Current clinical practice in the management of phyllodes tumors of the breast: an international cross-sectional study among surgeons and oncologists.

PURPOSE: Phyllodes tumors of the breast are rare fibroepithelial lesions that are classified as benign, borderline or malignant. There is little consensus on best practice for the work-up, management, and follow-up of patients with phyllodes tumors of the breast, and evidence-based guidelines are lacking. METHODS: We conducted a cross-sectional survey of surgeons and oncologists with the aim to describe current clinical practice in the management of phyllodes tumors. The survey was constructed in REDCap and distributed between July 2021 and February 2022 through international collaborators in sixteen countries across four continents. RESULTS: A total of 419 responses were collected and analyzed. The majority of respondents were experienced and worked in a university hospital. Most agreed to recommend a tumor-free excision margin for benign tumors, increasing margins for borderline and malignant tumors. The multidisciplinary team meeting plays a major role in the treatment plan and follow-up. The vast majority did not consider axillary surgery. There were mixed opinions on adjuvant treatment, with a trend towards more liberal regiments in patients with locally advanced tumors. Most respondents preferred a five-year follow-up period for all phyllodes tumor types. CONCLUSIONS: This study shows considerable variation in clinical practice managing phyllodes tumors. This suggests the potential for overtreatment of many patients and the need for education and further research targeting appropriate surgical margins, follow-up time and a multidisciplinary approach. There is a need to develop guidelines that recognize the heterogeneity of phyllodes tumors.

NBN, RAD51 and XRCC3 Polymorphisms as Potential Predictive Biomarkers of Adjuvant Radiotherapy Toxicity in Early HER2-Positive Breast Cancer.

Radiotherapy (RT) for breast cancer significantly impacts patient survival and causes adverse events. Double-strand breaks are the most harmful type of DNA damage associated with RT, which is repaired through homologous recombination (HRR). As genetic variability of DNA repair genes could affect response to RT, we aimed to evaluate the association of polymorphisms in HRR genes with tumor characteristics and the occurrence of RT adverse events in early HER2-positive breast cancer. Our study included 101 breast cancer patients treated with adjuvant RT and trastuzumab. All patients were genotyped for eight single nucleotide polymorphisms in NBN, RAD51 and XRCC3 using competitive allele-specific PCR. Carriers of XRCC3 rs1799794 GG genotype were less likely to have higher tumor differentiation grade (OR = 0.05, 95% CI = 0.01-0.44, p = 0.007). Carriers of RAD51 rs1801321 TT genotype were more likely to have higher NYHA class in univariable (OR = 10.0; 95% CI = 1.63-61.33; p = 0.013) and multivariable (OR = 9.27; 95% CI = 1.28-67.02; p = 0.027) analysis. Carriers of RAD51 rs12593359 GG genotype were less likely to have higher NYHA class in univariable (OR = 0.09; 95% CI = 0.01-0.79; p = 0.030) and multivariable (OR = 0.07; 95% CI = 0.01-0.81; p = 0.034) analysis. Carriers of XRCC3 rs1799794 GG genotypes experienced more skin adverse events based on LENT-SOMA scale in univariable (OR = 5.83; 95% CI = 1.22-28.00; p = 0.028) and multivariable (OR = 10.90; 95% CI = 1.61-73.72; p = 0.014) analysis. In conclusion, XRCC3 and RAD51 polymorphisms might contribute to RT adverse events in early HER2-positive breast cancer patients.

Radiotherapy-Induced Cardiotoxicity: The Role of Multimodality Cardiovascular Imaging.

