Targeting homologous recombination deficiency in uterine leiomyosarcoma.

BACKGROUND: Uterine leiomyosarcoma (uLMS) is a rare and aggressive gynaecological malignancy, with individuals with advanced uLMS having a five-year survival of < 10%. Mutations in the homologous recombination (HR) DNA repair pathway have been observed in ~ 10% of uLMS cases, with reports of some individuals benefiting from poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) therapy, which targets this DNA repair defect. In this report, we screened individuals with uLMS, accrued nationally, for mutations in the HR repair pathway and explored new approaches to therapeutic targeting. METHODS: A cohort of 58 individuals with uLMS were screened for HR Deficiency (HRD) using whole genome sequencing (WGS), whole exome sequencing (WES) or NGS panel testing. Individuals identified to have HRD uLMS were offered PARPi therapy and clinical outcome details collected. Patient-derived xenografts (PDX) were generated for therapeutic targeting. RESULTS: All 13 uLMS samples analysed by WGS had a dominant COSMIC mutational signature 3; 11 of these had high genome-wide loss of heterozygosity (LOH) (> 0.2) but only two samples had a CHORD score > 50%, one of which had a homozygous pathogenic alteration in an HR gene (deletion in BRCA2). A further three samples harboured homozygous HRD alterations (all deletions in BRCA2), detected by WES or panel sequencing, with 5/58 (9%) individuals having HRD uLMS. All five individuals gained access to PARPi therapy. Two of three individuals with mature clinical follow up achieved a complete response or durable partial response (PR) with the subsequent addition of platinum to PARPi upon minor progression during initial PR on PARPi. Corresponding PDX responses were most rapid, complete and sustained with the PARP1-specific PARPi, AZD5305, compared with either olaparib alone or olaparib plus cisplatin, even in a paired sample of a BRCA2-deleted PDX, derived following PARPi therapy in the patient, which had developed PARPi-resistance mutations in PRKDC, encoding DNA-PKcs. CONCLUSIONS: Our work demonstrates the value of identifying HRD for therapeutic targeting by PARPi and platinum in individuals with the aggressive rare malignancy, uLMS and suggests that individuals with HRD uLMS should be included in trials of PARP1-specific PARPi.

Addition of endocrine therapy to dual anti-HER2 targeted therapy in initial treatment of HER2 + /HR + metastatic breast cancer.

PURPOSE: Dual anti-HER2 targeted therapy and chemotherapy is the current first-line standard of care for HER2 + metastatic breast cancer (MBC), with endocrine therapy (ET) the backbone of treatment in hormone receptor positive (HR +) disease. The potential ET benefit in HER2 + /HR + patients is unknown as pivotal dual anti-HER2 clinical trials precluded ET use. METHODS: Real-world data from a multi-site registry of consecutive HER2 + MBC patients treated at clinician discretion were examined. Patients that were HR + (ER + and/or PR +) and had received first-line chemotherapy alongside trastuzumab and pertuzumab were explored. Of 362 patients in the registry, 215 were excluded due to being HR- (n = 210) or not receiving chemotherapy (n = 5). RESULTS: Of the 147 patients included, 91 (62%) received concurrent ET and 56 (38%) had not. Comparing the groups, there were no significant differences in age, performance status, metastatic sites, use of previous therapy and de novo metastatic disease. More patients with ER + PR + disease versus those with ER + PR- or ER-PR + received ET (73 vs 45%). The addition of ET was associated with significantly improved 5-year PFS (HR 0.58, CI 0.37-0.89, p = 0.014) and OS (HR 0.52, CI 0.31-0.90, p = 0.018), with no increase in adverse events noted. CONCLUSION: The addition of ET to first-line dual anti-HER2 therapy post chemotherapy in patients with HER2 + /HR + MBC was associated with major gains in PFS and OS with no safety concerns evident. Further studies of this combination are justified, along with studies of how best to integrate other agents that are active in this patient subset, including CDK4/6 inhibitors.

Immune and genomic biomarkers of immunotherapy response in cancer of unknown primary.

