Shoichiro Ohtani

Multicenter Phase I Study of Repeated Intratumoral Delivery of Adenoviral p53 in Patients With Advanced Non–Small-Cell Lung Cancer

PURPOSE To determine the feasibility, safety, humoral immune response, and biologic activity of multiple intratumoral injections of Ad5CMV-p53, and to characterize the pharmacokinetics of Ad5CMV-p53 in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Fifteen patients with histologically confirmed NSCLC and p53 mutations were enrolled onto this phase I trial. Nine patients received escalating dose levels of Ad5CMV-p53 (1 x 10(9) to 1 x 10(11) plaque-forming units) as monotherapy once every 4 weeks. Six patients were treated on a 28-day schedule with Ad5CMV-p53 in combination with intravenous administration of cisplatin (80 mg/m2). Patients were monitored for toxicity, vector distribution, antibody formation, and tumor response. RESULTS Fifteen patients received a total of 63 intratumoral injections of Ad5CMV-p53 without dose-limiting toxicity. The most common treatment-related toxicity was a transient fever. Specific p53 transgene expression was detected using reverse-transcriptase polymerase chain reaction in biopsied tumor tissues throughout the period of treatment despite of the presence of neutralizing antiadenovirus antibody. Distribution studies revealed that the vector was detected in the gargle and plasma, but rarely in the urine. Thirteen of 15 patients were assessable for efficacy; one patient had a partial response (squamous cell carcinoma at the carina), 10 patients had stable disease, with three lasting at least 9 months, and two patients had progressive disease. CONCLUSION Multiple courses of intratumoral Ad5CMV-p53 injection alone or in combination with intravenous administration of cisplatin were feasible and well tolerated in advanced NSCLC patients, and appeared to provide clinical benefit.

Adjuvant capecitabine for breast cancer after preoperative chemotherapy

BACKGROUND Patients who have residual invasive carcinoma after the receipt of neoadjuvant chemotherapy for human epidermal growth factor receptor 2 (HER2)‐negative breast cancer have poor prognoses. The benefit of adjuvant chemotherapy in these patients remains unclear. METHODS We randomly assigned 910 patients with HER2‐negative residual invasive breast cancer after neoadjuvant chemotherapy (containing anthracycline, taxane, or both) to receive standard postsurgical treatment either with capecitabine or without (control). The primary end point was disease‐free survival. Secondary end points included overall survival. RESULTS The result of the prespecified interim analysis met the primary end point, so this trial was terminated early. The final analysis showed that disease‐free survival was longer in the capecitabine group than in the control group (74.1% vs. 67.6% of the patients were alive and free from recurrence or second cancer at 5 years; hazard ratio for recurrence, second cancer, or death, 0.70; 95% confidence interval [CI], 0.53 to 0.92; P=0.01). Overall survival was longer in the capecitabine group than in the control group (89.2% vs. 83.6% of the patients were alive at 5 years; hazard ratio for death, 0.59; 95% CI, 0.39 to 0.90; P=0.01). Among patients with triple‐negative disease, the rate of disease‐free survival was 69.8% in the capecitabine group versus 56.1% in the control group (hazard ratio for recurrence, second cancer, or death, 0.58; 95% CI, 0.39 to 0.87), and the overall survival rate was 78.8% versus 70.3% (hazard ratio for death, 0.52; 95% CI, 0.30 to 0.90). The hand‐foot syndrome, the most common adverse reaction to capecitabine, occurred in 73.4% of the patients in the capecitabine group. CONCLUSIONS After standard neoadjuvant chemotherapy containing anthracycline, taxane, or both, the addition of adjuvant capecitabine therapy was safe and effective in prolonging disease‐free survival and overall survival among patients with HER2‐negative breast cancer who had residual invasive disease on pathological testing. (Funded by the Advanced Clinical Research Organization and the Japan Breast Cancer Research Group; CREATE‐X UMIN Clinical Trials Registry number, UMIN000000843.)

