The role of radiation therapy in the multidisciplinary management of male breast cancer: a systematic review and meta-analysis.

Male breast cancer (MaBC) is an uncommon disease. It is generally assimilated to post-menopausal female breast cancer and treated accordingly. However, the real impact of radiation therapy, after both mastectomy and breast conservation, has yet to be established. We performed a systematic review and meta-analysis to assess the clinical impact of radiation therapy in MBC patients to support the clinical decision-making process and to inform future research. We performed a systematic search of 'male', 'breast', 'cancer', 'radiotherapy' and corresponding synonyms on PubMed/MEDLINE and EMBASE databases. We included interventional studies reporting on radiation therapy effect on overall survival (OS) in MBC patients. Reviews, editorials, letters to the editor, conference abstracts and case reports, and studies with less than 20 MaBC patients or without data on OS were excluded. We extracted relevant characteristics and outcomes for each study, including the hazard ratio (HR) for OS, after adjustment for potential confounders. We calculated an overall adjusted hazard ratio (aHR) for OS for patients receiving radiation therapy compared to those who did not. A random effect model was used. The search strategy yielded 10,260 articles. After removal of duplicates (n = 8,254), 2,006 articles remained and underwent abstract screening. A total of 168 manuscripts was selected for full text screening. After full text screening, 22 articles were included in the qualitative systematic review. Among them, 14 were included in the quantitative synthesis, reporting on 80.219 MaBC patients. A statistically significant reduction in the risk of death was observed for patients receiving radiation therapy, with a pooled aHR = 0.73 (95%CI: 0.66-0.81) for OS. Significant heterogeneity among reported aHR estimates was seen (I2=77%). A significant clinical benefit on OS has been observed when including radiation therapy in the therapeutic algorithm of patients with MaBC. These findings, which are based on retrospective studies and tumour registry reports, deserve further investigation to identify MaBC patient subgroups who most benefit from radiation therapy.

Randomised controlled trials on radiation dose fractionation in breast cancer: systematic review and meta-analysis with emphasis on side effects and cosmesis.

OBJECTIVE: To provide a comprehensive assessment of various fractionation schemes in radiation therapy for breast cancer, with a focus on side effects, cosmesis, quality of life, risks of recurrence, and survival outcomes. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Ovid MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (from inception to 23 October 2023). STUDY SELECTION: Included studies were randomised controlled trials focusing on conventional fractionation (CF; daily fractions of 1.8-2 Gy, reaching a total dose of 50-50.4 Gy over 5-6 weeks), moderate hypofractionation (MHF; fraction sizes of 2.65-3.3 Gy for 13-16 fractions over 3-5 weeks), and/or ultra-hypofractionation (UHF; schedule of only 5 fractions). DATA EXTRACTION: Two independent investigators screened studies and extracted data. Risk of bias and quality of evidence were assessed using the Cochrane Collaboration's tool and the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) approach, respectively. DATA SYNTHESIS: Pooled risk ratios (RRs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using a random effects model. Heterogeneity was analysed using Cochran's Q test and I2 statistic. Network meta-analysis was used to integrate all available evidence. MAIN OUTCOME MEASURES: The pre-specified primary outcome was grade ≥2 acute radiation dermatitis and late radiation therapy related side effects; secondary outcomes included cosmesis, quality of life, recurrence, and survival metrics. RESULTS: From 1754 studies, 59 articles representing 35 trials (20 237 patients) were assessed; 21.6% of outcomes showed low risk of bias, whereas 78.4% had some concerns or high risk, particularly in outcome measurement (47.4%). The RR for grade ≥2 acute radiation dermatitis for MHF compared with CF was 0.54 (95% CI 0.49 to 0.61; P<0.001) and 0.68 (0.49 to 0.93; P=0.02) following breast conserving therapy and mastectomy, respectively. Hyperpigmentation and grade ≥2 breast shrinkage were less frequent after MHF than after CF, with RRs of 0.77 (0.62 to 0.95; P=0.02) and 0.92 (0.85 to 0.99; P=0.03), respectively, in the combined breast conserving therapy and mastectomy population. However, in the breast conserving therapy only trials, these differences in hyperpigmentation (RR 0.79, 0.60 to 1.03; P=0.08) and breast shrinkage (0.94, 0.83 to 1.07; P=0.35) were not statistically significant. The RR for grade ≥2 acute radiation dermatitis for UHF compared with MHF was 0.85 (0.47 to 1.55; P=0.60) for breast conserving therapy and mastectomy patients combined. MHF was associated with improved cosmesis and quality of life compared with CF, whereas data on UHF were less conclusive. Survival and recurrence outcomes were similar between UHF, MHF, and CF. CONCLUSIONS: MHF shows improved safety profile, cosmesis, and quality of life compared with CF while maintaining equivalent oncological outcomes. Fewer randomised controlled trials have compared UHF with other fractionation schedules, but its safety and oncological effectiveness seem to be similar with short term follow-up. Given the advantages of reduced treatment time, enhanced convenience for patients, and potential cost effectiveness, MHF and UHF should be considered as preferred options over CF in appropriate clinical settings, with further research needed to solidify these findings. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42023460249.

