Tomoaki Kitahara

Expected clinical applications of circulating tumor cells in breast cancer

Tumor cell invasion and intravascular filtration lead to the presence of circulating tumor cells (CTCs) in peripheral blood. CTCs have, thus, been counted in patients with cancer to analyze metastatic mechanisms or in the hope of developing clinical applications for diagnosis and therapy; various CTC-related studies have been performed. However, the clinical significance of CTCs remains to be established because of the extremely small number of CTCs in peripheral blood as compared with the number of blood cells. Technical problems (e.g. reproducibility and reliability) in the detection of CTCs also remain to be solved. The use of flow cytometric analysis, which can be performed with tumor-cell markers such as anti-epithelial cell adhesion molecule antibodies and anti-cytokeratin antibodies and non-tumor-cell markers such as anti-CD45 antibodies has enhanced specificity for the detection of tumor cells. The CellSearch System(®) can detect 1 CTC in 7.5 mL of peripheral blood, with high reproducibility. Its detection rate and accuracy for CTCs have been confirmed. In the United States, clinical trials have used this system to detect CTCs in patients with metastatic breast cancer, metastatic colorectal cancer, and metastatic prostate cancer, and CTCs have been confirmed to be a useful prognostic factor. This system was also suggested to be useful for monitoring treatment response in patients with metastatic breast cancer and was approved by the United States Food and Drug Administration in 2004. Measuring CTC counts can facilitate the early prediction of treatment response and thereby avoid unnecessary therapy. CTCs may also be a useful biomarker for molecular targeted agents, enabling the identification of patients most likely to respond to a given treatment and facilitating treatment selection. However, the widespread use of CTC monitoring as a routine examination requires a further improvement in measurement sensitivity, the establishment of criteria for quantitative and qualitative evaluations, and additional clear-cut evidence supporting the clinical significance of CTCs. We expect that CTCs will be established to be a new diagnostic and therapeutic index for breast cancer.

Does Surgery for Breast Cancer Induce Angiogenesis and Thus Promote Metastasis

At the time of surgery for breast cancer, cancer cells released from the primary tumor have most likely entered blood or lymphatic vessels, leading to the development of micrometastases. Cancer cells directly produce angiogenesis stimulators, provoke the release of stimulators bound to the surrounding extracellular matrix and induce macrophages to secrete angiogenesis stimulators, thereby promoting angiogenesis. Metastasis dormancy is characterized by a balance between cell proliferation and apoptosis and is thought to be controlled by increased apoptosis, indirectly induced by angiogenesis inhibitors. Many patients with solid tumors already have micrometastases at the time of detection and surgical removal of their primary tumors. Primary tumor resection is believed to stimulate angiogenesis, initiating the proliferation of latent micrometastases. Latent micrometastases have already acquired angiogenic potential. The provision of additional therapy to inhibit angiogenesis after surgery is therefore considered a rational approach. The effectiveness of dormancy therapy should be evaluated in the prospective clinical trials of chemotherapy with drugs such as cyclophosphamide and UFT, which have been reported to inhibit angiogenesis as demonstrated by the numbers of circulating endothelial cells and circulating endothelial progenitors in peripheral blood before and after surgery in women with primary breast cancer.

Triple-negative Breast Cancer and Poly(ADP-ribose) Polymerase Inhibitors

Recent gene profiling studies have identified at least 5 major subtypes of breast cancer, including normal type, luminal A type, luminal B type, human epidermal growth factor receptor (HER)-2 positive type, and basal-like type. Triple-negative breast cancer (TNBC), showing no or low expressions of estrogen receptor (ER), progesterone receptor (PgR), and HER2, considered important clinical biomarkers, accounts for 10% to 20% of all breast cancers. Hormonal therapy and molecular targeted therapy are not indicated for the management of TNBC, resulting in poor outcomes. Because TNBC lacks clear-cut therapeutic targets, effective treatment strategies remain to be established. However, TNBC is known to share similar biologic characteristics with basal-like type breast cancer and is often accompanied by loss of functional BRCA, a gene-modifying enzyme. Breast cancer with BRCA1 or BRCA2 mutations is accompanied by activation of the enzyme poly(ADP-ribose) polymerase (PARP). PARP, a DNA base-excision repair enzyme, is known to play a central role in gene repair, along with BRCA. Because some breast cancers with BRCA1 or BRCA2 mutations are TNBC, the suppression of PARP has attracted attention as a new treatment strategy for TNBC. In this article, we review the clinical characteristics of TNBC, discuss problems in treatment, and briefly summarize the international development status of PARP inhibitors.