Radiotherapy (RT) is one of the pillars of cancer therapy. High-dose radiation exposure on the thorax is mainly used in the context of adjuvant RT after breast surgery, in lung and esophageal cancer, and as a complement to systemic treatment in lymphoma. Due to the anatomical proximity, the heart inevitably receives some radiation that can result in acute and chronic cardiotoxicity, leading to heart failure, coronary artery disease, pericardial and valvular heart disease. Current evidence suggests there is no safe radiation dose to the heart, which poses a need for early recognition of RT-induced cardiac injury to initiate cardioprotective treatment and prevent further damage. Multimodality cardiac imaging provides a powerful tool to screen for structural and functional abnormalities secondary to RT. Left ventricular ejection fraction, preferably with three-dimensional echocardiography or cardiovascular magnetic resonance (CMR), and global longitudinal strain with speckle-tracking echocardiography are currently the key parameters to detect cardiotoxicity. However, several novel imaging parameters are tested in the ongoing clinical trials. CMR parametric imaging holds much promise as T1, T2 mapping and extracellular volume quantification allow us to monitor edema, inflammation and fibrosis, which are fundamental processes in RT-induced cardiotoxicity. Moreover, the association between serum biomarkers, genetic polymorphisms and the risk of developing cardiovascular disease after chest RT has been demonstrated, providing a platform for an integrative screening approach for cardiotoxicity. The present review summarizes contemporary evidence of RT-induced cardiac injury obtained from multimodality imaging-echocardiography, cardiovascular computed tomography, CMR and nuclear cardiology. Moreover, it identifies gaps in our current knowledge and highlights future perspectives to screen for RT-induced cardiotoxicity.

European Society for Radiotherapy and Oncology Advisory Committee in Radiation Oncology Practice consensus recommendations on patient selection and dose and fractionation for external beam radiotherapy in early breast cancer.

High-quality randomised clinical trials testing moderately fractionated breast radiotherapy have clearly shown that local control and survival is at least as effective as with 2 Gy daily fractions with similar or reduced normal tissue toxicity. Fewer treatment visits are welcomed by patients and their families, and reduced fractions produce substantial savings for health-care systems. Implementation of hypofractionation, however, has moved at a slow pace. The oncology community have now reached an inflection point created by new evidence from the FAST-Forward five-fraction randomised trial and catalysed by the need for the global radiation oncology community to unite during the COVID-19 pandemic and rapidly rethink hypofractionation implementation. The aim of this paper is to support equity of access for all patients to receive evidence-based breast external beam radiotherapy and to facilitate the translation of new evidence into routine daily practice. The results from this European Society for Radiotherapy and Oncology Advisory Committee in Radiation Oncology Practice consensus state that moderately hypofractionated radiotherapy can be offered to any patient for whole breast, chest wall (with or without reconstruction), and nodal volumes. Ultrafractionation (five fractions) can also be offered for non-nodal breast or chest wall (without reconstruction) radiotherapy either as standard of care or within a randomised trial or prospective cohort. The consensus is timely; not only is it a pragmatic framework for radiation oncologists, but it provides a measured proposal for the path forward to influence policy makers and empower patients to ensure equity of access to evidence-based radiotherapy.

Effect of Adjuvant Hormonal Therapy on the Development of Pulmonary Fibrosis after Postoperative Radiotherapy for Breast Cancer.

Breast cancer is the most common malignancy among women. Therefore, it is of paramount importance to study the adverse effects of oncological treatment of breast cancer, with one of adverse effects being pulmonary fibrosis (PF). PF is an irreversible condition and can significantly reduce the quality of life. Following lumpectomy, radiotherapy is the standard adjuvant treatment for breast cancer. Additionally, hormone receptor-positive breast cancers are treated with adjuvant hormonal therapy. While radiotherapy is one of the known causes of PF, the effect of hormone therapy on its development is not well-defined. Some studies have shown that the concomitant administration of endocrine therapy, primarily tamoxifen, and irradiation may potentiate the development of PF. However, guidelines regarding the timing of hormone therapy administration with respect to adjuvant radiotherapy are not clearly defined. This review aims to provide a comprehensive overview of the available information regarding the effect of hormone therapy and its timing of administration with respect to adjuvant radiotherapy on the incidence of PF.

Cyclin-Dependent Kinase 4/6 Inhibitors Combined With Radiotherapy for Patients With Metastatic Breast Cancer.

