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Adjuvant therapy; Breast cancer; Olaparib Terapia adyuvante; Cáncer de mama; Olaparib Teràpia adjuvant; Càncer de mama; Olaparib Background The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI −0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals. Funding for this work, which was conducted as a collaborative partnership among the Breast International Group, NRG Oncology, Frontier Science, AstraZeneca, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A. (MSD), was provided by the National Institutes of Health (grant numbers: U10CA 180868, UG1CA 189867, and U10CA 180822) and by AstraZeneca as part of an alliance between AstraZeneca and MSD. Provision of olaparib and placebo was from AstraZeneca.

Purpose:Sentinel lymph node biopsy (SLNB) is the gold-standard procedure for evaluating axillary lymph node (ALN) status in patients with breast cancer. However, the morbidity of SLNB is not negligible, and the procedure is invasive for patients without ALN metastasis. Here, we developed a diagnostic model for evaluating ALN status using a combination of serum miRNAs and clinicopathologic factors as a novel less-invasive biomarker.Experimental Design: Preoperative serum samples were collected from patients who underwent surgery for primary breast cancer or breast benign diseases between 2008 and 2014. A total of 958 serum samples (921 cases of primary breast cancer, including 630 cases in the no ALN metastasis group and 291 cases in the ALN metastasis group, and 37 patients with benign breast diseases) were analyzed by miRNA microarray. Samples were randomly divided into training and test sets. Logistic LASSO regression analysis was used to construct diagnostic models in the training set, which were validated in the test set.Results:An optimal diagnostic model was identified using a combination of two miRNAs (miR-629-3p and miR-4710) and three clinicopathologic factors (T stage, lymphovascular invasion, and ultrasound findings), which showed a sensitivity of 0.88 (0.84–0.92), a specificity of 0.69 (0.61–0.76), an accuracy of 0.818, and an area under the receiver operating characteristic curve of 0.86 in the test set.Conclusions:Serum miRNA profiles may be useful for the diagnosis of ALN metastasis before surgery in a less-invasive manner than SLNB.

Table S1. Definition criteria of categorical variables for logistic-LASSO regression analysis Table S2. Clinicopathological characteristics of patients with benign breast diseases Table S3. Clinicopathological characteristics of patients stratified into the training set and test set Table S4. Comparison of T staging between pre- and post-operative diagnosis Table S5. Comparison of lymphovascular invasion (LVI) between pre- and post-operative diagnosis Table S6. Clinicopathological characteristics of N-positive patients misdiagnosed as N-negative in the test set Table S7. Sensitivity and specificity analysis for the diagnostic index in the test set Table S8. Biomarker candidate miRNAs for N positivity Table S9. Comparison of post-operative lymphovascular invasion (LVI) between original and re-evaluated diagnosis in the training set Table S10. Characteristics of ultrasound findings of axillary lymph node status Table S11. Utility of ultrasonography for the detection of axillary lymph node metastasis Figure S1. Ultrasound findings of suspicious metastatic and negative axillary lymph nodes. Figure S2. Serum levels of miR-629-3p and miR-4710 in the training set. P-values were calculated by one-way ANOVA with Tukey's post-hoc analysis. Figure S3. ROC curves for histological grade and Ki-67 labeling index in the test set (postoperative pathology). Numbers in parentheses are 95% confidence intervals. Text. Materials and Methods

Background The V-Akt murine thymoma viral oncogene (AKT) 1 (E17K) is a subfamily of serine/threonine protein kinases that affects the survival, proliferation, and invasion of cancer cells. The clinicopathological features and frequencies in Asian populations with AKT1 mutations in breast and endometrial cancers are unclear. Hence, we aimed to determine the frequencies and relationships between clinicopathological features and AKT1 mutations in Asian women with cancer. Methods We extracted DNA from 311 and 143 samples derived from patients with breast and endometrial cancers to detect the AKT1 point mutation (hotspot), E17K. We examined correlations between clinicopathological features and AKT1 mutation status. Results The frequency of AKT1 mutations in breast cancer was 7.4%, and they were found more frequently in human epidermal growth factor receptor 2 (HER2)-negative breast cancer subtypes, although this was not statistically significant (P = 0.08). The frequency of AKT1 mutations in endometrial cancer was 4.1%, and the mutations were histologically detected only in endometrioid types. However, AKT1 mutations did not correlate with relapse-free or overall survival of patients with breast or endometrial cancer. Conclusions AKT1 mutations are associated with HER2-negative subtype in breast cancer and in endometrial cancer with endometrioid histology. The frequencies of AKT1 mutations in breast and endometrial cancers were similar between Asian and other regional women. The frequency of mutations is too low in both tumor types to talk about predictive significance.

