Assessment of body composition in breast cancer patients: concordance between transverse computed tomography analysis at the fourth thoracic and third lumbar vertebrae.

Introduction: Specific body composition markers derived from L3 axial computed tomography (CT) images predict clinical cancer outcomes, including chemotherapy toxicity and survival. However, this method is only applicable to those undergoing lumbar (L3) CT scanning, which is not universally conducted in early breast cancer cases. This study aimed to evaluate CT analysis at T4 as a feasible alternative marker of body composition in breast cancer. Method: All patients participated in the Investigating Outcomes from Breast Cancer: Correlating Genetic, Immunological, and Nutritional (BeGIN) Predictors observational cohort study (REC reference number: 14/EE/1297). Staging chest-abdomen-pelvic CT scan images from 24 women diagnosed with early breast cancer at University Hospital Southampton were analysed. Adipose tissue, skeletal muscle, and muscle attenuation were measured from the transverse CT slices' cross-sectional area (CSA) at T4 and L3. Adipose tissue and skeletal muscle area measurements were adjusted for height. Spearman's rank correlation coefficient analysis was used to determine concordance between body composition measurements using CT analysis at L3 and T4 regions. Results: Derived estimates for total adipose tissue, subcutaneous adipose tissue, and intramuscular adipose tissue mass following adjustment for height were highly concordant when determined from CSAs of CT slices at T4 and L3 (Rs = 0.821, p < 0.001; Rs = 0.816, p < 0.001; and Rs = 0.830, p < 0.001). In this cohort, visceral adipose tissue (VAT) and skeletal muscle estimates following height adjustment were less concordant when measured by CT at T4 and L3 (Rs = 0.477, p = 0.039 and Rs = 0.578, p = 0.003). The assessment of muscle attenuation was also highly concordant when measured by CT at T4 and L3 (Rs = 0.840, p < 0.001). Discussion: These results suggest that the CT analysis at T4 and L3 provides highly concordant markers for total adipose, subcutaneous adipose, and intramuscular adipose estimation, but not VAT, in this breast cancer population. High concordance between T4 and L3 was also found when assessing skeletal muscle attenuation. Lower concordance was observed for the estimates of skeletal muscle area, potentially explained by differences in the quantity and proportions of axial and appendicular muscle between the thorax and abdomen. Future studies will determine the value of T4 metrics as predictive tools for clinical outcomes in breast cancer.

The PARTNER trial of neoadjuvant olaparib with chemotherapy in triple-negative breast cancer.

PARTNER is a prospective, phase II-III, randomized controlled clinical trial that recruited patients with triple-negative breast cancer1,2, who were germline BRCA1 and BRCA2 wild type3. Here we report the results of the trial. Patients (n = 559) were randomized on a 1:1 basis to receive neoadjuvant carboplatin-paclitaxel with or without 150 mg olaparib twice daily, on days 3 to 14, of each of four cycles (gap schedule olaparib, research arm) followed by three cycles of anthracycline-based chemotherapy before surgery. The primary end point was pathologic complete response (pCR)4, and secondary end points included event-free survival (EFS) and overall survival (OS)5. pCR was achieved in 51% of patients in the research arm and 52% in the control arm (P = 0.753). Estimated EFS at 36 months in the research and control arms was 80% and 79% (log-rank P > 0.9), respectively; OS was 90% and 87.2% (log-rank P = 0.8), respectively. In patients with pCR, estimated EFS at 36 months was 90%, and in those with non-pCR it was 70% (log-rank P < 0.001), and OS was 96% and 83% (log-rank P < 0.001), respectively. Neoadjuvant olaparib did not improve pCR rates, EFS or OS when added to carboplatin-paclitaxel and anthracycline-based chemotherapy in patients with triple-negative breast cancer who were germline BRCA1 and BRCA2 wild type. ClinicalTrials.gov ID: NCT03150576 .

Impact of obesity, lifestyle factors and health interventions on breast cancer survivors.

The incidences of both breast cancer and obesity are rising in the UK. Obesity increases the risk of developing breast cancer in the postmenopausal population and leads to worse outcomes in those of all ages treated for early-stage breast cancer. In this review we explore the multifactorial reasons behind this association and the clinical trial evidence for the benefits of physical activity and dietary interventions in the early and metastatic patient groups. As more people with breast cancer are cured, and those with metastatic disease are living longer, cancer survivorship is becoming increasingly important. Therefore, ensuring the long-term implications of cancer and cancer treatment are addressed is vital. Although there remains a lack of definitive evidence that deliberate weight loss after a diagnosis of breast cancer reduces disease recurrence, a number of studies have reported benefits of weight loss and of physical activity. However, the limited data currently available mean that clinicians remain unclear on the optimal lifestyle advice to give their patients. Further high-quality research is needed to provide this evidence base, which will be required to optimise clinical care and for the commissioning of lifestyle interventions in the UK in breast cancer survivors.

