Non-surgical ablation for breast cancer: an emerging therapeutic option.

Non-surgical ablation is emerging as an alternative local therapy option for patients with early-stage breast cancer and encompasses two main types of percutaneous therapeutic procedures: radiofrequency ablation and cryoablation. Both techniques involve obliteration of a spherical lesion and feasibility studies have shown that complete tumour ablation is achievable with good or excellent cosmetic results. Although few clinical studies have directly compared non-surgical ablation with conventional surgical resection, observational studies indicate that clinical outcomes are favourable with acceptable rates of local control and no detriment to long-term survival. There remain outstanding issues with these percutaneous ablative techniques that require resolution before they could be incorporated into routine clinical practice. Hence, a consensus meeting was convened to discuss the challenges of non-surgical ablation and clarify indications for its use alongside clinical management pathways. In this Policy Review we will address some of the broader biological aspects of non-surgical ablation, including immune-modulatory effects and potential novel applications for the future.

mTOR inhibition abrogates human mammary stem cells and early breast cancer progression markers.

BACKGROUND: Mammary physiology is distinguished in containing adult stem/progenitor cells that are actively amending the breast tissue throughout the reproductive lifespan of women. Despite their importance in both mammary gland development, physiological maintenance, and reproduction, the exact role of mammary stem/progenitor cells in mammary tumorigenesis has not been fully elucidated in humans or animal models. The implications of modulating adult stem/progenitor cells in women could lead to a better understanding of not only their function, but also toward possible breast cancer prevention led us to evaluate the efficacy of rapamycin in reducing mammary stem/progenitor cell activity and malignant progression markers. METHODS: We analyzed a large number of human breast tissues for their basal and luminal cell composition with flow cytometry and their stem and progenitor cell function with sphere formation assay with respect to age and menopausal status in connection with a clinical study (NCT02642094) involving a low-dose (2 mg/day) and short-term (5-7 days) treatment of the mTOR inhibitor sirolimus. The expression of biomarkers in biopsies and surgical breast samples were measured with quantitative analysis of immunohistochemistry. RESULTS: Sirolimus treatment significantly abrogated mammary stem cell activity, particularly in postmenopausal patients. It did not affect the frequency of luminal progenitors but decreased their self-renewal capacity. While sirolimus had no effect on basal cell population, it decreased luminal cell population, particularly in postmenopausal patients. It also significantly diminished prognostic biomarkers associated with breast cancer progression from ductal carcinoma in situ to invasive breast cancer including p16INK4A, COX-2, and Ki67, as well as markers of the senescence-associated secretary phenotype, thereby possibly functioning in preventing early breast cancer progression. CONCLUSION: Overall, these findings indicate a link from mTOR signaling to mammary stem and progenitor cell activity and cancer progression. Trial registration This study involves a clinical trial registered under the ClinicalTrials.gov identifier NCT02642094 registered December 30, 2015.

Omission of sentinel node biopsy for breast cancer: Historical context and future perspectives on a modern controversy.

For older patients with clinically lymph node-negative breast cancer who have estrogen receptor-positive tumors and are treated with tamoxifen, randomized trials comparing axillary lymph node dissection (ALND) versus no ALND show that the omission of ALND improves patient quality of life and has no adverse effects on mortality. These results have served to justify sentinel node biopsy (SNB) omission in selected older patients with breast cancer. More recently, clinical trials were launched to assess SNB omission in younger patients, with recurrence and survival as the primary outcomes of interest. Three important considerations serve as the basis for these ongoing trials. First, it is assumed that SNB omission will improve patient quality of life, although, to date, there is no level I evidence to support this assumption. Second, axillary surgery has never been shown to reduce breast cancer mortality, but it does reduce the risk of axillary recurrences, although adjuvant systemic therapy and radiotherapy also reduce these recurrence risks. Finally, nodal status is losing importance as a guide for adjuvant systemic therapy decision making because these decisions are now increasingly predicated on tumor biomarkers and gene profiling, but it is gaining importance for adjuvant radiotherapy decision making. Because quality-of-life considerations are the primary motivation for abandoning SNB, there is a need for randomized trials comparing SNB versus no SNB/no axillary surgery, with quality of life as the primary end point (level I evidence). Moreover, suitable alternatives to guide adjuvant radiotherapy decision making will require validation before SNB omission can be justified for patients of all ages who have clinically node-negative breast cancer. LAY SUMMARY: In this review article, the authors provide a brief historical overview of the role of axillary surgery in breast cancer management and discuss additional studies and ramifications that should be considered before abandoning the sentinel node biopsy (SNB) procedure. Specifically, there is a need for level I evidence demonstrating that omission of the SNB procedure will improve patient quality of life and a need to validate suitable alternatives to SNB as a guide for adjuvant radiotherapy decision making.

