Childbirth after perioperative systemic therapy in patients with breast cancer: a retrospective single institutional study in Japan.

BACKGROUND: The number of breast cancer patients of childbearing age has been increasing. Therefore, we investigated the characteristics and the childbearing status of the patients who received systemic therapy for breast cancer during their childbearing age to better understand the clinical impact of childbirth. METHODS: Female patients with breast cancer younger than 40 years old who underwent surgery and received perioperative systemic therapy from 2007 to 2014 were included in this study. We compared the characteristics of patients with and without childbirth after treatment. RESULT: Of 590 patients, 26 delivered a child, and 355 did not bear a child during the median observation period of 8.1 years, whilst 209 had unknown childbirth data. The childbirth group had a lower mean age at surgery (32.2 vs. 35.1, P < 0.001). The proportion of patients who desired childbirth and used assisted reproductive technology was significantly higher in the childbirth group (65.4 vs. 23.9% and 45.2 vs. 5.1%, respectively, P < 0.001). The patients in the childbirth group had significantly less advanced disease (P = 0.002). In the childbirth group, the age at childbirth was significantly older in patients who received combined endocrine therapy and chemotherapy (40.8 years) than in patients who received either alone (endocrine therapy: 36.9 years, chemotherapy: 36.7 years, P = 0.04). However, survival was not different between those with and without childbirth. CONCLUSION: It is critical to recognize the desire for childbirth in patients with breast cancer who are receiving systemic therapy and to provide them with necessary fertility information before treatment to support their decision-making.

Smartphone Psychotherapy Reduces Fear of Cancer Recurrence Among Breast Cancer Survivors: A Fully Decentralized Randomized Controlled Clinical Trial (J-SUPPORT 1703 Study).

PURPOSE: Fear of cancer recurrence (FCR) is a common distressing condition. We investigated the efficacy of smartphone problem-solving therapy and behavioral activation applications in breast cancer survivors. METHODS: This was a decentralized randomized trial. Participants were disease-free breast cancer survivors age 20-49 years who were randomly assigned to the smartphone-based intervention or waitlist control. Both groups received treatment as usual. The control group could access the smartphone apps during weeks 8-24. The intervention comprised smartphone problem-solving therapy and behavioral activation apps. The primary end point was the Concerns About Recurrence Scale at week 8. Secondary outcomes included the Fear of Cancer Recurrence Inventory-Short Form (FCRI-SF), the Hospital Anxiety and Depression Scale (HADS), the Short-form Supportive Care Needs Survey (SCNS-SF34), and the Posttraumatic Growth Inventory at weeks 8 and 24 (trial registration: UMIN-CTR: UMIN000031140). RESULTS: The intervention group included 223 participants, and the control group included 224 participants. Primary outcome data were obtained for 444 participants, and 213 participants in the intervention arm completed the week 24 assessment. The intervention group had statistically greater improvements than controls at week 8 on the Concerns About Recurrence Scale (difference -1.39; 95% CI, -1.93 to -0.85; P < .001), FCRI-SF (difference -1.65; 95% CI, -2.41 to -0.89; P < .001), HADS depression (difference -0.49; 95% CI, -0.98 to 0; P < .05), and SCNS-SF34 psychological domain (difference -1.49; 95% CI, -2.67 to -0.32; P < .05). These scores at week 24 were not statistically significant compared with week 8 although the HADS depression score at week 24 was significantly reduced (P = .03). CONCLUSION: Novel smartphone psychotherapy offers a promising way to reduce FCR given the large number of survivors and a limited number of therapists to competently conduct psychotherapy.

Clinical significance of the neutrophil-to-lymphocyte ratio in oligometastatic breast cancer.

