Zealand Breast Cancer Trials Group Research Articles

Abstract P1-12-05: Aromatase inhibitor induced musculoskeletal syndrome (AIMSS) in Australian women with early breast cancer: An Australia and New Zealand Breast Cancer Trials Group (ANZBCTG) survey of members of the Breast Cancer Network Australia (BCNA)

Abstract Background: AIMSS is experienced by approximately half of women taking an aromatase inhibitor (AI), impairing quality of life and in some leading to AI discontinuation. There is a lack of evidence for effective AIMSS treatments. Aim: To investigate the importance of AIMSS in Australian women with early breast cancer. Method: A survey invitation was distributed to 2390 members of the BCNA Review and Survey Group in April 2014. The online questionnaire consisted of 45 questions covering demographics, AI use, clinical manifestations and risk factors for AIMSS, reasons for AI discontinuation and efficacy of interventions used for AIMSS. AIMSS was defined as joint pain or stiffness that developed or worsened after commencing an AI. Results: Of 594 respondents, 370 (62%) were eligible. Reasons for exclusion were: preinvasive disease, locally advanced/metastatic breast cancer, or other reason. Eligible respondents had a median age range of 50-59 years. Duration of AI use varied (26%1year, 64% 1-5years, 10% 5years). 57% had received adjuvant chemotherapy. 43% of these commenced AI within 3 months of chemotherapy and 30% within 3-6 months of chemotherapy. A vitamin D test was performed in 64% of women and 68% were currently using vitamin D supplements. Joint pain during menopause was reported by 22% of respondents. AIMSS occurred in 302/370 women (81%). Of those who developed AIMSS, sites affected were feet (68%), hands or wrists (65%), knees (62%), hips (56%), shoulders or elbows (49%), back (46%), or neck (3%). 34% of women had considered stopping an AI because of AIMSS. 99 (27%) of respondents had discontinued AI for any reason and of these 68% discontinued because of AIMSS. Non-AIMSS symptoms identified as reasons for discontinuation included fatigue, vaginal/urinary symptoms and hot flushes. In respondents who discontinued AI, 20% ceased use in the first 3 months, 30% during months 3-12 and 38%12 months. 42% of respondents who discontinued an AI restarted the same or a different AI after a treatment break. To manage AIMSS 23% of respondents used doctor prescribed medications (eg anti-inflammatories, codeine, morphine,), 55% over the counter (OTC) or complementary medicines (eg low dose anti-inflammatories, paracetamol, chondroitin, fish or krill oil, glucosamine, and vitamin D) and 29% alternative therapies (eg acupuncture, massage, Tai Chi and yoga). Respondents identified the following in each of the above categories as most successful in relieving AIMSS symptoms: doctor prescribed anti-inflammatories, paracetamol and yoga. Doctor prescribed medications and OTC/complementary medicine either completely or significantly relieved AIMSS in 12% and 25% of cases respectively. 27% of respondents found that one or more of the interventions that they had used to manage AIMSS helped prevent AI discontinuation. Conclusion: AIMSS is a significant issue for Australian women and is an important reason for AI discontinuation. Women use a number of interventions to manage AIMSS, however their efficacy appears limited. Effective AIMSS interventions are needed, to improve quality of life and reduce AI discontinuation. Citation Format: Janine M Lombard, Nicholas Zdenkowski, Kathy Wells, Nicca Grant, Linda Reaby, John F Forbes, Jacquie Chirgwin. Aromatase inhibitor induced musculoskeletal syndrome (AIMSS) in Australian women with early breast cancer: An Australia and New Zealand Breast Cancer Trials Group (ANZBCTG) survey of members of the Breast Cancer Network Australia (BCNA) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-12-05.

