Systemic Treatments in Pregnancy-Associated Breast Cancer.

Available data on systemic treatments in pregnancy-associated breast cancer (PABC) is reviewed in this section. These treatments include chemotherapy, endocrine therapy (ET), small molecule inhibitors, monoclonal antibodies against human epidermal growth factor receptor 2 (EGFR-2) also known as HER2; and human epidermal growth factor receptor 3 (EGFR-3), also known as HER3.In local disease, systemic treatment can be delivered as neoadjuvant (before surgery) or adjuvant (after surgery) treatment. In metastatic disease, systemic therapy is the main modality of treatment.Approach to PABC is based on available data in the general population, limited only by safety issues for use of medications during gestation and lactation. Therefore, treatments are similar to non-PABC patients while trying to minimize the risk to the fetus. Available data on different chemotherapies, anti-HER2 monoclonal antibodies, ET and small molecule inhibitors are discussed in detail.

Brain metastases from cervical cancer reduce longevity independent of overall tumor burden.

BACKGROUND: Isolated brain metastasis (IBM) from cervical cancer is a very rare encounter in neurosurgery. We sought to understand how patients with isolated brain metastases differ from those with metastases in the setting of widespread disease. METHODS: A systematic review was completed using PubMed and the Cochrane Library. Patients with isolated brain metastases (IBM) and non-isolated brain metastases (NIBM, or brain metastases in the setting of disseminated disease), were compared. Two-sided statistical tests were used to determine significance. Survival function was carried out using the Kaplan-Meier method. RESULTS: A total of 89 patients, 25 with IBM and 64 with NIBM, were identified. The time interval between initial diagnosis of cervical cancer and diagnosis of brain lesion was significantly shorter in the IBM group (median 7.5 vs. 20.05 months, and IBM vs. NIBM, respectively; P = 0.006). Overall survival from initial diagnosis of cervical cancer was significantly shorter for the IBM group versus the NIBM group (7.63 vs. 26.3 months, respectively; P = 0.0005). Data demonstrate a 3.4-fold reduction of median life expectancy to 7.63 months. Survival after diagnosis of brain metastases did not differ between groups (median, IBM 7 months vs. NIBM 4 months, P = 0.08). CONCLUSION: Taken together, our data suggest that for cervical cancer patients with brain metastasis intracranial metastasis itself (and not overall tumor burden) represent a sentinel event in limiting longevity. While the present study is underpowered to compare treatment options directly, further work should be focused on determining the optimal treatment for these patients.

A Pilot Trial Evaluating Zoledronic Acid Induced Changes in [18F]FMAU-Positron Emission Tomography Imaging of Bone Metastases in Prostate Cancer.

PURPOSE: We conducted a pilot trial utilizing [18F]FMAU [1-(2'-deoxy-2'-[18F]fluoro-ß-D-arabinofuranosyl thymine] as a tumor tracer in positron emission tomography (PET) and evaluated its reproducibility, and changes in maximum and peak standardized uptake value (SUVmax and SUVpeak) with zoledronic acid treatment in castrate resistant prostate cancer (CRPC) patients with bone metastases (BM). PROCEDURES: Eligible patients had CRPC with radiographic evidence of BM and creatinine clearance >30 ml/min. Two baseline [18F]FMAU-PET scans (about 1 week apart, range 2-12 days) were obtained for testing reproducibility. Zoledronic acid 4 mg was infused over 15 min within 1 week after second scan and a third PET scan was obtained 7 days later. The bony lesion with the highest uptake on the first scan was compared with later scans. Bone turnover markers and prostate-specific antigen (PSA) were obtained pre- and post-therapy. PET response was defined as decline in SUVmean of ≥15 % after zoledronic acid. RESULTS: Eleven patients were evaluated, median age was 65 years, five were African-American and six were Caucasian, and median PSA level was 36.3 ng/ml (range 1.0-1209.3). Notably, the range of absolute percent SUVmax changes varied between 0.77 and 54.7, and only nine measurements were greater than one (1.09-2.19). Zoledronic acid did not appreciably change FMAU uptake. No clinical response was noted. Urine N-telopeptide (NTx) was markedly decreased in all patients after zoledronic acid and serum bone-specific alkaline phosphatase (BSAP) registered a modest change. Urine NTx correlated more closely with SUV max than serum BSAP. CONCLUSIONS: FMAU tracer was able to detect bone metastases in CRPC patients but uptake was highly variable in bony lesions. Zoledronic acid did not produce an appreciable change in scans. Future investigations of FMAU tracer as a marker of early response in CRPC is recommended.

