Christobel Saunders

Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): an international, prospective, randomised, non-inferiority phase 3 trial

BACKGROUND After breast-conserving surgery, 90% of local recurrences occur within the index quadrant despite the presence of multicentric cancers elsewhere in the breast. Thus, restriction of radiation therapy to the tumour bed during surgery might be adequate for selected patients. We compared targeted intraoperative radiotherapy with the conventional policy of whole breast external beam radiotherapy. METHODS Having safely piloted the new technique of single-dose targeted intraoperative radiotherapy with Intrabeam, we launched the TARGIT-A trial on March 24, 2000. In this prospective, randomised, non-inferiority trial, women aged 45 years or older with invasive ductal breast carcinoma undergoing breast-conserving surgery were enrolled from 28 centres in nine countries. Patients were randomly assigned in a 1:1 ratio to receive targeted intraoperative radiotherapy or whole breast external beam radiotherapy, with blocks stratified by centre and by timing of delivery of targeted intraoperative radiotherapy. Neither patients nor investigators or their teams were masked to treatment assignment. Postoperative discovery of predefined factors (eg, lobular carcinoma) could trigger addition of external beam radiotherapy to targeted intraoperative radiotherapy (in an expected 15% of patients). The primary outcome was local recurrence in the conserved breast. The predefined non-inferiority margin was an absolute difference of 2.5% in the primary endpoint. All randomised patients were included in the intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT00983684. FINDINGS 1113 patients were randomly allocated to targeted intraoperative radiotherapy and 1119 were allocated to external beam radiotherapy. Of 996 patients who received the allocated treatment in the targeted intraoperative radiotherapy group, 854 (86%) received targeted intraoperative radiotherapy only and 142 (14%) received targeted intraoperative radiotherapy plus external beam radiotherapy. 1025 (92%) patients in the external beam radiotherapy group received the allocated treatment. At 4 years, there were six local recurrences in the intraoperative radiotherapy group and five in the external beam radiotherapy group. The Kaplan-Meier estimate of local recurrence in the conserved breast at 4 years was 1.20% (95% CI 0.53-2.71) in the targeted intraoperative radiotherapy and 0.95% (0.39-2.31) in the external beam radiotherapy group (difference between groups 0.25%, -1.04 to 1.54; p=0.41). The frequency of any complications and major toxicity was similar in the two groups (for major toxicity, targeted intraoperative radiotherapy, 37 [3.3%] of 1113 vs external beam radiotherapy, 44 [3.9%] of 1119; p=0.44). Radiotherapy toxicity (Radiation Therapy Oncology Group grade 3) was lower in the targeted intraoperative radiotherapy group (six patients [0.5%]) than in the external beam radiotherapy group (23 patients [2.1%]; p=0.002). INTERPRETATION For selected patients with early breast cancer, a single dose of radiotherapy delivered at the time of surgery by use of targeted intraoperative radiotherapy should be considered as an alternative to external beam radiotherapy delivered over several weeks. FUNDING University College London Hospitals (UCLH)/UCL Comprehensive Biomedical Research Centre, UCLH Charities, National Institute for Health Research Health Technology Assessment programme, Ninewells Cancer Campaign, National Health and Medical Research Council, and German Federal Ministry of Education and Research (BMBF).

Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial

BACKGROUND The TARGIT-A trial compared risk-adapted radiotherapy using single-dose targeted intraoperative radiotherapy (TARGIT) versus fractionated external beam radiotherapy (EBRT) for breast cancer. We report 5-year results for local recurrence and the first analysis of overall survival. METHODS TARGIT-A was a randomised, non-inferiority trial. Women aged 45 years and older with invasive ductal carcinoma were enrolled and randomly assigned in a 1:1 ratio to receive TARGIT or whole-breast EBRT, with blocks stratified by centre and by timing of delivery of targeted intraoperative radiotherapy: randomisation occurred either before lumpectomy (prepathology stratum, TARGIT concurrent with lumpectomy) or after lumpectomy (postpathology stratum, TARGIT given subsequently by reopening the wound). Patients in the TARGIT group received supplemental EBRT (excluding a boost) if unforeseen adverse features were detected on final pathology, thus radiotherapy was risk-adapted. The primary outcome was absolute difference in local recurrence in the conserved breast, with a prespecified non-inferiority margin of 2·5% at 5 years; prespecified analyses included outcomes as per timing of randomisation in relation to lumpectomy. Secondary outcomes included complications and mortality. This study is registered with ClinicalTrials.gov, number NCT00983684. FINDINGS Patients were enrolled at 33 centres in 11 countries, between March 24, 2000, and June 25, 2012. 1721 patients were randomised to TARGIT and 1730 to EBRT. Supplemental EBRT after TARGIT was necessary in 15·2% [239 of 1571] of patients who received TARGIT (21·6% prepathology, 3·6% postpathology). 3451 patients had a median follow-up of 2 years and 5 months (IQR 12-52 months), 2020 of 4 years, and 1222 of 5 years. The 5-year risk for local recurrence in the conserved breast was 3·3% (95% CI 2·1-5·1) for TARGIT versus 1·3% (0·7-2·5) for EBRT (p=0·042). TARGIT concurrently with lumpectomy (prepathology, n=2298) had much the same results as EBRT: 2·1% (1·1-4·2) versus 1·1% (0·5-2·5; p=0·31). With delayed TARGIT (postpathology, n=1153) the between-group difference was larger than 2·5% (TARGIT 5·4% [3·0-9·7] vs EBRT 1·7% [0·6-4·9]; p=0·069). Overall, breast cancer mortality was much the same between groups (2·6% [1·5-4·3] for TARGIT vs 1·9% [1·1-3·2] for EBRT; p=0·56) but there were significantly fewer non-breast-cancer deaths with TARGIT (1·4% [0·8-2·5] vs 3·5% [2·3-5·2]; p=0·0086), attributable to fewer deaths from cardiovascular causes and other cancers. Overall mortality was 3·9% (2·7-5·8) for TARGIT versus 5·3% (3·9-7·3) for EBRT (p=0·099). Wound-related complications were much the same between groups but grade 3 or 4 skin complications were significantly reduced with TARGIT (four of 1720 vs 13 of 1731, p=0·029). INTERPRETATION TARGIT concurrent with lumpectomy within a risk-adapted approach should be considered as an option for eligible patients with breast cancer carefully selected as per the TARGIT-A trial protocol, as an alternative to postoperative EBRT. FUNDING University College London Hospitals (UCLH)/UCL Comprehensive Biomedical Research Centre, UCLH Charities, National Institute for Health Research Health Technology Assessment programme, Ninewells Cancer Campaign, National Health and Medical Research Council, and German Federal Ministry of Education and Research.

Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial

BACKGROUND Aromatase inhibitors effectively prevent breast cancer recurrence and development of new contralateral tumours in postmenopausal women. We assessed the efficacy and safety of the aromatase inhibitor anastrozole for prevention of breast cancer in postmenopausal women who are at high risk of the disease. METHODS Between Feb 2, 2003, and Jan 31, 2012, we recruited postmenopausal women aged 40-70 years from 18 countries into an international, double-blind, randomised placebo-controlled trial. To be eligible, women had to be at increased risk of breast cancer (judged on the basis of specific criteria). Eligible women were randomly assigned (1:1) by central computer allocation to receive 1 mg oral anastrozole or matching placebo every day for 5 years. Randomisation was stratified by country and was done with blocks (size six, eight, or ten). All trial personnel, participants, and clinicians were masked to treatment allocation; only the trial statistician was unmasked. The primary endpoint was histologically confirmed breast cancer (invasive cancers or non-invasive ductal carcinoma in situ). Analyses were done by intention to treat. This trial is registered, number ISRCTN31488319. FINDINGS 1920 women were randomly assigned to receive anastrozole and 1944 to placebo. After a median follow-up of 5·0 years (IQR 3·0-7·1), 40 women in the anastrozole group (2%) and 85 in the placebo group (4%) had developed breast cancer (hazard ratio 0·47, 95% CI 0·32-0·68, p<0·0001). The predicted cumulative incidence of all breast cancers after 7 years was 5·6% in the placebo group and 2·8% in the anastrozole group. 18 deaths were reported in the anastrozole group and 17 in the placebo group, and no specific causes were more common in one group than the other (p=0·836). INTERPRETATION Anastrozole effectively reduces incidence of breast cancer in high-risk postmenopausal women. This finding, along with the fact that most of the side-effects associated with oestrogen deprivation were not attributable to treatment, provides support for the use of anastrozole in postmenopausal women at high risk of breast cancer. FUNDING Cancer Research UK, the National Health and Medical Research Council Australia, Sanofi-Aventis, and AstraZeneca.

