Radiation doses and fractionation schedules in non-low-risk ductal carcinoma in situ in the breast (BIG 3-07/TROG 07.01): a randomised, factorial, multicentre, open-label, phase 3 study.

BACKGROUND: Whole breast irradiation (WBI) after conservative surgery for ductal carcinoma in situ (DCIS) reduces local recurrence. We investigated whether a tumour bed boost after WBI improved outcomes, and examined radiation dose fractionation sensitivity for non-low-risk DCIS. METHODS: The study was an international, randomised, unmasked, phase 3 trial involving 136 participating centres of six clinical trials organisations in 11 countries (Australia, New Zealand, Singapore, Canada, the Netherlands, Belgium, France, Switzerland, Italy, Ireland, and the UK). Eligible patients were women aged 18 years or older with unilateral, histologically proven, non-low-risk DCIS treated by breast-conserving surgery with at least 1 mm of clear radial resection margins. They were assigned to one of four groups (1:1:1:1) of no tumour bed boost versus boost after conventional versus hypofractionated WBI, or randomly assigned to one of two groups (1:1) of no boost versus boost after each centre prespecified conventional or hypofractionated WBI. The conventional WBI used was 50 Gy in 25 fractions, and hypofractionated WBI was 42·5 Gy in 16 fractions. A boost dose of 16 Gy in eight fractions, if allocated, was delivered after WBI. Patients and clinicians were not masked to treatment allocation. The primary endpoint was time to local recurrence. This trial is registered with ClinicalTrials.gov (NCT00470236). FINDINGS: Between June 25, 2007, and June 30, 2014, 1608 patients were randomly assigned to have no boost (805 patients) or boost (803 patients). Conventional WBI was given to 831 patients, and hypofractionated WBI was given to 777 patients. Median follow-up was 6·6 years. The 5-year free-from-local-recurrence rates were 92·7% (95% CI 90·6-94·4%) in the no-boost group and 97·1% (95·6-98·1%) in the boost group (hazard ratio 0·47; 0·31-0·72; p<0·001). The boost group had higher rates of grade 2 or higher breast pain (10% [8-12%] vs 14% [12-17%], p=0·003) and induration (6% [5-8%] vs 14% [11-16%], p<0·001). INTERPRETATION: In patients with resected non-low-risk DCIS, a tumour bed boost after WBI reduced local recurrence with an increase in grade 2 or greater toxicity. The results provide the first randomised trial data to support the use of boost radiation after postoperative WBI in these patients to improve local control. The international scale of the study supports the generalisability of the results. FUNDING: National Health and Medical Research Council of Australia, Susan G Komen for the Cure, Breast Cancer Now, OncoSuisse, Dutch Cancer Society, Canadian Cancer Trials Group.

Use of Non-Cancer Medications in New Zealand Women at the Diagnosis of Primary Invasive Breast Cancer: Prevalence, Associated Factors and Effects on Survival.

BACKGROUND: Assessing the use of multiple medications in cancer patients is crucial as such use may affect cancer outcomes. This study reports the prevalence of non-cancer medication use at breast cancer diagnosis, its associated factors, and its effect on survival. METHODS: We identified all women diagnosed with primary invasive breast cancer between 1 January 2007 and 31 December 2016, from four population-based breast cancer registries, in Auckland, Waikato, Wellington, and Christchurch, New Zealand. Through linkage to the pharmaceutical records, we obtained information on non-cancer medications that were dispensed for a minimum of 90 days' supply between one year before cancer diagnosis and first cancer treatment. We performed ordered logistic regressions to identify associated factors and Cox regressions to investigate its effect on patient survival. RESULTS: Of 14,485 patients, 52% were dispensed at least one drug (mean-1.3 drugs; maximum-13 drugs), with a higher prevalence observed in patients who were older, treated at a public facility, more economically deprived, and screen-detected. The use of 2-3 drugs showed a reduced non-breast cancer mortality (HR = 0.75, 95%CI = 0.60-0.92) in previously hospitalised patients, with other groups showing non-significant associations when adjusted for confounding factors. Drug use was not associated with changes in breast cancer-specific mortality. CONCLUSIONS: Non-cancer medication use at breast cancer diagnosis was common in New Zealand, more prevalent in older and disadvantaged women, and showed no effect on breast cancer-specific mortality, but a reduction in other cause mortality with the use of 2-3 drugs.

