Absence of post-treatment changes in sentinel lymph nodes does not translate into increased regional recurrence rate in initially node-positive breast cancer patients.

PURPOSE: To determine whether the absence of post-treatment changes in the negative sentinel lymph nodes (SLN) in the neoadjuvant setting for biopsy-proven cN + disease results in an increased regional recurrence (RR) rate in patients after SLN biopsy (SLNB) only. METHODS: Breast cancer patients with biopsy-proven cN + disease who converted to node-negative disease after neoadjuvant systemic treatment (NAST) and underwent SLNB only were included. Retrospective analysis was performed for patients diagnosed between 2008 and 2021. Pathohistological specimens were reviewed for the presence of post-treatment changes in the SLNs. Patients with negative SLNs (ypN0) were divided into two groups: (i) with post-treatment changes, (ii) without post-treatment changes. Patients' characteristics were compared between groups. Crude RR rates were compared using the log-rank test. Recurrence-free (RFS) and overall survival (OS) for the entire cohort were calculated using Kaplan-Meier. RESULTS: Of 437 patients with cN + disease, 95 underwent SLNB only. 82 were ypN0, 57 with post-treatment changes (group 1), 25 without post-treatment changes (group 2). During the median follow-up of 37 months (range 6-148), 1 isolated regional recurrence occurred in group 2 (RR rate 0% for group 1 vs. 4% for group 2, p = 0.149). There were no differences in 3-year RFS and OS between groups. CONCLUSION: Absent post-treatment changes in negative SLNs for biopsy-proven cN + disease that covert to node-negative after NAST did not result in increased regional recurrence rates in our cohort. Multidisciplinary input is essential to determine whether additional treatment is needed in these patients.

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.

Leptomeningeal metastases in patients with human epidermal growth factor receptor 2 positive breast cancer: Real-world data from a multicentric European cohort.

In patients with human epidermal growth factor receptor 2 positive (HER2+) breast cancer, leptomeningeal metastases (LM) are a rare but often a fatal clinical scenario. In this multicentric study, clinical and pathologic characteristics of patients with HER2+ breast cancer developing LM were described, as well as survival outcomes. Data were gathered retrospectively from medical records of 82 patients with advanced HER2+ breast cancer and LM treated between August 2005 and July 2020. Following LM diagnosis, 79 (96.3%) patients received at least one line of anti-HER2 therapy, 25 (30.5%) patients received intrathecal therapy and 58 (70.7%) patients received radiotherapy. Overall survival (OS) was 8.3 months (95% confidence interval [CI] 5.7-11), 1-year OS was 42%, and 2-year OS was 21%. At univariate analysis, patients who were treated after 2010, had better Karnofsky performance status, were free of neurological symptoms, had better prognostic, received chemotherapy (OS difference 9.4 months, P = .024), or monoclonal antibodies (trastuzumab ± pertuzumab; OS difference 6.1 months; P = .013) after LM diagnosis, had a statistically significantly longer OS. Presence of neurological symptoms (hazard ratio 3.32, 95% CI 1.26-8.73; P = .015) and not having received radiotherapy (hazard ratio 2.02, 95% CI 1.09-3.72; P = .024) were all associated with poorer OS at multivariate analysis. To summarize, not having neurological symptoms and receiving RT at LM diagnosis were associated with prolonged OS in our cohort. Survival seemed to be prolonged with multimodality treatment, which included targeted therapy, chemotherapy, and RT to the LM sites.

Stereotactic radiosurgery for patients with breast cancer brain oligometastases - molecular subtypes and clinical outcomes.