Volatile biomarkers in the breath of women with breast cancer

We sought biomarkers of breast cancer in the breath because the disease is accompanied by increased oxidative stress and induction of cytochrome P450 enzymes, both of which generate volatile organic compounds (VOCs) that are excreted in breath. We analyzed breath VOCs in 54 women with biopsy-proven breast cancer and 204 cancer-free controls, using gas chromatography/mass spectroscopy. Chromatograms were converted into a series of data points by segmenting them into 900 time slices (8 s duration, 4 s overlap) and determining their alveolar gradients (abundance in breath minus abundance in ambient room air). Monte Carlo simulations identified time slices with better than random accuracy as biomarkers of breast cancer by excluding random identifiers. Patients were randomly allocated to training sets or test sets in 2:1 data splits. In the training sets, time slices were ranked according their C-statistic values (area under curve of receiver operating characteristic), and the top ten time slices were combined in multivariate algorithms that were cross-validated in the test sets. Monte Carlo simulations identified an excess of correct over random time slices, consistent with non-random biomarkers of breast cancer in the breath. The outcomes of ten random data splits (mean (standard deviation)) in the training sets were sensitivity = 78.5% (6.14), specificity = 88.3% (5.47), C-statistic = 0.89 (0.03) and in the test sets, sensitivity = 75.3% (7.22), specificity = 84.8 (9.97), C-statistic = 0.83 (0.06). A breath test identified women with breast cancer, employing a combination of volatile biomarkers in a multivariate algorithm.

Analysis of cancer risk and BRCA1 and BRCA2 mutation prevalence in the kConFab familial breast cancer resource.

IntroductionThe Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab) is a multidisciplinary, collaborative framework for the investigation of familial breast cancer. Based in Australia, the primary aim of kConFab is to facilitate high-quality research by amassing a large and comprehensive resource of epidemiological and clinical data with biospecimens from individuals at high risk of breast and/or ovarian cancer, and from their close relatives.MethodsEpidemiological, family history and lifestyle data, as well as biospecimens, are collected from multiple-case breast cancer families ascertained through family cancer clinics in Australia and New Zealand. We used the Tyrer-Cuzick algorithms to assess the prospective risk of breast cancer in women in the kConFab cohort who were unaffected with breast cancer at the time of enrolment in the study.ResultsOf kConFabs first 822 families, 518 families had multiple cases of female breast cancer alone, 239 had cases of female breast and ovarian cancer, 37 had cases of female and male breast cancer, and 14 had both ovarian cancer as well as male and female breast cancer. Data are currently held for 11,422 people and germline DNAs for 7,389. Among the 812 families with at least one germline sample collected, the mean number of germline DNA samples collected per family is nine. Of the 747 families that have undergone some form of mutation screening, 229 (31%) carry a pathogenic or splice-site mutation in BRCA1 or BRCA2. Germline DNAs and data are stored from 773 proven carriers of BRCA1 or BRCA1 mutations. kConFabs fresh tissue bank includes 253 specimens of breast or ovarian tissue – both normal and malignant – including 126 from carriers of BRCA1 or BRCA2 mutations.ConclusionThese kConFab resources are available to researchers anywhere in the world, who may apply to kConFab for biospecimens and data for use in ethically approved, peer-reviewed projects. A high calculated risk from the Tyrer-Cuzick algorithms correlated closely with the subsequent occurrence of breast cancer in BRCA1 and BRCA2 mutation positive families, but this was less evident in families in which no pathogenic BRCA1 or BRCA2 mutation has been detected.

Breast cancer in young women and its impact on reproductive function

BACKGROUND Breast cancer is the most common cancer in women in developed countries, and 12% of breast cancer occurs in women 20–34 years. Survival from breast cancer has significantly improved, and the potential late effects of treatment and the impact on quality of life have become increasingly important. Young women constitute a minority of breast cancer patients, but commonly have distinct concerns and issues compared with older women, including queries regarding fertility, contraception and pregnancy. Further, they are more likely than older women to have questions regarding potential side effects of therapy and risk of relapse or a new primary. In addition, many will have symptoms associated with treatment and they present a management challenge. Reproductive medicine specialists and gynaecologists commonly see these women either shortly after initial diagnosis or following adjuvant therapy and should be aware of current management of breast cancer, the options for women at increased genetic risk, the prognosis of patients with early stage breast cancer and how adjuvant systemic treatments may impact reproductive function. METHODS No systematic literature search was done. The review focuses on the current management of breast cancer in young women and the impact of treatment on reproductive function and subsequent management. With reference to key studies and meta-analyses, we highlight controversies and current unanswered questions regarding patient management. RESULTS Chemotherapy for breast cancer is likely to negatively impact on reproductive function. A number of interventions are available which may increase the likelihood of future successful pregnancy, but the relative safety of these interventions is not well established. For those who do conceive following breast cancer, there is no good evidence that pregnancy is detrimental to survival. We review current treatment; effects on reproductive function; preservation of fertility; contraception; pregnancy; breastfeeding and management of menopausal symptoms following breast cancer. CONCLUSION This paper provides an update on the management of breast cancer in young women and is targeted at reproductive medicine specialists and gynaecologists.

Tolerability of hormone therapies for breast cancer: how informative are documented symptom profiles in medical notes for 'well-tolerated' treatments?

