Fertility Preservation and Assisted Reproduction in Patients With Breast Cancer Interrupting Adjuvant Endocrine Therapy to Attempt Pregnancy.

PURPOSE: We investigated time to pregnancy, efficacy and safety of fertility preservation, and assisted reproductive technologies (ARTs) in women with early hormone receptor-positive breast cancer (BC) desiring future pregnancy. PATIENTS AND METHODS: POSITIVE is an international, single-arm, prospective trial, in which 518 women temporarily interrupted adjuvant endocrine therapy to attempt pregnancy. We evaluated menstruation recovery and factors associated with time to pregnancy and investigated if ART use was associated with achieving pregnancy. The cumulative incidence of BC-free interval (BCFI) events was estimated according to the use of ovarian stimulation at diagnosis. The median follow-up was 41 months. RESULTS: Two hundred seventy-three patients (53%) reported amenorrhea at enrollment, of whom 94% resumed menses within 12 months. Among 497 patients evaluable for pregnancy, 368 (74%) reported at least one pregnancy. Young age was the main factor associated with shorter time to pregnancy with cumulative incidences of pregnancy by 1 year of 63.5%, 54.3%, and 37.7% for patients age <35, 35-39, and 40-42 years, respectively. One hundred and seventy-nine patients (36%) had embryo/oocyte cryopreservation at diagnosis, of whom 68 reported embryo transfer after enrollment. Cryopreserved embryo transfer was the only ART associated with higher chance of pregnancy (odds ratio, 2.41 [95% CI, 1.75 to 4.95]). The cumulative incidence of BCFI events at 3 years was similar for women who underwent ovarian stimulation for cryopreservation at diagnosis, 9.7% (95% CI, 6.0 to 15.4), compared with those who did not, 8.7% (95% CI, 6.0 to 12.5). CONCLUSION: In POSITIVE, fertility preservation using ovarian stimulation was not associated with short-term detrimental impact on cancer prognosis. Pregnancy rates were highest among those who underwent embryo/oocyte cryopreservation followed by embryo transfer.

Primary ovarian insufficiency associated with lenvatinib therapy in a patient with hepatocellular carcinoma: A case report.

The therapeutic effects of molecular targeted drugs are, in some cases, more pronounced than those of conventional chemotherapy, and their introduction as a standard treatment is increasing. The present report describes a case of ovarian insufficiency in a young woman caused by tyrosine kinase inhibitor lenvatinib. The 25-year-old woman received lenvatinib (8 mg/day) for 98 days as preoperative chemotherapy for hepatocellular carcinoma. Blood testing the day before starting lenvatinib administration indicated 4.40 mIU/ml luteinizing hormone (LH), 5.2 mIU/ml follicle-stimulating hormone (FSH) and age-equivalent hormone values. Amenorrhea occurred after the start of administration, and 48 days later, the LH level was 41.8 mIU/ml and the FSH level was 44 mIU/ml, indicating a decrease in ovarian function. The patient underwent hepatectomy, and 49 days after the end of lenvatinib administration, the LH level had improved to 4.5 mIU/ml and the FSH level had improved to 2.5 mIU/ml. After the hepatectomy, the patient began to have regular menstrual cycles once again. Ovarian toxicity has not been recognized as a side effect of lenvatinib. However, the present report describes primary ovarian insufficiency considered to be caused by this drug. Potential damage to ovarian function may need to be considered when molecular targeted drugs with the same mechanism of action as lenvatinib are used in young women.

Interrupting Endocrine Therapy to Attempt Pregnancy after Breast Cancer.

