claims Database.

BACKGROUND: Although functional outcomes are important in surgery for elderly patients, the long-term functional prognosis following oncologic surgery is unclear. We retrospectively investigated the long-term, functional and survival prognosis following major oncologic surgery according to age among elderly patients. METHODS: We used a Japanese administrative database to identify 11,896 patients aged ≥ 65 years who underwent major oncological surgery between June 2014 and February 2019. We investigated the association between age at surgery and the postoperative incidence of bedridden status and mortality. Using the Fine-Gray model and restricted cubic spline functions, we conducted a multivariable, survival analysis with adjustments for patient background characteristics and treatment courses to estimate hazard ratios for the outcomes. RESULTS: During a median follow-up of 588 (interquartile range, 267-997) days, 657 patients (5.5%) became bedridden and 1540 (13%) died. Patients aged ≥ 70 years had a significantly higher incidence of being bedridden than those aged 65-69 years; the subdistribution hazard ratios of the age groups of 70-74, 75-79, 80-84, and ≥ 85 years were 3.20 (95% confidence interval [CI], 1.53-6.71), 3.86 (95% CI 1.89-7.89), 6.26 (95% CI 3.06-12.8), and 8.60 (95% CI 4.19-17.7), respectively. Restricted cubic spline analysis demonstrated an increase in the incidence of bedridden status in patients aged ≥ 65 years, whereas mortality increased in patients aged ≥ 75 years. CONCLUSIONS: This large-scale, observational study revealed that older age at oncological surgery was associated with poorer functional outcomes and higher mortality among patients aged ≥ 65 years.

Post-traumatic growth and cancer-related communication among adolescents having mothers with breast cancer.

PURPOSE: This study aimed to clarify the characteristics of post-traumatic growth (PTG) among adolescents having mothers diagnosed with breast cancer and the relationship between PTG and cancer-related communication with breast cancer survivors. METHODS: A cross-sectional study was conducted using anonymous self-report questionnaires with breast cancer survivors and adolescent children. PTG in adolescents was measured using the Japanese version of the revised PTG Inventory for Children (PTGI-C-R-J). Furthermore, hierarchical multiple regression analysis was implemented. To evaluate the impact of cancer-related communication on each subscale, the total score of cancer-related communication was switched with other subscales individually within the constructed model. RESULTS: A total of 97 breast cancer survivors and their adolescent children were included. The mean scores of the total PTGI-C-R-J and subscale scores for "personal strength," "new possibilities," "relating to others," "appreciation of life," and "spiritual change" were 9.0, 1.7, 1.8, 2.3, 2.4, and 0.9, respectively. The connection between PTG and cancer-related communication was partially clarified. The PTGI-C-R-J score was higher when adolescents shared more information regarding breast cancer with their mothers and lower when adolescents expressed more negative feelings toward their mothers. Communication regarding relationships with mothers was not correlated with PTG. CONCLUSIONS: Of all PTG domains, "relating to others" and "appreciation of life" were comparatively higher in adolescents. Health professionals should support breast cancer survivors to ensure that they convey appropriate information regarding their treatment plans and side effects to their adolescent children. Health professionals should help adolescent children express their negative feelings calmly and clearly.

Treatments and outcomes of adult parapharyngeal and retropharyngeal abscess: 1882 cases from a Japanese nationwide database.

PURPOSE: Although parapharyngeal and retropharyngeal abscesses are potentially fatal deep neck abscesses, there is limited evidence for the treatment courses for adult patients with these abscesses. We aimed to describe the practice patterns and clinical outcomes of adult patients undergoing an emergency surgery for parapharyngeal or retropharyngeal abscesses using a nationwide database. MATERIALS AND METHODS: We identified patients aged ≥18 years who underwent emergency surgery for parapharyngeal (para group, n = 1148) or retropharyngeal (retro group, n = 734) abscesses from July 2010 to March 2020, using a nationwide inpatient database. We performed between-group comparisons of the baseline characteristics, treatment course, and outcomes. RESULTS: Compared with the retro group, the para group was more likely to be older (median, 66 vs. 60 years; P < 0.001) and have several comorbidities, such as diabetes (21 % vs 16 %; P = 0.010) and epiglottitis (33 % vs. 26 %; P = 0.002), except for peritonsillar abscess (14 % vs. 22 %; P < 0.001) and tonsillitis (2.1 % vs. 13 %; P < 0.001). Regarding intravenous drugs administered within 2 days of admission, approximately half of the patients received steroids, non-antipseudomonal penicillins, and lincomycins. The para group received more comprehensive treatments, such as tracheostomy, intensive care unit admissions, and swallowing rehabilitation, within total hospitalization than the retro group. Moreover, it demonstrated higher in-hospital mortality (2.7 % vs. 1.1 %; P = 0.017) and morbidity (16 % vs. 9.7 %; P < 0.001), and longer length of hospitalization than the retro group. CONCLUSION: The current nationwide study provided an overview of the characteristics, treatments, and outcomes for patients who underwent an emergency surgery for parapharyngeal or retropharyngeal abscess.

