Breast Neoplasms: Jones AL

Jones AL, Barlow M, Barrett-Lee PJ, Canney PA, Gilmour IM, Robb SD, Plummer CJ, Wardley AM, Verrill MW. · Department of Oncology, Royal Free and University College London Hospitals, UK. · Br J Cancer. · Pubmed #19259090 links to  free full text

Abstract: More women are living with and surviving breast cancer, because of improvements in breast cancer care. Trastuzumab (Herceptin) has significantly improved outcomes for women with HER2-positive tumours. Concerns about the cardiac effects of trastuzumab (which fundamentally differ from the permanent myocyte loss associated with anthracyclines) led to the development of cardiac guidelines for adjuvant trials, which are used to monitor patient safety in clinical practice. Clinical experience has shown that the trial protocols are not truly applicable to the breast cancer population as a whole, and exclude some women from receiving trastuzumab, even though they might benefit from treatment without long-term adverse cardiac sequelae. Consequently, five oncologists who recruited patients to trastuzumab trials, some cardiologists with whom they work, and a cardiovascular lead general practitioner reviewed the current cardiac guidelines in the light of recent safety data and their experience with adjuvant trastuzumab. The group devised recommendations that promote proactive pharmacological management of cardiac function in trastuzumab-treated patients, and that apply to all patients who are likely to receive standard cytotoxic chemotherapy. Key recommendations include: a monitoring schedule that assesses baseline and on-treatment cardiac function and potentially reduces the overall number of assessments required; intervention strategies with cardiovascular medication to improve cardiac status before, during, and after treatment; simplified rules for starting, interrupting and discontinuing trastuzumab; and a multidisciplinary approach to breast cancer care.

Jones AL. · No affiliation provided · BMJ. · Pubmed #15677633 links to  free full text

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Turner NC, Jones AL. · Department of Medical Oncology, Royal Free Hospital NHS Foundation Trust, London NW3 2QG. · BMJ. · Pubmed #18621762 No free full text.

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Turner NC, Jones AL. · Department of Medical Oncology, Royal Free Hospital NHS Foundation Trust, London NW3 2QG. · BMJ. · Pubmed #18614462 No free full text.

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Jones AL. · Department of Oncology, Royal Free and University College Hospitals, London, UK. · Breast. · Pubmed #17382863 No free full text.

Abstract: Breast cancer during pregnancy remains a challenge for clinicians and a difficult experience for women and the families. Any breast symptom during pregnancy warrants triple assessment and any lump should have a definite diagnosis. If cancer is diagnosed it is usually possible to continue with the pregnancy without compromising any of the treatment modalities (except radiotherapy). The outcome for women diagnosed with breast cancer during pregnancy is the same as for age and stage-matched non-pregnant counterparts. There is no evidence of adverse foetal outcome if chemotherapy is given during the second or third trimester. However, the reported series are relatively small and more systematic long-term follow-up is needed.

Jones AL. · Department of Oncology, Royal Free and University College Hospitals, London, UK. · Breast. · Pubmed #17382862 No free full text.

Abstract: The mortality rate from breast cancer has decreased over the last two or three decades and issues of survivorship have become increasingly important. Approximately 1 in 200 women under the age of 40 develop breast cancer, and with the increasing age at first and subsequent pregnancies in the UK and Europe the issue of fertility for young women who may not have started their families may be a major consideration. The increasing use of adjuvant chemotherapy in breast cancer means that many women diagnosed with breast cancer will undergo temporary or permanent chemotherapy-induced amenorrhoea. This may be associated with physical, psychological and psychosocial implications, with women experiencing the acute toxicities associated with menopause as well as long-term health risks including loss of bone mineral density and possibly some increased cardiovascular risk. Following chemotherapy very few women become pregnant, and this may partly be due to concerns about the risks of pregnancy, both to themselves and in relation to their potential future offspring. Modern techniques used to preserve fertility in the general population may be applicable to some women with breast cancer. The use of such techniques needs to be considered on an individual basis for each woman in light of the recommended systemic adjuvant treatment, the woman's age and her own risk of recurrence with and without systemic treatment. Further clinical research is necessary to substantiate the safety of these approaches to fertility in women who have been diagnosed with breast cancer.

Langley RE, Carmichael J, Jones AL, Cameron DA, Qian W, Uscinska B, Howell A, Parmar M. · Department of Oncology, University College of London, UK. · J Clin Oncol. · Pubmed #16293863 No free full text.