BACKGROUND: Prospective data on the risk of recurrence among women with hormone receptor-positive early breast cancer who temporarily discontinue endocrine therapy to attempt pregnancy are lacking. METHODS: We conducted a single-group trial in which we evaluated the temporary interruption of adjuvant endocrine therapy to attempt pregnancy in young women with previous breast cancer. Eligible women were 42 years of age or younger; had had stage I, II, or III disease; had received adjuvant endocrine therapy for 18 to 30 months; and desired pregnancy. The primary end point was the number of breast cancer events (defined as local, regional, or distant recurrence of invasive breast cancer or new contralateral invasive breast cancer) during follow-up. The primary analysis was planned to be performed after 1600 patient-years of follow-up. The prespecified safety threshold was the occurrence of 46 breast cancer events during this period. Breast cancer outcomes in this treatment-interruption group were compared with those in an external control cohort consisting of women who would have met the entry criteria for the current trial. RESULTS: Among 516 women, the median age was 37 years, the median time from breast cancer diagnosis to enrollment was 29 months, and 93.4% had stage I or II disease. Among 497 women who were followed for pregnancy status, 368 (74.0%) had at least one pregnancy and 317 (63.8%) had at least one live birth. In total, 365 babies were born. At 1638 patient-years of follow-up (median follow-up, 41 months), 44 patients had a breast cancer event, a result that did not exceed the safety threshold. The 3-year incidence of breast cancer events was 8.9% (95% confidence interval [CI], 6.3 to 11.6) in the treatment-interruption group and 9.2% (95% CI, 7.6 to 10.8) in the control cohort. CONCLUSIONS: Among select women with previous hormone receptor-positive early breast cancer, temporary interruption of endocrine therapy to attempt pregnancy did not confer a greater short-term risk of breast cancer events, including distant recurrence, than that in the external control cohort. Further follow-up is critical to inform longer-term safety. (Funded by ETOP IBCSG Partners Foundation and others; POSITIVE ClinicalTrials.gov number, NCT02308085.).

Oncofertility-related psycho-educational therapy for young adult patients with breast cancer and their partners: Randomized controlled trial.

BACKGROUND: A couples' psycho-educational program called Oncofertility! Psycho-Education and Couple Enrichment (O!PEACE) therapy was created and its effect when provided before cancer treatment was examined. METHODS: This multicenter randomized controlled trial with nonmasking, parallel two-group comparison enrolled women aged 20 to 39 years with early-stage breast cancer and their partners. They were randomly assigned to receive O!PEACE (37 couples) or usual care (37 couples). Primary end points were cancer-related posttraumatic stress symptoms, symptoms of depression, and anxiety. Secondary end points were stress-coping strategies, resilience, and marital relationship. RESULTS: Women receiving psycho-educational therapy had significantly reduced Impact of Event Scale-revised version for Japanese scores (p = .011, ηp 2  =  = .089). For patients with Impact of Event Scale-revised version for Japanese scores at baseline ≥18.27, O!PEACE therapy improved these scores when compared with usual care (U = 172.80, p = .027, r = 0.258). A >5-point reduction was present in 59.3% and 30% of women in the O!PEACE therapy and usual-care groups, respectively. For partners, O!PEACE therapy significantly improved stress-coping strategies (95% CI, -0.60 to -0.05; p = .018, ηp 2  =  = .074) and escape-avoidance marital communication (95% CI, -0.33 to -0.08; p = .001, ηp 2  = .136). O!PEACE therapy significantly improved the partners' support (95% CI, 0.10-0.50; p = .001, ηp 2  = .127), the rate of receiving fertility preservation consultations, and knowledge levels. CONCLUSIONS: O!PEACE therapy before cancer treatment can improve posttraumatic stress symptoms, stress-coping behavior, and marital relationships. Larger sample sizes and longer term follow-up are required. PLAIN LANGUAGE SUMMARY: A psycho-educational program, the Oncofertility! Psycho-Education and Couple Enrichment (O!PEACE) therapy program was developed and evaluated for women diagnosed with breast cancer and their partners. A multicenter randomized controlled trial showed that the O!PEACE psycho-educational therapy, with only two precancer treatment sessions, can reduce cancer-related posttraumatic stress symptoms and improve oncofertility knowledge and marital relationships in young adult patients with breast cancer. The therapy could also improve stress-coping strategies in marital communications with their partners. Couples may use O!PEACE psycho-educational therapy to consider fertility preservation and improve their psychosocial aspects.

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.

The impact of obesity and endocrine therapy on the prognosis of premenopausal women with hormone receptor-positive breast cancer: A single-institute retrospective study.