International comparison of cosmetic outcomes of breast conserving surgery and radiation therapy for women with ductal carcinoma in situ of the breast.

PURPOSE: To assess the cosmetic impact of breast conserving surgery (BCS), whole breast irradiation (WBI) fractionation and tumour bed boost (TBB) use in a phase III trial for women with ductal carcinoma in situ (DCIS) of the breast. MATERIALS AND METHODS: Baseline and 3-year cosmesis were assessed using the European Organization for Research and Treatment of Cancer (EORTC) Cosmetic Rating System and digital images in a randomised trial of non-low risk DCIS treated with postoperative WBI +/- TBB. Baseline cosmesis was assessed for four geographic clusters of treating centres. Cosmetic failure was a global score of fair or poor. Cosmetic deterioration was a score change from excellent or good at baseline to fair or poor at three years. Odds ratios for cosmetic deterioration by WBI dose-fractionation and TBB use were calculated for both scoring systems. RESULTS: 1608 women were enrolled from 11 countries between 2007 and 2014. 85-90% had excellent or good baseline cosmesis independent of geography or assessment method. TBB (16 Gy in 8 fractions) was associated with a >2-fold risk of cosmetic deterioration (p < 0.001). Hypofractionated WBI (42.5 Gy in 16 fractions) achieved statistically similar 3-year cosmesis compared to conventional WBI (50 Gy in 25 fractions) (p ≥ 0.18). The adverse impact of a TBB was not significantly associated with WBI fractionation (interaction p ≥ 0.30). CONCLUSIONS: Cosmetic failure from BCS was similar across international jurisdictions. A TBB of 16 Gy increased the rate of cosmetic deterioration. Hypofractionated WBI achieved similar 3-year cosmesis as conventional WBI in women treated with BCS for DCIS.

Influence of comorbidity on chemotherapy use for early breast cancer: systematic review and meta-analysis.

PURPOSE: Patients with early breast cancer and coexistent comorbidities generally experience worse prognosis which may be in part related to inferior treatment. Randomised data on chemotherapy use and tolerance in comorbid patients are limited. We aimed to review the available literature regarding the use of chemotherapy in such patients. METHODS: A systematic search of databases was performed for English-language articles evaluating the impact of comorbidity on chemotherapy use for early breast cancer. Comorbidity was assessed as a specific condition, summary count or index. Outcomes of interest were receipt of chemotherapy, change in chemotherapy delivery and occurrence of toxicity. RESULTS: Sixty studies met inclusion criteria for systematic review. Thirty-three studies evaluated receipt of chemotherapy, with 19 reporting reduced treatment, particularly with higher levels of comorbidity. Meta-analysis of 10 eligible studies returned odds ratios (OR's) of 0.88 [95% confidence interval (CI) 0.80-0.96] and 0.63 (95% CI 0.49-0.80) for receipt of chemotherapy by patients with comorbidity scores of 1 and ≥2, respectively, compared with no comorbidity. Comorbidity had a generally adverse impact on the quality of chemotherapy delivery, although outcomes were heterogeneous. Toxicity was greater in patients with comorbidity, with 10 out of 13 studies reporting greater odds of toxicity or hospitalisation during chemotherapy. Meta-analysis of three studies addressing chemotherapy-associated hospitalisation produced OR's of 1.42 (95% CI 1.20-1.67) and 2.23 (95% CI 1.46-3.39) for comorbidity scores of 1 and ≥2, respectively. CONCLUSIONS: Compared with their non-comorbid counterparts, comorbid patients with early breast cancer receive less quality adjuvant chemotherapy and experience greater toxicity.

Breast cancer survival in New Zealand women.

