Shunji Kamigaki

Neoadjuvant anastrozole versus tamoxifen in patients receiving goserelin for premenopausal breast cancer (STAGE): a double-blind, randomised phase 3 trial

BACKGROUND Aromatase inhibitors have shown increased efficacy compared with tamoxifen in postmenopausal early breast cancer. We aimed to assess the efficacy and safety of anastrozole versus tamoxifen in premenopausal women receiving goserelin for early breast cancer in the neoadjuvant setting. METHODS In this phase 3, randomised, double-blind, parallel-group, multicentre study, we enrolled premenopausal women with oestrogen receptor (ER)-positive, HER2-negative, operable breast cancer with WHO performance status of 2 or lower. Patients were randomly assigned (1:1) to receive goserelin 3·6 mg/month plus either anastrozole 1 mg per day and tamoxifen placebo or tamoxifen 20 mg per day and anastrozole placebo for 24 weeks before surgery. Patients were randomised sequentially, stratified by centre, with randomisation codes. All study personnel were masked to study treatment. The primary endpoint was best overall tumour response (complete response or partial response), assessed by callipers, during the 24-week neoadjuvant treatment period for the intention-to-treat population. The primary endpoint was analysed for non-inferiority (with non-inferiority defined as the lower limit of the 95% CI for the difference in overall response rates between groups being 10% or less); in the event of non-inferiority, we assessed the superiority of the anastrozole group versus the tamoxifen group. We included all patients who received study medication at least once in the safety analysis set. We report the primary analysis; treatment will also continue in the adjuvant setting for 5 years. This trial is registered with ClinicalTrials.gov, number NCT00605267. FINDINGS Between Oct 2, 2007, and May 29, 2009, 204 patients were enrolled. 197 patients were randomly assigned to anastrozole (n=98) or tamoxifen (n=99), and 185 patients completed the 24-week neoadjuvant treatment period and had breast surgery (95 in the anastrazole group, 90 in the tamoxifen group). More patients in the anastrozole group had a complete or partial response than did those in the tamoxifen group during 24 weeks of neoadjuvant treatment (anastrozole 70·4% [69 of 98 patients] vs tamoxifen 50·5% [50 of 99 patients]; estimated difference between groups 19·9%, 95% CI 6·5-33·3; p=0·004). Two patients in the anastrozole group had treatment-related grade 3 adverse events (arthralgia and syncope) and so did one patient in the tamoxifen group (depression). One serious adverse event was reported in the anastrozole group (benign neoplasm, not related to treatment), compared with none in the tamoxifen group. INTERPRETATION Given its favourable risk-benefit profile, the combination of anastrozole plus goserelin could represent an alternative neoadjuvant treatment option for premenopausal women with early-stage breast cancer. FUNDING AstraZeneca.

Clinical Significance of the 21-Gene Signature (Oncotype DX) in Hormone Receptor-Positive Early Stage Primary Breast Cancer in the Japanese Population

The 21‐gene signature has been intensively studied and incorporated into major guidelines for treatment decision in early breast caner. However, it remains to be examined whether this system is applicable to Asian populations.

Analysis of Ki-67 expression with neoadjuvant anastrozole or tamoxifen in patients receiving goserelin for premenopausal breast cancer

The increasing costs associated with large‐scale adjuvant trials mean that the prognostic value of biologic markers is increasingly important. The expression of nuclear antigen Ki‐67, a marker of cell proliferation, has been correlated with treatment efficacy and is being investigated for its value as a predictive marker of therapeutic response. In the current study, the authors explored correlations between Ki‐67 expression and tumor response, estrogen receptor (ER) status, progesterone receptor (PgR) status, and histopathologic response from the STAGE study (S_tudy of T_amoxifen or A_rimidex, combined with G_oserelin acetate to compare E_fficacy and safety).

Down-regulation of intratumoral aromatase messenger RNA levels by docetaxel in human breast cancers.