Background Noninvasive detection of early stage cancers with accurate prediction of tumor tissue-of-origin could improve patient prognosis. Because miRNA profiles differ between organs, circulating miRNomics represent a promising method for early detection of cancers, but this has not been shown conclusively. Methods A serum miRNA profile (miRNomes)–based classifier was evaluated for its ability to discriminate cancer types using advanced machine learning. The training set comprised 7931 serum samples from patients with 13 types of solid cancers and 5013 noncancer samples. The validation set consisted of 1990 cancer and 1256 noncancer samples. The contribution of each miRNA to the cancer-type classification was evaluated, and those with a high contribution were identified. Results Cancer type was predicted with an accuracy of 0.88 (95% confidence interval [CI] = 0.87 to 0.90) in all stages and an accuracy of 0.90 (95% CI = 0.88 to 0.91) in resectable stages (stages 0-II). The F1 score for the discrimination of the 13 cancer types was 0.93. Optimal classification performance was achieved with at least 100 miRNAs that contributed the strongest to accurate prediction of cancer type. Assessment of tissue expression patterns of these miRNAs suggested that miRNAs secreted from the tumor environment could be used to establish cancer type–specific serum miRNomes. Conclusions This study demonstrates that large-scale serum miRNomics in combination with machine learning could lead to the development of a blood-based cancer classification system. Further investigations of the regulating mechanisms of the miRNAs that contributed strongly to accurate prediction of cancer type could pave the way for the clinical use of circulating miRNA diagnostics.

BackgroundWhile many studies have verified the effect of recent anti-cancer treatment in patients with COVID-19, there are no data on the optimal time for cancer treatment resumption, as well as the safety of chemotherapy in COVID-19 patients. As many cancer patients are recovering from COVID-19, there is an urgent need for reliable clinical information. Herein, we report a case of invasive ductal carcinoma in which we were able to successfully resume chemotherapy after infection with SAR-CoV-2.Case presentationThe patient was a 38-year-old non-smoking Japanese woman with no significant medical history. She had fever on days 5 and 6 of her second course of adjuvant FEC therapy, and on day 7, she tested positive for SARS-CoV-2 by RT-PCR. She was hospitalized for 11 days. We resumed the therapy on day 25 after discharge, as she had no remaining clinical symptoms. The patient completed four courses of the initial chemotherapy without any major adverse events nor the recurrence of COVID-19, and subsequently completed four courses of docetaxel as her second regimen therapy.ConclusionsEvaluating the risk for each patient is essential when resuming anti-cancer therapy in cancer patient’s post-COVID-19.

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.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.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.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.Public Health Research Foundation (Japan), Taiho Pharmaceutical.

Background Most patients with hormone receptor (HR)-positive, human epidermal growth factor receptor type 2 (HER2)-negative breast cancer can be cured by surgery and endocrine therapy, but a significant proportion suffer recurrences. Actinin-4 is associated with cancer invasion and metastasis, and its genetic alteration may be used for breast cancer prognostication. Methods The copy number of the actinin-4 (ACTN4) gene was determined by fluorescence in situ hybridisation (FISH) in two independent cohorts totalling 597 patients (336 from Japan and 261 from the USA) with HR-positive, HER2-negative, node-negative breast cancer. Results In the Japanese cohort, multivariate analysis revealed that a copy number increase (CNI) of ACTN4 was an independent factor associated with high risks of recurrence (P = 0.01; hazard ratio (HR), 2.95) and breast cancer death (P = 0.014; HR, 4.27). The prognostic significance of ACTN4 CNI was validated in the US cohort, where it was the sole prognostic factor significantly associated with high risks of recurrence (P = 0.04; HR, 2.73) and death (P = 0.016; HR, 4.01). Conclusions Copy number analysis of a single gene, ACTN4, can identify early-stage luminal breast cancer patients with a distinct outcome. Such high-risk patients may benefit from adjuvant chemotherapy.

Dysfunctional processing of fear memory may be involved in the pathophysiology of fear of cancer recurrence (FCR), which is cited as the major unmet psychological need of cancer survivors. Emerging evidence has shown that the microbiota-gut-brain (MGB) axis affects depressive and anxiety disorders, and chemotherapy-associated psychological distress. We therefore hypothesized that the gut microbiota is associated with FCR in cancer survivors.This cross-sectional study enrolled women diagnosed with invasive breast cancer who were not currently undergoing chemotherapy. Fecal samples were obtained to assess the gut microbiota. FCR grade was assessed using the Concerns About Recurrence Scale (CARS).Mean age of the participants (n = 126) was 58 years; 47% had stage I disease. Multiple regression analysis with adjustment for possible confounders showed that the relative abundance of the Bacteroides genus (beta = 0.180, p = 0.03) was significantly and directly associated with FCR. In the 57 participants with a history of chemotherapy, higher FCR was associated with lower microbial diversity (p = 0.04), lower relative abundance of Firmicutes (p = 0.03) and higher relative abundance of Bacteroidetes (p = 0.04) at the phylum level, and higher relative abundance of Bacteroides (p 0.01) and lower relative abundance of Lachnospiraceae.g (p = 0.03) and Ruminococcus (p = 0.02) at the genus level.Our findings provide the first evidence of an association between the gut microbiota and FCR and suggest that chemotherapy-induced changes in gut microbiota can influence FCR. Further studies should examine the effects of the gut microbiota on FCR using a prospective design.

