Kimito Yamada

Photodynamic Therapy (PDT) for Lung Cancers

Photodynamic therapy (PDT), a treatment for cancer, uses a photosensitizer and laser irradiation to produce reactive oxygen in cells. In Japan, the United States, and many other countries, PDT is a treatment option for stage 0 (TisN0M0) and stage I (T1N0M0) centrally located early stage lung cancer. PDT can preserve lung function, can be repeated, and can be combined with other therapeutic modalities such as chemotherapy. Recently, mono-l-aspartyl chlorine e6 (NPe6, Laserphyrin), a second-generation photosensitizer with lower photosensitivity than Photofrin (porfimer sodium), was approved by the Japanese government and a phase II clinical study using NPe6 with a new diode laser demonstrated an excellent antitumor effect and low skin photosensitivity. We expect PDT to be widely employed in many fields and the applications of PDT to be extended because of the decreasing cost of laser equipment and lower systemic photosensitivity induced by the photosensitizer. The purpose of this review is to introduce not only recent clinical trials of PDT for centrally located early lung cancer, but also new applications of PDT for cases of peripheral-type, early-stage lung cancers. We also discuss the applications of PDT for advanced lung cancer and combined therapy using PDT and other treatments for lung cancer.

Epidermal growth factor‐dependent enhancement of invasiveness of squamous cell carcinoma of the breast

Factors that promote the aggressiveness of squamous cell carcinoma of the breast are not well understood. To examine the involvement of cell motility and the mechanism of this behavior, a squamous cell carcinoma cell line of the breast (HBC9) was established from a metastatic lymph node of a Japanese woman. HBC9 expressed epidermal growth factor receptor (EGFR), but was negative for Her2 or Her3.The invasive ability of HBC9 was compared with that of four breast ductal carcinoma cell lines by Matrigel invasion assay. EGF stimulation induced the formation of surface protrusions and cell migration in HBC9 cells, and significantly increased the number of cells migrating through the Matrigel. The invasive ability of HBC9 was compared with other cell lines of breast carcinoma; it was much greater than that of MCF‐7, BT474, or HBC5, but did not differ significantly from that of MDA‐MB‐231. Observation of the surface protrusions of HBC9 by confocal laser microscopy revealed co‐localization of Arp2 and N‐WASP with actin polymerization, detected by visualization with phalloidin, indicating that the protrusions induced by EGF were invadopodia. In HBC9 cells, cortactin also co‐localized with the N‐WASP/Arp2/3 complex in the protrusions. Immunohistochemistry of 12 cases of squamous cell carcinoma of the breast revealed expression of cortactin and EGFR in all of them, and this was confirmed by western blotting in two cases. These results suggest that EGF‐dependent enhancement of cell motility by formation of invadopodia associated with cortactin is a cause of the clinical aggressiveness of squamous cell carcinoma of the breast.

Assessment of Cancer-Related Fatigue, Pain, and Quality of Life in Cancer Patients at Palliative Care Team Referral: A Multicenter Observational Study (JORTC PAL-09)

Introduction Cancer-related fatigue greatly influences quality of life in cancer patients; however, no specific treatments have been established for cancer-related fatigue, and at present, no medication has been approved in Japan. Systematic research using patient-reported outcome to examine symptoms, particularly fatigue, has not been conducted in palliative care settings in Japan. The objective was to evaluate fatigue, pain, and quality of life in cancer patients at the point of intervention by palliative care teams. Materials and Methods Patients who were referred to palliative care teams at three institutions and met the inclusion criteria were invited to complete the Brief Fatigue Inventory, Brief Pain Inventory, and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 15-Palliative. Results Of 183 patients recruited, the majority (85.8%) were diagnosed with recurrence or metastasis. The largest group (42.6%) comprised lung cancer patients, of whom 67.2% had an Eastern Cooperative Oncology Group Performance Status of 0–1. The mean value for global health status/quality of life was 41.4, and the highest mean European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 15-Palliative symptom item score was for pain (51.0). The mean global fatigue score was 4.1, and 9.8%, 30.6%, 38.7%, and 20.8% of patients’ fatigue severity was classified as none (score 0), mild (1–3), moderate (4–6), and severe (7–10), respectively. Discussion Cancer-related fatigue, considered to occur more frequently in cancer patients, was successfully assessed using patient-reported outcomes with the Brief Fatigue Inventory for the first time in Japan. Results suggested that fatigue is potentially as problematic as pain, which is the main reason for palliative care.