Body composition and chemotherapy toxicity in women with early breast cancer (CANDO-3): protocol for an observational cohort study.

INTRODUCTION: Systemic anticancer therapy is given to selected patients with early breast cancer (EBC) before or after surgery with the aim of eradicating micrometastatic spread and reducing the risk of cancer recurrence. Chemotherapy treatment is most effective when patients receive the optimum dose, on time and without delays or reductions in their treatment doses. Most chemotherapy drugs are dosed according to body surface area calculated from a patient's height and weight. These calculations were however designed based on data from normal weight patients. This has resulted in uncertainty as to the optimal dosing for patients with different amounts of blood, muscle and fatty tissue (body composition). This study uses segmental bioelectrical impedance analysis (using the Seca mBCA 515) to determine whether differences in the measures of resistance and reactance, and derived estimates of body composition, are predictive of chemotherapy toxicity in the treatment of EBC. METHODS AND ANALYSIS: A prospective observational cohort study of women with EBC in whom adjuvant or neoadjuvant chemotherapy is planned. A total of 300 participants will be recruited across nine UK hospital sites. The primary outcome is to determine if higher fat mass index is associated with increased National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 grade 3 (or higher) chemotherapy toxicity. ETHICS AND DISSEMINATION: This study has received ethical approval from the South Central Hampshire B Research Ethics Committee, England (19/SC/0596: IRAS: 263666). The chief investigator and coinvestigators will be responsible for publication of the study findings in a peer-reviewed journal, on behalf of all collaborators. TRIAL REGISTRATION NUMBER: ISRCTN79577461.

The impact of race and ethnicity in breast cancer-disparities and implications for precision oncology.

Breast cancer is the most commonly diagnosed cancer worldwide and is one of the leading causes of cancer death. The incidence, pathological features, and clinical outcomes in breast cancer differ by geographical distribution and across racial and ethnic populations. Importantly, racial and ethnic diversity in breast cancer clinical trials is lacking, with both Blacks and Hispanics underrepresented. In this forum article, breast cancer researchers from across the globe discuss the factors contributing to racial and ethnic breast cancer disparities and highlight specific implications of precision oncology approaches for equitable provision of breast cancer care to improve outcomes and address disparities.

A Review of Modifiable Risk Factors in Young Women for the Prevention of Breast Cancer.

Breast cancer is the most common cancer diagnosis in women aged less than 40 years and the second most common cause of cancer death in this age group. Global rates of young onset breast cancer have risen steadily over the last twenty years. Although young women with breast cancer have a higher frequency of underlying pathogenic mutations in high penetrance breast cancer susceptibility genes (CSG) than older women, the vast majority of young breast cancer patients are not found to have a germline CSG mutation. There is therefore a need to inform young women regarding non-genetic breast cancer risk factors which have the potential to be influenced by changes in individual behaviour. A Pubmed search was performed using the search terms "young" or "early onset", and "breast cancer" and "modifiable risk". Titles and abstracts from peer-reviewed publications were screened for relevance. This review presents evidence for potentially modifiable risk factors of breast cancer risk in young women, including lifestyle factors (physical activity, body habitus, alcohol use, smoking, shift work and socioeconomic factors), reproductive and hormonal factors and iatrogenic risks. The extent to which these factors are truly modifiable is discussed and interactions between genetic and non-genetic risk factors are also addressed. Health care professionals have an opportunity to inform young women about breast health and risk when presenting at a "teachable moment", including the benefits of physical activity and alcohol habits as risk factor. More focussed discussions regarding individual personal risk and benefit should accompany conversations regarding reproductive health and take into consideration both non-modifiable and iatrogenic BC risk factors.

Cancer survivorship, excess body fatness and weight-loss intervention-where are we in 2020?

