Dr Nick Zdenkowski

Background: Concomitant intake of proton pump inhibitors (PPIs) may create drug¿drug interactions, potentially impacting efficacy of anticancer agents. In the phase III PALLAS trial, the addition of palbociclib capsules to standard adjuvant endocrine therapy in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer did not improve invasive disease-free survival (iDFS). We explored whether concomitant use of PPIs affected survival outcomes in patients treated with palbociclib in PALLAS. Methods: This is an exploratory analysis of PALLAS including patients who received at least one dose of palbociclib capsules. We aimed to determine the association of concomitant PPI use with iDFS, distant relapse-free survival and overall survival. Uni- and multivariable Cox models with time-dependent PPI were used. The association between PPI use and neutropenia was also investigated. Results: Of 2840 patients treated with palbociclib + endocrine therapy, 525 (18.5%) had concomitant PPI and palbociclib intake. PPI intake was significantly associated with older age, post-menopausal status, use of aromatase inhibitors, higher body mass index, and worse Eastern Cooperative Oncology Group status (all P < 0.001). Concomitant PPI intake was not significantly associated with survival outcomes (iDFS, distant relapse-free survival, overall survival). All-grade neutropenia rates were numerically lower in patients who initiated a PPI before study start compared with patients never initiating PPIs (adjusted odds ratio 0.81, 95% confidence interval 0.60-1.09). Conclusions: Our exploratory analysis did not demonstrate worse survival outcomes in patients receiving concomitant palbociclib and PPIs in PALLAS. Nonetheless, careful consideration of possible drug¿drug interactions is important, especially when studying novel agents in the early breast cancer setting.

Background: Treatment options for low-risk differentiated thyroid cancer (DTC) include active surveillance (AS), hemithyroidectomy (HT), or total thyroidectomy (TT). Improved understanding of patient values and preferences is required to inform shared decision-making. This study examined factors influencing patient treatment preferences and trade-offs for low-risk DTC. Methods: Adult participants with benign thyroid nodules or low-risk DTC completed an online discrete choice experiment (DCE). Utilizing the scenario of a 50-year-old person with a small solitary DTC, participants chose between three unlabeled treatment options (representing AS, HT, and TT). Risk profiles varied across 5 domains: voice change, thyroid hormone supplementation, hypocalcaemia, chance of future thyroid surgery, and 10-year risk of cancer recurrence. Participants self-reported demographics, disease factors, and answered a decisional regret scale. A conditional logit model was utilized. Results: The DCE was completed by 143 patients across three sites. The conditional logit model demonstrated that participants preferred AS (49%) over TT (29%) or HT (22%). All five domains influenced choices (all p¿<¿0.001), but perceived risk of cancer recurrence exerted most influence. Cancer survivors chose AS less often than those with benign disease (46% vs. 57%), driven by perceived risks of further surgery and cancer recurrence. As the perceived risk of cancer recurrence increased, more participants preferred HT over AS. Conclusion: This study demonstrates that when blinded to the actual treatment, patients prefer the trade-offs associated with AS rather than TT or HT. Perceived risk of cancer recurrence exerted the greatest influence. Accurate risk stratification for cancer recurrence is critical to shared decision-making.

Background: Adjuvant breast radiotherapy as a standard component of breast-conserving treatment for early cancer can overtreat many women. Breast MRI is the most sensitive modality to assess local tumour burden. The aim of this study was to determine whether a combination of MRI and pathology findings can identify women with truly localised breast cancer who can safely avoid radiotherapy. Methods: PROSPECT is a prospective, multicentre, two-arm, non-randomised trial of radiotherapy omission in patients selected using preoperative MRI and postoperative tumour pathology. It is being conducted at four academic hospitals in Australia. Women aged 50 years or older with cT1N0 non-triple-negative breast cancer were eligible. Those with apparently unifocal cancer had breast-conserving surgery (BCS) and, if pT1N0 or N1mi, had radiotherapy omitted (group 1). Standard treatment including excision of MRI-detected additional cancers was offered to the others (group 2). All were recommended systemic therapy. The primary outcome was ipsilateral invasive recurrence rate (IIRR) at 5 years in group 1. Primary analysis occurred after the 100th group 1 patient reached 5 years follow-up. Quality-adjusted life-years (QALYs) and cost-effectiveness of the PROSPECT pathway were analysed. This study is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12610000810011). Findings: Between May 17, 2011, and May 6, 2019, 443 patients with breast cancer underwent MRI. Median age was 63·0 years. MRI detected 61 malignant occult lesions separate from the index cancer in 48 patients (11%). Of 201 group 1 patients who had BCS without radiotherapy, the IIRR at 5 years was 1·0% (upper 95% CI 5·4%). In group 1, one local recurrence occurred at 4·5 years and a second at 7·5 years. In group 2, nine patients had mastectomy (2% of total cohort), and the 5-year IIRR was 1·7% (upper 95% CI 6·1%). The only distant metastasis in the entire cohort was genetically distinct from the index cancer. The PROSPECT pathway increased QALYs by 0·019 (95% CI 0·008¿0·029) and saved AU$1980 (95% CI 1396¿2528) or £953 (672¿1216) per patient. Interpretation: PROSPECT suggests that women with unifocal breast cancer on MRI and favourable pathology can safely omit radiotherapy. Funding: Breast Cancer Trials, National Breast Cancer Foundation, Cancer Council Victoria, the Royal Melbourne Hospital Foundation, and the Breast Cancer Research Foundation.

