Shinji Ohno

Impact of clinical response to neoadjuvant endocrine therapy on patient outcomes: a follow-up study of JFMC34-0601 multicentre prospective neoadjuvant endocrine trial

Background Neoadjuvant endocrine therapy (NET) has been demonstrated to improve breast-conserving rate and is a widely accepted treatment option for postmenopausal patients with hormone receptor-positive breast cancer. There are few reports on the association of NET response and long-term outcomes. Objectives To investigate the prognostic value of clinical response to NET. Methods Long-term outcomes of NET were examined in 107 patients who participated in the multicentre prospective neoadjuvant exemestane study, JFMC34-0601. Patients were treated with 25 mg/day exemestane for 16 weeks followed by an 8-week extension depending on the treatment response. Results Clinical response included partial response (PR) in 58 patients, stable disease in 41 patients and progressive disease (PD) in 8 patients. Clinical response was significantly associated with disease-free survival (DFS), distant disease-free survival (DDFS) and overall survival (OS) (P<0.0001 for all). Especially, patients with PD showed markedly poor outcomes with median DFS=17.8 months (HR (vs PR): 7.7 (95% CI 1.6 to 33)) and median OS=37.7 months (HR (vs PR): 26.3 (95% CI 2.4 to 655)). Preoperative endocrine prognostic index (PEPI) were associated with DFS and marginally with OS (P=0.022 and 0.066, respectively). PEPI=0 indicated an excellent prognosis with 95% 5-year DFS (95% CI 73 to 99). In the multivariate analysis including T stage, nodal status and Ki67, clinical response was an independent prognostic factor for DFS, DDFS and OS (P=0.032, 0.0007 and 0.020, respectively), whereas PEPI was marginally associated with DFS and OS (P=0.079 and 0.068, respectively). Conclusions Clinical response to NET showed an independent prognostic value. Patients with PD had markedly poor prognosis, indicating a need of additional therapy. PEPI=0 indicated an excellent prognosis. The integration of clinical response and PEPI would improve decision-making with regard to treatment options for endocrine-responsive breast cancer when these results are validated in a larger clinical trial. Trial registration number UMIN C000000345.

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.

Prognostic significance of histological therapeutic effect in preoperative chemotherapy for breast cancer

To establish a prognostic prediction system, we examined the relationships between prognosis and histological therapeutic effect or ypTNM classification in 258 breast cancer patients who received neoadjuvant chemotherapy. The case distribution according to therapeutic effect was nine patients (3.5%) with Grade 0, 169 (65.5%) with Grade 1, 58 (22.5%) with Grade 2, and 22 (8.5%) with Grade 3. The 5‐year overall survival (OS) rate by therapeutic effect was 56% in Grade 0, 81% in Grade 1, 87% in Grade 2, and 96% in Grade 3. The higher the therapeutic effect the better the prognosis, with a significant difference among the groups (P = 0.008). The case distribution according to ypTNM classification was 20 patients (7.8%) with Stage 0, 83 (32.2%) with Stage I, 77 (29.8%) with Stage II, and 78 (30.2%) with Stage III. The 5‐year OS rate by ypTNM classification was 95% in Stage 0, 94% in Stage I, 89% in Stage II, and 59% in Stage III. While prognosis was mostly comparable in Stages 0 and I, in the other stages it became significantly worse as residual cancer increased (P < 0.001). The prognosis of breast cancer patients with neoadjuvant chemotherapy can be predicted by histological therapeutic effect and staging classification of residual cancer.

Predictive Factors and Value of ypN+ after Neoadjuvant Chemotherapy in Clinically Lymph Node-Negative Breast Cancer

Background Pathological complete response (pCR) with neoadjuvant chemotherapy (NAC) has been regarded as a surrogate endpoint for disease-free survival (DFS) and overall survival (OS) of patients with breast cancer. No consensus regarding the definition of pCR has been established; there are several definitions according to a variety of classifications. Eradication of cancer cells in both breast and lymph nodes has been better associated with improved prognosis than in the breast alone. Even in patients diagnosed as having clinically node-negative cancer before NAC, postoperative pathological examination often shows axillary lymph node metastases. Patients and Methods Of the 771 patients with breast cancer who underwent NAC in the Cancer Institute Hospital between January 2000 and May 2009, 146 patients preoperatively diagnosed as having node-negative breast cancer were retrospectively evaluated. We have made the definition of clinically lymph node-negative (N0) as follows: first, ultrasonography before NAC did not show any lymphadenopathy. Second, a cytological procedure confirmed negative study for each patient when ultrasonography suggested lymphadenopathy. Results The median observation period was 79.7 months, and the median age of the subjects was 51 years. Pathological examination at the time of the surgery showed lymph node metastases (ypN+) in 46 patients (31.5%). Histological therapeutic effects revealed ypT0/is in 9 patients (6.2%) and ypTinv in 137 (93.8%). Multivariate analysis demonstrated that younger age (49>), large tumor size, NG3, and ypN+ were significant poor prognostic factors for DFS (p = 0.020, p = 0.008, P = 0.022 and p = 0.010, respectively). Moreover, ypN+ was the only significant poor prognostic factor for OS (p = 0.022). The predictive factors of ypN+ in clinically lymph node–negative breast cancer were ypTinv (p = 0.036) and the luminal type (HR+ and HER2-) (p = 0.029). Conclusion The prognosis of clinically lymph node negative breast cancer depended on ypN+, which was associated with ypTinv and luminal subtype.