BACKGROUND: Higher body mass index (BMI) is associated with worse prognosis in pre- and postmenopausal patients with breast cancer (BC). However, there is insufficient evidence regarding the optimal adjuvant endocrine therapy for obese premenopausal women with hormone receptor (HR)-positive BC. AIM: To evaluate the impact of obesity and adjuvant endocrine therapy on prognosis in premenopausal patients with BC. METHODS AND RESULTS: We retrospectively reviewed the medical record of premenopausal women who received curative surgery for clinical stage I-III HR-positive BC from 2007 to 2017. Patients were classified into five groups according to BMI: underweight (UW), normal weight (NW), obese 1 degree (OB1), obese 2 degree (OB2), and obese 3 degree (OB3) categories. The primary analysis was a comparison of BC-specific survival (BCSS) according to BMI (UW/NW vs. OB1-3) and adjuvant endocrine therapy (with or without ovarian function suppression [OFS]). Of 13 021 patients, the data of 3380 patients were analyzed. BCSS in OB1-3 patients was significantly worse than that in patients with UW/NW (hazard ratio [HR] 2.37; 95% confidence interval [CI], 1.40-4.02: p = .0009). In OB1-3 patients who received tamoxifen (TAM), BCSS was significantly worse than that in UW/NW patients (p = .0086); however, a significant difference was not shown in patients who received TAM and OFS (p = .0921). CONCLUSION: High BMI was associated with worse prognosis in premenopausal patients with HR-positive BC who received adjuvant TAM. The role of OFS as adjuvant endocrine therapy remains unclear, and further studies are required to explore the adequate management of obese premenopausal patients.

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.

Who are the women who enrolled in the POSITIVE trial: A global study to support young hormone receptor positive breast cancer survivors desiring pregnancy.

BACKGROUND: Premenopausal women with early hormone-receptor positive (HR+) breast cancer receive 5-10 years of adjuvant endocrine therapy (ET) during which pregnancy is contraindicated and fertility may wane. The POSITIVE study investigates the impact of temporary ET interruption to allow pregnancy. METHODS: POSITIVE enrolled women with stage I-III HR + early breast cancer, ≤42 years, who had received 18-30 months of adjuvant ET and wished to interrupt ET for pregnancy. Treatment interruption for up to 2 years was permitted to allow pregnancy, delivery and breastfeeding, followed by ET resumption to complete the planned duration. FINDINGS: From 12/2014 to 12/2019, 518 women were enrolled at 116 institutions/20 countries/4 continents. At enrolment, the median age was 37 years and 74.9 % were nulliparous. Fertility preservation was used by 51.5 % of women. 93.2 % of patients had stage I/II disease, 66.0 % were node-negative, 54.7 % had breast conserving surgery, 61.9 % had received neo/adjuvant chemotherapy. Tamoxifen alone was the most prescribed ET (41.8 %), followed by tamoxifen + ovarian function suppression (OFS) (35.4 %). A greater proportion of North American women were <35 years at enrolment (42.7 %), had mastectomy (59.0 %) and received tamoxifen alone (59.8 %). More Asian women were nulliparous (81.0 %), had node-negative disease (76.2%) and received tamoxifen + OFS (56.0 %). More European women had received chemotherapy (69.3 %). INTERPRETATION: The characteristics of participants in the POSITIVE study provide insights to which patients and doctors considered it acceptable to interrupt ET to pursue pregnancy. Similarities and variations from a regional, sociodemographic, disease and treatment standpoint suggest specific sociocultural attitudes across the world.

Physician's knowledge, attitudes and practice pattern for breast cancer diagnosed during pregnancy: a survey among breast care specialists in Japan.