Association between body mass index and incidence of breast cancer in premenopausal women: a Japanese nationwide database study.

PURPOSE: The association between body mass index (BMI) and the incidence of premenopausal breast cancer in the Asian population remains unclear. We investigated this association using data from a Japanese nationwide administrative database. METHODS: We retrospectively identified 785,703 females aged < 45 years with available health checkup data on BMI from January 2005 and April 2020 from a Japanese nationwide database. Cox proportional hazards model was used to estimate hazard ratios for breast cancer (total breast cancer, breast cancer with hormonal drug and trastuzumab administration, and breast cancer by age ≤ 45 years) associated with BMI recorded at the first health checkup. We conducted restricted cubic spline analysis without BMI categorization to investigate potential nonlinear associations with adjustment for backgrounds such as smoking and alcohol consumption. RESULTS: Overall, the median BMI was 20.5 (interquartile range [IQR], 18.9-22.7) kg/m2, and the median age was 37 (IQR, 29-41) years. Breast cancer occurred in 5597 participants (0.71%) at a median age of 44 (IQR, 42-46) years during a median follow-up of 1034 (IQR, 634-1779) days. A BMI of ≥ 22.0 kg/m2 was significantly associated with lower incidences of total breast cancer, breast cancer with hormonal drug administration, and breast cancer by age ≤ 45 years, whereas no significant associations were observed for breast cancer with trastuzumab administration. CONCLUSION: This study, which used a Japanese nationwide database, demonstrated that BMI was inversely associated with premenopausal breast cancer development in Japanese women, similar to that observed in Western women.

Surgical and obstetric outcomes of breast cancer surgery during pregnancy: a nationwide database study in Japan.

PURPOSE: Although the incidence of breast cancer during pregnancy is increasing, little is known about short-term outcomes following breast cancer surgery during pregnancy. We aimed to compare the characteristics and outcomes of breast cancer surgery with and without pregnancy, and describe the obstetric outcomes following surgery. METHODS: The data of 249,257 female patients aged < 60 years who underwent breast cancer surgery between July 2010 and March 2020 were analyzed using a nationwide Japanese database; we generated a 1:10 matched-pair cohort (260 and 2597 patients with and without pregnancy, respectively) matched according to age and treatment year. We conducted multivariable analyses to compare surgical procedures and outcomes, adjusting for potential confounders in the matched-pair cohort. Additionally, we described the obstetric outcomes of patients with pregnancy. RESULTS: Patients with pregnancy were more likely to undergo total mastectomy [odds ratio: 1.48 (95% confidence interval: 1.13-1.94)] and axillary dissection [1.62 (1.17-2.24)], but less likely to undergo reconstruction [0.14 (0.07-0.31)], than patients without; however, postoperative complications, postoperative length of stay, and total hospitalization costs did not differ significantly with pregnancy. Additionally, some pregnant patients experienced premature delivery [n = 18 (6.9%)] and miscarriage [n = 4 (1.5%)], and 31 of 101 patients in the third trimester at breast cancer surgery underwent a cesarean section. CONCLUSION: This study demonstrated significant differences regarding surgical procedures; however, there were no significant differences regarding surgical outcomes between patients who underwent breast cancer surgery with and without pregnancy. Obstetric outcomes following breast cancer surgery were also reported.

Short-Term Outcomes Following Breast Cancer Surgery With and Without Neoadjuvant Chemotherapy: A Nationwide Administrative Database Study in Japan.