Adenovirus-Mediated p14ARF Gene Transfer Cooperates with Ad5CMV-p53 to Induce Apoptosis in Human Cancer Cells

p14(ARF), a product of the INK4A/ARF locus, induces p53 upregulation by neutralizing the effects of MDM2, a transcriptional target of p53 that antagonizes its function. Here we report that adenovirus-mediated p14(ARF) gene transfer leads to the accumulation of ectopically transduced p53 and to apoptosis in human cancer cells. We constructed an adenoviral vector expressing p14(ARF) (Ad-ARF) and examined its synergistic effect with p53-expressing adenovirus (Ad5CMV-p53 or Ad-p53) in human lung and esophageal cancer cells. Simultaneous Ad-ARF and Ad-p53 infection increased p53 protein levels not only in a wild-type p53-expressing cell line, but also in cell lines with deleted p53. This resulted in a significant in vitro cytotoxicity compared with Ad-p53 infection alone. Coinfection of Ad-ARF and Ad-p53 also resulted in an increase in expression of p53-inducible genes, including p21(WAF-1/Cip1), p53R2, and Noxa. In addition, the growth of human lung cancer tumors subcutaneously implanted into nu/nu mice was inhibited significantly by intratumoral injection with Ad-ARF and Ad-p53. Our data demonstrate that overexpression of ectopic p14(ARF) may render cells more sensitive to p53-mediated apoptosis, an outcome that has important implications for the treatment of human cancers.

Late resistance to adenoviral p53-mediated apoptosis caused by decreased expression of Coxsackie-adenovirus receptors in human lung cancer cells

Adenovirus‐mediated wild‐type p53 gene transfer induces apoptosis in a variety of human cancer cells. Although clinical trials have demonstrated that a replication‐deficient recombinant adenovirus expressing the wild‐type p53 gene (Ad‐p53) is effective in suppressing growth of non‐small cell lung cancer (NSCLC), we often experienced late resistance to this treatment. To elucidate the mechanism of late resistance to Ad‐p53 in human lung cancer cells, we generated 5 different resistant variants from p53‐susceptible H1299 NSCLC cells by repeated infections with Ad‐p53. We first examined the transduction efficiency of adenoviral vector by Ad‐LacZ transduction followed by X‐gal staining in parental and 5 resistant H1299 cell lines. Their sensitivity to viral infection decreased in correlation with the magnitude of resistance, and Ad‐p53‐mediated tumor suppression could be restored by dose escalation of Ad‐p53 in the resistant variants. The expression of Coxsackie and adenovirus receptor (CAR) and αV integrins, which are cellular receptors for attachment and internalization of the virus, respectively, was next investigated in these cell lines. Flow cytometry revealed that αVβ3 and αVβ5 integrin expression was consistent, while p53‐resistant cell lines showed that diminished CAR expression correlated with the magnitude of the resistance. Our results demonstrated that decreased CAR expression could be one of the mechanisms of late resistance to Ad‐p53, which may have a significant impact on the outcome of adenovirus‐based cancer gene therapy.

Neoadjuvant Chemotherapy with or without Concurrent Hormone Therapy in Estrogen Receptor -Positive Breast Cancer: NACED-Randomized Multicenter Phase II Trial

Although in the neoadjuvant setting for estrogen receptor (ER)-positive breast cancers, chemotherapy or hormone therapy alone does not result in satisfactory tumor response, it is unknown whether concurrent chemo-endocrine therapy is superior to chemotherapy alone in clinical outcomes. We conducted a randomized phase II trial to test the responses of ER-positive patients to concurrent administration of chemo-endocrine therapy in the neoadjuvant setting. Women with stage II-III, ER-positive, invasive breast cancer (n=28) received paclitaxel followed by fluorouracil, epirubicin, cyclophosphamide (T-FEC) and were randomized to receive concurrent chemo-endocrine therapy consisting of goserelin administered subcutaneously for premenopausal women or an aromatase inhibitor for postmenopausal women. The primary endpoint was the pathological complete response (pCR) rate after neoadjuvant therapy. Twenty-eight patients were randomized. There were no significant differences in pCR rate between the concurrent group (12.5%;2/16) and the chemotherapy alone group (8.3%;1/12). Tumor size after therapy was significantly reduced in the concurrent therapy group (p=0.035), but not in the chemotherapy-alone group (p=0.622). Neoadjuvant chemotherapy with concurrent hormone therapy provided no significant improvement in pCR rate in ER-positive breast cancers. These preliminary results should be followed up by further studies.