Characteristics of the early stages of intravenous bisphosphonate-related osteonecrosis of the jaw in patients with breast cancer

Abstract Objective. The clinical features of the early stages of bisphosphonate-related osteonecrosis of the jaw (BRONJ) in patients with breast cancer remain unclear. A retrospective cohort study was conducted of patients with breast cancer who received intravenous bisphosphonate (BP) treatment in a single center in order to clarify the status of the early stages of BRONJ. Materials and methods. A BRONJ oral monitoring program was established in 247 breast cancer patients given intravenous BP treatment at the institution. The differences in age, BP treatment period, number of remaining teeth, oral hygiene status, presence of regular oral monitoring and the existence of suspected BRONJ (stage 0) among eight BRONJ and 36 non-BRONJ subjects who completed oral examinations were then compared. Results. BRONJ was observed in 0.4% of subjects on the first visit to the oral surgery clinic and in 3.2% of subjects during the follow-up period. Logistic regression analysis revealed that the odds ratio for identifying patients with BRONJ during follow-up by the presence of stage 0 at first visit was 24.0 (95% confidence interval [CI] = 3.6–161.7). The area under the receiver operating characteristic curve for identifying subjects with BRONJ by the presence of stage 0 was 0.82 (95% CI = 0.63–1.00). Conclusion. The results suggest that patients with stage 0 BRONJ on the first visit may progress to advanced BRONJ during the follow-up period. The oral monitoring program may contribute to the early detection of BRONJ.

89Sr Imaging With Bremsstrahlung in Patients With Metastatic Breast Cancer

Purpose In this study, we investigated the clinical and laboratory factors that may enhance 89Sr uptake to strengthen its tumoricidal effect. Methods We enrolled 21 patients with multiple bone metastases (n = 23) from breast cancer and classified them into 2 groups according to their zoledronic acid (ZOL) treatment history. 89Sr imaging with bremsstrahlung was performed 2 to 6 weeks after administration and 89Sr index was measured using combined imaging with bone scintigraphy. We compared the 89Sr index with the levels of alkaline phosphatase, bone-specific alkaline phosphatase, serum cross-linked N-telopeptides, carboxy-terminal telopeptide of type 1 collagen, C-reactive protein, calcium, and hemoglobin on administration and evaluated the differences among the groups. Results The 89Sr index ranged from 0.01 to 2.0 and was significantly correlated with C-reactive protein and alkaline phosphatase and moderately correlated with carboxy-terminal telopeptide of type 1 collagen, serum cross-linked N-telopeptides, and bone-specific alkaline phosphatase. The 89Sr index was not significantly correlated with calcium or hemoglobin. The group with less than 1 year of ZOL treatment demonstrated a mean (SD) 89Sr index of 1.11 (0.59), and the group with 1 or more years of ZOL treatment showed a mean 89Sr index of 0.36 (0.26). The Wilcoxon signed-rank test demonstrated a significant difference between the 2 groups (P < 0.001). Conclusions 89Sr accumulation seemed to be associated with bone turnover, in particular bone resorption, and vascularization due to inflammation or tumor growth. Long-term ZOL treatment may reduce bone resorption and vascularization. To enhance the tumoricidal effect and palliation of bone pain by 89Sr, combined therapy must be established.