PURPOSE: Although neoadjuvant chemotherapy (NAC) has become common for breast cancer, its impact on short-term surgical outcomes and the feasible chemotherapy-surgery interval remain unclear. Using a Japanese nationwide database, this study investigated the impact of NAC on short-term outcomes following breast cancer surgery. METHODS: In this study of 11,722 patients with NAC and 120,538 patients without NAC who underwent surgery for stage 0-III breast cancer July 2010-March 2017, to cancel out site-specific effects, we generated a 1:4 matched-pair cohort matched for age, institution, and fiscal year of admission. We then conducted multivariable analyses adjusting for potential confounders to compare postoperative complications, duration of anesthesia, and total hospitalization costs. Additionally, we conducted three sensitivity analyses for patients with a short interval from NAC to surgery, patients receiving a particular NAC regimen, and patients undergoing a particular surgical procedure. RESULTS: In total, the occurrence of postoperative complications was 6.0%, and the median interval from NAC to surgery was 31 (interquartile range, 24-39) days. The two groups did not differ significantly in terms of complications (odds ratio, 0.95; 95% confidence interval, 0.88-1.04), including local and general complications. NAC was significantly associated with shorter duration of anesthesia and lower total hospitalization costs. The sensitivity analyses showed similar results. CONCLUSIONS: Our matched-pair cohort analyses revealed no significant differences in postoperative complications between patients with and without NAC for breast cancer, regardless of the interval, regimen, and surgical procedure. Patients can safely receive surgery and NAC without a lengthened interval.

Cost-effectiveness analysis of trastuzumab monotherapy versus adjuvant chemotherapy plus trastuzumab in elderly patients with HER2-positive early breast cancer.

BACKGROUND: In elderly patients with human epidermal growth factor 2-positive breast cancer, adjuvant chemotherapy was associated with decreased quality of life, with relatively small benefits for prognosis. We examined the cost-effectiveness of trastuzumab monotherapy versus adjuvant chemotherapy plus trastuzumab in elderly patients with human epidermal growth factor 2-positive breast cancer. METHODS: A Markov model was developed to evaluate the costs and benefits of trastuzumab monotherapy over adjuvant chemotherapy plus trastuzumab for elderly patients with human epidermal growth factor 2-positive breast cancer. We built the model with a yearly cycle over a 20-year time horizon and five health states: disease-free, relapse, post-relapse, metastasis and death. The parameters in the model were based on a previous randomized controlled trial and a nationwide administrative database in Japan. The incremental cost-effectiveness ratio, expressed as Japanese yen per the quality-adjusted life-years, was estimated from the perspective of health care payers. One-way deterministic sensitivity analysis and probabilistic sensitivity analysis with Monte-Carlo simulations of 10 000 samples were conducted. RESULTS: The incremental cost-effectiveness ratio of trastuzumab monotherapy over adjuvant chemotherapy plus trastuzumab was $\sim$1.8 million Japanese yen /quality-adjusted life-year. The one-way deterministic sensitivity analysis showed that transition probability from disease-free to metastasis status and cost of metastasis status had the greatest influence on the incremental cost-effectiveness ratio. More than half the estimates in the probabilistic sensitivity analysis were located below a threshold of willingness-to-pay of 5 million Japanese yen /quality-adjusted life-year. CONCLUSION: In this first comparative cost-effectiveness analysis of adjuvant chemotherapy plus trastuzumab versus trastuzumab monotherapy in the elderly, the latter was found favorable for elderly patients with human epidermal growth factor 2-positive breast cancer.

Risk Factors for Postoperative Bleeding Following Breast Cancer Surgery: A Nationwide Database Study of 477,108 Cases in Japan.

BACKGROUND: Although postoperative bleeding is a common and serious complication in breast cancer surgery, the risk factors remain unclear. Therefore, we examined the risk factors using a Japanese nationwide database. METHODS: Patients who underwent breast cancer surgery between July 2010 and March 2020 were identified from a Japanese nationwide database. Multivariable analyses for 47 candidate risk factors (4 patient characteristics, 32 comorbidities, 5 tumor characteristics, 3 preoperative drug uses, and 3 surgical procedures) were conducted to investigate risk factors associated with postoperative bleeding requiring reoperation. Two sensitivity analyses were conducted: an analysis for postoperative bleeding with or without reoperation and an analysis for patients who underwent total mastectomy without breast reconstruction. RESULTS: Among the 477,108 patients included, 7048 (1.5%) developed postoperative bleeding and 2357 (0.5%) underwent reoperation for postoperative bleeding. Male sex, old age, body mass index ≥ 25.0 kg/m2, several comorbidities (deficiency anemia, cardiac arrhythmias, hypertension, liver disease, psychoses, and valvular disease), preoperative heparin use, and several procedures were identified as risk factors. Deficiency anemia showed the highest odds ratio among the risk factors (4.41 [95% confidence interval, 3.63-5.36]). High odds ratios were also observed in total mastectomy (2.32 [2.10-2.56]), flap reconstruction (1.93 [1.55-2.40]), and preoperative heparin use (1.64 [1.26-2.14]). The results corresponded with the sensitivity analyses. CONCLUSIONS: This study identified several risk factors for postoperative bleeding in breast cancer surgery, such as high body mass index, anemia, cardiovascular diseases, liver diseases, psychoses, preoperative heparin use, and surgical procedures.

