Microarray-based comparative genomic hybridisation of breast cancer patients receiving neoadjuvant chemotherapy

We analysed the molecular genetic profiles of breast cancer samples before and after neoadjuvant chemotherapy with combination doxorubicin and cyclophosphamide (AC). DNA was obtained from microdissected frozen breast core biopsies from 44 patients before chemotherapy. Additional samples were obtained before the second course of chemotherapy (D21) and after the completion of the treatment (surgical specimens) in 17 and 21 patients, respectively. Microarray-based comparative genome hybridisation was performed using a platform containing approx5800 bacterial artificial chromosome clones (genome-wide resolution: 0.9 Mb). Analysis of the 44 pretreatment biopsies revealed that losses of 4p, 4q, 5q, 12q13.11–12q13.12, 17p11.2 and 17q11.2; and gains of 1p, 2p, 7q, 9p, 11q, 19p and 19q were significantly associated with oestrogen receptor negativity. 16q21–q22.1 losses were associated with lobular and 8q24 gains with ductal types. Losses of 5q33.3–q4 and 18p11.31 and gains of 6p25.1–p25.2 and Xp11.4 were associated with HER2 amplification. No correlations between DNA copy number changes and clinical response to AC were found. Microarray-based comparative genome hybridisation analysis of matched pretreatment and D21 biopsies failed to identify statistically significant differences, whereas a comparison between matched pretreatment and surgical samples revealed a statistically significant acquired copy number gain on 11p15.2–11p15.5. The modest chemotherapy-driven genomic changes, despite profound loss of cell numbers, suggest that there is little therapeutic selection of resistant non-modal cell lineages.

Progressive resistance training and stretching following surgery for breast cancer: study protocol for a randomised controlled trial

Background: Currently 1 in 11 women over the age of 60 in Australia are diagnosed with breast cancer. Following treatment, most breast cancer patients are left with shoulder and arm impairments which can impact significantly on quality of life and interfere substantially with activities of daily living. The primary aim of the proposed study is to determine whether upper limb impairments can be prevented by undertaking an exercise program of prolonged stretching and resistance training, commencing soon after surgery. Methods/design: We will recruit 180 women who have had surgery for early stage breast cancer to a multicenter single-blind randomized controlled trial. At 4 weeks post surgery, women will be randomly assigned to either an exercise group or a usual care ( control) group. Women allocated to the exercise group will perform exercises daily, and will be supervised once a week for 8 weeks. At the end of the 8 weeks, women will be given a home-based training program to continue indefinitely. Women in the usual care group will receive the same care as is now typically provided, i.e. a visit by the physiotherapist and occupational therapist while an inpatient, and receipt of pamphlets. All subjects will be assessed at baseline, 8 weeks, and 6 months later. The primary measure is arm symptoms, derived from a breast cancer specific questionnaire (BR23). In addition, range of motion, strength, swelling, pain and quality of life will be assessed. Discussion: This study will determine whether exercise commencing soon after surgery can prevent secondary problems associated with treatment of breast cancer, and will thus provide the basis for successful rehabilitation and reduction in ongoing problems and health care use. Additionally, it will identify whether strengthening exercises reduce the incidence of arm swelling. Trial Registration: The protocol for this study is registered with the Australian Clinical Trials Registry (ACTRN012606000050550).

Prediction of BRCA1 status in patients with breast cancer using estrogen receptor and basal phenotype

Purpose: To investigate the proportion of breast cancers arising inpatients with germ line BRCA1 and BRCA2 mutations expressing basal markers and developing predictive tests for identification of high-risk patients. Experimental Design: Histopathologic material from 182 tumors in BRCA1 mutation carriers, 63 BRCA2 carriers, and 109 controls, collected as part of the international Breast Cancer Linkage Consortium were immunohistochemically stained for CK14, CK5/6, CK17, epidermal growth factor receptor (EGFR), and osteonectin. Results: All five basal markers were commoner in BRCA1 tumors than in control tumors (CK14: 61% versus 12%; CK5/6: 58% versus 7%; CK17: 53% versus 10%; osteonectin: 43% versus 19%; EGFR: 67% versus 21%; P < 0.0001 in each case). In a multivariate analysis, CK14, CK5/6, and estrogen receptor (ER) remained significant predictors of BRCA1 carrier status. In contrast, the frequency of basal markers in BRCA2 tumors did not differ significant from controls. Conclusion: The use of cytokeratin staining in combination with ER and morphology provides a more accurate predictor of BRCA1 mutation status than previously available, that may be useful in selecting patients for BRCA1 mutation testing. The high percentage of BRCA1 cases positive for EGFR suggests that specific anti-tyrosine kinase therapy may be of potential benefit in these patients.

