Phase I study of weekly nab-paclitaxel plus carboplatin and concurrent thoracic radiotherapy in elderly patients with unresectable locally advanced non-small cell lung cancer.

Few clinical studies have been designed for elderly patients with locally advanced non-small cell lung cancer (NSCLC). We conducted a phase I study to evaluate the tolerability of carboplatin/nab-paclitaxel and concurrent thoracic radiotherapy in elderly patients with locally advanced NSCLC. The eligibility criteria were: unresectable stage III NSCLC, performance status 0 or 1, and age ≥ 75 years. Eligible patients received 6 weeks of weekly carboplatin/nab-paclitaxel and concurrent thoracic radiotherapy with a total dose of 64 Gy in 32 fractions. Carboplatin was fixed to an area under the plasma concentration time curve (AUC) of 2 mg/mL/min, and the recommended dose of nab-paclitaxel was evaluated using a dose-escalation study (30 or 40 mg/m2). Tolerability at the recommended dose was evaluated in an expansion study. Nineteen patients were enrolled at four institutions, all of whom were eligible and assessable. The recommended nab-paclitaxel dose was set at 30 mg/m2 because two patients experienced dose-limiting toxicity at 40 mg/m2. The treatment completion rate of the 17 patients analyzed at the recommended dose was 100% (80% confidence interval (CI), 83.8-100%). The overall response rate was 76.5%, and the median progression free survival was 13.4 months (95% CI, 4.2-21.4 months). Common grade 3 and 4 toxicities included leukopenia (23.5%), neutropenia (17.6%), anemia (5.9%), and infection (5.9%). One treatment-related death due to pneumonitis was observed six months after the end of the study. In conclusion, carboplatin/nab-paclitaxel and concurrent thoracic radiotherapy show good tolerability and exhibit promising efficacy in elderly patients with locally advanced NSCLC. This trial was registered with the Japan Registry of Clinical Trials on March 11, 2019 (trial no. jRCTs042180077).

Clinical benefit of treatment after trastuzumab emtansine for HER2-positive metastatic breast cancer: a real-world multi-centre cohort study in Japan (WJOG12519B).

BACKGROUND: Trastuzumab emtansine (T-DM1) treatment for human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer after taxane with trastuzumab and pertuzumab is standard therapy. However, treatment strategies beyond T-DM1 are still in development with insufficient evidence of their effectiveness. Here, we aimed to evaluate real-world treatment choice and efficacy of treatments after T-DM1 for HER2-positive metastatic breast cancer. METHODS: In this multi-centre retrospective cohort study involving 17 hospitals, 325 female HER2-positive metastatic breast cancer patients whose post-T-DM1 treatment began between April 15, 2014 and December 31, 2018 were enrolled. The primary end point was the objective response rate (ORR) of post-T-DM1 treatments. Secondary end points included disease control rate (DCR), progression-free survival (PFS), time to treatment failure (TTF), and overall survival (OS). RESULTS: The median number of prior treatments of post-T-DM1 treatment was four. The types of post-T-DM1 treatments included (1) chemotherapy in combination with trastuzumab and pertuzumab (n = 102; 31.4%), (2) chemotherapy concomitant with trastuzumab (n = 78; 24.0%), (3), lapatinib with capecitabine (n = 63; 19.4%), and (4) others (n = 82; 25.2%). ORR was 22.8% [95% confidence interval (CI): 18.1-28.0], DCR = 66.6% (95% CI 60.8-72.0), median PFS = 6.1 months (95% CI 5.3-6.7), median TTF = 5.1 months (95% CI 4.4-5.6), and median OS = 23.7 months (95% CI 20.7-27.4). CONCLUSION: The benefits of treatments after T-DM1 are limited. Further investigation of new treatment strategies beyond T-DM1 is awaited for HER2-positive metastatic breast cancer patients.

Osimertinib for patients with poor performance status and EGFR T790M mutation-positive advanced non-small cell lung cancer: a phase II clinical trial.

Osimertinib is a molecularly targeted agent used to treat non-small cell lung cancer (NSCLC) patients with an epidermal growth factor receptor (EGFR) T790M mutation. However, its efficacy and safety profile when patients have poor performance status (PS) is unknown. Therefore, we conducted an open-label, multi-center, single-arm phase II study to evaluate its efficacy and safety in EGFR T790M mutation-positive NSCLC patients with Eastern Cooperative Oncology Group PS scores of between 2 and 4. Patients received 80 mg of osimertinib once daily. Our primary endpoint was progression-free survival. Eighteen patients were enrolled between June 2017 and November 2018. The median age was 77 years (range: 55-85 years). Ten, six, and two patients had PS scores of 2, 3, and 4, respectively. All patients had adenocarcinoma with common EGFR mutations and had been treated with first- or second-generation EGFR- tyrosine kinase inhibitors previously. The overall median progression-free survival was 7.0 months (90% confidence interval: 5.5-8.9 months). The overall response rate and median overall survival were 53% and 12.7 months, respectively. Moreover, improved PS scores were observed in 72% of the patients. Although the incidence of grade 3 adverse events was low, with no grade 4 or 5 events observed, three patients required treatment cessation due to the development of interstitial lung disease. Osimertinib therapy could be beneficial for EGFR T790M mutation-positive advanced NSCLC patients with poor PS. This trial was registered with the Japan Registry of Clinical Trials on March 12, 2019 (trial no. jRCT1041180081).

Plasma screening for the T790M mutation of EGFR and phase 2 study of osimertinib efficacy in plasma T790M-positive non-small cell lung cancer: West Japan Oncology Group 8815L/LPS study.