BACKGROUND: We sought to determine the clinical outcomes of patients with breast cancer (BC) who had undergone stereotactic radiosurgery (SRS) for a limited number of brain metastases (BM) and to identify factors influencing overall survival (OS) and local control. MATERIALS AND METHODS: The records of 45 patients who underwent SRS for 72 brain lesions were retrospectively evaluated. Statistics included the chi-squared test, Kaplan-Meier method, and the multivariate Cox model. RESULTS: The median number of treated BM was 2 (range 1-10). Median OS from BM diagnosis and post-SRS were 27.6 [95% confidence interval (CI): 14.8-40.5) and 18.5 months (95% CI: 11.1-25.8), respectively. One-year and two-year survival rates after BM diagnosis were 55% and 41%, respectively. In a univariate analysis, the Luminal-B-human-epidermal-growth-receptor-positive (HER2+) subtype had the longest median OS at 39.1 months (95% CI: 34.1-44.1, p = 0.004). In an adjusted analysis, grade 2 [hazard ratio (HR): 0.1; 95% CI: 0.1-0.6, p = 0.005), craniotomy (HR: 0.3; 95% CI: 0.1-0.7; p = 0.006), and ≥ 2 systemic therapies received (HR: 0.3; 95% CI: 0.1-0.9, p = 0.028) were associated with improved OS. One-year and two-year intracranial progression-free survival rates were 85% and 63%, respectively. Four factors for a higher risk of any intracranial recurrence remained significant in the adjusted analysis, as follows: age < 50 years (HR: 4.2; 95% CI: 1.3-36.3; p = 0.014), grade 3 (HR: 3.7; 95% CI: 1.1-13.2; p = 0.038), HER2+ (HR: 6.9; 95% CI: 1.3-36.3; p = 0.023), and whether the brain was the first metastatic site (HR: 4.7; 95% CI: 1.6-14.5; p = 0.006). CONCLUSION: Intrinsic BC characteristics are important determinants for both survival and intracranial control for patients undergoing SRS for oligometastatic brain disease.

Explaining variation in quality of breast cancer care and its impact: a nationwide population-based study from Slovenia.

PURPOSE: To assess and explain variation in quality of care in breast cancer patients and estimate its impact on disease outcome. METHODS: The Slovenian National Cancer Registry database and clinical records of 1053 women with unilateral primarily non-metastatic invasive breast cancer diagnosed in 2013 were reviewed in this retrospective analysis. Quality care was defined as care fully compliant with quality indicators (QI) defined by European Society of Breast Cancer Specialists (EUSOMA). Multivariate logistic regression was used to determine the predictors of receiving quality care. Differences in overall survival (OS) and event-free survival (EFS, relapse, or progression of disease or death considered an event) based on adherence to QI were analyzed using Kaplan-Meier method and Cox models. RESULTS: Younger age, no comorbidities, and HER2-negative tumor were associated with increased odds ratios for receiving quality care, whereas tumor stage and type of hospital had no significant association. Median follow-up was 54.5 months. Not receiving quality care resulted in an increased risk of dying [hazard ratio (HR) 1.68; 95% confidence interval (CI) 1.06-2.66; p = 0.026]. Difference in EFS between two groups was significant after adjusting for case mix and type of hospital (HR 1.80; 95% CI 1.29-2.52; p = 0.001) but disappeared when type of treatment was added into the model (HR 1.30; 95% CI 0.89-1.90; p = 0.178). CONCLUSION: Observed comorbidity and age bias in delivering quality breast cancer care could be medically justifiable, whereas observed deviations dependent on HER2 status are puzzling. Complete adherence of treatment to quality indicators resulted in better OS.

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.

Cardiotoxicity of mediastinal radiotherapy.

AIM: To explore available recent literature related to cardiotoxicity following mediastinal radiation. BACKGROUND: Radiotherapy-related heart injury is well documented, with no apparent safety threshold dose. The number of long-term cancer survivors exposed to mediastinal radiotherapy at some point of their treatment is increasing. Heart dosimetric parameters are of great importance in developing a treatment plan, but few data are available regarding radiosensitivity and dose-volume constraints for specific heart structures. MATERIALS AND METHODS: In October 2018, we identified articles published after 1990 through a PubMed/MEDLINE database search. The authors examined rough search results and manuscripts not relevant for the topic were excluded. We extracted clinical outcomes following mediastinal radiotherapy of childhood cancers, lymphoma, medulloblastoma, thymic cancers and hematopoietic cell transplantation survivors and evaluated treatment planning data, whenever available. RESULTS: A total of 1311 manuscripts were identified in our first-round search. Of these manuscripts, only 115 articles, matching our selection criteria, were included. CONCLUSIONS: Studies uniformly show a linear radiation dose-response relationship between mean absorbed dose to the heart (heart-Dmean) and the risk of dying as a result of cardiac disease, particularly when heart-Dmean exceeds 5 Gy. Limited data are available regarding dose-volume predictors for heart substructures and the risk of subsequent cardiac toxicity. An individual patient's cardiotoxicity risk can be modified with advanced treatment planning techniques, including deep inspiration breath hold. Proton therapy is currently showing advantages in improving treatment planning parameters when compared to advanced photon techniques in lymphoma, thymic malignancies, malignant mesothelioma and craniospinal irradiation.