Purpose: The reason why chemotherapy induces resistance to subsequent hormonal therapy remains to be clarified in postmenopausal breast cancers. We hypothesized that chemotherapy might down-regulate the intratumoral biosynthesis of estrogens. Thus, we have studied the influence of chemotherapy (docetaxel) on intratumoral aromatase mRNA expression because aromatase is a key enzyme for intratumoral biosynthesis of estrogens. Experimental Design: The mRNA levels of aromatase and its inducers [tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and cyclooxygenase 2 (COX-2)] were determined by a real-time polymerase chain reaction assay in breast cancer tissues obtained before and after neoadjuvant chemotherapy with docetaxel (four cycles of 60 mg/m2 every 3 weeks) in 16 postmenopausal patients with estrogen receptor (ER)- and/or progesterone receptor (PR)-positive breast cancers. ER and PR levels in tumor tissues were also determined by enzyme immunoassay before and after chemotherapy. Results: The intratumoral aromatase mRNA levels decreased significantly (P < 0.05) after chemotherapy from 0.84 ± 0.28 (mean ± SE) to 0.47 ± 0.28. The intratumoral TNF-α mRNA levels also decreased significantly (P < 0.05) after chemotherapy from 2.40 ± 0.52 to 0.95 ± 0.25. On the contrary, the intratumoral IL-6 and COX-2 mRNA levels showed a marginally significant increase (P = 0.07) and a significant increase (P < 0.05), respectively, after chemotherapy. PR levels showed a marginally significant decrease (P = 0.08) after chemotherapy, whereas ER levels were almost constant before and after chemotherapy. Conclusions: Antitumor activity of docetaxel is mediated, at least in part, through a down-regulation of aromatase expression in tumor tissues, resulting in the suppression of intratumoral estradiol synthesis. Aromatase expression seems to be regulated mostly by TNF-α, but not IL-6 and COX-2.

Phase II trial of neoadjuvant 5-fluorouracil, epirubicin and cyclophosphamide (FEC100) followed by weekly paclitaxel and trastuzumab (PH) for HER2 positive breast cancer (Kinki Multidisciplinary Breast Oncology Group; KMBOG-0402).

Abstract #3160 Background: Achievement of pathological complete response (pCR) by primary systemic chemotherapy (PST) correlates with improved disease-free survival in operable breast cancer patients. Based on data of the higher pCR rate with concomitant chemotherapy and trastuzumab (H) presented by the randomized prospective trial (Buzdar AU, et al: JCO 23:3676-85; 2005), we performed a multi-center, prospective phase II study to assess the addition of H to primary systemic chemotherapy in HER2+ pts in Japan.
 Methods: Generally, the concomitant combination therapy with anthracycline-containing regimens and H is not recommended because of the increasing rate of cardiac toxicity. This study was designed to evaluate the efficacy and safety of PST for the operable breast cancer with HER2+ phenotype. PST is the sequential chemotherapy with 4 cycles of FEC100 followed by 12 times in combination with weekly paclitaxel (P) 80mg/m 2 and H 2mg/kg (PH x 12) . . The inclusion criteria is pts with histopathologically confirmed invasive breast carcinoma, T1-3N+M0/T2-3N0M0, HER2 positive by FISH or immunohistochemistry (IHC) 3+, PS=0-1, adequate hematologic, renal, hepatic and cardiac function and a written informed consent. The study was designed to detect a pCR rate of >43% in at least 42 pts. The evaluation of pathological response was carried out on all the surgical specimens sliced every 5 mm interval.
 Results: From Dec 2004 to Dec 2007, 43 pts were enrolled. Pre-reviewed data is now available for all pts: median age 56 [26-75 years]; 15 (35%) pre-menopausal; median clinical tumor size 40 mm [15-80]; 14 (33%) were ER-positive phenotype. All pts had a normal cardiac function before entry and after FEC→PH. No episodes of serious adverse events were reported. Febrile neutropenia was observed on 5 pts (12%). Grade 2 or 3 neuropathy was limited to 4 pts (9%). Other grade 3 non-hematological toxicities were not observed. Two pts requested to stop the treatment with P after 6 times of infusion because of neuropathy, edema and hyperpigmentation on the face, however, they had completed 12 times of H infusion. After PST, breast conservative surgery was done in 38 patients (88%) and mastectomy in 5 (12%). The overall pCR rate was 60% (26/43), and 6 of 26 pts had only component of DICS.
 Conclusions : In HER2+ pts, PST with FEC100x4 followed by PHx12 was active and promising, achieving high pathological complete response without significant toxicity. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3160.