Efficacy of fulvestrant 500 mg in Japanese postmenopausal advanced/recurrent breast cancer patients and factors associated with prolonged time-to-treatment failure.

Objective: We aimed to confirm the efficacy of fulvestrant in Japanese postmenopausal advanced/recurrent breast cancer (ABC) patients, and investigate factors contributing to time-to-treatment failure (TTF) prolongation. Research design and methods: This retrospective study included 194 ABC patients who received fulvestrant (500 mg) from January 2012 to December 2014. Main outcome measures: TTF (efficacy measure), overall survival (OS), factors prolonging TTF and adverse events were evaluated. Results: The median age was 65 (42 – 90) years. Overall, TTF was 5.48 months. In patients without prior chemotherapy (n = 59), OS was significantly longer (p = 0.0131) than in patients with prior chemotherapy (n = 135). There was no strong correlation between TTF with fulvestrant and other endocrine therapies, total duration of endocrine therapy and maximum duration of endocrine therapy. TTF was significantly longer in patients with less than two prior chemotherapy regimens (p = 0.0093), de novo metastatic disease (p = 0.0124) and without liver metastasis (p = 0.0024). We observed one case each of pulmonary infarction and psychiatric disorder. Conclusions: Fulvestrant is effective for ABC patients and may show greater efficacy in patients with few prior chemotherapy regimens, de novo metastatic disease and absence of liver metastasis. Prior endocrine therapy duration might not be a predictive factor for fulvestrant TTF in heavily treated ABC patients.

Mutation status of RAD51C, PALB2 and BRIP1 in 100 Japanese familial breast cancer cases without BRCA1 and BRCA2 mutations

In addition to BRCA1 and BRCA2, RAD51C, PALB2 and BRIP1 are known as breast cancer susceptibility genes. However, the mutation status of these genes in Japanese familial breast cancer cases has not yet been evaluated. To this end, we analyzed the exon sequence and genomic rearrangement of RAD51C, PALB2 and BRIP1 in 100 Japanese patients diagnosed with familial breast and ovarian cancer and without BRCA1 and BRCA2 mutations. We detected a large deletion from exons 6 to 9 in RAD51C, 4 novel BRIP1 missense variants containing 3 novel non‐synonymous variants, c.89A>C, c.736A>G and c.2131A>G, and a splice donor site variant c.918+2T>C. No deleterious variant of PALB2 was detected. The results of pedigree analysis showed that the proband with a large deletion on RAD51C had a family history of both breast and ovarian cancer, and the families of probands with novel BRIP1 missense variants included a male patient with breast cancer or many patients with breast cancer within the second‐degree relatives. We showed that the mutation frequency of RAD51C in Japanese familial breast cancer cases was similar to that in Western countries and that the prevalence of deleterious mutation of PALB2 was possibly lower. Furthermore, our results suggested that BRIP1 mutation frequency in Japan might differ from that in Western countries.

Factors associated with prolonged time to treatment failure with fulvestrant 500 mg in patients with post-menopausal estrogen receptor-positive advanced breast cancer: a sub-group analysis of the JBCRG-C06 Safari study

Abstract Objective: The JBCRG-C06 Safari study showed that earlier fulvestrant 500 mg (F500) use, a longer time from diagnosis to F500 use, and no prior palliative chemotherapy were associated with significantly longer time to treatment failure (TTF) among Japanese patients with estrogen receptor-positive (ER+) advanced breast cancer (ABC). The objective of this sub-group analysis was to further examine data from the Safari study, focusing on ER + and human epidermal growth factor receptor-negative (HER2−) cases. Methods: The Safari study (UMIN000015168) was a retrospective, multi-center cohort study, conducted in 1,072 patients in Japan taking F500 for ER + ABC. The sub-analysis included only patients administered F500 as second-line or later therapy (n = 960). Of these, 828 patients were HER2−. Results Multivariate analysis showed that advanced age (≥65 years; p = .035), longer time (≥3 years) from ABC diagnosis to F500 use (p < .001), no prior chemotherapy (p < .001), and F500 treatment line (p < .001) were correlated with prolonged TTF (median = 5.39 months). Conclusions: In ER+/HER2− patients receiving F500 as a second-line or later therapy, treatment line, advanced age, no prior palliative chemotherapy use, and a longer period from ABC diagnosis to F500 use were associated with longer TTF.