Semaphorin signaling via MICAL3 induces symmetric cell division to expand breast cancer stem-like cells.

Cancer stem-like cells (CSCs) are expanded in the CSC niche by increased frequency of symmetric cell divisions at the expense of asymmetric cell divisions. The symmetric division of CSCs is important for the malignant properties of cancer; however, underlying molecular mechanisms remain largely elusive. Here, we show a cytokine, semaphorin 3 (Sema3), produced from the CSC niche, induces symmetric divisions of CSCs to expand the CSC population. Our findings indicate that stimulation with Sema3 induced sphere formation in breast cancer cells through neuropilin 1 (NP1) receptor that was specifically expressed in breast CSCs (BCSCs). Knockdown of MICAL3, a cytoplasmic Sema3 signal transducer, greatly decreased tumor sphere formation and tumor-initiating activity. Mechanistically, Sema3 induced interaction among MICAL3, collapsin response mediator protein 2 (CRMP2), and Numb. It appears that activity of MICAL3 monooxygenase (MO) stimulated by Sema3 is required for tumor sphere formation, interaction between CRMP2 and Numb, and accumulation of Numb protein. We found that knockdown of CRMP2 or Numb significantly decreased tumor sphere formation. Moreover, MICAL3 knockdown significantly decreased Sema3-induced symmetric divisions in NP1/Numb-positive BCSCs and increased asymmetric division that produces NP1/Numb negative cells without stem-like properties. In addition, breast cancer patients with NP1-positive cancer tissues show poor prognosis. Therefore, the niche factor Sema3-stimulated NP1/MICAL3/CRMP2/Numb axis appears to expand CSCs at least partly through increased frequency of MICAL3-mediated symmetric division of CSCs.

Validity of operative information in Japanese administrative data: a chart review-based analysis of 1221 cases at a single institution.

PURPOSE: To evaluate the validity of operative information recorded in the Diagnosis Procedure Combination (DPC) database, a national inpatient database including administrative claims data. METHODS: We reviewed the medical charts of 1221 patients who underwent one of six surgeries (breast, esophageal, gastric, thyroid cancer surgery, appendectomy, or inguinal hernia repair) at a surgery department of a university hospital from April 2016 to March 2019. We compared operative information (type, date, laterality of procedure; type of anesthesia; transfusion; and duration of anesthesia) recorded in the DPC database with the information recorded in the medical charts. RESULTS: The DPC data for type, date, laterality of surgery, and type of anesthesia were accurate in 99% of the reviewed patients. The sensitivity and specificity for identifying whether a patient received a transfusion procedure were 97.5% and 99.6%, respectively. Data regarding the duration of anesthesia in the DPC database were identical to those in medical chart records in 1114 of 1216 cases that received general or spinal anesthesia (91.5%). The duration of anesthesia in the DPC data was 53 min longer on average than the recorded operative time in the medical charts. CONCLUSION: The DPC database had high validity for operative information.

MCM10 compensates for Myc-induced DNA replication stress in breast cancer stem-like cells.

Cancer stem-like cells (CSCs) induce drug resistance and recurrence of tumors when they experience DNA replication stress. However, the mechanisms underlying DNA replication stress in CSCs and its compensation remain unclear. Here, we demonstrate that upregulated c-Myc expression induces stronger DNA replication stress in patient-derived breast CSCs than in differentiated cancer cells. Our results suggest critical roles for mini-chromosome maintenance protein 10 (MCM10), a firing (activating) factor of DNA replication origins, to compensate for DNA replication stress in CSCs. MCM10 expression is upregulated in CSCs and is maintained by c-Myc. c-Myc-dependent collisions between RNA transcription and DNA replication machinery may occur in nuclei, thereby causing DNA replication stress. MCM10 may activate dormant replication origins close to these collisions to ensure the progression of replication. Moreover, patient-derived breast CSCs were found to be dependent on MCM10 for their maintenance, even after enrichment for CSCs that were resistant to paclitaxel, the standard chemotherapeutic agent. Further, MCM10 depletion decreased the growth of cancer cells, but not of normal cells. Therefore, MCM10 may robustly compensate for DNA replication stress and facilitate genome duplication in cancer cells in the S-phase, which is more pronounced in CSCs. Overall, we provide a preclinical rationale to target the c-Myc-MCM10 axis for preventing drug resistance and recurrence of tumors.