Are advancements in screening technology contributing to breast cancer over-diagnosis?

PURPOSE OF REVIEW: Advancements in breast screening technology have increased the sensitivity of screening and thereby increased the detection rates of nonlethal cancers. Thus, improvements in breast screening technology may contribute to 'over-diagnosis', which refers to detection of cancers that pose no threat to life and that, in the absence of screening, might never have been detected. The purpose of this review is to draw attention to risks of over-diagnosis and provide a rationale for evaluating screening clinical breast examination (CBE) as an alternative to modern technology-based (mammography) screening. RECENT FINDINGS: Novel screening technologies have been adopted largely on the basis of their abilities to increase tumor-detection rates. However, as breast cancer treatments have improved, the mortality benefits of screening have declined. Moreover, there is evidence suggesting that, in the modern era of effective adjuvant systemic therapies, the mortality benefit of screening CBE may now be comparable to that of modern screening mammography, but screening CBE carries less risk of over-diagnosis. SUMMARY: A randomized trial comparing modern mammography screening versus screening CBE is warranted. If confirmed that the mortality benefits of the two screening strategies are now comparable, then screening CBE might be considered a reasonable alternative to mammography screening.

Surgical Decision-Making Surrounding Contralateral Prophylactic Mastectomy: Comparison of Treatment Goals, Preferences, and Psychosocial Outcomes from a Multicenter Survey of Breast Cancer Patients.

BACKGROUND: Differences in patient characteristics and decision-making preferences have been described between those who elect breast-conserving surgery (BCS), unilateral mastectomy (UM), or contralateral prophylactic mastectomy (CPM) for breast cancer. However, it is not known whether preferred and actual decision-making roles differ across these surgery types, or whether surgery choice reflects a woman's goals or achieves desired outcomes. METHODS: Women diagnosed with stage 0-III unilateral breast cancer across eight large medical centers responded to a mailed questionnaire regarding treatment decision-making goals, roles, and outcomes. These data were linked to electronic medical records. Differences were assessed using descriptive analyses and logistic regression. RESULTS: There were 750 study participants: 60.1% BCS, 17.9% UM, and 22.0% CPM. On multivariate analysis, reducing worry about recurrence was a more important goal for surgery in the CPM group than the others. Although women's preferred role in the treatment decision did not differ by surgery, the CPM group was more likely to report taking a more-active-than-preferred role than the BCS group. On multivariate analysis that included receipt of additional surgery, posttreatment worry about both ipsilateral and contralateral recurrence was higher in the BCS group than the CPM group (both p < 0.001). The UM group was more worried than the CPM group about contralateral recurrence only (p < 0.001). CONCLUSIONS: Women with CPM were more likely to report being able to reduce worry about recurrence as a very important goal for surgery. They were also the least worried about ipsilateral breast recurrence and contralateral breast cancer almost two years postdiagnosis.

BRCA1-associated R-loop affects transcription and differentiation in breast luminal epithelial cells.

BRCA1-associated basal-like breast cancer originates from luminal progenitor cells. Breast epithelial cells from cancer-free BRCA1 mutation carriers are defective in luminal differentiation. However, how BRCA1 deficiency leads to lineage-specific differentiation defect is not clear. BRCA1 is implicated in resolving R-loops, DNA-RNA hybrid structures associated with genome instability and transcriptional regulation. We recently showed that R-loops are preferentially accumulated in breast luminal epithelial cells of BRCA1 mutation carriers. Here, we interrogate the impact of a BRCA1 mutation-associated R-loop located in a putative transcriptional enhancer upstream of the ERα-encoding ESR1 gene. Genetic ablation confirms the relevance of this R-loop-containing region to enhancer-promoter interactions and transcriptional activation of the corresponding neighboring genes, including ESR1, CCDC170 and RMND1. BRCA1 knockdown in ERα+ luminal breast cancer cells increases intensity of this R-loop and reduces transcription of its neighboring genes. The deleterious effect of BRCA1 depletion on transcription is mitigated by ectopic expression of R-loop-removing RNase H1. Furthermore, RNase H1 overexpression in primary breast cells from BRCA1 mutation carriers results in a shift from luminal progenitor cells to mature luminal cells. Our findings suggest that BRCA1-dependent R-loop mitigation contributes to luminal cell-specific transcription and differentiation, which could in turn suppress BRCA1-associated tumorigenesis.

Factors related to re-excision procedures following primary breast-conserving surgery for women with breast cancer in the U.S. Military Health System.