Earlier diagnosis and more effective treatments mean that the estimated number of cancer survivors in the United Kingdom is expected to reach 4 million by 2030. However, there is an increasing realisation that excess body fatness (EBF) is likely to influence the quality of cancer survivorship and disease-free survival. For decades, the discussion of weight management in patients with cancer has been dominated by concerns about unintentional weight loss, low body weight and interventions to increase weight, often re-enforced by the existence of the obesity paradox, which indicates that high body weight is associated with survival benefits for some types of cancer. However, observational evidence provides strong grounds for testing the hypothesis that interventions for promoting intentional loss of body fat and maintaining skeletal muscle in overweight and obese cancer survivors would bring important health benefits in terms of survival outcomes and long-term impact on treatment-related side effects. In this paper, we outline the need for studies to improve our understanding of the health benefits of weight-loss interventions, such as hypocaloric healthy-eating plans combined with physical activity. In particular, complex intervention trials that are pragmatically designed are urgently needed to develop effective, clinically practical, evidence-based strategies for reducing EBF and optimising body composition in people living with and beyond common cancers.

Multifocal breast cancers are more prevalent in BRCA2 versus BRCA1 mutation carriers.

Multifocal (MF)/multicentric (MC) breast cancer is generally considered to be where two or more breast tumours are present within the same breast, and is seen in ~10% of breast cancer cases. This study investigates the prevalence of multifocality/multicentricity in a cohort of BRCA1/2 mutation carriers with breast cancer from Northern Ireland via cross-sectional analysis. Data from 211 women with BRCA1/2 mutations (BRCA1-91, BRCA2-120) and breast cancer were collected including age, tumour focality, size, type, grade and receptor profile. The prevalence of multifocality/multicentricity within this group was 25% but, within subgroups, prevalence amongst BRCA2 carriers was more than double that of BRCA1 carriers (p = 0.001). Women affected by MF/MC tumours had proportionately higher oestrogen receptor positivity (p = 0.001) and lower triple negativity (p = 0.004). These observations are likely to be driven by the higher BRCA2 mutation prevalence observed within this cohort. The odds of a BRCA2 carrier developing MF/MC cancer were almost four-fold higher than a BRCA1 carrier (odds ratio: 3.71, CI: 1.77-7.78, p = 0.001). These findings were subsequently validated in a second, large independent cohort of patients with BRCA-associated breast cancers from a UK-wide multicentre study. This confirmed a significantly higher prevalence of MF/MC tumours amongst BRCA2 mutation carriers compared with BRCA1 mutation carriers. This has important implications for clinicians involved in the treatment of BRCA2-associated breast cancer, both in the diagnostic process, in ensuring that tumour focality is adequately assessed to facilitate treatment decision-making, and for breast surgeons, particularly if breast conserving surgery is being considered as a treatment option for these patients.

A Context-Specific Digital Alcohol Brief Intervention in Symptomatic Breast Clinics (Abreast of Health): Development and Usability Study.

BACKGROUND: Potentially modifiable risk factors account for approximately 23% of breast cancer cases. In the United Kingdom, alcohol consumption alone is held responsible for 8% to 10% of cases diagnosed every year. Symptomatic breast clinics focus on early detection and treatment, but they also offer scope for delivery of low-cost lifestyle interventions to encourage a cancer prevention culture within the cancer care system. Careful development work is required to effectively translate such interventions to novel settings. OBJECTIVE: The aim of this study was to develop a theory of change and delivery mechanism for a context-specific alcohol and lifestyle brief intervention aimed at women attending screening and symptomatic breast clinics. METHODS: A formative study combined evidence reviews, analysis of mixed method data, and user experience research to develop an intervention model, following the 6 Steps in Quality Intervention Development (6SQuID) framework. RESULTS: A Web app focused on improving awareness, encouraging self-monitoring, and reframing alcohol reduction as a positive choice to improve health was found to be acceptable to women. Accessing this in the clinic waiting area on a tablet computer was shown to be feasible. An important facilitator for change may be the heightened readiness to learn associated with a salient health visit (a teachable moment). Women may have increased motivation to change if they can develop a belief in their capability to monitor and, if necessary, reduce their alcohol consumption. CONCLUSIONS: Using the 6SQuID framework supported the prototyping and maximized acceptability and feasibility of an alcohol brief intervention for women attending symptomatic breast clinics, regardless of their level of alcohol consumption.

Alcohol use and breast cancer risk: A qualitative study of women's perspectives to inform the development of a preventative intervention in breast clinics.