Droplet-digital PCR reveals frequent mutations in TERT promoter region in breast fibroadenomas and phyllodes tumours, irrespective of the presence of MED12 mutations.

BACKGROUND: Breast fibroadenoma (FA) and phyllodes tumour (PT) often have variations of gene mediator complex subunit 12 (MED12) and mutations in the telomerase reverse transcriptase promoter region (TERTp). TERTp mutation is usually tested by Sanger sequencing. In this study, we compared Sanger sequencing and droplet-digital PCR (ddPCR) to measure TERTp mutations in FA and PT samples. METHODS: FA and PT samples were collected from 82 patients who underwent surgery at our institution from 2005 to 2016. MED12 mutations for all cases and TERTp mutations for 17 tumours were detected by Sanger sequencing. ddPCR was performed to analyse TERTp mutation in all cases. RESULTS: A total of 75 samples were eligible for analysis. Sanger sequencing detected MED12 mutations in 19/44 FA (42%) and 21/31 PT (68%). Among 17 Sanger sequencing-tested samples, 2/17 (12%) were TERTp mutation-positive. In ddPCR analyses, a significantly greater percentage of PT (19/31, 61%) was TERTp mutation-positive than was FA (13/44, 30%; P = 0.0046). The mutation positivity of TERTp and MED12 did not correlate, in either FA or PT. CONCLUSIONS: ddPCR was more sensitive for detecting TERTp mutation than Sanger sequencing, being able to elucidate tumorigenesis in FA and PT.

Association between body mass index and localization of breast cancer: results from a nationwide inpatient database in Japan.

PURPOSE: Although both localization of breast cancer and body mass index (BMI) are associated with prognosis, the association between localization of breast cancer and BMI remains unclear. This study aimed to investigate the association between localization of breast cancer and BMI at diagnosis. METHODS: Patients who underwent surgery for stage 0-III breast cancer July 2010-March 2017 were identified retrospectively in a Japanese nationwide inpatient database. Multinomial logistic regression analyses adjusting for patient's age were conducted to compare the outcomes among five BMI groups: < 18.5 kg/m2 (n = 31,724; 9.3%), 18.5-24.9 kg/m2 (n = 218,244; 64.3%), 25.0-29.9 kg/m2 (n = 69,813; 20.6%), 30.0-34.9 kg/m2 (n = 16,052; 4.7%), and ≥ 35.0 kg/m2 (n = 3716; 1.1%). The outcomes were the quadrant and side of the breast where tumors were detected. RESULTS: In total, about half of the patients had breast cancer in the upper-outer quadrant (49.7%) and in the left breast (51.1%). In the multinomial analysis, BMI ≥ 25.0 kg/m2 was associated with the occurrence of breast cancer in the upper-inner and lower-outer quadrants and in the central area, whereas BMI < 18.5 kg/m2 was associated with the occurrence of breast cancer in the central area only. The side of breast cancer did not differ significantly among the five BMI groups. CONCLUSIONS: Localization of breast cancer was associated with BMI in this large nationwide cohort. The findings may benefit patients' self-checks and doctors' examinations, potentially resulting in early detection and treatment.

Comparison of short-term surgical outcomes between men and women with breast cancer: a retrospective study using nationwide inpatient data in Japan.