BACKGROUND: Breast cancer diagnosed during pregnancy (BCP) is uncommon, and thus there is limited evidence on its treatment. However, the incidence of BCP is increasing probably due to women having children at an older age. We aimed to clarify the practice patterns and limitations in treatment for BCP in Japan. METHODS: A cross-sectional survey was developed for board-certified Japanese breast cancer specialists (n = 1583) to evaluate their knowledge, attitude, experience, and practice patterns regarding BCP. Survey items also included questions regarding potential barriers of practice toward patients diagnosed during pregnancy and respondents' background. RESULTS: In March 2018, 492 (31.1%) breast oncologists responded to the survey. Among them, 234 (48%) respondents had the experience of treating at least one case of BCP. The accuracy of knowledge about BCP was evaluated by three items regarding BCP treatment from the latest Japanese Breast Cancer Society treatment guideline, and 265 (54%) were categorized to have "appropriate knowledge". Majority of the physicians (89%) have responded that patients should be treated in a center where both a cancer-treating team and obstetrician exist, and 48% responded that treating patients by the collaboration of cancer-treating team and obstetric team in different institutes is an alternative reasonable option. CONCLUSIONS: Interest, knowledge, and awareness of the guidelines appear to influence physician attitude, and thus it is urgently important to lay out educational materials and learning opportunities regarding BCP for breast specialists. A regional network of oncologists, obstetricians, and pediatricians to support the BCP patients should be developed.

Surgical excision without whole breast irradiation for complete resection of ductal carcinoma in situ identified using strict, unified criteria.

BACKGROUND: The definition of complete resection of ductal carcinoma in situ (DCIS) is difficult to standardize because of the high variety of surgical breast conserving procedures, specimen handling, and pathological examinations. Using strictly controlled criteria in a single institute, the present study aimed to determine the ipsilateral breast cancer rate when radiotherapy is omitted following complete resection of DCIS. METHODS: We retrospectively examined 363 consecutive DCIS patients who underwent breast-conserving surgery, and of these, 125 (34.4%) had complete resection according to the criteria. We finally included 103 patients who omitted radiotherapy. Ipsilateral and contralateral breast cancer events were assessed. RESULTS: The median follow-up period was 118 months. The incidences of ipsilateral and contralateral breast cancer and ipsilateral invasive breast cancer at 10 years were 10.8%, 9.1%, and 3.6%, respectively. No patient died of breast cancer. CONCLUSION: If complete resection of DCIS can be ensured, the annual incidence of ipsilateral breast cancer, even without irradiation, can be limited to approximately 1%, which equals the incidence of contralateral breast cancer.

Young adult breast cancer patients have a poor prognosis independent of prognostic clinicopathological factors: a study from the Japanese Breast Cancer Registry.

PURPOSE: The aim of this study was to investigate whether young age at onset of breast cancer is an independent prognostic factor in patients from the Japanese Breast Cancer Registry, after adjustment of known clinicopathological prognostic factors. METHODS: Of the 53,670 patients registered between 2004 and 2006 and surveyed after a 5-year follow-up prognosis, 25,898 breast cancer patients (48.3 %), who were obtained prognostic data, were examined. Clinicopathological factors were compared between young adult (YA; <35 years), middle-aged adult (MA; 35-50 years), and older adult (OA; >50 years) patients. Five-year disease-free survival (DFS) and overall survival (OS) rates were studied. RESULTS: YA patients were associated with an advanced TNM stage and aggressive characteristics (e.g. human epidermal growth factor receptor 2 (HER2)-positive or oestrogen receptor (ER)-negative breast cancers) compared to MA and OA patients (P < 0.001). The 5-year DFS and OS rates were 79.4 % and 90.8, 88.5 and 95.0 %, and 87.8 % and 91.6 % for YA, MA, and OA patients, respectively. From the multivariable regression analysis, young age at onset was confirmed as an independent prognostic factor for both DFS (hazard ratio 1.73, 95 % confidence interval 1.42-2.10; P < 0.001) and OS (hazard ratio 1.58, 95 % confidence interval 1.16-2.15; P = 0.004). CONCLUSIONS: Young age at onset is an independent negative prognostic factor in breast cancer. Further studies are required to develop new therapeutic strategies for YA breast cancer patients.

Decreased hormonal sensitivity after childbirth rather than the tumor size influences the prognosis of very young breast cancer patients.