Background: An increased risk of breast cancer is associated with high serum concentrations of oestradiol and testosterone in postmenopausal women, but little is known about how these hormones affect response to endocrine therapy for breast cancer prevention or treatment. We aimed to assess the effects of serum oestradiol and testosterone concentrations on the efficacy of the aromatase inhibitor anastrozole for the prevention of breast cancer in postmenopausal women at high risk. Methods: In this case-control study we used data from the IBIS-II prevention trial, a randomised, controlled, double-blind trial in postmenopausal women aged 40¿70 years at high risk of breast cancer, conducted in 153 breast cancer treatment centres across 18 countries. In the trial, women were randomly assigned (1:1) to receive anastrozole (1 mg/day, orally) or placebo daily for 5 years. In this pre-planned case-control study, the primary analysis was the effect of the baseline oestradiol to sex hormone binding globulin (SHBG) ratio (oestradiol¿SHBG ratio) on the development of all breast cancers, including ductal carcinoma in situ (the primary endpoint in the trial). Cases were participants in whom breast cancer was reported after trial entry and until the cutoff on Oct 22, 2019, and who had valid blood samples and no use of hormone replacement therapy within 3 months of trial entry or during the trial. For each case, two controls without breast cancer were selected at random, matched on treatment group, age (within 2 years), and follow-up time (at least that of the matching case). For each treatment group, we applied a multinominal logistic regression likelihood-ratio trend test to assess what change in the proportion of cases was associated with a one-quartile change in hormone ratio. Controls were used only to determine quartile cutoffs. Profile likelihood 95% CIs were used to indicate the precision of estimates. A secondary analysis also investigated the effect of the baseline testosterone¿SHBG ratio on breast cancer development. We also assessed relative benefit of anastrozole versus placebo (calculated as 1 ¿ the ratio of breast cancer cases in the anastrozole group to cases in the placebo group). The trial was registered with ISRCTN (number ISRCTN31488319) and completed recruitment on Jan 31, 2012, but long-term follow-up is ongoing. Findings: 3864 women were recruited into the trial between Feb 2, 2003, and Jan 31, 2012, and randomly assigned to receive anastrozole (n=1920) or placebo (n=1944). Median follow-up time was 131 months (IQR 106¿156), during which 85 (4·4%) cases of breast cancer in the anastrozole group and 165 (8·5%) in the placebo group were identified. No data on gender, race, or ethnicity were collected. After exclusions, the case-control study included 212 participants from the anastrozole group (72 cases, 140 controls) and 416 from the placebo group (142 cases, 274 controls). A trend of increasing breast cancer risk with increasing oestradiol¿SHBG ratio was found in the placebo group (trend per quartile 1·25 [95% CI 1·08 to 1·45], p=0·0033), but not in the anastrozole group (1·06 [0·86 to 1·30], p=0·60). A weaker effect was seen for the testosterone¿SHBG ratio in the placebo group (trend 1·21 [1·05 to 1·41], p=0·011), but again not in the anastrozole group (trend 1·18 [0·96 to 1·46], p=0·11). A relative benefit of anastrozole was seen in quartile 2 (0·55 [95% CI 0·13 to 0·78]), quartile 3 (0·54 [0·22 to 0·74], and quartile 4 (0·56 [0·23 to 0·76]) of oestradiol¿SHBG ratio, but not in quartile 1 (0·18 [¿0·60 to 0·59]). Interpretation: These results suggest that serum hormones should be measured more routinely and integrated into risk management decisions. Measuring serum hormone concentrations is inexpensive and might help clinicians differentiate which women will benefit most from an aromatase inhibitor. Funding: Cancer Research UK, National Health and Medical Research Council (Australia), Breast Cancer Research Foundatio...

PURPOSEBMI affects breast cancer risk and prognosis. In contrast to cytotoxic chemotherapy, CDK4/6 inhibitors are given at a fixed dose, irrespective of BMI or weight. This preplanned analysis of the global randomized PALLAS trial investigates the impact of BMI on the side-effect profile, treatment adherence, and efficacy of palbociclib.METHODSPatients were categorized at baseline according to WHO BMI categories. Neutropenia rates were assessed with univariable and multivariable logistic regression. Time to early discontinuation of palbociclib was analyzed with Fine and Gray competing risk models. Unstratified Cox models were used to investigate the association between BMI category and time to invasive disease-free survival (iDFS). 95% CIs were derived.RESULTSOf 5,698 patients included in this analysis, 68 (1.2%) were underweight, 2,082 (36.5%) normal weight, 1,818 (31.9%) overweight, and 1,730 (30.4%) obese at baseline. In the palbociclib arm, higher BMI was associated with a significant decrease in neutropenia (unadjusted odds ratio for 1-unit change, 0.93; 95% CI, 0.91 to 0.94; adjusted for age, race ethnicity, region, chemotherapy use, and Eastern Cooperative Oncology Group at baseline, 0.93; 95% CI, 0.92 to 0.95). This translated into a significant decrease in treatment discontinuation rate with higher BMI (adjusted hazard ratio [HR] for 10-unit change, 0.75; 95% CI, 0.67 to 0.83). There was no significant improvement in iDFS with the addition of palbociclib to ET in any weight category (normal weight HR, 0.84; 95% CI, 0.63 to 1.12; overweight HR, 1.10; 95% CI, 0.82 to 1.49; and obese HR, 0.95; 95% CI, 0.69 to 1.30) in this analysis early in follow-up (31 months).CONCLUSIONThis preplanned analysis of the PALLAS trial demonstrates a significant impact of BMI on side effects, dose reductions, early treatment discontinuation, and relative dose intensity. Additional long-term follow-up will further evaluate whether BMI ultimately affects outcome.