OBJECTIVE: This study aimed to explore women's views about breast cancer risk and alcohol use, to inform the design of a prototype for an intervention in breast clinics about alcohol as a modifiable risk factor for breast cancer. METHODS: Women recruited in NHS breast screening and symptomatic clinics in Southampton, UK, were invited to take part in semi-structured telephone interviews or a focus group to discuss their perspectives of breast cancer risk, alcohol consumption and their information needs about these topics. Data were analysed thematically. Twenty-eight women took part in telephone interviews, and 16 attended one of three focus groups. RESULTS: While most women reported a personal responsibility for their health and were interested in advice about modifiable risk factors, few without (or prior to) experience of breast symptoms independently sought information. Many considered alcohol advice irrelevant as the association with breast cancer was largely unknown, and participants did not consider their drinking to be problematic. Women reported trusting information from health organisations like the NHS, but advice needs to be sensitive and non-blaming. CONCLUSION: NHS breast screening and symptomatic clinics offer a "teachable moment" to engage women with context-specific advice about alcohol and cancer risk that, if targeted correctly, may assist them in making informed lifestyle choices.

Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study.

BACKGROUND: Retrospective studies provide conflicting interpretations of the effect of inherited genetic factors on the prognosis of patients with breast cancer. The primary aim of this study was to determine the effect of a germline BRCA1 or BRCA2 mutation on breast cancer outcomes in patients with young-onset breast cancer. METHODS: We did a prospective cohort study of female patients recruited from 127 hospitals in the UK aged 40 years or younger at first diagnosis (by histological confirmation) of invasive breast cancer. Patients with a previous invasive malignancy (except non-melanomatous skin cancer) were excluded. Patients were identified within 12 months of initial diagnosis. BRCA1 and BRCA2 mutations were identified using blood DNA collected at recruitment. Clinicopathological data, and data regarding treatment and long-term outcomes, including date and site of disease recurrence, were collected from routine medical records at 6 months, 12 months, and then annually until death or loss to follow-up. The primary outcome was overall survival for all BRCA1 or BRCA2 mutation carriers (BRCA-positive) versus all non-carriers (BRCA-negative) at 2 years, 5 years, and 10 years after diagnosis. A prespecified subgroup analysis of overall survival was done in patients with triple-negative breast cancer. Recruitment was completed in 2008, and long-term follow-up is continuing. FINDINGS: Between Jan 24, 2000, and Jan 24, 2008, we recruited 2733 women. Genotyping detected a pathogenic BRCA mutation in 338 (12%) patients (201 with BRCA1, 137 with BRCA2). After a median follow-up of 8·2 years (IQR 6·0-9·9), 651 (96%) of 678 deaths were due to breast cancer. There was no significant difference in overall survival between BRCA-positive and BRCA-negative patients in multivariable analyses at any timepoint (at 2 years: 97·0% [95% CI 94·5-98·4] vs 96·6% [95·8-97·3]; at 5 years: 83·8% [79·3-87·5] vs 85·0% [83·5-86·4]; at 10 years: 73·4% [67·4-78·5] vs 70·1% [67·7-72·3]; hazard ratio [HR] 0·96 [95% CI 0·76-1·22]; p=0·76). Of 558 patients with triple-negative breast cancer, BRCA mutation carriers had better overall survival than non-carriers at 2 years (95% [95% CI 89-97] vs 91% [88-94]; HR 0·59 [95% CI 0·35-0·99]; p=0·047) but not 5 years (81% [73-87] vs 74% [70-78]; HR 1·13 [0·70-1·84]; p=0·62) or 10 years (72% [62-80] vs 69% [63-74]; HR 2·12 [0·82-5·49]; p= 0·12). INTERPRETATION: Patients with young-onset breast cancer who carry a BRCA mutation have similar survival as non-carriers. However, BRCA mutation carriers with triple-negative breast cancer might have a survival advantage during the first few years after diagnosis compared with non-carriers. Decisions about timing of additional surgery aimed at reducing future second primary-cancer risks should take into account patient prognosis associated with the first malignancy and patient preferences. FUNDING: Cancer Research UK, the UK National Cancer Research Network, the Wessex Cancer Trust, Breast Cancer Now, and the PPP Healthcare Medical Trust Grant.

Local Recurrence and Breast Oncological Surgery in Young Women With Breast Cancer: The POSH Observational Cohort Study.