PURPOSE: There is a significant difference in the mean tumor size between very young breast cancer patients and their elder counterparts. A simple comparison may show obvious prognostic differences. We investigated the prognostic impact of age by reducing the influence of the tumor size, which is thought to be a confounding factor. PATIENTS AND METHODS: We investigated 1,880 consecutive pT1-4N0-3M0 breast cancer patients treated at less than 45 years of age between 1986 and 2002 and conducted a case-control study of breast cancer subjects less than 30 years of age. Each patient (Younger than 30) was matched with a corresponding control subject (Elder counterpart) based on an age 15 years above the patient's age, a similar tumor size and a status of being within 1 year after surgery. In addition, we assessed 47 patients with pregnancy-associated breast cancer (PABC). The levels of hormone receptors were measured using an enzyme immunoassay (EIA), and receptor-positive cases were divided into "weakly" and "strongly" positive groups based on the median value. Years from the last childbirth (YFLC) was categorized as "recent" and "past" at the time point of 8 years. RESULTS: There were fewer past YFLC cases, more partial mastectomy cases, a higher rate of scirrhous carcinoma or solid-tubular carcinoma in the Younger than 30 group than in the Elder counterpart group. The rates of a PgR-negative status in the Younger than 30 and Elder counterpart groups were 45.1 and 29.9%, respectively, As for the relationship between the PgR-negative rate and YFLC, the rates of a PgR-negative status in the past YFLC, nulliparous, recent YFLC and PABC groups were 31.9, 37.7, 44.4 and 65.7%, respectively. On the other hand, the rates of strongly positive cases were 42.6, 30.2, 22.2 and 8.6%, respectively. The 10-year recurrence-free survival rates in the Younger than 30, Elder counterpart and PABC groups were 61.7, 65.6 and 54.1%, respectively. The differences between the groups were not significant. In a multivariate analysis, independent prognostic facers included the number of lymph node metastases (4-9, HR:3.388, 95% CI 1.363-8.425, p = 0.0086, over 10, HR: 6.714, 2.033-22.177, p = 0.0018), solid-tubular carcinoma (HR 3.348, 1.352-8.292, p = 0.0090), scirrhous carcinoma (HR 2.294, 1.013-5.197, p = 0.0465) and past YFLC (HR 0.422, 0.186-0.956, p = 0.0387). An age younger than 30 was not found to be an independent prognostic factor. CONCLUSIONS: The prognosis of the very young women was the same as their elder counterparts with a matched tumor size, and age was not identified to be an independent prognostic factor according to the multivariate analysis. Recent childbirth probably influences the prognosis of patients younger than 30 years of age with breast cancer by lowering hormonal sensitivity.

No increase in breast cancer risk in Japanese women taking oral contraceptives: a case-control study investigating reproductive, menstrual and familial risk factors for breast cancer.

BACKGROUND: Low-dose oral contraceptives (OC) were approved by the Japanese Ministry of Health, Labor and Welfare in 1999, yet despite their contraceptive and non-contraceptive health benefits, only 5% of the target population use them. Fear of increased cancer risk, particularly breast cancer, is one reason for this. Due to low OC uptake and low screening participation, a paucity of data is available on the risk of OC use and breast cancer in Japanese women. The present study investigated OC use and breast cancer risk, as well as menstrual, reproductive and family factors. MATERIALS AND METHODS: This was a clinic-based case-control study of women aged 20-69yrs who had undergone breast screening between January 2007 and December 2013 in central Tokyo. In all, 28.8% of the participants had experience with OC use. Cases were 155 women with a pathologically confirmed diagnosis of breast cancer. Controls were the remaining 12,333 women. RESULTS: Increased age was a significant risk factor for breast cancer (p<0.001). A lower risk was found in premenopausal women presently taking OC compared to never users (OR 0.45; 95% CI 0.22-0.90) after adjusting for age, parity and breast feeding, and a family history of breast cancer. CONCLUSIONS: Increased age rather than OC use had a greater effect on breast cancer risk. This risk may be decreased in premenopausal women with OC use, but further long-term prospective studies are necessary.

Unmet Information Needs and Quality of Life in Young Breast Cancer Survivors in Japan.