Role of [18F]FDG PET/CT in patients with invasive breast carcinoma of no special type: Literature review and comparison between guidelines.

PURPOSE: The recently released EANM/SNMMI guideline, endorsed by several important clinical and imaging societies in the field of breast cancer (BC) care (ACR, ESSO, ESTRO, EUSOBI/ESR, EUSOMA), emphasized the role of [18F]FDG PET/CT in management of patients with no special type (NST) BC. This review identifies and summarizes similarities, discrepancies and novelties of the EANM/SNMMI guideline compared to NCCN, ESMO and ABC recommendations. METHODS: The EANM/SNMMI guideline was based on a systematic literature search and the AGREE tool. The level of evidence was determined according to NICE criteria, and 85 % agreement or higher was reached regarding each statement. Comparisons with NCCN, ESMO and ABC guidelines were examined for specific clinical scenarios in patients with early stage through advanced and metastatic BC. RESULTS: Regarding initial staging of patients with NST BC, [18F]FDG PET/CT is the preferred modality in the EANM-SNMMI guideline, showing superiority as a single modality to a combination of contrast-enhanced CT of thorax-abdomen-pelvis plus bone scan in head-to-head comparisons and a randomized study. Its use is recommended in patients with clinical stage IIB or higher and may be useful in certain stage IIA cases of NST BC. In NCCN, ESMO, and ABC guidelines, [18F]FDG PET/CT is instead recommended as complementary to conventional imaging to solve inconclusive findings, although ESMO and ABC also suggest [18F]FDG PET/CT can replace conventional imaging for staging patients with high-risk and metastatic NST BC. During follow up, NCCN and ESMO only recommend diagnostic imaging if there is suspicion of recurrence. Similarly, EANM-SNMMI states that [18F]FDG PET/CT is useful to detect the site and extent of recurrence only when there is clinical or laboratory suspicion of recurrence, or when conventional imaging methods are equivocal. The EANM-SNMMI guideline is the first to emphasize a role of [18F]FDG PET/CT for assessing early metabolic response to primary systemic therapy, particularly for HER2+ BC and TNBC. In the metastatic setting, EANM-SNMMI state that [18F]FDG PET/CT may help evaluate bone metastases and determine early response to treatment, in agreement with guidelines from ESMO. CONCLUSIONS: The recently released EANM/SNMMI guideline reinforces the role of [18F]FDG PET/CT in the management of patients with NST BC supported by extensive evidence of its utility in several clinical scenarios.

The EORTC 22922/10925 trial investigating regional nodal irradiation in stage I-III breast cancer: Outcomes according to locoregional and systemic therapies.

