Prospective analysis of the expression status of FGFR2 and HER2 in colorectal and gastric cancer populations: DS-Screen Study.

PURPOSE: Fibroblast growth factor receptor 2 (FGFR2) and human epidermal growth factor receptor 2 (HER2) proteins are both molecular targets for cancer therapy. The objective of this study was to evaluate the expression status of FGFR2 and HER2 in patients with gastric cancer (GC) or colorectal cancer (CRC). METHODS: Archived tumor tissue samples from patients with histologically-confirmed GC or CRC suitable for chemotherapy were analyzed for FGFR2 and HER2 expression using immunohistochemistry and fluorescence in situ hybridization (HER2 in CRC only). RESULTS: A total of 176 GC patients and 389 CRC patients were enrolled. Among patients with GC, 25.6% were FGFR2-positive and 26.1% were HER2-positive. Among patients with CRC, 2.9% were FGFR2-positive and 16.2% were HER2-positive. No clear relationship was found between FGFR2 and HER2 status in either GC or CRC. In GC, FGFR2 and HER2 statuses did not differ between different primary cancer locations, whereas there were some differences between histological types. Based on FGFR2- and/or HER2-positive status, 117 patients were identified as potentially suitable for inclusion in clinical trials of therapeutic agents targeting the relevant protein (GC = 45, CRC = 72; FGFR = 56, HER2 = 62), of whom 7 were eventually enrolled into such clinical trials. CONCLUSIONS: This study indicated the prevalence of FGFR2 and HER2 in GC and CRC in the Japanese population. The screening performed in this study could be useful for identifying eligible patients for future clinical trials of agents targeting these proteins. TRIAL REGISTRATION: Clinical trial registration Japic CTI No.: JapicCTI-163380.  https://www. CLINICALTRIALS: jp/cti-user/trial/ShowDirect.jsp?directLink=RNlzx1PPCuT.PrVNPxPRwA .

Portal Vein Thrombosis in Metastatic Colorectal Cancer During FOLFIRI-bevacizumab Chemotherapy Successfully Treated with Apixaban.

Portal vein thrombosis (PVT) while using an angiogenesis inhibitor is relatively rare. A 70-year-old Asian man was diagnosed with PVT two months after initiating 5-fluorouracil/leucovorin, irinotecan, and bevacizumab therapy for rectal cancer with liver metastases. Because the metastases were small and shrinking, we suspected that the thrombosis might have been caused by bevacizumab-containing chemotherapy. We stopped bevacizumab and started apixaban, a direct oral anticoagulant (DOAC). Eight months later, the complete dissolution of the thrombus and recanalization of the portal vein were attained. Our case suggests that PVT can occur during bevacizumab-containing chemotherapy, and DOAC therapy might be beneficial for treating PVT in patients with cancer.

Disseminated Carcinomatosis of the Bone Marrow from Occult Breast Cancer Responding to a Sequence of Endocrine Therapy.

Patients with cancer of unknown primary (CUP) are generally treated with chemotherapy. Bone marrow involvement suggests an advanced stage, and CUP with disseminated carcinomatosis of the bone marrow (DCBM) appears to have a dismal prognosis. However, our case of CUP with DCBM was successfully treated with a sequence of endocrine therapy over a long period. A woman presenting with low back pain was found to have multiple bone metastasis without an identifiable primary tumor on imaging studies. Blood tests revealed anemia and thrombocytopenia. A bone marrow biopsy was performed and showed relatively uniform small cells, strongly positive for estrogen receptor and progesterone receptor expression. We considered chemotherapy to be risky due to bicytopenia and an aromatase inhibitor, letrozole, was initiated. The patient's symptoms and laboratory findings gradually improved and bone lesions almost disappeared on FDG-PET/CT after 1 year of treatment. After 2 years on letrozole, hemoglobin levels and platelet counts had been gradually decreasing. Although she had no symptoms and no significant changes were observed on a CT scan, disease progression was highly likely. Thus, second-line treatment with fulvestrant and palbociclib was commenced, and hemoglobin levels and platelet counts were restored to within the normal ranges. She currently continues to receive fulvestrant and palbociclib over a year later. CUP complicated with DCBM might be metastatic occult breast cancer, and endocrine therapy can be a valuable treatment option if tumors express hormone receptors.

Pilot study of MDR1 gene transfer into hematopoietic stem cells and chemoprotection in metastatic breast cancer patients.