PET imaging of proliferation with pyrimidines.

Several new tracers are being developed for use with PET to assess pathways that are altered in cancers, including energy use, cellular signaling, transport, and proliferation. Because increased proliferation is a hallmark of many cancers, several tracers have been tested to track the DNA synthesis pathway. Thymidine, which is incorporated into DNA but not RNA, has been used in laboratory studies to measure tumor growth. Because thymidine labeled with (11)C undergoes rapid biologic degradation and has a short physical half-life, tracers labeled with (18)F have been preferred in PET imaging. One such tracer is (18)F-labeled 3'-deoxy-3'-fluorothymidine ((18)F-FLT). (18)F-FLT is trapped after phosphorylation by thymidine kinase 1, whose expression is increased in replicating cells. Several studies on breast, lung, and brain tumors have demonstrated that retention of (18)F-FLT correlated with tumor proliferation. Although (18)F-FLT has been used to image and stage several tumor types, the standardized uptake value is generally lower than that obtained with (18)F-FDG. (18)F-FLT can be used to image many areas of the body, but background uptake is high in the liver, marrow, and renal system, limiting use in these organs. (18)F-FLT PET imaging has primarily been studied in the assessment of treatment response. Rapid declines in (18)F-FLT retention within days to weeks have been demonstrated in several tumor types treated with cytotoxic drugs, targeted agents, and radiotherapy. Further work is ongoing to validate this approach and determine its utility in the development of new drugs and in the clinical evaluation of standard treatment approaches.

Sudden suffocation with cancer of unknown primary: a case report and review of diagnostic approach.

A case of a 31-year-old woman with sudden respiratory distress is presented. Preliminary evaluations and imaging studies did not reveal the underlying cause. Workup during hospital stay showed advanced metastatic cancer of unknown primary origin. This is an unusual presentation of cancer of an unknown primary involving the thyroid with sudden suffocation. It suggests that malignancies involving the thyroid gland should be considered in patients with abrupt onset of respiratory distress. Also, this case shows the application of fine needle aspiration in diffuse thyroid enlargements mimicking thyroiditis without nodules. Diagnostic approach to cancer of unknown primary origin (CUP) is reviewed in further detail.

Interferon regulatory factors IRF5 and IRF7 inhibit growth and induce senescence in immortal Li-Fraumeni fibroblasts.

Cellular immortalization is one of the prerequisite steps in carcinogenesis. By gene expression profiling, we have found that genes in the interferon (IFN) pathway were dysregulated during the spontaneous cellular immortalization of fibroblasts from Li-Fraumeni syndrome (LFS) patients with germ-line mutations in p53. IFN signaling pathway genes were down-regulated by epigenetic silencing during immortalization, and some of these same IFN-regulated genes were activated during replicative senescence. Bisulfite sequencing of the promoter regions of two IFN regulatory transcription factors (IRF5 and IRF7) revealed that IRF7, but not IRF5, was epigenetically silenced by methylation of CpG islands in immortal LFS cells. The induction of IRF7 gene by IFNalpha in immortal LFS cells was potentiated by pretreatment with the demethylation agent 5-aza-2'-deoxycytidine. Overexpression of IRF5 and IRF7 revealed that they can act either alone or in tandem to activate other IFN-regulated genes. In addition, they serve to inhibit the proliferation rate and induce a senescence-related phenotype in immortal LFS cells. Furthermore, polyinosinic:polycytidylic acid treatment of the IRF-overexpressing cells showed a more rapid induction of several IFN-regulated genes. We conclude that the epigenetic inactivation of the IFN pathway plays a critical role in cellular immortalization, and the reactivation of IFN-regulated genes by transcription factors IRF5 and/or IRF7 is sufficient to induce cellular senescence. The IFN pathway may provide valuable molecular targets for therapeutic interventions at early stages of cancer development.

Tracking cellular stress with labeled FMAU reflects changes in mitochondrial TK2.

