Jacqueline S. Lewis

Serum Molecular Signatures of Weight Change during Early Breast Cancer Chemotherapy

Purpose: Weight gain in women receiving chemotherapy for breast cancer is associated with a higher risk of recurrence but its mechanisms are poorly understood. Experimental Design: To investigate this, we assessed the metabolic, cytokine, and appetite-related peptide alterations during adjuvant chemotherapy for early breast cancer in postmenopausal women, and correlated these with body mass measurements. Specifically, we performed global metabolic profiling using 1H-nuclear magnetic resonance spectroscopy of sequential sera, examined ghrelin immunoreactivity, RIAs for GLP-1 and peptide YY, and electrochemiluminescent cytokine analyses (tumor necrosis factor-α and interleukin-6) on sequential samples. Results: In those who gained >1.5 kg, several metabolite levels were positively associated with weight gain, specifically lactate, which was 63.5% greater in patients with increased body weight during chemotherapy compared with those with no weight gain (P < 0.01; the prespecified primary end point). A strong correlation (r = 0.7, P < 0.001) was detected between the rate of weight change and serum lactate levels, and on average, lactate levels exhibited the greatest metabolic response to chemotherapy, increasing by up to 75%. Normalized levels of peptide YY were also observed to be elevated in patients not gaining weight posttreatment (+30% compared with −7% for the weight gain group; P < 10−4). Baseline lactate, alanine, and body fat were all prognostic for weight gain (area under the receiver operator characteristic curves, >0.77; P < 0.05). No associations were observed between any other parameter and weight gain, including cytokine levels. Conclusions: Metabonomics identifies excess energy expenditure pathways perturbed during chemotherapy for breast cancer, and establishes a significant association between serum lactate, body fat, and substantive weight gain during chemotherapy. (Clin Cancer Res 2009;15(21):6716–23)

The efficacy of percutaneous vertebroplasty for vertebral metastases associated with solid malignancies.

BACKGROUNDnPercutaneous vertebroplasty appears beneficial for patients with acute compression fractures of multiple aetiologies including myeloma, osteoporosis and trauma. There are few reports on its use in the setting of metastatic solid malignancy.nnnMETHODSnWe identified all individuals who had undergone percutaneous vertebroplasty at our institution since 2004 and focused on those with metastatic solid malignancies. Their clinical characteristics and outcomes were investigated.nnnRESULTSnFrom 136 cases that underwent percutaneous vertebroplasties, 19 were performed mainly in breast, prostate, lung and renal cancers. Of these 19 cases, 10 patients (53%) were treated for solitary lesions, 3 (16%) were injected at two levels and the remaining 6 cases (31%) underwent cement injection at three levels. The majority of individuals (84%) reported short- and long-term symptomatic improvements. At a median follow-up of one year, six patients have died.nnnCONCLUSIONSnPercutaneous vertebroplasty appears as an effective palliative procedure in patients with compression fractures secondary to metastatic solid malignancy. Its use can be successfully combined with other treatment modalities (radiotherapy and chemotherapy).

[11C]Choline Positron Emission Tomography in Estrogen Receptor–Positive Breast Cancer

Purpose: Novel radiotracers could potentially allow the identification of clinically aggressive tumor phenotypes. As choline metabolism increases during malignant transformation and progression of human mammary epithelial cells, we examined the ability of [11C]choline (CHO) positron emission tomography imaging to detect clinically aggressive phenotype in patients with estrogen receptor (ER)–positive breast cancer in vivo. Experimental Design: CHO positron emission tomography was done in 32 individuals with primary or metastatic ER–positive breast cancer. Semiquantitative (standardized uptake value) and fully quantitative (net irreversible transfer rate constant of CHO, Ki) estimates of CHO uptake in the tumors were calculated and compared with tumor grade, size, involved nodes, and also ER, progesterone receptor, Ki-67, and human epidermal growth factor receptor-2 scores. Results: Breast tumors were well visualized in 30 of 32 patients with good tumor background ratios. A wide range of uptake values were observed in primary and metastatic tumors. CHO uptake variables correlated well with tumor grade. For most imaging variables, a poor association was found with tumor size, ER, progesterone receptor, human epidermal growth factor receptor-2, Ki-67, and nodal status. Conclusions: CHO showed good uptake in most breast cancers and merits further investigation as a breast cancer imaging agent. (Clin Cancer Res 2009;15(17):5503–10)

Peritoneal disease in breast cancer: A specific entity with an extremely poor prognosis

