Tatsunori Shimoi

Tumour-infiltrating lymphocytes are correlated with higher expression levels of PD-1 and PD-L1 in early breast cancer

Background The presence of tumour-infiltrating lymphocytes (TILs) is a favourable prognostic factor in patients with early breast cancer. Programmed cell death-1 (PD-1) and its ligand PD-L1 are associated with a variety of adverse features. The purpose of this study was to clarify the relationships between TILs, PD-1 and PD-L1 as well as their prognostic implications in early breast cancer. Methods We investigated 180 patients with breast cancer who received neoadjuvant chemotherapy and underwent subsequent surgery for stage II–III invasive breast carcinoma between 1999 and 2007. TIL expression was classified as low or high using a previously reported scoring model. PD-1 and PD-L1 expression levels were determined by immunohistochemistry. The correlation between PD-1 expression in TILs and PD-L1 expression in cancer cells was also investigated. Results Higher tumour grade was significantly correlated with PD-L1 expression in tumours (p<0.0001). PD-1 and PD-L1 expression levels were associated with tumour subtype and were highest in triple-negative tumours (p<0.0001). Furthermore, expression of each of PD-1 and PD-L1 was significantly correlated with higher TIL expression and pathological complete response (pCR) (p<0.0001). PD-L1 expression in cancer cells was significantly correlated with PD-1 expression in TILs (p=0.03). The correlations between pCR and expression of each of PD-L1 and PD-1 were not significant. Conclusion Expression of PD-L1 and PD-1 in early breast cancer is associated with higher TIL scores and pCR; conversely, expression of these proteins correlates with poor prognostic clinicopathological factors such as tumour grade and subtype. TILs, PD-1 and PD-L1 can potentially predict the response to treatment.

Safety, pharmacokinetics, and antitumour activity of trastuzumab deruxtecan (DS-8201), a HER2-targeting antibody–drug conjugate, in patients with advanced breast and gastric or gastro-oesophageal tumours: a phase 1 dose-escalation study

BACKGROUND Antibody-drug conjugates have emerged as a powerful strategy in cancer therapy and combine the ability of monoclonal antibodies to specifically target tumour cells with the highly potent killing activity of drugs with payloads too toxic for systemic administration. Trastuzumab deruxtecan (also known as DS-8201) is an antibody-drug conjugate comprised of a humanised antibody against HER2, a novel enzyme-cleavable linker, and a topoisomerase I inhibitor payload. We assessed its safety and tolerability in patients with advanced breast and gastric or gastro-oesophageal tumours. METHODS This was an open-label, dose-escalation phase 1 trial done at two study sites in Japan. Eligible patients were at least 20 years old with breast or gastric or gastro-oesophageal carcinomas refractory to standard therapy regardless of HER2 status. Participants received initial intravenous doses of trastuzumab deruxtecan from 0·8 to 8·0 mg/kg and dose-limiting toxicities were assessed over a 21-day cycle; thereafter, dose reductions were implemented as needed and patients were treated once every 3 weeks until they had unacceptable toxic effects or their disease progressed. Primary endpoints included identification of safety and the maximum tolerated dose or recommended phase 2 dosing and were analysed in all participants who received at least one dose of study drug. The dose-escalation study is the first part of a two-part study with the second dose-expansion part ongoing and enrolling patients as of July 8, 2017, in Japan and the USA. This trial is registered at ClinicalTrials.gov, number NCT02564900. FINDINGS Between Aug 28, 2015, and Aug 26, 2016, 24 patients were enrolled and received trastuzumab deruxtecan (n=3 for each of 0·8, 1·6, 3·2, and 8·0 mg/kg doses; n=6 for each of 5·4 and 6·4 mg/kg). Up to the study cutoff date of Feb 1, 2017, no dose-limiting toxic effects, substantial cardiovascular toxic effects, or deaths occurred. One patient was removed from the activity analysis because they had insufficient target lesions for analysis. The most common grade 3 adverse events were decreased lymphocyte (n=3) and decreased neutrophil count (n=2); and grade 4 anaemia was reported by one patient. Three serious adverse events-febrile neutropenia, intestinal perforation, and cholangitis-were reported by one patient each. Overall, in 23 evaluable patients, including six patients with low HER2-expressing tumours, ten patients achieved an objective response (43%, 95% CI 23·2-65·5). Disease control was achieved in 21 (91%; 95% CI 72·0-98·9) of 23 patients. Median follow-up time was 6·7 months (IQR 4·4-10·2), with nine (90%) of ten responses seen at doses of 5·4 mg/kg or greater. INTERPRETATION The maximum tolerated dose of trastuzumab deruxtecan was not reached. In this small, heavily pretreated study population, trastuzumab deruxtecan showed antitumour activity, even in low HER2-expressing tumours. Based on safety and activity, the most likely recommended phase 2 dosing is 5·4 or 6·4 mg/kg. FUNDING Daiichi Sankyo Co, Ltd.