BACKGROUND: Young breast cancer survivors have specific needs related to age. Clarifying the relationships between unmet information needs and quality of life (QOL) in young breast cancer survivors can contribute to constructing a support system to enhance QOL in patients. OBJECTIVE: This study aimed to identify the unmet information needs and examine the relationships between unmet information needs and QOL in young breast cancer survivors in Japan. METHODS: Participants completed an information needs questionnaire containing 26 items, the World Health Organization Quality of Life Instrument-Short Form (WHOQOL-BREF), and a demographic and medical information questionnaire. RESULTS: Fifty participants (30.7%) were unsatisfied with "overall communication with medical professionals." The mean scores on all subscales of the WHOQOL-BREF of the participants who were satisfied with "overall communication with medical professionals" were significantly higher than those of the unsatisfied group. "follow-up tests," "treatment for recurrence of breast cancer," "strategies about communication with medical staff," and "nutrition" were significantly related with all subscales in the WHOQOL-BREF. "Secondary menopause caused by hormonal therapy" was significantly related with physical and psychological health. CONCLUSIONS: Japanese young breast cancer survivors have unmet information needs, including age-specific issues. These unmet information needs are related to QOL. In particular, "overall communication with medical professionals," which is the most unmet information need, is related to QOL. IMPLICATIONS FOR PRACTICE: Oncology nurses should teach patients communication skills, provide adequate information, and provide education and emotional support to medical professionals to improve QOL in young breast cancer survivors.

Clinicopathological features of young patients (<35 years of age) with breast cancer in a Japanese Breast Cancer Society supported study.

BACKGROUND: To clarify the clinicopathological features of breast cancer in young females, surveillance data of the Registration Committee of the Japanese Breast Cancer Society were analyzed. METHODS: The clinicopathological characteristics were compared between young (<35) patients and non-young (≥35) patients among 109,617 records registered between 2004 and 2009. RESULTS: The numbers of young and non-young patients were 2,982 (2.7 %) and 106,295 (97.0 %), respectively. The young patients had more cases of a familial history of breast cancer, more subjective symptoms, fewer bilateral tumors, lower BMIs, larger tumors, more positive lymph nodes, fewer instances of an ER-positive status, more instances of an HER2-positive status, more triple-negative tumors and more advanced TNM stages. The young patients more frequently received neoadjuvant chemotherapy and breast-conserving therapy (BCT) compared with the non-young patients. Eighty percent of all patients received adjuvant therapy. The young patients were more frequently treated with chemotherapy, molecular targeted therapy and radiation therapy than the non-young patients. CONCLUSIONS: In this study, young patients with breast cancer were diagnosed at more advanced stages and had more endocrine-unresponsive tumors than non-young patients. Further prognostic analyses should be conducted in this cohort.

Vascular endothelial growth factor receptor-1 mRNA overexpression in peripheral blood as a useful prognostic marker in breast cancer.

INTRODUCTION: Identification of useful markers associated with poor prognosis in breast cancer patients is critically needed. We previously showed that expression of vascular endothelial growth factor receptor-1 mRNA in peripheral blood may be useful to predict distant metastasis in gastric cancer patients. However, expression of vascular endothelial growth factor receptor-1 mRNA in peripheral blood of breast cancer patients has not yet been studied. METHODS: Real-time reverse transcriptase-PCR was used to analyze vascular endothelial growth factor receptor-1 mRNA expression status with respect to various clinical parameters in 515 patients with breast cancer and 25 controls. RESULTS: Expression of vascular endothelial growth factor receptor-1 mRNA in peripheral blood was higher in breast cancer patients than in controls. Increased vascular endothelial growth factor receptor-1 mRNA expression was associated with large tumor size, lymph node metastasis and clinical stage. Patients with high vascular endothelial growth factor receptor-1 mRNA expression also experienced a poorer survival rate than those with low expression levels, including those patients with triple-negative type and luminal-HER2(-) type disease. CONCLUSIONS: Expression of vascular endothelial growth factor receptor-1 mRNA in peripheral blood may be useful for prediction of poor prognosis in breast cancer, especially in patients with triple-negative type and luminal-HER2(-) type disease.

Identification of recurrence-related microRNAs in the bone marrow of breast cancer patients.