P199 Neoadjuvant systemic therapy for breast cancer: a survey of Australian and New Zealand specialists

P199 Neoadjuvant systemic therapy for breast cancer: a survey of Australian and New Zealand specialists N. Zdenkowski *, P. Butow, G.B. Mann, S. Fewster, C. Beckmore, R. Isaacs, F.M. Boyle. Trials Coordination Department, Australia and New Zealand Breast Cancer Trials Group, Waratah, Australia, University of Sydney, Sydney, Australia, University of Melbourne, Melbourne, Australia, MidCentral Regional Cancer Treatment Service, Palmerston North, New Zealand

Chemotherapy for isolated locoregional recurrence of breast cancer (CALOR): a randomised trial

Patients with isolated locoregional recurrences (ILRR) of breast cancer have a high risk of distant metastasis and death from breast cancer. We aimed to establish whether adjuvant chemotherapy improves the outcome of such patients. The CALOR trial was a pragmatic, open-label, randomised trial that accrued patients with histologically proven and completely excised ILRR after unilateral breast cancer who had undergone a mastectomy or lumpectomy with clear surgical margins. Eligible patients were enrolled from hospitals worldwide and were centrally randomised (1:1) to chemotherapy (type selected by the investigator; multidrug for at least four courses recommended) or no chemotherapy, using permuted blocks, and stratified by previous chemotherapy, oestrogen-receptor and progesterone-receptor status, and location of ILRR. Patients with oestrogen-receptor-positive ILRR received adjuvant endocrine therapy, radiation therapy was mandated for patients with microscopically involved surgical margins, and anti-HER2 therapy was optional. The primary endpoint was disease-free survival. All analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00074152. From Aug 22, 2003, to Jan 31, 2010, 85 patients were randomly assigned to receive chemotherapy and 77 were assigned to no chemotherapy. At a median follow-up of 4·9 years (IQR 3·6-6 ·0), 24 (28%) patients had disease-free survival events in the chemotherapy group compared with 34 (44%) in the no chemotherapy group. 5-year disease-free survival was 69% (95% CI 56-79) with chemotherapy versus 57% (44-67) without chemotherapy (hazard ratio 0·59 [95% CI 0·35-0·99]; p=0·046). Adjuvant chemotherapy was significantly more effective for women with oestrogen-receptor-negative ILRR (pinteraction=0·046), but analyses of disease-free survival according to the oestrogen-receptor status of the primary tumour were not statistically significant (pinteraction=0·43). Of the 81 patients who received chemotherapy, 12 (15%) had serious adverse events. The most common adverse events were neutropenia, febrile neutropenia, and intestinal infection. Adjuvant chemotherapy should be recommended for patients with completely resected ILRR of breast cancer, especially if the recurrence is oestrogen-receptor negative. US Department of Health and Human Services, Swiss Group for Clinical Cancer Research (SAKK), Frontier Science and Technology Research Foundation, Australian and New Zealand Breast Cancer Trials Group, Swedish Cancer Society, Oncosuisse, Cancer Association of South Africa, Foundation for Clinical Research of Eastern Switzerland (OSKK), Grupo Español de Investigación en Cáncer de Mama (GEICAM), and the Dutch Breast Cancer Trialists' Group (BOOG).

Australia and New Zealand Breast Cancer Trials Group Annual Scientific Meeting

The annual scientific meeting of the Australia and New Zealand Breast Cancer Trials Group is structured to include a combination of ‘working meetings’, including workshops open to all members (this year on local therapy trial proposals and supportive care proposals), then a half day review and report on all currently open trials that involve the group. This is followed by one and a half days of scientific sessions reviewing basic biology relevant to clinical trial design, clinical reviews of recent data, and early reports of trial proposals. The program ranges from prevention to metastatic disease, with an emphasis on multidisciplinary care and specific sessions on local therapy, systemic therapy and supportive care.

ANZ1001 SORBET: Study of estrogen receptor beta and efficacy of tamoxifen, a single arm, phase II study of the efficacy of tamoxifen in triple-negative but estrogen receptor beta-positive metastatic breast cancer.