Background: Carcinomatous meningitis (CM) is a severe complication of breast cancer. The Breast International Group (BIG) carried out a survey to describe the approach to CM internationally. Patients and methods: A questionnaire on the management of CM was developed by the Brain Metastases Task Force of BIG and distributed to its groups, requesting one answer per group site. Results: A total of 241 sites responded, 119 from Europe, 9 from North America, 39 from Central/South America, 58 from Asia, and 16 in Australia/New Zealand, with 24.5% being general hospitals with oncology units, 44.4% university hospitals, 22.4% oncology centers, and 8.7% private hospitals. About 56.0% of sites reported seeing <5 cases annually with 60.6% reporting no increase in the number of cases of CM recently. Nearly 63.1% of sites investigate for CM when a patient has symptoms or radiological evidence, while 33.2% investigate only for symptoms. For diagnosis, 71.8% of sites required a positive cerebrospinal fluid cytology, while magnetic resonance imaging findings were sufficient in 23.7% of sites. Roughly 97.1% of sites treat CM and 51.9% also refer patients to palliative care. Intrathecal therapy is used in 41.9% of sites, mainly with methotrexate (74.3%). As many as 20 centers have a national registry for patients with breast cancer with central nervous system metastases and of those 5 have one for CM. Most (90.9%) centers would be interested in participating in a registry as well as in studies for CM, the latter preferably (62.1%) breast cancer subtype specific. Conclusions: This is the first study to map out the approach to CM from breast cancer globally. Although guidelines with level 1 evidence are lacking, there is a high degree of homogeneity in the approach to CM globally and great interest for conducting studies in this area.

Objective: Care for fear of cancer recurrence (FCR) is considered the most common unmet need among cancer survivors. Yet the prevalence of FCR and predisposing factors remain inconclusive. To support targeted care, we provide a comprehensive overview of the prevalence and severity of FCR among cancer survivors and patients, as measured using the short form of the validated Fear of Cancer Recurrence Inventory (FCRI-SF). We also report on associations between FCR and clinical and demographic characteristics. Methods: This is a systematic review and individual participant data (IPD) meta-analysis on the prevalence of FCR. In the review, we included all studies that used the FCRI-SF with adult (=18¿years) cancer survivors and patients. Date of search: 7 February 2020. Risk of bias was assessed using the Joanna Briggs Institute critical appraisal tool. Results: IPD were requested from 87 unique studies and provided for 46 studies comprising 11,226 participants from 13 countries. 9311 respondents were included for the main analyses. On the FCRI-SF (range 0¿36), 58.8% of respondents scored =13, 45.1% scored =16 and 19.2% scored =22. FCR decreased with age and women reported more FCR than men. FCR was found across cancer types and continents and for all time periods since cancer diagnosis. Conclusions: FCR affects a considerable number of cancer survivors and patients. It is therefore important that healthcare providers discuss this issue with their patients and provide treatment when needed. Further research is needed to investigate how best to prevent and treat FCR and to identify other factors associated with FCR. The protocol was prospectively registered (PROSPERO CRD42020142185).