BACKGROUND: Although long-term prognostic outcomes of primary breast cancer (PBC) patients have been improved remarkably in recent years, the disease recurrence remains a serious problem. We have previously investigated a role for oral fluoropyrimidines in postoperative adjuvant treatments.In this study, we aimed to verify the usefulness of S-1 in combination with adjuvant endocrine therapy for PBC patients having luminal disease. PATIENTS AND METHODS: This open-label, randomized, phase 3 trial was carried out in 139 centers in Japan. StageI-IIIPBC patients, who had hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negativestatus and intermediate or higher risk of recurrence were randomly assigned (1:1) to receive standard endocrine therapy alone (control arm) or endocrine therapy plus S-1 (S-1 arm). Recurrence risk assessment was performed using anatomical stage, pathological findings such as histologic grade, and centrally confirmed proliferative marker status. S-1 was administered postoperatively in combination with standard endocrine therapy. For patients who underwent multi-drug postoperative adjuvant or preoperative neoadjuvant chemotherapy, S-1 was administered following the multi-drug chemotherapy. Cases having no residual cancer in the breast and axillary node after the preoperative chemotherapy were excluded from this study. The S-1 dosage was chosen among 80 mg/day, 100 mg/day, and 120 mg/day according to the body surface area of each patient, and S-1 was administered for one year with a 2 weeks on/1 week off administration schedule. The primary endpoint was invasive disease-free survival (iDFS), defined as time from randomization to invasive disease recurrence, occurrence of second invasive cancer event, or death, and was analyzed on an intent-to-treat basis. Secondary endpoints included DFS, distant DFS, overall survival, and safety profile. RESULTS: From Feb 2012 to Feb 2016, 1959 patients were enrolled and 1932 patients were included in the full analysis set (control arm, 973; S-1 arm, 959). The results of the prespecified interim analysis met the primary end point, and this trial was terminated early. Median follow-up was 51.4 months. S-1 significantly reduced invasive events; 153 iDFS events were reported in the control arm and 99 iDFS events were reported in the S-1 arm [hazard ratio, 0.63 (95%CI, 0.49-0.81); p-value, 0.0003]. The 5-year iDFS estimate was 81.5% in the control arm and 86.9% in the S-1 arm. Distant recurrence as the first disease event was observed in 6.8% of patients in the S-1 arm and in 9.5% of those in the control arm. The safety data in patients treated with S-1 was consistent with the known profile of S-1. The S-1 treatment was well tolerated and manageable. CONCLUSIONS: It was concluded that the postoperative adjuvant use of an oralfluoropyrimidine S-1 significantly reduced iDFS events and improved 5-year iDFS estimate in PBC patients having HR-positive and HER2-negative disease, in the combination with standard endocrine therapy, with a feasible safety profile. Funding: This study was funded by the Comprehensive Support Project (CSP) of the Public Health Research Foundation. The research fund was provided to CSP by Taiho Pharmaceutical Co., Ltd. This trial was conducted as a study of ‘Advanced Medical Care,’ the Ministry of Health, Labour and Welfare, Japan. JRCT ID: jRCTs051180057, UMIN000003969 Citation Format: Masakazu Toi, Shigeru Imoto, Takanori Ishida, Yoshinori Ito, Hiroji Iwata, Norikazu Masuda, Hirofumi Mukai, Shigehira Saji, Akira Shimizu, Takafumi Ikeda, Hironori Haga, Toshiaki Saeki, Kenjiro Aogi, Tomoharu Sugie, Takayuki Ueno, Takayuki Kinoshita, Yuichiro Kai, Masahiro Kitada, Yasuyuki Sato, Kenjiro Jimbo, Nobuaki Sato, Hiroshi Ishiguro, Masahiro Takada, Yasuo Ohashi, Shinji Ohno. Addition of S-1 to endocrine therapy in the post-operative adjuvant treatment of hormone receptor-positive and human epidermal growth factor receptor 2-negative primary breast cancer: A multicenter, open-label, phase 3 randomized trial (POTENT trial) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS1-09.

Maintaining high levels of physical activity not only helps to maintain and improve physical health and quality of life, but also plays a role in reducing adverse effects due to cancer treatments. Moreover, a greater degree of cardiorespiratory fitness is associated with reduced risk of all-cause mortality in breast cancer survivors. However, there are no home-based programs for improving cardiorespiratory fitness using body weight exercises for breast cancer survivors. This study assesses the efficacy of the newly developed habit-B program (12-weeks, high-intensity interval training exercise, exercise counseling + guidance, home-based exercise support using information and communication technology, and a wearable device (fitbit versa®)) on peak oxygen uptake (VO2peak; mL/kg/min) compared with treatment as usual. This is a parallel-group, single blind, randomized controlled trial. Subjects are sedentary women aged 20 to 59 years who have received breast surgery in the past 2 to 13 months after diagnosis of invasive breast cancer (Stage I-IIa) and have never received chemo-therapy except for hormone therapy. The primary outcome is difference of change in VO2peak between the groups after 12 weeks. The planned sample size is 60 patients to detect the increase of 2.0 ml/kg/min change in VO2peak with a one-sided significance level of 2.5% and 80% power. The effects of this program on exercise habits, physical activity, physical fitness, fatigue, health-related quality of life, and psychological distress are also be investigated. We have already enrolled 6 subjects as of 2019.7.2, and study will be planned to be finished by 2020 April. Citation Format: Katsunori Tsuji, Eisuke Ochi, Yoichi Shimizu, Aya Kuchiba, Tomomi Narisawa, Yuri Ishino, Ryo Okubo, Taro Ueno, Taichi Shimazu, Takayuki Kinoshita, Naomi Sakurai, Yutaka Matsuoka. Effect of home-based high-intensity interval training and behavioral modification using information and communication technology on cardiorespiratory fitness and exercise habits among sedentary breast cancer survivors: The habit-B randomized controlled trial in progress [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT3-12-01.