The EORTC 22922/10925 trial aimed to investigate the impact on overall survival (OS) of elective internal mammary and medial supraclavicular (IM-MS) radiation therapy (RT) in breast cancer stage I-III. Surgery for the primary tumour and axillary lymph nodes, chest wall RT, boost RT after whole breast RT in breast conserving therapy (BCT), RT to operated axilla, and systemic therapy were per physician's preference. The aim of the current analysis is to assess breast cancer outcomes according to different locoregional and systemic therapy used in the trial. MATERIAL/METHODS: Data with a median follow-up of 15.7 years were extracted from the trial's case report forms. Kaplan-Meier curves of disease-free and OS and cumulative incidence curves of breast cancer events were produced. An exploratory analysis of the effect of the type of locoregional and systemic therapy on breast cancer outcomes was conducted using the Cox model or the Fine & Gray model accounting for competing risks, both models being adjusted for baseline patient and disease characteristics and treatment. The significance level was set at 5 %, 2-sided. RESULTS: Of the 4,004 patients included, 625 (16%) did not receive any postoperative systemic therapy, 1,185 (30%) received endocrine therapy only, 994 (25%) chemotherapy only, and 1,200 (30%) both chemotherapy and endocrine therapy, without differences between the randomisation arms. Administration and type of therapy was associated with age, menopausal status, clinical T- and N-stage and ER status (p < 0.0001). Local control was better with mastectomy (with/without postmastectomy RT) as compared to BCT, but mastectomy was associated with more distant metastasis (DM) as first event. Similarly, DM as first event occurred more in the BCT group that received a boost as compared to no boost and in those who received RT to the lower axillary level. IM-MS RT reduced significantly regional recurrences and improved disease-free survival in a sensitivity stratified analysis. OS was worse with mastectomy as compared to BCT and with irradiation of the axilla but better with sentinel node dissection and adjuvant combined chemo and hormonal therapy. CONCLUSION: Different components of therapy influenced the site of first event. IM-MS RT improved outcomes in different breast cancer outcomes were most probably related that the group were balanced due to the trial arms and stratification methods.

Residual breast tissue after mastectomy and reconstruction: A substudy of the Spatial location of breast cancer local rECurRence aftEr masTectomy (SECRET) project.

The current project is part of the Spatial location of breast cancer local rECurRence aftEr masTectomy (SECRET) study (NCT06130111). Herein we compared the chest wall thickness after non-skin sparing mastectomy (non-SSM) with the chest wall thickness after SSM, as a surrogate for residual breast tissue after mastectomy. METHODS: The study was approved by the ethics committee of relevant institutions. Data of patients with a local recurrence (LR) after non-SSM was collected from the Netherlands Cancer Registry (NCR); data of patients undergoing SSM were collected from Sheba Medical Center. Student's t-test was used to evaluate the difference between the cohorts. Chest wall thickness was measured on postoperative images. RESULTS: Out of 4949 patients who underwent mastectomy from the NCR cohort, a total of 173 (3.5 %) had a LR at 5 years, of these a total of 153 patients included in the non-SSM cohort. The median age was 59 years (age 33-92), LR occurred at a median of 23.6 months (2.5-60 months). The SSM cohort included 84 patients, with a median age of 38.4 years (28-63.5), overall, 5 LRs occurred at a median of 15 months (5-46 months). The SSM cohort had significantly thicker chest walls compared to non-SSM (p < 0.001). Most LRs in both groups occurred in the subcutis. CONCLUSION: The chest wall thickness differed according to mastectomy procedures. Most of the LR occurred at the subcutis. The role of residual breast tissue and residual cancer in relation to type of mastectomy should be further investigated.

A BRILLIANT-BRCA study: residual breast tissue after mastectomy and reconstruction.