BACKGROUND: Cancer of unknown primary (CUP) is a heterogeneous group of metastatic cancers where a primary tissue of origin (TOO) is uncertain. Most patients with CUP have limited treatment options and poor survival outcomes. Immune checkpoint inhibitors (ICIs) can be efficacious in some patients with CUP, but the optimal predictive biomarkers are unknown. We therefore assessed immune and genomic biomarkers as well as predicted TOO in patients with CUP, including a subset treated with ICIs. METHODS: Patients with CUP were subject to gene-expression profiling (GEP) and DNA panel sequencing. Immune and stromal-related gene expression was explored by NanoString, including genes associated with immunotherapy response (IR) in other solid malignancies. ICI responsive cancer types were assigned based on Food and Drug Administration-approved indications, and either detection of a latent primary tumor or the TOO was suspected based on genomics informed pathology review. Tumor mutation burden (TMB) and gene mutations were also assessed. RESULTS: A total of 219 patients with CUP were included, 215 assessed for TOO in a previous study, with the majority (163) receiving both RNA and DNA tests. Of GEP profiled cases, 33% (59/175) had a high IR gene-expression score. Of the DNA sequenced cases, 16% (32/203) had high TMB (>10 mutations/Mb), including two with mismatch repair deficiency. Low correlation was observed between TMB and an IR score (R=0.26, p<0.001). Among 110 CUPs with a latent primary or suspected TOO, 47% (52/110) belonged to ICI-responsive cancer types. More than half of the CUPs had at least one feature that may predict ICI response (high IR score, high TMB, ICI-responsive cancer type). Among patients with CUP treated with ICIs, 8/28 (29%) responded (2 complete responses and 6 partial responses). Among non-responders, 9 had stable and 11 had progressive disease. All responders had a high IR score (7/8) and/or high TMB (3/8), while most (5/8) belonged to ICI-responsive cancer types. These features were detected at a lower frequency in non-responders and mostly in patients with stable disease. CONCLUSIONS: A significant fraction of CUP tumors had genomic features previously associated with ICI response. High IR score was the most sensitive predictive feature of ICI response, warranting evaluation in a larger patient series.

Workforce challenges across Victorian medical oncology services.

BACKGROUND: Cancer incidence is growing, with increasing treatment options and durations. This has led to an increase workload on the current oncology workforce. The global pandemic has increased this pressure further. AIMS: To determine the current medical oncology workforce in Victoria, current shortfalls and future anticipated shortfalls beyond the COVID-19 pandemic. METHODS: A self-reported, cross-sectional observational study of all current adult Victorian cancer services in June 2020 examining workforce, workload and early effects of the COVID-19 pandemic. RESULTS: The current average workload of 242 new patients per full-time equivalent consultant in medical oncology across Victoria. This is higher than optimal to deliver a safe and efficient cancer service. The significant variation in workforce between sites highlights the areas in need of most urgent resource allocation. Use of safe prescribing practises such as electronic chemotherapy prescribing are not universal but urgently needed. CONCLUSIONS: The medical oncology workforce in Victoria is inadequate to meet current and future demands. This needs to be addressed urgently to avoid an adverse impact on cancer measures and quality standards. Better, standardised data collection is needed to allow for ongoing measures of workforce activity. Novel workforce solutions will also need to be implemented in the short and medium term in the face of global workforce shortages.

A comparison of DNA sequencing and gene expression profiling to assist tissue of origin diagnosis in cancer of unknown primary.

Cancer of unknown primary (CUP) is a syndrome defined by clinical absence of a primary cancer after standardised investigations. Gene expression profiling (GEP) and DNA sequencing have been used to predict primary tissue of origin (TOO) in CUP and find molecularly guided treatments; however, a detailed comparison of the diagnostic yield from these two tests has not been described. Here, we compared the diagnostic utility of RNA and DNA tests in 215 CUP patients (82% received both tests) in a prospective Australian study. Based on retrospective assessment of clinicopathological data, 77% (166/215) of CUPs had insufficient evidence to support TOO diagnosis (clinicopathology unresolved). The remainder had either a latent primary diagnosis (10%) or clinicopathological evidence to support a likely TOO diagnosis (13%) (clinicopathology resolved). We applied a microarray (CUPGuide) or custom NanoString 18-class GEP test to 191 CUPs with an accuracy of 91.5% in known metastatic cancers for high-medium confidence predictions. Classification performance was similar in clinicopathology-resolved CUPs - 80% had high-medium predictions and 94% were concordant with pathology. Notably, only 56% of the clinicopathology-unresolved CUPs had high-medium confidence GEP predictions. Diagnostic DNA features were interrogated in 201 CUP tumours guided by the cancer type specificity of mutations observed across 22 cancer types from the AACR Project GENIE database (77,058 tumours) as well as mutational signatures (e.g. smoking). Among the clinicopathology-unresolved CUPs, mutations and mutational signatures provided additional diagnostic evidence in 31% of cases. GEP classification was useful in only 13% of cases and oncoviral detection in 4%. Among CUPs where genomics informed TOO, lung and biliary cancers were the most frequently identified types, while kidney tumours were another identifiable subset. In conclusion, DNA and RNA profiling supported an unconfirmed TOO diagnosis in one-third of CUPs otherwise unresolved by clinicopathology assessment alone. DNA mutation profiling was the more diagnostically informative assay. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Real-World Outcomes in Patients With Brain Metastases Secondary to HER2-Positive Breast Cancer: An Australian Multi-centre Registry-based Study.