Abstract: PURPOSE: To compare the effectiveness and tolerability of epirubicin and paclitaxel (EP) with epirubicin and cyclophosphamide (EC) as first-line chemotherapy for metastatic breast cancer (MBC). PATIENTS AND METHODS: Patients previously untreated with chemotherapy (except for adjuvant therapy) were randomly assigned to receive either EP (epirubicin 75 mg/m2 and paclitaxel 200 mg/m2) or EC (epirubicin 75 mg/m2 and cyclophosphamide 600 mg/m2) administered intravenously every 3 weeks for a maximum of six cycles. The primary outcome was progression-free survival; secondary outcome measures were overall survival, response rates, and toxicity. RESULTS: Between 1996 and 1999, 705 patients (353 EP patients and 352 EC patients) underwent random assignment. Patient characteristics were well matched between the two groups, and 71% of patients received six cycles of treatment. Objective response rates were 65% for the EP group and 55% for the EC group (P = .015). At the time of analysis, 641 patients (91%) had died. Median progression-free survival time was 7.0 months for the EP group and 7.1 months for the EC group (hazard ratio = 1.07; 95% CI, 0.92 to 1.24; P = .41), and median overall survival time was 13 months for the EP group and 14 months for the EC group (hazard ratio = 1.02; 95% CI, 0.87 to 1.19; P = .8). EP patients, compared with EC patients, had more grade 3 and 4 mucositis (6% v 2%, respectively; P = .0006) and grade 3 and 4 neurotoxicity (5% v 1%, respectively; P < .0001). CONCLUSION: In terms of progression-free survival and overall survival, there was no evidence of a difference between EP and EC. The data demonstrate no additional advantage to using EP instead of EC as first-line chemotherapy for MBC in taxane-naïve patients.

Evans TR, Yellowlees A, Foster E, Earl H, Cameron DA, Hutcheon AW, Coleman RE, Perren T, Gallagher CJ, Quigley M, Crown J, Jones AL, Highley M, Leonard RC, Mansi JL. · Cancer Research United Kingdom Department of Medical Oncology, University of Glasgow, Beatson Laboratories, Garscube Estate, Switchback Rd, Glasgow G61 1BD, United Kingdom. · J Clin Oncol. · Pubmed #15860854 No free full text.

Abstract: PURPOSE To compare the clinical and pathologic response rates of doxorubicin and cyclophosphamide (AC) with doxorubicin and docetaxel (AD) as primary chemotherapy in women with primary or locally advanced breast cancer. PATIENTS AND METHODS Eligible patients with histologically proven breast cancer with primary tumors >/= 3 cm, inflammatory or locally advanced disease, and no evidence of metastases were randomly assigned to receive a maximum of six cycles of either doxorubicin (60 mg/m(2)) plus cyclophosphamide (600 mg/m(2)) administered intravenously (IV) every 3 weeks or doxorubicin (60 mg/m(2)) plus docetaxel (75 mg/m(2)) IV every 3 weeks, followed by surgery on completion of chemotherapy. Results A total of 363 patients were randomly assigned to AC (n = 180) or AD (n = 183). A complete clinical response was observed in 17% and 20% of patients treated with AC and AD, respectively (P = .42). Overall (complete and partial) clinical response rates for AC and AD were 61% and 70%, respectively (P = .06). There was no significant difference in either the pathologic complete response rates in the breast with AC (24%) and AD (21%; P = .61) or in the number of patients with positive axillary nodes at surgery with AC (61%) and AD (66%; P = .28). At a median follow-up of 32 months, there is no significant difference between the two groups for the number of relapses. CONCLUSION In contrast to the positive results reported for sequential docetaxel after AC as primary chemotherapy of breast cancer, our data do not suggest a benefit for simultaneous AD over AC.

Allen SD, Garrett JT, Rawale SV, Jones AL, Phillips G, Forni G, Morris JC, Oshima RG, Kaumaya PT. · Ohio State Biochemistry Program, and Department of Obstetrics and Gynecology, The Ohio State University, Columbus, OH 43210, USA. · J Immunol. · Pubmed #17579068 links to  free full text

Abstract: Human epidermal growth factor receptor-2 (HER-2)/neu (ErbB2), a member of the epidermal growth factor family of receptors, is overexpressed in 20-30% of breast cancers. It is an attractive target for receptor-directed antitumor therapy using mAbs. Unlike other epidermal growth factor receptor family members, HER-2/neu does not bind a high-affinity ligand, but rather functions as the preferred dimerization partner. Pertuzumab (Omnitarg) is a humanized mAb directed against the HER-2/neu dimerization domain that inhibits receptor signaling. The recent definition of the crystal structure of the HER-2/neu-pertuzumab complex demonstrated that the receptor dimerization region encompassed residues 266-333. Based on the three-dimensional structure of the complex, we have designed three conformational peptide constructs (sequences 266-296, 298-333, and 315-333) to mimic regions of the dimerization loop of the receptor and to characterize their in vitro and in vivo antitumor efficacy. All the constructs elicited high-affinity peptide Abs that inhibited multiple signaling pathways including HER-2/neu-specific inhibition of cellular proliferation and cytoplasmic receptor domain phosphorylation. All the peptide Abs showed Ab-dependent cellular cytotoxicity to varying degrees with the 266-296 constructs being equally effective as compared with Herceptin. The 266-296 peptide vaccine had statistically reduced tumor onset in both transplantable tumor models (FVB/n and BALB/c) and significant reduction in tumor development in two transgenic mouse tumor models (BALB-neuT and VEGF(+/-)Neu2-5(+/-)). The 266-296 construct represents the most promising candidate for antitumor vaccination and could also be used to treat a variety of cancers with either normal or elevated expression of HER-2 including breast, lung, ovarian, and prostate.

