Changes in Recurrence Score by neoadjuvant endocrine therapy of breast cancer and their prognostic implication.

BACKGROUND: Neoadjuvant endocrine therapy (NET) can improve surgical outcomes in postmenopausal patients with hormone receptor-positive breast cancer. The Ki67 labelling index after NET has a better prognostic power than that at baseline. However, it remains unknown whether a multigene assay with post-treatment samples could predict the prognosis better than that with pretreatment samples. METHODS: The prognostic value of the multigene assay Oncotype DX Recurrence Score (RS) was investigated using pretreatment and post-treatment samples from a multicentre NET trial, JFMC34-0601 (UMIN C000000345), where exemestane was given at 25 mg/day for 24 weeks. RESULTS: Both pretreatment and post-treatment RSs were significantly associated with disease-free survival (DFS) (p=0.005 and 0.002, respectively). The combination of pretreatment and post-treatment RSs was also a predictor of DFS (p=0.002) and superior to preoperative endocrine prognostic index (PEPI). Furthermore, combined RS was the only independent prognostic factor in the multivariate analysis among the three RSs (p=0.04). In addition, combined RS could differentiate early recurrence in the high-risk group from mid/late recurrence in the intermediate-risk group, suggesting possible differential treatment strategies based on the risk categories indicated by the combined RS. CONCLUSIONS: The combination of pretreatment and post-treatment RSs could provide pivotal information for predicting DFS and differentiating early recurrence in the high-risk group from mid/late recurrence in the intermediate-risk group in patients with hormone receptor-positive breast cancer. A larger study is required to validate the results.

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.

Clinical significance of the expression of autophagy-associated marker, beclin 1, in breast cancer patients who received neoadjuvant endocrine therapy.

BACKGROUND: Neoadjuvant endocrine therapy (NAE) has been employed to improve surgical outcomes for hormone receptor-positive breast cancers in postmenopausal women. Endocrine responsiveness is estimated by expressions of hormone receptors, but its heterogeneity has been recognized. Autophagy is an evolutionally conserved process associated with cell survival and cell death and has been implicated in cancer treatment. METHODS: In order to examine the possible association between autophagy and response to endocrine therapy, we evaluated the status of autophagy-associated markers, beclin 1 and LC3, and apoptosis-associated markers, TUNEL and M30, in pre- and post-treatment specimens from 71 patients in a multicenter prospective study of neoadjuvant exemestane (JFMC34-0601). RESULTS: Immunoreactivity of the autophagy-associated markers, beclin 1 and LC3, in carcinoma cells increased in 14% and 52% of the patients, respectively, following the exemestane treatment. These increases were statistically significant (beclin 1, p = 0.016, N = 49; LC3, p < 0.0001, N = 33). The status of M30 immunoreactivity decreased (p = 0.008, N = 47) and TUNEL remained unchanged (N = 53). In addition, tumors with pre-treatment stromal beclin 1 immunoreactivity revealed poor clinical and pathological responses compared with those without stromal beclin 1 immunoreactivity (25% vs 67% for clinical response, p = 0.011, N = 51; 0% vs 41% for pathological response, p = 0.0081, N = 49). Tumors with positive pre-treatment stromal beclin 1 had a higher baseline Ki-67 labeling index (both hot spot and overall average) than those without (p = 0.042 and 0.0075, respectively, N = 53). Results of logistic regression analyses revealed that stromal beclin 1 was a predictor for clinical and pathological responses while ER, PR, Ki-67, and stromal LC3 expressions were not. CONCLUSIONS: Results of our present study demonstrated that beclin 1 and LC3 immunoreactivity increased in carcinoma cells following exemestane treatment and that the status of pre-treatment stromal beclin 1 is associated with higher carcinoma cell proliferation and poor clinical and pathological responses to NAE. TRIAL REGISTRATION: UMIN C000000345 (2006/03/06).

Evaluating the 21-gene assay Recurrence Score® as a predictor of clinical response to 24 weeks of neoadjuvant exemestane in estrogen receptor-positive breast cancer.