BACKGROUND: The cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) represent the standard treatment for hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer. Data about the balance between efficacy and toxicity of combined palliative radiotherapy (RT) and CDK4/6 inhibition are lacking. PATIENTS AND METHODS: We undertook a review of 46 patients with metastatic breast cancer on systemic treatment with CDK4/6i who underwent 62 metastases-directed RT. Clinical, laboratory, and RT treatment planning data were collected. Statistical analyses included Student t test, paired sample t test, and logistic regression modeling. RESULTS: Thirty patients (65.2%) received palbociclib, 15 (32.6%) received ribociclib, and one patient received abemaciclib (2.2%). Median total prescribed RT dose was 20 Gy (range, 8-63 Gy). Sites of RT were bone (n = 50; 80.7%), visceral (n = 7; 11.3%), or brain metastases (n = 3; 4.8%), as well as primary tumor of the breast (n = 2; 3.2%). Overall, the rates of grade 3 or higher adverse events (AEs) were 6.5%, 4.3%, 15.2%, and 23.9% before the start of RT, during RT, 2 and 6 weeks after RT completion, respectively. We found no correlation between dose distribution to organs at risk and the development of AEs. The local control rates for the entire cohort were 98% at 6 months and 90% at 12 months. Overall, pain relief (complete or partial) was experienced by 80% (24/30) of patients who initially reported pain at the treated metastatic site. CONCLUSION: We observed a modest increase in the rates of grade 3 or higher AEs after combined RT and CDK4/6i, with maintained efficacy of concomitant RT.

Genetic Variability of Antioxidative Mechanisms and Cardiotoxicity after Adjuvant Radiotherapy in HER2-Positive Breast Cancer Patients.

BACKGROUND: Breast cancer treatment is associated with the occurrence of various cardiac adverse events. One of the mechanisms associated with cardiotoxicity is oxidative stress, against which cells are protected by antioxidative enzymes. Genetic variability of antioxidative enzymes can affect enzyme activity or expression, which modifies the ability of cells to defend themselves against oxidative stress and could consequently contribute to the occurrence of treatment-related cardiotoxicity. Our aim was to evaluate the association of common polymorphisms in antioxidative genes with cardiotoxicity after adjuvant radiotherapy (RT) in HER2-positive breast cancer patients. METHODS: Our retrospective study included 101 HER2-positive early breast cancer patients who received trastuzumab and adjuvant RT. We isolated DNA from buccal swabs and used competitive allele-specific PCR for genotyping of PON1 rs854560 and rs662, GSTP1 rs1138272 and rs1695, SOD2 rs4880, CAT rs1001179, and HIF1 rs1154965 polymorphisms. N-terminal pro B-type natriuretic peptide (NT-proBNP), left ventricular ejection fraction, and NYHA class were used as markers of cardiotoxicity. We used logistic regression to evaluate the association of genetic factors with markers of cardiotoxicity. RESULTS: Carriers of at least one polymorphic PON1 rs854560 allele were less likely to have increased NT-proBNP (OR = 0.34; 95% CI = 0.15-0.79; P = 0.012), even after adjustment for age (OR = 0.35; 95% CI = 0.15-0.83; P = 0.017). Carriers of at least one polymorphic PON1 rs662 allele were more likely to have increased NT-proBNP (OR = 4.44; 95% CI = 1.85-10.66; P = 0.001), even after adjustment for age (OR = 5.41; 95% CI = 2.12-13.78; P < 0.001). GSTP1 rs1695 was also associated with decreased NT-proBNP in the multivariable analysis (P = 0.026), while CAT rs1001179 was associated with NYHA class in the univariable (P = 0.012) and multivariable analysis (P = 0.023). CONCLUSION: In our study, polymorphisms PON1 rs662 and rs854560, CAT rs1001179, and GSTP1 rs1695 were significantly associated with the occurrence of cardiac adverse events after adjuvant RT and could serve as biomarkers contributing to treatment personalization.