Recently, bone marrow has been considered as playing a critical role in the generation of both metastasis and recurrent disease. The accumulation of a single microRNA in the bone marrow has the potential to regulate the translation of multiple genes in cancer metastasis and may therefore serve as a prognostic marker for cancer recurrence. MicroRNA microarray analysis was performed to compare microRNA levels in bone marrow from 4 breast cancer patients with recurrent disease and 4 patients without recurrence. Accumulation of two of these microRNAs, miR-21 and miR-181a, in the recurrent breast cancer cases was validated by RT-PCR in bone marrow from 291 additional breast cancer cases. Expression of a common target gene, PDCD4, was also determined in bone marrow from 291 breast cancer cases. Increased miR-21 and miR-181a levels were significantly associated with shortened disease-free survival (DFS; p=0.0003, 0.0007) and overall survival (OS; p=0.0351, 0.0443), respectively. While low PDCD4 expression was also significantly associated with poorer DFS (p=0.036). Multivariate analysis identified bone marrow miR-21 and mR-181a levels as valuable independent prognostic factors, with correlation coefficients that were significantly higher than that of the transcript of their common target gene. Accumulation of miR-21 and miR-181a in bone marrow appears to be associated with prognosis in breast cancer patients. The much higher significant correlation with microRNA levels and prognosis suggests epistatic effects on multiple target genes in the bone marrow of breast cancer patients.

Correlated expression of CD47 and SIRPA in bone marrow and in peripheral blood predicts recurrence in breast cancer patients.

PURPOSE: CD47 plays a variety of roles in intercellular signaling. Herein, we focused on the clinicopathologic significance of CD47 expression in human breast cancer. Our data suggest that the correlation between CD47 and signal regulatory protein α (SIRPA) expression may play a key role in the progression of breast cancer. EXPERIMENTAL DESIGN: Quantitative real-time PCR was used to evaluate CD47 mRNA and SIRPA mRNA expression in bone marrow and in peripheral blood from 738 cases of breast cancer. RESULTS: In patients with high levels of CD47 expression in the bone marrow, survival was significantly poorer compared with patients with low levels of CD47 expression [disease-free survival (DFS), P = 0.0035; overall survival (OS), P = 0.015]. Furthermore, high CD47 expression group in a multivariate analysis showed significance as an independent variable for poorer prognosis in DFS (P = 0.024). In the peripheral blood, however, high CD47 expression in patients was not an independent and significant prognostic factor for DFS and OS in a multivariate analysis. CD47 expression was strongly correlated with SIRPA expression in both the bone marrow (P < 0.0001) and peripheral blood (P < 0.0001) of breast cancer patients. CONCLUSIONS: This is one of the first studies to show that a host factor in bone marrow confers prognostic importance. CD47 is an important biomarker in breast cancer, and functions as a prognostic factor for DFS. Moreover, we suggest that the poor prognosis of breast cancer patients with high expression of CD47 is due to an active CD47/SIRPA signaling pathway in circulating cells.

Preoperative u-PAR gene expression in bone marrow indicates the potential power of recurrence in breast cancer cases.

INTRODUCTION: The clinical significance of isolated tumor cells (ITC) in peripheral blood (PB) and bone marrow (BM) as predictive markers in the recurrence or metastasis of breast cancer has not yet been determined. In the current study, we focused on the urokinase plasminogen activator receptor (u-PAR) gene as a powerful indicator of the potential to relapse after surgery. PATIENTS AND METHODS: We examined CK-7 and CK19 as an ITC marker and u-PAR as a candidate indicator for metastasis in PB and BM from 800 cases of breast cancer by quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR). Serum tumor markers, carcinoembryonic antigen (CEA) and cancer antigen 15-3 (CA15-3), were compared with u-PAR or CK status. RESULTS: CK7 in PB was positive in 262 cases that showed a poorer disease-free survival (DFS) than 478 CK7(-) cases (P < 0.05). The 153 cases of u-PAR(+) in BM showed significantly poorer DFS and overall survival (OS) than did the 579 cases of u-PAR(-) in BM (P < 0001 and P < 0.0001, respectively). In PB, a significant difference was also observed between 330 cases of u-PAR(+) and 437 cases of u-PAR(-) (P < 0.0001). The hazard ratio (HR) for prediction of recurrence was significantly higher in u-PAR (P < 0.0001; HR 0.0519) than the level of three serum tumor markers. DISCUSSION: u-PAR expresses in cancer cells during the dormant phase. The current findings revealed that the expression levels of u-PAR in PB and BM evaluated preoperatively indicate the potential to relapse or metastasize after surgery.