General Overview and Treatment Recommendations for Young Women with Breast Cancer.

Breast cancer in young women is a complex disease to manage due to its biological heterogeneity and special issues related to toxicity of different treatment strategies. Defining a cut-off for young age has been challenging since it is not clear whether the prognostic effect of age is continuously variable or whether there are certain thresholds at which the prognosis changes (e.g. those < 50 years of age or ≤ 35 years of age). In this review article, we define young patients as those being premenopausal. In addition, we discuss the most recent data of the biological diversity of breast cancer arising in premenopausal patients and current treatment modalities in early and advanced settings. Survivorship, with special emphasis on the importance of early supportive care, is also discussed.

Preoperative treatment with radiochemotherapy for locally advanced gastroesophageal junction cancer and unresectable locally advanced gastric cancer.

BACKGROUND: To purpose of the study was to analyze the results of preoperative radiochemotherapy in patients with unresectable gastric or locoregionally advanced gastroesophageal junction (GEJ) cancer treated at a single institution. PATIENTS AND METHODS: Between 1/2004 and 6/2012, 90 patients with locoregionally advanced GEJ or unresectable gastric cancer were treated with preoperative radiochemotherapy at the Institute of Oncology Ljubljana. Planned treatment schedule consisted of induction chemotherapy with 5-fluorouracil and cisplatin, followed by concomitant radiochemotherapy four weeks later. Three-dimensional conformal external beam radiotherapy was delivered by dual energy (6 and 15 MV) linear accelerator in 25 daily fractions of 1.8 Gy in 5 weeks with two additional cycles of chemotherapy repeated every 28 days. Surgery was performed 4-6 weeks after completing radiochemotherapy. Following the surgery, multidisciplinary advisory team reassessed patients for the need of adjuvant chemotherapy. The primary endpoints were histopathological R0 resection rate and pathological response rate. The secondary endpoints were toxicity of preoperative radiochemotherapy and survival. RESULTS: Treatment with preoperative radiochemotherapy was completed according to the protocol in 84 of 90 patients (93.3%). Twenty patients (22.2%) did not undergo the surgery because of the disease progression, serious comorbidity, poor performance status or still unresectable tumour. In 13 patients (14.4%) only exploration was performed because the tumour was assessed as unresectable or diffuse peritoneal carcinomatosis was established. Fifty-seven patients (63.4%) underwent surgery with the aim of complete removal of the tumour. Radical resection was achieved in 50 (55.6%) patients and the remaining seven (7.8%) patients underwent non-radical surgery (R1 in five and R2 in two patients). In this group of patients (n = 57), pathological complete response of tumour was achieved in five patients (5.6% of all treated patients or 8.8% of all operated patients). Down-staging was recorded in 49 patients (86%), in one patient (1.8%) the stage after radiochemotherapy was unchanged while in seven patients (12.3%) the pathological stage was higher than clinical, mainly due to higher pN stage. No death was recorded during preoperative radiochemotherapy. Most grade 3 and 4 toxicities were due to vomiting, nausea and bone marrow suppression (granulocytopenia). Twenty-six (45.6%) patients died due to GEJ or gastric carcinoma, one died because of septic shock following the surgery and a reason for two deaths was unknown. Twenty-eight patients (49.1%) were disease free at the time of analysis, while 29 patients (50.9%) developed the recurrence, mostly as distant metastases. At two years, locoregional control, disease-free survival, disease-specific survival and overall survival were 82.9%, 43.9%, 56.9% and 53.9%, respectively. CONCLUSIONS: Preoperative radiochemotherapy was feasible in our group of patients and had acceptable toxicity. Majority of patients achieved down-staging, allowing greater proportion of radical resections (R0), which are essential for patients' cure.