BACKGROUND AND OBJECTIVES: Re-excision surgery is undertaken to obtain clear margins after breast-conserving surgery (BCS) for localized breast cancer. This study examines patient and tumor characteristics related to re-excision surgery in the universal-access Military Health System (MHS). METHODS: Retrospective analysis of patients with pathologically confirmed stage I-III breast cancer between 1998 and 2014 in the Department of Defense Central Cancer Registry and MHS Data Repository-linked databases who received primary BCS. Multivariable stepwise logistic regression methods identified characteristics associated with re-excision surgery (lumpectomy and mastectomy) and conversion to mastectomy, given as adjusted odds ratios (AOR) and 95% confidence intervals (CIs). RESULTS: Of 7637 women receiving BCS, 26.3% had a re-excision and 9.9% converted to mastectomy. Tumor location, larger tumor size (≥4 cm), and regional lymph node involvement were associated with a greater likelihood of re-excision and mastectomy conversion. Pathology before BCS (AOR, 0.39; 95% CI, 0.35, 0.44 for re-excision) and neoadjuvant treatment (AOR, 0.50; 95% CI, 0.36, 0.69 for re-excision) were associated with a decreased likelihood of these outcomes. Additionally, age, tumor histology, and military-specific variables were associated with mastectomy conversion. CONCLUSION: Comprehensive preoperative workup, including tumor pathology, may better inform surgical decision-making and reduce re-excision rates.

Extended endocrine therapy in early breast cancer: how long and who for?

Endocrine therapy for early stage breast cancer is currently in a state of flux with much uncertainty about choice of agents and duration of therapy. The standard treatment span of 5 years usually incorporates an aromatase inhibitor in the majority of postmenopausal patients. Hormonal therapy has a cytostatic action that provides a biological rationale for continuing treatment for more prolonged periods to reduce risk of late recurrence in estrogen receptor-positive disease. Several trials of extended endocrine therapy for periods varying from 7.5 to 10 years have shown mixed results for gains in disease-free survival. The challenge is to assimilate available data and apply clinical judgment to tailor therapies taking account of intrinsic risk of disease recurrence, patient preference, tolerability to date, and co-morbidities.

BRCA1 mutations attenuate super-enhancer function and chromatin looping in haploinsufficient human breast epithelial cells.

BACKGROUND: BRCA1-associated breast cancer originates from luminal progenitor cells. BRCA1 functions in multiple biological processes, including double-strand break repair, replication stress suppression, transcriptional regulation, and chromatin reorganization. While non-malignant cells carrying cancer-predisposing BRCA1 mutations exhibit increased genomic instability, it remains unclear whether BRCA1 haploinsufficiency affects transcription and chromatin dynamics in breast epithelial cells. METHODS: H3K27ac-associated super-enhancers were compared in primary breast epithelial cells from BRCA1 mutation carriers (BRCA1mut/+) and non-carriers (BRCA1+/+). Non-tumorigenic MCF10A breast epithelial cells with engineered BRCA1 haploinsufficiency were used to confirm the H3K27ac changes. The impact of BRCA1 mutations on enhancer function and enhancer-promoter looping was assessed in MCF10A cells. RESULTS: Here, we show that primary mammary epithelial cells from women with BRCA1 mutations display significant loss of H3K27ac-associated super-enhancers. These BRCA1-dependent super-enhancers are enriched with binding motifs for the GATA family. Non-tumorigenic BRCA1mut/+ MCF10A cells recapitulate the H3K27ac loss. Attenuated histone mark and enhancer activity in these BRCA1mut/+ MCF10A cells can be partially restored with wild-type BRCA1. Furthermore, chromatin conformation analysis demonstrates impaired enhancer-promoter looping in BRCA1mut/+ MCF10A cells. CONCLUSIONS: H3K27ac-associated super-enhancer loss is a previously unappreciated functional deficiency in ostensibly normal BRCA1 mutation-carrying breast epithelium. Our findings offer new mechanistic insights into BRCA1 mutation-associated transcriptional and epigenetic abnormality in breast epithelial cells and tissue/cell lineage-specific tumorigenesis.

Factors associated with genetic testing in a cohort of breast cancer survivors.

We examined factors associated with self-reported use of genetic testing among breast cancer survivors based on a 2015 cross-sectional survey at eight Midwestern sites. Genetic testing was reported in 39% of our 1235 study participants, with higher utilization among those aged <50 and with a triple-negative cancer. Bilateral mastectomy, having relatives with breast cancer, and younger age were associated with increased genetic testing use. Increasing income, in interaction with age, was associated with use of genetic testing among younger but not older patients. Rural residency emerged as a possible barrier for genetic testing among women with triple-negative cancer.

Tailoring breast cancer therapies to reduce mortality and improve quality of life: San Antonio Breast Cancer Symposium 2017 (part 1).