BACKGROUND: The aim of this study was to investigate the association between the results of the Recurrence Score (RS) assay and the clinical response to neoadjuvant endocrine therapy in postmenopausal women with breast cancer. METHODS: Core biopsy samples at baseline and post-treatment surgical samples were obtained from 80 and 77 of 116 patients, respectively, enrolled in the multicenter prospective study of neoadjuvant exemestane therapy (JFMC34-0601). The 21-gene assay was performed after appropriate manual microdissection. The estrogen receptor (ER), progesterone receptor, HER2 and Ki-67 were assayed by immunohistochemistry at a central laboratory. Clinical response was assessed based on the RECIST (Response Evaluation Criteria In Solid Tumors) guideline. RESULTS: Sixty-four core biopsy samples and 52 resection samples met the RS quality requirements. The clinical response rate in those patients with a low RS result (low RS group; 19/32, 59.4 %) was significantly higher than that in those patients with a high RS result (high RS group; 3/15, 20.0 %) (P = 0.015) and similar to that in patients with an intermediate RS result (intermediate RS group; 10/17, 58.8 %). The rates of breast-conserving surgery (BCS) were 90.6 % (29/32) in the low RS group, 76.5 % (13/17) in the intermediate RS group and 46.7 % (7/15) in the high RS group. The odds ratio for BCS adjusted for continuous baseline Ki-67 was 0.114 [95 % confidence interval (CI) 0.014-0.721; P = 0.028] between the high and low RS groups. RS values in pre-treatment samples were highly correlated with those in post-treatment samples (Spearman correlation coefficient 0.745, 95 % CI 0.592-0.846). CONCLUSION: Our results demonstrate the predictive value of the RS for clinical response to neoadjuvant exemestane therapy in postmenopausal women with ER-positive breast cancer.

Relationship between body mass index and preoperative treatment response to aromatase inhibitor exemestane in postmenopausal patients with primary breast cancer.

BACKGROUND: Some studies have shown that high body mass index (BMI) is associated with inferior outcome after adjuvant therapy with anastrozole in breast cancer patients. We aimed to investigate predictive effect of BMI on clinical response to neoadjuvant therapy with exemestane in postmenopausal patients with primary breast cancer. PATIENTS AND METHODS: The study group consisted of 109 patients from the JFMC 34-0601 neoadjuvant endocrine therapy trial. Patients were categorized into three groups according to BMI: low (BMI < 22 kg/m(2)), intermediate (22 ≤ BMI < 25 kg/m(2)) and high (BMI ≥ 25 kg/m(2)). Statistical analyses were performed to explore the predictive effect of BMI on clinical response. RESULTS: Higher BMI correlated with positive progesterone receptor status (p < 0.01) and low Ki-67 index (p = 0.03). Objective response rates (ORR) were 21.7% in low BMI, 56.0% in intermediate BMI and 60.6% in high BMI, respectively (p = 0.01). In a multivariate analysis, low BMI was an independent negative predictor of clinical response. CONCLUSION: Low BMI was associated with a decreased ORR to neoadjuvant endocrine therapy with exemestane. Our results may suggest that the predictive effect of BMI varies according to the type of aromatase inhibitor and objective outcome.

Ki67 index changes, pathological response and clinical benefits in primary breast cancer patients treated with 24 weeks of aromatase inhibition.

Aromatase inhibitor shows efficacy for hormone receptor positive postmenopausal breast cancer. We evaluated the activity of 24 weeks of aromatase inhibition with exemestane for primary breast cancer in a neoadjuvant setting. Patients with stage II/IIIA invasive breast cancer with estrogen receptor (ER) and/or progesterone receptor (PgR)-positive status were eligible. Primary endpoints were objective response rate (ORR) and safety. A steroidal aromatase inhibitor exemestane of 25 mg/day was administered for 16 weeks with an 8-week extension. Secondary endpoints were rates of breast-conserving surgery (BCS), and change of Ki67 index and ER/PgR expression in central laboratory analyses. Between March 2006 and December 2007, 116 patients were enrolled. Among those, 102 patients completed 24 weeks of administration. The ORR was 47% (55/116) at Week 16 and 51% (59/116) at Week 24, respectively. No serious toxicity was seen. ORR was associated with ER Allred scores but not with PgR scores. The significant reduction in Ki67 index was confirmed. No progression was experienced in tumors with less than 15% Ki67 index. Pathological response was observed in 28 (30%) of 94 evaluated cases. No statistical correlation between pre-treatment Ki67 index and pathological response was detected; however, a trend of correlation was found between the post-treatment preoperative endocrine prognostic index (PEPI), a prognostic score and the pathological response. At diagnosis, 59 patients (51%) would have required mastectomy but 40 patients were converted to BCS, showing an increase in the rate of BCS (77%). The 24-week aromatase inhibition provided preferable clinical benefits with significant reduction in Ki67 index. More precise mechanisms of the response need to be investigated.