PURPOSE: This study investigated the clinical impact of pretreatment neutrophil-to-lymphocyte ratio (NLR) on survival in patients with oligometastatic breast cancer. PATIENTS AND METHODS: We collected data from 397 patients who underwent primary breast surgery from 2004 to 2015 and developed recurrence during the follow-up. We reviewed the images and clinical information and defined OMD according to the European Society for Medical Oncology advanced breast cancer guidelines. The NLR was calculated using pretreatment data of primary breast cancer. The cutoff value of the NLR was determined by receiver operating characteristic curve with Youden Index. RESULTS: Among 397 patients, 131 had OMD at recurrence. The low-NLR group included patients of significantly older age at primary cancer than those in the high-NLR group. A low NLR indicated a better overall survival (p = 0.023) after adjusting for relevant factors, including estrogen receptor status, surgical resection of metastatic disease, metastatic organ number, disease-free interval, and liver metastasis than did the high-NLR group. We developed prognostic models for OMD using six independent prognostic factors, including the NLR. The number of factors was associated with overall survival; patients with all six favorable factors showed a good overall survival of 90.9% at 8 years and those with four or more factors showed 70.4%. CONCLUSIONS: The NLR was an independent prognostic factor for overall survival in OMD. The number of favorable prognostic factors was associated with overall survival. A prognostic model, including the NLR, will help identify patients with a favorable prognosis.

Characteristics, treatment trends, and long-term outcomes of Japanese patients with pregnancy-associated breast cancer (PABC).

PURPOSE: To clarify the characteristics, treatment trends, and long-term outcomes of patients with pregnancy-associated breast cancer (PABC). METHODS: PABC includes breast cancer diagnosed during pregnancy (PBC) and breast cancer diagnosed within 1 year after childbirth or during lactation (LBC). We compared clinical characteristics of 126 patients with LBC and 49 patients with PBC who underwent surgery at our hospital from 1946 to 2018. Survival was compared between patients with LBC and those with PBC in terms of breast cancer-specific disease-free survival (BC-DFS) and overall survival (OS). RESULTS: Patients with LBC were more likely to have family history, lymph node metastasis, lymphatic invasion, and to receive chemotherapy than patients with PBC. Patients with LBC showed poorer BS-DFS and OS than patients with PBC. Among patients with LBC, those treated after 2005 were older at surgery, had a smaller tumor size, received more systemic therapy, and had a more favorable prognosis than patients treated before 2004. Family history, breast cancer within 1 year after childbirth, and surgery before 2004 as well as cStage, lymph node metastasis, and lymphatic invasion were significantly associated with poor prognosis in patients with LBC. In the multivariate analysis for BC-DFS and OS among patients with PABC, LBC vs PBC did not remain as an independent prognostic factor while cStage remained. CONCLUSION: Patients with LBC had a poorer prognosis than those with PBC, most likely due to disease progression rather than biological characteristics. Early detection and optimization of systemic treatments are critical for improving the outcomes of patients with LBC.

Circulating cell-free DNA-based epigenetic assay can detect early breast cancer.

BACKGROUND: Circulating cell-free DNA (cfDNA) has recently been recognized as a resource for biomarkers of cancer progression, treatment response, and drug resistance. However, few have demonstrated the usefulness of cfDNA for early detection of cancer. Although aberrant DNA methylation in cfDNA has been reported for more than a decade, its diagnostic accuracy remains unsatisfactory for cancer screening. Thus, the aim of the present study was to develop a highly sensitive cfDNA-based system for detection of primary breast cancer (BC) using epigenetic biomarkers and digital PCR technology. METHODS: Array-based genome-wide DNA methylation analysis was performed using 56 microdissected breast tissue specimens, 34 cell lines, and 29 blood samples from healthy volunteers (HVs). Epigenetic markers for BC detection were selected, and a droplet digital methylation-specific PCR (ddMSP) panel with the selected markers was established. The detection model was constructed by support vector machine and evaluated using cfDNA samples. RESULTS: The methylation array analysis identified 12 novel epigenetic markers (JAK3, RASGRF1, CPXM1, SHF, DNM3, CAV2, HOXA10, B3GNT5, ST3GAL6, DACH1, P2RX3, and chr8:23572595) for detecting BC. We also selected four internal control markers (CREM, GLYATL3, ELMOD3, and KLF9) that were identified as infrequently altered genes using a public database. A ddMSP panel using these 16 markers was developed and detection models were constructed with a training dataset containing cfDNA samples from 80 HVs and 87 cancer patients. The best detection model adopted four methylation markers (RASGRF1, CPXM1, HOXA10, and DACH1) and two parameters (cfDNA concentration and the mean of 12 methylation markers), and, and was validated in an independent dataset of 53 HVs and 58 BC patients. The area under the receiver operating characteristic curve for cancer-normal discrimination was 0.916 and 0.876 in the training and validation dataset, respectively. The sensitivity and the specificity of the model was 0.862 (stages 0-I 0.846, IIA 0.862, IIB-III 0.818, metastatic BC 0.935) and 0.827, respectively. CONCLUSION: Our epigenetic-marker-based system distinguished BC patients from HVs with high accuracy. As detection of early BC using this system was comparable with that of mammography screening, this system would be beneficial as an optional method of screening for BC.