Background: Palbociclib added to endocrine therapy improves progression-free survival in hormone-receptor-positive, HER2-negative, metastatic breast cancer. The PALLAS trial aimed to investigate whether the addition of 2 years of palbociclib to adjuvant endocrine therapy improves invasive disease-free survival over endocrine therapy alone in patients with hormone-receptor-positive, HER2-negative, early-stage breast cancer. Methods: PALLAS is an ongoing multicentre, open-label, randomised, phase 3 study that enrolled patients at 406 cancer centres in 21 countries worldwide with stage II¿III histologically confirmed hormone-receptor-positive, HER2-negative breast cancer, within 12 months of initial diagnosis. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance score of 0 or 1. Patients were randomly assigned (1:1) in permuted blocks of random size (4 or 6), stratified by anatomic stage, previous chemotherapy, age, and geographical region, by use of central telephone-based and web-based interactive response technology, to receive either 2 years of palbociclib (125 mg orally once daily on days 1¿21 of a 28-day cycle) with ongoing standard provider or patient-choice adjuvant endocrine therapy (tamoxifen or aromatase inhibitor, with or without concurrent luteinising hormone-releasing hormone agonist), or endocrine therapy alone, without masking. The primary endpoint of the study was invasive disease-free survival in the intention-to-treat population. Safety was assessed in all randomly assigned patients who started palbociclib or endocrine therapy. This report presents results from the second pre-planned interim analysis triggered on Jan 9, 2020, when 67% of the total number of expected invasive disease-free survival events had been observed. The trial is registered with ClinicalTrials.gov (NCT02513394) and EudraCT (2014-005181-30). Findings: Between Sept 1, 2015, and Nov 30, 2018, 5760 patients were randomly assigned to receive palbociclib plus endocrine therapy (n=2883) or endocrine therapy alone (n=2877). At the time of the planned second interim analysis, at a median follow-up of 23·7 months (IQR 16·9¿29·2), 170 of 2883 patients assigned to palbociclib plus endocrine therapy and 181 of 2877 assigned to endocrine therapy alone had invasive disease-free survival events. 3-year invasive disease-free survival was 88·2% (95% CI 85·2¿90·6) for palbociclib plus endocrine therapy and 88·5% (85·8¿90·7) for endocrine therapy alone (hazard ratio 0·93 [95% CI 0·76¿1·15]; log-rank p=0·51). As the test statistic comparing invasive disease-free survival between groups crossed the prespecified futility boundary, the independent data monitoring committee recommended discontinuation of palbociclib in patients still receiving palbociclib and endocrine therapy. The most common grade 3¿4 adverse events were neutropenia (1742 [61·3%] of 2840 patients on palbociclib and endocrine therapy vs 11 [0·3%] of 2903 on endocrine therapy alone), leucopenia (857 [30·2%] vs three [0·1%]), and fatigue (60 [2·1%] vs ten [0·3%]). Serious adverse events occurred in 351 (12·4%) of 2840 patients on palbociclib plus endocrine therapy versus 220 (7·6%) of 2903 patients on endocrine therapy alone. There were no treatment-related deaths. Interpretation: At the planned second interim analysis, addition of 2 years of adjuvant palbociclib to adjuvant endocrine therapy did not improve invasive disease-free survival compared with adjuvant endocrine therapy alone. On the basis of these findings, this regimen cannot be recommended in the adjuvant setting. Long-term follow-up of the PALLAS population and correlative studies are ongoing. Funding: Pfizer.

Introduction: CYP2D6 protein activity can be inferred from the ratio of N-desmethyl-tamoxifen (NDMT) to endoxifen (E). CYP2D6 polymorphisms are common and can affect CYP2D6 protein activity and E level. Some retrospective studies indicate that E < 16 nM may relate to worse outcome. Materials and methods: A target NDMT/E ratio was defined as associated with an E level of 15 nM in the 161 patient Test cohort of tamoxifen-treated patients, dichotomizing them into 'Normal' (NM) and 'Slow' (SM) CYP2D6 metabolizer groups. This ratio was then tested on a validation cohort of 52 patients. Patients were phenotyped based on the standard method (ultrarapid/extensive, intermediate or poor metabolizers; UM/EM, IM, PM) or a simplified system based on whether any variant allele (V) vs wildtype (wt) was present (wt/wt, wt/V, V/V). Comprehensive CYP2D6 genotyping was undertaken on germline DNA. Results: A target NDMT/E ratio of 35 correlated with the 15 nM E level, dichotomizing patients into NM (<35; N = 117) and SM (>35; N = 44) groups. The ratio was independently validated by a validation cohort. The simplified system was better in predicting patients without slow metabolism, with specificity and sensitivity of 96% and 44% respectively, compared with the standard method - sensitivity 81% and specificity 83%. Conclusions: The simplified classification system based on whether any variant was present better identified patients who were truly not CYP2D6 slow metabolizers more accurately than the current system. However, as CYP2D6 genotype is not the only determinant of endoxifen level, we recommend that direct measurement of endoxifen should also be considered.

Treatment strategies for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2¿) metastatic breast cancer in young women (<40 years at diagnosis) have traditionally been extrapolated from data obtained from trials conducted either exclusively or predominantly in the postmenopausal setting. These young patients are usually treated with ovarian function suppression (OFS) + endocrine therapy (ET) ± targeted therapy, except if there is a concern about endocrine resistance or a need to gain rapid disease control due to the onset of visceral crisis. This review examines evidence that supports the use of a cyclin-dependent kinase 4/6 inhibitor, in combination with OFS and ET, when treating premenopausal or perimenopausal women with HR+/HER2¿ metastatic breast cancer. This includes data from the MONALEESA-7 study (treating only premenopausal/perimenopausal women in the first-line setting), and the results of subgroup analyses from the PALOMA-3 and MONARCH-2 trials. We also consider a number of age-specific challenges that younger breast cancer patients can face, highlighting the importance of a multidisciplinary approach to ongoing care.

Only 2¿3% of cancer patients enrol in a trial. We surveyed patients' willingness to change clinician or treating centre, or to travel, to participate in trials, to improve trial recruitment. Of 188 respondents, 79% were willing to participate in a trial in at least one scenario. Increasing travel time, change in oncologist, private health insurance and out of pocket expenses decreased likelihood of joining a trial. Rural and regional patients, and those from lower socio-economic areas, were more willing to travel. To optimise access to trials, clinicians should refer within and between institutions.

