Patient and clinician factors influencing the choice of breast cancer surgery : a qualitative and quantitative study.

Background and aims: In women with breast cancers up to 5 cm diameter, breast conservation therapy (BCT) and mastectomy are equivalent for survival and morbidity, although recurrence and body image vary. This mixed-method study in a UK region (population 5 million) aims to identify reasons for mastectomy rate (MR) variation between units. Methods and findings The study comprised five components; two in 14 units: (1) An audit of the NHS Breast Screening Programme (n=5060 cases from 11 screening units) established MR variation was not due to case-mix or caseload (P=O.OOl). (2) A Discrete Choice Experiment (n=68/93) employing multinomial logistic regression confirmed clinicians surgical preferences (25 scenarios, n=1695) vary based on cancer (size, site and centricitv, P<O.OOl){ patient (age and breast size, P<O.OOl) and clinician variables (gender and clinician role, P=0.015 and P<O.OOl respectively). Three within units representing hiqh, medium and low case-mix adjusted MRs: (3) A validated questionnaire established that patients (n=356) preferred and achieved more autonomy in treatment selection than before; particularly among those choosing mastectomy (P<O.OOl). (4) Interviews with clinicians (n=26; 13 nurses and 13 doctors) highlighted variation in local ethos. Clinicians' focus in the low MR unit was the promotion of BCT and in others, autonomous decision-making. Communication strategies and processes optimised this. (5) Interviews with patients (n=65) demonstrated varied experiences between breast units. While patient factors influenced decisions, breast team factors predominated. Patients from the high and medium MR units described more informed autonomous decision-making processes and support. Conclusions In this study low MRs were associated with clinicians preferring BCT and higher MRs with clinicians supporting patients' decision-making. Clinician factors related to treatment preferences associated with high MRs were not identified. This does not preclude their existence in other regions. Understanding surgical variation factors could facilitate treatment decision- making equity, but is unlikely to reduce MRs.

Efficient development and usability testing of decision support interventions for older women with breast cancer

Around a third of breast cancers diagnosed each year in the UK are in women aged 70 years and older. However, there are currently no decision support interventions for older women who have a choice between primary endocrine therapy and surgery followed by adjuvant endocrine therapy (surgery+endocrine therapy), or who can choose whether or not to have chemotherapy following surgery. There is also little evidence-based guidance specifically on the management of these older patients. A large UK cohort study is currently underway to address this lack of evidence and to develop two decision support interventions (DESIs) to facilitate shared decision-making with older women about breast cancer treatments. Here we present the development and initial testing of these two DESIs. An initial prototype DESI was developed for the choice of primary endocrine therapy or surgery+endocrine therapy. Semi-structured interviews with healthy volunteers and patients explored DESI acceptability, usability and utility. A framework approach was used for analysis. A second DESI for the choice of having chemotherapy or not was subsequently developed based on more focused development and testing. Participants (n=22, aged 75-94 years, 64% healthy volunteers, 36% patients) found the primary endocrine therapy/surgery+endocrine therapy DESI acceptable, and contributed to improved wording and illustrations to address misunderstandings. The chemotherapy DESI (tested with 14 participants, aged 70-87 years, 57% healthy volunteers, 43% patients) was mostly understandable, however suggestions for re-wording sections were made. Most participants considered the DESIs helpful, but highlighted the importance of complementary discussions with clinicians. It was possible to use a template DESI to efficiently create a second prototype for a different treatment option (chemotherapy). Both DESIs were acceptable and considered helpful to support/augment consultations. Development of acceptable additional DESIs for similar target populations using simplified methods may be an efficient way to develop future DESIs. Further research is needed to test the effectiveness of the DESIs

Understanding older women's decision making and coping in the context of breast cancer treatment