Highlights • Breast cancer arising in association with a fibroadenoma (FA) is rare and usually early-stage. • We report a rare case of an advanced triple negative breast cancer, with lymph node metastases, within a long-standing FA. • Pathological complete response was achieved after neoadjuvant chemotherapy, as proven on mastectomy with axillary clearance., Introduction Breast cancer arising from benign fibroadenoma (FA) is rare. The histological type of the former was either carcinoma in situ or early-stage invasive breast carcinoma with hormone receptor positive/HER2 (human epidermal growth factor receptor-2)-negative phenotype. Meanwhile, advanced breast cancer of triple negative (TN) phenotype such as our case is extremely uncommon and clinically challenging. Presentation of case We experienced a case of a 53-year-old woman that had invasive ductal carcinoma of TN phenotype in FA with multiple lymph node metastases. After receiving neoadjuvant chemotherapy (NAC), she underwent breast mastectomy and axillary dissection. The pathological examination on postoperative specimens revealed the dense fibrous stroma in the FA without any residual viable tumor cells and was considered as pathological complete response (pCR). Discussion This is the first report presenting a case of NAC treatment for invasive ductal carcinoma (IDC) in FA. Furthermore, the patient achieved pCR even if IDC was located within FA. Diagnosing breast cancer in FA may be challenging as the carcinoma component may be hidden by the FA component. If imaging of FA became larger or abnormal changes during follow-up examinations, needle biopsy should be recommended for assessment of the lesion positively. Conclusion This is the first report presenting a case of advanced breast cancer in FA of TN phenotype with multiple lymph node metastases who achieved pCR even if IDC was located within FA.

Adding taxane to an anthracycline-based regimen improves survival in node-positive breast cancer patients, as shown by clinical trials and meta-analyses. However, no studies have analyzed the number of metastatic lymph nodes in patients with estrogen receptor (ER)-positive cancer. This study investigated whether adding a taxane to an anthracycline-based regimen improved prognosis in node-positive, ER-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients in a real-world setting. Using Japanese Breast Cancer Society registry data, we compared disease-free survival (DFS) of patients with ER-positive, HER2-negative breast cancer, excluding those receiving neoadjuvant chemotherapy, between those who received an anthracycline-based regimen followed by a taxane-based regimen (A + T) and those who received only an anthracycline-based regimen (A w/o T), stratified by lymph node status. A Cox proportional hazards model was used to evaluate DFS in both groups. There were 4566 eligible patients with ER-positive, HER2-negative breast cancer. During the median follow-up period of 60 months, there were 481 recurrences and 149 deaths. There was no significant difference in DFS between the A + T and A w/o T groups among patients with 1–3 positive nodes, while there was a significant difference among patients with ≥ 4 positive nodes. In patients with ER-positive, HER2-negative breast cancer, adding taxane to an anthracycline regimen did not improve DFS in patients with metastasis in 1–3 lymph nodes. We considered that the group without the addition of taxane might be present in patients with ER-positive, HER2-negative lymph node metastases.

Purpose: Sentinel lymph node biopsy (SLNB) is the gold-standard procedure for evaluating axillary lymph node (ALN) status in patients with breast cancer. However, the morbidity of SLNB is not negligible, and the procedure is invasive for patients without ALN metastasis. Here, we developed a diagnostic model for evaluating ALN status using a combination of serum miRNAs and clinicopathologic factors as a novel less-invasive biomarker. Experimental Design: Preoperative serum samples were collected from patients who underwent surgery for primary breast cancer or breast benign diseases between 2008 and 2014. A total of 958 serum samples (921 cases of primary breast cancer, including 630 cases in the no ALN metastasis group and 291 cases in the ALN metastasis group, and 37 patients with benign breast diseases) were analyzed by miRNA microarray. Samples were randomly divided into training and test sets. Logistic LASSO regression analysis was used to construct diagnostic models in the training set, which were validated in the test set. Results: An optimal diagnostic model was identified using a combination of two miRNAs (miR-629-3p and miR-4710) and three clinicopathologic factors (T stage, lymphovascular invasion, and ultrasound findings), which showed a sensitivity of 0.88 (0.84–0.92), a specificity of 0.69 (0.61–0.76), an accuracy of 0.818, and an area under the receiver operating characteristic curve of 0.86 in the test set. Conclusions: Serum miRNA profiles may be useful for the diagnosis of ALN metastasis before surgery in a less-invasive manner than SLNB.

Background Discordance in biomarker expression between primary and metastatic tumor sites has been reported in several studies; yet, few have examined this feature in bone lesions. Methods We retrospectively enrolled patients with breast cancer metastasis to the bone or bone marrow, excluding cases where samples from both the primary and metastatic lesions were not available. Expression patterns of the estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2) and Ki67 were compared in primary tumors and bone or bone marrow lesions. Results Forty-six patients with a median age of 52 years (range, 34-72 years) were included in the study. Discordant rates of ER, PgR and HER2 were 20%, 46% and 0%, respectively. Physicians usually determined treatment options considering the results of biomarker re-evaluation. It is unlikely that biomarker discordance was related to prior treatment. Conclusions Biomarker discordance in bone or bone marrow lesions is common in patients with breast cancer. An accurate and thorough analysis of biomarkers and metastatic tumor properties is important for clinical decision-making.