Phase III randomized adjuvant study of tamoxifen alone versus sequential tamoxifen and anastrozole in Japanese postmenopausal women with hormone-responsive breast cancer: N-SAS BC03 study.

Clinical trials conducted in Western countries have shown that aromatase inhibitors are associated with better disease-free survival (DFS) than tamoxifen in postmenopausal early breast cancer. Because pharmacogenetic differences in drug-metabolizing genes may cause ethnic differences, assessment of the efficacy and tolerability of aromatase inhibitors in non-white women is warranted. This open-label, randomized clinical trial included 706 postmenopausal Japanese women with hormone-receptor-positive breast cancer, who had received tamoxifen for 1 to 4 years as adjuvant therapy. This study was closed early after entry of approximately 28% of the initially planned patients. They were randomly assigned to either switch to anastrozole or to continue tamoxifen for total treatment duration of 5 years. Primary endpoints were DFS and adverse events. At a median follow-up of 42 months, the unadjusted hazard ratio was 0.69 (95% confidence interval, 0.42-1.14; P = 0.14) for DFS and 0.54 (95% CI, 0.29-1.02; P = 0.06) for relapse-free survival (RFS), both in favor of anastrozole. The incidence of thromboembolic events in the tamoxifen group and bone fractures in the anastrozole group was not excessively high. Switching from tamoxifen to anastrozole was likely to decrease disease recurrence in postmenopausal Japanese breast cancer patients. Ethnic differences in major adverse events may be attributable to a low baseline risk of these events in Japanese.

Phase II study of weekly paclitaxel for advanced or metastatic breast cancer in Japan.

BACKGROUND: The efficacy and safety of weekly paclitaxel was evaluated in Japanese women with advanced or metastatic breast cancer. PATIENTS AND METHODS: Paclitaxel was given by single weekly intravenous infusion at 100 mg/m2 on days 1, 8, 15, 22, 29 and 36 of a 49-day cycle to women with advanced or metastatic breast cancer not responding to other chemotherapy. RESULTS: A total of 69 enrolled patients received a median of 3 (range 1-13) cycles of treatment. The overall response rate was 44.9%, comprising 3 complete responses (CRs) and 28 partial responses (PRs). Median durations of CR and PR were 64.0 (range 57-499) and 113.0 (range 29-590) days, respectively. Grade 3 or greater adverse reactions included neutropenia in 37.7%, leukopenia in 31.9% and neuropathy in 5.8%. CONCLUSION: A weekly regimen of paclitaxel was well tolerated and achieved a relatively high response rate in Japanese breast cancer patients with advanced or metastatic disease.

Prospective assessment of chemotherapy-induced peripheral neuropathy due to weekly paclitaxel in patients with advanced or metastatic breast cancer (CSP-HOR 02 study).

GOALS OF WORK: The aim of this study was to prospectively evaluate chemotherapy-induced peripheral neuropathy (CIPN) using a patient-based instrument, the Patient Neurotoxicity Questionnaire (PNQ) and a physician-based instrument, the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) in patients with advanced or metastatic breast cancer who were treated with weekly paclitaxel. MATERIALS AND METHODS: CIPN symptoms were prospectively assessed in 35 patients using the PNQ, NCI-CTC, and the Functional Assessment of Cancer Therapy (FACT)-Taxane including neurotoxicity component (Ntx) at the baseline, and 8 and 16 weeks after starting chemotherapy. RESULTS: For sensory neuropathy symptoms, the reported incidence of CIPN was significantly increased during active treatment in terms of both the PNQ and NCI-CTC assessments. In contrast, there was a notable increase of patient motor neuropathy symptoms that were elucidated only by the PNQ. The PNQ grades of CIPN were widely distributed in the patient population as compared with the NCI-CTC grades for both sensory and motor neuropathy. The sensory PNQ grade was correlated with sensory NCI-CTC grade (r = 0.58) and Ntx (r = 0.51), and the motor PNQ grade was correlated with Ntx (r = 0.57). CONCLUSIONS: The PNQ appears to be more sensitive and responsive than the NCI-CTC for CIPN; the PNQ appears to have diagnostic validity for evaluating CIPN in patients who are receiving neurotoxic chemotherapy.