BACKGROUND: The Quality Audit (BQA) of Breast Surgeons of Australia and New Zealand includes a broad range of data and is the largest New Zealand (NZ) breast cancer (BC) database outside the NZ Cancer Registry. We used BQA data to compare BC survival by ethnicity, deprivation, remoteness, clinical characteristic and case load. METHODS: BQA and death data were linked using the National Health Index. Disease-specific survival for invasive cases was benchmarked against Australian BQA data and NZ population-based survivals. Validity was explored by comparison with expected survival by risk factor. RESULTS: Compared with 93% for Australian audit cases, 5-year survival was 90% for NZ audit cases overall, 87% for Maori, 84% for Pacific and 91% for other. CONCLUSIONS: BC survival in NZ appears lower than in Australia, with inequities by ethnicity. Differences may be due to access, timeliness and quality of health services, patient risk profiles, BQA coverage and death-record methodology.

Analysing risk factors for poorer breast cancer outcomes in residents of lower socioeconomic areas of Australia.

OBJECTIVE: To investigate patient, cancer and treatment factors associated with the residence of female breast cancer patients in lower socioeconomic areas of Australia to better understand factors that may contribute to their poorer cancer outcomes. METHODS: Bivariable and multivariable analyses were performed using the Breast Quality Audit database of Breast Surgeons of Australia and New Zealand. RESULTS Multivariable regression indicated that patients from lower socioeconomic areas are more likely to live in more remote areas and to be treated at regional than major city centres. Although they appeared equally likely to be referred to surgeons from BreastScreen services as patients from higher socioeconomic areas, they were less likely to be referred as asymptomatic cases from other sources. In general, their cancer and treatment characteristics did not differ from those of women from higher socioeconomic areas, but ovarian ablation therapy was less common for these patients and bilateral synchronous lesions tended to be less frequent than for women from higher socioeconomic areas. CONCLUSIONS: The results indicate that patients from lower socioeconomic areas are more likely to live in more remote districts and have their treatment in regional rather than major treatment centres. Their cancer and treatment characteristics appear to be similar to those of women from higher socioeconomic areas, although they are less likely to have ovarian ablation or to be referred as asymptomatic patients from sources other than BreastScreen. What is known about this topic? It is already known from Australian data that breast cancer outcomes are not as favourable for women from areas of socioeconomic disadvantage. The reasons for the poorer outcomes have not been understood. Studies in other countries have also found poorer outcomes in women from lower socioeconomic areas, and in some instances, have attributed this finding to more advanced stages of cancers at diagnosis and more limited treatment. The reasons are likely to vary with the country and health system characteristics. What does this paper add? The present study found that in Australia, women from lower socioeconomic areas do not have more advanced cancers at diagnosis, nor, in general, other cancer features that would predispose them to poorer outcomes. The standout differences were that they tended more to live in areas that were more remote from specialist metropolitan centres and were more likely to be treated in regional settings where prior research has indicated poorer outcomes. The reasons for these poorer outcomes are not known but may include lower levels of surgical specialisation, less access to specialised adjunctive services, and less involvement with multidisciplinary teams. Women from lower socioeconomic areas also appeared more likely to attend lower case load surgeons. Little difference was evident in the type of clinical care received, although women from lower socioeconomic areas were less likely to be asymptomatic referrals from other clinical settings (excluding BreastScreen). What are the implications for practitioners? Results suggest that poorer outcomes in women from lower socioeconomic areas in Australia may have less to do with the characteristics of their breast cancers or treatment modalities and more to do with health system features, such as access to specialist centres. This study highlights the importance of demographic and health system features as potentially key factors in service outcomes. Health system research should be strengthened in Australia to augment biomedical and clinical research, with a view to best meeting service needs of all sectors of the population.

Survival from breast cancer: an analysis of Australian data by surgeon case load, treatment centre location, and health insurance status.