INTRODUCTION: Different types of mastectomies leave different amounts of residual breast tissue. The significance of the residual breast volume (RBV) is not clear. Therefore, we developed an MRI tool that allows to easily assess the RBV. In this study we evaluated factors associated with RBV after skin or nipple sparing mastectomy (SSM/NSM) in breast cancer BRCA pathogenic variant (PV) carriers who underwent both therapeutic and risk reducing SSM/NSM and its relation to breast cancer outcomes using an innovative MRI-based tool. METHODS: Data of breast cancer BRCA PV who were treated between 2006 and 2020 were retrieved from of the oncogenetics unit databases. Only patients who underwent SSM/NSM and had a postoperative breast MRI available for analysis were included. Data collected included demographics, clinicopathological features, and outcomes. The MRI tool was developed by a breast cancer imaging laboratory. A logistic regression test and 95% confidence interval (CI) were used to assess the associated risk of increased RBV. A forward stepwise linear regression was used to correlate tumour-patient specific factors and RBV, and a Kaplan-Meier curve to show the probability of locoregional relapse. RESULTS: A total of 84 patients undergoing 89 mastectomies were included. At a median follow-up of 98 months, 5 local, 2 regional, and 4 distant recurrences were observed. RBV was not significantly related with breast cancer outcomes (p value = NS). A higher body mass index (BMI) was associated with a higher RBV (p < 0.0001). A larger number of involved axillary nodes was associated with a smaller RBV (p = 0.025). The RBV on the risk-reducing mastectomy side was significantly higher compared to the breast cancer side (p value = 0.007). Local recurrences occurred in the vicinity of the primary tumour.

Tailoring neoadjuvant systemic therapy in breast cancer: "The advent of a personalized approach"-The Breast-Gynecological and Immuno-Oncology International Cancer Conference (BGICC) consensus and recommendations.

BACKGROUND: The management of early breast cancer (BC) has witnessed an uprise in the use of neoadjuvant therapy and a remarkable reshaping of the systemic therapy postneoadjuvant treatment in the last few years, with the evolution of many controversial clinical situations that require consensus. METHODS: During the 14th Breast-Gynecological and Immuno-Oncology International Cancer Conference held in Egypt in 2022, a panel of 44 BC experts from 13 countries voted on statements concerning debatable challenges in the neo/adjuvant treatment setting. The recommendations were subsequently updated based on the most recent data emerging. A modified Delphi approach was used to develop this consensus. A consensus was achieved when ≥75% of voters selected an answer. RESULTS AND CONCLUSIONS: The consensus recommendations addressed different escalation and de-escalation strategies in the setting of neoadjuvant therapy for early BC. The recommendations recapitulate the available clinical evidence and expert opinion to individualize patient management and optimize therapy outcomes. Consensus was reached in 63% of the statements (52/83), and the rationale behind each statement was clarified.

Joint EANM-SNMMI guideline on the role of 2-[18F]FDG PET/CT in no special type breast cancer : (endorsed by the ACR, ESSO, ESTRO, EUSOBI/ESR, and EUSOMA).

INTRODUCTION: There is much literature about the role of 2-[18F]FDG PET/CT in patients with breast cancer (BC). However, there exists no international guideline with involvement of the nuclear medicine societies about this subject. PURPOSE: To provide an organized, international, state-of-the-art, and multidisciplinary guideline, led by experts of two nuclear medicine societies (EANM and SNMMI) and representation of important societies in the field of BC (ACR, ESSO, ESTRO, EUSOBI/ESR, and EUSOMA). METHODS: Literature review and expert discussion were performed with the aim of collecting updated information regarding the role of 2-[18F]FDG PET/CT in patients with no special type (NST) BC and summarizing its indications according to scientific evidence. Recommendations were scored according to the National Institute for Health and Care Excellence (NICE) criteria. RESULTS: Quantitative PET features (SUV, MTV, TLG) are valuable prognostic parameters. In baseline staging, 2-[18F]FDG PET/CT plays a role from stage IIB through stage IV. When assessing response to therapy, 2-[18F]FDG PET/CT should be performed on certified scanners, and reported either according to PERCIST, EORTC PET, or EANM immunotherapy response criteria, as appropriate. 2-[18F]FDG PET/CT may be useful to assess early metabolic response, particularly in non-metastatic triple-negative and HER2+ tumours. 2-[18F]FDG PET/CT is useful to detect the site and extent of recurrence when conventional imaging methods are equivocal and when there is clinical and/or laboratorial suspicion of relapse. Recent developments are promising. CONCLUSION: 2-[18F]FDG PET/CT is extremely useful in BC management, as supported by extensive evidence of its utility compared to other imaging modalities in several clinical scenarios.