OBJECTIVE: To assess clinical and surgical factors affecting local recurrence and survival in young breast cancer patients in the Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH). BACKGROUND: Emerging data suggest young age is a predictor of increased local recurrence. METHODS: POSH is a prospective cohort of 3024 women of 18 to 40 years with breast cancer. Cohort characteristics were grouped by mastectomy or BCS. Endpoints were local-recurrence interval (LRI), distant disease-free interval (DDFI), and overall survival (OS); described using cumulative-hazard and Kaplan-Meier plots and multivariable analyses by Flexible Parametric and Cox regression models. RESULTS: Mastectomy was performed in 1464 patients and breast-conserving surgery (BCS) in 1395. Patients undergoing mastectomy had larger tumors and higher proportions of positive family history, estrogen receptor+, progesterone receptor+, and/or human epidermal growth factor receptor 2+ tumors. Local events accounted for 15% of recurrences. LRI by surgical type varied over time with LRI similar at 18 months (1.0% vs 1.0%, P = 0.348) but higher for BCS at 5 and 10 years (5.3% vs 2.6%, P < 0.001; and 11.7% vs 4.9%, P < 0.001, respectively). Similar results were found in the adjusted model. Conversely, distant-metastases and deaths were lower for BCS but not after adjusting for prognostic factors. After mastectomy chest-wall radiotherapy was associated with improved LRI (hazard ratio, HR = 0.46, P = 0.015). Positive surgical margins, and development of local recurrence predicted for reduced DDFI (HR = 0.50, P < 0.001; and HR = 0.29, P = 0.001, respectively). CONCLUSIONS: Surgical extent appears less important for DDFI than completeness of excision or, where appropriate, chest-wall radiotherapy. Despite higher local-recurrence rates for BCS, surgical type does not influence DDFI or OS after adjusting for known prognostic factors in young breast cancer patients.

Mindfulness for the self-management of fatigue, anxiety, and depression in women with metastatic breast cancer: a mixed methods feasibility study.

The impact of living with metastatic breast cancer (MBC) is considerable and psychosocial support can be beneficial. Mindfulness-based stress reduction (MBSR) can help self-management of anxiety, depression, quality of life (QoL), and fatigue and has been evaluated in early-stage breast cancer but not MBC. This study investigated the acceptability and feasibility of providing MBSR for women with MBC and of introducing MBSR into a National Health Service (NHS) setting. A mixed methods convergent design was used. Eligible women with MBC, an Eastern Cooperative Oncology Group (ECOG) score of 0 to 2, stable disease, and life expectancy of at least 6 months were invited to attend (by their oncologist) an 8-week MBSR course. Qualitative interviews with patients, a focus group, and interview with NHS staff were held to explore acceptability and feasibility of MBSR. Questionnaires at baseline, during (weeks 4, 8), and after (weeks 16, 24) the course measured fatigue, anxiety and depression, mindfulness, disease-specific QoL, and generic preference based QoL. Of 100 women approached, 20 joined the study. One woman dropped out prior to the intervention due to illness progression. Nineteen women took part in 3 MBSR courses. Recruitment to 2 of the 3 courses was slow. Commitment to 8 weeks was a reason for non-participation, and proved challenging to participants during the course. Participants found the course acceptable and reported many cumulative and ongoing benefits. These included feeling less reactive to emotional distress and more accepting of the disruption to life that occurs with living with MBC. There was high attendance, completion of course sessions, adherence to home practice, excellent follow-up rates, and high questionnaire return rates. MBSR was acceptable to MBC patients, who perceived benefits such as improved anxiety and QoL; but the MBSR course requires a considerable time commitment. There is scope to tailor the intervention so that it is less intensive.

Influence of the MDM2 single nucleotide polymorphism SNP309 on tumour development in BRCA1 mutation carriers.

BACKGROUND: The MDM2 gene encodes a negative regulator of the p53 tumour suppressor protein. A single nucleotide polymorphism (SNP) in the MDM2 promoter (a T to G exchange at nucleotide 309) has been reported to produce accelerated tumour formation in individuals with inherited p53 mutations. We have investigated the effect of the MDM2 SNP309 on clinical outcome in a cohort of patients with germline mutations of BRCA1. METHODS: Genomic DNA was obtained for 102 healthy controls and 116 patients with established pathogenic mutations of BRCA1 and Pyrosequencing technologytrade mark was used to determine the genotype at the MDM2 SNP309 locus. RESULTS: The polymorphism was present in 52.9% of the controls (G/T in 37.3% and G/G in 15.6%) and 58.6% of the BRCA1 mutation carriers (47.4% G/T and 11.2% G/G). Incidence of malignancy in female BRCA1 carriers was not significantly higher in SNP309 carriers than in wildtype (T/T) individuals (72.7% vs. 75.6%, p = 1.00). Mean age of diagnosis of first breast cancer was 41.2 years in the SNP309 G/G genotype carriers, 38.6 years in those with the SNP309 G/T genotype and 39.0 years in wildtype subjects (p = 0.80). CONCLUSION: We found no evidence that the MDM2 SNP309 accelerates tumour development in carriers of known pathogenic germline mutations of BRCA1.