Background The pathophysiology of fear of cancer recurrence (FCR), the leading unmet psychological need of cancer survivors, may involve the dysfunctional processing of fear memory. n-3 polyunsaturated fatty acids (PUFAs) have beneficial effects on psychiatric disorders, including depressive disorder and anxiety disorders, and are involved in fear memory processing. We hypothesized that n-3 PUFA composition is associated with FCR in cancer survivors. Methods We conducted a cross-sectional study to examine the relationship between n-3 PUFAs and FCR among breast cancer survivors. Adults who had been diagnosed with invasive breast cancer and were not undergoing chemotherapy were asked to participate. Blood PUFA composition was evaluated by using capillary blood. We directly administered the Concerns About Recurrence Scale (CARS) to assess the grade of FCR. Results Among 126 participants used for the analysis, the mean age (SD) was 58 (11) years and 47% had stage I cancer. Multiple regression analysis controlling for possible confounders, depressive symptoms, and post-traumatic stress disorder (PTSD) symptoms revealed that the alpha-linolenic acid (ALA) level was significantly inversely associated with the average score on the CARS overall fear index (beta = −0.165, p = 0.04). No significant associations were found for other PUFAs. Limitations Our findings were obtained from a cross-sectional study in a single institute. Conclusion These findings provide the first evidence of a beneficial effect of ALA on FCR and indicate the need for prospective study of this association. FCR among breast cancer survivors might be controllable by prudent selection of ALA-containing cooking oil.

Prospective randomized trials have demonstrated that postmastectomy radiotherapy (PMRT) improves not only locoregional recurrence-free survival, but also overall survival for node-positive breast cancer patients. Subset analyses in previous trials have shown that improvement of overall survival with PMRT is not always demonstrated for patients with 1-3 positive nodes. Indications for PMRT are still marginal for patients with pathological invasion 5 cm in diameter and 1-3 positive nodes. The aim of this study was to clarify poor prognostic factors for breast cancer patients with pathological invasion size 5 cm and 1-3 positive nodes. Participants comprised 428 breast cancer patients with T1-2 tumor and 1-3 positive axillary nodes (pT1-2 N1) treated using total mastectomy without radiotherapy. Correlations between clinicopathological characteristics and 10-year Kaplan-Meier estimates of locoregional recurrence-free survival, disease-free survival, and overall survival were retrospectively analyzed. Median follow-up was 98 months. Locoregional recurrence was observed in 20 patients (4.7%), and distant recurrence was observed in 70 patients (16.4%). Disease-free survival rate was 80.8%, and overall survival rate within the study period was 90%. Multivariate analysis demonstrated that favorable prognostic factors for locoregional recurrence-free survival were the presence of chemotherapy and positive hormone receptor status, and for disease-free survival were presence of chemotherapy, pT1 tumor, and single positive node. Physicians may consider these favorable prognostic factors in decision to eliminate PMRT from patients with the borderline indications.

Limited knowledge exists concerning the clinicopathological features of breast cancers (BCs) occurring in adolescent and young adult (AYA) women. We evaluated tumor characteristics in AYA women in comparison with those in middle-aged premenopausal women. From consecutive AYA patients (

In contrast to the cumulative evidence suggesting the inverse association of n-3 polyunsaturated fatty acids (PUFAs) with depression, few studies have examined the association of n-6 PUFAs with depression. In particular, no study has examined the relationship between n-6 PUFAs and depression in cancer patients. Thus, we conducted this cross-sectional study to comprehensively examine the association of n-3 and n-6 PUFAs with depressive symptoms in breast cancer survivors. Adults who had been diagnosed with invasive breast cancer and were not undergoing chemotherapy were enrolled. Blood PUFA composition was determined using capillary blood. Depressive symptoms were assessed using the Hospital Anxiety and Depression Scale (HADS). Among 126 participants, the mean age (standard deviation) was 58 (11) years and 47% had stage I cancer. Multiple regression analysis controlling for possible confounders revealed that the level of total n-6 PUFAs and linoleic acid was significantly associated with the HADS total score (beta = 0.175, p = 0.046 for total n-6 PUFAs; beta = 0.174, p = 0.048 for LA). No significant associations were found for other PUFAs. These findings provide the first evidence suggesting that a higher blood level of total n-6 PUFAs and linoleic acid is significantly associated with higher depressive symptoms among breast cancer survivors. Further studies should examine the positive effects of a reduction in n-6 PUFAs on depressive symptoms in breast cancer survivors using prospective studies, including randomized control trials.