Abstract PD5-03: TransNEOS: Validation of the oncotype DX recurrence score (RS) testing core needle biopsy samples from NEOS as predictor of clinical response to neoadjuvant endocrine therapy for postmenopausal estrogen receptor positive (ER+), HER2 negative (HER2-) breast cancer patients

Background: Neoadjuvant therapy for locally advanced breast cancer has the potential to improve surgical therapeutic outcomes without sacrificing the survival advantages of adjuvant therapy. However, determining whether ER+ patients (pts) will respond to neoadjuvant (NA) chemotherapy (CT) or hormone therapy (HT) can be difficult. Not all ER+ pts respond to NACT, while response to NAHT can vary across ER+ pts. Thus, the ability to select pts more likely to benefit from NAHT would represent progress in clinical management of breast cancer. NEOS is a randomized phase III study assessinglong-term prognosis of ER+ primary breast cancer with/without adjuvant CT following NAHT (UMIN 000001090, http://www.umin.ac.jp/). We used archived core biopsy tumor samples from the NEOS study to validate the RS result as a predictor of clinical response and its association with successful breast conserving surgery (BCS) in pts treated with 6 months of NAHT. Methods: NEOS enrolled 904 postmenopausal pts with ER+, HER2-, clinically node negative (cN0) breast cancer to evaluate whether adjuvant CT was necessary for pts who responded to NAHT. In this current study, we enrolled pts with tumors ≥2cm from the NEOS study. Biopsy samples of 333 pts were assessed for the Oncotype DX assay. Response to NAHT was recorded as complete/partial response (CR/PR), or stable/progressive disease (SD/PD). Primary endpoint of this study was to evaluate clinical response (CR/PR) to NA letrozole between pts with low ( Results: The analysis included 294 pts with median age of 63 yrs, median tumor size of 25mm, and 66% were nuclear grade 1. 156 (53.0%), 83 (28.6%) and 54(18.4%) cases were low, intermediate, and high RS groups by Oncotype DX, respectively. Six (2%), 126 (42.8%), 149 (50.3%), 13 (4.4%) cases experienced CR, PR, SD, PD as clinical response, respectively, similar to that of all NEOS pts. Clinical response rate was 54%, 42% and 22% in low, intermediate, and high RS groups, respectively. The proportion of pts with clinical response was significantly higher in the low RS group vs the high RS group (p Conclusion: The Oncotype DX RS test in core biopsy samples is validated as a predictive assay for clinical response of NAHT in postmenopausal, ER+/HER2-, cN0, primary early breast cancer pts. Further results on the association of RS results with BCS outcomes following NAHT will be presented. These results when combined with previously published data on RS in NACT studies help guide pts with ER+, HER2- breast cancer with NAHT vs NACT treatment options to maximize clinical response. Citation Format: Yamamoto Y, Iwata H, Masuda N, Fujisawa T, Toyama T, Kashiwaba M, Ohtani S, Taira N, Sakai T, Hasegawa Y, Nakamura R, Akabane H, Shibahara Y, Sasano H, Yamaguchi T, Sakamaki K, Chao C, McCullough D, Sugiyama N, Ohashi Y. TransNEOS: Validation of the oncotype DX recurrence score (RS) testing core needle biopsy samples from NEOS as predictor of clinical response to neoadjuvant endocrine therapy for postmenopausal estrogen receptor positive (ER+), HER2 negative (HER2-) breast cancer patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD5-03.

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.