Breast cancer patients with brain metastases or leptomeningeal disease: 10-year results of a national cohort with validation of prognostic indexes.

Development of brain metastasis (BM) and leptomeningeal (LM) disease in breast cancer (BC) patients indicates poor prognosis and impairs patients' quality of life. Prognostic survival scores for BM can help predict expected survival in order to choose the most appropriate treatment. The aim of our study was to analyze national data for BC patients treated with radiation therapy for BM/LM disease and validate the applicability of different survival prognostic scores. We retrospectively evaluated medical records of 423 BC patients with BM/LM disease receiving radiation therapy between April 2005 and December 2015. Patients were classified by BC Recursive Partitioning Analysis (B-RPA), Breast Graded Prognostic Assessment (Breast-GPA), Modified Breast Graded Prognostic Assessment (MB-GPA), and Simple Survival score for patients with BM from BC (SS-BM). Overall survival (OS) was calculated from the development of BM/LM disease to death or last follow-up date. After a median follow-up of 7.5 years, the median OS was 6.9 months (95% CI 5.5-7.8, range 0-146.4) and 1- and 2-year survival rates were 35% and 17%, respectively. Survival analysis showed significant differences in median OS regarding biologic subtypes (P < 0.0001), as follows: 3.2 (95% Confidence Interval (CI) 2.5-3.9), 3.9 (95% CI 2.3-5.6), 7.1 (95% CI 4.3-9.8), 12.1 (95% CI 8.3-15.9), and 15.4 (95% CI 8.8-22.1) months for primary triple-negative BC (TNBC), Luminal B HER2-negative, Luminal A, HER2-enriched, and Luminal B HER2-positive tumors, respectively. Good Karnofsky Performance Status (KPS), single metastasis, and absence of LM or extracranial disease all demonstrated better OS in univariate and multivariate analysis. All four employed prognostic indexes provided good prognostic value in predicting survival. SS-BM and MB-GPA showed the best discriminating ability (Concordance indexes C were 0.768 and 0.738, respectively). This study presents one of the largest single-institution series validating prognostic scores for BC patients with BM/LM. SS-BM and MB-GPA proved to be useful tools in the clinical decision-making process.

ESTRO ACROP consensus guideline for target volume delineation in the setting of postmastectomy radiation therapy after implant-based immediate reconstruction for early stage breast cancer.

Immediate breast reconstruction (IBR) rates after mastectomy are increasing. Postmastectomy radiation therapy (PMRT) contouring guidelines for target volumes in the setting of IBR are lacking. Therefore, many patients who have had IBR receive PMRT to target volumes similar to conventional simulator-based whole breast irradiation. The aim of this paper is to describe delineation guidelines for PMRT after implant-based IBR based on a thorough understanding of the surgical procedures, disease stage, patterns of recurrence and radiation techniques. They are based on a consensus endorsed by a global multidisciplinary group of breast cancer experts.

Is postmastectomy radiotherapy really needed in breast cancer patients with many positive axillary lymph nodes?

Background Postmastectomy radiotherapy (PMRT) improves survival by eliminating potential occult lesions in the chest wall and lymphatic drainage area. Meta-analysis has shown that PMRT reduces mortality and local recurrence of patients with node positive breast cancer, but there is no specific data about the effectiveness of PMRT in a subgroup of patients with a high number of positive axillary lymph nodes (PALN). The aim of the study was to analyse the impact of the number of PALN on local and distant metastasis occurrence, overall survival (OS) and distant metastases free survival (DMFS) in patients treated with PMRT. Patients and methods We reviewed medical records of 129 consecutive breast cancer patients with PALN, treated at Institute of Oncology Ljubljana with PMRT between January 2003 and December 2004. We grouped patients according to the number of PALN as follows: Group 1 (less than 15 PALN) and Group 2 with more than 15 PALN. All patients received adjuvant systemic therapy according to the clinical guidelines. We analysed number of locoregional (LR) recurrences, distant metastasis, overall survival (OS), progression free survival (PFS) and DMFS. Results After the median follow-up time of 11.5 years, the Kaplan-Meier survival analysis of PALN showed significantly shorter OS (p = 0.006), shorter PFS (p = 0.002) and shorter DMFS (p < 0.001) in the group of > 15 PALN. Only one LR was found in the group of patients with more than 15 PALN. In multivariate analysis more than 15 PALN and treatment with anthracycline chemotherapy statistically significantly influenced OS and DMFS. For PFS presence of more than 15 PALN were the only independent factor of shorter survival. Conclusions Patients with more than 15 PALN have shorter DMFS, PFS and OS as compared to patients with less than 15 PALN, though they receive the same LR treatment. More studies with higher number of patients included are needed to further evaluate our findings.