The fear of cancer recurrence (FCR) is the most common and most severe unmet need among cancer survivors. Safe treatments for the FCR that are easily disseminated are greatly needed. Our primary aim is a preliminary evaluation of the efficacy and effect size of perilla oil, which is rich in omega-3 fatty acids, and Bifidobacterium, a probiotic, on FCR in breast cancer survivors after the completion of chemotherapy. This study has been planned as an exploratory clinical study (phase II) and will be conducted as a three-arm, 12-week parallel group, masked-rater randomized controlled trial. Fifteen participants will be randomized with 1:1:1 allocation to receive Bifidobacterium plus perilla oil, Bifidobacterium alone, or no intervention (control). Interventions will end within 12 weeks after the random allocation of each participant. The participants will be outpatients with invasive breast cancer aged 20 years or older whose chemotherapy was completed at least 6 months before registration; hormone therapy may be ongoing. The primary outcome will be severity of FCR at 12 weeks assessed by masked raters using the 4-item Concerns about Recurrence Scale concerning overall fear of recurrence. The study protocol for the current study is registered in the Japan Registry of Clinical Trials (jRCTs031200029).

Breast cancer survival outcomes vary across different ethnic groups. We clarified the differences in clinicopathological and survival characteristics of breast cancer among Japanese, US residents with Japanese origin (USJ), and US residents with other origins (USO). Using Surveillance, Epidemiology, and End Results (SEER) 18 dataset and Japanese Breast Cancer Society (JBCS) registry, we included patients first diagnosed with breast cancer between 2004 and 2015. We categorized the patients into three groups based on the database and the recorded ethnicity: Japanese (all those from the JBCS registry), USJ (those from SEER with ethnicity: Japanese), and USO (those from SEER with ethnicity other than Japanese). Excluding patients diagnosed after 2012, stage 0, and 4 patients, we examined the overall survival (OS) and breast cancer-specific survival (BCSS) using the Kaplan–Meier method and Cox proportional hazards models, adjusting for age, sex, cancer stage, and hormone receptor (HR) status. We identified 7362 USJ, 701,751 USO, and 503,013 Japanese breast cancer patients. The proportion of HR-positive breast cancer was the highest among USJ (71%). OS was significantly longer among Japanese and USJ than USO (Hazard ratio 0.46; 95% Confidence Interval [CI] 0.45–0.47 for Japanese and 0.66 [95% CI 0.59–0.74] for USJ) after adjusting for baseline covariates. BCSS was also significantly higher in the two groups (HR 0.53 [95% CI 0.51–0.55] for Japanese and 0.53 [95% CI 0.52–0.74] for USJ). In stage I–III breast cancer, Japanese and US residents with Japanese origin experienced significantly longer survival than US residents with non-Japanese origins.

Objectives To compare gynaecological and breast cancer patients in their information-seeking behaviours, usefulness of information sources and ongoing care needs after discharge to prevent the onset of lymphoedema. Methods We conducted a consecutive cross-sectional survey in an oncology hospital. Adult patients with stage I, II or III gynaecological or breast cancer who had undergone lymph node dissection and had not been diagnosed with lymphoedema were eligible for inclusion. The survey explored physical health status, knowledge of self-care, information-seeking behaviours, information sources and need for ongoing care from an oncology hospital and/or community health centre. Results Among 254 patients recruited, 202 responded (79.5% response rate). In total, 147 patients were eligible for statistical analysis. Irrespective of cancer type, the most commonly sought information was lymph drainage. Information on preventing weight gain was sought more often by breast cancer patients than gynaecological cancer patients. Regardless of cancer type, the most common information sources were nurses at an oncology hospital. Gynaecological cancer patients perceived nurses at the oncology hospital as useful for understanding risks, symptoms and prevention of lymphoedema. Irrespective of cancer type, ongoing need for help with lymphoedema prevention was reported both from the oncology hospital and the community centre. Limb symptoms, poor health status and poor knowledge affected the ongoing needs of gynaecological cancer patients at the oncology hospital, whereas poor health status affected ongoing needs in community health centres among both types of cancer patients. Conclusions Both gynaecological and breast cancer patients reported ongoing care needs, but that details of information-seeking behaviours differed.

About 5% of Triple negative breast cancer patients (TNBCs) who receive neoadjuvant chemotherapy (NAC) experience progressive disease (PD). Few reports are published on TNBCs with PD during NAC, whereas TNBCs that respond to NAC have been well-studied. We investigated kinase activity profiles of TNBCs to explore the biological differences underlying the lack of response to NAC. Among 740 TNBCs, 20 non-responders were identified. Seven non-responders and 10 TNBCs that did not receive NAC (control group) were evaluated. No correlation was observed between NAC response and age, menopausal status, tumor size and axillary lymph node status. Tyrosine kinase activity profiles of TNBC primary tissues from NAC non-responders and the controls were determined with a peptide microarray system. Kinase activity measurements showed that 35 peptides had significantly (p < 0.05) lower phosphorylation in non-responders. ZAP70, LCK, SYK and JAK2 were identified as differentially active upstream kinases. Pathway analysis suggested lower activity in immune-related pathways in non-responders. The number of tumor infiltrating lymphocytes (TILs) was significantly lower (p = 0.0053) in non-responders. Kinases related to the immune system are less activated in non-responders. TILs evaluation suggested that the immune system is hardly active in non-responders and is not activated by NAC treatment.