BACKGROUND: The development of brain metastases occurs commonly in HER2-positive metastatic breast cancer and is associated with a poorer prognosis. The advent of HER2-targeted therapy has improved overall survival, but the benefit in patients with brain metastases is unclear, as these patients are often excluded from clinical trials. This study aimed to explore real-world outcomes in patients with brain metastases in HER2-positive MBC. MATERIALS & METHODS: Data was extracted from the TABITHA registry, which consists of patient data collected prospectively from 16 Australian sites from 24th February 2015 to 31st October 2021. Data analysed included characteristics of brain metastases, treatment received and survival outcomes. RESULTS: A total of 135 (37%) of 361 patients with HER2-positive MBC were diagnosed with brain metastases during their clinical course, including 45 (12%) with brain metastases at time of MBC diagnosis. 61 (45%) had ≥4 brain lesions. The most common local therapy given was whole brain radiation therapy (WBRT) (36%) followed by multi-modality treatment with both surgery and radiation therapy (27%). The majority of patients received first-line HER2-targeted treatment with trastuzumab and pertuzumab followed by second-line trastuzumab emtansine (T-DM1) but third-line therapy was heterogenous. The median overall survival in patients who developed brain metastases was significantly shorter than those who did not develop brain metastases (58.9 vs. 96.1 months, P = .02). CONCLUSION: Real-world patients diagnosed with brain metastases in HER2-positive MBC have a relatively poor prognosis, despite advances in HER2-targeted treatment. As the range of HER2-targeted treatment expands, it is important to pursue clinical trials that focus on patients with brain metastases.

Uncertainty and the unmet informational needs of patients with cancer of unknown primary (CUP): a cross-sectional multi-site study.

OBJECTIVE: This study aimed to determine the healthcare experiences, quality of life, and psychosocial needs of patients with cancer of unknown primary (CUP) early after diagnosis; comparing their experiences to patients with advanced cancer of a known primary (non-CUP control patients) and published general population reference data where available. METHODS: This study was a cross-sectional, multi-site study comparing CUP patients (n = 139) compared to non-CUP controls (n = 45). Demographic, clinical information and patient-reported outcome questionnaire data were collected at baseline. RESULTS: Differences in healthcare experienced were found between CUP and non-CUP controls with CUP patients reporting higher scores for unmet medical communication/information needs compared with non-CUP control patients (p = 0.013) as well as greater uncertainty in illness (p = 0.042). Whilst no differences were found between CUP and non-CUP controls on the EORTC and PROMIS measures, of those that 'received written information about your cancer…' and asked '…how useful was it?' fewer CUP patients reported finding the information useful 40% vs 61%, and more were likely to not have received written information at all 59% vs 32%; (p = 0.002). Additionally, of those that found information about their cancer online, fewer patients with CUP reported finding it useful 32% vs 48% control patients (p = 0.005). CONCLUSIONS: CUP patients have unmet medical communication/information needs and greater uncertainty in illness but do not differ in health-related quality of life domains compared to patients with advanced cancer of a known primary.

Prostate cancer survival in South West Victoria.