Early Cardiotoxicity after Adjuvant Concomitant Treatment with Radiotherapy and Trastuzumab in Patients with Breast Cancer.

BACKGROUND: The purpose of the study was to find out whether there is a difference in the early parameters of cardiotoxicity (left ventricular ejection fraction [LVEF] and N-terminal pro-B-type natriuretic peptide [NT-proBNP]) between the two groups of patients: the patients treated for left breast cancer (left breast cancer group) and those treated for the right breast cancer (right breast cancer group), after the treatment had been completed. PATIENTS AND METHODS: The study included 175 consecutive patients with human epidermal growth factor receptor-2 (HER2) positive early breast cancer, treated concurrently with trastuzumab and radiotherapy (RT), between June 2005 and December 2010. Echocardiography with LVEF measurement was performed before adjuvant RT (LVEF0) and after the completed treatment (LVEF1,). After the treatment NT-proBNP measurement was done as well. The difference (Δ) between LVEF0 and LVEF1 was analysed (Δ LVEF = LVEF0 - LVEF1) and compared between the two groups. RESULTS: There were 84 patients in the left and 91 in the right breast cancer group. Median observation time was 57 (37-71) months. Mean Δ LVEF (%) was -1.786% in the left and -2.607% in the right breast cancer group (p = 0.562, CI: -2.004 to 3.648). Median NT-proBNP were 111.0 ng/l in the left and 90.0 ng/l in the right breast cancer group (p = 0.545). Echocardiography showed that the patients in the left breast cancer group did not have significantly worse systolic and diastolic left ventricular function in comparison with the patients in the right breast cancer group, but, they had higher incidence of pericardial effusion (9 [11%] vs. 1 [1%]) (p = 0.007). CONCLUSIONS: We did not find any significant differences in the early parameters of cardiotoxicity (LVEF, NT-proBNP) between the observed groups. Patients who received left breast/chest wall irradiation had higher incidence of pericardial effusion.

Pericardial disease after breast cancer radiotherapy.

Background Breast cancer is the second most common cancer worldwide. Thanks to the modern oncological treatments, disease specific survival has improved throughout the last decades. The number of breast cancer survivors has been increasing, and more and more attention has been paid to the breast cancer treatment side effects. Whereas there are many data regarding ischemic heart disease after radiotherapy for breast cancer, there is not much data in the literature about the incidence and clinical meaning of pericardial disease after breast cancer radiotherapy. Conclusions Although radiation-induced pericarditis is the earliest form of radiation-induced cardiovascular disease after irradiation of the heart, it seems that in clinical practice, especially by using modern radiotherapy treatment techniques, it is underdiagnosed because patients are mostly asymptomatic. In some cases, especially in its late form and after multimodal systemic oncological treatment in combination with radiotherapy, it could be presented in severe form and life threatening. Treatment modalities for radiation-induced pericardial diseases are the same as in the non-irradiated population, but in the irradiated patients, surgery may be difficult.

ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer.