PIK3CA mutations are common activating mutations associated with breast cancer (occurring in 20-30% of all cases) and are potent predictive markers for responses to PI3K inhibitors. Thus, it is important to develop sensitive methods to detect these mutations. We established a novel detection method using a quenching probe (QP) system to identify PIK3CA mutations, using DNA from 309 breast cancer tissues. In a developmental cohort, we determined the optimal detection threshold of the QP system with human tumor DNA from 119 freshly frozen tumor samples. We found a 96% concordance rate with the QP system between DNA from 26 matching fresh-frozen specimens and formalin-fixed paraffin-embedded (FFPE) specimens from the same patients, and known PIK3CA mutation status in the developmental cohort. In a validation cohort, we evaluated whether the threshold for judging mutations using the QP system with frozen specimen-derived DNA was applicable with FFPE-derived DNA. In the validation cohort, 30 DNA samples from 190 FFPE-derived DNA samples with known PIK3CA mutation status were analyzed by direct sequencing (DS) and droplet digital PCR, in a blinded manner. The sensitivity and specificity of the droplet digital PCR results were 100% and 100% (QP system), and 60% and 100% (DS), respectively. We also analyzed the relationship between clinical outcomes and the PIK3CA mutational status of 309 breast cancer samples, including the developmental cohort and validation cohort samples. Multivariate analysis suggested that PIK3CA mutations, especially H1047R, were prognostic factors of relapse-free survival. Our novel detection system could be more useful than DS for detecting clinical PIK3CA mutations.

Background One-step nucleic acid amplification (OSNA) for cytokeratin 19 messenger RNA is an intraoperative diagnostic procedure for the detection of lymph node metastasis.

The purpose of this study was to evaluate therapeutic response to neoadjuvant chemotherapy (NAC) and predict breast cancer recurrence using Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST). Fifty-nine breast cancer patients underwent fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) before and after NAC prior to planned surgical resection. Pathological complete response (pCR) of the primary tumor was evaluated using PERCIST, while effects of clinicopathological factors on progression-free survival (PFS) were examined using log-rank and Cox methods. Fifty-six patients and 54 primary tumors were evaluated. Complete metabolic response (CMR), partial metabolic response, stable metabolic disease, and progressive metabolic disease were seen in 45, 7, 3, and 1 patients, respectively, and 43, 7, 3, and 1 primary tumors, respectively. Eighteen (33.3%) of the 54 primary tumors showed pCR. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of PERCIST to predict pCR were 100% (18/18), 30.6% (11/36), 41.9% (18/43), 100% (11/11), and 53.7% (29/54), respectively. An optimal percent decrease in peak standardized uptake value for a primary tumor corrected for lean body mass (SULpeak) of 84.3% was found to have a sensitivity of 77.8% (14/18), specificity of 77.8% (28/36), PPV of 63.6% (14/22), NPV of 87.5% (28/32), and accuracy of 77.8% (42/54). Seven (12.5%) of the 56 patients developed recurrent disease (median follow-up 28.1 months, range 11.4–96.4 months). CMR (p = 0.031), pCR (p = 0.024), and early TNM stage (p = 0.033) were significantly associated with longer PFS. PERCIST is useful for predicting pathological response and prognosis following NAC in breast cancer patients. However, FDG-PET/CT showed a tendency toward underestimation of the residual tumor, and relatively low specificity and PPV of PERCIST showed that a combination of other imaging modalities would still be needed to predict pCR.

Aims Extraskeletal osteosarcoma (ESOS) is a sarcoma in the non-skeletal tissue that directly produces neoplastic osteoid or bone. De-differentiated liposarcoma (DDLPS) and malignant peripheral nerve sheath tumour (MPNST) are the two most common types of sarcoma that can harbour heterologous osteosarcomatous differentiation. We aimed to determine the potential relationship of ESOS to DDLPS and MPNST. Methods and results We investigated MDM2 and H3K27me3 status in 19 cases of ESOS, two of which contained a low-grade component. The ESOS affected deep soft tissues (n = 10), superficial soft tissues (n = 3) and organs (n = 6). Among 10 deep soft-tissue ESOS, six showed MDM2 amplification, four of which also harboured CDK4 co-amplification. Both ESOS with a low-grade component showed co-amplification for MDM2 and CDK4. Among the six organ-based ESOS three giant cell-rich ESOS showed an H3K27me3 deficiency (one in primary and two in metastatic sites). Using targeted next generation sequencing, an H3K27me3-deficient ESOS showed EED homozygous deletion, while none of the three showed alterations in NF1, CDKN2A or SUZ12 genes. During median follow-up of 20 months, all six patients with MDM2-amplified ESOS lived for 3-103 months, while two of the three patients with H3K27me3-deficient ESOS died from this disease in 4 and 20 months, respectively. Conclusion We demonstrate that ESOS may include at least two small subsets: an MDM2-amplified deep soft-tissue ESOS (which may be related to DDLPS) and an H3K27me3-deficient organ-based ESOS (which is probably unrelated to MPNST). Larger studies are required to validate the present observations and investigate the clinical implications of such subcategorisation.