OBJECTIVE: Early invasive breast cancer data from the Australian National Breast Cancer Audit were used to compare case fatality by surgeon case load, treatment centre location and health insurance status. METHOD: Deaths were traced to 31 December 2007, for cancers diagnosed in 1998-2005. Risk of breast cancer death was compared using Cox proportional hazards regression. RESULTS: When adjustment was made for age and clinical risk factors: (i) the relative risk of breast cancer death (95% confidence limit) was lower when surgeons' annual case loads exceeded 20 cases, at 0.87 (0.76, 0.995) for 21-100 cases and 0.83 (0.72, 0.97) for higher case loads. These relative risks were not statistically significant when also adjusting for treatment centre location (P ≥ 0.15); and (ii) compared with major city centres, inner regional centres had a relative risk of 1.32 (1.18, 1.48), but the risk was not elevated for more remote sites at 0.95 (0.74, 1.22). Risk of death was not related to private insurance status. CONCLUSION: Higher breast cancer mortality in patients treated in inner regional than major city centres and in those treated by surgeons with lower case loads requires further study.

National Breast Cancer Audit: overview of invasive breast cancer in New Zealand.

INTRODUCTION: The National Breast Cancer Audit collects data on the care of early breast cancer patients in Australia and New Zealand. An overview of invasive breast cancer in New Zealand is presented with emphasis on comparing the screened population with symptomatic referrals. METHODS: All New Zealand data in the National Breast Cancer Audit with a diagnosis date of 2008 have been included in the report. Data was analysed with an aim to compare the presenting features and management of screen detected invasive cancer with symptomatic referrals in New Zealand. RESULTS: There were 2371 cases of breast cancer, 52% of which were symptomatic referrals, 37% of which were BreastScreen Aotearoa referrals. Higher breast conservation rates were reported in the screening population. 3% of patients had involved margins after surgery. Almost two-thirds (62%) of BreastScreen patients underwent a sentinel node biopsy without further axillary surgery. 72% of screening patients and 86% of symptomatic patients who were high risk did not receive post mastectomy radiotherapy. A larger proportion of symptomatic patients received chemotherapy. Endocrine therapy was prescribed to 81% of hormone receptor positive patients. CONCLUSION: Patients with early invasive breast cancer in New Zealand were managed appropriately according to audit performance indicators and clinical guidelines. The numbers of high risk patients not receiving post mastectomy radiotherapy and the lack of endocrine treatment in some patients with hormone receptor positive tumours may warrant further investigation.

Age effects on survival from early breast cancer in clinical settings in Australia.

BACKGROUND: The study aim was to determine whether age is an independent risk factor for survival from early invasive breast cancer in contemporary Australian clinical settings. METHODS: The study included 31 493 breast cancers diagnosed in 1998-2005. Risk of death from breast cancer was compared by age, without and with adjustment for clinical risk factors, using Cox proportional hazard regression. RESULTS: Risk of breast cancer death was elevated for cancers of larger size, higher grade, positive nodal status, oestrogen receptor negative status, vascular invasion and multiple foci. Ductal lesions presented a higher risk than other lesions. Adjusting for these factors, the relative risk of breast cancer death (95% confidence limits) was lower for 40-49-year-olds at 0.80 (0.66, 0.96) than for the reference category under 40 years, but higher for 70-79-year-olds at 1.64 (1.36, 1.98) and women aged 80 years or more at 2.19 (1.79, 2.69). The risk for 50-69-year-olds and women under 40 years was similar. Risk-factor adjustment reduced the difference in risk between the reference category under 40 years and 40-49-year-olds, largely eliminated the lower relative risk for 50-69-year-olds, and increased the relative risks for women aged 70-79 years and older. DISCUSSION: Survivals in women under 40 and over 70 years of age are poorer than for 40-69-year-olds. Research is needed into the best treatment modalities for younger women and older women with co-morbidity.

Adherence to recommended treatments for early invasive breast cancer: decisions of women attending surgeons in the breast cancer audit of Australia and New Zealand.