Combining immunotherapy and radiation therapy in gastrointestinal cancers: A review.

INTRODUCTION AND PURPOSE: With a significant global impact, treatment of gastrointestinal (GI) cancers still presents with challenges, despite current multimodality approaches in advanced stages. Clinical trials are expanding for checkpoint inhibition (ICI) combined with radiation therapy (RT). This review intends to offer a comprehensive image of the current data regarding the effectiveness of this association, and to reflect on possible directions to further optimize the results. RESULTS: Several early phase studies demonstrated encouraging potential. However, translating preclinical outcomes to clinical settings proves challenging, especially in immunologically "cold" environments. GI cancers exhibit heterogeneity, requiring tailored approaches based on disease stage and patient characteristics. Current results, though promising, lack the power of evidence to influence the general practice. CONCLUSIONS: Finding biomarkers for identifying or converting resistant cancers is essential for maximizing responses, moreover in this context strategic RT parameters need to be carefully considered. Our review emphasizes the significance of having a thorough grasp of how immunology, tumour biology, and treatment settings interact in order to propose novel research avenues and efficient GI cancer therapy.

De-escalation of axillary treatment in the event of a positive sentinel lymph node biopsy in cT1-2 N0 breast cancer treated with mastectomy: nationwide registry study (BOOG 2013-07).

BACKGROUND: Trials have demonstrated the safety of omitting completion axillary lymph node dissection in patients with cT1-2 N0 breast cancer operated with breast-conserving surgery who have limited metastatic burden in the sentinel lymph node. The aim of this registry study was to provide insight into the oncological safety of omitting completion axillary treatment in patients operated with mastectomy who have limited-volume sentinel lymph node metastasis. METHODS: Women diagnosed in 2013-2014 with unilateral cT1-2 N0 breast cancer treated with mastectomy, with one to three sentinel lymph node metastases (pN1mi-pN1a), were identified from the Netherlands Cancer Registry, and classified by axillary treatment: no completion axillary treatment, completion axillary lymph node dissection, regional radiotherapy, or completion axillary lymph node dissection followed by regional radiotherapy. The primary endpoint was 5-year regional recurrence rate. Secondary endpoints included recurrence-free interval and overall survival, among others. RESULTS: In total, 1090 patients were included (no completion axillary treatment, 219 (20.1%); completion axillary lymph node dissection, 437 (40.1%); regional radiotherapy, 327 (30.0%); completion axillary lymph node dissection and regional radiotherapy, 107 (9.8%)). Patients in the group without completion axillary treatment had more favourable tumour characteristics and were older. The overall 5-year regional recurrence rate was 1.3%, and did not differ significantly between the groups. The recurrence-free interval was also comparable among groups. The group of patients who did not undergo completion axillary treatment had statistically significantly worse 5-year overall survival, owing to a higher percentage of non-cancer deaths. CONCLUSION: In this registry study of patients with cT1-2 N0 breast cancer treated with mastectomy, with low-volume sentinel lymph node metastasis, the 5-year regional recurrence rate was low and comparable between patients with and without completion axillary treatment.

Organ-sparing techniques and dose-volume constrains used in breast cancer radiation therapy - Results from European and Latin American surveys.