Background: Postmastectomy radiotherapy (PMRT) has been shown to be beneficial in node-positive breast cancer patients. However, the role of PMRT for patients receiving modern neoadjuvant chemotherapy (NAC) are controversial. We aimed to evaluate the efficacy of radiotherapy for breast cancer patients treated with NAC and mastectomy in the Japanese Breast Cancer Registry. Methods: Patients who received NAC and mastectomy for cT1-4 cN0-2 M0 breast cancer were included in this analysis. We assessed locoregional recurrence (LRR), distant disease-free survival (DDFS), and overall survival (OS) using the Kaplan-Meier method and compared them between the groups with and without PMRT by nodal status after NAC; ypN0, ypN1, and ypN2-3. We also performed multivariable cox regression analysis to evaluate the association of radiotherapy and these outcomes adjusting for baseline patient and cancer characteristics. Results: Of the 145,530 patients registered from 2004 to 2009, we identified 3,226 patients who met our inclusion criteria with the 5-year follow-up information including 1,299 ypN0, 1,036 ypN1, and 879 ypN2-3 cases. PMRT was performed in 185 patients (14.2%) with ypN0, 265 patients (25.6%) with ypN1, and 543 patients (61.8%) with ypN2-3. There was no difference in LRR, DDFS, and OS between the groups with and without radiotherapy for ypN1 patients who received NAC (P=0.72, P=0.29, and P=0.36, respectively). For patients with ypN2-3 breast cancer, radiotherapy significantly improved LRR (P Effect of PMRT on locoregional recurrence by the ypN subgroupsypN subgroupHazard ratio95%CI Low95%CI HighP valueypN00.8550.4581.5960.623ypN10.8320.5491.2620.387ypN2-30.6080.4520.8180.001 Effect of PMRT on overall survival by the ypN subgroupsypN subgroupHazard ratio95%CI Low95%CI HighP valueypN01.3250.8412.0870.224ypN10.8800.5991.2930.514ypN2-30.6850.5310.8850.004 Radiotherapy was not associated with OS among patients with ypN0 [HR: 1.325, 95% CI: 0.841–2.087, P=0.224] and ypN1 [HR: 0.880, 95% CI: 0.599–1.293, P=0.514]. There was no significant difference in DDFS with the addition of radiotherapy for all ypN subgroups. Conclusions: The results from this nationwide database study of breast cancer patients following modern NAC showed that PMRT did not improve survival for patients with ypN1 and ypN0. Radiotherapy might be only beneficial for ypN2-3 breast cancer patients who received NAC and mastectomy in the modern era. Randomized clinical trials are needed to optimize the use of PMRT for breast cancer patients treated with neoadjuvant chemotherapy. Citation Format: Miyashita M, Niikura N, Kumamaru H, Miyata H, Ishida T, Kinoshita T, Tsuda H, Nakamura S, Tokuda Y. Role of postmastectomy radiotherapy after neoadjuvant chemotherapy in breast cancer patients: A study from the Japanese breast cancer registry [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-11-11.

There has been little improvement in the prognosis for adolescent and young adult (AYA) tumor patients. Hence, there is an urgent need to understand the etiology of tumor development and identify actionable gene aberrations to improve prevention and therapy. Here, 76 sporadic tumors (48 breast, 22 ovarian, and six uterine) from 76 AYA females (age range, 25-39 years) were subjected to whole exome and RNA sequencing to determine their mutational signatures and actionable gene profiles. Two individuals with breast cancer (4.2% of cases) and one with ovarian cancer (5.3% of cases) carried germline BRCA2 mutations. The two cases with breast tumors also each carried an additional deleterious germline mutation: one in TP53 and the other in CHEK2. Mutational signature analysis of the 76 tumors indicated that spontaneous deamination of 5-methylcytosine and activity of the APOBEC cytidine deaminase protein family are major causes of mutagenesis. In addition, 18 breast or ovarian tumors (18/70, 26%), including the three cases with germline BRCA2 mutations, exhibited a predominant "BRCAness" mutational signature, an indicator of functional BRCA1/BRCA2 deficiency. Actionable aberrations and high tumor mutation burdens were detected in 24 breast (50%), 17 ovarian (77%), and five uterine (83%) tumor cases. Thus, mutational processes and aberrant genes in AYA tumors are largely shared with those identified in non-AYA tumors. The efficacy of molecular targeting and immune checkpoint inhibitory therapies should be explored for both AYA and non-AYA patients.

The fear of cancer recurrence (FCR) is the most common and most severe unmet need among cancer survivors. Safe treatments for the FCR that are easily disseminated are greatly needed. Our primary aim is a preliminary evaluation of the efficacy and effect size of perilla oil, which is rich in omega-3 fatty acids, and Bifidobacterium, a probiotic, on FCR in breast cancer survivors after the completion of chemotherapy. This study has been planned as an exploratory clinical study (phase II) and will be conducted as a three-arm, 12-week parallel group, masked-rater randomized controlled trial. Fifteen participants will be randomized with 1:1:1 allocation to receive Bifidobacterium plus perilla oil, Bifidobacterium alone, or no intervention (control). Interventions will end within 12 weeks after the random allocation of each participant. The participants will be outpatients with invasive breast cancer aged 20 years or older whose chemotherapy was completed at least 6 months before registration; hormone therapy may be ongoing. The primary outcome will be severity of FCR at 12 weeks assessed by masked raters using the 4-item Concerns about Recurrence Scale concerning overall fear of recurrence. The study protocol for the current study is registered in the Japan Registry of Clinical Trials (jRCTs031200029).