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.

Ultra-hypofractionated one-week locoregional radiotherapy for patients with early breast cancer: Acute toxicity results.

Purpose: Moderate hypofractionated radiotherapy is the standard of care for all patients with breast cancer, irrespective of stage or prior treatments. While extreme hypofractionation is accepted for early-stage tumours, its application in irradiating locoregional lymph nodes remains controversial. Materials and methods: A prospective registry analysis from July 2020 to September 2023 included 276 patients with early-stage breast cancer treated with one-week ultra-hypofractionation (UHF) at 26 Gy in 5 fractions on the whole breast (58.3 %) or thoracic wall (41.7 %) and ipsilateral regional lymph nodes and simultaneous integrated boost (58.3 %). Primary endpoint was assessment of acute adverse events (AEs). Secondarily, onset of early-delayed toxicity was assessed. A minimum 6-month follow-up was required for assessing potential treatment-related early-delayed complications. Acute or late complications attributable to treatment were assessed at inclusion using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 criteria. Results: With a median follow-up of 19 months (range 1-49 months), 159 (57.6 %) patients reported AEs, predominantly grade (G) 1 (n = 139, 50.4 %) and G2 (n = 20, 7.8 %). Skin acute toxicity was common (G1/2: 134, G3: 14), while breast oedema occurred in 10 patients (G1: 9, G2: 1), and 15.9 % reported breast pain (G1: 42, G2: 2). Ipsilateral arm oedema was observed in 1.8 % patients. For patients with a follow-up beyond 6 months (n = 213), 23.4 % patients reported G1/G2 skin AEs, 8.8 % had G1/G2 breast/chest wall oedema, and 8.9 % experienced arm lymphedema. There were no cases of brachial plexopathy or G3 toxicity in this group of patients. Conclusions: One-week UHF adjuvant locoregional radiation is well-tolerated, displaying low-toxicity profiles comparable to other studies using similar irradiation schedules.

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.

Acute toxicity in patients with oligometastatic cancer following metastasis-directed stereotactic body radiotherapy: An interim analysis of the E2-RADIatE OligoCare cohort.

AIM: To evaluate acute toxicity at 6 months after stereotactic body radiotherapy (SBRT) in patients with oligometastatic cancer within the OligoCare cohort. MATERIAL AND METHODS: OligoCare is a prospective, registry-based, single-arm, observational study that aims to report prospective real-world data of patients with oligometastases from solid cancer treated with SBRT (NCT03818503). Primary tumor included non-small cell lung cancer (NSCLC), breast cancer (BC), colorectal cancer (CRC), and prostate cancer (PC). This analysis addresses a secondary endpoint of the trial, acute toxicity within 6 months after SBRT. RESULTS: Out of 1,597registered patients, 1'468 patients were evaluated for acute toxicity. Globally, 290 (20 %) had NSCLC primary disease, 227 (16 %) had BC, 293 (20 %) had CRC, and 658 (45 %) had PC. Concomitant systemic treatment was administered in 527 (35.9 %) patients. According to the EORTC/ESTRO oligometastatic disease (OMD) classification, 828 (56 %) patients had de novo OMD, 464 (32 %) repeat OMD, and 176 (12 %) induced OMD. Acute grade ≥ 3 SBRT related adverse events were reported in 8 (0.5 %) patients, including 2 (0.1 %) fatal AEs. In particular, 6 (0.4 %) grade 3 events were: 1 empyema, 1 pneumonia, 1 radiation pneumonitis, 1 radiation skin injury, 1 decreased appetite, and 1 bone pain. Among those 2 occurred in NSCLC patients, 2 in BC patients, and 1 in CRC and PC patients each. The two (0.1 %) grade 5 toxicity were represented by: pneumonitis and cerebral hemorrhage. CONCLUSION: OligoCare is the largest prospective registry cohort on oligometastatic disease. Acute toxicity within 6 months was low, confirming the safety of SBRT in the treatment of oligometastases.

Cancer-specific dose and fractionation schedules in stereotactic body radiotherapy for oligometastatic disease: An interim analysis of the EORTC-ESTRO E2-RADIatE OligoCare study.