Visualization of HER2-specific breast cancer intratumoral heterogeneity using 64 Cu-DOTA-trastuzumab PET

Evaluation of human epidermal growth factor receptor 2 (HER2) expression in tumor tissues using immunohistochemistry (IHC) or in situ hybridization (ISH) has revealed heterogeneity in invasive breast cancers [1]. Previously, we reported that Cu-DOTA-trastuzumab PET (HER2 PET) imaging can noninvasively identify HER2-positive breast cancers [2–4]. A 53-year-old woman presented with right-side breast cancer. Her HER2 status of IHC 1+ was determined from a core needle biopsy specimen obtained from the center of the tumor. The patient underwent HER2 PET imaging, which revealed strong uptake at the tumor periphery. An additional biopsy from the shallow outer portion of the tumor, which exhibited the strongest uptake, had a HER2 expression IHC score of 2+. A dual-probe ISH test revealed a HER2/CEP17 ratio of 1.4 and an average HER2 copy number of 4.9 signals per cell (i.e., ISH equivocal) [5]. An additional ISH examination of a new specimen was also ISH equivocal, with a HER2/CEP17 ratio of 1.6 and an average HER2 copy number of 4.1 signals per cell. We have previously demonstrated HER2-specific CuDOTA-trastuzumab accumulation in a specimen of removed brain metastasis using IHC and autoradiography [3]. However, this is the first report describing the visualization of HER2-specific intratumoral heterogeneity (IHC 1+ and 2+) using HER2 PET imaging. This interesting finding suggests that HER2 PET imaging could facilitate decision making for clinical treatment strategies. The relationship between HER2 PET imaging and the effects of anti-HER2 therapy, as well as the use of a high-resolution dedicated breast PET scanner, remain to be evaluated.

Efficacy and Safety of Pazopanib for Recurrent or Metastatic Solitary Fibrous Tumor

Objective: To investigate the efficacy and safety of pazopanib for recurrent or metastatic solitary fibrous tumor (SFT) in first- and second-line settings. Methods: Patients histologically diagnosed with SFT at our hospital who received pazopanib monotherapy for inoperable disease between January 2013 and November 2016 were eligible. We retrospectively investigated treatment outcomes according to the treatment lines and assessed adverse events. Results: Nine patients were eligible. The median age was 67 years (range 42–81), and 6 patients (66.7%) were male. Four patients (50%) received pazopanib as second-line treatment. According to the RECIST and Choi criteria, the respective response rates were 0 and 50%, while the respective disease control rates were 88.9 and 75%. The median progression-free survival (PFS) was 6.2 months (95% confidence interval 3.2–8.8). Treatment line and high frequency of mitosis were not predictive of PFS (p = 0.67, 0.92). Two patients (22.2%) experienced elevated liver enzymes of grade 3 or higher. Conclusion: Pazopanib is an effective treatment option for recurrent or metastatic SFT in first- and second-line settings. Liver injury is a major adverse event and adequate treatment withdrawal and dose reduction should be considered when necessary.

A case of heavily pretreated metastatic cardiac angiosarcoma treated successfully using eribulin

Eribulin mesylate (eribulin) is a nontaxane microtubule inhibitor approved in Japan for treating soft tissue sarcoma irrespective of histological subtypes. Thus, our department routinely uses eribulin to treat any histological subtype of sarcoma for patients who have experienced disease progression during standard therapy. However, evidence on the efficacy of eribulin in treating sarcomas that are neither liposarcoma nor leiomyosarcoma is limited. Recently, we encountered a case of a heavily pretreated cardiac angiosarcoma that responded well to eribulin treatment. The patient was a 34-year-old Japanese woman with advanced angiosarcoma, who had been pretreated heavily using several lines of chemotherapy. Eribulin was administered as the eighth line of treatment and the dose was adjusted because of grade 4 neutropenia. After three cycles of treatment, contrast-enhanced computed tomography showed a partial tumor response, which was sustained for ~4 months. This case suggests that eribulin may be a potential therapeutic option for angiosarcoma. Further studies are needed to confirm the benefit of eribulin for patients with angiosarcoma and to establish predictive markers for eribulin sensitivity.

