Geoffrey Beadle

Prognostic value of quality of life scores in a trial of chemotherapy with or without interferon in patients with metastatic malignant melanoma

In a multi-centre randomised clinical trial comparing dacarbazine (DTIC) plus recombinant interferon-alfa2a (IFN) versus DTIC alone for patients with metastatic malignant melanoma, aspects of quality of life (QL) were measured prospectively by patients using linear analogue self assessment (LASA) scales including the GLQ-8 and by doctors using Spitzers QL Index. QL scores and performance status at the time of randomisation were available for 152 of 170 eligible patients. These scores carried significant prognostic information. In univariate analyses, Spitzer QL Index assessed by the doctor and LASA scores for physical wellbeing (PWB), mood, pain, appetite, nausea and vomiting, GLQ-8 total and overall QL were significant (P < 0.01) predictors of subsequent survival. QL Index and LASA scales for mood, appetite, and overall QL remained independently significant (all P < 0.05) in multivariate models allowing for significant prognostic factors other than QL (liver metastases and performance status). These findings closely parallel those in patients with metastatic breast cancer. They add further validity to the QL Index and LASA scores, provide the first evidence of the prognostic significance of the GLQ-8, and argue strongly for the routine assessment of QL in future therapy trials.

Bright-field in situ hybridization for HER2 gene amplification in breast cancer using tissue microarrays: correlation between chromogenic (CISH) and automated silver-enhanced (SISH) methods with patient outcome.

HER2 gene amplification or overexpression occurs in 15% to 25% of breast cancers and has implications for treatment and prognosis. The most commonly used methods for HER2 testing are fluorescence in situ hybridization (FISH) and immunohistochemistry. FISH is considered to be the reference standard and more accurately predicts response to trastuzumab, but is technically demanding, expensive, and requires specialized equipment. In situ hybridization is required to be eligible for adjuvant treatment with trastuzumab in Australia. Bright-field in situ hybridization is an alternative to FISH and uses a combination of in situ methodology and a peroxidase-mediated chromogenic substrate such as diaminobenzidine [chromogenic in situ hybridization (CISH)] or multimer technology coupled with enzyme metallography [silver-enhanced in situ hybridization (SISH)] to create a marker visible under bright-field microscopy. CISH was introduced into diagnostic testing in Australia in October 2006. SISH methodology is a more recent introduction into the testing repertoire. An evaluation of CISH and SISH performance to assess patient outcome were performed using tissue microarrays. Tissue microarrays were constructed in duplicate using material from 593 patients with invasive breast carcinoma and assessed using CISH and SISH. Gene amplification was assessed using the American Society of Clinical Oncology/College of American Pathologists guideline and Australian HER2 Advisory Board criteria (single probe: diploid, 1 to 2.5 copies/nucleus; polysomy >2.5 to 4 copies/nucleus; equivocal, >4 to 6 copies/nucleus; low-level amplification, >6 to 10 copies/nucleus and high-level amplification >10 copies/nucleus; dual probe HER2/CHR17 ratio: nonamplified 2.2). Results were informative for 337 tissue cores comprising 230 patient samples. Concordance rates were 96% for HER2 single probe CISH and SISH and 95.5% for single probe CISH and dual probe HER2/CHR17 SISH. Both bright-field methods correlated with immunohistochemistry results and with breast cancer-specific survival. HER2 SISH testing combines the advantages of automation and bright-field microscopy to facilitate workflow within the laboratory, improves turnaround time, and correlates with patient outcome.Introduction HER2 gene amplification or overexpression occurs in 15% to 25% of breast cancers and has implications for treatment and prognosis. The most commonly used methods for HER2 testing are fluorescence in situ hybridization (FISH) and immunohistochemistry. FISH is considered to be the reference standard and more accurately predicts response to trastuzumab, but is technically demanding, expensive, and requires specialized equipment. In situ hybridization is required to be eligible for adjuvant treatment with trastuzumab in Australia. Bright-field in situ hybridization is an alternative to FISH and uses a combination of in situ methodology and a peroxidase-mediated chromogenic substrate such as diaminobenzidine [chromogenic in situ hybridization (CISH)] or multimer technology coupled with enzyme metallography [silver-enhanced in situ hybridization (SISH)] to create a marker visible under bright-field microscopy. CISH was introduced into diagnostic testing in Australia in October 2006. SISH methodology is a more recent introduction into the testing repertoire. An evaluation of CISH and SISH performance to assess patient outcome were performed using tissue microarrays. Materials and Methods Tissue microarrays were constructed in duplicate using material from 593 patients with invasive breast carcinoma and assessed using CISH and SISH. Gene amplification was assessed using the American Society of Clinical Oncology/College of American Pathologists guideline and Australian HER2 Advisory Board criteria (single probe: diploid, 1 to 2.5 copies/nucleus; polysomy >2.5 to 4 copies/nucleus; equivocal, >4 to 6 copies/nucleus; low-level amplification, >6 to 10 copies/nucleus and high-level amplification >10 copies/nucleus; dual probe HER2/CHR17 ratio: nonamplified <1.8, equivocal 1.8 to 2.2, amplified >2.2). Results Results were informative for 337 tissue cores comprising 230 patient samples. Concordance rates were 96% for HER2 single probe CISH and SISH and 95.5% for single probe CISH and dual probe HER2/CHR17 SISH. Both bright-field methods correlated with immunohistochemistry results and with breast cancer-specific survival. Conclusions HER2 SISH testing combines the advantages of automation and bright-field microscopy to facilitate workflow within the laboratory, improves turnaround time, and correlates with patient outcome.