BACKGROUND AND INTRODUCTION: Optimal dose and fractionation in stereotactic body radiotherapy (SBRT) for oligometastatic cancer patients remain unknown. In this interim analysis of OligoCare, we analyzed factors associated with SBRT dose and fractionation. MATERIALS AND METHODS: Analysis was based on the first 1,099 registered patients. SBRT doses were converted to biological effective doses (BED) using α/ß of 10 Gy for all primaries, and cancer-specific α/ß of 10 Gy for non-small cell lung and colorectal cancer (NSCLC, CRC), 2.5 Gy for breast cancer (BC), or 1.5 Gy for prostate cancer (PC). RESULTS: Of the interim analysis population of 1,099 patients, 999 (99.5 %) fulfilled inclusion criteria and received metastasis-directed SBRT for NSCLC (n = 195; 19.5 %), BC (n = 163; 16.3 %), CRC (n = 184; 18.4 %), or PC (n = 457; 47.5 %). Two thirds of patients were treated for single metastasis. Median number of fractions was 5 (IQR, 3-5) and median dose per fraction was 9.7 (IQR, 7.7-12.4) Gy. The most frequently treated sites were non-vertebral bone (22.8 %), lung (21.0 %), and distant lymph node metastases (19.0 %). On multivariate analysis, the dose varied significantly for primary cancer type (BC: 237.3 Gy BED, PC 300.6 Gy BED, and CRC 84.3 Gy BED), and metastatic sites, with higher doses for lung and liver lesions. CONCLUSION: This real-world analysis suggests that SBRT doses are adjusted to the primary cancers and oligometastasis location. Future analysis will address safety and efficacy of this site- and disease-adapted SBRT fractionation approach (NCT03818503).

Association between PIK3CA activating mutations and outcomes in early-stage invasive lobular breast carcinoma treated with adjuvant systemic therapy.

BACKGROUND: The aim of the study was to evaluate the independent prognostic role of PIK3CA activating mutations and an association between PIK3CA activating mutations and efficacy of adjuvant endocrine therapy (ET) in patients with operable invasive lobular carcinoma (ILC). PATIENTS AND METHODS: A single institution study of patients with early-stage ILC treated between 2003 and 2008 was performed. Clinicopathological parameters, systemic therapy exposure and outcomes (distant metastasis-free survival [DMFS] and overall survival [OS]) were collected based on presence or absence of PIK3CA activating mutation in the primary tumor determined using a quantitative polymerase chain reaction (PCR)-based assay. An association between PIK3CA mutation status and prognosis in all patient cohort was analyzed by Kaplan-Meier survival analysis, whereas an association between PIK3CA mutation and ET was analyzed in estrogen receptors (ER) and/or progesterone receptors (PR)-positive group of our patients by the Cox proportional hazards model. RESULTS: Median age at diagnosis of all patients was 62.8 years and median follow-up time was 10.8 years. Among 365 patients, PIK3CA activating mutations were identified in 45%. PIK3CA activating mutations were not associated with differential DMFS and OS (p = 0.36 and p = 0.42, respectively). In patients with PIK3CA mutation each year of tamoxifen (TAM) or aromatase inhibitor (AI) decreased the risk of death by 27% and 21% in comparison to no ET, respectively. The type and duration of ET did not have significant impact on DMFS, however longer duration of ET had a favourable impact on OS. CONCLUSIONS: PIK3CA activating mutations are not associated with an impact on DMFS and OS in early-stage ILC. Patients with PIK3CA mutation had a statistically significantly decreased risk of death irrespective of whether they received TAM or an AI.

Intrathecal trastuzumab versus alternate routes of delivery for HER2-targeted therapies in patients with HER2+ breast cancer leptomeningeal metastases.