OBJECTIVE: To explore reasons for survival disparities for patients with prostate cancer in the Barwon South West area of Victoria. DESIGN, SETTING AND PARTICIPANTS: We have described incidence, diagnostics, treatment pathways, and survival for four regions of the Barwon South Western Victoria. Analysis included all newly diagnosed prostate cancer patients from 2009 to 2015 in the Evaluation of Cancer Outcomes Barwon South West Registry. Regions included 1: Queenscliffe 2: Geelong, Colac Otway and Corangamite 3: Moyne, Warrnambool and Southern Grampians and 4: Glenelg. Across the four regions, variables were compared using a chi square statistic or analysis of variance and survival data was assessed with the Kaplan-Meier curves. MAIN OUTCOME MEASURES: Incidence, treatment pathways and survival for prostate cancer patients. RESULTS: A total of 1776 patients were diagnosed with prostate cancer from 2009 to 2015 in the Barwon South West area. In regions 1-4, there were 298 (1.04%), 1085 (0.92%), 273 (0.97%) and 120 (1.2%) cases, respectively. There was no significant difference in Gleason score and treatment. The 5-year survival rate was 85%, 76%, 71% and 80%, respectively, as compared with the national average of 95%. PSA scores >20 ng/ml at diagnosis, as a surrogate for high-risk disease, occurred in 23%, 29%, 22% and 21%, respectively (p < 0.01). The proportions presenting with stage IV disease were 17%, 26%, 21% and 6%, respectively (p = 0.10). CONCLUSION: Men diagnosed with prostate cancer in South West Victoria have a considerably lower 5-year survival compared with the national average with later disease at presentation in some areas.

Uptake of bone-modifying agents in patients with HER2+ metastatic breast cancer with bone metastases - prospective data from a multi-site Australian registry.

BACKGROUND: International practice guidelines recommend administration of bone-modifying agents (BMA) in metastatic breast cancer (MBC) patients with bone metastases to reduce skeletal-related events (SRE). Optimal delivery of BMA in routine clinical practice, including agent selection and prescribing intervals, remains unclear. AIM: To describe real-world practice of Australian breast oncologists. METHODS: Prospective data from February 2015 to July 2020 on BMA delivery to MBC patients with bone metastases was analysed from Treatment of Advanced Breast Cancer in the Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Australian Patient (TABITHA), a multi-site Australian HER2+ MBC registry. RESULTS: Of 333 HER2+ MBC patients, 171 (51%) had bone metastases at diagnosis, with a mean age of 58.1 years (range, 32-87). One hundred and thirty (76%) patients received a BMA, with 90 (69%) receiving denosumab and 40 (31%) receiving a bisphosphonate. Patients who received a BMA were more likely to have received concurrent first-line systemic anti-HER2 therapy (95% vs 83%; P = 0.04), to present with bone-only metastases at diagnosis (24% vs 7%; P = 0.02) and less likely to have visceral metastases (51% vs 71%; P = 0.03). Ten of 40 (25%) bisphosphonate patients and 45 of 90 (50%) denosumab patients received their BMA at the recommended 4-weekly interval. Prescribing intervals varied over time. Adverse events reported were consistent with clinical trial data. CONCLUSION: Three-quarters of Australian HER2+ MBC patients with bone metastases receive a BMA, often at different schedules than guidelines recommend. Further studies, including all MBC subtypes, are warranted to better understand clinicians' prescribing rationale and potential consequences of current prescribing practice on SRE incidence.

Impact of prior (neo)adjuvant trastuzumab (NAT) exposure on the efficacy of HER2-targeted therapy for metastatic breast cancer.

PURPOSE: Trastuzumab, pertuzumab, and docetaxel are the standard first-line therapy for HER2-positive (HER2+) metastatic breast cancer (MBC). However, only 10% of patients received neoadjuvant and/or adjuvant trastuzumab (NAT) in the registration trial (NCT00567190). In contemporary practice, the majority of recurrent HER2+ MBC patients had prior NAT. We explore any impact of prior therapy on the efficacy of dual HER2-targeted antibody with taxane therapy for metastatic disease. METHODS: Utilising a prospective national registry, clinico-pathological, treatment, and outcome data for HER2+ MBC patients diagnosed between October 2006 and January 2019 were collected. Survival was estimated by the Kaplan-Meier method and compared among groups by log-rank test. RESULTS: Of 287 HER2+ MBC patients, 222 (77%) received first-line trastuzumab, pertuzumab, and taxane therapy. There were 130 (45%) with de novo MBC. Of the recurrent MBC patients 107/157 (68%) had received NAT. The median progression-free survival (PFS) among patients who received NAT was 15.8 months compared with 24.3 months without prior NAT (hazard ratio [HR] 1.45, 95% CI 1.05-2.03, p = 0.03). The median overall survival (OS) was 42.7 months in patients who had NAT, and was not reached in those who did not (HR 1.80, 95% CI 1.12-2.90, p = 0.02). However, when excluding de novo MBC patients, prior NAT exposure was no longer significantly associated with survival (p = 0.11). De novo MBC patients had the longest median PFS (25.2 months) and OS (91.2 months). CONCLUSIONS: Prior receipt of NAT was associated with inferior median PFS following first-line HER2-based therapy in the metastatic setting. However, prior NAT exposure did not significantly impact OS, supporting the efficacy of taxane, trastuzumab, pertuzumab combination for first-line HER2+ MBC regardless of prior NAT exposure. Patients with de novo MBC had the longest survival, suggesting stratification for synchronous versus metachronous disease in prospective clinical trials of MBC should be considered.