BACKGROUNDnPeritoneal metastases are now a significant cause of morbidity and mortality in patients with advanced breast cancer. There are few published data regarding the prognosis, clinical characteristics and management of individuals with peritoneal metastases from breast cancer.nnnMETHODSnThe electronic database at Imperial College Healthcare NHS Trust (Charing Cross Hospital) was searched for the terms breast, cancer or tumour, peritoneal and ascites from 2000 to 2008. Those with confirmed peritoneal disease from breast cancer, as described on ultrasound or staging CT reports with a clinico-pathologic confirmed diagnosis, were included.nnnRESULTSnA total of 1628 patients were screened and initially 168 patients were identified. A subsequent total of 44 individuals (2.7% of the cohort) were defined as having breast cancer with peritoneal secondaries and were included in the analysis. Of these, the majority (77%) had invasive ductal carcinomas (IDCs). While the median survival from the diagnosis of metastatic breast cancer measured 20.5 months (range 0.1-125 months), the median survival of patients with peritoneal disease was 1.56 months (range 0.2-27 months).nnnCONCLUSIONSnThese data demonstrate that the median survival of patients with peritoneal breast cancer metastasis is surprisingly poor, with only a minority surviving more than 6 months. A specific association with invasive lobular carcinoma (ILC) was not observed. The dismal outcome of these individuals, despite further active therapy, merits their inclusion into clinical trials designed specifically for this group of patients.

The Efficacy of Axillary Ultrasound in the Detection of Nodal Metastasis in Breast Cancer

OBJECTIVEnRecent reports indicate a lack of survival benefit for axillary lymph node dissection (ALND) versus sentinel lymph node biopsy in early breast cancer. To study this issue further, we assessed the accuracy and effectiveness of ultrasound examination in detecting axillary nodal involvement in breast cancer patients with the aim of refining our current clinical pathways.nnnMATERIALS AND METHODSnUltrasound data were collected from breast cancer cases over 3 years. Images were reviewed by experienced radiologists and the following characteristics were assessed: size, morphology, hyperechoic hilum, and cortical thickness of the ipsilateral axillary nodes. The findings were correlated with histologic outcomes after ALND.nnnRESULTSnTwo hundred twenty-four cases were included in the analysis, 113 (50.4%) of which had evidence of metastatic nodal involvement at final histology. Of these 113 cases, ultrasound findings for 59 (52.2%) were positive. The overall positive predictive value of ultrasound for detecting metastatic nodal involvement measured 0.81. The negative predictive value was 0.60. The sensitivity was 53.7%; specificity, 85.1%; and accuracy, 67.9%. The ultrasound morphologic lymph node features with the greatest correlation with malignancy were the absence of a hyperechoic hilum (p = 0.003) and increased cortical thickness (p = 0.03). Patients with a metastatic nodal burden density of at least 20% were more likely to have abnormal findings on axillary ultrasound examination (p = 0.009).nnnCONCLUSIONnAxillary ultrasound has a low negative predictive value and negative ultrasound results do not exclude axillary node metastases with sufficient sensitivity to justify its routine clinical use. Clinical pathways need to consider an evidence-based approach, focusing on the criteria by which we select breast cancer patients for ALND.

The clinico-pathologic role of microRNAs miR-9 and miR-151-5p in breast cancer metastasis.

BackgroundMicroRNAs (miRNAs) may function as suppressors or promoters of tumor metastasis according to their messenger RNA targets. Previous studies have suggested that miR-9 and miR-151-5p are associated with metastasis in breast cancer and hepatocellular carcinoma, respectively. We aimed to further establish the potential roles of miR-9 and miR-151–5p in tumor invasion and metastasis and investigate their use as biomarkers.MethodsWe used quantitative real-time PCR (qRT-PCR) to measure differences in miR-9 and miR-151–5p expression between primary breast tumors and their lymph-node metastases in 194 paired tumor samples from 97 patients. We also correlated expression levels with histologic data to investigate their utility as biomarkers.ResultsThere were no significant differences in miR-9 expression between the primary tumors and lymph nodes; however, miR-151-5p expression was significantly lower in the lymph-node metastases than in their corresponding tumors (p<0.05). miR-9 levels were elevated in primary breast tumors from patients diagnosed with higher-grade tumors (p<0.05); however, no differences were observed in miR-151–5p levels between different grades of tumor. Interestingly, miR-9 levels were elevated in invasive lobular carcinomas (ILC) compared with invasive ductal carcinomas (IDC; p<0.01).ConclusionsIn aggregate, these data suggest that miR-151–5p upregulation may suppress metastasis in primary breast tumors. Both miRNAs may serve as useful biomarkers in future clinical trials in breast cancer.