Purpose: The separate impacts of dose and dose intensity of chemotherapy for metastatic breast cancer remain uncertain. The primary objective of this trial was to compare a short, high-dose, intensive course of epirubicin and cyclophosphamide (EC) with a longer conventional dose regimen delivering the same total dose of chemotherapy. Methods: This open label trial randomised 235 women with metastatic breast cancer to receive either high-dose epirubicin 150¿mg/m2 and cyclophosphamide 1500¿mg/m2 with filgrastim support every 3 weeks for 3 cycles (HDEC) or standard dose epirubicin 75¿mg/m2 and cyclophosphamide 750¿mg/m2 every 3 weeks for 6 cycles (SDEC). Primary outcomes were time to progression, overall survival and quality of life. Results: In 118 patients allocated HDEC 90% of the planned dose was delivered, compared to 96% in the 117 participants allocated SDEC. There were no significant differences in the time to disease progression (5.7 vs. 5.8 months, P = 0.19) or overall survival (14.5 vs. 16.5 months, P = 0.29) between HDEC and SDEC, respectively. Patients on HDEC reported worse quality of life during therapy, but scores improved after completion to approximate those reported by patients allocated SDEC. Objective tumour response was recorded in 33 (28%) on HDEC and 42 patients (36%) on SDEC. HDEC produced more haematologic toxicity. Conclusion: For women with metastatic breast cancer, disease progression, survival or quality of life were no better with high-dose intensity compared to standard dose EC chemotherapy. Australian Clinical Trials Registry registration number ACTRN12605000478617.

Background: Neoadjuvant systemic therapy (NAST)is used for large operable or highly proliferative breast cancers. It is not known whether psychological outcomes differ according to the treatment sequence (chemotherapy or surgery first)or tumour response. Methods: This was a planned analysis of a multi-institutional single arm longitudinal study of patients considering NAST for operable breast cancer. Participants completed patient reported outcome questionnaires before and after the decision about NAST, between chemotherapy and surgery, and 12 months after diagnosis. Results: Fifty-nine women enrolled. Fourteen of 51 (28%)who received NAST experienced pathological complete response (pCR). Patients who had surgery first (n = 7)had higher baseline anxiety, and a greater decrease in anxiety at 12 months follow up, compared with patients who received NAST (n = 50)(a decrease from baseline of 34 pts vs 17 points; p = 0.033). Distress declined at a similar rate in surgery first and NAST groups. Mean satisfaction with decision score post-decision was significantly lower in the adjuvant group compared with NAST (22 vs 26, p = 0.02). No differences were seen between patients with pCR vs residual cancer in: distress, anxiety, satisfaction with decision, fear of progression, and decision regret. Conclusion: Most patients in this study proceeded with NAST when their surgeon offered it as an option. This exploratory analysis suggests that patients who chose surgery first tended to be more anxious, and had lower satisfaction with their decision, than those who had NAST. In patients who had NAST, lack of pCR does not appear to correlate with adverse psychological outcomes.

Background: The perceptions of those called on to make decisions on behalf of patients who lack capacity at the end of life must accurately reflect patient preferences. Aims: To establish the extent to which the views of medical oncology outpatients are understood by their support persons, specifically with regards to (i) preferred type and location of end-of-life care, (ii) preferred level of involvement in end-of-life decision-making and (iii) whether the patient has completed an advance care plan or appointed an enduring guardian. Methods: Adults with a confirmed cancer diagnosis and their nominated support persons were approached between September 2015 and January 2016 in the waiting room of an Australian tertiary referral clinic. Consenting participants completed a pen-and-paper survey. Nominated support persons answered the same questions from the patient's perspective. Results: In total, 208 participants (39% of eligible dyads) participated. Observed agreement across the five outcomes ranged from 54% to 84%. Kappa values for concordance between patient¿support person responses were fair to moderate (0.24¿0.47) for enduring guardian, decision-making, advance care plan and care location outcomes. A slight level of concordance (k = 0.15; 95% confidence interval: -0.02, 0.32) was found for the type of care outcome. Conclusion: Relying on support persons' views does not guarantee that patients' actual preferences will be followed. Strategies that make patient preferences known to healthcare providers and support persons while they still have the capacity to do so is a critical next step in improving quality cancer care.

Objectives: This study surveyed a sample of medical oncology outpatients to determine (1) the proportion who have already discussed and documented their end-of-life (EOL) wishes; (2) when and with whom they would prefer to convey their EOL wishes; (3) the EOL issues they would want to discuss; and (4) the association between perceived cancer status and advance care planning (ACP) participation. Methods: Adult medical oncology outpatients were approached in the waiting room of an Australian tertiary treatment center. Consenting participants completed a pen-and-paper survey assessing participation in ACP, preferences for conveying EOL wishes, timing of EOL discussions, and EOL issues they want to be asked about. Results: A total of 203 patients returned the survey (47% of eligible). EOL discussions occurred more frequently with support persons (47%) than with doctors (7%). Only 14% had recorded their wishes, and 45% had appointed an enduring guardian. Those who perceived their cancer as incurable were more likely to have participated in ACP. If facing EOL, patients indicated that they would want family involved in discussions (85%), to be able to write down EOL wishes (82%), and to appoint enduring guardians (91%). Many (45%) preferred the first discussion to happen when their disease became incurable. Slightly less than one-third thought discussions regarding EOL should be patient-initiated. Most agreed doctors should ask about preferred decision-making involvement (92%), how important it is that pain is managed well (95%), and how important it is to remain conscious (82%). Fewer (55%) wanted to be asked about the importance of care extending life. Conclusions: Many patients would like to have discussions regarding EOL care with their doctor and involve their support persons in this process. Only a small percentage of respondents had discussed EOL care with their doctors, recorded their wishes, or appointed an enduring guardian. The first step requires clinicians to ask whether an individual patient wishes to discuss EOL issues, in what format, and at what level of detail.