BACKGROUND AND PURPOSE: Delineation of clinical target volumes (CTVs) is a weak link in radiation therapy (RT), and large inter-observer variation is seen in breast cancer patients. Several guidelines have been proposed, but most result in larger CTVs than based on conventional simulator-based RT. The aim was to develop a delineation guideline obtained by consensus between a broad European group of radiation oncologists. MATERIAL AND METHODS: During ESTRO teaching courses on breast cancer, teachers sought consensus on delineation of CTV through dialogue based on cases. One teacher delineated CTV on CT scans of 2 patients, followed by discussion and adaptation of the delineation. The consensus established between teachers was sent to other teams working in the same field, both locally and on a national level, for their input. This was followed by developing a broad consensus based on discussions. RESULTS: Borders of the CTV encompassing a 5mm margin around the large veins, running through the regional lymph node levels were agreed, and for the breast/thoracic wall other vessels were pointed out to guide delineation, with comments on margins for patients with advanced breast cancer. CONCLUSION: The ESTRO consensus on CTV for elective RT of breast cancer, endorsed by a broad base of the radiation oncology community, is presented to improve consistency.

Cardiotoxicity of concomitant radiotherapy and trastuzumab for early breast cancer.

BACKGROUND: Trastuzumab therapy given in combination with one of several chemotherapy regimens is currently considered the standard of care for the treatment of early-stage, human epidermal growth factor receptor-2 (HER2) -positive breast cancer. The treatment with trastuzumab is due to a significant impact on the survival part of the standard adjuvant treatment of patients with HER2-positive breast cancer. Patients treated with postoperative breast or chest wall irradiation receive trastuzumab concomitant with radiotherapy. In a small proportion of patients trastuzumab causes cardiotoxicity. Preclinical findings indicate a radiosensibilizing effect of trastuzumab in breast cancer cells, but it is not yet clear whether it radiosensibilizes cells of healthy tissues too. CONCLUSIONS: Special attention is required when left breast or left thoracic wall is irradiated in patient receiving trastuzumab, because long-term effects of the concurrent treatment with trastuzumab and radiotherapy are not yet known. In an era where more patients are surviving a diagnosis of breast cancer, better understanding and earlier detection of therapy-induced cardiac toxicity will be of paramount importance.

Long-term use of metformin and the molecular subtype in invasive breast carcinoma patients - a retrospective study of clinical and tumor characteristics.

BACKGROUND: Metformin may exhibit inhibitory effects on cancer cells by inhibiting mTOR signaling pathway. The aim of our retrospective study was to examine if patients with breast carcinoma (BC) and diabetes mellitus (DM) receiving metformin have a lower stage of carcinoma in comparison to patients not receiving metformin, and if the use of metformin correlates with the molecular subtype of BC. METHODS: A chart review of 253 patients with invasive BC and DM (128 on metformin and 125 not on metformin) was performed. Control group consisted of 320 consecutive patients with invasive BC without DM. BC subtypes were classified by immunohistochemical surrogates as luminal A (estrogen receptor [ER] + and/or progesterone receptor [PR]+, HER-2-), luminal B (ER + and/or PR+, HER-2+), HER-2 (ER-, PR-, HER-2+), triple-negative/basal (ER-, PR-, HER-2-). RESULTS: Patients on metformin had a lower proportion of T3 or T4 tumors than patients who were not receiving metformin (16% vs. 26%; p = 0.035). No statistical difference was found between the two study groups in N stage. Patients with DM on metformin, with DM not on metformin and the control group had different molecular subtypes of BC (p = 0.01): the luminal A subtype was found in 78%, 83% and 71%, the luminal B in 12.6%, 9% and 11%, HER-2 in 0.8%, 1.6% and 8%, and the triple-negative/basal-like subtype in 8.6%, 6.4% and 10%, respectively. CONCLUSION: Our data indicate that long-term use of metformin use correlates with molecular subtype of BC in diabetics on metformin in comparison to diabetics not on metformin and patients without DM. However, most likely, different distribution of the molecular subtypes of BC in these three groups of patients was caused by other risk factors for breast carcinoma, such as age of patients or obesity.