TPS1136 Background: Targeted therapies are needed for triple negative breast cancer (BC). ERβ is expressed in at least 20% of triple negative BCs. ERβ binds estrogen and tamoxifen with a similar affinity to ERα. ERβ has 5 isoforms but only ERβ1 is fully functional. ERβ expression has been shown to be significantly associated with improved distant disease free survival and better overall survival in tamoxifen treated ERα negative patients in retrospective studies. This “proof of principle” study will determine the efficacy of tamoxifen in patients with triple negative but ERβ positive metastatic BC. Methods: This single arm phase II study, being conducted by the Australia and New Zealand Breast Cancer Trials Group, has a Simon's 2 stage optimal design. The primary end-point is objective response rate (complete and partial responses). Progression free survival and clinical benefit rate will also be assessed. Eligibility criteria include histologically or cytologically confirmed metastatic triple negative BC (ER and PR absent, HER2 ISH negative or IHC 0 or 1) and measureable disease as per RECIST 1.1. Consenting patients undergo central ERβ testing and confirmation of triple negative status on a metastatic biopsy sample. ERβ positive patients (ERβ1 nuclear staining with Allred score >4) are offered trial participation. To date 12 potentially eligible patients have been screened for ERβ; 4 had Allred score >4 (although 2 of these subsequently proved to be ineligible for the trial), 7 had Allred scores <4 and 1 result is pending. Consenting patients receive tamoxifen 20mg per oral daily until disease progression, unacceptable toxicity or withdrawal of consent. If there are ≥2 responses in the first stage of 28 patients, an additional 38 patients will be accrued. Tamoxifen will be considered worthy of further research if there are ≥6 responses in the total 66 patients recruited. Current accrual is 1. Registered on ANZCTR (12610000506099).

Cancer drugs in the real world

Cancer drugs in the real world

Australian New Zealand Breast Cancer Trials Group (ANZ BCTG)

This section provides current contact details and a list of recent or ongoing clinical trials that the Australian New Zealand Breast Cancer Trials Group(ANZ BCTG) participate in with other clinical trials groups, if applicable.

Relation between chemotherapy dose, oestrogen receptor expression, and body-mass index

Clinicians often reduce chemotherapy doses when treating obese patients because of concerns about overdosing. We assessed dose-response according to body-mass index (BMI) and oestrogen receptor (ER) expression of the primary tumour in premenopausal patients with node-positive breast cancer treated with classical CMF (cyclophosphamide, methotrexate, and 5-fluorouracil). Obese patients were significantly more likely to receive a lower chemotherapy dose (<85% of expected dose) for the first course than were those with normal or intermediate BMI (39%vs 16%, p<0.0001). For obese patients and for the total population, reducing the dose of chemotherapy was associated with a significantly worse outcome for the ER-negative cohort (total population hazards ratio 85%vs <85% 0.68 [95% CI 0.54-0.86] for disease free survival; 0.72 [0.56-0.94] for overall survival) but not for the ER-positive cohort (1.16 [0.97-1.40] for disease-free survival; 1.16 [0.94-1.44] for overall survival) [interaction p values=0.0001 for disease-free survival and 0.0019 for overall survival]. Our findings suggest that for women with ER-absent or ER-low tumours, reduction in chemotherapy dose should be avoided.

Trastuzumab (T) and CNS metastases in women with HER-2 positive metastatic breast cancer (MBC)

683 Background: A high rate of CNS metastases has been described in women with MBC over-expressing HER-2 who receive T-based therapy. The aim of this study was to examine the frequency of and potential risk factors for CNS metastases in these women. Our a priori hypotheses were that in MBC patients treated with T, CNS metastases occurred: 1) more frequently than historical controls, and 2) in women with controlled systemic disease. Methods: A retrospective cohort study of 28 patients with MBC cancer over-expressing HER-2 and treated with T and chemotherapy was performed. Results: 22/25 (88%) patients who initially responded to T had progressed by the time of analysis. CNS metastases occurred in 11/28 (39%) patients and the remaining 11 patients had progressed elsewhere. At diagnosis of CNS metastases, 9/11 (82%) patients had controlled systemic disease (CR=2, PR=6, SD=1, PD=2 patients). There were trends for patients with CNS metastases to have > 1 site of metastatic disease at the commencement of T therapy (P=0.06), and to be hormone receptor negative at initial diagnosis (P=0.14). The median time to diagnosis of CNS metastases after the commencement of T therapy was 30.8 months (range 16–49). The median survival after diagnosis of CNS metastases was 30.6 months (range 4–75). Conclusions: Historically, CNS metastases have been reported to occur in 10–16% of women with MBC, with a median survival of < 1 year. This study demonstrates a significantly higher rate of CNS metastases (39%) in HER-2 positive MBC patients treated with T. At CNS metastases most patients had controlled systemic disease and the median survival after CNS relapse was over 2 years. We suggest aggressive management of CNS disease in this population. Additional strategies to decrease the incidence of CNS metastases in these patients may include prophylactic whole brain irradiation and the development of novel pharmacological agents with successful CNS penetration. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Australian New Zealand Breast Cancer Trials Group, Genentech, Roche Roche

Barriers to participation in randomized clinical trials for early breast cancer among Australian cancer specialists.