Hormonal therapies for cancer are often viewed as a gentler option than many other cancer treatments, but is low toxicity an accurate perception of patients’ experiences? Side effects tend to be described as minimal or well tolerated, yet published symptoms from hormonal therapy vary considerably in their descriptions and frequencies. Previous research has highlighted under-reporting of side effects by clinical staff so as part of a wider study examining tamoxifen and goserelin treatment as adjuvant therapy for breast cancer, treatment- related symptoms documented in medical notes were compared with those that patients reported during a research interview. There was a significant difference in the frequency of many side effects reported by the two methods in this study. Sixty four out of 72 (89%) women who had received adjuvant tamoxifen or goserelin had side effects recorded in their medical notes, compared with 74/75 (99%) reporting side effects at interview. We compared the published frequencies of commonly reported symptoms with those found ourselves. The discrepancies between patient-reported and clinician-recorded (usually from clinical trial data) symptom profiles were similar to those found in our study. Without accurate comprehensive side effect profiles for hormone therapies, prospective patients cannot make informed judgements on proposed treatments.

Practical clinical guidelines for assessing and managing menopausal symptoms after breast cancer

BACKGROUND The purpose of this study was to provide practical, evidence-based guidelines for evaluating and treating common menopausal symptoms following breast cancer. METHODS Literature review of the causes, assessment and management of menopausal symptoms in breast cancer patients. RESULTS A number of nonhormonal treatments are effective in treating hot flashes. Whether pharmacological treatment is given will depend on the severity of symptoms and on patient wishes. For severe and frequent hot flashes, the best data support the use of venlafaxine, paroxetine and gabapentin in women with breast cancer. Side-effects are relatively common with all these agents. For vaginal dryness, topical estrogen treatment is the most effective but the safety of estrogens following breast cancer is not established. There are limited data on effective treatments for sexual dysfunction during menopause. CONCLUSION Menopausal symptoms after breast cancer should be evaluated and managed as warranted using a systematic approach and may benefit from multidisciplinary input.

Making hard choices easier: a prospective, multicentre study to assess the efficacy of a fertility-related decision aid in young women with early-stage breast cancer

Background:Fertility is a priority for many young women with breast cancer. Women need to be informed about interventions to retain fertility before chemotherapy so as to make good quality decisions. This study aimed to prospectively evaluate the efficacy of a fertility-related decision aid (DA).Methods:A total of 120 newly diagnosed early-stage breast cancer patients from 19 Australian oncology clinics, aged 18–40 years and desired future fertility, were assessed on decisional conflict, knowledge, decision regret, and satisfaction about fertility-related treatment decisions. These were measured at baseline, 1 and 12 months, and were examined using linear mixed effects models.Results:Compared with usual care, women who received the DA had reduced decisional conflict (β=−1.51; 95%CI: −2.54 to 0.48; P=0.004) and improved knowledge (β=0.09; 95%CI: 0.01–0.16; P=0.02), after adjusting for education, desire for children and baseline uncertainty. The DA was associated with reduced decisional regret at 1 year (β=−3.73; 95%CI: −7.12 to −0.35; P=0.031), after adjusting for education. Women who received the DA were more satisfied with the information received on the impact of cancer treatment on fertility (P<0.001), fertility options (P=0.005), and rated it more helpful (P=0.002), than those who received standard care.Conclusion:These findings support widespread use of this DA shortly after diagnosis (before chemotherapy) among younger breast cancer patients who have not completed their families.

Management of menopausal symptoms in patients with breast cancer: an evidence-based approach

Increasing numbers of women have menopausal symptoms after treatment for breast cancer. These symptoms can result directly from cancer treatments (such as oophorectomy, ovarian suppression, chemotherapy-induced ovarian failure, and antioestrogens), as a spontaneous event, or after discontinuation of hormone-replacement therapy. The onset of menopausal symptoms after treatment for breast cancer can have a long-lasting effect on quality of life, body image, sexual function, and self esteem. Hormone-replacement therapy that contains oestrogen is the most effective treatment for menopausal symptoms in healthy women. However, evidence from one randomised controlled trial suggests that use of hormone replacement therapy after breast cancer raises the risk of recurrence and of new primary breast cancer. As the incidence of breast cancer increases and survival continues to improve, the number of women with menopausal symptoms will probably rise. Safe and effective non-hormonal treatments for severe menopausal symptoms after breast cancer are urgently needed. Few studies have addressed the management of menopausal symptoms after breast cancer, and the quality of studies is generally poor. Progestagens, and selective inhibitors of serotonin and norepinephrine reuptake seem to offer reasonable symptom palliation, but the long-term effectiveness and safety of these preparations is not known. We propose that the management of menopausal symptoms in patients with a history of cancer requires a patient-centred, but multidisciplinary, approach.