BACKGROUND: Patients with HER2+ breast cancer (BC) frequently develop leptomeningeal metastases (LM). While HER2-targeted therapies have demonstrated efficacy in the neoadjuvant, adjuvant, and metastatic settings, including for parenchymal brain metastases, their efficacy for patients with LM has not been studied in a randomized controlled trial. However, several single-armed prospective studies, case series and case reports have studied oral, intravenous, or intrathecally administered HER2-targeted therapy regimens for patients with HER2+ BC LM. METHODS: We conducted a systematic review and meta-analysis of individual patient data to evaluate the efficacy of HER2-targeted therapies in HER2+ BC LM in accordance with PRISMA guidelines. Targeted therapies evaluated were trastuzumab (intrathecal or intravenous), pertuzumab, lapatinib, neratinib, tucatinib, trastuzumab-emtansine and trastuzumab-deruxtecan. The primary endpoint was overall survival (OS), with CNS-specific progression-free survival (PFS) as a secondary endpoint. RESULTS: 7780 abstracts were screened, identifying 45 publications with 208 patients, corresponding to 275 lines of HER2-targeted therapy for BC LM which met inclusion criteria. In univariable and multivariable analyses, we observed no significant difference in OS and CNS-specific PFS between intrathecal trastuzumab compared to oral or intravenous administration of HER2-targeted therapy. Anti-HER2 monoclonal antibody-based regimens did not demonstrate superiority over HER2 tyrosine kinase inhibitors. In a cohort of 15 patients, treatment with trastuzumab-deruxtecan was associated with prolonged OS compared to other HER2-targeted therapies and compared to trastuzumab-emtansine. CONCLUSIONS: The results of this meta-analysis, comprising the limited data available, suggest that intrathecal administration of HER2-targeted therapy for patients with HER2+ BC LM confers no additional benefit over oral and/or IV treatment regimens. Although the number of patients receiving trastuzumab deruxtecan in this cohort is small, this novel agent offers promise for this patient population and requires further investigation in prospective studies.

Results of postoperative radiochemotherapy of the patients with resectable gastroesophageal junction adenocarcinoma in Slovenia.

BACKGROUND.: Although the incidence of adenocarcinomas of the gastroesophageal junction (GEJ) is sharply rising in the Western world, there are still some disagreements about the staging and the treatment of this disease. The aim of this retrospective study was to analyse the effectiveness and safety of postoperative radiochemotherapy in patients with a GEJ adenocarcinoma treated at the Institute of Oncology Ljubljana. PATIENTS AND METHODS.: Seventy patients with GEJ adenocarcinoma, who were treated with postoperative radiochemotherapy between January 2005 and June 2010, were included in the study. The treatment consisted of 6 cycles of chemotherapy with 5-FU and cisplatin and concomitant radiotherapy with the total dose of 45 Gy. RESULTS.: Twenty-six patients (37.1%) completed the treatment according to the protocol. The median follow-up time was 17.7 months (range: 3.3-64 months). Acute toxicity grade 3 or more, such as stomatitis, dysphagia, nausea or vomiting, and infection, occurred in 2.9%, 34.3%, 38.6% and 41.5% of patients, respectively. At 3 years locoregional control (LRC), disease-free survival (DFS), disease-specific survival (DSS) and overall survival (OS) were 78.2%, 25.3%, 35.8%, and 33.9%, respectively. In the multivariate analysis of survival, splenectomy and level of Ca 19-9 >20 kU/L before the adjuvant treatment were identified as independent prognostic factors for lower DFS, DSS and OS. Age <60 years, higher number of involved lymph nodes and advanced disease stage were identified as independent prognostic factors for lower DSS and OS. CONCLUSIONS.: In patients with GEJ adenocarcinoma who first underwent surgery, postoperative radiochemotherapy is feasible, but we must be aware of a high risk of acute toxic side effects.

Safety of CDK4/6 inhibitors and concomitant radiation therapy in patients affected by metastatic breast cancer.

PURPOSE: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) currently represent the standard of care for the initial treatment of patients with metastatic hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer. The aim of our study is to evaluate the safety of the use of concomitant radiation therapy (RT) in a consecutive series of HR+/HER2- patients treated in two academic institutions with CDK4/6i in the metastatic setting. METHODS AND MATERIALS: From September 2017 to February 2020, we retrospectively collected and analysed data on a sequential series of patients treated with CDK4/6i, receiving RT or not, at two European institutions. Primary outcome of the study was the association between RT and any adverse events (AEs) ≥ G3. Secondary outcomes were the association between RT and any AEs (any grade), CDK4/6i dose reduction rate, and CDK4/6i treatment discontinuation rate. RESULTS: We analysed a total of 132 consecutive women; RT was prescribed in 57 (43.2%) patients (70 irradiated lesions). The median age of the series was 52.1 years (range 32.3-78.2). Concomitant RT administration was not significantly related to higher AEs ≥ G3 (p = 0.19) and any grade AEs (p = 1.0); there was no association with RT and CDK4/6i dose reduction (p = 0.49) and discontinuation rates (p = 0.14). At a median follow-up of 18.8 months, the progression-free survival (PFS) rate was 35% and the overall survival (OS) rate was 38.7% in the whole group. The use of concomitant RT did not affect both PFS (p = 0.71) and OS rates (p = 0.55). CONCLUSIONS: Our data are encouraging regarding the safety of this combination, showing that concurrent RT did not increase severe toxicity and did not have an impact on systemic treatment conduction.