PURPOSE: Although long-term survival is similar between men and women, little is known about the short-term outcomes following breast cancer surgery in men. This study was performed to compare postoperative outcomes adjusted for background factors between men and women with breast cancer using a Japanese nationwide inpatient database. METHODS: This study included 2126 men and 363,468 women who underwent surgery for stage 0-III breast cancer from July 2010 to March 2017. We generated a 1:4 matched-pair cohort matched for age, institution, and fiscal year at admission. We then conducted multivariable regression analyses to compare postoperative complications, 30-day readmission, duration of anesthesia, length of hospitalization, and total hospitalization costs between the sexes. RESULTS: Men were older, more likely to have comorbidities and advanced cancer, and more likely to undergo total mastectomy and axillary dissection than women. There were no significant differences in postoperative complications between the sexes, but men showed a lower risk of 30-day readmission (odds ratio 0.74; 95% confidence interval [CI] 0.57-0.95), shorter duration of anesthesia (difference - 22.0 min; 95% CI - 2.1 to - 0.5), shorter length of hospitalization (difference - 1.3 days; 95% CI - 2.1 to - 0.5), and lower total hospitalization costs (difference - 506 US dollars; 95% CI - 668 to - 334) than women. CONCLUSIONS: The matched-pair cohort analyses revealed no significant differences in postoperative complications between men and women with breast cancer. However, men showed better outcomes than women in terms of 30-day readmission, duration of anesthesia, length of hospitalization, and total hospitalization costs.

A phase II study of sequential treatment with anthracycline and taxane followed by eribulin in patients with HER2-negative, locally advanced breast cancer (JBCRG-17).

PURPOSE: The sequence of taxanes (T) followed by anthracyclines (A) as neoadjuvant chemotherapy has been the standard of care for almost 20 years for locally advanced breast cancer (LABC). Sequential administration of eribulin (E) following A/T could provide a greater response rate for women with LABC. METHODS: In this single-arm, multicenter, Phase II prospective study, the patients received 4 cycles of the FEC regimen and 4 cycles of taxane. After the A/T-regimen, 4 cycles of E were administered followed by surgical resection. The primary endpoint was the clinical response rate. Eligible patients were women aged 20 years or older, with histologically confirmed invasive breast cancer, clinical Stage IIIA (T2-3 and N2 only), Stage IIIB, and Stage IIIC, HER2-negative. RESULTS: A preplanned interim analysis aimed to validate the trial assumptions was conducted after treatment of 20 patients and demonstrated that clinical progressive disease rates in the E phase were significantly higher (30%) than assumed. Therefore, the Independent Data Monitoring Committee recommended stopping the study. Finally, 53 patients were enrolled, and 26 patients received the A/T/E-regimen. The overall observed clinical response rate (RR) was 73% (19/26); RRs were 77% (20/26) in the AT phase and 23% (6/26) in the E phase. Thirty percent (8/26) of patients had PD in the E phase, 6 of whom had achieved cCR/PR in the AT phase. Reported grade ≥ 3 AEs related to E were neutropenia (42%), white blood cell count decrease (27%), febrile neutropenia (7.6%), weight gain (3.8%), and weight loss (3.8%). CONCLUSION: Sequential administration of eribulin after the A/T-regimen provided no additional effect for LABC patients. Future research should continue to focus on identifying specific molecular biomarkers that can improve response rates.

Loss of BRCA1 expression and morphological features associated with BRCA1 promoter methylation status in triple-negative breast cancer.

Aberrant DNA methylation in the BRCA1 promoter region causes epigenetic silencing of BRCA1 gene expression, which is critical for breast cancer development. However, how BRCA1 promoter methylation status alters histological features remains poorly understood. Here, we investigated the possibility to predict BRCA1 promoter methylation status based on the morphological and immunohistochemical features of triple-negative breast cancers (TNBCs). The morphological features of 53 TNBCs were evaluated with hematoxylin-eosin staining, with immunohistochemical staining of BRCA1, androgen receptor, p53, cytokeratin 5/6, and epidermal growth factor receptor. BRCA1 promoter methylation status was used to distinguish BRCA1 promoter-methylated tumors (BPMTs) from BRCA1 promoter-unmethylated tumors (BPUTs) dependent on pathological characteristics. BPMTs comprised approximately 26% of the TNBCs. Immunohistochemical analysis found that BRCA1 protein expression was significantly lower in BPMT compared with BPUT (p = 0.016). Morphologically, BPMTs were associated with high mitotic index (p = 0.017), pushing margin (p = 0.017), a circumscribed growth pattern (p = 0.014), and a syncytial growth pattern (p = 0.034) compared with BPUTs. We then assessed the potential of predicting BRCA1 promoter methylation status by using published score systems based on these morphological characteristics. A receiver operating characteristic analysis showed an area under the curve of 0.80. This study found that BRCA1 promoter methylation status could be derived from morphological features and lower BRCA1 expression of TNBCs, which may help identify suitable cases for target treatment with PARP inhibitors.