Accuracy of Risk Estimates from the iPrevent Breast Cancer Risk Assessment and Management Tool.

BACKGROUND: iPrevent is an online breast cancer (BC) risk management decision support tool. It uses an internal switching algorithm, based on a woman's risk factor data, to estimate her absolute BC risk using either the International Breast Cancer Intervention Study (IBIS) version 7.02, or Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm version 3 models, and then provides tailored risk management information. This study assessed the accuracy of the 10-year risk estimates using prospective data. METHODS: iPrevent-assigned 10-year invasive BC risk was calculated for 15 732 women aged 20-70 years and without BC at recruitment to the Prospective Family Study Cohort. Calibration, the ratio of the expected (E) number of BCs to the observed (O) number and discriminatory accuracy were assessed. RESULTS: During the 10 years of follow-up, 619 women (3.9%) developed BC compared with 702 expected (E/O = 1.13; 95% confidence interval [CI] =1.05 to 1.23). For women younger than 50 years, 50 years and older, and BRCA1/2-mutation carriers and noncarriers, E/O was 1.04 (95% CI = 0.93 to 1.16), 1.24 (95% CI = 1.11 to 1.39), 1.13 (95% CI = 0.96 to 1.34), and 1.13 (95% CI = 1.04 to 1.24), respectively. The C-statistic was 0.70 (95% CI = 0.68 to 0.73) overall and 0.74 (95% CI = 0.71 to 0.77), 0.63 (95% CI = 0.59 to 0.66), 0.59 (95% CI = 0.53 to 0.64), and 0.65 (95% CI = 0.63 to 0.68), respectively, for the subgroups above. Applying the newer IBIS version 8.0b in the iPrevent switching algorithm improved calibration overall (E/O = 1.06, 95% CI = 0.98 to 1.15) and in all subgroups, without changing discriminatory accuracy. CONCLUSIONS: For 10-year BC risk, iPrevent had good discriminatory accuracy overall and was well calibrated for women aged younger than 50 years. Calibration may be improved in the future by incorporating IBIS version 8.0b.

The iPrevent Online Breast Cancer Risk Assessment and Risk Management Tool: Usability and Acceptability Testing.

BACKGROUND: iPrevent estimates breast cancer (BC) risk and provides tailored risk management information. OBJECTIVE: The objective of this study was to assess the usability and acceptability of the iPrevent prototype. METHODS: Clinicians were eligible for participation in the study if they worked in primary care, breast surgery, or genetics clinics. Female patients aged 18-70 years with no personal cancer history were eligible. Clinicians were first familiarized with iPrevent using hypothetical paper-based cases and then actor scenarios; subsequently, they used iPrevent with their patients. Clinicians and patients completed the System Usability Scale (SUS) and an Acceptability questionnaire 2 weeks after using iPrevent; patients also completed measures of BC worry, anxiety, risk perception, and knowledge pre- and 2 weeks post-iPrevent. Data were summarized using descriptive statistics. RESULTS: The SUS and Acceptability questionnaires were completed by 19 of 20 clinicians and 37 of 43 patients. Usability was above average (SUS score >68) for 68% (13/19) clinicians and 76% (28/37) patients. The amount of information provided by iPrevent was reported as "about right" by 89% (17/19) clinicians and 89% (33/37) patients and 95% (18/19) and 97% (36/37), respectively, would recommend iPrevent to others, although 53% (10/19) clinicians and 27% (10/37) patients found it too long. Exploratory analyses suggested that iPrevent could improve risk perception, decrease frequency of BC worry, and enhance BC prevention knowledge without changing state anxiety. CONCLUSIONS: The iPrevent prototype demonstrated good usability and acceptability. Because concerns about length could be an implementation barrier, data entry has been abbreviated in the publicly available version of iPrevent.