A multicenter phase II trial of neoadjuvant letrozole plus low‐dose cyclophosphamide in postmenopausal patients with estrogen receptor‐positive breast cancer (JBCRG‐07): therapeutic efficacy and clinical implications of circulating endothelial cells

Neoadjuvant endocrine therapy has been reported to decrease tumor size, which leads to increased breast conservation rates. To improve the clinical response, metronomic chemotherapy with endocrine therapy is a promising strategy. A multicenter phase II single‐arm neoadjuvant trial with letrozole and cyclophosphamide was conducted. Eligibility criteria included postmenopausal status, T2–4 N0–1, and estrogen receptor‐positive breast carcinoma. Letrozole (2.5 mg) plus cyclophosphamide (50 mg) was given orally once a day for 24 weeks. The primary endpoint was the clinical response rate (CRR). To investigate anti‐angiogenic effects, circulating endothelial cells (CECs) were quantified using the CellSearch system. From October 2007 to March 2010, 41 patients were enrolled. The CRR was 67.5% (52.0–80.0%), which was above the prespecified threshold (65%). The conversion rate from total mastectomy to breast‐conserving surgery was 64% (18/28). Grade 3 or greater nonhematological toxicity was not reported. Clinical response was associated with improved disease‐free survival (DFS) (P = 0.020). The increase in CEC counts at 8 weeks was observed in nonresponders (P = 0.004) but not in responders. Patients with higher CEC counts at baseline or post‐treatment showed worse DFS than those with lower counts (P < 0.001 at baseline and = 0.014 post‐treatment). Multivariate analysis showed that post‐treatment CEC counts but not pretreatment counts were independently correlated with DFS (P = 0.046). In conclusion, neoadjuvant letrozole plus cyclophosphamide showed a good clinical response for postmenopausal patients with estrogen receptor‐positive breast cancer. CEC quantification is a promising tool for treatment monitoring and prognostic stratification for metronomic therapy following validation of our results in larger studies. Clinical trial registration number: UMIN000001331 Phase II study of neoadjuvant letrozole combined with low‐dose metronomic cyclophosphamide for postmenopausal women with endocrine‐responsive breast cancer (JBCRG‐07)

Abstract P1-10-26: Frozen glove could be a new hope for prevention of chemotherapy induced peripheral neuropathy

Introduction Chemotherapy induced peripheral neuropathy (CIPN) is a major problem for patients who receive chemotherapy, and it sometimes deteriorate patients9 QOL. Many CIPN prevention trials have been conducted, but no one succeeded to date. Objectives To investigate if frozen glove (FG) prevents peripheral neuropathy induced by nanoparticle albumin-bound paclitaxel (nab-PTX). Methods We conducted CIPN prevention study using FG, as part of multi-institutional phase II study which analyze efficacy and safety of nab-PTX (260mg/m2 q3w) followed by FEC (500/100/500 mg/m2, q3w) in pre-operative setting (KBCSG-TR 1213 trial). Each patient wore an FGs for a total of 60 minutes (15mins before and after nab-PTX treatment) on both hands. CIPN were assessed during treatment period with nab-PTX by the Patient Neurotoxicity Questionnaire (PNQ) and the FACT/GOG (Gynecologic Oncology Group) Neurotoxicity (Ntx) subscale. Patients were asked to access PNQ and FACT/GOG Ntx on a daily basis and recorded in the CIPN diary. Results Sixty two patients were registered for KBCSG-TR 1213 trial. And forty two pts (68%) who turned in the diary were analyzed. Median age and median body mass index (BMI) was 48 years old and 21.6 kg/m2, respectively. We analyzed following 6 categories, 1) symptoms of hands and arms, 2) symptoms of foots, 3) symptoms of general, 4) symptoms of ears 5) muscle weakness of hands and arms and 6) muscle weakness of foots. Median time to each event was 1) 25.5 days, 2) 5days, 3) 3days, 4) not available, 5) 46.5days, 6)4 days. By using FG, time to event of hands and arms was much longer compared with that of foots. Conclusions CIPN could be prevented or lessened by FG. Randomized phase II CIPN prevention study has been just launched. Citation Format: Nakayama T, Yasojima H, Morimoto T, Yoshidome K, Mizutani M, Takashima T, Matsunami N, Enami A, Kagawa M, Nomura T, Shiba E, Nishi T, Kamigaki S, Kozuma Y, Yoshinami T, Masuda N. Frozen glove could be a new hope for prevention of chemotherapy induced peripheral neuropathy. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-10-26.