Amrubicin Monotherapy for Patients with Platinum-Pretreated Non-Gastrointestinal Non-Pancreatic Extrapulmonary Neuroendocrine Carcinoma

Objective: The aim of this study was to investigate the clinical usefulness of amrubicin therapy for patients with non-gastrointestinal (GI) non-pancreatic extrapulmonary neuroendocrine carcinoma (EP-NEC). Methods: The medical records of patients from the 2 participating institutions were retrospectively reviewed. The eligibility criteria were: patients with non-GI non-pancreatic EP-NEC who received amrubicin monotherapy after platinum-based chemotherapy. Patients in whom the platinum-free interval (interval between the last day of platinum administration and the first subsequent documentation of disease progression) was 90 days or longer were classified into the platinum-sensitive group. Results: The study was conducted in a total of 13 patients identified as eligible. The response rate was 45.4% (5/11). The median progression-free survival and overall survival were 6.0 and 10.6 months, respectively. A platinum-free interval of ≥90 days was identified as a significant predictor of a longer progression-free survival time. Grade 3 or 4 neutropenia was observed in 61.5% (8/13) of the patients. One patient died of treatment-related febrile neutropenia. Conclusions: Amrubicin monotherapy as second-line chemotherapy after failure of first-line platinum-based chemotherapy showed good efficacy in patients with non-GI non-pancreatic EP-NEC. Neutropenia was encountered as the most serious adverse event.

441OIMAGING MASS SPECTROMETRY OF NOVEL DRUG IN HUMAN TUMOR SPECIMENS: DISTRIBUTION OF UNLABELED DRUGS TO SUPPORT EARLY PHASE CLINICAL TRIAL

ABSTRACT Aim: Assessment of drug pharmacokinetics is an important component of early phase drug development. Imaging Mass Spectrometry (IMS) is an innovative technique in the preclinical study that allows for analysis of the distribution of target molecules in tumor tissues. The advantage of imaging technology is the detection of the molecule of interest in tissues without labeling. We performed tumor biopsies in patients with solid tumors who were participating in a phase I trial (NCT01813474) of olaparib. The aim of this study was to examine drug distribution in the tumor biopsy specimens by IMS, which provides a sensitive and label-free approach to imaging drugs. Methods: Patients with solid tumors received the tablet formulation of olaparib in dose escalation (200mg BID; 300mg BID) and expansion (300mg BID) cohorts. The timing of biopsies in consenting patients was during cycle 2 and/or at the time of progression. IMS was performed using an Imaging Mass Microscope (Shimadzu, Japan). The concentrations of olaparib in tissues were validated by using LC-MS/MS. Results: In total, seven tumor biopsies were performed in six patients with solid tumors; three breast cancer including one BRCA1 mutation positive, one ovarian cancer, one peritoneal cancer, one cervical cancer. One patient had biopsies performed at the time of drug administration and progression. One patient received olaparib 200mg BID; the remaining patients received olaparib 300mg BID. IMS signal levels of olaparib correlated well with the concentration of drug in tumor tissues derived from patients using LC-MS/MS, a conventional method used in pharmacokinetic studies. The distribution of Olaparib was in the tumor region and the signal level in areas of necrosis was higher than that observed in living cell areas. Conclusions: The use of IMS has allowed to follow the distribution of an unlabeled olaparib in target tissues. In addition, this technique can also allow further understanding of PK/PD relationships of olaparib in combination with other compound at clinical trial. Disclosure: All authors have declared no conflicts of interest.