Influence of socioeconomic factors and distance to radiotherapy on breast-conserving surgery rates for early breast cancer in regional Australia; implications of change.

AIMS: Breast conserving surgery rates are affected by many factors including distance to radiotherapy and tumor-related features. Numerous studies have found women who must travel further for radiotherapy are more likely to choose mastectomy and avoid radiotherapy. We examined relationships between socioeconomic group, distance to radiotherapy services and mastectomy rates across a range of rural and metropolitan settings. METHODS: We used a dataset extracted from the Evaluation of Cancer Outcomes Barwon South Western Registry, which captured data on new breast cancer diagnoses in the southwest region of Victoria, Australia. Using logistic regression, we modeled treatment choice of women with early breast cancer (mastectomy vs breast conserving surgery) using explanatory variables that included distance to radiotherapy, and area-level socioeconomic data from the Australian Bureau of Statistics, while controlling for clinical factors. RESULTS: Mastectomy was associated with tumor size, nodal burden and younger age at surgery. Distance to a radiotherapy center was also strongly associated with increased rates of mastectomy for women who traveled 100-200 km for radiotherapy (odds ratio = 1.663; P = 0.03) compared to the reference group who were within 100 km of radiotherapy. No socioeconomic differences were seen between the two groups. CONCLUSION: A strong association between distance to radiotherapy and the type of surgery for early breast cancer was found. Improving access to radiotherapy therefore has the potential to improve breast cancer outcomes for women in regional Australia.

Anti-Müllerian hormone serum concentrations of women with germline BRCA1 or BRCA2 mutations.

STUDY QUESTION: Do women with ITALIC! BRCA1 or ITALIC! BRCA2 mutations have reduced ovarian reserve, as measured by circulating anti-Müllerian hormone (AMH) concentration? SUMMARY ANSWER: Women with a germline mutation in ITALIC! BRCA1 have reduced ovarian reserve as measured by AMH. WHAT IS KNOWN ALREADY: The DNA repair enzymes encoded by ITALIC! BRCA1 and ITALIC! BRCA2 are implicated in reproductive aging. Circulating AMH is a biomarker of ovarian reserve and hence reproductive lifespan. STUDY DESIGN, SIZE, DURATION: This was a cross-sectional study of AMH concentrations of 693 women at the time of enrolment into the Kathleen Cuningham Foundation Consortium for research in the Familial Breast Cancer (kConFab) cohort study (recruitment from 19 August 1997 until 18 September 2012). AMH was measured on stored plasma samples between November 2014 and January 2015 using an electrochemiluminescence immunoassay platform. PARTICIPANTS/MATERIALS, SETTING, METHODS: Eligible women were from families segregating ITALIC! BRCA1 or ITALIC! BRCA2 mutations and had known mutation status. Participants were aged 25-45 years, had no personal history of cancer, retained both ovaries and were not pregnant or breastfeeding at the time of plasma storage. Circulating AMH was measured for 172 carriers and 216 non-carriers from families carrying ITALIC! BRCA1 mutations, and 147 carriers and 158 non-carriers from families carrying ITALIC! BRCA2 mutations. Associations between plasma AMH concentration and carrier status were tested by linear regression, adjusted for age at plasma storage, oral contraceptive use, body mass index and cigarette smoking. MAIN RESULTS AND THE ROLE OF CHANCE: Mean AMH concentration was negatively associated with age ( ITALIC! P < 0.001). Mutation carriers were younger at blood draw than non-carriers ( ITALIC! P ≤ 0.031). ITALIC! BRCA1 mutation carriers had, on average, 25% (95% CI: 5%-41%, ITALIC! P = 0.02) lower AMH concentrations than non-carriers and were more likely to have AMH concentrations in the lowest quartile for age (OR 1.84, 95% CI: 1.11-303, ITALIC! P = 0.02). There was no evidence of an association between AMH concentration and ITALIC! BRCA2 mutation status ( ITALIC! P = 0.94). LIMITATIONS, REASONS FOR CAUTION: AMH does not directly measure the primordial follicle pool. The clinical implications of the lower AMH concentrations seen in ITALIC! BRCA1 mutation carriers cannot be assessed by this study design. WIDER IMPLICATIONS OF THE FINDINGS: Women with a germline mutation in ITALIC! BRCA1 may have reduced ovarian reserve. This is consistent with other smaller studies in the literature and has potential implications for fertility and reproductive lifespan. STUDY FUNDING/COMPETING INTERESTS: kConFab is supported by a grant from the Australian National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. K.A.P. is an Australian National Breast Cancer Foundation Practitioner Fellow. J.L.H. is a NHMRC Senior Principal Research Fellow. M.H. is a NHMRC Practitioner Fellow. R.A.A. reports personal fees from Roche Diagnostics & Beckman Coulter outside the submitted work and C.S. reports other earnings from Melbourne IVF outside the submitted work. The remaining authors have nothing to declare and no conflicts of interest.