AIM: The study aim was to determine the frequency with which women decline clinicians' treatment recommendations and variations in this frequency by age, cancer and service descriptors. DESIGN: The study included 36,775 women diagnosed with early invasive breast cancer in 1998-2005 and attending Australian and New Zealand breast surgeons. Rate ratios for declining treatment were examined by descriptor, using bilateral and multiple logistic regression analyses. Proportional hazards regression was used in exploratory analyses of associations with breast cancer death. RESULTS: 3.4% of women declined a recommended treatment of some type, ranging from 2.6% for women under 40 years to 5.8% for those aged 80 years or more, and with parallel increases by age presenting for declining radiotherapy (p<0.001) and axillary surgery (p=0.006). Multiple regression confirmed that common predictors of declining various treatments included low surgeon case load, treatment outside major city centres, and older age. Histological features suggesting a favourable prognosis were often predictive of declining various treatments, although reverse findings also applied with women with positive nodal status being more likely to decline a mastectomy and those with larger tumours more likely to decline chemotherapy. While survival analyses lacked statistical power due to small numbers, higher risks of breast cancer death were suggested, after adjusting for age and conventional clinical risk factors, (1) for women not receiving breast surgery for unstated reasons (RR=2.29; p<0.001); and (2) although not approaching statistical significance p≥ 0.200), for women declining radiotherapy (RR=1.22), a systemic therapy (RR1.11), and more specifically, chemotherapy (RR=1.41). CONCLUSIONS: Women have the right to choose their treatments but reasons for declining recommendations require further study to ensure that choices are well informed and clinical outcomes are optimized.

Effective inhibition of aromatase inhibitor-associated bone loss by zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: ZO-FAST Study results.

BACKGROUND: Letrozole is safe and effective in postmenopausal women with estrogen receptor-positive early breast cancer, but long-term aromatase inhibitor use may cause bone loss and increase fracture risk. This study evaluated an immediate or delayed strategy of bone protection therapy with zoledronic acid. METHODS: A total of 1065 patients who were receiving adjuvant letrozole were randomized to immediate-start or delayed-start zoledronic acid (4 mg intravenously biannually for 5 years). The delayed group received zoledronic acid if lumbar spine or total hip T-score decreased below -2.0 or when a nontraumatic fracture occurred. The primary endpoint was change in lumbar spine bone mineral density (BMD) at Month 12. Secondary endpoints included changes in total hip BMD, serum bone turnover markers, and safety at Month 12. RESULTS: Lumbar spine BMD increased from baseline in the immediate arm, while it decreased from baseline in delayed-arm patients. At Month 12, the differences between the groups in lumbar spine and total hip BMD were 5.7% (P < .0001; 95% confidence intervals [CI], 5.2% to 6.1%), and 3.6% (P < .0001; 95% CI, 3.3 to 4.0%), respectively. Both regimens were well tolerated with few serious adverse events. Bone pain was higher in the immediate group, as expected, because some patients experienced acute-phase reactions after zoledronic acid infusion. CONCLUSIONS: At 12 months, immediate zoledronic acid therapy prevented bone loss in postmenopausal women who were receiving adjuvant letrozole.

Improved breast cytology results with near patient FNA diagnosis.

OBJECTIVE: To examine the impact of a cytopathologist using near patient fine needle aspiration diagnosis (NPFD) for breast diagnosis. STUDY DESIGN: The cytology results of all palpable solid breast lesions undergoing fine needle aspiration (FNA) during a two-year period were prospectively audited and categorized as definitely benign or malignant (definite), probably benign, indeterminate or suspicious (indefinite) or unsatisfactory. The final diagnosis (benign or malignant) was determined from a review of patients' charts and a survey of patients' family physicians. Aspirates were performed by surgical staffand reported either later (non-NPFD) or by NPFD. RESULTS: Of 720 FNAs, 230 were by NPFD and 490 by non-NPFD. NPFD was associated with a significantly greater proportion of definite reports (91.9% versus 82.4%). NPFD of discrete breast lumps was associated with higher specificity (89.1% versus 67.5%) and a lower unsatisfactory rate (9.4% versus 19.6%) than non-NPFD. NPFD did not improve the unsatisfactory rate of FNAs from diffuse breast thickenings. CONCLUSION: FNA by a dedicated specialist and immediate reporting should be an integral part of a breast diagnostic service.