Background: Advances in local and systemic therapies have improved the outcomes of patients with breast cancer (BC), leading to a possible increased risk for postoperative radiation therapy (RT) late adverse events. The most adequate technologies and dose constraints for organs at risk (OAR) in BC RT have yet to be defined. Methods: An online survey was distributed to radiation oncologists (ROs) practicing in Europe and Latin America including the Caribbean (LAC) through personal contacts, RO and BC professional groups' networks. Demographic data and clinical practice information were collected. Results:  The study included 585 responses from ROs practicing in 57 different countries. The most frequently contoured OAR by European and LAC participants were the whole heart (96.6 % and 97.7 %), the ipsilateral (84.3 % and 90.8 %), and contralateral lung (71.3 % and 77.4 %), whole lung (69.8 % and 72.9 %), and the contralateral breast (66.4 % and. 83.2 %). ESTRO guidelines were preferred in Europe (33.3 %) and the RTOG contouring guideline was the most popular in LAC (62.2 %), while some participants used both recommendations (13.2 % and 19.2 %). IMRT (68.6 % and 59.1 %) and VMAT (65.6 % and 60.2 %) were the preferred modalities used in heart sparing strategies, followed by deep inspiration breath-hold (DIBH) (54.8 % and 37.4 %) and partial breast irradiation (PBI) (41.6 % and 24.6 %). Only a small percentage of all ROs reported the dose-volume constraints for OAR used in routine clinical practice. A mean heart dose (Heart-Dmean) between 4 and 5 Gy was the most frequently reported parameter (17.2 % and 39.3 %). Conclusion:  The delineation approaches and sparing techniques for OAR in BC RT vary between ROs worldwide. The low response rate to the dose constraints subset of queries reflects the uncertainty surrounding this topic and supports the need for detailed consensus recommendations in the clinical practice.

International multidisciplinary consensus on the integration of radiotherapy with new systemic treatments for breast cancer: European Society for Radiotherapy and Oncology (ESTRO)-endorsed recommendations.

Novel systemic therapies for breast cancer are being rapidly implemented into clinical practice. These drugs often have different mechanisms of action and side-effect profiles compared with traditional chemotherapy. Underpinning practice-changing clinical trials focused on the systemic therapies under investigation, thus there are sparse data available on radiotherapy. Integration of these new systemic therapies with radiotherapy is therefore challenging. Given this rapid, transformative change in breast cancer multimodal management, the multidisciplinary community must unite to ensure optimal, safe, and equitable treatment for all patients. The aim of this collaborative group of radiation, clinical, and medical oncologists, basic and translational scientists, and patient advocates was to: scope, synthesise, and summarise the literature on integrating novel drugs with radiotherapy for breast cancer; produce consensus statements on drug-radiotherapy integration, where specific evidence is lacking; and make best-practice recommendations for recording of radiotherapy data and quality assurance for subsequent studies testing novel drugs.

Breast cancer highlights from 2023: Knowledge to guide practice and future research.

This narrative work highlights a selection of published work from 2023 with potential implications for breast cancer practice. We feature publications that have provided new knowledge immediately relevant to patient care or for future research. We also highlight guidelines that have reported evidence-based or consensus recommendations to support practice and evaluation in breast cancer diagnosis and treatment. The scope of selected highlights represents various domains and disciplines in cancer control, from prevention to treatment of early and advanced breast cancer.

Omission of radiation therapy after breast-conserving surgery for biologically favourable tumours in younger patients: The wrong answer to the right question.

In this perspective paper, the findings of the recently published LUMINA study are critically evaluated, with an emphasis on the need for careful interpretation and a thoughtful approach in clinical practice. The LUMINA trial, which investigates the role of adjuvant endocrine therapy in low-risk breast cancer patients, is assessed for its limitations, including a highly selective patient cohort and an insufficient follow-up period. The importance of long-term data and further trials to inform clinical decisions effectively is emphasized. While the LUMINA study does not support an immediate change in practice, it is seen as a foundation for generating hypotheses to guide ongoing clinical trials. This important study has served as inspiration to develop this perspective paper, which takes into account ongoing studies and the toxicity profile of postoperative treatments in low-risk recurrence breast cancer. The need for a patient-cantered approach is stressed, considering individual wishes and desires in decision-making, despite the complexity of articulating these aspects in guidelines. A wise interpretation of available findings is essential to ensure sound clinical decision-making before broadly applying omission of radiation therapy.