Improved Survival after Breast-Conserving Therapy Compared with Mastectomy in Stage I-IIA Breast Cancer.

In the current study, we sought to compare survival outcomes after breast-conserving therapy (BCT) or mastectomy alone in patients with stage I-IIA breast cancer, whose tumors are typically suitable for both locoregional treatments. The study cohort consisted of 1360 patients with stage I-IIA (T1-2N0 or T0-1N1) breast cancer diagnosed between 2001 and 2013 and treated with either BCT (n = 1021, 75.1%) or mastectomy alone (n = 339, 24.9%). Median follow-ups for disease-free survival (DFS) and overall survival (OS) were 6.9 years (range, 0.3-15.9) and 7.5 years (range, 0.2-25.9), respectively. Fifteen (1.1%), 14 (1.0%) and 48 (3.5%) patients experienced local, regional, and distant relapse, respectively. For the whole cohort of patients, the estimated 5-year DFS and OS were 96% and 97%, respectively. After stratification based on the type of local treatment, the estimated 5-year DFS for BCT was 97%, while it was 91% (p < 0.001) for mastectomy-only treatment. Inverse probability of treatment weighting matching based on confounding confirmed that mastectomy was associated with worse DFS (HR 2.839, 95% CI 1.760-4.579, p < 0.0001), but not with OS (HR 1.455, 95% CI 0.844-2.511, p = 0.177). In our study, BCT was shown to have improved disease-specific outcomes compared to mastectomy alone, emphasizing the important role of adjuvant treatments, including postoperative radiation therapy, in patients with early-stage breast cancer at diagnosis.

Hypofractionated radiation therapy for breast cancer: Preferences amongst radiation oncologists in Europe - Results from an international survey.

BACKGROUND AND PURPOSE: We aimed to assess the prescription preference about hypofractionated radiation therapy (HFRT) for breast cancer (BC) patients amongst radiation oncologists (ROs) practicing in Europe and to identify restraints on HFRT utilisation. MATERIALS AND METHODS: An online survey was circulated amongst ROs in Europe through personal, RO and BC societies' networks, from October 2019 to March 2020. The statistical analyses included descriptive statistics, chi-squared testing, and logistic regression analysis. RESULTS: We received 412 responses from 44 countries. HFRT was chosen as the preferred schedule for whole breast irradiation (WBI) by 54.7% and for WBI with regional nodes irradiation (RNI) by 28.7% of the responding ROs. In the case of postmastectomy RT with or without reconstruction, HFRT was preferred by 21.1% and 29.6%, respectively. Overall, 69.2% of the responding ROs selected at least one factor influencing the decision to utilise HFRT, the most frequent of which included age (51.4%), RNI (46.9%), internal mammary lymph nodes irradiation (39.7%), BC stage (33.5%) and implant-based breast reconstruction (31.6%). ROs working in academic centres (odds ratio, (OR), 1.7; 95% confidence interval, (CI); 1.1-2.6, p = 0.019), practicing in Western Europe (OR, 4.2; 95%CI; 2.7-6.6, p < 0.0005) and/or dedicating >50% of clinical time to BC patients (OR, 2.5; 95%CI; 1.5-4.2, p = 0.001) more likely preferred HFRT. CONCLUSION: Although HFRT is recognised as a new standard, its implementation in routine RT clinical practice across Europe varies for numerous reasons. Better dissemination of evidence-based recommendations is advised to improve the level of awareness about this clinical indication.