Current status of therapy for breast cancer worldwide and in Japan

The results of clinical trials conducted in Europe and North America have been incorporated into treatment strategies for breast cancer in Japan. Despite the use of similar treatment regimens, why has mortality from breast cancer been increasing in Japan? Procedures for surgical treatment and sentinel lymph node biopsy in breast cancer do not differ between Japan and Western countries, but the strategies for radiotherapy differ slightly. Hormonal therapy is now selected on the basis of scientific evidence, and similar regimens are used in Japan and Western countries. As for postoperative adjuvant chemotherapy, an anthracycline plus cyclophosphamide and taxane-based regimens are standard treatments in Japan and Western countries. In 2009, however, the results of two large clinical studies designed to determine whether intravenous or oral treatment was superior for postoperative adjuvant chemotherapy were reported in Japan. Both studies showed that relapse-free survival and overall survival (OS) at 5 years after surgery were similar for a combination of cyclophosphamide, methotrexate, and 5-fluorouracil and for tegafur/uracil. Many chemotherapeutic agents that are used to treat recurrent or metastatic breast cancer have not yet been approved in Japan. As for molecular targeted therapy, some agents that target the human epidermal growth factor receptor family have been approved in Japan, whereas angiogenesis inhibitors have not. The results of many clinical trials have been incorporated into clinical practice in Japan, therefore, the outcomes of breast cancer therapy have surpassed those in other countries. Many pivotal clinical trials have been conducted outside Japan. Treatment regimens that have been developed on the basis of these studies might be suitable for the management of breast cancer in Western women, but not for Japanese women because of differences in genetic factors, physique, body mass index, pharmacokinetics, and drug metabolism. Such regimens should be modified on the basis of the characteristics of breast cancer in Japan to develop treatment that is optimally suited for Japanese women. In particular, local studies of pharmacokinetics, pharmacodynamics, and optimal dose levels and treatment intervals should be carefully performed. The establishment of treatment regimens optimally suited for Japanese patients with breast cancer could put the brakes on the trend towards increasing mortality from breast cancer in Japan.

Tumor-like growth of giant inflammatory polyposis in a patient with ulcerative colitis.

We report a unique case of giant obstructing inflammatory polyposis associated with ulcerative colitis (UC). A 25-year-old Japanese man with an UC history of 2 years and 6 months was referred to our institution because of diarrhea and melena. His computed tomography scan showed marked dilation of the transverse and descending colon; therefore, we performed total colectomy. Macroscopic evaluation of the excised specimen indicated constricting lesions with giant polyposis in the transverse and descending colon. The polyposis consisted of narrow worm- or noodle-like polyps that bridged over the irregular ulcers. Histologic evaluation of the excised specimen indicated transmural inflammation with a thickened proper muscular layer overlaid with inflammatory polyposis. Based on these data, a diagnosis of giant inflammatory polyposis should be considered in patients who have had UC. Although giant inflammatory polyposis is considered benign, surgical treatment may be indicated to avoid serious complications.

Efficacy and tolerability of oxycodone for oxaliplatin-induced peripheral neuropathy and the extension of folfox therapy in colorectal cancer patients.

196 Background: The oxaliplatin-based regimen FOLFOX is widely used to treat patients with advanced colorectal cancer (CRC). However, dose-limiting toxicity after continuous oxaliplatin administration can lead to peripheral neuropathy. Several agents, including opioids, that have been employed to treat oxaliplatin-induced peripheral neuropathy (OIPN) have been examined in clinical settings regarding their protective and therapeutic effects. However, the pharmacotherapy of these agents has not yet been established. Therefore, we investigated the efficacy and tolerability of oxycodone for OIPN and subsequently with FOLFOX therapy in CRC patients. METHODS This was a single-center retrospective study of 64 CRC patients who underwent FOLFOX therapy at the Toho University Sakura Medical Center (Sakura, Japan). Controlled-release (CR) oxycodone was concomitantly administered to 29 patients (OXY group), whereas the additional 35 patients (non-OXY group) were not given oxycodone during the FOLFOX treatment course. The incidence and severity of OIPN and the number of FOLFOX cycles were measured and compared between the two groups. Neurological toxicities were assessed according to the Common Terminology Criteria for Advanced Events, version 3.0. RESULTS All study patients had OIPN. Most patients experienced grade 1 or 2 sensory neuropathy. Grade 3 sensory neuropathy was observed in two patients in the non-OXY group. All patients in the OXY group completed the scheduled FOLFOX therapy, whereas FOLFOX therapy was discontinued in ten patients in the non-OXY group due to severe peripheral neuropathy. The median numbers of FOLFOX cycles in the OXY and non-OXY groups were 13 (range, 6-46) and 7 (range, 2-18), respectively (P < 0.05). The median cumulative oxaliplatin doses were 1072.3 mg/m2 (range, 408.7-3385.3 mg/m2) in the OXY group and 483.0 mg/m2 (range 76.2-1414.1 mg/m2) in the non-OXY group (P < 0.05). CONCLUSIONS Our findings indicate that CR oxycodone might attenuate the severity of OIPN and extend the use of FOLFOX therapy.