Background: Primary endocrine therapy (PET) is a recognised alternative to surgery followed by endocrine therapy for a subset of older, frailer women with breast cancer. Choice of treatment is preference-sensitive and may require decision support. Older patients are often conceptualised as passive decision-makers. The present study used the Coping in Deliberation (CODE) framework to gain insight into decision making and coping processes in a group of older women who have faced breast cancer treatment decisions, and to inform the development of a decision support intervention (DSI). Methods: Semi-structured interviews were carried out with older women who had been offered a choice of PET or surgery from five UK hospital clinics. Women's information and support needs, their breast cancer diagnosis and treatment decisions were explored. A secondary analysis of these interviews was conducted using the CODE framework to examine women's appraisals of health threat and coping throughout the deliberation process. Results: Interviews with 35 women aged 75-98 years were analysed. Appraisals of breast cancer and treatment options were sometimes only partial, with most women forming a preference for treatment relatively quickly. However, a number of considerations which women made throughout the deliberation process were identified, including: past experiences of cancer and its treatment; scope for choice; risks, benefits and consequences of treatment; instincts about treatment choice; and healthcare professionals' recommendations. Women also described various strategies to cope with breast cancer and their treatment decisions. These included seeking information, obtaining practical and emotional support from healthcare professionals, friends and relatives, and relying on personal faith. Based on these findings, key questions were identified that women may ask during deliberation. Conclusions: Many older women with breast cancer may be considered involved rather than passive decision-makers, and may benefit from DSIs designed to support decision making and coping within and beyond the clinic setting

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Intravital imaging technology guides FAK-mediated priming in pancreatic cancer precision medicine according to Merlin status

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic, chemoresistant malignancy and is characterized by a dense, desmoplastic stroma that modulates PDAC progression. Here, we visualized transient manipulation of focal adhesion kinase (FAK), which integrates bidirectional cell-environment signaling, using intravital fluorescence lifetime imaging microscopy of the FAK-based Förster resonance energy transfer biosensor in mouse and patient-derived PDAC models. Parallel real-time quantification of the FUCCI cell cycle reporter guided us to improve PDAC response to standard-of-care chemotherapy at primary and secondary sites. Critically, micropatterned pillar plates and stiffness-tunable matrices were used to pinpoint the contribution of environmental cues to chemosensitization, while fluid flow–induced shear stress assessment, patient-derived matrices, and personalized in vivo models allowed us to deconstruct how FAK inhibition can reduce PDAC spread. Last, stratification of PDAC patient samples via Merlin status revealed a patient subset with poor prognosis that are likely to respond to FAK priming before chemotherapy

Intravital imaging technology guides FAK-mediated priming in pancreatic cancer precision medicine according to Merlin status

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic, chemoresistant malignancy and is characterized by a dense, desmoplastic stroma that modulates PDAC progression. Here, we visualized transient manipulation of focal adhesion kinase (FAK), which integrates bidirectional cell-environment signaling, using intravital fluorescence lifetime imaging microscopy of the FAK-based Forster resonance energy transfer biosensor in mouse and patient-derived PDAC models. Parallel real-time quantification of the FUCCI cell cycle reporter guided us to improve PDAC response to standard-of-care chemotherapy at primary and secondary sites. Critically, micro-patterned pillar plates and stiffness-tunable matrices were used to pinpoint the contribution of environmental cues to chemosensitization, while fluid flow-induced shear stress assessment, patient-derived matrices, and personalized in vivo models allowed us to deconstruct how FAK inhibition can reduce PDAC spread. Last, stratification of PDAC patient samples via Merlin status revealed a patient subset with poor prognosis that are likely to respond to FAK priming before chemotherapy

Patient and clinician factors influencing the choice of breast cancer surgery : a qualitative and quantitative study