Background: Neoadjuvant systemic therapy (NAST) is an increasingly used treatment option for women with large operable or highly proliferative breast cancer. With equivalent survival outcomes between NAST and up-front surgery, the situation-specific preference-sensitive nature of the decision makes it suitable for a decision aid (DA). This study aimed to develop and evaluate a DA for this population. Methods: A DA booklet was developed according to international standards, including information about adjuvant and neoadjuvant treatment, outcome probabilities, and a values clarification exercise. Eligible women, considered by investigators as candidates for NAST, were enrolled in a multi-institutional, single-arm, longitudinal study. Patient-reported outcome measure questionnaires were completed pre- and post-DA, between chemotherapy and surgery, and at 12 months. Outcomes were feasibility (percentage of eligible patients accessing the DA); acceptability to patients (percentage who would recommend it to others) and clinicians (percentage who would use the DA in routine practice); and decision-related outcomes. Results: From 77 eligible women, 59 were enrolled, of whom 47 (79.7%; 95% CI, 69.4-89.9) reported having read the DA; 51 completed the first post-DA questionnaire. Of these 51, 41 participants (80.4%; 95% CI, 69.5-91.3) found the DA useful for their decision about NAST. Of 18 responding investigators, 16 (88.9%; 95% CI, 74.4-103.4) indicated they would continue to use the DA in routine practice. Post-DA, decisional conflict decreased significantly (P<.01); anxiety and distress decreased significantly; and 86.3% (95% CI, 73.7-94.3) achieved at least as much decisional control as they desired. Conclusions: This DA was feasible and acceptable to patients and clinicians, and improvement in decision-related outcomes was demonstrated when used in combination with clinical consultations. This DA could safely be implemented into routine practice for women considering NAST for operable breast cancer.

Background: Helping people achieve their preferred location of care is an important indicator of quality end-of-life (EOL) care. Using a sample of Australian medical oncology outpatients, this study examined (1) their preferred location of EOL care; (2) their perceived benefits and worries of receiving care in that location; (3) the percentage who had discussed preferences with their doctor and/or support person; and (4) whether they wanted their doctor to ask them where they wanted to die. Methods: Adults with a confirmed diagnosis of cancer were approached between September 2015 and January 2016 in the waiting room of an Australian oncology outpatient clinic. Consenting participants completed a home-based pen-and-paper survey indicating preferred location of care, perceived benefits and worries of that location, whether they had discussed preferences with their doctors, and whether they were willing to be asked about their preferences. Results: A total of 203 patients returned the survey (47% of those eligible). Less than half preferred to be cared for at home (47%), 34% preferred a hospice/palliative care unit, and 19% preferred the hospital. Common benefits and worries associated with locations included perceived burden on others, familiarity of environment, availability of expert medical care, symptom management, and likelihood of having wishes respected. More patients had discussed preferences with their support persons (41%) than doctors (7%). Most wanted a doctor to ask them about preferred location of care (87%) and thought it was important to die in the location of their choice (93%). Conclusions: Patients were willing to have clinicians to ask them where they wanted to die, although few had discussed their preferences with doctors. Although home was the most preferred location for many patients, the overall variation suggests that clinicians should adopt a systematic approach to eliciting patient preferences.

Purpose: Cancer patients can be overwhelmed when being confronted with their diagnosis and treatment options. Such information is often provided during one consultation between the patient and treating clinician. In order to achieve optimal cancer care, there may be justification for alternative consultation styles. We assessed, in a sample of adult medical oncology patients, their preferences for (i) attending one 40-min consultation or two 20-min consultations and (ii) receiving written only or both written and online information, when making a cancer treatment decision. Methods: This was a cross-sectional survey using a discrete choice design of 159 adult medical oncology patients presenting for their second or subsequent outpatient consultation. Participants were presented with a set of hypothetical scenarios and asked to indicate their most and least preferred scenario. The scenarios contained a caveat explaining that there would be no difference between the available treatment options in terms of when treatment would be initiated and the impact it would have on patients' life expectancy. Results: One hundred forty-seven patients completed the DCE. Of these, 70% (n¿=¿103) preferred being provided with written and online information rather than just written information. This preference was statistically significant (p¿<¿0.01). Fifty-nine percent (n¿=¿86) of patients preferred two 20-min consultations over one 40-min consultation when making a treatment decision. Significantly, more patients preferred two shorter consultations rather than one longer consultation when this was combined with written and online information (p¿<¿0.01). Conclusion: When making a cancer treatment decision, clinicians should consider offering patients written and online information, combined with two shorter consultations.