Abstract P3-11-02: A randomized phase II trial of toremifene (120 mg) versus fulvestrant (500 mg) after prior non-steroidal aromatase inhibitor in postmenopausal women with hormone receptor-positive metastatic breast cancer (Hi-FAIR fx study)

Background: After the failure of a non-steroidal aromatase inhibitor (nsAI) for postmenopausal patients with advanced/metastatic breast cancer (BC), it is unclear which of the various kinds of endocrine monotherapy is the most appropriate. In a previous report it was found that toremifene 120 mg (TOR 120), a selective estrogen receptor modulator (SREM), was superior to steroidal AI in terms of progression-free survival after ns-AI in the Hi-FAIR ex trial. A phase II randomized trial of TOR 120 versus fulvestrant 500 mg (FUL 500), a selective estrogen receptor down regulator (SERD), was also conducted to select the most promising endocrine monotherapy after ns-AI in advanced/metastatic BC(Study registry number: UMIN000010087). Patients and Methods: Postmenopausal women (n=106) with advanced/metastatic hormone-receptor positive BC from October 2011 to September 2014 were enrolled in this study. Fifty-three of the patients were randomly assigned to the TOR 120 (120 mg daily p.) group and 53 of the patients were randomly assigned to the FUL 500 group. In the FUL 500 group they were administered 500 mg of fulvestrant intramuscularly (im) on day 0, then 500 mg im on days 14 and 28 and every 28 days thereafter). If treatment failure occurred in either of the randomly assigned groups the patients were then removed and treated accordingly. A full analysis set was targeted for all cases that received the protocol treatment even once (TOR 120 (n=53) and FUL 500 (n=52)). The primary end point was the clinical benefit rate (CBR). The secondary end points were the objective response rate (ORR), progression-free survival (PFS), time to chemotherapy (TTCT), overall survival (OS), toxicity, and CBR, ORR and PFS after crossover of non-assigned treatment. Results: A median follow up period of 30 months revealed that the CBR of FUL 500 (57.7%) tended to be superior to the CBR of TOR 120 (45.3%), the odds ratio (OR) was 1.70 (95% CI 0.74–3.62), and the median PFS was 7.8 months in the FUL 500 group and 5.8 months in the TOR 120 group. Moreover the hazard ratio (HR) was 0.79 (95% CI 0.52–1.21). However, there was no difference between the two groups in terms of ORR (17.7% and 15.1%, respectively), TTCT (13.3 months vs. 17.7 months, HR = 0.94 (95%CI 0.57 – 1.53)), and OS (33.4 months vs. not reached HR 1.29; 95% CI 0.80–2.09). At the cross-over phase, 33 and 24 patients after failure of assigned treatment were treated with FUL 500 and TOR 120, respectively. The CBR and PFS of FUL 500 after TOR 120 was better than that of TOR 120 after FUL 500 (CBR; 42.4% vs. 20.8%, OR = 0.33, 95%CI 0.09 – 1.11, median PFS; 6.2 months vs. 3.4 months; HR = 1.95, 95%CI 1.08–3.51). No difference between the two groups was observed in PFS from randomization to the end of the crossover phase. Moreover, there were few severe adverse events in either of the two groups. Conclusions: FUL 500 used as a subsequent endocrine therapy for advanced/metastatic BC patients who failed ns-AI could potentially be more effective than TOR 120. However, the efficacy of SERM after failure of FUL 500 may be limited. Citation Format: Nishimura R, Yamamoto Y, Narui K, Kijima Y, Hozumi Y, Ikeda M, Takao S, Ohtani S, Iwase H. A randomized phase II trial of toremifene (120 mg) versus fulvestrant (500 mg) after prior non-steroidal aromatase inhibitor in postmenopausal women with hormone receptor-positive metastatic breast cancer (Hi-FAIR fx study) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-11-02.

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.

Correction to: Phase I dose-finding study of eribulin and capecitabine for metastatic breast cancer: JBCRG-18 cape study

The article “Phase I dose-finding study of eribulin and capecitabine for metastatic breast cancer: JBCRG-18 cape study”, written by Masaya Hattori, Hiroshi Ishiguro, Norikazu Masuda, Akiyo Yoshimura, Shoichiro Ohtani, Hiroyuki Yasojima, Satoshi Morita, Shinji Ohno, and Hiroji Iwata, was originally published electronically on the publisher’s Internet portal (currently SpringerLink) on 31 August 2017 without open access. With the author(s)’ decision to opt for Open Choice the copyright of the article changed on [9 November 2017] to ©.