Background and aims: In women with breast cancers up to 5 cm diameter, breast conservation therapy (BCT) and mastectomy are equivalent for survival and morbidity, although recurrence and body image vary. This mixed-method study in a UK region (population 5 million) aims to identify reasons for mastectomy rate (MR) variation between units. Methods and findings The study comprised five components; two in 14 units: (1) An audit of the NHS Breast Screening Programme (n=5060 cases from 11 screening units) established MR variation was not due to case-mix or caseload (P=O.OOl). (2) A Discrete Choice Experiment (n=68/93) employing multinomial logistic regression confirmed clinicians surgical preferences (25 scenarios, n=1695) vary based on cancer (size, site and centricitv, P<O.OOl){ patient (age and breast size, P<O.OOl) and clinician variables (gender and clinician role, P=0.015 and P<O.OOl respectively). Three within units representing hiqh, medium and low case-mix adjusted MRs: (3) A validated questionnaire established that patients (n=356) preferred and achieved more autonomy in treatment selection than before; particularly among those choosing mastectomy (P<O.OOl). (4) Interviews with clinicians (n=26; 13 nurses and 13 doctors) highlighted variation in local ethos. Clinicians' focus in the low MR unit was the promotion of BCT and in others, autonomous decision-making. Communication strategies and processes optimised this. (5) Interviews with patients (n=65) demonstrated varied experiences between breast units. While patient factors influenced decisions, breast team factors predominated. Patients from the high and medium MR units described more informed autonomous decision-making processes and support. Conclusions In this study low MRs were associated with clinicians preferring BCT and higher MRs with clinicians supporting patients' decision-making. Clinician factors related to treatment preferences associated with high MRs were not identified. This does not preclude their existence in other regions. Understanding surgical variation factors could facilitate treatment decision- making equity, but is unlikely to reduce MRs. -EThOS - Electronic Theses Online ServiceGBUnited Kingdo

What influences clinicians' operative preferences for women with breast cancer? An application of the discrete choice experiment

Introduction: Little is known regarding cancer clinicians' treatment preferences. Aim: Determine the impact of pre-operative variables over specialist breast clinicians' operative preferences using discrete choice experiment methodology. Methods: Cross-sectional survey of operative preferences to hypothetical scenarios based on: patient age, bra cup size, cancer size, site and focality. Results: 73% response rate (68/93). Multinomial logistic regression across scenarios (n = 1695) with allowance for response clustering, comparing equal preference for mastectomy and breast conservation surgery (BCS) with preference for mastectomy or BCS. Increasing patient age, cancer size, central site, multi-focality and reducing cup size, all associated with preference for mastectomy, over equal preference, over BCS (p < 0.001). Doctors preferred specific treatments, females and nurses avoided mastectomy (p = 0.015 and p < 0.001 respectively). Conclusions: Clinician preferences were predominantly treatment guideline congruent, but significantly influenced by patient age, clinician gender and occupation. This methodology is capable of elucidating treatment preferences and could be applied elsewhere where treatment options and practice variability exist

Information needs of older women faced with a choice of primary endocrine therapy or surgery for early-stage breast cancer: a literature review

Primary endocrine therapy (PET) as an alternative to surgery is widely used in the UK for the treatment of older women with operable breast cancer. For women over 70 it has equivalent overall survival to surgery, although local control rates may be inferior. There are trade-offs to be made in deciding between surgery and PET. There has been little research to investigate the information needs of older women or the involvement in decision making they wish to have when faced with this breast-cancer treatment decision. This review examines the information needs of older women (>65 years) regarding the use of surgery or PET for treating operable primary breast cancer, and identifies their preferred format and media for the presentation of this information. The preference for involvement in treatment decision-making among this group will also be considered. © 2014 Springer Science+Business Media

Optimizing metastatic-cascade-dependent Rac1 targeting in breast cancer: Guidance using optical window intravital FRET imaging

Assessing drug response within live native tissue provides increased fidelity with regards to optimizing efficacy while minimizing off-target effects. Here, using longitudinal intravital imaging of a Rac1-Forster resonance energy transfer (FRET) biosensor mouse coupled with in vivo photoswitching to track intratumoral movement, we help guide treatment scheduling in a live breast cancer setting to impair metastatic progression. We uncover altered Rac1 activity at the center versus invasive border of tumors and demonstrate enhanced Rac1 activity of cells in close proximity to live tumor vasculature using optical window imaging. We further reveal that Rac1 inhibition can enhance tumor cell vulnerability to fluid-flow-induced shear stress and therefore improves overall anti-metastatic response to therapy during transit to secondary sites such as the lung. Collectively, this study demonstrates the utility of single-cell intravital imaging in vivo to demonstrate that Rac1 inhibition can reduce tumor progression and metastases in an autochthonous setting to improve overall survival. </p