Abstract OT3-1-04: A phase 2 study of eribulin in combination with pertuzumab and trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 (HER2)-positive breast cancer (SONG-02)

Background: Pertuzumab, an anti-HER2 humanized monoclonal antibody that inhibits receptor dimerization, has a mechanism of action that is complementary to that of trastuzumab, and the combination of pertuzumab plus trastuzumab plus taxanes, when used as first-line treatment for HER2-positive metastatic breast cancer, significantly prolonged progression-free survival (PFS). However, in the second and later line treatment of HER2-positive advanced or recurrent breast cancer, it has not settled whether it should be treated with pertuzumab plus trastuzumab plus chemotherapy or with trastuzumab plus chemotherapy. Eribulin mesylate is a non-taxane microtubule dynamics inhibitor that has been proved to prolong the overall survival of advanced or recurrent breast cancer patients compared with the treatment of physician9s choice. The benefit of eribulin in combination with trastuzumab for patients with locally recurrent or metastatic HER2-positive breast cancer has been reported. However, the efficacy and safety of eribulin in combination with pertuzumab and trastuzumab for advanced or recurrent HER2-positive breast cancer patients has not been reported. The purpose of this study is to evaluate the efficacy and safety of eribulin in combination with pertuzumab and trastuzumab as second and later line therapy for patients with advanced or recurrent HER2-positive breast cancer. Trial Design: This is a multicenter single arm phase 2 study for advanced or recurrent HER2-positive breast cancer patients who have experienced progression with anti-HER2 therapy. Patients received eribulin mesylate 1.4mg/m2 administered via intravenous (IV) infusion over 2 to 5 minutes on Days 1 and 8 each 21-day cycle and pertuzumab 840mg/kg IV and trastuzumab 8mg/kg IV over 90 minutes on Day 1 of Cycle 1. Thereafter eribulin mesylate 1.4mg/m2 and pertuzumab 420mg/kg and trastuzumab 6mg/kg was infused each 21-day cycle until disease progression or the appearance of toxic effects that could not be effectively managed. The primary endpoint is PFS of the combination therapy, based on local assessment of response using RECIST 1.1 criteria. Secondary endpoints are overall response rate (ORR), safety and tolerability. In addition, we examine PFS and safety according to the most recent treatment regimen. The study was conducted in accordance with the Declaration of Helsinki (2008), and the protocol and informed consent forms were submitted for approval to institutional review boards by the primary investigators. All patients provided written informed consent before undergoing any study-related procedures Statistical Method: All efficacy analyses were based primarily on the full analysis set (FAS), which included all patients who received over 1 dose(s) of study treatment. The PFS and ORR were calculated 95% confidence intervals (CIs). Treatment of 39 evaluable patients with the identified phase 2 doses will detect this difference with a power of 80% and alpha=5% (one-sided test). Accounting for a 10% invaluable rate and lead-in patients, a total of 43 patients will be enrolled on the study. Clinical trial information UMIN000014107. Citation Format: Hajime Abe, Shunji Kamigaki, Yoshifumi Komoike, Nobuki Matsunami, Yoshiaki Nakano, Kenji Tezuka, Junji Tsurutani, Jun Yamamura, Keiichi Yamazaki. A phase 2 study of eribulin in combination with pertuzumab and trastuzumab for advanced or recurrent human epidermal growth factor receptor 2 (HER2)-positive breast cancer (SONG-02) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT3-1-04.