Evaluation of oestrogen and progesterone receptor status in HER‐2 positive breast carcinomas and correlation with outcome

Aim: HER‐2/neu amplification occurs in 15–25% of breast carcinomas. This oncogene, also referred to as c‐erbB‐2, encodes a transmembrane tyrosine kinase receptor belonging to the epidermal growth factor receptor family. HER‐2 over‐expression is reported to be associated with a poor prognosis in breast carcinoma patients and in some studies is associated with a poorer response to anti‐oestrogen therapy. These patients are less likely to benefit from CMF (cyclophosphamide, methotrexate, fluorouracil)‐based chemotherapy compared with anthracycline‐based chemotherapy. The aim of this study was to evaluate breast carcinomas to determine hormone receptor status and if there is a difference in breast cancer specific survival for HER‐2 positive patients. Methods: A total of 591 breast carcinomas were evaluated using immunohistochemistry (IHC) for oestrogen receptor (ERp), progesterone receptor (PRp) and three different HER‐2 antibodies (CB11, A0485 and TAB250). Percentage of tumour cells and intensity of staining for ERp were evaluated using a semiquantitative method. Results: Of the 591 tumours, 91 (15.4%) showed 3+ membrane staining for HER‐2 with one or more antibodies. Of these 91 tumours, 41 (45.1%) were ERp+/PRp+, seven (7.7%) were ERp+/PR–, six (6.6%) were ERp–/PRp+ and 37 (40.7%) were ERp–/PR–. Of HER‐2 positive tumours, 5.5% showed >80% 3+ staining for ERp compared with 31.8% of 0–2+ HER‐2 tumours; 24.2% of HER‐2‐positive tumours showed 60% or more cells with 2+ or 3+ staining for ERp. Treatment data were available for 209 patients and no difference was observed in breast cancer specific survival (BCSS) with HER‐2 status and tamoxifen. Conclusion: Oestrogen receptor status cannot be used to select tumours for evaluation of HER‐2 status, and oestrogen and progesterone receptor positivity does not preclude a positive HER‐2 status. There is a higher proportion of ERp negative tumours associated with HER‐2 positivity, however, more than 20% of HER‐2 positive tumours show moderate or strong staining for ERp. HER‐2 positive patients in this study did not show an adverse BCSS with tamoxifen treatment unlike some previous studies.

Acute myeloid leukemia after breast cancer: a population-based comparison with hematological malignancies and other cancers

BACKGROUND Clinical trials frequently report acute myeloid leukemia (AML) as a complication of adjuvant chemotherapy for breast cancer (BC). PATIENTS AND METHODS This retrospective population-based study investigated AML risk after a prior BC diagnosis and compared the results with women after a prior diagnosis of hematological malignancies (HM), other cancers combined (OCC), and the age-matched Australian female population. RESULTS Women with a prior BC diagnosis had 2.56 times the risk of developing AML compared with the Australian female population (P<0.001). AML risk was also elevated after prior HM and OCC diagnoses (4.73, P<0.001, and 1.70, P<0.001, respectively). Although the incidence of AML rose sharply with age in all cohorts, the age-specific relative risk was highest in the 30- to 49-age-group and decreased with increasing age. AML risk increased with the duration of follow-up but there was no change of risk during the 23 years of this study. CONCLUSION AML risk was elevated after a prior diagnosis of BC but there was no evidence of an increasing risk of AML after a BC diagnosis or, in any of the other cancer cohorts, during this era of expansion of the evidence base for more intensive treatments.