Morphology of breast cancer as a means of triage of patients for BRCA1 genetic testing

Background: Women who have germline mutations in the BRCA1 gene are at substantially increased lifetime risk of developing breast and ovarian cancer but are otherwise normal. Currently. early age of onset of cancer and a strong family history are relied upon as the chief clues as to who should be offered genetic testing. Certain morphologic and immunohistochemical features are overrepresented in BRCA1-associated breast cancers but these differences have not been incorporated into the current selection criteria for genetic testing. Design: Each of the 4 pathologists studied 30 known cases of BRCA1- and BRCA2-associated breast cancer from kConFab families. After reviewing the literature, we agreed on a semiquantitative scoring system for estimating the chances of presence of an underlying BRCA1 mutation, based on the number of the reported prototypic features present. After a time lag of 12 months, we each examined a series of 62 deidentified cases of breast cancer, inclusive of cases of BRCA1-associated breast cancer and controls. The controls included cases of BRCA2-associated breast cancer and sporadic cases. Results: Our predictions had a sensitivity of 92%, specificity of 86%, positive predictive value of 61%, and negative predictive value of 98%. For comparison the sensitivity of currently used selection criteria are in the range of 25% to 30%. Conclusion: The inclusion of morphologic and immunohistochemical features of breast cancers in algorithms to predict the likelihood of presence of germline mutations in the BRCA1 gene improves the accuracy of the selection process.

Sentinel node biopsy for breast cancer: Using local results for estimation of risk to the patient

Background: Sentinel node biopsy (SNB) is being increasingly used but its place outside randomized trials has not yet been established. Methods: The first 114 sentinel node (SN) biopsies performed for breast cancer at the Princess Alexandra Hospital from March 1999 to June 2001 are presented. In 111 cases axillary dissection was also performed, allowing the accuracy of the technique to be assessed. A standard combination of preoperative lymphoscintigraphy, intraoperative gamma probe and injection of blue dye was used in most cases. Results are discussed in relation to the risk and potential consequences of understaging. Results: Where both probe and dye were used, the SN was identified in 90% of patients. A significant number of patients were treated in two stages and the technique was no less effective in patients who had SNB performed at a second operation after the primary tumour had already been removed. The interval from radioisotope injection to operation was very wide (between 2 and 22 h) and did not affect the outcome. Nodal metastases were present in 42 patients in whom an SN was found, and in 40 of these the SN was positive, giving a false negative rate of 4.8% (2/42), with the overall percentage of patients understaged being 2%. For this particular group as a whole, the increased risk of death due to systemic therapy being withheld as a consequence of understaging (if SNB alone had been employed) is estimated at less than 1/500. The risk for individuals will vary depending on other features of the particular primary tumour. Conclusion: For patients who elect to have the axilla staged using SNB alone, the risk and consequences of understaging need to be discussed. These risks can be estimated by allowing for the specific surgeon's false negative rate for the technique, and considering the likelihood of nodal metastases for a given tumour. There appears to be no disadvantage with performing SNB at a second operation after the primary tumour has already been removed. Clearly, for a large number of patients, SNB alone will be safe, but ideally participation in randomized trials should continue to be encouraged.

Assessing the support needs of women with early breast cancer in Australia

The purpose of the current study was to access the degree to which the support needs of women with a newly diagnosed, early invasive, primary breast cancer and their families are being met. A random sample of 544 women diagnosed with early breast cancer was recruited to participate in a telephone survey via state and territory cancer registries. Sixteen percent of women reported not receiving enough support during their diagnosis and treatment, and only 65% of these women reported that their families received enough support. The primary sources of support for women and their families were medical practitioners (eg, surgeons, oncologists, and general practitioner) with very few women or family members utilizing mental health professionals. Given the importance of adequate support when being diagnosed and treated for breast cancer, urgent attention needs to be paid to training medical professionals in providing appropriate support and referrals for their patients.

Columnar cell lesions of the breast: The missing link in breast cancer progression? A morphological and molecular analysis