PURPOSE: Fluoropyrimidines like 1-(2'-deoxy-2'-fluoro-beta-D: -arabinofuranosyl)-thymine (FMAU) and 3'-deoxy-3'-fluorothymidine (FLT) accumulate in tumors and are being used as positron emission tomography tumor-imaging tracers. Proliferating tissues with high thymidine kinase 1 (TK1) activity retain FLT; however, the mechanism of selective accumulation of FMAU in tumors and certain other tissues requires further study. METHODS: Retention of [(3)H]FLT and [(3)H]FMAU was measured in prostate cancer cell lines PC3, LNCaP, DU145, and the breast cancer cell line MD-MBA-231, and the tracer metabolites were analyzed by high-performance liquid chromatography (HPLC). FMAU retention, thymidine kinase 2 (TK2) activity, and mitochondrial mass were determined in cells stressed by depleted cell culture medium or by treating with oxidative, reductive, and energy stress, or specific adenosine monophosphate-activated protein kinase activator, or eIF2 inhibitor. TK1 and TK2 activities and mitochondrial mass were determined by FLT phosphorylation, 1-beta-D: -arabinofuranosylthymine (Ara-T) phosphorylation, and flow cytometry, respectively. RESULTS: FMAU retention in rapidly proliferating cancer cell lines was five to ten times lower than FLT after 10 min incubation. HPLC analysis of the cellular extracts showed that phosphorylated tracers are the main retained metabolites. Nutritional stress decreased TK1 activity and FLT retention but increased retained FMAU. TK2 inhibition decreased FMAU retention and phosphorylation with negligible effects on FLT. Oxidative, reductive, or energy stress increased FMAU retention and correlated with mitochondrial mass (r (2) = 0.88, p = 0.006). FMAU phosphorylation correlated with increased TK2 activity (r (2) = 0.87, p = 0.0002). CONCLUSION: FMAU is preferably phosphorylated by TK2 and can track TK2 activity and mitochondrial mass in cellular stress. FMAU may provide an early marker of treatment effects.

Tumor imaging using 1-(2'-deoxy-2'-18F-fluoro-beta-D-arabinofuranosyl)thymine and PET.

UNLABELLED: The kinetics of 1-(2'-deoxy-2'-fluoro-beta-d-arabinofuranosyl)thymine (FMAU) were studied using PET to determine the most appropriate and simplest approach to image acquisition and analysis. The concept of tumor retention ratio (TRR) is introduced and validated. METHODS: Ten patients with brain (n = 4) or prostate (n = 6) tumors were imaged using (18)F-FMAU PET (mean dose, 369 MBq). Sixty-minute dynamic images were obtained; this was followed by whole-body images. Mean and maximum standardized uptake values (SUVmean and SUVmax, respectively) of each tumor were determined as the mean over 3 planes of each time interval. For kinetic analyses, blood activity was measured in 18 samples over 60 min. Samples were analyzed by high-performance liquid chromatography at 3 selected times to determine tracer metabolites. FMAU kinetics were measured using a 3-compartment model yielding the flux (K1 x k3/(k2 + k3)) (K1, k2, and k3 are rate constants) and compared with TRR measurements. TRR was calculated as the tumor (18)F-FMAU uptake area under the curve divided by the product of blood (18)F-FMAU AUC and time. A similar analysis was performed using muscle to estimate (18)F-FMAU delivery. RESULTS: SUVmean measurements obtained from 5 to 11 min correlated with those obtained from 30 to 60 min (r(2) = 0.92, P < 0.0001) and 50 to 60 min (r(2) = 0.92, P < 0.0001) due to the rapid clearance of (18)F-FMAU. Similar results were obtained using SUVmax measurements (r(2) = 0.93, P < 0.0001; r(2) = 0.88, P < 0.0001, respectively). The measurement of TRR using either blood or muscle activity over 11 min provided results comparable to those of 60-min dynamic imaging and a 3-compartment model. This analysis required only 5 blood samples drawn at 1, 2, 3, 5, and 11 min without metabolite correction to produce comparable results. CONCLUSION: Tissue retention ratio measurements obtained over 11 min can replace flux measurements in (18)F-FMAU imaging. The SUVmean and the SUVmax in 5-11 min images correlated well with those of images obtained at 50-60 min. The quality of the images and tissue kinetics in 11 min of imaging makes it a desirable and shorter tumor imaging option.