Doctors' discomfort with the randomized trial process may significantly impact on accrual rates to clinical trials. However, there is little information regarding factors that influence accrual to clinical trials in Australia. The present study examines Australian cancer specialists' attitudes towards and participation in current breast cancer clinical trials. All medical and radiation oncologists across Australia and surgeons listed as participants in the Australian and New Zealand Breast Cancer Trials Group were sent questionnaires assessing attitudes towards and participation in current clinical trials for early stage breast cancer. The response rate was 71% (269/381). The mean age of respondents was 45 years and 85% were male. Respondents estimated that a mean of 5.2 (SD = 8.2) of their patients had been enrolled in a breast cancer clinical trial in the previous 12 months. Participation (in any trial) by medical oncologists (60.6%, 95% CI 54.5-66.7%) and surgeons (63.1%, 95% CI 57.1-69.1%) was significantly higher than for radiation oncologists (43.2%, 95% CI 37-49.4%, P = 0.03). The major barriers to participation in current breast cancer trials were lack of resources (44%) or issues related to specific trials (44%; e.g. relevance of the research questions or choice of standard therapies). The results of this study suggest that efforts to improve doctors' participation in clinical trials need to address a number of issues. More empirical research is needed to evaluate new strategies to raise participation in clinical trials.

Quality of life studies of the Australian New Zealand Breast Cancer Trials Group: approaches to missing data

The purpose of this paper is to describe the degree of compliance with quality of life measures in two clinical trials conducted by the Australian New Zealand Breast Cancer Trials Group comparing different chemotherapy policies for metastatic breast cancer. Quality of life was assessed by the patient using linear analogue scales and by the physician using the Spitzer QLI. Compliance was generally good, ranging from 66 per cent to 79 per cent in the earlier study, and from 63 per cent to 97 per cent in the later study. Compliance with physician rated quality of life was consistently slightly better than for patient self-assessment. The results of physician and patient assessments were generally consistent, but there was a systematic bias toward lower quality of life (as assessed by the physician) in patients who failed to comply with self-assessment. Our conclusions were that quality of life can be assessed in large scale multi-institution clinical trials in metastatic breast cancer. The results are important in assessing treatment comparisons. Missing data cannot be assumed to be similar to those available. Optimal assessment of quality of life therefore requires careful prospective attention to complete data collection.

Quality of life studies of the Australian New Zealand Breast Cancer Trials Group: approaches to missing data

Quality of life studies of the Australian New Zealand Breast Cancer Trials Group: approaches to missing data

Prognostic value of quality-of-life scores during chemotherapy for advanced breast cancer. Australian New Zealand Breast Cancer Trials Group.

We observed that quality-of-life (QL) scores, collected to evaluate treatment in a randomized trial in advanced breast cancer, predicted survival duration. This report explores the prognostic associations between QL and survival in more detail. In a randomized clinical trial comparing intermittent and continuous therapy policies for patients with advanced breast cancer, QL was measured by linear analog self-assessment (LASA) and the Quality-of-Life Index (QLI). Baseline scores and subsequent changes were included in statistical models of survival duration, with and without other prognostic factors. Physician assessment of QLI and patient LASA scores for physical well-being (PWB), mood, nausea and vomiting, appetite, and overall QL (but not pain) at the commencement of treatment were significant predictors of subsequent survival. Scores for PWB and QLI were independent of other prognostic factors. Changes in scores were also prognostically important. Both baseline and change in scores for PWB, mood, pain, and QLI after the first three treatment cycles, but before an arbitrary 180-day time point, were significantly predictive of survival beyond that time. Both QLI and PWB were prognostically independent of tumor response. Although QL improvement was correlated with tumor response, continuous therapy yielded significantly better QL scores, even in nonresponders. These findings support the validity of the simple QL measures used in the trial. They are compatible with the simple explanation that patients perceive disease progression before it is clinically evident, but also with a causal relationship between QL and survival duration.