Objection to postoperative radiation therapy in breast cancer with one to three lymph nodes involvements

My arguments regarding postmastectomy radiotherapy (PMRT) for this case are based on the following 4 reasons: (1) high rate of local recurrence in the no PMRT group in the Early Breast Cancer Trialists’ Collaborative Group meta-analysis on which the present guideline is based, (2) stage migration by sentinel node biopsy, (3) possible adverse events of radiotherapy, and (4) problems on extrapolation of data from western countries.

Randomized phase II study of nab-paclitaxel as first-line chemotherapy in patients with HER2-negative metastatic breast cancer

Weekly administration of nanoparticle albumin‐bound paclitaxel (nab‐paclitaxel) has been shown to be a safe and effective treatment for metastatic breast cancer (MBC) in clinical studies. We conducted a multicenter, randomized, open‐label phase II study to compare the efficacy and safety of weekly nab‐paclitaxel and docetaxel in Japanese patients with human epidermal growth factor receptor 2‐negative MBC. The primary endpoint was progression‐free survival (PFS). Patients were randomized to receive nab‐paclitaxel (150 mg/m2 nab‐paclitaxel once per week for 3 of 4 weeks; n = 100) or docetaxel (75 mg/m2 docetaxel every 3 weeks; n = 100). The median PFS by independent radiologist assessment was 9.8 months (90% confidence interval [CI]: 8.5–11.2) for nab‐paclitaxel and 11.2 months (90% CI: 8.4–13.8) for docetaxel (hazard ratio: 1.25, P = 0.363), and the median overall survival was 42.4 months and 34.0 months, respectively. The overall response rate was 56.1% for nab‐paclitaxel and 52.5% for docetaxel. Adverse events in both treatment arms were similar to previous reports. Neutropenia was the most common adverse event in both arms, with 35.0% of patients in the nab‐paclitaxel arm and 89.0% in the docetaxel arm experiencing grade 4 neutropenia. Grade 3 peripheral sensory neuropathy occurred in 22.0% of patients in the nab‐paclitaxel and 5.0% in the docetaxel arm. In this study, although weekly nab‐paclitaxel 150 mg/m2 did not show superiority in PFS compared with docetaxel, efficacy outcomes were similar in patients treated with weekly nab‐paclitaxel and docetaxel.

Hereditary breast cancer associated with Cowden syndrome-related PTEN mutation with Lhermitte-Duclos disease

BackgroundCowden syndrome is characterized by multiple hamartomas in various tissues, including the skin, brain, breast, thyroid, mucous membrane, and gastrointestinal tract, and is reported to increase the risk of malignant disease.Case presentationWe describe the case of a 52-year-old woman in whom a tumor was diagnosed in the left cerebellar hemisphere and treated by surgical resection. Phosphatase and tensin homolog (PTEN) mutation in exon 8 insertion was found in the brain tumor tissue and leukocytes. This finding supported the diagnosis of Cowden syndrome. She consequently developed endometrial cancer and underwent abdominal total hysterectomy with bilateral salpingo-oophorectomy. Four years later, hormone receptor-positive breast cancer was found in the right breast, and breast-conserving surgery with radiation therapy and sentinel lymph node biopsy was performed.ConclusionsHerein, we describe a patient who was diagnosed as having familial breast cancer associated with PTEN mutation-related Cowden syndrome. We also reviewed reports of this syndrome in the literature for disease appraisal.

Abstract CT126: Single arm study of neoadjuvant chemotherapy without taxane for BRCAness cases in triple-negative breast cancer