Survival Outcomes of Retreatment with Trastuzumab and Cytotoxic Chemotherapy for HER2-Positive Recurrent Patients With Breast Cancer Who Had Been Treated with Neo/adjuvant Trastuzumab Plus Multidrug Chemotherapy: A Japanese Multicenter Observational Study

Background: There are little data on the usefulness of trastuzumab (TZM) retreatment as the first-line treatment for patients with HER2 (human epidermal growth factor receptor 2)–positive breast cancer recurrence after perioperative treatment with TZM. Aim: To clarify the outcome and safety of TZM retreatment in patients with recurrent HER2-positive breast cancer. Method: An observational study was conducted on patients who relapsed after primary systemic therapy with TZM using the central registration system. The primary end point was progression-free survival (PFS). Secondary end points consisted of the response rate, overall survival (OS), and safety. Result: In total, 34 patients were registered between July 2009 and June 2012. The median follow-up time was 23.7 months (2-24 months). The 1- and 2-year PFS rates were 46.9% (95% confidence interval (95% CI): 29.2%-62.9%) and 29.8% (95% CI: 15.0%-46.3%), respectively (median 10.6 months). The median PFS time for patients receiving TZM combined with CTx was 13.9 months. The 1-and 2-year OR rates were 93.9 (95% CI: 77.9%-98.4%) and 84.8% (95% CI: 67.4%-93.4%). Trastuzumab-induced grade 3/4 adverse events were not observed. Conclusions: This study suggests that the PFS and OS in Japanese patients who relapsed after perioperative TZM therapy improved or were similar to those in previous reports. Differences in patient backgrounds and treatments must be considered when interpreting the results. Trastuzumab should be used combination with CTx and/or HTx for retreatment. Retreatment with TZM is safe. Trial registration: UMIN000002738.

Circulating Pre-microRNA-488 in peripheral blood is a potential biomarker for predicting recurrence in breast cancer

Background/Aim: Circulating microRNAs (miRs) in blood have been highlighted as diagnostic, prognostic and predictive biomarkers for “Precision medicine”. This study aimed to explore the possibility of using circulating precursor miRs (pre-miRs) as clinical biomarkers of recurrence in breast cancer. Materials and Methods: We performed miR microarray analyses of circulating miRs in blood from patients with or without recurrence of breast cancer and identified miR-488-5p as a recurrence-related miR. Then, the expression levels of pre-miR-488 or miR-488-5p were measured by RT-qPCR and the clinicopathological and prognostic significance of circulating pre-miR-488 was assessed in the blood of breast cancer patients. Results: A positive correlation was noted between pre-miR-488 and miR-488-5p expression in blood. In 330 cases of surgically-treated breast cancer, high expression of circulating pre-miR-488 was an independent poor prognostic factor for recurrence-free survival. Conclusion: Circulating pre-miR-488 expression could be a novel prognostic biomarker for predicting recurrence in breast cancer patients.

Clinical outcomes and prognostic factors in patients with stage II-III breast cancer treated with neoadjuvant chemotherapy followed by surgery and postmastectomy radiation therapy in the modern treatment era

Purpose There are no randomized studies on the indication for postmastectomy radiation therapy (PMRT) in patients who receive neoadjuvant chemotherapy (NAC) followed by a mastectomy. The aim of this study was to determine clinical outcomes and identify reliable prognostic factors in patients with locally advanced breast cancer treated with NAC followed by a mastectomy and PMRT. Methods and materials We retrospectively evaluated the relationship between clinicopathological factors and outcomes in 351 patients with stage II or III breast cancer who underwent NAC followed by radical mastectomy and PMRT between March 2005 and December 2013. Results The median follow-up duration was 81 months (Range, 12-156 months). For all patients, the 5-year locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), and overall survival (OS) rates were 91.3 %, 69.8 %, and 83.4 %, respectively. On multivariate analysis, estrogen-receptor positivity, and complete response of cancer in axillary nodes (ypN0) were significant prognostic factors for better LRFS, while lympho-vascular invasion and clinical stage IIIC were independent prognostic factors for worse LRFS. The number of axillary node metastasesafter surgery was an independent prognostic factor of DMFS and OS. Patients with hormone receptor- and human epidermal growth factor receptor 2 positivity had significantly better 5-year LRFS rates. Conclusions We identified several prognostic factors in our study. In particular, the number of axillary node metastases is significantly related to OS.