A major problem in high-dose chemotherapy with autologous hematopoietic stem cell transplantation is insufficient function of reconstituted bone marrow that limits the efficacy of post-transplantation chemotherapy. Because transduction of hematopoietic stem cells with the multidrug resistance 1 (MDR1) gene might circumvent this problem, we conducted a pilot study of MDR1 gene therapy against metastatic breast cancer. Peripheral blood stem cells were harvested, and one-third of the cells were transduced with MDR1 retrovirus. After the reconstitution of bone marrow function, the patients received high-dose chemotherapy with transplantation of both MDR1-transduced and unprocessed peripheral blood stem cells. The patients then received docetaxel chemotherapy. Two patients received transplantation of the MDR1-transduced cells in 2001. Peripheral blood MDR1-transduced leukocytes were 3-5% of the total cells after transplantation, but decreased gradually. During docetaxel chemotherapy, an increase in the rate of MDR1-transduced leukocytes (up to 10%) was observed. Comparison of docetaxel-induced granulocytopenia in the two patients suggested a bone marrow-protective effect of the MDR1-transduced cells. No serious side-effect was observed, and the patients were in complete remission for more than 3 years. The MDR1-transduced cells gradually decreased and disappeared almost entirely by the end of 2004. Results of linear amplification-mediated polymerase chain reaction of the MDR1-transduced leukocytes suggested no sign of abnormal amplification of the transduced cells. A third patient received transplantation of the MDR1-transduced cells in 2004. These results suggest the feasibility of our MDR1 gene therapy against metastatic breast cancer, and follow-up is ongoing.

[Neurotoxicity and dermatologic toxicity of cancer chemotherapy].

Neurological dysfunction is a common adverse effect of many chemotherapeutic agents. Any part of the peripheral or central nervous system can be affected. Various clinical syndromes including encephalopathy, cerebellar syndrome, cranial neuropathy, seizure,myelopathy, and peripheral neuropathy commonly occur. In several drugs, neurotoxicity is a dose-limiting toxicity. Multiple factors such as cumulative dose, route of administration, drug metabolism and synergistic effects of other drugs or radiotherapy impact the incidence and severity of neurotoxicity. Much of the research in chemotherapy-induced neuropathies has been focused on the goal of ameliorating or preventing the neurotoxicity without altering the effectiveness of the medication. Various dermatologic complications of cancer chemotherapy such as extravasation, hyperpigmentation, nail change, radiation recall reaction and hypersensitivity reaction can occur. In extravasation, many cytotoxic agents are irritants or non-vesicants, however,a significant number of commonly used drugs are classified as vesicants, including the vinca alkaloids anthracyclines and taxanes. Extravasation of vesicant drugs into the subcutaneous tissue results in severe local pain and ulceration with progressive tissue destruction. Strategies to reduce the incidence of extravasation and minimize its associated morbidity are crucial to quality of life for cancer patients. The more common clinical features of chemotherapy-induced neurologic and dermatologic toxicities are discussed below.

C421A polymorphism in the human breast cancer resistance protein gene is associated with low expression of Q141K protein and low-level drug resistance.

Breast cancer resistance protein (BCRP) confers multidrug resistance to cancer cells against agents such as SN-38 (an active metabolite of irinotecan), mitoxantrone, and topotecan. Among 59 human tumor cell lines tested, 6 cell lines, A549, NCI-H460, KM-12, HT-29, OVCAR-5, and RPMI8226, showed high BCRP expression. BCRP cDNA was isolated from 11 cancer cell lines and three variant cDNAs [G34A substituting Met for Val-12 (V12M), C421A substituting Lys for Gln-141 (Q141K), and 944-949 deletion lacking Ala-315 and Thr-316 (delta315-6)] were identified. G34A and C421A variants were polymorphisms, and 944-949 deletion was a splicing variant. C421A BCRP-transfected PA317 cells showed markedly decreased protein expression and low-level drug resistance compared with wild-type BCRP-transfected cells when transfectants expressed similar levels of BCRP mRNA. G34A or 944-949-deleted BCRP-transfected PA317 cells showed similar or somewhat lower protein expression and drug resistance compared with wild-type BCRP-transfected cells. Of 124 healthy Japanese volunteers, 67 were wild-type, 48 were heterozygous, and 9 were homozygous for the C421A allele. These results suggest that some people possess the C421A polymorphic BCRP gene and express low amounts of Q141K BCRP. In addition to that, C376T polymorphism in exon 4 substituting stop codon for Gln-126 was found in 3 of the 124 general Japanese population. This C376T polymorphism may also have high impact because active BCRP protein will not be expressed from the C376T allele. Therefore, people with C376T and/or C421A polymorphisms may express low amounts of BCRP, and this low BCRP expression might result in hypersensitivity of normal cells to such anticancer drugs as irinotecan and mitoxantrone.