Background: Despite the effectiveness of adjuvant endocrine therapy in preventing breast cancer recurrence, breast cancer events continue at a high rate for at least 10 years after completion of therapy. Patients and methods: This randomised open label phase III trial recruited postmenopausal women from 29 Australian and New Zealand sites, with hormone receptor-positive early breast cancer, who had completed =4 years of endocrine therapy [aromatase inhibitor (AI), tamoxifen, ovarian suppression, or sequential combination] =1 year prior, to oral letrozole 2.5 mg daily for 5 years, or observation. Treatment allocation was by central computerised randomisation, stratified by institution, axillary node status and prior endocrine therapy. The primary outcome was invasive breast cancer events (new invasive primary, local, regional or distant recurrence, or contralateral breast cancer), analysed by intention to treat. The secondary outcomes were disease-free survival (DFS), overall survival, and safety. Results: Between 16 May 2007 and 14 March 2012, 181 patients were randomised to letrozole and 179 to observation (median age 64.3 years). Endocrine therapy was completed at a median of 2.6 years before randomisation, and 47.5% had tumours of >2 cm and/or node positive. At 3.9 years median follow-up (interquartile range 3.1- 4.8), 2 patients assigned letrozole (1.1%) and 17 patients assigned observation (9.5%) had experienced an invasive breast cancer event (difference 8.4%, 95% confidence interval 3.8% to 13.0%, log-rank test P = 0.0004). Twenty-four patients (13.4%) in the observation and 14 (7.7%) in the letrozole arm experienced a DFS event (log-rank P = 0.067). Adverse events linked to oestrogen depletion, but not serious adverse events, were more common with letrozole. Conclusion: These results should be considered exploratory, but lend weight to emerging data supporting longer duration endocrine therapy for hormone receptor-positive breast cancer, and offer insight into reintroduction of AI therapy.

Background: Aromatase inhibitor induced musculoskeletal syndrome is experienced by approximately half of women taking aromatase inhibitors, impairing quality of life and leading some to discontinue treatment. Evidence for effective treatments is lacking. We aimed to understand the manifestations and impact of this syndrome in the Australian breast cancer community, and strategies used for its management. Methods: A survey invitation was sent to 2390 members of the Breast Cancer Network Australia Review and Survey Group in April 2014. The online questionnaire included 45 questions covering demographics, aromatase inhibitor use, clinical manifestations and risk factors for the aromatase inhibitor musculoskeletal syndrome, reasons for treatment discontinuation and efficacy of interventions used. Results: Aromatase inhibitor induced musculoskeletal syndrome was reported by 302 (82¿%) of 370 respondents. Twenty-seven percent had discontinued treatment for any reason and of these, 68¿% discontinued because of the musculoskeletal syndrome. Eighty-one percent had used at least one intervention from the following three categories to manage the syndrome: doctor prescribed medications, over-the-counter/complementary medicines or alternative/non-drug therapies. Anti-inflammatories, paracetamol (acetaminophen) and yoga were most successful in relieving symptoms in each of the respective categories. Almost a third of respondents reported that one or more interventions helped prevent aromatase inhibitor discontinuation. However, approximately 20¿% of respondents found no intervention effective in any category. Conclusion: We conclude that aromatase inhibitor induced musculoskeletal syndrome is a significant issue for Australian women and is an important reason for treatment discontinuation. Women use a variety of interventions to manage this syndrome; however, their efficacy appears limited.

Background: Neoadjuvant systemic therapy (NAST) has become an established treatment option for women with operable breast cancer. Aim: We aimed to better understand NAST treatment patterns, barriers and facilitators in Australia and New Zealand. Methods: We undertook a cross-sectional survey of the current clinical practice of Australian and New Zealand breast cancer specialists. Questions included referral patterns for NAST, patient selection, logistics, decision making and barriers. Results: Of 207 respondents, 162 (78%) reported routinely offering NAST to selected patients with operable breast cancer (median 9% of patients offered NAST). Specialty, location, practice type, gender or years of experience did not predict for offering NAST. In all, 45 and 58% wanted to increase the number of patients who receive NAST in routine care and in clinical trials respectively. Facilitators included the multidisciplinary team meeting and access to NAST clinical trials. Specialist-reported patient barriers included: patient desire for immediate surgery (63% rated as important/very important); lack of awareness of NAST (50%); concern about progression (43%) and disinterest in downstaging (32%). Forty-three per cent of participants experienced system-related barriers to the use of NAST, including other clinicians' lack of interest (27%); lack of clinical trials (24%) and unacceptable wait for a medical oncology appointment (37%). Conclusion: This group of Australian and New Zealand clinicians are interested in NAST for operable breast cancer in routine care and clinical trials. Patient- and system-related barriers that prevent the optimal uptake of this treatment approach will need to be systematically addressed if NAST is to become a more common approach.