Biological basis of [11C]choline-positron emission tomography in patients with breast cancer: comparison with [18F]fluorothymidine positron emission tomography

ObjectiveThe biological significance of [11C]choline (CHO) uptake in human tumours is unclear and probably linked to choline kinase-&agr; (CHK&agr;) expression and cell proliferation. We directly compared CHO with [18F]fluorothymidine (FLT), an imaging biomarker of proliferation, by positron emission tomography (PET) in patients with breast cancer to investigate whether cell proliferation is an important determinant of CHO uptake. Furthermore, we evaluated CHK&agr; and the Ki67-labelling index (LIKi67) in tumour biopsies. MethodsSequential CHO-PET and FLT-PET within the same imaging session were performed in 21 patients with oestrogen receptor (ER)-positive breast cancer (28 lesions). Average and maximum CHO standardized uptake values (SUV) at 60 min: SUV60,av, and SUV60,max, and the rate constant of net irreversible uptake, Ki, were compared with FLT uptake at 60 min: SUV60,av and SUV60,max. Biopsies were stained for CHK&agr; and LIKi67 in eight cases. ResultsTumours were equally visible on CHO-PET and FLT-PET imaging. Tumour CHO-PET strongly correlated with FLT imaging variables (Pearson’s r=0.83; P<0.0001 for CHO-SUV60,max vs. FLT-SUV60,max). A statistically significant association was found between CHO-PET variables and categorical scores of cytoplasmic CHK&agr; intensity and between FLT-PET and LIKi67 (P<0.05, one-way analysis of variance). ConclusionCholine metabolism and proliferation as assessed by PET were correlated in ER-positive breast cancer, indicating that high CHO uptake is a measure of cellular proliferation in this setting. CHO uptake was also found to be related to cytoplasmic CHK&agr; expression.

The clinical significance of radiologically detected silent pulmonary nodules in early breast cancer

BACKGROUNDnIncreasing numbers of patients with early cancer undergo routine staging using computerized tomography (CT). Those in whom indeterminate pulmonary nodules are visualized without the presence of other metastatic lesions represent a clinical dilemma regarding their management as early breast cancer or metastatic disease.nnnPATIENTS AND METHODSnMedical records of breast cancer patients who underwent thoracic CT scans between the years 2002 and 2008 were analyzed. Those with obvious metastatic disease were excluded. Patients were identified via the radiology database by searching for the terms: suspicious lung metastases and indeterminate nodules.nnnRESULTSnOut of 1578 new patients assessed from 2002 to 2008, we carried out 802 staging CT scans. Thirty-four cases (4.2%) with indeterminate pulmonary nodules were identified. We categorized cases by size and number of nodules. At a median follow-up of 18 months, there were no changes in lesion size in 86% of patients with a solitary nodule <1 cm and 89% with multiple subcentimeter nodules. In contrast, in 100% of cases with pulmonary nodules >1 cm, the nodules had progressed at follow-up (chi(2), P = 0.004).nnnCONCLUSIONSnBreast cancer cases with subcentimeter indeterminate pulmonary lesions and no evidence of metastases elsewhere are unlikely to represent metastatic disease. Treatment with curative intent or entry into clinical trials should not be excluded.

The phosphorylated membrane estrogen receptor and cytoplasmic signaling and apoptosis proteins in human breast cancer

Estrogens play a central role in breast cancer development, and the estrogen receptor‒α (ERα) remains the single most important predictor of breast cancer prognosis. Therefore, it is crucial to elucidate pathways that may contribute to ER signaling in clinical specimens.

Schizophrenia does not adversely affect the treatment of women with breast cancer: a cohort study.

BACKGROUNDnData on the natural course of patients with breast cancer and schizophrenia are limited. Although there have been studies in assessing the incidence of breast cancer in the setting of schizophrenia, there is very little information concerning the clinical profile of these women.nnnMETHODSnWe analyzed the data from our electronic notes system by searching for the terms schizophrenia or schizophrenic and breast cancer or tumour between 1993 and 2009. Information was collected on demographics, clinico-pathologic disease variables, treatment including anti-emetic use, chemotherapy delivery and outcomes.nnnRESULTSnFrom 90,676 patients screened, we identified 37 individuals who had breast cancer and a pre-existing underlying diagnosis of schizophrenia. Of these, 30 (81%) presented with early breast cancer and 7 (19%) presented with metastatic disease. Node positivity was observed in 14 individuals (38%). The average interval between diagnosis of schizophrenia and breast cancer was more than 20 years in the majority of the patients. Treatment outcomes, trial involvement, compliance and ability to provide informed consent were similar to our previously published cohort data.nnnCONCLUSIONSnSchizophrenia does not affect treatment delivery or outcomes in women with breast cancer. The presence of schizophrenia should not be a limiting factor for entry into clinical trials. Breast cancer patients with this illness should be offered standard treatment without discrimination, including entry into clinical trials.