Extensive analysis of signaling pathway molecules in breast cancer: association with clinicopathological characteristics.

BACKGROUND: The aim of this study was to extensively analyze the signaling pathway molecules in breast cancer and to explore candidate biomarkers for clinicopathological relevance. METHODS: We assessed the expression of key factors in cell signaling, namely p-AKT, cyclin D1, P27, p-p70S6 K, p-4EBP1, and p-MAPK/ERK, within 338 invasive breast cancer patients. These factors were immunohistochemically examined in tumor tissues and assessed by staining score. Staining scores were analyzed by a clustering method to devise a new classification based on pathway activity. We investigated the relationships among staining scores, the clustering classification, and patient characteristics. RESULTS: The proportion of patients displaying high expression levels were as follows: p-AKT, 75%; cyclin D1, 12%; P27, 53%; p-p70S6 K, 37%; p-4EBP1, 19%; and p-MAPK/ERK, 3%. Patients were classified into two groups on the basis of staining scores. Group 1 (39%) included more positive cases for p-4EBP1, p-MAPK/ERK, and p-p70S6 K and fewer positive cases for P27 and cyclin D1 than Group 2 (61%). The clustering classification was significantly related to subgrouping by hormone receptor and HER2 (P < 0.001), nuclear grade (P < 0.001) and histological subtype (P = 0.034). A strong positive correlation was identified between p-AKT and P27, cyclin D1 and P27, p-p70S6 K and p-4EBP1, p-p70S6 K and p-MAPK/ERK, and between p-4EBP1 and p-MAPK/ERK. Levels of p-p70S6 K were significantly related to recurrence in both univariate (RR = 0.75, P < 0.001) and multivariate (RR = 0.71, P = 0.049) analyses. CONCLUSIONS: The present study helps us to understand the characteristics of signaling pathway status in breast cancers. Moreover, p-p70S6 K expression may be of use in predicting clinical outcome.

Validation study of the UICC TNM classification of malignant tumors, seventh edition, in breast cancer.

BACKGROUND: The TNM classification of the Unio Internationalis Contra Cancrum was revised for the seventh edition. The major change concerning breast cancer is a change in the stages for patients with T0 or T1N1miM0. In the present study, the seventh edition of the TNM classification was validated in breast cancer. METHODS: The stages of 416 breast cancer patients, treated at our hospital in 1996, were classified according to the TNM classification, sixth and seventh editions, and their prognoses were compared. RESULTS: Case distribution using the sixth edition was stage 0, 56 cases (13.5 %); stage I, 158 cases (38.0 %); stage II, 130 [A, 102; B, 28] cases (31.2 [A, 24.5; B, 6.7] %); and stage III, 72 [A, 31; B, 8; C, 33] cases (17.3 [A, 7.5; B, 1.9; C, 7.9] %). According to the seventh edition, the stages for 20 patients, accounting for 19.6 % of IIA cases according to the sixth edition, decreased from IIA to IB. The 10-year overall survivals were stage 0, 91.1 %; stage I, 88.6 %; stage II, 80.8 %; and stage III, 63.9 % according to the sixth edition; and stage 0, 91.1 %; stage I, 88.8 %; stage II, 79.1 %; and stage III, 63.9 % according to the seventh edition. Although no significant differences were seen among the survival rates for stages 0 to II according to the sixth edition, there was a significant difference between stage I and II according to the seventh edition (p = 0.026). CONCLUSION: The latest revision of the TNM classification is appropriate for breast cancer from the perspective of prognosis.