BACKGROUND: BRCA1 impaired cancers are sensitive to DNA damage. This is associated with the defective homologous recombination (HR) pathway in these tumors. In contrast, these tumors are resistant to mitotic poisons, because BRCA1 protein activates the mitotic spindle checkpoint and triggers apoptosis in microtubule damage. Both preclinical evidence and clinical evidence have shown that the single-agent taxane is not active for BRCA1 mutated breast cancers. It is reported that BRCA1 function may be impaired in approximately 60% of triple negative breast cancer (TNBC) without mutation. This is called ‘BRCAness’. Previous studies have demonstrated that BRCAness identified tumors with HR deficiency. Thus, taxane may not be necessary for all TNBC cases, although combined treatments of anthracycline and taxane are standard at present. STUDY PROTOCOL: We have launched a single arm study of neoadjuvant chemotherapy (NAC) for TNBC to confirm that taxane is unnecessary in BRCAness cases. For the study protocol, TNBC cases requiring NAC are enrolled. Four cycles of an anthracycline-based regimen (FEC 100 or dose-dense EC) are started and BRCAness is examined simultaneously in core-needle specimens. BRCAness is determined by Multiple Ligation-dependent Probe Amplification (MLPA) methods (FALCO Biosystems), which consist of 2 steps. These include copy number analysis in 34 loci specific to BRCA1 mutant and scoring with prediction analysis for microarray. If BRCAness is determined by MLPA, surgery is performed without proceeding to taxane. The primary endpoint is a pathological complete response (pCR) in surgical specimens. The expected pCR and threshold pCR are estimated at 55% and 40%, respectively, based on our previous randomized phase II trial comparing docetaxel plus cyclophosphamide with epirubicin plus cyclophosphamide followed by docetaxel for hormone receptor-negative breast cancer (Ishikawa T. ASCO 2013). With a one-sided significance of 5%, 70 BRCA cases are required. This study was approved in September 2015 and has been started. Interim analysis is planned when 30 cases are completed. Citation Format: Takashi Ishikawa, Saeko Teraoka, Hiroshi Kaise, Kimito Yamada, Mari Hosonaga, Ai Ueda, Yoko Kawai, Miki Okazaki, Mari S. Oba, Eiichi Sato. Single arm study of neoadjuvant chemotherapy without taxane for BRCAness cases in triple-negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT126.

204PDJ-1 PROTEIN EXPRESSION IN INTRINSIC SUBTYPE AS A PREDICTOR OF PATHOLOGICAL COMPLETE REMISSION AFTER NEOADJUVANT CHEMOTHERAPY IN BREAST CANCER PATIENTS

ABSTRACT Aim: The DJ-1 gene was originally identified as an oncogene that, in conjunction with activated ras, and Parkinsons disease is associated with DJ-1/Parkinson protein 7 dysfunction. Neoplastic transformation is associated with the hyperactivity of DJ-1 . DJ-1 overexpression increases the resistance of neoplastic cells to apoptosis by inhibiting the phosphatase and tensin homolog(PTEN)-mediated protein kinase B/Akt pathway and/or other apoptotic pathways,including death-associated protein 6 and homeodomain-interacting protein kinase1. Recent genetic studies showed that, in addition to apoptosis pathways, DJ-1 is also involved in cellular defense against reactive oxygen species. The activity of apoptotic and cellular defense pathways is key in determining drug sensitivity. DJ-1 overexpression is associated with various cancers. We reported that low DJ-1 protein expression is a significant predictor of pCR after chemotherapy in reast cancer patients.(Kawate, BCRT2013) In this time, we will report that we classified Luminal-A subtype to new Lum-A and Lum-B subtype by ki67 and reanalyzed results. Methods: Expression of DJ-1 in pre-therapeutic needle biopsies and surgical specimens obtained from 198 breast cancer cases that received neoadjuvant chemotherapy was determined using immunohistochemistry and in situ hybridization.Chemotherapy comprised epirubicin / cyclophosphamide taxane-based regimens with or without trastuzumab. Univariate and multivariate analyses were used to evaluate the predictive value of DJ-1 on pCR. Results: Low DJ-1 protein expression was detected in 46.0 % (91/198) of all breast cancer cases and in 80.4 % (37/46) of pCR cases. In multivariate analysis, DJ-1 expression(k2 = 16.05, p Conclusions: Low DJ-1 protein expression is a significant predictor of pCR after neoadjuvant chemotherapy at any Sub Type in breast cancer patients. Disclosure: All authors have declared no conflicts of interest.