Jones AL, Leyland-Jones B. · Royal Free Hospital, London, UK. · Semin Oncol. · Pubmed #15490372 No free full text.

Abstract: The primary goal of therapy for metastatic breast cancer is to improve the outcome for patients. Ideally, this should be achieved with minimal short-term side effects and without long-term irreversible toxicity. Trastuzumab (Herceptin; F. Hoffmann-La Roche, Basel, Switzerland) is proven to be efficacious in women with metastatic breast cancer who have HER2-positive disease. Data from pivotal clinical trials and postmarketing surveillance in women with metastatic breast cancer confirm that trastuzumab is also well tolerated with a low incidence of conventional chemotherapeutic side effects. Severe adverse events are confined to serious infusion-related reactions and cardiac issues, which are infrequent and readily managed. Patients at risk of these severe events can be identified before starting trastuzumab therapy. Ideally, treatment should also be convenient for the patient. This can be achieved through less frequent dosing. A 3-weekly trastuzumab schedule, with higher individual loading and maintenance doses than the conventional weekly schedule, has been investigated. This has similar efficacy, tolerability, and pharmacokinetics (exposure) to the weekly regimen, providing a convenient schedule.

Harms JF, Welch DR, Samant RS, Shevde LA, Miele ME, Babu GR, Goldberg SF, Gilman VR, Sosnowski DM, Campo DA, Gay CV, Budgeon LR, Mercer R, Jewell J, Mastro AM, Donahue HJ, Erin N, Debies MT, Meehan WJ, Jones AL, Mbalaviele G, Nickols A, Christensen ND, Melly R, Beck LN, Kent J, Rader RK, Kotyk JJ, Pagel MD, Westlin WF, Griggs DW. · Jake Gittlen Cancer Research Institute, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA. · Clin Exp Metastasis. · Pubmed #15168729 No free full text.

Abstract: INTRODUCTION: Breast cancer is one of the most common malignancies affecting women in the United States and Europe. Approximately three out of every four women with breast cancer develop metastases in bone which, in turn, diminishes quality of life. The alpha(v)beta3 integrin has previously been implicated in multiple aspects of tumor progression, metastasis and osteoclast bone resorption. Therefore, we hypothesized that the alpha(v)beta3-selective inhibitor, S247, would decrease the development of osteolytic breast cancer metastases. MATERIALS AND METHODS: Cells were treated in vitro with S247 and assessed for viability and adhesion to matrix components. Athymic mice received intracardiac (left ventricle) injections of human MDA-MB-435 breast carcinoma cells expressing enhanced green-fluorescent protein. Mice were treated with vehicle (saline) or S247 (1, 10, or 100 mg/kg/d) using osmotic pumps beginning either one week before or one week after tumor cell inoculation. Bones were removed and examined by fluorescence microscopy and histology. The location and size of metastases were recorded. RESULTS AND CONCLUSIONS: IC50 for S247 adhesion to alpha(v)beta3 or alpha(IIB)beta3a substrates was 0.2 nM vs. 244 nM, respectively. Likewise, S247 was not toxic at doses up to 1000 microM. However, osteoclast cultures treated with S247 exhibited marked morphological changes and impaired formation of the actin sealing zone. When S247 was administered prior to tumor cells, there was a significant, dose-dependent reduction (25-50% of vehicle-only-treated mice; P = 0.002) in osseous metastasis. Mice receiving S247 after tumor cell inoculation also developed fewer bone metastases, but the difference was not statistically significant. These data suggest that, in the MDA-MB-435 model, the alpha(v)beta3 integrin plays an important role in early events (e.g., arrest of tumor cells) in bone metastasis. Furthermore, the data suggest that alpha(v)beta3 inhibitors may be useful in the treatment and/or prevention of breast cancer metastases in bone.

Boudioni M, McPherson K, Mossman J, Boulton M, Jones AL, King J, Wilson E, Slevin ML. · CancerBACUP, London, UK. · Br J Cancer. · Pubmed #10408705 No free full text.

Abstract: A retrospective comparison of cancer incidence data and, where relevant, population data with 16,955 first-time users (patients, relatives and friends) of a national cancer information service (CancerBACUP) during the period April 1995 to March 1996 is presented. The number of events observed was compared with the number of events expected, were the national rates of cancer incidence and population demographics apply. Standardized incidence ratios (SIRs) (observed - expected ratios) were used to indicate any differences. Statistically significant differences (P < 0.001) in the observed and expected sex, age and primary site distribution of patients enquired about were found. Statistically significant differences (P < 0.001) were also identified for the age, employment status, socioeconomic class and geographical location of first-time enquirers (patients, relatives and friends). Enquiries about brain, testis and breast cancers and non-Hodgkin's lymphoma (NHL) were substantially higher than expected; enquiries about bladder, lung, stomach and colorectal cancers were much lower than expected. As the service is provided via a freephone number, it is available to all, and users might be expected to be randomly distributed across the variables listed. The underlying reasons for the differences identified need to be investigated, and the role of information in the care of cancer patients should be formally evaluated.