Symptom management: the utility of regional cooling for hand-foot syndrome induced by pegylated liposomal doxorubicin in ovarian cancer

PurposeHand-foot syndrome (HFS) is a major side effect of pegylated liposomal doxorubicin (PLD). Regional cooling during PLD infusion was shown to improve severe HFS. We investigated the utility of frozen gloves and socks (FGS) as a simpler cooling method.MethodsTo evaluate the utility and safety of regional cooling with FGS for PLD-induced HFS, we retrospectively analyzed patients with advanced ovarian cancer who used FGS during PLD-containing regimens.ResultsNinety-six patients were analyzed. The incidence of HFS was 51% (≥ grade 2, 32%) in the PLD group and 38% (≥ grade 2, 6%) in the PLD + CBDCA group. The respective percentages of patients who underwent PLD dose modification/discontinuation were 41%/75% in the PLD group and 9%/30% in the PLD + CBDCA group. The reasons for discontinuation of PLD and PLD + CBDCA therapy were progressive disease, HFS, allergy, oral mucositis, and others. HFS was the only reason for PLD dose modification in both the PLD and PLD + CBDCA groups. The completion rate of FGS was 96%, with discontinuation in three cases due to pain from cooling.ConclusionsOur study indicates that FGS is a safe, simple method with good tolerability. A prospective study is needed for further assessment.

Impact of Surgical Margin in Skull Base Surgery for Head and Neck Sarcomas

Objective This study aimed to determine the adequate resection margin in skull base surgery for head and neck sarcoma. Design We retrospectively reviewed 22 sarcomas with skull base invasion. Induction chemotherapy, followed by surgery and postoperative radiotherapy and adjuvant chemotherapy, was performed in 18 patients with chemosensitive sarcomas, and surgery with or without postoperative radiotherapy was performed in four patients with chemoresistant sarcomas. Radical resection was performed in patients with chemosensitive sarcomas with a poor response to induction chemotherapy and in patients with chemoresistant sarcomas. Conservative resection with close surgical margin was performed in patients with chemosensitive sarcomas with a good response to induction chemotherapy. Setting and Participants This single‐centered retrospective study included patients from the National Cancer Center Hospital, Japan. Results The response to induction chemotherapy was significantly associated with the 3‐year local control rate (LCR; good response versus poor response: 100% versus 63%, p = 0.048). Patients with a good response to chemotherapy had a favorable local prognosis even when the local therapy was conservative resection. In radical skull base surgery, patients whose surgical margins were classified as “wide margin positive” had significantly poorer 3‐year LCR than did patients with “margin negative” or “micro margin positive” margins (25% versus 83%, p = 0.014). Conclusion Conservative resection with close surgical margins might be acceptable for chemosensitive sarcomas with a good response to chemotherapy. Resection margin status was an important predictive factor for local recurrence after radical skull base surgery. Microscopic microresidual tumor might be controlled by postoperative treatment.

PIK3CA mutation profiling in patients with breast cancer, using a highly sensitive detection system

PIK3CA mutations are common activating mutations associated with breast cancer (occurring in 20–30% of all cases) and are potent predictive markers for responses to PI3K inhibitors. Thus, it is important to develop sensitive methods to detect these mutations. We established a novel detection method using a quenching probe (QP) system to identify PIK3CA mutations, using DNA from 309 breast cancer tissues. In a developmental cohort, we determined the optimal detection threshold of the QP system with human tumor DNA from 119 freshly frozen tumor samples. We found a 96% concordance rate with the QP system between DNA from 26 matching fresh‐frozen specimens and formalin‐fixed paraffin‐embedded (FFPE) specimens from the same patients, and known PIK3CA mutation status in the developmental cohort. In a validation cohort, we evaluated whether the threshold for judging mutations using the QP system with frozen specimen‐derived DNA was applicable with FFPE‐derived DNA. In the validation cohort, 30 DNA samples from 190 FFPE‐derived DNA samples with known PIK3CA mutation status were analyzed by direct sequencing (DS) and droplet digital PCR, in a blinded manner. The sensitivity and specificity of the droplet digital PCR results were 100% and 100% (QP system), and 60% and 100% (DS), respectively. We also analyzed the relationship between clinical outcomes and the PIK3CA mutational status of 309 breast cancer samples, including the developmental cohort and validation cohort samples. Multivariate analysis suggested that PIK3CA mutations, especially H1047R, were prognostic factors of relapse‐free survival. Our novel detection system could be more useful than DS for detecting clinical PIK3CA mutations.