[Results of survey conducted on perioperative chemotherapy and supportive care in primary breast cancer (JBCRG01)].

We carried out a survey of supportive care at institutions that participated in the JBCRG01 study (FEC followed by docetaxel) as neoadjuvant therapy for operable breast cancer. The purpose was to share the information of supportive care for the treatment effect of perioperative intensive chemotherapy among institutions. Appropriate supportive care for nausea, vomiting, edema and febrile neutropenia (FN) is important with respect to the safety of chemotherapy. According to the results of the questionnaire, support from the family and the relationships with doctors, nurses and pharmacists familiar with the chemotherapy were important. The equipment and service for outpatients' cancer chemotherapy center are also important. This multicenter study enhances the exchange of information among institutes. The results of this survey suggest that adequate supportive care makes anthracycline and taxane chemotherapy manageable in the outpatient setting.

Interim analysis of a phase II trial of cyclophosphamide, epirubicin and 5-fluorouracil (CEF) followed by docetaxel as preoperative chemotherapy for early stage breast carcinoma.

PURPOSE: A single-arm phase II multicenter trial of the combination of cyclophosphamide (C), epirubicin (E), and 5-fluorouracil (F) followed by docetaxel as neoadjuvant chemotherapy is being conducted by the Japan Breast Cancer Research Group. This report describes an interim analysis of the clinical response and safety of 79 patients who finished preoperative chemotherapy and surgery. PATIENTS AND METHODS: Patients with operable breast cancer received C at 500 mg/m2, E at 100 mg/m2, and F at 500 mg/m2 every 21 days for 4 cycles followed by docetaxel at 75 mg/m2 every 21 days for 4 cycles. RESULTS: Of the 79 patients evaluable for analysis the median age was 46 years (28-59), and 61 patients (77.2%) had T2 tumors. A total of 312 of 316 (98.7%) cycles of CEF and 296 of 312 (94.9%) cycles of docetaxel were administered. Average total cumulative dose was 92% and 95% for CEF and docetaxel, respectively. The rate and grade of edema, neuropathy, arthralgia and myalgia were higher with docetaxel than with CEF. The overall clinical response rate was 70.9%. Breast conserving surgery was performed in 31 of 42 patients (73.8%) with a base-line tumor size of more than 3 cm. CONCLUSIONS: Interim data suggest that CEF followed by docetaxel is an active and tolerable neoadjuvant chemotherapy regimen. A final analysis is planned for 2005.

3D imaging of intraductal spread of breast cancer and its clinical application for navigation surgery.

BACKGROUND: To perform optimal tumor resection of breast cancer, preoperative information concerning intraductal spread of cancer (ISC) is very important. METHODS: To detect ISC, three-dimensional (3D) imaging methods including helical CT, MRI, and ultrasound were examined in patients with primary breast cancer by comparison with multi-sliced pathological specimens. RESULTS: The sensitivity of each modality for detecting ISC was 64.7%, 90.2% and 78.6%, and the specificity was 97.1%, 62.9% and 100%, respectively. Subsequently, the potential of each modality for navigation in breast conserving surgery was assessed. Three-dimensional helical CT navigation could reduce the positive rate of the specimen margins, and 3D MRI navigation using a special mapping sheet enabled removal of non-palpable breast cancer without positive margins in 66.7% of patients preliminarily. Real-time 3D ultrasound images correlated with the resected tumor size, with the difference between the two less than 2 cm in 72.7 % of the patients with ISC. CONCLUSION: Three-dimensional images from each modality were reliable enough for diagnosis of tumor spread, and surgical navigation using these images seemed to have potential clinical application for breast conserving surgery. Prospective studies for navigation surgery with more patients are needed.