The 40th annual San Antonio Breast Cancer Symposium was convened in San Antonio, TX, USA on 5-9 December 2017. More than 7500 clinicians and scientists from around the world participated in the symposium which featured a range of presentations and keynote talks pertaining to breast cancer screening, prevention, loco-regional and systemic therapies. This two-part report highlights a selection of important studies presented at this premier breast cancer event with part 1 focusing on dose-intense radiotherapy, perioperative endocrine therapy, duration of bisphosphonates, immunotherapy, ovarian function suppression and acupuncture. The second part of this report will discuss a range of topics related to de-escalation of loco-regional therapies, the significance of complete pathological response, older patients and CDK 4/6 inhibitors, circulating tumor cells and plasma DNA as a tumor marker.

Tailoring breast cancer therapies to reduce mortality and improve quality of life: San Antonio Breast Cancer Symposium 2017 (part 2).

The 40th annual San Antonio Breast Cancer Symposium was convened in San Antonio, TX, USA on 5-9 December 2017. More than 7500 clinicians and scientists from around the world participated in the symposium which featured a range of presentations and keynote talks pertaining to breast cancer screening, prevention, loco-regional and systemic therapies. This two-part report highlights a selection of important studies presented at this premier breast cancer event with part 1 focusing on dose-intense radiotherapy, perioperative endocrine therapy, duration of bisphosphonates, immunotherapy, ovarian function suppression and acupuncture. The second part of this report will discuss a range of topics related to de-escalation of loco-regional therapies, the significance of complete pathological response, older patients and CDK 4/6 inhibitors, circulating tumor cells and plasma DNA as a tumor marker.

Highlights of the San Antonio Breast Cancer Symposium 2016.

The 39th annual San Antonio Breast Cancer Symposium (SABCS) was convened in San Antonio, Texas, on 9-13 December 2016. More than 7000 clinicians and scientists from around the world participated in the symposium which featured a range of presentations and keynote talks pertaining to breast cancer screening, prevention, locoregional and systemic therapies. This two-part report highlights a selection of important studies presented at this premier breast cancer event with Part 1 focusing onmetastatic breast cancer, extended endocrine therapy and the prognostic significance of BRCA1/2 gene mutations. The second part of this report will discuss a range of topics including anti-HER2 directed treatments, the impact of radiotherapy on implant and autologous flap based reconstruction, biological risk predictors for ductal carcinoma-in situ (DCIS), longer term effects of dietary fat modification and the influence of aromatase inhibitors on endothelial cell function.

Highlights of the San Antonio Breast Cancer Symposium 2016: Part 2.

The 39th annual San Antonio Breast Cancer Symposium (SABCS) was convened in San Antonio, Texas, on 9-13 December 2016. More than 7000 clinicians and scientists from around the world participated in the symposium which featured a range of presentations and keynote talks pertaining to breast cancer screening, prevention, locoregional and systemic therapies. This two-part report highlights a selection of important studies presented at this premier breast cancer event with Part 1 focusing onmetastatic breast cancer, extended endocrine therapy and the prognostic significance of BRCA1/2 gene mutations. The second part of this report will discuss a range of topics including anti-HER2 directed treatments, the impact of radiotherapy on implant and autologous flap based reconstruction, biological risk predictors for ductal carcinoma-in situ (DCIS), longer term effects of dietary fat modification and the influence of aromatase inhibitors on endothelial cell function.

De-escalation of axillary surgery in early breast cancer.

With the advent of sentinel lymph node biopsy, surgical methods for accurately staging the axilla in patients with early-stage breast cancer have become progressively less extensive, with formal axillary lymph node dissection confined to a dwindling group of patients. Although details of methods for sentinel lymph node biopsy have yet to be standardised, this technique is now widely practised and accepted as standard of care worldwide. In the past 5 years, attention has focused on minimisation of surgical morbidity by restricting further axillary surgery or considering radiotherapy in patients with a small tumour burden in their sentinel nodes. This change in approach to patients with positive sentinel lymph node biopsies has increased the complexity of axillary management, and any policy of de-escalation and avoidance of morbidity must not compromise patient outcomes. This trend for de-escalation has accompanied a shift in understanding of how any residual tumour burden can be adequately managed without surgical extirpation and reliance on effective adjuvant therapies. Indications for omission of completion axillary lymph node dissection in patients with two or fewer nodes containing macrometastases demand further clarification, together with the roles of preoperative imaging in defining axillary nodal burden, deselection of patients for sentinel lymph node biopsy, and provision of radiotherapy. Downstaging of biopsy-proven node-positive patients with neoadjuvant chemotherapy could safely permit sentinel lymph node biopsy alone when the index node has been successfully retrieved at surgery, while nodal deposits of any size continue to mandate completion axillary lymph node dissection. Developments in molecular imaging technologies and percutaneous biopsy techniques could potentially render sentinel lymph node biopsy redundant in the future.