BACKGROUND: Liquid biopsy allows the identification of patients whose tumors harbor specific mutations in a minimally invasive manner. No prospective data have been available for the efficacy of osimertinib in patients with non-small cell lung cancer (NSCLC) who develop resistance to first- or second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and who test positive for the TKI resistance-conferring T790M mutation of EGFR by liquid biopsy. Therefore, a phase 2 study was conducted to assess the efficacy and safety of osimertinib in such patients. METHODS: Eligible patients had advanced or recurrent NSCLC with known TKI-sensitizing mutations of EGFR, had documented disease progression after treatment with at least 1 first- or second-generation EGFR TKI, and were positive for the T790M mutation in plasma according to the Cobas EGFR Mutation Test v2 (Roche Diagnostics) or droplet digital polymerase chain reaction analysis. Patients were treated with osimertinib (80 mg/d) until disease progression. The primary endpoint was the overall response rate (ORR) in patients positive for T790M in plasma by the Cobas assay. RESULTS: Between June 2016 and November 2017, 276 patients were screened for their T790M status with a liquid biopsy. Seventy-four patients were positive for T790M in plasma, and 53 of these individuals were enrolled in the study. The ORR for evaluable patients positive for T790M in plasma by the Cobas assay (n = 49) was 55.1% (95% confidence interval [CI], 40.2%-69.3%). The median progression-free survival for all evaluable patients (n = 52) was 8.3 months (95% CI, 6.9-12.6 months). CONCLUSIONS: The results demonstrate the utility of liquid biopsy for the detection of T790M with the Cobas EGFR Mutation Test v2. Plasma genotyping with this assay is informative for treatment selection in clinical practice when tumor sampling is not feasible.

Super-elderly patient-specific perioperative complications in breast cancer surgery.

PURPOSE: Geriatric surgery poses specific challenges due to patient vulnerability in relation to aging. We analyzed perioperative challenges concerning super-elderly patients with breast cancer. METHODS: Between 2013 and 2018, 908 patients with breast cancer were treated surgically. Of these, two patient groups were compared: Group A (≥ 85 years old, n = 34, 3.7%) and Group B (75-84 years old, n = 136, 15%). RESULTS: In Groups A and B, 26.4% and 36.8% of patients lived alone, respectively. Group A patients had higher rates of psychiatric and cardiovascular disease (32.4% and 41.2%) than Group B (8.8% and 16.2%) (p = 0.0009 and p = 0.0031, respectively). There was no marked difference in the type of surgery or length of hospital stay between groups, and most complications involved surgical site disorders. Postoperatively, Group A had a higher rate of delirium (29.4%) than Group B (3.7%) (p < 0.0001). The 30-day postoperative mortality rate was 0, and 76.5% of Group A and 45.6% of Group B patients received no adjuvant therapy (p = 0.0024). CONCLUSIONS: Age alone does not constitute a contraindication for appropriate surgery, although there are some challenges necessary to consider for super-elderly patients.

Sentinel node biopsy for axillary management after neoadjuvant therapy for breast cancer: a single-center retrospective analysis with long follow-up.

PURPOSE: Sentinel node biopsy (SNB) after neoadjuvant therapy (NAT) for breast cancer remains controversial. We conducted a retrospective study of patients who underwent SNB after NAT to evaluate the effectiveness of this procedure. METHODS: A consecutive 105 women with locally advanced breast cancer (cT1-4, cN0-3, M0) were treated with NAT between 2006 and 2015. The subjects were 80 of these patients who became or remained clinically node-negative after NAT, 53 of whom had axillary management determined by SNB (group A) and the other 27 underwent axillary lymph node dissection (ALND) without SNB (group B). SNB was performed using a modified dye method. RESULTS: The sentinel node (SN) identification rate was 94.3% and the mean number of removed SNs was 2.4. ALND was avoided in 33 patients, who were confirmed as SN-negative. There was no difference in recurrence-free and overall survival rates between groups A and B (p = 0.71 and p = 0.46, respectively) during the median follow-up time of 63 months. Of the 33 patients who did not undergo ALND, 10 suffered recurrence (33%). One patient (3%) had recurrence in an axillary lymph node and four had recurrence in a supraclavicular lymph node. CONCLUSION: Axillary SNB after NAT did not affect the axillary failure rate or the prognosis. SNB may be a reliable procedure, even after NAT.

mDia1 targets v-Src to the cell periphery and facilitates cell transformation, tumorigenesis, and invasion.

The small GTPase Rho regulates cell morphogenesis through remodeling of the actin cytoskeleton. While Rho is overexpressed in many clinical cancers, the role of Rho signaling in oncogenesis remains unknown. mDia1 is a Rho effector producing straight actin filaments. Here we transduced mouse embryonic fibroblasts from mDia1-deficient mice with temperature-sensitive v-Src and examined the involvement and mechanism of the Rho-mDia1 pathway in Src-induced oncogenesis. We showed that in v-Src-transduced mDia1-deficient cells, formation of actin filaments is suppressed, and v-Src in the perinuclear region does not move to focal adhesions upon a temperature shift. Consequently, membrane translocation of v-Src, v-Src-induced morphological transformation, and podosome formation are all suppressed in mDia1-deficient cells with impaired tyrosine phosphorylation. mDia1-deficient cells show reduced transformation in vitro as examined by focus formation and colony formation in soft agar and exhibit suppressed tumorigenesis and invasion when implanted in nude mice in vivo. Given overexpression of c-Src in various cancers, these findings suggest that Rho-mDia1 signaling facilitates malignant transformation and invasion by manipulating the actin cytoskeleton and targeting Src to the cell periphery.