iPrevent®: a tailored, web-based, decision support tool for breast cancer risk assessment and management.

We aimed to develop a user-centered, web-based, decision support tool for breast cancer risk assessment and personalized risk management. Using a novel model choice algorithm, iPrevent(®) selects one of two validated breast cancer risk estimation models (IBIS or BOADICEA), based on risk factor data entered by the user. Resulting risk estimates are presented in simple language and graphic formats for easy comprehension. iPrevent(®) then presents risk-adapted, evidence-based, guideline-endorsed management options. Development was an iterative process with regular feedback from multidisciplinary experts and consumers. To verify iPrevent(®), risk factor data for 127 cases derived from the Australian Breast Cancer Family Study were entered into iPrevent(®), IBIS (v7.02), and BOADICEA (v3.0). Consistency of the model chosen by iPrevent(®) (i.e., IBIS or BOADICEA) with the programmed iPrevent(®) model choice algorithm was assessed. Estimated breast cancer risks from iPrevent(®) were compared with those attained directly from the chosen risk assessment model (IBIS or BOADICEA). Risk management interventions displayed by iPrevent(®) were assessed for appropriateness. Risk estimation model choice was 100 % consistent with the programmed iPrevent(®) logic. Discrepant 10-year and residual lifetime risk estimates of >1 % were found for 1 and 4 cases, respectively, none was clinically significant (maximal variation 1.4 %). Risk management interventions suggested by iPrevent(®) were 100 % appropriate. iPrevent(®) successfully integrates the IBIS and BOADICEA risk assessment models into a decision support tool that provides evidence-based, risk-adapted risk management advice. This may help to facilitate precision breast cancer prevention discussions between women and their healthcare providers.

Assessing and managing breast cancer risk: clinicians' current practice and future needs.

Decision support tools for the assessment and management of breast cancer risk may improve uptake of prevention strategies. End-user input in the design of such tools is critical to increase clinical use. Before developing such a computerized tool, we examined clinicians' practice and future needs. Twelve breast surgeons, 12 primary care physicians and 5 practice nurses participated in 4 focus groups. These were recorded, coded, and analyzed to identify key themes. Participants identified difficulties assessing risk, including a lack of available tools to standardize practice. Most expressed confidence identifying women at potentially high risk, but not moderate risk. Participants felt a tool could especially reassure young women at average risk. Desirable features included: evidence-based, accessible (e.g. web-based), and displaying absolute (not relative) risks in multiple formats. The potential to create anxiety was a concern. Development of future tools should address these issues to optimize translation of knowledge into clinical practice.

Women's preferences for selective estrogen reuptake modulators: an investigation using protection motivation theory.

OBJECTIVE: Selective estrogen receptor modulators (SERMs) reduce breast cancer risk by 38%. However, uptake is low and the reasons are not well understood. This study applied protection motivation theory (PMT) to determine factors associated with intention to take SERMs. METHODS: Women at increased risk of breast cancer (N=107), recruited from two familial cancer clinics in Australia, completed a questionnaire containing measures of PMT constructs. Hierarchical multiple linear regression analysis was used to analyze the data. RESULTS: Forty-five percent of women said they would be likely or very likely to take SERMs in the future. PMT components accounted for 40% of variance in intention to take SERMs. Perceived vulnerability, severity and response efficacy appeared the most influential in women's decisions to take or not take SERMs. CONCLUSION: Many women are interested in SERMs as a risk management option. Accurate risk estimation and an understanding of the benefits of SERMs are critical to women's decision making. PRACTICE IMPLICATIONS: Health professionals need to explore women's perceptions of their risk and its consequences, as well as providing clear evidence-based information about the efficacy of SERMs. Exploring the source and strength of beliefs about SERMs may allow more effective, tailored counseling.