Cognitive effects of chemotherapy-induced menopause in breast cancer

This study examined whether chemotherapy-induced menopause affects cognitive functioning in women with early breast cancer. The neuropsychological performance of 121 breast cancer patients (age M = 49.62, SD = 8.11, range = 25.25–67.92) treated with chemotherapy was assessed pre-chemotherapy, as well as 1, 6, and 18 months post-chemotherapy completion. Linear mixed modeling was used to evaluate the data. Type of menopause (pre, chemotherapy-induced, and post menopause) was found to significantly interact with cognitive performance on two cognitive variables. Specifically, chemotherapy-induced menopausal women did not show any significant changes in performance on an abstract reasoning task, while the pre-menopausal and post-menopausal groups significantly improved over time. A significant interaction on a test of finger dexterity and coordination was also found, although inspection of the results indicated that this was due to a significant improvement in the pre-menopausal groups at 6 months post chemotherapy. After chemotherapy most cognitive variables showed improvements over time, although two indicators of verbal memory showed significant declines immediately after chemotherapy, with improvement by 18 months post completion. The current study found little evidence to suggest that chemotherapy-induced menopause broadly affects cognitive functioning after treatment administration. However, longer follow-up assessments are warranted to assess the long-term effects of combined chemotherapy and endocrine treatment.

Differential subcellular and extracellular localisations of proteins required for insulin-like growth factor- and extracellular matrix-induced signalling events in breast cancer progression

BackgroundCancer metastasis is the main contributor to breast cancer fatalities as women with the metastatic disease have poorer survival outcomes than women with localised breast cancers. There is an urgent need to develop appropriate prognostic methods to stratify patients based on the propensities of their cancers to metastasise. The insulin-like growth factor (IGF)-I: IGF binding protein (IGFBP):vitronectin complexes have been shown to stimulate changes in gene expression favouring increased breast cancer cell survival and a migratory phenotype. We therefore investigated the prognostic potential of these IGF- and extracellular matrix (ECM) interaction-induced proteins in the early identification of breast cancers with a propensity to metastasise using patient-derived tissue microarrays.MethodsSemiquantitative immunohistochemistry analyses were performed to compare the extracellular and subcellular distribution of IGF- and ECM-induced signalling proteins among matched normal, primary cancer and metastatic cancer formalin-fixed paraffin-embedded breast tissue samples.ResultsThe IGF- and ECM-induced signalling proteins were differentially expressed between subcellular and extracellular localisations. Vitronectin and IGFBP-5 immunoreactivity was lower while β1 integrin immunoreactivity was higher in the stroma surrounding metastatic cancer tissues, as compared to normal breast and primary cancer stromal tissues. Similarly, immunoreactive stratifin was found to be increased in the stroma of primary as well as metastatic breast tissues. Immunoreactive fibronectin and β1 integrin was found to be highly expressed at the leading edge of tumours. Based on the immunoreactivity it was apparent that the cell signalling proteins AKT1 and ERK1/2 shuffled from the nucleus to the cytoplasm with tumour progression.ConclusionThis is the first in-depth, compartmentalised analysis of the distribution of IGF- and ECM-induced signalling proteins in metastatic breast cancers. This study has provided insights into the changing pattern of cellular localisation and expression of IGF- and ECM-induced signalling proteins in different stages of breast cancer. The differential distribution of these biomarkers could provide important prognostic and predictive indicators that may assist the clinical management of breast disease, namely in the early identification of cancers with a propensity to metastasise, and/or recur following adjuvant therapy.

Effect of age at diagnosis of breast cancer on the patterns and risk of mortality from all causes: a population-based study in Australia.

This retrospective, population‐based study investigated the patterns and risks of mortality from breast cancer, other cancers and non‐cancer causes according to the age at diagnosis of breast cancer.

Latent class piecewise linear trajectory modelling for short-term cognition responses after chemotherapy for breast cancer patients

This paper investigates the impact of chemotherapy on cognitive function of breast cancer patients and whether this response is homogeneous for all patients. Latent class piecewise linear trajectory (growth) models were employed to describe changes and identify subgroups in three Auditory Verbal Learning Test measures (learning, immediate retention and delayed recall) in 130 breast cancer patients taken at three time periods: before chemotherapy and 1 and 6 months post-chemotherapy. Two distinct subgroups of women exhibiting different patterns of response were identified for learning and delayed recall and three for immediate retention. The groups differed in level (intercept) at 1 month post-chemotherapy and patterns of decline and recovery. Binomial and multinomial logistic regressions on the latent classes found that age, initial National Adult Reading Test (NART)-predicted IQ, stage of cancer and the initial Functional Assessment of Cancer Therapy-Breast subscale (or subsets thereof) to be significant predictors of classes.

Memory loss after adjuvant chemotherapy for breast cancer: a preliminary analysis of mediating variables utilizing cross-sectional correlations and multilevel longitudinal analysis

General Sessions [#11-82] S5–S23 Poster Discussion Sessions [#101-511] S24–S40 Poster Session I [#1001-1119] S41–S83 Poster Session II [#2001-2121] S84–S125 Poster Session III [#3001-3113] S126–S165 Poster Session IV [#4001-4117] S166–S206 Poster Session V [#5001-5119 (excl. 5015)] S207–S246 Poster Session VI [#6001-6119 plus 5015] S247–S287 Author index for abstracts S288–S302