Columnar cell lesions (CCLs) of the breast are a spectrum of lesions that have posed difficulties to pathologists for many years, prompting discussion concerning their biologic and clinical significance. We present a study of CCL in context with hyperplasia of usual type (HUT) and the more advanced lesions ductal carcinoma in situ (DCIS) and invasive ductal carcinoma. A total of 81 lesions from 18 patients were subjected to a comprehensive morphologic review based upon a modified version of Schnitt's classification system for CCL, immunophenotypic analysis (estrogen receptor [ER], progesterone receptor [PgR], Her2/neu, cytokeratin 5/6 [CK5/6], cytokeratin 14 [CK14], E-cadherin, p53) and for the first time, a whole genome molecular analysis by comparative genomic hybridization. Multiple CCLs from 3 patients were studied in particular detail, with topographic information and/or showing a morphologic spectrum of CCL within individual terminal duct lobular units. CCLs were ER an PgR positive, CK5/6 and CK14 negative, exhibit low numbers of genetic alterations and recurrent 16q loss, features that are similar to those of low grade in situ and invasive carcinoma. The molecular genetic profiles closely reflect the degree of proliferation and atypia in CCL, indicating some of these lesions represent both a morphologic and molecular continuum. In addition, overlapping chromosomal alterations between CCL and more advanced lesions within individual terminal duct lobular units suggest a commonality in molecular evolution. These data further support the hypothesis that CCLs are a nonobligate, intermediary step in the development of some forms of low grade in situ and invasive carcinoma. Copyright: © 2005 Lippincott Williams & Wilkins, Inc.

Randomized controlled trial of an educational intervention for managing fatigue in women receiving adjuvant chemotherapy for early-stage breast cancer

Purpose To evaluate the efficacy of a psychoeducational intervention in improving cancer-related fatigue. Patients and Methods This randomized controlled trial involved 109 women commencing adjuvant chemotherapy for stage I or II breast cancer in five chemotherapy treatment centers. Intervention group patients received an individualized fatigue education and support program delivered in the clinic and by phone over three 10- to 20-minute sessions 1 week apart. Instruments included a numeric rating scale assessing confidence with managing fatigue; 11-point numeric rating scales measuring fatigue at worst, average, and best; the Functional Assessment of Cancer Therapy-Fatigue and Piper Fatigue Scales; the Cancer Self-Efficacy Scale; the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30; and the Hospital Anxiety and Depression Scale. For each outcome, separate analyses of covariance of change scores between baseline (T1) and the three follow-up time points (T2, T3, and T4) were conducted, controlling for the variable's corresponding baseline value. Results Compared with the intervention group, mean difference scores between the baseline (T1) and immediate after the test (T2) assessments increased significantly more for the control group for worst and average fatigue, Functional Assessment of Cancer Therapy-Fatigue, and Piper fatigue severity and interference measures. These differences were not observed between baseline and T3 and T4 assessments. No significant differences were identified for any pre- or post-test change scores for confidence with managing fatigue, cancer self-efficacy, anxiety, depression, or quality of life. Conclusion Preparatory education and support has the potential to assist women to cope with cancer-related fatigue in the short term. However, further research is needed to identify ways to improve the potency and sustainability of psychoeducational interventions for managing cancer-related fatigue.

How to recognize and manage psychological distress in cancer patients

Psychological distress is common in cancer patients, however, it is often unrecognized and untreated. We aimed to identify barriers to cancer patients expressing their psychological concerns, and to recommend strategies to assist oncologists to elicit, recognize, and manage psychological distress in their patients. Medline, Psychlit, and the Cochrane databases were searched for articles relating to the detection of emotional distress in patients. Patients can provide verbal and non-verbal information about their emotional state. However, many patients may not reveal emotional issues as they believe it is not a doctor's role to help with their emotional concerns. Moreover, patients may normalize or somatize their feelings. Anxiety and depression can mimic physical symptoms of cancer or treatments, and consequently emotional distress may not be detected. Techniques such as active listening, using open questions and emotional words, responding appropriately to patients' emotional cues, and a patient-centred consulting style can assist in detection. Screening tools for psychological distress and patient question prompt sheets administered prior to the consultation can also be useful. In conclusion, the application of basic communication techniques enhances detection of patients' emotional concerns. Training oncologists in these techniques should improve the psychosocial care of cancer patients.

Information giving and decision-making in patients with advanced cancer: A systematic review

Patients with advanced, non-curable cancer face difficult decisions on further treatment, where a small increase in survival time must be balanced against: the toxicity of the treatment. If patients want to be involved in these decisions, in keeping with current notions of autonomy and empowerment, they also require to be adequately informed both on the treatments proposed and on their own disease status and prognosis. A systematic review was performed on decision-making and information provision in patients with advanced cancer. Studies of interventions to improve information giving and encourage participation in decision-making were reviewed, including both randomised controlled trials and uncontrolled studies. Almost all patients expressed a desire for full information, but only about two-thirds wished to participate actively in decision-making. Higher educational level, younger age and female sex were predictive of a desire to participate in decision-making. Active decision-making was more common in patients with certain cancers (e.g. breast) than others (e.g. prostate). A number of simple interventions including question prompt sheets, audio-taping of consultations and patient decision aids have been shown to facilitate such involvement. (c) 2005 Elsevier Ltd. All rights reserved.