Background: There is evidence to suggest that decision aids improve a number of patient outcomes. However, little is known about the progression of research effort in this area over time. This literature review examined the volume of research published in 2000, 2007 and 2014 which tested the effectiveness of decision aids in improving cancer patient outcomes, coded by cancer site and decision type being targeted. These numbers were compared with the volume of research examining the effectiveness of strategies to increase the adoption of decision aids by healthcare providers. Methods: A literature review of intervention studies was undertaken. Medline, Embase, PsychInfo and Cochrane Database of Systematic Reviews were searched. The search was limited to human studies published in English, French, or German. Abstracts were assessed against eligibility criteria by one reviewer and a random sample of 20 % checked by a second. Eligible intervention studies in the three time periods were categorised by: i) whether they tested the effectiveness of decision aids, coded by cancer site and decision type, and ii) whether they tested strategies to increase healthcare provider adoption of decision aids. Results: Over the three time points assessed, increasing research effort has been directed towards testing the effectiveness of decision aids in improving patient outcomes (p < 0.0001). The number of studies on decision aids for cancer screening or prevention increased statistically significantly (p < 0.0001) whereas the number of studies on cancer treatment did not (p = 1.00). The majority of studies examined the effectiveness of decision aids for prostate (n = 10), breast (n = 9) or colon cancer (n = 7). Only two studies assessed the effectiveness of implementation strategies to increase healthcare provider adoption of decision aids. Conclusions: While the number of studies testing the effectiveness of decision aids has increased, the majority of research has focused on screening and prevention decision aids for only a few cancer sites. This neglects a number of cancer populations, as well as other areas of cancer care such as treatment decisions. Also, given the apparent effectiveness of decision aids, more effort needs to be made to implement this evidence into meaningful benefits for patients.

Several complex treatment decisions may be offered to women with early stage breast cancer, about a range of treatments from different modalities including surgery, radiotherapy, and endocrine and chemotherapy. Decision aids can facilitate shared decision-making and improve decision-related outcomes. We aimed to systematically identify, describe and appraise the literature on treatment decision aids for women with early breast cancer, synthesise the data and identify breast cancer decisions that lack a decision aid.A prospectively developed search strategy was applied to MEDLINE, the Cochrane databases, EMBASE, PsycINFO, Web of Science and abstract databases from major conferences. Data were extracted into a pre-piloted form. Quality and risk of bias were measured using Qualsyst criteria. Results were synthesised into narrative format. Thirty-three eligible articles were identified, evaluating 23 individual treatment decision aids, comprising 13 randomised controlled trial reports, seven non-randomised comparative studies, eight single-arm pre-post studies and five cross-sectional studies. The decisions addressed by these decision aids were: breast conserving surgery versus mastectomy (+/- reconstruction); use of chemotherapy and/or endocrine therapy; radiotherapy; and fertility preservation. Outcome measures were heterogeneous, precluding meta-analysis. Decisional conflict decreased, and knowledge and satisfaction increased, without any change in anxiety or depression, in most studies. No studies were identified that evaluated decision aids for neoadjuvant systemic therapy, or contralateral prophylactic mastectomy. Decision aids are available and improved decision-related outcomes for many breast cancer treatment decisions including surgery, radiotherapy, and endocrine and chemotherapy. Decision aids for neoadjuvant systemic therapy and contralateral prophylactic mastectomy could not be found, and may be warranted.

Objective: Conduct a systematic review of quantitative and qualitative studies exploring patient reported factors and psychological variables influencing the decision to have contralateral prophylactic mastectomy (CPM), and satisfaction with CPM, in women with early stage breast cancer. Methods: Studies were identified via databases: Medline, CINAHL, Embase and PsycINFO. Data were extracted by one author and crosschecked by two additional authors for accuracy. The quality of included articles was assessed using standardised criteria by three authors. Results: Of the 1346 unique citations identified, 17 were studies that met the inclusion criteria. Studies included were primarily cross-sectional and retrospective. No study utilised a theoretical framework to guide research and few studies considered psychological predictors of CPM. Fear of breast cancer was the most commonly cited reason for CPM, followed by cosmetic reasons such as desire for symmetry. Overall, women appeared satisfied with CPM, however, adverse/diminished body image, poor cosmetic result, complications, diminished sense of sexuality, emotional issues and perceived lack of education regarding alternative surveillance/CPM efficacy were cited as reasons for dissatisfaction. Conclusion: Current literature has begun to identify patient-reported reasons for CPM; however, the relative importance of different factors and how these factors relate to the process underlying the decision to have CPM are unknown. Of women who considered CPM, limited information is available regarding differences between those who proceed with or ultimately decline CPM.

Aim: We aimed to systematically review and summarize data from the available clinical trials that examined the treatment of HER2-positive metastatic breast cancer. Methods: We reviewed phase 2 and 3 studies in which an anti-HER2 agent was used in one or both arms of the study. While formal meta-analysis was not possible for such a heterogeneous group of trials, resulting forest plots outline some generalizable findings. Results: There is strong evidence that the addition of an anti-HER2 agent to standard chemo- or endocrine therapy improves clinically relevant measurable outcomes. There is also consistent evidence that initial treatment with trastuzumab alone (and subsequent use of a cytotoxic) is inferior to the initial combination of trastuzumab plus chemotherapy, and that either T-DM1 or dual anti-HER2 agents are superior to single anti-HER2 agent regimens. There is no strong evidence that the use of more than one cytotoxic agent together with an anti-HER2 agent confers any benefit over a single cytotoxic, anti-HER2 combination. Conclusion: This review provides a strong evidence base for current clinical practice with a discussion of treatment in the Australian setting. © 2014 Wiley Publishing Asia Pty Ltd.